MXPA03005941A

MXPA03005941A - Neurotrophic tacrolimus analogs.

Info

Publication number: MXPA03005941A
Application number: MXPA03005941A
Authority: MX
Inventors: Goldberg Bruce
Original assignee: Fujisawa Pharmaceutical Co
Priority date: 2000-12-29
Filing date: 2001-12-31
Publication date: 2005-02-14
Also published as: PL366301A1; CN1538843A; WO2002053159A1; IL156664A0; ZA200305806B; CA2433384A1; KR100794204B1; NZ527209A; NO20032913D0; EP1353671A4; CN1293877C; HUP0302521A3; RU2003123493A; BR0116762A; EP1353671A1; JP2004527472A; HUP0302521A2; AU2002231277B2; KR20070030331A; RU2288716C2

Abstract

Tacrolimus derivatives having high levels of neurotrophic activity and low levels of immunosuppresive activity. These compounds are useful as neurotrophic agents, particularly, for preventing or treating neuronal injury/dysfunction.

Description

ANALOGS TACROLIMUS NEUROTROPHIC BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a tacrolimus derivative having a high level of neurotrophic activity and a reduced level of immunosuppressive activity.

Background Analysis It is known that certain macrolide compounds, for example tacrolimus compounds and related thereto, help to prevent or treat cerebral ischemia (WO 94/14443). Particular derivatives of pipecolic acid, which have an affinity for FKBP-type immunophilins, such as tacrolimus, are known to stimulate the growth of damaged peripheral nerves or promote neuronal regeneration (WO 96/40140). Certain non-immunosuppressive compounds, ie geldanamycin and its analogs, are known to alter the spheroid receptor complex and promote nerve growth (WO 99/21552).

BRIEF DESCRIPTION OF THE INVENTION It has been found that a particular tacrolimus analogue, ie Compound (I) mentioned below, has excellent neurotrophic activity but, unlike tacrolimus, it has little or no immunosuppressive activity. As shown below, Compound (I) exerts higher levels of neurotropic activity compared to tacrolimus, for example, measured as. its ability to increase the length of the neurite. Similarly, administration of Compound (I) has been shown to induce axonal regeneration and accelerate recovery after nerve compression or spinal cord injury. In addition, Compound (I) exerts these advantageous neurotropic effects causing little or no immunosuppressive activity compared to tacrolimus. Accordingly, the present invention provides new uses for Compound (I) as a superior neotropic agent, as well as a neurotropic agent that causes little or no immunosuppressive activity. In addition, the invention provides a neurotrophic agent or composition comprising Compound (I). Also, the present invention provides a method for preventing or treating neuronal injury or dysfunction, which comprises administering Compound (I) to a mammal.

DETAILED DESCRIPTION OF THE INVENTION Unexpectedly, it has been discovered that Compound (I) is useful for improving, preventing or treating injury or neurological dysfunction caused by damage or injury, to deterioration of or disease of the nervous system, while, of advantageously, it has little or no immunosuppressive effect. Compound (I) is useful for treating damage, deterioration or dysfunction caused by physical damage, nutrition disorders, ischemia, degenerative diseases, malignant diseases, infectious diseases and by interactions with drugs, toxins or poisons. For example, Compound (I) is useful for treating damage and neurological dysfunction caused by neurosurgery, peripheral nerve injury, burns, encephalomyelitis, HIV, herpes, cancer, radiation treatment, drug interaction, folic acid deficiency or vitamin B12, and by exposure to neurotoxins or chemicals such as lead. Accordingly, Compound (I) is useful for preventing or treating neuronal damage and dysfunction, such as polymyositis (multiple myositis), Guillan Barre syndrome, Meniere's disease, polyneuritis (multiple neuritis), mononeuritis (neuritis) solitary), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, radiculopathy, neuropathy (such as diabetic neuropathy, neuropathy induced by chemotherapy, etc.), spinal cord injury, senile dementia , vascular dementia, multiple sclerosis, physical paralysis, etc. Compound (I), the analog of. tacrolimus used in the present invention, has the following chemical formula: This compound can be produced as described in U.S. Patent No. 5,376,663, Example 29. With respect to Compound (I) - used in the present inventionit should be understood that there may be conformers and one or more stereoisomers, such as for example optical and geometric isomers due to an asymmetric carbon atom or atoms or double bond or linkages, and said conformers and isomers are also within the scope of the compound of the present invention. Compound (I) may also be presented in the form of a pharmaceutically acceptable salt, derivative, solvate or pro-pharmaceutical, all of which fall within the scope of the present invention. Preferably, the solvate includes a hydrate and an ethanolate.

