JPH0352473B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to ergot alkaloids, and more particularly to novel ergot peptide alkaloids with pharmacological activity. The present invention is exemplified below as compounds of the present invention.
5'S-(2R-butyl) peptide alkaloids and acid addition salts thereof can be provided. The ergot 5'S-(2R-butyl) compound of the present invention is a hitherto completely unknown ergot peptide alkaloid epimer, and ergot peptide alkaloids can be produced by chemical synthesis or, in some cases, naturally produced. or by fermentation methods, for example. These may be substituted and also in isomeric forms, such as 8R or 8S.
Can exist as isomers. The chemistry of ergot peptide alkaloids has recently
“Ersot alkaloids” edited by B. Berde and HOShild
and related compounds” (based in Berlin,
Published by Springer Verlag (1978), chapter 29-85 (written by J. Rutschman and P. Stadler). Known 5'S-(2-butyl) derivatives, such as β
-Ergocryptine has an S configuration in its sec-butyl side chain [B.Berde and HO, supra.
Schild's publication page 37 and Dictionary of
Organic Compounds, 5th Edition, Volume 3 (New York, Chapman and Hall (1982)), p. 2468]. A 2-butyl carbon atom with S configuration is
Under the Chemical Abstracts nomenclature used in the Eighth Collective Index, it is known as the 13' carbon atom. The present invention [In the formula, R ₁ represents methyl, ethyl or isopropyl. ] Compounds represented by the following and acid addition salts thereof can be provided. The compound of the present invention [] has the formula: [In the formula, R ₁ has the same meaning as above. ] A compound represented by or an acid addition salt thereof or a precursor thereof, and a compound represented by the formula: It can be produced by a method including a step of condensing the compound represented by the above, a reactive derivative thereof, or a precursor thereof, and a step of recovering the produced compound [] or an acid addition salt thereof. The condensation process of the invention can be carried out by conventional methods for the production of similar ergot peptide alkaloids. The acid addition salt of the aminocyclo compound is, for example, its hydrochloride. Corresponding reactive acid derivatives of lysergic acid derivatives are, for example, acid chlorides or mixed anhydrides with sulfuric acid or trifluoroacetic acid. This derivative also gives the corresponding lysergic acid (i)
dimethylformamide or acetamide and
(ii) It may be an addition product prepared by addition of thionyl chloride, phosgene or oxalyl chloride. The reaction is preferably carried out in the presence of triethylamine or pyridine. Suitable solvents are, for example, chloroform, methylene chloride, dimethylformamide or acetonitrile. The reaction temperature may be, for example, about -30 to +20°C. As a precursor of lysergic acid derivatives or aminocycloles as described above, these compounds can be converted, for example, in conventional manner and, following a condensation reaction, the product can be converted into a compound of the invention or an acid addition salt thereof. Compounds that can be used can be used. Thus, the lysergic acid derivative and/or the aminocyclo compound may be, for example, in a temporarily protected form. The compounds of the present invention can be converted into their acid addition salts and vice versa in a conventional manner. Suitable acid addition salts are the hydrochloride or methanesulfonate. The starting materials are known or can be prepared from known compounds by conventional methods. For example, as described below regarding compound [], this compound has the formula: [In the formula, R ₁ has the same meaning as above. ] It can be produced from the compound shown in the formula below via a hydrazide form and a benzyl ester form. Compound [] has the formula: [In the formula, R ₁ has the same meaning as above. ] A compound represented by and the formula: It can be obtained by reacting the compound represented by and hydrogenating the generated tripeptide benzyl ether, for example, as described in Examples. Compound [] can be produced from an optically active substance, for example, as shown in the process diagram below: Aminocycloles are preferably obtained in optically pure form from optically active compounds as described above. Certain preferred starting materials are racemic and can be separated as diastereomers by conventional methods, such as chromatography, if desired to be reacted with an optically active starting material. For example, compound [] can be separated from an epimer prepared from a mixture of diastereomers and epimers obtained from isoleucine and glycine containing compound []. The compound of the present invention and its acid addition salt thus obtained are isolated according to a known method, and then
For example, it can be purified by high performance liquid chromatography, other chromatography, or crystallization methods. The purity of the compounds of the invention is determined by the amount of the corresponding 5'S-(2S-butyl) epimer (e.g. dihydro-β-ergocryptine) or its acid addition salt as an impurity not exceeding 5% and not exceeding 2%. Preferably, it is present in no amount or in an amount of no more than 1%. The presence of epimers can be detected by conventional analytical methods, such as high performance liquid chromatography or nuclear racemic resonance. Compounds of the present invention in which R ₁ is isopropyl (hereinafter referred to as
5′S-(2R-butyl)) or its acid addition salts and dihydro β-ergocryptine (hereinafter referred to as
5′S-(2S-butyl)) can be distinguished according to nmr peak shifts. ^1H・NMR
The results of testing according to the spectrum (360 MHz; solvent CDCl ₃ ; standard tetramethylsilane) are shown below.

