CA1178582A - Ergoline derivatives, their production and pharmaceutical compositions thereof - Google Patents
Ergoline derivatives, their production and pharmaceutical compositions thereofInfo
- Publication number
- CA1178582A CA1178582A CA000396775A CA396775A CA1178582A CA 1178582 A CA1178582 A CA 1178582A CA 000396775 A CA000396775 A CA 000396775A CA 396775 A CA396775 A CA 396775A CA 1178582 A CA1178582 A CA 1178582A
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- Prior art keywords
- alkyl
- compound
- formula
- pharmaceutically acceptable
- urea
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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
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract A compound of formula I
I
in which R1 is H,(C1-4)alkyl or a precursor thereof, R2 is (C1-4)alkyl, R3 and R4 independently are H, (C1-4)alkyl or together (C2-5)-alkylene, R5 is H or alkyl, and A and B each are H or both together are a bond with the proviso that, when R1 and R2 are each CH3,R3 and R4 are each C2H5 and A and B are each H, then R5 is alkyl in free base form or in pharmaceutically acceptable acid addition salt form.
The compounds are used in the treatment of hypertension and cardiac insufficiency.
I
in which R1 is H,(C1-4)alkyl or a precursor thereof, R2 is (C1-4)alkyl, R3 and R4 independently are H, (C1-4)alkyl or together (C2-5)-alkylene, R5 is H or alkyl, and A and B each are H or both together are a bond with the proviso that, when R1 and R2 are each CH3,R3 and R4 are each C2H5 and A and B are each H, then R5 is alkyl in free base form or in pharmaceutically acceptable acid addition salt form.
The compounds are used in the treatment of hypertension and cardiac insufficiency.
Description
~178~
NEh' ERGOLINE DERIVATIVES~ THEIR PRCDUCTION AND PHARMACEU-TICAL COMPOSITIONS THEREOF
. . .
This invention relates to ergoline derivatives, their pro-duction and pharmaceutical compos;tions containing them.
German Offenlegungsschrift No 1910~30 discloses a very broad class of N-acyl-N-(12-hydroxy-1,6-dimethylergol-in-8-yl-methyl)amino der;vatives, which are stated to be especially clinically useful in the treatment of migraine, trigeminal neuralgia, general allergies and inflanllnation disorders as indicated by antagonism of serotonin. A wide variety of acyl derivatives are specifically suggested.
One such acyl derivative is the derivative from diethyl carbamin;c acid. No other carbaminic derivatives are specifically suggested. There are only 5 characterised examples, but none of these are carbaminic acid deriva-tives. We have now found that the ergoline derivatives encompassed by the following formula I which are nowhere specifically mentioned or suggested by the above German Offenlegungsschrift possess especially interesting anti-hypertensive activity as indicated by e.g. potency in the tests hereinafter.
The present invention provides compounds of formula I
H R
CH2-N-C-N~
n ~ n ~R
~R5 ~ 4 .. ~' .
NEh' ERGOLINE DERIVATIVES~ THEIR PRCDUCTION AND PHARMACEU-TICAL COMPOSITIONS THEREOF
. . .
This invention relates to ergoline derivatives, their pro-duction and pharmaceutical compos;tions containing them.
German Offenlegungsschrift No 1910~30 discloses a very broad class of N-acyl-N-(12-hydroxy-1,6-dimethylergol-in-8-yl-methyl)amino der;vatives, which are stated to be especially clinically useful in the treatment of migraine, trigeminal neuralgia, general allergies and inflanllnation disorders as indicated by antagonism of serotonin. A wide variety of acyl derivatives are specifically suggested.
One such acyl derivative is the derivative from diethyl carbamin;c acid. No other carbaminic derivatives are specifically suggested. There are only 5 characterised examples, but none of these are carbaminic acid deriva-tives. We have now found that the ergoline derivatives encompassed by the following formula I which are nowhere specifically mentioned or suggested by the above German Offenlegungsschrift possess especially interesting anti-hypertensive activity as indicated by e.g. potency in the tests hereinafter.
The present invention provides compounds of formula I
H R
CH2-N-C-N~
n ~ n ~R
~R5 ~ 4 .. ~' .
-2- 100-555 in which Rl is H (C.l 4)alkylror A precursor thereof R2 i5 (C~ -4)al kyl, P~3 and R4 independently are H or (Cl_4)~1kyl o~ to-gether are (C2 5)alkylene R5 is H or alkyl and A and B each are H or both toge~ller are a bond with the proviso ~nat .~en "~1 and R~ are each CH3 R3 and R~l a~e each C~H~ and A and B are each H~ then R5 is alkyl hereinafter referred to as compounds of the inYention.
As precursors in position 1 are meant such substituents 15 which under physiologically conditions may be converted into the other indicated signi-ficances of Rl particularly il.
Such substituents are e.9- CH20H (Cl 22)alkanOyloxymetnyl or acetyl. R5 if alkyl contains preferably 1~20 especial-ly 1-4 carbon atoms. Preferred substituents in the com-20 pounds of formula I are Rl = H (Cl 4)alkylg CH20~ or(Cl 4)alkanoyloxymethyl R3 = H or (Cl 4)alkyl P~4 =(C1_4) alkyl and/or R5 = H or (C1 4)alkyl.
These preferences are especially combined togetherg A and B preferably form together a bond.
25 Especially preferred substituents are individually or combined Rl = H R2 = CH3 R3 = CH3s R4 3 5 or CH3 especially CH3.
A group of compo~lnds com,)rises the compounds of formula Ia ~l d ~ p) r ?~
H / R3a CH ~N-C -N
0 ~ R4a Ia EIN
in which R2 is as defined above, R3a and R4a are independen~ly (Cl 4~ alkyl and R5a is H or CH3.
Another group of compounds comprises compounds of formula I
wherein when Rl and R2 are each CH3, R3 and R4 are each (Cl 4)alkyl and A and B are each H, then R5 is alkyl.
