CA1071623A - 8-thiomethylergolines - Google Patents
8-thiomethylergolinesInfo
- Publication number
- CA1071623A CA1071623A CA228,332A CA228332A CA1071623A CA 1071623 A CA1071623 A CA 1071623A CA 228332 A CA228332 A CA 228332A CA 1071623 A CA1071623 A CA 1071623A
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- Prior art keywords
- methyl
- alk
- formula
- phenyl
- didehydroergoline
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
Abstract of the Disclosure 8-Thiomethylergolines, which are useful as pro-lactin inhibitors, are described hereinO These compounds are prepared by reacting via nucleophilic displacement an ester of a D-6-methyl-8-hydroxymethylergoline or of a 9,10-didehydroergoline with salts of thio-phenol, a thioalkanoic acid, or an alkylthiol.
Description
Compounds based on the ergoline ring system, formula (I), --H-~' have a surprising variety of pharmaceutical activities. For example, lysergic and isolysergic acid are 8-carboxy-6-methyl-~9-ergolines (9,10-didehydroergolines). The amides of lysergic acid, many of which have valuable and unique pharma-cologic properties, include the naturally occurring oxytocic alkaloids - ergocornine, ergokryptine, ergonovine, ergo-; cristine, ergosine, ergotamine etc. - and-synthetia oxytocics such as methergine as well as the synthetic hallucinogen---lysergic acid diethylamide or LSD. The amides of 6-methyl-8-carboxyergoline, known generically as dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Ergotamine, a ~9-ergo-line, has been used in the treatment o~ migraine and recently both ergocornine and 2-bromo-a-ergokryptine have been shown to be inhibitors of prolactin and of dimethylbenzan~hracene (DMBA)-induced tumors in rats, accordin~ to Nagasawa and Meites, Proc. Soc. ExE~tl. Biol. Med. 135, 469 (1970~ and to Heuson et al., Europ. J. Cancer, 353 (1970). (See also U.S.
Patents 3,752,8B8 and 3,752,81~).
D-6-methyl-8-cyanomethylergoline was first pre-~ .
. .
~: . -, .. , . :
pared by Semonsky and co-workers, Coll, Czech. Chem. Commun., 33, 577 (1968), and its use in preventing pregnancy in rats was published by the Same group in Nature, 221, 666 (1969).
(See also U.S. Patent 3,732,231) The compound was thought to interfere with the secretion of hypophysial leuteotropic hormone and the hypophysial gonadotropins. It was also sug-gested that the compound inhibited the secretion of pro-lactin. [See Seda et al., Reprod. Fert., 24, 263 (1971) and Mantle and Finn, id. 441)]. Semonsky and co-workers C _ , Czech. Chem. Comm., 36, 220 (1971), described the prep-_ aration of D-6-methyl-8-ergolinylacetamide, a compound which is stated to have anti-fertility and anti-lactating effects on rats. The effect of these compounds in neoplastic disease is unknown. Ergolines with a thiomethyl substituent or a derivative thereof have not previously been prepared.
This invention provides 8-thiomethylergolines of the formula:
CH --S--R
~
CH
HN-- R
wherein R is H, ~-alk, phenyl, or alk;
~1 is H, Cl, or Br;
alk is Cl-C3 alkyl; and the dotted line represent5 the optional presence of a double bond, or ., .
1~7~ii23 a non-toxi~, pharmaceutically-acceptable acid addition salt thereof.
The term alk in the above formula, comprehending as it does Cl-C3 alkyl groups, includes the following radicals:
methyl, ethyl, _-propyl and isopropyl. In formula tII), when the ~9,10 bond is saturated, the compounds are generically denominated as D-6-methyl-8-thiométhyl (or mercaptomethyl) ergolines. When the ~9,10 hond is unsaturated, the resulting compounds are known generically as D-6-methyl-8-thiomethyl or mercaptomethyl-9,10-didehydroergolines. Compounds illustrative of the scope of the above formula include the following:
D-2-chloro-6-methyl-8-propionylthiomethylergoline D-2-chloro-6-methyl-8-butyrylthiomethyl-9,10-didehydro-ergoline D-2-chloro-6-methyl-8-phenylmercaptomethyl-9,10-didehydro-ergoline D-2-bromo-6-methyl-8-phenylmercaptomethyl-9,10-didehydro-ergoline D-2-chloro-6-methyl-8-ethylmercaptomethyl-9,10-didehydro-ergoline D-6-methyl-8-n-propylmercaptomethylergoline D-6-methyl-8-isopropylmercaptomethylergoline.
The compounds of formula (II) are prepared by reacting a compound of the formula .: , ' :, 6~3 C~12OR
1~
N-CH
(III) .: ,1 11 .
wherein Rl and the dotted line are defined as before; and R2 is a methanesulfonyl or p-toluenesulfonate group, with a nucleophilic reagent of the formula - O HSR (IV) wherein R3 is C-alk, phenyl, or alk, followed by O
Il hydrolysis when R3 is C-alk and the compounds of formula ~II) wherein R is H are desired. However, compounds in which R is other than H are particularly preferred.
The compounds of this invention in which R is other than H are prepared by reacting via nucleophilic dis-placement an ester of a D-6~methyl-8-hydroxymethylergoline or of a 9,10-didehydroergoline, optionally substituted at C-2 with chlorine or bromine, with salts of thio-phenol, a thioalkanoic acid (alk-COSH) or an alkylthiol talk-SH). Esters useful as starting materials in the above synthetic procedure include the mesyl (methanesulfonyl), the ~-toluenesulfonyl (~-tosyl) and the like esters formed with the hydroxy group of 8-hydroxymethyl-6-methylergoline, 8-hydroxymethyl-6-methyl-9,10-didehydroergoline or of a 2-halo derivative of either of the ~9 compounds of formula II. These mesyloxy and p-tosyloxy derivatives are either known compounds or can be prepared from the corresponding hydroxy derivativ~s by processes available in the art. In carrying out reactions .~ ,,. I .
with thiophenol or with an alkyl thiol, the sodium salt of the mercaptan group is usually formed, using sodium methylate or sodium hydride.