[Table] ¹³ C NMR spectrum (360MHz; 30mg/1.5
ml; pD=3.4), the compounds can be distinguished as follows.

[Table] As shown above, in the compounds of the present invention, 5'S-(2S
The presence of 1% or more of the -butyl) epimer can be detected. Suitable systems for high performance liquid chromatography include a mixed solvent system of (a) 1% triethylamine in water and (b) 1% triethylamine in acetonitrile. The solvent system initially contains 15% (b) and is increased to 50% (b) over 20 minutes. This system was run on a column RF18 with a length of 25 cm and a diameter of 4.6 mm at 2 ml/min.
(Knauer). 5'S- of Example 1 below
The (2R-butyl) compound had a retention time of 19 minutes, and β-dihydroergocryptine had a retention time of 20 minutes. Other suitable solvent systems are water/acetonitrile/tetramethylammonium chloride/trimethylamine (755g:240g:4g:1g); solid phase
LiChromosorb (Merck) R18 (particle size 10 mm, column diameter 16 mm, length 25 cm). Unless otherwise specified for the preparation of starting materials, e.g. starting materials for compounds of the invention other than compound [], these starting materials are
It can be prepared and purified by methods similar to those described for or conventional methods for similar compounds. Next, a method for producing a preferred compound of the present invention will be specifically described in detail with reference to Examples. In the examples, temperatures are uncorrected and altitude vacuum refers to approximately 0.01 mmHg.
Unless otherwise specified, all optical rotations are at 20°C and at the sodium D line. All NMR shifts (δ values) are values referenced to ppm. m = multiplet, s
= single line, q = quartet, t = triplet. Example 1 (5R, 8R, 10R)-N- [(2R, 5S, 11S, 12S)
-5-(2R-butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H
-oxazolo[3,2-a]pyrrolo[2,1-
c] pyrazin-2-yl]-6-methylergoline-8-carboxylic acid amide (named according to the Chemical Abstracts Ninth Collective Index nomenclature (5′α, 10α)-9,10- dihydro-
12'-Hydroxy-2'-(1-methylethyl)-5'-
[(R)-1-methylpropyl]ergotaman-3',
6′,18-trione) 9,10-dihydrolysergic anhydride (5R, 8R,
10R) 5.36g (20mM), anhydrous dimethylformamide
In a mixture of 40 ml and 20 ml of anhydrous acetonitrile,
Add 1.8 ml (22.5 mM) of trifluoroacetic acid. −
Add 2.8 ml trifluoroacetic anhydride (20 ml) and 20 ml pyridine at 10 °C. The mixture was further heated at -10°C for 5
Stir for (2R,5S,11S,12S)-2-amino-5-(2R-butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-
8H-Oxazolo[3,2-a]pyrrolo[2,1
-c] Add 3.62g (10mM) of pyrazine monohydrochloride. The mixture is stirred and allowed to rise to 22°C for 2 hours. The mixture was partitioned between methylene chloride and water, the organic layer was dried with sodium sulfate,
Filter and concentrate. The residue is crystallized from ethyl acetate/ether. m.p190~191°C; [α] ²⁰ = -43.5° (in pyridine,
c=0.5). NMR360MHz (CDCl ₃ ), 0.98ppm (6H, t),
1.08-1.17 (6H, q), 1.3 (1H, mC-13-H), ^13C -NMR360MHz (30mg/1.5ml, pD=3.4),
There is no visible signal at 16.4 or 28.6 ppm (both due to the epimer, dihydro-β-ergocryptine). This indicates that no more than 1% of epimer is present. Starting material (2R,5S,11S,12S)-2-amino-5-(2R-butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-dioxo
