WO1998018469A1 - Agents protecteurs des cellules des nerfs craniens - Google Patents

Agents protecteurs des cellules des nerfs craniens Download PDF

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Publication number
WO1998018469A1
WO1998018469A1 PCT/JP1997/003974 JP9703974W WO9818469A1 WO 1998018469 A1 WO1998018469 A1 WO 1998018469A1 JP 9703974 W JP9703974 W JP 9703974W WO 9818469 A1 WO9818469 A1 WO 9818469A1
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WIPO (PCT)
Prior art keywords
nerve cell
group
protective agent
cell protective
cyclic amino
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PCT/JP1997/003974
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English (en)
Japanese (ja)
Inventor
Akinori Akaike
Yojiro Ukai
Original Assignee
Nippon Shinyaku 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 Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Priority to AU47265/97A priority Critical patent/AU4726597A/en
Publication of WO1998018469A1 publication Critical patent/WO1998018469A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles

Definitions

  • the present invention relates to a preventive or therapeutic agent for cranial nerve disorder or retinal disorder.
  • Cerebral neuropathy due to ischemic injury and the like particularly the mechanism of delayed neuronal cell death in the cerebral cortex or hippocampus, has been studied as a mechanism of glutamate neurotoxicity.
  • Glutamate is thought to have two aspects: excitatory neurotransmitters and neurotoxins. That is, under physiological conditions, glutamate acts as an exciting neurotransmitter. On the other hand, under pathological conditions such as ischemia, it is known that excessive release of glutamate acts as a neurotoxin and causes cell damage in the central nervous system.
  • anticoagulants and thrombolytic agents for cerebral thrombi and emboli are used as drugs for suppressing such cranial nerve disorders. Also the brain
  • Fibrinolytic inhibitors are used for bleeding and subarachnoid hemorrhage.
  • various drugs such as glutamate receptor antagonists, calcium influx inhibitors, and free 'radical' scavengers are being developed.
  • Glutamate toxicity in the retina has been postulated to cause various retinal degenerations. That is, glutamate is attracting attention as a factor in retinal degeneration due to various diseases in the ophthalmic field such as glaucoma, diabetes-central retinal artery occlusion, central retinal vein occlusion, macular degeneration, and retinopathy of prematurity. Is coming. Retinal cell damage resulting from such degeneration results in loss of vision and, in the worst case, blindness. In the treatment, a therapeutic agent for the disease causing the disorder is used as a symptomatic treatment.
  • drugs for lowering intraocular pressure eg, diclofenamide, acetazolamide, isosorbide, pilocarpine, etc.
  • drugs for lowering intraocular pressure eg, diclofenamide, acetazolamide, isosorbide, pilocarpine, etc.
  • thrombolytic agents oral kinase, streptokinase, etc.
  • An object of the present invention is to provide a medicament useful as a new type of cranial nerve cell protective agent having few side effects.
  • an object of the present invention is to provide a medicament useful for preventing or treating neuropathy or retinal cell damage caused by excitatory amino acid (eg, glutamate) neurotoxin.
  • excitatory amino acid eg, glutamate
  • the present inventors searched for various compounds in search of compounds that suppress cerebral neuropathy, particularly cerebral neuropathy or retinal cell damage caused by excitatory amino acid poisoning.
  • the pyroglutamide derivative represented by the formula (1) has an excellent inhibitory effect on cerebral nerve damage, an inhibitory effect on excitatory amino acid neurotoxicity, or an inhibitory effect on retinal cell damage, and has completed the present invention.
  • the present invention relates to the following (1) to (8).
  • A represents an optionally substituted saturated or unsaturated 5- to 10-membered cyclic amino group.
  • a cyclic amino group may be selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring in addition to the nitrogen atom bonded to the carbonyl group. May be included.
  • the A of the pyroglutamide derivative represented by the formula (I) is an unsubstituted cyclic amino, a cerebral nerve cell protective agent, and in particular, a neuropathy caused by an excitatory amino acid neurotoxin.
  • a preventive or therapeutic agent or a preventive or therapeutic agent for retinal cell disorder is an unsubstituted cyclic amino, a cerebral nerve cell protective agent, and in particular, a neuropathy caused by an excitatory amino acid neurotoxin.
  • a preventive or therapeutic agent or a preventive or therapeutic agent for retinal cell disorder is an unsubstituted cyclic amino, a cerebral nerve cell protective agent, and in particular, a neuropathy caused by an excitatory amino acid neurotoxin.
