[go: up one dir, main page]

WO2007061554A2 - Dosage de derives de 4-aminopyridine pour le traitement des lesions du systeme nerveux central - Google Patents

Dosage de derives de 4-aminopyridine pour le traitement des lesions du systeme nerveux central Download PDF

Info

Publication number
WO2007061554A2
WO2007061554A2 PCT/US2006/041302 US2006041302W WO2007061554A2 WO 2007061554 A2 WO2007061554 A2 WO 2007061554A2 US 2006041302 W US2006041302 W US 2006041302W WO 2007061554 A2 WO2007061554 A2 WO 2007061554A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
nerve
pharmaceutically acceptable
spinal cord
pyridyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2006/041302
Other languages
English (en)
Other versions
WO2007061554A3 (fr
Inventor
Ryi Shi
Richard B. Borgens
Daniel T. Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Purdue Research Foundation
Original Assignee
Purdue Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Purdue Research Foundation filed Critical Purdue Research Foundation
Publication of WO2007061554A2 publication Critical patent/WO2007061554A2/fr
Publication of WO2007061554A3 publication Critical patent/WO2007061554A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the invention provides novel pyridines, pharmaceutical compositions comprising such pyridines, and methods of using such compositions in treating injured mammalian nerve tissue, including but not limited to an injured spinal cord.
  • the compounds, compositions, and methods of the instant invention treat a mammalian nerve tissue injury by restoring action potential or nerve impulse conduction though a nerve tissue lesion.
  • the compounds provide longer lasting effects at lower concentrations than comparable treatment with the known agent 4-aminopyridine ("4 AP" or "4- AP").
  • the methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
  • the biological basis for functional loss after spinal cord injury is the elimination of nerve impulse transmission "up and down" the spinal cord.
  • the basis for a partial functional recovery, independent of how old the injury is, is the restoration of such nerve impulses - in the case of the instant invention, by pharmacological means.
  • Traumatic injury to the spinal, axons (Waxman, S.G., Kocsis, J.D., Stys, P.K., Eds.): The Axon, New York: Oxford UP, pp 480- 503; Maxwell, W.L. (1996): Histopathological Changes at Central Nodes of Ranvier After Stretch-injury, Microscopy Research and Technique, 34: 522-535; Maxwell, W.L., Watt, C, Graham, DL, Gennarelli, LA.
  • the loss of the electrical insulating capacity of myelin facilitates short circuit potassium current that aids in extinguishing the nerve impulse before it can begin to cross the nodal region.
  • Drugs that block this exodus of potassium from inside the nerve fiber to the outside milieu are believed to be the biological basis for the restoration of action potential (or nerve impulse) conduction through spinal lesions associated with variable recoveries of functions in human patients.
  • the compounds upon in vivo administration, reduced the deleterious effect of traumatic CNS tissue injury though restoration of nerve impulse conduction through nerve tissue lesions. Testing indicates that the compounds themselves are active, as the compounds were shown to remain stable and nondegrading in the test solution, yet showed lasting effects at low concentrations in vitro.
  • R 1 is H or a C 1 -C 4 alkyl group
  • R is a -C-R group, a -P-R group or an OR group
  • R is a C 1 -C 20 alkyl group (preferably a C 1 -C 6 alkyl group), an aryl (preferably phenyl) group or an alkylene aryl group (where the alkylene group is a C 1 -C 20 alkylene group, preferably a C 1 -C 3 alkylene group, and the aryl group is preferably a phenyl group),
  • R 1 is a C 1 -C 10 alkyl group (preferably, a C 1 -C 3 alkyl group), n is 1 to 20 (preferably 1 to 3),
  • R 11 is selected from H, C 1 - C 4 alkyl,
  • each of R7, R8 and R9 is independently selected from H, C 1 -C 4 alkyl, F, Cl, Br, I or NO 2 , preferably, at least two, and more preferably three of R 7 , R 8 and R 9 are H.
  • the compounds of this invention include all stereoisomers (i.e., cis and trans isomers) and all optical isomers of compounds of the formula (I) (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers, as well as all polymorphs of the compounds.
  • alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), maybe linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • Methyl carbamate enhanced conduction maximally at 100 ⁇ M in vitro.
  • Ethyl carbamate and t-butyl carbamate enhanced conduction maximally at concentrations of 10 ⁇ M and 1 ⁇ M. At higher concentrations, each of these compounds continued to increased CAP amplitude. Additionally, ethyl and t-butyl carbamate have effects on CAP amplitude when administered at or beyond 100 ⁇ M.
  • the present invention also relates to a method for treating injured mammalian nerve tissue, especially injured human nerve tissue, including reducing the deleterious effect of CNS or PNS tissue injury, comprising administering to a mammal, preferably a human, requiring such treatment an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • the present invention also relates to a pharmaceutical composition for treating injured mammalian nerve tissue, especially injured human nerve tissue, including reducing the deleterious effect of CNS or PNS tissue injury, comprising:
