MXPA96006131A - Neuroprotect agents - Google Patents
Neuroprotect agentsInfo
- Publication number
- MXPA96006131A MXPA96006131A MXPA/A/1996/006131A MX9606131A MXPA96006131A MX PA96006131 A MXPA96006131 A MX PA96006131A MX 9606131 A MX9606131 A MX 9606131A MX PA96006131 A MXPA96006131 A MX PA96006131A
- Authority
- MX
- Mexico
- Prior art keywords
- rapamycin
- compound
- administration
- nmda
- adduct
- Prior art date
Links
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- 229960002930 sirolimus Drugs 0.000 claims abstract description 35
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- HEPAOWNMAYQHNY-UHFFFAOYSA-N 1-phenyltriazole-4,5-dione Chemical compound O=C1C(=O)N=NN1C1=CC=CC=C1 HEPAOWNMAYQHNY-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 4- (dimethylamino) phenyl Chemical group 0.000 claims abstract description 10
- AGSKZZIPIUOHNI-UHFFFAOYSA-N 1-methyltriazole-4,5-dione Chemical compound CN1N=NC(=O)C1=O AGSKZZIPIUOHNI-UHFFFAOYSA-N 0.000 claims abstract description 8
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- MGRVRXRGTBOSHW-UHFFFAOYSA-N Aminomethylphosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims description 10
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Abstract
This invention provides a method for the use of repamicin, the 1,3-Diels Alder duct of repamicin with phenyltriazolinedione, the 42-ester of repamicin with 4 - ((4- (dimethylamino) phenyl) azo) benzenesulfonic duct, adduct 1, 3-Diels Alder of rapamycin with methyltriazolinedione and rapamycin-O-benzyl-27-oxime as neuroprotect agent
Description
NEUROPROTECTING AGENTS
BACKGROUND OF THE INVENTION It has been thought that glutamate-induced toxicity is the mechanism of nerve cell death in ischemia, aploplastic attack and head injuries (Simón RP, Science 226: 850 (1984); H, J. Neuroc. Em 43: 1369 (1984)). It is also involved in other neurological disorders, such as Alzheimer's, ALS, Epilepsy, Huntington's disease and Parkinson's disease. (Beal F, Nature 321: 168 (1986), Maragos WF, Trends Neurosci, 10:65 (1987), Greenamyre JT, Neurobiol.Aging 10: 593 (1989), Koh JY, Brain Res. 533: 315 (1990); Mattson MP, J. Neurosci 12: 376 (1992); Rothstein, JD, New England J. Med. 326: 1464 (1992); Choi, DW, New England J. Med 326 (22): 1 * 93- 4 (1992)). Under normal conditions, glutamate functions as an excitatory neurotransmitter in the brain. It is released from presynaptic terminals and activates receptors in postsynaptic neurons. Activated receptors allow sodium and calcium ions to flow into the cell to produce an arousal response. The action of these excitatory amino acids is mediated by several different subtypes of receptors, of which the best studied is the receptor of
N-methyl-D-aspartate (NMDA). Excessive activation of the NMDA receptor complex can cause neuronal overstimulation with neurological consequences. Under REF: 23580 pathological conditions, excessive levels of glutamate accumulated in the extracellular space lead to over stimulation of glutamate receptors. This induces a greater influx of sodium and calcium, resulting in high levels of intracellular calcium, which initiates the still unknown processes of cell death. Currently, glutamate receptor antagonists are being developed to prevent the death of nerve cells after a stroke or trauma to the head. (Hirose K, Neurochem, Res. 18: 479 (1993), Dugan LL, Annals of Neurology, Vol. 35 suppl. S17-19 (1994)). Several studies have shown that obstruction of the NMDA subclass receptor significantly reduces the neuronal damage and loss that occurs in animal models in which various neuropathological situations are simulated. These observations strongly indicate that NMDA antagonists offer neuroprotection in several clinical cases. However, many of these medications are effective only when they occur within 6 hours after the trauma or injury. This may be due to the fact that intracellular calcium levels may also rise due to calcium entering the cell through voltage-controlled calcium channels. In addition, because activation of glutamate receptors is required for normal synaptic transmission and brain activity, prolonged treatments with glutamate receptor blockers are not feasible. This limits their use as neuroprotective agents in chronic neurodegenerative disorders. Therefore, drugs that can prevent the death of nerve cells, after the increase of intracellular calcium levels, are appropriate for the delayed treatment of stroke and head injuries, as well as for the chronic treatment of diseases neurodegenerative Several hypotheses have been proposed to explain how high levels of intracellular calcium lead to cell death. One is that it activates calcium-dependent proteases, such as calpain. Another is that it activates calcineurin, a calcium / calmodulin-dependent phosphatase that dephosphorylates nitric oxide (NOS) syntax. The dephosphorylation of NOS allows the production of nitric oxide, which is toxic to cells. A third hypothesis is that high levels of intracellular calcium induce apoptosis, or programmed cell death. These various hypotheses are not mutually exclusive and it is more likely that all these events, as well as others that have not been discovered, are triggered by high levels of intracellular calcium to cause cell death. In apoptosis, some genes are activated that are necessary for cell division, as if the cell were trying to divide. (Heintz N, Trends-Biochem-Sci. 18: 157 (1993)). Many highly differentiated cells, such as neurons, have lost the ability to divide and by not being able to do this, they die; therefore, it is possible that drugs that can inhibit the division of cells can also prevent them from suffering apoptosis.