  • a of the pyrromide amide derivative represented by the formula [I] is an alkyl, diarylalkyl, aralkyl, aryl, hydroxyalkyl, hydroxy, alkanoy.
  • Substituted cyclic amino a neuroprotective agent for brain cells, especially due to excitatory amino acid neurotoxin Prevention young properly warp disorder treatment agent or preventive young properly therapeutic agent for a retinal cell damage.
  • aminoalkyl aminoalkylcarbonyl, aminocarbonyl, carbamoylalkyl, carbamoylalkyl which is a substituent of A of the pyroglutamide derivative represented by the formula [I]
  • the amino moiety of carbonyl is a cyclic amino with 4 to 8 members (such a cyclic amino group).
  • the amino may contain 1 to 3 identical or different hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring.
  • Cerebral nerve cell protective agents especially preventive or therapeutic agents for neuropathy caused by excitatory amino acid neurotoxin, or preventive or therapeutic agents for retinal cell damage.
  • a of the pyrromide amide derivative represented by the formula [I] is a substituent selected from the group consisting of alkoxycarbonyl, optionally substituted aralkyl and morpholinocarbonylalkyl.
  • a cerebral nerve cell protective agent which is a substituted piperazino, especially a preventive or therapeutic agent for neuropathy due to excitatory aminoacid neurotoxin, or a preventive or therapeutic agent for retinal cell damage.
  • the pyroglucamide derivative A represented by the formula (I) is piperidino, in which A is piperidino, in particular, prevention of neuropathy caused by excitatory amino acid neurotoxin. Is a therapeutic agent or a preventive or therapeutic agent for retinal cell damage.
  • the pyroglutamide derivative represented by the formula [I] in (1) which is (10) -toluene (5-oxo-D-prolyl) piperidine or its monohydrate.
  • Cerebral nerve cell protective agent especially preventive or therapeutic agent for neurological disorders caused by excitatory amino acid neurotoxin, or preventive or therapeutic agent for retinal cell damage.
  • the present inventors have proposed a public drug having an effect of improving learning and memory disorders and an antidepressant effect.
  • a known pyroglutamide derivative was found to have a protective effect on brain neurons (among others, an inhibitory effect on excitatory amino acid neurotoxin) or an inhibitory effect on retinal neuropathy, which was completely unrelated to these effects.
  • the “cerebral nerve cell protective agent” refers to a drug that suppresses cerebral nerve cell death due to cerebrovascular disorder or aging, and is particularly effective in preventing or treating ischemic encephalopathy and the like. More specifically, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage, transient cerebral ischemic attack, stroke due to hypertensive encephalopathy, etc., cerebral injury and pause of heartbeat, hypoxia, hypoxia A drug that suppresses ischemic changes in brain nerve cells and degeneration and necrosis of brain nerve cells due to glycemia.
  • Excitatory substances such as glutamate, N-methyl-d-aspartate (NMDA), asparaginate, and quisqualate A drug that suppresses neurotoxicity induced by amino acids and is effective in preventing or treating neuropathy.
  • NMDA N-methyl-d-aspartate
  • quisqualate A drug that suppresses neurotoxicity induced by amino acids and is effective in preventing or treating neuropathy.
  • a ⁇ preventive or therapeutic agent for retinal disorder '' refers to a drug that inhibits retinal nerve cell death due to blood circulation disorders such as aging, increased intraocular pressure, and obstruction of retinal blood vessels, and is effective in preventing or treating retinal cell disorders.
  • blood circulation disorders such as aging, increased intraocular pressure, and obstruction of retinal blood vessels
  • retinal cell disorders caused by disorders, diabetes, central retinal artery occlusion, central retinal vein occlusion, macular degeneration, retinopathy of prematurity, and the associated loss of visual acuity Or a drug effective for treatment.
  • the “cyclic amino group” having 5 to 10 atoms constituting the ring represented by A is a monocyclic or condensed cyclic, saturated or unsaturated ring.
  • Such a cyclic amino group may be substituted at any position of the ring-constituting atoms with an 'alkyl, diarylalkyl, aralkyl, aryl, hydroxyalkyl, hydroxy, alkanoyl, a Aralkylcarbonyl, aralkyloxycarbonyl, arylalkenylcarbonyl, arylcarbonyl, heterocycliccarbonyl, alkoxycarbonyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, dirubamoylalkyl, It may have the same or different 1 to 4 substituents selected from the group consisting of carbamoylalkylcarbonyl, oxo, heterocyclic group, aryloxyalkyl and alkanoylamino.
  • Alkyl means a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl, tert-butyl,
  • Aryl includes those having 6 to 14 carbon atoms, for example, phenyl, 1-naphthyl, ⁇ -ten thousand, 1-biphenyl, 2-anthryl. Can be mentioned.
