NZ207963A - Ergoline derivatives,processes for their preparation and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £07963 2 07963 Priority Date(s): i »: mplete Specification Filed: "f.

Class: ^ Publication Date: .

P.O. Journal, No: m DRAWINGS NEW ZEALAND No.: Datr ERGOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM $/We, FARMITALIA CARLO ERBA S.p.A., Via Carlo Imbonati n.24, Milan, Italy, an Italian company, hereby declare the invention for which ? / we pray that a patent may be granted to i¥&/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 -(followed by la) -la- 2 079 Ergoline derivatives, processes for their preparation and pharmaceutical compositions containing same The invention relates to ergoline derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

The invention provides ergoline derivatives having group; R^ represents a hydrogen or halogen atom or a methyl, cyano, C -C^ alkylthio or phenylt-hio group; R„ and R represent hydrogen atoms and R represents / 8 3 a hydrogen atom or a methoxy group, or R represents a hydrogen atom and R and R taken 7 " 3 8 together represent a bond or P.^ represents a hydrogen atom or a methoxy group and R? and R& taken together represent a bond; represents a hydrocarbon group having from 1 to 4 carbon atoms; R^ represents a hydrogen atom or a 207963 hydrocarbon group having from 1 to 4 carbon atoms or a phenyl group; X represents an oxygen or and B taken together represent a -C- group wherein W V represents an cxyger. atom or an imino group; A represents a group of the formula CHn_, CH„-CKR, or 0 2 Q CH=CR. wherein represents a hydrogen atom or a C ,-C, alkyl group; and n is 0, 1 or 2.

Pharmaceutically acceptable salts of these ergoline derivatives are included in the invention.

In the definition of the term "halogen" should be construed to preferably encompass chlorine and bromine atom; nevertheless, term "halogen" also encompasses fluorine atom. In the definition of P and F. , a hydrocarbon group having ^ J from 1 to 4 carbon atoms is intended to include alkyl, cycloalkyl and unsaturated (both ethylenically and acetylenically) groups.

Representative moieties include methyl, ethyl, n-propvl isopropyl, butyl, t-butyl, isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl.

"Pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not sulphur atom or an imino group, Rgrepresents a hydrogen atom and B represents a cyano, a C -C alkoxycarfcjcnyl or carbamoyl group, or R w w J? 3- 207963 biologically or otherwise undesiderable, formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnarcic, mandelic, methanesulfonic, ethanesulfonic, p-toluen sulfonic or salicylic acid.

The subs ti tuer. ts R , F.„, R_, R_ and R_ are preferably 1 <; j ~ 8 s J hydrogen atoms. Preferably is a methyl group, n is 1, B and R are taken together and represent -C- group.

W Preferably V and X are oxygen atoms, and A represents a group of formula -CH5~ or -CH^-CH^-, most preferably A is a group of formula The present invention also provides a process for the preparation of a compound of formula 3 as described above which includes the step of condensing an ergoline derivative of the formula II II wherein R^ , R^, Rq> A, B anc n are as above defined with a comDQund of formula III X=C=N-R (III) wherein R 207063 and X are as above defined.

The resultant compounds of formula I wherein R^ is a hydrogen atom may be converted by cyclization into other compounds of formula I wherein R^ and 3 taken together represent a -C- group, wherein W V is as above defined.

The condensation process may be carried out in a solvent such as water, ethar.ol, acetic acid or pyridine with or without addition of acid, such as hydrogen chloride, at a temperature of from 50 to 1003 C .

The cycliEation may be carried out in the same medium as the condensation, or by heating in vacuo at 130- 160°C the isolated coranounds of formula I wherein R =H. 9 When the reaction is over, the crude product can be purified by crystallization or by chromatography.

The ergoline derivatives of the general formula II, the starting materials for the process, are known compounds or can be prepared by established procedures starting from known compounds. According to one preferred method, the compounds of the general formula II wherein A represents a CH -CKR. grouo can be 2 o6- obtained by reacting an appropriate ergoline primary R _ I o amine with an acryl derivative of formula CH =C-3 wherein R. and B are as above defined. Alternatively a R_ compound of formula 3r(CH„) -Cn-3 wherein R„ and 3 are 2 m o ' o 2 0?96 as above defined and m is 0 or 1 can be made to react with an appropriate ergoline primary amine to give the compounds of the general formula II.

The compounds of formula III, the other starting materials for the process, are known compounds and may be generated In situ by reaction of an appropriate salt thereof with an acid, such as hydrochloric acid.

Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa.

The compounds according to the invention and their pharmaceutically acceptable salts exhibit pharmacological activities.

For example they exhibit prolactin secretion inhibition activity as indicated by an inhibition of the implantation 0f fertilized eggs in the uterus on day 5 after insemination of female rats /according to the principles of E. Fluckiger et al., HANDS. EXP. PHAF.MAC. , 49,615,1978?.

In particular the compounds and the salts thereof of the present invention are active as antihypertensive agents. 207963 : t [ Indirect measurements of systolic blood pressure were carried out in groups of 4 spontaneously hypertensive rats (SHR, Kyoto), 8-10 weeks of age, supplied by Charles River, Italy.

The animals were maintained In an environment of 36°C for 10-15 minutes to allow pulse pressure to be recorded and then systolic blood pressure and heart rate were measured by indirect tail cuff method using a W+W, BP Recorder, model 8005.

The compounds were given orally, suspended in 5% arabic gum, once a day for 4 consecutive days and measurements were carried out before beginning .the treatment and 1 and 5 hours after dosing, in both the first and forth day of treatment.Drug doses refer to the free base.

Controls animals received the vehicle only (0.2 ml/100 g b.w.).

As reference standards, hydralazine (1-5 mg.Kg 1 p.o.) and^ -methyldopa (30-100 mg.Kg 1 p.o.) were also tested.