  • composition is effective in treating injured mammalian nerve tissue , including reducing the deleterious effects of CNS or PNS tissue injury.
  • the present invention also relates to a method of reducing the deleterious effect of CNS or PNS tissue injury, and treating an associated nerve tissue lesion, by restoring action potential or nerve impulse conduction through the nerve tissue lesion by in vivo administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • neurotrophic factor refers to compounds which are capable of stimulating growth or proliferation of nervous tissue.
  • they may be administered alone or with known neurotrophic factors including, but are not limited to, nerve growth factor (NGF), insulin growth factor (IGF-I) and its active truncated derivatives such as gIGF-1, acidid and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5).
  • NGF nerve growth factor
  • IGF-I insulin growth factor
  • aFGF and bFGF basic fibroblast growth factor
  • PDGF platelet-derived growth factors
  • BDNF brain-derived neurotrophic factor
  • CNTF ciliary neurotrophic factors
  • GDNF glial cell line-derived neurotrophic factor
  • NT-3)
  • FIGURE 1 illustrates (i) a double sucrose gap isolation and recording chamber used to test compound action potential propagation through a standardized crush lesion to strips of guinea pig spinal cord white matter in organ culture (section A), (ii) a single elicited CAP (section B), (iii) a number of repetitive CAPs (section C), (iv) CAP conduction through the cord after being subjected to standardized crush injury (section D), and (v) a CAP beginning to reappear after pharmacological intervention.
  • FIGURE 2 illustrates a SSEP testing protocol used to test compounds of the instant invention in vivo and reflects normal recordings in intact animals, the elimination of sensory impulses after a mid-thoracic spinal cord injury, and the importance of a median nerve control procedure.
  • FIGURE 4 illustrates the structural formulae of certain examples of pyridine derivatives of the instant invention.
  • FIGURE 6 illustrates the measurement of SSEP's in a sedated guinea pig.
  • FIGURE 7 illustrates responses of recovered compound nerve impulses to in the presence of compounds of the present invention.
  • Figure 8 illustrates the change in CAP in response to specific concentrations of N-(4- pyridyl)methyl carbamate according to one aspect of the present application.
  • FIGURE 9 illustrates the change in CAP in response to specific concentrations of N-(4- pyridyl)ethyl carbamate according to one aspect of the present application.
  • the double sucrose gap chamber is an exceptional means to "prescreen” numerous pharmacological interventions prior to the more arduous and time consuming means of testing similar functioning in the "whole" animal independent of other practical considerations such as the best route of administration (for example intravenous or oral administration) that can only be evaluated in animal testing.
  • the isolated spinal cord (stippled band) is shown mounted in the chamber, with the central well continuously perfused with oxygenated Krebs solution (similar to extracellular fluid).
  • the test drugs were added to this chamber.
  • the two ends of the spinal cord lie in separate wells filled with isotonic KCl (similar to intracellular fluid) divided from the central well by narrow gaps filled with flowing, isotonic sucrose solution.
  • Electrodes were formed from Ag/ AgCl wires. Action potentials were generated through a pair of electrodes at the left hand sucrose gap, conducted through the central part of the spinal cord and recorded by another pair of electrodes in the right-hand gap by conventional bridge amplification techniques. A compression to the cord is performed at its approximate midpoint, within the central Krebs solution containing chamber. This then interferes with conduction of compound action potentials through the cord to the pair of recording electrodes on the far side.
  • a strip of isolated spinal cord white mailer obtained from adult guinea pigs, approximately 35-40 mm in length, is placed in the chamber and continuously supervised with oxygenated Krebs' solution (c. 2 ml/mm) by means of a peristaltic pump.
  • the free ends of the spinal cord strip are placed across the sucrose gap channels to side compartments filled with isotonic (120 mM) potassium chloride.
  • the temperature of the chamber is maintained with a Peltier unit in the base, thermostatically controlled with a thermistor system (Cambion Instruments).
  • the axons are stimulated and compound action potentials, as well as compound membrane potential (in the form of gap potential) are recorded at opposite ends of the strip of white matter by silver/silver chloride wire electrodes positioned within the side chambers and the central bath.
  • the central bath is connected to instrument ground.