  • “Aral kill” is carbon number? ⁇ 12 are preferred, for example, benzyl, phenethyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylmethyl, 1- (1-naphthyl) ethyl, 2- (1-naphthyl) ethyl, —naphthyl Methyl, 1- (naphthyl) ethyl
  • alkoxy a straight or branched chain having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n_propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec- Butoxy and tert-butyloxy can be mentioned.
  • alkanoyl refers to a straight or branched chain having 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl, n-butyryl. Sonoraku, Vivaloyl, Hexanoyl, Heptanoyl.
  • the “arylalkenyl” preferably has 8 to 10 carbon atoms, and includes, for example, cinnamyl.
  • heterocyclic group is aromatic and contains 1 to 4 identical or different hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom. Or a 6-membered monocyclic ring or a fused ring group containing the same.
  • Specific examples of the heterocyclic group include 2-, 3- or 4-pyridyl, 2-phenyl, 2- or 3-furyl, and 2-, 3- or 6-benzofuranyl. , 2-, 3- or 6-quinolyl, or 5- or 6-benzochenyl.
  • Such a heterocyclic group may have the same or different 1 to 4 substituents at any position.
  • substituents include alkyl, aryl, alkoxy, aryloxy, alkylthio, trifluoroalkanol, canoleboxy, alkoxycarbonyl, dirubamoyl, monoalkyldirubamoyl, dialkyldirubamoyl, halogen, cyano. And so on.
  • Halogen includes chlorine, fluorine, bromine, and iodine.
  • substituents are trifluoroalkyl, aralkyl, diarylalkyl, hydroxyalkyl, aralkylcarbonyl.
  • alkyl having a substituent such as alkyl, carbamoylalkylcarbonyl, aryloxyalkyl, etc., these substituents can be present at any position.
  • the above substituent A is aryl, aralkyl, diarylalkyl, arylalkenyl, aralkylcarbonyl, aralkyloxy carbonyl, arylalkenylcarbonyl, arylalkenylcarbonyl, aryl
  • aryl is contained, such as lukinalkyl
  • the aryl group is selected from the group consisting of alkyl, alkoxy, aralkyloxy, alkanol, alkoxycarbonyl, logen, logenoalkyl, nitro or methylenedioxy. It may be substituted by the same or different 13 substituents selected.
  • the ring may include a ring having 48 members (in this case, the ring may further contain, in addition to the nitrogen atom, 13 nitrogen, oxygen, or sulfur atoms).
  • these cyclic amino groups include pyrrolidino, piperidino, homopiperazino, piperazino, morpholino, and thiomorpholino.
  • the amino group may be substituted by 1 to 4 identical or different substituents selected from the group consisting of alkyl, aralkyl, aralkyloxycarbonyl and levamoyl.
  • compounds having particularly excellent neuroprotective effects, excitatory amino acid neurotoxicity-producing or retinal damage-suppressing effects include compounds in which A is pyridino in formula (I).
  • A is pyridino in formula (I).
  • those having an asymmetric carbon in the pyrrole-mido skeleton having an absolute configuration of R are more preferable.
  • the “pharmaceutically acceptable salt” of the compound [I] of the present invention hereinafter, referred to as the present compound [I]
  • the glutamic amide derivative represented by the above general formula [I] and Any substance that forms a toxic salt may be used.
  • salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, or formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, Salts of organic acids such as succinic acid, methansulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid and camphorsulphonic acid can be mentioned.
  • the compound [I] has an asymmetric carbon in the pyrrodaltamide skeleton, and its absolute configuration is an enantiomer of R and an enantiomer of S.
  • Any substance having an action of suppressing the cranial nerve disorder or retinal cell disorder is included in the scope of the present invention.
  • some of the substituents of A have an asymmetric carbon depending on the position and type of the substituent, and all stereoisomers based on the asymmetric carbon and mixtures thereof are included in the scope of the present invention. Things. Solvates (including hydrates) of the present compound [I] or a salt thereof are also included in the present invention.
  • the present compound [I] may take a crystalline polymorph. That
  • the present compound [I] can be easily produced according to the production methods described in JP-A-62-252762 and JP-A-63-146857.
  • the solvate (including hydrate) of the compound [I] or a salt thereof may be obtained by recrystallization of the solvate from the corresponding solvent or a suitable mixed solvent containing the corresponding solvent. is there.
  • this compound
  • the hydrate of [I] may be obtained by recrystallizing the present compound [I] from aqueous alcohol.
  • the present compound [I] is administered as a cranial nerve cell protective agent, in particular, as a preventive or therapeutic agent for a disorder caused by excitatory aminoacid toxicosis, or a preventive or therapeutic agent for a retinal cell disorder
