CA1203531A - 1-substituted n-(8 alfa-ergolinyl)-n',n' diethyl- ureas and processes for producing thereof - Google Patents
1-substituted n-(8 alfa-ergolinyl)-n',n' diethyl- ureas and processes for producing thereofInfo
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- CA1203531A CA1203531A CA000423264A CA423264A CA1203531A CA 1203531 A CA1203531 A CA 1203531A CA 000423264 A CA000423264 A CA 000423264A CA 423264 A CA423264 A CA 423264A CA 1203531 A CA1203531 A CA 1203531A
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- ergolinyl
- alpha
- diethylurea
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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
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to 1-substituted N-[8.alpha.-ergolinyl]-N',N'-diethylureas of the general formula (I):
(I) wherein R1 represents alkyl group having 1 to 4 carbon atoms and R2 represents lower alkyl group having 1 to 4 carbon atoms, benzyl group, allyl group or a group of general formula -[CH2]nCOOR3, where R3 stands for hydrogen atom or alkyl group having 1 to 2 carbon atoms and n is integer 1 to 4, and to a process for their preparation.
Compounds of the above general formula I exhibit dopamin-ergic action on the respective receptors, significant inhibiting effect to prolactine and growth hormone secre-tion and stimulative effect to secretion of gonadotropine.
The present invention relates to 1-substituted N-[8.alpha.-ergolinyl]-N',N'-diethylureas of the general formula (I):
(I) wherein R1 represents alkyl group having 1 to 4 carbon atoms and R2 represents lower alkyl group having 1 to 4 carbon atoms, benzyl group, allyl group or a group of general formula -[CH2]nCOOR3, where R3 stands for hydrogen atom or alkyl group having 1 to 2 carbon atoms and n is integer 1 to 4, and to a process for their preparation.
Compounds of the above general formula I exhibit dopamin-ergic action on the respective receptors, significant inhibiting effect to prolactine and growth hormone secre-tion and stimulative effect to secretion of gonadotropine.
Description
The invention is related to l-substituted N-~8~-ergolinyl7-N',N'-diethylureas of the general formula (I):
~ ,~NHCON[C2H~72
~ ,~NHCON[C2H~72
2 ~ _ Rl (I~
R
5 wherein Rl represents a lower alkyl group having 1 to 4 carbon atoms and R represents a lower alkyl group having 1 to 4 carbon atoms, a benzyl group, an allyl group or a group of general formula - CcH2-7ncooR3~ where R3 stands for a hydrogen atom or an alkylgroup having 1 to 2 carbon atoms and n is an integer of from 1 to 4, and to a process for their preparation.
It is known that 1-unsubstituted 8a-ergolinyl-N',N'-diethylureas of the general formula II presented below, for example N-~-6-methyl-8a-ergolinyl7-N',N'-diethylurea (Czechoslovak Author's Certificate no. 152 153) and 6-propyl analogue thereof, exhibit on animals strong inhibiting effect on secretion of prolactine and growth hormone and stimulative effect on secretion of gonadotro-pins. Authors of this invention have now found that also l-substituted derivatives of these ureas of the general formula I are strong inhibitors of prolactine secretion on experimental animals.
-~r .. -- 1 --lZ03~, 8~-Ergolinylureas of the general formula I contain in the molecule, three asymmetric carbons in positions 5,8 and 10, spatial arrangement of which is the same as for the D-9,10-dihydroisolysergic acid - I: hydrogen at C/5~ has a ~-position (configuration at this carbon is 5R), urea residue at C/8/ is in ~-position (configuration at this carbon is 8S) and hydrogen at C/lo/ is in ~-position (con-figuration at this carbon is lOR).
According to the invention the l-substituted 8~-ergolinylureas of the general formula I can be produced inthe way that in position 1 unsubstituted 8~-ergolinyl-N',N'-diethylurea of the general formula (II):
H ,NHCON[C2H ~ 2 ~ ~H ~II) H
wherein Rl has the above meaning, is reacted with alkylating agent of the general formula (III):
R2 _ X (III) wherein R2 has the meaning presented in general formula I
and X represents a halogen atom or a residue of ester-bound aliphatic or aromatic sulfonic acid or a residue of ester-bound sulfuric acid.