A preferred form of Compound (I) is as follows: Compound (I) of the present invention can be administered as a pure compound or as a mixture with another compound or other ingredients, preferably, in a carrier or pharmaceutical carrier. When Compound (I) is used in the form of a pharmaceutical composition or preparation, it can be mixed with an organic or inorganic carrier, vehicle or excipient suitable for external (topical), oral, enteral, subcutaneous, intravenous, intramuscular or parenteral For example, it may be present in a solid, semi-solid or liquid composition containing Compound (I) in the form of an active ingredient and one or more carriers, vehicles or excipients. Typical carriers, vehicles or excipients include, but are not limited to, conventional pharmaceutical carriers, medicinal or pharmaceutical agents, regulators, dispersants, emulsifying agents and adjuvants. Compound (I) can also be compounded with the usual non-toxic and pharmaceutically acceptable carriers for tablets, tablets, capsules, eye drops, suppositories, solutions (saline, for example), emulsions, suspensions (olive oil, for example). ), ointments, s'prays in spray, creams, plasters for the skin, patches and any other suitable form for the use. • Suitable carriers include water, dextrose and aqueous saline solutions, oils, including animal, vegetable and synthetic oils, and petroleum products. Other useful carriers include glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloid silica, potato starch, urea and other suitable carriers for use in preparations. of manufacture, in solid, semi-solid or liquid form. Additionally, auxiliary agents, stabilizers, emulsifiers, thickeners, colorants, flavors and perfumes can also be used. Compound (I) is included in the pharmaceutical composition in an amount effective to produce the desired effect before a particular disease condition or process. Preferably, Compound (I) is included in an amount sufficient to provide a neurotropic effect or stimulate the growth of nerve cells. Mammals that can be treated by the method of the present invention include livestock mammals such as cows, horses, pigs, etc., domestic animals such as dogs, cats, rats, mice, rabbits, hamsters, etc., primates and humans. - The preferred routes of administration or application of the. Products or compositions containing Compound I in humans, include injection or oral administration. . Although the therapeutically effective amount or dose of Compound (I) may vary according to the individual patient, and also. it will depend on the age and condition of each individual patient to be treated, usually a daily dose ranging between about 0.0001 and 1000 mg, preferably 0.001 to 500 mg and more preferably still 0.01 to 100 mg of the ingredient is given. active, for the treatment of diseases, and usually administered a single average dose of about 0.001 to 0.01 mg, 0.2 to 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg. Daily doses for chronic administration in humans will be in the range of about 0.1 to 30 mg / kg / day. Compound (I) can also be administered or applied simultaneously, separately or sequentially with other agents that possess neurotrophic or nerve cell growth stimulating activity.

