Alkyl cyanomethyl ergoline-I derivatives and salts thereof, and methods for their preparation

A procedure is described for the preparation of a novel group of alkyl cyanomethyl ergoline-I derivatives and pharmaceutically acceptable salts thereof. The compounds are D-6-alkyl-8-cyanomethylergoline-I derivatives of the formula ##STR1## wherein R is an alkyl group of 2-4 carbon atoms.

This invention relates to ergoline derivatives. More particularly, the 
present invention relates to alkylcyanomethyl ergoline-I derivatives and 
to a process for the preparation thereof. 
During the past decade, there has been a birth of interest within the 
pharmaceutical industry in a class of compounds which evidence prolactin 
inhibition and antinidation characteristics, so suggesting their use in 
human and veterinary therapy. 
In accordance with the present invention, a procedure is described for the 
preparation of a novel group of alkylcyanomethyl ergoline-I derivatives 
and pharmaceutically acceptable salts thereof which have been found to 
inhibit prolactin secretion of gonadotropins, the former characteristic 
being manifested as an antinidation and antilactation effect and the 
latter by the ability to induce oestrus. The novel compounds described 
herein may be classified as D-6-alkyl-8-cyanomethylergoline-I compounds of 
the formula 
##STR2## 
wherein R is an alkyl group, either straight or branched chain, of 2-4 
carbon atoms. Studies of the described compounds have revealed that the 
activity thereof with respect to both prolactin inhibition and 
gonadotropin secretion is significantly higher in certain cases than the 
activity of prior art compositions such as those described in U.S. Pat. 
No. 3,732,231 and Belgian Pat. No. 811,610. 
The cyanomethylergoline-I derivatives herein may conveniently be prepared 
by 
(I) reaction of D-8-cyanomethylergoline-I of the formula 
##STR3## 
with an alkylation agent of the formula X--R wherein R is an alkyl group, 
either straight or branched chain, of from 2-4 carbon atoms and X is 
selected from the group consisting of 
(a) a halogen atom, 
(b) a moiety of a sulfonic acid, either aromatic or aliphatic, and 
(c) a sulfuric acid moiety, or 
(II) reaction of an ester of D-6-alkyl-8-hydroxymethylergoline-I of the 
formula 
##STR4## 
wherein X and R are as designated above with an alkali metal cyanide. The 
resultant composition of formua (1), above, may then be converted to a 
pharmaceutically acceptable addition salt by reaction with an acid. 
Turning first to the aforementioned alkylation reaction, this end may 
readily be attained by reacting the alkylation agent with the 6-nor 
derivative of formula (2), above, in an inert organic solvent, in the 
presence or absence of an acidbonding agent at temperatures ranging from 
0.degree.-150.degree. C. A general preference has been found for a 
temperature range of 20.degree.-100.degree. C. Solvents found to be of 
particular interest for this purpose include ethanol, ethylene glycol, 
ethylene glycol dimethyl ether, dimethylformamide, dimethylsulfoxide, 
hexamethylphosphoric triamide and the like. 
Alkylation agents employed herein may be chosen from among the alkyl 
chlorides, bromides and iodides, esters of sulfonic acid such as 
methanesulfonates, p-toluenesulfonate and the like, or esters of sulfuric 
acid such as diethyl sulfate. 
The acid-bonding agent whose use herein is optional may be either organic 
or inorganic bases. Typical of the former are tertiary amines such as 
triethylamine, N-methylpiperadine and the like. Suitable inorganic bases 
include the carbonates of sodium, potassium and calcium. Acid formed 
during the course of the reaction can be neutralized with the 
D-8-cyanomethylergoline-I employed as a starting material. 
The duration of the alkylation reaction is dependent upon several factors, 
namely, the reactivity of the alkylating agent chosen and the temperature 
of reaction. Thus, the duration may range from several hours to several 
days. 