Starting compounds of the general formula II can be prepared by known processes and according to the above mentioned references.-Alkylation of compounds of the general formula II
is performed according to the present invention by the 1~3S31 action o 1 to 5 molequivalents of alkylating agent of the general formula II with a solution of compound of the -general formula II in an inert solvent in the presence of a base for binding liberated acid at a temperature ranging from -40 to +50C.
As an alkylating agent of the general formula III, alkylhalogenides can be used, preferably iodides or alkyl bromides, allyl bromide, benzyl bromide or ~-bromoalkanoic acids and esters thereof of alkyl esters of sulfuric acid such as dimethylsulphate or diethyl sulfate, or esters of aliphatic or aromatic sulfonic acids, for example alkyl-methane sulfonates or alkyl-p-toluene sulfonates.
As an inert solvent polar aprotic solvents can be used such as dimethylformamide, dimethylsulfoxide, hexa-methyltriamide of phosphoric acid or acetone, or liquid ammonia.
As a base for binding released acid, strong bases can be used, for example sodium or potassium amide, lithium diisopropylamide, sodium methylate or sodium or potassium hydroxide. Especially advantageous process for preparation -of compounds of the general formula (I) consists in alkylat-ing of compounds of the general formula (II) with alkyl halogenides in a medium of liquid ammonia in the presence of sodium amide or potassium amide prepared in situ in the existing medium. The originated compounds of the general formula (I) can be isolated from the reaction mixture using common separating and isolating methods, for example by evaporating the solvent and by chromatography and/or by crystallization of the crude products thus obtained.
l-substituted N-L8~-ergoliny~7-N',N'-diethylureas of the general formula (I) are colourless crystalline com-pounds of basic character which yield addition salts with strong inorganic and organic acids. For therapeutic purposes water-soluble salts with pharmaceutically accept-
R
5 wherein Rl represents a lower alkyl group having 1 to 4 carbon atoms and R represents a lower alkyl group having 1 to 4 carbon atoms, a benzyl group, an allyl group or a group of general formula - CcH2-7ncooR3~ where R3 stands for a hydrogen atom or an alkylgroup having 1 to 2 carbon atoms and n is an integer of from 1 to 4, and to a process for their preparation.
It is known that 1-unsubstituted 8a-ergolinyl-N',N'-diethylureas of the general formula II presented below, for example N-~-6-methyl-8a-ergolinyl7-N',N'-diethylurea (Czechoslovak Author's Certificate no. 152 153) and 6-propyl analogue thereof, exhibit on animals strong inhibiting effect on secretion of prolactine and growth hormone and stimulative effect on secretion of gonadotro-pins. Authors of this invention have now found that also l-substituted derivatives of these ureas of the general formula I are strong inhibitors of prolactine secretion on experimental animals.
-~r .. -- 1 --lZ03~, 8~-Ergolinylureas of the general formula I contain in the molecule, three asymmetric carbons in positions 5,8 and 10, spatial arrangement of which is the same as for the D-9,10-dihydroisolysergic acid - I: hydrogen at C/5~ has a ~-position (configuration at this carbon is 5R), urea residue at C/8/ is in ~-position (configuration at this carbon is 8S) and hydrogen at C/lo/ is in ~-position (con-figuration at this carbon is lOR).
According to the invention the l-substituted 8~-ergolinylureas of the general formula I can be produced inthe way that in position 1 unsubstituted 8~-ergolinyl-N',N'-diethylurea of the general formula (II):
H ,NHCON[C2H ~ 2 ~ ~H ~II) H
wherein Rl has the above meaning, is reacted with alkylating agent of the general formula (III):
R2 _ X (III) wherein R2 has the meaning presented in general formula I
and X represents a halogen atom or a residue of ester-bound aliphatic or aromatic sulfonic acid or a residue of ester-bound sulfuric acid.
Starting compounds of the general formula II can be prepared by known processes and according to the above mentioned references.-Alkylation of compounds of the general formula II
is performed according to the present invention by the 1~3S31 action o 1 to 5 molequivalents of alkylating agent of the general formula II with a solution of compound of the -general formula II in an inert solvent in the presence of a base for binding liberated acid at a temperature ranging from -40 to +50C.
