JPS58148888A - Ergot alkaloids - 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 The present invention relates to ergot alkaloids, and more particularly to novel ergot peptide alkaloids with pharmacological activity.

The present invention applies to 5'S-(2R
-butyl) peptide alkaloids or their acid addition salts.

The modified 5'F3-(2R-butyl) compounds of the present invention are hitherto completely unknown modified peptide alkaloid epimers, and these latter alkaloids can be produced by chemical synthesis or, in some cases, It can be obtained naturally or by fermentation, for example. These may be substituted and may also exist in isomeric forms, such as the 8R or 88 isomer.

Jl [Chemistry of peptide alkamides has recently been studied by B.

13erde and 0.5hild “Ergol”
alkaloids and related comp
ounds” (Berlin, 8pringer V
erlag (1978)) Chapter ■, pp. 29-85 (
Reviewed in J. Rutschman and P. Tadler). A known 5'S-(2-butyl) derivative, Tatoe β-ergocributine, has an 8-configuration in its sec-butyl side chain [B above.

Berde and ILO, 5child Publication 3
7 pages Narahini Dictionary of Organ
ic Compounds 5th edition Volume 3 (=:x, -
Chapman and Hall (19
(1982) p. 2468]. The 2-butyl carbon atom with the S configuration is known as the 13' carbon atom and ]- under the Chemical Abstract nomenclature used in the Eighth Collective Index.

The present invention particularly relates to the following formula: [wherein R1 represents methyl, ethyl or isopropyl]. ] Compounds represented by the following and acid addition salts thereof can be provided.

In aspects other than the above, the present invention provides corresponding 5'5-
A step of condensing an acid addition salt of (2R-buty/I/)aminocyclole or its precursor with a corresponding reactive acid derivative of lysergic acid derivative or its precursor, and the produced 5'5-(2R- butyl) peptide alkaloid or an acid addition salt thereof.
-(2R-butyl)peptide alkamides and methods for producing acid addition salts thereof can be provided.

The term aminocyclole covers typical hydroxy-containing tripeptides used in the synthesis of modified peptide alkaloids, which are cyclic tripeptides with an amino group in the 2' position and a hydroxy group in the 12' position. It is.

The compound [I] of the present invention has, for example, the formula: [wherein R1 has the same meaning as above. ] A compound represented by the formula or an acid addition salt thereof is also a step of condensing these precursors with a compound represented by the formula: or a reactive derivative thereof. It can be produced by a method including a step of recovering the compound [I'l or its acid addition salt.

The condensation process of the invention can be carried out in a conventional manner for the production of analogous angular peptide alkaloids.

The acidified 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.

The derivative may also be an addition product prepared by adding (1) dimethylformamide or acetamide and (11) thionyl chloride, phosgene or oxalyl chloride to the corresponding lysergic acid. 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 -80 to +20°C.

As a precursor of a lysergic acid derivative or an aminocyclole, as described above, these compounds can be converted, for example, in a conventional manner and, following a condensation reaction, the product can be converted into a compound of the invention or its acid-adding salt. Compounds that can be converted to can be used. The lysergic acid derivative and/or the aminochloride may thus 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 by conventional methods. A suitable acid addition salt is salt f! #Salt or methanesulfonate.

The starting materials are known or can be prepared from known compounds by conventional methods. For example, compound rI
As described below regarding [], this compound can be prepared by formula 1, for example, as in the example of leprosy described below: [wherein, 雇 has the same meaning as above. ] It can be produced from the compound shown in the following formula via a hydrazide form and a benzyl ester form.

The compound [fV] has the formula: [wherein, R4 has the same meaning as above. ] The compound represented by the following formula: can be reacted with the compound represented by the formula: and the resulting tripeptide benzyl ether can be obtained by hydrogenation, for example, as described in the Examples.

Compound rVI), for example, as shown in the process diagram below,
Can be produced from optically active substances: rVI] Compounds [X], [IX], [■], [■], [■], [
IV]b and [■] each constitute a part of the present invention.

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, provided that it is advantageous to react with optically active starting materials. For example, compound [VI] can be separated from an epimer prepared from a mixture of diastereomers and epimers obtained from isoleucine and glycine containing compound [X].

The compound of the present invention and its acid addition salt thus obtained can be isolated according to known methods and then purified by, for example, high performance liquid chromatography, other chromatography, or crystallization methods.

