WO2003092606A2 - Inhibiteurs de cholinesterase pour prevenir les blessures causees par des produits chimiques - Google Patents

Inhibiteurs de cholinesterase pour prevenir les blessures causees par des produits chimiques Download PDF

Info

Publication number
WO2003092606A2
WO2003092606A2 PCT/US2003/013575 US0313575W WO03092606A2 WO 2003092606 A2 WO2003092606 A2 WO 2003092606A2 US 0313575 W US0313575 W US 0313575W WO 03092606 A2 WO03092606 A2 WO 03092606A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
unsubstituted
phenyl
chr
Prior art date
Application number
PCT/US2003/013575
Other languages
English (en)
Other versions
WO2003092606A3 (fr
Inventor
John Ieni
Raymond Pratt
Original Assignee
Eisai Co., Ltd.
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 Eisai Co., Ltd. filed Critical Eisai Co., Ltd.
Priority to AU2003228796A priority Critical patent/AU2003228796A1/en
Priority to GB0424188A priority patent/GB2405336A/en
Publication of WO2003092606A2 publication Critical patent/WO2003092606A2/fr
Publication of WO2003092606A3 publication Critical patent/WO2003092606A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • the invention provides methods for treating and preventing injuries caused by chemicals by administering to a patient a therapeutically effective amount of at least one cholinesterase inhibitor.
  • the cholinesterase inhibitor is donepezil, a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof.
  • Nerve gases have played a dominant role since the Second World War. Nerve gases are so-called because they affect the transmission of nerve impulses within the nervous system. Nerve gases belong chemically to the group of organophosphorus compounds. Organophosphorus compounds are stable, easily dispersed, highly toxic, and take effect rapidly both when absorbed through the skin and via respiration. They can be manufactured by means of fairly simple chemical techniques and the raw materials to manufacture them are inexpensive and generally readily available. Sarin, one of the more familiar nerve gases, dates from the Second World War. In the mid-1950' s, a group of more stable nerve gases known as V-agents were developed, with VX being one of the more successful variants.
  • V-agents a group of more stable nerve gases known as V-agents were developed, with VX being one of the more successful variants.
  • Nerve gases in the pure state are colorless liquids with volatiles that vary depending on the particular compound.
  • the consistency of VX may be likened to a non- volatile oil and is classified as belonging to a group of persistent chemical warfare agents. It enters the body mainly through direct contact with the skin. Sarin is at the opposite extreme, being a relatively volatile liquid, and is mainly taken up through the respiratory organs.
  • Nerve gases either as a gas, aerosol or liquid, enter the body through inhalation or through the skin. Poisoning may also occur through consumption of liquids or foods contaminated with nerve gases.
  • the route through which the poison enters the body largely determines the time required for the nerve gases to begin having an effect. It also influences the symptoms developed and, to some extent, the sequence of the different symptoms.
  • poisoning takes place more rapidly when the nerve gas is absorbed through the respiratory system than when it enters via other routes such as the skin. This is because the lungs contain numerous blood vessels which provide for rapid assimilation and transmission to the target organs. Nerve gases are more or less fat-soluble and can penetrate the outer layers of the skin. However, it takes some time before the poison reaches the deeper blood vessels.
  • nerve gases act by binding to an enzyme in the body of the victim, acetylcholinesterase, which inhibits this vital enzyme's normal biological activity in the cholinergic nervous system.
  • Acetylcholinesterase terminates nerve impulse transmission at cholinergic synapses by hydrolyzing the neurotransmitter acetylcholine to acetate and choline.
  • Organophosphorus compounds such as insecticides and nerve gases, inhibit acetylcholinesterase, which inhibition results in a build up of acetylcholine, thereby causing constant transmission of nerve signals.
  • Atropine has historically been the drug of choice to treat patients affected by nerve gases. Atropine, however, is toxic and has numerous side effects, such as supraventricular or ventricular tachycardia, and ventricular fibrillation.
  • the invention provides safe and effective methods for preventing one or more injuries caused by organophosphorus compounds by administering to a patient in need thereof a therapeutically effective amount of at least one cholinesterase inhibitor.
  • the at least one cholinesterase inhibitor can be administered prior to the patient's exposure to the chemicals, hi one embodiment, the cholinesterase inhibitor is donepezil, a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof.
  • the invention provides safe and effective methods for preventing one or more injuries caused by chemical weapons by administering to a patient in need thereof a therapeutically effective amount of at least one cholinesterase inhibitor.
