Ergoline derivatives and acid addition salts thereof

Novel ergoline derivatives and acid addition salts thereof are disclosed. These ergoline derivatives possess excellent anti-hypertensive activity, vasodilating activity, anti-ulcer activity, gastric secretion inhibitory activity, brain metabolism improving activity, anti-depressive activity and dopamine-like activity, and, therefore, are useful for prevention and treatment of various diseases such as hypertension, a wide variety of vein disorders, peptic ulcer, brain absormality, depression, Parkinson's disease, high prolactin blood disease, etc.

FIELD OF THE INVENTION 
This invention relates to novel ergoline derivatives and the acid addition 
salts thereof which are useful as pharmaceutical agent. More particularly, 
the present invention relates to novel ergoline derivatives represented by 
the formula (I) below having excellent anti-hypertensive activity, 
vasodilating activity, anti-ulcer activity, gastric secretion inhibitory 
activity, brain metabolism improving activity, anti-depressive activity 
and dopamine-like activity and, therefore, are useful for prevention and 
treatment of various diseases such as hypertension, a wide variety of vein 
disorders, peptic ulcer, brain abnormality, depression, Parkinson's 
disease, high prolactin blood disease, etc. 
BACKGROUND OF THE INVENTION 
Hitherto, ergotamine and ergometrine which are ergot-alkaloids have been 
used as pharmaceutical agents for treatment of migrain and as an uterine 
contracting agent, respectively. Also, various semi-synthesized alkaloids 
have been used clinically, and typical examples of such alkaloids include 
methylergometrine (as uterine contracting agent), dihydroergotamine (as 
agents for treatment of orthostatic hypotensive asthenia and migrain), 
dihydroergotoxine (as agent for improving brain and peripheral circulation 
disorders and as anti-hypertensive agent), bromocryptin (as agent for 
treatment of acromegalia, pituitary giantism and Parkinson's disease). 
These ergot-alkaloids and compounds related thereto possess various 
pharmacological activities, and have been known to have hypotensive, 
vasodilating, anti-ulcer, gastric secretion inhibitory, brain metabolism 
improving activity, anti-depressive activities as well as dopamine-like 
activity as described in, for example, The Alkaloids, Vol. 15, Academic 
Press, 1975, pp1-40 and literature references cited therein; Life Science, 
27, 349 (1980); Br. J. Pharmacol., 75, 143p (1982); Arzneim.-Forsch., 29, 
1227 (1979); ibid., 29, 1213 (1979); German Offen., No. 2,617,738; J. Med. 
Chem., 21, 754 (1978); Life Science, 29, 2227 (1981); J. Pharm. 
Pharmacol., 28, 563 (1976); J. Med. Chem., 17, 300 (1974); ibid, 18, 892 
(1975); ibid, 20, 1473 (1977); Experientia., 35, 1677 (1979); Br. Med. J., 
4, 442 (1974), etc. 
Further, extensive studies have been conducted on alkaloids for the purpose 
of developing pharmaceutical agents having excellent pharmacological 
activities as described in, for example, Collect. Czech. Chem. Commun., 
39, 1768 (1974), ibid, 42, 1407 (1977), ibid, 47, 1757 (1982); J. Pharm. 
Sci., 70, 1319 (1981); Experientia, 28, 819 (1972); Yakuri to Chiryo 
(Pharmacology and Treatment), 12, 402 (1984); Arzneim.-Forsch., 33, 1094 
(1983), ibid, 33, 1098 (1983); Swiss Pat. Nos. 551,975 and 551,976 (1976); 
Czech. Pat. No. 171,570 (1978); German Offen., Nos. 2,802,023 and 
2,810,774 (1978), 2,935,685 and 2,935,684 (1980), 3,026,271 (1981), 
3,240,727 (1983); European Patent Application No. 1,115 (1979), 8,802 
(1980), 56,358 (1982); Fr. Demmande Nos. 2,421,176 (1979), 2,434,814 
(1980), 2,479,829 (1981); U.S. Pat. Nos. 4,199,579 (1980), 4,321,381 
(1982); Belgian Pat. Nos. 870,414 (1979), 896,609 (1983); Spanish Pat. No. 
508,102 (1982); Japanese Patent Application (OPI) Nos. 53-84996, 
54-115400, 55-89282, 56-156279, 57-156485, 58-194884, 58-85886, 59-176285, 
etc. (The term "OPI" as used herein refers to an unexamined published 
Japanese patent application.) 
On the other hand, the compounds having an ergolin-8-ylmethyl group bonded 
to a 5-membered heterocyclic group have been reported in a small number of 
prior art references, e.g., Japanese Patent Application (OPI) Nos. 
58-194884 59-206382 and 60-84286. Further, there is only a very limited 
number of publications, e.g., Japanese Patent Application (OPI) No. 
59-206382 and 60-84286, with respect to the compounds wherein an 
ergolin-8-ylmethyl group is directly bonded to the nitrogen atom of a 
5-membered heterocyclic group containing at least one nitrogen atom, which 
are closely related to the compounds of this invention. 
Although these prior art compounds have excellent pharmacological 
activities, they are still unsatisfactory because of their weak activity, 
low selectivity of effects, and/or high toxicity. 
As a result of extensive studies on ergot-alkaloid related compounds, the 
present inventors found that ergoline derivatives of the formula (I) of 
the present invention and the pharmaceutically acceptable acid addition 
salts thereof have excellent pharmacological activities. 
DETAILED DESCRIPTION OF THE INVENTION 
The ergoline derivatives of the present invention are represented by the 
formula (I) 
##STR1## 
wherein R represents a 5-membered heterocyclic group which contains at 
least one nitrogen atom as a hetero atom and which is a monovalent group 
on the nitrogen atom thereof, selected from the group consisting of an 
imidazol-1-yl group, a 2-oxooxazolidin-3-yl group, a 1,2,4-triazol-1-yl 
group, a tetrazole group, a succinimido group, a 2-methylimidazol-1-yl 
group, a 2-ethylimidazol-1-yl group, a 2-isopropylimidazol-1-yl group, a 
2-propylimidazol-1-yl group, a 2-phenylimidazol-1-yl group, a 
2-ethyl-4-methylimidazol-1-yl group, a 
5-ethoxycarbonyl-4-methylimidazol-1-yl group and a 
4-ethoxycarbonyl-5-methylimidazol-1-yl group, and acid addition salts 
thereof. 
The compounds of the formula (I) of this invention can be prepared easily 
by reacting a sulfonate represented by the formula (II) 
##STR2## 
which is described in Helv. Chim. Acta., 41, 1984 (1958), Collect. Czech. 
Chem. Commun., 33, 577 (1968), etc., with imidazole, oxazolidin-2-one, 
1,2,4-triazole, tetrazole, succinimide, 2-methylimidazole, 
2-ethylimidazole, 2-isopropylimidazole, 2-propylimidazole, 
2-phenylimidazole, 2-ethyl-4-methylimidazole or ethyl 
4-methylimidazole-5-carboxylate, in the presence of a base such as sodium 
hydride, potassium carbonate, sodium carbonate, etc. Alternatively, the 
reaction can be effected using a metal salt of the above 5-membered 
heterocyclic reactant such as sodium salt or potassium salt. In either 
case, the reaction can be carried out in an inert solvent such as 
dimethylformamide, dimethyl sulfoxide, hexamethylphosphortriamide, 
acetone, methyl ethyl ketone, etc. at a temperature of about 30.degree. to 
about 120.degree. C. for a period of from about 0.5 to about 15 hours, 
using 1 mole to a large molar excess of the 5-membered heterocyclic 
reactant or a metal salt thereof per mole of the sulfonate represented by 
the formula (II), i.e., 6-methylergolin-8.beta.-ylmethyl tosylate. 
The compounds of the formula (I) according to the present invention can be 
converted into pharmaceutically acceptable acid addition salts thereof in 
a conventional manner. Preferred examples of the acid addition salts 
include those formed with pharmaceutically acceptable acids such as 
fumaric acid, maleic acid, tartaric acid, hydrochloric acid, sulfuric 
acid, methanesulfonic acid and the like. 
The compounds of the formula (I) and the acid addition salts thereof 
exhibit markedly excellent anti-hypertensive activity, vasodilating 
activity, anti-ulcer activity, gastric secretion inhibitory activity, 
brain metabolism improving activity, anti-depressive activity and 
dopamine-like activity as demonstrated in Examples 16 to 21 hereinafter 
described. 
In administering the compounds of this invention, these compounds can be 
formulated, alone or in combination with other ingredients, into various 
pharmaceutical preparations such as tablets, troches, pills, granules, 
powders, capsules, ampules, suppositories and the like. Examples of other 
ingredients include pharmaceutical diluents, carriers or excipients, 
lubricating agents, disintegrating agents, etc., for example, starch, 
dextrin, sucrose, lactose, silicic acid, carboxymethyl cellulose, gelatin, 
polyvinylpyrrolidone, glycerin, agar, calcium carbonate, sodium 
bicarbonate, paraffins, cetyl alcohol, stearic acid esters, kaolin, 
bentonite, talc, calcium stearate, magnesium stearate, polyethylene 
glycol, water, ethanol, isopropyl alcohol, polypropylene glycol, etc. 
The daily dosage of the compounds of the formula (I) and the acid addition 
salts thereof for oral administration may vary from about 0.05 to about 20 
mg per Kg of the body weight. The dosage level can, of course, be varied 
depending upon the severity of conditions and the particular type of 
disease to be treated, and so on. These compounds can be administered in a 
single dose or multiple doses.

The present invention is further illustrated in greater detail by the 
following Examples, but the present invention is not limited thereto. 
EXAMPLE 1 
1-(6-Methylergolin-8.beta.-ylmethyl)imidazole 
1.0 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 2.0 g of imidazole and 20 ml of dimethylformamide, and the 
resulting mixture was stirred for 30 minutes. 3.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 3 hours. After allowing the mixture to 
cool, ice-water was added to the reaction mixture, and the precipitated 
crystals were filtered and washed with water. The crystals thus obtained 
were dissolved in ethanol, and the solution was concentrated to a volume 
of about 1/3, followed by allowing to cool to obtain 1.3 g of the titled 
compound as colorless prisms having a melting point of higher than 
260.degree. C. (with decomposition). 
NMR (CD.sub.3 OD) .delta.: 1.12 (1H, q, J=11.6 Hz), 1.80-3.05 (7H, m), 2.40 
(3H, s), 3.96 (2H, d, J=6.3 Hz), 6.63-7.20 (6H, m), 7.64 (1H, br s). 
NMR (DMSO-d.sub.6) .delta.: 1.01 (1H, q, J=11.9 Hz), 1.68-2.94 (7H, m), 
3.26 (1H, dd, J=14.2, 5.4 Hz), 3.91 (2H, d, J=6.6 Hz), 6.57-7.23 (6H, m), 
7.60 (1H, s), 10.73 (1H, br s). 
Elementary Analysis for C.sub.19 H.sub.22 N.sub.4 : Calc'd: C, 74.48; H, 
7.24; N, 18.29. Found: C, 74.58; H, 7.47; N, 18.02. 
The furmarate salt of the above compound was colorless needles and had a 
melting point of 205.degree.-212.degree. C. (with decomposition) after 
recrystallization from methanol-ethanol. 
EXAMPLE 2 
3-(6-Methylergolin-8.beta.-ylmethyl)oxazolidin-2-one 
0.5 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 2.0 g of oxazolidin-2-one and 15 ml of dimethylformamide, and 
the resulting mixture was stirred for 30 minutes. 2.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 1 hour. The solvent was distilled off 
under reduced pressure, and the residue (which was dissolved in 
dichloromethane and adsorbed on silica gel) was purified by silica gel 
column chromatography (eluted with ethyl acetate:isopropyl alcohol=1:1 by 
volume). The product was recrystallized from isopropyl alcohol to obtain 
1.3 g of the titled compound as colorless needles having a melting point 
higher than 240.degree. C. (with decomposition). 
NMR (CDCl.sub.3) .delta.: 1.15 (1H, q, J=11.8 Hz), 1.82-3.83 (12H, m), 2.47 
(3H, s), 4.20-4.47 (2H, m), 6.75-7.23 (4H, m), 7.98 (1H, br). 
IR (KBr) cm.sup.-1 : 1764 (CO). 
Elementary Analysis for C.sub.19 H.sub.23 N.sub.3 O.sub.2 : Calc'd: C, 
70.13; H, 7.12; N, 12.91. Found: C, 70.01; H, 7.34; N, 12.88. 
EXAMPLE 3 
1-Methyl-3-(6-methylergolin-8.beta.-ylmethyl)imidazolidin-2,4-dione 
A mixture of 0.5 g of 6-methylergolin-8.beta.-ylmethyl tosylate, 1.0 g of 
1-methylimidazolidin-2,4-dione, 1.0 g of potassium carbonate, 10 ml of 
methyl ethyl ketone and 10 ml of dimethylformamide was refluxed for 4 
hours with stirring, and the solvent was distilled off under reduced 
pressure. Water was added to the residue, and the mixture was extracted 
with dichloromethane. The organic layer was washed with water, dried over 
magnesium sulfate, and the solvent was distilled off. The residue (which 
was dissolved in dichloromethane and adsorbed on silica gel) was purified 
by silica gel column chromatography (eluted with ethyl acetate and then 
with ethyl acetate:isopropyl alcohol=1:1 by volume). The product was 
recrystallized from dichloromethane-hexane to obtain 0.3 g of the titled 
product as colorless needles having a melting point higher than 
210.degree. (with decomposition). 
NMR (CDCl.sub.3) .delta.: 1.18 (1H, q, J=11.8 Hz), 1.86-3.10 (7H, m), 2.45 
(3H, s), 3.01 (3H, s), 3.38 (1H, dd, J=14.4, 4.2 Hz), 3.49 (2H, d, J=6.2 
Hz), 3.87 2H, s), 6.77-7.26 (4H, m), 7.88 (1H, br). 
IR (KBr) cm.sup.-1 : 3410 (NH), 1768 (CO), 1715 (CO). 
Elementary Analysis for C.sub.20 H.sub.24 N.sub.4 O.sub.2.1/12CH.sub.2 
Cl.sub.2 : Calc'd: C, 67.10; H, 6.78; N, 15.58. Found: C, 67.21; H, 7.04; 
N, 15.38. 
EXAMPLE 4 
1-(6-Methylergolin-8.beta.-ylmethyl)pyrazole 
0.7 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 2.5 g of pyrazole and 20 ml of dimethylformamide, and the 
resulting mixture was stirred for 30 minutes. 2.5 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 1 hour. The solvent was distilled off 
under reduced pressure, and water was added to the residue. The 
precipitated crystals were separated by filtration, washed with water and 
recrystallized from dichloromethane-isopropyl ether to obtain 1.7 g of the 
titled compound as colorless flakes having a melting point of 
192.degree.-194.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.15 (1H, q, J=12.5 Hz), 1.81-3.10 (7H, m), 3.41 
(3H, s), 3.35 (1H, dd, J=14.7, 4.4 Hz), 3.85-4.27 (2H, m), 6.24 (1H, t, 
J=2.3 Hz), 6.69-7.17 (4H, m), 7.35 (1H, d, J=2.3 Hz), 7.48 (1H, d, J=2.1 
Hz), 8.13 (1H, br). 
Elementary Analysis for C.sub.19 H.sub.22 N.sub.4 : Calc'd: C, 74.48; H, 
7.24; N, 18.29. Found: C, 74.56; H, 7.60; N, 18.08. 
EXAMPLE 5 
3,5-Dimethyl-1-(6-methylergolin-8.beta.-ylmethyl)pyrazole 
0.7 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 1.9 g of 2,5-dimethylpyrazole and 50 ml of dimethylformamide, 
and the resulting mixture was stirred for 30 minutes. 2.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 3 hours. The solvent was distilled off 
under reduced pressure, and the residue was purified by silica gel column 
chromatography (eluted with ethyl acetate:ethanol=10:1 by volume). The 
product was recrystallized from isopropyl alcohol to obtain 0.8 g of the 
titled compound as colorless prisms having a melting point of 
187.degree.-190.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.19 (1H, q, J=12.5 Hz), 1.83-3.11 (7H, m), 2.21 
(3H, s), 2.25 (3H, s), 2.43 (3H, s), 3.37 (1H, dd, J=14.3, 4.1 Hz), 3.92 
(2H, d like), 5.76 (1H, s), 6.74-6.95 (2H, m), 7.84 (1H, br). 
EXAMPLE 6 
1-(6-Methylergolin-8.beta.-ylmethyl)-1,2,4-triazole 
0.4 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 2.0 g of 1,2,4-triazole and 20 ml of dimethylformamide, and the 
resulting mixture was stirred for 30 minutes. 2.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 1 hour. After allowing the mixture to 
cool, water was added to the reaction mixture, and the precipitated 
crystals were separated by filtration, washed with water and purified by 
alumina column chromatography (eluted with dichloromethane). The product 
was recrystallized from methanol to obtain 0.8 g of the titled compound as 
colorless needles having a melting point of 245.degree.-253.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.19 (1H, q, J=12.9 Hz), 1.85-3.13 (7H, m), 2.44 
(3H, s), 3.37 (1H, dd, J=14.3, 3.8 Hz), 4.14 (2H, d like), 6.71-6.94 (2H, 
m), 6.97-7.23 (2H, m), 7.90 (1H, br), 7.93 (1H, s), 8.48 (1H, s). 
Elementary Analysis for C.sub.18 H.sub.21 N.sub.5 : Calc'd: C, 70.33; H, 
6.89; N, 22.73. Found: C, 70.42; H, 7.07; N, 22.73. 
EXAMPLE 7 
1-(6-Methylergolin-8.beta.-ylmethyl)tetrazole 
1.7 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 5.1 g of tetrazole and 30 ml of dimethylformamide, and the 
resulting mixture was stirred for 30 minutes. 3.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 11 hours. The solvent was distilled 
off under reduced pressure, and the residue was purified by alumina column 
chromatography (eluted with acetone). The product was recrystallized from 
acetone to obtain 0.7 g of the titled compound as colorless needles having 
a melting point of 206.degree.-209.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.26 (1H, q, J=12.5 Hz), 1.82-3.13 (7H, m), 2.42 
(3H, s), 3.37 (1H, dd, J=14.3, 3.9 Hz), 4.60 (2H, d, J=6.3 Hz), 6.68-6.92 
(2H, m), 6.97-7.20 (2H, m), 7.89 (1H, br), 8.46 (1H, s). 
Elementary Analysis for C.sub.17 H.sub.20 N.sub.6 : Calc'd: C, 66.21; H, 
6.54; N, 27.25. Found: C, 66.46; H, 6.53; N, 27.65. 
EXAMPLE 8 
N-(6-methylergolin-8.beta.-ylmethyl)succinimide 
0.8 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 3.4 g of succinimide and 50 ml of dimethylformamide, and the 
resulting mixture was stirred for 30 minutes. 2.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 30 minutes. The solvent was distilled 
off under reduced pressure, and water was added to the residue. The 
precipitated crystals were separated by filtration, and washed with water. 
The crystals thus obtained were treated with charcoal in ethanol and 
recrystallized from ethanol to obtain 0.9 g of the titled compound as 
colorless needles having a melting point of 233.degree.-238.degree. C. 
(with decomposition). 
NMR (CDCl.sub.3) .delta.: 1.19 (1H, q, J=11.2 Hz), 1.82-3.10 (7H, m), 2.43 
(3H, s), 2.72 (4H, s), 3.21-3.74 (3H, m), 6.70-7.20 (4H, m), 7.89 (1H, 
br). 
Elementary Analysis for C.sub.20 H.sub.23 N.sub.3 O.sub.2 : Calc'd: C, 
71.19; H, 6.87; N, 12.45. Found: C, 71.30; H, 6.95; N, 12.49. 
EXAMPLE 9 
2-Methyl-1-(6-methylergolin-8.beta.-ylmethyl)imidazole 
0.8 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 1.2 g of 2-methylimidazole and 16 ml of dimethylformamide, and 
the resulting mixture was stirred for 30 minutes. 2.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 3 hours. After allowing the mixture to 
cool, ice-water was added to the reaction mixture, and the precipitated 
crystals were separated by filtration, washed with water and purified by 
silica gel column chromatography (eluted with chloroform). The product was 
recrystallized from ethanol to obtain 1.1 g of the titled compound as 
colorless needles having a melting point higher than 300.degree. C. (with 
decomposition). 
NMR (CDCl.sub.3) .delta.: 1.18 (1H, q, J=12.0 Hz), 1.79-3.10 (7H, m), 2.41 
(3H, s), 2.43 (3H, s), 3.37 (1H, dd, J=14.2, 4.2 Hz), 3.77 (2H, d, J=6.9 
Hz), 6.74-6.93 (4H, m), 7.89 (1H, br). 
Elementary Analysis for C.sub.20 H.sub.24 N.sub.4 : Calc'd: C, 74.97; H, 
7.55; N, 17.48. Found: C, 74.71; H, 7.85; N, 17.18. 
EXAMPLE 10 
2-Ethyl-1-(6-methylergolin-8.beta.-ylmethyl)imidazole 
0.9 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 3.0 g of 2-ethylimidazole and 60 ml of dimethylformamide, and 
the resulting mixture was stirred for 30 minutes. 3.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 1.5 hours. The solvent was distilled 
off under reduced pressure, and the residue was purified by silica gel 
column chromatography (eluted with acetone). The product was 
recrystallized from methanolisopropyl alcohol to obtain 1.5 g of the 
titled compound having a melting point of 232.degree.-237.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.18 (1H, q, J=12.0 Hz), 1.38 (3H, t, J=7.4 Hz), 
1.70-3.10 (7H, m), 2.43 (3H, s), 2.71 (2H, q, J=7.4 Hz), 3.37 (1H, dd, 
J=14.4, 3.9 Hz), 3.78 (2H, d, J=6.9 Hz), 6.70-7.23 (6H, m), 8.30 (1H, br). 
Elementary Analysis for C.sub.21 H.sub.26 N.sub.4 : Calc'd: C, 75.41; H, 
7.84; N, 16.75. Found: C, 75.01; H, 7.86; N, 16.84. 
EXAMPLE 11 
2-Isopropyl-1-(6-methylergolin-8.beta.-ylmethyl)imidazole 
0.9 g of 50% sodium hydride in an oil was added to a mixture of 4.0 g of 
2-isopropylimidazole and 40 ml of dimethylformamide, and the mixture was 
stirred for 30 minutes. 2.0 g of 6-methylergolin-8.beta.-ylmethyl tosylate 
was added to the mixture which was then heated on a water bath for 2 
hours. The solvent was distilled off under reduced pressure, and water was 
added to the residue. The precipitated crystals were filtered, washed with 
water and purified by silica gel column chromatography (eluted with 
acetone). The crystals thus obtained were dissolved in methanol, and 
isopropyl alcohol was added thereto. The mixture was concentrated and 
allowed to cool to obtain 0.6 g of the titled compound as colorless 
needles having a melting point of 283.degree.-288.degree. C. (with 
decomposition). 
NMR (CDCl.sub.3) .delta.: 1.18 (1H, q, J=11.7 Hz), 1.34 (3H, d, J=6.7 Hz), 
1.35 (3H, d, J=6.7 Hz), 1.80-3.09 (7H, m), 2.43 (3H, s), 3.37 (1H, dd, 
J=14.3, 4.4 Hz), 3.80 (2H, d, J=6.8 Hz), 6.65-7.25 (6H, m). 
Elementary Analysis for C.sub.22 H.sub.28 N.sub.4 : Calc'd: C. 75.82; H, 
8.10; N, 16.03. Found: C, 76.15; H, 8.39; N, 16.25. 
EXAMPLE 12 
1-(6-Methylergolin-8.beta.-ylmethyl)-2-propylimidazole 
0.68 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 2.1 g of 2-propylimidazole and 50 ml of dimethylformamide, and 
the resulting mixture was stirred for 30 minutes. 2.0 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 2.5 hours. The solvent was distilled 
off under reduced pressure, and the residue was purified by alumina column 
chromatography (eluted with ethyl acetate:benzene=1:2, and then with ethyl 
acetate). The resulting product was recrystallized from acetone-hexane to 
obtain 0.8 g of the titled compound as colorless needles having a melting 
point of 223.degree.-227.degree. C. (with decomposition). 
NMR (CDCl.sub.3) .delta.: 1.01 (3H, t, J=6.9 Hz), 1.17 (1H, q, J=12.0 Hz), 
1.60-3.12 (11H, m), 2.43 (3H, s), 3.37 (1H, dd, J=14.4, 3.8 Hz), 3.78 (2H, 
d, J=6.8 Hz), 6.71-7.25 (6H, m), 7.94 (1H, br). 
EXAMPLE 13 
1-(6-Methylergolin-8.beta.-ylmethyl)-2-phenylimidazole 
1.0 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 10.5 g of 2-phenylimidazole and 60 ml of dimethylformamide, and 
the resulting mixture was stirred for 30 minutes. 3.5 g of 
6-methylergolin-8.beta.-ylmethyl tosylate was added to the mixture which 
was then heated on a water bath for 2 hours. The solvent was distilled off 
under reduced pressure, and the residue was purified by silica gel column 
chromatography (eluted with acetone). The product thus obtained was 
treated with charcoal in dichloromethane, and recrystallized from 
dichloromethaneisopropyl acetate to obtain 1.0 g of the titled compound as 
colorless prisms having a melting point of 193.degree.-195.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.03 (1H, q, J=12.0 Hz), 1.58-3.04 (7H, m), 2.39 
(3H, m), 3.34 (1H, dd, J=14.7, 3.9 Hz), 3.97 (2H, d, J=6.6 Hz), 6.62-6.88 
l (2H, m), 6.94-7.24 (4H, m), 7.28-7.67 (5H, m), 8.04 (1H, br). 
Elementary Analysis for C.sub.25 H.sub.26 N.sub.4 : Calc'd: C, 77.10; H, 
6.75; N, 14.33. Found: C, 77.10; H, 6.96; N, 14.34. 
EXAMPLE 14 
2-Ethyl-4-methyl-1-(6-methylergolin-8.beta.-ylmethyl)imidazole 
1.6 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 9.0 g of 2-ethyl-4-methylimidazole and 70 ml of 
dimethylformamide, and the resulting mixture was stirred for 30 minutes. 
4.1 g of 6-methylergolin-8.beta.-ylmethyl tosylate was added to the 
mixture which was then heated on a water bath for 2 hours. The solvent was 
distilled off under reduced pressure, and water was added to the resulting 
residue. The precipitated crystals were separated by filtration, washed 
with water and recrystallized from methanol to obtain 1.0 g of the titled 
compound as colorless needles having a melting point of 
172.degree.-174.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.14 (1H, q, J=11.7 Hz), 1.33 (3H, t, J=7.3 Hz), 
1.76-3.10 (9H, m), 2.20 (3H, d, J=1.2 Hz), 2.43 (3H, s), 3.37 (1H, dd, 
J=14.8, 4.1 Hz), 3.69 (2H, d, J=6.8 Hz), 6.51 (1H, s like), 6.63-7.23 (4H, 
m), 8.14 (1H, br). 
EXAMPLE 15 
Ethyl 4-methyl-1-(6-methylergolin-8.beta.-ylmethyl)-5-imidazolecarboxylate 
and ethyl 
5-methyl-1-(6-methylergolin-8.beta.-ylmethyl)-4-imidazolecarboxylate 
1.6 g of 50% sodium hydride in an oil was added in small portions to a 
mixture of 10 g of ethyl 4-methyl-5-imidazolecarboxylate and 70 ml of 
dimethylformamide, and the resulting mixture was stirred for 30 minutes. 
4.1 g of 6-methylergolin-8.beta.-ylmethyl tosylate was added to the 
mixture which was then heated on a water bath for 2 hours. The solvent was 
distilled off under reduced pressure, and the residue was subjected to 
alumina column chromatography eluting with ethyl acetate to obtain ethyl 
4-methyl-1-(6-methylergolin-8.beta.-ylmethyl)-5-imidazolecarboxylate from 
the first fraction. The product was recrystallized from 
dichloromethane-diethyl ether and was colorless prisms having a melting 
point of 225.degree.-227.degree. C. Yield, 0.7 g. This compound is 
hereinafter referred to as Compound 15A. 
NMR (CDCl.sub.3) .delta.: 1.13 (1H, q, J=11.7 Hz), 1.38 (3H, t, J=7.1 Hz), 
1.76-3.08 (7H, m), 2.41 (3H, s), 2.50 (3H, s), 3.37 (1H, dd, J=14.4, 4.2 
Hz), 3.83-4.44 [4H, m, 4.30 (2H, q, J=7.1 Hz)], 6.67-6.92 (2H, m), 
6.96-7.23 (2H, m), 7.39 (1H, s), 8.02 (1H, br). 
From the subsequent fractions of the above alumina column chromatography, 
ethyl 5-methyl-1-(6-methylergolin-8.beta.-ylmethyl)-4-imidazolecarboxylate 
was obtained. The product was recrystallized from ethanol-dichloromethane 
and was colorless prisms having a melting point of 248.degree.-251.degree. 
C. Yield, 0.8 g. This compound is hereinafter referred to as Compound 15B. 
NMR (CDCl.sub.3) .delta.: 1.15 (1H, q, J=11.5 Hz), 1.40 (3H, t, J=7.0 Hz), 
1.76-3.09 (7H, m), 2.41 (3H, s), 2.57 (3H, s), 3.37 (1H, dd, J=14.1, 2.6 
Hz), 3.79 (2H, d, J=6.5 Hz), 4.34 (2H, q, J=7.0 Hz), 6.64-6.79 (2H, m), 
6.94-7.25 (2H, m), 7.36 (1H, s), 8.11 (1H, br). 
EXAMPLE 16 
Anti-hypertensive Activity 
The anti-hypertensive activity of the compounds was determined by the tail 
cuff method using unanesthetized spontaneously hypertensive rats weighing 
300 to 350 g (21 to 25 week old). In this experiment, the systolic blood 
pressure was determined by the bloodless method using a hemodynamometer. 
The heart rate was determined simultaneously using a sphygmometer 
connected to the pulse output. After rats were placed under condition of 
40.degree. C. for 10 minutes, the blood pressure was determined by holding 
the rats in a holder. The test compounds were suspended in a 0.5 wt% 
aqueous gum arabic. Hydralazine hydrochloride used as a comparative agent 
was administered as an aqueous solution thereof. The volume of oral 
administration was 0.5 ml per 100 g of body weight. The results obtained 
are shown in Tables 1 and 2 below. 
TABLE 1 
______________________________________ 
Changes in Systolic Blood Presure 
Compound Dose (.DELTA. mmHg) 
(Example No.) 
mg/kg 1 2 4 6 24 (hrs)* 
______________________________________ 
Control -- -5 -1 -7 -5 1 
Example 1 10 -78 -49 -48 -60 -14 
Example 2 10 -64 -36 -37 -52 -11 
Example 3 10 -57 -66 -31 -27 -4 
Example 4 10 -37 -51 -58 -49 -15 
Example 6 10 -64 -67 -62 -65 -14 
Example 8 10 -64 -77 -59 -66 
Example 9 10 -50 -59 -60 -55 -9 
Example 10 10 -69 -64 -68 -66 
Example 11 10 -53 -56 -54 -58 
Example 12 10 -69 -59 -63 -59 
Example 13 10 -52 -46 -54 -48 
Example 15B 10 - 49 -49 -59 -59 
Dihydroergotoxine 
10 -19 -20 -13 -13 -16 
Methanesulfonate 
Hydralazine 10 -47 -52 -67 -41 -22 
Hydrochloride 
______________________________________ 
*Time (hour) after administration of the test compound. 
TABLE 2 
______________________________________ 
Compound Dose Changes in Heart Rate (.DELTA./min.) 
(Example No.) 
mg/kg 1 2 4 6 24 (hrs)* 
______________________________________ 
Control -- -10 -11 -18 -9 -7 
Example 1 10 -39 -56 -25 -58 -44 
Example 2 10 -39 -74 -58 -56 -23 
Example 3 10 26 1 2 -4 1 
Example 4 10 -16 -38 -52 -41 -7 
Example 6 10 -8 -30 -33 -21 -10 
Example 8 10 6 3 -32 -40 
Example 9 10 -12 -27 -36 -32 -3 
Example 10 10 2 -15 -6 -11 
Example 11 10 -37 -21 -24 -46 
Example 12 10 -25 -7 -8 -5 
Example 13 10 -46 -49 -49 - 55 
Example 15B 10 -4 5 -8 -11 
Dihydroergotoxine 
10 -21 -42 -41 -25 -6 
Methanesulfonate 
Hydralazine 10 65 66 75 64 44 
Hydrochloride 
______________________________________ 
*Time (hour) after administration of the test compound. 
EXAMPLE 17 
Gastric Secretion Inhibitory Activity 
Rats weighing 200 to 250 g (8 rats per group) which have been fasting for 
24 hours before testing were subjected to abdominal section under ether 
anesthesia, and the pylorus portion was ligated. Immediately after 
ligation, the test compound was administered into the duodenum as a 
suspension in a 5 wt% aqueous gum arabic at a volume of 2 ml/kg. The rats 
were sacrificed after 6 hours, and the stomach was extracted. The gastric 
juice was collected to determine the volume thereof, and the acidity of 
the gastic juice was titrated to a pH 7.0 with a 0.02N aqueous sodium 
hydroxide solution using a pH meter. The acid secretion amount per 6 hours 
(.mu.Eq/6 h) was calculated by (volume of gastric juice.times.acidity of 
gastric juice). The results obtained are shown in Table 3 below. 
TABLE 3 
__________________________________________________________________________ 
Compound Dose Volume of Gastric Juice Total Acidity 
Volume of Acid Secreted 
(Example No.) 
mg/kg 
ml/rat Inhibition (%) 
pH (mEq/liter) 
.mu.Eq/6 h 
Inhibition 
__________________________________________________________________________ 
(%) 
Control -- 3.78 .+-. 0.42 
-- 1.88 .+-. 0.08 
74.7 .+-. 6.3 
421.5 .+-. 114.7 
-- 
Example 1 
10 1.70** .+-. 0.31 
67.8 2.57* .+-. 0.23 
62.9 .+-. 3.8 
112.8* .+-. 29.4 
73.3 
Example 2 
10 1.94** .+-. 0.20 
63.3 2.64* .+-. 0.24 
61.4 .+-. 7.5 
122.9* .+-. 25.4 
70.8 
Example 3 
10 2.73* .+-. 0.32 
48.4 2.07 .+-. 0.22 
70.0 .+-. 5.3 
198.7 .+-. 34.3 
52.9 
Cimetidine 
100 2.10* .+-. 0.62 
60.2 3.10* .+-. 0.45 
43.5* .+-. 9.4 
142.5 .+-. 60.5 
66.2 
Dihydroergo- 
10 3.81 .+-. 0.62 
27.8 2.09 .+-. 0.15 
65.9 .+-. 3.5 
257.9 .+-. 49.0 
38.8 
toxine methane- 
sulfonate 
__________________________________________________________________________ 
*p &lt; 0.05 
**p &lt; 0.01 
EXAMPLE 18 
Anti-ulcer Activity 
The test compound was administered orally to Donryu male rats weighing 240 
to 300 g (7 rats per group) which have been fasting for 24 hours before 
testing, and, after 30 minutes, indomethacin was administered orally to 
the rats at a dose of 25 mg/kg. The rats were then maintained for 7 hours 
without feeding water and foods and then sacrificed. The stomach was 
extracted and fixed by infusing 7.5 ml of a 2% formalin solution into the 
stomach. The stomach was incised along the greater curvature thereof, and 
length (mm) of each ulcer generated in gastric glands was determined. The 
total length of the ulcer per rat was expressed in terms of an ulcer 
index. 
In this experiment, the test compound was suspended in a 0.5% aqueous gum 
arabic and administered at a volume of 5 ml/kg. Indomethacin (manufactured 
by Sigma Co., Ltd.) was administered as a 0.5 wt% aqueous suspension in 
sodium carboxymethyl cellulose at a volume of 5 ml/kg. As a control, a 0.5 
wt% suspension of aqueous gum arabic was orally administered at a volume 
of 5 ml/kg. The results obtained are shown in Table 4 below. 
TABLE 4 
______________________________________ 
Compound Dose Ulcer Index Inhibition 
(Example No.) 
(mg/kg) (mm) (%) 
______________________________________ 
Control -- 61.2 .+-. 6.6 
-- 
Example 2 10 4.4 .+-. 2.3*** 
92.7 
Cimetidine 100 28.3 .+-. 8.4** 
53.7 
Cetraxate 100 52.1 .+-. 8.7 
14.9 
Sofalcone* 100 59.2 .+-. 10.5 
3.4 
______________________________________ 
*Sofalcone: 
[5[(3methyl-2-butenyl)oxy2-[3[4[(3methyl-2-butenyl)oxy]phenyl1-oxo-2-prop 
nyl]phenoxy]acetic acid 
**p &lt; 0.01 
***p &lt; 0.001 
EXAMPLE 19 
Activity on KCN-induced Anoxia in Mice 
The test compound was administered intraperitoneally to ddY male mice (4 
week old), and, after 30 minutes, KCN (2.5 mg/kg) was administered 
intravenously from the tail. The time from KCN administration to death was 
determined. When the mouse survived longer than 3 minutes after KCN 
administration, the survival time of this mouse was calculated as 180 
seconds. The death was judged by respiratory standstill. The number of 
mice which survived longer than 3 minutes after KCN administration was 
counted and referred to as number of survival. The results obtained are 
shown in Table 5 below. 
TABLE 5 
______________________________________ 
Dose Number of 
Compound (mg/ Survival Time 
Survived Mice/ 
(Example No.) 
kg; i.p) 
(sec.) Total Mice 
______________________________________ 
Control -- 45.2 .+-. 2.2 
0/40 
Example 2 10 144.4 .+-. 17.6*** 
5/8 
Example 3 10 101.6 .+-. 17.8** 
2/8 
Dihydroergotoxine 
10 124.3 .+-. 16.5*** 
2/8 
methanesulfonate 
Calsium 500 43.8 .+-. 2.5 
0/9 
Hopantenate 
Meclofenoxate 
200 47.7 .+-. 4.4 
0/6 
Hydrochloride 
______________________________________ 
**p &lt; 0.01 
***p &lt; 0.001 
EXAMPLE 20 
Activity on Reserpine-induced Immobility 
Reserpine was administered intraperitoneally to ddY male mice (4 week old) 
at a dose of 2 mg/kg, and, after 18 to 20 hours, the test compound was 
administered intraperitoneally to the mice. Thereafter, the ambulation 
(the number of times of the animal crossed the demarcation line) of the 
mice was counted for a period of 1 minute at 15, 30, 45 and 60 minutes 
after the administration of the test compound, respectively, according to 
the open-field method. The total number of ambulation determined at 4 
times in each mouse and compared with that of the control. The results 
obtained are shown in Table 6 below. 
TABLE 6 
______________________________________ 
Compound Dose 
(Example No.) 
(mg/kg; i.p.) 
n Ambulation 
______________________________________ 
Control -- 16 19.1 .+-. 8.5 
Example 6 10 6 198.8 .+-. 32.2*** 
Bromocriptine 
10 6 36.7 .+-. 12.3 
Methanesulfonate 
Apomorphine 
3 10 71.0 .+-. 7.0*** 
Hydrochloride 
______________________________________ 
***p &lt; 0.001 
EXAMPLE 21 
Rotational Activity in Rats with Unilateral 6-Hydroxydopamine Lesion of the 
Substantia Nigra 
Rats under pentobarbital sodium anesthesia (50 mg/kg, i.p.) were fixed on 
an apparatus for fixing brain, and 6-hydroxydopamine (8 .mu.g/4 .mu.l) was 
injected in the substantia nigra (A:3.0, L:2.6, D:7.8) according to 
Pellegrino & Cushman's atlas. Seven days after the injection of 
6-hydroxydopamine, apomorphine was administered subcutaneously at a dose 
of 0.25 mg/kg, and the rats showing apparatus rotating movement to one 
side opposite to the destroyed side were selected. After 7 days, the test 
compound was administered intraperitoneally and, thereafter, rotating 
movement of the rats was observed over 1 minute at an interval of 5 
minutes during a period of 60 minutes. The results obtained are shown in 
Table 7 below. 
TABLE 7 
______________________________________ 
Compound Dose Number of Rotating 
(Example No.) 
(mg/kg, i.p.) 
Movement over 60 min. 
______________________________________ 
Example 6 10 0* 
Apomorphine 0.5 147 
Hydrochloride 
______________________________________ 
*Increase in spontaneous movement and sniffing occurred markedly and were 
continued for more than 5 hours. 
As is apparent from the data shown above, the compounds represented by the 
formula (I) of this invention possess excellent pharmacological 
activities. 
For example, as shown in Table 1, the compounds of this invention exhibited 
a very strong and long lasting hypotensive activity as compared with that 
of the comparative compound, dihydroergotamine. Further, the comparative 
compound, hydralazine, exhibited tachycardia in human as one of 
side-effects and also a marked increase in heart rate as shown in Table 2, 
whereas the compounds of this invention did not increase the heart rate 
and, rather, did not affect or reduce it. 
The compounds of this invention also exhibited a strong gastric secretion 
inhibitory activity as shown in Table 3, and the degree of inhibition was 
more than 10 times that of an anti-ulcer agent, Cimetidine 
(1-cyano-2-methyl-3-[2-[[(5-methylimidazole-4-yl)methyl]thio]ethyl]guanidi 
ne). Dihydroergotoxine did not reveal any significant gastric secretion 
inhibitory activity. Further, as shown in Table 4, the compounds of this 
invention exhibited a very strong anti-ulcer activity as compared with the 
comparative compound, Cimetidine. Cetraxate (p-hydroxyhydrocinnamic acid 
trans-(4-aminomethyl)cyclohexane carboxylate) and Sofalcone did not show 
any significant anti-ulcer activity. 
The compounds of this invention exhibited an excellent brain projection 
activity as shown in Table 5. In particular, the compound of Example 2 
exhibited the activity higher that that of dihydroergotoxine 
methanesulfonate. Calcium hopatenate and meclofenoxate hydrochloride which 
are known to have brain protection activity did not show any significant 
activity. 
Bromocriptine has been known to have an anti-depressive activity as 
reported in J. Affect. Disord., Vol. 1, 173 (1979), but the compound of 
this invention exhibited an excellent anti-depressive activity markedly 
higher than that of bromocriptine as shown in Table 6 as determined by 
reserpine-induced immobility, one of the anti-depressant test methods. 
Further, as shown in Table 7, the compound of this invention exhibited an 
excellent dopamine-like activity. 
The compounds of the formula (I) according to the present invention possess 
excellent anti-hypertensive activity, vasodilating activity, anti-ulcer 
activity, gastric secretion inhibitory activity, brain metabolism 
improving activity, anti-depressive activity and dopamine-like activity, 
and therefore, are useful for prevention and treatment of various diseases 
such as hypertension, a wide variety of vein disorders, peptic ulcer, 
brain abnormality, depression, Parkinson's disease, high prolactin blood 
disease, etc. 
REFERENCE EXAMPLE 1 
6-Methylergolin-8.beta.-ylmethyl [Compound described in J. Biol. Chem., 
Vol. 108, 595 (1935), Helv. Chim. Acta., Vol. 32, 1947 (1949), Collect. 
Czech. Chem. Commun., Vol. 33, 577 (1968)] 
The above compound was prepared by a modified method of the process 
described in Collect. Czech. Chem. Commun., Vol. 33, 577 (1968). 
10 g of sodium borohydride was added in small portions to a mixture of 10 g 
of 9,10-dihydrolysergic acid methyl ester, 80 ml of methanol and 40 ml of 
water, and the resulting mixture was refluxed for 1 hour. The reaction 
mixture was concentrated under reduced pressure, and ice-water was added 
thereto. The precipitated crystals were separated by filtration, washed 
with water and dried to obtain 7.2 g of the titled compound as colorless 
crystals. 
REFERENCE EXAMPLE 2 
6-Methylergolin-8.beta.-ylmethyl tosylate [Compound described in Helv. 
Chem. Acta., Vol. 41, 1984 (1958); Collect. Czech. Chem. Commun., Vol. 33, 
577 (1968); etc.] 
5.0 g of p-toluenesulfonyl chloride was added in small portions to a 
mixture of 5.0 g of 6-methylergolin-8.beta.-ylmethanol and 50 ml of 
pyridine while stirring, and the resulting mixture was stirred for 3 
hours. After completion of the reaction, 4 ml of water was added to the 
mixture which was then stirred for 30 minutes. The mixture was diluted 
with ice-water, rendered alkaline with potassium carbonate and allowed to 
stand. The precipitated crystals were separated by filtration, washed with 
water and dried to obtain 6.9 g of the titled compound as colorless 
crystals. The crystals thus obtained were recrystallized from 
dichloromethane-isopropyl acetate to obtain colorless leaflets having a 
melting point of 195.degree.-199.degree. C. (with decomposition). 
NMR (CDCl.sub.3) .delta.: 1.07 (1H, br q, J=11.8 Hz), 1.70-3.16 (7H, m), 
2.41 (3H, s), 2.44 (3H, s), 3.33 (1H, dd, J=14.6, 4.1 Hz), 3.78-4.13 (2H, 
m), 6.63-6.88 (2H, m), 6.96-7.40 [4H, m, 7.33 (2H, AB type d, J=8.2 Hz)], 
7.78 (2H, AB type d, J=8.2 Hz), 8.04 (1H, br). 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.