Anti-hypertensive derivatives of ergoline-2-thioethers and their sulphoxides

Abstract

A method for preparing ergoline derivatives in which the ergoline structure is variously substituted by morpholino-piperazino- and other active radicals to obtain novel compounds useful in cardiology as alpha-blocking, vasodilating, antihypertensive active ingredients of pharmaceutical preparations.

Description

The present invention concerns new ergoline derivatives of formula I and their use as pharmaceutically acceptable products ##STR1## wherein R=CH.sub.2 --OH, ##STR2## (where R.sub.A and R.sub.B are alkyls (C.sub.1 -C.sub.4) straight or branched, or R.sub.A is simply linked to R.sub.B to form heterocycles, with C.sub.3 -C.sub.8 carbon atoms, e.g. ##STR3## or linked with insertion of heteroatoms to form heterocycles ##STR4## such as morpholine (Z=O) and piperazine (Z=NH or N--R.sub.III, where R.sub.III =alkyl C.sub.1 -C.sub.4, phenyl) COOCH.sub.3, ##STR5## (where R.sub.IV=H, alkyl C.sub.1 -C.sub.6), CH.sub.2 --CN, ##STR6## (where R.sub.V =R.sub.VI =H or R.sub.V =R.sub.VI =CH.sub.3 ##STR7## M=S--R.sub.II or SO--R.sub.II R.sub.I =H, alkyl C.sub.1 -C.sub.4

R.sub.II =alkyl (C.sub.1 -C.sub.6), phenyl x Y=CH.sub.2 --CH<, CH.dbd.C<.

It has been found that the new compounds of general formula I, wherein M=S--R.sub.II can be prepared by reacting ergolines which are not substituted at position 2 with sulphochlorides such as R.sub.II --S--Cl (where R.sub.II is the above identified group) in aprotic solvents, such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethylene glycol dimethylether, etc., in a temperature range from -75 to +25.degree. C., possibly in the presence of acid acceptors, such as NaHCO.sub.3, Na.sub.2 CO.sub.3, K.sub.2 CO.sub.2, triethylamine, propyleneoxide. The reaction products can be separated and purified with usual methods such as for example crystallization, column chromatographic separation on SiO.sub.2, Al.sub.2 O.sub.3, etc. Separation, purification and yield are greatly simplified and improved when the reaction products are treated with Raney Ni in alcoholic solvents such as methanol, ethanol, in a temperature range from 25.degree. C. to 150.degree. C. to eliminate all the labile secondary products of polysubstitution.

Furthermore, it has been found that the compounds of general formula I where M=SO--R.sub.II can be prepared by oxidizing the corresponding sulphurated compounds M=S--R.sub.II with, for example, NaIO.sub.4 in aqueous dioxane or acetontrile or methanol, or with N-chlorobenzotriazole in solvents such as methylene chloride, CHCl.sub.3, tetrahydrofuran, methanol, or mixtures thereof, at low temperature (from -75.degree. C. to -30.degree. C.).

The compounds of general formula I are generally solid, crystalline and provide pharmaceutically acceptable salts with inorganic acids such as hydrochloric, hydrobromic, sulphuric, phosphoric acid, or organic acids, such as maleic, tartaric, citric, methansulphonic, etc.

The new compounds can be used as drugs as such or in the form of suitable salts with pharmaceutically acceptable acids, in doses of 0.1-10 mg.

The pharmaceutical dosage form can be tablets, sugar-coated tablets, drops, vials, suppositories. The solid forms for oral use can be formulated by mixing the active ingredient with various vehicles and diluents, such as lactose, mannitol, starch, cellulose and derivatives thereof, and lubricants such as magnesium or calcium stearate. The mixtures so obtained as treated to provide tablets or cores and these latter can be subsequently coated with sugar containing gum arabic, talc and a suitable lake or dye.

Or else, the said pharmaceutical product can be formulated as hard or soft gelatin capsules. In the soft gelatin capsules the active ingredient is preferably dissolved or suspended in a suitable liquid such as polyoxyethyleneglycol in the presence of a stabilizer such as sodium metabisulphite or ascorbic acid. In this way it is possible also to provide a pharmaceutical dosage form with prolonged release over time (sustained release form).

Finally, for rectal use, the active ingredient can be formulated for example in gelatin capsules for rectal use or with a vehicle for suppositories, for instance natural triglycerides such as cocoa butter.