As an alkylating agent of the general formula III, alkylhalogenides can be used, preferably iodides or alkyl bromides, allyl bromide, benzyl bromide or ~-bromoalkanoic acids and esters thereof of alkyl esters of sulfuric acid such as dimethylsulphate or diethyl sulfate, or esters of aliphatic or aromatic sulfonic acids, for example alkyl-methane sulfonates or alkyl-p-toluene sulfonates.
As an inert solvent polar aprotic solvents can be used such as dimethylformamide, dimethylsulfoxide, hexa-methyltriamide of phosphoric acid or acetone, or liquid ammonia.
As a base for binding released acid, strong bases can be used, for example sodium or potassium amide, lithium diisopropylamide, sodium methylate or sodium or potassium hydroxide. Especially advantageous process for preparation -of compounds of the general formula (I) consists in alkylat-ing of compounds of the general formula (II) with alkyl halogenides in a medium of liquid ammonia in the presence of sodium amide or potassium amide prepared in situ in the existing medium. The originated compounds of the general formula (I) can be isolated from the reaction mixture using common separating and isolating methods, for example by evaporating the solvent and by chromatography and/or by crystallization of the crude products thus obtained.
l-substituted N-L8~-ergoliny~7-N',N'-diethylureas of the general formula (I) are colourless crystalline com-pounds of basic character which yield addition salts with strong inorganic and organic acids. For therapeutic purposes water-soluble salts with pharmaceutically accept-
3 --able nontoxic acids are suitable, such acids as hydrochloric, sulfuric, methane sulfonic, ethane sulfonic, maleic, malic, tartaric, citric and similar acids. The salts named can be prepared by the reaction of at least 1 molequivalent of the acid with 1 molequivalent of the compound of the general formula (I) in a suitable inert solvent, preferably in methanol, ethanol, acetone, water of in mixtures thereof.
The compounds of the general formula (I) are significant inhibitors of secretion of prolactine and growth hormone and stimulators of secretion of gonadotropins on animals, affect the physiological and pathological processes controlled by the named hormones and exert dopaminergic action on the physiological and pathological dopamine-receptor controlled functions. They can be therefore used in human and veterinary therapy for suppression of the levels of prolactin and growth hormone, for example in medical treatment of hyperpropactinemies, acromegaly and parkinsonism or they can be used for enhancement the levels of gonadotropins, for example at inducing estrus to mammals and for inducing laying of eggs to birds.
The process for producing l-substituted 8a-ergolinylureas of the general formula (I) is further eluci-dated by the following examples of embodiment which never-theless do not limit the scope of the invention. Melting temperatures of the compounds were determined using the Kofler stage and they are presented, as well as other tem-perature data, in C. The values of specific rotation are related to compounds free of crystal solvent.
- Example 1 N-L~-1,6-Dimethyl-8a-ergolinyl~-N',N'-diethylurea 0.225 g (4 mmoles) of powdered potassium hydroxide - is added to a solution of 0.34 g (1 mmole) of N-~D-6-methyl-8a-ergolinyl7-N',N'-diethylurea in 20 ml of anhydrous acetone, the mixture is stirred 10 minutes at 23 to 26C
-12~1 and 0.284 g (2 mmoles) of methyl iodide is then added drop-wise at the same temperature. Reaction mixture is stirred 2 hours at room temperature, further 0.284 g (2 mmoles) of methyl iodide are then added and the mixture is stirred three more hours. Inorganic fraction is filtered off, solvent is distilled out from the filtrate under reduced pressure, evaporation residue is taken off into a mixture of chloroform and water, organic fraction is dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. Crude product (0.4 g) is purified using column chromatography at silica gel using a mixture of chloroform and ethanol (95:5) for elution of the com-pounds and united homogeneous fractions are recrystallized from acetone after evaporation of the solvents. The so desired compound is obtained (I, Rl=R2=methyl) in the form of colourless crystals having m. p. 136 to 138C, specific rotation ~]D = +24.4 [c = 0.2, pyridine~.
Example 2 N-L~ Methyl-6-n-propyl-8~-ergolinyl7-N',N'-diethylurea Approximately 10 mg of iron III nitrate is added under mixing to a solution of 62.4 mg (2.715 mmoles) of sodium in approximately 100 ml of liquid ammonia and after decolour-izing the solution 500 mg (1.357 mmoles) of N-CD-6-propyl-8~-ergoliny~7-N',N'-diethylurea is added to the originated suspension of sodium amide. After dissolution of the urea, approximately after 30 minutes, 385 mg (2.715 mmoles) of methyl iodide is added dropwise and the reaction mixture is stirred for 1 hour at the boiling point of ammonia. Ammonia is then evaporated, evaporation residue is taken off into a mixture of chloroform and water, chloroform fraction is washed with water, dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. Crude product (0.55 g) yields after recrystallization from acetone the so desired compound; (I, R2 = methyl, Rl = propyl) in lZO~l`' "
the form of colourless crystals havin~ m. p. 117 to 119C;
~]D = +26.3 rc = O.2, pyridine~7.
Example 3 N-L~D-l-Methyl-6-ethyl-8~-ergolinyl7-N',N'-diethylurea, m. p. 103 to 105C, C~]20 = +26.3 L~ = 0.2, pyridine~7, and N-rD-l-methyl-6-butyl-8~-ergolinyl~-N',N'-diethylurea, m. p. 75 to 77C, ~DO = +32.9 [c = 0.2, pyridine7, are prepared by the same process as in the Example 2 with the difference that equimolar amounts of N-[D-6-ethyl-8~-ergolinyl~7- or N-L~-6-butyl-8a-ergoliny y N',N'-diethyl-ureas are used instead of N-L~D-6-propyl-8~-ergolinyl~-N',N'-diethylurea.
Example 4 N-L~-l-Ethyl-6-propyl-8a-ergolinyl7-N',N'-diethylurea, m. p. 85 to 85C, C~20 = +30 4O ~c = 0.2, pyridine~, and N-L~-1,6-dipropyl-8~-ergolinyl~-N' ,N'-diethylurea are prepared by the same process as in the Example 2 with the difference that equimolar amounts of ethyl iodide or propyl bromide are used instead of methyl iodide.
Example 5 Following compounds:
N-L~-l-ethyl-6-methyl-8~-ergolinyl7-N',N'-diethylurea, m. p. 124 to 126C, C~]DO = +20.5 L~c = 0.2, pyridine~;
N-cD-l-propyl-6-methyl-8~-ergolinylJ-N~,N~-diethylurea, m. p. 63 to 66C, ~DO = +21.9 Cc = 0.2, pyridinç7;
N-[D-l-butyl-6-methyl-8~-ergolinylJ-N~,N~-diethylurea;
N- @-l-allyl-6-methyl-8~-ergolinyl~7-N',N'-diethylurea, m. p. 82 to 84C; ~D0 = +18,0 [c = 0.2, pyridin~7;
N- CD-l-benzyl-6-methyl-8~-ergoliny y -N',N'-diethylurea, m. p. 167 to 169C, ~]DO = +15.0 L~c = 0.2, pyridine~7; and N-Lp-l-ethoxycarbonylmethyl-6-methyl-8~-ergolinyl~-N',N'-diethylurea, m. p. 57 to 59C, [~ D0 = +17,0 E = 0,2, pyridin~7 are prepared by the same process as in the :~53~.
Example 2 with the difference that equimolar amounts of N-L~-6-methyl-8~-ergolinyl~ -N',N'-diethylurea is used instead of N-~p-6-propyl-8~-ergoliny Y -N',N'-diethylurea and that equimolar amounts of alkyl bromides, allyl bromide, benzyl bromide or ethyl bromoacetate are used.
The compounds of the general formula (I) are significant inhibitors of secretion of prolactine and growth hormone and stimulators of secretion of gonadotropins on animals, affect the physiological and pathological processes controlled by the named hormones and exert dopaminergic action on the physiological and pathological dopamine-receptor controlled functions. They can be therefore used in human and veterinary therapy for suppression of the levels of prolactin and growth hormone, for example in medical treatment of hyperpropactinemies, acromegaly and parkinsonism or they can be used for enhancement the levels of gonadotropins, for example at inducing estrus to mammals and for inducing laying of eggs to birds.
The process for producing l-substituted 8a-ergolinylureas of the general formula (I) is further eluci-dated by the following examples of embodiment which never-theless do not limit the scope of the invention. Melting temperatures of the compounds were determined using the Kofler stage and they are presented, as well as other tem-perature data, in C. The values of specific rotation are related to compounds free of crystal solvent.
