JPH0129168B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to prostaglandin D ₂ (hereinafter referred to as PGD ₂ ) or its derivatives, prostaglandin
The present invention relates to a therapeutic agent for anoxia-deficient diseases of brain nerve cells, which contains E ₁ (hereinafter referred to as PGE ₁ ) or a derivative thereof, or a clathrate compound or non-toxic salt thereof as an active ingredient. More specifically, the present invention relates to the general formula (In the formula, A is an ethylene group or a trans-vinylene group, R ₁ is a hydroxyl group, a lower alkoxy group, or an amino group, and R ₂ is an alkyl group having 5 to 7 carbon atoms that may be substituted with a methyl group at the 1st position. ) or _a derivative thereof, or the general formula (In the formula, X is a methylene group or a carbonyl group,
Y is an ethylene group or a trans-vinylene group,
R ₃ is a carboxyl group, lower alkoxycarbonyl group, glycoloyl group or hydroxymethyl group, R ₄ is a pentyl group, 2-methylhexyl group,
1-cyclohexylethyl group, a cycloalkyl group optionally substituted with a lower alkyl group, or 3
-trifluoromethyl-phenoxymethyl group, respectively. However, when X is a methylene group, Y is an ethylene group or a trans-vinylene group, and R ₃ is a carboxyl group or a lower alkoxycarbonyl group. When X is a carbonyl group, Y is an ethylene group, and R ₃ is a carboxyl group, a lower alkoxycarbonyl group, a glycoloyl group or a hydroxymethyl group. ), or a cyclodextrin clathrate compound of the compound represented by the above general formula () or (), or a compound in which R ₁ of the compound represented by the above general formula () is a hydroxyl group or a general formula () _. When R ₃ of the represented compound 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. PGD ₂ and its derivatives (), PGE ₁ and its derivatives (), and their cyclodextrin clathrate compounds and salts, which are the active ingredients of the therapeutic agent according to the present invention, are disclosed in Japanese Patent Publication No. 53-36458, 54-32773, 57
-20305, JP-A-49-47352, 51-101961, 51-
122040, 52−27753, 52−42856, 53−84942, 54
−44639, 55−100360, 58−4762, 58−203964,
58−203911, 59−1463, 59−20267, U.S. Patent
3878239, 3931296, 3966792, 4215142, UK Patent
1398291 or according to the method described therein. 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 Mitsugu, 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 dura mater.
It is one of the organs with the most active energy metabolism,
The rate of oxygen consumption is among the highest 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, it provides a stable energy source for the brain tissue,
In order to maintain a constant external environment for brain neurons, the cerebrovascular vessels themselves have 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. When brain neurons become oxygen deficient (hereinafter referred to as cerebral anoxia), the permeability of the brain neuron membrane changes, and edema is caused by the infiltration of extracellular fluid. 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, further intensifying cerebral edema and increased cerebral pressure, causing pressure on the brainstem and impaired passage of cerebrospinal fluid. These further form a vicious cycle of increasing cerebral anoxia, promoting cerebral edema, and increasing cerebral pressure. As a result, the lesion expands and even healthy brain tissue undergoes cerebral anoxia, resulting in a state of cerebral circulation failure and the disorder becoming serious.
Cerebral anoxia is the common denominator for most diseases based on cerebral circulation disorders (Eur. Neurol. 17 (supple. 1), 113−
120, 1978). Currently, hypnotic anesthetics such as phenobarbital and thiobarbital 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 throughout the central nervous system, and as a result,
Adverse effects on the respiratory and circulatory systems due to inhibition of the respiratory or blood pressure regulating center are associated as side effects. Therefore, in the treatment of anoxic diseases of nerve cells, there is a strong desire to develop a drug that does not have the side effects of hypnotic anesthetics and exhibits excellent therapeutic effects at very low doses. As a result of intensive research, the present inventor discovered that PGD ₂ and its derivatives (), PGE ₁ and its derivatives (),
In particular, we obtained a completely new finding that PGE ₁ derivatives exhibit excellent protective effects against brain anoxia at very low doses without being based on suppressive effects on nerve cell function, leading us to complete the present invention. That is, the present invention relates to PGD ₂ or a derivative thereof represented by the general formula (),
The present invention relates to a therapeutic agent for anoxia-deficient diseases of brain nerve cells, which contains PGE ₁ or a derivative thereof, or a cyclodextrin clathrate compound or a non-toxic salt thereof as an active ingredient. Its preferred active ingredients include:
PGD ₂ , PGE ₁ , 16-cyclohexyl-ω-trinor-PGE ₁ -methyl ester, 17(S)-methyl-ω-homo-trans-Δ ² -PGE ₁ , 16,18-ethanol-ω-dihomo-6 -keto-PGE ₁ -methyl ester, 2-decarboxy-2-glycoloyl-17(S)-methyl-ω-homo-6-keto-
PGE ₁ ,17(S)-methyl-ω-homo-6-keto-
PGE ₁ -alcohol, 16,18-ethano-ω-dihomo-6-keto-PGE ₁ -alcohol, 2-decarboxy2-glycoloyl-16,18-ethanol ω
-Homo-6-keto- _PGE1 , 16-(3-trifluoromethyl-phenoxy)-ω-tetranor-trans- ^Δ2- _PGE1 -ethyl ester, and cyclodextrin inclusion compounds thereof. 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 does not exert a protective effect on nerve cell function by suppressing neural activity in the brain, like the hypnotic anesthetics conventionally used for anoxic diseases of brain nerve cells. Therefore, it does not cause side effects such as respiratory depression or circulatory failure due to depression of the central nervous system in general. Additionally, whereas hypnotic anesthetics could only be administered during the acute phase,
Since the therapeutic agent according to the present invention does not exhibit a hypnotic anesthetic effect, it can be administered for the purpose of preventing the chronic phase and recurrence of seizures. 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-homo-trans-△ ²
- PGE ₂ shows no lethality when subcutaneously administered to mice at 10 mg/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. In addition, as a preparation for oral administration,
Examples include solid preparations such as tablets, pills, powders, capsules and granules, and liquid preparations such as emulsions, solutions, suspensions, syrups and elixirs. The dosage of the therapeutic agent according to the present invention is usually per day.
The amount is preferably 0.0003 to 100 mg/Kg, preferably 0.0003 to 10 mg/Kg for intramuscular, subcutaneous or intravenous administration, and 0.0003 to 30 mg/Kg 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 to these. Hereinafter, the present invention will be explained in further detail with reference to Examples and Formulation Examples. Experimental Example 1 [Survival prolonging effect on mouse mortality due to hypoxia] STD-ddY male mice (body weight 20-24 g) were set in a group of 5 mice, the required amount of sample was dissolved in 0.1 ml of ethanol, and then diluted with distilled water. The solution was subcutaneously administered at a rate of 0.1 ml per 10 g of mouse body weight. 30 minutes after administration of the sample, the mouse was placed in a 2.5 volume plastic container, and a hypoxic gas mixture consisting of 4% oxygen and 96% nitrogen was aerated at a rate of 4 parts per minute, and the mouse was allowed to breathe until it died. It was measured using the stoppage 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 samples used are as follows.