Another aspect of the invention provides that a compound of the invention and a corresponding 5'S-(28-butyl) epimer (e.g. dihydro-β-ergocributine) or an acid addition salt thereof in an amount not exceeding 5%, 2 It is possible to provide compounds in which there is an amount of not more than 1% or more than 1%.

The presence of epimers can be detected by conventional analytical methods, such as high performance liquid chromatography or nuclear racemic resonance.

The compound of the present invention in which R1 is inopropyl (hereinafter referred to as 5'8
-(2R-buty/L/)) or its acid addition salts and dihydro-β-ergocributine (hereinafter referred to as 5'8-
(distinguished by 2S-butyl)) can be distinguished according to H, m, r, peak shift. ■・N'M Ry,
The results of testing according to Pect# (360Mn2 *solvent CDCl3; standard tetramethylsilane) are shown below.

C-5'-H4,5a 4.50C-18'
-H1,801,50 18C@NMR spectrum tV (860MHz; 80
mg/1.5, /; PD=8.4), the compounds can be distinguished as follows:

It is possible to detect the presence of 1% or more of the 5'S-(28-butyl) epimer in compounds of the invention such as CH317,516,4 cm1a' on Cf(227,428, on C-18'). can.

A suitable system for high performance liquid chromatography is (
The solvent system includes a mixture of 1% triethylamine in al water and 1% triethylamine in bl acenitrile.

The solvent system initially contains 15% (b) and increases to 50% (b) over 20 minutes.

The system is run through a column RF18 (Knauer) with a length of 25 mm and a diameter of 4.6 mm in 2-7 minutes. Actual power example 1 below
The 5'5-(2R-butyl) compound had a retention time of 19 minutes, and the β-dihydroergocributine had a retention time of 20 minutes.

Other suitable solvent systems include water/acetonitrile/tetramethylammonium chloride/trimethylamine (755 g
:2401:4f:IN); Solid phase Li Chromos
orb (Merck) R18 (particle size 10++ m, column diameter i6 m, length 25 m).

Unless otherwise specified for the preparation of starting materials, e.g. starting materials for compounds of the invention other than compound [I], these starting materials may be prepared by methods similar to those described for compound [I] or for analogous compounds. It can be produced and purified by conventional methods.

Next, a method for producing a preferred compound of the present invention will be specifically explained in detail by giving practical examples. In the actual example, temperature is uncorrected and altitude vacuum is approximately 0.01 ws Hg. All optical rotations are values at 20° C. and sodium D line, unless otherwise specified. All NMR shifts (δ values) are 1-values matched to pPm. m = multiplet, S - single line, 9 = quartet, t = triplet, real example 1 (5R, 8R, 10R) -N- [(2R, 58, 11
8゜128)-5-(2R-butyl)-octahydro-
12-Hydroxy-2-isopropyl-8,6-thioxo 8■-oxazolo[:lI, 2-alpyrrolo[2,
1-Cl pyrazin-2-yl]-6-methylergoline-8-carboxylic acid amide (Chemical Abstract No. 9)
Named according to collective index nomenclature (
5'α, 10α)-9,10-dihydro-12'-hydroxy-2'-(1-methylethyl A/)-5'-[(R
)-1-methylpropyl]ergotaman-8:6. '1
8- Trion! : Same-') Anhydrous 9. lO-dihydrolysergic acid (5R, 8R, 10R) 5J6F (20mM
), trifluoroacetic acid 1,
Add 8,t (22,5mM). 2 at -lO°C.
8-) Lifluoroacetic anhydride (20,z) and pyridine 2
Add o-. The mixture was further stirred at -lO°C for 5 minutes @ (2R, 58°118.128)-2-amino-5-
(2R-butyl)-octahydro-12-hydroxy-
Add 8.62f (10 mM) of 2-isopropyl-8,6-thioxo 8-oxazolo[8,2-alpyrrolo[2,1-c]pyrazine Φ-hydrochloride. The mixture is stirred and allowed to rise to 22°C for 2 hours. Partition the mixture between methylene chloride and water and sulfate the organic layer)
Dry with IJum, filter, and boil. The residue is crystallized from ethyl acetate/ether.

rrLP, 190-191℃i [α]20=-48
, 5° (in pilin, C=0.5).

