MXPA99004420A - Methods and compositions for stimulating neurite growth using compounds with affinity for fkbp12 in combination with neurotrophic factors - Google Patents

Abstract

The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound and a neurotrophic factor, such as nerve growth factor (NGF). The methods comprise treating nerve cells with the above compositions or compositions comprising the compound without a neurotrophic factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.

Description

METHODS AND COMPOSITIONS TO STIMULATE THE GROWTH OF NEURITES TECHNICAL FIELD OF THE INVENTION The present invention relates to methods and pharmaceutical compositions for the stimulation of neurite growth in nerve cells. The compositions comprise a neurotrophic amount of a compound and a neurotrophic factor, such as nerve growth factor (NGF). The methods comprise treating the nerve cells with the above compositions or the compositions comprising the compound without a neurotropic factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.

BACKGROUND OF THE INVENTION Neurological diseases are associated with death or damage of neuronal cells. The loss of dopaminergic neurons in the substantia nigra is the etiological cause of Parkinson's disease. Even "that the molecular mechanism in neurodegeneration in Alzheimer's disease is not yet established, it is clear that inflammation of the brain and deposition of beta-amyloid proteins and other such agents can inhibit the survival of neurons and mitigate the growth of neurites used for communication between neurons. In patients suffering from is < cerebral quemia or damage to the spinal cord, extensive neuronal cell death is observed. Currently, there are no satisfactory treatments for these diseases. The typical treatment of neurological diseases involves drugs capable of inhibiting the death of neuronal cells. A more recent approach involves the promotion of nerve regeneration by promoting increased neurite growth. The increased growth of neurites, "which is critical for the survival of neurons, is stimulated in vitro by means of nerve growth factors (NGF). For example, the neurotrophic factor derived from the glial cell line (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for treatment for Parkinson's disease. Insulin and insulin-like growth factors have been shown to stimulate the growth of neurites in PC12 rat pheochromocytoma cells and cultured sympathetic and sensory system neurons [Recio-Pinto et al., J. Neurosci. , 6, pp. 1211-1219 (1986)]. Insulin-like and insulin-like growth factors also stimulate the regeneration of P800 damaged motor nerves in vivo and in vitro [Near et al., PNAS, pp. 89, 11716-11720 (1992); and Edbladh et al., Brain Res., 641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodaro izc et al., Cell Differ. , 19, p. 1 (1986)] and growth [M. A. Walter et al., Lvmphokiune C tokine Res. , 12, p. 135 (1993)]. There are, however, several disadvantages associated with the use of nerve growth factors for the treatment of neurological diseases. They do not easily cross the blood-brain barrier. They are unstable in plasma. They have poor drug supply properties. Recently, small molecules have been shown to stimulate the increased growth of neurites in vivo. In individuals who suffer from a neurological disease, this stimulation of increased neurite growth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, "which are neurites sent by nerve cells to communicate with one another in a developed or damaged adult brain [(C. Domini« that Toran-Allerand et al. , J. Steroid Biochem, Mol. Biol., 56, pp. 169-78 (1996), and BS McEwen et al., Brain Res. Dev. Brain. Res., P800 87, pp. 91-95 (1995)]. The progress of Alzheimer's disease is diminished in women "who take estrogen. Estrogen hypothetically complements NGF and other neurotrophins and thus helps the differentiation and survival of neurons. Tacrolimus, an immunosuppressive drug, has been shown to act synergistically with NGF in stimulating the additional growth of neurites in PC12 cells as well as in sensory ganglia [Lyons et al., PNAS, 91, p. 3191-3195 (1994)]. This compound has also been shown to be neuroprotective in focal cerebral ischemia (J. Sharkey and SP Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in damaged sciatic nerves [Gold et al., J Neurosci., 15, pp. 7509-16 (1995)]. Even though "a wide variety of neurogenic degenerative disorders can be treated by stimulating the additional growth of neurites, there are relatively few known agents" that possess these properties. , there remains a great need for pharmaceutically acceptable compounds and compositions that have the ability to stimulate the further growth of neurites in patients.

P800 SUMMARY OF THE INVENTION Applicants have solved the above problem by discovering "that the compounds invented by one of the applicants for use in reversing multidrug resistance previously also surprisingly and unexpectedly possess neurotropic activity. These compounds stimulate the increased growth of neurites in the presence of exogenous or endogenous NGF. The compositions described herein comprise a compound from the genus described above and a neuronal growth factor. The methods to stimulate the greater growth of neurites described to < The former amino acid derivatives are used either alone or in combination with neuronal growth factor. The methods are used in the treatment of nerve damage caused by various neurological diseases and physical traumas and also in nerve regeneration ex vivo.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides pharmaceutical compositions comprising three components. The first component is a compound "having the formula (I): P800 Formula (I) and pharmaceutically acceptable derivatives thereof, wherein A, B and C are independently selected from hydrogen, straight or branched (C 1 -C 6) alkyl, straight or branched O-alkyl (C 1 -C 6), (CH 2) n -Ar, Y (CH2) n-Ar, or halogen; where n = 0-; wherein Y = 0, S, or NRX, where Rx = straight or branched alkyl (C1-C6) or hydrogenated where each Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl, -furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2 , 3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trityanyl, indolizinyl, indolyl, isoindolyl, 3H -indolyl, indolinyl, benzo [b] furanyl, benzo [b] P800 thiophenyl, lH-indazolyl, benzyl idazolyl, benzthiazolyl, purinyl, 4H- < quinolizinyl, "quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, eftalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, peridinyl, carbazolyl, acridinyl , phenazinyl, phenothiazinyl or phenoxazinyl; wherein each Ar optionally contains one to three substituents independently selected from hydrogen, hydroxyl, halogen, nitro, S03H, trifluoromethyl, trifluoromethoxy, to "straight or branched (C1-C6) chylethyl, 0-benzyl, 0-phenyl, 1, 2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, NR2R3, NR2R3 carboxamides, wherein R ^ and R3 are independently selected from hydrogen, on "straight or branched chlyle (Cl-C5) or benzyl; wherein D is selected from hydrogen or (CH2) m-E; wherein E is Ar or NR4R5; where m = 1-3, and each R4 and R5 are independently selected from hydrogen, the "chyle (straight or branched C1-C5), or (CH2) Ar or can be taken together to form a 5-6 membered heterocyclic ring; wherein X is O or NR6, where R6 is selected from hydrogen, to "straight or branched chill (C1-C6), or (CH2) m-Ar, where m = 1-3; wherein J and K are independently to "straight or branched chill (C1-C6) or Ar substituted with straight or branched alkyl (C1-C6), or where J and K are taken together to form a five or six membered ring or a benzofused ring of 5 or 6 members; wherein M is straight or branched alkyl (C1-C6), or Ar; wherein the stereochemistry in carbon 1 and carbon 2 is independently R or S. As defined herein, the compounds of this invention include all optical and racemic isomers. A "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt, ether, or salt of such ester, of a compound of this invention or of any other compound which, when administered to a patient, is capable of delivering (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to promote or increase the increased growth of neurites. According to a preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound having the formula (II): Formula (II); and pharmaceutically acceptable derivatives thereof, wherein M, X, A, B, C, and D are as defined above. According to another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound having the formula (III): Formula (III); and pharmaceutically acceptable derivatives thereof, wherein M, X, A, B, C, and D are as defined above. In accordance with still another preferred embodiment, the pharmaceutical compositions of the present invention comprise a compound "having the formula (IV): Formula (IV); and pharmaceutically acceptable derivatives thereof, wherein M, X, A, B, C, and D are as defined above; J is methyl or hydrogen; and K is (CH2) m-Ar or "straight or branched chyle (Cl-C6). More preferably, in a compound of formula (IV), K is substituted or unsubstituted benzyl. More preferably, K is benzyl or 4-halobenzyl in compound of formula (IV). Examples of pharmaceutical compounds within the scope of formula (I) of the present invention are those indicated in Table I, below.

