JPS5850965B2 - Parkinson's disease treatment drug - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a therapeutic agent for Parkinson's disease, more specifically, a drug of the following formula (
1), relates to a therapeutic drug for Parkinson's disease containing 3-amino-4-homisolystane or a salt thereof as a main component.

The fact that 3-amino-4-homisolystane has antiviral activity has been reported, for example, in the Journal of Medi.
Cinal Chemistry, Vol. 19, p. 536 (1976), but there are no reports of its effectiveness as a therapeutic drug.

The present inventor conducted a wide search for the pharmacological effects of 3-amino-4-homisolystane, and found that it is extremely effective in treating Parkinson's disease, thereby completing the present invention.

Parkinson's disease was diagnosed in 1817 by James Parkin.
Since its discovery by Son, there are currently 10
It is estimated that there are 00,000 patients.

Parkinson's syndrome is caused by tranquilizers, brain tumors, brain trauma, post-encephalitis, cerebrovascular injury, cerebral syphilis, heavy metal poisoning, etc., and is clinically recognized as akinesia, rigidity, tremor, and autonomic nervous disorder.

Its pathogenesis is currently believed to be due to degenerative degeneration of the substantia nigra, globus pallidus, and corpus striatum in the patient's tissues, and dopamine (DA) in these tissues.
A decrease in the amount of DA and a decrease in the content of homovanillic acid, a metabolite, in the cerebrospinal fluid indicates that cholinergic nerves (facilitating system) and dopaminergic nerves (facilitating system) in the striatum. It is thought that the disease develops as a result of a disturbance in the balance of the cholinergic nerve system (inhibitory system), and cholinergic nerve activity becomes dominant.

Furthermore, it is thought that serotonin and histamine may be involved.

Based on these etiological grounds, centrally acting anticholinergic drugs have traditionally been used, which are effective to some extent for rigidity, tremor, and autonomic dysfunction, but are ineffective for akinesia. Ta.

In recent years, L-dihydroxyphenylalanine (L-D
A treatment method was discovered that administered OPA, which improved immobility by 62%, which was previously thought to be impossible, and improved stiffness by 57%, and was 61% effective against tremor, making it the best treatment at present. has been done.

However, when large doses of L-DOPA are administered, side effects include anorexia, nausea, vomiting, intestinal pain, diarrhea, fecal orthostatic hypotension, headache, insomnia, hypersexuality, and psychotic symptoms and involuntary movements.

Moreover, since this needs to be used continuously for a long period of time, the dosage needs to be kept as low as possible.

Therefore, ① methods to prevent the decomposition of L-DOPA in the periphery and increase the amount transferred to the central nervous system to reduce the amount of L-DOPA administered, for example, seryltrihydroxybenzylhydrazine, α-methyl-α- hydrazino-3,
L-DOP such as 4-dihydroxyphenylpropionic acid
A method of administering an A decarboxylase inhibitor, and a method of reducing the amount of L-DOPA administered by pre-stimulating the central nervous system by administering amantadine or the like have been found.

However, method (2) has the disadvantage that central side effects such as involuntary movements and psychiatric symptoms are rather increased.

3-amino-4-homisolystane, which is the active ingredient of the present invention, has the effect of (1) mentioned above, that is, it acts on the central nervous system and excites the central DA agonist nerves, thereby increasing DA uptake (DA upt).
ake) has the effect of inhibiting and liberating stored DA, and has intrinsic activity on its own, so it can treat Parkinson's disease alone, and when used in combination with drugs that supplement dopamine such as L-DOPA, its synergistic effect The dosage of L-DOPA can be reduced.

3-amino-4-homisolystane and its salts are
For example, by reacting a 3-mono-substituted-4-homoisolyscune represented by the following formula (It), (wherein X represents chloro, bromo, iodo, hydroxyl, or acetoxy group) with acetonitrile in the presence of sulfuric acid, 3-acetylamino-4-homoisolystan and nashiku patent application 1982-1986
No. 814) and then by hydrolyzing this (Japanese Patent Application No. 79437/1983).

This 3-amino-4-homisolystane can be made into oral preparations such as tablets, powders, capsules, and injections according to conventional methods.The dosage varies depending on the administration method, but it can be administered intramuscularly at once Injection: 0,3-3" to 197?, intravenous injection: 0.1-1 m9/Ky, oral administration: 1
~10m9/Kp is preferred.

Next, an example will be given and explained.

In the Examples, unless otherwise specified, a group of 10 ICR male mice weighing around 25 g were used.

Example 1 Effect of haloperidol on catalepsy: 3-amino-4-homisolystane was injected intraperitoneally into mice,
Ten minutes later, haloperidol 500 gamma/2 was injected intraperitoneally, and the time and intensity of catalepsy were measured every 30 minutes from 30 minutes later according to the method of Marputgo.

The results are shown in Figure 1 (influence of haloperidol on the intensity of catalepsy) and Figure 2 (influence of haloperidol on the onset time of catalepsy). It is found that it has a stimulating effect.

