JPS5973522A - Remedy for anoxia of cerebral neurocyte - Google Patents

Abstract

PURPOSE:To provide the titled drug having high safety, effective to the anoxia of cerebral neurocyte, and containing prostaglandin D2, prostaglandin E1, their derivatives, or their cyclodextrin clathrate compounds as active component. CONSTITUTION:The agent contains as an active component, (A) prostaglandin D2 (PGD2) of formula I (A is ethylene group, etc.; R1 is OH, lower alkoxy, etc.; R2 is 5-7C alkyl which may be substituted with CH3 at the 1-position) or its derivative, (B) prostaglandin E1 (PGE1) of formula II (X is methylene group, etc.; Y is ethylene group, etc.; R3 is carboxyl, etc.; R4 is pentyl, etc.) or its derivative, or (C) a cyclodextrin clathrate of the compound of formula I or II. PGD2 and PGE1 and their derivatives exhibit excellent protecting activity to cerebral anoxia at an extremely low dose without suppressing the function of neurocytes.

Description

Detailed Description of the Invention The present invention provides glostaglandin D2 (hereinafter referred to as PGD2) or its derivatives, prostaglandin E+ (hereinafter referred to as PGEt) or its derivatives, or clathrates or non-toxic salts thereof. The present invention relates to a therapeutic agent for anoxia-deficient diseases of brain nerve cells, which contains the active ingredient. More specifically, the present invention is based on the general formula -□ (wherein A is an ethylene group or a trans-vinylene group, R1 is a hydroxyl group, lower alkoxy group, or amino group, and R2 is substituted with a methyl group at the 1-position). Each refers to an optional alkyl group having 5 to 7 carbon atoms.

) or a derivative thereof, or the general formula (wherein, X is a methylene group or a carbonyl group, Yld
ethylene group or trans-vinylene group, R3 is carboxyl group, lower alkoxycarbonyl group, glycoloyl group or hydroxymethyl group, R4 is pentyl group,
2-methylhexyl group.

1-cyclohexylethyl group, cycloalkyl group optionally substituted with lower alkyl group, or U 3- ) I
J fluoromethyl-phenoxymethyl group, respectively. However, when X is a methylene 7- group, Y is an ethylene group or a trans-vinylene group, and R3 is a carboxyl group or a lower alkoxycarbonyl group. When X is a carbonyl group,
Y is an ethylene group, and R3 is a carboxyl group, a lower alkoxycarbonyl group, a glycoloyl group, or a hydroxymethyl group. ) PGE1 or its derivatives represented by the formula (1) or the compound represented by the general formula (1) or (It). General formula (II)
When R3 in the compound represented by is a carboxyl group, the present invention relates to a therapeutic agent for anoxia-deficient diseases of brain nerve cells, which contains a non-toxic salt of the acid as an active ingredient. However, in the present invention, the cycloalkyl group means a cycloalkyl group having 4 to 7 carbon atoms in its ring.

PGD2 and its derivatives (1), PGE1 and its derivatives (It”), which are active ingredients of the therapeutic agent according to the present invention
, and their cyclodextrin clathrate compounds or 8-salts are disclosed in Japanese Patent Publication No. 53-36458j54-32773.
57-20305, JP-A-49-47352.51-1
01961゜51-122040.52-27753.
52-42856゜53-84942.54-4463
9.55-100360.

Patent application 1986-99724.57-87229.57-8
7230°57-109806.57-126665.
US Patent 3878239°3931296j 3966
792,4215142. Manufactured by the method described in British Patent No. 1,398,291° or in accordance therewith.

It is already known that most of these compounds have platelet aggregation inhibiting effects, vascular smooth muscle relaxing effects, body temperature lowering effects, etc. (Monthly Yakuji Vol. 22, No. 2).

49-57, 1980, etc.).

Unlike other organs, the brain exists in a special environment where it is submerged in cerebrospinal fluid within a rigid body such as the skull or brain dura mater, and is one of the organs with the most active energy metabolism, and its oxygen consumption rate is It belongs to the best of all organs. Most of the energy required by brain neurons is supported by oxygen and glucose, and these energy sources are hardly stored in the brain and are constantly supplied from the blood.

Therefore, in order to stably supply an energy source to the brain tissue and maintain a constant external environment for brain neurons, the cerebrovascular system has a well-developed mechanism for regulating cerebral blood flow.

