JPS61191615A - Medicinal composition for treating parkinsonism or parkinsonic syndrome - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Belgian Patents Nos. 684,515 and 771.33
For No. 0, in particular, the general formula (wherein R1 is a hydrogen atom, R1 is a hydrogen atom, and hydrogen atoms having 1 to 4 carbon atoms) is used.
An alkyl group optionally substituted with a halogen atom, a benzyl group optionally substituted with a methyl group or a methoxy group: or an allyl group, where n is 2 and X is a sulfur atom: 771.330, the compounds of the general formula I and their physiological combinations with inorganic or organic acids. The acceptable acid addition salts have valuable pharmacological properties, especially analgesic, sedative, antitussive, antipyretic and antiinflammatory properties, and the compound described in Belgian Patent No. 771.330 has hypotensive, sedative, antitussive properties depending on its substituents. and/or has an anti-inflammatory effect. From the above-mentioned Patent No. 111-s, thiazolo derivatives in which R1 is an alkyl group or an allyl group having 1 to 4 carbon atoms, n is 2, and x is a sulfur atom in the general formula I have a particularly antihypertensive effect. and in the general formula I, R1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms and optionally substituted with a hydroxyl group, or an allyl group, n is 2, and x is an oxygen atom. Certain oxazolo derivatives have also been shown to have particularly antitussive properties.

From EliP-AI-0005732, the above general formula I
It is also known that compounds in which n is 2 have anti-angina activity.

Furthermore, according to US Pat. No. 4,400,378, compounds of general formula I have been shown to exhibit anti-glaucoma activity.

According to previously published literature, the compound @2-amino-6-allyl-5,6,7,8-tetra? :Fo-48
-Thiazo0(4,5-d)Azepine di-salt (B-HT
920) is also known as an agonist that selectively acts on presynaptic dopamine receptors [for example, Anaen et al.
l, TOXiOOl, ), 52.5l-56 (19
8! l); Journal of Neural Transmission (J, No+!ragTransmiasi
on), Jiang, 129-137 (1983)].

The present invention surprisingly shows that B-HT920 also has an adenistic effect on denervated or degenerated postsynaptic dopamitergic tissue in the brain! -! All that can be accomplished has been discovered and perfected. This discovery is particularly important as it indicates that the compound has application in the treatment of Parkinson's disease or parkinsonism. These patients have a disorder of degeneration of the V-paminergic neurons of the brain. Therefore, during nerve activity, the release of the chemical transmitter dopamine is insufficient, leading to parkin symptoms.

(Ni1l180n and Carlsson
) states that substances that exhibit specific agonistic effects on postsynaptic dopaminergic neurons are most effective for the treatment of Parkinson's syndrome or Parkinson's disease [T.I.P. engineering p
Klavier Biomedica 7+, Press (Klavier Biomedica
Press), May 1982, pp. 322 et seq.].

Furthermore, Goodale et al., 5science, 210.1141-114.
3 (1980), 1... In cases where dopamine release is reduced, such as in Parkinson's disease, compounds that first activate postsynaptic receptors are suitable. "There is," he said.

A first aspect of the invention provides an effective amount of 2-amino-6-allyl-5,6,7 to reduce or eliminate parkin symptoms.
,8-tetrahillero 4H-thiazolo(4,5-(L)
This is a method for treating Parkinson's disease or Parkinson's syndrome, which comprises administering azene (hereinafter referred to as compound @A) or its acid addition salt.

In one aspect, the present invention further includes the use of Compound A or an acid addition salt thereof for the production of a medicament for treating Parkinson's disease or Parkinson's syndrome.

Treatment of Parkinson's disease or parkinsonism includes:
Compound mA and its appropriate acid addition salts t1 oral, parenteral,
It is prepared in a conventional pharmaceutical dosage form for rectal or transdermal administration.

A single oral dose for humans is usually 2.5 to 550
III % tL<tzl 00~250. u#deQ
In the case of repeated administration (6 times a day), the daily dose is 15-900 μg, preferably 60-750 μg. The dosage for parenteral and rectal administration is also approximately the same range as for oral administration.

B-H'! A study of the antiparkinsonian effect of '920 is described in German patent application no. p35 06963.9. The test was conducted using rats.

The following test method was used.

Spontaneous locomotor activity in "pure" rats
arimex) 3J.

d] "locomotor" movements during the first 5 minutes after subcutaneous injection of B-HT 920; this motor function phase is the so-called of the rat in a new environment. “exploratory activity” (equivalent to: b) “non-ambulatory” movements that essentially constitute daily movements; ), started recording.

Test Results Search Activities and Daily Operations B-a'r920 was tested at doses of 0-02% 0.2, 2.0 and 4-09/kf (subcutaneous administration). As a comparative substance, apomorphine was tested at a dose of 9 (subcutaneous administration) at 0°1 jllP/.

The obtained values are shown in the following table: Table 1 b++ta- indicates that no test was performed.