The solution for parenteral use or the drops for oral use can be prepared by dissolving the active ingredient as such or in the form of a salt in a suitable dissolving and stabilizing agent comprising for example only sterile water or water containing 5-20% of ethanol, glycerol, propyleneglycol.

The following Examples illustrate the invention though without any way limiting it:

EXAMPLE 1

3 g of methyldihydrolysergate in 100 ml of CHCl.sub.3 is cooled to -60.degree. C. with dry ice and treated under agitation with 1.32 g of freshly distilled CH.sub.3 --S--Cl. The mixture is left under agitation for 30' at -60.degree. C. then the temperature is allowed to increase to -5.degree. C. and a basic pH is obtained with 5% NH.sub.4 OH. The organic phase is separated, washed with water to neutrality, then concentrated to dryness. The residue is chromatographed on a column of SiO.sub.2 disactivated with 10% H.sub.2 O, eluting with CH.sub.2 Cl.sub.2 /MeOH 99:1. The purified product is crystallized from benzene thus obtaining 1.9 g of methyl-2-methylthio-dihydrolysergate (compound 1); m.p. 188-190 [.alpha.]-15.3 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 295 m.mu. flex (.epsilon. 12.120) 290 m.mu. (.epsilon.13.500) 226 m.mu. (.epsilon.29.200); M.sup.+ 330; C.sub.18 H.sub.22 N.sub.2 O.sub.2 S calc. 65,42; %H 6.71; %N 8.48; found %C 64.35; %H 6.43; %N 8.33. The compounds from 7 to 17 are prepared similarly.

EXAMPLE 2

1.5 g of D-6-methyl-8beta (perhydroazepinyl-carbonyloxymethyl) didehydro-ergoline in 100 ml of methylene chloride is cooled to -30.degree. C. and 0.86 g of phenylsulphochloride is added. Leave at +4.degree. C. for 18 hrs., then quench with 5% NH.sub.4 OH; the organic phase is separated, washed with water to neutrality, then concentrated to dryness. The oily residue is dissolved in 99% EtOH and treated with 0.42 g of Maleic acid. The maleate is twice crystallized from 99% EtOH thus obtaining 1.15 g, of D-6-methyl-2-phenylthio-8beta (perhydroazepinyl carbonyloxymethyl)-didehydro-ergoline maleate (compound 2); m.p. 213-5 [.alpha.]-11 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 314 m.mu. (.epsilon.14.900) 252-242 m.mu. flex, 213 m.mu. (.epsilon.39.000); M.sup.+ 487 C.sub.33 H.sub.37 N.sub.3 O.sub.6 S calc. %C 65.55; %H 6.18; %N 6.96; found %C 65.20; %H 6.06; %N 6.63. D-6-methyl-z-phenylthio-8beta (perhydroazepinil carbonyloxymethyl)-ergoline (compound No. 20) is similarly prepared.

EXAMPLE 3

To 4.2 g of hydroergocristine in 250 ml of chloroform cooled to -60.degree. C. there is added 1.8 g of freshly distilled CH.sub.3 SCl. It is left under agitation, until a chromatographic control shows that there is no longer any dihydroergocristine. The solution is quenched with 5% NH.sub.4 OH, the organic phase is separated, washed to neutrality, then dried. The residue is dissolved in 250 ml methanol and treated under reflux with Raney Nickel in portions for a total of 35 ml. After boiling for 2 hrs., the reaction is complete. Cool, filter to separate Nickel and concentrate to dryness. The residue is chromatographed on SiO.sub.2, disactivated with 10% H.sub.2 O, by eluting with CH.sub.2 Cl/MeOH 99:1 and 95:5. The homogeneous fractions are collected, dissolved in acetone, and there is added methansulphonic acid to obtain an acid reaction. The salt is completely precipitated with anhydrous ether, the solid is filtered and crystallized from ethyl acetate obtaining 3.5 g of 2-methylthio-dihydro ergocristine methansulphonate (compound 3); m.p. 186-9 [.alpha.]-60 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 290 m.mu. (.epsilon.13.800) 220-4 flex 208 m.mu. (.epsilon.36.300) C.sub.37 H.sub.47 N.sub.5 O.sub.8 S.sub.2.1 H.sub.2 O--calc; %C 57.57; %H 6.39; %N 9.07--found %C 57.01; %H 5.81; %N 8.93.