When the brain's homeostatic mechanisms are disrupted by physical pressure such as hematoma, tumor, or brain trauma, brain neurons are exposed to hypoxic conditions and are unable to function normally. Brain nerve cells are in an oxygen-deficient state (hereinafter referred to as cerebral anoxia).
When this occurs, the permeability of brain nerve cell membranes changes,
Edema is caused by extracellular fluid infiltration. When cerebral edema increases beyond a certain level, cerebral pressure increases and cerebral circulation disorders occur. The resulting enhancement of brain anoxia, glucose deficiency, and accumulation of its metabolites promote brain edema.
Cerebral edema and cerebral pressure reversal become even stronger, causing compression of the brainstem and obstruction of cerebrospinal fluid passage, which further forms a vicious cycle of reinforcing cerebral anoxia, promoting brain edema, and reversing cerebral pressure.

As a result, the lesion expands and even healthy brain tissue undergoes cerebral anoxia, leading to cerebral circulation failure and the disorder becoming serious.

Cerebral anoxia is the total denominator of most diseases based on cerebral circulation disorders (Eur, Neurol, 17 (5upp
This is why it is called ``Le, I'), 113-120゜1978).

Currently, hypnotic anesthetics such as phenobarbicur and thiobarpital are used to treat oxygen deficiency diseases of brain nerve cells. Hypnotic anesthetics suppress nerve activity in the brain, reducing the energy demand of nerve cells themselves and exerting a protective effect on nerve cell function. In other words, hypnotic anesthetics exert their effects by forcibly suppressing nerve cell function to below normal levels. Therefore, in order to expect the desired effect, it is necessary to administer the drug in an amount that can exert a suppressive effect on the entire central nervous system, and as a result, the respiratory and circulatory systems are affected by suppression of the respiratory or blood pressure regulating center. The negative effects of this come with it as a side effect.

Therefore, when treating anoxic diseases of nerve cells,
There is a strong desire for the development of a drug that does not have side effects like hypnotic anesthetics, but that exhibits excellent therapeutic effects at very low doses.

As a result of intensive research, the present inventor discovered that PGD2 and its derivatives (1), PGEI and its derivatives (■), especially 1
The present invention was completed based on the completely new finding that l-PGE + derivatives exhibit excellent protective effects against cerebral anoxia at very low doses without being based on suppressive effects on nerve cell function.

That is, the present invention provides PG represented by the general formula (1)
The present invention relates to a therapeutic agent for anoxia-deficient diseases of brain nerve cells, which contains D 2 or a derivative thereof, PGE1 represented by the general formula (II) or a derivative thereof, or a cyclodextrin clathrate compound or a nontoxic salt thereof as an active ingredient. Its preferred active ingredient is PGD2.

PGE1.16-cyclohexyl-ω-trinor-PG
E r-methyl ester, 17 (S)-methyl-ω
-homo-trans-d-PGE+, 16, 18-
Ethano-ω-dihomo-6-kedoPGEI-methyl ester.

2-Decarboxy-2-glycoloyl-17(s)-methyl-ω-homo-6-kedo PC; El, 17 (
S)-Methyl-ω-homo-6-kedo PGE 1-alcohol, 16.18-ethano-ω-dihomo-6-kedo PGE 1-alcohol, 2-decarboxy-2-glycoloyl-16,18-ethano-ω -Homo-612- monoketo PGE+, 16-(3-)lifluoromethyl-phenoxy)-ω-tetratrue-trans-d-P
GE+-ethyl esters and their cyclodextrin inclusion compounds.

Since the therapeutic agent according to the present invention has a protective effect against cerebral anoxia, it can be used to treat intracranial diseases that cause cerebral anoxia.

Furthermore, the therapeutic agent according to the present invention exerts a protective effect on neuronal function by suppressing neuronal activity in the brain, like the hypnotic anesthetics conventionally used for anoxia-deficient diseases of cerebral neurons. Therefore, it does not cause side effects such as respiratory depression or circulatory failure due to depression of the central nervous system in general. Furthermore, whereas hypnotic anesthetics can only be administered during the acute phase, the therapeutic agent according to the present invention does not exhibit hypnotic anesthetic effects, and therefore can be administered during the chronic phase and for the purpose of preventing seizure recurrence. . Furthermore, the therapeutic agent according to the present invention exhibits a protective effect against cerebral anoxia at a very low dose, and in addition to its strong effect, it also has low toxicity and therefore has high safety. For example, 17(S)-methyl-ω-homotransmerase PGE 1 shows no lethality at all when subcutaneously administered to mice at 10 μg/Kg, and the ratio to the minimum effective dose is more than 3000 times.