Therefore, the inhibitory effect of B-HT920 on exploratory activity is almost maximal at a dose of 0.219/m and a dose of 0.119/m of apomorphine (this dose also reduces the number of contact interruptions within 5 minutes). 150 per day).

Regarding daily activities, B-■T920 does not lead to an increase in the number of daily activities at any of the doses tested.

Contrary to B-HT92Q, apomorphine 4#0ff9
/kg administration increases the number of daily activities to the 650 level.

Tested similarly to the corresponding kaLnic acid model by Schwartz et al. [Brain Res.
, 170 (1979), pp. 485-495]. This model shows that unilateral intrastriatal (stereotaxic) injection of the neurotoxin ibotenic acid destroys striatal cells and postsynaptic WF therein.
- Pamin (DA) and destroy the Seven Shitars [Experiment by Schwartz et al., Zorein Research (Wxpe
r, Brain Res, ) 37 (1979)
, pp. 199-216], thereby allowing the post-synaptic DA receptor to act only on the corresponding DA receptor on the healthy side, thus forcing the animal to move to the damaged side of the striatum. A rotational movement occurs.

Test results B-uT920 are 0.2, o, s, 10 and 2. Ow
/In doses (subcutaneous administration) were tested. As a comparison substance, apomorphine is 0.1! ! A dose of 9 (subcutaneous administration) was tested on 9/2. The obtained values are shown in the following table: Table 2 Comparison of apomorphine and B-111'I'920 shows that B-HT920 has a post-synaptic DAergic activity of apomorphine against a normally sensitive DA receptor of about 50%/s.
It is found that it has only a weak activity in this respect.

(C) Contralateral rotation in the 6-OHD A model tested by the method of Undestat [Actaphysiol Scand. Samerimento (Actaphysio)
l 5cand, 5upp1. ) 567 (19
1971) Pages 69 onwards; Tsuba Yoda Journal Ode
Pharmacology (Europ, J, Pharma
col, ), 9f3 (1984) 165-176
page〕. This model shows that stereotaxic unilateral injection of the neurotoxin 6-0 HDA disrupts the punctal striatal DA pathway on one side, thereby causing postsynaptic DA in the ipsilateral striatal It is based on the fact that they are deprived of their DA innervation, ie become denervated and therefore have hypersensitivity (denervation). In this model, DA-agonists with postsynaptic activity produce a dominant activity on hypersensitive DA receptors, causing contralateral rotation even at much lower doses.

Test result B-HT92Q is 0.02.0.05.0.5 and 1
．． A dose of 9 was tested on 019/. As a comparison substance,
Apomorphine was tested at a dose of 0.05119/k19 (subcutaneous administration). The obtained values are shown in the following table: Table 3 B-f (Compared with T92Q, apomorphine 0.05 l/U produced 557 contralateral rotations per active time. Therefore, normal Compared to its weak activity against DA receptors, B-HT920 has an exceptionally strong activity χ against denervated receptors.

One and a half years ago, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-titrahydropyridine (MPTP)
) discovery [Langston et al.:
Science (5science), 219.297(1
98! l)) has provided a new animal model for Parkinson's disease.

MPTP causes an irreversible neurological disease syndrome in humans and monkeys that is clinically, pathologically, biochemically and pharmacologically similar to Parkinson's disease [Marke et al.
y) and others, Nature (Nat+ure), 311
．． 464 (1984)). The close agreement between the two is due to the fact that MPTP also destroys a group of dopaminergic neurons in the brain's punctata that are damaged during the naturally occurring degenerative process of Parkinson's disease. Iatrogenic Parkinson's disease is caused by M.
It is thought to be caused by PTP or similar compounds [Snyder, Nature (Na.
ture), 311.514 (1984)). So far, the reason that MP'I'P Parkinson's symptoms have only been observed in monkeys other than humans is probably due to the involvement of specific metabolites of MPTP. The MPTP animal model using the method is particularly suitable for demonstrating the effects of anti-parkinone agents. MPTP to 7 Lusus monkeys (1 x O daily for 3 days)
, 15 doses/intramuscular injection, followed by administration at 6-day intervals [administered 3 o~0.40 rny/'qo daily for 3 days] When I applied this, I showed the following symptoms. That is, the animal exhibited akinesia and water and feed intake ceased. It exhibits a typical bent posture and often falls into catalepsy. The limbs became rigid and developed passive movements due to chronic spasms. Spontaneous movements of the trunk and limbs were usually absent due to intense painful stimulation.

When a-ar920c (50-100 μI/kl/) was injected intramuscularly, spontaneous movements were observed for the first time after 5-10 minutes, and the movements gradually normalized within 10-30 minutes. He has started eating and his behavior has returned to normal in the cage, including alertness and aggressive behavior. Most of the other symptoms disappeared, but mild resting tremors and muscle weakness remained. No sedation was observed. B-HT
Compared to before the administration of 920, the patient's complexion looked better and hehehehe.