The nucleophilic displacement reaction is carried out in an inert solvent such as dimethyl formamide (DMF), or dimethyl-sulfoxide (DMSO). Ordinarily, the reaction is carried out at room temperature or if desired ~y heating to a temperature in the range from room temperature to 100C. The products of the reaction are customarily isolated by standard tech-niques and purified b~ chromatography, preferably over "Florisil"*. The compounds of this invention in which R is H
are prepared by hydrolysis in base of the corresponding com-; l pound in which R is C-alk. '¦
The compounds of this invention are white crystal-line solids and form pharmaceutically acceptable salts with nontoxic acids. These pharmaceutically acceptable salts are included within the scope of ~his invention. Nontoxic acids useful in forming the salt3 of this invention include such inorganic acids as hydrochloric acid, nitric acid, phos-phoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid, phosphorus acid and the like, as well as non-toxic organic acids including aliphatic mono and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkandioic acids, arvmatic acids, and aliphatic and aromatic sulfonic acids. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate~ monohydrogenphosphate~
dihydrogenpho5phate, metaphosphate, pyrophosphate, chloride, bromide, iodide, iluoride, acetate, propionate, decanoat~, *Trademark for a highly selective adsorbent oE hard granular or powdered magnesium silicate.
. . ,~
.
caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, ben-zoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonates, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl-butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, propanesulfonates, naphthalene-l-sulfonate and naphthalene-2-sulfonate.
The compounds of this invention are useful as prolactin inhibitors. The inhibition of prolactin secretion by the compounds of this invention is evidenced by the fol-lowing experiment: Adult male rats of the Spraque-Dawley strain weighing about 200 g. were used. All rats were housed in an air-conditioned room with controlled lighting (lights on 6 a.m. - 8 p.m.) and fed lab chow and water ad libi~um.
In each experiment the rats were killed by de-20 capitation, and 150 ~1 aliquots of serum were assayed forprolactin. Each male rat received an intraperitoneal in-jection of 2.0 mg of reserpine in aqueous suspension 18 hours before administration of the ergoline derivative. The pur-pose of the reserpine was to keep prolactin levels uniformly elevated. The derivatives were dissolved in 10% ethanol at a concentration of 10 ~g/ml, and were injected intraperi-toneally at a standard dose of 50 ~g/kg. Each compound was administered to a group of 10 rats, and a control group of 10 intact males received an equivalent arnount of 10 percent 30 ethanol. One hour after treatment all rats were killed by ; X-4228 7 .
~ 7~ 3 decapitation, and the serum was collected and assayed for pro-lactin as previousl~ described. The results were evaluated statistically using Student's "t" test (a mathematical comparison between means) to calculate the level of significance, "p."
The difference between the prolactin level oE the treated rats and prolactin level of the control rats, divided by the prolactin level of the control rats gives the percent inhibition of prolactin secretion attributable to the com-10 pounds of this invention. The table which follows gives pro-lactin inhibition percentages for a series of compounds coming within the scope of formula (II) above. In the table, column 1 gives the name of the compound; column 2, the dose level of the compound in the prolactin inhibition test; column 3, the percent prolactin inhibition; and column 4, the level of sig-nificance.
Being prolactin inhibitors, the compounds of this invention are also potentially useful for suppressing the growth of breast adenocarcinomas in female mammals.
This invention is further illustrated by Examples 1-6 which follow.
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dP
O OO O O O O
a) ~ ~~ _l ~ ~, E~ I I
Orl O-rl ~ o ~ o a) .
e h a) ~ E~
a) o ~ o ~ o a) co :: k ~1~ ~ ~ ~ E3 1 rl ~-~
0~ ~ >~ >1 0 ~ O
o ~ ~~ ~ o a) ~ ~ ~ o Q) ,, ~-r~ O ,, I ~I ~ I I I ~: I ~ I h O I OI O I I I ~1 1 IJ I
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a ~ Q aJ
X-4228 g ' ~
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. .
~'7~ 3 Example 1 A reaction mixture was prepared from 2 g~ of D-6-methyl-8-~-toluenesulfonyloxymethylergoline, 2 g. of sodium thiocyanate and 100 ml. of dimethylsulfoxide (DMSO) . The mixture was heated in the range 100 110C. for 4.5 hour~. The reaction mixture was then cooled and poured over an ice water mixture. 6-Methyl-8-thiocyanomethylergoline was in~oluble in water and precipitated. The solid was collected by filtration and melted at about 181-3C. with decomposition after re-10 crystallization from an ether-hexane olvent mixture.
Analysis: Calc.: C, 68.65; H, 6.44; N, 14.13; S, 10.78;
Found: C, 68.31; H, 6.66; N, 13.99; S, 10.48.
Example 2 A suspension of 10 g. of D-6-m~thyl-8-hydroxy-methylergoline in 200 ml. of pyridine was prepared. To this --suspension was added slowly a solution containing 6.0 ml. of methanesulfonyl chloride and 200 ml. of pyridine. The r~-sulting mixture was stirred at room temperature under a nitrogen atmosphere for about one half hour and was then poured 20 into 2.5 1. of saturated aqueous sodium bicarbonate. The alkaline aqueous layer was diluted to 6 liters with water, and the diluted layer allowed to stand at room temperature.
D-6-methyl-8-mesyloxymethylergoline ormed in the above reaction slowly crystallized. The ~olution was chilled to about 0C. in order to cause more of the compound to precipi-tate. The solution was then filtered, and the filter cake recrystallized from ethanol. A furthex quantity of D-6-methyl- -8-mesyloxymethylergoline was obtained by extracting the fil trate with ethyl acetate, separating the ethyl acetate layer ; 30 and removing the ethyl acetate therefrom by evaporation in X-~228 10 .
' . ~ ., ' ' . : . ' ' , vacuo. Recrystallization of D-6-methyl-8-mesyloxymethylergO~
line prepared as above from ethanol yielded material ~nelting at about 192-4C. with decomposition.
Analysis: Calc.: C, 61.05; H, 6.63; N, 8.38; S, 9.59;
Found: C, 60.85; N, 6.46; N, 8.45; S, 9.30.
A solution of 2.5 ml. of thiophenol in 25 ml. of DMSO was prepared. 1.1 g. of sodium me~hylate were a~ded.
Next a solution of 700 mg. of D-6-methyl-8-mesyloxymethylergo-line in 50 ml. of DMSO was added in drop-wise fashion to the 10 sodium thiophenate solution. After the addition had been completed, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for about 2 hours, and was ~en poured into a saturated aqueous tartaric acid solution. The acidic layer was extracted wi~h chloroform. The chloroform extract was separated and discarded. The acidic layer was then made basic with the excess of 14N ammonium hydroxide, and the resulting alkaline layer extracted with chloroform.
The chloroform extract was separated and dried. Evaporation of ~he chloroform left a residue which was dissolved in ethyl 20 acetate. The ethyl acetate solution was thoroughly washed with water followed by a wash with saturated aqueou~ sodium chloride solution. The e~hyl acetate layer was dried. Removal of the ethyl acetate by evaporation in vacuo yielded a residue comprising D-6-methyl-8-phenylmercaptome~hylergoline which was recrystallized from ethanol and melted at 194-5C. with dec~mposition. The compound was ~hen dissolved in chloroform and chromatographed over "Florisil" (25g.). The chromatogram was developed with a chloxoform-methanol (19:1) solvent mixture~
Fractions containing D-6-methyl-8-phenylmercaptomethylergoline 30 as determined by ~hin layer chromatography were combined.
X-4~8 ll Evaporation of the solvent from the comblned fraction~ and recrystallization of the resulting residue from an ether-hexane solvent mixture yielded D-6-methyl-8-phenylmercapto-methylergoline; MP=195-6C. with decomposition.
~nalysis: Calc.: C, 75.82; H, 6.95; N, 8.04; S, 9.20;
Found: C, 75.85; H, 6.69; N, 7.97; S, 9.19.
Following the above procedure D-6-methyl-8-mesyloxy-methyl-9,10-didehydroergoline was reacted with thiophenol to yield D-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline 10 which melted at about 200-3C. with decomposition after re-crystallization from methanol.
Analysis: Calc.: C, 76.26; H, 6.40; N, 8.08; S, 9.25;
Found; C, 76.02i H, 6.42i N, 7.99; S, 9.02.
- The corresponding 3,10-didehydro maleate salt was prepared by dissolving the compound in tetrahydrofuran and adding an equivalent amount of maleic acid also in tetra-hydrofuran. The maleate salt melted at 188-9C. after recrystallization from methanol.
; Analysis: Calc.: C, 67.51; H, 5.67; N, 6.06i S, 6.93;
Found: C, 67.29; H, 5.89; N, 5.79; S, 6.71.
Exam~le 3 Ten milliliters of dimethyl formamide (DMF) were cool~d to about 0C. 1 ml. of methanethiol was added followed by 1.0 g. of sodium hydride as a 50 percent suspension in mineral oil in portio~s. The resulting mixture was stirred for about 1 hour and then allowed to warm to room temperature.
Then, following the procedure of Example 2, a solution of 1 g.
of D-6-methyl-8-mesyloxymethylergoline in 50 ml. of DMF was added in drop-wise fashion to the sodium salt of methanethiol.
30 The resulting product was i~olated and purified by the pxo-cedure of Example 2 to yield D-6~methyl-8-methylmercapto-methylergoline melting at about 153-5C. Recrystallization of the compound thus obtained (omitting the chromatographic purificatiOn step of Example 2) from an ether-hexane solvent mixture yielded ~-6-methyl-8-methylmercaptomethylergoline, MP = 153-4C.
Analysis: Calc.: C, 71.2~; H, 7.74; N, 9.78; S, 11.19;
Found: C, 71.08; H, 7.59; N~ 9.83; S, 10.99.
Following the above procedure D-6-methyl-8-methyl-10 mercaptomethyl-9,10-didehydroergoline was prepared from the corresponding 8-mesyloxymethyl derivative by reaction with methylmercaptan. The compound melted at 181-3C. with de-composition after recrystallization from ether-hexane sol-vent mixture.
~'"Analysis: Calc.: C, 71.79; H, 7.0g; N, 9.85; S, 11.27;
Found: C, 72.01; H~ 6.84; N~ 9.62; S, 11.270 The-corresponding 9,10-didehydro maleate salt was prepared by dissolving the compound in ether and adding an ; equivalent amount of maleic acid al~o in ether. Maleate salt 20 melted at 159-160C. with decomposition.
Analysis: Calc.: C, 62.98; ~, 6.07; M, 6.99; S, 8.01;
Found: C, 62.99; H, 6.13; N, 6.787 S, 7.~6.
Example 4 Following the procedure of Example 2, thioacetic acid (as the sodium salt) was rPacted wi~h D-6-methyl-8-mesyloxy-methylergoline in DMF solution to yield D-6-methyl-8-acetyl-mercaptomethylergoline which was isolated and purified by ~he procedure of that example. Chromatography of the cruae product over "Florisil" using chlorofonm containing 2 percent 30 ethanol as eluent yielded purified D-6-methyl-8-acetylmer-X-42~8 13 ,~
. . .
~'7~6~3 captomethylergoline MP=153-5C. wlth decomposition.
Analysis: Calc.: C, 68.75; H, 7.05; N, 8.91; S, 10.20;
- Found: C, 68.70; il, 7.22; N, 8.62; S, 10.47.
Following the above procedure, D-6-methyl-8~acetyl-mercaptomethyl-9,10-didehydroergollne was prepared from the corresponding 8-mesyloxymethyl compound. The purified com-pound thus prepared melted in the range 165-7C. with de-composition after recrystallization from an ether-hexane solvent mixture.
Analysis: Calc.: C, 69.20; H, 6.45; N, 8.97; S, 10,26;
Found: C, 69.48; H, 6.71; N, 9.00; S, 10.56.
The corresponding 9,10-didehydro maleate salt wa~
prepared by dissolving the base in ether and adding an equivalent amount of maleic acid in ether. The maleate salt melted at 178-9C. with decomposition.
Analysis: Calc.: C, 61.67; H, 5.65; N, 6.54; S, 7.48;
Found: C, 61.95; H, 5.50; N, 6.84; S, 7.63.
D~2-chloro-6-methyl-8-acetylmercaptomethylergoline was also prepared by the above procedure. Recrystallization 20 of the residue remaining after combining fractions from chromatography shown to contain D-2-chloro-6~methyl-8-acetyl-mercaptomethylergoline by thin layer chromatography, using a solvent mixture of ether and hexane for recrystallization yielded purified material melting at 140-1C.
Analysis: Calc.: C, 61.97; H, 6.07; N, 8.03; S, 9.19;
Cl, 10.16;
Found: C, 61.75; H, 5.78; N, 7.75; S, 9.41;
Cl, 10.32.
Example 5 A reaction mixture containing 1.0 g. of D-6-methyl-. . ~. ' . ' 8-acetylmercaptomethyler~oline (from Example 4), 100 ml. of ethanol and 100 ml. of 4N aqueous hydrochloric acid was re-fluxed under a nitrogen atmosphere ~or fi~e and one~half hours. The reaction mixture was cooled and made basic with an excess of 14N ammonium hydroxide. The aqueous alkaline layer was extracted with chloroform, and the chloroform yielded a residue comprising D-6-methyl-8-mercaptomethylergoline formed in the above reaction. The residue was chromatographed over 75 g, of "Florisil" using chloroform containing 5 percent ethanol 10 as the eluant. D-6-methyl-8-mercaptome~hylergoline was identified in chromatographic fractions by thin layer chroma-tograph~ as a more polar, and therefore more slowly moving, material than starting material. Fractions containing D-6-methyl-8-mercaptomethylergoline were combined and recrystallized from ethanol. The compound thus purified melted at 255-7C.
with decomposition.
Analysis: Calc.: C, 70.55; H, 7.40; N, l0.?8; s, 11.77;
Found: C, 70.31; H, 7.65; N, 10.-04; S, 12.00.
The above procedure was repeated except that methyl-20 mercaptan wa~ used in place of thioacetic acid for reaction wlth D-2-chloro-6-methyl-8-mesyloxymethylergoline to form D-2-chloro-6-methyl-8-methylmercaptomekhylergoline. Chroma-tography over "Florisil" of the residue obtained by combiningchromatographic fractions 5hown to contain the desired material u~ing an ether-hexane mixture for recry~tallization yielded purified D-2-chloro-6-methyl~8-me~hylmercaptomethylergoline melting at 194-5C.
' ,: ' ' , '. ' ~07~ 3 Analysis: Calc.: C, 63.63; }I, 6.60i N, 8.73; S, 9.99;
Cl, 11.05;
; Found: C, 63.42; H, 6.55; N, 8.47; S, 10.12;
Cl, 11 . 35 .
~, '.
, . . ' . . .
Patents 3,752,8B8 and 3,752,81~).
D-6-methyl-8-cyanomethylergoline was first pre-~ .
. .
~: . -, .. , . :
pared by Semonsky and co-workers, Coll, Czech. Chem. Commun., 33, 577 (1968), and its use in preventing pregnancy in rats was published by the Same group in Nature, 221, 666 (1969).
(See also U.S. Patent 3,732,231) The compound was thought to interfere with the secretion of hypophysial leuteotropic hormone and the hypophysial gonadotropins. It was also sug-gested that the compound inhibited the secretion of pro-lactin. [See Seda et al., Reprod. Fert., 24, 263 (1971) and Mantle and Finn, id. 441)]. Semonsky and co-workers C _ , Czech. Chem. Comm., 36, 220 (1971), described the prep-_ aration of D-6-methyl-8-ergolinylacetamide, a compound which is stated to have anti-fertility and anti-lactating effects on rats. The effect of these compounds in neoplastic disease is unknown. Ergolines with a thiomethyl substituent or a derivative thereof have not previously been prepared.
This invention provides 8-thiomethylergolines of the formula:
CH --S--R
~
CH
HN-- R
wherein R is H, ~-alk, phenyl, or alk;
~1 is H, Cl, or Br;
alk is Cl-C3 alkyl; and the dotted line represent5 the optional presence of a double bond, or ., .
1~7~ii23 a non-toxi~, pharmaceutically-acceptable acid addition salt thereof.
The term alk in the above formula, comprehending as it does Cl-C3 alkyl groups, includes the following radicals:
methyl, ethyl, _-propyl and isopropyl. In formula tII), when the ~9,10 bond is saturated, the compounds are generically denominated as D-6-methyl-8-thiométhyl (or mercaptomethyl) ergolines. When the ~9,10 hond is unsaturated, the resulting compounds are known generically as D-6-methyl-8-thiomethyl or mercaptomethyl-9,10-didehydroergolines. Compounds illustrative of the scope of the above formula include the following:
D-2-chloro-6-methyl-8-propionylthiomethylergoline D-2-chloro-6-methyl-8-butyrylthiomethyl-9,10-didehydro-ergoline D-2-chloro-6-methyl-8-phenylmercaptomethyl-9,10-didehydro-ergoline D-2-bromo-6-methyl-8-phenylmercaptomethyl-9,10-didehydro-ergoline D-2-chloro-6-methyl-8-ethylmercaptomethyl-9,10-didehydro-ergoline D-6-methyl-8-n-propylmercaptomethylergoline D-6-methyl-8-isopropylmercaptomethylergoline.
The compounds of formula (II) are prepared by reacting a compound of the formula .: , ' :, 6~3 C~12OR
1~
N-CH
(III) .: ,1 11 .
wherein Rl and the dotted line are defined as before; and R2 is a methanesulfonyl or p-toluenesulfonate group, with a nucleophilic reagent of the formula - O HSR (IV) wherein R3 is C-alk, phenyl, or alk, followed by O
Il hydrolysis when R3 is C-alk and the compounds of formula ~II) wherein R is H are desired. However, compounds in which R is other than H are particularly preferred.
The compounds of this invention in which R is other than H are prepared by reacting via nucleophilic dis-placement an ester of a D-6~methyl-8-hydroxymethylergoline or of a 9,10-didehydroergoline, optionally substituted at C-2 with chlorine or bromine, with salts of thio-phenol, a thioalkanoic acid (alk-COSH) or an alkylthiol talk-SH). Esters useful as starting materials in the above synthetic procedure include the mesyl (methanesulfonyl), the ~-toluenesulfonyl (~-tosyl) and the like esters formed with the hydroxy group of 8-hydroxymethyl-6-methylergoline, 8-hydroxymethyl-6-methyl-9,10-didehydroergoline or of a 2-halo derivative of either of the ~9 compounds of formula II. These mesyloxy and p-tosyloxy derivatives are either known compounds or can be prepared from the corresponding hydroxy derivativ~s by processes available in the art. In carrying out reactions .~ ,,. I .
with thiophenol or with an alkyl thiol, the sodium salt of the mercaptan group is usually formed, using sodium methylate or sodium hydride.
The nucleophilic displacement reaction is carried out in an inert solvent such as dimethyl formamide (DMF), or dimethyl-sulfoxide (DMSO). Ordinarily, the reaction is carried out at room temperature or if desired ~y heating to a temperature in the range from room temperature to 100C. The products of the reaction are customarily isolated by standard tech-niques and purified b~ chromatography, preferably over "Florisil"*. The compounds of this invention in which R is H
are prepared by hydrolysis in base of the corresponding com-; l pound in which R is C-alk. '¦
The compounds of this invention are white crystal-line solids and form pharmaceutically acceptable salts with nontoxic acids. These pharmaceutically acceptable salts are included within the scope of ~his invention. Nontoxic acids useful in forming the salt3 of this invention include such inorganic acids as hydrochloric acid, nitric acid, phos-phoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid, phosphorus acid and the like, as well as non-toxic organic acids including aliphatic mono and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkandioic acids, arvmatic acids, and aliphatic and aromatic sulfonic acids. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate~ monohydrogenphosphate~
dihydrogenpho5phate, metaphosphate, pyrophosphate, chloride, bromide, iodide, iluoride, acetate, propionate, decanoat~, *Trademark for a highly selective adsorbent oE hard granular or powdered magnesium silicate.
. . ,~
.
caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, ben-zoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonates, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl-butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, propanesulfonates, naphthalene-l-sulfonate and naphthalene-2-sulfonate.
The compounds of this invention are useful as prolactin inhibitors. The inhibition of prolactin secretion by the compounds of this invention is evidenced by the fol-lowing experiment: Adult male rats of the Spraque-Dawley strain weighing about 200 g. were used. All rats were housed in an air-conditioned room with controlled lighting (lights on 6 a.m. - 8 p.m.) and fed lab chow and water ad libi~um.
In each experiment the rats were killed by de-20 capitation, and 150 ~1 aliquots of serum were assayed forprolactin. Each male rat received an intraperitoneal in-jection of 2.0 mg of reserpine in aqueous suspension 18 hours before administration of the ergoline derivative. The pur-pose of the reserpine was to keep prolactin levels uniformly elevated. The derivatives were dissolved in 10% ethanol at a concentration of 10 ~g/ml, and were injected intraperi-toneally at a standard dose of 50 ~g/kg. Each compound was administered to a group of 10 rats, and a control group of 10 intact males received an equivalent arnount of 10 percent 30 ethanol. One hour after treatment all rats were killed by ; X-4228 7 .
~ 7~ 3 decapitation, and the serum was collected and assayed for pro-lactin as previousl~ described. The results were evaluated statistically using Student's "t" test (a mathematical comparison between means) to calculate the level of significance, "p."
The difference between the prolactin level oE the treated rats and prolactin level of the control rats, divided by the prolactin level of the control rats gives the percent inhibition of prolactin secretion attributable to the com-10 pounds of this invention. The table which follows gives pro-lactin inhibition percentages for a series of compounds coming within the scope of formula (II) above. In the table, column 1 gives the name of the compound; column 2, the dose level of the compound in the prolactin inhibition test; column 3, the percent prolactin inhibition; and column 4, the level of sig-nificance.
Being prolactin inhibitors, the compounds of this invention are also potentially useful for suppressing the growth of breast adenocarcinomas in female mammals.
This invention is further illustrated by Examples 1-6 which follow.
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1~77~Z;3 o o o ~
~ oo o o o o o : ~ V V V V V V V
..
.,, o .,, t, ~
,, O~ O ~ ~ ~D
O-rl U~
~;
H :
dP
O OO O O O O
a) ~ ~~ _l ~ ~, E~ I I
Orl O-rl ~ o ~ o a) .
e h a) ~ E~
a) o ~ o ~ o a) co :: k ~1~ ~ ~ ~ E3 1 rl ~-~
0~ ~ >~ >1 0 ~ O
o ~ ~~ ~ o a) ~ ~ ~ o Q) ,, ~-r~ O ,, I ~I ~ I I I ~: I ~ I h O I OI O I I I ~1 1 IJ I
--j h O O .1 U ~ I
o I o l .~ l O
a ~ Q aJ
X-4228 g ' ~
. ~ _ . .
- .,, ,.~. . .
. .
~'7~ 3 Example 1 A reaction mixture was prepared from 2 g~ of D-6-methyl-8-~-toluenesulfonyloxymethylergoline, 2 g. of sodium thiocyanate and 100 ml. of dimethylsulfoxide (DMSO) . The mixture was heated in the range 100 110C. for 4.5 hour~. The reaction mixture was then cooled and poured over an ice water mixture. 6-Methyl-8-thiocyanomethylergoline was in~oluble in water and precipitated. The solid was collected by filtration and melted at about 181-3C. with decomposition after re-10 crystallization from an ether-hexane olvent mixture.
Analysis: Calc.: C, 68.65; H, 6.44; N, 14.13; S, 10.78;
Found: C, 68.31; H, 6.66; N, 13.99; S, 10.48.
Example 2 A suspension of 10 g. of D-6-m~thyl-8-hydroxy-methylergoline in 200 ml. of pyridine was prepared. To this --suspension was added slowly a solution containing 6.0 ml. of methanesulfonyl chloride and 200 ml. of pyridine. The r~-sulting mixture was stirred at room temperature under a nitrogen atmosphere for about one half hour and was then poured 20 into 2.5 1. of saturated aqueous sodium bicarbonate. The alkaline aqueous layer was diluted to 6 liters with water, and the diluted layer allowed to stand at room temperature.
D-6-methyl-8-mesyloxymethylergoline ormed in the above reaction slowly crystallized. The ~olution was chilled to about 0C. in order to cause more of the compound to precipi-tate. The solution was then filtered, and the filter cake recrystallized from ethanol. A furthex quantity of D-6-methyl- -8-mesyloxymethylergoline was obtained by extracting the fil trate with ethyl acetate, separating the ethyl acetate layer ; 30 and removing the ethyl acetate therefrom by evaporation in X-~228 10 .
' . ~ ., ' ' . : . ' ' , vacuo. Recrystallization of D-6-methyl-8-mesyloxymethylergO~
line prepared as above from ethanol yielded material ~nelting at about 192-4C. with decomposition.
Analysis: Calc.: C, 61.05; H, 6.63; N, 8.38; S, 9.59;
Found: C, 60.85; N, 6.46; N, 8.45; S, 9.30.
A solution of 2.5 ml. of thiophenol in 25 ml. of DMSO was prepared. 1.1 g. of sodium me~hylate were a~ded.
Next a solution of 700 mg. of D-6-methyl-8-mesyloxymethylergo-line in 50 ml. of DMSO was added in drop-wise fashion to the 10 sodium thiophenate solution. After the addition had been completed, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for about 2 hours, and was ~en poured into a saturated aqueous tartaric acid solution. The acidic layer was extracted wi~h chloroform. The chloroform extract was separated and discarded. The acidic layer was then made basic with the excess of 14N ammonium hydroxide, and the resulting alkaline layer extracted with chloroform.
The chloroform extract was separated and dried. Evaporation of ~he chloroform left a residue which was dissolved in ethyl 20 acetate. The ethyl acetate solution was thoroughly washed with water followed by a wash with saturated aqueou~ sodium chloride solution. The e~hyl acetate layer was dried. Removal of the ethyl acetate by evaporation in vacuo yielded a residue comprising D-6-methyl-8-phenylmercaptome~hylergoline which was recrystallized from ethanol and melted at 194-5C. with dec~mposition. The compound was ~hen dissolved in chloroform and chromatographed over "Florisil" (25g.). The chromatogram was developed with a chloxoform-methanol (19:1) solvent mixture~
Fractions containing D-6-methyl-8-phenylmercaptomethylergoline 30 as determined by ~hin layer chromatography were combined.
X-4~8 ll Evaporation of the solvent from the comblned fraction~ and recrystallization of the resulting residue from an ether-hexane solvent mixture yielded D-6-methyl-8-phenylmercapto-methylergoline; MP=195-6C. with decomposition.
~nalysis: Calc.: C, 75.82; H, 6.95; N, 8.04; S, 9.20;
Found: C, 75.85; H, 6.69; N, 7.97; S, 9.19.
Following the above procedure D-6-methyl-8-mesyloxy-methyl-9,10-didehydroergoline was reacted with thiophenol to yield D-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline 10 which melted at about 200-3C. with decomposition after re-crystallization from methanol.
Analysis: Calc.: C, 76.26; H, 6.40; N, 8.08; S, 9.25;
Found; C, 76.02i H, 6.42i N, 7.99; S, 9.02.
- The corresponding 3,10-didehydro maleate salt was prepared by dissolving the compound in tetrahydrofuran and adding an equivalent amount of maleic acid also in tetra-hydrofuran. The maleate salt melted at 188-9C. after recrystallization from methanol.
; Analysis: Calc.: C, 67.51; H, 5.67; N, 6.06i S, 6.93;
Found: C, 67.29; H, 5.89; N, 5.79; S, 6.71.
Exam~le 3 Ten milliliters of dimethyl formamide (DMF) were cool~d to about 0C. 1 ml. of methanethiol was added followed by 1.0 g. of sodium hydride as a 50 percent suspension in mineral oil in portio~s. The resulting mixture was stirred for about 1 hour and then allowed to warm to room temperature.
Then, following the procedure of Example 2, a solution of 1 g.
of D-6-methyl-8-mesyloxymethylergoline in 50 ml. of DMF was added in drop-wise fashion to the sodium salt of methanethiol.
30 The resulting product was i~olated and purified by the pxo-cedure of Example 2 to yield D-6~methyl-8-methylmercapto-methylergoline melting at about 153-5C. Recrystallization of the compound thus obtained (omitting the chromatographic purificatiOn step of Example 2) from an ether-hexane solvent mixture yielded ~-6-methyl-8-methylmercaptomethylergoline, MP = 153-4C.
Analysis: Calc.: C, 71.2~; H, 7.74; N, 9.78; S, 11.19;
Found: C, 71.08; H, 7.59; N~ 9.83; S, 10.99.
Following the above procedure D-6-methyl-8-methyl-10 mercaptomethyl-9,10-didehydroergoline was prepared from the corresponding 8-mesyloxymethyl derivative by reaction with methylmercaptan. The compound melted at 181-3C. with de-composition after recrystallization from ether-hexane sol-vent mixture.
~'"Analysis: Calc.: C, 71.79; H, 7.0g; N, 9.85; S, 11.27;
Found: C, 72.01; H~ 6.84; N~ 9.62; S, 11.270 The-corresponding 9,10-didehydro maleate salt was prepared by dissolving the compound in ether and adding an ; equivalent amount of maleic acid al~o in ether. Maleate salt 20 melted at 159-160C. with decomposition.
Analysis: Calc.: C, 62.98; ~, 6.07; M, 6.99; S, 8.01;
Found: C, 62.99; H, 6.13; N, 6.787 S, 7.~6.
Example 4 Following the procedure of Example 2, thioacetic acid (as the sodium salt) was rPacted wi~h D-6-methyl-8-mesyloxy-methylergoline in DMF solution to yield D-6-methyl-8-acetyl-mercaptomethylergoline which was isolated and purified by ~he procedure of that example. Chromatography of the cruae product over "Florisil" using chlorofonm containing 2 percent 30 ethanol as eluent yielded purified D-6-methyl-8-acetylmer-X-42~8 13 ,~
. . .
~'7~6~3 captomethylergoline MP=153-5C. wlth decomposition.
Analysis: Calc.: C, 68.75; H, 7.05; N, 8.91; S, 10.20;
- Found: C, 68.70; il, 7.22; N, 8.62; S, 10.47.
Following the above procedure, D-6-methyl-8~acetyl-mercaptomethyl-9,10-didehydroergollne was prepared from the corresponding 8-mesyloxymethyl compound. The purified com-pound thus prepared melted in the range 165-7C. with de-composition after recrystallization from an ether-hexane solvent mixture.
Analysis: Calc.: C, 69.20; H, 6.45; N, 8.97; S, 10,26;
Found: C, 69.48; H, 6.71; N, 9.00; S, 10.56.
The corresponding 9,10-didehydro maleate salt wa~
prepared by dissolving the base in ether and adding an equivalent amount of maleic acid in ether. The maleate salt melted at 178-9C. with decomposition.
Analysis: Calc.: C, 61.67; H, 5.65; N, 6.54; S, 7.48;
Found: C, 61.95; H, 5.50; N, 6.84; S, 7.63.
D~2-chloro-6-methyl-8-acetylmercaptomethylergoline was also prepared by the above procedure. Recrystallization 20 of the residue remaining after combining fractions from chromatography shown to contain D-2-chloro-6~methyl-8-acetyl-mercaptomethylergoline by thin layer chromatography, using a solvent mixture of ether and hexane for recrystallization yielded purified material melting at 140-1C.
Analysis: Calc.: C, 61.97; H, 6.07; N, 8.03; S, 9.19;
Cl, 10.16;
Found: C, 61.75; H, 5.78; N, 7.75; S, 9.41;
Cl, 10.32.
Example 5 A reaction mixture containing 1.0 g. of D-6-methyl-. . ~. ' . ' 8-acetylmercaptomethyler~oline (from Example 4), 100 ml. of ethanol and 100 ml. of 4N aqueous hydrochloric acid was re-fluxed under a nitrogen atmosphere ~or fi~e and one~half hours. The reaction mixture was cooled and made basic with an excess of 14N ammonium hydroxide. The aqueous alkaline layer was extracted with chloroform, and the chloroform yielded a residue comprising D-6-methyl-8-mercaptomethylergoline formed in the above reaction. The residue was chromatographed over 75 g, of "Florisil" using chloroform containing 5 percent ethanol 10 as the eluant. D-6-methyl-8-mercaptome~hylergoline was identified in chromatographic fractions by thin layer chroma-tograph~ as a more polar, and therefore more slowly moving, material than starting material. Fractions containing D-6-methyl-8-mercaptomethylergoline were combined and recrystallized from ethanol. The compound thus purified melted at 255-7C.
with decomposition.
Analysis: Calc.: C, 70.55; H, 7.40; N, l0.?8; s, 11.77;
Found: C, 70.31; H, 7.65; N, 10.-04; S, 12.00.
The above procedure was repeated except that methyl-20 mercaptan wa~ used in place of thioacetic acid for reaction wlth D-2-chloro-6-methyl-8-mesyloxymethylergoline to form D-2-chloro-6-methyl-8-methylmercaptomekhylergoline. Chroma-tography over "Florisil" of the residue obtained by combiningchromatographic fractions 5hown to contain the desired material u~ing an ether-hexane mixture for recry~tallization yielded purified D-2-chloro-6-methyl~8-me~hylmercaptomethylergoline melting at 194-5C.
' ,: ' ' , '. ' ~07~ 3 Analysis: Calc.: C, 63.63; }I, 6.60i N, 8.73; S, 9.99;
Cl, 11.05;
; Found: C, 63.42; H, 6.55; N, 8.47; S, 10.12;
Cl, 11 . 35 .
~, '.
, . . ' . . .
Claims (14)
1. A process for the preparation of a compound of the formula (II) wherein R is H, , phenyl, or alk;
R1 is H, C1, or Br;
alk is Cl-C3 alkyl; and the dotted line represents the optional presence of a double bond, or a non-toxic, pharmaceutically-acceptable acid addition salt thereof, which comprises reacting a compound of the formula (III) wherein R1 and the dotted line are defined as before; and R2 is a methanesulfonyl or p-tolueneul-fonyl group, with a nucleophilic reagent of the formula HSR3 (IV) wherein R3 is , phenyl, or alk, followed by hydrolysis when R3 is and the compounds of formula (II) wherein R is H are desired.
R1 is H, C1, or Br;
alk is Cl-C3 alkyl; and the dotted line represents the optional presence of a double bond, or a non-toxic, pharmaceutically-acceptable acid addition salt thereof, which comprises reacting a compound of the formula (III) wherein R1 and the dotted line are defined as before; and R2 is a methanesulfonyl or p-tolueneul-fonyl group, with a nucleophilic reagent of the formula HSR3 (IV) wherein R3 is , phenyl, or alk, followed by hydrolysis when R3 is and the compounds of formula (II) wherein R is H are desired.
2. The process according to claim 1 wherein R is , phenyl or alk, and R3 is , phenyl or alk.
3. The process for the preparation of D-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline which comprises reacting D-6-methyl-8-mesyloxymethyl-9,10-didehydroergoline with thiophenol.
4. The process for the preparation of D-6-methyl-8-methylmercaptomethyl-9,10-didehydroergoline which comprises reacting D-6-methyl-8-mesyloxymethyl-9,10-didehydro-ergoline with methylmercaptan.
5. The process for the preparation of D-6-methyl-8-methylmercaptomethylergoline which comprises reacting D-6-methyl-8-mesyloxymethylergoline with methanethiol.
6. The process for the preparation of D-6-methyl-8-acetylmercaptomethylergoline which comprises reacting D-6 methyl-8-mesyloxymethylergoline with sodium thioacetate.
7. The process for the preparation of D-6-methyl-8-mercaptomethylergoline which comprises reacting D-6-methyl-8-mesyloxymethylergoline with sodium thioacetate to yield D-6-methyl-8-acetylmercaptomethylergoline followed by hydrolysis.
8. A compound of the formula (II) wherein R is H, , phenyl, or alk;
R' is H, Cl, or Br;
alk is Cl-C3 alkyl; and the dotted line represents the optional presence of a double bond, or a non-toxic, pharmaceutically-acceptable acid addition salt thereof, whenever prepared by the process of claim 1.
R' is H, Cl, or Br;
alk is Cl-C3 alkyl; and the dotted line represents the optional presence of a double bond, or a non-toxic, pharmaceutically-acceptable acid addition salt thereof, whenever prepared by the process of claim 1.
9. A compound of the formula (II) wherein R is C-alk, phenyl, or alk;
R' is H, Cl, or Br;
alk is Cl-C3 alkyl; and the dotted line represents the optional presence of a double bond,or a non-toxic, pharmaceutically-acceptable acid addition salt thereof, whenever pre-pared by the process of claim 2.
R' is H, Cl, or Br;
alk is Cl-C3 alkyl; and the dotted line represents the optional presence of a double bond,or a non-toxic, pharmaceutically-acceptable acid addition salt thereof, whenever pre-pared by the process of claim 2.
10. D-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline, whenever prepared by the process of claim 3.
11. D-6-methyl-8-methylmercaptomethyl-9,10-didehydroergoline, whenever prepared by the process of claim 4.
12. D-6-methyl-8-methylmercaptomethylergoline, whenever prepared by the process of claim 5.
13. D-6-methyl-8-acetylmercaptomethylergoline, whenever prepared by the process of claim 6.
14. D-6-methyl-8-mercaptomethylergoline, whenever prepared by the process of claim 7.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US477136A US3901894A (en) | 1974-06-06 | 1974-06-06 | 8-thiomethylergolines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071623A true CA1071623A (en) | 1980-02-12 |
Family
ID=23894677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA228,332A Expired CA1071623A (en) | 1974-06-06 | 1975-06-03 | 8-thiomethylergolines |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US3901894A (en) |
| JP (1) | JPS582946B2 (en) |
| AR (1) | AR210736A1 (en) |
| AT (1) | AT344333B (en) |
| AU (1) | AU507574B2 (en) |
| BE (1) | BE829887A (en) |
| BG (1) | BG24812A3 (en) |
| CA (1) | CA1071623A (en) |
| CH (1) | CH617196A5 (en) |
| CS (1) | CS199591B2 (en) |
| DD (1) | DD120438A5 (en) |
| DE (1) | DE2524575A1 (en) |
| DK (1) | DK144160C (en) |
| ES (1) | ES438313A1 (en) |
| FR (1) | FR2273542A1 (en) |
| GB (1) | GB1505296A (en) |
| HU (1) | HU173590B (en) |
| IE (1) | IE41474B1 (en) |
| IL (1) | IL47424A (en) |
| NL (1) | NL180911C (en) |
| PH (1) | PH10992A (en) |
| PL (1) | PL95738B1 (en) |
| RO (1) | RO77543A (en) |
| SE (1) | SE420095B (en) |
| SU (1) | SU613724A3 (en) |
| YU (1) | YU145575A (en) |
| ZA (1) | ZA753638B (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4147789A (en) * | 1974-03-14 | 1979-04-03 | Sandoz Ltd. | 6-Methyl-8-thiomethyl-ergolene derivatives |
| US3959288A (en) * | 1974-12-13 | 1976-05-25 | Eli Lilly And Company | 8-Oxymethylergolines and process therefor |
| JPS5283894A (en) * | 1976-01-01 | 1977-07-13 | Lilly Co Eli | 88thiomethyl ergoline |
| GB1549829A (en) * | 1976-05-26 | 1979-08-08 | Farmaceutici Italia | 10'-methoxy-1',6'-dimethylergoline-8'-beta-methyl-amino(or thio)-pyrazines |
| IT1192260B (en) * | 1977-07-05 | 1988-03-31 | Simes | ERGOLINE-2-THIOETHERS AND THEIR SULPHOXIDES DERIVATIVES |
| US4166182A (en) * | 1978-02-08 | 1979-08-28 | Eli Lilly And Company | 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4180582A (en) * | 1978-02-08 | 1979-12-25 | Eli Lilly And Company | 6-n-Propyl-8-methoxy-methyl or methylmercaptomethylergolines and related compounds as prolactin inhibitors and to treat Parkinson's syndrome |
| US4202979A (en) * | 1979-01-11 | 1980-05-13 | Eli Lilly And Company | 6-Ethyl(or allyl)-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4246265A (en) * | 1979-10-01 | 1981-01-20 | Eli Lilly And Company | 6-n-Propyl-8α-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4382940A (en) * | 1979-12-06 | 1983-05-10 | Farmitalia Carlo Erba S.P.A. | Ercoline derivatives and therapeutic compositions having CNS affecting activity |
| DE3216870A1 (en) * | 1982-05-03 | 1983-11-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | PHARMACEUTICAL PREPARATIONS WITH A CYTOSTATIC EFFECT |
| FR2526797A1 (en) * | 1982-05-12 | 1983-11-18 | Roussel Uclaf | NOVEL 9-OXALYSERGIC ACID DERIVATIVES, THEIR SALTS, PREPARATION METHOD, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME |
| CH649998A5 (en) * | 1982-08-09 | 1985-06-28 | Sandoz Ag | ERGOL DERIVATIVES, A METHOD FOR THEIR PRODUCTION AND HEALING AGENTS, CONTAINING THESE ERGOL DERIVATIVES AS AN ACTIVE SUBSTANCE. |
| GB8427536D0 (en) * | 1984-10-31 | 1984-12-05 | Lilly Industries Ltd | Ergoline derivatives |
| US4675322A (en) * | 1984-12-10 | 1987-06-23 | Eli Lilly And Company | 1-Substituted-6-n-propyl-8β-methylthio-methylergolines |
| US4801712A (en) * | 1985-06-24 | 1989-01-31 | Eli Lilly And Company | 2-Alkyl(or phenyl)thio-6-n-alkylergolines are dopamine D-1 antagonists without D-2 agonist activity |
| FR2589734B1 (en) * | 1985-11-13 | 1988-09-02 | Roussel Uclaf | USE OF ERGOLIN DERIVATIVES FOR OBTAINING A GERIATRIC MEDICINE |
| HU196394B (en) * | 1986-06-27 | 1988-11-28 | Richter Gedeon Vegyeszet | Process for preparing 2-halogenated ergoline derivatives |
| ES2325880T3 (en) | 2001-06-08 | 2009-09-23 | Ipsen Pharma | CHEMICAL ANALOGS OF SOMATOSTATINA-DOPAMINA. |
| DE60324776D1 (en) * | 2002-03-15 | 2009-01-02 | Antibioticos Spa | PROCESS FOR SYNTHESIS OF PERGOLID |
| TWI523863B (en) | 2012-11-01 | 2016-03-01 | 艾普森藥品公司 | Somatostatin-dopamine chimeric analogs |
| US9777039B2 (en) | 2012-11-01 | 2017-10-03 | Ipsen Pharma S.A.S. | Somatostatin analogs and dimers thereof |
| US20190374534A1 (en) | 2018-06-08 | 2019-12-12 | Boehringer Ingelheim Vetmedica Gmbh | Liquid pharmaceutical compositions comprising pergolide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH507248A (en) * | 1967-03-16 | 1971-05-15 | Spofa Vereinigte Pharma Werke | Process for the preparation of D-6-methylergolin (I) ylacetic acid |
| DE1935556A1 (en) * | 1969-07-12 | 1971-01-21 | Hoechst Ag | Process for the production of lysergol |
| JPS5012398A (en) * | 1973-06-08 | 1975-02-07 |
-
1974
- 1974-06-06 US US477136A patent/US3901894A/en not_active Expired - Lifetime
-
1975
- 1975-05-16 JP JP50059191A patent/JPS582946B2/en not_active Expired
- 1975-06-03 HU HU75EI623A patent/HU173590B/en unknown
- 1975-06-03 NL NLAANVRAGE7506584,A patent/NL180911C/en not_active IP Right Cessation
- 1975-06-03 PH PH17225A patent/PH10992A/en unknown
- 1975-06-03 CS CS753882A patent/CS199591B2/en unknown
- 1975-06-03 SE SE7506327A patent/SE420095B/en not_active IP Right Cessation
- 1975-06-03 IE IE1221/75A patent/IE41474B1/en unknown
- 1975-06-03 GB GB23869/75A patent/GB1505296A/en not_active Expired
- 1975-06-03 DE DE19752524575 patent/DE2524575A1/en not_active Ceased
- 1975-06-03 CA CA228,332A patent/CA1071623A/en not_active Expired
- 1975-06-04 IL IL47424A patent/IL47424A/en unknown
- 1975-06-04 DK DK249975A patent/DK144160C/en not_active IP Right Cessation
- 1975-06-04 AU AU81827/75A patent/AU507574B2/en not_active Expired
- 1975-06-04 BG BG7500030188A patent/BG24812A3/en unknown
- 1975-06-04 PL PL1975180897A patent/PL95738B1/en unknown
- 1975-06-05 YU YU01455/75A patent/YU145575A/en unknown
- 1975-06-05 ZA ZA3638A patent/ZA753638B/en unknown
- 1975-06-05 SU SU752140862A patent/SU613724A3/en active
- 1975-06-05 RO RO7582445A patent/RO77543A/en unknown
- 1975-06-05 AT AT427975A patent/AT344333B/en not_active IP Right Cessation
- 1975-06-05 BE BE1006709A patent/BE829887A/en not_active IP Right Cessation
- 1975-06-05 FR FR7517652A patent/FR2273542A1/en active Granted
- 1975-06-06 AR AR259118A patent/AR210736A1/en active
- 1975-06-06 ES ES438313A patent/ES438313A1/en not_active Expired
- 1975-06-06 CH CH731075A patent/CH617196A5/de not_active IP Right Cessation
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1976
- 1976-06-05 DD DD186472A patent/DD120438A5/xx unknown
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