P800 TABLE I If the pharmaceutically acceptable salts of the compounds are used, those salts are preferably derived from inorganic and organic acids and bases. Included among such acid salts are the P800 following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tocylate and undecanoate. 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-methyl-D- glucamine, and salts with amino acids such as alginin, lysine, and so on. Also, groups containing basic nitrogen can be quaternized with such agents as "low alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water or dispersible or oil soluble products P800 are obtained by means of this. The compounds used in the compositions and methods of this invention can also be modified by means of the appropriate functionalities of the final part to improve the selective biological properties. Such modifications are known in the art and include those that increase biological penetration in a given biological system (eg, blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection , alter the metabolism and alter the rate of excretion. The second component- in each of the pharmaceutical compositions described above is a neurotrophic factor. The term "neurotrophic factor", as used herein, refers to compounds that are capable of stimulating the growth or proliferation of nervous tissue. As used in this application, the term "neurotrophic factor" excludes the compounds described herein. Numerous neurotrophic factors have been identified in the art and any of those factors can be used in the compositions of this invention. These neurotrophic factors include, but are not limited to, nerve growth factor (NGF), P800 insulin growth factor (IGF-1) and its active truncated derivatives such as gIGF-1, acid and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), neurotrophic factor Brain derived (BDNF), ciliary neurotrophic factors (CNTF), neurotrophic factor derived from glial cell lines (GDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in the compositions of this invention is NGF. The third component of the pharmaceutically acceptable compositions of this invention is a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, seroproteins, such as human serum albumin, buffering substances such as phosphates, glycine, acid sorbic, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolyte salts, such as protamine sulfate, disodium acid phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, trisilicate of magnesium, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, carboxymethylcellulose P800 sodium, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease. The compositions of the present invention can be administered orally, parenterally, by inhalation by spraying, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasinobial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable forms of the compositions of this invention may be aqueous or an oil suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or a suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents "that can be used are water, P800 the ringer solution and the isotonic sodium chloride solution. In addition, fixed sterile oils are conventionally employed as a solvent or suspension medium. For this purpose, any fixed soft oil may be employed including synthetic mono or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain or dispersant alcohol diluent, such as Ph. Helv or similar alcohol. The pharmaceutical compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, the carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in the form of capsules, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying agents P800 and suspension. If desired, certain flavoring or coloring agents can also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention can also be administered topically, especially when the purpose of the treatment includes areas or organs easily accessible for topical application, "which include diseases of the eyes, the skin, or the lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be done in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal compresses may also be used. For topical applications, the compositions P800 Pharmaceuticals can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, wax and water emulsifier. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, waxes of cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions can be formulated as micronized suspensions in isotonic solutions, sterile saline with adjusted pH, or, preferably as solutions in sterile isotonic saline medium with adjusted pH, or with or without a preservative such as benzyl chloride. Alternatively, for ophthalmological uses, the pharmaceutical compositions can be formulated into an ointment such as petrolatum. The pharmaceutical compositions of this invention P800 can also be administered by means of a nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline medium, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other solubilizing agents or dispersants. The amount of both the compound and the neurotrophic factor "that can be combined with the carrier materials to produce a single dose form will vary depending on the host treated, the particular mode of administration. The two active ingredients of the pharmaceutical compositions of this invention act synergistically to stimulate the increased growth of neurites. Therefore, the amount of neurotrophic factor in such compositions will be less "than the one wanted in a monotherapy" that uses only that factor. Preferably, the compositions should be formulated in such a way that doses between 0.01-100 mg / kg per body weight / day of the compound can be administered and a dose between 0.01-100 μg / kg body weight / Neurotrophic day can be administered to a patient receiving these compositions. It should also be understood «that a specific dose and treatment regimen for any patient P800 particular will depend on a variety of factors, which include the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, the rate of excretion, the combination of drugs and the judgment of the attending physician and the severity of the particular disease "that is being treated. The amount of active ingredients will also depend on the particular compound and the neurotrophic factor in the composition. According to another embodiment, this invention provides methods for stimulating the increased growth of neurites, in one aspect of this embodiment, the method is used to stimulate greater neurite growth in a patient and is achieved by administering a pharmaceutically composition to the patient. acceptable comprising any of the compounds described above and a pharmaceutically acceptable carrier. The amount of compound used in these methods is between 0.01 and 100 mg / kg of body weight / day. In another aspect of this embodiment, the method is used to stimulate nerve growth ex vivo. For this aspect the compounds described above can be applied directly to the nerve cells in culture. This aspect of the invention is useful for regeneration of nerves ex vivo.

P800 According to an alternative embodiment, the method for stimulating the increased growth of neurites comprises the additional step of treating a patient or nerve cells ex vivo in culture cpn a neurotrophic factor, such as that contained in the pharmaceutical compositions of this invention described previously. This embodiment includes administering the compound and the neurotrophic agent in a single dose form or in multiple multiple dose forms when they must be administered to a patient. If the separate dosage forms are used, they can be administered concurrently, consecutively or in less than about 5 hours of each other. The methods and compositions of this invention can be used to treat nerve damage caused by a wide variety of diseases or physical traumas. These include, but are not limited to, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, neuromotor diseases, sciatic pressure, peripheral neuropathy, neuropathy particularly associated with diabetes, diseases of the spinal cord and pressure of the facial nerve. In order that the invention described here P800 can be more fully understood, the following examples are established. It should be understood that these examples are for illustrative purposes only and are not construed as limiting this invention in any way.

EXAMPLES General Methods Proton nuclear magnetic resonance (XH NMR) spectra were recorded at 500 MHZ on a Bruker AMX 500. The chemical changes are reported in parts per million (d) relative to Me4Si (d 0.0) - The chromatography l < High performance analytical fluid was used in a Waters 6OOE liquid chromatograph or in a Hewlett Packard 1050.

Example 1 7- (pyridin-4-ylmethoxy) -1,2,3,4-tetrahydronaph-alen-1-one (compound 1): To a solution of 7-hydroxy-l-tetralone (15.0 g, 92%). 59 mmol) in dimethyl sulfoxide (150 ml) powdered potassium carbonate (30.66 g, 0.11 mol) was added in portions followed by the addition of 4-picoyl hydrochloride chloride (18.22 g, 0.22 mol). The resulting mixture was heated to 502 C for 30 minutes. The resulting dark brown mixture was diluted with water (200 ml) and extracted with ethyl acetate P800 (500 ml). The aqueous phase was re-extracted with ethyl acetate (300 ml) and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 40-60% ethyl acetate: hexane) provided 20.82 g of compound 1 as an oil "which crystallized when stopped.

