JPS58192821A - Remedy for anoxia of cranial nerve cells - Google Patents

Abstract

PURPOSE:The titled remedy that contains a PGI1 or PGI2 derivative or a clathrate thereof with cyclodextrin as an active ingredient, permitting the administration at an aim of prevention without side-effects such as respiratory insufficiency or circulatory faliure, further preventing recurrence. CONSTITUTION:The objective remedy contains a PGI1 derivative of the formula I (R1 is H, alkyl; R2 is 2-methylhexyl, cycloalkyl), e.g., 16,19-ethano-omega-dihomo-6, 9alpha-nitrilo-PGI1 methyl ester or PG2 of formula II (X is O, ethylene; R3 is R2 or may be cycloalkyl substituted with chloro-lower-alkyl or benzyl) or its derivative such as 16,19-ethano-omega-homo-PGI2 methyl ester having actions of inhibiting platelet coagulation, relaxing blood muscles and inhibiting gastric juice secretion or their clathrate with cyclodextrin as an active ingredient. It develops an action of protecting from cranial anoxia with small doses not originating from suppression of nerve cells.

Description

[Detailed description of the invention] The present invention provides prostagrange 1. (Hereinafter referred to as PGI1.

) Derivatives, prostagranges 1. (hereinafter referred to as PG1.) or a derivative thereof, or a clathrate compound or non-toxic salt thereof as an active ingredient, the present invention relates to a therapeutic agent for anoxia-deficient diseases of brain nerve cells. More specifically, in the present invention, RI represents a hydrogen atom or a lower alkyl group, and Re represents a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. ) PGl, derivatives, or general formula C, in which R
, is a hydrogen atom or a lower alkyl group, X is an oxygen atom or a methylene group, and is a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group.

However, when X is an oxygen atom, a cycloalkyl group substituted with a chloro-lower alkyl group, a cycloalkylmethyl group that may be substituted with a lower a4-alkyl group, a pentyl group that may be substituted with a methyl group at the 1st position, It may also be a 1- or 2-position methyl-substituted -5-chloropentyl group. ) or a derivative thereof, or a cyclodextrin clathrate compound of a compound represented by the general formula CI+ or (), or the general formula +I> or (
When R in the compound represented by 0) 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 with 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.

PCI, a derivative (
I), PGL and its derivatives, as well as their cyclodextrin clathrate compounds and salts, are disclosed in JP-A-53-'
103464.53-116365.54-11536
8.54-. 125653.54-130543.55
-64541゜55-111465, USP41783
67.4232009.4234597, Tetra
hedron Ij3tters & 32, pp28
05-2808.1977 or according to the method described therein. It is already known that these compounds have platelet aggregation inhibiting effects, vascular smooth muscle relaxing effects, gastric acid secretion suppressing effects, etc. (Monthly Yakuji Vol. 22, No. 2, 49)
~57 pages, 1980).

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, and is the organ 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 supply the brain tissue with a stable energy source 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 cannot 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 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 cerebral circulation failure and the disorder becoming serious. Cerebral anoxia is the common denominator for most diseases based on cerebral circulation disorders (&r, Neurol, 17 (Supplement, 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 produce a suppressive effect throughout the central nervous system, and as a result, the respiratory and circulatory systems may be affected by suppression of the respiratory or blood pressure regulating center. Negative effects accompany it as side effects.

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 intensive research, the present inventors discovered that “P(d, derivative (I)
), PGl, and its derivative {circle over (2)} exert a protective effect on neuronal function against cerebral anoxia, and we have now completed the present invention.

That is, the present invention provides PG represented by the general formula (I)
The present invention relates to a therapeutic agent for anoxia-deficient diseases of brain nerve cells, which contains as an active ingredient PGl represented by the above-mentioned general formula PGl, or a derivative thereof, or a non-toxic salt thereof. Suitable active ingredients thereof include 16.19-ethano-ω-dipho%-6,9α-nitrilo-PGI,-methyl ester, 17(S)-methyl-ω-homo-6,9α-nitrilo-PGll-methyl Ester, 17(S)-/chill-ω-homo-6,9α
-nitrilo-PGl, PGl, ,17(S)-methyl-ω-homo-6,9α-me9/-5EZ-PGL-
1f Louet 7. f, 15-cyclohexyl-ω-pentano-PGI, -methyl ester, 16.19-
Ethano-ω-homo PGI.