DESCRIPTION OF THE INVENTION This invention provides a method of using a compound selected from the group of rapamycin, the 1,3-Diels Alder adduct of rapamycin with phenyltriazolinedione, the 42-ester of rapamycin with 4- (4 - (dimethylamino) phenyl) azo) benzenesulfonic, the 1,3-Diels Alder adduct of rapamycin with methyltriazolinedione and rapamycin-O-benzyl-27-oxime (referred to collectively as the compounds of this invention), as a neuroprotective agent; which comprises administering the compound, to a mammal in need thereof, orally, parenterally, intravascularly, intranasally, intrabronchially, transdermally or rectally. More particularly, this invention provides a method for the treatment of stroke, head trauma and neurodegenerative disorders, such as Alzheimer's disease, lateral amitropic sclerosis (ALS), epilepsy, Huntington's disease or Parkinson's disease, in a mammal that requires the same, which comprises administering an effective amount of a compound selected from the rapamycin group, the 1,3-Diels Alder adduct of rapamycin with phenyltriazolinedione, the 42-ester of rapamycin with 4- ((4- (dimethylamino) -phenyl) azo) -benzenesulfonic acid, the 1,3-Diels Alder adduct of rapamycin with methyltriazolinedione and rapamycin-O-benzyl-27-oxime, to the mammal orally , parenteral, intravascular, intranasal, intrabronchial, transdermal or rectal. The compounds of this invention are also useful for inhibiting the death of nerve cells related to the pathological conditions mentioned above. This invention also provides a method for using a compound selected from the rapamycin group, the 1,3-Diels Alder adduct of rapamycin with phenyltriazolinedione, the 42-ester of rapamycin with 4- ((4- (dimethylamino)) phenyl) azo) benzenesulfonic. The 1,3-Diels Alder adduct of rapamycin with methyltriazolinedione and rapamycin-O-benzyl-27-oxime, in combination with an NMDA antagonist and / or AMPA as a neuroprotective agent and treat stroke, trauma to the head and neurodegenerative disorders, such as Alzheimer's disease, lateral amitrophic sclerosis (ALS), epilepsy, Huntington's disease or Parkinson's disease. The compounds of this invention are also useful for inhibiting nerve cell death related to the disease states mentioned above, when used in combination with an NMDA antagonist and / or AMPA. When the compounds of this invention are used in combination with an NMDA antagonist and / or AMPA, the combination can be administered simultaneously or sequentially, without taking into account the order of administration. Preferred NMDA antagonists include (2- (8,9-dioxo-2,6-diazabicyclo (5.2.0) -non-l (7) -en-2-yl) -ethyl) phosphonic acid (described in U.S. Patent No. 5,168,103, which is incorporated herein by reference), D-amino-5-phosphonopentanoate (D-AP5), 4-phosphonomethyl-2-iperidinecarboxylic acid (CGS19755), D, L- (E) acid ) -2-amino-4-methylphosphono-3-? Entanóico (CGP37849), the
,7-dichloroquinurenate, trans-2-carboxy-5, 7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline (L689560) and 5,7-dinitroquinoxolin-2,3-dione (MNQX ); and preferred AMPA antagonists include 6- (1H-imidazol-1-yl) -7-nitro-2,3 (1H, 4H) -quinoxalindione (YM90K) hydrochloride (J. Med. Chem. 37: 647 ( 1994), 1- (4-aminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine HC1 (GYKI52466) and 6-nitro-7-sulfamobenzo (f) quinoxalin-2, 3 -dione (NBQX), 6-cyano-7-nitroquinoxalin-2, 3-dione (CNQX) and 6,7-dinitroquinoxalin-2, 3-dione (DNQX) The treatment covers the treatment of an existing condition, inhibiting the progress or development of the condition, improving the condition and providing relief of the condition The ability of the compounds of this invention to act as neuroprotective agents was demonstrated in the following standard in vitro pharmacological evaluation procedures that simulate the neurotoxicity of mammals The first standard pharmacological evaluation procedure demonstrated the ability of the compounds of this invention to inhibit cell death. erviose resulting from the toxicity induced by glutamate. Soon, hippocampal and cortical cultures of the rat were prepared, according to the Furshpan and Potter method with some modifications (Neuron 3: 199 (1989)). Brains were extracted from Long Evans newborn puppies, anesthetized with an injection of 0.1 ml of 20% chloral hydrate. The hippocampi were dissected and separated from the rest of the cortex. Both tissues were enzymatically digested in 5 ml of Earle's balanced salt solution (EBSS) containing 20 u / ml of papain, 1 mM L-cysteine and 0.5 mM EDTA for 30 minutes at 37 ° C with gentle agitation. The hippocampi and cortical tissues were then washed once with EBSS and the digestion stopped by incubating at 37 C for 30 minutes with 3 to 5 ml of inhibitor solution containing 1 mg / ml of ovomucoid and 1 mg / ml of albumin in EBSS . The digested hippocampal and cortical tissues were washed twice with DME, without L-glutamine, with 4.5 g / 1 dextrose, before being triturated in 2 ml of DME supplemented with 5% fetal bovine serum, 5% serum rat, 50 u / ml of penicillin, 0.05 mg / ml of streptomycin and MITO + serum extender (a supplement for the medium, from Collaborative Biomedical Products) (10% DME). After 50 triturations, the undissociated tissue was allowed to settle and the suspension of dissociated cells was removed. 2 ml of fresh 10% DME was added to the remaining tissue and the grinding was repeated. The two aliquots of cell suspension were stored and the cell density was determined with a hemacytometer. 30,000 hippocampal cells were plated at 150 icrolitres per well in 96-well plates and incubated at 37 C in 5% CO ~. Cortical cells were plated at a density of 500,000 cells per well in 24-well plates. When confluent glia cells were made (after approximately 3 days), cytosine β-D-arabinofuranoside from 4 to 10 micromolar was added to each well to prevent further proliferation. One week after plating the medium was removed and replaced with DME supplemented with 2.5% fetal bovine serum, 2.5% rat serum, 50 u / ml penicillin and 0.05 mg / ml streptomycin, MITO +, quinurea 1 mM and 10 mM MgCl2 (DME 5% + KM). Quinureate is a nonspecific blocker of glutamate receptors and high magnesium levels block the influx of calcium and sodium through the NMDA receptor channels. The addition of KM prevents the neurotoxicity that occurs with the glutamate found in the serum and allows the neurons to remain in culture for several months. The cells were fed weekly changing half of the medium with 5% DME + fresh KM. The compound that was evaluated was dissolved in DMSO to make 10 mM stock solutions and stored in aliquots at -80 ° C. Just before each procedure was performed aliquots of the stock solutions were thawed and diluted in DME or Hank's balanced salt solution (HBSS) containing 44 mM sodium bicarbonate, 10 mM glucose and 30 uM glutamate to obtain test concentrations from 1 nM to 10 μM. After 4 to 12 weeks in culture, the hippocampal cells were washed three times and fed with the test compound in HBSS or serum free DME (SF DME) and glutamate, at a concentration of 30 to 150 micromolar. At least three wells in each test procedure were treated with each concentration of the medication. 30 micromolar glutamate kills 70 to 80% of neurons in younger cultures and more in older cultures. The toxicity induced by 30 micromolar glutamate was blocked with 1 mM quinureaate + 10 mM MgCl 2 (KM). After incubation overnight at 37 ° C, the number of hippocampal neurons remaining in five fields representing the north, south, east and west ends and the center of each well were counted. Each field was visualized through an objective lens with a 15x eyepiece and was approximately 1.54 mm 2 in area. The conditions were generally carried out in triplicate. The average number of neurons per well and the standard deviation for each condition were calculated. The average number of neurons that remained in the 30 micromolar glutamate control condition reflects those that were not sensitive to glutamate toxicity. The following table shows the results obtained for the compound of Example 1.
Compound Concentration No. of Living Neurons D.E. *
Example 1 10 nM 114 5 Example 1 100 nM 92 38 Example 1 1 uM 46 10 E Ejjeemmpplloo 11 1 100 μμMM 47 20 SF DME 28 4 Quiruneate 1 mM 82 17 * Standard deviation.
The following table shows the test results obtained for the compounds of this invention.
