JPH0346471B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to ergot alkaloid derivatives. US Pat. No. 4,348,391 and Japanese Patent Publication No. 52-78900 describe a wide range of (8α)-ergolin-8-yl sulfamides as anti-Parkinsonian agents, antidepressants, and prolactin secretion inhibitors. All of the exemplified compounds are allyl at the 1st position.
allyl) group or methyl group (US patent) or methyl group (published publication). This inventor believes that the compound of the following formula (), which is neither specifically disclosed nor suggested in the above patent, has surprising pharmacological effects, especially as an anti-Parkinsonian agent, as shown by the test results described below, especially when administered orally. It was found to have significant long-term effects and to be well tolerated. This invention provides compounds of formula (). (wherein R means ethyl or isopropyl) The above compound may be either in the form of a free base or in the form of an acid addition salt. The free base form or acid addition salt form of the compound of formula () above is the compound of formula () and recovering the resulting compound in free base form or in acid addition salt form. The above process is carried out according to conventional methods for alkylation of indole nitrogens in analogous compounds. For example, a compound represented by the formula () R-X () (wherein X means an acid residue of a reactive ester, e.g. a halogen such as iodine or an organic sulfonic acid residue) is used as an alkylating agent. be able to. This reaction is carried out in a solvent such as liquid ammonia.
from about -40°C to the boiling point, optionally a base;
For example, it is carried out in the presence of sodium butoxide or iron trichloride. The resulting compound of formula () is isolated and purified by conventional methods. The free base form of the compound of formula () can be transformed into the acid addition salt form and vice versa by conventional methods. Compounds of formula () are known. Examples are shown below. Example 1 N,N-diethyl-N'-[(8α)-1-ethyl-6
-Production of methylergolin-8-yl]sulfamide. A mixture of 35 mg (0.22 mmol) of iron trichloride, 7.52 ml (80 mmol) of tertiary butyl alcohol, and 40 ml of ammonia was cooled and stirred with dry ice, 1.61 g (70 mmol) of sodium metal was added little by little, and then N,N -diethyl-N′-[(8α)-6-
Methylergolin-8-yl]sulfamide 7.53
g (20 mmol). Ethyl iodide 1.938
ml (24 mm) are added dropwise to the reaction mixture under reflux over a period of 4 hours. The reaction mixture is further stirred under reflux for 3 hours. The ammonia is evaporated under stirring overnight. The reaction mixture is brought to room temperature and partitioned between 2M aqueous ammonia sulfate and methylene chloride. The organic layer is washed, dried over sodium sulfate and applied to a chromatography column (170 g of silica gel) using toluene/methanol (98/2). The title compound crystallizes, eluting with toluene/hexane (50/50). mp101−102℃, [α] ²⁰ _D = −64.6° (C=
(1.018%, chloroform) The following compound was produced in the same manner as in Example 1. Example 2 N,N-diethyl-N'-[(8α)-1-isopropyl-6-methylergolin-8-yl]sulfamide. mp 108-110°C, [α] ²⁰ _D = -63.5° (1.038%, chloroform) The free form or pharmaceutically acceptable acid addition salt form of the compound of formula () has pharmacological effects and can therefore be used for e.g. It is useful as a medicine. More particularly, standard tests have shown that the compounds are useful as central dopamine receptor agents, for example, for the treatment of Parkinson's disease. For example, by injecting 6-hydroxydopamine into the substantia nigra, the nigro-neostratal
In rats with unilateral lesions of the dopamine pathway, the above compounds
69-93 (1971) and substantially the same method as that of Bigre et al., Pharmacology Volume 16 (Supplement 1).
156-193 (1978), doses of about 3 to about 30 mg/Kg (oral) induced turning of the nondenerved side over an extended period of time (eg, several hours). Therefore, the above compounds are useful as anti-Parkinson's agents. The compound of Example 1 has anti-parkinsonian activity as a preferred manifestation, particularly a potent anti-parkinsonian activity compared to the experimental prolactin secretion activity. The activity of the above compound will be explained in more detail as follows. 1. Rubbing behavior in rats with unilateral lesions of the substantia nigra. 6-hydroxydopamine (6-
(OHDA) injection results in degeneration of unilateral nigrostriatal processes and subsequent hypersensitivity of ipsilateral postsynaptic striatal dopamine (DA) receptors. Direct-acting DA receptor agonists, such as apomorphine, induce contralateral circling behavior, whereas indirect-acting drugs, such as amphetamine,
Inducing ipsilateral turning behavior [Ungerstedt and Arbutnott, "Brain Research"]
Brain Res.), 24, 485 (1970)]. Male OFA rats (140-160 g) were anesthetized with pentobarbitone (Nembutal) and placed in a David-Kopler stereotaxic apparatus. A cannula with an outer diameter of 0.3 mm was then introduced at a subdural depth of 7.5 mm, +4.2 mm anterior and 1 mm lateral to bregma. Then 6-OHDA solution (2 mg/ml 6-OHDA in 0.9% NaCl containing 0.2 mg/ml ascorbic acid)
4μ was injected. This injection was performed over a period of 10 minutes with the aid of a Hamilton syringe. Two weeks later, the rats were examined for nigrostriatal degeneration by subcutaneous administration of 0.25 mg/Kg apomorphine. To facilitate comparisons between different compounds and different animal groups, the total number of circling movements was corrected by a factor derived from the response to a standard dose of 0.25 mg/Kg (s.c.) apomorphine. Animals were not used more than twice a week. With the help of an automatic turn meter, the number of turns was recorded for 7 hours. Representative results are shown in Table 1 below.