  • Stimuli are delivered through stimulus isolation units and are usually in the form of 0.1 msec constant current unipolar pulses. Recordings are made using a bridge amplifier and Neurocorder (both from Neurodata Instruments Inc.) for digital data storage on videotape. Subsequent analysis are performed using custom Labview® software (National Instruments) on a Macintosh Power PC G3 computer.
  • Effective amount when used herein with reference to a novel pyridine of the instant invention denotes a quantity of the compound which, when administered to a patient or subject, is sufficient to result in a measurable improvement in electrical and/or behavioral function of a nerve which has been so damaged or injured that normal functioning is not possible.
  • the efficacy of the treatment may be determined in a variety of ways, including methods which detect restoration of nerve function.
  • effective amount with other agents, for example, 4 AP, that term is used to describe an amount of an agent effective within the context of that agent's use in the present invention.
  • Nerv tissue refers to any vertebrate nerve tissue, particularly including mammalian cells of the central nervous system (CNS) and peripheral nervous system (PNS). More particularly, nerve tissue includes spinal cord neuronal structures, peripheral nervous system nerves, and even nerve cells of the brain.
  • CNS central nervous system
  • PNS peripheral nervous system
  • Neve tissue injury includes any damage to relevant nerve tissue irrespective of cause, e.g., injuries attributable to trauma including but not limited to nerve tissue lesions, traumatically-induced compression, tumors, hemorrhage, infectious processes, spinal stenosis, or impaired blood supply.
  • FIGURE 2 is a diagram of this testing protocol and provides examples of normal recordings in intact animals, the elimination of sensory impulses after a mid-thoracic spinal cord injury, and explains these issues in detail, as well as, emphasizing the importance of a median nerve control procedure.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)] salts.
  • non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphat
  • Those compounds of the formula (I) which are also acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula (I). These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before, hi either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable earners that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally, or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions maybe formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyothylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyothylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. HeIv or similar alcohol.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention maybe administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may 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, emulsifying wax and water.
  • 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, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions should be formulated so that a dosage of between about 5-100 mg/kg, more preferably about 10-50 mg/kg body weight/day of the novel pyridine can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or injury being-treated.
  • the invention provides a method of administering a novel pyridine compound and a neurotrophic agent in a single dosage form or in separate, multiple dosage forms. If separate dosage forms are utilized, they may be administered concurrently, consecutively or within less than about 12 hours, more preferably within less than about 8 hours of one another, depending upon the bioavailability and pharmacokinetics of the agents.
  • the methods of this invention are used to restore nerve impulse conduction through nerve tissue lesions in a patient.
  • the composition of the Krebs' solution was as follows (in niM): 124 NaCl, 2 KCl, 1.2 KH 2 PO 4 , 1.3 MgSO 4 , 1.2 CaCl 2 , 10 dextrose, 5.6 sodium ascorbate, and 26 NaHCO 3 , equilibrated with 95%-0 2 5%- CO 2 to produce a pH of 7.2-7.4.
  • the term "ventral white matter strips” will be used interchangeably below with “cords” or “spinal cords” for ease of description.
  • the biological basis for the loss of behavior after spinal cord injury is the interruption of nerve impulse "traffic” ascending the cord to the brain from nerve "inputs” from the body, and the reverse - loss of impulse traffic arising in the brain "descending” the spinal cord to targets in the body.
  • this test vehicle is a.- first evaluation of the crucial and relevant biological basis for paralysis.
  • the length of the spinal cord spans all three chambers along with two small reservoirs located in- between the chambers. These small reservoirs contain sucrose which is continuously pumped and aspirated.
  • sucrose helps to electrically isolate the ends of the cord from the center section in a physiological solution.
  • Stimulation at one end of the spinal cord produces compound action potentials (CAPs) that are conducted through the white matter to be recorded at the other end of the chamber. It is the electrical isolation of the ends, permitted by the flowing sucrose, and the fact that the ends of the cord segment are closer to intracellular potential than the center (at extracellular potential) that provides unexcelled resolution of CAPs.
