JPS5948480A - Ergot alkaloid - 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] This invention relates to ergot alkaloids.

This invention provides 2-methyl-8-lysergylether and thioether, as well as acid addition salts thereof, hereinafter referred to as compounds of this invention.

The compounds of this invention are substituted at positions 2 and 8 of the ergoline nucleus, and may be substituted at other positions. These compounds can exist as isomeric forms, such as the 8 and 8S isomers.

This invention is particularly applicable to formula (1) [wherein, X is -0- or =5-11 (□ is hydrogen, (C
1-4) Alkyl, Ma or Feninope R2 is < C1-
3) Alkyl, R3 is unsubstituted or halogen with atomic number 9 to 35, (C1-4)alkyl or (C1-
4) phenyl or pyridyl mono- or independently di- or tri-substituted with alkoxy, or (C1-4
) means alkyl] and acid addition salts thereof.

The compound of this invention can be obtained by a method including the step of substituting the group Y of the corresponding 8-CII, Y (Y represents a leaving group) derivative with an ether or thioether group and recovering the compound as it is or as an acid addition salt. It can be manufactured by

In particular, a compound of formula (1) or an acid addition salt thereof is a compound of formula (I
I) (wherein k□ and ni2 have the above-mentioned meanings, Y means a leaving group)
I) (wherein R3 and X have the same meanings as above) and can be produced by a method including the step of recovering the compound of formula CI) as it is or as an acid addition salt.

The above method can be carried out in a conventional manner. Y
For example, a salt, a halogen such as bromine, or a compound of the formula -
It is preferred that Y is mesyloxy or tosyloxy.

The reaction is suitably carried out in a solvent such as an organic carboxylic acid amide such as dimethylformamide, hexamethylphosphoric acid triamide, or an inert aprotic polar solvent such as acetonitrile.

Preferred reaction temperatures are heating temperatures, such as about 50 to about 100°C.

The reaction is preferably carried out in an atmosphere of an inert gas, such as nitrogen.

The group of formula (][) is introduced using a compound of formula (1v) MXR3(IV) (wherein X and R3 have the meanings given above and M means hydrogen or preferably an alkali metal) is preferable.

It is preferred to use an excess of the compound of formula (III). For example, 2 to 10 per mole of the compound of formula (1)
Compounds of molar formula (■[) can be used.

The side chain at position 8 in the compound of formula (I) can be in the α or β configuration. Preferably, the alkyl and alkoxy groups have 2, especially 1, carbon atoms. As the halogen, chlorine and bromine are preferred. As for X-
S- is preferred.

Hydrogen is preferred as kl. Unsubstituted pyridyl, particularly 2-pyridyl, is preferred as k3.

One group of compounds is that X is -5-1R or hydrogen, and k3 is 2
- of pyridyl.

The compounds of this invention can be isolated and purified by conventional methods.

The compounds of this invention can be converted into acid addition salts and vice versa by conventional methods. Suitable acids for forming salts include hydrochloric acid.

The starting materials can be manufactured by conventional methods.

It is produced by reducing the compound shown in The compound of formula (V) can be added to the compound of formula (VI) by adding 1.3
-Produced by anti-LLI of dithiane.

Alternatively, compounds of formula (II) can be prepared from the known lysergic acid or its 6-homogeneous by reducing it to the alcohol and replacing the hydroxy with a group Y.

For individual starting materials whose production methods are not specifically described, the compounds are known or can be produced by conventional methods.

In the following examples, all temperatures are given in degrees Celsius and are uncorrected. Optical rotation is 20℃ unless otherwise specified.
, the substance was dissolved in ethanol/water=1=1 and measured by D line.

As an abbreviation, 1 = optical rotation in pyridine 2 = decomposition 3- Hydrochloride shows.

In nomenclature, lysergil means 9.10-didehydro-6-methylergolin-8β-ylmethyl.

Example 1 9.10-didehydro-2,6-cymethyl-8β-(2
-pyridylthiomethyl)ergoline a) 2-(1,3-dithian-2-yl)lycerkyl mesylate 2.9 ml of sulfuryl chloride and 1.5 m of chloroporm/
' solution was added dropwise to a solution of 4.2 g of 1,3-dithiane and 100 ml of chloroporm at -30°C within 30 minutes.

The temperature is raised to 20°C and the mixture is stirred at 20°C for 3°. A solution of 7.5 fl lysergyl mesylate and 100% chloroform is added at -10"C.