The present invention in another aspect provides a process for the production of a compound of the invention, which includes the step of a) oxidizing a compound of formula II
H ~R3 c~2-N-C-N ~R
B~ ~ II
RlN
wherein Rl to R4 and A and B are as defined above, and R6 is hydrogen or hydroxyl, or a precursor thereof, to produce a compound of formula I wherein R5 is hydrogen, or li78582 b) alkylating a compound of formula I wherein at least one of Rl,- R3, ~4 and R5 is hydrogen~or a precursor to produce the corresponding compound wherein at least 5 Rl is (Cl_4)alkyl, CH20H or (Cl_22)alkanoyloxymethyl and/or at least R3,~ and R5 is alkyl and if desired converting a resultant formula ~ compound into another fonmula I~compound . ~
The oxidation according to process a) may be effected in conventional manner for the introduction of a double bond into the 2,3 position, and when R6 is hydrogen for the lOintroduct;on of a hydroxyl ~roup in the 12 position of the ergoline nucleus. When R6 is hydrogen if desired the oxidation may be effected simultaneously or in two stages, one stage being the introduction of the hydroxyl group and the other stage being the introduction of the double bond.
15The introduction of the 2,3 double bond may be effected in conventional manner for the conversion of indolines into the corresponding indoles, e.g. by passing a stream of air through a solution of the compound. The reaction may be effected at room temperature..
20The ;ntroduction of the hydro~yl group may be effected wi~h an appropriate oxidizing agent such as a nitrosodisulphonate, e.g.in the form of the potassium salt. Generally such reac-tions also lead to the introduction of the double bond in the 2,3 position (see Helv.Chim.Acta, 756-769,1964).
25The reactionis preferably effected with the nitrosodisulphonate in an aqueous~medium at a pH about 3 to about 9,preferably at pH of about 7.
The ergoline may be di~solved in an organic solvent,e.g.chloro-form, and the system stirred rigorously. The reaction tem-- perature may be for example from about O~C to abcut 50C.
~.~i7~2, If there is a group present e.g. CH20H in the 1 position of the ergoline nucleus, then R6 is preferably hydroxy.
Preferably such groups are introduced after the oxidation reaction.
The alkylation process b) may be effected in conventional manner,using appropriate alkylating agents to alkylate the appropriate group. The term alkylation includes not only the introduction of unsubstituted alkyl rad;cal but - also the introduction of CH20H and alkanoyloxymethyl. Where selective alkylation is required, it may be desirable to 10 block temporarily other reactive groups present.
- Etherification of the hydroxy radical may be effected with a diazoalkane,e.g. diazomethane. Introduction of the CH20H
radical in position 1 may be effected with formaldehyde.The CH20H radical may be subsequen~ly acylated with for example 15 an acid halide.
The compounds of formula II wherein R6 is hydrogen are known or may be prepared in conventional manner.Some compounds of formula II wherein R6 is hydrogen hereinafter referred to as compounds of formula III are in general new and may be pre-20 pared e.g. as described in the following reaction schemeand exemplified for compounds III in which Rl is hydrogen.
5~2 _6 - 1 00-5555 \/ \/
~ T--- ~
I ~ ~ ~
c~ ~ ~ n~ ~ c~
\z/ 2 \~/
.~, ','-, ~
C
~ ~ C C E
\ / c~ ~ 3 E ~, In the reaction scheme R2 to R4 are as defined above.The several reaction steps are described in extenso in example 1 for the production of a 9,10-didehydro-ergoline compound of the invention.
The cornpounds of formula I in which R5 is hydrogen may be converted into other compounds of formula I in conventional manner,e.g.they may be alkylated or, for the production of the above mentioned precursor groups,acetylated or formy-lated in position 1 and the formylated products preferably 10 acylated. The compounds may be optionally alkylated in the ureamethyl radical and hydrogenated in position 9,10.
The etherification of the 12-hydroxylated product may be effected in conventional manner for the synthesis of ana-logous phenol-ethers.
- 15 The alkylation may be effected in conventional manner.The acetylation and the formylation which may be carried out conventionally by reaction with ketene, and with formal-dehyde and an acid respectively.
The acylation of a CH20H radical in position 1 formed by 20 formylation may also be effected by kno~n metllods,e.g.
with an acid halide. Other precursor groups in position 1 may be produced in conventional manner.
The hydrogenation may be carried out in conventional manner, particularly by catalytic hydrogenation,e.g.with Pd-C as a 25 catalyst.
The compounds of formula I may be recovered in,for example, free ba~e form or ac;d addition salt form.
The acid addition salt forms of a compound of formula I may be produced in conventional manner from the free base forms 30 and vîce versa. Suitable acids include fumaric acid and hydrochloric ac;d.
358~
If compounds of formula I are to be prepared in which one or more of the subst;tuents are (C1 4)alkyl or A and B
are H, the required alkylation or hydrogenation in posi-tion 9,10 may occur either before or after the formation of the 12-hydroxy radical. Precursors of Rl are pre-ferably introduced after the introduction of the hydroxyl group.
, ' ' .
;
d ~ 2
As precursors in position 1 are meant such substituents 15 which under physiologically conditions may be converted into the other indicated signi-ficances of Rl particularly il.
Such substituents are e.9- CH20H (Cl 22)alkanOyloxymetnyl or acetyl. R5 if alkyl contains preferably 1~20 especial-ly 1-4 carbon atoms. Preferred substituents in the com-20 pounds of formula I are Rl = H (Cl 4)alkylg CH20~ or(Cl 4)alkanoyloxymethyl R3 = H or (Cl 4)alkyl P~4 =(C1_4) alkyl and/or R5 = H or (C1 4)alkyl.
These preferences are especially combined togetherg A and B preferably form together a bond.
25 Especially preferred substituents are individually or combined Rl = H R2 = CH3 R3 = CH3s R4 3 5 or CH3 especially CH3.
A group of compo~lnds com,)rises the compounds of formula Ia ~l d ~ p) r ?~
H / R3a CH ~N-C -N
0 ~ R4a Ia EIN
in which R2 is as defined above, R3a and R4a are independen~ly (Cl 4~ alkyl and R5a is H or CH3.
Another group of compounds comprises compounds of formula I
wherein when Rl and R2 are each CH3, R3 and R4 are each (Cl 4)alkyl and A and B are each H, then R5 is alkyl.
The present invention in another aspect provides a process for the production of a compound of the invention, which includes the step of a) oxidizing a compound of formula II
H ~R3 c~2-N-C-N ~R
B~ ~ II
RlN
wherein Rl to R4 and A and B are as defined above, and R6 is hydrogen or hydroxyl, or a precursor thereof, to produce a compound of formula I wherein R5 is hydrogen, or li78582 b) alkylating a compound of formula I wherein at least one of Rl,- R3, ~4 and R5 is hydrogen~or a precursor to produce the corresponding compound wherein at least 5 Rl is (Cl_4)alkyl, CH20H or (Cl_22)alkanoyloxymethyl and/or at least R3,~ and R5 is alkyl and if desired converting a resultant formula ~ compound into another fonmula I~compound . ~
The oxidation according to process a) may be effected in conventional manner for the introduction of a double bond into the 2,3 position, and when R6 is hydrogen for the lOintroduct;on of a hydroxyl ~roup in the 12 position of the ergoline nucleus. When R6 is hydrogen if desired the oxidation may be effected simultaneously or in two stages, one stage being the introduction of the hydroxyl group and the other stage being the introduction of the double bond.
15The introduction of the 2,3 double bond may be effected in conventional manner for the conversion of indolines into the corresponding indoles, e.g. by passing a stream of air through a solution of the compound. The reaction may be effected at room temperature..
20The ;ntroduction of the hydro~yl group may be effected wi~h an appropriate oxidizing agent such as a nitrosodisulphonate, e.g.in the form of the potassium salt. Generally such reac-tions also lead to the introduction of the double bond in the 2,3 position (see Helv.Chim.Acta, 756-769,1964).
25The reactionis preferably effected with the nitrosodisulphonate in an aqueous~medium at a pH about 3 to about 9,preferably at pH of about 7.
The ergoline may be di~solved in an organic solvent,e.g.chloro-form, and the system stirred rigorously. The reaction tem-- perature may be for example from about O~C to abcut 50C.
~.~i7~2, If there is a group present e.g. CH20H in the 1 position of the ergoline nucleus, then R6 is preferably hydroxy.
Preferably such groups are introduced after the oxidation reaction.
The alkylation process b) may be effected in conventional manner,using appropriate alkylating agents to alkylate the appropriate group. The term alkylation includes not only the introduction of unsubstituted alkyl rad;cal but - also the introduction of CH20H and alkanoyloxymethyl. Where selective alkylation is required, it may be desirable to 10 block temporarily other reactive groups present.
- Etherification of the hydroxy radical may be effected with a diazoalkane,e.g. diazomethane. Introduction of the CH20H
radical in position 1 may be effected with formaldehyde.The CH20H radical may be subsequen~ly acylated with for example 15 an acid halide.
The compounds of formula II wherein R6 is hydrogen are known or may be prepared in conventional manner.Some compounds of formula II wherein R6 is hydrogen hereinafter referred to as compounds of formula III are in general new and may be pre-20 pared e.g. as described in the following reaction schemeand exemplified for compounds III in which Rl is hydrogen.
5~2 _6 - 1 00-5555 \/ \/
~ T--- ~
I ~ ~ ~
c~ ~ ~ n~ ~ c~
\z/ 2 \~/
.~, ','-, ~
C
~ ~ C C E
\ / c~ ~ 3 E ~, In the reaction scheme R2 to R4 are as defined above.The several reaction steps are described in extenso in example 1 for the production of a 9,10-didehydro-ergoline compound of the invention.
The cornpounds of formula I in which R5 is hydrogen may be converted into other compounds of formula I in conventional manner,e.g.they may be alkylated or, for the production of the above mentioned precursor groups,acetylated or formy-lated in position 1 and the formylated products preferably 10 acylated. The compounds may be optionally alkylated in the ureamethyl radical and hydrogenated in position 9,10.
The etherification of the 12-hydroxylated product may be effected in conventional manner for the synthesis of ana-logous phenol-ethers.
- 15 The alkylation may be effected in conventional manner.The acetylation and the formylation which may be carried out conventionally by reaction with ketene, and with formal-dehyde and an acid respectively.
The acylation of a CH20H radical in position 1 formed by 20 formylation may also be effected by kno~n metllods,e.g.
with an acid halide. Other precursor groups in position 1 may be produced in conventional manner.
The hydrogenation may be carried out in conventional manner, particularly by catalytic hydrogenation,e.g.with Pd-C as a 25 catalyst.
The compounds of formula I may be recovered in,for example, free ba~e form or ac;d addition salt form.
The acid addition salt forms of a compound of formula I may be produced in conventional manner from the free base forms 30 and vîce versa. Suitable acids include fumaric acid and hydrochloric ac;d.
358~
If compounds of formula I are to be prepared in which one or more of the subst;tuents are (C1 4)alkyl or A and B
are H, the required alkylation or hydrogenation in posi-tion 9,10 may occur either before or after the formation of the 12-hydroxy radical. Precursors of Rl are pre-ferably introduced after the introduction of the hydroxyl group.
, ' ' .
;
d ~ 2
-3- 100-5555 x a m p l e 1 `~ dimethyl-3~(12~hydroxy 5-n1ethyl-,10-dt-yl -methyl )urea a) l~l~dimeth~1-3~ acetyl-6-methvl-2 3B-dih~dro~9 710-di-del~dro~er~olin~ eth~ rea 14 ml of triethylamine are added to a suspension of 13 9 (35.8 mM) of 1 l-di1~ethyl-3$(6-Methyl-2 3B-dihydro-9 10-didehydro~er~olin-8~-ylmethyl)urea-hydrochloride ln 300 ml of absolllte methylene chloride. When the substrate has dissolved~a solution of 3 6 ml (50.7 mM) of acetyl chloride in 20 ml of ab,olute methylene chloride is added in drops at 10 - 15 and the solution is stirred for 1 hour at room temperature. It is subsequently poured onto water/ice then 20 ml of saturated ~HC03 solution are added and the solution is extracted twice with me-thylene chloride which contains S% isopropanol. The combined organic phases are dried with sodium sulphate filtered and evaporated on a rotary evaporator. After drying in a high vacuum the title connpound in free base form is obtained in the form of a yellow-brown foam.The hydrogen fumarate of the title compound is obtained and crystallised from 2-butanone/water/methanol (5:3:2).M.p.:
decomposition froln 135 [a~20 = + 36 [c = 0.355 in ethanol/water (1:1)].
.10- 100_5555.
b) l,l~dimethx~3-~1-acet~ -6-~eth~ 12-nitro_2,3~-dii!ydro~
9,10-dideh~Jdro-er~olin-8~-~lmethyl~urea _______ - __ _Y_ ____~ ____ . ___ 1~45 ml (35 mM) of nitric acid (100%) are added in drops at 10 over the course of 3 minutes to a solut1On of 13 9 (35 mM) of the crude iiase obtained under a) in 80 ml of sulphuric acid (100%), the solution being maintained in an argon atmosphere. After stirring for 20 minutes at room tempe-rature, the solution is poured onto ice, set to a pi-l of 8 with 10 N sodium hydroxide at a temperature of 5 - 10, and extracted with methylene chloride which contains 10~
isopropanol~ The organic phases are combined, dried with sodium sulphate, Filtered and dried on a rotary evaporator.
After drying in a high vacuum, the title compound is ob-tained, and this can be reduced further without purifi-cation.
c) 1 Ll -dimethyl-3-(1-acetyl-12-amino-6-meth~1-2,3i3-dihydro-9,10-dideh~dro-eroolin-8B-vlmethvl~urea ________-- __ _ ~______ _~___ _ _ _ A solut;on of 13.5 9 (32.7 mM) of 1,1-dimethyl-3-(1-acetyl-6-methyl-12-nitro-2,3~-dihydro-9,10-didehydroergolin-8~-ylmethyl)urea in 300 ml of ethyl acetate and 100 ml of methanol is hydrogenated under normal conditions in the presence of 1.5 9 of palladium on carbon (10%) until the calculated amount of hydrogen has been absorbed.
The mi>ture is filtered and evaporated.The resultant crude product is sub~iected to chromatography on 300 9 of silicagel with methylene chloride containing 15% methanol and 0.5% aqueous ammonia,obtaining the title compound.
d) l,l-dimeth~1-3-(12-hyc!rox~-6-lneth~l-9~10-didehydro-_____ _ ___ _ __. _ ., _ _ _ ____ ergolin-8~-ylmeth~llurea A solution of 4.5 9 (11.7 mM) of the product obtained under c) in 100 ml o' 1 N HCl is heated with stirring for 17 hours to 95. l~ith cooling by ice, the solution is subsequently adjusted to at a pH of 7 ~ith concen-trated ammonia solution, and is extracted 4 times with methylene chloride which contairls 10~ isopropanol. The combined organic phase are dried w-ith sodium sulphate, filtered and evaporated in a rotary evaporator. The residue of evaporation, l,l-dimethyl-3-(12-hydroxy-6-methyl-2,3~-dihydro-9,10-didehydro-ergolin-8~-ylmethyl) urea, is dissolved in 10 ml of ethanol. After adding 1 ml of concentrated ammonia solutioll, air is blown through the solution for 1 hour. After evaporation, the crude product is subjected to chromatoyraphy on 100 9 of silicagel, with methylene chloride containing 10~ methanol and 0.2% ammonia solution. The title com-pound in free base form is obtained as a beige residue.
In order to produce the hydrochloride, the base ob-tained is dissolved in methylene chloride/methanol (1:1), then 2.94 ml (5.9 mM) of 2 N HCl are addecl, and concentration follows in a rotary evaporator until crystallisation commences. The hydrochloride of the title compound is obtained as beige crystals.
M.p.: decomposition from 220C, ~a]20 = + 126.2 [c = 0.435 in ethanol/water (1:1)].
E)~AMPLE 2~ dimethyl-3-~12-methoxy-6-methyl-9,1a-didehydro ... .. _ _. _ .. . _ _ _ . _ -er~olin-8~-~lmeth~1~urea 200 ml (about 71.5 mM) of an approximately 1.5,c ethereal diazo-methane solution kept in an argon atmosphere are carefully poured into a solution wllich i5 cooled to -15~ of 5 ml of 0.08 N methanolic tetrafluoroboric acid in 150 ml of methanol, and 2.55 9 ~7.5 m,'~) of the base obtained under ld). Stirring is subsenuently effected for 20 hours at room temperature and in an argoll atmocphere. rhe pro-cess is finished by concentrating the mixture to ahout 20~ of the original volume under a water-jet vacuum, arld concentrating further in a rotary evaporator. After the addition of 50 ml of ethar,ol and 1 ml of concerltrated ammonia solution, concentration is again effected, and the residue is subjected ~o chrolnatography on 120 9 of silicagel with methvlene chloride, containing 10~ methanol and 0.2% concentrated ammonia solu~ion. The title compound is obtained as in free base form, wilich crystallises from acetone. '~l.p.:
decomposition from 180; [~]20 - ~- 85~ [c = 0.450 in methanol~.
EXAMPLE 3: 1,1 dimethyl-3-~12-hydroxy-6 methyl-9,10-dideh~dro-ergol~n-8~-yllne-thyl~urea A solution of 3.0 y (9.2 mM) of l~l-dinlethyl-3-(~6-lnethyl-2~3~-dihydro-9~lQ
didehydro-eryolin-8~-ylmethyl)urea in 46 ml of isopropanol and 165 ml of chloroform is added at room temperature, while stirring, to a solution of 10.1 9 (37.7 mM) of potassium nitrosodisulphonate in water, buffered with phosphate at pH 7Ø
The reaction mixture is stirred further at room temperature for 5 min., the organic phase is separated and the aqueous phase is extrac-ted with isopropanol chloroform (5:18).
The collected organic phases are dried over sodium sulphate, fil-traied and evaporated to dryness.
-13- 100-555~
The residue is chromatographed on silicagel with a mixture of me-thylene chloride, methanol and ammonia (85:15:o.5), obtaining the pure title compound.
The following compounds of formula I are produced wherein:-~it~
-~ 4- 1~0~5555 . ~
' ~ 6~ ' s . o ' E
', o e~ a~, a) s '~
., o o o ~ ^ ^ o ^ ----~r- ~ ~ ~ cn cn cn cn cn ~ ~ cn cn >' >' >' m m m m m ~ C
O o o o o o o o o o o o C~ L~ O ~ I~ O O 00 L~
~ = c ~cr) o c ~ ~ ~ ~:
m ~ ~ ::~ ~ ~ ~ ~ ~ ~ ~ ~
. ~ oo^oooooooo C a~ m I m 1:~ m CD crl c~ m m _,~
1~> I I I I I 1: I I ~-tY c_, ~ I >
_ . m ~r> ; E ~
. c~ . O Q~ Q_ ~ ~ c~ O~
~ I I I ~ ~ CI~ I I C~ C~ X Qr~ ~ O ~
r E E C~l ~s a~ a lY ~ I I o o I I I o o E E ~
. . ~ J X
~ ~ ~ s ~
I ~ I E
I ~_) ~ C~ cn ~n~
c~ I I I I I I I I I I ~ O O
~Y: ~ C~ C'_~ ~ (_) ~_) <-) ~-) ~ ' O 0~ ~,r~,. 5 . ~ ~ t~ s_ I ~S ~.5 ~ ~ s -r 0= .C-.C- >~
C~l ' N ~ ~ ~ ~ -O ~
CY I I I I T ~ C ) C_~ I _- c c s_ s_ S_ . . . _ ~
~ ~ ~ ~ ~ ~ C C C
X r-d' '--U') ~ 00 c~ O -- ~ ~ ~ C~
W r- ~ _~
. , ~ ~ c_~n _~ 5 100-5555 .
i~
, ~ ~ 'o C~ ~ ~
Cll Q' ~ o ON
~, , Cl ~ Cl __ ~i ..
., ' ~ 3 5~3~
In a 1st group of compounds Rl ;s H
" " 2nd " " " Rl is CH20H
~l 1' 3rd " " Rl is alkanoyloxymethyl 5 " " 5th " '' ' Rl is (Cl 4)alkyl 7th ~ ', ,, R3 is (cl_4)alkyl 9th '' '' '' R4 is (Cl 4)alkyl " 11th " " " R5 is alkyl " " 12th " " " A and B are together a bond " " 13th " " " A and B both are H.
A.~ 1~3 !6 - 17 - lO0-5555 The compounds of the invention exhibit pharmacological activity and are therefore indi-cated for use as pharmaceuticals.
In particular tney lead to a lowering of the blood pressure as indicated in tests with the conscious spontaneously hypertensive rat upon administration of from 0,OOl to 0,l mg/kg s.c.
In addition theJ lo~er blood r)ressure and decrease vascular resistance in the anaesthetised,normotensive dog upon administration of a dose of fronl 0,OOl to lO mg~g i.~, especially of frcin 0,OOl to 0,2 mg/i~g i.v,.
The compounds are iherefore indicated f-or use in t:~e t,eatment lO of hypertension and cardiac insufficiency.
An indicated daily dosage is in the range ~I^Om about 0.2 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day or in sustained release form~ and dosage forms suitable for oral administration compose from about O.û5 to about l5 l50 mg of the compound, admixed witll a solid or liquid pharmaceu-tic~l carrier or diluent. The compounds of Examples l and 2 are particularly interesting, especially the compound of Example 2.
- 18 - 100~5555 compound of formula I may be adminlstered in free base or in phar~aceutically accepta~le acid addition salt form. Such salt forms exhibit the same order of activi-ty as the free base forms.
The present inventi~on also provides a pharmaceutical composi~
tion comprising a compound of the invention in association witll a pharmaceutical carrier or diluent.
Such compositions may be prepared by conventional techniques to be in con~entional forms for example capsules or tablets.
decomposition froln 135 [a~20 = + 36 [c = 0.355 in ethanol/water (1:1)].
.10- 100_5555.
b) l,l~dimethx~3-~1-acet~ -6-~eth~ 12-nitro_2,3~-dii!ydro~
9,10-dideh~Jdro-er~olin-8~-~lmethyl~urea _______ - __ _Y_ ____~ ____ . ___ 1~45 ml (35 mM) of nitric acid (100%) are added in drops at 10 over the course of 3 minutes to a solut1On of 13 9 (35 mM) of the crude iiase obtained under a) in 80 ml of sulphuric acid (100%), the solution being maintained in an argon atmosphere. After stirring for 20 minutes at room tempe-rature, the solution is poured onto ice, set to a pi-l of 8 with 10 N sodium hydroxide at a temperature of 5 - 10, and extracted with methylene chloride which contains 10~
isopropanol~ The organic phases are combined, dried with sodium sulphate, Filtered and dried on a rotary evaporator.
After drying in a high vacuum, the title compound is ob-tained, and this can be reduced further without purifi-cation.
c) 1 Ll -dimethyl-3-(1-acetyl-12-amino-6-meth~1-2,3i3-dihydro-9,10-dideh~dro-eroolin-8B-vlmethvl~urea ________-- __ _ ~______ _~___ _ _ _ A solut;on of 13.5 9 (32.7 mM) of 1,1-dimethyl-3-(1-acetyl-6-methyl-12-nitro-2,3~-dihydro-9,10-didehydroergolin-8~-ylmethyl)urea in 300 ml of ethyl acetate and 100 ml of methanol is hydrogenated under normal conditions in the presence of 1.5 9 of palladium on carbon (10%) until the calculated amount of hydrogen has been absorbed.
The mi>ture is filtered and evaporated.The resultant crude product is sub~iected to chromatography on 300 9 of silicagel with methylene chloride containing 15% methanol and 0.5% aqueous ammonia,obtaining the title compound.
d) l,l-dimeth~1-3-(12-hyc!rox~-6-lneth~l-9~10-didehydro-_____ _ ___ _ __. _ ., _ _ _ ____ ergolin-8~-ylmeth~llurea A solution of 4.5 9 (11.7 mM) of the product obtained under c) in 100 ml o' 1 N HCl is heated with stirring for 17 hours to 95. l~ith cooling by ice, the solution is subsequently adjusted to at a pH of 7 ~ith concen-trated ammonia solution, and is extracted 4 times with methylene chloride which contairls 10~ isopropanol. The combined organic phase are dried w-ith sodium sulphate, filtered and evaporated in a rotary evaporator. The residue of evaporation, l,l-dimethyl-3-(12-hydroxy-6-methyl-2,3~-dihydro-9,10-didehydro-ergolin-8~-ylmethyl) urea, is dissolved in 10 ml of ethanol. After adding 1 ml of concentrated ammonia solutioll, air is blown through the solution for 1 hour. After evaporation, the crude product is subjected to chromatoyraphy on 100 9 of silicagel, with methylene chloride containing 10~ methanol and 0.2% ammonia solution. The title com-pound in free base form is obtained as a beige residue.
In order to produce the hydrochloride, the base ob-tained is dissolved in methylene chloride/methanol (1:1), then 2.94 ml (5.9 mM) of 2 N HCl are addecl, and concentration follows in a rotary evaporator until crystallisation commences. The hydrochloride of the title compound is obtained as beige crystals.
M.p.: decomposition from 220C, ~a]20 = + 126.2 [c = 0.435 in ethanol/water (1:1)].
E)~AMPLE 2~ dimethyl-3-~12-methoxy-6-methyl-9,1a-didehydro ... .. _ _. _ .. . _ _ _ . _ -er~olin-8~-~lmeth~1~urea 200 ml (about 71.5 mM) of an approximately 1.5,c ethereal diazo-methane solution kept in an argon atmosphere are carefully poured into a solution wllich i5 cooled to -15~ of 5 ml of 0.08 N methanolic tetrafluoroboric acid in 150 ml of methanol, and 2.55 9 ~7.5 m,'~) of the base obtained under ld). Stirring is subsenuently effected for 20 hours at room temperature and in an argoll atmocphere. rhe pro-cess is finished by concentrating the mixture to ahout 20~ of the original volume under a water-jet vacuum, arld concentrating further in a rotary evaporator. After the addition of 50 ml of ethar,ol and 1 ml of concerltrated ammonia solution, concentration is again effected, and the residue is subjected ~o chrolnatography on 120 9 of silicagel with methvlene chloride, containing 10~ methanol and 0.2% concentrated ammonia solu~ion. The title compound is obtained as in free base form, wilich crystallises from acetone. '~l.p.:
decomposition from 180; [~]20 - ~- 85~ [c = 0.450 in methanol~.
EXAMPLE 3: 1,1 dimethyl-3-~12-hydroxy-6 methyl-9,10-dideh~dro-ergol~n-8~-yllne-thyl~urea A solution of 3.0 y (9.2 mM) of l~l-dinlethyl-3-(~6-lnethyl-2~3~-dihydro-9~lQ
didehydro-eryolin-8~-ylmethyl)urea in 46 ml of isopropanol and 165 ml of chloroform is added at room temperature, while stirring, to a solution of 10.1 9 (37.7 mM) of potassium nitrosodisulphonate in water, buffered with phosphate at pH 7Ø
The reaction mixture is stirred further at room temperature for 5 min., the organic phase is separated and the aqueous phase is extrac-ted with isopropanol chloroform (5:18).
The collected organic phases are dried over sodium sulphate, fil-traied and evaporated to dryness.
-13- 100-555~
The residue is chromatographed on silicagel with a mixture of me-thylene chloride, methanol and ammonia (85:15:o.5), obtaining the pure title compound.
The following compounds of formula I are produced wherein:-~it~
-~ 4- 1~0~5555 . ~
' ~ 6~ ' s . o ' E
', o e~ a~, a) s '~
., o o o ~ ^ ^ o ^ ----~r- ~ ~ ~ cn cn cn cn cn ~ ~ cn cn >' >' >' m m m m m ~ C
O o o o o o o o o o o o C~ L~ O ~ I~ O O 00 L~
~ = c ~cr) o c ~ ~ ~ ~:
m ~ ~ ::~ ~ ~ ~ ~ ~ ~ ~ ~
. ~ oo^oooooooo C a~ m I m 1:~ m CD crl c~ m m _,~
1~> I I I I I 1: I I ~-tY c_, ~ I >
_ . m ~r> ; E ~
. c~ . O Q~ Q_ ~ ~ c~ O~
~ I I I ~ ~ CI~ I I C~ C~ X Qr~ ~ O ~
r E E C~l ~s a~ a lY ~ I I o o I I I o o E E ~
. . ~ J X
~ ~ ~ s ~
I ~ I E
I ~_) ~ C~ cn ~n~
c~ I I I I I I I I I I ~ O O
~Y: ~ C~ C'_~ ~ (_) ~_) <-) ~-) ~ ' O 0~ ~,r~,. 5 . ~ ~ t~ s_ I ~S ~.5 ~ ~ s -r 0= .C-.C- >~
C~l ' N ~ ~ ~ ~ -O ~
CY I I I I T ~ C ) C_~ I _- c c s_ s_ S_ . . . _ ~
~ ~ ~ ~ ~ ~ C C C
X r-d' '--U') ~ 00 c~ O -- ~ ~ ~ C~
W r- ~ _~
. , ~ ~ c_~n _~ 5 100-5555 .
i~
, ~ ~ 'o C~ ~ ~
Cll Q' ~ o ON
~, , Cl ~ Cl __ ~i ..
., ' ~ 3 5~3~
In a 1st group of compounds Rl ;s H
" " 2nd " " " Rl is CH20H
~l 1' 3rd " " Rl is alkanoyloxymethyl 5 " " 5th " '' ' Rl is (Cl 4)alkyl 7th ~ ', ,, R3 is (cl_4)alkyl 9th '' '' '' R4 is (Cl 4)alkyl " 11th " " " R5 is alkyl " " 12th " " " A and B are together a bond " " 13th " " " A and B both are H.
A.~ 1~3 !6 - 17 - lO0-5555 The compounds of the invention exhibit pharmacological activity and are therefore indi-cated for use as pharmaceuticals.
In particular tney lead to a lowering of the blood pressure as indicated in tests with the conscious spontaneously hypertensive rat upon administration of from 0,OOl to 0,l mg/kg s.c.
In addition theJ lo~er blood r)ressure and decrease vascular resistance in the anaesthetised,normotensive dog upon administration of a dose of fronl 0,OOl to lO mg~g i.~, especially of frcin 0,OOl to 0,2 mg/i~g i.v,.
The compounds are iherefore indicated f-or use in t:~e t,eatment lO of hypertension and cardiac insufficiency.
An indicated daily dosage is in the range ~I^Om about 0.2 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day or in sustained release form~ and dosage forms suitable for oral administration compose from about O.û5 to about l5 l50 mg of the compound, admixed witll a solid or liquid pharmaceu-tic~l carrier or diluent. The compounds of Examples l and 2 are particularly interesting, especially the compound of Example 2.
- 18 - 100~5555 compound of formula I may be adminlstered in free base or in phar~aceutically accepta~le acid addition salt form. Such salt forms exhibit the same order of activi-ty as the free base forms.
The present inventi~on also provides a pharmaceutical composi~
tion comprising a compound of the invention in association witll a pharmaceutical carrier or diluent.
Such compositions may be prepared by conventional techniques to be in con~entional forms for example capsules or tablets.
Claims (6)
1. A process for the production of a compound of formula I
I
in which R1 is H, (C1-4)alkyl, or a precursor thereof, R2 is (C1-4)alkyl, R3 and R4 independently are H, or (C1-4)alkyl or together (C2-5)alkylene, R5 is H or alkyl, and A and B each are H or both together are a bond, with the proviso that, when R1 and R2 are each CH3,R3 and R4 are each C2H5 and A and B are each H, then R5 is alkyl, and pharmaceutically acceptable salts thereof, which includes the step of a) oxidizing a compound of formula II
II
wherein R1 to R4 and A and B are as defined above, and R6 is hydrogen or hydroxyl, or a precursor thereof, to produce a compound of formula I wherein R5 is hydrogen, or b) alkylating a compound of formula I wherein at least one of R1, R3, R4 and R5 is hydrogen, or a precursor thereof, to produce the corresponding compound wherein at least R1 is (C1-4)alkyl, CH2OH or (C1-22)alkanoyloxymethyl and/or at least R3, R4 and R5 is (C1-4)alkyl, and when required, converting a resultant formula I compound into another formula I compound, and when a pharmaceutically acceptable acid addition salt is required, reacting the free base obtained with a corresponding acid.
I
in which R1 is H, (C1-4)alkyl, or a precursor thereof, R2 is (C1-4)alkyl, R3 and R4 independently are H, or (C1-4)alkyl or together (C2-5)alkylene, R5 is H or alkyl, and A and B each are H or both together are a bond, with the proviso that, when R1 and R2 are each CH3,R3 and R4 are each C2H5 and A and B are each H, then R5 is alkyl, and pharmaceutically acceptable salts thereof, which includes the step of a) oxidizing a compound of formula II
II
wherein R1 to R4 and A and B are as defined above, and R6 is hydrogen or hydroxyl, or a precursor thereof, to produce a compound of formula I wherein R5 is hydrogen, or b) alkylating a compound of formula I wherein at least one of R1, R3, R4 and R5 is hydrogen, or a precursor thereof, to produce the corresponding compound wherein at least R1 is (C1-4)alkyl, CH2OH or (C1-22)alkanoyloxymethyl and/or at least R3, R4 and R5 is (C1-4)alkyl, and when required, converting a resultant formula I compound into another formula I compound, and when a pharmaceutically acceptable acid addition salt is required, reacting the free base obtained with a corresponding acid.
2. Ergoline derivatives of formula I
I
in which R1 is H, (C1-4)alkyl, or a precursor thereof, R2 is (C1-4)alkyl, R3 and R4 independently are H, or (C1-4)alkyl or together (C2-5)alkylene, R5 is H or alkyl, and A and B each are H or both together are a bond, with the proviso that, when R1 and R2 are each CH3,R3 and R4 are each C2H5 and A and B are each H, then R5 is alkyl, and pharmaceutically acceptable salts thereof, whenever produced by the process of claim 1 or an obvious chemical equivalent thereof.
I
in which R1 is H, (C1-4)alkyl, or a precursor thereof, R2 is (C1-4)alkyl, R3 and R4 independently are H, or (C1-4)alkyl or together (C2-5)alkylene, R5 is H or alkyl, and A and B each are H or both together are a bond, with the proviso that, when R1 and R2 are each CH3,R3 and R4 are each C2H5 and A and B are each H, then R5 is alkyl, and pharmaceutically acceptable salts thereof, whenever produced by the process of claim 1 or an obvious chemical equivalent thereof.
3. A process for producing 1,1-dimethyl-3-(12-hydroxy-6-methyl-9,10-didehydro-ergolin-8.beta.-ylmethyl)urea or a pharmaceutically acceptable salt thereof, which comprises oxidizing 1,1-dimethyl-3-(12-hydroxy-6-methyl-2,3.beta.-dihydro-9,10-didehydro-ergolin-8.beta.-ylmethyl)urea and when the salt is required, reacting the free base with a corresponding acid.
4. The compound 1,1-dimethyl-3-(12-hydroxy-6-methyl-9,10-didehydro-ergolin-8.beta.-ylmethyl)urea or a pharmaceutically acceptable salt thereof, whenever produced by the process of claim 3 or an obvious chemical equivalent thereof.
5. A process according to claim 3 wherein the product obtained is reacted with a methylating agent to produce 1,1-dimethyl-3-(12-methoxy-6-methyl-9,10-didehydro-ergolin-8.beta.-ylmethyl)urea, and when a pharmaceutically acceptable salt is required, reacting the free base obtained with a corresponding acid.
6. The compound 1,1-dimethyl-3-(12-methoxy-6-methyl-9,10-didehydro-ergolin-8.beta.-ylmethyl)urea, or a pharmaceutically acceptable salt thereof whenever produced by the process of claim 5 or an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH121081A CH645894A5 (en) | 1981-02-24 | 1981-02-24 | Ergoline derivatives, their preparation and use |
| CH1211/81 | 1981-02-24 | ||
| CH1210/81 | 1981-02-24 | ||
| CH121181A CH645895A5 (en) | 1981-02-24 | 1981-02-24 | Ergoline derivatives, their preparation and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1178582A true CA1178582A (en) | 1984-11-27 |
Family
ID=25687002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000396775A Expired CA1178582A (en) | 1981-02-24 | 1982-02-22 | Ergoline derivatives, their production and pharmaceutical compositions thereof |
Country Status (16)
| Country | Link |
|---|---|
| AU (1) | AU8068282A (en) |
| CA (1) | CA1178582A (en) |
| DE (1) | DE3205169A1 (en) |
| DK (1) | DK77082A (en) |
| ES (1) | ES8304578A1 (en) |
| FI (1) | FI820526L (en) |
| FR (1) | FR2500454A1 (en) |
| GB (1) | GB2093452B (en) |
| HU (1) | HU187650B (en) |
| IL (1) | IL65074A0 (en) |
| NL (1) | NL8200694A (en) |
| NZ (1) | NZ199795A (en) |
| PH (1) | PH17494A (en) |
| PT (1) | PT74468B (en) |
| SE (1) | SE8201098L (en) |
| WO (1) | WO1982002892A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3309493A1 (en) * | 1983-03-14 | 1984-09-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW ERGOLIN DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND USE AS A MEDICINAL PRODUCT |
| DE3402392A1 (en) * | 1984-01-25 | 1985-08-01 | Sandoz-Patent-GmbH, 7850 Lörrach | NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND THEIR USE |
| DE3445784A1 (en) * | 1984-12-13 | 1986-06-26 | Schering AG, Berlin und Bergkamen, 1000 Berlin | METHOD FOR PRODUCING ERGOLIN DERIVATIVES |
| DE3528584A1 (en) * | 1985-08-06 | 1987-02-19 | Schering Ag | NEW 1-ALKYL-ERGOLIN-THIOURINE DERIVATIVES |
| DE3528576A1 (en) * | 1985-08-06 | 1987-02-19 | Schering Ag | METHOD FOR THE PRODUCTION OF ERGOLIN THIOUROS |
| DE3533672A1 (en) * | 1985-09-19 | 1987-03-26 | Schering Ag | NEW 12- AND 13-SUBSTITUTED ERGOL DERIVATIVES |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1910930A1 (en) * | 1968-03-07 | 1969-10-16 | Farmaceutici Italia | Process for the production of new 1,6-dimethyl-10alpha-ergoline derivatives |
| DK140596B (en) * | 1971-05-19 | 1979-10-08 | Sandoz Ag | Analogous process for the preparation of 8beta- (ureidomethyl) -ergolene derivatives. |
| CH628049A5 (en) * | 1977-03-25 | 1982-02-15 | Sandoz Ag | Process for the preparation of ergolene derivatives |
| FR2421176A1 (en) * | 1978-03-29 | 1979-10-26 | Sandoz Sa | 2,3-Di:hydro-ergolenyl-methyl urea derivs. - useful as antihypertensives |
-
1982
- 1982-02-13 DE DE19823205169 patent/DE3205169A1/en not_active Withdrawn
- 1982-02-17 FI FI820526A patent/FI820526L/en not_active Application Discontinuation
- 1982-02-19 WO PCT/CH1982/000025 patent/WO1982002892A1/en unknown
- 1982-02-19 FR FR8202991A patent/FR2500454A1/en active Granted
- 1982-02-22 IL IL65074A patent/IL65074A0/en unknown
- 1982-02-22 DK DK77082A patent/DK77082A/en not_active Application Discontinuation
- 1982-02-22 NZ NZ199795A patent/NZ199795A/en unknown
- 1982-02-22 CA CA000396775A patent/CA1178582A/en not_active Expired
- 1982-02-22 NL NL8200694A patent/NL8200694A/en not_active Application Discontinuation
- 1982-02-22 AU AU80682/82A patent/AU8068282A/en not_active Abandoned
- 1982-02-22 SE SE8201098A patent/SE8201098L/en not_active Application Discontinuation
- 1982-02-22 GB GB8205176A patent/GB2093452B/en not_active Expired
- 1982-02-22 PT PT74468A patent/PT74468B/en unknown
- 1982-02-23 HU HU82544A patent/HU187650B/en unknown
- 1982-02-23 PH PH26900A patent/PH17494A/en unknown
- 1982-02-23 ES ES509825A patent/ES8304578A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| SE8201098L (en) | 1982-08-25 |
| PT74468A (en) | 1982-03-01 |
| WO1982002892A1 (en) | 1982-09-02 |
| FI820526L (en) | 1982-08-25 |
| IL65074A0 (en) | 1982-04-30 |
| HU187650B (en) | 1986-02-28 |
| DE3205169A1 (en) | 1982-10-14 |
| ES509825A0 (en) | 1983-03-01 |
| FR2500454A1 (en) | 1982-08-27 |
| PH17494A (en) | 1984-09-04 |
| GB2093452B (en) | 1984-11-07 |
| ES8304578A1 (en) | 1983-03-01 |
| PT74468B (en) | 1984-08-01 |
| NZ199795A (en) | 1985-08-30 |
| DK77082A (en) | 1982-08-25 |
| AU8068282A (en) | 1982-09-02 |
| GB2093452A (en) | 1982-09-02 |
| NL8200694A (en) | 1982-09-16 |
| FR2500454B1 (en) | 1984-11-09 |
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