  • continuous monitoring of the compound membrane potential (gap potential) can also be followed during the course of each experiment.
  • the spinal cord is allowed to stabilize in the recording chamber for about 1 h in order to produce a characteristic response to electrical stimulation.
  • the cord is stretched in its center (in the central chamber) using an impactor at about 1.5 m/s. This stretches the spinal cord in a standardized fashion. The stretching induces a transitory loss in CAP propagation across the lesion, which improves with time.
  • Once spontaneous recovery produces a stable "recovery CAP”, drug is added to the medium bathing the central chamber. Recording of CAPs is continuous, however about 0.5 h is required for the drug induced changes in amplitude to stabilize. This response is reported as an increase (or decrease) in the "pre-drug" recovered potential (which is normalized to 100%).
  • the drug is washed out of the chamber, and the cord's lesion exposed to fresh aerated Krebs solution for approximately 1 h prior to obtaining "post-drug” electrical recordings.
  • FIG. 1, Section A illustrates features of a slightly different embodiment of this apparatus.
  • a schematic 3D drawing at the top right of FIG. 1 shows its dimensions - the chamber is fashioned from clear Plexiglas.
  • the four compartments are diagrammed and labeled according to the solutions that are pumped into them. These solutions are drawn off by aspiration, producing a modest, but continuous, flow of media using a capillary pump (not shown).
  • the outside compartments are at or near intracellular potential while the middle chamber (containing a balanced physiological organ culture solution) is at extracellular potential. Therefore, the inversion of the membrane potential during a nerve impulse episode is directly measured in a similar manner to "single" unit intracellular electrophysiological recordings - producing an increase in resolution of the Compound Action Potential (CAP).
  • CAP Compound Action Potential
  • the CAP is produced by the synchronous firing of individual nerve fibers (called axons) numbering in the tens of thousands spanning the length of the guinea pig spinal cord.
  • the cord is stimulated to synchronously "fire" CAPs on one side of the chamber (in the example shown, the left side) and the arrival of the CAPs are recorded on the right end.
  • Mixing of the two-different solutions is greatly reduced by a swiftly flowing boundary of sucrose through the indicated chambers, which also electrically isolates the ends of the spinal cord segment which spans the entire width of the chamber.
  • the physiological solution (Krebs 1 ) is also pH stabilized and oxygenated in the reservoir that provides the media pumped though the middle chamber.
  • Compound nerve impulse (CAP) conduction though the cord following a standardized crush injury to the cord in its, middle - that is - in the, central physiological compartment is shown in Section D.
  • the passage of the nerve impulses stimulated on the left side reaches the injury and is blocked - failing to traverse the chamber to be recorded on the right side.
  • a CAP is beginning to reappear after pharmacological intervention: the compound of the instant invention was introduced into the physiological solution bathing the injury site in the middle compartment, i.e. the compartment containing Kreb's solution.
  • the most precise means of comparing the quantitative aspects of recovery of nerve impulse conduction is to compute the derivative of the magnitude and duration of the CAP (i.e., the "area under the curve") for comparison of the pre-injury values to those values produced by the introduction of a "test" drug.
  • novel pyridine derivatives of the instant invention were administered through a gastric tube to large adult guinea pigs which had previously received a standardized compression injury to their mid-thoracic spinal cords.
  • the ability of these compounds to restore conduction in this second technique was determined by a quantitative evaluation of SSEPs. The following protocols and routes of administration were employed.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouvelles pyridines, des compositions pharmaceutiques comprenant ces pyridines et l'utilisation de ces compositions dans le traitement des lésions du tissu nerveux mammifère, y compris mais non de façon limitative, une lésion de la moelle épinière. Dans un mode de réalisation, les composés, les compositions et les méthodes selon l'invention traitent une lésion du tissu nerveux mammifère en rétablissant le potentiel d'action ou la conduction nerveuse à travers une lésion du tissu nerveux. De manière significative, l'application in vivo de composés selon l'invention établit, sur la base d'un test de potentiel évoqué somesthésique, que les composés produisent à de faibles concentrations des effets plus durables qu'un traitement comparable à l'aide de l'agent 4-aminopyridine (4 AP) connu.
PCT/US2006/041302 2005-10-21 2006-10-23 Dosage de derives de 4-aminopyridine pour le traitement des lesions du systeme nerveux central Ceased WO2007061554A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US72896005P 2005-10-21 2005-10-21
US60/728,960 2005-10-21