  • the at least one cholinesterase inhibitor can be administered prior to the patient's exposure to the chemical weapons.
  • the cholinesterase inhibitor is donepezil, a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof.
  • the invention provides safe and effective methods for treating one or more injuries in patients exposed to chemicals (e.g., organophosphorus compounds, chemical weapons and the like) by administering to the patient a therapeutically effective amount of at least one cholinesterase inhibitor.
  • the cholinesterase inhibitor is donepezil, a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof.
  • the invention provides methods for preventing injuries caused by organophosphorus compounds by administering to a patient in need thereof a therapeutically effective amount of at least one cholinesterase inhibitor.
  • the cholinesterase inhibitor is preferably administered prior to the patient's exposure to the organophosphorus compounds.
  • the organophosphorus compounds can be gases, liquids and/or solids. Gases includes aerosols.
  • Exemplary organophosphorus compounds include agricultural compounds, chemical weapons, and the like.
  • Exemplary agricultural compounds are pesticides, insecticides, herbicides, fungicides, and the like.
  • the invention provides methods for preventing injuries caused by chemical weapons by administering to a patient in need thereof a therapeutically effective amount of at least one cholinesterase inhibitor.
  • the cholinesterase inhibitor is preferably administered prior to the patient's exposure to the chemical weapons.
  • the chemical weapons can be gases, liquids and/or solids.
  • the chemical weapons can be any in the art.
  • the chemical weapons are nerve gases.
  • Nerve gases are organophosphorus compounds.
  • Exemplary nerve gases are G gases, V gases, lewisite (i.e., L), and the like.
  • G gases can include, for example, soman (i.e., GD), tabun (i.e., GA), sarin (i.e., GB), GF (i.e., cyclohexyl methylphosphono-fluoridate), GE, and the like.
  • V-gases can include, for example, VX (i.e., O-ethyl S-diisopropylaminomethyl methylphosphonothiolate), VE, VG, VM, and the like.
  • VX i.e., O-ethyl S-diisopropylaminomethyl methylphosphonothiolate
  • VE vascular endothelial growth factor
  • VG methylphosphonothiolate
  • VM i.e., vascular endophosphate
  • Injuries caused by organophosphorus compounds e.g., chemical weapons, agricultural compounds, and the like
  • organophosphorus compounds e.g., chemical weapons, agricultural compounds, and the like
  • Such injuries can include, for example, blurred vision, sore eyes, teary eyes, runny nose, increased salivation, chest pains, nausea, vomiting, tremors, involuntary secretions, loss of consciousness, convulsions, bronchospasms, paralysis, ataxia, respiratory failure, and death.
  • the cholinesterase inhibitors can be taken prophylatically when there is a potential or an expected exposure to the organophosphorus compounds.
  • the cholinesterase inhibitors can be taken anywhere from 30 minutes to 24 hours prior to exposure to the organophosphorus compounds; or from about 1 hour to about 22 hours prior to exposure to the organophosphorus compounds; or from about 2 hours to about 20 hours prior to exposure to the organophosphorus compounds; or from about 3 hours to about 12 hours prior to exposure to the organophosphorus compounds. h the event the patient is exposed to the organophosphorus compounds, the cholinesterase inhibitors will provide safe and effective protection from injuries generally caused by the organophosphorus compounds.
  • Preventing and “protection” means that no injuries result from the patient's exposure to the organophosphorus compounds or that the severity or intensity of the injuries that result from the patient's exposure to the organophosphorus compounds is reduced or minimized when compared to the injuries that would have resulted absent prophylactic treatment with the cholinesterase inhibitors.
  • the cholinesterase inhibitors will not cause any significant side effects and will simply be metabolized and eliminated by the patient's body.
  • the invention provides methods for treating injuries in patients exposed to organophosphorus compounds, such as chemical weapons, by administering a therapeutically effective amount of at least one cholinesterase inhibitor.
  • organophosphorus compounds can be gases, liquids or solids.
  • the organophosphorus compounds can be, for example, agricultural chemicals, chemical weapons, and the like.
  • cholinesterase inhibitor can be any in the art. Exemplary cholinesterase inhibitors include donepezil, tacrine, physostigmine, pyridostigmine, neostigmine, rivastigmine, galantamine, citicoline, velnacrine, huperzine (e.g., huprezine A), metrifonate, heptastigmine, edrophonium, phenserine, tolserine, phenethylnorcymserine, ganstigmine, epastigmine, TAK-147 (i.e., 3-[l- (phenylmethyl)-4-piperidinyl]-l-(2,3,4,5-tetral ⁇ ydro-lH-l-benzazepin-8-yl)-l-prop
  • one or more cholinesterase inhibitors can be used.
  • one cholinesterase inhibitor is used.
  • donepezil, a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof and a second cholinesterase inhibitor is used in the methods of the invention.
