WO1998018469A1

WO1998018469A1 - Cranial nerve cell protectives

Info

Publication number: WO1998018469A1
Application number: PCT/JP1997/003974
Authority: WO
Inventors: Akinori Akaike; Yojiro Ukai
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 1996-10-31
Filing date: 1997-10-31
Publication date: 1998-05-07
Also published as: AU4726597A

Abstract

Cranial nerve cell protectives, in particular, preventives/remedies for neuropathy caused by excitatory amino acid neurotoxins or preventives/remedies for retinal disorders, which contain as the active ingredient pyroglutamide derivatives represented by general formula (I), their pharmaceutically acceptable salts, or solvates thereof. In said formula, A represents optionally substituted, 5- to 10- membered cyclic amino optionally containing 1 to 3 heteroatoms, which may be the same or different and selected from the group consisting of nitrogen, oxygen and sulfur, in addition to the nitrogen bonded to the carbonyl.

Description

Specification

Brain cell protectant technology

The present invention relates to a preventive or therapeutic agent for cranial nerve disorder or retinal disorder. Background technology

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.

Short-term application of dalminic acid in cultured cerebral cortex and hippocampal neurons induces delayed cell death, and its mechanism of action is the mechanism of delayed cell death in ischemic animal models. The similarity to that has led to the use of glutamate toxicity in primary cultured neurons as a model for neuronal cell death. Therefore, research on drugs for suppressing cranial nerve disorders has been conducted from the viewpoint that the development of drugs that suppress glutamate neurotoxicity leads to the development of clinically effective neuroprotective drugs.

At present, anticoagulants and thrombolytic agents for cerebral thrombi and emboli are used as drugs for suppressing such cranial nerve disorders. Also the brain

1

Replacement form (Rule 26) Fibrinolytic inhibitors are used for bleeding and subarachnoid hemorrhage. On the other hand, focusing on the mechanism of neuronal degeneration and necrosis, various drugs such as glutamate receptor antagonists, calcium influx inhibitors, and free 'radical' scavengers are being developed.

On the other hand, Lucas et al. Reported that glutamate is a neurotoxin to the retina because subcutaneous injection of glutamate into young mice damages the inner retinal lining, including the ganglion cell layer. Suggests a possible work [Lucas et al .: Arch. Ophthalmol. 58, 193-201 (1957)]. Recently, it has been reported that a phenomenon similar to the neuronal cell death due to glutamate, which is observed in the cerebral cortex and hippocampal nerve, is also observed in the retinal nerve.

[Bresnick et al .: Arch. Ophthalmol. 107, 339-341 (1989); Choi et al .: J. Neurosci. 7, 357-368 (1987)].

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. For example, drugs for lowering intraocular pressure (eg, diclofenamide, acetazolamide, isosorbide, pilocarpine, etc.) have been used for glaucoma. For central retinal vein occlusion, thrombolytic agents (oral kinase, streptokinase, etc.) have been used. However, these cannot be regarded as drugs that act on the retinal cells themselves to suppress retinal damage, and new therapeutic agents in this field have been developed.

2 Replacement paper ¾ 26) Was desired. It is known that the pyroglutamide derivative according to the present invention has a remarkable action for improving learning and memory impairment and an antidepressant action, and has extremely low toxicity (Japanese Patent Publication No. 4-55405, JP-A-62-252762, International Publication No. 95/03801).

Disclosure of the invention

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. In particular, 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. From the above viewpoint, 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. As a result, the following general formula [I The present inventors have found that 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). (1) A pyroglutamide derivative represented by the following general formula [I], a pharmaceutically acceptable salt thereof, or a solvate thereof, a cranial nerve cell protective agent comprising an active ingredient; A preventive or therapeutic agent for a neurological disorder due to a noacid neurotoxin or a preventive or therapeutic agent for a retinal cell disorder.

[I]

0 ヽ GO— A

H

Difference 'Replacement paper legs'] 26) Here, A represents an optionally substituted saturated or unsaturated 5- to 10-membered cyclic amino group. Such 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.

(2) In (1), 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.

(3) In (1), A of the pyrromide amide derivative represented by the formula [I] is an alkyl, diarylalkyl, aralkyl, aryl, hydroxyalkyl, hydroxy, alkanoy. Aralkylcarbonyl, aralkyloxycarbonyl, arylalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkoxycarbonyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, By 1 to 3 identical or different substituents selected from the group consisting of carbamoylalkyl, carbamoylalkylcarbonyl, oxo, heterocyclic group, aryloxyalkyl, and alkanoylamino 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.