Drug induced changes in systolic blood pressure and heart rate were calculated as differences from the pretreatment values and reported as means of 4 rats. §*> antihypertensive activity: methods 2 07963 ANTIHYPERTENSIVE ACTIVITY: RESULTS Tables 1 and 2 show the results concerning the presently claimed compounds along with data concerning control vehicle and two reference standards, hydralazine and -methyldopa.

Systolic blood pressure (SBP) and heart rate (HR) remained stable troughout the duration of the experiment in vehicle treated rats; on the other hand, all our compounds were very active in reducing SBP in doses ranging from 1 to 20 mg.Kg * p.o. This effect was not accompanied by a reflex increase in HR, whilst a moderate decrease in HR was instead observed with same of them. The antihypertensive activity of all the compounds had a prompt onset and remained very marked at all the experimental times. The effects were similar on the 1st and 4th days of treatment showing tachyphylaxis not to occur with our compounds. In particular the compounds prepared in examples l arid 3 both showed a very marked and prolonged activity without substantially modifying HR.

Comparison with the reference standards showed how the compounds of examples 4,5,8,9,12,13,16,1-9,23,24 and 28 (tested in doses ranging from 1 to 7.5 mg.Kg * p.o.) were more active than hydralazine (1-5 mg.Kg * p.o.) and oj -methyldopa (30-100 mg.Kg 1p.o.) without inducing the reflex increase in HR observed with these latter drugs. - v- - -9~ TABLE 1 2 °79 63 Effects on systolic blood pressure (SBP) in SHR rats.

Mean differences from pretreatment values (mmHg) (4 rats per group) are reported.

Changes in S.B.

P. (a mmHg) Compound Dose 1st day 4th day mg.Kg" lh 5h lh 5h p.o. post post post post drug drug drug drug Vehicle - + 2.5 -7.5 -6.4 -5.0 Prepared in Ex. 1 -90.0 -62.5 -62. 5 -46.2 it ii ii g -60.0 -72.5 -90.0 -62.5 it ii ti 4 -53.3 -45.0 -42.5 -50.0 ii ii ii ii -35.0 -40.0 -43.7 -45.0 " ii ii 5 7.5 -55.0 -56.2 -55.0 -53.7 ti n ii g -30.0 -10.0 -36.2 -37.5 11 ii ii q 7.5 -51 . 2 -65.0 -82. 5 -55.0 ii ii "12 7.5 -52.5 -38.7 -37.5 -41.2 n ii n 13 7.5 -37.5 -26.2 -50.0 -31.7 ii ii ii 1 -20.0 -28.7 -43.7 -52.5 ii ii it 29 -50.0 -33.7 -62.5 -23.7 ii ii ii 23 -51 .2 -60.0 -85.0 -72. 5 n ii ii 24 -38.7 -66.7 -41.7 -38.3 ii n ii 28 1 -27. 5 -31 .2 -70.0 -30.0 Hydralazine 1 -5.1 -15.7 -5.0 -0.3 -40.2 -20.0 -20.4 -7.0 <3) -methyldopa -10.4 -20.1 -10.0 + 0.5 100 -10.0 -25.4 -20.2 -25.0 TABLE 2 Effects on heart rate (HR) in SHR rats. Mean differences from pretreatment values (beats/min) are reported (4 rats per group).

Changes in H.R. (beats/min) Compound Dose ^ 1st day 4th day mg.Kg lh 5h lh 5th p.o. post post post post drug drug drug drug Vehicle - -5.0 + 12.0 i o o -19.0 Prepared in Ex. 1 + 4.0 -40.0 -33.0 -8.0 II II II 3 -20 -10.0 -25.0 -7.0 ti n ii 4 + 13.0 + 23.0 -11.0 -40.0 ii II n n -15.0 -30.0 -40.0 -23.0 ii n ii 5 7.5 -37.0 -20.0 -42.0 i-» o o n ii ii g -13.0 +0.4 + 40.0 i ro o o ii ii ii g 7.5 -60.0 -32.0 -75.0 -28.0 ii ii ii 22 7.5 -40.0 -28.0 + 8.0 + 2.0 ii n "13 7.5 + 13.0 -55.0 + 37.0 -20.0 " " " 16 1 0 CO cvj 1 -8.0 -60.0 -35.0 11 ii h 10 1 00 o -22.0 -35.0 + 15.0 ii ii ii 23 -8.0 + 17 + 42.0 -18.0 m ii ti 24 -23.0 + 17.0 + 30.0 -27.0 ii ii i» 28 1 -13.0 -23.0 + 15.0 -15.0 Hydralazine 1 + 30.0 + 35.0 + 25.0 + 15.0 + 40.0 + 45.0 + 18.0 + 15.0 d) -methyldopa + 35.0 + 40.0 + 45.0 + 30.0 100 + 70.0 + 40.0 + 50.0 + 10.0 2 079 6 3 The Invention further comprises a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. The administration of compounds I and their non-toxic pharmaceutically acceptable acid addition salts or mixtures thereof may be achieved either parenterally or orally, preferably orally.

As used herein, the term "effective amount" encompasses those amounts which yield the desired activity without causing adverse side effects. However, an effective dosage is in the range of about 0.001 to 0.5 mg/Kg day, preferably 0.01 to 0.25 mg/Kg day.

The pharmaceutical carriers which are typically employed with the compounds of the invention may be solid or liquid and are generally selected dependent on the planned manner of administration. Thus, for example, solid carriers include lactose, sucrose, gelatin and agar and the like, while liquid carriers include water, syrup, peanut oil and olive oil and the like.

The combination of the selected compound and the carrier may be fashioned into numerous acceptable forms such as tablets, capsules, suppositories, solutions, emulsion, powders and syrups.

The following Examples illustrate the invention.