- Example 1 N-L~-1,6-Dimethyl-8a-ergolinyl~-N',N'-diethylurea 0.225 g (4 mmoles) of powdered potassium hydroxide - is added to a solution of 0.34 g (1 mmole) of N-~D-6-methyl-8a-ergolinyl7-N',N'-diethylurea in 20 ml of anhydrous acetone, the mixture is stirred 10 minutes at 23 to 26C
-12~1 and 0.284 g (2 mmoles) of methyl iodide is then added drop-wise at the same temperature. Reaction mixture is stirred 2 hours at room temperature, further 0.284 g (2 mmoles) of methyl iodide are then added and the mixture is stirred three more hours. Inorganic fraction is filtered off, solvent is distilled out from the filtrate under reduced pressure, evaporation residue is taken off into a mixture of chloroform and water, organic fraction is dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. Crude product (0.4 g) is purified using column chromatography at silica gel using a mixture of chloroform and ethanol (95:5) for elution of the com-pounds and united homogeneous fractions are recrystallized from acetone after evaporation of the solvents. The so desired compound is obtained (I, Rl=R2=methyl) in the form of colourless crystals having m. p. 136 to 138C, specific rotation ~]D = +24.4 [c = 0.2, pyridine~.
Example 2 N-L~ Methyl-6-n-propyl-8~-ergolinyl7-N',N'-diethylurea Approximately 10 mg of iron III nitrate is added under mixing to a solution of 62.4 mg (2.715 mmoles) of sodium in approximately 100 ml of liquid ammonia and after decolour-izing the solution 500 mg (1.357 mmoles) of N-CD-6-propyl-8~-ergoliny~7-N',N'-diethylurea is added to the originated suspension of sodium amide. After dissolution of the urea, approximately after 30 minutes, 385 mg (2.715 mmoles) of methyl iodide is added dropwise and the reaction mixture is stirred for 1 hour at the boiling point of ammonia. Ammonia is then evaporated, evaporation residue is taken off into a mixture of chloroform and water, chloroform fraction is washed with water, dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. Crude product (0.55 g) yields after recrystallization from acetone the so desired compound; (I, R2 = methyl, Rl = propyl) in lZO~l`' "
the form of colourless crystals havin~ m. p. 117 to 119C;
~]D = +26.3 rc = O.2, pyridine~7.
Example 3 N-L~D-l-Methyl-6-ethyl-8~-ergolinyl7-N',N'-diethylurea, m. p. 103 to 105C, C~]20 = +26.3 L~ = 0.2, pyridine~7, and N-rD-l-methyl-6-butyl-8~-ergolinyl~-N',N'-diethylurea, m. p. 75 to 77C, ~DO = +32.9 [c = 0.2, pyridine7, are prepared by the same process as in the Example 2 with the difference that equimolar amounts of N-[D-6-ethyl-8~-ergolinyl~7- or N-L~-6-butyl-8a-ergoliny y N',N'-diethyl-ureas are used instead of N-L~D-6-propyl-8~-ergolinyl~-N',N'-diethylurea.
Example 4 N-L~-l-Ethyl-6-propyl-8a-ergolinyl7-N',N'-diethylurea, m. p. 85 to 85C, C~20 = +30 4O ~c = 0.2, pyridine~, and N-L~-1,6-dipropyl-8~-ergolinyl~-N' ,N'-diethylurea are prepared by the same process as in the Example 2 with the difference that equimolar amounts of ethyl iodide or propyl bromide are used instead of methyl iodide.
Example 5 Following compounds:
N-L~-l-ethyl-6-methyl-8~-ergolinyl7-N',N'-diethylurea, m. p. 124 to 126C, C~]DO = +20.5 L~c = 0.2, pyridine~;
N-cD-l-propyl-6-methyl-8~-ergolinylJ-N~,N~-diethylurea, m. p. 63 to 66C, ~DO = +21.9 Cc = 0.2, pyridinç7;
N-[D-l-butyl-6-methyl-8~-ergolinylJ-N~,N~-diethylurea;
N- @-l-allyl-6-methyl-8~-ergolinyl~7-N',N'-diethylurea, m. p. 82 to 84C; ~D0 = +18,0 [c = 0.2, pyridin~7;
N- CD-l-benzyl-6-methyl-8~-ergoliny y -N',N'-diethylurea, m. p. 167 to 169C, ~]DO = +15.0 L~c = 0.2, pyridine~7; and N-Lp-l-ethoxycarbonylmethyl-6-methyl-8~-ergolinyl~-N',N'-diethylurea, m. p. 57 to 59C, [~ D0 = +17,0 E = 0,2, pyridin~7 are prepared by the same process as in the :~53~.
Example 2 with the difference that equimolar amounts of N-L~-6-methyl-8~-ergolinyl~ -N',N'-diethylurea is used instead of N-~p-6-propyl-8~-ergoliny Y -N',N'-diethylurea and that equimolar amounts of alkyl bromides, allyl bromide, benzyl bromide or ethyl bromoacetate are used.
Claims (14)
1. Process for producing l-substituted N-[8.alpha.-ergolinyl]-N',N'-diethylureas of the general formula (I):
(I) wherein R1 represents an alkyl group having 1 to 4 carton atoms and R2 represents a lower alkyl group having 1 to 4 carbon atoms, a benzyl group, an allyl group or a group of general formula - [CH2]nCOOR3, where R3 stands for a hydrcgen atom or an alkyl group having 1 to 2 carbon atoms and n is an integer of from 1 to 4, which comprises reacting in position 1 unsubstituted 8.alpha.-ergolinyl-N',N'-diethylurea of the general formula (II):
(II) wherein R1 has the above meaning, with an alkylating agent of the general formula (III):
R2 _ x (III) wherein R2 has the above meaning and X represents a halogen atom or a residue of ester-bound aliphatic or aromatic sulfonic acid or a residue of ester-bound sulfuric acid.
(I) wherein R1 represents an alkyl group having 1 to 4 carton atoms and R2 represents a lower alkyl group having 1 to 4 carbon atoms, a benzyl group, an allyl group or a group of general formula - [CH2]nCOOR3, where R3 stands for a hydrcgen atom or an alkyl group having 1 to 2 carbon atoms and n is an integer of from 1 to 4, which comprises reacting in position 1 unsubstituted 8.alpha.-ergolinyl-N',N'-diethylurea of the general formula (II):
(II) wherein R1 has the above meaning, with an alkylating agent of the general formula (III):
R2 _ x (III) wherein R2 has the above meaning and X represents a halogen atom or a residue of ester-bound aliphatic or aromatic sulfonic acid or a residue of ester-bound sulfuric acid.
2. A process according to claim 1, characterized in that, the reaction is carried out in liquid ammonia in the presence of 1 to 5 molar equivalents of an alkali metal amide.
3. Process according to claim 2, characterized in that the alkali metal amide used in the reaction is sodium amide or potassium amide.
4. A process according to claim 1, characterized in that, the reaction is carried out in acetone in the presence of 1 to 5 molar equivalents of an alkali metal hydroxide.
5. Process according to claim 4, characterized in thet the alkali metal hydroxide used in the reaction is sodium hydroxide or potassium hydroxide.
6. Process for producing N-[D-1,6-Dimethyl-8.alpha.-ergolinyl]-N',N'-diethylurea, which comprises reacting N-[D-6-methyl-8.alpha.-ergolinyl]-N',N'-diethylurea with methyl iodide to obtain the desired compound.
7. Process for producing N- [D-l-Methyl-6-ethyl-8.alpha.-ergolinyl]-N',N'-diethylurea, which comprises reacting N-[D-6-ethyl-8.alpha.-ergolinyl]-N',N'-diethylurea with methyl iodide to obtain the desired compound.
8. Process for producing N- [D-l-Methyl-6-n-propyl-8.alpha.-ergolinyl]-N',N'-diethylurea, which comprises reacting N-[D-6-propyl-8.alpha.-ergolinyl]-N',N'-diethylurea with methyl iodide to obtain the desired compound.
_ 9 _
_ 9 _
9. Process for producing N-[D-l-Methyl-6-butyl-8.alpha.-ergolinyl]-N',N'-diethylurea, which comprises reacting N-[D-6-butyl-8.alpha.-ergolinyl]-N',N'-diethylurea with methyl iodide to obtain the desired compound.
10. l-substituted N-[8.alpha.-ergolinyl]-N',N'-diethylureas of the general formule (I):
(I) wherein R1 represents alkyl group having 1 to 4 carbon atoms and R2 represents lower alkyl group having 1 to 4 car-bon atoms, benzyl group, allyl group or a group of general formula -[CH2]nCOOR3, where R3 stands for hydrogen atom or alkyl group having 1 to 2 carbon atoms and n is integer 1 to 4, whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.
(I) wherein R1 represents alkyl group having 1 to 4 carbon atoms and R2 represents lower alkyl group having 1 to 4 car-bon atoms, benzyl group, allyl group or a group of general formula -[CH2]nCOOR3, where R3 stands for hydrogen atom or alkyl group having 1 to 2 carbon atoms and n is integer 1 to 4, whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.
11. N-[D-1,6-Dimethyl-8.alpha.-ergolinyl]-N',N'-diethylurea, whenever obtained by a process as claimed in claim 6 or its obvious chemical equivalents.
12. N-[D-l-Methyl-6-ethyl-8.alpha.-ergolinyl]-N',N'-diethylurea, whenever obtained by a process as claimed in claim 7 or its ovbious chemical equivalents.
13. N- [D-l-Methyl-6-propyl-8.alpha.-ergolinyl]-N',N'-diethylurea, whenever obtained by a process as claimed in claim 8 or its obvious chemical equivalents.
14. N-[D-l-Methyl-6-butyl-8.alpha.-ergolinyl]-N',N'-diethylurea, whenever obtained by a process as claimed in claim 9 or its obvious chemical equivalents.
_11
_11
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS821734A CS231214B1 (en) | 1982-03-12 | 1982-03-12 | Processing method of 1-substituted n+l8alpha-ergoline+p-n,diethyl urea |
| CSPV1734-82 | 1982-03-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1203531A true CA1203531A (en) | 1986-04-22 |
Family
ID=5352449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000423264A Expired CA1203531A (en) | 1982-03-12 | 1983-03-10 | 1-substituted n-(8 alfa-ergolinyl)-n',n' diethyl- ureas and processes for producing thereof |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS58180484A (en) |
| AT (1) | AT383349B (en) |
| AU (1) | AU555961B2 (en) |
| BE (1) | BE896122A (en) |
| CA (1) | CA1203531A (en) |
| CH (1) | CH652125A5 (en) |
| CS (1) | CS231214B1 (en) |
| DE (1) | DE3308719A1 (en) |
| DK (1) | DK84683A (en) |
| FI (1) | FI830754L (en) |
| FR (1) | FR2523131B1 (en) |
| GB (1) | GB2116548B (en) |
| IT (1) | IT1161209B (en) |
| NL (1) | NL8300829A (en) |
| SE (1) | SE452321B (en) |
Families Citing this family (11)
| 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 |
| EP0208417A3 (en) * | 1985-06-12 | 1989-09-06 | SPOFA Spojené Podniky Pro Zdravotnickou Vyrobu | Use of 1-(8-alpha-ergolinyl)-3,3-diethyl urea derivatives in the treatment of endometritis |
| DE3522894A1 (en) * | 1985-06-24 | 1987-01-02 | Schering Ag | USE OF TERGURID AS GERIATRIC |
| FR2584720B1 (en) * | 1985-07-11 | 1987-10-02 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF ERGOLINE |
| DE3620293A1 (en) * | 1986-06-16 | 1987-12-17 | Schering Ag | 1 AND / OR 2 SUBSTITUTED ERGOL DERIVATIVES |
| DE3623503A1 (en) * | 1986-07-09 | 1988-01-21 | Schering Ag | 1-ARYL-ERGOLINYL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE USE OF THESE COMPOUNDS AS A MEDICINAL PRODUCT |
| DE10212564B4 (en) * | 2002-03-12 | 2007-04-19 | Neurobiotec Gmbh | 1-Allyl ergot alkaloid derivatives and their use for the prophylaxis and treatment of migraine |
| WO2012062676A1 (en) * | 2010-11-11 | 2012-05-18 | Sinoxa Pharma Ug | Lisuride, terguride and derivatives thereof for use in the prophylaxis and/or treatment of fibrotic changes |
| US9657020B2 (en) | 2015-01-20 | 2017-05-23 | Xoc Pharmaceuticals, Inc. | Ergoline compounds and uses thereof |
| BR112017015510A2 (en) | 2015-01-20 | 2018-01-30 | Xoc Pharmaceuticals Inc | compound of formula (i), method of treatment and / or prevention, d2 receptor agonizing method in one individual, d3 receptor antagonizing method in one individual, 5-ht1d receptor agonizing method in one individual, 5-ht1a receptor agonization in one individual, selective 5-ht1d receptor agonizing method instead of 5-ht1b receptor in one individual, 5-ht2c re-receptor selective agonizing method instead of 5-ht2a or 5 receptor -ht2b in one individual, method of 5-ht2c receptor agonization in one individual, method of providing functional antagonist activity at 5-ht2b receptor or 5-ht7 receptor, and, method of providing functional antagonist activity at adrenergic receptors in one individual |
| CA3064274A1 (en) | 2017-06-01 | 2018-12-06 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH344731A (en) * | 1956-05-18 | 1960-02-29 | Sandoz Ag | Process for the production of new derivatives of the lysergic acid series alkylated on the indole nitrogen |
| AT231082B (en) * | 1960-10-12 | 1964-01-10 | Sandoz Ag | Process for the production of new urea derivatives |
| EP0021206B1 (en) * | 1979-06-13 | 1983-06-22 | Schering Aktiengesellschaft | (ergolin-yl)-n', n'-diethyl urea derivatives, their preparation and pharmaceutical compositions containing them |
-
1982
- 1982-03-12 CS CS821734A patent/CS231214B1/en unknown
-
1983
- 1983-02-24 DK DK84683A patent/DK84683A/en not_active Application Discontinuation
- 1983-03-02 AT AT0072783A patent/AT383349B/en not_active IP Right Cessation
- 1983-03-02 GB GB08305735A patent/GB2116548B/en not_active Expired
- 1983-03-07 FI FI830754A patent/FI830754L/en not_active Application Discontinuation
- 1983-03-07 NL NL8300829A patent/NL8300829A/en not_active Application Discontinuation
- 1983-03-07 IT IT19935/83A patent/IT1161209B/en active
- 1983-03-08 SE SE8301257A patent/SE452321B/en not_active IP Right Cessation
- 1983-03-08 AU AU12167/83A patent/AU555961B2/en not_active Ceased
- 1983-03-10 CA CA000423264A patent/CA1203531A/en not_active Expired
- 1983-03-10 BE BE0/210287A patent/BE896122A/en not_active IP Right Cessation
- 1983-03-11 JP JP58039349A patent/JPS58180484A/en active Pending
- 1983-03-11 CH CH1351/83A patent/CH652125A5/en not_active IP Right Cessation
- 1983-03-11 DE DE3308719A patent/DE3308719A1/en not_active Withdrawn
- 1983-03-11 FR FR8304005A patent/FR2523131B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2116548B (en) | 1985-03-20 |
| AU1216783A (en) | 1983-09-15 |
| NL8300829A (en) | 1983-10-03 |
| BE896122A (en) | 1983-07-01 |
| IT1161209B (en) | 1987-03-18 |
| GB2116548A (en) | 1983-09-28 |
| FI830754L (en) | 1983-09-13 |
| SE452321B (en) | 1987-11-23 |
| IT8319935A0 (en) | 1983-03-07 |
| AT383349B (en) | 1987-06-25 |
| AU555961B2 (en) | 1986-10-16 |
| GB8305735D0 (en) | 1983-04-07 |
| JPS58180484A (en) | 1983-10-21 |
| DK84683D0 (en) | 1983-02-24 |
| SE8301257D0 (en) | 1983-03-08 |
| ATA72783A (en) | 1986-11-15 |
| FR2523131B1 (en) | 1987-08-28 |
| CS231214B1 (en) | 1984-10-15 |
| DK84683A (en) | 1983-09-13 |
| FI830754A0 (en) | 1983-03-07 |
| SE8301257L (en) | 1983-09-13 |
| DE3308719A1 (en) | 1983-09-22 |
| FR2523131A1 (en) | 1983-09-16 |
| CH652125A5 (en) | 1985-10-31 |
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| MKEX | Expiry |