(4) In (1), 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).

4 Replacement ¾Paper ¾¾1] 26) 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.

(5) In (1), 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.

(6) In (1), 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.

(7) In (1), a protective agent for a brain nerve cell in which the absolute configuration of the asymmetric carbon of the pyroglutamide skeleton of the pyroglutamide derivative represented by the formula [I] is R, and especially an excitatory amino acid nerve. A preventive or therapeutic agent for a neurological disorder due to a poison, or a preventive or therapeutic agent for a retinal cell disorder.

(8) 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.

5 Difference paper rule 26) 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.

Hereinafter, the present invention will be described in detail.

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.

What is “a preventive or therapeutic agent for neuropathy caused by excitatory amino acid neurotoxin”? 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.

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. To tell. More specifically, the prevention of 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.

In the formula (I), 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. , E.g., pyrrolidino, piperidino, homopiperidino, heptamethylenedino, piperazino, homopiperidino, morpholino, thiomorpholino, 1-pyrrolyl, 1-I Midazolyl, 1-pylori

6 Replacement form (Rule 26) Nil, 1,2,3,6-Tetrahydro-11-pyridyl, 1,4,5,6-Tetrahydro-1—pyrimidinyl, 1,2.3,4-Tetrahydro- 2—Can be listed. Of these, piperidino or piperazino is preferred, and piperidino is particularly preferred. 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.

Specific examples of the substituents used in the present specification include the following.

"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, β-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

7 Replacement form (Rule 26) And 2-(-naphthyl) ethyl. These kills may be divided.

As the "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.

The term "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.

The “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. Examples of such a substituent include alkyl, aryl, alkoxy, aryloxy, alkylthio, trifluoroalkanol, canoleboxy, alkoxycarbonyl, dirubamoyl, monoalkyldirubamoyl, dialkyldirubamoyl, halogen, cyano. And so on.

8 Replacement form (Rule 26) "Halogen" includes chlorine, fluorine, bromine, and iodine.

Here, the above-mentioned substituents are trifluoroalkyl, aralkyl, diarylalkyl, hydroxyalkyl, aralkylcarbonyl. Aralkyloxycarbonyl, aminoalkyl, aminoalkylcarbonyl, divalmomoyl In the case of “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 When 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.

Further, when the above-mentioned substituent A contains an amino group such as aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, alkamoylalkyl, alkamoylalkylcarbonyl, and the like, (A) In this case, 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). . Examples of these cyclic amino groups include pyrrolidino, piperidino, homopiperazino, piperazino, morpholino, and thiomorpholino. These ami

9 Replacement form (Rule 26) 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.

Among them, 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). Among them, those having an asymmetric carbon in the pyrrole-mido skeleton having an absolute configuration of R are more preferable. As 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. For example, 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. Among these enantiomers and mixtures thereof, Any substance having an action of suppressing the cranial nerve disorder or retinal cell disorder is included in the scope of the present invention. Further, 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

1 0 Replacement paper m) Crystal polymorphs are also included in the present invention.

As typical compounds included in the present compound [I], the following compounds can be exemplified.

1- (5-oxoprolyl) piperidine,

(+)-1- (5-oxo-D-prolyl) pyridine,

(+)-1- (5-oxo-D-prolyl) piperidine monohydrate,

1-Morpholino-Luponylmethyl-4- (5-oxoprolyl) piperazine.

(+)-1-morpholino-propionylmethyl-4- (5-oxo-D-prolyl) piperazine,

(-1-morpholino carbonylmethyl-4- (5-oxo-D-prolyl) piperazine maleate,

(-)-1-morpholino carbonylmethyl-4- (5-oxo-di-prolyl) piperazine maleate,

U- (2-morpholinocarbonylethyl) -4- (5-oxoprolyl) pi-azine,

Tolethoxycarponyl-4- (5-oxoprolyl) piperazine,

(+)-Tethoxycarbonyl-4- (5-oxo-D-prolyl) piperazine, 1- [3- (4-Methylphenyl) propyl] -4--(5-oxoprolyl) Le) Pilazine,

1- (4-methylbenzyl) -4- (5-oxoprolyl) piperazine, (+)-1- (4-methylbenzyl) -4- (5-oxo-D-prolyl) Piperazine ₀

The above is an example of a part of the present compound [I].

The present compound [I] can be easily produced according to the production methods described in JP-A-62-252762 and JP-A-63-146857.

