JPH0574570B2 - - Google Patents

Description

[Detailed description of the invention] Belgian patents No. 684515 and No. ₇₇₁₃₃₀ contain, inter alia, the general formula an alkyl group which may be substituted with a halogen atom, a methyl group or a methoxy group; or an allyl group, where n is 2, but may be 1 if X is a sulfur atom; thiazolo and oxazolo derivatives, and their physiologically acceptable acid addition salts with inorganic or organic acids, are described. It is known from Belgian patents No. 684415 and No. 771330 that compounds of the general formula and their physiologically acceptable acid addition salts exhibit valuable pharmacological effects. That is, the compound described in Belgian Patent No. 684415 has inter alia analgesic, sedative, antitussive,
It has antipyretic and anti-inflammatory properties, and has Belgian patent no.
The compounds described in No. 771330 have hypotensive, sedative, antitussive, and/or antiinflammatory effects depending on their substituents. From the above-mentioned patent specifications, thiazolo derivatives in which R ₁ 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 have a particularly antihypertensive effect; In addition, in the general formula, R ₁ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms and optionally substituted with a hydroxy group, or an allyl group, and n
It has also been revealed that oxazolo derivatives in which 2 and X is an oxygen atom have particularly antitussive effects. It is also known from EP-A1-0 005 732 that compounds in which n is 2 in the above general formula have anti-angina activity. Furthermore, according to US Pat. No. 4,400,378, it has been shown that compounds of the general formula exhibit anti-endocytic activity. According to previously published literature, compound 2
-Amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride (B-HT920) is an agonist that selectively acts on presynaptic dopamine receptors. Also known as (for example, Anden)
et al., Acta Pharmacol. Toxicol., 52 , 51−
56 (1983); Journal of Neural Transmission, 59 ,
129-137 (1983)]. The present invention was completed based on the surprising discovery that B-HT920 also exerts an agonistic effect on denervated or degenerated postsynaptic dopaminergic tissues in the brain. This discovery is of particular importance as it indicates that this compound has application in the treatment of Parkinson's disease or parkinsonism. These patients have a disorder called degeneration of dopaminergic neurons in the brain. Therefore,
During nerve activity, the release of the chemical transmitter dopamine is insufficient, leading to the development of Parkinson's symptoms. Nilsson et al. (Nilsson and Carlsson) state that the most effective treatments for Parkinson's syndrome or Parkinson's disease are substances that exhibit agonistic effects specific to postsynaptic dopaminergic neurons [T.I.P.・TIPS Reviews, Elsvier Biomedical Press
Press), May 1982, pp. 322 et seq.]. Furthermore, Goodale et al.
210, 1141-1143 (1980), ``...in cases where dopamine release is reduced, such as in Parkinson's disease, compounds that primarily activate postsynaptic receptors are suitable. "It has said. A first aspect of the present invention provides an effective amount of 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine ( The present invention is a method for treating Parkinson's disease or Parkinson's syndrome, which comprises administering Compound A (hereinafter referred to as Compound A) or an acid addition salt thereof. 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. For the treatment of Parkinson's disease or syndrome, Compound A and its appropriate acid addition salts are
It is prepared in a conventional pharmaceutical dosage form for oral, parenteral, rectal or transdermal administration. A single oral dose for humans is usually 2.5 to
350 μg, preferably 100-250 μg, and for repeated administration (e.g. three times a day) the daily dose
~900 μg, preferably 30-750 μg. The dosage for parenteral and rectal administration is also approximately the same range as for oral administration. A study of the antiparkinsonian effect of B-HT920 is described in German patent application no. P35 03 963.9. The test was conducted using rats. The following test method was used. (A) Spontaneous locomotor activity in "pure" rats Two types of motor functions were recorded with the known "Opto-Varimex 3". a “Walking” movement during the first 5 minutes after subcutaneous injection of B-HT920; this motor function phase corresponds to the so-called “exploratory activity” of the rat in a new environment; b “Walking” movement; this is the movement that occurs after the test animal is placed in the recording cage.
