GB2074566A - Ergoline Derivatives - Google Patents
Ergoline Derivatives Download PDFInfo
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- GB2074566A GB2074566A GB8109949A GB8109949A GB2074566A GB 2074566 A GB2074566 A GB 2074566A GB 8109949 A GB8109949 A GB 8109949A GB 8109949 A GB8109949 A GB 8109949A GB 2074566 A GB2074566 A GB 2074566A
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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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Abstract
There are provided ergoline derivatives of the formula: <IMAGE> R1=H or CH3, R2=H, halogen, CH3, CHO, SR7 or SOR7, R3=H or CH3O, R4=C1-C4 hydrocarbon group, benzyl or phenethyl, R5 and R6 independently= C1-C4 alkyl, cyclohexyl, substituted or unsubstituted phenyl or acid and water soluble group such as (CH2)nN (CH3)2, R7=C1-C4 alkyl or phenyl, n=an integer, R5=R6=acid and water soluble group excluded. Pharmaceutically acceptable acid addition salts are a/so provided. A method for their preparation is also provided. The compounds have anti-hypertensive and anti-prolactin activity.
Description
SPECIFICATION
Ergoline Derivatives
The invention relates to ergoline derivatives, to a process for their preparation and to therapeutic compositions containing them.
The invention provides ergoline derivatives having the general formula I
wherein R, represents a hydrogen atom or a methyl group; R2 represents a hydrogen or halogen atom, a methyl or formyl group or a group of the formula S--R, or SO-R7 wherein R, represents an alkyl group having from 1 to 4 carbon atoms or a phenyl group; R3 represents a hydrogen atom or a methoxy group;R4 represents a hydrocarbon group having from 1 to 4 carbon atoms or a benzyl or phenethyl group; and each of R5 and R0 independently represents an alkyl group having from 1 to 4 carbon atoms, a cyclohexyl group or a substituted or unsubstituted phenyl group or an acid-and water-soluble group such as (CH2)nN(CH3)2 in which n is an integer, with the proviso that R5 and R0 do not simultaneously represent said acid and water soluble group, and pharmaceutically acceptable acid addition salts thereof.
The halogen atom which R2 may represent is preferably a chlorine ol bromine atom; nevetheless, it may be a fluorine atom. The hydrocarbon group which R4 may represent may be an alkyl or cycloalkyl group or an ethylenically or acetylenically unsaturated group. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl groups. In the definition of R5 and R0 n is preferably 1, 2, 3 or 4.
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 the general formula Ill
R5-N=C=N-R6 III wherein R1, R2, R3, R4, R5 and R6 having the meanings given above.
The reaction is suitably carried out at a temperature of from 50-1 000C for a period of from 5 to 24 hours in a 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 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 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 a-methyl-Dopa were used as reference drugs. Results are reported in Tables 1 and 2.
Table 1
Changes in Blood Pressure (BP) in SHR Rats. The Values
Represents the Mean Obtained with 4 Animals
ist day 4th day Change in BP (# mm Hg) Dose 1 hour 5 hours 1 hour 5 hours mg/kg) after after after after Compound os dosing dosing dosing dosing 1,3-dicyclohexyl-3-(10'-α;- 25 -28 -41 -51 -40 methoxy-1'6'-dimethylergoline- 5 -11 -22 -15 -16 8'ss-carbonyl)-urea 1,3-dicyclohexyl-3-(6'- 25 -30 -57 -30 -10 methylergoline-8'ss-carbonyl)- 5 -12 -10 -15 -7 urea 1,3-dicyclohexyl-3-(10'a- 25 -30 -37 -5 -23 methoxy-6'-methylergoline 8ss-carbonyl)-urea 1,3-diisopropyl-3-(6'-methyl- 1 -40 -37 -40 -32 ergoline-8'ss-carbonyl)- 0.5 -27 -20 -20 0 urea 1,3-di-t-butyl-3-(10'α-methoxy- 10 -26 -37 -71 -28 6'-methylergoline-8'ss- 2 -17 -17 -10 -24 carbonyl)-urea 1,3-dicyclohexyl-3-(6'-alkyl- 25.0 -35 -27 -47 -38 ergoline-8'ss-carbonyl) urea 1,3-di-t-butyl-3-(10'α;-methoxy- 0.1 -5 -7 -4 -10 1',6'-dimethylergoline-8'ss- 1.0 -20 -19 -43 -66 carbonyl)-urea 10.0 -47 -60 -59 -93 1,3-di-t-butyl-3-(1',6'-dimethyl- 1.0 -15 -10 -8 -14 ergoline-8'ss-carbonyl)- 12.5 -19 -19 -38 -47 urea Hydralazine 1 -5 -15 -5 0 5 -40 -20 -20 -7 a-methyl-Dopa 30 -10 -20 -10 0 100 -10 -25 -20 -25 Table 2