NMR369MHz (CDCI3), 0
．． 98PPmr6H,t), 1.08-1.17 (6
fi, q), 1.3 (in.

m, C-18-H), 13C-NMR860MH1 (301W/ 1.5+v
, pD-34), 16.4 or 2'8.6 ppm
None of the visible tunnels in can contribute to the epimer. Dihydro-β-ergocributine is L%
This indicates the existence of an unreliable epimer.

Starting material (2R,58,llS,128)-2-amino-5-(2R-butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-thioxo 811
-oxazo"[3,2-a]pyrrolo[2,lc]pyrazine-hydrochloride is prepared as described below.

a, (38,8a8)-3-(2R-buty)Lt)
-hexahydro-pyrrolo[1,2-alpiperazine-
1,4-dione (compound [■]) fil(28,8R)-L-arrowinleucine-methyl ester (28,8R)-L-arrowinleucine ([α]20
-+45±2° (13M, in LIcI, c:5)4
6) 30f (229mM) Jl) /-1vf46.8
Dissolve in 300 rnl of N-hydrochloric acid and stir at room temperature for 18 hours.

The mixture was concentrated and the residue was dissolved in saturated potassium carbonate solution
- and Aete/L/600-.

The aqueous layer is extracted with ether (600, v x 3).

Combine the organic layers and sulfuric acid) Dry over IJum, filtrate, and concentrate 1-1 Dry to constant weight under high vacuum to give (28,8R)-L-arrowinleucine as a clear light yellow oil.
The methyl ester is obtained. A methyl ester is further obtained by extracting the aqueous layer.

0 [α]-45° (C=8 in CH2C12), NMR1
00MHz (CD CI 3').

o, s i ~1. ．． o lPPm (6H, 4 peaks,
CH, -C-3, CH3-CH2-C-8), 8.4
6 (IH, d, J=4 Hz, C-2-f(),
8-71 (8H,s, C00CHs j.

(iilc BO-L-proline condensation in 600 rnl of tetrahydrofuran, 2S-carbobenzoxy-
Proline 40.85F (161.5mM), solid N,
N-Carponyldiimidazolyl 26.15g (161,
5mM) is added with stirring. After 5 minutes, the release of CO2 ends. The light yellow mixture is stirred for an additional hour at room temperature. To this mixture was added 22.95 f of (2S,3R)-L-alloinleucine methyl ester (158.3mM
) in tetrahydrofuran 155-solution.

The mixture is stirred at room temperature for 2 hours, shaken and extracted with ether. 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, and concentrated.
Dry at 30°C under high vacuum to form a clear light yellow oil.
− to obtain compound [■].

(iii) Desorption of CBO O group 1O% palladium/activated carbon catalyst 1 previously hydrogenated
To a mixture of 2g and methano/L'500-, compound [■
] Add 64f (170mM) ethanol 800+d/J solution. The mixture is hydrogenated (room temperature, 757 g, reaction time 2.5 hours, 111 tl), absorbing 2.9 t of hydrogen. The reaction mixture is filtered through an Oki filter such as Hyflo, washed with CH2Cl2/CH30H (1:1), dried and concentrated to give compound [■] as a yellow oil.

(1) Ring closure to produce a diketopiperazine (compound [■]) Compound [■] is heated at 120°C for 2.5 hours under highly reduced pressure. The partially crystalline mixture produced is stirred with ether.

Add hexane to make the crystal component 8.66F and the oil component 27.
Generate 4f. 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.

m, p-132-185°c; E120=-156° (c=1 in CH2C12).

NMR860MHz (CD Cl 3) (1,
80P Pm (8H.

(1, J = 6.51-Lz, CH2O9), 0.
98 (3H, t, J = 711z, eft6-C1
(,,-C-9), 1.42 (2H,m), 1゜9
2 (LH,m), 2.45 (2H,m), 2.
88 (double circle m), 3.52 screw 8.59 (2H,
m), 4.08 (21(, m).

b.
2-albi0Or2.1-C]pyrazine-2-carboxylic acid ethylester (compound [ba]) (1) Under nitrogen atmosphere, (88,8a8)-8-(2R-butyl)-hexahydro-pyrrolo [1,2-alpiperazine-1,4-dio721Q (l 00mM) was dissolved in anhydrous dioxane 2
00-1N-ethyl-N,N-diinpropylamine 5
7.8mz (384mM) and 8-(+)-2-benzyloxy-2-chloroformyl-3-methyl-butyric acid ethyl ester 53°829 (178.5mM) and boiled under reflux for 3 hours. The reaction mixture is cooled and partitioned between ether 11 and cold IN hydrochloric acid. Remove the organic layer with saturated carbonated water. The organic layers were combined, washed with sulfuric acid, dried over IJum, filtered, and evaporated to obtain a yellow oily condensation product.