  • the cholinesterase inhibitor can be a compound of formula I, a stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof:
  • J is (a) a substituted or unsubstituted group selected from the group consisting of (1) phenyl, (2) pyridyl, (3) pyrazyl, (4) quinolyl, (5) cyclohexyl, (6) quinoxalyl, and (7) furyl;
  • B is -(CHR 22 ) r , -CO-(CHR 22 ) r -, -NR 4 -(CHR 22 ) r -, -CO-NR 5 -(CHR 2 ) r -,
  • R 4 is hydrogen, lower alkyl, acyl, lower alkylsulfonyl, phenyl, substituted phenyl, benzyl, or substituted benzyl
  • R 5 is hydrogen, lower alkyl or phenyl
  • r is zero or an integer of about 1 to about 10
  • R 22 is hydrogen or methyl so that one alkylene group can have no methyl branch or one or more methyl branches
  • b is an integer of about 1 to about 3
  • c is zero or an integer of about 1 to about 9
  • d is zero or an integer of about 1 to about 5;
  • T is nitrogen or carbon
  • Q is nitrogen, carbon or
  • K is hydrogen, phenyl, substituted phenyl, arylalkyl in which the phenyl can have a substituent, cinnamyl, a lower alkyl, pyridylmethyl, cycloalkylalkyl, adamantanemethyl, furylmenthyl, cycloalkyl, lower alkoxycarbonyl or an acyl; and is a single bond or a double bond.
  • J is preferably (a) or (b), more preferably (b).
  • a monovalent group (2), (3) and (5) and a divalent group (2) are preferred.
  • the group (b) preferably includes, for example, the groups having the formulae shown below: wherein t is an integer of about 1 to about 4; and each S is independently hydrogen or a substituent, such as a lower alkyl having 1 to 6 carbon atoms or a lower alkoxy having 1 to 6 carbon atoms. Among the substituents, methoxy is most preferred. The phenyl is most preferred to have 1 to 3 methoxy groups thereon.
  • (S) t can form methylene dioxy groups or ethylene dioxy groups on two adjacent carbon atoms of the phenyl group.
  • indanonyl, indanedionyl and indenyl are the most preferred.
  • the preferable groups of B can be connected with (b) of J, in particular (b)(2).
  • the ring containing T and Q in formula I can be 5-, 6- or 7-membered. It is preferred that Q is nitrogen, T is carbon or nitrogen, and q is 2; or that Q is nitrogen, T is carbon, and q is 1 or 3; or that Q is carbon, T is nitrogen and q is 2. It is preferable that K is a phenyl, arylalkyl, cinnamyl, phenylalkyl or a phenylalkyl having a substituent(s) on the phenyl.
  • the compounds of formula I are the compounds of formula ⁇ , a stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof:
  • lower alkyl group as used herein means a straight or branched alkyl group having 1 to 6 carbon atoms.
  • exemplary “lower alkyl groups” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2- methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methyl-pentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimthyl-butyl, 2,3-dimethylbutyl, 3,3- dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl
  • substituents for the substituted or unsubstituted phenyl, pyridyl, pyrazyl, quinolyl, indanyl, cyclohexyl, quinoxalyl and furyl groups in the definition of R 1 include lower alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups; lower alkoxy groups corresponding to the above-described lower alkyl groups, such as methoxy and ethoxy groups; a nitro group; halogen atoms, such as chlorine, fluorine and bromine; a carboxyl group; lower alkoxycarbonyl groups corresponding to the above-described lower alkoxy groups, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n- propoxycarbonyl, and n-buty
  • G is -C(O)-, -O-C(O)-, -O-, -CH 2 -NH-C(0)-, -CH 2 -0-, -CH 2 -SO 2 -,
  • Preferred examples of the substituents (i.e., "D") for the phenyl group include lower alkyl, lower alkoxy, nitro, halogenated lower alkyl, lower alkoxycarbonyl, formyl, hydroxyl, and lower alkoxy lower alkyl groups, halogen atoms, and benzyol and benzylsulfonyl groups.
  • the substituent can be two or more of them, which can be the same or different.
  • Preferred examples of the substituent for the pyridyl group include lower alkyl and amino groups and halogen atoms.
  • Preferred examples of the substituent for the pyrazyl group include lower alkoxycarbonyl, carboxyl, acylamino, carbamoyl, and cycloalkyloxycarbonyl groups.
  • the pyridyl group is preferably a 2-pyridyl, 3-pyridyl, or 4- ⁇ yridyl group;
  • the pyrazyl group is preferably a 2-pyrazinyl group;
  • the quinolyl group is preferably a 2-quinolyl or 3- quinolyl group;
  • the quinoxalinyl group is preferably a 2-quinoxalinyl or 3-quinoxalinyl group;
  • the furyl group is preferably a 2-furyl group.
  • Examples of preferred monovalent or divalent groups derived from an indanone having an unsubstituted or substituted phenyl ring include those represented by formulas (A) and (B):
  • each A is independently a hydrogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, an amino group, a lower monoalkylamino group, a lower dialkylamino group, a carbamoyl group, an acylamino group derived from aliphatic saturated monocarboxylic acids having 1 to 6 carbon atoms, a cycloalkyloxycarbonyl group, a lower alkylaminocarbonyl group, a lower alkylcarbonyloxy group, a halogenated lower alkyl group, a hydroxyl group, a formyl group, or a lower alkoxy lower alkyl group; preferably a hydrogen atom, a lower alkyl group or a lower alkoxy group; most preferably the indanone group is unsub