The therapeutic agent according to the present invention is administered parenterally or orally, preferably parenterally.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions, and sterile solid preparations which are dissolved in sterile injection solvents immediately before use. Further examples include suppositories for intrarectal administration, petalsari for intravaginal administration, and the like. Preparations for oral administration include solid preparations such as tablets, pills, powders, capsules, and granules, and liquid preparations such as emulsions, solutions, suspensions, syrups, and elixirs. It will be done.

The dosage of the therapeutic agent according to the present invention is usually 0.00 per day.
03 to 100 my/Ky, preferably 0.0003 to 1101 n/Ky for intramuscular, subcutaneous or intravenous administration, and 0.0003 to 30 mg/Ky for oral administration. However, the dosage varies depending on the patient's age, weight, severity of symptoms, type of disease, number of administrations, etc., and should not be limited thereto.

The present invention will be explained in further detail below using experimental examples and formulation examples.

Example [Survival prolonging effect on mouse mortality due to hypoxia] 5TD
-ddY male mice (body weight 2oSI24y)
A solution of the required amount of the specimen dissolved in 0.1 me ethanol and diluted with distilled water was subcutaneously administered to each group of 5 mice at a rate of 0.1 me (102 V) per mouse body weight. 30 minutes after administration of the sample, the mouse was placed in a plastic container with a capacity of 2.5 ml, and 1 ml of a hypoxic gas mixture consisting of 4% oxygen and 96% nitrogen was added to the container.
Aeration was carried out at a rate of 4 tons per minute, and the time until the mouse died was measured using the cessation of breathing as an index. Distilled water containing the same concentration of ethanol was similarly administered to the comparison group. The results are shown in Table 1.

The following is a list of the samples used.

15- *: TLO of product [: developing solvent is chloroform:tetrahydrofuran:acetic acid-10:2:1):Rf-0,2
616- Table 1 Example [Effect of prolonging panting exercise time due to complete ischemia] 5TD-d
A group of 5 male dY mice (body weight 20-24 years) is used, and the required amount of sample is O, hytl? The solution was dissolved in ethanol and then diluted with pre-preserved water at a concentration of 0.0% per 101 mice body weight.
It was administered subcutaneously at a rate of 1 ml. Thirty minutes after administration of the sample, the neck of the mouse was cut with decapitation scissors, and the duration until the panting movement that appeared in the separated head disappeared was measured. Distilled water containing the same concentration of ethanol was similarly administered to the comparison group. The results are shown in Table 2. Note that the sample Nα in the table is the same as that shown in Experimental Example 1.

Table 2 Formulation Example 1 17 (S)-Methyl-ω-homo-trans-Δ-PG
El (sample Na4') 50■ ethanol 10ml! This is mixed with mannitol 18.1, 30-
After passing through a mesh sieve and drying at 30° C. for 90 minutes, it was passed through a 30-mesh sieve again.

Aerosil (micro fine silica) 200 is added to the powder.
Add ~ and fill 100 L 3-hydride gelatin capsules with 17C8" of 0.5cm per capsule)
-Methyl-ω-homotransume PGE+ (Gastric soluble capsules containing sample N (L4) were obtained.

Formulation Example 2 17 (S')-Methyl-ω-homo-trans-d-P
GEI (specimen Nα4) 0.5■ was dissolved in 5 ml of ethanol, passed through a bacteria retention filter, and sterilized.
By adding 0.1 me per 1 me capacity ampoule, 10)'y of 17-(S)-methyl-ω-homotransme PGEl (sample N[L4)
was contained, and the ampoule was sealed. The contents of the ampoule are diluted to an appropriate volume, eg, 1 rnl, with a pH 8.6 Tris-HCl buffer and used as an injection.

Formulation Example 3 17 (S)-Methyl-ω-homo-trans-Δ-PG
In a solution of 50 fng of E1 (sample NI14), 1.62 g of α-cyclodextrin, and 10 g of distilled water, 10 g of citric acid was added.
tng, lactose 50y and distilled water 800Wd! Add and dissolve, and make the total amount to 1 t with distilled water. After sterile filtration in accordance with a conventional method, each ampoule was filled into ampoules, freeze-dried, and melted to obtain a freeze-dried preparation for injection.

Formulation Example 4 Sample N (Ll, 2°3
．． 5, 6, 7, 8, 9.10 can also be produced into gastric capsules, injections, and freeze-dried preparations for injection.