(11) This product was pre-hydrogenated with 10% palladium/activated carbon catalyst 1 (l) and anhydrous ethanol/l/2°6
Treat with a mixture of t. The mixture is hydrogenated at normal pressure for 18 hours, filtered through a filter aid such as Hyflo and evaporated. The residue is dried under high vacuum and the resulting yellow oil is recrystallized from ether/petroleum ether to give the title compound.

m, p, 95-96°C; [α] 20-+9° (xri/
- C=1).

C, (2R,58,118,128)-5-(2R-butyl)-octahythro-12-hydroxy-2-inpropyl-3,6-dioquine-8H to oxazo 1:I[8
, 2-alpyrrolo[2,1-Cl pyrazine-2-carboxylic acid To the methanol/L' 20- suspension of the ester 28.64F obtained in the above step, IN sodium hydroxide]7
Add 2-. The resulting colorless solution was 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 water layers to 0°
Acidify with 2N hydrochloric acid 103.2 at C and separate the title compound from the solution as an oil. After treating this in an ultrasonic bath, crystals are obtained and then dried at 5° C. for 24 hours. The title compound is colorless and in crystalline form.

m, p-114~l l 5°C; second crystal form: m, p
.

172-173°Ci [α]20=-11,7° (C=1.5 in pyricin).

d, (2R,58,118,128)-5-(2R-butyl)-octahydro-12-hydroxy-2-inpropyl-8,6-cyoquine-8H-oxazolo[3,2
-al pyrrolo[2,l-(]]pyrazine-2-carboxylic acid hydrazide methylformamide 9.04- of methylene chloride 132
-To the solution was added a solution of 8.37- of oxalyl chloride in methylene chloride at -10'C.

The resulting white suspension is stirred for an additional 15 minutes at -10'C. 28.36 g of solid acid obtained in step C ((i
5.43 mM) (temperature of the mixture is 16°C)
rise to ). The resulting bright yellow solution is stirred for a further 80 minutes at -60°C. A solution of 42.9 g of sodium azide in 204 g of water is added over a period of 4 minutes.

The mixture warms up to +5°C and becomes red. 1 part of the mixture
Stir for a further 15 minutes at 0°C and extract with 900°C of methylene chloride. The organic layer is shaken with 420.7 g of ice-cold saturated potassium bicarbonate solution. Pour the aqueous layer into methylene chloride 800
- Back-extract twice. The organic layers were combined, washed with sulfuric acid, dried over IJum, filtered, concentrated, and evaporated to dryness under high vacuum. The residue is recrystallized from ether tLy/methylene chloride to give colorless crystals.

m, p, 175°C (decomposition).

e, (2R,58,118,128)-5-(2R-butyl)-octahydro-12-hydroxy-2-inpropyl-8,6-cyoquine-8H-oxazolo[8,2
-alpyrroloff[2,1-Cl pyrazine-2-carbamic acid benzyl ester Acid hydrazide obtained in step d above 16.54'!
(48.6mM) in glue aa form 1lo-solution.

Anhydrous benzyl alcohol 13.52. nt(18Q, 8
(mM) and boil under reflux for 35 minutes. The easily evaporated portion of the resulting clear yellow solution is distilled off and the excess benzyl alcohol is removed under high vacuum at 120°C.

The resulting crystalline yellow residue is stirred in ether and purified by crystallization from methylene chloride/ether.

0 m, p, l 97-199°Ci[α] =+40°
(c=0.6 in methanol).

f, r 2R, 58, l i's, 128) -2-
Amino-5-(2R-buty1v)-octahyto'rho1
2-human'roxy2-inpropyl-3,6-thioquine-8H-oxazolo[8,2-alpyrrolo[2,l-
C] Pyrazine-hydrochloride (compound [■]) Carbamic acid derivative 16f (84
, 8mM), 8g of 10% haladium/activated carbon catalyst, 1.12t of methanol/l' and 112crystalline hydrochloric acid mixture [1,
Hydrogenation is carried out at 19° C. under normal pressure. Pass the mixture through yti p
Mix with concentrated L and 500 ml of ether and stir at 80° C. until crystallization starts from Ig. The crystals are off-shored, washed with ether, and dried to constant weight under high vacuum. m, p,
145° C. (decomposition), [α]20=+55° (C=0.15 in dimethylformamide).