Recordings began at 45 minutes (and 55 minutes after subcutaneous injection). Test Results Exploration Activities and Daily Activities B-HT920 was tested at doses of 0.02, 0.2, 2.0 and 4.0 mg/Kg (subcutaneous administration). As a comparative substance, apomorphine was tested at a dose of 0.1 mg/Kg (subcutaneous administration). The obtained values are shown in the following table: [Table] Therefore, the inhibitory effect of B-HT920 on exploration activity is almost the highest at a dose of 0.2 mg/Kg;
This is comparable to the corresponding effect of a dose of 0.1 mg/Kg of apomorphine, which is also the amount that reduces the number of contact interruptions to 150 per 5 minutes. Regarding daily activities, B-HT920 does not lead to an increase in the number of daily activities at any of the doses tested. Contrary to B-HT920, apomorphine 4.0mg/
Kg administration increases the number of daily activities to the 650 level. (B) Ibotenic acid in rats
Ipsilateral rotation of the model Tested similarly to the corresponding kainic acid model by Schwarcz et al. [Brain Res.
(1979), pp. 485-495]. This model shows that unilateral intrastriatal (stereotaxic) injection of the neurotoxin ibotenic acid destroys striatal cells and their postsynaptic dopamine (DA) receptors [Experiment Brain Research by Schwartz et al. .Brain Res.) 37 (1979), pp. 199-216], thereby allowing postsynaptic DA agonists to act only on the corresponding DA receptors on the healthy side, and thus in the damaged striatum. A rotational movement of the animal towards the side occurs. Test Results B-HT920 was tested at doses of 0.2, 0.5, 10 and 2.0 mg/Kg (subcutaneous administration). As a comparison substance,
Apomorphine dose of 0.1mg/Kg (subcutaneous administration)
Tested with. The obtained values are shown in the table below: [Table] Comparing apomorphine and B-HT920,
It is found that B-HT920 has only about ⅛ of the postsynaptic DAergic activity of apomorphine on normally sensitive DA receptors, ie only weak activity in this respect. (C) Contralateral rotation in the 6-OHDA model Tested by Ungestadt's method
physiol scand.suppl.) 367 (1971) p. 69 onwards;
European Journal of Pharmacology, 98 (1984) 165~
176 pages]. In this model, stereotaxic unilateral injection of the neurotoxin 6-OHDA disrupts the nigrostriatal DA pathway on one side, thereby allowing postsynaptic DA receptors in the ipsilateral striatum to direct their DA innervation. It is based on the fact that the human body is deprived of its natural state, that is, becomes denervated, and therefore has hypersensitivity (denervation). In this model, DA-agonists with postsynaptic activity produce contralateral rotation even at very low doses due to their dominant activity on hypersensitive DA receptors. Test results B-HT920 is 0.02, 0.05, 0.5 and 1.0mg/Kg
tested at a dosage of As a comparative substance, apomorphine was tested at a dose of 0.05 mg/Kg (subcutaneous administration). The obtained values are shown in the following table: [Table] Compared with B-HT920, apomorphine 0.05mg/
Kg produced 557 contralateral rotations per active hour. Therefore, compared to its weak activity against normal DA receptors, B-HT920 has exceptionally strong activity against denervated receptors. About a year and a half ago, the neurotoxin 1-methyl-4-
Discovery of phenyl-1,2,3,6-tetrahydropyridine (MPTP) [Langston]
et al.: Science, 219 , 297 (1983)]
has provided a new animal model for Parkinson's disease. MPTP is clinically, pathologically, biochemically and pharmacologically similar to Parkinson's disease in humans and monkeys. It causes the development of irreversible neurological disease [Markey et al., Nature, 311 , 464 (1984)]. The striking agreement between the two is due to the fact that MPTP also destroys a group of dopaminergic neurons in the substantia nigra of the brain that are damaged during the naturally occurring degenerative process of Parkinson's disease. The cause of iatrogenic Parkinson's disease is thought to be due to MPTP or similar compounds generated in the body [Snyder, Nature,
311, 514 (1984)]. The reason why MPTP Parkinson's symptoms have so far been observed only in monkeys other than humans is probably due to the involvement of specific metabolites of MPTP. The MPTP animal model using the Lusus monkey is particularly suitable for demonstrating the effects of antiparkinsonian drugs. When MPTP (1 x 0.15 mg/Kg intramuscularly administered daily for 3 days, followed by 0.30-0.40 mg/Kg daily for 3 days at 3-day intervals) was applied to 7 Lusus monkeys, they exhibited the following symptoms: Ta. 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 strong painful stimuli. When B-HT920 (50-100 μg/Kg) was injected intramuscularly, spontaneous movements were observed for the first time after 5-10 minutes, and the movements gradually returned to normal within 10-30 minutes. Food intake began and behavior returned to normal in the cage, including agility and species-specific behavior. Most of the other symptoms disappeared, but mild resting tremors and muscle weakness remained. No sedation was observed. Compared to before B-HT920 administration,
His complexion seemed to have improved. The effect of B-HT920 lasted for approximately 3 hours, and the animal again began exhibiting the above-mentioned parkinsonian symptoms. When B-TH920 was newly administered, the above clinical pathological conditions improved or disappeared. This beneficial effect of B-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 advantages over conventional DA agonists because this substance acts only on postsynaptic DA receptors in denervated states of the brain, making it an effective drug for B-HT920 in Parkinson's disease patients. Physical (motor) effects are primarily limited to the brain's DA system, which is damaged by the disease. In other words, Compound A and its acid addition salts have a particularly strong effect on severe parkinsonism (on severe denervation of striatal DA receptors). Moreover, Compound A and its physiologically acceptable acid addition salts are well tolerated, eg, the LD ₅₀ for oral administration in mice is 455 mg/Kg. Example 1 Core tablet composition Content in one tablet B-HT920 50 μg Lactose 38.45 mg Corn starch 10.0 mg Gelatin 1.0 mg Magnesium stearate 0.5 mg 50.0 mg Manufacturing method Add a 10% aqueous gelatin solution to a mixture of the active ingredient, lactose, and corn starch. granulate through a 1 mm sieve, dry at 40°C, and pass through the same sieve again. The granules thus obtained are mixed with magnesium stearate and compressed to form a core tablet. Manufacturing must be carried out in a darkroom. Core tablet weight: 50 mg Shape: 5 mm convex The core tablet thus obtained is coated by a known method with a coating agent consisting essentially of sugar and talc. The resulting coated tablets are polished with beeswax. Weight of coated tablet: 100mg Example 2 Suppository Content in 1 tablet B-HT920 100.0μg Suppository base 1690.0mg (e.g. Witepsol W 45) Manufacturing method Suppository made by melting the finely powdered active ingredient and cooling it to 40℃ Add to the base while stirring with an immersion homogenizer. Pour the mixture into slightly cooled molds at 35°C. Example 3 Ampoule containing 200 μg of B-HT920 Content in 1 ampoule B-HT920 200 μg Citric acid 7.0 mg Dibasic sodium phosphate (2H ₂ O) 3.0 mg Sodium pyrosulfite 1.0 mg Distilled water Total volume 1.0 ml Manufacturing method Buffer, The active ingredient and sodium pyrosulfite are added sequentially to boiled water and cooled under a stream of carbon dioxide. Adjust this solution to the specified volume with boiled water,
Filter to remove pyrogens. Packaging: Filled in brown ampoules under protective gas Sterilization: 20 minutes at 120°C The preparation and filling of ampoule solutions must be carried out in the dark. Example 4 Coated tablet containing 0.1mg B-HT920 Ingredients in 1 tablet B-HT920 100μg Lactose 36.0mg Corn starch 12.4mg Gelatin 1.0mg Magnesium stearate 0.5mg 50.0mg Manufacturing method Proceed as in Example 1. Core tablet weight: 50 mg Shape: 5 mm, convex Coated tablet weight: 100 mg Example 5 Coated tablet containing 0.2 mg B-HT920 Ingredients in one tablet B-HT920 0.2 mg Digoxin 0.25 mg Lactose 66.55 mg Potato starch 25.0 mg Polyvinylpyrrolidone 2.0 mg Stearin Magnesium chloride 1.0 mg 95.0 mg Manufacturing method An intimate mixture of the active ingredient, lactose and potato starch is granulated using an alcoholic solution of 10% polyvinylpyrrolidone through a 1.5 mm sieve and
Dry at °C and pass through a 1.0 mm sieve. The resulting granules are mixed with magnesium stearate and compressed to form core tablets. Weight of 1 core tablet: 95 mg Punch: 7 mm, convex The produced core tablet is coated with a coating agent consisting of sugar and talc by a known method.
Polish the resulting coated tablet with beeswax. Weight of 1 coated tablet: 175 mg Example 6 Gelatin capsule containing 300 μg of B-HT920 Content in 1 capsule B-HT920 0.3 mg Codeine phosphate 10.0 mg Tartaric acid 3.0 mg Corn starch 86.7 mg 100.0 mg Manufacturing method Mix each ingredient intimately and fill into opaque capsules of appropriate size. Weight in 1 capsule: 100mg

Claims (1)

[Claims] 1. 2-Amino-6-allyl- as an active ingredient
A pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome, comprising 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine or an acid addition salt thereof.