Changes in Heart Rate (HR) in SHR Rats.The Values
Represent the Mean Obtained with 4 Animals
1st day 4th day Change in HR {1N beats/minute) dose 1 hour 5 hours 1 hour 5 hours (mg/kg) after after after after Compound os dosing dosing dosing dosing 1,3-dicyclohexyl-3-(10'-α;- 25 -2 -12 -17 -20 methoxy-1',6'-dimethylergoline- 5 -5 -20 -20 +15 8'ss-carbonyl)-urea 1,3-dicyclohexyl-3-(6'- 25 +5 -20 -17 -2 methylergoline-8'p-carbonyl)- 5 -10 0 0 urea 3,5-dicyclohexyl-3-(10'α;- 25 -20 -10 0 -20 methoxy-6'-methylergoline 8'ss-carbonyl-urea 1 ,3-diisopropyl-3-(6'-methyl- 1 -30 -35 -35 -30 ergoline-8' -carbonyl)- 0.5 -20 -12 -20 -7 urea 1,3-di-t-butyl-3-(10'α;-methoxy- 10 0 -30 +17 -10 6'-methylergoine-8'ss- 2 -10 -10 -20 -12 carbonyl)-urea 1 ,3-dicyclohexyl-3-(6'-allyl 25 -20 -20 -27 -10 ergoline-8'p-carbonyl)- urea 1,3-di-t-butyl-3-(10'α;-methoxy- 0.1 -2 +3 -8 1',6'-dimethylergoline-8'ss- 1.0 -20 -23 -27 -22 carbonyl)-urea 10.0 +15 -13 -2 +6 1,3-di-t-butyl-3-(1',6'-dimethyl- 1.0 -22 -20 +7 -8 ergoline-8'ss-carbonyl)-urea 12.5 -10 -15 +2 +5 Hydralazine 1 +30 +35 +25 +15 5 +40 +45 +18 +15 a-methyl-Dopa 30 +35 +40 +45 +30 100 +70 +40 +50 +10 With the compound 1,3-dicyclohexyl-3-(10'α;-methoxy-1',6'-dimethylergoline-8'ss-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 1,3-dicyclohexyl-3-(6'-methylergoline-8'ss-carbonyl)-urea 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 1,3-dicyclohexyl-3-(10'α-methoxy-6'-methylergoline-8'ss-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'-methylergoline-8'ss-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-butyl-3-(10'α-methoxy-6'-methylergolin3-8'ss-carbonyl)-urea tested at the doses of 10 and 2 mg/kg also reduced BP in a dose dependent manner; the greatest hypotensive effective was observed on the fourth day, one hour after the administration of 10 mg/kg.
Compound 1,3-dicyclohexyl-3-(6'-allylergoline-8'p-carbonyl)-urea was administered at the dose of 25 mg/kg and produced a decrease in BP both on the 1 st 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-(10'α-methoxy-1',6'-dimethylergoline-8'ss-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 1 st and 4th day of treatment. No effect was obtained with the lowest dose (0.1 mg/kg b.w.).
Compound 1,3-di-t-butyl-3-(1 ',6'-dimethyulergoline-8'ss-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 the compounds tested produced only a moderate bradycardia.
Compounds 1,3-dicyclohexyl-3-(10'α-methoxy-1',6'-dimethylergoline-8'ss-carbonyl)-urea, 1,3- dicyclohexyl-3-(6'-methylergoline-8',B-carbonyl)-urea and 1 ,3-dicyclohexyl-3-(l O'ct-methoxy-6'- methylergoline-8'p-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 1,3-diisopropyl- 3-(6'-methyl-ergoline-8'P-carbonyl)-urea shows a greater and longer lasting hypotensive activity than Hydralazine. The compound 1,3-di-t-butyl-3-(10'α-methoxy- 6'-methyl-ergoline-8'ss-carbonyl)-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'-al lylergoline-8'-carbonyl)-urea (25 mg/kg); 1,3-di-t-butyl-3-(10'α-methoxy-1',6'-dimethoxycgoline-8'ss-carbonyl)-urea (1 mg/kg) and 1 ,3-di-t-butyl-3-(1 ',6'-dimethylergoline-8'P-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-butyl-3-(10'α-methoxy-1',6'-dimethoxyergoline-8'ss-carbonyl)-urea at its higher dose (10 mg/kg), also produced a hypotensive effect larger than Hydralazine on both the 1 st 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-methyi-Dopa do, but, on the contrary, a moderate bradycardia is observed.