  • Examples of the monovalent group derived from a cyclic amide compound include quinazolone, tetrahydroisoquinolinone, tetrahydrobenzodiazepinone, and hexahydrobenzazocinone.
  • the monovalent group can be any one having a cyclic amide group in the structural formula thereof, and is not limited to the above-described specific examples.
  • the cyclic amide group can be one derived from a monocyclic or condensed heterocyclic ring.
  • the condensed heterocyclic ring is preferably one formed by condensation with a phenyl ring, this case, the phenyl ring can be substituted with a lower alkyl group having 1 to 6 carbon atoms, preferably a methyl group, or a lower alkoxy group having 1 to 6 carbon atoms, preferably a methoxy group.
  • Preferred examples of the monovalent group include the following:
  • Y is a hydrogen atom or a lower alkyl group
  • V and U are each a hydrogen atom or a lower alkoxy group (preferably dimethoxy)
  • W 1 and W 2 are each a hydrogen atom, a lower alkyl group, or a lower alkoxy group
  • W 3 is a hydrogen atom or a lower alkyl group.
  • the right hand ring in formulae (j) and (1) is a 7-membered ring, while the right hand ring in formula (k) is an 8-membered ring.
  • R 1 includes a monovalent group derived from an indanone having an unsubstituted or substituted phenyl group and a monovalent group derived from a cyclic amide compound.
  • the most preferred examples of the above-defined X include -(CH 2 ) n -, an amide group, or groups represented by the above formulae where n is 2. Thus, it is most preferred that any portion of a group represented by the formula R X have a carbonyl or amide group.
  • substituents involved in the expressions "a substituted or unsubstituted phenyl group” and "a substituted or unsubstituted arylalkyl group” in the above definition of R 2 are the same substituents as those described for the above definitions of a phenyl group, a pyridyl group, a pyrazyl group, a quinolyl group, an indanyl group, a cyclohexyl group, a quinoxalyl group or a furyl group in the definition of R 1 .
  • arylalkyl group is intended to mean an unsubstituted benzyl or phenethyl group or the like.
  • pyridylmethyl group examples include 2-pyridylmethyl, 3-pyridylmethyl, and 4-pyridylmethyl groups.
  • R 2 examples include benzyl and phenethyl groups.
  • the symbol means a double or single bond.
  • the bond is a double bond only when R 1 is the divalent group (B) derived from an indanone having an unsubstituted or substituted phenyl ring, while it is a single bond in other cases.
  • the compound of formula II is a compound of formula III, a stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof:
  • r is an integer of about 1 to about 10; each R 22 is independently hydrogen or methyl;
  • K is a phenalkyl or a phenalkyl having a substituent on the phenyl ring; each S is independently a hydrogen, a lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms; t is an integer of 1 to 4; q is an integer of about 1 to about 3; with the proviso that (S) t can be a methylenedioxy group or an ethylenedioxy group joined to two adjacent carbon atoms of the phenyl ring.
  • the compound of formula m is l-benzyl-4-((5,6-dimethoxy-l- indanon)-2-yl)methylpiperidine; l-benzyl-4-((5,6-dimethoxy-l-indanon)-2-ylidenyl)methyl- piperidine; l-benzyl-4-((5-methoxy-l-indanon)-2-yl)methylpiperidine; l-benzyl-4-((5,6-diethoxy-l- indanon)-2-yl)methylpiperidine; 1 -benzyl-4-((5 ,6-methnylenedioxy- 1 -indanon)-2- yl)methylpiperidine; l-(m-nitrobenzyl)-4-((5,6-dimethoxy-l-indanon)-2-yl)methylpiperidine; 1- cyclohexylmethyl-4-((5,6-dimethoxy-l-indanon)-2-
  • the compound of formula HI is l-benzyl-4-((5,6-dimethoxy-l- indanon)-2-yl)methylpiperidine, a stereoisomer thereof and/or a pharmaceutically acceptable salt thereof, which is represented by formula IV:
  • the compound of formula III is l-benzyl-4-((5,6-dimethoxy-l- indanon)-2-yl)methylpiperidine hydrochloride or a stereoisomer thereof, which is also known as donepezil hydrochloride or ARICEPT® (Eisai Inc., Teaneck, NJ), and which is represented by formula IVa:
  • the compounds of the invention can have an asymmetric carbon atom(s), depending upon the substituents, and can have stereoisomers, which are within the scope of the invention.
  • donepezil or pharmaceutically acceptable salts thereof can be in the forms described in Japanese Patent Application Nos. 4-187674 and 4-21670, the disclosures of which are incorporated by reference herein in their entirety.
  • v ⁇ which can be in the form of a pharmaceutically acceptable salt, such as a hydrochloride salt; and compounds of formula VHI:
  • the cholinesterase inhibitors can be administered in the form of a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts are well known in the art and include those of inorganic acids, such as hydrochloride, sulfate, hydrobromide and phosphate; and those of organic acids, such as formate, acetate, trifluoroacetate, methanesulfonate, benzenesulfonate and toluenesulfonate.