Example 2 7- (pyridin-4-ylmethoxy) -1,2,3,4-tetrahydronaphthalen-1-ol (compound 2): To a solution of compound 1 (16.41 g, 64.9 mmol) in tetrahydrofuran ( 75 mL) at 02 C were added dropwise to a 1 M solution of diisobutyraluminium hydride in toluene (97.3 mL). After one hour, the reaction was quenched with aqueous sodium potassium tartrate and diluted with ethylacetate followed by heating to room temperature. After stirring for an additional hour, the layers were separated and the aqueous phase was re-extracted with ethyl acetate (2x). The extracts were combined, washed with saline water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with ethyl acetate) gave 12.96 g of compound 2 as an oil "which crystallized upon stopping.

P800 Examples 2 (S) v 3 (R) 7- (pyridin-4-ylmethoxy) -1,2,3,4-tetrahydronaphthalen-1- (S) -ol (compound 2 (S)) and 1 (R) -acetoxy-7- (pyridin-4-ylmethoxy) -1,2,3,4-tetrahydronaphthalene (cpmpuestp 3 (R)): A solution of compound 2 (12.96, 50.82 mmol) in tetrahydrofuran (20 mL ) was diluted with tert-butyl methyl ether (260 mL) followed by the addition of vinylacetate (19.1 mL,, 21 mol) and Amano PS-30 Lipase (13.0 g). After stirring for eight hours, the reaction was filtered and concentrated in vacuo to give an oil. Chromatography on silica gel (elution with 20% acetone: hexane) provides 7.41 g of 3 (R) acetate as a white crystalline material. Further elution with 60% acetone: hexanes gave 6.1 g of compound 2 (S) as a white crystalline material. The enantiomeric purity of compound 2 (S) was established by HPLC using a Chiralpak OD column that was greater than 99.8% ee.

Example 2 (R) 7- (pyridin-4-ylmethoxy) -1, 2, 3, 4-tetrahydronaphthalen-1 (R) -ol (compound 2 (R)) To a solution of compound 3 (R) (6.1 g, 20.9 mmol) in methanol (35 mL) was added powdered potassium carbonate (2.88 g, 20.9 mmol. ) after being stirred for 45 P800 min., The reaction was concentrated in vacuo. The residue was quenched in methylene chloride and 50% saline water. The layers were separated and the aqueous phase re-extracted with methylene chloride. The organics were combined, washed with saline water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 4.7 g of compound 2 (R) as a white crystalline material. The enantiomeric purity of compound 2 (S) was established by HPLC using a Chiralpak OD column "greater than 99.4% ee.

Use 4 ^ ester of (S) -piperidine-1,2-dicarboxylic acid 1-allylester (2- (7-pyridin-4-ylmethoxy) -1,2,3,4-tetrahydronaphthales-1-yl) ( compound 4): To a solution of compound 2 (663 mg, 2.6 mmol), Alloc (S) -pipecolic acid (610 mg, 2.86 mmol) and dimethylaminopyridine (32 mg, 0.26 mmol), in Methylene chloride (5 mL) was added (3-dimethylaminopropyl) -3-ethyl-carbodimide hydrochloride (5.48 mg, 2.86 mmol). After stirring for 24 hours, the reaction was diluted with ethyl acetate and water. The layers were separated and the aqueous phase was re-extracted with ethyl acetate. The extracts were combined, washed with saturated sodium bicarbonate, water, saline water, dried over sodium sulfate, P800 anhydrous magnesium, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 20% acetone: hexane) gave 940 mg of compound 4 as a mixture of diastereomers.

Use 5 (S) -pyridine-2-carboxylic acid ester (2- (7-pyridin-4-ylmethoxy) -1, 2, 3, 4-tetrahydronaphthalene-1-yl) (compound 5): To one solution of compound 4 (940 mg, 2.09 mmol) in tetrahydrofuran (5.0 mL) was added morpholine (1.1 mL, 12.6 mmol) and tetrakistriphenylphosphine palidiun (0) (241 mg, 0.21 mmol). After one hour, the heterogeneous mixture was diluted with ethyl acetate, washed with 50% saline, 5% sodium bicarbonate, saline, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 50-100% acetone: hexanes) gave 510 mg of compound 5.

Example 6 and 7 1- (2-Oxo-2- (3,4,5-trimethoxyphenyl) -acetyl) -piperidine-2 (S) -carboxylic acid 2- ((7-pyridin-4-ylmethoxy) - acid ester 1, 2, 3, 4-tetrahydronaphthalen-1 (S) -yl) (compound 6) and 1- (2-Oxo-2- (3,4,5-trimethoxyphenyl) -acetyl) -piperidine-2-acid ester (S) -carboxylic 2- ((7-pyridin-4-ylmethoxy) - P800 1, 2, 3, 4-tetrahydronaphthalen-1 (S) -yl) (compound 7): To a solution of compound 5 (510 mg, 1.4 mmol) and 3, 4, 5-trimethoxybenzothioloric acid (505 mg , 2.1 mmol) in methylene chloride (6 mL) was added (3-dimethylaminopropyl) -3-ethyl-carbodimide hydrochloride (400 mg, 2.1 mmol).

After being stirred for 24 hours, the reaction was diluted with ethyl acetate and water. The layers were separated and the aqueous phase was re-extracted with ethyl acetate. The extracts were combined, washed with saturated sodium bicarbonate, water, saline water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 25% acetone: hexanes) provided 558 mg of the product as a mixture of diastereomers. Reverse phase MPLC supplied compound 6 and diastereomerically pure compound 7. Alternatively, the replacement of compound 2 with resolved compound 2 (S) in Examples 4-5 and the previous example provided compound 6 directly, while compound 2 (R) supplied compound 7. Compound 6:? NMR as a rotomere mixture (500 MHz, CDC13) d 8.53 (d), 8.55 (d), 7.38 (s), 7.34-7.28 (m), 7.17 (s), 7.05 (d), 7.01 (d), 6.88-6.79 (m), 6.64 (d), 6.00 (t), 5.93 (t), 5.39 (br d), 5.05-5.00 (m), 4.58 (br d), 4.34 (br d), 3 , 93-3.88 (m), 3.79 (s), 3.49 (br d), 3.28 P800 (dt), 3.02 (dt), 2.80 (dt), 2.73-2.60 (m), 2.36-2.28 (m), 2.08-1.49 () , 1.37-1.27 (m). Compound 7: ^ NMR as a rotomere mixture (500 MHz, CDC13) d 8.56-8.54 (m), 7.35 (s), 7.29-7.28 (m), 7.16 (s), 7.05 (d), 7.00 (d), 6.86-6.81 (m), 6.73 (d), 6.00 (t), 5.87 (t), 5.35 (br d ), 5.07-4.93 (m), 4.58 (br d), 4.34 (m), 3.94-3.89 (m), 3.84 (s), 3.45 ( br d), 3.22 (dt), 3.09 (dt), 2.79 (dt), 2.72-2.60 (m), 2.25 (m), 2.10 (m), 2.03-1.47 (m), 1.40-1.30 (m), 1.27-1.17 (m).