8H-Oxazolo[3,2-a]pyrrolo[2,1
-c] Pyrazine monohydrochloride is prepared as described below. a (3S,8aS)-3-(2R-butyl)-hexahydro-pyrrolo[1,2-a]piperazine-1,
4-dione (compound []) (i) (2S,3R)-L-arrowisoleucine methyl ester (2S,3R)-L-arrowisoleucine ([α]
²⁰ ₅₄₆ = +45±2゜ (in 6M HCl, c=5)) 30g
(229mM) in 300ml of methanolic 6.8N hydrochloric acid and stirred at room temperature for 18 hours. The mixture is concentrated and the residue is shaken with 300 ml of saturated potassium carbonate solution and 600 ml of ether. Water layer with ether (600
ml x 3 times). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to constant weight as a clear light yellow oil (2S,
3R)-L-arrow isoleucine methyl ester is obtained. A methyl ester is further obtained by extracting the aqueous layer. [α] ²⁰ = 45° (in CH ₂ Cl ₂ , c = 3); NMR100M
Hz ( _CDCl3 ). 0.81-1.01ppm (6H, 4 peaks, CH3 _- C-3,
CH ₃ −CH ₂ −C-3), 3.46 (1H, d, J=4Hz,
C-2-H), 3.71 (3H, s, _COOCH3 ). (ii) Condensation with CBO-L-proline 26.15 g of solid N,N-carbonyldiimidazolyl is added to 40.35 g (161.5 mM) of 2S-carbobenzoxy-L-proline in 600 ml of tetrahydrofuran.
(161.5mM) is added with stirring. After 5 minutes, the release of _CO2 ceases. The light yellow mixture is stirred for an additional hour at room temperature. In this mixture (2S, 3R) −
L-arrow isoleucine methyl ester 22.95g
(158.3mM) in 155ml of tetrahydrofuran solution. The mixture is stirred at room temperature for 2 hours, shaken and extracted with ether 1. Wash the organic layer twice with water. The aqueous washings are re-extracted with ether. The organic layers were combined, dried over sodium sulfate, filtered,
Concentrate and dry under high vacuum at 30° C. to obtain compound [ ] as a clear light yellow oil. (iii) Elimination of CBO group Add a solution of 64 g (170 mM) of compound [] in 800 ml of ethanol to a mixture of 12 g of previously hydrogenated 10% palladium/activated carbon catalyst and 500 ml of methanol. The mixture is hydrogenated (room temperature, 757 mmHg, reaction time 2.5 hours) and absorbs 2.9 l of hydrogen. The reaction mixture is passed through a filtering agent such as Hyflo, washed with 1 l of CH ₂ Cl ₂ /CH ₃ OH (1:1), dried and concentrated to give the compound [ ] as a yellow oil. (iv) Ring closure to form a diketopiperazine compound (compound [])
Formation of Compound [] is heated at 120°C for 2.5 hours under high vacuum. The partially crystalline mixture formed is stirred with ether. Add hexane to 8.66g of crystalline components and oily components
Generates 27.4g. The oily component is again subjected to a ring-closing reaction. The crystalline component (title compound) is recrystallized from ether/hexane to give colorless needles. mp132~135℃; [α] ²⁰ = -156゜ (in CH ₂ Cl ₂ ,
c=1). NMR360MHz (CDCl ₃ ) 0.80ppm (3H, d, J
=6.5Hz, CH3 _- C-9), 0.98(3H, t, J=7
Hz, _CH3 - _CH2 -C-9), 1.42 (2H, m), 1.92
(1H, m), 2.45 (2H, m), 2.38 (2H, m), 3.52
Screw 3.59 (2H, m), 4.08 (2H, m). b (2R, 5S, 11S, 12S)-5-(2R-butyl)
-Octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-2-carboxylic acid ethyl ester (compound []) (i ) Under nitrogen atmosphere, (3S,8aS)-3-(2R-butyl)-hexahydro-pyrrolo[1,2-a]
Piperazine-1,4-dione 21g (100mM)
, 200 ml of anhydrous dioxane, N-ethyl-N,
N-diisopropylamine 57.3ml (334mM)
and S-(+)-2-benzyloxy-2-