-methyl ester, 16(a-methyl-20-chloro-
PGl, -methyl ester, 16(ξ)-methyl-20
-chloro-PGI, -sodium salt, 17(R)-methyl-20-chloro-PGI, -methyl 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. Furthermore, whereas hypnotic anesthetics could only be administered during the acute phase, the therapeutic agent according to the present invention does not exhibit hypnotic anesthetic effects, so it can be administered during the chronic phase and for the purpose of preventing seizure recurrence. It is possible. 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-
Subcutaneous administration of dihomo-6,9α-nitriloPGL)'chill x Stelha 30 e/kg to mice showed no lethality, and the ratio to the minimum effective dose was 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. Additionally, suppositories for intrarectal administration,
Examples include pessaries for intravaginal administration. 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 0,001 ml per day.
-100 mJkg, preferably o, o o i -10 nmkg for intramuscular, subcutaneous or intravenous administration, and 0.001 to 30 IIIg/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 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] 5TD
A group of 5 -ddY male mice (body weight 20-249) was prepared, and the required amount of the sample was dissolved in 0.1 ml of ethanol. IM glycine-sodium hydroxide buffer (pH
10.0) per 10g of mouse body weight.
It was administered subcutaneously at a rate of 11 hl. Maximum effect onset time for each sample (2.0 hours for sample Oboro 1.2.3.5.11, 0.5 hour for sample &4., 0.5 hour for sample &6.7.8.9
．． 10 is 0.25 hours), the mouse is 2.51! A low-oxygen gas mixture consisting of 4% oxygen and 96% nitrogen is poured into a plastic container with a capacity of 41% per minute. The time until the mouse died was measured using the stoppage 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.

*: The TLCC developing solvent for the product is benzene:methanol:triethylamine = 15:2:1, the plate is MercArt ■5747): Rf = 0.41 Umbrella: The TLCC developing solvent for the product is ethyl acetate: cyclohexane = 3 = 1 mixed solvent with 2% of the total amount of acetic acid added 3: Rf-0, 23 Table 1 Experimental Example 2 [Prolonging effect of panting exercise time due to complete ischemia] 5TD-
A group of 5 male ddY mice (body weight 20-24 g) was used. After dissolving the required amount of the sample in 0.1 ml of ethanol, the sample was dissolved in 0.1 M glycine-sodium hydroxide buffer (pH
A solution diluted with 10,0) was administered subcutaneously at a rate of 0.1 ml per log of mouse body weight. Maximum effect onset time of each specimen (sample & 1.2.3.5.11 is 2.
0 hours, sample Haruka 4 is 0.5 hours, sample A6.7,8゜9
．． At 0.25 hours (0.25 hours), 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. 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. Note that the specimen heights in the table are the same as those shown in Experimental Example 1.

Table 2 Formulation example 1゜16.19-ethano-ω-dihomo-6,9α-nitrio
PGI+-methyl ester (sample/F0.1) 50
Mu was dissolved in 10 ml of ethanol, mixed with 185 g of mannitol, passed through a 30-mesh sieve, dried at 30°C for 90 minutes, and then passed through a 30-mesh sieve again.

Aerosil (micro fine silica) 200 is added to the powder.
(2) was added and filled into 100 fish 3 hard gelatin capsules, and each capsule contained 16.19-ethano-ω-dihomo-6,9α-yo”) Relo PG1.-methyl ester ( Gastric soluble capsules containing sample 1) were obtained.

Formulation Example 2 Dissolve 0.5 ml of 16.19-ethano-ω-dihomo-6,9a-nitrilo-PGI,-methyl ester (sample AI) in 5 ml of ethanol, sterilize it through a bacteria retention filter, and make 1 ml. Capacity 0.1m per ampoule
By adding 16 l of 10 μ9 per ampoule
．． 19-ethano-ω-dihomo-6,9α-nitrilo-
P.G.I.

- Methyl ester (sample &1) was contained, and the ampoule was sealed. The contents of the ampoule are diluted to an appropriate volume, e.g. 1 ml with a pH 8.6 Tris-HCl buffer.
Used as an injection.