  • the compounds of the invention can form, for example, alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic arr-ine salts, such as a salt with trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or N,N'-dibenzylethylenediamine.
  • alkali metal salts such as sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • organic arr-ine salts such as a salt with trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or N,N'-dibenzylethylenediamine.
  • the cholinesterase inhibitors can be prepared by processes known in the art and described, for example, in U.S. Patent No. 4,895,841, WO 98/39000, and Japanese Patent Application Nos. 4- 187674 and 4-21670, the disclosures of which are incorporated by reference herein in their entirety.
  • Donepezil hydrochloride a preferred cholinesterase inhibitor for use in the methods described herein, is commercially available as ARICEPT® from Eisai Inc., Teaneck, NJ.
  • the dosage regimen for treating and preventing the injuries described herein with the cholinesterase inhibitors can be selected in accordance with a variety of factors, including the age, weight, sex, and medical condition of the patient, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the drugs, and whether a drug delivery system is used.
  • the cholinesterase inhibitors can be administered in doses of about 0.1 milligram to about 300 milligrams per day, preferably about 1 milligram to about 100 milligrams per day, more preferably about 5 milligrams to about 10 milligrams per day.
  • the doses can be administered in one to four portions over the course of a day, preferably once a day.
  • the dose can be smaller than the dose administered to adults, and that the dose can be dependent upon the size and weight of the patient.
  • a child can be administered the cholinesterase inhibitors in doses of about 0.1 milligrams to about 15 milligrams per day, preferably about 0.5 milligrams to about 10 milligrams per day, more preferably about 1 milligram to about 3 milligrams per day.
  • donepezil hydrochloride which is commercially available as ARICEPT® (Eisai Inc., Teaneck, NJ) can be administered as tablets containing either 5 milligrams donepezil hydrochloride or 10 milligrams donepezil hydrochloride.
  • ARICEPT® Engelbreviations®
  • the dose can be smaller than the dose that is administered to adults.
  • the cholinesterase inhibitors can be administered orally, topically, parenterally, by inhalation (nasal or oral), or rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral includes subcutaneous, intravenous, intramuscular, intrastemal injection, or infusion techniques.
  • the cholinesterase inhibitors are orally administered as tablets.
  • the cholinesterase inhibitors are preferably orally administered in a liquid dosage fo ⁇ n.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, of the cholinesterase inhibitors can be formulated according to the art using suitable dispersing or wetting agents, suspending agents (e.g., methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate and the like), pH modifiers, buffers, solubilizing agents (e.g., polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, an ethyl ester of castor oil fatty acid, and the like) and preservatives.
  • suspending agents e.g., methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally used as a solvent or suspending medium.
  • any bland fixed oil can be used including synthetic mono- or diglycerides, in addition, fatty acids, such as oleic acid, can be used in the preparation of injectables.
  • the preparations can be lyophilized by methods known in the art.
  • Solid dosage forms for oral administration of the cholinesterase inhibitors can include chewing gum, capsules, tablets, sublingual tablets, powders, granules and gels; preferably tablets.
  • the active compound can be admixed with one or more inert diluents such as lactose or starch.
  • such dosage forms can also comprise other substances including lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • the tablets can be prepared with enteric or film coatings, preferably film coatings.
  • Sublingual administration refers to the administration of the cholinesterase inhibitors in the mouth (e.g., under the tongue, between the cheek and gum, between the tongue and roof of the mouth).
  • the highly vascular mucosal lining in the mouth is a convenient location for the cholinesterase inhibitors to be administered into the body.
  • the cholinesterase inhibitors can be admixed with pharmaceutically acceptable carriers known in the art such as, for example, vehicles (e.g., lactose, white sugar, mannitol, glucose, starches, calcium carbonate, crystalline cellulose, silicic acid, and the like), binders (e.g., water, ethanol, myranol, glucose solution, starch solution, gelatin solution, polyvinylpyrrolidone, and the like), disintegrators (e.g., dry starch, sodium, alginate, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, and the like), absorption promoters (e.g., quaternary ammonium base, sodium laurylsulfate, and the like), wetting agents (e.g.
  • vehicles e.g., lactose, white sugar, mannitol,
  • the tablets can be in the form of a conventional tablet, a molded tablet, a wafer and the like.