1 1 Replacement Form Rule 26) 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. For example, this compound

The hydrate of [I] may be obtained by recrystallizing the present compound [I] from aqueous alcohol.

When 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.

As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries are used. 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. For example, oral administration or ophthalmic administration is particularly preferred.

The dosage as a cranial nerve cell protective agent, especially a preventive or therapeutic agent for damage caused by excitatory amino acid neurotoxin, or a preventive or therapeutic agent for retinal cell damage, 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,

1 2 Replacement ぇ Hiro U¾ 26 Lower doses are sufficient, and conversely, higher doses may be required. It can also be administered in several divided doses daily.

For oral administration, 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.

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.

Also, 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. .

1 3 Replacement rule 26) Tablets are made by adding an excipient, forming a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and pressing.

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. 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. . Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules. 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.

In addition, 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.

1 4 Replacement ore (Rule 26) can do. Syrup is produced by dissolving the present compound in an appropriate aqueous flavor solution, and 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, flavor enhancers (eg, peppermint oil, saccharin), etc. Can also be added as needed

If desired, 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. As the ointment base, purified lanolin, white petrolatum, liquid petrolatum, or the like can be used. In the manufacture of eye ointments, it is preferable to include a powdery compound step of the present compound and a sterilization step of the preparation.

In addition, injections, suppositories and the like can be used for parenteral administration.

1 5

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.

For rectal administration, 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. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Formulation Examples and Test Examples of typical compounds of the present invention, but the present invention is not limited thereto. Formulation Example 1

Capsule (in 1 capsule)

(-O- (5-oxo-D-prolyl) piperidine · monohydrate 300 mg lactose l OOmg corn starch 53 mg hydrous silicon dioxide 5 mg magnesium stearate 2 m weighed and mixed Thereafter, capsules can be produced by filling the hard capsules with a capsule filling machine.

1 6 Replacement form (Rule 26) Formulation Example 2

Tablets (per 1 tablet)

H) 1- (5-oxo-D-prolyl) piperidine 'monohydrate 200 mg Lactose 20 mg Crystalline cellulose 60 mg Hydrous silicon dioxide 3 mg Magnesium sulphate 2 mg The tablets are manufactured using a tablet machine. Formulation Example 3

Tablets (per 1 tablet)

(+)-1- (5-oxo-D-prolyl) piperidine 'monohydrate 200 mg lactose 50 mg corn starch 30 mg polyvinyl alcohol 3 mg magnesium sulphate--2 mg

(+) -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.

Formulation Example 4

Injection

Dissolve (+)-1- (5-oxo-D-prolyl) piperidine · monohydrate in physiological saline to make a 10 W / V% solution. After filtering this solution through a membrane filter, add 1 ml, 2 ml, 5 ml, 1 Oml or 20 ml to each volume.

1 7 Replacement form (Rule 26) Fill into appropriate ampoules and sterilize in autoclaves to produce injections.

Formulation Example 5

Eye drops (in lral)

(+)-1- (5-oxo-D-propyl) piperidine 'monohydrate 20 mg methyl paraoxybenzoate 1.5 mg propyl parabenzoic acid 0.2 mg ninadium hydrogen phosphate 1.6 mg Sodium hydrogen phosphate 7.6 mg Sodium chloride weighed 4.4 mg, and sterile purified water was added in an appropriate amount to 1 ml, and the solution was filtered through a membrane filter and heated. After sterilization, aseptically fill the container to produce eye drops.

Formulation Example 6

Eye ointment (in lg)

(+)-1- (5-oxo-D-prolyl) piperidine 'monohydrate 20 mg purified lanolin lOOmg white cerin

Weigh in proportions. (+)-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.

The following tests could confirm the neuroprotective effect, the inhibitory effect of the excitatory amino acid neurotoxin or the inhibitory effect of retinal cell neuropathy of the present compound [I]. As the test drug, (+)-1- (5-oxo-D-lipid) piperidine monohydrate (hereinafter referred to as compound 2A) was used.

1 8 Replacement paper Rule 26> Was.

Test example 1.

Effects on cortical neurons (1) Effects on glutamate-induced neurotoxin death

(Preparation of primary cultured cells) 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. Non Nu bite down cells glyceraldehyde §钿胞etc. expressed in culture, on day 8 of culture, cytosine § la Pinot shea de culture solution ^{(cytosine arabinoside) (10- 5 M} ) for 2 days administration child And removed.