[Table] As is clear from Table 1, there is a significant latency of 30 and 60 minutes for onset of action after intraperitoneal and oral administration, respectively. Also, maximum strength is reached much later (2.5 and 1.5 hours after intraperitoneal and oral administration, respectively). This shows that the compound has a long duration in this test. 2 Stereotypy test. Stereotypy testing is based on the evaluation of side effects commonly observed with centrally active dopaminergic compounds. Male OFA rats (180-250 g) were placed in a 230 cm diameter Perspex cylinder. After 30 minutes to acclimatize to the cage, animals were given the above compounds.
A subcutaneous injection of 30 mg/Kg (intraperitoneal) was performed, and observations were made at 30 minute intervals for 2 hours and then at 60 minute intervals for a total of 7 hours.
Six rats were studied at each dose level. Kostor et al., "Eur. J. Pharmacol." (1972) 18,
The degree of stereotypic behavior was assessed using a scoring system based on the description by 83. The scores and criteria were as follows. 1: Intermittent sniffing of the nose with moderate intensity; 2: Continuous sniffing, occasional licking; 3: Significant licking, occasional to light biting; 4: Vigorous and persistent chewing. The occurrence of stereotypic behavior can be achieved by activating central dopamine receptors as a whole (and not just in the striatum, as in the case of the circling behavior test described in Section 1), either directly or by increasing dopamine activity. It is believed that it depends on the ability of the test compound to be tested. This stereotypic behavior is caused by tongue-
Involved in the pathophysiology of facial-buccal dyskinesia. These are abnormal, involuntary, and persistent effects on the tongue, lips, and facial muscles. This syndrome is found in humans as a side effect of long-term L-dopa therapy for Parkinson's disease. Thus, a high score in this test indicates a high tendency to induce the dyskinesia and confirms the efficacy of compounds with established central dopaminergic activity (eg, in the Ungershutt test). A low score confirms inactivity at central dopaminergic receptors or, in the case of compounds with established central dopaminergic activity, suggests that the compound is less likely to induce unwanted side effects, e.g. dyskinesias. This indicates that the The last profile mentioned is an ideal profile. The results obtained are shown in Table 2 below. Table 2 Compound Dose (mg/Kg) Score Example 1 30 (intraperitoneal) 2.5 Same as above 30 (oral) 1.3 As is clear from Table 2, the compounds of the present invention rarely induce dyskinesia. . 3 MPTP-treated squirrel monkeys. MPTP (1-methyl-4-phenyl-1,2,
3,6-tetrahydropyridine) induces parkinsonism in primates. This was first observed in humans [Davis et al., “Psychiatry Research” Psychiatr. Res.) 1:249
−254 (1979)]. When MPTP is administered to squirrel monkeys,
It induces bradykinesia and rigidity, two of the three characteristic symptoms of Birkinson's disease (the third
The characteristic hallmark of tremors, tremors, is also observed in MPTP-treated monkeys, but this cannot be said for Parkinson's in humans, as the tremors observed in monkeys are not parkinsonian-type resting tremors). Substances that are effective in this model are also effective in Parkinson's disease patients. MPTP (0.3-2 mg/Kg i.p.) was administered to male or female squirrel monkeys weighing approximately 1 Kg for 7 days until bradykinesia, rigidity, postural abnormalities, and impaired dynamic behavior were observed.
I gave it every day. These conditions remained stable for approximately 3-4 weeks, after which the animals usually recovered slowly. The test drug was administered orally. By comparing with placebo-treated animals using the modified disability rating scale first proposed by Webster (1968),
Drug effects were evaluated. 0 = absent, 1 = mild;
The degree of stiffness was evaluated separately for the trunk and extremities using a 4-point rating scale: 2 = mild to moderate, 3 = moderate and 4 = severe. Same as above 4
By using a point rating scale, the degree of bradykinesia was evaluated separately for postural abnormalities, body position control, gait, and movement control. Multiplying the score for bradykinesia by 4 took into account that this symptom was the most severe. Maximum possible scores were rigidity = 20 and bradykinesia = 64. The results are shown in Table 3 below.

Table 3 As evident from Table 3, the compound reduces the intensity of parkinsonism induced by MPTP administration in squirrel monkeys in a dose-dependent manner.
The beneficial effects of the compounds on bradykinesia, the most debilitating symptom, are unexpected and significant. The doses administered do not induce vomiting or significant hypotensive effects. Note that the above compounds also have other activities.
Conventional tests include inhibition of reserpine-induced akinesia in rats by doses of about 0.5 to about 10 mg/Kg (s.c.) of the compound, and inhibition of tetrabenzine-induced akinesia in rats by about 10 mg/Kg (s.c.) of the compound.
It showed antidepressant activity when inhibited by doses ranging from 30 to 30 mg/Kg (oral). This test was based on Bigle et al., Pharmacology, Vol. 16 (Supplement 1), pp. 156-193 (1978). Therefore, the above compounds are further useful as antidepressants. Furthermore, the above compounds have been tested in standard tests such as Friyutskiger et al., Experiencia, Vol.
(1978) showed inhibition of prolactin secretion. For example, the above compound is effective in female rats at approximately
Application of 0.03 to about 3 mg/Kg (subcutaneously) inhibits implantation (of fertilized eggs), and in male rats approximately
Administration of 0.001 to about 0.5 mg/Kg inhibited prolactin secretion. (By the method of Friyukiger et al., Postgraduate Medical Journal, Vol. 52 (Supplement 1), p. 57 (1976)) This effect lasted for an unexpectedly long time (eg, several hours). Therefore, the above compound is useful as a prolactin secretion inhibitor, for example, for diseases accompanied by hyperprolactinism. The compound of Example 2 is preferred for this use. In all of the above applications, the dosage will, of course, vary depending on the compound used, the mode of administration and the treatment desired.
However, in general, daily doses range from about 0.001mg to about 30mg.
Satisfactory results are obtained when mg/Kg of animal body weight is administered at appropriate times, preferably from 1 to 4 times a day, or as a sustained release formulation. In large animals, the total daily dose ranges from about 0.5 to about 100 mg, with dosage forms suitable for oral administration containing about 0.1 mg to about 50 mg of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent. included. The above compound was found to be well tolerated by pharmacological tests. For example, in a cat injection test, approximately 37mcg/Kg
(intravenous injection), the blood pressure drop and heart rate drop were lower than expected, indicating that the compound was well tolerated from a cardiovascular point of view. Furthermore, the above compound can be used in beagle dogs.
A dose of 0.3 mg/Kg/day (oral) showed satisfactory tolerability, and the compound of Example 1 showed almost no emetic effect. Furthermore, the above compound exhibited sustained activity in the above anti-Parkinsonian, anti-depressant and prolactin secretion inhibiting oral administration tests, and showed a reduction in initial side effects such as vomiting. In acute toxicity studies, non-toxic levels are 5-17 mg/Kg/day in rats and 0.3-1.0 mg/Kg/day in dogs. A preferred compound is that of Example 1 and a preferred use is as an anti-Parkinsonian agent. Compounds of formula () can be administered in a similar manner to known standard drugs in the same use, such as bromocriptine. The appropriate daily dose of a particular compound to be administered will depend on a number of factors, particularly activity. For example, the compound of Example 1, which is a preferred compound, has the following activity according to experiments.

Table 1 Compounds of formula () can therefore be administered at doses on the same order of magnitude as bromocriptine. Of course, to determine the appropriate therapeutic dose for an individual patient, the lowest dose, eg 0.5, should be tried first and the dose increased until the desired effect is achieved. Typical oral doses are 20 mg or less, and as an anti-Parkinsonian agent, up to 75 mg due to the well-tolerated nature of this compound. The above compounds can be administered in the form of pharmaceutically acceptable acid addition salts. Such salts exhibit activity on the same order of magnitude as the free base. Therefore,
This invention provides compositions comprising a free base or pharmaceutically acceptable salt form of a compound of formula () in association with a pharmaceutical carrier or diluent. Such compositions are formulated in conventional manner, eg, as solutions or tablets.

Claims (1)

[Claims] 1 Formula () (wherein R means ethyl or isopropyl) A free base form or a pharmaceutically acceptable acid addition salt form of a compound represented by the formula: 2 formula () (wherein R means ethyl or isopropyl) A drug for treating Parkinson's disease, which contains as an active ingredient a free base form or a pharmaceutically acceptable acid addition salt form of a compound represented by the following.