Mix with 53.32 g (178.6 mM) of chloroformyl-3-methyl-butyric acid ethyl ester and boil under reflux for 3 hours. The reaction mixture is cooled and partitioned between ether 1 and cold 1N hydrochloric acid. The organic layer is washed twice with saturated potassium bicarbonate solution and the aqueous layer is re-extracted with ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a yellow oily condensation product. (ii) 10 g of a 10% palladium/activated carbon catalyst previously hydrogenated with this product and anhydrous ethanol.
Process with the mixture of 2.6. Mixture at normal pressure
Hydrogenate for 18 hours, pass through a supernatant such as Hyflo, and evaporate. The residue is dried under high vacuum and the resulting yellow oil is recrystallized from ether/petroleum ether to give the title compound. mP95-96℃; [α] ²⁰ = +9゜ (in ethanol,
c=1). c (2R, 5S, 11S, 12S)-5-(2R-butyl)
-Octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-2-carboxylic acid Ester obtained in step b above Suspension of 28.64 g in 20 ml of methanol and 172 ml of 1N sodium hydroxide
Add. The resulting colorless solution is stirred at room temperature for 19 hours and washed twice with 500 ml of ether. Combine the organic washings and back-extract with water. All aqueous layers are acidified with 103.2 ml of 2N hydrochloric acid at 0° C. and the title compound is separated from the solution as an extract. After treating this with an ultrasonic bath, crystals are obtained and then dried at 50° C. for 24 hours.
The title compound is in colorless crystalline form. mp114~115℃; Second crystal form: mp172~173
°C: [α] ²⁰ = -11.7° (in pyridine, c = 1.5). d (2R, 5S, 11S, 12S)-5-(2R-butyl)
-octahydro-12-hydroxy-2-isopropyl-3,6-dioquine-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-2-carboxylic acid hydrazide dimethylformamide 9.04 ml methylene chloride
A solution of 8.37 ml of oxalyl chloride in 33 ml of methylene chloride is added to the 132 ml solution at -10°C and the resulting white suspension is stirred for a further 15 minutes at -10°C. Add 23.36g (65.8mM) of the solid acid obtained in step c above (the temperature of the mixture rises to -6°C). The resulting light yellow solution is stirred for an additional 30 minutes at -60°C. A solution of 42.9 g of sodium azide in 204 ml of water is added over 4 minutes. The mixture warms up to +5°C and becomes red. The mixture is stirred for a further 15 minutes at -10°C and extracted with 900 ml of methylene chloride. The organic layer is shaken with 420 ml of ice-cold saturated potassium bicarbonate solution.
The aqueous layer is back-extracted twice with 800 ml of methylene chloride. The organic layers are combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum. The residue is recrystallized from ether/methylene chloride to give colorless crystals. mp Greater than 175℃ (decomposition). e (2R, 5S, 11S, 12S)-5-(2R-butyl)
-Octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-2-carbomic acid benzyl ester obtained in step d above Acid hydrazide 16.54g
(43.6mM) in chloroform, add 13.52ml (130.8mM) of anhydrous benzyl alcohol,
Boil at reflux for 35 minutes. The easily evaporated portion of the resulting clear yellow solution was distilled off and the solution was purified under high vacuum.