(Examination of Cell Protective Effect) All experiments for histologically examining cell necrosis were performed in a 37 ° C. single solution. Cultured cells were treated with excitatory amino acid alone or excitatory amino acid and the test drug for 10 minutes, and then incubated with the test drug alone for 60 minutes. Judgment was made using the pan blue (trypan blue) staining method. That is, the cultured cells were stained with a 1.5% trypan blue solution for 10 minutes at room temperature. After the staining was completed, the cells were immediately fixed with a neutral isotonic formalin solution under ice-cooling, and washed with physiological saline. By such treatment, cells stained blue were judged as dead cells, unstained cells were judged as viable cells, and at least 200 or more cells were counted in one experiment, and counted as viable cells. The ratio of the total number of cells was determined, and the viability of the cultured cells was determined. Glucamic acid was used as the excitatory amino acid. As a control compound, a glutamate antagonist known as MK-801 (dizoci lpine maleate), which is known to exhibit a cerebral nerve cell protective effect, was used.

The protective effect of a drug on the neurotoxicity of excitatory amino acids is calculated as follows:

1 9 Difference Paper Rule 26) It was calculated by the equation. Protection rate () = (([D]-[E]) Z ([C] — [E])) X 100

In this equation, [D] is the survival rate of cells to which the drug and excitatory amino acid were administered.

[E] shows the viability of cells treated with excitatory amino acid, and [C] shows the viability of untreated cells used as control. Table 1 shows the results

Shown in Figure 2.

Table 1 Effect of compound 2 A on glutamate-induced neurotoxicity Treatment N Survival rate (Protection rate 00 No treatment 5 81.2 ± 0.7

Glutamic acid ImM 5 34.5 Sat 0.7

Glutamic acid lmM + compound 2A 10- • ⁸ M5 37.4 Sat 1.3 6.1 ± 2.7

+ Compound 2A 10 "• ⁷ M 5 42.0 K 1.5" 16.0 ± 3.2

+ Compound ^{2A 10- 6 M 5 73.1 ± 1.3} "82.8 ± 2.7

+ Compound 2A 10 " ⁵ M 5 77.6 Sat 2.0" 92.3 Sat 4.3

N indicates the number of animals used.

**: P <0.01 (test the difference from glutamate 1 mM alone treatment group by Dunnett's method) Table 2 Effect of MK-801 on glutamate-induced neurotoxicity Treatment N Survival rate <<) Protection rate <<) No treatment 5 90.0 Sat 0.8

Glutamic acid ImM 5 35.4 2.3

Glutamate ^{lmM + MK-801 10- 8 M} 5 35.2 ± 1.2 -0.4 ± 2.1 Untreated 5 83.1 1.0

Glutamic acid ImM 5 27.8 1.8

Glutamic acid lm + MK-801 10 one ^{7 M 5 46.3 1.7 ** 33.4 ±} 3 · 1

+ MK-801 10— ⁶ M 5 70.2 2.5 "84.4 ± 3.0

+ MK-801 10— ⁵ M 5 77.8 0.7 "93.5 ± 0.8

N indicates the number of animals used.

: P 0.01 (Test the difference from the group treated with 1 mM glutamate alone by the Dunnett's method)

2 0 Replacement form (Rule 26) 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.

Effects on cerebral cortical neurons (2) Protective effects on NMDA-induced neurotoxicity

Using NMDA (N-methyl-d-aspartate) as an excitatory amino acid, treatment was performed for 10 minutes in a magnesium-free solution, and then the cells were incubated for 60 minutes without NMDA. Compounds 2A and 801 were used as test drugs. Both drugs in Test Example 1 showed the maximum density 10- ⁵ M concentration NM

Treatment was performed with DA, and then during the 60-minute incubation. Other operations were performed in the same manner as in Test Example 1, and the survival rate was measured. Table 3 shows the results. Table 3 Compound 2A (10- ⁵ M) and - 801 (10- ⁵ M)

Effect on NMDA-induced neurotoxicity Treatment N Survival rate) Protection rate (%) No treatment 5 83.1 ± 1.7

NMDA Im 5 40.9 ± 1.2

NMDA lmM + compound 2A 5 74.0 Sat 3.0 "78.6 ± 7.2 Untreated 5 94.9 ± 0.7

NMDA ImM 5 39.8 ± 2.1

NMDA lmM + K-801 5 84.7 Sat 3.81.5 Sat 5.4

N indicates the number of animals used.