  • Liquid dosage forms for oral administration of the cholinesterase inhibitors can include pharmaceutically acceptable emulsions, solutions, sublingual solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the cholinesterase inhibitors can be admixed with various carriers, excipients, pH adjusters, and the like (e.g., water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavoring and coloring agents).
  • the cholinesterase inhibitors can be delivered from an insufflator, a nebulizer or a pressured pack or other convenient mode of delivering an aerosol spray. Pressurized packs can include a suitable propellant.
  • the cholinesterase inhibitors can be administered in the form of a dry powder composition or in the form of a liquid spray.
  • Suppositories for rectal administration of the cholinesterase inhibitors can be prepared by mixing the active compounds with suitable nonirritating excipients such as cocoa butter and polyethylene glycols that are solid at room temperature and liquid at body temperature.
  • the cholinesterase inhibitors can be formulated as ointments, creams or lotions, or as the active ingredient of a transdermal patch.
  • the cholinesterase inhibitors can also be administered via iontophoresis.
  • Ointments, creams and lotions can be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • ointments, creams and lotions can be formulated with an aqueous or oily base and 'can also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, and/or coloring agents.
  • the cholinesterase inhibitors can be mixed to form a smooth, homogeneous cream or lotion with, for example, one or more of a preservative (e.g., benzyl alcohol 1% or 2% (wt/wt)), emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water, sorbitol solution.
  • a preservative e.g., benzyl alcohol 1% or 2% (wt/wt)
  • emulsifying wax e.g., benzyl alcohol 1% or 2% (wt/wt)
  • glycerin emulsifying wax
  • glycerin emulsifying wax
  • isopropyl palmitate e.glycerin
  • lactic acid e.glycerin
  • purified water e.glycerin
  • sorbitol solution e.glycerin
  • Such topically administrable compositions can contain polyethylene
  • the cholinesterase inhibitors can be mixed with one or more of a preservative (e.g., benzyl alcohol 2% (wt/wt)), petrolatum, emulsifying wax, and Tenox (II) (e.g., butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol).
  • a preservative e.g., benzyl alcohol 2% (wt/wt)
  • petrolatum emulsifying wax
  • Tenox (II) e.g., butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol.
  • Woven pads or rolls of bandaging material e.g., gauze, can be impregnated with the transdermally administrable compositions for topical application.
  • the cholinesterase inhibitors can also be topically applied using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the cholinesterase inhibitors and laminated to an impermeable backing.
  • a transdermal system such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the cholinesterase inhibitors and laminated to an impermeable backing.
  • the cholinesterase inhibitors can be administered in the form of a transdermal patch, such as a sustained-release transdermal patch.
  • Transdermal patches can include any conventional form such as, for example, an adhesive matrix, a polymeric matrix, a reservoir patch, a matrix- or monolithic-type laminated structure, and are generally comprised of one or more backing layers, adhesives, penetration enhancers, and/or rate-controlling membranes.
  • Transdermal patches generally have a release liner which is removed to expose the adhesive/active ingredient(s) prior to application.
  • Transdermal patches are described in, for example, U.S. Patent Nos. 5,262,165, 5,948,433, 6,010,715 and 6,071,531, the disclosures of which are incorporated by reference herein in their entirety.
  • Each of the patents, patent applications, and publications cited herein are incorporated by reference herein in their entirety. It will be apparent to one skilled in the art that various modifications can be made to the invention without departing from the spirit or scope of the appended claims.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Catching Or Destruction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à des procédés permettant de traiter et de prévenir les blessures causées par des produits chimiques, et consistant à cet effet à administrer à un patient au moins un inhibiteur de cholinestérase en une quantité thérapeutiquement efficace. Ces produits chimiques peuvent être notamment des composés utilisés en agriculture ou des armes chimiques. Dans un mode de réalisation, l'inhibiteur de cholinestérase est constitué par du donepezyl, un stéréo-isomère de celui-ci et/ou un sel de celui-ci acceptable sur le plan pharmaceutique.
PCT/US2003/013575 2002-05-01 2003-05-01 Inhibiteurs de cholinesterase pour prevenir les blessures causees par des produits chimiques WO2003092606A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003228796A AU2003228796A1 (en) 2002-05-01 2003-05-01 Cholinesterase inhibitors to prevent injuries caused by chemicals
GB0424188A GB2405336A (en) 2002-05-01 2003-05-01 Cholinesterase inhibitors to prevent injuries caused by chemicals

