IE51130B1 - Ergoline derivatives - Google Patents
Ergoline derivativesInfo
- Publication number
- IE51130B1 IE51130B1 IE754/81A IE75481A IE51130B1 IE 51130 B1 IE51130 B1 IE 51130B1 IE 754/81 A IE754/81 A IE 754/81A IE 75481 A IE75481 A IE 75481A IE 51130 B1 IE51130 B1 IE 51130B1
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- urea
- carbonyl
- ergoline
- methoxy
- dicyclohexyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
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- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
FC-51+a Novel ergoline derivatives formed by reaction of an 8-carboxy ergoline with a carbodiimide having hypotensive and antiprolatinic activity.
Description
The invention relates to ergoline derivatives, to a 5 process for their preparation and to therapeutic compositions containing them.
The invention provides ergoline derivatives having the general formula I wherein Rj represents a hydrogen atom or a methyl group; Rg represents a hydrogen or halogen atom, a methyl or formyl group or a group of the formula S-R? or SO-R? wherein R? represents an alkyl group having from 1 to 4 carbon atoms or a phenyl group; Rg represents a hydrogen atom or a methoxy group; R^ represents a hydrocarbon group having from 1 to 4 carbon atoms or a benzyl or phenethyl group; and each of Rg and Rg independently represents an alkyl group - 3having from 1 to 4 carbon atoms, a eyclohexyl group or a substituted or unsubstituted phenyl group or a dimethylaminoalkyl group of the formula (CHj^N (CHj) jin which n is an integer, with the proviso that and Rgdo not g simultaneously represent said dimethylaminoaklyl group, and pharmaceutically acceptable acid addition salts thereof.
The halogen atom which R, may represent is preferably a chlorine or bromine atom; nevertheless, it may be a 1° fluorine atom. The hydrocarbon group which R4 may represent may be an alkyl or cycloalkyl group or an ethylenically or acetylenieally unsaturated group. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, isobutyl, cyclopropyl, me thylcyclopropyl, 15 vinyl, allyl and propargyl groups.
The invention further provides a process for the preparation of ergoline derivatives of the general formula I as herein defined, which process comprises reacting an acid of the general formula II with a carbodiimide of go the general formula III Rs-N=C=N-Rg III wherein R,,R2>R3,R4,R and Rg have the meanings given above.
The reaction is suitably carried out at a temperature of from 50-100°C for a period of from 5 to 24 hours in-an aprotic solvent such as tetrahydrofuran, dimethylformamide or dioxan, optionally in the presence of an organic base such as pyridine or triethylamine. At the end of the reaction the products may be isolated and purified following conventional procedures, for example chromatography and/or crystallization. The acids having the general formula II are either known compounds or can be prepared from the corresponding esters by saponification. Formation of the desired pharmaceutically acceptable addition salts with organic or inorganic acids may be carried out by conventional methods, for example reaction with an appropriate acid.
The compounds according to the invention and their pharmaceutically acceptable salts are useful antihypertensive agents and they also display from moderate to good antiprolactinic activity and from moderate to good activity against tumours, markedly prolactin dependent tumours.
Evaluation of anti-hypertensive activity Four spontaneously hypertensive male rats strain SHR weighing 250-300 g for each group were used.
The animals were treated once a day for four - 5 consecutive days. Drugs were administered by gastric gavage, suspended in 5% arabic gum (0.2 ml/100 g body weight) and blood pressure (BP) and heart rate (HR) were measured by indirected tail cuff method (BP Recorder W + W). Blood pressure and heart rate were measured on the first and fourth days of treatment 1 hour before and 1 and 5 hours after drug administration. Hydralazine and α-methyl-Dopa were used as reference drugs. Results are reported in Tables 1 and 2.