【table】

【table】

[Effect of prolonging panting exercise time due to complete ischemia]

A group of 5 STD-ddY male mice (body weight 20-24 g) was prepared by dissolving the required amount of the sample in 0.1 ml of ethanol, diluting it with distilled water, and subcutaneously administering the solution at a rate of 0.1 ml per 10 g of mouse body weight. did. 30 minutes after administration of the sample, the neck of the mouse was cut with decapitation scissors.
The sustained time 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. In addition, the specimens in the table
No. is the same as that shown in Experimental Example 1.

【table】

[Table] Formulation example 1 17(S)-methyl-ω-homo-trans-△ ² −
Dissolve 50 mg of PGE ₁ (specimen No. 4) in 10 ml of ethanol, mix this with 18.5 g of mannitol, pass through a 30-mesh sieve, dry at 30°C for 90 minutes, and then pass through a 30-mesh sieve again. . Add 200mg of Aerosil (Micropore Silica) to the powder and create NO.3 hard gelatin capsules.
Packed into 100 capsules, each capsule contains 0.5mg of 17 (S)
A gastric soluble capsule containing -methyl-ω-homo-trans-Δ ² -PGE ₁ (sample No. 4) was obtained. Formulation example 2 17(S)-methyl-ω-homo-trans-△ ² −
Dissolve 0.5 mg of PGE ₁ (sample No. 4) in 5 ml of ethanol, sterilize it through a bacteria retention filter, and add 0.1 ml per 1 ml ampoule to obtain 10 μg of 17-(S)-methyl-ω- per ampoule. Homo-trans-△ ² -PGE ₁ (Sample No. 4)
was contained, and the ampoule was sealed. The contents of the ampoule are diluted to an appropriate volume, for example, 1 ml with Tris-HCl buffer of pH 8.6, and used as an injection. Formulation example 3 17(S)-methyl-ω-homo-trans-△ ² −
In a solution of 50 mg of PGE ₁ (specimen No. 4), 1.6 g of α-cyclodextrin, and 10 ml of distilled water, 10 mg of citric acid,
Add 50g of lactose and 800ml of distilled water and dissolve.
Bring the total volume to 1 with distilled water. After sterile filtration in accordance with a conventional method, the mixture was filled into ampoules of 1 ml each, freeze-dried, and melted to obtain a freeze-dried preparation for injection. Formulation Example 4 In the same manner as Formulation Examples 1, 2, and 3, sample No. 1,
2, 3, 5, 6, 7, 8, 9, and 10 can also be produced into gastrosoluble capsules, injections, and freeze-dried preparations for injection.