The effect of B-HT920 lasted for approximately 3 hours, and the animal again began to exhibit the above-mentioned parkinone symptoms. New B
- After administration of HT920, the above clinical pathological conditions improved or disappeared. This beneficial effect of HT920 was replicated repeatedly in each animal.

No side effects have been observed at the doses used so far.

Compound A and its acid addition salts have an advantage over conventional DAafests because this substance acts only on postsynaptic DA receptors in the denervated state of the brain, and is useful for Parkinson's disease patients. Yuru B-) The pharmacological (motor) action of IT920 is mainly limited to the DA system of the brain damaged by the disease. ! striae DA
It has a particularly powerful effect on patients with severe denervation conditions (9).

In addition, the compound incised and its physiologically acceptable acid addition salts are well tolerated, eg, the ID5o for oral administration in mice is 455 Da/9.

Example 1 Core tablet composition Content in 1 tablet B-HT920 50 μg lactose
58.451v Tomorokosidenzon 10.0q Gelatin
1.0 m950.0 II kg Production method A 10% gelatin aqueous solution is added to a mixture of the active ingredient, lactose and corn starch, granulated through an 11iI sieve, dried at 40°C and passed through the same sieve again. The granules thus obtained are mixed with magnesium stearate and compressed to form a core tablet. Manufacturing must be done with dark guidance.

Center tablet ml: 50 ~ Star: 51aI Convex The center tablet thus obtained is coated with a coating agent consisting basically of sugar and Merck by a known method. The resulting coated tablets are polished with beeswax.

I view of coated tablets: 100 Da Example 2 Content in 1 drug for cattle B-ET 920 100.0 μl
Suppository base 1690.0 da (9 eg Witepsol W 45) Manufacturing method The micronized active ingredient is added to the melted bovine base, which has been cooled to 40°C, with stirring in an immersion homogenizer. The mixture is cooled slightly at 65°C and poured into T-moulds.

Example 3 Amuffle 1 containing 200 jig OB-HT 920
Content in ampoule B -HT 920 2001111
Quen II! 7.0
119 Sodium diphosphate (2111,O) 3
゜Oag sodium pyrosulfite 1゜01
11 g distilled water, total amount 1.0 d Production method Buffer, active ingredient, and sodium chloride were boiled, cooled under a stream of carbon dioxide gas, and added sequentially to nine bottles. The solution is adjusted to the desired volume with boiling water and filtered to remove pyrogens.

Packaging: Under protective gas, filling brown ampoules for 11:20 minutes at 120°C. Preparation and filling of the ampoule solution must be done in a dark room.

Example 4 0.1 #B Ingredients in one tablet containing HT 920 n-aT920 100 μg lactose
66゜09 corn starch 12.49 gelatin
1.0 Dust Magnesium Stearate
0.59so, om9 Proceed in the same manner as in Production Method Example 1.

Center tablet weight: 501v W: 51m, 1 convex coated tablet fiiii: 100~ Example 5 0゜2QB-HT920 shoulder coated tablet 1 tablet Ingredients B -H'r 920 0.2 9 Dibuxin 0.25~Lactose
66.5519 Potato starch
25.09 Polyvinylpyrrolidone
2.0 11995.0IIv Manufacture An intimate mixture of the active ingredient, lactose and potato starch is granulated with an alcoholic solution of 10% polyvinylpyrrolidone through a 1.5EI sieve and dried at 40°C;
1.0 Pass through a parrot sieve. The resulting nine granules are mixed with magnesium stearate and compressed to form a core tablet.

Amount of 11 core tablets: 95 Dapunch: 7 m+, core tablets with convex surface t1 Coated with a coating agent consisting of sugar and Merck by a known method.

The generated original coated tablet is polished with beeswax.

Amount per coated tablet: 175# Example 6 Content in one gelatin capsule containing 300 μs of B-H'r 920 B-)I? 920 0.3 codeine daric acid 10.0 da1 [i
a' 3.0 IR 9 to 7 locosidenzone 86.7 da 100.0 ■ Production method Ingredients 'f: Mix intimately and fill into non-slip capsules of appropriate size.

Claims (4)

[Claims] (1) Administration of 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine or its acid addition salt in an amount effective to reduce or eliminate Parkinson's symptoms. A method for treating Parkinson's disease or Parkinson's syndrome, characterized by (2) 2-Amino-6-allyl-5,6 for the production of a drug for treating Parkinson's disease or Parkinson's syndrome
,7,8-tetrahydro-4H-thiazolo[4,5-d
] Use of azepine or its acid addition salts (3) 2-Amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine or its acid addition salt for the treatment of Parkinson's disease or Parkinson's syndrome (4) 2-amino-6-allyl-5,6 as an active ingredient
,7,8-tetrahydro-4H-thiazolo[4,5-d
]A drug for treating Parkinson's disease or Parkinson's syndrome, characterized by containing azepine or an acid addition salt thereof