Compound Concentration No. of Living Neurons DE * Example 1 200 nM 229 30 Example 1 20 nM 71 3 Example 1 2 nM 63 4 Example 2 200 nM 127 38 Example 2 20 nM 180 64 Example 2 2 nM 110 36 Example 3 200 nM 241 46 Example 3 20 nM 285 40 Example 3 2 nM 98 21 Example 4 200 nM 157 56 Example 4 20 nM 130 29 Example 4 2 nM 117 32 Example 5 200 nM 135 11 Example 5 20 nM 96 12
Example 5 2 nM 131 19
Qumureato 1 mM 202 40 HBSS 53 25 * Standard Deviation
The results of this standard pharmaceutical test procedure show that the compounds of this invention inhibit glutamate-induced neurotoxicity and are therefore useful as neuroprotective agents. As shown in the first table, lower concentrations of the compound of Example 1 (10 and 100 nM) were shown to be higher than the higher concentrations of the compound of Example 1 (1 and 10 micromolar), possibly due to some cytotoxic effects of the compound of Example 1 at these higher concentrations. The evaluation of the compounds of this invention in concentration ranges between 2 and 200 nM demonstrated neuroprotective activity against glutamate-induced toxicity, which simulates neurotoxicity in mammals. At higher concentrations of glutamate (75 micromolar), the compounds did not prevent neuronal cell death. The compounds of this invention were less effective as neuroprotective agents against glutamate-induced toxicity in older hippocampal cultures (greater than 8 weeks), which are more sensitive to glutamate toxicity. The second standard in vitro pharmacological test procedure demonstrates the ability of the compounds of the invention to increase the neuroprotective effects observed with the NMDA and AMPA inhibitors. Briefly, cortical cultures were maintained for eight weeks in 24-well plates, as described above. The cortical neurons were washed six times with DME, without glucose, which had been deoxygenated by bubbling the medium with a mixture of N_95% / CO-5% for at least 10 minutes, to induce an ischemic state that caused cell death and that can be observed by measuring lactate dehydrogenase levels, since the amount of LDH activity in each well correlates directly with the number of cells left. Acid (2- (8,9-Dioxo-2,6-diazabicyclo (5, 2, 0) non-l (7) -en-2-yl) -ethyl) -phosphonic acid 100 micromolar (described in the patent) was added. North American No. 5,168,103 which is incorporated herein by reference) and YM90K 10 raicromolar to certain wells to block glutamate NMDA and AMPA receptors, respectively. To the test wells, 1 micromole of the compound of Example 1 was added. The control wells were washed with normal DME with glucose and acid (2- (8,9-dioxo-2,6-diazabicyclo (5.2)) 100 micromolar non-l (7) -en-2-yl) ethyl) phosphonic acid. Samples of 5 microliters were taken from each well at different times, after ischemia, and the LDH activity was determined in those samples by adding 250 microliters of a mixture of NADH 2 mg / 25 ml of phosphate buffer to each sample. After incubating for 20 to 30 minutes, 10 microliters of 22.7 mM pyruvate was added and the optical density (OD) was read at 340 nm. The change in optical density over time (mDO / min) reflects the amount of LDH in the sample. Major changes in optical density mean increased LDH activity, which indicates increased cell death. The samples were taken from 4 to 8 wells per condition and the average and standard deviation were determined for each condition. The results obtained are shown in the following table.
The compounds of this invention were also evaluated in the standard test procedure that simulates ischemic neurotoxicity, with the exception that one-week cortical cell cultures, which are less sensitive to isotope-mediated neurotoxicity, were used. The test compounds were administered with inhibitors of NMDA and AMPA, as described above. Cyclosporin was also evaluated for comparison purposes.
