JPH0147478B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to ergot peptide derivatives, their production, and pharmaceutical compositions containing them. As is known, ergot peptide alkaloids are
It may be a natural product, a modified natural product, or it may be obtained only by synthetic methods. Swiss Patent No. 588485 discloses the synthesis of a wide variety of pharmaceutically active 7-ergolene-8-carboxylic acid esters and amides, including peptide moieties such as the cyclic tripeptide moiety of ergopeptins. Amides having the following are included. The 7-ergolene moiety may be substituted in the 2-position, particularly by methyl. These methyl compounds are disclosed to be prepared from the corresponding 8(R)ergoline esters and amides. However, the Swiss patent does not indicate whether these (8) ergoline derivatives have any uses other than as intermediates. The inventors have surprisingly discovered that the 2-methyl-8 (R) and (S) ergot peptide alkaloids, which are not specifically disclosed anywhere in the above-mentioned Swiss patent and are not proposed by it. , was found to have significant pharmaceutical properties. Accordingly, the present invention provides 2-methyl-8 (R) or (S) ergot peptide alkaloids. These compounds are hereinafter referred to as compounds of the invention. Furthermore, the present invention provides the formula [In the formula, R ₁ is (C _1-4 ) alkyl, R ₂ is (C _1-6 )
alkyl or benzyl, R ₃ and R ₄ are independently hydrogen or (C _1-4 )alkyl, R ₅ is hydrogen or bromine, R ₆ and R ₇ together are a single bond, R ₆
and R ₇ are each hydrogen, or R ₆ is methoxy and R ₇
is hydrogen. However, when R ₅ is bromine, R ₇ is hydrogen. ] provides a compound. In the formula, R ₁ is advantageously methyl or isopropyl. R ₂ is advantageous for benzyl,
Further, a branched alkyl (for example, one having 3 or 4 carbon atoms) is preferred. R ₃ is advantageously n- or isopropyl, preferably methyl. R ₄ is advantageously hydrogen. R ₅ is preferably hydrogen. R ₆ and
Advantageously, R ₇ forms a single bond. It should be appreciated that the side chain at position 8 of the ergot moiety may be in the alpha or beta configuration. The above compound of the present invention can be produced by the following method. a formula [In the formula, R ₁ and R ₂ have the same meanings as above. ] The acid addition salt of the compound with the formula [In the formula, R ₃ to R ₇ have the same meanings as above. ] or condensation with a reactive acid derivative of a compound of formula b [In the formula, R ₁ to R ₇ have the same meanings as above. R ₈ has the formula -CHR ₁₀ -S-R ₉ (wherein R ₁₀ is hydrogen or -S-R ₁₁ group (R ₁₁
is a lower alkyl or benzyl group), and R ₉ is a lower alkyl or benzyl group, or R ₁₀ is a -S-R ₁₂ group, and R ₁₂
together with R ₉ gives the formula -(CH ₂ )n- (n is 2
or 3), -CH ₂ -S-CH ₂ or

It is a group of [Formula]. ) is a group that can be reduced to methyl. ] or reduce the compound of c formula [In the formula, R ₁ to R ₇ have the same meanings as above. ] Provides a method for producing a compound of the above-defined formula, which comprises introducing a methyl group into the 2-position of the compound. Process a) may be carried out in the usual manner for the production of analogous ergot peptide alkaloids in order to form an amide bond between the ergot moiety and the aminocyclole by condensation. Advantageously, the acid addition salt of aminocyclole is the hydrochloride. Suitable reactive acid derivatives of 2-methyllysergic acid are, for example, acid chlorides, acid azides, or mixed anhydrides formed from sulfuric acid or trifluoroacetic acid. On the other hand, the reactive acid derivative may be an addition product prepared by treating 2-methyllysergic acid with dimethylformamide or acetamide and thionyl chloride, phosgene or oxalyl chloride. Preferably, the reaction is carried out in the presence of triethylamine or pyridine. Suitable solvents are, for example, chloroform, methylene chloride, dimethylformamide or acetonitrile. Preferably, the reaction is carried out at a temperature of about -30 to +20°C. Process b) may be carried out in the customary manner for analogous reductions, for example employing contact conditions and in particular using moderately active Raney nickels (eg Raney nickel W6) as catalyst. The reaction may be carried out in solution, for example in an acetone/dimethylformamide mixture. If the catalyst is pretreated with a solvent, the reduction may be carried out at room temperature. In other cases, slightly heated reaction temperatures (eg up to 50°C) are appropriate. The ergot part is 9,
When having 10 double bonds, it is preferred to employ lower temperatures to minimize saturation of this double bond. To obtain a suitable catalyst for satisfactory operation at low temperatures, the Raney Nickel W6 catalyst was prepared by diluting its aqueous suspension in an acetone/dimethylformamide mixture with stirring and diluting a sample of the supernatant 2-3 volumes with methylene chloride. It is sufficient to perform pretreatment until it does not become significantly opaque even when diluted. On the other hand, suitable reducing agents (e.g. sodium borohydride, lithium aluminum hydride and similar hydrides) in the presence of metal salts (e.g. salts of copper, zinc, titanium and nickel) in a protic or aprotic solvent You can also make a reduction. A particularly suitable salt is nickel boride prepared in ethylene glycol. Preferred R ₈ includes 1,3-dithian-2-yl group. On the other hand, the 2-(1,3)-dithiolano group is preferred. Process c) may be carried out in the usual manner for such methylation of analogous compounds, for example in a two-step reaction. For example, 9,10-zahydroergot peptide alkaloids may be substituted with an aminomethyl group at the 2-position and then hydrogenated. The introduction of the methyl group is preferably carried out in two steps,
The second step is the same as method b). The first step of the reaction may be carried out in a manner analogous to the preparation of the starting materials in method b) below. The starting material for the formula is an acid addition salt of a compound of the formula above. [In the formula, R ₃ to R ₈ have the same meanings as above. ] with reactive acid derivatives, for example by condensation in a manner analogous to method a). A compound of the formula may be, for example, a compound of the formula [In the formula, R ₃ to R ₇ have the same meanings as above. ] A compound of the formula L-R ₈ [wherein R ₈ has the same meaning as above. L is a leaving group. ] may be produced by reacting with the compound. The reaction may be carried out in the presence of a Lewis acid (eg titanium trichloride). Leaving groups can be for example chlorine, lower alkoxy or [In the formula, n has the same meaning as above. ] May be the basis of The reaction may be carried out in an inert solvent such as chloroform or methanol. Suitable reaction temperatures are about -10 to +40°C. A compound of formula may be, for example, 2-methoxy-1,3
-dithiolane, 2-chloro-1,3-dithiane or 1,2-bis-(1,3-dithiolane-2-
It may be ylthio)ethane. Advantageously, the first two compounds are prepared in situ in the reaction system. Its use in 2-chloro-1,3-dithiane (see J.Org.Chem., 44 , 1847 (1979)) facilitates the introduction of the 1,3-dithianyl moiety under mild conditions and without the Lewis acid. do. In the other two compounds it is advantageous to use Lewis acids. On the other hand, compounds of formula 2-chloro-1, 2-chloro-1,
It may be prepared by reacting 3-dithiane in the absence of a Lewis acid (see Example 18). Unless otherwise stated, the preparation of starting materials is known and may be prepared by methods known or analogous to those described herein. In particular, starting materials other than compounds of formula for process b) may be prepared in a manner analogous to the above-mentioned methods for the preparation of compounds of formula. Compounds of the invention may be isolated and purified from reaction mixtures in conventional manner. The ergot part is 9,
With a double bond at position 10, isomerization appears to occur at position 8, especially when contacted with polar aprotic solvents. The mixture of 8R and 8S isomers can be prepared in the usual manner by
For example, they may be separated by chromatography. If desired, these 8R and 8S compounds can be
Epimerization may be carried out in conventional manner, for example by treatment with 2N sulfuric acid. The free base form of the compound of the present invention may be converted into an acid addition salt form, or vice versa, by conventional methods. Suitable salts for the formation of acid adducts are, for example, hydrochloric acid, maleic acid, sulfuric acid, fumaric acid and tartaric acid. Next, the present invention will be specifically explained with reference to Examples. Note that the temperature is not corrected. Example 1: 2-Methyl-α-ercocriptine and 2-methyl-α-ergocriptine (method a) 2.82 g (10 mmol) of 2-methyllysergic anhydride (lysergic acid instead of α-ergocriptine) obtained by the same procedure as in Example 18a) and b). ) is dissolved in 25 ml of anhydrous dimethylformamide by adding 2.28 g (20 mmol) of trifluoroacetic acid and brought to −10° C. with stirring. At this temperature, in 12 ml of anhydrous acetonitrile
A mixture of 2.52 g (12 mmol) of trifluoroacetic anhydride is added dropwise and the resulting clear solution is stirred for 10 minutes. 12 ml of pyridine and 1.81 g (5 mmol) of (2R,5S,10aS,10bS)-2-amino-
5-isobutyl-10b-hydroxy-2-isopropyl-octahydro-3,6-dioxo-8H
-Oxazolo [3,2-a] Pirolo [2,1-
c] Add pyrazine hydrochloride and bring the reaction mixture to -10~
Stir at 0°C for 1 hour. For post-treatment, add 200 ml of methylene chloride,
The mixture is thoroughly shaken with 100 ml of 2N sodium carbonate solution. Separate the organic layer and reduce the aqueous layer to 100%
Wash 3 times with ml methylene chloride. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel with 2% methanol in methylene chloride as eluent to give frame pure 2-methyl-α-ergocriptinine. Melting point 225-227°C from methylene chloride/ether (decomposition), [α] ²⁰ _D = +412° (C = 0.4 in chloroform). Elution with 3% methanol in methylene chloride was 2-
Generates methyl-α-ergocryptine. Reaction with 1 equivalent of fumaric acid gives the acidic fumarate salt. Melting point 181-184℃ (decomposition), [α] ²⁰ _D =
+25.0° (C=0.2, in ethanol). The following compounds are prepared in a similar manner to Example 1. Example 2: 2-Methyl-ergotamine Crystallization from methylene chloride/ether. melting point
219-221℃ (decomposition), [α] ²⁰ _D = +398゜ (C = 1.0,
in chloroform). Example 3: 2-Methyl-ergotamine Crystallization from methylene chloride/benzene. melting point
169-171℃ (decomposition), [α] ²⁰ _D = -100゜ (C = 1.0,
in chloroform). Example 4: 1,2-Dimethyl-ergotamine Crystallized as acidic tartrate from absolute ethanol. Melting point 178-179°C, [α] ²⁰ _D = +44° (C = 1.0, in dimethylformamide). Example 5: 2-Methyl-6-nor-6-isopropyl-9,10-dihydroergotamine Crystallization from methanol. Melting point 172℃ (decomposition),
[α] ²⁰ _D = -60.2° (C = 1.3 in methylene chloride). Example 6: 2-methyl-9,10-dihydro-β-
Ergocriptine Crystallization from methylene chloride/ether. melting point
187-190℃ (decomposition), [α] ²⁰ _D = -3.8゜ (C = 0.4,
in chloroform). Example 7: 2-Methyl-9,10-dihydroergotamine Crystallization from methylene chloride/ethyl acetate. melting point
185-186℃ (decomposition), [α] ²⁰ _D = -77.5° (C = 1.0,
in pyridine). Example 8: 2-Methyl-9,10-dihydroergocristine Crystallized from methylene chloride/ethyl acetate as the acidic fumarate salt. Melting point 191-192°C, [α] ²⁰ _D = -13.9° (C = 0.6, in methanol). Example 9: 2-Methyl-9,10-dihydro-ergonine Crystallization from methylene chloride/benzene. melting point
174-176°C (decomposed), [α] ²⁰ _D = -57° (C = 0.1, in pyridine). Example 10: 2-Methyl-9,10-dihydro-ergocornine Crystallization from methylene chloride/benzene. melting point
172-174°C (decomposed), [α] ²⁰ _D = -58° (C = 1.0, in pyridine). Example 11: 2-methyl-9,10-dihydro-α-
Ergocriptine Crystallization from methylene chloride/ether. melting point
179-182°C (decomposition), [α] ²⁰ _D = 2.4° (C = 0.55, in chloroform). Example 12: 2-methyl-2′β-isopropyl-5′α
-n-Butyl-ergopeptine Crystallized from ethyl acetate/acetone as acidic fumarate. Melting point 157-160℃ (decomposition), [α] ²⁰ _D = +
54.0° (C=0.55, in dimethylformamide). Example 13: 2-Methyl-ergocristine Crystallization from methylene chloride/isopropyl ether. Melting point 165-168°C (decomposition), [α] ²⁰ _D = +40.9° (C = 0.45, in dimethylformamide). Example 14: 2-Methyl-β-ergocriptine Crystallization from methylene chloride/isopropyl ether. Melting point 177-180°C (decomposition), [α] ²⁰ _D = +30.0° (C = 0.53, in dimethylformamide). Example 15: 2-Methyl-ergocornine Crystallized from ethyl acetate/ethanol as the acidic fumarate salt. Melting point 186-189℃ (decomposition), [α] ²⁰ _D =
+40.7° (C=0.59 in dimethylformamide). Example 16: 2-Methyl-6-demethyl-2'β-isopropyl-5'α-isobutyl-ergopeptine Crystallization from methylene chloride/ether. melting point
172-175℃ (decomposition), [α] ²⁰ _D = +60.0° (C = 0.21
,
in dimethylformamide). Example 17: 2-Methyl-6-demethyl-6-ethyl-2'β-isopropyl-5'α-isobutyl-ergopeptine Crystallized from ethyl acetate/ether as the acidic sulfate. Melting point 142-147°C (decomposition), [α] ²⁰ _D = +43.2° (C = 0.45, in dimethylformamide). Example 18: 2-Methyl-α-ergocriptine (method b or c) a 2-(1,3-dithian-2-yl)-α-
Ergocriptine in anhydrous chloroform, cooled to -15°C, approximately 1.2
A solution of 11.5 g (20 mmol) of α-ergocryptine in anhydrous chloroform is quickly added dropwise to a vigorously stirred solution of an equivalent amount of 2-chloro-1,3-dithiane. When the reaction mixture is warmed to 5-10°C, a dark-black precipitate forms. mix 10
Stir and work up at °C. Work-up consists of making the mixture alkaline with 2N sodium carbonate solution and extracting with methylene chloride/methanol (9:1). The organic layer is washed with saturated acidic sodium carbonate solution, dried over sodium sulfate, filtered and evaporated. 16.7g containing the listed compound
_A form _of
can be chromatographed on silica gel using 2% CH ₃ OH to yield the title compound. The acidic maleate salt of the listed compound has a melting point of 163
~165℃ (from ethyl acetate/ether), [α] ²⁰ _D =
+111° (C=0.55 in dimethylformamide). b 2-Methyl-α-ergocriptine 105 ml of an aqueous suspension of Raney Nickel W6,
Wash repeatedly with 100 ml volumes of acetone/dimethylformamide (8:2). A sample of the supernatant liquid is taken while adding acetone/dimethylformamide. When the sample becomes no longer opaque after treatment with methylene chloride, stop the acetol/dimethylformamide wash. 7.5 g of 2-(1,3-dithiane-
2-yl)-α-ergocriptine was added to 105 ml of Ranney Nickel in 100 ml of the same solvent.
Process with. After 15 minutes, strain the catalyst and let it approx.
Wash several times with 300 ml of solvent mixture.
Distillation of the solvent from the combined organic layers gave a brown foam, which was taken up in ethanol and diluted with fumaric acid (1
equivalent amount) to give the acidic fumarate salt of the title compound. Melting point 181-184℃ (decomposition), [α] ²⁰ _D = +
25.1° (C=0.2, in ethanol). In a similar manner, the title compounds of Examples 2-17 may be prepared. Example 19: 2-Methyl-6-nor-6-isopropyl-9,10-dihydro-ergotamine (method b) a 2-[2-(1,3)-dithiolane]-6-
nor-6-isopropyl-9,10-dihydro-
Ergotamine 60 ml of anhydrous dimethylformamide at -20°C with 2.7 g of oxalyl chloride in 8.5 ml of acetonitrile, then 7.1 g (17.7 mmol) of dry 2-[2-(1,3)-dithiolano]-6 -Nor-6-isopropyl-9,10-dihydro-lysergic acid (α-ergocriptine and 2-chloro-1,
6-isopropyl-9,10 instead of 3-dithiane
-dihydrolysergic acid and 2-chloro-(1,3-
dithiolane) by the same procedure as in Example 18a). ) to form a dark brown precipitate. The mixture was cooled to 0 °C for 30 min and heated to 18
ml of anhydrous pyridine, then 3.24 g (8.8
mmol) of (2R, 5S, 10aS, 10bS)-2-amino-5-benzyl-10b-hydroxy-2-methyl-octahydro-3,6-dioxo-8H-
Oxazolo [3,2-a] - Pirolo [2,1-
c] Treatment with pyrazine hydrochloride. Mixture at -10℃
Stir vigorously for 2 hours and warm to 0°C. For work-up, the mixture is treated with citrate buffer at PH4 and then made alkaline with 2N sodium carbonate solution. After extraction with methylene chloride, drying and concentration of the methylene chloride extract, chromatography on silica gel yielded the title compound, which was further used as is. b 2-methyl-6-nor-6-isopropyl-
9,10-dihydroergotamine 3.58 g (5 mmol) of 2-[2-(1,3)-thiolano] in 120 ml of ethylene glycol
6-nor-6-isopropyl-9,10-dihydro-ergotamine and 11.9 g of nickel chloride 6
3.8 g of sodium borohydride in 50 ml of water are slowly added dropwise to the hydrate solution. mixture
Heat to 90°C for 2 hours. The resulting black suspension is decanted and the liquid is extracted with methylene chloride. The organic extracts are washed with water, dried and concentrated to give a whitish foam which is chromatographed on silica gel eluting with 3% CH ₃ OH in CH ₂ CI ₂ to give the title compound. Melting point: 172℃ (decomposition,
from CH ₃ OH), [α] ²⁰ _D = −60.2° (C = 1.3,
CH ₂ CI ₂ medium). Compounds of Examples 1-4 and 6-17 may be prepared in a similar manner. The compounds of the present invention exhibit pharmacological activity in animals. The compounds of the present invention exhibit dopaminergic stimulatory effects as shown in standard animal tests.
lating effect). For example, compound approximately 0.03
When administered at ~3 mg/Kg, ip injection of 6-hydroxydopamine into the substantia nigra can induce the nigra-neostriatala dopamine pathway.
The rotation that occurs on one side of the pathway is inhibited [U.Ungerstaedt Acta physiol.scand.Suppl. 367 ,
64-93 (1973)]. Also, the compound is approximately
Apomorphine stereotypy test at 30 mg/Kg of compound administered ip inhibits stereotypy. Such compounds are therefore useful for use as antiparkinsonian agents, such as Morbus. Has therapeutic uses for Parkinson's. The indicated daily dosage ranges from about 0.5 to about 100 mg, so that it can be administered in unit dosage form containing about 0.1 mg to about 50 mg of the compound in two to four divided doses per day, or Advantageously, it is applied in a sustained form. The compounds of the present invention further exhibit inhibition of implantation in rats, e.g., at sc administration of about 0.01 to about 1 mg/Kg of the compound, and about 1 to about 10 mg/Kg, as shown in standard tests.
It exhibits prolactin secretion suppressing activity by suppressing milk secretion when mg/Kg of the compound is administered po. Therefore, such compounds are indicated for use as prolactin secretion inhibitors. The indicated daily dosage ranges from about 0.5 to about 100 mg, in unit dosage form containing about 0.1 to about 50 mg of compound, in divided doses 2 to 4 times per day.
Alternatively, it is advantageous to provide it in a specific form. In addition, the compounds of the invention exhibit antidepressant activity as demonstrated by the inhibition of ptosis and catalepsy produced by reserpine in rats upon ip administration of 1 to 50 mg/Kg of compound. Such compounds are therefore indicated for use as antidepressants. The indicated daily dosage ranges from about 0.5 to about 100 mg, in unit dosage form containing about 0.1 to about 50 mg of compound, in divided doses 2 to 4 times per day.
Alternatively, it is advantageous to apply it in a sustained-release form. The compounds of the present invention further exhibit the following effects: as shown by an increase in the wake phase and a decrease in parasleep and classical sleep phases in a rat sleep/wake cycle test upon po administration of about 5 to about 20 mg/Kg of the compound. Shows arousal-enhancing activity. Such compounds are therefore indicated for use as alertness enhancers. In addition, the compounds of the invention may be tested in standard animal tests, such as the Melander cat test [Angiologica 3, 77-99].
(1966)], an ia dose of about 5 to about 45 μg/Kg of animal body weight exhibits a vasoconstrictive effect due to the arterial vasotonizing effect. Such compounds therefore find use in the treatment of migraine and orthostatic disorders. For the above two applications, the indicated daily dosage ranges from about 0.5 to about 100 mg, conveniently about
It is given in unit dosage form containing from 0.1 mg to about 50 mg of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent in two to four divided doses per day. The test results regarding the above pharmacological activity are as follows. Tests were conducted on the following compounds. a formula The acidic fumaric acid form of the compound of the present invention represented by [hereinafter referred to as compound A]. shown in Example 1]. b formula The methanesulfonic acid salt form of the known compound α-ergocriptine shown in [hereinafter referred to as compound B]. For example, ergot alkaloids and
Related Compounds (Ergot Alkaloids)
and Related Compounds), page 36 (Springer Publishing, New York, 1978)]. 1 Overview As is clear from Section 2 below, Compound B, which is unsubstituted at the 2-position, has significant toxicity. Compound B has never been considered as a promising drug and was excluded from pharmacological screening at an early stage. In the following pharmacological activity tests, Compound A exhibits similar activity to Compound B or is more potent than Compound B. however,
When considering the difference in tolerability between these two compounds, Compound A is surprisingly clearly superior. The amounts in the data below indicate the amount of the ergot cyclic peptide alkaloid moiety, ie, the amount ignoring the weight of the acid addition salt. 2 Toxicity After intravenous injection in cats, both compounds
_LD50 was measured. The following results were obtained.

Table: Evaluation of results Compound A is surprisingly 30 times less toxic than Compound B. 3.1 Wake phase enhancing activity Wake phase enhancing activity was measured by measuring the sleep and wake phases in a rat sleep/wake cycle test. This method is described in "Pharmacology" by the present inventor as described below.
16, Appendix 1), 156-173 (1978). Experiments were performed in unanesthetized, unrestrained male Wistar rats fitted with long-term implanted electrodes for electroencephalogram (EEG) and electromyography (EMG) recordings. Animals were housed individually in cages indoors, maintained at a constant temperature of 22°C, and artificially illuminated for 12 hours during the day. Before the start of the experiment, animals were placed in the recording cage for 3 days.
An acclimatization period of 1 day was given. These cages were tall plastic tubes within which the animals had complete freedom of movement even when recording cables were attached. The standard procedure was as follows. On the first day of the experiment, 15 minutes after drug vehicle administration;
EEG and EMG recordings were performed continuously for 6 hours. On the second day of the experiment, similar recordings were started 15 minutes after drug administration. Each animal was used as its own control. The effects of these compounds on the persistence of the paradoxical sleep phase are shown in the table below.

Table: Evaluation of results Compounds A and B exhibit the same order of activity. Despite its low toxicity, Compound A appears to exhibit unexpected activity in this test. 3.2 Reserpine-induced PGO wave suppression Cat pontine-geniculate-occipital (PGO) waves (100 microvolts) were measured after intravenous administration of the compound. This test also shows arousal phase enhancing activity. The method used is described in “Pharmacology Volume 16” Appendix 1) by the present inventor.
156-173 (1978) (as described below). All studies were performed in unanesthetized cats fixed with galamin under mechanical ventilation. Before the start of surgery, animals received an intraperitoneal dose of 0.5 mg/Kg reserpine dissolved in dilute acetic acid solution. Animals were treated under ether anesthesia. Cannulae were inserted into the trachea for artificial ventilation, both femoral veins for drug injection, and one femoral artery for blood pressure measurement. After infiltrating the wound with novocaine, the animal was placed in a stereotaxic apparatus. Bipolar concentric electrodes were inserted into the left and right lateral geniculate nuclei using Horsley-Clark coordinates (A:7:L:10, right and left:H: +3.5). A 3 mm long screw electrode was inserted into the skull to allow recording of cortical activity. Pressure points were infiltrated with novocaine, and animals were immobilized by continuous infusion of garamin trithiodide (20 mg/hr), artificially ventilated, and maintained at a rectal temperature of 37.5°C. A Grass Model 78 polygraph system was used as the recording system. Statum blood pressure
Recorded by P23A pressure transducer. EEG, electrocardiogram and blood pressure were recorded by polygraph. After surgery, until 4 1/2 hours after reserpine administration,
Animals were allowed a recovery period. At this point, PGO waves occur at a frequency of 40–60 spikes/min in recordings from the lateral geniculate nucleus and from the cortex.
EEG exhibited fast activity at low voltage. Compounds were administered intravenously in increasing doses at 30 minute intervals thereafter. The table below shows the inhibition of reserpine-induced PGO waves by compounds. Compound ED ₅₀ (mg/Kg intravenously) A 0.18 B 0.08 Evaluation of results Same as for the test in 3.1. 4 Prolactin secretion inhibitory activity The prolactin secretion inhibitory activity of the compound was determined by a conventional method by measuring the ability of the compound to inhibit implantation after subcutaneous administration in rats. This test method was described by Frijutzkiger et al. in Experientia, vol. 34, 1330-1332 (1978).
This is what was written in . Adult proestrus rats (Ivanovus strain) were combined with males of proven reproductive potential. The next morning (1st
Day), sperm positive females were randomly assigned to different treatment groups (10 animals per group). On the fifth day,
A single dose of this material was injected subcutaneously. On the 12th day, rats were killed and autopsied. The uterus was examined for fetuses or implantation sites arising from fertilized eggs. If none were found, egg implantation was considered inhibited. That is, the results were of an all-or-nothing type. The dose required to inhibit implantation in 50% of the animals was calculated (ED ₅₀ ). The results obtained were as follows. Compound ED ₅₀ (mg/Kg sc) A 0.14 B 1.15 Evaluation of Results Compound A is unexpectedly significantly more potent than Compound B. 5. Antiparkinsonian Activity The antiparkinsonian activity of these compounds was determined by measuring their central nervous system dopaminergic stimulating activity. This activity is demonstrated by the induction of contralateral rotation in rats in which 6-hydroxydopamine unilaterally lesions the nigrostriatal tract, thereby inducing a hypersensitivity response in dopamine receptors. This method is described in Acta Physiologica Scandinavica by Ungerstät et al.
(Acta physiol.
- 173 (1978). Under pentobarbital (Nembutal) anesthesia,
Male OFA rats (140-160 g) were placed in a David Kopf stereotaxic frame. A sagittal suture cut of the skin was made and the underlying tissue was scraped to expose the bregma. A 2 mm wide hole is made +4.2 mm anterior and 1 mm lateral (right) from bregma, and a cannula (2R2 number 3 cardiac needle) with an outer diameter of 0.3 mm is inserted through the dura.
It was inserted to a depth of 7.5mm. 6-Hydroxydopamine hydrochloride solution (2 mg/ml 6-OHDA in saline,
(containing 0.2 mg/ml ascorbic acid as an antioxidant) was injected into the medial substantia nigra over 2 minutes using an "Agra" micrometer gauge propelled Hamilton syringe. The cannula was then withdrawn and the wound closed with clips. After one week, the animals
Challenged with 0.25 mg/Kg (s.c.) apomorphine and total number of rotations measured. Animals that responded by contralateral rotation to the lesion side were selected for another experiment. To facilitate comparisons between different compounds and between different animal groups, an average of 560 total rotations per animal obtained from 40 rats injected intraperitoneally with 0.25 mg/Kg apomorphine. The number of rotations in each animal was corrected by the derived coefficient. Animals were used after the initial 4 weeks of lesions and were subsequently treated only once a week. Rotation was recorded by observation with the aid of a manual counter. The direction of rotation was recorded in all cases. The results obtained were as follows. Compound 1000 revolutions induction dose (mg/Kg subcutaneous) A 0.31 B 0.27 Evaluation of results Compound A shows equal potency to Compound B. General Comments The 2-methyl analog (Compound A) of α-ergocriptine (Compound B) surprisingly has significant and useful pharmacological activity and is well tolerated. In fact, in clinical trials, the compound was well tolerated at single oral doses of 2.0 mg or less. The compounds of the invention may be administered in the form of pharmaceutically acceptable acid addition salts. Such acid addition salt forms are
It exhibits similar activity to the free base form and is easily produced by conventional methods. The present invention also provides pharmaceutical compositions comprising a compound of formula in free base form or in pharmaceutically acceptable acid addition salt form in combination with a pharmaceutical carrier or diluent. Such compositions advantageously contain more than 1% by weight of the compound of the invention and are in the usual forms for enteral or parenteral administration, such as capsules, tablets, suppositories, dispersible powders, syrups, elixirs. ,
They may be prepared by conventional techniques as suspensions or solutions. Suitable pharmaceutical diluents or carriers are compatible with the ergot alkaloids and include:
For example, water, alcohols, natural or hardened oils and waxes, calcium carbonate, sodium carbonate, calcium phosphate, kaolin, talc and lactose, as well as suitable preservatives such as ethyl-p -hydroxy-benzoates), suspending agents (e.g. methylcellulose, tragacanth and sodium alginate), wetting agents (e.g. lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate), granulating and disintegrating agents (e.g. starch and alginic acid), binders (e.g. starch, gelatin and gum arabic)
and lubricants such as magnesium stearate, stearic acid and talc. Compositions in tablet form may be coated by conventional techniques to delay disintegration of the tablet in the gastrointestinal tract and absorption of the active ingredient, thereby imparting a sustained action over a long period of time. Tablet composition Compound of formula [ ] (e.g. 2-methyl-9,10
-dihydro-ergotamine mesylate
...1.025mg Tartaric acid ...0.1mg Finely ground lactose ...84.975mg Cornstarch ...8mg Gelatin ...0.3mg Magnesium stearate ...0.5mg Stearic acid ...1.1mg Talc ...4mg The resulting composition was made into 100mg tablets. to press. Capsule composition Compound of formula [ ] (e.g. 2-methyl-9,10
-Dihydro-ergotamine...1mg Inert diluent (starch etc.)...299mg The composition is filled into hard gelatin capsules. Liquid Compositions The following compositions may be used to make liquid compositions.

[Table] In a group of compounds of formula [], R ₂ is (C _1-4 ) alkyl or benzyl, and R ₅ is hydrogen or bromine, provided that (i) when R ₅ is bromine
R ₆ and R ₇ are each hydrogen, and (ii) when R ₅ , R ₆ and R ₇ are each hydrogen, R ₃ is hydrogen or (C _2-4 )alkyl. In the second group of compounds of formula [], R ₂ is (C _1-4 )alkyl or benzyl, R ₃ is methyl,
and R ₅ , R ₆ and R ₇ are each hydrogen. In the third group of compounds of formula [], R ₅ is hydrogen and R ₆ and R ₇ together form a bond, or R ₆ and R ₇ are each hydrogen. In a fourth group of compounds, R ₃ is other than methyl when R ₅ , R ₆ and R ₇ are each hydrogen, and the 8 carbon atoms of the ergot moiety have the R configuration. In the fifth group of compounds, R ₃ is methyl, R ₅ and
R ₆ and R ₇ are each hydrogen, and the 8 carbon atoms of the ergot moiety have an R configuration. The compound of Example 18 exhibits particularly interesting properties.

Claims (1)

[Claims] 1 formula [In the formula, R ₁ is (C _1-4 ) alkyl, R ₂ is (C _1-6 )
alkyl or benzyl, R ₃ and R ₄ are independently hydrogen or (C _1-4 )alkyl, R ₅ is hydrogen or bromine, R ₆ and R ₇ together are a single bond, R ₆
and R ₇ are each hydrogen, or R ₆ is methoxy and R ₇
is hydrogen. However, when R ₅ is bromine, R ₇ is hydrogen. ] A method for producing a compound of the formula [In the formula, R ₁ and R ₂ have the same meanings as above. ] The acid addition salt of the compound with the formula [In the formula, R ₃ to R ₇ have the same meanings as above. ] A method consisting of condensation of a compound of with a reactive acid derivative. 2 formulas [In the formula, R ₁ is (C _1-4 ) alkyl, R ₂ is (C _1-6 )
alkyl or benzyl, R ₃ and R ₄ are independently hydrogen or (C _1-4 )alkyl, R ₅ is hydrogen or bromine, R ₆ and R ₇ together are a single bond, R ₆
and R ₇ are each hydrogen, or R ₆ is methoxy and R ₇
is hydrogen. However, when R ₅ is bromine, R ₇ is hydrogen. ] A method for producing a compound of the formula [In the formula, R ₁ to R ₇ have the same meanings as above. R ₈ has the formula -CHR ₁₀ -S-R ₉ , where R ₁₀ is hydrogen or a -S-R ₁₁ group (R ₁₁ is a lower alkyl or benzyl group), and
R ₉ is a lower alkyl or benzyl group,
or R ₁₀ is a -S-R ₁₂ group, where R ₁₂ together with R ₉ has the formula -(CH ₂ ) _o - (n is 2 or 3), -CH ₂ -S-CH ₂ - or a group of [Formula]. ) is a group that can be reduced to methyl. ] A method consisting of reducing a compound of 3 formulas [In the formula, R ₁ is (C _1-4 ) alkyl, R ₂ is (C _1-6 )
alkyl or benzyl, R ₃ and R ₄ are independently hydrogen or (C _1-4 )alkyl, R ₅ is hydrogen or bromine, R ₆ and R ₇ together are a single bond, R ₆
and R ₇ are each hydrogen, or R ₆ is methoxy and R ₇
is hydrogen. However, when R ₅ is bromine, R ₇ is hydrogen. ] compound. 4 When R ₅ , R ₆ and R ₇ are each hydrogen, R ₃
is other than methyl, and the 8 carbon atoms of the ergot moiety have an R configuration. 5 R ₂ is (C _1-4 ) alkyl or benzyl, and R ₅ is hydrogen or bromine (provided that (i) when R 5 is bromine, R ₆ and R ₇ are each hydrogen, ₍ ii) R ₅ ,
The compound of item 3 above, wherein R ₆ and R ₇ are each hydrogen and R ₃ is hydrogen or (C _2-4 )alkyl. 6 R ₂ is (C _1-4 ) alkyl or benzyl, R ₈
is methyl, and R ₅ , R ₆ and R ₇ are each hydrogen. 7. The compound of item 3 above, wherein R ₅ is hydrogen, and R ₆ and R ₇ together form a bond, or R ₆ and R ₇ are each hydrogen. 8 The third above which is 2-methyl-ergotamine
compound of term. 9 The compound of item 3 above which is 2-methyl-ergotamine. 10 The compound of item 3 above which is 1,2-dimethyl-ergotamine. 11 The third above which is 2-methyl-6-nor-6-isopropyl-9,10-dihydroergotamine
compound of term. 12 The compound of item 3 above, which is 2-methyl-9,10-dihydro-α-ergocryptine. 13 The compound of item 3 above which is 2-methyl-9,10-dihydroergotamine. 14 The compound of item 3 above which is 2-methyl-9,10-dihydroergocristine. 15 The compound of item 3 above which is 2-methyl-9,10-dihydroergonine. 16 The compound of item 3 above which is 2-methyl-9,10-dihydroergocornine. 17 2-methyl-2′β-isopropyl-5′α-n
-Butyl-ergopeptine, the compound of item 3 above. 18 The compound of item 3 above which is 2-methyl-ergocristine. 19 The compound of item 3 above, which is 2-methyl-β-ergocryptine. 20 The compound of item 3 above which is 2-methyl-ergocornine. 21 The compound of item 3 above which is 2-methyl-6-demethyl-2'β-isopropyl-5'α-isobutyl-ergopeptine. 22 2-methyl-6-demethyl-6-ethyl-
The compound of item 3 above which is 2'β-isopropyl-5'α-isobutyl-ergopeptine. 23 The compound of item 3 above which is 2-methyl-α-ergocryptine. 24 The compound of item 3 above which is 2-methyl-α-ergocriptinine. 25 The compound according to any one of the above items 4 to 24, which is a free base. 26 The compound according to any one of the above items 4 to 24, which is an acid addition salt. 27 Formula of free base or pharmaceutically acceptable acid addition salt [In the formula, R ₁ is (C _1-4 ) alkyl, R ₂ is (C _1-6 )
alkyl or benzyl, R ₃ and R ₄ are independently hydrogen or (C _1-4 )alkyl, R ₅ is hydrogen or bromine, R ₆ and R ₇ together are a single bond, R ₆
and R ₇ are each hydrogen, or R ₆ is methoxy and R ₇
is hydrogen. However, when R ₅ is bromine, R ₇ is hydrogen. ] An anti-Parkinsonian and prolactin secretion inhibitor containing a compound as an active ingredient. 28 Formula of free base or pharmaceutically acceptable acid addition salt [In the formula, R ₁ is (C _1-4 ) alkyl, R ₂ is (C _1-6 )
alkyl or benzyl, R ₃ and R ₄ are independently hydrogen or (C _1-4 )alkyl, R ₅ is hydrogen or bromine, R ₆ and R ₇ together are a single bond, R ₆
and R ₇ are each hydrogen, or R ₆ is methoxy and R ₇
is hydrogen. However, when R ₅ is bromine, R ₇ is hydrogen. ] An antidepressant and arousal enhancer whose active ingredient is the compound . 29 Formula of free base or pharmaceutically acceptable acid addition salt [In the formula, R ₁ is (C _1-4 ) alkyl, R ₂ is (C _1-6 )
alkyl or benzyl, R ₃ and R ₄ are independently hydrogen or (C _1-4 )alkyl, R ₆ is hydrogen or bromine, R ₆ and R ₇ together are a single bond, R ₆
and R ₇ are each hydrogen, or R ₆ is methoxy and R ₇
is hydrogen. However, when R ₅ is bromine, R ₇ is hydrogen. ] A therapeutic agent for migraine or orthostatic disorder, which contains a compound as an active ingredient.