EXAMPLE 4

To 2 g of D-6-methyl-2-methylthio-8beta(perhydroazepinyl-carbonyloxymethyl) ergoline in 200 ml acetonitrile, maintained at 50.degree. C., there is added over 3 hours 4.5 g sodium metaperiodate, dissolved in 30 ml H.sub.2 O at 50.degree.-60.degree. C. for 6 hrs, then dilute with water and extract with CHCl.sub.3. The CHCl.sub.3 residue is chromatographed on SiO.sub.2 disactivated with 10% water, eluting with CH.sub.2 Cl/MeOH 99:1-80:20. The homogeneous fractions are collected and crystallized from CH.sub.3 COOEt thus obtaining 0.70 g of D-6-methyl-2-methylsulphonyl-8beta(perhydroazepinyl carbonyloxymethyl) ergoline (compound 4); m.p. 230.degree.-2.degree. C. [.alpha.]-73 (c=0.5 C.sub.2 H.sub.5 N) .lambda..sub.max.sup.MeOH 286 m.mu. (.epsilon.17.800) 226 m.mu. (.epsilon.26.500) 214 m.mu. (.epsilon.21.400); M.sup.+ 443; C.sub.24 H.sub.33 N.sub.3 O.sub.3 S calc. %C 64.98; %H 7.50; %N 9.47; found %C 65.23; %H 7.56; %N 9.36.

EXAMPLE 5

2 g of D-6-methyl-2-methylthio-8beta(dimethylamino carbonyloxymethyl) ergoline, dissolved on 50 ml of a mixture CH.sub.2 Cl.sub.2 /MeOH 4:1 is cooled to -60.degree. C. and treated with 0.82 g of 1-chlorobenzotriazol, dissolved in 10 ml CH.sub.2 Cl.sub.2 /MeOH 1:1. After agitation for 2 hrs at -20.degree. C., 25 ml of 1 N NaOH, is added, the organic phase is separated and the water phase is extracted with CH.sub.2 Cl.sub.2. After drying and concentrating the organic phase, the residue is chromatographed in order to carry out a partial purification, on SiO.sub.2, by eluting with CH.sub.2 Cl.sub.2 /MeOH 99:1 and 95:5. The crude material is further purified by chromatography on acid Al.sub.2 O.sub.3 (IV) again eluting with CH.sub.2 Cl.sub.2 /MeOH 99:1. After crystallization from CH.sub.3 COOEt, D-6-methyl-2-methylsulphonyl-8beta(dimethylaminocarbonyloxymethyl)ergoline (compound 5) 0.45 g is obtained; m.p. 233- 5 [.alpha.]-73 (c=0.5 C.sub.5 H.sub.5 N).lambda..sub.max.sup.MeOH 286 m.mu. (.epsilon.17.000) 228 m.mu.(.epsilon.25.400) 214 m.mu. (.epsilon.19.000) M.sup.+ 389 C.sub.20 H.sub.27 N.sub.3 O.sub.3 S calc. %C 61.67; %H 6.99; %N 10.79; found %C 62.37; %H 6.85; %N 10.68. The compounds Nos. 18 and 19 are prepared similarly.

The compounds claimed in the present invention show interesting pharmacological properties, evidenced by means of classical tests on laboratory animals at extremely low doses.

In particular, the new compounds show alpha-blocking and vasodilator, anti-hypertensive, anti-serotonic both peripheral and central- and anti-asthmatic, anti-depressive and, in two cases, analgesic properties. In particular, compounds 11 and 9 have a broad spectrum of pharmacologycal properties, shown in the following table, compared to known substances used as comparison.

______________________________________ Antiadre- nalin Anti Anti 5HT Antitripta-(a) activity BaCl.sub.2 activity nic activityin in vivo activity in vitro in vivovitro (b) (e) (f) (g)EC.sub.50 ED.sub.50 EC.sub.50 EC.sub.50 ED.sub.50ng/ml .mu.g/kg/iv .mu.g/ml ng/ml mg/kg/sc______________________________________11.degree. 1.3 18.8 10 0.01 0.05 9.degree. 1.8 31 2.2 1 10nicergoline 7 (c) 20 (d)papaverine 8.9metergoline 0.005 0.062______________________________________ (a) J. Brugger, Helv. Physiol. Pharm. Acta 3, 117, (b) F. P. Luduena et al., Arch. Int. Pharmacodyn. 122, 111, (c) G. Arcari & coll., Brit. J. Pharmacol. 34, 700, (d) G. Arcari et Coll., Experientia 28, 819, (e) Magnus Pflugers Arch. ges. Physiol., 102, 123, (f) V. Ersparmer, Arch. Int. Pharmacodyn. 93, 293, (g) S. J. Corne et al., Brit. J. Pharmacol., 20, 106, 1963