Time (hours) Acti ida Deviation Standard
Control - 8 0.30 0.54 13 1.37 1.58 24 2.97 2.67 30 4.44 2.50 Isquemiai 8 0.49 0.36 13 6.17 1.10 24 16.40 4.29 30 21.49 3.35 Example 1 8 1.04 0.20 13 3.08 0.71 24 9.00 1.64 30 14.02 2.4 Example 2 8 1.08 0.34 13 2.31 1.41 24 7.69 3.13 30 12.43 3.85 Example 3 8 0.84 0.20 13 2.36 1.41 24 7.03 3.24 30 11.25 2.62 Time (hours) LDH Activity Standard Deviation
Example 4 8 0.91 0.34 13 2.54 1.02 24 8.21 4.14 30 13.31 3.41 Example 5 8 0.74 0.38 13 1.65 0.81 24 4.82 1.42 30 8.83 2.41 Cyclosporine 8 1.54 0.63 13 3.31 1.37 24 8.45 1.94 30 13.59 2.34
The results obtained in this standard pharmaceutical test procedure demonstrate that the compounds of this invention increase the neuroprotective effects of the NMDA and AMPA inhibitors by inhibiting the neurotoxicity induced by ischemia. The compounds of this invention can be formulated as such or with a pharmaceutical carrier for a mammal that requires them. The pharmaceutical carrier can be solid or liquid. When formulated orally it has been found that 0.01% Tween 80 in. PHOSAL PG-50 (phospholipid concentrate with 1,2-propylene glycol, A. Nattermann &Cié. GmbH) provides an acceptable oral formulation. A solid carrier can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents, it can also be an encapsulating material. In the powders, the carrier is a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets, preferably, contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting point waxes and resins of ion exchange Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (which partially contains additives, such as those mentioned above, eg cellulose derivatives, preferably a solution of sodium carboxy ethylcellulose), alcohols (including monohydric alcohols and alcohols) polyhydric, eg glycols) and their derivatives, lecithins and oils (eg fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be a fatty acid ester, such as ethyl oleate and isopropyl iristate. Sterile liquid carriers are useful in sterile compositions in liquid form for parenteral administration. The liquid carrier for pressurized compositions may be a halogenated hydrocarbon and another pharmaceutically acceptable propellant. Liquid pharmaceutical compositions that are sterile solutions or suspensions can be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally, either in the form of a liquid or solid composition. The compounds of this invention can also be administered rectally, in the form of a conventional suppository. For administration by inhalation or intranasal or intrabronchial insufflation, rapamycin can be formulated in an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of this invention can also be transdermally administered through the use of a transdermal patch containing the active compound and a carrier which is inert to the active compound, which is not toxic to the skin and which allows the distribution of the agent for systemic absorption in the bloodstream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be viscous liquids or semi-solid emulsions of the oil-in-water or water-in-oil type. Pastes comprised of absorbent powders dispersed in petroleum or in hydrophilic petroleum containing the active ingredient, may also be useful. A variety of occlusive devices can be used to release the active ingredient into the bloodstream, such as a semipermeable membrane that covers a reservoir containing the active ingredient, with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. Dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, the projected intravenous daily doses of the active compound would be 0.1 μg / kg to 100 mg / kg, preferably between 0.001 to 0.25 mg / kg, and more preferably between 0.01 to 5. mg / kg. The projected daily oral doses would be from 0.005 to 50 mg / kg, preferably from 0.01 to 25 mg / kg, and more preferably from 0.05 to 10 mg / kg. The treatment, in general, will start with small doses lower than the optimum dose of the compound. Subsequently, the dose is increased until the optimum effect is achieved under the circumstances; The precise doses for oral, parenteral, nasal or intrabronchial administration will be determined by the doctor, based on the experience with the individual subject being treated. Preferably, the pharmaceutical composition is in unit dose form, e.g., as tablets or as capsules. In this form, the composition is subdivided into the dosage unit containing the appropriate amounts of the active ingredient; Dosage unit forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre-filled syringes or sachets containing liquids. The dosage unit form can be, for example, a capsule or a tablet, or it can be the appropriate number of any of these compositions in package form.
The following examples illustrate the preparation of the compounds of this invention.
Example 1
Rapamycin The preparation of rapamycin has been described in
U.S. Patent No. 3,929,992, which is incorporated herein by reference.
Example 2
Adduct 1,3-Diels Alder of rapamycin with Phenyltriazolinedione Rapamycin (0.66 g, 721 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 C. To this was added, dropwise, a solution of phenyltriazolinedione ( 0.133 g, 758 mmol) in dichloromethane (10 ml). The solution was stirred overnight, analysis by TLC showed that the reaction was not complete. Additional phenyltriazolinedione (0.Q25 g, 27 mmol) was added. The reaction was purified using HPLC (4.4 x 31 cm, SiO_) with ethyl acetate as eluent, to give the title compound as a solid. The solid was triturated with 30 mL of hexane and 1 mL of ethyl acetate, filtered and air dried to give the title compound as a powder.
(0.383 g). Anal Calculated for C5gH84 4 ° i5: c '65'05' * H '7.77; N, 5.14.
Found: C, 65.39; H, 7.98; N, 4.92. IR (KBr, cm "1) 3450, 1715 NMR (DMSO) S 7.50 (m, 3H), 7.40 (m, 2H), 3.11 (s, 3H), 3.00 (s,
3H), 2.95 (s, 3H), 0.8 (q, 1H) MS (-FAB) 1088 (M ~)
Example 3
42-Rapamycin ester with 4- ((4- (dimethylamino) phenyl) azo) benzenesulfonic acid The preparation of the compound of Example 3 has been described in US Pat. No. 5,177,203, which is incorporated herein by reference.