Evaluation of Toxicity
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 some cases largely inferior. The tested compounds according to the invention also have a better therapeutic index than a-methyl-Dopa.
Table 3
Acute Toxicity
Compound Orientative toxicity in mice (mg/kg per os) 1,3-dicyclohexyl-3-(10'α-methoxy-1',6' dimethylergoline-8'ss-carbonyl)-urea > 800 1,3-dicyclohexyi-3-(6'-methylergoline -8'p-carbonyl)-urea > 800 1 ,3-dicyclohexyl-3-( 1 O' -m ethoxy-6'- -methylergoline-8',B-carbonyl )-u rea > 800 1 ,3-diisopropyl-3-(6'-methylergoline- -8'p-carbonyl)-urea > 250 < 500 1 ,3-di-t-butyl-3-( 1 0'a-methoxy-6'- -methylergoline-8'P-carbonyl)-u rea > 200 < 400 1,3-dicylcohexyl-3-(6'-allylergoline 8'p-carbonyl)-urea > 800 1,3-di-t-butyl-3-(10'α-methoxy-1',6'- dimethylergoine-8'ss-carbonyl)-u rea > 100 < 200 1,3-di-t-butyl-3-(1',6'-dimethylergoline -8'ss-carbonyl)-urea > 200 < 400 Hydralazine* 122 cg-methyl-Dopa* 5300 *as reference compounds. Data of LD, from the literature.
Evaluation of Anti-prolactin 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 Pozo, 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. Korishige and I. 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 oraliy 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 were taken as the criterion of anti-prolactin activity. Several doses were tested for the ED50 evaluation. As reference standard bromocriptine was used.
The emetic activity of the compounds was investigated by oral administration to male beagle dogs weighing 1 5-20 kg. The animals were observed for 6 hours after the treatment. Four to six animals per dose were employed for the ED50 evaluation.
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 exploitation in all the situations in which it is desirable to reduce prolactin levels such as inhibition of puerperal lactation, inhibition of galactorrhoea and treatment of infertility due to hyperprolactinaemia. The compounds may also find utility, like bromocriptine, for the treatment of
Parkinson's disease and acromegaly.
Table 4
Nidation Emetic inhibition in Activity in ratsD50 dogs 5 D50 Name of Compound mg/kg p. o. mg/kgp.o.
1 -ethyl-3-(3'-dimethylaminopropyl)-3-(6'-methylergoline 0.3 0.01 -8'P-carbonyl)-urea 1 -ethyl-3-(3'-dimethylaminopropyl)-3-(6'-n-propylergo 0.02 0.02--0.04 line-8'-carbonyl)-urea 1 -ethyl-4-(3'-dimethylaminopropyl)-3-(6'-allylergoline- 0.03 0.02 -8P-carbonyl)-urea 1 -(3'-dimethylaminopropyl)-3-ethyl-3-(6'-allyl- 0.27 ergoline-8',B-carbonyl)-urea 2-bromo-a-ergocryptine (as reference compound) 5.7 0.01-0.02 The following Examples illustrate the invention.
Example 1 1,3-diisopropyl-3-(6'-methyl-ergoline-8'p-carbonyl)-urea (I: R1=R2=R3=H, R4=CH3, R5=Re=(CH3)2CH) A mixture of 5 g of 6-methyl-8p-carboxy-ergoline and 2.3 g of diisopropyl carbodiimide 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 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. 202-2040C, after crystallization from diethyl ether.
Example 2 1,3-diisopropyl-3-(1',6'-dimethyl-ergoline-8'ss-carbonyl)-urea (1:R1=R4=CH3, R2=R3=H,
R5=R6=(CH3)2CH)
Operating as in Example 1, but employing 1 ,6-dimethyl-8P-carboxy-ergoline in place of 6 methyl-8p-carboxy-ergoline, the title compound, m.p. 172-1 740C, was obtained in 75% yield.
Example 3 1,3-diisopropyl-3-(10'-methoxy-6'-methylergoline-8'A-carbonyl)-urea (I: R=R2=H, R3=CH3O, R4=CH3, R5=Re=(CH3)2CH) Operating as in Example 1, but employing 10α-methoxy-6-methyl-8ss-carboxy-ergoline in place of 6-methyl-8p-carboxy-ergoline, the title compound, m.p. 190-1 920C, was obtained in 79% yield.
Example 4 1,3-diisporpyl-3-(10'α-methoxy-1',6'-dimethylergoline-8'ss-carbonyl)-urea (1: R1 = R4 = CH3,
R2=H, R3=CH3O, R5=R6=(CH3)2CH) Operating as in Example 1, but employing 10α-methoxy-1,6-dimethyl-8ss-carboxy-ergoline in place of 6-methyl-8ss-carboxy-ergoline, the title compound, m.p. 180-182 C, was obtained in 80% yield.
Example 5 1,3-diisopropyl-3-(6'-n-propylergoline-8'ss-carbonyl)-urea (I: R,=R2=R3=H, R4=CH3CH2CH2, R5=R6=(CH3)2CH) Operating as in Example 1, but employing 6-n-propyl-8p-carboxy-ergoiine in place of 6-methyl8ss-carboxy-ergoline. the title compound, m.p. 188-1 900C, was obtained in 82% yield.
Example 6 1,3-diisopropyl-3-(2' 6'-dimethylergoline-8'ss-carbonyl)-ures (I: R,=R3=H, R2=R4=CH3, R5=R6=(CH3)2CH) Operating as in Example 1, but employing 2,6-dimethyl-8ss-carboxy-ergoline in place of 6 methyl-8P-carboxy-ergoline, the title compound, m.p. 192-1940C, was obtained in 85% yield.
Example 7 1,3-dicyclohexyl-3-(6'-methylergoline-8'ss-carbonyl)-urea (I: R1=R2=R3=H, R4=CH3, R5=R6=cyclohexyl) Operating as in Example 1, but employing dicyclohexyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 205-2070C, was obtained in 77% yield.
Example 8 1 ,3-dicyclohexyl-3-(1 ',6'-dimethylergoline-8'ss-carbonyl)-urea (I: R1=R4=CH3, R2=R3=H, R5=R=cyclohexyl) Operating as in Example 2, but employing dicyclohexyl carbodiimide in place of diisopropyl carbodimide, the title compound, m.p. 182-1 840C, was obtained in 83% yield.
Example 9 1,3-dicyclohexyl-3-(10'α-methoxy-6'-methylergoline-8'ss-carbonyl)-urea (I: R1=R2=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'α-methoxy-1',6'-dimethylergoline-8'ss-carbonyl)-urea (1:R1=R4=CH3, R2=H, R3=CH3O, R5=R6=cyclohexyl)
Operating as in Example 4, but employing dicyclohexyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 1 98-2000C, was obtained in 80% yield.
Example 11 1,3-di-tert-butyl-3-(6'-methyl-ergoline-8' -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'α-methoxy-6'-methyl-ergoline-8'ss-carbonyl)-urea (I: R1=R2=H, R3=CH30,
R4=CH3, R5=R8=(CH3)3c) Operating as in Example 3, but employing di-t-butyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 138-140 C, was obtained in 65% yield.
Example 13 1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-methyl-ergoline-8'ss-carbonyl)-urea (1:R1=R2=R3=H, R4=CH3, R5=(CH3)2 NCH2CH2CH2, R6=C2H5
Operating as in Example 1, but employing N-(3-dimethylaminopropyl)-N-ethyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 179-181 0C, was obtained in 75% yield.
Example 14 1-ethyl-3-(3'-dimethylaminopropyl)-3-(10'-methoxy-6'-rnethylergoline-8'A-carbonyl)-urea (I: R1=R2=H, R3=CH3O, R4=CH3, R5=(CH3)2NCH2CH2CH2,R6=C2H5) 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-dicyclohexyl-3-(6'-allylergoline-8'ss-carbonyl)-urea (1:R1,=R2=R3=H, R4=CH2=CH-CH2, R5=R6=cyclohexyl).
Operating as in Example 7, but employing 6-allyl-8ss-carboxyergoline in place of 6-methyl-8sscarboxy-ergoline, the title compound, m.p. 152-154 C, was obtained in 80% yield.
Example 16 1,3-dimethyl-3-(6'-methylergoline-8',B-carbonyl)-urea (I: R1=R2=R3=H, R4=Rs=R6=CH3).
Operating as in Example 1, but employing dimethyl carbodiimide in place of diisopropyl carbodiimide, the title compound, m.p. 21 5-217 OC, was obtained in 74% yield.
Example 17 1,3-di-t-butyl-3-(10'α-methoxy-1',6'-dimethylergoline-8'ss)-carbonyl)-urea (I: R1=R4=CH3, R2=H, R3=CH3O, R5=R6=(CH3)3C).
Operating as in Example 4, but employing di-t-butyl carbodiimide in place in diisopropyl carbodiimide, the title compound was obtained in 60% yield; m.p. 140-1 420C.
Example 18 1,3-di-t-butyl-3-(1',6'-dimethylergoline-8'ss-carbonyl)-urea (1:R1=R4=CH3, R2=R3=H,
R5=R8=CH3)3C).
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. 180-181 OC.
Example 19 1-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'ss-carbonyl)-urea (1:R1=R2=R3=H,
R4=CH2=CH-CH2, R5=(CH3)2 NCH2CH2CH2, R5=C7H5).
Operating as in Example 13, but employing 6-allyl-8p-carboxyergoline in place in 6-methyl-8p- carboxy-ergoline, the title compound was obtained in 60% yield, m.p. 1 53-1 550C (as its diphosphate salt).
Example 20 1-(3'-dimethylaminopropyl)-3-ethyl-3'(6'-allylergoline-8'ss-carbonyl)-urea (1: R1=R2=R3=H,
R4=CH2=CH-CH2, R5=C2H5, R8=(CH3)2NCH2CH2CH2).
The mother liquor obtained in Example 19 after separation of the 1 -ethyl-3-(3'dimethylaminopropyl)-3-(6'-allylergoline-8'ss-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).
Example 21 1-Ethyl-3-(3'-dimethylaminorpopyl)-3-(6'-n-propylergoline-8'ss-carbonyl)-urea (1: R1=R2=R3=H,
R4=CH3CH2CH2, R5=(CH3)2 NCH2CH2CH2, R3=C2H5).
Operating as in Example 13, but employing 6-n-propyl-8ss-carboxy-ergoline in place of 6-methyl8ss-carboxyergline, the title compound was obtained in 70% yield, mp. 205-207 C (as its dichloride salt).
Example 22 1-Ethyl-3-(3'-dimethylaminorpopyl)-3-(6'-=isopropylergoline-8'ss-carbonyl)-urea (1:R1=R2=R3=H
R4=(CH3)2CH, R5=(CH3)2NCH2CH2CH2, R8=C2H5).
Operating as in Example 13, but employing 6-isopropyl-8p-carboxy-ergoline in place of 6-methyl8ss-carboxy-ergoline, the title compound, m.p. 106-1 080C, was obtained in 55% yield.
Example 23 1,3-dicyclohexyl-3-(1'-methyl-allylergoline-8'ss-carbonyl)-urea (1:R1=CH3, R2=R3=H,
R4=CH2CH=CH2, R5=R6\cyclohexyl).
Operating as in Example 7, but employing 1-methyl-6-allyl-8ss-carboxy-ergoline in place of 6methyl-8ss-carboxy-ergoline, the title compound, m.p. 137-139 C, was obtained in 75% yield.
Claims (30)
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'ss-carbonyl)-urea.
3. 1,3-Diisopropyl-3-(1',6'-dimethyl-ergoline-8'ss-carbonyl)-urea.
4. 1,3-Diisopropyl-3-(10'α-methoxy-6'-methylergoline-8'ss-carbonyl)-urea.
5. 1,3-Diisopropyl-3-(10'α-methoxy-1',6'-dimethylergoline-8'ss-carbonyl)-urea.
6. 1,3-Diisopropyl-3-(6'-n-propylergoline-8'ss-carbonyl)-urea.
7. 1,3-Diisopropyl-3-( 1 ',6'-dimethylergoline-8'P-carbonyl)-urea
8. 1,3-Dicyclohexyl-3-(6'-methylergoline-8'ss-carbonyl)-urea.
9. 1 ,3-Dicyclohexyl-3-( 1 ',6'-dimethylergoline-8'p-carbonyl)-urea.
10. 1,3-Dicyclohexyl-3-(10'α-methyloxy-6'-methylergoline-8'ss-carbonyl)-urea.
11. 1,3-Dicyclohexyl-3-(10'α-methoxy-1',6'-dimethylergoline-8'ss-carbonyl)-urea.
12. 1,3-Di-t-butyl-3-(6'-methyl-ergoline-8'ss-carbonyl)-urea.
