IL44160A - D-6-alkyl-2,8-disubstituted ergolines and their preparation - Google Patents

Abstract

1451724 D - 2 - substituted - 8 - substituted ergoline derivatives ELI LILLY CO 5 Feb 1974 [28 Nov 1973] 05346/74 Addition to 1423065 Heading C2C Novel ergoline derivatives of the Formula II wherein X is Cl, Br, I, CH 3 or CN, R is CH 2 CN or CH 2 CONH 2 , and R<SP>1</SP> is C 2-4 primary alkyl, or a radioactive C 14 methyl group and pharmaceutically acceptable acid-addition salts thereof may be prepared by demethylation of the corresponding 6-methyl ergoline to give the 6-unsubstituted ergoline II and then alkylation at the 6-position. Pharmaceutical compositions of the compounds II are prolactin inhibitors. [GB1451724A]

Description

D-6-alkyl-2,8~di0ubstituted ergolliiee and their preparation ELI LILLY AND COMPANY 0, 42335 The presen invention relates to D-2-substi- tuted-6-alkyl-8-substituted ergolihes and related compounds, prolactin inhibitors, and to a process for preparing said er oline compounds.

More particularly the present invention provides an improvement of our "earlier filed application serial number 42730 which relates to compounds of the formula wherein X is halo, methyl, or cyano and R is CH2-CN or CH2-C-NH2 and their salts formed with pharmaceutically 0 acceptable acids, and to a process for preparing said compounds.

Said improvement comprises compounds of the formula R wherein X and R are as defined above and R' is C2-¾ rimar alk l, H or CN and non-toxic salts thereof formed with pharmaceutically acceptable acids.

Otherwise unsubstituted ergolines having a group other than methyl in the 6-position have been pre- \ pared by Fehr et al. , Helv. Chlm. Acta, 3., 2197 (19711 and Nakaharo et al. , Chem. Pharm. Bull. , 1 , 2337 (1971).

Compounds of formula II in which R» is a cyano group are preferably prepared by reacting a compound of formula I with cyanogen bromide. A suitable inert solvent such as methylene dichloride is customarily used. The product of this reaction is a 6-cyano derivative in which the groups at 8 and 2.. remain unchanged. Reduction or hydrolysis of the β-cyano derivative produces the secondary amine compound (III) in which X and R are defined as hereinabove. Alkylation of this secondary amine by an alkyl halide (R' -Hal wherein Hal is preferably chloro, bromo or lodo) in a suitable inert solvent produces a compound of formula II above in which R · is alkyl of σ2~σ4' The a¾ove procedure is useful not only in preparing the hitherto unavailable 6-alkyl ergolines wherein the alkyl group is other than methyl but is' also useful in the case where the alkyl group (R') is methyl in preparing radio-active labeled ergoline derivatives of formula II above in which Cg methyl group. Alternatively, the methyl group of a D-6-methyl-$-substituted ergoline can be replaced with a higher alkyl group by the above procedure. to yield a D-6-alkyl-8-substituted ergoline, which latter compound can then be halogenated or otherwise substituted in the 2-position of the ergoline ring by the procedures set forth above for the 6-methyl ergolines to yield 6-alkyl compounds of formula II above, in which R' is other than methyl.

Example 1 Preparation D-2-chloro-6-ethyl-8-cyanomethylergollne A solution was prepared containing 6.11 g. of D-2-chloro-6-methyl-8-cyanomethylergoline (as furnished by the procedure of Example 1 of our earlier filed application serial number 42730 ). 13.5 G. of cyanogen bromide were added, and the reaction mixture stirred at room temperature under anhydrous conditions for 69 hours. The reaction mixture was poured into aqueous tartaric acid and the acidic solution extracted with chloroform. The chloroform layer was separated, washed with water and dried. Evaporation of the chloroform yielded a residue comprising D-2-chloro-6-cyano-8-cyanomethylergbline formed in the above reaction. Recrystallization of the residue from ethanol yielded purified D-2-chloro-6-cyano-8-cyanomethylergoline melting at about 231-2°C.

Analysis calc. : C, 65.70; H, 4.87; N, 18.03; CI, 11.41; Found: C, 65.46; H, 4.6l; N, 18.01; CI, 11.49.

A mixture of 5.4 g. of D-2-chloro-6-cyano-8-cyanomet'hylergoline," 30 g. of zinc dust, 2210 ml. of a nitrogen atmosphere for 8 hours. The reaction mixture was filtered, and the filtrate diluted with water and then made basic by the addition of l4N aqueous ammonium hydroxide. The alkaline solution was extracted with chloroform, the chloroform layer separated, washed with water and dried1, and the chloroform evaporated therefrom by evaporation in vacuo. The resulting residue, comprising D-2-chloro-8-cyanomethylergoline formed in the above reaction, was recrystallized from ethanol to yield crys-tals melting at 228-9°C. with decomposition.

Analysis calc. : C, 67. 24; H, 5.64; N, 14.70; CI, 12.41; Found: C, 66.99; H, 5.4θ; N, 14. 87; CI, 12.42.

About 300 mg. of D-2-chloro-8-cyanomethylergo-line were dissolved in 10 ml. of DMF (dimethylformamide) . 220 Mg. of potassium carbonate were added to the reaction mixture, followed by 0.12 ml. of ethyl iodide. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5.5 hours. The reaction mixture was then diluted with water, and the aqueous layer ex-tracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, followed by a wash with saturated aqueous sodium chloride and was then dried.

Evaporation of the ethyl acetate in vacuo, yielded D-2-chloro-6-ethyl-8-cyanomethylergoline melting at 225-7°C. ξ with decomposition after chromatography over lorisil usj.ng chloroform containing 2 percent ethanol as the eluting solvent.

Analysis calc; C, 68. 89 ; H, 6.42; N, 13. 39; Cl, 11.30; Founds C, 68.64; H, 6.15; N, 13.45; Cl, 11. 37. r the appropriate alkyl halide with ethyl iodide, the following compound was prepared: D-2-chloro-6-n-propyl-8- cyanomethylergoline melting at l85-7°C.

Analysis calc. : C, 69.6l; H, 6.76; N, 12.82; CI, 10.8l; Found: C, 69.57; H, 6.98; N, 12.59; CI, 10.64.

Alkylation. of D-2-chloro-8-cyanomethylergoline' with methyl iodide in the presence of. potassium carbonate in DMF solution yields D-2-chloro-6-methyl-8-cyano-methylergoline. The compound has identical properties to the starting material provided for this series of reactions.

Following , the above procedure, D-2-chloro-6-methyl-8 SSF¾o¾a¾tdemethylergoline has been demethylated, and the resulting secondary amine . alkylated to yield sition of the e.rgoline ring other than chloro as, for example, the 2-bromo^2-iodo, 2-methyl or 2-cyano derivatives, can also be demethylated to yield the corresponding secondary amine which compound can in turn be re-alkylated to yield higher homologs as in i the D-2-chloro-8-cyanomethyl · reaction series outlined above.

Compounds coming within the scope of formula II above-..wherein R' is primary alkyl are extremely effective prolactin inhibitors, showing an inhibition of prolactin comparable to that of D-2-bromo-6-methyl-8-cyanomethylergoline and D-2-chloro-6-methyl-8-cyano- - - - propyl analogs showed a comparable prolactin inhibition activity to that of the 6-methyl compound.

Claims (4)

1. Compounds of the formula R wherein X is CI, Br, I, CH3 or CN, R is CH2-CN or CH2-C-NH2 0 and R' is C2-C4 primary alkyl, H or C.¾f and non-toxic salts thereof formed with pharmaceutically- acceptable acids.

2. A compound according to claim 1 in which R' is C2-C4 primary alkyl and R and X are as defined.

3. A process for preparing a compound of the formula Π as defined in claim 1 wherein R' is hydrogen comprising demethylating a compound of formula I R wherein X is CI, Br, I, CH3 or CN and R is CH2~CN or ,CH2-C-NH2. 0 44160/2

4. A process for preparing a compound of the Formula II as defined in claim 1 wherein R' is C2-C alkyl comprising realkylating a compound of Formula III: wherein X and R are as defined in claim 1. wherein X and' R are as defined in claim 1, with cyanogen bromide to give the 6-cyano substituted' compound of formula II and if desired removing the 6-cyano substituent by reduction or hydrolysis to form a compound of the formula III. 44160/2 6. Compounds of the formula II In Claim 1, substantially as hereinbefore described. * 7· A process for preparing compounds of the formula II in Claim 1, substantially as hereinbefore described with particular referenoe to the Bzamplea.