The pharmaceutical compositions according to the invention can be administered periodically to a mammalian subject (for example a human patient) in need of such treatment, to promote neuronal regeneration and functional recovery, and to stimulate neurite re-growth and, thus, treat several neuropathological states, including damage to peripheral nerves and the central nervous system caused by physical damage (eg injury and trauma to the spinal cord, injury or damage to the facial or sciatic nerve, transplantation of a limb after amputation) ); diseases (for example, diabetic neuropathy); cancer chemotherapy (eg neuropathy induced by acrylamide, taxol, vinca alkaloids and doxorubicin); sequelae, for example allophasis (such as disorders of articulation), clouding of consciousness, dyskinesia, etc. associated with cerebral infarction, hemorrhagic infarction, etc; and neurological disorders including, but not limited to, various peripheral neurological and neuropathic disorders including, but not limited to: trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar congenital muscular atrophy, herniated, altered or prolapsed spinal disc syndromes, cervical spondylosis, plexoral disorders, syndromes of destruction of the thoracic outlet, peripheral neuropathies such as those caused by lead, acrylamides, gamma-diketones (neuropathy by glue aspiration) ), carbon disulfide, dapsone, tics, porphyria, Gullain Barre syndrome, Alzheimer's disease, Parkinson's disease and Huntington's chorea. A transection of a peripheral nerve or spinal cord injury can be treated by administering to the mammal an amount of the agent that stimulates nerve growth, and by transplantation into the peripheral nerve or spinal cord a nerve graft such as an allograft (Osawa). et al., J. Neurocytol., 19: 833-849, 1990; Buttenmeyer et al., Ann. Plástic Surgery 35: 396-401, 1995) or an artificial nerve graft (Madison and Archibald, Exp. Neurol., 128: 266- 275, 1994 Wells et al., Exp. Neurol., 146: 395-402, 1997). The space between the transected ends of the peripheral nerve or spinal cord is preferably filled with a non-cellular material to fill gaps, such as collagen, methylcellulose, etc., or cell suspensions that promote the growth of the nerve cell, such as Schwann (Xu et al., J. Neurocytol. 26: 1-16, 1997), olfactory cells and enveloping cells (Li et al., Science 277: 2000-2002, 1997). The nerve growth promoting agent may be included together with said cellular or non-cellular materials to fill gaps, or administered systemically before, during or after the nerve grafting procedure. In particular, Compound (I) is useful for treating or prevent polymyositis due to neuronal dysfunction or damage (multiple myositis), Gullain Barre syndrome, Meniere's disease, polyneuritis (multiple neuritis), mononeuritis (solitary neuritis), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), disease of Huntington, radiculopathy, diabetic neuropathy, neuropathy induced by chemotherapy, senile dementia, vascular dementia, multiple sclerosis, physical paralysis or injury to the spinal cord. The following examples illustrate the present invention in further detail. It should be understood that these examples describe certain aspects or embodiments of the invention but are not intended to limit the scope thereof.

Example 1: Treatment with Compound (I) significantly increases neurite lengths in hippocampal neurons Preparation of cell cultures: Embryonic rat breeding hippocampal neurons were obtained on embryonic day 18.5 ("E 18.5"), according to Banker and Cowan (Brain Research, 1917, 126: 397-425). In brief, the hippocampal regions were removed, crushed and incubated in papain 100 I.U. at 37 ° C for 45 minutes, and the cells were resuspended in a complete neuronal medium: minimal essential medium without L-glutamine (GIBCO, Grand Island, NY), a medium of 1 -5 ml / 100 ml of the minimum essential medium of high glucose (GIBCO), 0.1 ml / 100 ml serum extender medium (Milestone + Tm, Collaborative Research Inc., Lexington, MA), glutamine (GIBCO), 5% fetal bovine serum (GIBCO). Cells were seeded on coverslips (500 cells per coverslip) coated with poly-L-lysine. The coverslips were inverted onto dishes that had previously been coated with a single layer of cortical astrocytes.

