JPH0213644B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is directed to the use of prostagrange I ₁ (hereinafter referred to as PGI ₁ ) derivatives, prostagrange I ₂ (hereinafter referred to as PGI ₂ ) or derivatives thereof, or clathrates or non-toxic salts thereof as active ingredients. This invention relates to a therapeutic agent for oxygen deficiency diseases. For more details,
The present invention is based on the general formula (In the formula, R ₁ is a hydrogen atom or a lower alkyl group,
_R2 means a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. ) PGI ₁ derivative represented by or general formula (In the formula, R ₁ is a hydrogen atom or a lower alkyl group,
X is an oxygen atom or a methylene group, and _R3 is a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. However, X
is an oxygen atom, a chloro-lower alkyl-substituted cycloalkyl group, a cycloalkylmethyl group optionally substituted with a lower alkyl group, a pentyl group optionally substituted with a methyl group at the 1-position, methyl at the 1- or 2-position It may also be a substituted-5-chloropentyl group. ) or a cyclodextrin clathrate compound of the compound represented by the general formula () or (), or _{R 1 of} the compound represented by the general formula () or ()
is a hydrogen atom, 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. PGI ₁ derivatives (), PGI ₂ 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 JP-A-53-103464, 53-116365, 54-
115368, 54−125653, 54−130543, 55−64541,
55−111465, USP4178367, 4232009, 4234597,
Tet rahedron Letters No.32, pp2805−2808,
1977 or according to the method described therein. It is already known that these compounds have activities such as inhibiting platelet aggregation, relaxing vascular smooth muscle, and suppressing gastric acid secretion (Monthly Yakuji Vol. 22, No. 2).
49-57, 1980). Unlike other organs, the brain exists in a special environment where it is submerged in cerebral fluid within a rigid body such as the skull or brain 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 cannot function normally. When brain neurons become oxygen-deficient (hereinafter referred to as cerebral anoxia), the permeability of the brain nerve cell 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 cerebral 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 obstruction of cerebrospinal fluid passage. Furthermore, a vicious cycle is formed in which brain anoxia is enhanced, brain edema is promoted, and cerebral pressure is increased. As a result, the lesion expands and even healthy brain tissue undergoes cerebral anoxia, leading to 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 cells. 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 due to suppression of the respiratory or blood pressure regulating center are required. The negative effects on the body accompany it as a side effect. Therefore, in the treatment of anoxia-deficient diseases of brain nerve cells, there is a strong desire to develop a drug that does not have the side effects of hypnotic anesthetics and that exhibits excellent therapeutic effects at very low doses. As a result of extensive research, the present inventors have found that PGI ₁ derivatives (), PGI ₂ and their derivatives () exhibit excellent protective effects against cerebral