  • the present compound [I] is a pharmaceutical composition containing 0.1 to 99.5% by weight, preferably 0.5 to 90% by weight, as it is or in a pharmaceutically acceptable nontoxic and inert carrier. And administered to mammals including humans.
  • one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries are used as the carrier.
  • the pharmaceutical compositions are preferably administered in unit dosage forms.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (e.g., eye drops, injections, rectal) of course be administered in dosage form suitable for c these administration methods that can and child administered.
  • parenterally e.g., eye drops, injections, rectal
  • oral administration or ophthalmic administration is particularly preferred.
  • the dosage as a cranial nerve cell protective agent depends on the patient's age, weight, etc. It is desirable to adjust the dose taking into account the condition, route of administration, nature and extent of the disease, etc., but usually the amount of the active ingredient of the present invention for adults will be The range is from 10 mg to 2 gZ human, preferably from 100 mg to 1 gZ human. When administered to the eye, the daily dose ranges from 0.01 mg to 100 mgZ, preferably from 0.1 mg to 100 mgZ. In some cases,
  • solid or liquid dosage units such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other dosage forms can be done by
  • Powders are prepared by comminuting the compound to an appropriate degree. Powders are prepared by bringing the compound into an appropriate bulk and then mixing with a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
  • a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like.
  • flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
  • Capsules are prepared by first powdering powders as described above, granules as described in the section of powders or tablets, and filling the capsule shell such as gelatin capsules. It is manufactured by Lubricants and glidants, such as colloidal silica and talc; magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed into a powdered form, The charging operation can be performed later. Disintegrants and solubilizers, for example, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmethylene sodium, carboxymethyl starch sodium, calcium carbonate However, the addition of sodium carbonate can improve the efficacy of the medicine when the capsule is taken.
  • the fine powder of the present compound can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapped in a gelatin sheet to prepare a soft capsule. .
  • the powder mixture is made by mixing the appropriately powdered material with the above-mentioned diluents and bases and, if necessary, binding agents (eg, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone). , Polyvinyl alcohol), dissolution retardants (eg, paraffin), resorbents (eg, quaternary salts), and adsorbents (eg, bentonite, kaolin, dicalcium phosphate) ) May also be used in combination.
  • binding agents eg, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone.
  • binding agents eg, carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone.
  • dissolution retardants eg, paraffin
  • resorbents eg, quaternary salts
  • the powder mixture can first be moistened with a binder, for example, syrup, starch paste, arabic gum, a cellulose solution or a polymer solution, stirred and mixed, dried and pulverized into granules. .
  • a binder for example, syrup, starch paste, arabic gum, a cellulose solution or a polymer solution
  • the granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salt, talc, mineral oil or the like as a lubricant.
  • the mixture thus lubricated is then compressed.
  • the uncoated tablets thus produced can be coated with a film or coated with sugar.
  • the present compound may be directly tableted after mixing with a fluid inert carrier without going through the steps of granulation and slag formation as described above.
  • Transparent or translucent protective coatings consisting of a hermetic hermetic coating, encouraging or polymeric material coatings, and waxing polish coatings may also be used.
  • Other oral dosage forms such as solutions, syrups and elixirs may also be presented in dosage unit form so that a given quantity contains a fixed amount of the drug.
  • Syrup is produced by dissolving the present compound in an appropriate aqueous flavor solution
  • elixir is produced by using a non-toxic alcoholic carrier.
  • Suspensions are formulated by dispersing the compound in a non-toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives eg, peppermint oil, saccharin
  • flavor enhancers eg, peppermint oil, saccharin
  • dosage unit formulations for oral administration may be microbubulated.
  • the formulation can also provide a prolonged action or sustained release by coating or by embedding in a polymeric wax or the like.
  • Eye drops and eye ointments can be used for parenteral administration.