The temperature was increased to 20°C and the mixture was further heated at 20°C for 30 minutes.
Stir for a minute. The mixture is treated with ice water, neutralized with 2N sodium carbonate, and extracted with methylene chloride containing 10% Impropatol. Dry the extracted Bi solution with sodium sulfate, filter and concentrate. The resulting product is chromatographed on silica gel and eluted with methylene chloride containing 2% methanol to give the title compound.

1)) 2~Methyllyselkyl mesylate - Wash 100 ml of a solution of nickel suspended in water four times with each iomg of dimethylformamide/acetonate (1/4). The washed Raney nickel was treated with dimethylformamide/acetone (1/4) 115me in argon, which was stirred and treated with 2-(1,3-dithiane-2-
4.3 g of lysergyl mesylate and 80 ml of dimethylformamide/acetone (1/4). The mixture was stirred for 2 1/2 hours at room temperature, filtered,
Dimethylformamide/acetone (1/2)
Wash twice with 115 m6 each. Concentration of the p-liquid and drying under high vacuum gives the crude product, which is chromatographed on 90 g of silica gel and eluted with methylene chloride containing 2% methanol to give the title compound as a beige foam.

C) 9.10-didehydro-2,6-cymethyl-8β-
A solution of 1.3 g of (2-pyridylthiomethyl)ergoline 2-methyllysergyl sylate, 2-mercaptopyridine and 20 rne of dimethylformamide is treated with 4.5 me of 2N sodium hydroxide and stirred at room temperature. The mixture is stirred with water and extracted with methylene chloride containing 10% Impropatol. Dry the extract over sodium sulfate, filter, concentrate and dry under high vacuum. The crude product was subjected to chromatography with 120 g of silica gel,
Elution with 2% methanol and chloroform containing 0.1% concentrated ammonia gives the title compound. mp (decomposition)
From 253°C, [α') −1−58° (c=.

37).

The following compounds having 8β-side chains in formula CI) are prepared analogously.

Similarly, compounds of formula (I) where x=o, R1-tertiary butyl, k2-isopropyl, (3=the following group) can be produced.

a).

c) Br Br The compound of this invention has pharmacological activity and is useful as a medicine.

The compounds of this invention exhibit antagonistic effects on dopamine receptors in standard animal experiments using, for example, rat brains. That is, the above compound is approximately] OII9 /
When administered via kq, dopamine metapolide, 3,4-dihydroxyphenylacetic acid () OPA in the striatum
C) and the concentration of homovanillic acid (1-IVA) increases.

Biochemical parameters are described in Caroum et al., European Journal of Pharmacology, Vol. 44, No. 311-
318 (1977) and Bürki et al., Psychotourmacology, Vol. 57, pp. 227-237 (19>78
It can be measured according to the method of

At the same dose, Carlson et al.
According to the method of Vol. 5, pp. 163-168, the activity of tyrosine hydroxylase in vivo is increased.

The above compounds are further described by Markstein, Journal.
Antagonizes the effects of apomorphine on electrically stimulated acetylcholine release in off-neural transmission.

The above compounds are therefore useful as neuroleptics, particularly in the treatment of schizophrenia.

The compounds of this invention also exhibit serotonin antagonist activity according to standard animal studies.

For example, the compound is about 3 x 10 mol/l;
Electrical stimulation increases acetylcholine release in the rat hippocampus.

According to the method of Picolet et al., Pharmacology, Vol. 16, Supplement 1.1, pp. 156-173 (1978), about 30 to about 50 #1 g/kq are administered intraperitoneally to rats, or about 3 g/kq to mice. This was confirmed by the fact that the compound induced a prolongation of the wakefulness phase and an increased response to external stimuli when administered orally at doses ranging from about 1 omyi to about 1 kq body weight and observed over a period of 6 hours.

Once upon a time, the above compounds can be used against dementia, especially senile dementia.

The compounds of this invention also exhibit antidepressant activity according to proprietary animal studies. For example, according to the method of Talaine Rogel et al., Walking and Sleeping, 1980, Vol. 4, pp. 77-85, rat clonal transplantation 4
In an 8-hour test, the compound contained about 3 to about 30
Oral administration of m9/kQ resulted in a decrease in reversal sleep and a marked rebound.

Therefore, the compound is also used as an antidepressant, especially in the elderly.

In addition, the compound No. 1 may be prepared by the method of Müller-Schweinisoer, Tyrosine Schmiedebergs Alhif Pharmacolologi, Vol. 292, pp. 113-118 (1976), about 10-10 to 108 M/IJ.
At a dose of 1,000,000, it exhibits in vitro noradrenaline synergistic effects on canine external carotid artery resection IJ tubercle, and has a vasoconstrictor effect.