Remove excess benzyl alcohol at 120°C.
The resulting crystalline yellow residue was stirred in ether and
Purify by crystallization from methylene chloride/ether. mp197-199℃; [α] ²⁰ = +40゜ (in methanol,
c=0.6). f (2R, 5S, 11S, 12S)-2-amino-5-
(2R-Butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-
8H-oxazolo[3,2-a]pyrrolo[2,
1-c] Pyrazine monohydrochloride (compound []) 16 g of the carbamic acid derivative obtained in step e above
(34.8mM), 8g of 10% palladium/activated carbon catalyst, 1.12m of methanol and 112mM of hydrochloric acid are mixed and hydrogenated at 19°C under normal pressure. The mixture is filtered and concentrated at 30°C until crystallization begins, and then diluted with ether.
Mix with 500ml and stir. The crystals are collected, washed with ether, and dried under high vacuum to constant weight. mp greater than 145°C (decomposition), [α] ²⁰ = +55° (in dimethylformamide, c = 0.15). The compounds of the present invention and their pharmacologically acceptable acid addition salts (hereinafter referred to as pharmacological compounds of the present invention) are novel and exhibit pharmacological activity, and are therefore useful as drugs. It is. In particular, the pharmacological compounds of the invention exhibit prolactin secretion inhibiting activity as demonstrated in standard animal tests. For example, the method of E. Fluckiger et al.
34, 1330-1332 (1978)], the pharmacological compounds of the present invention were administered subcutaneously to rats at a dose of about 0.1 to 10 mg/Kg (animal body weight). This suppresses implantation in rats. In this test, the title compound of Example 1 was
It has an ED ₅₀ value of approximately 1.84 mg/Kg (subcutaneous administration). The activity of the compound in this test is therefore higher than codergoline, approximately 5 times more active. Therefore, the pharmacological compounds of the present invention are suitable for use as prolactin secretion inhibitors, for example in lactation,
Lactation hypersecretion, hyperprolactin (hyperpro-
It is useful for the treatment of lactinaemic sexual dysfunction, acromegaly or prolactinoma. The pharmacological compounds of the invention also have serotonergic properties as shown in standard animal studies.
ninergic) activity. For example JMVigouret
et al; Pharmacology Volume 16 (Suppl.1) 156-173
(1978), the compound was administered intraperitoneally at a dose of about 0.3 to 10 mg/Kg or orally at a dose of about 1 to 10
By administering in the amount of mg/Kg (animal body weight),
Paradoxically induces a decrease in the sleep phase and a prolongation of the wake phase. Serotonergic-like activity is determined by the aforementioned JMVigouret
According to the paper of et al., the compound of the present invention
Reserpine syndrome in the PGO-potential model when administered to implanted cats at Kg (intravenous) doses.
syndrome). In this test, the compound of Example 1 was 0.11
It has an ID ₅₀ value of mg/Kg (intravenous administration) and was therefore shown to be higher and 3 times more active than codergocline in this study. Additionally, the compound affects the sensory and motor cortex (e.g. hippocampus and hand omentum) as shown by carbon-14-2-deoxyglucose autoradiography in the brains of rats administered intraperitoneally at approximately 0.01-3 mg/Kg. increase local cerebral glucose availability in the nucleus) [For test methods, see e.g. L. Solokoff: Journal of Cerebral Blood
Flow and Metabolism, 1981(1) pp. 7-36; HE
Savaki et al.: Brain Research (1982) Volume 233
pp. 347-358; and J. McCulloch et al.: Journal of
Cerebral Blood Flow and Metabolism (1981
2010), Volume 1, pp. 133-136]. The pharmacological compounds of the invention are therefore additionally useful for use in the treatment of brain disorders, such as senile dementia, particularly in its early forms, and in enhancing vigilance. Furthermore, the pharmacological compounds of the invention exhibit sympatholytic alpha-blocking activity as demonstrated in standard tests. For example, it can exhibit its activity in infused cats when administered at doses of about 0.01 to 1 mg/Kg (sc). The antihypertensive effect was shown in anesthetized normally catatonic dogs.