anoxia at very low doses, and are not based on suppressive effects on nerve cell function. We have obtained completely new knowledge and have completed the present invention. That is, the present invention provides a method for treating brain nerve cells containing a PGI ₁ derivative represented by the above general formula (), a PGI ₂ represented by the above general formula () or a derivative thereof, or a cyclodextrin clathrate compound or a non-toxic salt thereof as an active ingredient. This invention relates to a therapeutic agent for oxygen deficiency diseases. Preferred active ingredients include 16,19-ethano-ω-dihomo-6,9α-nitrilo-PGI ₁ methyl ester, 17(S)-methyl-ω-homo-6,
9α-Nitrilo-PGI ₁ methyl ester, 17(S)-
Methyl-ω-homo-6,9α-nitrilo-PGI ₁ ,
PGI ₂ sodium salt, 17(S)-methyl-ω-homo-6,9α-methano-5EZ-PGI ₂ methyl ester,
15-cyclohexyl-ω-pentanol-PGI ₂ methyl ester, 16,19-ethano-ω-homo-
PGI ₂ methyl ester, 16(ξ)-methyl-20-chloro-PGI ₂ methyl ester, 16(ξ)-methyl-
20-Chloro- _PGI disodium salt, 17(R)-methyl-20-chloro-PGI _dimethyl ester, 15-cyclopentyl-ω-pentanol-5E-6,9α-
Methano- _PGI2 , 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 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, 16,19-ethano-ω-dihomo-6,9α-nitrilo-PGI ₁ methyl ester shows no lethality when subcutaneously administered to mice at 30 mg/Kg, and the ratio to the minimum effective dose is more than 100 times. . The therapeutic agent for anoxia-deficient diseases of brain nerve cells of 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 that are dissolved in sterile water or sterile injectable solvents immediately before use. It will be done. 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. . The dosage of the therapeutic agent according to the present invention is usually per day.
0.001 to 100 mg/Kg, 0.001 to 10 mg/Kg for intramuscular, subcutaneous or intravenous administration, and 0.001 to 10 mg/Kg for oral administration.
0.001-30mg/Kg is preferred. However, the dosage varies depending on the patient's age, weight, severity of symptoms, type of disease, number of administrations, etc., and is not limited thereto. The present invention will be explained in further detail below using experimental examples and formulation examples. Experimental Example 1 [Survival prolonging effect on mouse mortality due to hypoxia] A group of 5 STD-ddY male mice (body weight 20-24 g) was dissolved in 0.1 ml of ethanol, and then 0.1 M glycine was added to the sample. A solution diluted with sodium hydroxide buffer (PH10.0) was added to the body weight of the mouse.
It was administered subcutaneously at a rate of 0.1 ml per 10 g. Maximum effect onset time of each sample (sample No. 1, 2, 3,
5 and 11 for 2.0 hours, sample No. 4 for 0.5 hours, sample No.
6, 7, 8, 9, 10, 13, 14, 15, and 16 for 0.25 hours), mice were placed in a 2.5-volume plastic container and exposed to 1 hour of a hypoxic gas mixture consisting of 4% oxygen and 96% nitrogen. Aeration was performed at a rate of 4 per minute, and the time until the mouse died was measured using the cessation of breathing as an index. A 0.1M glycine-sodium hydroxide buffer containing the same concentration of ethanol was administered to the comparison group in the same manner. The results are shown in Table 1. The samples used are as follows.

【table】

【table】

【table】

【table】

[Table] Experimental example 2 [Effect of prolonging panting exercise time due to complete ischemia] A group of 5 male STD-ddY mice (weight 20-24 g) was prepared, and the required amount of sample was dissolved in 0.1 ml of ethanol. A solution diluted with 0.1M glycine-sodium hydroxide buffer (PH10.0) was added to the mouse body weight.
It was administered subcutaneously at a rate of 0.1 ml per 10 g. Maximum effect onset time of each sample (sample No. 1, 2, 3,
5, 11, 12 for 2.0 hours, sample No. 4 for 0.5 hours, sample
Nos. 6, 7, 8, 9, 10, 13, 14, 17, and 18 at 0.25 hours), the neck of the mouse was cut with decapitation scissors, and the period of time until the panting movement that appeared in the separated head disappeared. The duration was measured. A 0.1M glycine-sodium hydroxide buffer containing the same concentration of ethanol was administered to the comparison group in the same manner. The results are shown in Table 2. The sample numbers in the table are the same as those shown in Experimental Example 1.

【table】

【table】

[Table] Formulation example 1 Dissolve 50 mg of 16,19-ethano-ω-dihomo-6,9α-nitrilo-PGI ₁ methyl ester (sample No. 1) in 10 ml of ethanol, and add mannitol.
Mix 18.5g and pass through a 30-mesh sieve.
After drying at 30°C for 90 minutes, it was passed 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, 0.5mg per capsule16,19
-Ethano-ω-dihomo-6,9α-nitrilo-
Gastric soluble capsules containing PGI ₁ methyl ester (Sample No. 1) were obtained. Formulation example 2 Dissolve 0.5 mg of 16,19-ethano-ω-dihomo-6,9α-nitrilo-PGI ₁ methyl ester (sample No. 1) in 5 ml of ethanol, sterilize it through a bacteria retention filter, and add it per 1 ml ampoule.
10μg per ampoule by adding 0.1ml each
16,19-ethano-ω-dihomo-6,9α-nitriloPGI ₁ -methyl ester (sample No. 1) 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 Add 10 mg of citric acid and 50 g of lactose to a solution of 50 mg of 16,19-ethano-ω-dihomo-6,9α-nitrilo-PGI ₁ methyl ester (sample No. 1), 1.6 α-cyclodextrin, and 10 ml of distilled water. and distilled water
Add 800ml to dissolve, and 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. 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
Regarding 14, 15, 16, 17, and 18, gastrosoluble capsules,
Injections and freeze-dried preparations for injection can be produced.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is a hydrogen atom or a lower alkyl group,
_R2 means a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. ) Prostaglandin I ₁ derivative represented by or the general formula (In the formula, R ₁ is a hydrogen atom or a lower alkyl group,
X is an oxygen atom or a methylene group, and _R3 is a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. However, X
is an oxygen atom, a cycloalkyl group substituted with a chloro-lower alkyl group, a cycloalkylmethyl group optionally substituted with a lower alkyl group, a pentyl group optionally substituted with a methyl group at position 1, 1 or 2
A methyl-substituted -5-chloropentyl group may also be used. ), or a cyclodextrin clathrate compound of the compound represented by the general formula () or (), or _{R 1 of} the compound represented by the general formula () or (), A therapeutic agent for oxygen deficiency diseases of brain nerve cells, which contains a non-toxic salt of the acid when it is a hydrogen atom as an active ingredient. 2 General formula (In the formula, R ₁ is a hydrogen atom or a lower alkyl group,
_R2 means a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. ) or its cyclodextrin inclusion compound or _{R 1}
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 as an active ingredient when is a hydrogen atom. 3 General formula (In the formula, R ₁ is a hydrogen atom or a lower alkyl group,
X is an oxygen atom or a methylene group, and _R3 is a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. However, X
is an oxygen atom, a chloro-lower alkyl-substituted cycloalkyl group, a cycloalkylmethyl group optionally substituted with a lower alkyl group, a pentyl group optionally substituted with a methyl group at the 1-position, methyl at the 1- or 2-position It may also be a substituted-5-chloropentyl group. ), or _a cyclodextrin clathrate compound thereof, or a non-toxic salt of an acid thereof when R ₁ is a hydrogen atom, as an active ingredient. A therapeutic agent for oxygen deficiency diseases of brain nerve cells. 4 Claim 1 or 2 containing 16,19-ethano-ω-dihomo-6,9α-nitrilo-prostaglandin I ₁ methyl ester as an active ingredient
A therapeutic agent for anoxia-deficient diseases of brain nerve cells as described in Section 2. 5 17(S)-Methyl-ω-homo-6,9α-nitrilo-prostaglandin I ₁ methyl ester as an active ingredient; anoxia-deficient disease of brain nerve cells according to claim 1 or 2; therapeutic agent. Treatment of anoxia-deficient diseases of brain nerve cells according to claim 1 or 2, which contains 6 17 (S)-methyl-ω-homo-6,9α-nitrilo-prostaglandin I ₁ as an active ingredient. agent. 7. The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains prostaglandin I _disodium salt as an active ingredient. 8. Oxygen deficiency in brain nerve cells according to claim 1 or 3, which contains 17(S)-methyl-ω-homo-6,9α-methano-5EZ-prostaglandin I ₂ methyl ester as an active ingredient. Treatment for sexual diseases. 9. The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains 9 15-cyclohexyl-ω-pentanol-prostaglandin I ₂ methyl ester as an active ingredient. 10 10 16,19-Ethano-ω-homo-prostaglandin I ₂ methyl ester The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains methyl ester as an active ingredient.