US3901894A - 8-thiomethylergolines - Google Patents
8-thiomethylergolines Download PDFInfo
- 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
- Authority
- US
- United States
- Prior art keywords
- methyl
- compound
- acid
- prolactin
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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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)
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 |
PH17225A PH10992A (en) | 1974-06-06 | 1975-06-03 | 6-methyl-8-thiomethylergolines |
GB23869/75A GB1505296A (en) | 1974-06-06 | 1975-06-03 | 8-thiomethylergolines |
CA228,332A CA1071623A (en) | 1974-06-06 | 1975-06-03 | 8-thiomethylergolines |
NLAANVRAGE7506584,A NL180911C (nl) | 1974-06-06 | 1975-06-03 | Werkwijze ter bereiding van farmaceutische preparaten en werkwijze ter bereiding van ergolinederivaten. |
CS753882A CS199591B2 (en) | 1974-06-06 | 1975-06-03 | Process for preparing 8-thimethylergolines |
IE1221/75A IE41474B1 (en) | 1974-06-06 | 1975-06-03 | -thiomethylergolines |
SE7506327A SE420095B (sv) | 1974-06-06 | 1975-06-03 | Analogiforfarande for framstellning av 8-tiometyl-ergoliner |
HU75EI623A HU173590B (hu) | 1974-06-06 | 1975-06-03 | Sposob poluchenija proizvodnykh d-6-metil-8-tiometil-ehrgolina |
DE19752524575 DE2524575A1 (de) | 1974-06-06 | 1975-06-03 | 8-thiomethylergoline |
BG7500030188A BG24812A3 (en) | 1974-06-06 | 1975-06-04 | Method of obtaining 8-thiomethylergolins |
IL47424A IL47424A (en) | 1974-06-06 | 1975-06-04 | 8-thiomethylergolines |
PL1975180897A PL95738B1 (pl) | 1974-06-06 | 1975-06-04 | Sposob wytwarzania nowych 8-tiometyloergolin |
DK249975A DK144160C (da) | 1974-06-06 | 1975-06-04 | Analogifremgangsmaade til fremstilling af 8-thiomethylergoliner |
AU81827/75A AU507574B2 (en) | 1974-06-06 | 1975-06-04 | 8-thiomethyl ergolines |
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 |
BE1006709A BE829887A (fr) | 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 |
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 |
AR259118A AR210736A1 (es) | 1974-06-06 | 1975-06-06 | Procedimiento para obtener nuevos derivados de d-2-halo-6 metil 8-tiometilergolina |
ES438313A ES438313A1 (es) | 1974-06-06 | 1975-06-06 | Un procedimiento para la preparacion de 3-tiometilergolinas. |
CH731075A CH617196A5 (da) | 1974-06-06 | 1975-06-06 | |
DD186472A DD120438A5 (da) | 1974-06-06 | 1976-06-05 |
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 |
---|---|
US3901894A true US3901894A (en) | 1975-08-26 |
Family
ID=23894677
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US477136A Expired - Lifetime US3901894A (en) | 1974-06-06 | 1974-06-06 | 8-thiomethylergolines |
Country Status (27)
Country | Link |
---|---|
US (1) | US3901894A (da) |
JP (1) | JPS582946B2 (da) |
AR (1) | AR210736A1 (da) |
AT (1) | AT344333B (da) |
AU (1) | AU507574B2 (da) |
BE (1) | BE829887A (da) |
BG (1) | BG24812A3 (da) |
CA (1) | CA1071623A (da) |
CH (1) | CH617196A5 (da) |
CS (1) | CS199591B2 (da) |
DD (1) | DD120438A5 (da) |
DE (1) | DE2524575A1 (da) |
DK (1) | DK144160C (da) |
ES (1) | ES438313A1 (da) |
FR (1) | FR2273542A1 (da) |
GB (1) | GB1505296A (da) |
HU (1) | HU173590B (da) |
IE (1) | IE41474B1 (da) |
IL (1) | IL47424A (da) |
NL (1) | NL180911C (da) |
PH (1) | PH10992A (da) |
PL (1) | PL95738B1 (da) |
RO (1) | RO77543A (da) |
SE (1) | SE420095B (da) |
SU (1) | SU613724A3 (da) |
YU (1) | YU145575A (da) |
ZA (1) | ZA753638B (da) |
Cited By (19)
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 |
EP0030351A2 (en) * | 1979-12-06 | 1981-06-17 | 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 |
WO2003078432A2 (en) * | 2002-03-15 | 2003-09-25 | Antibioticos S.P.A. | 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 |
Families Citing this family (4)
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)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5012398A (da) * | 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/ja not_active Expired