Table 1 Changes in blood pressure (BP) in SHRxats. represent the mean obtained with 4 animals The values Compound Dose mg/kgj os 1st .day.......| . . . ,4th .day Change in BP^SmmHg) 1 hour after 5 hours , after 1 hour after · 5 hours after ’ dosing- dosing · dosing do s.ing 1,3-dicyclohexy1-3- (lo'a-methoxy-11 61 - 25 -26 -41 -51 -40 -dime thy lergoline-8'βcarbonyl) - urea 5 -11 -22 . -15 -16 1,3-dicyclohexy1-3- 25 -30 -57 -30 ; -10 - (6 ' -methy lergoline-8'β· -carbonyl)-urea 5 -12 -10 -15 ··· -7 1,3-dicyclohexyl-3- (10'a -methoxy-6 !- . -methyle rgoline-8 β-carbonyl)-urea 25 -30 -37 -5 -23 1,3-diisopropy1-3- (6 1 -40 -37 -40 . -32 -methylergoline-8^-carbonyl)-urea 0.5 -27 -20 -20 0 1,3-di-t-butyl-3- 10 -26 -37 -71 -28 - (10' a-methoxy-6'--methyl e rgo line-δ’β-carbonyl)-urea 1,3-dicyclohexyl-3-(6’- 2 -17 -17 -10 -24 -allylergoline-8 '(5-carbc nyl)-urea 25.0 -35 -27 -47 -38 1,3-di-t-butyl-3-(10 W-- 0.1 -5 -,7 -4 -10 methoxy-1’,61-dimethyl- 1.0 -20 -19 -43 -66 -ergoline-8 -carbonyl)urea 10.0 -47 -60 -59 -93 1,3-di-t-butyl-3-(1',6'- 1.0 -15 -10 •8 -14 · ' dimethylergoline-8'^-cai bonyl)-urea . 12.5 -19 -19 -38 -47 Hydralazine 1 -5 -15 -5 0 5 -40 -20 -20 -7 J^-me thyl-Dopa 30 -10 -20 -10 0 100 -10 -25 -20 -25 - 7 TABLE 2 Changes in heart rate (HR) in SHR rats. The values represent the mean obtained with 4-animals.
COMPOUND dose [my/k 1st day 4th day change in HR^ Jbeats /minute) 1 hour after dosing 5 hours after dosing 1 hour after dos ing 5 hours after dosing 1,3-di cyclohexy1-3- 25 5 -2 -5 -12 -20 - -17 -20 -20 +15 -{10’a -methoxy-1* ,6'-dimethylergoline-eTjcarbonyl)-urea l,3-dicyclohexyl-3- 25 +5 -20 -17 ' -2 -(6 *-methylergoline- 8’ fb ca rbony 1) -u re a 5 O -10 0 0 1,3-dicyclohexyl-3-J 25 -20 -IO 0 -20 (10 fcrme thoxy-6 ’ -me thy1eryol ine-8(}-carbcnyl) -urea l,3-diisopropyl-3-(6*- 1 -30 -35 -35 -30 -methylergoline-8‘β- -carbonyl)-urea 0.5 -20 -12 -20 -7 l,3-di-t-butyl-3- (10'a- 10 0 -30 +17 -10 -methoxy-G'-metaylergoline-8'β-carbony J}- 2 . -IO -10 -20 -12 -urea . 1,3-dicyclohexyl-3-(6 *-allylergoline-8 'p-car- 25 -20 -20 -27 -10 bonyl)-urea 1,3-di-t-butyl-3-(10 vt- 0.1 -2 +3 -4 -8 methoxy-1',6’-dimethyl- 1.0 -20 -23 -27 -22 -ergoline-8 '^-carbonyl) 10.0 +15 -13 -2 +6 urea 1,3-di-t-butyl-3-(ι',6'· 1.0 -22 -20 +7 -8 dimethylergoline-8 ’(1-carbonyl)-urea 12.5 -10 -15 +2 +5 Hydralazine 1 +30 +35 +25 +15 5 +40 +45 +18 +15 Λ-methyl-Dopa 30 +35 +40 +45 +30 100 +70 +40 +50 +10 With the compound l.S-dicyclohexyl-l-ilO’a-methoxy-l'jfi'-dimethylergoline-8'8-carbonyl)-urea at both the doses tried of 25 and 5 mg/kg a decrease of BP was observed; this effect was long lasting because it was still marked on the fourth day at both the first and fifth hour after dosing.
The compound ljS-dicyclohexyl-S-fS'-methylergoline-S'B-carbonylhurea was tried at the doses of 25 and 5 mg/kg; a significant decrease BP was observed with the higher dose used both on the first and fourth days of treatment; with the dose of 5 mg/kg the antihypertensive effect was less remarkable.
The compound l,3-dicyclohexyl-3-(10'a-methoxy-6'-methylergoline-8'8-carbonyl)-urea at the dose of 25 mg/kg produced a marked decrease of BP on the first day of treatment; the hypotensive effect was still observed on the fourth day even if less remarkable at the first hour after dosing.
The compound 1,3-diisopropyl-3-(6'-methy1-ergoline-8'8-carbonyl)-urea was tried at the doses of 1 and 0.5 mg/kg and it produced a marked decrease of BP in a dose-dependent manner.
The compound 1,3-di-t-buty1-3-(10'a-methoxy-6'-methyl-ergoline-8'β-carbonyl)-urea tested at the doses of 10 and 2 mg/kg also reduced BP in a dose dependent manner; - 9 the greatest hypotensive effect was observed on the fourth day, one hour after the administration of 10 mg/kg.
Compound 1,3-dicyclohexyl-3-(6'-allylergoline-8'8-carbonyl)-urea was administered at the dose of 25 mg/kg and produced a decrease in BP both on the 1st and 4th days of treatment but more pronounced on the 4th day.
This was a long lasting activity and was still at its peak 5 hours after administration.
The dose responsive curve was determined in order to evaluate the hypotensive activity of compound 1,3-di-t-butyl-3-(lO’a-methoxy-1',6'-dimethylergoline-8'8-carbonyl)-urea. The tried doses were 10, 1 and 0.1 mg/kg. The hypotensive effect was dose related as well as very marked with the highest dose tried (10 mg/kg b.w.) on both the 1st and 4th day of treatment. No effect was obtained with the lowest dose (0.1 mg/kg b.w.).
Compound l,3-di-t-butyl-3-(l',6'-dimethylergoline-8'8 -carbonyl)-urea reduced BP with both the tested doses (12.5 and 1 mg/kg); this effect was dose dependent. The hypotensive activity observed with the highest dose was very remarkable on the 4th day of treatment and still lasting 5 hours after administration.
All th- compounds tested produced only a moderate bradycardia. - 10 Compounds 1,3-dicyclohexyl-3-(10'α-methoxy-1',6'-dimethy1ergoline-8' β-carbonyl)-urea, 1,3-dicyclohexy1-3-(6’-methylergoline-8'β-carbonyl)-urea and 1,3-dicylcohexyl-3-(10'a-methoxy-6'-methylergoline-8·β-carbonyl)-urea at the dose of 25 mg/kg have a hypotensive activity comparable to that of Hydralazine at the dose of 5 mg/kg, but show no tolerance on the 4th day, unlike Hydralazine.
The compound l,3-diisopropyl-3-(6'-methyl-ergoline-8'β-carbonyl)-urea shows a greater and longer lasting hypotensive activity than Hydralazine. The compound 1.3- di-t-buty1-3-(10'a-methoxy-6'-methyl-ergoline-8'βcarbonyl)-urea at the dose of 10 mg/kg shows comparable activity to that of Hydralazine at the dose of 5 mg/kg on the 1st day, but a greater activity on the 4th day because tolerance does not occur.
The hypotensive activity of compounds 1,3-dicyclohexyl-3-(6'-allylergoline-8'8-carbonyl)-urea (25 mg/kg); 1.3- di-t-buty1-3-(10'a-methoxy-1',6'-dimethoxyergoline-8’β-carbonyl)-urea (1 mg/kg) and 1,3-di-t-buty1-3—(1',6'-dimethylergoline-8'β-carbonyl)-urea (12.5 mg/kg) was comparable to that of Hydralazine (5 mg/kg) on the first day of treatment, but was much more remarkable on the 4th day.
Compound 1,3-di-t-buty1-3-(10'α-methoxy-11,6'-dimethoxyergoline-8'β-carbonyl)-urea at its higher dose (10 mg/kg), also produced a hypotensive effect larger than Hydra51130 - 11 lazine on. both the 1st and 4th days of treatment.
Compared with α-methyl-Dopa tested at the doses of 30 and 100 mg/kg, those compounds according to the invention that were tested all show a greater hypotensive effect. Considering the activity on HR, the tested compounds according to the invention do not produce any increase of HR as Hydralazine and a-methyl-Dopa do, but, on the contrary, a moderate bradycardia is observed.
Evaluation of toxicity 10 The male mice for each group were orally treated with drugs at different dose levels for the determination of orientative toxicity. Mice were observed for seven days after administration. The data obtained are summarized in Table 3.