Publications (2)

Publication Number Publication Date
WO2007061554A2 true WO2007061554A2 (fr) 2007-05-31
WO2007061554A3 WO2007061554A3 (fr) 2007-10-11

Family

ID=38067700

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/041302 Ceased WO2007061554A2 (fr) 2005-10-21 2006-10-23 Dosage de derives de 4-aminopyridine pour le traitement des lesions du systeme nerveux central

Country Status (1)

Country Link
WO (1) WO2007061554A2 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9745311B2 (en) 2012-08-10 2017-08-29 Incyte Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9801889B2 (en) 2015-02-20 2017-10-31 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10040790B2 (en) 2013-04-19 2018-08-07 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
EP4274546A4 (fr) * 2021-01-06 2024-12-11 The Penn State Research Foundation Méthodes et matériaux de traitement contre la perte de cheveux
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242468B1 (en) * 1997-02-27 2001-06-05 Jia-He Li Carbamate and urea compositions and neurotrophic uses
CA2508165C (fr) * 2002-12-06 2014-05-06 Purdue Research Foundation Pyridines destinees au traitement de tissus nerveux mammaliens leses

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US10131667B2 (en) 2012-06-13 2018-11-20 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9745311B2 (en) 2012-08-10 2017-08-29 Incyte Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10040790B2 (en) 2013-04-19 2018-08-07 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US10450313B2 (en) 2013-04-19 2019-10-22 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11173162B2 (en) 2015-02-20 2021-11-16 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9801889B2 (en) 2015-02-20 2017-10-31 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10738048B2 (en) 2015-02-20 2020-08-11 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10251892B2 (en) 2015-02-20 2019-04-09 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10214528B2 (en) 2015-02-20 2019-02-26 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11014923B2 (en) 2015-02-20 2021-05-25 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10016438B2 (en) 2015-02-20 2018-07-10 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US12473286B2 (en) 2018-05-04 2025-11-18 Incyte Corporation Salts of an FGFR inhibitor
US12024517B2 (en) 2018-05-04 2024-07-02 Incyte Corporation Salts of an FGFR inhibitor
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12083124B2 (en) 2019-10-14 2024-09-10 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12168660B2 (en) 2019-12-04 2024-12-17 Incyte Corporation Derivatives of an FGFR inhibitor
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
EP4274546A4 (fr) * 2021-01-06 2024-12-11 The Penn State Research Foundation Méthodes et matériaux de traitement contre la perte de cheveux
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

Also Published As

Publication number Publication date
WO2007061554A3 (fr) 2007-10-11

Similar Documents

Publication Publication Date Title
US8097638B2 (en) Pyridines for treating injured mammalian nerve tissue
WO2007061554A2 (fr) Dosage de derives de 4-aminopyridine pour le traitement des lesions du systeme nerveux central
CA2595544C (fr) Composes presentant une activite analgesique ou immunostimulante
RU2292344C2 (ru) Производные пиридилцианогуанидинов и фармацевтическая композиция на их основе
JP2019514877A (ja) 抗アポトーシス性Ｂｃｌ−２ファミリータンパク質の分解を誘導する化合物及びその使用
CN102762207A (zh) 用于治疗神经精神疾患的nmda受体拮抗剂
CN102341380A (zh) 布美他尼、呋塞米、吡咯他尼、佐塞米和托拉塞米类似物、组合物和使用方法
BRPI0609650A2 (pt) inibidores heterobicìlicos de hvc
KR20060010717A (ko) 신규한 아릴피페라지닐 화합물
KR100859758B1 (ko) 뉴런 활성을 가진 화합물
JP2011231094A (ja) ブメタニド、フロセミド、ピレタニド、アゾセミド、およびトルセミドのアナログ、組成物および使用方法
US8729107B2 (en) Pyridines for treating injured mammalian nerve tissue
LT3918B (en) 2,4- and 2,5- substituted pyridin-n-oxides, methods for the production thereof, pharmaceutical compositions and preparation the same
WO2023143386A1 (fr) Composé cyclique hétérocyclique fusionné à un cycle aromatique utilisé en tant que régulateur du canal potassique, sa préparation et son utilisation
CN101906105A (zh) 吡唑并[1，5-a]嘧啶酮衍生物及其药物组合物以及其用途
Smith et al. Development of novel 4-aminopyridine derivatives as potential treatments for neurological injury and disease
KR20180031532A (ko) 말초신경계 질환의 치료 또는 예방용 약학 조성물
JP2013514379A (ja) 神経障害の治療のための化合物
CN109602734A (zh) 用于治疗白血病的化合物和方法
CN105348302B (zh) 一种噻唑并[3,2‑a]嘧啶酮衍生物及其药物组合物和用途
JP5189367B2 (ja) 新規シアノグアニジン化合物
KR20230008908A (ko) 신규 메틸설폰아미드 유도체 화합물의 암전이 억제용 조성물
PT2307375E (pt) Compostos da fenantrenona, composições e métodos
JP2023507461A (ja) ＲＯＲγモジュレーターのホスフェート誘導体及びその使用
KR20060117262A (ko) 페닐피리딜피페라진 화합물, 이의 제조 방법, 및 이를함유하는 약제 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06826478

Country of ref document: EP

Kind code of ref document: A2