The method of D.Chu.A.Hofmann and E.Sturmer [Naunyn-Schmiedeberg's Arch.Pharmacol.
(1975) Suppl. Vol. 287 R18]
0.001 mg/10 mg/Kg (animal body weight) intravenously and 0.01 mg to spontaneously hypertensive rats.
(subcutaneous administration) ~10 mg/Kg (ic). In general, the compound of Example 1 is on average 1-3 times more effective than codergocline in this test. Therefore, this compound may also be used as an antihypertensive agent.
Particularly useful for geriatrics. The pharmacological compounds of the invention increase cerebral vascular flow as shown in standard tests. For example N.Wiern
−sperger, P. Gygax, O. Hunziker and A.
Schweizer's method (see J. Pharmacol. (Paris) 1979, Vol. 10, 4bis, pp. 489-501 (on p. 495)),
and the method of P. Gygax and N. Wiernsperger (Proc. Int. Cere−brovascular diseases, SIR
(1980) pp. 234-254), in which the compound of the present invention was administered to the cranial carotid artery of excised rats at a dose of approximately 0.2 to 0.4 μg/min, the compound of the present invention was found to be effective in postischemic electroencephalogram (electroencephalogram). ) recovery (post-ischemic
EEG recovery). The pharmacological compounds of the invention are therefore useful in the treatment of cerebral ischemic stroke. As described above, the compounds of the present invention and their pharmacologically acceptable acid addition salts can be used as pharmaceuticals, prolactin secretion inhibitors, and for enhancing alertness, or for treating senile dementia, hypertension, or cerebral ischemic attack (stroke).
Its use as a drug for the treatment of is indicated.
The indication of use as an antisenile dementia agent or an antihypertensive agent is a favorable indication. The title compound of Example 1 is a preferred compound. The dosage for all these uses will, of course, depend on the compound used, the method of administration, the treatment required, etc. But generally about 0.001 to 10 per day
Satisfactory results are obtained when doses of mg/Kg (animal body weight) are administered in 2 to 4 divided doses per day or when administered as a sustained release form. For larger animals the total daily dose is about 0.3 to 30 mg; for example, suitable dosage forms for oral administration contain about 0.0 to 15 mg of the active compound in a pharmaceutically acceptable solid or liquid. It is formulated by mixing it with a carrier or diluent. For the title compound of Example 1, the preferred daily oral dosage is 2-4 mg. The exact dosage of the pharmacological compounds of this invention will depend on the activity in the above tests relative to standard compounds such as codergoculin (identical to the ergoloid mesylates used for senile dementia and hypertension). Depends on factors. As shown by the above test results, the title compound of Example 1 is more active than codergocline, and therefore the compound of Example 1 can be administered at the same or lower dosages than codergocline. Generally, unit dosage form pharmacological compositions of the invention include:
To this, at least 0.01 to 0.1 mg of the compound of the present invention or a pharmacologically acceptable acid addition salt thereof, and at least 0.1 to 90% by weight (for example, 1 to 90% by weight of the compound of the present invention or a pharmacologically acceptable acid addition salt thereof). 10% by weight). A particularly suitable unit dosage form, such as an oral or rectal dosage form, contains about 0.1 to 15 mg of a compound of the invention or a pharmacologically acceptable acid addition salt thereof.
In particular, it is contained in an amount of 0.1 to 9 mg. The unit dosage form may be, for example, a tablet, capsule, dragee or suppository. Liquid solutions for oral administration, such as drop solutions, contain at least 0.1 mg/ml.
ml, for example 0.5 to 2 mg/ml. Particularly suitable unit dosage forms, such as parenteral dosage forms, such as sterile injection suspensions, contain a compound of the invention or a pharmaceutically acceptable acid addition salt thereof.