Analysis of axonal lengths in hippocampal neurons: Hippocampal neurons (identified by their characteristic dendrites and polarity) were examined daily and photographed at random (9-12 frames per coverslip) at 72 hours. Axon lengths (defined as the most extensive process) were measured on photographic prints using a HI-PAD digitizing tablet from Houston Instrument connected to an IBM XT computer equipped with suitable software (Bioquant IV, R &M Biometrics, Nashville, TN ); only the processes of more than three times the length of the cell body were measured. The information from coverslips treated in the same way (three or four per group) was not different, and therefore was combined. "The mean values were calculated and compared by means of A-NOVA one-way (groups treated with Compound (a) or tacrolimus against an untreated control group), followed by a multiple comparisons test by Newman Kuels (ENKS 4.62, professional edition).

Results: At 72 hours, there was no significant difference between the untreated control group and the group treated with ???? of tacrolimus. However, the group treated with a concentration of ???? of Compound (la) 'caused a statistically significant increase in neurite lengths. See the results in Table I below: Table 1: Effects of Compound (a) and tacrolimus on average neurite lengths in primary hippocampal cell culture in rats at 72 hours.

* - = P < 0.05 versus No Treatment (one-way ANOVA followed by Newman-Kuels multiple comparisons test) Example 2: Treatment with Compound (I) increases the average neurite lengths in human neuroblastoma cells SH-SYSY Preparation of cultures of neuroblastoma cells SH-SY5Y: SH-SYSY human neuroblastoma cells were maintained in a DME medium (GIBCO), supplemented with 10% fetal bovine serum (SIGMA), 50 I. OR . / ml of penicillin and 50 ug / ml of streptomycin (GIBCO) at 37 ° C in 7% C02. The cells were placed in six-well plates at a ratio of 15,000 cells per well, and treated with 0.4 uM of aphidicolin (SIGMA). After 5 days, the cells were washed and treated with nerve growth factor (NGF) at 10 ng / ml (to induce regeneration of the process) in the presence or absence of tacrolimus (10 nM) or Compound (1). nM). The medium was changed at 96 hours and replaced with a fresh medium for an additional 72 hours (total time: 168 hours). Duplicate cavities were performed in all the experiments, and the information was averaged for each treatment group.

Analysis of neurite lengths in neuroblastoma cells SH-SY5Y: For the analysis of the length of the process, cells were photographed (20 fields per cavity) at random at 168 hs. The neurite lengths were measured on photographic prints by means of a HI-PAD digitizing tablet from Houston Instrument connected to an IBM X computer. Equipped with the appropriate software (Bioquant IV, R & M Biometrics, Nasville, TN); only the processes of more than twice the length of the cell body were measured. The information coming from cavities treated in the same way was not different, and therefore was combined. The average values were calculated and compared by means of a one-way ANOVA (samples treated with Compound (a) or tacrolimus against samples treated with NGF only), followed by a multiple comparison test of Newman-Kuels (WINKS 4.62, professional edition).

Results: The measurement of the lengths of the neurite processes showed that both Compound (la) (1 nM) and tacrolimus (10 nM) significantly increased the length of the neurite processes at 168 hours compared to NGF (10 ng / ml) alone. However, the effects of 1 nM of Compound (la) in combination with NGF were superior to the effects of 10 nM of tacrolimus in combination with NGF. Table 2: Effect of Compound (a) and tacrolimus on average neurite lengths in human neuroblastoma SH-SY5Y cells at 168 hours.

Neurite lengths (μ ??) No treatment 94.75 ± 3.734 NGF (10 ng / mJ) 198.8 ± 8.991 Tacrolimus (10 nM) + NGF (10 ng / ml) 227.6 1 9,130 * Compound (la) (1 nM) + NGF (10 ng.ml) 256.0 ± 9,067 * * = P < 0.05 against NGF (one-way ANOVA followed by Newman-Kuels multiple comparison test).

Example 3: Treatment with Compound (I) promotes functional recovery in the sciatic nerve compression model in the rat.

Animals and surgical procedure: Six six-week-old male Sprague-Dawley rats were anesthetized with 2% halothane, the right sciatic nerve was exposed and it was compressed twice (for a total of 60 s using Dumont nro jeweler forceps) .7), at the level of the hip The compression site was marked by attaching a sterile 9-0 suture through the epineural envelope.