As can be seen from the said Table, the two new compounds 9 and 11 possess high adrenolytic and anti-serotininic activity and for such compounds a pharmaceutical use as psychopharmacologic drugs and vasedilators is foreseen. On the other hand, compound No. 10 shows itself to be active both as adrenolytic (EC.sub.50 3.7 ng/ml and ED.sub.50 20 .mu.g/kg) and as spasmolytic (EC.sub.50 2 .mu.g/ml) and as antiasthmatic.

In this latter test (Goose, Immunology 16, 749, 1969) said compound shows an ED.sub.100 per os equal to 1 mg/kg compared to sodium chromoglycate which shows an ED.sub.100 of 5 mg/kg i.v. (it is to be noted that sodium chromoglycate is active only by the parenteral route, not by the oral route).

Furthermore, the antidepressive activity of many of such compounds is especially evident and considerably as the following Table shows:

______________________________________Antagonism to ptosis due to reserpine (B. M.Ashew, Life Sciences, 2, 725, 1963)______________________________________imipramine ED.sub.100 mg/kg/os 25N.degree. 12 " " 0.025N.degree. 13 " " 0.5N.degree. 14 " " 0.025N.degree. 15 " " 0.01N.degree. 16 " " 0.1N.degree. 17 " " 0.5______________________________________

This Table shows how some of the compounds listed are exceptionally active, up to 1000-2500 times the standard, and, in the absence of other important pharmacological activities except for a potent analgesic activity of compounds Nos. 12 and 14, the ED.sub.100 which is 2.5 mg/kg/sc and 5 mg/kg/sc respectively, versus the ED.sub.100 of D-propoxyphene, which is 10 mg/kg/sc, a pharmaceutical use is foreseen for said compounds, as anti-depressive drugs.

The physico-chemical data of the remaining compounds according to the present invention are reported below.

(6) D-6-methyl-2-methylthio-8beta(dimethylaminocarbonyloxymethyl)ergoline, m.p. 197.degree.-8.degree. (EtoAc)[.alpha.]-103 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 291 m.mu.(.epsilon.6.700) 226 m.mu. (.epsilon.14.350)M.sup.+ 373 C.sub.20 H.sub.27 N.sub.3 O.sub.2 S calc. %C 64.31; %H 7.29; %N 11.25 found %C 64.30: %H 7.21; %N 11.16.

(7) D-6-methyl-2-methylthio-8beta(diethylaminocarbonyloxymethyl)ergoline, m.p. 134.degree.-7.degree. (EtoAc)[.alpha.]-95.7 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 292 m.mu. (.epsilon.13.100) 226 m.mu. (.epsilon.28.400) M.sup.+ 401 C.sub.22 H.sub.31 N.sub.3 O.sub.2 S calc. %C 65.80; %H 7.78; %N 10.46; found %C 64.72; %H 7.22; %N 10.24.

(8) D-6-methyl-2-methylthio-8beta(pyrrolidinocarbonyloxymethyl)ergoline, m.p. 118.degree.-120.degree. (MeOH) [.alpha.]-97 (c=0.5 C.sub.5 H.sub.5 N) .epsilon..sub.max.sup.MeOH 290 m.mu. (.epsilon.13.400) 226 m.mu. (.epsilon.28.800) 210 m.mu. (.epsilon.21.600)M.sup.+ 399 C.sub.20 H.sub.27 N.sub.3 O.sub.2 S calc. %C 66.13; %H 7.32; %N 10.52; found %C 62.41; %H 6.97; %N 9.97.

(9) D-6-methyl-2-methylthio-8beta(piperidinocarbonyloxymethyl)ergoline, m.p. 135.degree.-7.degree. (EtoAc) [.alpha.]-91 (c=0.5 MeOH).epsilon..sub.max.sup.MeOH 292 m.mu. (.epsilon.15.300) 226 m.mu. (.epsilon.33.600) M.sup.+ 413 C.sub.23 H.sub.31 N.sub.3 O.sub.2 S calc. %C 66.79; %H 7.55; %N 10.16; found %C 66.27; %H 7.40; %N 9.83.