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37656002P 2002-05-01 2002-05-01
US60/376,560 2002-05-01

Publications (2)

Publication Number Publication Date
WO2003092606A2 true WO2003092606A2 (fr) 2003-11-13
WO2003092606A3 WO2003092606A3 (fr) 2004-01-08

Family

ID=29401361

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/013575 WO2003092606A2 (fr) 2002-05-01 2003-05-01 Inhibiteurs de cholinesterase pour prevenir les blessures causees par des produits chimiques

Country Status (3)

Country Link
AU (1) AU2003228796A1 (fr)
GB (1) GB2405336A (fr)
WO (1) WO2003092606A2 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1576955A1 (fr) * 2004-02-17 2005-09-21 Axonyx, Inc. Médicament combinant un inhibiteur d'acètylcholinesterase et un (3aR) 1,3a,8 triméthyl 1,2,3,3a,8,8a hexahydropirrolo[2,3 b]indol 5 yl phénylcarbamate
JP2007091685A (ja) * 2005-09-30 2007-04-12 Japan Health Science Foundation 心不全治療薬
EP1791904A2 (fr) * 2004-09-24 2007-06-06 University of Maryland, Baltimore Methode destinee a traiter une intoxication par un organophosphore
US7563808B2 (en) 2000-03-03 2009-07-21 Eisai Co., Ltd. Methods for treating cognitive impairments or dementia
US7723349B2 (en) 2003-04-24 2010-05-25 Incyte Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
EP2334182A1 (fr) * 2008-08-27 2011-06-22 University of Maryland, Baltimore Procédé de traitement d une intoxication par des composés organophosphorés
AU2012200612B2 (en) * 2004-09-24 2014-11-20 The Government Of The United States, As Represented By The Secretary Of The Army Method of treating organophosphorus poisoning
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9840491B2 (en) 2015-02-05 2017-12-12 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US9902728B2 (en) 2014-12-30 2018-02-27 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10000495B2 (en) 2014-12-30 2018-06-19 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939095A (en) * 1993-12-10 1999-08-17 Lts Lohmann Therapie-Systeme Gmbh Transdermal therapeutic system and a process for the combined transdermal application of physostigmine and scopolamine for the prophylaxis and pretreatment of a poisoning caused by highly toxic organophosphorus neurotoxins in particular soman
US6114347A (en) * 1993-12-10 2000-09-05 Lts Lohmann Therapie-Systeme Gmbh Pharmaceutical formulation for the prophylaxis and pretreatment of a poisoning caused by organophosphorus cholinesterase inhibitors
US6264974B1 (en) * 1998-07-07 2001-07-24 Salvagnini Italia Spa Buccal and sublingual administration of physostigmine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939095A (en) * 1993-12-10 1999-08-17 Lts Lohmann Therapie-Systeme Gmbh Transdermal therapeutic system and a process for the combined transdermal application of physostigmine and scopolamine for the prophylaxis and pretreatment of a poisoning caused by highly toxic organophosphorus neurotoxins in particular soman
US6114347A (en) * 1993-12-10 2000-09-05 Lts Lohmann Therapie-Systeme Gmbh Pharmaceutical formulation for the prophylaxis and pretreatment of a poisoning caused by organophosphorus cholinesterase inhibitors
US6264974B1 (en) * 1998-07-07 2001-07-24 Salvagnini Italia Spa Buccal and sublingual administration of physostigmine

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7563808B2 (en) 2000-03-03 2009-07-21 Eisai Co., Ltd. Methods for treating cognitive impairments or dementia
US10226459B2 (en) 2003-04-24 2019-03-12 Incyte Holdings Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
US9801877B2 (en) 2003-04-24 2017-10-31 Incyte Corporation AZA spiro alkane derivatives as inhibitors of metalloproteases
US7723349B2 (en) 2003-04-24 2010-05-25 Incyte Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
EP1576955A1 (fr) * 2004-02-17 2005-09-21 Axonyx, Inc. Médicament combinant un inhibiteur d'acètylcholinesterase et un (3aR) 1,3a,8 triméthyl 1,2,3,3a,8,8a hexahydropirrolo[2,3 b]indol 5 yl phénylcarbamate
EP2813225A1 (fr) * 2004-09-24 2014-12-17 University of Maryland, Baltimore Procédé de traitement d'un empoisonnement organophosphoré
US9132135B2 (en) 2004-09-24 2015-09-15 University Of Maryland, Baltimore Method of treating organophosphorous poisoning
US7888346B2 (en) 2004-09-24 2011-02-15 Universtiy of Maryland, Baltimore Method of treating organophosphorous poisoning
AU2005289808B2 (en) * 2004-09-24 2011-11-03 The Government Of The United States As Represented By The Secretary Of The Army, U.S. Army Medical Research Institute Of Chemical Defense Method of treating organophosphorous poisoning
JP2013173773A (ja) * 2004-09-24 2013-09-05 Univ Of Maryland Baltimore 有機リン中毒を治療する方法
US8703762B2 (en) 2004-09-24 2014-04-22 University Of Maryland Baltimore Method of treating organophosphorous poisoning
EP1791904A2 (fr) * 2004-09-24 2007-06-06 University of Maryland, Baltimore Methode destinee a traiter une intoxication par un organophosphore
AU2012200612B2 (en) * 2004-09-24 2014-11-20 The Government Of The United States, As Represented By The Secretary Of The Army Method of treating organophosphorus poisoning
JP2008514609A (ja) * 2004-09-24 2008-05-08 ユニヴァーシティ オヴ メリーランド、バルティモア 有機リン中毒を治療する方法
EP1791904A4 (fr) * 2004-09-24 2009-01-21 Univ Maryland Methode destinee a traiter une intoxication par un organophosphore
JP2007091685A (ja) * 2005-09-30 2007-04-12 Japan Health Science Foundation 心不全治療薬
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
EP2334182A4 (fr) * 2008-08-27 2014-04-23 Univ Maryland Procédé de traitement d une intoxication par des composés organophosphorés
EP2334182A1 (fr) * 2008-08-27 2011-06-22 University of Maryland, Baltimore Procédé de traitement d une intoxication par des composés organophosphorés
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US11028098B2 (en) 2013-03-14 2021-06-08 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US11919913B2 (en) 2013-03-14 2024-03-05 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10377760B2 (en) 2014-12-30 2019-08-13 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US9902728B2 (en) 2014-12-30 2018-02-27 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US10000495B2 (en) 2014-12-30 2018-06-19 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US11795171B2 (en) 2014-12-30 2023-10-24 Valo Health, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10351571B2 (en) 2014-12-30 2019-07-16 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10981915B2 (en) 2014-12-30 2021-04-20 Valo Early Discovery, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10934299B2 (en) 2014-12-30 2021-03-02 Valo Early Discovery, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US12018030B2 (en) 2014-12-30 2024-06-25 Valo Health, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10927130B2 (en) 2015-02-05 2021-02-23 Valo Early Discovery, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10519130B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US9840491B2 (en) 2015-02-05 2017-12-12 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10836741B2 (en) 2015-02-05 2020-11-17 Valo Early Discovery, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10906916B2 (en) 2015-02-05 2021-02-02 Valo Early Discovery, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10519129B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519128B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519127B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10513508B2 (en) 2015-02-05 2019-12-24 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10513507B2 (en) 2015-02-05 2019-12-24 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10508098B2 (en) 2015-02-05 2019-12-17 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US11739071B2 (en) 2015-02-05 2023-08-29 Valo Health, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10377773B2 (en) 2015-02-05 2019-08-13 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10377767B2 (en) 2015-02-05 2019-08-13 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors

Also Published As

Publication number Publication date
WO2003092606A3 (fr) 2004-01-08
GB2405336A (en) 2005-03-02
AU2003228796A8 (en) 2003-11-17
AU2003228796A1 (en) 2003-11-17
GB0424188D0 (en) 2004-12-01

Similar Documents

Publication Publication Date Title
WO2003092606A2 (fr) Inhibiteurs de cholinesterase pour prevenir les blessures causees par des produits chimiques
US6576646B1 (en) Methods for treating cognitive impairments caused by traumatic brain injuries
US20040242634A1 (en) Methods for treating prion diseases
JP5180816B2 (ja) 神経変性疾患および認知症のためのジヒドロピリジン化合物
WO2005074535A2 (fr) Inhibiteurs de cholinesterase pour des troubles de la colonne vertebrale
US20040192732A1 (en) Methods for treating substance abuse with cholinesterase inhibitors
US20080312189A1 (en) Cadasil Treatment with Cholinesterase Inhibitors
WO2003024456A1 (fr) Methodes de traitement et de prevention des migraines
US4444758A (en) Nonapeptide for treating addictive drug withdrawal conditions
US20090042940A1 (en) Methods and compositions using cholinesterase inhibitors
US6353004B1 (en) Peripherally acting anti-pruritic opiates
DE4342174C1 (de) Transdermales therapeutisches System sowie ein Verfahren zur Herstellung eines transdermalen therapeutischen Systems zur kombinierten transdermalen Anwendung von Physostigmin und Scopolamin für die Prophylaxe und zur Vorbehandlung einer Vergiftung durch hochtoxische phosphororganische Nervengifte, insbesondere Soman und seine Verwendung
CA2076816A1 (fr) Antidote contre un gaz neurotoxique
GB2162745A (en) Nasal compositions
SK134395A3 (en) Transdermal therapeutical agent and preparation method thereof
CA2405202A1 (fr) Composition pharmaceutique contenant deux principes actifs pour l'abandon du tabac
KR100374086B1 (ko) 유기인콜린스테라아제억제제에의해야기되는중독의예방및예비치료를위한약제제형
FR2556216A1 (fr) Nouveau medicament analgesique contenant du proglumide, eventuellement en association avec des medicaments analgesiques-narcotiques
US3959485A (en) Method of reducing intraocular pressure in warm-blooded animals
US20060183796A1 (en) Method for the medicinal prophylaxis of cholinesterase inhibitor intoxication, and active substances and medicaments suitable therefor
EP0728479A1 (fr) Désacétyl moxisylyte dans le traitement des rétentions aigues d'urine
EP0397211A2 (fr) Administration percutanée de la 3'-azido-3'-déoxythymidine
US20010056091A1 (en) Therapeutic use of a thienylcyclohexylamine derivative
GB2189703A (en) Vinpocetine
CA2132209A1 (fr) Combinaisons d'agents parasympathomimetiques et d'antagonistes muscariniques pour le traitement de la dependance a la nicotine en vue de l'arret du tabagisme

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase in:

Ref document number: 0424188

Country of ref document: GB

Kind code of ref document: A

Free format text: PCT FILING DATE = 20030501

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP