DE2407904A1 - D-2-SUBST.-6-ALKYL-8-SUBST.-ERGOLINE AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

PAT Π N ΤΛ Κ WÄ LT 2

ο *, ι. MAAH o / n7Qn /

dr. G. ridicule Z4U / yU4

8000 MONKS 40

X-3806A SCHLEISSHEiMERSTR. 299 Wt / Mv

TEL. 3592201/205

Eli Lilly and Company, Indianapolis, Indiana / USA

D-2-substituted-6-alkyl-8-substituted-ergoline and processes for their

Manufacturing

Addendum to patent (patent application P 23 35 750.8)

The present invention relates to D-Z-ergoline and related compounds that act as prolactin inhibitors are useful, and methods of making these ergoline compounds

The invention relates in particular to an improvement of the invention described in the German patent specification · ... ... (patent application P 23 35 750.8) _# , the compounds of the formula

h £ JL

wherein X is a halogen atom, a methyl group or cyano group and R is CH ₂ -CN or CH ₂ -C-NHg, and their salts, prepared

provides with pharmaceutically acceptable acids ,, and a method relates to the preparation of these compounds.

The present invention relates to compounds of the general formula

II

-X

wherein X and R are as defined above and R ^{1 is} C1 -C4 primary alkyl, H or CN, and the nontoxic salts thereof prepared with pharmaceutically acceptable acids.

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Otherwise unsubstituted ergolines with one group, with the exception of the methyl group in the 6-position, have been described by Fehr et al, Helv.Chim.Acta, £ 2, 2197 (1971) and Nakaharo et al, Chem. Pharm. Bull, Ij ?, 2337 (1971).

Compounds of the formula II in which R ^{1 has} a meaning other than methyl are preferably prepared by reacting with cyanogen bromide a compound in which X and R have the definitions given above and R ^! Means methyl. A suitable inert solvent such as methylene dichloride is usually used. The product of this reaction is a 6-cyano derivative in which the groups in the 8- and 2-positions remain unchanged. Reduction or hydrolysis of the 6-cyano derivatives gives the secondary amine compound (III)

III

wherein X and R have the definitions given above. Alkylation of this secondary amine with an alkyl halide (R ¹ -Hai, in which Hal is preferably chlorine, Brcm or iodine) in a suitable inert solvent gives a compound of the formula II above. The above process is useful not only in the preparation of heretofore unknown 6-alkylergolines in which the alkyl group is other than methyl, it is also useful in the case of compounds in which the alkyl group (R ¹ ) is methyl , wherein radioactive labeled ergoline derivatives of the formula II are produced in which

14th
the radioactive site is a C atom attached to the

5Π98 2-3 / 0926

Cg methyl group. Alternatively, the methyl group of the D-6-methyl-8-substituted-ergoline can be replaced by a higher alkyl group according to the above procedure, a D-6-alkyl-e-substituted-ergoline being obtained and the latter compound then being obtained halogenated or otherwise substituted in the 2-position of the ergoline ring by the processes given above for the 6-methyl-ergolines, 6-alkyl compounds der.Formel II above being obtained, in which R ^{1 has} a meaning other than methyl.

The following example explains the invention without restricting it.

example

Production of D-2-chloro-6-ethyl-8-cyanomethyl-ergoline

A solution is prepared which contains 6.11 g of D-2-cyanomethyl-ergoline (prepared according to the method of Example 1 of the earlier application by the same applicant with the number P 23 35 750.8). 13.5 g of cyanogen bromide are added and the reaction mixture is stirred at room temperature under anhydrous conditions for 69 hours. The reaction mixture is poured into aqueous tartaric acid and the acidic solution is extracted with chloroform. The chloroform layer is separated, washed with water and dried. Evaporation of the chloroform gives a residue which contains D-2-chloro-cyano-S-cyanomethyl-ergoline, which is formed in the above reaction. Recrystallization of the residue from ethanol gives purified D - ^ - chloro-ö-cyano-e-cyanomethylergolin, m.p. about 231-232 ⁰ C. Yield SB%.

Analysis:

Calculated: C 65.70% H 4.87% N 18.03% Cl 1 ^ 41%

Found: 65.46 4.61 18.01 11.49

A mixture of 5.4 g of D-2-chloro-6-cyano-8-cyanomethyl-ergoline, 30 g of zinc dust, 2210 ml of glacial acetic acid and 45 ml of water are added on

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Heated to reflux in a nitrogen atmosphere for 8 hours. The reaction mixture is filtered and the filtrate is diluted with water and then made basic by the addition of 14N aqueous ammonium hydroxide. The alkaline solution is extracted with chloroform, the chloroform layer is separated, washed with water and dried, the chloroform is separated therefrom by evaporation in vacuo. The resulting residue, which contains D-2-chloro-8-cyanomethyl-ergoline and which is formed in the above reaction, is recrystallized from ethanol, crystals having a melting point of 228 to 229 ^° C. (with decomposition) being obtained. Au & 6 <? Irfe fä% _u

Analysis: / · * £ ■. "" ■ "

Calculated: C 67.24% H 5.64% N 14.70% Cl 12.41% Found: 66.99 5.40 14.87 12.42

Approximately 300 mg of D-2-chloro-8-cyanomethyl-ergoline are dissolved in 10 ml of DMF (dimethylformamide). 2 & 0 mg of potassium carbonate are added to the reaction mixture and then 0.12 ml of ethyl iodide is added. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 5.5 hours. The reaction mixture is diluted with water and the aqueous layer is extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water and then washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the ethyl acetate in vacuo gives D ^ -chloro-ö-ethyl-S-cyanomethylergoline, melting point 225 to 227 ° C (with decomposition) according to chromatography over Florisil using chloroform, which contains 2% ethanol, as the eluting solvent. / ^^^ eoT ^ c *

Analysis: <f ^t * ^r " ^e * '~ Jf ^e ^ ■

Calculated: C 68.89% H 6.42% N 13.39% Cl 11.30% * ' ^ * fe ^ Found: 68.64 6.15 13.45 11.37

Following the above procedure but using the appropriate alkyl halide in place of ethyl iodide, the

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the following compound produced: D ^ -Chlor-ö-n-propyl-ecyanomethyl-ergoline, mp. 185 to 187 ⁰ C yield 8% analysis: Jl

Calculated: C 69.61% H 6.76% N 12.82% Cl 10.81% 0 ^ Found: 69.57 6.98 12.59 10.64

Alkylation of D-2-chloro-8-cyanomethyl-ergoline with methyl iodide in the presence of potassium carbonate in DMF solution D ^ -Chlor-ö-methyl-e-cyanomethyl-ergoline. The connection owns identical properties to the starting material used in this series of reactions.

Following the above procedure becomes D-2-chloro-6-methyl-8-carboxamidomethyl-ergoline demethylated and the resulting secondary amine is alkylated, higher alkyl analogues produces, for example D ^ -Chlor-ö-ethyl-S-carboxamidomethyl-ergoline and D-2 ~ chloro-6-n-propyl-8-carboxamidomethylergoline. Similarly, 8-cyanomethyl can be 1- or 8-carboxamidomethylergoline with groups other than chlorine in the 2-position of the ergoline ring, for example the 2-bromine, 2-iodine, 2-methyl or 2-cyano derivatives, are demethylated to give the corresponding secondary amine, this compound in turn can be realkylated again in order to produce higher homologs, as is the case with the D-2-chloro-8-cyanomethyl reaction series above has been described.

Compounds that come under the formula II, in which R ^{1 is} primary C2 ~ C ^ -alkyl, are particularly effective prolactin inhibitors and they show prolactin inhibition, comparable to that of D ^ -Bromo-ö-methyl-S- cyanomethyl-ergoline and D ^ -Chlor-ö-methyl-S-cyanomethyl-ergoline. In particular, the 6-ethyl and 6-n-propyl analogs show prolactin inhibition activity comparable to that of the 6-methyl compound.

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Claims (6)

Claims Compounds of the formula NR ¹ HN X Cl, Br, _{I, CH 3} or CN, R CH ₀ -CN or CH ₀ -C-NH ₀ and R ^{1 is} a primary Cp-C ^ -alkyl group, H or CN, and the non-toxic salts thereof formed with pharmaceutically acceptable acids. 2. A compound according to claim 1, wherein R ^{1 is} a primary Cp-C ^ -alkyl group and R and X are as defined above. 3. Process for the production of ergoline derivatives according to patent specification (patent application P 23 35 750.8), thereby characterized in that a compound of the formula I N-CH ₃ 509823/0926 X Cl, Br, J, CH ₃ or CN and R is CH ₂ -CN or CH ₂ -C-NH ₂ , 8th
is demethylated, a compound of the formula II II obtained, in which X and R have the definitions given above, and the compound of the formula II is reakylated to give a compound of the formula III NO' III produce, wherein X and R have the definitions given above and JR. ¹ denotes a C 1-4 primary alkyl group. 4. The method according to claim 3 »characterized in that that the demethylation stage is carried out by reacting a compound of the formula I with cyanogen bromide, whereby one a 6-cyano-substituted compound is obtained and the 6-cyano substituent is removed to give a compound of 509823/0926 Formula II to manufacture. 5. The method according to claim 4, characterized in that the 6-cyano substituent is removed by reduction. 6. The method according to claim 4, characterized in that the 6-cyano substituent is removed by hydrolysis. 509823/0926