The toxicity of the compounds according to the invention, expressed as orientative toxicity in mice, is not greater than Hydralazine, being in seme cases largely inferior. The tested compounds according to the invention also have a better therapeutic index than 20 a-methy1-Dopa. - 12 TABLE 3 Acute Toxicity Compound . . . . . . Orientative toxicity in mice (mg/kg per os) 1,3-dicyclohexyl-3-(10'a-methoxy-1',6'dimethylergoline-8‘8-carbonyl)-urea >800 1,3-dicyclohexyl-3-(6'-methylergoline-8'g-carbonyl)-urea >800 1,3-dieyclohexyl-3-(10'a-methoxy-6'-methylergoline-8'β-carbonyl)-urea >800 1,3-diisopropyl-3-(61-methylergoline-8'β-carbonyl)-urea >250 <500 1,3-di-t-butyl-3-(10'a-methoxy-6'-methylergoline-8'8-carbonyl)-urea > 200 < 400 1,3-dicylcohexyl-3-(6'-allylergoline8'β-carbonyl)-urea >800 1,3-di-t-butyl-3-(10'a-methoxy-1',6'dimethylergoline-8'β-carbonyl)-urea >100 < 200 1,3-di-t-butyl-3-(1',6'-dimethylergoline-8'β-carbonyl)-urea > 200 < 400 Hydralazine * 122 s- 3-methyl-Dopa 5300 * as reference compounds. Data of LD^q from the literature. - 13 Evaluation of anti-prolactih activity The compounds of the invention have proved to possess a strong anti-prolactin activity in rats and a low emetic activity in dogs. The prolactin secretion inhibitory action of the compounds has been indirectly evaluated by determining the egg-nidation inhibitory action in rats. For the ergoline derivatives this activity is considered to be correlated with the anti-prolactin activity (E. FLUCKIGER and E. DEL ΡΟΖΟ, Handb. exp. Pharmac, 49 , 615, 1978), prolactin being the only hypophysial hormone involved in the maintenance of the first part of pregnancy in rats (W.K. MORISHIGE and X. ROTHCHILD, Endocrinology 95, 260, 1974).
Pregnant Sprague Dawley rats weighing 200-250 g were used. The compounds to be tested, dissolved in diluted mineral acids, were administered orally to groups of from six to eight rats on day 5 of pregnancy. The animals were sacrificed on day 14 and the uteri were examined. The absence of implantation sites was taken as the criterion of anti-prolactin activity. Several doses were tested for the evaluation. As reference standard bromocriptine was used.
The emetic activity of the compounds was investigated by oral administration to male beagle dogs weighing 15-20 kg. The animals were observed for 6 hours after the treatment. Four to six animals per dose were employed for the ED,-0 evaluation. - 14 The results obtained are reported in Table 4. From this Table it appears that the new ergoline derivatives are from 19 to 285 times more active than Bromocriptine as nidation inhibitors. The emetic activity of the compounds is similar to that of Bromocriptine. The ratio between activity and tolerance of the new ergoline derivatives accordingly seems very high.
From the above results it is logical to predict that the new derivatives may find an advantageous clinical - 15 TABLE 4 Name of Compound Nidation inhibition in rats KED50 mgAg Ρ·ο. Emetic Activity in dogs "ED50 mgAg p.o. 1-ethy1-3-(3’-dimethylaminopropyl)— 3—(6 *-methylergoline -β'β-carbonyl)-urea 0.3 0.01 1-ethy1-3-(31-dimethylaminopropyl)-3-(6'-n-propylergoline-8 ’β-carbonyl)-urea 0.02 0.02-0.04 1-ethy1- 3-(3'-dimethylaminopropyl) -3-(61-allylergoline-8'0-carbonyl)-urea 0.03 0.02 1-(31-dimethylaminopropy1)-3-ethyl-3-(6'-allylergoline-8'8-carbonyl)-urea 0.27 2-bromo-a-ergocryptine (as reference compound) 5.7 0.01-0.02 - 16 The following Examples illustrate the invention.
Example 1 1.3- diisopropyl-3-(61-methy1-ergoline-8'g-carbonyl)-urea (I: R1=R2=R3=H, R4=CH3, R5=Rg= (CH,) 2CH) A mixture of 5 g of 6-methyl-88-carboxy-ergoline and 2.3 g of diisopropyl earbodiimide in 500 ml of tetrahydrofuran were refluxed, with stirring and under nitrogen, for 24 · hours. The resultant solution was evaporated in vacuo to dryness and the residue taken up with chloroform and XO 5% sodium hydroxide solution. The organic phase was separated, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was chromatographed on silica (eluant chloroform with 1% methanol) to give 5.8 g of the title compound, m.p. 2O2-2O4°C, after crystallization X5 from diethyl ether.
Example 2 1.3- diisopropyl-3-(1',61-dimethyl-ergoline-81β-carbonyl)urea (I: R^R^CH^ R^R-^H,. Kg-Rg-(CH,.) ,ΟΗ) Operating as in Example 1, but employing 1,6-dimethyl-882o -carboxy-ergoline in place of 6-methyl-8g-carboxy-ergoline, the title compound, m.p. 172-174°C, was obtained in 75% yield.
Example 3 1.3- diisopropyl-3-(10 'a -methoxy-6'-methyiergoline-8'β 25 -carbonyl)-urea (J^R^R^H, R,=CH,0, R4=CH3, Rg=Rg= (ch3)2ch) Operating as in Example 1, but employing 10a-methoxy-651130 - 17 -methyl-8 β-carboxy-ergoline in pfece of 6-methyl-8B-carboxy-ergoline, the title compound, m.p. 19O-192°C, was obtained in 7 9% yield.
Example 4 1.3- diisopropy 1-3-(10'«-methoxy-1* ,6'-dimethylergoline-8'β-carbonyl)-urea (I: R2=H, R3=CH30,. Rg= r6=(ch3)2ch) Operating as in Example 1, but employing 10a-methoxy-l,6-dimethyl-88-carboxy-ergoline in place of 6-methyl-88-carboxy-ergoline, the title compound, m.p. 180-182°C, was obtained in 80% yield.
Example 5 1.3- diisopropy1-3-(61-n-propylergoline-8 *P -carbonyl)-urea (I: R1=R2=R3=H, R4=CH3CH2CH2, R5=Rg=(CH3)2CH) Operating as in Example 1, but employing 6-n-propy1-86-carboxy-ergoline in place of 6-methyl-88-carboxy-ergoline, the title compound, m.p. 188-19O°C, was obtained in 82% yield.
Example 6 1.3- dlisopropyl-3-(21,6'-dimethylergoline-81^-carbonyl)-urea (I: RX=R3=H, R2=R4=CH3' R5=Rg=(CH3)2CH) Operating as in Example 1, but employing 2,6-dimethyl-88-carboxy-ergoline in place of 6-methyl-88-carboxy-ergoline, the title compound, m.p. 192-194°C, was obtained in 85% yield. - 18 Example 7 1.3- dicyclohexyl-3-(6'-methylergoline-8'8 -carbonyl)-urea {I: R1=R2=R3=H, R4=CH3, R5=Rg=cyclohexyl) Operating as in Example 1, but employing dicyclohexyl 5 carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 2O5-2O7°C, was obtained in 77% yield.
Example 8 1.3- dicyclohexyl-3- (I1 ,6'-dimethylergolih'e-8'β-carbonyl) -urea (I: Rj=R4=CH3, R2=R3=H.,. R,-=Rg=cycIohexyl} 1° Operating as in Example 2, but employing dicyclohexyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 182-184°C, was obtained in 83% yield.
Example 9 1.3- dicyclohexyl-3-(lO,a-me thoxy-61-methylergoline-81β15 -carbonyl)-urea (I : R^R^H,. R3=CH3O, R4=CH3.,/ R5=R6= cyclohexyl) Operating as in Example 3, but employing dicyclohexyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 229-231°C, was obtained in 75% yield.
Example 10 1.3- dicyclohexyl-3-(10' ot-methoxy-l1,6'-dimethylergoline8'e-carbonyl)-urea (I: R^R^CHj, R2=H, R^CR^., R5==Rg= cyclohexyl) Operating as in Example 4, but employing dicyclohexyl 25 carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 198-2OO°C, was obtained in 80% yield. - 19 Example 11 1.3- di-tert-butyl-3-(6*-methyl-ergoline-8'S -carbonyl) -urea (I: R1=R2=R3=H, R4=CH3, R5=R6=(CH3)3C) Operating as In Example 1, but employing di-t-butyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 194-196°C, was obtained in 75% yield.
Example 12 1.3- di-t-butyl-3- (10' a-methoxy-6'' -methyl-ergollne-8'8 -carbonyl)-urea . (I: Rj=Rg=H, R3=CH3O, R4=CH3, Rg=Rg= (ch3)3c) Operating as in Example 3, but employing di-t-butyl carbodiimide in place of diisopropylcarbodiimide, the title compound, m.p. 138-14O°C, was obtained in 65% yield.
Example 13 1-ethy1-3-(31-dimethylaminopropyl)-3 (61-methyi-ergoline-8'8-carbonyl)-urea (I: R.g-R^R^H, R4=CH3, R5=(CH3)2 nch2ch2ck2, r6=c2h5 Operating as in Example 1, but employing N-(3-dimethy1aminopropyl)-N-ethyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 179-181°C, was obtained in 75% yield.
Example 14 1-ethy1-3-(31-dimethylaminopropyl)-3-(10 'a -methoxy-6 * -methylergoline-8'8-carbonyl)-urea (I: R3=R2=H, Rg= CH3O, R4=CH3, R5=(CH3)2NCH2CH2CH2, Rg=C2H5) - 20 Operating as in Example 3, but employing N-(3-dimethylaminopropyl) -N-ethyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 169-171°C was obtained in 78% yield.
Example 15 1.3- dieyclohexyl-3-(61-allylergoline-81β-carbonyl)-urea (I: R1=R2=R3=H, R4=CH2=CH-CH2, · Operating as in Example 7, but employing 6-allyl-8B-carboxyergoline in place of 6-methyl-8(5-carboxy-ergoline, jq the title compound, m.p. 152-154°C, was obtained in 80% yield.
Example 16 1.3- dimethyl-3-(6'-methylergoline-8'8-carbonyl)-urea (I: R1=R2=R3=H, R4=R5=Rg=CH3).
Operating as in Example 1, but employing dimethyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 215-217°C, was obtained in 74% yield.
Example 17 1.3- di-t-butyl-3-(10'a-methoxy-1',6'-dimethylergoline2o 8' 8)-carbonyl)-urea (I: R1=R4=CH3, R2=H, R3=CH3O, R5=Rg=(CH3)3C).
Operating as in Example 4, but employing di-t-butyl carbodiimide in place of diisopropyl carbodiimide, the title compound was obtained in 60% yield; m.p. 14O-142°C. - 21 Example '18 1,3-di-t-bUtyl-3-(11,61-dimethylergoline-81 β-carbonyl)urea · li:R1=R4=CH3, Λ2=Ρ3=Η, R5=K€= (CH3) 3O .
Operating as in Example 2, but employing di-t-butyl carbodiimide in place of diisopropyl carbodiimide, the title compound was obtained in 65% yield; m.p. 18O-181°C.
Example 19 l-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'β-carbonyl)-urea (I: RjfIL,=R3=H, R4=CH2=CH-CH2, R5=(CH3)2 NCH2CH2CH2,. Rg=C.2H5) .
Operating as in Example 13, but employing 6-allyl-8gcarboxyergoline in place in 6-methy1-8β-carboxy-ergoline, the title compound was obtained in 60% yield, m.p. 153-155°C (as its diphosphate salt).
Example 20 1-(3'-dimethylaminopropyl)-3-ethy1-3-(61-allylergoline-8'β-carbonyl)-urea (iiR-^R^R-^H, R4=CH2=CH-CH2, R5=C2H5' V(CH3)2NCH2CH2CH2).
The mother liquor obtained in Example 19 after separation of the l-ethyl-3-(3'-dimethylaminopropyl)-3-(6,-allylergoline-8'β-carbonyl)-urea was chromatographed on silica gel using chloroform/1-2% methanol as eluant to give the title compound in 30% yield, m.p. 149-151°C (as its diphosphate salt). 511^0 - 22 Example '21 · 1-E thy 1-3- (3'-dimethy laminopropyl)-3- (6 '-n-propylergoline-8'β-carbonyl)-urea (IiR^R^R =H, R4=CH,CH2CH2, r5=(ch,)2 nch2ch2ch2, r6=c2h5).
Operating as in Example 13, but employing 6-n-propyl-8g-carboxy-ergoline in place of 6-methyl-8B_carboxy-ergoline, the title compound was obtained in 70% yield, m.p. 2O5-2O7°C (as its dichloride salt).
Example 22 1-Ethy1-3-(3'-dimethylaminopropyl)-3-(61-isopropy1ergoline-8'β-carbonyl)-urea (I: R1=R2=R3=H, R4=(CH3)2CH, R5=(CH3)2NCH2CH2CH2, Rg=C2H5).
Operating as in Example 13, but employing 6-isopropyl-8B-carboxy-ergoline in place of 6-methyl-8B-carboxy-ergoline, the title compound, m.p. 106-108°C, was obtained in 55% yield.
Example 23 1,3-di cyclohexyl-3- (1' -methyl-6 ' -allylercoline-81 β-carbonyl) -urea (I: R-^CH,, R2=R3=H, R4=CH2CH=CH2, R5=Rg=cyclohexyl).
Operating as in Example 7, but employing l-methyl-6-allyl-8B-carboxy-ergoline in place of 6-methyl-8E-carboxy-ergoline, the title compound, m.p. 137-139°C, was obtained in 75% yield.
Claims (20)
1. An ergoline derivative of the general formula I as herein defined, or a pharmaceutically acceptable acid addition salt thereof.
2. 1,3-Diisopropyl-3-(6'-methyl-ergoline-8'β-carbonyl)urea.
3. 1,3-Diisopropy1-3-(1 1 ,6'-dimethyl-ergoline-8'B-carbonyl)-urea.
4. 1,3-Diisopropyl-3-(10'a-methoxy-6'-methylergoline-8'β-carbonyl)-urea. 5. Organic base is pyridine or triethylamine. 28. A process according to any of claims 25 to 27 in which the aprotic solvent is tetrahydrofuran, dimethylformamide or dioxan. 29. A process according to any of clairas 25 to 28 in
5. l,3-Diisopropyl-3-(10' α-methoxy-l',6'-dimethy1ergoline-8'B-carbonyl)-urea.
6. l,3“Diisopropyl-3-(6'-n-propylergoline-8'β-carbonyl)-urea.
7. l,3-Diisopropyl-3-(2',6 1 -dimethylergoline-8'β-carbonyl)-urea.
8. 1,3-Dicyclohexyl-3-(6'-methylergoline-8 'β -carbonyl)-urea.
9. 1,3-Dicyclohexyl-3-(1 1 ,6'-dimethylergoline-8'β-carbonyl)-urea. 10. Which the reaction is carried out at a temperature of from 50°C to 1OO°C for from 5 to 2-1 hours. 30. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any of claims 1 to 24 in admixture with a
10. 1,3-Dicyclohexyl-3-(10'a-methoxy-6 1 -methylergoline-8'B -carbonyl)-urea.
11. l,3-Dicyclohexyl-3-(10'«-methoxy-l',6'-dimethylergoline-8'β-carbonyl)-urea. ·
12. 1,3-Di-t-butyl-3-(6'-methyl-ergoline-8'g-carbonyl)urea.
13. 1,3-Di-t-but/l-3-(10'a-methoxy-6'-methy1-ergoline51130 - 24 -δ'β-carbonyl)-urea.
14. l-Ethyl-3-(3'-dimethylaminopropyl)-3-(6 *-methy1-ergoline-8'β-carbonyl)-urea. 15. Pharmaceutically acceptable diluent or carrier for oral or parenteral administration. 31. A process according to claim 25 for the preparation of a compound of the general formula I, substantially as herein described with reference to any of the Examples.
15. l-Ethyl-3-(3'-dimethylaminopropyl)-3- (10'a-methoxy-6'-methylergoline-8'β-carbonyl)-urea.
16. 1,3-Dicyclohexyl-3-(6'-allylergoline-8'β-carbonyl)urea.
17. 1,3-Dimethyl-3-(6'-methylergoline-8'- β-carbonyl)-urea.
18. 1,3-Di-t-butyl-3-(ΙΟ'α-methoxy-l',6'-dimethy1ergoline-8'β-carbonyl)-urea.