  • Ophthalmic solutions may contain about 0.001 to 3% (W / V), preferably about 0.01 to 1% (W / V) of the present compound in a non-toxic liquid carrier suitable for the purpose of eye drops, for example, It is manufactured by suspending or dissolving in an aqueous or oily medium, and then sterilizing the suspension or aqueous solution.
  • the pH of the eye drops is adjusted to about 4 to 10, preferably about 5 to 9.
  • Non-toxic salts or salt solutions may be added to the eye drops to make them isotonic.
  • the ophthalmic ointment is formulated with a normal ointment base such that the concentration of the compound is about 0.001 to 3% (W / V), preferably about 0.01 to 1% (W / V). It is manufactured by mixing.
  • a normal ointment base such that purified lanolin, white petrolatum, liquid petrolatum, or the like can be used.
  • injections, suppositories and the like can be used for parenteral administration.
  • Replacement paper (milJ26) It can be carried out by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension. For these, a certain amount of the compound is suspended or dissolved in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and the suspension or solution is then sterilized. It is manufactured by Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, a stabilizer, a preservative, an emulsifier and the like can be used in combination.
  • the present compound is treated with a low-melting, water-soluble or insoluble solid, for example, polyethylene glycol, cocoa butter, semi-synthetic fat (for example, Vitebsol®), higher esters (for example, palmitin). (Acid myristyl ester) and a suppository produced by dissolving or suspending in a mixture thereof.
  • capsules can be produced by filling the hard capsules with a capsule filling machine.
  • (+) -1- (5-oxo-D-prolyl) Piperidine ⁇ monohydrate, lactose, and corn starch are weighed in the above ratio and dissolved in purified water with a granulator. . Polyvinyl alcohol is added to this solution in the ratio described above. After the granules are mixed with magnesium stearate in the above ratio, tablets are manufactured using a tableting machine.
  • (+)-Dol (5-oxo-D-prolyl) Dissolve peridin 'monohydrate in a small amount of purified water, absorb it into purified lanolin, and knead the white cellulose. To produce an eye ointment.
  • (+)-1- (5-oxo-D-lipid) piperidine monohydrate (hereinafter referred to as compound 2A) was used.
  • the cerebral cortex was extracted from rat embryos on the 16th to 18th days of embryogenesis, and cerebral cortical neurons were isolated.
  • the nerve cells were cultured in Eagle's solution at 37 ° C for 10 days or more.
  • [D] is the survival rate of cells to which the drug and excitatory amino acid were administered.
  • N indicates the number of animals used.
  • N indicates the number of animals used.
  • Tables 1 and 2 show the concentration-effect relationships of the protective effects of compound 2A and ⁇ -801 on glutamate neurotoxicity, respectively. Similar to the glutamate antagonist MK-801, this compound exerted approximately the same degree of cranial nerve protection as glutamate antagonist, depending on the treatment concentration ⁇ Test Example 2.
  • NMDA N-methyl-d-aspartate
  • N indicates the number of animals used.
  • the retina was excised from the eyes of a rat fetus on the 19th day of the embryo, the retina was minced using a female blade, and the retinal cells were isolated by passing through a stainless steel mesh. Thereafter, the cells were cultured and stained in the same manner as the cerebral cortical neurons, judged, and the survival rate of the cultured cells was determined. Compound 2A was used as a test drug. Table 4 shows the results.
  • N indicates the number of animals used.
  • Test example 4 Acute toxicity test
  • mice (ddy strain 6-7 weeks old) were used as a group of 5 mice. After fasting the day before (16-18 hours before), Compound 2A was orally administered as a test drug, and LD 5 was determined by the probit method based on the mortality rate for the next two weeks. The value was calculated. As a result, the compound 2A is replaced with D 5 . The value was 4,162 mg / k.
  • Rats SD strain ⁇ 71 280-360 mg were used as a group of 5 animals. Oral administration after fasting from the previous day (16-18 hours before), and death for 2 weeks thereafter
  • the present compound [I] suppresses neuronal necrosis by excitatory amino acid, it has a neuroprotective effect and a neurotoxicity inhibitory effect by excitatory amino acid. Is evident. Moreover, since it has extremely low toxicity, it can be used safely for the prevention or treatment of cerebral dysfunction in the chronic phase due to cerebrovascular disorder or cranial nerve disorder. That is, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage, transient cerebral ischemic attack, stroke due to hypertensive encephalopathy, etc., cerebral damage and temporary cessation of heartbeat, hypoxia. It is useful for suppressing ischemic changes and degeneration / necrosis of brain nerve cells due to such factors.