Preparation of Compound (a) and administration: Compound (a) was dissolved in a vehicle comprising 30% dimethyl sulfoxide (DMSO) and 70% saline. Three axotomized rats received daily subcutaneous injections of Compound (la) (1 or 5 mg / kg) or an equivalent volume of vehicle (30% DMSO in saline) (5 ml / kg).

Behavioral evaluation: The animals were examined daily until the day of perfusion (18 days). The following was used. semi-quantitative scale to evaluate the functional recovery of the animals: 0 rparálisis, with the foot rotated out when walking and the fingers curved 1: ability to straighten the foot and move the fingers 2: ability to walk constantly on the foot 3: demonstrates separation of the toes when walking 4: walk with the heel up and exhibit almost normal finger separation. Animals that demonstrated intermediate abilities were assigned "tip is partial: + = 0.25; ++ = 0.5; +++ = 0. 75 Tissue fixation and preparation: 18 days after nerve compression, the rats were deeply anesthetized with 4% halothane, heparinized and perfused with 4% formaldehyde in 0.1 sodium phosphate buffer (pH 7.4) for 10 s, followed by 5% glutaraldehyde (IL) in 0.1 M sodium phosphate buffer (pH 7.4), and fixed at 4 ° C for 24 h. A tissue sample of the sciatic nerve was taken at a known distance (5 mm) from the compression site. In the present study, only the information of the branching of the posterior tibial nerve that provides the soleus muscle is reported. The tissues were placed in 01 M of sodium phosphate buffer (pH 7.4), subsequently fixed with 1% osmium tetraoxide (in 0.1 M phosphate buffer) for 2.5 hours, dehydrated in ethanol and sank in plastic. The semi-thin sections were stained with uranyl acetate and lead citrate, mounted on 75-mesh grids held on film, and examined under a JEOL 100 CX electron microscope.

Orphometric analysis: Analysis of the axonal calibers was carried out on the soleus nerve. The amounts of regenerating myelinated axons were counted by means of electron microscopy. The mean values and standard errors were calculated for the group treated with vehicle, the group treated with Compound (la) (1 mg / kg) and the group treated with Compound (la) (5 mg / kg).

Statistic analysis: For the analysis of the behavior, the average values for the recovery of the function were compared using one-way ANOVA followed by the Newman Keuls multiple comparisons test, to compare individual values. For the morphometric analysis, the average values for the number of axons were compared using "Single sense ANOVA • followed by the Newman Keuls multiple comparisons test, to compare individual values.

Results: Functional recovery Functional recovery was observed on days 15-17 and occurred earlier in the rats treated with 1 mg / kg and 5 mg / kg than in rats treated with vehicle. See table 3 below.

Table Effect of Compound (a) on functional recovery of damage in sciatic nerve in rats P < 0.05 against Vehicle (one-way ANOVA followed by multiple comparisons test Newman Kuels.

Electron microscopy The morphological examination of the animals was carried out 18 days after the axotomy. The amounts of regenerating myelinated axons per nerve area (5,000 μp? 2) increased dramatically from 5.5 ± 2.7 '(mean ± SE) in the vehicle-treated rats? at 19 ± 2.4 - and 20 ± 2.9 in the rats treated with 1 and 5 mg / kg respectively (P <0.05). See Table 4 below.

Table 4: Effect of the compound (la) on the. amounts of regenerating myelinated axons per nerve area (5,000 um2.) in the soleus nerve 18 days after compression of the sciatic nerve in rats *: P < 0.05 against Vehicle (one-way ANOVA followed by multiple comparisons test Newman Kuels.

Example 4: Treatment with compound (I) promotes functional recovery in the model of spinal cord damage in rats. (1) Methods - - '' '- · Animals and Surgical Procedures - Twenty-eight Sprague Dawley rats were anesthetized, a six-week-old male with 2% halothane, a T10 / T11 laminectomy and hemisectional damage. in the spinal cord at the level of the spinal cord T10 / T11.