Example 4
Alde 1,3-Diels adduct of rapamycin with methyltriazolinedione The title compound was prepared according to the method described in Example 2.
Example 5
Rapamycin-O-benzyl oxime The preparation of the compound of Example 5 has been described in U.S. Patent No. 5,023,265, which is incorporated herein by reference.
It is noted that, in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or substances to which it refers. Having described the invention as above, the content of the following is claimed as property.
Claims (14)
- CLAIMS 1. A method for inhibiting the death of neuronal cells in a mammal that requires it, wherein the method is characterized in that it comprises the administration of an effective amount of a compound selected from the group consisting of rapamycin, the adduct 1,3- Diels Alder of rapamycin with phenyltriazolinedione, the 42-ester of rapamycin with 4- ((4- (dimethylamino) phenyl) azo) benzenesulfonic acid, the adduct 1,3-Diels Alder of rapamycin with methyltriazolinedione and rapamycin-O-benzyl 27-oxime, to the mammal orally parenterally, intravascularly, intranasally, intrabronchially, transdermally or rectally.
- 2. The method, according to claim 1, characterized in that the compound is rapamycin.
- 3. A method for the treatment of stroke, trauma to the head or a neurodegenerative disorder, in a mammal in need thereof, wherein the method is characterized in that it comprises the administration of an effective amount of rapamycin, the adduct 1,3- Diels Alder of rapamycin with phenyltriazolinedione, the 42-ester of rapamycin with 4- ((4- (dimethylamino) phenyl) azo) benzenesulfonic acid, the adduct 1,3-Diels Alder of rapamycin with methyltriazolinedione and rapamycin-O-benzyl 27-oxime, to the mammal, orally parenterally, intravascularly, intranasally, intrabronchially, transdermally or rectally.
- 4. The method, according to claim 3, characterized in that the compound is rapamycin.
- 5. The method, according to claim 3, characterized in that the neurodegenerative disorder is • selected from the group consisting of the Disease of Alzheimer's, lateral amitrophic sclerosis (ALS), epilepsy, Huntington's disease and Parkinson's disease.
- 6. The method, according to claim 5, characterized in that the compound is rapamycin.
- 7. A method for the use of a compound selected from the group consisting of rapamycin, the 1,3-Diels Alder adduct of rapamycin with phenyltriazolinedione, the 42-ester of rapamycin with 4- ((4- (dimethylamino) phenyl) azo) benzenesulfonic, the 1,3-Diels Alder adduct of rapamycin with methyltriazolinedione and rapamycin-O-benzyl-27-oxime, as a neuroprotective agent, wherein the method is characterized in that it comprises administering an effective amount of the compound to a mammal in need of it, orally, parenterally, intravascularly, intranasally, intrabronchially, transdermally or rectally.
- 8. The method, according to claim 7, characterized in that the compound is rapamycin.
- 9. The method, according to claim 1, characterized in that it further comprises the administration of the compound in combination with an NMDA or AMPA antagonist.
- 10. The method, according to claim 1, characterized in that it also comprises the administration of the compound in combination with an NMDA antagonist and of AMPA, at the same time.
- 11. The method, according to claim 3, characterized in that it further comprises the administration of the compound in combination with an NMDA or AMPA antagonist.
- 12. The method according to claim 3, characterized in that it also comprises the administration of the compound in combination with an NMDA antagonist and of AMPA at the same time.
- 13. The method according to claim 7, further comprising administering the compound in combination with an NMDA or AMPA antagonist.
- 14. The method according to claim 3, characterized in that it further comprises the administration of the compound in combination with an NMDA antagonist and AMPA antagonist at the same time.