Example 1 6-Methyl— SB—/(1H,3H)-2,4-dioxo-dihydro-l-pyrimi dinyl--methy1/-ergoline I: R =R =R„=R =R =H, R =CH_, n=l , A=CH_CHP., cd RC=H, Band R =-C=W, W=X=0, R =H. by b A mixture of 5.1 g of 813-aminomethyl-6-methyl-ergoline and 1.8 ml of methyl acrylate in 100 ml of methanol was refluxed for four hours. The solvent was evaporated off under reduced pressure and the residue was crystallized from diethyl ether to give 6 g of 6-methyl -8B-/N- ( 2-methoxycarbonylethyl) - aminoroe thy 1_/-ergo 1 ine (II: Ri=R2=R3=R7=Rg=H, R4=CH3, n = l, A=CH2~CHR6, R6=H, B=COOCH ) melting at 130-132°C.

To a solution of 2.86 g of potassium cyanate in 30 ml of water, a solution of 6 g of 6-methyl-8fi-_/N-( 2--methoxycarbonylethyl)-aminomethyl_/-ergoline in 120 ml of water and 35 ml of IN hydrochloric acid was added.

This reaction mixture was heated for four hours at 80°C and allowed to stand overnight at room temperature. The solid separated out and was filtered off and recrystal1ized from ethanol to give 4.5 g of the title compound melting at 330°C with decomposition. "1 .IL.."'. .......... 20796 Example 2 6-Methyl-8fl-/N-(2-methoxycarbonylethyl)-N-carbamoyl--aminomethy1/-ergollne I: R3=R2=R3=R5=H, R4=CH3, n=l, A=CH2CHR6, R6=H, X-0, b=cooch3, r?=r8=r9=h.

A mixture of 8.5 g of 6-methyl-8I3-/N-(2-methoxycarbo-nyl-ethyl)aminomethy_l/-ergoline (II: R = R =R =H, i C O R =CH , n=l, A=CH -CHR., R =H, B=COOCH_; prepared as 4 o — 2 D o 3 described in Example 1) and 2.86 g of potassium .-cyanate in 120 ml of water and 35 ml of IN hydrochloric acid was heated at 60°C for one hour. The solution was then neutralized with IN sodium hydroxide and extracted with chloroform. The organic layer was evaporated off, and the residue was purified by column chromatography on silica gel, to give 6.5 g of the title compound.

Rf in ethyl acetate: dimethylformamide: n-butanol: pyridine (4:3:3:1 by volume) = 0.45 MS (F.D.): 384 (M+), 352 (M+-CH30H).

Example 3 * 6-Methyl-8fl-(2,4-dioxo-1-imidazolidinyl-methyl)-ergoline I: R^R^R^H. R4=CH3. n=l, A=CHRg, R5=H> R7="s=^5=^ B and R =-tsW, W=X=0.

A solution of 1.3 ml of ethyl bromoacetate in 30 ml of dimethylformamide was added to a warmed solution of 6g of 8fl-aminomethyl-6-methyl-ergoline in 90 ml of dimethylformamide. At the end of the reaction, the solution was reduced in volume by evaporation in vacuo, poured into iced water and extracted with chloroform.

The organic layer was removed in vacuo and the residue was purified by column chromatography on silica gel, using ethyl acetate: methanol (9:1 by volume) as eluent, to give 3.5 g of 6-methyl-8fl--(N-ethoxycartonylmethyl-aminomethyl)-ergoline (II: R1=R2=R3=H, R4=CH3, n=l, A=CHR5, R6=H, B^CO^H^), m.p. 174-176°C, after crystallization from diethyl ether. 3.5 g of 6-methyl-8fi-(N-ethoxycarbonylmethyl-amino-methyl)-ergoline were treated with 1.75 g of potassium cyanate, as described in Example 1, and the title compound, m.p. > 300°C, was obtained in 72% yield.

ExamDle 4 6-Kethyl-Sfi-/N-(2-methoxycarbonylethyl)-N-methylcarbamoyl-aminomethyl/-ergoline 1 : R1=R2=R3=H, R4=CH„, n=l, A=CH2CHR6, R6=R7=R8=Rg=H, R =CH„, B=COOCH X=0 o 3 A mixture of 8.5 g of 6-methyl-8fl-/N-(2-methoxycarbonylethyl )-aminomethyl/-ergoline (prepared as described in Example 1) and 2.95 ml of methyl isocyanate' in 100 ml of 2 079 <$ pyridine was heated at 60#C for one hour. After evaporating off the solvent, the residue was crystallized from methanol to give 8.5 g of the title compound, m.p. 140-142°C.

Example 5 6-Methy1-8R-/(1H,3H)-2,4-dioxo-3-methyl-dihydro--1-pyrimi diny1-methy1/-ergoline I : Ri=R2=R3=H, R4=CH3, n = l, A=CH2CHR5, R5=H, Band Rg=-C=W R5=CH3> R?=Re=H, X=W=0 On heating for one hour at 145°C in vacuo 6-methyl-8B-/N-(2-methoxycarbonylethyl)-N--methylcarbamoyl-aminomethyl/-ergoline, (prepared as described in example 4) gave 6.5 g of the title compound, m.p. 118-120°C, after crystallization from methanol.

Example 6 6- rrethyl-Sfi-(N-ethoxycarbonylmethy1-N-methy1carbamoyl-aminomethyl)-ergolIne I : R =R =R =H, R =CH„, n=l, A=CHR,_ , R =R_=R =R =H, 1 2 3 4 3 - 6 6 7 6 9' R =CH„, 3=C00C„H , X=0 j 2 5 Operating as in Example 4, but employing 6-methyl-8fi- -(N-ethoxycarbonylmethyl-aminomethyl)-ergoline (prepared as described in Example 3) instead of 6-methyl-8B- -/N- (2-methoxycarbonylethyl)-aminomethyl/-ergoline , the title compound, m.p. 165-167°C, was obtained.

Example 7 6-Methyl-8fl-(2,4-dioxo-3-methyl-l-imidazolidinyl--methyl)-ergoline 1 : R1=R2=R3=H' R4=CH3' -*1, A=CHR6- R6=R7=R8=H* R5=CH3 B and F »-CaW, W=X=0 From 6-methyl-8fl-(N-ethoxycarbonylmethyl-N-methyl--carbamoyl-aminomethyl)-ergoline, the title compound, m.p. 250°C with decomposition, was obtained in 77% yield by heating In vacuo for one hour at 140°C.

Example 8 6-Methyl-8fl-/jN-( 2-methoxycarbonylethyl )-N-propy 1--carbamoyl-aminomethyl/-ergoline I : Ri=R2=R3=H, R4=CH3, R5=CH2CH2CH3, n=l, A=CH2CHR6, WW9' X=0, B=C00CH3 The title compound was prepared as described in Example but employing propyl isocyanate instead of methyl isocyanate.

The yield was 85% and the mp was 130-132°C.

Example 9 6-Hethyl-8JB-/_ (1H. 3H )-2, 4-dicxo-3-propy 1-dihydro-1 --pyrimidinyl-methyl/-ergoline I : R =R =R„=H, R =CH , n=l, A=CH.CHR,, R =R =R =H, 1 2 j 4 3 — 2 5 5 7 8 R5=CH2CH2CH3 B and R9=~^W' x=w=0 Operating as in example 5, but employing 6-methyl-8i3--/~N- (2-methoxycarbonylethyl)-N-propylcarbamoyl-amino-methyl/-ergoline (prepared in example 8) instead of 2 0796 6-methyl-8fi-_/N-( 2-methoxycarbcnyletnyl rN-methylcarba--moyl-aminomethyl_/-ergoline, the title compound, m.p. 201-202°C, was obtained in 70% yield.

Example 10 6-Nethyl-8fl-/N-(2-methoxycarbonylethyl)-N-lsopropylcar -bamoyl-aminomethy1/-ergoline 1 : VR2=R3=H' R4 = CH3' n=1, a=CH2CHR6' R5=CH(CH3)2 R6=R7=Rg=R9=H, B=C00CH3, X=0 Operating as in Example 4 , but employing isopropyl isocyanate instead of methyl isocyainate, the title compound, m.p. 112-115°C, was obtained.

Example 11 6-Methy 1 -8f3-/ (1H, 3H) -2, 4-dioxo-3-i sopropyl-dihydro-1--pyrimidinyl-methyl/-ergoline I : R1=R2=R3=H, R4=CH3, n=l, A=CH2CHR5, R^R^R^H, R =CH(CH )„, B and R =-t-V, X=W=0 d 3 2 y From 6-methyl-813-/N- ( 2-methoxycarbonylethyl )-N- -isopropylcarbamoyl-aminomethyl/-ergoline, (prepared in example 10^, the title compound (m.p. 175-177°C) was obtained in 60% yield by heating for 2 hours at 150°C.

Example 12 6-Methyl-8B-/N-ethoxycarbonylmethy1-N-propy1carbamoyl--aminomethyl/-ergoline I : Ri=R2=R3=H, R4=CH3, R5=CH2CH2CH3, n=l, A=CHR6, Rg=R7=R8=R9=H, X=0, B=C00CH2CH3 7 0 7 9 Operating as in Example 6, but employing propyl isocyanate instead of methyl isocyanate, the title compound, m.p. 109-1100C, was obtained in 80% yield.

Example 13 6-Methy1-83-(2,4-dioxo-3-propyl-l-imidazolidinyl)--me thyl)-ergcline i : R1=R2=R3=H» vCH3' S*1' A=CHR6, R6=R7=Rg=H, R =CH_CH CH B and R =-£=W, X=W=0 5 2 2 3 9 ' From 6-methy1-8fl-/N-ethoxycarbonylmethy1-N-propy1- carbamoyl-aminomethyl/-ergoline prepared in example 12, the title compound, m.p. 188-190°C, was obtained in 68% yield by heating in vacuo for one hour at 140°C.

Example 14 6-Methyl-8B-(N-ethoxycarbonylmethy1-N-isopropylcarbamoyl--aminomethyl)-ergoline.

I : Ri=R2=R3=H, R4=CH3, £2=1, A=CHR6, R6=R7=R8=Rg=H, r5=ch(ch3)2, b=cooc2h5, x=0 Operating as in Example 6, but employing isopropyl isocyanate instead of methyl isocyanate, the title compound, m.p. 118-120°C, was obtained.

Example 15 6-Methyl-8fi-(2,4-dioxo-3-isopropyl-1-imidazolidinyl--methyl)-ergoline 2 0796 1 : WR3=H' R4=CH3' £=1' A=CHR6- R6=R7=R8=H R5=CH(CH3)2 B and R =-C*W, X=W=0 Starting from 6-methyl-8J3-(N-ethoxycarbonylmethyl-N-isopropylcarbamoyl-aminomethyl )-ergoline (prepared in example 14), the title compound (m.p. 210-212°C) was obtained in 75% yield by heating in vacuo for 2 hours at 160°C.

Example 16 6-MethyI -8fl- f*2-/(1H,3H)-2, 4-dioxo-dihydro-l-pyrimidi--nyl/-ethyl^ -ergoline I ; R =R =R =H, R =CH., n=2, A=CH nCHR_ R =R =R =R =H, 1 2 3 4 3' - 2 6 5 6 7 8 B and Rg=-C=W, W=X=0 Operating as in Example 1, but employing 813-aminoethyl--6-methyl-ergoline instead of 8fi-aminomethyl-6-methyl--ergoline, the title compound, m.p. 140-142°C, was obtained in 74% yield.

Example 17 6-Methyl-8fi-/2-(2,4-dioxo-l-imidazolidinyl )-ethyl/~ -ergoline I : Ri=R2=R3=h, R4=CH3, n=2, A=CHR5, R5=R6=R7=RQ=H, B and Rg=-i-W, X=W=0 Operating as in Example 3, but employing 813-aminoethyl--6-methyl-ergoline instead of 81B-aminomethyl-6-methyl--ergoline, the title compound, m.p. 242-244°C, was obtained in 68% yield. 19 - 7 o Example 18 6-Methy1-8B-/ (1H, 3H)-2 , 4-dioxo-dihydro- 1-pyrimidinyl7--ergoline I : Ri = R2=R3=H, R4=CH3> n=0, AsCHgCHRg, R5=R5=R7=RQ=H, B and Rg=-fc=W, X=W=0 Operating as in Example 1, but employing 8f3-amino-6--methyl-ergoline instead of 83-aininomethyl-6-methyl--ergoline, the title compound, m.p. 312-314°C, was obtained in 79% yield.

Example 19 6-Methyl-8B- ( 2 , 4-dloxo-l-imidazolidinyl)-ergol ine I : Ri=R2=R3=H, R4=CH3, n=0, A=CHR6> R5=R5=R7=Rg=H B and Rg=-£=W, X=W=0 Operating as in Example 3, but employing 8B-amino-6--methyl-ergoline instead of 8fl-airiinomethyl-6-methyl--ergoline, the title compound, m.p. 295-297°C, was obtained in 80% yield.

Example 20 1,6-Pimethyl-SB-/(1H,3H)-2,4-dioxo-dihydro-1-pyrimidinyl--me thy1/-ergoline.

I : R2=R3=R5=R6=R7=R8=H, Ri=R4=CH,, n=l, A=CH2CHR5, B and Rg=-t-=W, X=V/= 0 Operating as in Example 1, but employing 8B-aminomethyl--1,6-dimethyl-ergoline instead of 8B-aminomethyl-6-methyl- 2°7963 -ergoline, the title compound, m.p. 314-316°C, was obtained in 75% yield.

Exajriple 21 1, 6-Dlmethyl-8J3-( 2,4-dioxo-l -imidazol idinyl -methyl) --ergoline.

I : R2=R3=R5SR6=R7=R8=H, R1=R4=CH3, n=l, A=CHR6, E and R a-fc=W, X=W=0 Operating as in Example 3, but employing 813-aJninomethyl--1,6-dimethyl-ergoline instead of 8fl-aminomethyl--6-methyl-ergoline, the title compound, m.p. 292-294°C, was obtained in 65% yield.

Example 22 6-Methyl-10-methoxy-8B- ( 2 ,4-di oxo-l-imidazol idinyl --methyl)-ergoline .

I : R1=R2=R5=R6=R7=R8=H, R3=0CH3, R4=CH3> n=l, A=CHR5, B and Rg=-t=W, X*W*0 Operating as in Example 3, but employing 813-aminomethyl--6-methyl-10-methoxy-ergoline instead of 813-aminomethyl--6-methyl-ergoline, the title compound, m.p. 234-236°C, was obtained in 68% yield.

Example 23 6-Methy 1-813-/ (1H,3H)-2, 4-dioxo-l-pyrimidinyl-methyI/--ergoline.

E) ***■ I : R=R=R=R=R=R=R=H, R =OCH„, n=l, A=CH=CRc, 1 d J 3 D / O 4 J b B and R^=-t-V, X=V=0 £ Operating as in Example 1, but employing 6-methy1-6B--/(3-acrylic acid ethyl ester)-3-ajnino-methyl_/-ergoline instead of 6-methyl-8fl-/N-2-methoxycarbonylethyl)--aminomethy 1/-ergoline, the title compound, m.p.> 320°C, was obtained in 48% yield.

Example 24 I : R1=R2=R3=R5=R6=R7=R8=H, R4=CH3, n=l, A=CH2CHR6, B and RW=0 X=S 6-Methyl-8f3-/(lH)-2-thioxo-4-oxo-tetrahydro-l-pyrimidinyl-methyl/-ergoline.

Operating as in Example 1, but employing potassium thiocyanate instead of potassium cyanate, the title compound, m.p. > 300°C, was obtained in 58% yield.

Example 25 6-Methyl-8fl-/(lH)-2-thioxo-4-oxo-3-methyl-tetrahydro-l-pyrimi dinyl-methyl/-ergoline I : R^ = R2=R3=Rg=Ry=Rg=H, R4=R5=Ch'3, n=l, A=CH2CHR6> B and Rg=-t=W, W=0; X=S Operating as in Example 1, but employing methyl isothiacyanate instead of potassium cyanate, the title compound, m.p. 266-258°C, was obtained in 74% yield. 2°7$63 Example 26 6-n-Propyl-8fl-/~(1H)-2-thioxo-4-oxo-3-methyl-tetrahydro--1-pyrimidinyl-methyl/-ergoline I : r1=R2=R3=R6=R7=R8=H• R4=n_C3H7' R5=CH3* n=1' A=CH2CHR6, B and R =-6=W, W=0, X = S Operating as in Exajnple 25, but employing 813-aminomethyl--6-n-propyl-ergoline instead of 8fi-aminomethyl-6-methyl--ergoline, the title compound was obtained in 63% yield.

Example 27 6-Allyl-8fl-/TlH)-2-thioxo-4-oxo-3-methy1-tetrahydro-1--pyrimidinyl-methyl/-ergoline.

I : Ri=R2=R3=R6=R7=R8=H, R4=allyl, R5=CH3, n=l, A=CH CHR , B and R.=-t=W, W=0, X=S £ 5 y Operating as in Example 25, but employing 8fl-aminomethyl--6-allyl-ergoline instead of 8fB-aminomethyi-6-m^hyl--ergoline, the title compound was obtained in 77% yield.