Claims (1)

[Claims] 1. General formula (In the formula, A is an ethylene group or a trans-vinylene group, R ₁ is a hydroxyl group, a lower alkoxy group, or an amino group, and R ₂ is an alkyl group having 5 to 7 carbon atoms that may be substituted with a methyl group at the 1st position. ) _or a derivative thereof, or the general formula (In the formula, X is a methylene group or a carbonyl group,
Y is an ethylene group or a trans-vinylene group,
R ₃ is a carboxyl group, lower alkoxycarbonyl group, glycoloyl group or hydroxymethyl group, R ₄ is a pentyl group, 2-methylhexyl group,
1-cyclohexylethyl group, a cycloalkyl group optionally substituted with a lower alkyl group, or 3
-trifluoromethyl-phenoxymethyl group, respectively. However, when X is a methylene group, Y is an ethylene group or a trans-vinylene group, and R ₃ is a carboxyl group or a lower alkoxycarbonyl group. When X is a carbonyl group, Y is an ethylene group, and R ₃ is a carboxyl group, a lower alkoxycarbonyl group, a glycoloyl group or a hydroxymethyl group. ) or a cyclodextrin clathrate compound of _the compound represented by the above general formula () or (); or a cyclodextrin clathrate compound of the compound represented by the above general formula ();
When R ₁ is a hydroxyl group or R ₃ of the compound represented by the general formula () is a carboxyl group, a therapeutic agent for anoxia-deficient diseases of brain nerve cells, which contains a non-toxic salt of the acid as an active ingredient. 2 General formula (In the formula, A is an ethylene group or a trans-vinylene group, R ₁ is a hydroxyl group, a lower alkoxy group, or an amino group, and R ₂ is an alkyl group having 5 to 7 carbon atoms that may be substituted with a methyl group at the 1st position. or a cyclodextrin clathrate compound thereof, or _a non-toxic salt of the acid when R ₁ is a hydroxyl group, as the active ingredient. A therapeutic agent for anoxia-deficient disease of brain nerve cells according to item 1. 3 General formula (In the formula, X is a methylene group or a carbonyl group,
Y is an ethylene group or a trans-vinylene group,
R ₃ is a carboxyl group, lower alkoxycarbonyl group, glycoloyl group or hydroxymethyl group, R ₄ is a pentyl group, 2-methylhexyl group,
1-cyclohexylethyl group, a cycloalkyl group optionally substituted with a lower alkyl group, or 3
-trifluoromethyl-phenoxymethyl group, respectively. However, when X is a methylene group, Y is an ethylene group or a trans-vinylene group, and R ₃ is a carboxyl group or a lower alkoxycarbonyl group. When X is a carbonyl group, Y is an ethylene group, and R ₃ is a carboxyl group, a lower alkoxycarbonyl group, a glycoloyl group or a hydroxymethyl group. ), or a cyclodextrin clathrate thereof, or a non-toxic salt of an acid thereof when R ₃ is a carboxyl group _, as the active ingredient. A therapeutic agent for oxygen deficiency diseases of brain nerve cells. 4. The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 2, which contains prostaglandin D ₂ as an active ingredient. 5. The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains prostaglandin E ₁ as an active ingredient. 6. The therapeutic agent for anoxia-deficiency diseases of brain nerve cells according to claim 1 or 3, which contains 6 16-cyclohexyl-ω-trinor-prostaglandin E ₁ -methyl ester as an active ingredient. 7 17(S)-methyl-ω-homo-trans-△ ²
- A therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains prostaglandin E ₁ as an active ingredient. 8 17(S)-methyl-ω-homo-trans-△ ²
-Claim 1 in which the active ingredient is a prostaglandin E ₁ /cyclodextrin clathrate compound
The therapeutic agent for anoxia-deficient disease of brain nerve cells according to item 1 or 3. 9. Treatment of anoxia-deficient disease of brain nerve cells according to claim 1 or 3, which contains 16,18-ethanol-ω-dihomo-6-keto-prostaglandin E ₁ -methyl ester as an active ingredient. agent. 10 2-Decarboxy-2-glycoloyl-17
The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains (S)-methyl-ω-homo-6-keto-prostaglandin E ₁ as an active ingredient. 11 17(S)-Methyl-ω-homo-6-keto-prostaglandin E ₁ -Treatment of oxygen deficiency disease of brain nerve cells according to claim 1 or 3, which contains alcohol as an active ingredient agent. 12 The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains 16,18-ethanol-ω-dihomo-6-keto-prostaglandin E ₁ -alcohol as an active ingredient. . 13 2-Decarboxy-2-glycoloyl-
The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains 16,18-ethanol-ω-homo-6-keto-prostaglandin E ₁ as an active ingredient.