US3901894A - 8-thiomethylergolines - Google Patents

8-thiomethylergolines Download PDF

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Publication number
US3901894A
US3901894A US477136A US47713674A US3901894A US 3901894 A US3901894 A US 3901894A US 477136 A US477136 A US 477136A US 47713674 A US47713674 A US 47713674A US 3901894 A US3901894 A US 3901894A
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United States
Prior art keywords
methyl
compound
acid
prolactin
compounds
Prior art date
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Expired - Lifetime
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US477136A
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English (en)
Inventor
Edmund C Kornfeld
Nicholas J Bach
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Eli Lilly and Co
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Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to US477136A priority Critical patent/US3901894A/en
Priority to JP50059191A priority patent/JPS582946B2/ja
Priority to HU75EI623A priority patent/HU173590B/hu
Priority to NLAANVRAGE7506584,A priority patent/NL180911C/xx
Priority to GB23869/75A priority patent/GB1505296A/en
Priority to CS753882A priority patent/CS199591B2/cs
Priority to DE19752524575 priority patent/DE2524575A1/de
Priority to SE7506327A priority patent/SE420095B/xx
Priority to PH17225A priority patent/PH10992A/en
Priority to IE1221/75A priority patent/IE41474B1/en
Priority to CA228,332A priority patent/CA1071623A/en
Priority to IL47424A priority patent/IL47424A/xx
Priority to DK249975A priority patent/DK144160C/da
Priority to BG030188A priority patent/BG24812A3/xx
Priority to PL1975180897A priority patent/PL95738B1/pl
Priority to AU81827/75A priority patent/AU507574B2/en
Priority to SU752140862A priority patent/SU613724A3/ru
Priority to AT427975A priority patent/AT344333B/de
Priority to YU01455/75A priority patent/YU145575A/xx
Priority to ZA3638A priority patent/ZA753638B/xx
Priority to BE1006709A priority patent/BE829887A/xx
Priority to RO7582445A priority patent/RO77543A/ro
Priority to FR7517652A priority patent/FR2273542A1/fr
Priority to AR259118A priority patent/AR210736A1/es
Priority to CH731075A priority patent/CH617196A5/de
Priority to ES438313A priority patent/ES438313A1/es
Application granted granted Critical
Publication of US3901894A publication Critical patent/US3901894A/en
Priority to DD186472A priority patent/DD120438A5/xx
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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