- 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 NL NLAANVRAGE7506584,A patent/NL180911C/xx not_active IP Right Cessation
- 1975-06-03 PH PH17225A patent/PH10992A/en unknown
- 1975-06-03 CA CA228,332A patent/CA1071623A/en not_active Expired
- 1975-06-03 SE SE7506327A patent/SE420095B/xx not_active IP Right Cessation
- 1975-06-03 HU HU75EI623A patent/HU173590B/hu unknown
- 1975-06-03 CS CS753882A patent/CS199591B2/cs unknown
- 1975-06-03 DE DE19752524575 patent/DE2524575A1/de not_active Ceased
- 1975-06-04 BG BG7500030188A patent/BG24812A3/xx unknown
- 1975-06-04 PL PL1975180897A patent/PL95738B1/pl unknown
- 1975-06-04 IL IL47424A patent/IL47424A/xx unknown
- 1975-06-04 DK DK249975A patent/DK144160C/da not_active IP Right Cessation
- 1975-06-04 AU AU81827/75A patent/AU507574B2/en not_active Expired
- 1975-06-05 BE BE1006709A patent/BE829887A/xx not_active IP Right Cessation
- 1975-06-05 AT AT427975A patent/AT344333B/de not_active IP Right Cessation
- 1975-06-05 RO RO7582445A patent/RO77543A/ro unknown
- 1975-06-05 SU SU752140862A patent/SU613724A3/ru active
- 1975-06-05 ZA ZA3638A patent/ZA753638B/xx unknown
- 1975-06-05 YU YU01455/75A patent/YU145575A/xx unknown
- 1975-06-05 FR FR7517652A patent/FR2273542A1/fr active Granted
- 1975-06-06 CH CH731075A patent/CH617196A5/de not_active IP Right Cessation
- 1975-06-06 ES ES438313A patent/ES438313A1/es not_active Expired
- 1975-06-06 AR AR259118A patent/AR210736A1/es active
-
1976
- 1976-06-05 DD DD186472A patent/DD120438A5/xx unknown
Patent Citations (2)
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 (33)
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 |
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 |
JPS54115400A (en) * | 1978-02-08 | 1979-09-07 | Lilly Co Eli | 66nnpropyll88methoxymethyl or methylmercapto methylergolenes and their relative compounds |
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 |
EP0003667A1 (en) * | 1978-02-08 | 1979-08-22 | Eli Lilly And Company | Ergoline compounds, their preparation and pharmaceutical compositions containing them |
JPS6363544B2 (da) * | 1978-02-08 | 1988-12-07 | ||
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 |
EP0030351A2 (en) * | 1979-12-06 | 1981-06-17 | FARMITALIA CARLO ERBA S.p.A. | Ergoline derivatives, their preparation and therapeutic composition containing them |
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 |
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 |
US4703050A (en) * | 1985-11-13 | 1987-10-27 | Roussel Uclaf | Methods of inducing neuron protective activity |
US4816587A (en) * | 1986-06-27 | 1989-03-28 | Richter Gedeon Vegyeszeti Gyar Rt. | Process for the preparation of 2-halogenated ergoline derivatives |
EP2062914A2 (en) | 2001-06-08 | 2009-05-27 | Ipsen Pharma | Somatostatin-dopamine chimeric analogs |
CZ305160B6 (cs) * | 2001-06-08 | 2015-05-27 | Ipsen Pharma S.A.S. | Chimérické somatostatin-dopaminové analogy |
US8324386B2 (en) | 2001-06-08 | 2012-12-04 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
US20100179304A1 (en) * | 2001-06-08 | 2010-07-15 | Culler Michael D | Somatostatin-Dopamine Chimeric analogs |
US7019140B2 (en) | 2002-03-15 | 2006-03-28 | Antibioticos S.P.A. | Process for the synthesis of pergolide |
US20050124812A1 (en) * | 2002-03-15 | 2005-06-09 | Walter Cabri | Process for the synthesis of pergolide |
WO2003078432A3 (en) * | 2002-03-15 | 2004-01-15 | Antibioticos Spa | Process for the synthesis of pergolide |
WO2003078432A2 (en) * | 2002-03-15 | 2003-09-25 | Antibioticos S.P.A. | Process for the synthesis of pergolide |
US8952128B2 (en) | 2012-11-01 | 2015-02-10 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
US9603942B2 (en) | 2012-11-01 | 2017-03-28 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
US9731027B2 (en) | 2012-11-01 | 2017-08-15 | 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 |
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