Formulation example 3゜16.19-ethano-ω-dihomo-6,9α-nitrio
-PGL-methyl ester (sample AI) 50 mg and α
- In a solution of 1.6 g of cyclodextrin and 10 ml of distilled water, 10 μg of citric acid, 509 g of lactose and 80 g of distilled water.
Add 0ml to dissolve, and make the total volume to 11 with distilled water. After sterile filtration according to a conventional method, 1 ml of the mixture was filled into ampoules, freeze-dried, and melted to obtain a freeze-dried preparation for injection.

Formulation example 4゜Formulation example 1.2.3. Sample 42.3.4.
5.6°7, 8.9.10.11 can also be used to produce gastrosoluble capsules, injections, and freeze-dried preparations for injection.

Claims (1)

[Claims] 1) General formula (wherein R1 means a hydrogen atom or a lower alkyl group, and R5 means a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group.) Prostaglandin 11 derivatives represented by the formula (wherein R1 is a hydrogen atom or a lower alkyl group, X is an oxygen atom or a methylene group, and R-rich is substituted with a 2-methylhexyl group or a lower alkyl group) However, when X is an oxygen atom, it is a cycloalkyl group substituted with a chloro-lower alkyl group, a cycloalkylmethyl group optionally substituted with a lower alkyl group, a cycloalkyl group substituted with a methyl group at the 1-position. pentyl group, optionally substituted with methyl at 1 or 2 position -
It may also be a 5-chloropentyl group. ) Prostaglandin 1. or a derivative thereof, or a cyclodextrin clathrate compound of the compound represented by the general formula (I) or α), or a cyclodextrin clathrate compound of the compound represented by the general formula (I) or α);
I) or all of the compounds represented by blood are hydrogen atoms,
A therapeutic agent for oxygen deficiency diseases of brain nerve cells that contains a non-toxic salt of that acid as an active ingredient. 2) A prostaglan represented by the general formula (wherein, R8 is a hydrogen atom or a lower alkyl group, R2 is a 2-methyl-expressed xyl group, or a cycloalkyl group optionally substituted with a lower alkyl group) The method for treating oxygen deficient diseases of brain nerve cells according to claim 1, wherein the active ingredient is a non-toxic salt such as a gin-11 derivative, or a cyclodextrin clathrate compound thereof, or an acid thereof when R1 is a hydrogen atom. therapeutic agent. In the H c formula, R1 is a hydrogen atom or a lower alkyl group, X is an oxygen atom or a methylene group, and R1 is a 2-methylhexyl group or a cycloalkyl group optionally substituted with a lower alkyl group. However, when 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, 1 or It may also be a 5-chloropentyl group substituted with methyl at the 2-position. ) Prostaglandin 1. or its derivative, or its cyclodextrin inclusion compound or R8
2. The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1, which contains a non-toxic salt with an acid thereof as an active ingredient when is a hydrogen atom. 4) 16.19-ethano-ω-dihomo-6,9α-
The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 2, which contains nitrilo-prostaglandin I,-methyl ester as an active ingredient. 5) Oxygen deficiency in brain nerve cells according to claim 1 or 2, wherein the active ingredient is 17(S)-methyl-ω-homo-6,9α-nitrilo-prostaglandin ■,-methyl ester. Treatment for sexual diseases. 6) 17(S)-methyl-ω-homo-6.,9α-
The therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 2, which contains nitrilo-prostaglandin (2) as an active ingredient. 7) Prostaglandin 1. A therapeutic agent for anoxia-deficient diseases of brain nerve cells according to claim 1 or 3, which contains as an active ingredient. 3) 17(S)-methyl-ω-homo-6,9α-methane-5EZ-prostaglandin 1. - A therapeutic agent for anoxia-deficiency diseases of brain nerve cells according to claim 1 or 3, which contains a methyl ester as an active ingredient. 9) A therapeutic agent for anoxia-deficiency diseases of brain nerve cells according to claim 1 or 3, which contains 15-cyclohexyl-ω-pentanol-prostaglandin 1,-methyl ester as an active ingredient. 10) 16.19-Ethano-ω-homo-prostaglandin 1. - A treatment for anoxia-deficiency diseases of brain nerve cells according to claim 1 or 3, which contains methyl ester as an active ingredient.