Preparation of Compound (a) and Administration Compound (a) was dissolved in a vehicle comprising 30% dimethyl sulfoxide (D SO): 70% saline. Damaged rats in the spinal cord received daily subcutaneous injections of compound (la) (2 mg / kg) or an equivalent volume of vehicle (30% DMSO in saline) (5 ml / kg) for seven weeks after surgery .

Evaluation of functional recovery Functional recovery was evaluated by means of a Tarlov / Klinger scale, narrow-bar test and fingerprint test at 2 weeks after the injury.

? Modified Tarlov Klinger Scale The rats were allowed to move freely in an open field for one minute and were classified from 0 to 6 according to the scale presented below. 0: no movement of the extremity-injured posterior. "*. .1: 'movement barely noticeable" .in - the injured hind limb -. '2: brief movements in the. "joints of the injured hind limb (hip, knee or ankle) but lack of coordination and weight support 3: alternate steps and propulsion movements of the injured hind limb absence of weight bearing 4: can support the weight on the limb injured posterior 5: walk with a slightly mild deficit 6: walk normally B. Test on narrow bars A test was carried out with the rats on narrow bars (1.5 m long) of decreasing width: 7.7 cm, 4.7 cm, 2.7 cm and 1.7 cm. The rats were allowed to walk on the bars and the narrowest bar was recorded on which they could walk without falling on at least two routes. 0: you can not walk on any bar "- 1: you can walk on the bar of 7.7 cm 2: you can walk on the bar of 4.7 cm 3: you can walk on the bar of 2.7 cm 4: you can walk on the bar of 1.7 cm C. Fingerprinting The hind limbs of the rats were stained with ink and the footprint was marked on paper, covering a narrow footbridge 60 cm long and 7.5 cm wide. A series of at least six sequential steps was used to determine the fingerprint score over 5 points. 0: constant dorsal passage or drag of the hind limb, that is to say no trace is discernible: there are visible traces of at least three digits in at least three footprints 2: shows exo- or endo-rotation of the feet of a value more than double compared to its own baseline values 3: it shows no signs of finger drag, but if foot rotation 4: shows no signs of exo- or endo-rotation (less than twice the angle of the values baseline), but you see more than one heel footprint. 5: there are no visible heel prints.

Statistical analysis For the behavior analysis, the average values for the score of each functional test were compared, using one-way ANOVA followed by the Newman Keuls multiple comparisons test to compare the individual values. (2) Results Functional recovery In the three measurements of functional recovery carried out by means of a modified Tarlov Klinger scale (Table 5), test on narrow bars (Table 6) and fingerprint test (Table 7), the compound ( la) improved motor functional disability on a modified Tarlov Klinger scale (Table 5), test on narrow bars (Table 6) and fingerprint test (Table 7).

Table 5: Effect of compound (la) on Tarlov Klinger score modified from spinal cord damage in rats *: P < 0.05 against Vehicle (unique sentiment ANOVA followed by multiple comparisons test Newman Kuels). Table 6: Effect of compound (la) on the score on narrow bars of spinal cord damage in rats *: P < 0.05 against Vehicle (ANOVA of sense - only followed by test of multiple comparisons Newman Kuels).

Table 7: Effect of compound (la) on the score of damage traces -in spinal cord in rat-s *: P < 0.05 against Vehicle (one-way ANOVA followed by multiple comparisons test Newman Kuels).