Example 28 6-Kethyi-S3-(2-thioxo-4-oxo-3-methy1-1-imidazolidinyl--methyl)-ergoline I : R1=R2=R3=R6=R7=R8=H, R4=R5=CH^, n=l , A=CKRg, B and Rg=-fc=V, W=0, X=S Operating as in Example 3 , but employing methyl isothiocyanate instead of potassium cyanate, the title compound, m.p. 263-265°C, was obtained in 83% yield. i i i "y f j> " v .is *'■ u / 9 § Example 29 6-Propy 1-813- ( 2-thioxo-4-oxo-3-methy1-1-Imidazol jdlnyl--methyl)-ergol ine 1 : R1=R2=R3=R6=R7=R8=H' R4=n~C3H7,R5=CH3' n=1' A=CHR6, B and Rg=-t=W, W=0, X=S Operating as in example 28, but employing 8fl-aminomethyl--6-propyl-ergoline instead of 8I3-aminomethyl-6-methyl--ergoline, the title compound was obtained in 88% yield.

Example 30 6-A1 ly 1 — 8f3— C 2-thioxo-4-oxo-3-methy 1-1-imidazolIdinyJ-methyl) -ergoline I : F1=R2=R3=R6=R7=R8=H, R4=allyl, R5=CH3> n=l, A=CHR6, B and R «-fc=W, W=0, X=S Operating in example 28, but employing 813-aminomethyl--6-allyl-ergoline instead of 8B-aminomethyl-6-methyl-ergoline, the title compound was obtained in 69% yield.

Example 31 6-Kethyl-8f3-/N- ( 2-cyanoethyl) -N-carbamoyl-aminomethyl/--ergoline.

I : R1.B^R3.R5.B6=R7.Ra=R9.H, R^, n*l. A=CH.,CHR6, X«C, B*CN Operating as in Example 1, but employing acrylonitrile instead of methyl acrylate, 6-methyl-8B-/N-(2-cyanoethyl)--aminomethyl/-e^goline (m.p. 169-17l°C) was obtained in 80% yield.

I- ' • ••= "V -;v_ .. 7 0 79 From this operatingas in Exa/nple 2, the title compound m.p. 252-254°C, was obtained.

Example 32 6-Methy 1-8f3-/~lH , 3H)-2-oxo-4-imino-dihydro-l--pyrimi dinyl-methyl/-ergoline I : R1=R2=R3=R5=R6=R7=R8=H, R4=CH3, n=l, A=CH2CHR6, B and Rg=-£=W, W=NH X=0 The compound prepared in example 31, on gating for one * hour at 150°C, in vacuo, gave the title compound m.p. 248-250°C, in 45% yield.

Example 33 2-Bromo-6-methyl-8fl-(2,4-dioxo-l-imidazolidinyl-methyl)--ergoline I : Ri=R3=R5=R6=R7=R8=Hi R2=Br, R4»CH , n=l, A=CHR6, B and RQ=-£=W, X=W=0 Operating as in Example 3, but employing 8J3-aminomethyl--2-bromo-6-methyl-ergoline instead of 8fi-aminomethyl--5-methyl-ergoline, the title compound, m.p. 279-281°C, was obtaining in 64% yield.

Examole 34 ♦ 2, 6-Dimethy 1 -813- ( 2 , 4-dioxo-l-imidazolidinyl-me thyl )--ergoline I : Ri=R3=R5=R6=R7=Rg=H, R2=R4=CH3, n=l, A=CHRg, B and R =-fc=W, X=W=0 - 2S - ? 079* o Operating as in Example 3, but employing 8/3-amino-methyl-2,6-dimethyl-ergoline instead of 8/3-amino-ethyl-6-methyl-ergoline, the title compound, m.p. 215-217°C, was obtained in 75% yield.

Exajr.pl e 35 2-Thiomethyl-6-methyl-8/3-( 2, 4-di ox o-l- imidazol idinyl --methyl)-ergoline I : Rl=fl3=R5.R6=R7=B8=H, R2=SCH3, R4=CH3, n.l, A=CHR6, B and R =-t«W, X=W=0 Operating as in Example 3, but employing 8/3-aminomethyl--2-thiomethyl-6-methyl-ergoline, instead of 8/3-amino-methyl-6-methyl-ergoline, the title compound, m.p. 255-257°C, was obtained in 62% yield.

Example 36 6-n-Propy 1-8/3- ( 2 , 4-dioxo-l-imidazol idinyl-me thy 1) --ergoline. 1 : Rl=R2=R3=R5=R6=R7=R8=h' R4=riC3H7' A=CHR6» B and Rg=-t=W, X=W=0 .

Operating as in Example 3, but employing 8/3-aminomethyl--6-n-propyl-ergoline instead of 8/3-aminomethy 1-6-methy 1--ergoline, the title compound, m.p. 168-170°C, was obtained in 80% yield.

Example 37 6-Methyl-8^>-(2 , 4-di oxo-1- imidazol idinyl-me thyl )- -ergoline 2 07963 I : Ri=R2=R3=R5=R6=R7=Re=H, R4=CH3, n=l, A=CHR5> B and Rg=-fc=W, X=W=0 Operating as in Example 3, but employing 8<^-amino-methyl-6-methyl-ergoline instead of 8/3-aminomethyl-6-methyl-ergoline the title compound, m.p. 199-201°C, was obtained in 58% yield.

Example 38 6-Me thy 1-8-/ (1H, 3H)-2 , 4-dioxo-dihydro-l-pyrimidinyl--methyl/-8,9-dldehydro-ergoline I : R -R .R -R -R -H, R4=CH3, R? and Rg=bond, n=l, A=CH CHR , B and R =-£=W, X=W=0 2 6 9 Operating as in Example 1 but employing 8-aminomethyl--6-methyl-8,9-didehydro-ergoline instead of 8fl-amino-methyl-6-methyl-ergoline, the title compound, m.p. 190-192°C, was obtained in 63% yield.