Patent applicant: Dainippon Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Agent Yushibe Tsuboi

Claims (1)

[Claims] l) General formula (wherein A is an ethylene group or a trans-vinylene group, R1 is a hydroxyl group, a lower alkoxy group or an amino group,
R2 has 5 carbon atoms, which may be substituted with a methyl group at the 1st position.
~7 alkyl groups, respectively. ) Prostaglandin D2 or its derivatives represented by the general formula % formula % (wherein, group, glycoloyl group or hydroxymethyl group, R4 is a pentyl group, 2
-Methylhexyl group, 1-cyclohexylethyl group. Each means a cycloalkyl group or a 3-trifluoromethyl-phenoxymethyl group which may be substituted with a lower alkyl group. However, when X is a methylene group, Y is an ethylene group or a trans-vinylene group, and R3 is a carboxyl group or a lower alkoxycarbonyl group. When X is a carbonyl group, Y is an ethylene group and R3 is a carboxyl group, a lower alkoxycarbonyl group, a glycoloyl group or a hydroxymethyl group. ) or a derivative thereof, or a cyclodextrin clathrate compound of the compound represented by the general formula (1) or (TI), or R1 of the compound represented by the general formula (1) is a hydroxyl group or R3 of the compound represented by the general formula (II) is a carboxyl group, a therapeutic agent for anoxic diseases of brain nerve cells containing a non-toxic salt of the acid as an active ingredient. 2) General formula (Formula where A is an ethylene group or a trans-vinylene group, R1 is a hydroxyl group, a lower alkoxy group or an amine group,
R2 has 5 carbon atoms, which may be substituted with a methyl group at the 1st position.
~7 alkyl groups, respectively. ), prostaglandin D2 or its derivative, or its cyclodextrin clathrate compound or R1
2. The therapeutic agent for anoxia-deficient diseases of cerebral nerve cells according to claim 1, which contains a non-toxic salt of the acid as an active ingredient when is a hydroxyl group. 3) General formula (wherein, X is a methylene group or a carbonyl group, and Y is:
r-fv group or (ri) lance-vinylene group, R3
represents a carboxyl group, lower alkoxycarbonyl group, glycoloyl group or hydroxymethyl group, and R4 represents a pentyl group, 2-methylhexyl group, or 1-cyclohexylethyl group. Each means a cycloalkyl group or a 3-trifluoromethyl-phenoxymethyl group which may be substituted with a lower alkyl group. However, when X is a methylene group, Y is an ethylene group or a trans-vinylene group, and R3 is a carboxyl group or a lower alkoxycarbonyl group. When X is a carbonyl group, Y is an ethylene group, and R3 is a carboxyl group, a lower alkoxycarbonyl group, a glycoyl group or a hydroxymethyl group. ) Prostaglandin E1 or its derivative, or its cyclodextrin clathrate compound or R3
2. The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1, which contains a non-toxic salt of the acid when is a carboxyl group as an active ingredient. 4) A therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 2, which contains glosstaglandin D2 as an active ingredient. 5) The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains grosstaglandin El as an active ingredient. 6) The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains 16-cyclohexyl-ω-trinor-prostaglandin El-methyl ester as an active ingredient. 7) Patent 4 containing 17(S)-methyl-ω-homo-trans-Δ-prostaglandin E+ as an active ingredient for treating oxygen deficient diseases of brain nerve cells as described in claim 1 or 3. therapeutic agent. 8) Oxygen deficiency of brain nerve cells according to claim 1 or 3, which contains a 17(S)-methyl-ω-homo-trans-Δ-prostaglandin El/cyclodextrin clathrate compound as an active ingredient. Treatment for sexual diseases. 9) Treatment of oxygen deficiency disease of brain nerve cells according to claim 1 or 3, which contains 16.18-ethano-ω-dihomo-6-keto-prostaglandin E+-methyl ester as an active ingredient. agent. 10) 2-Decarboxy-2-glycoloyl-17 (S
)-Methyl-ω-homo-6-keto-prostaglandin El as an active ingredient
A therapeutic agent for anoxia-deficient diseases of brain nerve cells as described in Section 2. 11) 17 (S)-methyl-ω-homo-6-keto-
The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains prostaglandin E1-alcohol as an active ingredient. 12) The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains 16,18-ethano-ω-dihomo-6-keto-prostaglandin E1-alcohol as an active ingredient. . 13) 2-Decarboxy-2-glycoloyl-16゜1
Claim 1 or 3, which contains 8-ethano-ω-homo-6-keto-prostaglandin E1 as an active ingredient
A therapeutic agent for anoxia-deficient disease of brain nerve cells as described in Section 1.