0.01 to 3 mg, especially 0.03 to 1 mg. The compounds of the present invention can be administered as their pharmacologically acceptable acid addition salts, if necessary. Such salts exhibit the same degree of activity as the free base form of the compounds of the invention. Preferably, the compounds of the invention are administered in free base form. As described above, the present invention can provide a pharmacological composition containing a compound of the present invention or a pharmacologically acceptable acid addition salt thereof in combination with a pharmacological carrier or diluent. Such agents may be formulated in conventional manner, for example those known for other ergot peptide alkaloids such as codergocline. A drug for oral, rectal or parenteral administration by mixing the compound of the present invention and its pharmacologically acceptable acid addition salt with a pharmacologically acceptable carrier and diluent and, if necessary, other excipients. Physical compositions can be formulated. For oral administration, tablets,
Granules, dispersible powders, sugar coatings, capsules,
It can be formulated into syrups, suspensions, solutions and elixirs. Suppositories for rectal administration and solutions or suspensions for parenteral administration may also be formulated. Oral pharmacological compositions may contain one or more excipients, such as sweetening agents, flavoring agents, coloring agents, and preservatives, to provide an orally acceptable and palatable composition. can. For example, tablets may contain a compound of the present invention or a pharmacologically acceptable acid addition salt thereof, a diluent (e.g. calcium carbonate or lactose), a dispersant (e.g. starch, alginic acid), a binder (e.g. starch, polyvinyl pyrrolidone or gelatin),
A lubricant (for example magnesium stearate, stearic acid or talc) can be incorporated. The tablets can be coated in a conventional manner to delay their disintegration and absorption in the gastrointestinal tract to prolong their activity. Capsules contain the ergot 5S-(2R-butyl) peptide alkaloid of the present invention, or a pharmacologically acceptable acid addition salt thereof, in a solid diluent (e.g. lactose or starch) and a lubricant (e.g. magnesium stearate). ) can be mixed and contained. Suspensions, syrups and elixirs contain the ergot 5'S-(2R-butyl) peptide alkaloids of the invention in excipients such as suspending agents such as methylcellulose, tragacanth and alginic acid. sodium), tensioactive agents (eg lecithin, polyoxyethylene stearate or polyoxyethylene sorbitan monooleate) and preservatives (eg ethyl parahydroxybenzoate). Injectable compositions, suppositories and other pharmacological compositions can be formulated in the same manner as described above in a conventional manner. Solid dosage forms, such as tablets or capsules, are preferred from the standpoint of ease of formulation and tolerability. Examples of pharmacological compositions that can be formulated in conventional manner are listed below. Tablet Ingredients Weight Compound of the invention (e.g. the compound of Example 1) 0.1mg Tartaric acid 0.1mg Lactose 85.9mg Cornstarch 10mg Gelatin 0.3mg Magnesium stearate 0.3mg Talc 2mg Capsule Compound of the invention (e.g. the compound of Example 1) 0.1mg Dilution Agents and lubricants (lactose, starch, magnesium stearate) 299.9mg

【table】

[Table] Water reaches 1mg reaches 1mg
enough to do enough to do enough
amount amount
The above composition can be administered, for example, once a day for the treatment of senile dementia. The compounds of the present invention or their pharmacologically acceptable acid addition salts can be administered to dogs at doses of about 1-30 mg/Kg (animal body weight)/day for 4 weeks and have good overall tolerance. gender (general tolerabi−
ity). For example, when the title compound of Example 1 was orally administered at 10 mg/Kg (animal body weight) for 4 weeks, it showed very few side effects typical of ergot, such as vomiting, salivation, weight loss, and There is only a slight decrease in food absorption. No significant cardiotoxic effects are observed at an oral dose of 30 mg/Kg (animal body weight). The title compound of Example 1 therefore shows good tolerability, even better than codergocline.