EXAMPLE 8 1- (2-Oxo-2- (3,4,5-trimethoxyphenyl) -acetyl) -piperidine-2 (S) -carboxylic acid 2- ((6-Prididin-4-ylmetpxi) -1 acid ester 2, 3, 4-te rahidronaphthalen-1-yl) (Compound 8) Compound 8 was prepared as described in Examples 1-2 and 4-6 using 6-hydroxy-1-tetralone instead of 7-hydroxy- I-tetralone to deliver compound 8 as a mixture of diastereomers. '' H NMR as a mixture of diastereomers and rotomers (500 MHz, CDC13) d 8.59 (d), 7.38 (s), 7.37 (s), 7.33 (m), 7.22 (d), 7.18 (dd), 7.04 (d), 6.77 (dt), 6.70 (m), 6.64 (m), 6.04 (m) .92 (t), 5.88 (t), 5.35 (m), 5.06 (s), 5.05 (s), 5.03 (s), 4. 58 (m), 4.31 (dd), 3.94 (s), 3.93 (s), 3.92 (s), 3.87 (s), 3.86 (s), 3.47 (br d), 3.27 (dq), 3.13 (dt), 3.07 (dt), 2.87-2.61 (m), 2.34 (br d), 2.26 (br d), 2.18-1.18 P800 (m) EXAMPLE 9 1- (2-Oxo-2- (3,4,5-trimethoxyphenyl) -acetyl) -piperidine-2 (S) -carboxylic acid 2- ((5-pyridin-4-ylmethoxy) -1 acid ester 2, 3, 4-tetrahydronaphthalen-1-yl) (Compound 9) Compound 9 was prepared as described in Examples 1-2 and 4-6 using 5-hydroxy-1-tetralone instead of 7-hydroxy-1 -tetralone to deliver compound 9 as a mixture of diastereomers. "NMR as a mixture of diastereomers and rotomers (500 MHz, CDC13) d 8.64 (m), 7.39 (m), 7.27 (s), 7.20 (d), 7.17 (q), 6.98 (d), 6.92 (d), 6.80 (t), 6.73 (dd), 6.40 (d), 6.10 (q), 5.99 (t), 5.95 (t), 5.40 (m), 5.12 (m), 5.12 (s), 5.08 (d), 4.60 (m), 4.35 ( m), 3.96 (s), 3.85 (s), 3.94 (s), 3.90 (s), 3.89 (s), 3.50 (br d), 3.30 (dq), 3.19-3.08 (m), 3.0-2.86 (m), 2.74-2.58 (m), 2.38 (), 2.30 (m), 2.10-1.50 (m), 1.45-1.25 (m).

Example 10 1-Amino-7- (pyridin-4-ylmethoxy) -1,2,3,4-tetrahydronaphthalene (Compound 10): To a solution of compound 1 (1.71 g, 6.75 mmol) and methoxyamine hydrochloride (845 mg, 10.12 mmol) in abs. Ethanol. (20 mL) potassium carbonate was added in P800 powder (2.25 g, 16.88 mmol) and the reaction was heated to reflux. After two hours, the reaction was cooled and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with 5% sodium bicarbonate, water, saline water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue chromatography on silica gel (elution with 40% ethyl acetate: hexanes) provides 1.9 g of oxime. To a solution of the above oxime in tetrahydrofuran (5 mL) was added a 1 M solution of borane in tetrahydrofuran (20.25 L) and the reaction was heated to reflux and stirred for 18 hours. The reaction was quenched and quenched with saturated methanolic hydrochloric acid (20 mL) and the reaction was reheated to reflux and stirred for an additional thirty minutes. The reaction was cooled and concentrated to dryness. The residue was extracted into water (10 mL) and washed with diethyl ether (3 x 20 mL). The aqueous phase was adjusted to pH 8.0 with saturated sodium bicarbonate and extracted with ethyl acetate (3 x 650 L). The extracts were combined, washed with brine, dried over magnesium sulfate anhydride, filtered and concentrated in vacuo to give 945 mg of compound 10.

P800 Example HA and 11B 1- (2-Oxp-2- (3,4,5-trimethoxy) -acetyl) -piperidine 2 (S) -carboxylic 2- ((7-pyridine-4-ylmethoxy) -1,2 , 3,4-tetrahydronaphthalene-1 (R), -yl ', tray and 1- (2-Oxo-2- (3,4,5-trimethoxyphenyl) -acetyl) -piperidine-2 (S) -carboxylic acid 2 - ((7-pyridine-4-ylmethoxy) -1, 2, 3, 4-tetrahydronaphthalene-1 (S) -yl) amide (Compound 11 A and 11 B) Compounds HA and 11B were prepared as described in examples 4 to 6 by replacing compound 2 with compound 10 for provide a mixture of diastereomers. Chromatography of the residue on silica gel (elution with 20% acetone: hexanes) provides an HA compound. an additional elution provided compound 11B. Compound HA: compound ^? NMR as a mixture of diastereomers and rotomers (500 MHz, CDCl 3) d 8.57 (m),7.36 (d), 7.34 (s), 7.30 (d), 7.13 (s), 7.02 (t), 6.97 (d), 6.82 (dd), 6.79 (dd), 6.73 (d), 6.11 (d), 5.21 (m), 5.18- 5.08 (m), 5.02 (d) s), 4.66 (br d), 4.18 (d), 3.92 (s), 3.87 (s), 3.81 (5), 3.60 (br d), 3.32 (dt), 2.81-2.64 (m), 2.40 (br d), 2.26 (m), 2.11-2.01 (m), 1.84-1.65 (m), 1.51-1.42 (). Compound 11B: Compound XH NMR as a mixture of diastereomers and rotomers (500 MHz, CDC13) d 8.58 (m), 8.48 (m), 7.34 (s), 7.33 (m), 7, 29 (m), 7.21 (d), 7.17 (s), P800 7.02 (t), 6.86 (d), 6.86-6.76 (m), 6.01 (d), 5.19-5.10 (m), 5.02 (m) , 4.99 (q), 4.58 (br d), 4.18 (d), 3.93 (s), 3.89 (s), 3.86 (s), 3.48 (br d) ), 3.41 (dt), 2.80-2.62 (m), 2.41 (br d), 2.21 (br d), 2.12-2.00 (m), 1.88 -1,40 ().

Example 12 N-Benzyl-l-amino-7- (pyridin-4-ylmethoxy) -1,2,3,4-tetrahydronaphthalene (Compound 12): A solution of compound 1 (820 mg, 3.24 mmol) and Benzyl amine (354 L, 3.24 mmol) in benzene (10 mL) was heated to reflux under azeotropy conditions. After the calculated amount of water was collected, the reaction was cooled and concentrated in vacuo. The residue was taken up in ethanol (5 mL) and added to a suspension of sodium borohydride (246 mg, 6.48 mmol) in ethanol (15 L). The reaction was heated to 802 C, stirred for 30 minutes, cooled and concentrated in vacuo. The residue was diluted with ethyl acetate followed by a slow addition of 1N hydrochloric acid. The layers were separated. The aqueous phase was adjusted to pH 7 with 2N sodium hydroxide and extracted with methylene chloride (2X). The organics were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatographies on silica gel (elution with 5% methanol: chloride P800 methylene) provided 1.09 of compound 12 as an oil.

Example 13 A and 13 B (S) -piperidine-1,2-dicarboxylic acid 1-tert-butylester (-N-benzyl- (7-pyridin-4-ylmethoxy) -1, 2, 3, 4-tetrahydronaphthalene-1 (R) -yl) amide and (S) -piperidine-1,2-dicarboxylic acid 1-tert-butylester 2- (N-benzyl- (7-pyridin-4-ylmethoxy) -1,2,3,4- tetrahydrnaphthalen-1 (S) -yl) amide (compounds 13 A and 13 B): To a solution of compound 12 (1.09 g, 3.16 mmol) and Boc (S) -pipecolic acid 868 mg, 3, 59 mol) in methylene chloride (10 mL) were added (3-dimethylaminopropyl) -3-ethyl-carbodimide hydrochloride ((725 mg, 3.79 mmol) after stirring for 72 hours, the reaction was diluted with ethyl acetate The lids were separated and the aqueous phase was reextracted with ethyl acetate.The extracts were combined, washed with saturated sodium bicarbonate, water, brine, dried over magnesium sulfate anhydride, filtered and concentrated in vacuo. residue on silica gel (elution with 40% acetone : hexanes) gave 601 mg of compound 13A and an additional elution gave 181 mg of compound 13B as white solids.

P800 Example 14 (S) -piperidine-2-2-dicarboxylic acid 2- (-N-benzyl- (7-pyridin-4-ylmethoxy) -1,2,3-tetrahydrodronaphthalen-1 (R) -yl) amide (compound 14): To a solution of compound 13A 8601 mg, 1.08 mmol) in methylene chloride (10 L) was added trifluoroacetic acid (1 mL). After stirring for 1.5 hours, the reaction was concentrated in vacuo. The residue was neutralized with saturated potassium carbonate and extracted with ethyl acetate (2X). The extracts were combined washed with brine, dried over magnesium sulfate anhydride, filtered and concentrated in vacuo, to give 450 mg of compound 14.

Example 15 1- (2-0x0-2- (3,4,5-trimethoxyphenyl) -acetyl) -piperidine-2 (S) carboxylic acid 2- (N-benzyl (7-pyridin-4-ylmethoxy) -1 , 2, 3, 4-tetrahydronaphthalen-1-yl) amide (Compound 15): Compound 15 was prepared according to example 6, but replacing compound 5 with 14, H NMR as a mixture of rotomers (500 MHz, CDC13) d 8.52 (d), 8.39 (dd), 7.51 (m), 7.44 (s), 7.37 (s), 7.37 (t), 7.30-7 , 15 (m), 7.09 (d), 7.05 (d), 6.99 (d), 6.89 (dd), 6.74 (m), 6.39 (m), 5, 69 (d), 5.41 (m), 5.21 (m), 5.15 (q), 4.90 (q), 4.72 (d), 4.64 (d), 3.95 -3.86 (m), 3.70-3.67 (m), 3.57 P800 (br d), 3.54 (d), 3.48 (m), 2.74-2.64 (m), 2.20-1.58 (m) Example 16 1- (2-0x0-2- (3,4,5-trimethoxyphenyl) -acetyl) -piperidine-2 (S) carboxylic acid (2-N-benzyl (7-pyridin-4-ylmethoxy) -1, 2,3,4-tetrahydronaphthalen-1-yl) amide (Compound 16): Compound 16 was prepared according to example 14-15, but replacing compound 13A with 13B, H NMR as a mixture of rotomers (500 MHz , CDCl3) d 8.63 (d), 7.37-7.33 (m), 7.30-7.22 (m), 7.13-7.10 (m), 7.03 (dd) , 6.87 (br s), 6.79 (dt), 5.83 (m), 5.06 (q), 4.96 (q), 4.90 (d), 4.83 (q) , 4.38 (d), 4.13 (d), 3.94 (s), 3.90 (s), 3.87 (s), 3.85 (s), 2.70-2.62 (m), 2.14 (m), 1.91 (m), 1.88-1.68 (m), 1.54-1.44 (m), 1.35-1.22 (m) .

Example 17 2- (2-OXO-2- (3,4,5-trimethoxyphenyl) -acetyl) -1,2,3,4-tetrahydroisosurinoline-3 (S) -carboxylic acid 2 - ((7-pyridin-4) -ylmethoxy) -1, 2, 3, 4-tetrahydronaphthalen-1 (R) -yl) ester (Compound 17): Compound 17 was prepared according to examples 4-6, but replacing (S) -Alloc-acid pipecolic with (S) -Alloc-3-carboxyl-l, 2, 3, 4-tetrahydroiso «guinoline and using compound 2 (R). 1H NMR as a mixture of rotomers (500 MHz, CDC13) d 8.62 (d), 8.54 (d), 7.44 (s), P800 7.33 (d), 7.27 (d), 7.26-7.08 (m), 7.05 (d), 7.01 (d), 6.98 (d), 6.88 -6.78 (m), 6.43 (d), 5.93 (t), 5.77 (t), 5.32 (t), 5.08 (d), 5.02 (q), 4.90 (s), 4.83 (q), 4.67 (d), 4.57 (q), 3.96-3.82 (m), 3.34-3.20 (), 2 , 80 (dt), 2.77-2.57 (), 1.88-1.82 (m), 1.79-1.64 (m).

Example 18 2- (2-0x0-2- (3, 4, 5-trimethoxyphenyl) -acetyl) -1.2, 3,4-tetrahydroisoauinoline-3 (S) -carboxylic acid 2- ((7-pyridin-4-ylmethoxy) ) -1, 2, 3, 4-tetrahydronaphthalen-1 (S) -yl) ester (Compound 18): Compound 18 was prepared according to examples 4-6, but replacing (S) -Alloc-pipecolic acid with (S) -Alloc-3-carboxyl-l, 2, 3, 4-tetrahydroisoquinoline and using compound 2 (S). H NMR as a mixture of rotomers (500 MHz, CDC13) d 8.61 (m), 7.41 (s), 7.40 (s), 7.31-6.96 (m), 6.88- 6.80 (m), 6.47 (m), 5.88 (m), 5.74 (m), 5.39 (m), 5.07 (d), 4.87-4.74 ( m), 4.60 (q), 3.98-3.82 (m), 3.28-3.18 (m), 2.02-1.62 (m), 1.53-1.45 (m).

Example 19 3-Benzyl-2 (S) - ((2-oxo-2- (3,4,5-trimethoxyphenyl) cetyl) amino) propanoic acid ((7-pyridin-4-ylmethoxy) -1, 2, 3 , 4-tetrahydronaphthalen-1 (R) -yl) ester Compound 19 was prepared in accordance with P800 examples 4-6, but replacing (S) -Alloc-pipecolic acid with (S) -Alloc-phenylalanine and using compound 2 (R). XH NMR as a mixture of rotomers (500 MHz, CDC13) d 8.57 (dd), 7.66 (s), 7.52 (d), 7.32-7.23 (m), 7.19 ( d), 7.05 (d), 6. 87 (m), 6.86 (s), 6.00 (t), 5.03 (q), 4.88 (q), 3.94 (s), 3. 88 (s), 3.20 (dq), 2.78 (dt), 2.69-2.63 (), 1.97-1.73 (m).

Example 20 3-Benzyl-2 (S) - (methyl- (2-oxo-2- (3,4,5-trimethoxyphenyl) acetyl) amino) propanoic acid ((7-pyridin-4-ylmethoxy) -1, 2 , 3, 4-tetrahydronaphthalen-1 (R) -yl) ester (Compound 20): Compound 20 was prepared according to examples 4-6, but replacing (S) -Alloc-pipecolic acid with (S) -Alloc -N-methyl-phenylalanine and using the 1. compound 2 (R) H NMR as a mixture of rotomers (500 MHz, CDC13) d 8.55 (d), 8.52 (d), 7.34 (s), 7.31-7.19 (m), 7.12 (m), 7.06-6.99 (m), 6.94-6.82 (m), 6.06 (t), 5.94 (t), .05 (q), 4.99 (q), 4.56 (q), 3.90 (s), 3.91 (s), 3.82 (s), 3.75 (s), 3.37 (dd), 3.28 (dd), 3.16 (dd), 3.08 (s), 2.99 (dd), 2.82-2.62 (dd) m), 2.76 (s), 2.05-1.74 (m).

P800 Example 21 3-Benzyl-2 (S) - (methyl- (2-oxo-2- (3, 4, 5-trimethoxyphenyl) acetyl) amino) propanoic acid ((7-pyridin-4-ylmethoxy) -1, 2, 3, 4-tetrahydronaphthalen-1 (S) -yl) ester (Compound 20): Compound 21 was prepared according to examples 4-6, but replacing (S) -Alloc-pipecolic acid with (S) - Alloc-N-methyl-phenylalanine and using compound 2 (S). "NMR as a mixture of rotomers (500 MHz, CDC13) d 8.58 (dd), 8.53 (dd), 7.36 (d), 7.31-7.20 (), 7.14 ( s), 7.13-7.08 (), 7.04 (d), 6.97 (dd), 6.88-6.84 (m), 6.04 (m), 5.18 (t) ), 5.13 (q), 4.98 (q), 4.53 (q), 3.89 (s), 3.88 (s), 3.78 (s), 3.67 (s) , 3.44 (dd), 3.22 (dd), 3.19 (dd), 3.03 (s), 2.98 (dd), 2.82-2.62 (m), 2.78 (s), 2.01-1.87 (m), 1.83-1.73 (m).

Example 22 4- (6-Methyl-5,7-dimethoxyphenyl) butyric acid (Compound 22): To a solution of 2,4-dimethoxybenzaldehyde (5.1 g, 28.3 mmol) and triphenylphosphonium propanoic bromide (14.4 g, 34.9 mmol) in methylene chloride (40 mL) at 02 ° C were added 1.0 M potassium t-butoxide in tetrahydrofuran (70 mmol). The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the addition of hydrochloric acid P800 at 2 N and extracted with ethyl acetate (2 X). The extracts were combined, washed with brine, dried over magnesium sulfate anhydride, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (elution with 5% methanol: methylene chloride) to give 5.81 g of a yellow oil. This material was dissolved in ethyl acetate (20 mL), treated with 10% palladium on carbon (581 mg) and hydrogenated at 40 psi. After 12 hours the hydrogen was replaced with nitrogen, the reaction was filtered and concentrated in vacuo to give 5.73 g of compound 22.

Example 23 6-methy1-5, 7-dimethoxy-1, 2,3,4-tetrahydronaphthalen-1-one (compound 23): To a solution of compound 22 (5.73 g, 24.07 mmol) and 85% of phosphoric acid (2.36 g, 24.07 mmol) in acetonitrile (50 L) at 50 ° C was added trifluoroacetic anhydride (3.5 mL, 25 mmol). After 15 minutes, the reaction was cooled, diluted with ethyl acetate and washed with water, 10% sodium bicarbonate, brine, dried over magnesium sulfate anhydride, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 5% ethyl acetate: hexanes) P800 supplied 3.54 g of compound 23.

Example 24 6-methyl-5,7-dipropoxy-1,3,4-tetrahydronaphthalen-1-one (compound 24): To a solution of compound 23 (3.54 g, 16.1 mmol) in toluene ( 50 mL) aluminum chloride was added (10.7 g, 80.5 mmol) in portions. Once the addition was complete, the mixture was heated to reflux, stirred for 30 minutes and cooled to 02 ° C. the reaction was quenched by the reaction of 1 N hydrochloric acid and the product extracted with ethyl acetate (2). X) The extracts were combined, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel (elution with 20% ethyl acetate: hexane) to give 2.78 g of diol. This material was dissolved in 2-butanone (25 mL) treated with 1-bromopropane (6.6 mL, 72.6 mmol) and powdered potassium carbonate (9.68 g, 72.6 mmol) and heated to reflux. After 12 hours the reaction was cooled, diluted with water and extracted with ethyl acetate (2 X). The extracts were combined, washed with water, brine, dried over magnesium sulfate anhydride, filtered and concentrated in vacuo. Chromatography of the residue on silica gel P800 (elution with 10% ethyl acetate: hexanes) provided 3.42 g of compound 24.

Example 25 7- (pyridin-4-ylmethoxy) -2-pyridin-3-ylmethylene-3,4-dihydro-2-naphthalen-1-one (compound 25): To a solution of compound 24 (3.42 g, 21.4 mmol) and 3-pyridinecarboxaldehyde (1.59 g, 14.9 mmol) in absolute ethanol (25 mL) were added potassium hydroxide (350 mg, 6.2 mmol) and the reaction was allowed to stir during 5 minutes. The reaction was concentrated and the residue dissolved in ethyl acetate washed with water, brine, dried over magnesium sulfate anhydride, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (50% ethyl acetate: hexanes solution) gave 4.26 g of compound 25 as a white separated solid.

Example 26 6-methyl-5,7-dipropoxy-2- (pyridin-3-ylmethyl) -1,2,3,4-tetrahydronaph alen-1-one (compound 26): A mixture of compound 25 (3.96 g, 10.8 mmol) and % palladium on carbon (600 mg) in absolute methanol (100 mL) was hydrogenated at one atmosphere for 12 hours. The hydrogen was replaced with nitrogen, the reaction was P800 filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 20% ethyl acetate: hexane) yielded 2.72 g of compound 26.

Examples 27 and 28 Svn-6-methyl-5,7-dipropoxy-2- (pyridin-3-ylmethyl) -1, 2,3,4-tetrahydronaphthalen-1-ol compound (27) ^ v Anti-6-methyl -5,7-dipropoxy-2- (pyridin-3-ylmethyl) -1,2,3,4-tetrahydronaphthalene-l-ol (compound 28): To a solution of compound 26 (1.10 g, 2.98 mmol) in absolute methanol (10 mL) was slowly added sodium borohydride (226 mg, 98 mmol). After stirring for one hour, the reaction was concentrated and the residue partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with brine, dried over magnesium sulfate anhydride filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 10% ethyl acetate: hexanes) gave 502 mg of compound 27. An additional elution gave 4765 mg of compound 28.

Examples 29A and 29B 1- (2-0x0-2- (3,4,5-trimethoxy) -acetyl) -piperidine 2 (S) -carboxylic acid (7-pyridine-4-ylmethoxy) -2 (R) -pyridine -3-ylmethyl) -1, 2, 3, 4-tetrahydronaphthalene-1 (S) -yl) ester and 1- P800 (2-0x0-2- (3, 4, 5-trimethoxyphenyl) -acetyl) -piperidine-2 (S) -carboxylic acid (7- (pyridin-4-ylmethoxy) -2 (S) -? Iridin-3 -ylmethyl) -1, 2, 3, 4-tetrahydronaphthalen-1 (R) -yl) ester (Compound 29A and 29B): Examples 9A and 29B were prepared as described in Examples 4 to 6, but replacing compound 2 with Compound 28 to deliver a diastereomeric mixture. Chromatography of the mixture on silica gel (elution 10% acetone: hexane) provided compound 29A. An additional elution supplied compound 29B. Compound 29A:?: NMR as a mixture of rotomers (500 MHz, CDC13) d 8.54-8.43 (m), 7.60 (d), 7.41 (s), 7.31 (s), 7.30-7.28 (), 6.61 (s), 6.57 (s), 5.97 (d), 5.93 (d), 5.40 (d), 4.63 (br) d), 4.43 (d), 3.98 (s), 3.97-3.68 (m), 3.93 (s), 3.89 (s), 3.50 (br d), (dt), 3.32 (dt), 3.22 (dt), 3.01 (dt), 2.91 (m), 2.78 (dq), 2.56 (quintet), 2.44 (dt) m), 2.23-2.10 (m), 2.17 (S), 1.85-1.17 (m), 1.69-1.49 (m), 1.1 (t), 1.03 (t), 1.00 (t). Compound 29B: XH NMR as a mixture of rotomers (500 MHz, CDC13) d 8.49 (s), 8.47 (s), 7.54 (m), 7.36 (s), 7.38-7.216 , 62 (m), 6.62 (s), 6.53 (s), 6.03 (d), 5.39 (d), 4.55 (br d), 4.38 (d), 3 , 96 (s), 3.95 (s), 3.93 (s), 3.90 (s), 3.83 (dt), 3.69 (dt), 3.48 (q), 3, 44 (br d), 3.16 (dt), 3.00 (br d), 2.83 (dd), 2.72-2.49 (m), 2.45 (bd) P800 r), 2.18 (m), 2.15 (s), 2.14 (s), 1.94-1.68 (m), 1.61 (m), 1.49 (m), 1.35 (m), 1.20 (t), 1.04 (t), 0.97 (t).

Examples 30A and 30B 1- (2-OXQ-2- (3,4,5-trimethoxyphenyl) acetyl) piperidine 2 (S) -carboxylic acid (7- (pyridin-4-ylmethoxy) -2 • (R) (pyridine -3-ylmethyl) -1,2, 3, 4-tetra.hydronaphthalen-1 (R) -yl) ester and 1- (2-Oxo-2- (3,4,5-trimethoxyphenyl) acetyl) piperidine- 2 (S) - carboxylic acid (7- (pyridin-4-ylmethoxy) -2 (_ £ Q - (pyridin-3-ylmethyl) -1,2,3,4-tetrahydronaphthalen-1 (S) -yl) ester (Compound 30A and 30B): Examples 30A and 30B were prepared as described in Examples 4 to 6, but replacing compound 2 with compound 29 to deliver a diastereomeric mixture.Chromatography of the mixture on silica gel (elution 10% acetone: hexanes) provided compound 30 A. Additional elution provided compound 30B, Compound 30A: XH NMR as a mixture of rotomers (500 MHz, CDC13) d 8.48 (m), 7.57 (m), 7.37 (s), 7.33-7.27 (m), 7.20 (s), 6.51 (s), 6.49 (s), 5.85 (s), 5.38 (s) d), 4.60 (br d), 4.39 (d), 3.97 (s), 3.95-3.28 (m) ), 3.94 (3), 3.87 (s), 3.73 (t), 3.50 (dd), 3.30 (dt), 2.98 (dt), 2.84-2, 65 (m), 2.51 (dd) 2.42 (br d), 2.32 (m), 2.17 (t), 1.98 (m), 1.87-1.73 (m) , 1.68-1.50 (m), 1.47 (m), 1.09 (t), P800 1.07 (t), 1.04 (t), 0.99 (t). Compound 30B: '"H NMR as a mixture of rotomers (500 MHz, CDC13) d 8.49 (m), 8.43 (d), 8.32 (d), 7.57 (m), 7.36 (s), 7.35 (s), 7.30-7.25 (m), 7.18 (s), 6.63 (s), 6.48 (s), 6.35 (s), 6.02 (d), 5.87 (d), 5.77 (d), 5.38 (m), 4.66 (br d), 4.44 (d), 3.98-3.67 (m), 3.52 (br d), 3.44 (br d), 3.33 (dt), 3.26 (dt), 3.14 (dt), 3.01 (br d), 2 , 88-2.49 (m), 2.32 (m), 2.17 (s), 2.16 (s), 2.12 (s), 2.01 (m), 1.87-1 , 72 (m), 1.68-1.53 (m), 1.09 (t), l, 04 (t), 1.02 (t), 0.98 (t).

Example 31 In order to directly determine the neurotrophic activity of the compounds described in this invention, the highest neurite growth assay was carried out with pheochromocyte cells at PC12 as described by Lyons et al. (1994). PC12 cells are maintained at 372 and 5% C02 in a Dulbecco's Modified Eagle medium (DMEM) supplemented with 10% heat-inactivated horse wax, 5% heat inactivated fetal bovine wax (FBS), and 1% of glutamate. The cells are then placed in a dish at a rate of 105 per well in 96-well plates coated with 5 μg / cm2 rat tail and allowed to bind overnight. The medium is then P800 replaced with DMEN, 2% heat-inactivated horse wax, 1% glutamate, 1-5 ng / ml NGF (Sigma) and varying compound concentrations (0.1 nM-10 nM). The control culture for background is administered with 105 ng / ml of NGF alone without compound- The positive control cultures are administered with high concentration of NGF (50 ng / ml). The compounds described in this invention cause a significant increase in the greater growth of neurites over the background control cultures. While a number of embodiments of this invention have been presented in the foregoing, it is evident that my basic construction may be altered or added with other embodiments which use the methods of this invention. Therefore, it will be appreciated that the scope of this invention should be defined by the final claims to this in lieu of the specific embodiments that have been presented above by way of the examples.

P800

Claims (31)

1. CLAIMS 1. A pharmaceutically acceptable composition comprises: a) A neurotropic amount of a compound having the formula (I):
2. (I) and pharmaceutically acceptable derivatives thereof, wherein A, B and C are independently: hydrogen, straight or branched (C 1 -C 6) alkyl, straight or branched 0-alkyl (C 1 -C 6), (CH 2) n Ar, Y (CH 2) n-Ar, or halogen; where: n is 0-4; And it is O, S, or NR1; Rx = straight or branched alkenyl (C1-C6) or hydrogen; wherein each Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and
3. P800 anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, piraxolilo, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl , 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trityanyl, indolizinyl, indolyl , isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, isoquinolinyl , 1,2,3,4-tetrahydro-iso "quinolinyl, cinnolinyl, eftalazinilo 'quinazolinyl," quinoxalinyl, 1, 8-naphthyridinyl, peridinilo, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl; wherein each Ar optionally contains one to three substituents independently selected from hydrogen, hydroxyl, halogen, nitro, S03H, trifluoromethyl, trifluoromethoxy, to "straight or branched chill (C1-C6), O-benzyl, Q-phenyl, 1, 2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, and NRJNRJ NR..NR, carboxamides; wherein R, R, are independently selected from hydrogen, straight or branched alkyl (Cl-C5) or benzyl;
4. P800 where D is selected from hydrogen or (CH2) m-E; wherein: E is Ar or NR4R5; m = 1-3, and R4 and R5 are independently selected from hydrogen, alkyl (straight or branched C1-C5), or (CH2) Ar or can be taken together to form a 5-6 membered heterocyclic ring; wherein X is 0 or NR6, wherein: R6 is selected from hydrogen, straight or branched alkyl (C1-C6), or (CH2) m-Ar; m = 1-3; where J and K are independently straight alcguilo
5. Or branched (C1-C6) or Ar substituted with straight or branched alkyl (C1-C6), or wherein J and K are taken together to form a five or six membered ring or a 5 or 6 membered benzofused ring; where M is to "straight or branched chyle (C1-C6), or Ar; wherein the stereochemistry in carbon 1 and carbon 2 is independently R or S; b) a neurotropic factor; and c) a pharmaceutically suitable carrier. 2. The pharmaceutically acceptable composition of claim 1, wherein said compound has the
6. P800 formula:
7. Formula (II); where M, X, A, B, C, and D are as defined above. 3. The pharmaceutically acceptable composition according to claim 1, wherein said compound has the formula:
8. Formula (III); where M, A, B, C, and D are as defined above. 4. The pharmaceutically acceptable composition according to claim 1, wherein said compound has the formula:
9. P800 Formula (IV); wherein M, X, A, B, C, and D are as defined above; J is methyl or hydrogen; and K is (CH2) m-Ar or straight or branched alkyl (Cl6). 5. The pharmaceutically acceptable composition according to claim 4, wherein J is substituted or unsubstituted with benzyl. 6. The pharmaceutically acceptable composition according to any one of claims 1 to 5, wherein: A and C are independently selected from -0-CH2-4-pyridine, -0-propyl or hydrogen; B is selected from -0-CH2-4-pyridine, O-propyl or hydrogen; and D is selected from -CH2-3-pyridine or hydrogen. 7. The pharmaceutically acceptable composition
10. P800 according to any one of claims 1 to 5, wherein M is 3, 4, 5-trimethoxyphenyl. 8. The pharmaceutically acceptable composition according to any one of claims 1 to 5, wherein X is selected from oxygen, NH2 or N-benzyl. . The pharmaceutically acceptable composition according to claim 1, wherein said neurotrophic factor is selected from the nerve growth factor, insulin growth factor and its truncated active derivatives of the above, acid fibroblast growth factor, growth factor. of basic fibroblasts, growth factors derived from platelets, neurotrophic factor derived from the brain, ciliary neurotrophic factors, neurotrophic factor derived from glial cell lines, neurotrophin-3 or neurotrophin 4/5. 10. The pharmaceutically acceptable composition according to claim 9, wherein said neurotropic factor is the nerve growth factor. 11. A method for stimulating the growth of neurites in a patient or in an ex vivo nerve cell comprising the step of administering to said patient or said nerve a neurotropic amount of a compound having the formula (I):
11. P800 Formula (I) and pharmaceutically acceptable derivatives thereof, wherein M, J, K, A, B, C, and D are as defined in claim 1. 12. The method according to claim 11, wherein said compound has the formula:
12. Formula (II); wherein M, A, B, C, and D are as defined in claim 1. 13. The method according to claim 11, wherein said compound has the formula:
13. P800 Formula (III); wherein M, X, A, B, C, and D are as defined in claim 1. 14. The method according to claim 11, wherein said compound has the formula:
14. Formula (IV); wherein M, J, K, X, A, B, C, and D are as defined in claim 4.
15. 15. The method according to claim 14, wherein J is unsubstituted or substituted with benzyl.
16. 16. The method according to any one of claims 11 to 15, wherein: A and C are independently selected from P800 from -0-CH2-4-pyridine, -O-propyl or hydrogen; B is selected from -0-CH2-4-pyridine-0-, -O-propyl or hydrogen; and D is selected from -CH2-3-pyridine or hydrogen.
17. 17. The method according to claims 11 to 15, wherein M is 3,4,5-trimethoxyphenyl.
18. 18. The method according to any one of claims 11 to 15, wherein X is selected from oxygen NH2 or N-benzyl.
19. 19. The method according to claim 12, wherein said compound is selected from any of the compounds shown below. P800
20. 20. The method according to claim 13, wherein said compound is selected from compound 17 or 18: P800
21. 21. The method according to claim 14, wherein said compound is selected from any one of compounds 19, 20 or 21, as shown below:
22. 22. The method according to any one of claims 14 to 18, wherein said compound is administered to a patient and is formulated together with a P800 pharmaceutically suitable carrier in a pharmaceutically acceptable composition. The method according to claim 22, wherein said method is used to treat a patient suffering from Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, strokes and ischemia associated with neural paropathy and strokes, degenerative diseases neural diseases, neuromotor diseases, sciatic pressure, peripheral neuropathy, neuropathy associated with diabetes, spinal cord diseases or facial nerve pressure. 24. The method according to the claim 23, "comprising the additional step of administering to said patient a neurotrophic factor either as part of a multiple dose with said compound or a separate dosage form. 25. The method according to the claim 24, wherein said neurotrophic factor is selected from the nerve growth factor, insulin growth factor and its active truncated derivatives of the above, acid fibroblast growth factor, basic fibroblast growth factor, growth factors derived from platelets, neurotrophic factor derived from the brain, ciliary neurotrophic factors, neurotrophic factor derived from cell lines P800 glial, neurotrophin-3 or neurotrophin 4/5. 26. The method according to claim 24, wherein said neurotrophic factor is the nerve growth factor. 27. The method according to any one of claims 23 to 26, wherein said patient suffers from diabetes associated with peripheral neuropathy. The method according to any one of claims 11 to 18, wherein said method is used to stimulate the regeneration of the ex vivo nerve. 29. The method according to claim 28, comprising the additional step of contacting said nerve cell with a neurotrophic factor. 30. The method according to claim 29, wherein said neurotrophic factor is selected from nerve growth factor (NGF)., insulin growth factor (IGF) and its truncated active derivatives of the above, acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), platelet derived growth factors (PDGF), neurotrophic factor Brain derived (BDNF), ciliary neurotrophic factors (CNTF), neurotrophic factor derived from glial cell lines (GDNF), neurotrophin-3 (NT-3) or neurotrophin 4/5 (NT-4/5). 31. The method according to claim 30, P800 wherein said neurotrophic factor is the nerve growth factor (NGF). P800