Example 5: Compound (a) binds to FIBP12 but, in the direction of tacrolimus, exerts little or no immunosuppressive effect (1) Binding assay with FKBP12 The binding assay was carried out in a manner similar to that explained in Tamura, K et al. (Biochemical arid Biophysical Research Communications, Vol 202, No. 1, 437-499, 1994). The results are shown in Table 8. (2) Mixed lymphocyte reaction (MLR) The MLR test was carried out in a manner similar to that explained in U.S. Patent No. 4,929,611. The results are shown in Table 8. Table 8: Pharmacological profiles of compound (la) and tacrolimus in vitro These results indicate that the compound does not possess immunosuppressive activity even though it can be linked to FKBP12. The results shown above illustrate the potent neurotrophic effects of Compound (I) using both in vitro and in vivo models. In two cell culture models, Compound (I) even at low concentrations, increased neurite growth. In addition, the systemic administration of Compound (I) in low doses accelerated functional recovery after a nerve compression injury, by increasing the rate of axonal regeneration in the sciatic nerve, and promoted the functional recovery of damage in the spinal cord. Furthermore, as already shown above, the compound (I) provides a potent neurotrophic activity or stimulator of cell growth in the nerve, although it does not possess immunosuppressive activity. Accordingly, the present invention provides a useful neurotrophic agent for stimulating or promoting neuronal growth or regeneration, particularly when an immunosuppressive effect is not desired or is not advantageous. Other aspects of the present invention include: A manufacturing article comprising packaging material and Compound (I) identified therein, within said packaging material, wherein said Compound (I) is therapeutically effective in preventing or treating neuronal dysfunctions, and wherein said packaging material comprises a label or written material indicating that Compound (I) can or should be used to prevent or treat neuronal dysfunction or damage. A commercial package comprising the pharmaceutical composition containing Compound (I) identified therein, and a written material related thereto, wherein the written material states that Compound (I) can or should be used to prevent or treat dysfunction or neuronal damage.

A composition, such as a graft, - cell tissue or suspension comprising a cell treated with Compound (I). Such compositions are useful for repairing damage to the nervous system. These compositions may also include other nerve cell growth stimulating agents, such as for example other types of cell suspensions that promote or collaborate with the growth of the nerve cell, such as myelin-producing cells such as Sch ann cells or oligodendrocytes, glial cells and enveloping cells; Excellular matrix material, such as collagen; u _ other specific neuroregulators such as cytokines, mitogenic factors, immunophilins and neurotrophins, such as NGF-1, BDNF, CNTF, NT-3, NT-4 and NT-5. Grafts, such as homoinj ertos, allografts or xenografts can also be treated with Compound (I) in order to facilitate neuronal growth and its use as transplants or in other applications.

Incorporation by Reference The content of each document, patent application or patent publication cited or referred to in this description, is incorporated by reference in its entirety. The content of any Patent document before which this application claims priority, is also incorporated by reference in its entirety. Specifically, the content of US Provisional Application No. 60 / 258,500 is incorporated by reference.

Modifications and other embodiments It will be apparent that numerous modifications and variants of the present invention are possible in the light of the teachings explained. Therefore, it should be understood that within the scope of the appended claims, the invention may be practiced in a manner different from that specifically described herein. Various modifications and variants of the compositions and methods described, as well as the concept of the invention, will be apparent to those skilled in the art, without departing from the scope and spirit of the invention. While the invention has been described in connection with preferred specific embodiments, it should be understood that the invention, as claimed, is not intended to be limited to said specific embodiments. Various modifications of the modes described for carrying out the invention, which are obvious to those with experience in the medical, biological, chemical or pharmacological arts or their related fields, are also within the scope of the present invention.

Claims

Use of a compound with the following formula for the manufacture of a neurotrophic agent. 2. Use according to claim 1, wherein the neurotrophic agent is for preventing or treating neuronal dysfunction or damage.
3. Use according to claim 1, wherein the neurotrophic agent is to stimulate or promote regeneration. or growth of the nerve cell.
4. Use according to claim 1, wherein the neurotropic agent is for promoting functional recovery from damage to a nerve.
5. Use according to claim 1, wherein the neuronal dysfunction or damage is polyiaiositis (multiple myositis), Guillan Barré syndrome, Meniere's disease, polyneuritis (multiple neuritis), mononeuritis (solitary neuritis), Alzheimer's disease, malignancy Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, radiculopathy, diabetic neuropathy, neuropathy induced by chemotherapy, senile dementia, vascular dementia, multiple sclerosis, physical paralysis or damage to the spinal cord.
6. Use according to claim 1, wherein the neuronal dysfunction or damage is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetic neuropathy, neuropathy induced by chemotherapy or spinal cord damage.
7. Use according to claim 1, in which the compound (I) is presented in the form of its pharmaceutically acceptable salt, derivative, pro-drug or solvate.
8. Composition comprising the compound (I) and having the following formula:
9. Composition according to claim 8, in which the compound (I) is presented in the form of its pharmaceutically acceptable salt, derivative, pro-drug or solvate.
10. The composition according to claim 8, in which the compound (I) is in the form of compound da).
11. The composition according to claim 8, further comprising at least one other neurotrophic agent.
12. Manufacturing article or kit, comprising packaging material and compound (I) contained within said packaging material, wherein said packaging material comprises a label or written material indicating that said compound (I) can or it must be used to prevent, improve or treat neuronal dysfunction or damage.
13. A commercial packaging or kit comprising: a pharmaceutical composition comprising the compound (I) and written material associated therewith, wherein the written material states that the compound (I) can or should be used to prevent, improve or treat neuronal dysfunction or damage
14. Method for making or making a neurotrophic agent comprising mixing the compound (I) with a pharmaceutically acceptable carrier, vehicle or excipient.
15. Method for stimulating or promoting the regeneration or growth of the nerve cell, comprising contacting a nerve cell with the compound (I).
16. Method for increasing the rate of regeneration or axonal growth, or length of the nerve cell, comprising contacting a nerve cell with the compound (I).
17. Method for increasing the growth of the nerve cell in a tissue in need thereof, which comprises administering the compound (I) to said tissue.
18. Method according to claim 17, wherein said tissue is selected from the group consisting of brain tissue, spinal cord tissue or peripheral nerve tissue.
19. Method for repairing a transected peripheral nerve or spinal cord, comprising contacting the transected ends of said peripheral nerve or spinal cord with an effective amount of compound (I)
20. Method for repairing a peripheral nerve or spinal cord transected in a subject, comprising: administering a stimulatory amount of the nerve growth, of the compound (I) to said subject, and grafting to the peripheral nerve or spinal cord.
21. Method according to claim 20, in which said graft is an allograft.
22. Method according to claim 20, wherein said graft is an artificial nerve graft.
23. Method according to claim 20, further comprising filling the space between the transected ends of the peripheral nerve or spinal cord, with a non-cellular material for filling gaps
24. Method according to claim 20, further comprising filling the space between the transected ends of the peripheral nerve or spinal cord, with a cell suspension.
25. Composition comprising a nerve cell treated with the compound (I).
26. Tissue comprising a nerve cell treated with the compound (I).
27. Graft comprising a nerve cell treated with the compound (I).
28. Graft according to claim 27, wherein said graft is a homograft, allograft or xenograft.
29. A method for repairing a transected peripheral nerve or spinal cord comprising contacting the transected ends of said peripheral nerve or spinal cord with an effective amount of a composition comprising a cell treated with the compound (I).
30. Composition comprising a cell, tissue or graft treated with the compound (I) and at least one agent promoting the growth of the nerve cell.
31. Composition according to claim 30, wherein said nerve cell growth promoting agent is selected from the group consisting of a cell suspension that promotes neuronal growth, a non-cellular material to fill gaps, or a growth factor of the nerve.
32. The composition according to claim 30, comprising collagen or methyl cellulose as a nerve growth promoting agent.
33. The composition according to claim 30, which comprises a cell suspension as a nerve growth promoting agent.