It should also be noted that D-8-cyanomethylergoline-I, formula (2) above, 
is a novel compound which may be prepared by reacting 
D-6-methyl-8-cyanomethylergoline-I with cyanogen bromide at room 
temperature in an inert solvent such as dichloromethane or chloroform to 
yield D-6-cyano-8-cyanomethylergoline-I of the formula 
##STR5## 
by reduction or hydrolysis, selective reduction of the 6 organo group 
being the preferred procedure. Reduction may readily be effected with 
hydrogen in the presence of a catalyst such as Raney nickel in the 
presence of an organic solvent such as dimethylformamide, or by the action 
of zinc in acetic acid. Alternatively, this end may be attained by 
reaction with sodium borohydride in methanol or pyridine. 
Returning now to the alternative technique for preparing ergolines herein 
(reaction II), a reactive ester of D-6-alkyl-8-hydroxymethylergoline-I of 
formula (3) is reacted with an alkali metal cyanide such as cyanide of 
sodium or potassium in an inert solvent of the type described above (in 
reaction I) at a temperature ranging from 20.degree.-160.degree. C., a 
general preference being found for temperatures ranging from 
100.degree.-130.degree. C. 
The esters of formula (3) may be selected from among the corresponding 
halides or the sulfonic acid esters. The chloride and an ester of 
p-toluenesulfonic acid are of particular interest for this purpose. Once 
again, it is to be noted that these compounds, that is, the esters of 
formula (3) are novel compounds. They may readily be obtained by 
alkylation of the methyl ester of D-6-nor-9,10-dihydrolysergic acid 
(prepared according to T. Fehr et al, Helv. Chim. Acta 53, 2197 (1970)) 
with an alkyl halide to yield a D-6-nor-6-alkyl-9,10-dihydrolysergic acid 
methyl ester of the formula 
##STR6## 
wherein R is as stated above, the methyl ester being reduced to yield the 
corresponding D-6-alkyl-8-hydroxymethylergoline-I of the formula 
##STR7## 
wherein R is as stated above. The hydroxy compound (6) is then converted 
to the reactive ester of formula (3). 
Alkylation of the aforementioned methyl ester may be implemented with a 
corresponding alkyl halide, typically the bromide or iodide, in an inert 
organic solvent such as dimethylformamide in the presence of an acid 
bonding agent such as potassium carbonate. This reaction is carried out at 
a temperature ranging from 20.degree.-100.degree. C. 
Reduction of compound (5) to compound (6) is effected by means of complex 
metal hydrides in an inert organic solvent. Hydrides suitable for this 
purpose include lithium aluminum hydride, sodium bis-(2-methoxyethoxy) 
aluminum hydride, sodium borohydride and the like. A preferred material is 
lithium aluminum hydride in anhydrous diethyl ether or tetrahydrofuran. 
The 8-hydroxymethyl derivative of formula (6) may be converted to the 
reactive ester of formula (3) by chlorination of the former with reagents 
such as phosphorous pentachloride, phosphorous oxychloride, thioxyl 
chloride and the like at elevated temperatures. A preferred procedure for 
effecting this end involves reacting a D-6-alkyl-8-hydroxymethylergoline-I 
of formula (6) with an excess of phosphorous oxychloride at the boiling 
point of the reaction mixture. 
Pharmaceutically acceptable addition salts of 
D-6-alkyl-8-cyanomethylergoline-I compounds of formula (1) may be prepared 
by reacting at least 1 mole-equivalent of an inorganic or organic acid 
with 1 mole-equivalent of ergoline-I in a solvent. Solvents found suitable 
for this purpose are methanol, ethanol, water and mixtures thereof. Acids 
employed in this reaction may be chosen from among sulfuric, hydrochloric, 
hydrobromic, methanesulfonic, tartaric, maleic, citric and the like acids. 
As noted previously, the novel ergoline-I derivatives described herein 
evidence pharmacological activity which suggests their use in human and 
veterinary therapy. From the pathophysiological point, the novel compounds 
can be advantageously employed therapeutically in any case wherein it is 
desirable to decrease the prolactin level or to increase the level of 
gonadoptropins in the blood system of animals or humans. Typical of such 
applications are termination of postpartum lactation, galactorrhea, 
acromegalia, cerebral lesions of organic origin, hypertrophy or carcinoma 
of the prostate, certain hypofunctional states of the gonads, etc. 