Claims (1)

[Claims] 1 Formula: [In the formula, R ₁ represents methyl, ethyl or isopropyl. ] Ergot 5'S-(2R-butyl) peptide alkaloids and their addition salts. 2 (5R, 8R, 10R)-N- [(2R, 5S, 11S,
12S)-5-(2R-butyl)-octahydro-12-
Hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo[3,2-a]pyrrolo[2,
The compound according to claim 1, which is 1-c]pyrazinyl]-6-methyl-ergoline-8-carboxylic acid amide and its acid addition salt. 3 formula: [In the formula, R ₁ represents methyl, ethyl or isopropyl. ] A pharmacological composition for inhibiting prolactin secretion, which contains a compound represented by the following or a pharmacologically acceptable acid addition salt thereof in combination with a pharmacologically acceptable carrier or diluent. 4. The pharmaceutical composition according to claim 3, which is in a unit dosage form containing at least 0.01 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 5. The pharmaceutical composition according to claim 3, which contains at least 0.1 to 15 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 6. The pharmaceutical composition according to claim 5 for oral or rectal administration, containing 0.1 to 9 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 7. The pharmacological composition according to claim 4, which contains 0.01 to 3 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 8. The pharmaceutical composition according to claim 4 for parenteral use, which contains 0.01 to 1 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 9. The solution-type pharmacological composition according to claim 3, which contains at least 0.1 mg/ml of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 10 Formula: [In the formula, R ₁ represents methyl, ethyl or isopropyl. ] Pharmacology for enhancing alertness or treating senile dementia, comprising a compound represented by or a pharmacologically acceptable acid addition salt thereof in combination with a pharmacologically acceptable carrier or diluent. composition. 11. The pharmaceutical composition according to claim 10, which is in a unit dosage form containing at least 0.01 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 12. The pharmaceutical composition according to claim 10, which contains at least 0.1 to 15 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 13. The pharmaceutical composition according to claim 12 for oral or rectal administration, containing 0.1 to 9 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 14. The pharmaceutical composition according to claim 11, which contains 0.01 to 3 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 15. The pharmaceutical composition according to claim 11 for parenteral use, which contains 0.01 to 1 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 16. The pharmaceutical composition according to claim 10 in a solution form, containing at least 0.1 mg/ml of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 17 Formula: [In the formula, R ₁ represents methyl, ethyl or isopropyl. ] A pharmacological composition for the treatment of hypertension, comprising a compound represented by the following or a pharmacologically acceptable acid addition salt thereof in combination with a pharmacologically acceptable carrier or diluent. 18. The pharmaceutical composition according to claim 17, which is in a unit dosage form containing at least 0.01 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 19. The pharmaceutical composition according to claim 17, which contains at least 0.1 to 15 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 20. The pharmaceutical composition according to claim 19 for oral or rectal use, containing 0.1 to 9 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 21. The pharmaceutical composition according to claim 18, which contains 0.01 to 3 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 22. The pharmaceutical composition according to claim 18 for parenteral use, which contains 0.01 to 1 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 23. The pharmaceutical composition according to claim 17 in a solution form, containing at least 0.1 mg/ml of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 24 Formula: [In the formula, R ₁ represents methyl, ethyl or isopropyl. ] A pharmacological composition for the treatment of cerebral ischemic attack, comprising a compound represented by or a pharmacologically acceptable acid addition salt thereof in combination with a pharmacologically acceptable carrier or diluent. . 25. The pharmaceutical composition according to claim 24, which is in a unit dosage form containing at least 0.01 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 26. The pharmaceutical composition according to claim 24, which contains at least 0.1 to 15 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 27. The pharmaceutical composition according to claim 26 for oral or rectal use, containing 0.1 to 9 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 28. The pharmaceutical composition according to claim 25, which contains 0.01 to 3 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 29. The pharmaceutical composition according to claim 25 for parenteral use, which contains 0.01 to 1 mg of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof. 30. The pharmaceutical composition according to claim 24 in a solution form containing at least 0.1 mg/ml of the compound of formula [] or a pharmacologically acceptable acid addition salt thereof.