Example 39 6-Methyl-8-(2,4-dioxo-l-imidazolidinyl-methyl)-8,9-di dehydro-ergoline I : R =R =R =R =R =H, R =CH , R_, and R =bond, n=l, 1 g J J o 4 J / o A=CHR6, B and R =-fc=W, X=W=0 Operating as in Example 3, but employing 8-aminomethyl--6-methyl-8, S-aidehydro-ergoline instead of 8/3-aminomethy 1--6-methyl-ergoline, the title compound, m.p. 204-206°C, was obtained in 72% yield.

Claims (6)

27 > h J Example 40 6-Kethyl-8J3-/( 1H, 3H)-2, 4-dioxo-dihy dro-1-pyri mi dinyl--methyl/-9,10-didehydro-ergoline I : Ri=R2=R5=R6=R7=H, R3 and Rg=bond, R4=CH3, n=l, A=CH CHR , B and R =-C=W, X=W=0 2 o y Operating as in Example 1, but employing 8G-aminomethyl--6-methyl-9,10-didehydro-ergoline, instead of 8i3-amino-methyl-6-methyl-ergoline, the title compound, m.p. 290-292°C, was obtained in 77% yield. Example 41 6-Methyl-6fi-(2,4-dioxo-l-imidazolidinyl-methyl)-9,10-didehydro-ergoline I : Ri=R2=R5=R6=R7=H, R3 and R0=bond, R4=CH3, n=l, A=CHR6> B and R9=-fc=W, X=W=0 Operating as in Example 3 but employing 813 - aminomethy 1--6-methyl-9,10-didehydro-ergoline instead of 8fl-ajnino-methyl-6-methyl-ergoline, the title compound, m.p. 282-284°C was obtained in 78% yield. - 28 - 2 079 What we claim is: A compound of formula I: group; represents a hydrogen or halogen atom or a methyl, cyano, alkylthio or phenylthio group; R and R represent hydrogen atoms and R represents 7 © 3 a hydrogen atom or a methoxy group, or R represents a hydrogen atom and R and R taken 7 3 8 together represent a bond or R^ represents a hydrogen atom or a methoxy group and and Rg taken together represent a bond; R^ represents a hydrocarbon group having from 1 to A carbon atoms; Rc represents a hydrogen atom or a b hydrocarbon group having from 1 to A carbon atoms or a phenyl group; X represents an oxygen or sulphur atom or an imino group, Rg represents a hydrogen atom and 5 represents a cyano, a alkoxycarfc.cnyl or carbamoyl group, or RQ and B taken together represent a -C- group wherein ft — OQ _ r:070G3 V represents an oxygen •torn or an imino group; A represents b group of the formula CHRc, CH.-CHR, or o 2 o CH=CRg wherein Rg represents a hydrogen atom or a C,-Ca alkyl group; and n is 0, 1 or 2. or a 14 — ' pharmaceutically acceptable salt thereof. 2, A compound according to claim 1, wherein R^ is hydrogen atom or a methyl group; R? is hydrogen or bromine atom, a methyl or a thiornethyl group; R and R represent hydrogen atoms and R represents 7 o 3 a hydrogen atom or a methoxy group, or R, represents a hydrogen atom and R and R taJ<en 7 3 8 together represent a bond, or R^ represents a hydrogen atom and R^ and Rg taken together represent a bond; R, represents a C ,-C. alkyl or a C -C. alkenyl group; 4 1 c 4 X represents an oxygen or a sulphur atom, represents a hydrogen atom or a c^~c4 alkyl group, Rg represents a hydrogen atom and B represents a cyano or a C -C alkoxycarbonyl group, or R. and B taken i together represent a ~C=W group, wherein W represents an oxygen atom or an imino group; A represents a group of the formula ZW^, CH2CH2 or CH=CH; n is 0,1 or 2 or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 or claim 2 wherein and Rg represent hydrogen atoms and represents a hydrogen atom or a methoxy group and R^ and B taken together represent a -C- group wherein W represents an oxygen atom II W or an imino group. - 30 - 207963 4. A compound according to claim 1 or claim 2 wherein R_ and R represent hydrogen atoms and R_ represents a / O J liydrogen atom or a methoxy group and RQ represents a hydrogen atom and B represents a cyano, a alkoxy- carbonyl or carbamoyl group. 5. A compound according to claim 1 which is 6-methyl-- 8 6-/71H,3H)-2,4-dioxo-dihydro-1-pyrimidiny1-methyl/--ergoline, or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 1 which is 6-methyl--83-/2,4-dioxo-l-imidazolidinylmethyl7-ergoline, or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is: 6-Methy 1-83-/N- ( 2-methoxycarbonylethyl)-N-carbamoyl--ar,inomethyl_/-ergoline , 6-Methyl-83-/N-(2-methoxycarbonylethyl)-N-methylcarba- moyl-aminomethyl7~ergoline, 6-Me thyl — 8i3 —_/ (1H , 3H) -2 , 4-cii oxo-3-methyl-dihydro-2 --pyrimidinyl-methyl/-ergoline , 6-Me thy 1 - 83 - / N-e thcxycarbor.ylrr.ethyl -N-me thy 1 carbamoy 1--aminomethyl)-ergoline, 6-Me thy 1 -83- ( 2 , 4-dioxo-3-methyl -1 -imi dazol idinyl -methyl )--ergoline , 6-Methyl-83-/N-(2-methoxycarbonylethyl)-N-propy1--carbamoyl - aminomethy 1_/-ergol ine , 6-Me thyl- 83-/_(1H, 3H)-2 , 4-dioxo-3-propyl-dihydro-l--pyrimidinyl-me thy 1/-ergoline , ^ fn* ° \ fe I *2HOVl986 : / - 31 - 207963 6-Methy 1-BB-j/N- ( 2-methoxycarbonylethyl) -N-d sopropy1-carb moy 1 -aminomethy 1/-ergoline , 6-Me thy l-8£-,/{1H , 3K)-2 , 4-dicxo-2-isopropyl-dihydro-1--pyrimi dinyl -methyl/-ergoline , 6-Me thy1-8B-/N-ethoxycarbcnylmethy1-N-propy1carbamoyl-- a,-i none thyl/-ergo line , 6-Me thy1-8B-(2,4-dioxo-3-propy1-1-imidazolidinyl-methyl) -ergoline, 6-Methy1-8B-(N-e thoxycarbonylme thyl-N-i sopropyl- -carbamoyl-ami nonethyl)-ergoline, 6-Methy 1-SB-(2,4-dioxo-3-isopropy1-1-imidazolidi- ny1-me thyl)-ergoline, 6-Methyl-8B-^2-/(1H,3H)-2,4-dioxo-dihydro-l--pyrimi <2inyl_/-ethyl^ -ergoline , 6-Me thy1-8B-/2- ( 2,4-dioxo-l-imidazolidinyl) -e thyl/--ergoline, 6-Me thy l-8B-_/( IH,3H)-2, 4-dioxo-di hydro -1-pyri mid inyl/ --ergoline, 6-Methy1-8B-(2,4-di oxo-l-imidazolidinyl)-ergoline, 1,6-Dimethyl-8fl-/(1H,3H)-2,4-dioxo-dihydro-1-pyrimidinyl -me t.hyl/-ergol ine,