13. 1,3-di-butyl-3-(10'α-methoxy-6'-methyl-erglline-8'ss-carbonyl-urea.
14. 1-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-methylergoline-8'ss-carbonyl)-urea.
15. 1-Ethyl-3-(3'-dimethylaminopropyl)-3-(10'α-methoxy-6'-methylergoline-8'sscarbonyl)-urea.
16.1,3-Dicyclohexyl-3-(6'-allylergoline-8'-carbonyl)-urea.
17.1,3-Dimethyl-3-(6'-methylergoline-8'-p-carbonyl)-urea.
18. 1 ,3-Di-t-butyl-3-( 1 0'a-methoxy- 1 ',6'-dimethylergoline-8',-carbonyl)-urea.
1 9. 1 ,3-Di-t-butyl-3-( 1 ',6'-dimethylergoline-8'p-carbonyl)-urea.
20. 1 -Ethyl-3-(3'-dimethylaminop?opyl)-3-(6'-allylergoline-8'carbonyl)-u rea.
21. 1-(3'-Dimethylaminoropyl)3-ethyl-3-(6'-allylergoline-8'ss-carbonyl)-urea.
22. 1-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-n-propylergoline-8'ss-carbonyl)-urea.
23. 1-Ethyl-3-(3'-dimethylaminopropyl)-3-(6'-isopropylergoline-8'ss-carbonyl)-urea.
24. 1,3-Dicyclohexyl-3-(1'-methyl-6'-allylergoline-8'ss-carbonyl)-urea.
25. A process for the preparation of an ergoline derivative according to claim 1, which process comprises reacting in aprotic solvent an acid of the general formula II as herein defined with a carbodiimide of the general formula Ill as herein defined.
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 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 claims 25 to 28 in which the reaction is carried out at a temperature of from 500C to 1 000C for from 5 to 24 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 pharmaceutically acceptable diluent or carrier for oral or parenteral administration.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8109949A GB2074566B (en) | 1980-04-03 | 1981-03-31 | Ergoline derivatives |
| MX9203120A MX9203120A (en) | 1980-04-03 | 1992-06-22 | DERIVATIVES OF ERGOLINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8011234 | 1980-04-03 | ||
| GB8109949A GB2074566B (en) | 1980-04-03 | 1981-03-31 | Ergoline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2074566A true GB2074566A (en) | 1981-11-04 |
| GB2074566B GB2074566B (en) | 1983-11-02 |
Family
ID=26275074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8109949A Expired GB2074566B (en) | 1980-04-03 | 1981-03-31 | Ergoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2074566B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4632990A (en) * | 1982-04-13 | 1986-12-30 | Farmitalia Carlo Erba S.P.A. | Ergoline carboxamides |
| WO1990012796A1 (en) * | 1989-04-21 | 1990-11-01 | Schering Aktiengesellschaft Berlin Und Bergkamen | 8-beta-substituted ergolines, a process for manufacturing them, and their use |
| EP0418990A2 (en) * | 1989-09-20 | 1991-03-27 | Schering Aktiengesellschaft | 13-Bromo and 13,14-dibromo ergoline, their preparation and their use |
| US7217822B2 (en) | 2005-03-17 | 2007-05-15 | Synthon Ip Inc. | Process for making cabergoline |
-
1981
- 1981-03-31 GB GB8109949A patent/GB2074566B/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4632990A (en) * | 1982-04-13 | 1986-12-30 | Farmitalia Carlo Erba S.P.A. | Ergoline carboxamides |
| WO1990012796A1 (en) * | 1989-04-21 | 1990-11-01 | Schering Aktiengesellschaft Berlin Und Bergkamen | 8-beta-substituted ergolines, a process for manufacturing them, and their use |
| US5219862A (en) * | 1989-04-21 | 1993-06-15 | Schering Aktiengesellschaft | 8 beta-substituted ergolines, process for their production and their use |
| EP0418990A2 (en) * | 1989-09-20 | 1991-03-27 | Schering Aktiengesellschaft | 13-Bromo and 13,14-dibromo ergoline, their preparation and their use |
| EP0418990A3 (en) * | 1989-09-20 | 1991-07-03 | Schering Aktiengesellschaft Berlin Und Bergkamen | 13-bromo and 13,14-dibromo ergoline, their preparation and their use |
| US7217822B2 (en) | 2005-03-17 | 2007-05-15 | Synthon Ip Inc. | Process for making cabergoline |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2074566B (en) | 1983-11-02 |
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