Example 2 Effect of phenothiazine compounds on catalepsy: 3-amino-4-homisolystane was injected intraperitoneally into mice, and 10 minutes later, chloropromacin 5/Kp was injected intraperitoneally, following the method of Marputgo. The intensity of catalepsy was measured.

The results are shown in FIG. 3, and remarkable inhibition was observed in the 3-amino-4-homisolystane 30'1lQlKf group.

Phenothiazines are thought to cause sedation and catalepsy by antagonizing catecholaminergic nerves in the central nervous system, but chronic use of phenothiazines is known to cause Parkinson-like symptoms.
This substance is shown to antagonize Parkinson's syndrome.

Example 3 Anticonvulsant and tremor effects: After intraperitoneal injection of 3-amino-4-homisolystane into mice, nicotine 5 μ/Kp was intraperitoneally injected, and the presence or absence of convulsions was examined.

The results are shown in Table 1, and showed that it suppressed nicotine-induced spasticity and had an anti-Parkinsonian effect.

Example 4 Effect of apomorphine on stereotypic behavior in rats: Group of 5 male Wistar rats (body weight 200-2
30g) was injected intraperitoneally with 3-amino-4-homisolystane, and 30 minutes later, apomorphine 0,07''97? was injected intravenously.

After 5 minutes, the behavior of the rats was observed every 5 minutes for 60 minutes, the stereotypic behavior was scored, and the highest score given by each rat was taken as the score for each rat.

Stereotypic behavior was scored using the following criteria.

Same behavior as normal control rats O more sniffing 1 weaker lic
There is a king 2 typical lickin
There is a 3 weak biting.
4 There is typical writing 5
Strong biting 6 The results are as shown in Figure 4, and 3-amino-4-homisolystane showed a significant apomorphine-enhancing effect when administered at 3 and 30 μ/Kp.

Furthermore, since apomorphine is known to directly excite central dopaminergic nerves, it was confirmed that this substance is effective in treating Parkinson's syndrome by enhancing its effect.

Example 5 Effect on locomotor activity: Physiological saline (0.1 ml/10 & body weight) or haloperidol 0.3"9/? was administered intraperitoneally to 7 DD male mice (20-25 g) per group. injection, and 30 minutes later, 3-amino-4-homisolyscine was injected intraperitoneally,
After 30 minutes, locomotor activity was measured using a Varimex device for 1 hour.

The results are shown in FIG. 5, and locomotor activity was significantly reversed by 3-amino-4-homisolystane and antagonized by haloperidol.

This indicates that 3-amino-4-homoinostane has a dopaminergic nerve excitatory effect.

Example 6 Effect of haloperidol on catalepsy in mice: Haloperidol 0.37119/Kp was subcutaneously injected into a group of 10 DD male mice (20-25 g), and 3 hours later, 3-amino-4-homisolyscune was administered. was injected intraperitoneally, and the presence or absence of catalepsy was measured 1 hour later.

Catalepsy was determined by placing both forelimbs of the mouse on a bar with a height of 4C:rIl and maintaining that position for 15 seconds or more.

The results are shown in Table 2, and 3-amino-4-
Haloperidol-induced catalepsy was antagonized by homoisolystane.

This indicates that 3-amino-4-homisolysquine has a dopaminergic nerve excitatory effect.

Example 7 Effect of haloperidol on catalepsy in rats: 10 male Wistar rats (190-23
Haloperidol 57729/ was injected subcutaneously at 0g), and 4 hours later, 3-amino-4-homisolysquone was injected intraperitoneally, and the presence or absence of catalepsy was determined 1 hour later.

Catalepsy was determined by placing both forelimbs of a rat on a pole with a height of 8.8 cm and maintaining that position for 30 seconds or more.

The results are shown in Table 3, and 3-amino-4-
Haloperidol-induced catalepsy was antagonized by homoisolystane.

This indicates that 3-amino-4-homisolystane has a dopaminergic nerve excitatory effect.

Example 8 The acute toxicity of 3-amino-4-homisolystane was measured using mice, and the results were as shown in Table 4.

[Brief explanation of drawings]

Figure 1 shows the effect of 3-amino-4-homisolystane on the catalepsy intensity caused by haloperidol, Figure 2 shows the effect of the same substance haloperidol on the onset time of catalepsy, and Figure 3 shows the effect of the same substance haloperidol on the onset time of catalepsy. Figure 4 shows the effect of the same substance apomorphine on lightning behavior in rats, and Figure 5 shows the effect of the same substance on spontaneous momentum.

Claims (1)

[Scope of Claims] 1. A therapeutic agent for Parkinson's disease containing 3-amino-4-homisolystane or a salt thereof represented by the following formula as a main component. 2. Claim 1 containing a drug that supplements dopamine and 3-amino-4-homisolystane or a salt thereof
A drug for treating Parkinson's disease as described in Section 1. 3. The drug for treating Parkinson's disease according to claim 2, wherein the drug that supplements dopamine is L-dihydroxyphenylalanine.