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US833795P | 1995-12-07 | 1995-12-07 | |
US008337 | 1995-12-07 |
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JP (1) | JPH09183727A (en) |
KR (1) | KR970032856A (en) |
CN (1) | CN1112925C (en) |
AR (1) | AR008747A1 (en) |
AT (1) | ATE234095T1 (en) |
AU (1) | AU700653B2 (en) |
BR (1) | BR9605895A (en) |
CA (1) | CA2192298A1 (en) |
CZ (2) | CZ6498A3 (en) |
DE (1) | DE69626610T2 (en) |
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HU (1) | HUP9603370A3 (en) |
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MX (1) | MX9606131A (en) |
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SK (1) | SK154796A3 (en) |
TW (1) | TW427904B (en) |
ZA (1) | ZA9610245B (en) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1002535A1 (en) * | 1998-10-28 | 2000-05-24 | Hrissanthi Ikonomidou | New use of glutamate antagonists for the treatment of cancer |
US6417189B1 (en) * | 1999-11-12 | 2002-07-09 | Gpi Nil Holdings, Inc. | AZA compounds, pharmaceutical compositions and methods of use |
US7253169B2 (en) | 1999-11-12 | 2007-08-07 | Gliamed, Inc. | Aza compounds, pharmaceutical compositions and methods of use |
FR2806626B1 (en) * | 2000-03-22 | 2003-11-28 | Centre Nat Rech Scient | USE OF MODULATING SUBSTANCES FOR THE EXPRESSION OR FUNCTION OF A PROTEIN INVOLVED IN THE CELL CYCLE FOR THE TREATMENT OR PREVENTION OF ACUTE NEURAL INJURIES |
WO2001079177A1 (en) * | 2000-04-17 | 2001-10-25 | Gpi Nil Holdings, Inc. | Cyclic diaza compounds for treating neurodegenerative disorders |
GB0117645D0 (en) * | 2001-07-19 | 2001-09-12 | Isis Innovation | Therapeutic stratergies for prevention and treatment of alzheimers disease |
UA78529C2 (en) * | 2001-10-10 | 2007-04-10 | Wyeth Corp | Derivatives of [[2-(amino-3,4-dioxo-1-cyclobutene-1-yl)amino]alkyl] acid for treating pain |
US20030176455A1 (en) * | 2002-03-13 | 2003-09-18 | Wyeth | Method of inhibiting cell death |
AU2004230895B2 (en) | 2003-04-09 | 2010-09-09 | Wyeth | Derivatives of 2-(8,9-dioxo-2,6-diazabicyclo(5.2.0)non-1(7)-en-2-yl)alkyl phosphonic acid and their use as N-methyl-D-aspartate (NMDA) receptor antagonists |
MXPA05010763A (en) * | 2003-04-09 | 2005-12-12 | Wyeth Corp | Pharmaceutical compositions for intranasal administration of [2-(8, 9-dioxo-2, 6-diazabicyclo [5.2.o] non-1 (7)-en- 2-yl) alkyl] phosphonic acid and derivatives and methods of use thereof. |
US20070155771A1 (en) * | 2003-04-11 | 2007-07-05 | David Rubinsztein | Methods and means for treating protein conformational disorders |
US7485706B2 (en) * | 2003-07-30 | 2009-02-03 | The Board Of Trustees Of The Leland Stanford Junior University | Neurodegenerative protein aggregation inhibition methods and compounds |
GT200400213A (en) | 2003-10-22 | 2007-09-05 | METHODS FOR THE PREPARATION OF ACID {2 - [(8,9) -DIOXO-2,6-DIAZA-BICICLO [5.2.0] -NON-1 (7) -EN-2-IL] ETIL} PHOSPHONE AND ESTERES OF SAME | |
MX2007007408A (en) * | 2004-12-20 | 2007-07-12 | Wyeth Corp | Rapamycin analogues and the uses thereof in the treatment of neurological, proliferative, and inflammatory disorders. |
BRPI0519593A2 (en) | 2004-12-20 | 2009-02-25 | Wyeth Corp | methods of treating neurodegenerative disorders and complications due to stroke or trauma to the head, and of preparing a compound, and use of a compound |
JP4857071B2 (en) * | 2006-10-12 | 2012-01-18 | 潤平 笹部 | Method for detecting amyotrophic side sclerosis (ALS) |
EP2065038A1 (en) | 2007-11-30 | 2009-06-03 | Pharnext | New therapeutic approaches for treating Charcot-Marie-Tooth disease |
EP2135607A1 (en) | 2008-06-18 | 2009-12-23 | Pharnext | Combination of pilocarpin and methimazol for treating Charcot-MarieTooth disease and related disorders |
EP2965763B8 (en) * | 2009-04-10 | 2018-08-15 | Haiyan Qi | Anti-aging agents |
US9393241B2 (en) | 2009-06-02 | 2016-07-19 | Pharnext | Compositions for treating CMT and related disorders |
EP2263665A1 (en) | 2009-06-02 | 2010-12-22 | Pharnext | New compositions for treating CMT and related disorders |
WO2011009193A1 (en) * | 2009-07-24 | 2011-01-27 | Institut National De La Recherche Scientifique | Combinations of curcummoids and mtor inhibitors for the treatment of tauopathies |
US9283211B1 (en) | 2009-11-11 | 2016-03-15 | Rapamycin Holdings, Llc | Oral rapamycin preparation and use for stomatitis |
US9121859B2 (en) * | 2012-12-04 | 2015-09-01 | Siemens Healthcare Diagnostics Inc. | Compounds and methods for determination of FKBP-binding immunosuppressant drugs |
EP3003268B1 (en) | 2013-06-05 | 2018-07-25 | Pharnext | Stable oral solutions for combined api |
US9700544B2 (en) | 2013-12-31 | 2017-07-11 | Neal K Vail | Oral rapamycin nanoparticle preparations |
US10383870B2 (en) | 2016-06-10 | 2019-08-20 | Pharnext | Early treatment of CMT disease |
WO2019099671A1 (en) * | 2017-11-15 | 2019-05-23 | Vanderbilt University | Methods and compositions for the improvement of lysosomal function and treatment of neurodegenerative disease |
CN114366738A (en) * | 2021-12-20 | 2022-04-19 | 中国人民解放军军事科学院军事医学研究院 | Application of rapamycin in promoting expansion of neural stem cells |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5206018A (en) * | 1978-11-03 | 1993-04-27 | Ayerst, Mckenna & Harrison, Inc. | Use of rapamycin in treatment of tumors |
JPH04230389A (en) * | 1990-07-16 | 1992-08-19 | American Home Prod Corp | Rapamycin derivative |
US5078999A (en) * | 1991-02-22 | 1992-01-07 | American Home Products Corporation | Method of treating systemic lupus erythematosus |
IL101353A0 (en) * | 1991-04-03 | 1992-11-15 | American Home Prod | Pharmaceutical compositions for treating diabetes |
DE4118740A1 (en) * | 1991-06-05 | 1992-12-10 | Schering Ag | NEW COMBINATION DEVICES FOR TREATING MORBUS PARKINSON |
ZA924953B (en) * | 1991-07-25 | 1993-04-28 | Univ Louisville Res Found | Method of treating ocular inflammation |
US5260299A (en) * | 1992-03-05 | 1993-11-09 | American Home Products Corporation | Rapamycin 42-sulfonates and 42-(N-Carboalkoxy)Sulfamates Useful as Immunosuppressive Agents |
IL111003A0 (en) * | 1993-09-30 | 1994-11-28 | American Home Prod | Multi-component oral rapamycin formulation |
-
1996
- 1996-11-28 TW TW085114700A patent/TW427904B/en not_active IP Right Cessation
- 1996-12-04 CZ CZ9864A patent/CZ6498A3/en unknown
- 1996-12-04 SI SI9630586T patent/SI0778023T1/en unknown
- 1996-12-04 ES ES96308786T patent/ES2188730T3/en not_active Expired - Lifetime
- 1996-12-04 DE DE69626610T patent/DE69626610T2/en not_active Expired - Fee Related
- 1996-12-04 EP EP96308786A patent/EP0778023B1/en not_active Expired - Lifetime
- 1996-12-04 CZ CZ963544A patent/CZ354496A3/en unknown
- 1996-12-04 PT PT96308786T patent/PT778023E/en unknown
- 1996-12-04 DK DK96308786T patent/DK0778023T3/en active
- 1996-12-04 SK SK1547-96A patent/SK154796A3/en unknown
- 1996-12-04 AT AT96308786T patent/ATE234095T1/en not_active IP Right Cessation
- 1996-12-05 NZ NZ299888A patent/NZ299888A/en unknown
- 1996-12-05 KR KR1019960062011A patent/KR970032856A/en not_active Application Discontinuation
- 1996-12-05 ZA ZA9610245A patent/ZA9610245B/en unknown
- 1996-12-05 AU AU74178/96A patent/AU700653B2/en not_active Ceased
- 1996-12-05 MX MX9606131A patent/MX9606131A/en unknown
- 1996-12-06 CA CA002192298A patent/CA2192298A1/en not_active Abandoned
- 1996-12-06 NO NO965238A patent/NO309966B1/en not_active IP Right Cessation
- 1996-12-06 HU HU9603370A patent/HUP9603370A3/en unknown
- 1996-12-06 AR ARP960105543A patent/AR008747A1/en not_active Application Discontinuation
- 1996-12-06 CN CN96123098A patent/CN1112925C/en not_active Expired - Fee Related
- 1996-12-06 IL IL11977896A patent/IL119778A/en not_active IP Right Cessation
- 1996-12-06 JP JP8326582A patent/JPH09183727A/en active Pending
- 1996-12-06 BR BR9605895A patent/BR9605895A/en not_active Application Discontinuation
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