Definitions

  • lysergic and isolysergic acid are 8- carboxy-(i-methyl-. ⁇ "-ergolines (9. IO- didehydroergolines).
  • the amides oflysergic acid many of which have valuable and unique pharmacologic properties. include the naturally occurring oxytocic alkaloids ergocornine. ergokryptine. ergonovine. ergocristine. ergosinc. ergotamine etc. and synthetic oxytocics such as mcthergine as well as the synthetic hallucinogen lysergic acid diethylamide or LSD
  • the amides of b-methyl-8carhoxyergoline are 8- carboxy-(i-methyl-. ⁇ "-ergolines (9. IO- didehydroergolines).
  • the amides oflysergic acid are 8- carboxy-(i-methyl-. ⁇ "-ergolines (9. IO- didehydroergolines).
  • dihydroergot alkaloids are oxytoeic agents of lower potency and also lower toxicity than the ergot alkaloids themselves.
  • Ergotamine. a A"ergoline. has been used in the treatment of migraine anad recently.
  • both ergocornine and 2-bromoaergokryptine have been shown to be inhibitors of prolactin and of dimethylbenzanthracene (DMBA)-induced tumors in rats. according to Nagasawa and Meites. Proc'. Soc. [:Ivp'rl. Biol. Med. I35. 469 I970 and to Heuson et al.. EllfU/J. J. Cancer. 353 (1970). (See also US. Pat. Nos. 3.752.888 and 3.752.814).
  • D-6-methyl-8-cyanomethylergolinc was first prc pared by Semonsky and eo-workers. ('oll. (bet-Ii. (ht n1. ('ommmL. 33. S77 (1968). and its use in preventing pregnancy in rats was published by the same group in iN'urure, 22l. 66b I969). (See also US. Pat. No. 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 prolactin. [See Seda et al.. Reprod. Fert.. 24.
  • R is H. CN.
  • R is H. Cl. or Br.
  • alk is C -C alkyl
  • R" and R' when taken singly are H; and. when taken together with the carbon atoms to which they are attached. form a double bond.
  • alk in the above formula. comprehending as it does C -C alkyl groups. includes the following radicals: methyl. ethyl. n-propyl and isopropyl.
  • R" and R' are hydrogen. the compounds are generically denominated as D-o-alkyl- R-thiomethyl (or mercaptomethyl) ergolines. When R" and R' are taken together with the carbon atoms to which they are attached to form a double bond. the rcsulting compounds are known generically as D-o-alkyl- S-thiomcthyl or mercaptomethyl-9. I didehydroergolines.
  • Compounds illustrative of the scope of the above formula include the following:
  • R is other than H
  • R is other than H
  • esters use ful as starting materials in the above synthetic procedure include the mesyl (methanesulfonyl). the ptolucnesulfonyl (p-tosyl) and the like esters formed with the hydroxy group of 8-hydroxymethyl-6- methylergoline.
  • the reaction is carried out at room :mpcrature of ifdesired by heating to a temperature in te range from room temperature to l()t)C.
  • the prodcts of the reaction are customarily isolated by stanard techniques and purified by chromatography. prefrably over florisil.
  • the compounds of this invention in :hich R is H are prepared by hydrolysis in base of the orrcsponding compound in which R is
  • the compounds of this invention are white crystaline solids and form pharmaceutically acceptable salts with nontoxic acids. These pharmaeeutically accept- .ble salts are included within the scope of this invenion.
  • Nontoxic acids useful in forming the salts of this nvention include such inorganic acids as hydrochloric icid. nitric acid.
  • phosphoric acid sulfuric acid. hydroiromic acid. hydriodic acid. nitrous acid. phosphorus tcid and the like. as well as non-toxic organic acids in- :luding aliphatic mono and dicarboxylic acids. phenyl- .ubstituted alkanoic acids. hydroxy alkanoic and alkanlioic acids. aromatic acids. aliphatic and aromatic sul- 'onic acids. etc.
  • Such pharmaceutically-aeceptable aalts thus include sulfate. pyrosulfate. bisulfate. sulfite. visulfite. nitrate. phosphate. monohydrogenphosphate. lihydrogenphosphate, metaphosphate.
  • Each male rat received an intraperitoneal injection ol 2.0 mg of reserpine in aqueous suspension 18 hours before administration of the ergoline derivative
  • the purpose ofthe reserpine was to keep prolactin levels uniformly elevated.
  • the derivatives were dissolved in lllfil ethanol at a concentration of it) pg/ml. and were injected intraperitoneally at a standard dose of pglkg.
  • Each compound was administered to a group of ill rats. and a control group of ill intact males received an equitalent amount of it) percent ethanol.
  • One hour after treatment all rats were killed by decapitation. and the serum was collected and assayed for prolactin as previously described. The results were evaluated statistically using Students r test to calculate the level of significance. 1.
  • prolactin level of the treated rats The difference between the prolactin level of the treated rats and prolactin level of the control rats. di vided by the prolactin level of the control rats gives the percent inhibition of prolactin secretion attributable to the compounds of this invention.
  • the table which follows gives prolactin inhibition percentages for a series of compounds coming within the scope of Formula ll above. In the table. column I 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 significance.
  • EXAMPLE I robenzoate. methylbenzoate. dinitrobenzoate. hydroxybcnzoate. methoxybenzoatc. phthalate. terephthalate. benzcnesulfonates. toluenesulfonate. ehlorobenxcne. sulfonate. xylenesulfonate. phenylacetate. phenylpropionate. phenylbutyrate. citrate. lactate. B- hydroxybutyrate. glycollate. malate. tartrate. methanesultonate. propanesulfonates. naphthalene-l-sulfonate and naphthalenc-Z-sulfonatc and like salts.
  • 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 following experiment: Adult male rats of the Spraque' Dawlcy strain weighing about 200 g. were used. All rats were housed in an air-conditioned room with con :rolled lighting (lights on o a.m. pm.) and fed lab :how and water ad libitum.
  • a solution of 2.5 ml. of thiophenol in ml. of DMSO was prepared. 1.1 g. of sodium methylate were added. Next a solution of 700 mg. of D-6-methyl-8 mesyloxymethylergoline in 50 ml. of DMSO was added in drop-wise fashion to the 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 then poured into a saturated aqueous tartaric acid solution. The acidic layer was extracted with chloroform. The chloroform extract was separated and discarded. The acidic layer was then made basic with the excess of l4N ammonium hydroxide. and the resulting alkaline layer extracted with chloroform.
  • the chloroform extract was separated and dried. Evaporation of the chloroform left a residue which was dissolved in ethyl acetate. The ethyl acetate solution was thoroughly washed with water followed by a wash with saturated aqueous sodium chloride solution. The ethyl acetate layer was dried. Removal of the ethyl acetate by evaporation in vacuo yielded a residue comprising D-6-methyl-8- phenylmercaptomethylergoline which was recrystallized from ethanol and melted at l945C. with do composition. The compound was then dissolved in chloroform and chromatographed over florisil (25 g.
  • the corresponding inaleate salt was prepared by dis solving the compound in tetrahydrot'uran and adding an equivalent amount of maleic acid also in tetrahydroluran.
  • lhc maleate salt melted at 1 8 9C. alter rccrystallixation from methanol.
  • Example 2 The resulting product was isolated and purified by the procedure of Example 2 to yield D-6-methyl-8- methylmcrcaptomethylergoline melting at about l535C. Recrystallization of the compound thus ob taincd (omitting the chromatographic purification step of Example 2) from an ether-hexane solvent mixture yielded D-o-rnethyl-8-methy
  • the corresponding maleate salt was prepared by dissolving the compound in ether and adding an equivalent amount of maleic acid also in ether. Maleate salt melted at l59-
  • the corresponding maleate salt was prepared by disolving the base in ether and adding an equivalent mount ofmaleic acid in ether.
  • the maleatc salt melted t l789C. with decomposition.
  • D2-chloro-o-mcthyl-l'lcetylmercaptomethylergoline was also prepared by he above procedure. Recrystallization of the residue emaining after combining fractions from chromatogaphy shown to contain DQ-chlorolw-methyl-8- ectylmcrcaptomcthylergoline by thin layer chroma ography. using a solvent mixture of ether and hexane or recrystallization yielded purified material melting at 40-1C.
  • the ethyl acetate layer was separated and filtered to remove an insoluble purple decomposition product.
  • the ethyl acetate layer was washed with water and with saturated aqueous sodium chloride. and was then dried.
  • the solvent was removed therefrom by evaporation in vacuo.
  • the resulting resi due was chromatographed over 30 g. of florisil using an eluant composed of chloroform containing 15 percent ethanol. Fractions shown to contain D-(i-meIhyLB- thiocyanomcthyl ).10-didehydrocrgolinc (formed in the above reaction] by thin layer chromatography were combined. the solvent removed therefrom.
  • the compounds of this invention are also potentially useful for suppressing the growth of breast adcnocarcinomas in female mammals.
  • D-(Hnethyl-8-thiocyanomethylergolinc has demonstrated an ability to suppress the growth of adcnocarcinomas induced by administration of dimethylbenzanthracene in female rats at a dose level of 1.2 tug/kg.
  • the compound is administered to the female rat suspended in corn oil. although it would also be practicable to administer the compound in the form of a pharmaceutically-acceptable acid addition salt in aqueous solution.
  • R is H. CN.
  • R is H. Cl. or Br.
  • alk is C,C alkyl:
  • R" and R"' when taken singly are H; and, when taken together with the carbon atoms to which they urc attached. form a double bond or u non-toxic. phurmaceuticzillyacceptahlc acid addition sult thercol'.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US477136A 1974-06-06 1974-06-06 8-thiomethylergolines Expired - Lifetime US3901894A (en)

Priority Applications (27)

Application Number Priority Date Filing Date Title
US477136A US3901894A (en) 1974-06-06 1974-06-06 8-thiomethylergolines
JP50059191A JPS582946B2 (ja) 1974-06-06 1975-05-16 ８− チオメチルエルゴリンルイノ セイホウ
NLAANVRAGE7506584,A NL180911C (nl) 1974-06-06 1975-06-03 Werkwijze ter bereiding van farmaceutische preparaten en werkwijze ter bereiding van ergolinederivaten.
GB23869/75A GB1505296A (en) 1974-06-06 1975-06-03 8-thiomethylergolines
CS753882A CS199591B2 (en) 1974-06-06 1975-06-03 Process for preparing 8-thimethylergolines
DE19752524575 DE2524575A1 (de) 1974-06-06 1975-06-03 8-thiomethylergoline
SE7506327A SE420095B (sv) 1974-06-06 1975-06-03 Analogiforfarande for framstellning av 8-tiometyl-ergoliner
PH17225A PH10992A (en) 1974-06-06 1975-06-03 6-methyl-8-thiomethylergolines
IE1221/75A IE41474B1 (en) 1974-06-06 1975-06-03 -thiomethylergolines
CA228,332A CA1071623A (en) 1974-06-06 1975-06-03 8-thiomethylergolines
HU75EI623A HU173590B (hu) 1974-06-06 1975-06-03 Sposob poluchenija proizvodnykh d-6-metil-8-tiometil-ehrgolina
AU81827/75A AU507574B2 (en) 1974-06-06 1975-06-04 8-thiomethyl ergolines
BG030188A BG24812A3 (en) 1974-06-06 1975-06-04 Method of obtaining 8-thiomethylergolins
PL1975180897A PL95738B1 (pl) 1974-06-06 1975-06-04 Sposob wytwarzania nowych 8-tiometyloergolin
IL47424A IL47424A (en) 1974-06-06 1975-06-04 8-thiomethylergolines
DK249975A DK144160C (da) 1974-06-06 1975-06-04 Analogifremgangsmaade til fremstilling af 8-thiomethylergoliner
BE1006709A BE829887A (fr) 1974-06-06 1975-06-05 8-thiomethylergolines
YU01455/75A YU145575A (en) 1974-06-06 1975-06-05 Process for obtaining 8-thiomethyl ergoline
ZA3638A ZA753638B (en) 1974-06-06 1975-06-05 8-thiomethylergolines
SU752140862A SU613724A3 (ru) 1974-06-06 1975-06-05 Способ получени 8-тиометил-эрголинов или их солей
RO7582445A RO77543A (ro) 1974-06-06 1975-06-05 Procedeu de preparare a unor 8-tiometil-ergoline
FR7517652A FR2273542A1 (fr) 1974-06-06 1975-06-05 8-thiomethylergolines
AT427975A AT344333B (de) 1974-06-06 1975-06-05 Verfahren zur herstellung von neuen 8-thiomethylergolinen
CH731075A CH617196A5 (en, 2012) 1974-06-06 1975-06-06
ES438313A ES438313A1 (es) 1974-06-06 1975-06-06 Un procedimiento para la preparacion de 3-tiometilergolinas.
AR259118A AR210736A1 (es) 1974-06-06 1975-06-06 Procedimiento para obtener nuevos derivados de d-2-halo-6 metil 8-tiometilergolina
DD186472A DD120438A5 (en, 2012) 1974-06-06 1976-06-05

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US477136A US3901894A (en) 1974-06-06 1974-06-06 8-thiomethylergolines

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US (1) US3901894A (en, 2012)
JP (1) JPS582946B2 (en, 2012)
AR (1) AR210736A1 (en, 2012)
AT (1) AT344333B (en, 2012)
AU (1) AU507574B2 (en, 2012)
BE (1) BE829887A (en, 2012)
BG (1) BG24812A3 (en, 2012)
CA (1) CA1071623A (en, 2012)
CH (1) CH617196A5 (en, 2012)
CS (1) CS199591B2 (en, 2012)
DD (1) DD120438A5 (en, 2012)
DE (1) DE2524575A1 (en, 2012)
DK (1) DK144160C (en, 2012)
ES (1) ES438313A1 (en, 2012)
FR (1) FR2273542A1 (en, 2012)
GB (1) GB1505296A (en, 2012)
HU (1) HU173590B (en, 2012)
IE (1) IE41474B1 (en, 2012)
IL (1) IL47424A (en, 2012)
NL (1) NL180911C (en, 2012)
PH (1) PH10992A (en, 2012)
PL (1) PL95738B1 (en, 2012)
RO (1) RO77543A (en, 2012)
SE (1) SE420095B (en, 2012)
SU (1) SU613724A3 (en, 2012)
YU (1) YU145575A (en, 2012)
ZA (1) ZA753638B (en, 2012)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3959288A (en) * 1974-12-13 1976-05-25 Eli Lilly And Company 8-Oxymethylergolines and process therefor
US4123613A (en) * 1976-05-26 1978-10-31 Societa Farmaceutici Italia S.P.A. Substituted pyrazines as inhibitors of platelet aggregation
US4147789A (en) * 1974-03-14 1979-04-03 Sandoz Ltd. 6-Methyl-8-thiomethyl-ergolene derivatives
EP0003667A1 (en) * 1978-02-08 1979-08-22 Eli Lilly And Company Ergoline compounds, their preparation and pharmaceutical compositions containing them
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
US4197299A (en) * 1977-07-05 1980-04-08 Simes Societa Italiana Medicinali e Sintetici Anti-hypertensive derivatives of ergoline-2-thioethers and their sulphoxides
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
EP0030351A3 (en) * 1979-12-06 1981-12-02 Farmitalia Carlo Erba S.P.A. Ergoline derivatives, their preparation and therapeutic composition containing them
FR2589734A1 (fr) * 1985-11-13 1987-05-15 Roussel Uclaf Utilisation de derives de l'ergoline a l'obtention d'un medicament a visee geriatrique
US4675322A (en) * 1984-12-10 1987-06-23 Eli Lilly And Company 1-Substituted-6-n-propyl-8β-methylthio-methylergolines
US4720498A (en) * 1984-10-31 1988-01-19 Lilly Industries Limited 2-alkyl-thioergolines and their use for treating anxiety
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
US4816587A (en) * 1986-06-27 1989-03-28 Richter Gedeon Vegyeszeti Gyar Rt. Process for the preparation of 2-halogenated ergoline derivatives
WO2003078432A3 (en) * 2002-03-15 2004-01-15 Antibioticos Spa Process for the synthesis of pergolide
EP2062914A2 (en) 2001-06-08 2009-05-27 Ipsen Pharma Somatostatin-dopamine chimeric analogs
US8952128B2 (en) 2012-11-01 2015-02-10 Ipsen Pharma S.A.S. Somatostatin-dopamine chimeric analogs
US9777039B2 (en) 2012-11-01 2017-10-03 Ipsen Pharma S.A.S. Somatostatin analogs and dimers thereof
WO2019234069A1 (en) 2018-06-08 2019-12-12 Boehringer Ingelheim Vetmedica Gmbh Liquid pharmaceutical compositions comprising pergolide
EP4403230A2 (en) 2014-09-25 2024-07-24 Boehringer Ingelheim Vetmedica GmbH Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283894A (en) * 1976-01-01 1977-07-13 Lilly Co Eli 88thiomethyl ergoline
DE3216870A1 (de) * 1982-05-03 1983-11-03 Schering AG, 1000 Berlin und 4709 Bergkamen Pharmazeutische zubereitungen mit zytostatischer wirkung
FR2526797A1 (fr) * 1982-05-12 1983-11-18 Roussel Uclaf Nouveaux derives de l'acide 9-oxalysergique, leurs sels, procede de preparation, application a titre de medicaments et compositions les renfermant
CH649998A5 (de) * 1982-08-09 1985-06-28 Sandoz Ag Ergolinderivate, ein verfahren zu ihrer herstellung und heilmittel, enthaltend diese ergolinderivate als wirkstoff.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3709891A (en) * 1969-07-12 1973-01-09 Hoechst Ag Manufacture of lysergols
US3732231A (en) * 1967-03-16 1973-05-08 Spofa Vereinigte Pharma Werke D-6-methyl-8-cyano methylergoline (i) and method of making the same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5012398A (en, 2012) * 1973-06-08 1975-02-07

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3732231A (en) * 1967-03-16 1973-05-08 Spofa Vereinigte Pharma Werke D-6-methyl-8-cyano methylergoline (i) and method of making the same
US3709891A (en) * 1969-07-12 1973-01-09 Hoechst Ag Manufacture of lysergols

Cited By (31)

* Cited by examiner, † Cited by third party
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
US4123613A (en) * 1976-05-26 1978-10-31 Societa Farmaceutici Italia S.P.A. Substituted pyrazines as inhibitors of platelet aggregation
US4197299A (en) * 1977-07-05 1980-04-08 Simes Societa Italiana Medicinali e Sintetici Anti-hypertensive derivatives of ergoline-2-thioethers and their sulphoxides
JPS54115400A (en) * 1978-02-08 1979-09-07 Lilly Co Eli 66nnpropyll88methoxymethyl or methylmercapto methylergolenes and their relative compounds
FR2416891A1 (fr) * 1978-02-08 1979-09-07 Lilly Co Eli 6-n-propyl-8-methoxymethyl ou methylmercaptomethylergolines et composes apparentes, et leur utilisation therapeutique
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
US4166182A (en) * 1978-02-08 1979-08-28 Eli Lilly And Company 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds
EP0003667A1 (en) * 1978-02-08 1979-08-22 Eli Lilly And Company Ergoline compounds, their preparation and pharmaceutical compositions containing them
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
EP0030351A3 (en) * 1979-12-06 1981-12-02 Farmitalia Carlo Erba S.P.A. Ergoline derivatives, their preparation and therapeutic composition containing them
US4720498A (en) * 1984-10-31 1988-01-19 Lilly Industries Limited 2-alkyl-thioergolines and their use for treating anxiety
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
US4703050A (en) * 1985-11-13 1987-10-27 Roussel Uclaf Methods of inducing neuron protective activity
FR2589734A1 (fr) * 1985-11-13 1987-05-15 Roussel Uclaf Utilisation de derives de l'ergoline a l'obtention d'un medicament a visee geriatrique
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BE829887A (fr) 1975-12-05
NL180911C (nl) 1987-05-18
DK144160B (da) 1981-12-28
IE41474L (en) 1975-12-06
PH10992A (en) 1977-10-20
AU507574B2 (en) 1980-02-21
JPS50160300A (en, 2012) 1975-12-25
JPS582946B2 (ja) 1983-01-19
YU145575A (en) 1982-02-28
SE7506327L (sv) 1975-12-08
NL180911B (nl) 1986-12-16
FR2273542A1 (fr) 1976-01-02
IE41474B1 (en) 1980-01-16
CA1071623A (en) 1980-02-12
NL7506584A (nl) 1975-12-09
AT344333B (de) 1978-07-10
BG24812A3 (en) 1978-05-12
FR2273542B1 (en, 2012) 1978-10-06
AU8182775A (en) 1976-12-09
AR210736A1 (es) 1977-09-15
RO77543A (ro) 1982-02-26
ES438313A1 (es) 1977-05-16
DE2524575A1 (de) 1975-12-18
HU173590B (hu) 1979-06-28
DD120438A5 (en, 2012) 1976-06-12
IL47424A0 (en) 1975-08-31
IL47424A (en) 1979-11-30
SE420095B (sv) 1981-09-14
PL95738B1 (pl) 1977-11-30
ZA753638B (en) 1977-01-26
CH617196A5 (en, 2012) 1980-05-14
GB1505296A (en) 1978-03-30
DK249975A (da) 1975-12-07
ATA427975A (de) 1977-11-15
SU613724A3 (ru) 1978-06-30
DK144160C (da) 1982-06-07
CS199591B2 (en) 1980-07-31

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