Based upon studies made with compounds of the type described, it has been 
concluded that such compounds evidence an exceptionally high antilactation 
activity in rats. Thus, for example, D-6-n-propyl-8-cyanomethylergoline-I 
evidences significant activity at a dosage of 10 .mu.g/kg and 
D-6-ethyl-8cyanomethylergoline-I is still active at a dosage of 100 
.mu.g/kg. 
Antilactation effect is lactating female Wistar rats was assessed from the 
weight gain and survival of the sucklings, as well as from the degree of 
filling of their stomachs with milk on the basis of evaluation of the 
"milk spots" (see method described by L. Flueckiger, H. R. Wagner: 
Experientia 24, 1130 (1968); M. Auskova, K. Rezabek, M. Semonsky: 
Arzneimittelforsch., 4, 617 (1973). 
In the case of D-6-isobutyl-8-cyanomethylergoline-I a significant 
stimulating effect was found on the secretion of gonadotropins. 
Stimulation of secretion of pituitary gonadotropins was assessed from the 
degree of hypertrophy of the ovary remaining after a unilateral 
ovariectomy of adult female rats (see Benson et al, Endocrinology 84, 369 
(1969). 
Several examples of the application of the present invention are set forth 
below. It will be appreciated by those skilled in the art that the 
examples are for purposes of exposition only and are not to be construed 
as limiting. The melting points of the compound were determined on a 
Kofler block and are given in 0.degree. C., all other temperatures being 
in the same temperature system. Given values of specific rotation relate 
to compounds which are free of crystal solvent.

EXAMPLE 1--D-6-n-propyl-8-cyanomethylergoline-I 
210 mg (1.5 mmoles) of anhydrous potassium carbonate and 184 mg (1.5 
mmoles) of n-propyl bromide were added to 251 mg (1 mmole) of 
D-8-cyanomethylergoline-I in 10 ml of anhydrous dimethylformamide and the 
mixture stirred at 65.degree. C. for 24 hours. The major portion of the 
dimethylformamide solvent was distilled off under reduced pressure and the 
residue mixed with 25 ml of water. Then, the mixture was made alkaline by 
the addition of ammonia, the pH thereof ranging between 7.5 and 8. The 
resultant crude product was filtered (280 mg; 96%) and chromatographed on 
a silica gel column using a 9:1 chloroform-ethanol mixture as eluant. 
Crystallization from ethanol yielded pure 
D-6-n-propyl8-cyanomethylergoline-I as colorless needles, m.p. 
264.degree.-266.degree. C. (decomposition) [.alpha.].sub.D.sup.20 
-83.degree. C. (C=0.4 pyridine). 
Hydrogen tartrate of the foregoing base was prepared by dissolving 293 mg 
(1 mmole) of D-6-n-propyl-8-cyanomethylergoline-I in 20 ml of a hot 
aqueous solution of tartaric acid (300 mg, 2 mmoles). The water was 
distilled off under reduced pressure and the salt crystallized from 
ethanol, m.p. 207.degree.-210.degree. C. (decomposition). 
The D-8-cyanomethylergoline-I employed was prepared by adding 0.7 grams 
(6.5 mmoles) of cyanogen bromide to a solution of 1.33 grams (5 mmoles) of 
D-6-methyl-8-cyanomethylergoline-I in 175 ml of methylene chloride and 
stirring the mixture at room temperature for 2 days. A small portion of 
the separated compound was filtered, the filtrate extracted with a 10% 
tartaric acid solution and the organic layer removed under reduced 
pressure. The residue was crystallized from 95% aqueous alcohol and 
yielded 0.8 gram of D-6-cyano-8-cyanomethylergoline-I as colorless 
needles, m.p. 276.degree.-278.degree. C. (decomposition); 
[.alpha.].sub.D.sup.20 +46.degree. C. (C=0.4 pyridine). 3.4 grams of zinc 
powder was added to a solution comprising 0.60 gram of the above-described 
D-6-cyano derivative in a mixture comprising 120 ml of acetic acid and 2.4 
ml of water. The mixture was refluxed under nitrogen for 7 hours and 
filtered while hot, the solvent being distilled under reduced pressure 
from the filtrate. The residue was then shaken between 25 ml of water and 
25 ml of chloroform. The aqueous layer was next extracted with 25 ml of 
chloroform three times and made alkaline by the addition of ammonia to a 
pH of about 8. The resultant compound was filtered, dried and purified by 
chromatography as described previously. The resultant product was 
crystallized from 90% ethanol to yield D-8-cyanomethylergoline-I as 
colorless needles, m.p. 273.degree.-275.degree. C. (decomposition), 
[.alpha.].sub.D.sup.20 -49.degree. C. (C=0.4 pyridine). 
EXAMPLE 2--D-6-n-butyl-8-cyanomethylergoline-I 
The procedure of Example 1 was repeated with the exception that n-butyl 
iodide was used instead of n-propyl bromide. The reaction time was 24 
hours at 80.degree.-85.degree. C. and yielded 
D-6-n-butyl-8-cyanomethylergoline-I, [.alpha.].sub.D.sup.20 -79.degree. C. 
(C=0.4 pyridine). 
EXAMPLE 3--D-6-Isopropyl-8-cyanomethylergoline-I 
500 mg (3.6 mmoles) of anhydrous potassium carbonate and 3.1 grams (25 
mmoles) of isopropyl bromide were added to a solution of 301 mg (1.2 
mmoles) of D-8-cyanomethylergoline-I in 10 ml of dimethylformamide. The 
mixture was heated for 50 hours at a temperature from 
95.degree.-100.degree. C. and the procedure of Example 1 followed. The 
reaction yielded D-6-isopropyl-8-cyanomethylergoline-I, m.p. 
256.degree.-258.degree. C. (decomposition) [.alpha.].sub.D.sup.20 
-100.degree. C. (C=0.4 pyridine). 
EXAMPLE 4--D-6-Isobutyl-8-cyanomethylergoline-I 
The procedure of Example 3 was repeated with the exception that isobutyl 
bromide was used as the alkylation reagent rather than isopropyl bromide. 
The resultant D-6-isobutyl-8-cyanomethylergoline-I evidenced a m.p. of 
237.degree.-239.degree. C. (decomposition) (ethanol); 
[.alpha.].sub.D.sup.20 -91.degree. C. (C=0.4 pyridine). 
EXAMPLE 5--D-6-Ethyl-8-cyanomethylergoline-I 
152 mg (1.5 mmoles) of triethylamine and 232 mg (1.5 mmoles) of 
diethylsulfate were added to a solution of 251 mg (1 mmole) of 
D-8-cyanomethylergoline-I in 10 ml of anhydrous dimethylformamide and the 
mixture stirred at room temperature for 24 hours. The procedure of Example 
1 was then followed, so yielding D-6-ethyl-8-cyanomethylergoline-I, m.p. 
253.degree.-255.degree. C. (decomposition) (ethanol); 
[.alpha.].sub.D.sup.20 -95.degree. C. (C=0.4 pyridine). 
EXAMPLE 6--D-6-n-Butyl-8-cyanomethylergoline-I 
A mixture comprising 0.32 grams (1 mmole) 
D-6-n-butyl8-chloromethylergoline-I, 0.25 grams of sodium cyanide and 6.5 
ml of dimethylsulfoxide were heated under nitrogen to 120.degree. C. for 3 
hours. Next, the reaction mixture was poured into 30 ml of water and the 
separated product filtered, heated to 65.degree. C. with 20 ml of water 
for 15 minutes and, after cooling, refiltered. 0.24 grams (78% yield) of 
crude compound was crystallized from ethanol, yielding 
D-6-n-butyl-8-cyanomethylergoline-I, m.p. 187.degree.-189.degree. C. 
(decomposition); [.alpha.].sub.D.sup.20 -79.degree. C. (C=0.4 pyridine). 
The D-6-n-butyl-8-chloromethylergoline-I was prepared in accordance with 
the following procedure: 
0.11 grams of anhydrous potassium carbonate and 0.15 gram of n-butyl 
bromide were added to a solution of D-6-nor-9,10-dihydrolysergic acid 
methyl ester (0.135 g) in 7 ml of dimethylformamide and the mixture 
stirred at room temperature for 8 hours and maintained thereat for 24 
hours. Then, the reaction mixture was poured into 400 ml of water and the 
precipitated product filtered, dried and crystallized from methanol, 
yielding D-6-nor-6-n-butyl-9,10-dihydrolysergic acid methyl ester, m.p. 
169.degree.-171.degree. C., [.alpha.].sub.D.sup.20 -63.degree. C. (C=0.4 
methanol). 
0.436 g of the so-prepared methyl ester was dissolved in 120 ml of ether 
and the solution added dropwise under nitrogen to a stirred suspension of 
0.84 g of lithium aluminum hydride in 200 ml of anhydrous ether. The 
resultant mixture was stirred at room temperature for 2 hours. The excess 
of hydride formed was destroyed by adding dropwise a mixture of 5 ml of 
ethanol and 1.65 ml of water, the organic portion being filtered, 
extracted three times with 35 ml of an 8:2 hot chloroformethanol mixture 
and the combined organic extracts removed under reduced pressure. The 
residue of 0.31 g (78%) was crystallized twice from aqueous ethanol, 
yielding D-6-n-butyl-8-hydroxymethylergoline-I monohydrate, m.p. 
152.degree.-154.degree. C. It contained 5.87% of crystal water which was 
lost by drying at 117.degree. C. (0.2 torr); [.alpha.].sub.D.sup.20 
-68.degree. C. (C=0.5 pyridine). 
0.494 g of D-6-butyl-8-hydroxymethylergoline-I and 30 ml of phosphorous 
oxychloride were refluxed for 1 hours. The volatile material was distilled 
off under reduced pressure and the residue mixed with a 5% aqueous 
solution of sodium hydrogen carbonate. The resultant suspension was heated 
to 90.degree.-95.degree. C. for 15 minutes, cooled and the product 
filtered and washed with water. A chromatographic analysis of the dried 
crude product on a silica gel column using chloroform with 1% of ethanol 
as eluant yielded 0.33 g (63%) of D-6-n-butyl-8-chloromethylergoline-I 
which on crystallization from a mixture of ethanol and n-hexane melted at 
186.degree.-188.degree. C. (decomposition); [.alpha.].sub.D.sup.20 
-62.degree. C. (C=0.4 pyridine). 
The procedure followed in preparing the 6-n-butyl derivatives was used in 
preparing the following intermediates: 
D-6-nor-6-n-propyl-9,10-dihydrolysergic acid methyl ester, m.p. 
2.2.degree.-2.4.degree. C. (ethyl acetate), [.alpha.].sub.D.sup.20 
-63.degree. C. (C=0.4 dichloromethane); 
D-6-ethyl-8-hydroxymethylergoline-I, m.p. 252.degree.-254.degree. C. 
(ethanol-chloroform-cyclohexane), [.alpha.].sub.D.sup.20 -91.degree. C. 
(C=0.5 pyridine); 
D-6-n-propyl-8-hydroxymethylergoline-I, m.p. 181.degree.-182.degree. C. 
(aqueous ethanol), [.alpha.].sub.D.sup.20 -66.degree. C. (C=0.5 pyridine); 
D-6-ethyl-8-chloromethylergoline-I, m.p. 239.degree.-241.degree. C. 
(ethanol-hexane), [.alpha.].sub.D.sup.20 -87.degree. C. (C=0.2 pyridine); 
and 
D-6-n-propyl-8-chloromethylergoline-I, m.p. 232.degree.-234.degree. C. 
(chloroform-ethanol-cyclohexane), [.alpha.].sub.D.sup.20 -68.degree. C. 
(C=0.4 pyridine). 
EXAMPLE 7--D-6-n-propyl-8-cyanomethylergoline-I 
The procedure of Example 6 was repeated in preparing 
D-6-n-propyl-8-cyanomethylergoline-I, m.p. 264.degree.-266.degree. C. 
(decomposition) (ethanol), [.alpha.].sub.D.sup.20 -83.degree. C. (C=0.4 
pyridine) and D-6-ethyl-8-cyanomethylergoline-I, m.p. 
253.degree.-255.degree. C. (decomposition) (ethanol), 
[.alpha.].sub.D.sup.20 -95.degree. C. (C=0.4 pyridine) with the exception 
that D-6-n-propyl-8-cyanomethylergoline-I and 
D-6-ethyl-8-cyanomethylergoline-I, respectively, were employed rather than 
D-6-n-butyl-8-cyanomethylergoline-I.