Therefore, the "-compounds are useful as anti-migraine agents, particularly in the treatment of tension headaches.

Furthermore, the above compound was tested using rat brain for carbon-14-
In 2-thioxycurcose autoradiography, from about 0.01 to about Q, l Irfj /kQ
Intravenous or intravenous administration of 10 THfl/kQ increases local cerebral glucose consumption in the sensorimotor cortex, such as the lateral nucleus deca. [For methods, see Zorokotsu, Journal of Cerebral Flood Flow and Metaporism, 1981 (1) 弗 7-3
6, → Nohaki et al., Frein Research, 1982, Vol. 233, pp. 347-358, and McCulloch et al., Twilight Off Serifural Flood Flow and Metaphorism, 1981, J1 No. 133-
See page 136].

As such, the compounds of this invention are further useful in the treatment of cerebral dysfunction.

In all of the above applications, the dosage will, of course, vary depending on the compound used, the method of administration and the treatment intended. Generally, however, satisfactory results are obtained when a daily dose of about 0.01 R9 to about 50 kg/kg of animal body weight is administered, preferably in divided doses of 2 to 4 times per day or as a sustained release formulation. In large animals, the total daily dose is from about 1 to about 100, and dosage forms suitable for oral administration include about 0.3 to about 509 of the compound mixed with a solid or liquid pharmaceutical carrier or diluent. It is something.

The compounds of this invention can be used similarly to standard compounds used for the same indications, such as co-dirgoculin in senile dementia. The exact dosage will, of course, vary depending on a variety of factors, such as the activity of the compound in pharmacological studies. For example, the preferred compound, the compound of Example 1, was 10 times more active than co-dergocline in the hippocampal acetylcholine release test described above.

Therefore, the compound of Example 1 is effective in the treatment of senile dementia at doses equivalent to or lower than the standard co-dergoculin, such as oral administration at 2 to 3° my 7 days.

This invention also provides pharmaceutically acceptable forms of the compounds of this invention for use as antidepressants, neuroleptics, and in the treatment of dementia, cerebral dysfunction, or migraine.

A preferred indication is senile dementia. A preferred compound is the compound of Example 1.

The compounds of this invention can be administered neat or as their pharmaceutically acceptable acid addition salts. Such acid addition salts exhibit activity on the same order of magnitude as the free base.

Accordingly, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable form of a compound of this invention and a pharmaceutical carrier or diluent. Such compositions are formulated in conventional manner, eg, as tablets or solutions.

The first compound group is ■ (□ is H).

The second group of compounds are those in which Ri is alkyl.

A third group of compounds are those in which R1 is phenyl.

A fourth group of compounds are those in which R3 is alkyl.

A fifth group of compounds are those in which R3 is optionally substituted phenyl.

A sixth group of compounds is those in which R3 is optionally substituted pyridyl.

The seventh group of compounds is X or -0-.

In the eighth group of compounds, X is -S-.

Patent applicant: Sand Akchengesellschaft, patent attorney Aoyama Aoyama, and 1 other person

Claims (1)

[Scope of Claims] (1) 2-methyl-8-lysergyl ether or thioether, or an acid addition salt thereof. (,2) Formula (I) [wherein, X is -0- or -5-1R1 is hydrogen, (C]
-4) Alkyl or phenyl, k2 is (C1-3)
alkyl, k3 is unsubstituted, or atomic number 9 to 35
halogen, (C1-4)alkyl or (C1-4)
phenyl or pyridyl mono- or independently di- or mono-substituted with alkoxy, or (C1-4)
means alkyl] or its acid addition salt. (3) A compound represented by the formula (Jl) (wherein k□ and 1 (2, meaning as defined in claim 2, Y means a leaving group). (4) X or sulfur A compound or an acid addition salt thereof according to claim 2. (5) A compound or an acid addition salt thereof according to claim 4, wherein R is hydrogen, k3 or 2-pyridyl. (6 ) k3 is unsubstituted or substituted with (C1-4) alkyl, phenyl, pyridyl, or (C1-4) alkyl, and the side chain at position 8 has a beta configuration; Compound or acid addition salt thereof. (7) 9.10-didehydro-2,6-simethyl-8β
-(2-pyridylthiomethyl)ergoline mata is an acid addition salt thereof. (8) A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical carrier or diluent. (9) comprising administering to an animal in need of treatment a therapeutically effective amount of the compound according to claim 1;
A method for treating schizophrenia, cerebral dysfunction, migraine, dementia or inducing a vasoconstrictive effect.