GB2116548A

GB2116548A - >Ergolinylureas

Info

Publication number: GB2116548A
Application number: GB08305735A
Authority: GB
Inventors: Antonin Cerny; Jiri Krepelka; Karel Rezabek; Miroslav Seda
Original assignee: Spofa Spojene Podniky Pro Zdravotnickou Vyrobu; Spofa Vereinigte Pharma Werke
Current assignee: Spofa Spojene Podniky Pro Zdravotnickou Vyrobu; Spofa Vereinigte Pharma Werke
Priority date: 1982-03-12
Filing date: 1983-03-02
Publication date: 1983-09-28
Also published as: NL8300829A; JPS58180484A; DK84683D0; SE8301257L; AU555961B2; GB8305735D0; FI830754L; IT1161209B; DE3308719A1; CS231214B1; FR2523131A1; SE452321B; AT383349B; ATA72783A; FI830754A0; AU1216783A; GB2116548B; CH652125A5; FR2523131B1; SE8301257D0

Abstract

1-Substituted N-(8 alpha -ergolinyl)- N',N'-diethylureas of general formula (I> <IMAGE> (wherein R<1> represents an alkyl group having from 1 to 4 carbon atoms and R<2> represents an alkyl group having from 1 to 4 carbon atoms, a benzyl group, an allyl group or a group of general formula -(CH2)nCOOR<3>, where R<3> represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms and n is integer from 1 to 4) and their salts exhibit dopaminergic action on the respective receptors, significant inhibiting effect on prolactin and growth hormone secretion and a stimulating effect on the secretion of gonadotrophins.

Description

SPECIFICATION 1-Substituted N-(8a-ergolinyl)-N',N'-diethylureas and processes for producing thereof This invention relates to ergolinyl ureas, and the preparation thereof, having pharmaceutical application.

According to the present invention there is provided a 1.-substituted N-(8a-ergolinyl)-N',N'- diethylureas of general formula I.

wherein R' represents an alkyl group having from 1 to 4 carbon atoms and R2 represents an alkyl group having from 1 to 4 carbon atoms, a benzyl group, an allyl group or a group having the general formula (CH2)COOR3, where R3 represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms and n is an integer from 1 to 4.

There are known 8a-ergolinyl-N',N'-diethylureas, which are not substituted in position 1 ,that is compounds having general formula II,

in which R1 is as defined above.

For example N-(D-6-methyl-8a-ergolinyl)-N',N'-diethylurea (Czechoslovak Author's Certificate no. 1 52 1 53) and the 6-propyl analogue thereof (Czechoslovak Patent applications of the invention PV 7113-79 and PV 4168-80) are known to exhibit in animals a strong inhibiting effect on the secretion of prolactin and of growth hormone and to have a stimulating effect on the secretion of gonadotrophins. In the present invention the 1-substituted derivatives of these ureas of general formula I are strong inhibitors of prolactin secretion at experimental animals.

8m-Ergolinylureas of general formula I contain in the molecule three asymmetric carbon atoms in positions 5, 8 and 10, the spatial arrangement of which is the same as that of D-9,10dihydroisolysergic acid: hydrogen at C5 has the JB-position (configuration at this carbon is 5R), urea residue at C(8) is in the position (configuration at this carbon is 8S) and hydrogen at C(10) is in the a- position (configuration at this carbon is 1 OR).

According to the invention a method of preparing the 1-substituted Ba-ergolinylureas of general formula I comprises reacting position 1 unsubstituted 8a-ergolinyl-N',N'-diethylurea of general formula II, wherein R' is as defined above, with an alkylating agent of general formula Ill R2-X (111), wherein R2 is as defined above and X represents a halogen atom or a residue of an ester-bound aliphatic or aromatic sulphonic acid or a residue of an ester-bound sulphuric acid.

Starting compounds of general formula II can be prepared by known processes (references to patent literature see above).

The alkylating of the compounds of general formula II may be performed according to the invention by the reaction of from 1 to 5 molequivalents of the alkylating agent of general formula II with a solution of the compound of general formula II in an inert solvent in the presence of a base for binding liberated acid at temperature of from 4or to +500C.

As an alkylating agent of general formula Ill alkylhalogenides can be used, preferably the iodides or alkyl bromides, allyl bromide, benzyi bromide or -bromoaikanoic acids and the esters thereof, or alkyl esters of sulphuric acid such as dimethylsulphate or diethyl sulphate, or esters of aliphatic or aromatic sulphonic acids, for example alkyl-methane sulphonates or alkyl-p-toluene sulphonates.

As an inert solvent polar aprotic solvents can be used such as dimethylformamide, dimethylsulphoxide, the hexamethyltriamide or phosphoric acid or acetone, or liquid ammonia.

As a base for binding the liberated acid strong bases can be used, for example sodium or potassium amide, lithium diisopropylamide, sodium methylate or sodium or potassium hydroxide. An especially preferred process for the preparation of compounds of general formula I comprises alkylating a compound of general formula II with an alkyl halogenides in a medium of liquid ammonia in the presence of sodium amide or potassium amide prepared in situ. The compounds of 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 prdducts obtained.

1-Substituted N-(8a-ergolinyl)-N',N'-diethylureas of general formula I are colourless crystalline compounds of basic character which yield addition salts with strong inorganic and organic acids. For therapeutic purposes water-soluble salts with pharmaceutically acceptable nontoxic acids are suitable, for example hydrochloric, sulphuric, methane sulphonic, ethane sulphonic, 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 general formula I in a suitable inert solvent, preferably in methanol, ethanol, acetone, water or in mixtures thereof.

The compounds of general formula I are significantly inhibit the secretion of prolactin and growth hormone and stimulate the secretion of gonadotrophins in animals, effect 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 the medical treatment of hyperpropactinemies, acromegaly and parkinsonism or they can be used for enhancement of the levels of gonadotrophins, for example to induce oestrus in mammals and the laying of eggs by birds.

The process for producing 1 -substituted 8a-ergolinylureas of general formula I is further elucidated by the following examples of embodiment which nevertheless 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 temperature data, in OC. The values of specific rotation relate to compounds free of crystallising solvent.

Example 1 N-(D-1 6-Dimethyl-8-ergolinyl)-N',N'-diethylurea 0.225 g (4 mmoles) of powdered potassium hydroxide was added to a solution of 0.34 9 (1 mmole) of N-(D-6-methyl-8cz-ergolinyl)-N',N'-diethylurea in 20 ml of anhydrous acetone. The mixture was stirred for 10 minutes at 23 to 260C and then 0.284 g (2 mmoles) of methyliodide was added dropwise at the same temperature. The reaction mixture was stirred for 2 hours at room temperature, a further 0.284 g (2 mmoles) of methyl iodide was then added and the mixture stirred three more hours.

The inorganic fraction was fiitered off and solvent distilled off from the filtrate under reduced pressure.

The evaporation residue was partitioned in a mixture of chloroform and water, the organic fraction dried with anhydrous sodium sulphate and the solvent distilled off under reduce pressure. The crude product (0.4 g) was purified using column chromatography on silica gel using a mixture of chloroform and ethanol (95:5) for elution of the compounds. The combined homogeneous fractions were recrystallized from acetone after evaporation of the solvents. The target compound obtained (R'=R2=methyl) in the form of colourless crystals having m.p. 136 to 1 380C, specific rotation [a]20=+24.40 (c=0.2, pyridine).

Example 2 N-(D-1 -methyl-6-n-propyl-8cz-ergolinyl)-N',N'-diethylurea Approximately 10 mg of iron (III) nitrate were added under mixing to a solution of 62.4 mg (2.715 mmoles) of sodium in approximately 100 ml of liquid ammonia and afterdecolourizingthe solution 500 mg (1.357 mmoles) of N-(D-6-propyl-8a-ergolinyl)-N',N'-diethylurea were added to the obtained suspension of sodium amide. After dissolution of the urea (approximately after 30 minutes) 385 mg (2.715 mmoles) of methyl iodide were added dropwise and the reaction mixture stirred for 1 hour at the boiling point of the ammonia. Ammonia was then evaporated, the evaporation residue being partitioned in a mixture of chloroform and water. The chloroform fraction was washed with water, dried with anhydrous sodium sulphate and the solvent distilled off under reduced pressure. The crude product (0.55 g) yields after recrystallization from acetone the target compound, (R2=methyl, R'=propyl) in the form of colourless crystals having m.p. 117 to 1 90C; [a]20=+26.30 (c=0.2, pyridine).

Example 3 N-(D-1 -Methyl-6-ethyl-8a-ergolinyl)-N',N'-diethylurea, m.p. 103 to 1 050C, [α]D20=+26.3 (c=0.2, pyridine), and N-(D-1-methyl-6-butyl-8a-ergolinyl)-N',N'-diethylurea, m.p. 75 to 770C, [α]D20=+32.9 (c=0.2, pyridine) were prepared by the same process as in the Example 2 with the difference that equimolar amounts of N-(D-6-ethyl-8a-ergolinyl)- or N-(D-6-butyl-8a-ergolinyl)-N',N'- diethylureas are used instead of N-(D-6-propyl-8α-ergolinyl)-N',N1.-diethylurna.

Example 4 N-(D- 1 -Ethyl-6-propyl-8α-ergolinyl)-N',N'-diethylurea, m.p. 85 to 860 C, [a]D =+30.4 (c=0.2, pyridine), and N-(D-1 ,6-dipropyl-8a-ergolinyl)-N',N'-diethylurea were prepared by the same process as in the Example 2 with the difference that equimolar amounts of ethyl iodide or propyl bromide were used instead of methyl iodide.

Example 5 The following compounds: N-(D- 1 -ethyl-6-methyl-8α-ergolinyl)-N',N' diethylurea, m.p. 124 to 1 260C, [a]020=+20.50 (c=0.2, pyridine); N-(D-1-propyl-6-methyl-8α-ergolinyl)-N',N'-diethylurea, m.p. 63 to 660C, [α]D20=+21.9 (c=0.2, pyridine); N-(D- 1 -butyl-6-methyl-8α-ergolinyl)-N',N'-diethylurea; N-(D-1-allyl-6-methyl-8α-ergolinyl)-N',N'-diethylurna, m.p. 82 to 840C, [ce]D =+18.0 (c=0.2, pyridine); ; N-(D-1-benzyl-6-methyl-8sx-ergolinyl)-N',N'-diethylurea, m.p. 167 to 169 C, [a]20-+1 5.00 (c=0.2, pyridine); and N-(D-1 -ethoxycarbonylmethyl-6-methyl-8a-ergolinyl)-N',N'-diethylurea, m.p. 57 to 590 C, [x]D =+ 17.0 (c=0.2, pyridine) were prepared by the same process as in the Example 2 with the difference that equimolar amounts of N-(D-6-methyl-8a-ergolinyl)-N',N'-diethylurea were used instead of N-(D-6-propyl-8a-ergolinyl)-N',N'- diethylurea and equimolar amounts of alkyl bromides, allyl bromide, benzyl bromide or ethyl bromoacetate were used.

Claims

1. 1-Substituted N-(8a-ergolinyl)-N',N'-diethylureas of general formula I

wherein R1 represents an alkyl group having from 1 to 4 carbon atoms and R2 represents an alkyl group having from 1 to 4 carbon atoms, a benzyl group, an allyl group or a group of general formula(CH2)nCOOR3, where R3 represents a hydrogen atom or an alkyl group having 1 or 2 carbon atoms and n is an integer from 1 to 4.

2. N-(D-1 ,6-Dimethyl-8a-ergolinyl)-N',N'-diethylurea.

3. N-(D-1 -Methyl-6-ethyl-8a-ergolinyl)-N',N1diethylurna.

4. N-(D-1 -Methyl-6-propyl-8a-ergolinyl)-N',N'-diethylurea.

5. N-(D- 1 -Methyl-6-bul-8a-ergolinyl)-N',N'-diethylurna.

6. A process for preparing a 1 -substituted 8a-ergolinylurea of general formula I, defined in claim 1 comprising reacting a 8a-ergolinyl-N',N'-diethylurea unsubstituted in position 1 having general formula II

wherein R1 is as defined in claim 1, with an alkylating agent of general formula Ill R2-X (111), wherein R2 is as defined in claim 1 and X represents a halogen atom or a residue of ester-bound aliphatic or an aromatic sulphonic acid or a residue of an ester-bound sulphuric acid.

7. A process according to Claim 6, in which the reaction is carried out in liquid ammonia in the presence of from 1 to 5 moiar equivalents of an alkali metal amide.

8. A process according to Claim 7, in which the alkali metal amide is sodium amide or potassium amide.

9. A process according to Claim 6, in which the reaction is carried out in acetone in the presence of from 1 to 5 molar equivalents of an alkali metal hydroxide.

10. process according to Claim 9, in which the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.

11. A process for preparing the compounds of general formula I defined in claim 1, according to any one of Examples 1 to 5 hereinbefore.

12. Compounds of general formula I defined in claim 1 whenever prepared by the process claimed in any of Claims 6 to 10.