1,6-Dimethyl-8B-(2,4-dioxo-l-imi dazolidinyl-me thyl)--ergoline, 6-Methy1-10-methoxy-8B-(2,4-dioxo-l-imi dazo1idinyl--methyl)-ergoline, 6-Me thy l-6fl-_/( 1H , 3H)-2 ,4-di oxo-l-py rim idinyl-me thyl./--ergoline, ► 6-Methy1-BB-//1H)-2-thioxo-4-oxo-tetrahydro-1-pyrimidinyl -methy!_/-ergol ine , - 32 - 207963 6-Me thyl -813-/(lH)-2-thioxo-4-oxo-3-me thyl -tetrahydro-1--pyrimi dinyl-methyl/-ergoline, 6-n-PropyI -Sfi-_/ (IH) - 2- thioxo-4-oxo- 2-me thy 1 - tet rahy crc--1-pyrimidinyl-me thyl/-ergoline, 6-Allyl-8B-/(IH)-2-thioxo-4-oxo-3-methyl-tet rahy dro-1-pyri mi diny1-me thyl7-ergol ine, 6-Me thyl-813- ( 2-thioxo-4-oxo-3-me thy 1 -1 -imidazol i -dinyl-methyl)-ergoline, 6-Propyl-8B- ( 2-thioxo-4-oxo-3-methyl -1-imidazol idi^ nyl-methyl)-ergoline, 6-Al lyl-8/3- ( 2-thioxo-4-oxo-3-methyl-1-imidazol idinyl -methyl)-ergoline, 6-Methyl-83-/N-(2-cyanoethyl)-N-carbamoy1-ami no-methy17-ergoline, 6-Methy 1-8/3-/^IH,3H)-2 - oxo-4-imino-dihydro-l--pyrimidinyl-methy 1_/-ergol ine , 2-Bromo-6-methy1-83-(2,4-dioxo-l-imidazolidinyl--methyl)-ergoline, 2, 6-Dimethyl-813- ( 2 ,4-dioxo-l-imi dazolidinyl--me thyl)-ergoline,

2-Thi ome thy 1-6-me thy 1-8/3- (2,4-dioxo-l-imidazolidi- nyl-methyl)-ergoline, 6-n-Propyl-8/

3- ( 2 , 4-di oxo-1-imi dazol id inyl-me thyl h--ergoline, 6-Methy 1-8a-(2,4-dioxo-1-imidazolidinyl-methyl)--ergoline, 6-Me thy 1-8-/ (IH , 3H )-2 , 4-di oxo-dihydro-1-py rirr.i dinyl --methyl_/-8, 9-didehydro-ergoline, - 33 - 207063 6-Methy1-8-(2,4-dioxo-l-imidazolidinyl-methyl )--8,9-didehydro-ergoline, 6-Me thy 1-813-/ (IH, 3H)-2 ,

4-d ioxo-dihydro-1-pyr imi dinyl-me thy 1_/-9 ,10-didehydro-ergoline,

5 or

6-Me thyl-813-( 2 , 4-dioxo-l-imidazolidinyl-methyl)--9,10-didehydro-ergoline. 8. A process for preparing a compound of formula I as defined in claim 1, which comprises condensing a 1C compound of the formula II ■•yS" Qtyr 15 (CHJ -NH-A-B II u wherein R^,R2,,Rg, A, B and n are as defined In claim 1 with a compound of formula III X=C=N-Rr III wherein and X are as defined in.claim 1, and, if desired, 20 cyclizing the resultant compound of the formula I wherein Rg=H to obtain another compound of formula I wherein B and R„ taken together represent a -C- 9 group, wherein W is as defined in claim 1. 9. A process according to claim 8, wherein the condensa-25 tion is carried out in water, ethanol, acetic acid or pyridine. /«* c,': t- IS 2 4 A I ft M ■ - 34 - 207963 10. A process according to claim 8 or 9, wherein the condensation is carried out at from 50 to 100°C. 11. A process according to any one of claims 8 to 10, wherein the cyclization is carried out in the same medium as the condensation. 12. A process according to any one of claims 8 to 10, wherein an isolated compound of formula I wherein Rg=H is cyclized by heating in vacuo at 130 to 160°C. 13. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. 14. Antihypertensive agents comprising a compound of formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. [ . ' r to<s*(> .r; SON FL;i Ji ■ ^ JCAa.ca A6LN: -> rc.I ft .Ti APPLICANTS