: P <0. The difference from the group treated with 1 mM DA alone was tested by the OKDunnetfs method. Compound 2A suppressed NMDA-induced neurotoxicity in the same manner as the glucanic acid antagonist MK-801.

2 1 Replacement form G job 26) Test Example 3. Effect on neurotoxicity in retina

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.

Table 4.Compound 2A activity in cultured rat retinal nerves

Effects on NMD A-induced neurotoxicity

Treatment N Survival rate (! ¾) Protection rate 0 No treatment 5 90.8 ± 1.1

Listen A lmM 5 32.5 Sat 1.0

N DA lmM + compound 2A 10〃M 5 70.6 Sat 0.6 "65.4 ± 1.0

N indicates the number of animals used.

The difference from the group treated with glutamate or 丽 DA 1 mM alone according to the P.O.O Dunnett's method was tested.) Compound 2A exerted a remarkable protective effect against the toxicity induced by NMDA.

Test example 4. Acute toxicity test

(1) 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.

(2) Rats (SD strain σ 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

2 2 Replacement form (Rule 26) LD ₅ by the probit method from the death rate. Values were calculated. As a result, LD _{5 of} compound 2A. The value was 5,000 mg / kg or more.

As mentioned above, this compound has extremely low toxicity. Industrial availability

As described above, since 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. In addition, because of its protective effect on retinal cells, retinal cell disorders caused by cataract, diabetes, central retinal artery occlusion, central retinal vein occlusion, macular degeneration, retinopathy of prematurity, etc. It is useful for prevention or treatment of accompanying visual loss.

2 3 Replacement paper 麵 26)

Claims

The scope of the claims

1. A brain nerve cell protective agent comprising a pyroglutamide derivative represented by the following general formula [I], a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

0 N N CO-A ^{C l]}

H

Here, A represents an optionally substituted saturated or unsaturated 5- to 10-membered cyclic amino group. Such a cyclic amino group may have the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom in the ring in addition to the nitrogen atom bonded to the carbonyl group. May be included.

2. The brain nerve cell protective agent according to claim 1, wherein A is an unsubstituted cyclic amino.

3.A is alkyl, arylalkyl, aralkyl, aryl, hydroquinylalkyl, hydroxy, alkanol, aralkylcarbonyl, aralkyloxycarbonyl, arylalkenylcarbonyl, a Real carbonyl, heterocyclic carbonyl, alkoxycarbonyl, aminoalkyl, aminoalkylcarbonyl, aminocarbonyl, carbamoylalkyl, carmoylalkylcarbonyl.Oxo, heterocyclic group, arylo The cranial nerve cell protective agent according to claim 1, which is a cyclic amino which is selected from the group consisting of xylalkyl and alkanoylamino and is substituted by the same or different 1 to 3 substituents. .

4. Aminoalkyl, aminoalkylcarbonyl which is a substituent of A

2 4 Replacement paper (brain IJ26) The amino group of aminocarbonyl, carbamoylalkyl, carbamoylalkyl carbonyl is a cyclic amino having 4 to 8 members (such a cyclic amino has a nitrogen atom, an oxygen atom, 2. The brain nerve cell protective agent according to claim 1, wherein the agent comprises 1 to 3 identical or different hetero atoms selected from the group consisting of sulfur atoms.

5. The brain nerve cell protective agent according to claim 1, wherein A is piperazino substituted with a substituent selected from the group consisting of alkoxycarbonyl, optionally substituted aralkyl and morpholinocarbonylalkyl.

6. The brain nerve cell protective agent according to claim 1, wherein A is piperidino ₍

7. The brain nerve cell protective agent according to claim 1, wherein the absolute configuration of the asymmetric carbon in the pyroglutamide skeleton is R.

8. The agent for protecting brain nerve cells according to claim 1, wherein the pyroglutamide derivative is (0-1- (5-oxo-D-prolyl) piperidine).

9. The brain nerve cell protective agent according to claim 1, wherein the pyroglutamide derivative is (+)-tri (5-oxo-D-prolyl) piperidin monohydrate.

10. A preventive / therapeutic agent for a neurological disorder caused by excitatory aminoacid toxicosis, wherein the cerebral nerve cell protective agent according to claim 1 is used.

11. A prophylactic or therapeutic agent for retinal disorders comprising the pyroglutamide derivative according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

12. A preventive or therapeutic agent for glaucoma comprising the pyroglutamide derivative according to claim 1, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

2 5 Replacement form (Rule 26)