The compounds of the present invention and their pharmacologically acceptable acid addition salts (hereinafter referred to as pharmacological compounds of the present invention) are:
It is novel and exhibits pharmacological activity and is therefore useful as a drug.

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. [Experi-
84, 1180-1882 (1978)], the pharmacological compounds of the present invention were administered subcutaneously to rats at a dose of about 0.1-10 da/kf (animal body weight). -i mituto implantation (i
plantation).

In this test, the title compound of Example 1 had an ED5o
It has a value of about 1.84 to 1.8% per day (subcutaneous administration).

Therefore, the activity of the compound in this test is higher than Cobblebotarin, about 5 times more active.

Therefore, the pharmacological compounds of the present invention have applications as prolactin secretion inhibitors, such as lactation, hyperlactation,
hyperpro-Iactin
aemic) sexual dysfunction, acromegaly or prolactinoma.

The pharmacological compounds of the invention also have serotonergic properties as shown in standard animal studies.
rgic) exhibits activity. For example, J-Jun Vigo
u re t et al.: Ph21 rmacology No. 16
Volume (8uppl-1) pages 156-17B (1978)
In a sleep/wake cycle test conducted according to the principles described in
, or orally, by administering approximately 1-10 η/rostrum (animal body weight), which induces a paradoxical decrease in the sleep phase and prolongation of the wake phase.

Serotonergic-like activity is determined by J.M. Vigoure, supra.
According to the paper of T et al.
/implant at a dose of 9 (intravenous)
ea) t'GO-potential when administered to cats
This is confirmed by suppressing reserpine syndrome.

In this test, the compound of Example 1 was 0.11 Da/4
(intravenous administration) and was therefore shown to be higher and 8 times more active than Cobblebotarin in this study.

Further, this compound is added to about 0. Compounds inhibit sensory and motor cortices (e.g. seabird and habenula) as shown by carbon-14-2-deoxyglucose autoradiography in the brains of rats administered intraperitoneally at O1~By/m.
[Regarding the test method, e.g.
ow and Metabolism, l 931
(1) Pages 7-B6; KE, 5avaki et al.:
Brain Re-5earch (1982) Vol. 233, pp. 847-858; and McCullo, J.
ch et al.: Journal of Cerebral B
load Flow and Metabolism
(1981) Vol. 1, pp. 18.8-186].

The pharmacological compounds of the invention may additionally be used to treat brain disorders such as senile dementia, especially its early forms and senile dementia.
vigi 1ance) for use in the treatment of progression.

Furthermore, the pharmacological compounds of the present invention exhibit sympatholytic neuroleptic activity as demonstrated in standard tests. For example, in cats injected with 1nfusion, approximately 0
．． It can exhibit its activity when administered at a dosage of 01-l'Ill/ky (s, C,). The antihypertensive effect was demonstrated in anesthetized normally catatonic dogs.
Chu, A., Hofmann and E+8turm.
Erno method [Naunyn-8chmiedeberg
's Arch, Pharmacol, (19
1975) 8upp1. 287, R18], and approximately 0.001 lal/10'9/moan (animal body weight) is administered intravenously to spontaneously hypertensive rats.
01mg (subcutaneous administration) ~l 0I11y/1w (i
, c, ) are shown to be false in administering.

In general, the compound of Example 1 is on average 1 to 3 times more effective than Cobblebotaline in this test.

This compound is therefore further useful as an antihypertensive agent, especially for geriatrics.

The pharmacological compounds of the invention increase cerebral vascular flow as shown in standard tests. For example, N, Wiern-spe.
rger+P, Gygax, αHunziker and A.

8chweizer (7) Method (J, Pharma
col, (Paris) 1979 Volume 1θ 4bi
8489-501 (on page 495)), and P, Gygax and N, Wiernspe.
rger (2) Method (Proc, Int, Cer
e-brovascular diseases,
SIR (1980) pp. 234-254),
In a test in which the compound of the present invention was administered to the excised rat cranial carotid artery at a dose of approximately 0.2 to 0.4 μf/min, the compound of the present invention was found to be effective in post-ischemic FEG recovery (post-ischemic FEG recovery).
FEG recovery).