19. 1,3-Di-t-butyl-3-(l’,6'-dimethylergoline-8'B-carbonyl)-urea. 20. l-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'β-carbonyl)-urea. 21. 1-(3'-Dimethylaminopropyl)-3-ethy1-3-(6 1 -allylergoline-8' β-carbonyl)-urea. 22. l-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-n-propylergoline-8'β-carbonyl)-urea. 23. l-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-isopropy1ergoline-8'8-carbonyl)-urea. 24. 1,3-Dicyclohexyl-3-(1'-methyl-6'-allylergoline-8'β-carbonyl)-urea. 25. A process for the preparation of an ergoline derivative according to claim 1, which process comprises reacting in an aprotic solvent an acid of the general formula II as herein defined with a carbodiimide of the general formula III as herein defined. 2b 26. A process according to claim 25 in which the reaction is carried out in the presence of an organic base. 27. A process according to claim 26 in which the
20. 32. An ergoline derivative according to claim 1, when orepared by a process according to any of claims 25 to 29 or 31.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8011234 | 1980-04-03 | ||
| GB8040575 | 1980-12-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE810754L IE810754L (en) | 1981-10-03 |
| IE51130B1 true IE51130B1 (en) | 1986-10-15 |
Family
ID=26275073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE754/81A IE51130B1 (en) | 1980-04-03 | 1981-04-01 | Ergoline derivatives |
Country Status (20)
| Country | Link |
|---|---|
| AT (1) | AT375076B (en) |
| AU (1) | AU540621B2 (en) |
| CA (1) | CA1156648A (en) |
| CH (1) | CH645896A5 (en) |
| CS (1) | CS415291A3 (en) |
| DE (1) | DE3112861A1 (en) |
| DK (1) | DK148686C (en) |
| ES (1) | ES8202003A1 (en) |
| FI (1) | FI70412C (en) |
| FR (1) | FR2479829B1 (en) |
| GR (1) | GR74806B (en) |
| HK (1) | HK67287A (en) |
| IE (1) | IE51130B1 (en) |
| IL (1) | IL62519A (en) |
| IT (2) | IT1210473B (en) |
| NL (3) | NL189462C (en) |
| NZ (1) | NZ196670A (en) |
| PT (1) | PT72785B (en) |
| SE (1) | SE442637B (en) |
| YU (1) | YU43011B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2173189B (en) * | 1985-02-21 | 1988-04-27 | Maruko Pharmaceutical Co | Ergoline derivatives and salts thereof and pharmaceutical compositions thereof |
| GB0409785D0 (en) | 2004-04-30 | 2004-06-09 | Resolution Chemicals Ltd | Preparation of cabergoline |
| US7339060B2 (en) | 2005-03-23 | 2008-03-04 | Resolution Chemicals, Ltd. | Preparation of cabergoline |
| GB0505965D0 (en) | 2005-03-23 | 2005-04-27 | Resolution Chemicals Ltd | Preparation of cabergoline |
| US7939665B2 (en) | 2007-05-04 | 2011-05-10 | Apotex Pharmachem Inc. | Efficient process for the preparation of cabergoline and its intermediates |
| EP2083008A1 (en) * | 2007-12-07 | 2009-07-29 | Axxonis Pharma AG | Ergoline derivatives as selective radical scavengers for neurons |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE396753B (en) * | 1970-05-18 | 1977-10-03 | Richter Gedeon Vegyeszet | ANALOGICAL PROCEDURE FOR PREPARING AN ASSOCIATION OF THE DIHYDROLYSERG ACID SERIES |
-
1981
- 1981-03-26 NL NLAANVRAGE8101509,A patent/NL189462C/en not_active IP Right Cessation
- 1981-03-30 CA CA000374134A patent/CA1156648A/en not_active Expired
- 1981-03-30 AT AT0148481A patent/AT375076B/en not_active IP Right Cessation
- 1981-03-30 NZ NZ196670A patent/NZ196670A/en unknown
- 1981-03-30 IL IL62519A patent/IL62519A/en not_active IP Right Cessation
- 1981-03-30 CH CH214481A patent/CH645896A5/en not_active IP Right Cessation
- 1981-03-31 FR FR8106422A patent/FR2479829B1/en not_active Expired
- 1981-03-31 YU YU851/81A patent/YU43011B/en unknown
- 1981-03-31 DE DE19813112861 patent/DE3112861A1/en active Granted
- 1981-03-31 AU AU68937/81A patent/AU540621B2/en not_active Expired
- 1981-03-31 ES ES500911A patent/ES8202003A1/en not_active Expired
- 1981-04-01 IT IT8120866A patent/IT1210473B/en active
- 1981-04-01 PT PT72785A patent/PT72785B/en unknown
- 1981-04-01 GR GR64542A patent/GR74806B/el unknown
- 1981-04-01 IE IE754/81A patent/IE51130B1/en not_active IP Right Cessation
- 1981-04-01 IT IT20865/81A patent/IT1205241B/en active Protection Beyond IP Right Term
- 1981-04-02 DK DK150781A patent/DK148686C/en not_active IP Right Cessation
- 1981-04-02 SE SE8102131A patent/SE442637B/en not_active IP Right Cessation
- 1981-04-02 FI FI811025A patent/FI70412C/en not_active IP Right Cessation
-
1987
- 1987-09-17 HK HK672/87A patent/HK67287A/en not_active IP Right Cessation
-
1991
- 1991-12-30 CS CS914152A patent/CS415291A3/en unknown
-
1993
- 1993-06-24 NL NL930091C patent/NL930091I2/en unknown
- 1993-06-24 NL NL930092C patent/NL930092I1/en unknown
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