(10) D-6-methyl-2-methylthio-8beta(perhydroazepinylcarbonyloxymethyl)ergoline, m.p. 154.degree.-5.degree. (EtoAc) [.alpha.]-115.degree. (c=0.5 C.sub.5 H.sub.5 N).lambda..sub.max.sup.MeOH 292 m.mu. (.epsilon.13.500) 226 m.mu. (.epsilon.29.000) M.sup.+ 427 C.sub.24 H.sub.33 N.sub.3 O.sub.2 S calc. %C 67.41; %H 7.78; %N 9.83 found %C 67.17; %H 7.93; %N 9.55.

(11) D-6-methyl-2-methylthio-8beta(morpholinocarbonyloxymethyl)ergoline, m.p. 97.degree.-102.degree. (MeOH) [.alpha.]-98.7 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 291 m.mu. (.epsilon.7350) 226 m.mu. (.epsilon.16.000) M.sup.+ 415 C.sub.22 H.sub.29 N.sub.3 O.sub.3 S calc. %C 63.59; %H 7.03; %N 10.11 found %C 63.37; %H 6.68; %N 10.11.

(12) D-1,6-dimethyl-2-methylthio-8beta(dimethylamino carbonyloxymethyl)ergoline maleate, m.p. 167.degree. (MeOH) [.alpha.]-63.degree. (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 295 m.mu. (.epsilon.12.430) 226 m.mu. (.epsilon.36.600) M.sup.+ 384 C.sub.25 H.sub.33 N.sub.3 O.sub.6 S calc.%C 59.62; %H 6.60; %N 8.34; found %C 57.81; %H 6.04; %N 7.96.

(13) D-1.6-dimethyl-2-methylthio-8beta(diethylaminocarbonyloxymethyl)ergoline maleate, m.p. 99-103 (EtOH 99%) [.alpha.]-52.7 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 288 m.mu. (.epsilon.11.400) 223 m.mu. (.epsilon.34.800) 212 m.mu. (.epsilon.34.800) M+ 415 C.sub.27 H.sub.37 N.sub.3 O.sub.6 S calc. %C 60.99; %H 7.01; %N 7.90; found %C 61.44; %H 7.01; %N 7.70.

(14) D-1,6-dimethyl-2-methylthio-8beta(pyrrolidinocarbonyloxymethyl)ergoline maleate, p.m. 180.degree.-3.degree. (EtOH 99) [.alpha.]-56 (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 296 m.mu. (.epsilon.11.500) 214 m.mu. (.epsilon.37.600) M.sup.+ 413 C.sub.27 H.sub.35 N.sub.3 O.sub.6 S calc. %C 61.23; %H 6.66; %N 7.93; found %C 60.83; %H 6.49; %N 7.44.

(15) D-1,6-dimethyl-2-methylthio-8beta(piperidinocarbonyloxymethyl)ergoline maleate, p.m. 155.degree.-158.degree. (EtOH ass.) [.alpha.]-68.8.degree. (c=0.5% C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 286 m.mu. (.epsilon.12.600) 225 m.mu. (.epsilon.37.500) 212 m.mu. (.epsilon.37.000) C.sub.28 H.sub.37 N.sub.3 O.sub.6 S calc. %C 61.86; %H 6.86; %N 7.73; found %C 62.38; %H 6.48; %N 7.81 M.sup.+ 427.

(16) D-1,6-dimethyl-2-methylthio-8beta(perhydroazepinylcarbonyloxymethyl)ergoline maleate, p.m. 133.degree.-136.degree. (EtOH-ether)[.alpha.].sub.D.sup.20 -62.degree. (c=0.5% C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 294 m.mu. (.epsilon.12.600) 225 m.mu. (.epsilon.35.700) M.sup.+ 441 C.sub.29 H.sub.39 N.sub.3 O.sub.6 S calc. %C 62.45; %H 7.04; %N 7.53; found %C 62.72; %H 6.71; %N 7.70.

(17) D-1,6-dimethyl-2-methylthio-8beta(morpholinecarbonyloxymethyl)ergoline, m.p. 223.degree.-225.degree. (EtOH as) [.alpha.].sub.D.sup.20 -88.degree. (c=0.5% C.sub.5 H.sub.5 N).lambda..sub.max.sup.MeOH 288 m.mu. (.epsilon.28.800) 228 m.mu. (.epsilon.73.050), 210 m.mu. (.epsilon.61.500)M.sup.+ 429 C.sub.23 H.sub.31 N.sub.3 O.sub.3 S calc. %C 64.31; %H 7.27; %N 9.78 found %C 61.06; %H 6.64; %N 9.48.