Several pharmacological compounds of the present invention are useful in the treatment of palpitations.

As mentioned above, the compounds of the present invention and their pharmacologically acceptable acid addition salts can be used as pharmaceuticals, prolactin secretion inhibitors, and agents for enhancing alertness or treating senile dementia, hypertension, or agitation. It has been pointed out that it is used as a An anti-senile dementia drug or an anti-hypertensive drug and 1. It is a good point to point out the use of this product. The title compound of Example 1 is a preferred compound.

The final dosage for all these uses will, of course, depend on the compound used, the method of projection, the treatment required, etc. However, in general, the dosage is approximately 0.001-10af/kt (animal body weight) per day, divided into 2 to 4 times a day, or
Alternatively, satisfactory results can be obtained when projected as a sustained release type. For larger animals the total daily dose is about 0.3 to 30 μg; dosage forms suitable for oral administration, for example, contain 0.1 to 15 Iv of active compound. It is formulated by mixing it with a solid or liquid carrier or diluent.

For the title compound of Example 1, the preferred daily oral dosage is from 2 to 4.

Precise dosages of the pharmacological compounds of the invention include activity in the above tests relative to standard compounds such as cobblebotaline (identical to ergoloid mesylates used for senile dementia and hypertension). Depends on many factors. As shown by the above test results, the title compound of Example 1 is more active than Cobblebotaline, and therefore the compound of Example 1 can be administered at the same or lower dosages than Cobblebotaline.

Generally, unit dosage form pharmacological compositions of the present invention.

The compound of the present invention or a pharmacologically acceptable acid addition salt thereof may contain at least 0. O1 to 0.1 MI, and at least 0.1 to 90% by weight (for example 1 to 10
% by weight).

Particularly suitable unit dosage forms, such as oral or rectal dosage forms, contain a compound of the invention or a pharmacologically acceptable addition salt thereof.
jv. The unit dosage form may be, for example, a tablet, capsule, dragee or suppository.

Liquid solutions for oral administration, such as drop solutions
gougtion) is at least 0.1 M
g/-1, for example 0.5 to 2 M9/-.

Particularly suitable unit dosage forms, such as parenteral dosage forms, such as sterile injection suspensions, contain from about 0.01 to 0.01 amg of the compound of the invention or of its pharmacologically acceptable acid addition salt, especially 0. Contains .03 to 1.

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 provides a pharmacological composition containing a compound of the present invention or a pharmacologically acceptable acid addition salt thereof in combination with a pharmacological carrier and a diluent. be able to. Such agents may be formulated in conventional manner, e.g., by methods known for other modified peptide alkaloids such as codergocline. Pharmaceutical compositions can be formulated for oral, rectal or parenteral administration by mixing with acceptable carriers and diluents and optionally other excipients. For oral administration, they can be formulated into tablets, granules, dispersible powders, dragees, capsules, syrups, suspensions, solutions and elixirs. Suppositories for rectal administration and solutions or suspensions for parenteral administration may also be formulated.

The edible pharmacological composition may contain one or more excipients, such as sweetening agents, flavoring agents, coloring agents and preservatives, in order to obtain a palatable and palatable composition. Can be done.

For example, a tablet 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, algine), a binder (e.g. starch, Polyvinylpyrrolidone or gelatin), lubricants (eg magnesium stearate, stearic acid or talc) can be mixed and included. Tablets may be coated in conventional manner to delay their disintegration and absorption in the gastrointestinal tract to prolong their activity.

The capsules are made of the modified angle 58-(2R-buty/l/
) Peptide alkaloids or pharmacologically acceptable acid addition salts thereof may be included in admixture with solid diluents (eg lactose or starch) and lubricants (eg magnesium stearate).