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

Abstract

La présente invention concerne des agents protecteurs des cellules des nerfs crâniens, en particulier des médicaments préventifs et thérapeutiques contre les neuropathies imputables aux neurotoxines des acides aminés excitateurs ou des médicaments préventifs et thérapeutiques contre les troubles rétiniens. Les principes actifs intégrés aux agents protecteurs de l'invention sont des dérivés de pyroglutamide représentés par la formule générale (I), certains de leurs sels pharmaceutiquement admis ou leurs solvates. Dans cette formule générale, A est un acide aminé cyclique, éventuellement substitué, pourvu de 5 à 10 segments, et portant de 1 à 3 hétéroatomes. Ces hétéroatomes, qui peuvent être identiques ou différents, appartiennent au groupe azote - oxygène - soufre, et ce, en plus de l'azote lié au carbonyle.
PCT/JP1997/003974 1996-10-31 1997-10-31 Agents protecteurs des cellules des nerfs craniens WO1998018469A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47265/97A AU4726597A (en) 1996-10-31 1997-10-31 Cranial nerve cell protectives

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Application Number Priority Date Filing Date Title
JP8/290266 1996-10-31
JP29026696 1996-10-31

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WO1998018469A1 true WO1998018469A1 (fr) 1998-05-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007291129A (ja) * 1999-01-04 2007-11-08 Allergan Inc 神経損傷の処置に（２−イミダゾリン−２−イルアミノ）キノキサリンを使用する方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63146857A (ja) * 1986-07-24 1988-06-18 Nippon Shinyaku Co Ltd ピログルタミド誘導体及び製法
JPH07509721A (ja) * 1992-07-31 1995-10-26 クリエイティブ　バイオモレキュルズ，インコーポレイテッド 組織形成因子誘導による神経の再生と修復

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63146857A (ja) * 1986-07-24 1988-06-18 Nippon Shinyaku Co Ltd ピログルタミド誘導体及び製法
JPH07509721A (ja) * 1992-07-31 1995-10-26 クリエイティブ　バイオモレキュルズ，インコーポレイテッド 組織形成因子誘導による神経の再生と修復

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007291129A (ja) * 1999-01-04 2007-11-08 Allergan Inc 神経損傷の処置に（２−イミダゾリン−２−イルアミノ）キノキサリンを使用する方法

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