(18) D-6-methyl-2-methylsulphynil-8beta(piperidinocarbonyloxymethyl)ergoline, m.p. 228.degree.-230.degree. (EtoAc) [.alpha.]-70.degree. (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 286 m.mu. (.epsilon.17.800) 226 m.mu. (.epsilon.28.700) 210 m.mu. (.epsilon.21.400) M.sup.+ 429 C.sub.23 H.sub.31 N.sub.3 O.sub.3 S calc. %C .sub.63.31; %H 7.27; %N 9.78 found %C 64.10; %H 7.17; %N 9.65.

(19) D-6-methyl-2-methylsulphynil-8beta(morpholinocarbonyloxymethyl)ergoline, m.p. 222.degree.-4.degree. (EtoAc) [.alpha.]-77.degree. (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 286 m.mu. (.epsilon.16.700) 228 m.mu. (.epsilon.24.800) 214 m.mu. (.epsilon.18.500) M.sup.+ 431 C.sub.22 H.sub.29 N.sub.3 O.sub.4 S calc. %C 61.23; %H 6.77; %N 9.74; found %C 59.37; %H 6.36; %N 9.66.

(20) D-6-methyl-2-phenylthio-8beta(perhydroazepynilcarbonyloxymethyl)ergoline maleate, m.p. 208.degree.-9.degree. (EtOH 99) [.alpha.]-58.degree. (c=0.5 C.sub.5 H.sub.5 N) .lambda..sub.max.sup.MeOH 290 m.mu. (.epsilon.19.000) 224 m.mu. flex, 213 m.mu. (.epsilon.45.000) M.sup.+ 489 C.sub.33 H.sub.39 N.sub.3 O.sub.6 S calc. %C 65.43; %H 6.49; %N 6.94; found %C 65.90; %H 6.61; %N 6.69.

Claims

1. An ergoline derivative having the formula ##STR8## wherein R=CH.sub.2 --OH, ##STR9## (where R.sub.A and R.sub.B are alkyls (C.sub.1 -C.sub.4) straight or branched, or R.sub.A is simply linked to R.sub.B to form heterocycle ##STR10## which is perhydroazepine, pyrrolidine, morpholine (Z=O) or piperazine (Z=NH or N-R.sub.III, where R.sub.III =alkyl C.sub.1 -C.sub.4, phenyl), COOCH.sub.3, ##STR11## (where R.sub.IV =alkyl C.sub.1 -C.sub.6), CH.sub.2 --CN, or ##STR12## (where R.sub.V =R.sub.VI =H or R.sub.V =R.sub.VI =CH.sub.3 ##STR13## or M=S--R.sub.II or SO--R.sub.II

R.sub.I =H, alkyl C.sub.1 -C.sub.4

R.sub.II =alkyl (C.sub.1 -C.sub.6), phenyl and

x y=CH.sub.2 --CH< or CH.dbd.C< or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 which is D-6-methyl-2-methylthio-8 beta-(piperidinocarbonyloxymethyl) ergoline.

3. A compound according to claim 1 which is D-6-methyl-2-methylthio-8 beta-(morpholinocarbonyloxymethyl) ergoline.

4. A compound according to claim 1 which is D-1, 6-dimethyl-2-methylthio-8 beta-(dimethylaminocarbonyloxymethyl) ergoline maleate.

5. A compound according to claim 1 which is D-1,6-dimethyl-2-methylthio-8 beta-(diethylaminocarbonyloxymethyl) ergoline maleate.

6. A compound according to claim 1 which is D-1,6-dimethyl-2-methylthio-8 beta-(pyrrolidinocarbonyloxymethyl) ergoline maleate.

7. A compound according to claim 1 which is D-1,6-dimethyl-2-methylthio-8 beta-(piperidinocarbonyloxymethyl) ergoline maleate.

8. A compound according to claim 1 which is D-1,6-dimethyl-2-methylthio-8 beta (perhydroazepinylcarbonyloxymethyl) ergoline maleate.

9. A compound according to claim 1 which is D-1,6-dimethyl-2-methylthio-8 beta-(morpholinocarbonyloxymethyl) ergoline.

10. An anti-hypertensive composition containing a pharmaceutically acceptable carrier and as active ingredient an effective antihypertensive amount of an ergoline derivative as defined in claim 1 or a pharmaceutically acceptable salt thereof.