Suspensions, syrups and elixirs
The modified 5'5-(2R-butyl) peptide alkaloid of 1 is combined with excipients such as suspending agents (e.g. methylcellulose, tragacanthiohyalginate, IJum), tensile activity ( tensioactive
e) agents (eg lecithin, 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 components Weight Compound of the present invention (for example, the compound of Example 1) 0.1 m9 Tartaric acid
0.1'ILiLactose
85.9 Cape Cornstarch 1
0jv gelatin 0, ajv magnesium stearate 0.8 m9 talc
2~Capsule Compound of the present invention (for example, the compound of Example 1) 0, l
II9 Diluent and lubricant (lactose, starch, magnesium stearate) 299.9'9 liquid <4-composition
Weight (~) Compound of the invention (for example, the compound of Working Example 1) 0.05 0.1 Sodium carboxymethylcellulose USP 1.25 12.5 Methylcellulose 0.4-Polyvinylpyrrolidone 5-Lecithin 3-Pencyl alcohol 0.01-Magnesium Aluminum silicate -47,5 Flavor remover 9・S・Coloring agent q, s.

Methylparaben U8P 4.5 Propylparaben USP -1,0 Porin Rubate 80
(e.g. Tween 80) U8P 50% Rubitol Solution 70% U8P-2,500 Stabilization Buffer 9.S.9.S.Water
Sufficient amount to reach Img Sufficient amount to reach Img Sufficient amount of 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 for 4 weeks at a dosage of about 1 to 80 to 7 days of animal body weight, resulting in good overall general tolerance
) is shown. For example, the compound titled Actual Example 1 is l10
1a/kg (animal body weight) was administered lightly for 4 weeks [-], the side effects specific to keratosis were very slight, such as vomiting, salivation, weight loss, and decreased food absorption. It's only a small amount.

No significant cardiotoxic effects are observed at an oral dose of 809/kg (animal body weight). The title compound of Example 1 therefore shows good tolerability, even better than codergocline.

Patent applicant: Sand Akchengesellschaft 209100 6807-4
C2411007431-4C 263100) 7306-4C
Priority claim @November 29, 1982 ■Switzerland (CH
)■6924782

Claims (1)

[Claims] 1. Variable 5'S-(2R-butyl) peptide alkaloids and addition salts thereof 2. Formula: [wherein R1 represents methyl, ethyl or inpropyl]. ] The compound according to claim 1, which is a compound represented by the following and an acid addition salt thereof. A compound according to claim 1 which is the compound or its acid addition salt in a mixture containing not more than 8.5% by weight of the corresponding 5'8-(28-butyl) epimer. The corresponding 5'8- (2B-
2. The compound according to claim 1, which is a compound in a mixture containing a (butyl) epimer or an acid addition salt thereof. 5, (5be8R,lOR)-N-[(2R,58,11
8,128)-5-(2R-butyl)-octahydro-
12-Hydroxy-2-isopropyl/l/-8,6-thioxo8H-oxazolo[8,2-alpyrrolo[2,
1-C]pyrazinyl]-6-methyl-ergoline-8-
The compound according to claim 1, which is a carboxylic acid amide and an acid addition salt thereof. 6. A compound according to claim 5 which is a compound or an acid addition salt thereof in a mixture containing not more than 6.5% by weight of dihydro-β-ergocributine or an acid addition salt thereof. 7. The compound according to claim 5, which is a compound or an acid addition salt thereof in a mixture containing not more than 1% of dihydro-β-ergocributine or an acid addition salt thereof. 8. A pharmacological pA composition comprising a compound according to item 1 or a pharmacologically acceptable acid addition salt thereof in combination with a pharmacologically acceptable carrier or diluent. 9. The pharmaceutical composition according to claim 8, which is in a unit dosage form containing at least 0.011 ng of the compound according to claim 1 or a pharmacologically acceptable acid addition salt thereof. 10. The pharmaceutical composition according to claim 8, which contains the compound according to claim 1 or a pharmacologically acceptable acid addition salt thereof at least 01 to 15"9. 11. Claim 1. A pharmacological composition according to claim 1θ for oral or rectal administration, containing 0.1 to 9 fng of the described compound or a pharmacologically acceptable acid addition salt thereof.12. The pharmaceutical composition according to claim 9, which contains 0.01 to 8 mg of the compound according to claim 1 or a pharmacologically acceptable acid addition salt thereof. 18. The compound according to claim 1 The pharmaceutical composition according to claim 9 for parenteral use, containing 0.01 to 1 to 0.0 of a pharmacologically acceptable acid addition salt thereof. 15. (115'8- A compound represented by (2R-buty/L/)aminocyclol 1, a compound represented by the formula (1), a compound represented by the formula (v), or a compound represented by the formula (vl), or A compound selected from compounds represented by the formula: