IE41426B1 - 8 -substituted ergoline i derivatives - Google Patents

8 -substituted ergoline i derivatives

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Publication number
IE41426B1
IE41426B1 IE1596/75A IE159675A IE41426B1 IE 41426 B1 IE41426 B1 IE 41426B1 IE 1596/75 A IE1596/75 A IE 1596/75A IE 159675 A IE159675 A IE 159675A IE 41426 B1 IE41426 B1 IE 41426B1
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IE
Ireland
Prior art keywords
compound
carbon atoms
formula
methyl
hydrogen
Prior art date
Application number
IE1596/75A
Other versions
IE41426L (en
Original Assignee
Sandoz Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from CH998374A external-priority patent/CH605936A5/en
Priority claimed from CH1103174A external-priority patent/CH605938A5/en
Application filed by Sandoz Ltd filed Critical Sandoz Ltd
Priority to IE2047/78A priority Critical patent/IE41427B1/en
Priority to IE2048/78A priority patent/IE41428B1/en
Publication of IE41426L publication Critical patent/IE41426L/en
Publication of IE41426B1 publication Critical patent/IE41426B1/en

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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
    • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
    • 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
    • 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
    • C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
    • C07D457/12—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

8?-ERGOLINE I COMPOUNDS This invention provides new compounds of formula I, I wherein X is hydrogen, chlorine or bromine, R1 is methyl or ethyl, and R2 is CH2-CN, or a group NR3R4, wherein R3 is hydrogen or alkyl of 1 to 4 carbon atoms, and R4 is formyl, alkanoyl of 2 to 5 carbon atoms in the aggregate thereof, alkoxycarbonyl of 2 to 5 carbon atoms in the aggregate thereof, mono- to trihalogenalkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by halogen in a position other than .alpha. to the oxygen, or the radical SO2R5, wherein R5 is alkyl of 1 to 4 carbon atoms, monoto tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosubstituted by halogen or alkoxy of 1 to 4 carbon atoms, or a group NR6R7, wherein each of R6 and R7 is independently hydrogen or alkyl of 1 to 4 carbon atoms, or R6 and R7 together are one of the groups (CH2)n or (CH2)2-A-(CH2)2, wherein n is a number from 3 to 7, and A is oxygen, sulphur or nitrogen substituted by alkyl of 1 to 4 carbon atoms or phenyl, useful as prolactin secretion agents and antiparkinson agents.

Description

The present invention provides new compounds of formula I, wherein X is hydrogen, chlorine or bromine, R^ is methyl or ethyl, and R2 is CH2~CN, or a group NR^R^, wherein R^ is hydrogen or alkyl of 1 to 4 carbon atoms , and R^ is formyl, alkanoyl of 2 to 5 carbon atoms in the aggregate thereof, alkoxycarbonyl of 2 to 5 carbon atoms in the aggregate thereof, mono- to trihalogenalkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by halogen in a position other than a - 2 to the oxygon, or the radical SO^Rg, wherein Rg 1b alkyl of 1 to 4 carbon atonia, mono- to trihalogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosubstituted by halogen or alkoxy of 1 to 4 carbon atoms, or a group NR.R_, b 7 wherein each of Rg and R? is independently hydrogen or alkyl of 1 to 4 carbon atoms, or Rg and R? together are one of the groups (CH2)n or (CH2)2-A-(CH2)2 wherein n is a number from 3 to 7, and A is oxygen; sulphur; or nitrogen substituted by alkyl of 1 to 4 carbon atoms or phenyl with the proviso that when R^ is methyl and X is hydrogen, then R2 is other than cyanomethyl and other than N,N~dimethylsulphamoylamino.
X .preferably signifies chlorine, especially hydrogen. R,j. especially denotes methyl.
Rg especially signifies hydrogen, methyl or ethyl, preferably hydrogen.
When the radical R^ or Rg has a halogen substituent, this signifies fluorine, chlorine or bromine. When the radical R^ or Rg is di- or trihalogenated, the halogen substituents of these radicals are preferably identical.
The preferred radicals R^ are methoxycarbonyl, - 3 thoxycarbonyl, (2,2,2-tri-halogenalkoxy)carbonyl or the group s°2R5 Preferably wherein R^ is alkyl or phenyl.
Any halogen substituents in the radical R^ especially signify fluorine or chlorine.
When Rg is alkyl of 1 to 4 carbon atoms or mono- to tri-halogenalkyl of 1 to 4 carbon atoms, these radicals preferably contain 1 or 2 carbon atoms.
When Rg is phenyl monosubstituted by alkoxy of 1 to 4 carbon atoms, the alkoxy substituent especially contains 1 or 2, preferably 1 carbon atom .
Rj. preferably signifies methyl, phenyl, pyridyl or a group NR,R_.
O Z When both of Rg and R? are alkyl of 1 to 4 carbon atoms, each of these groups preferably contains 1 or 2 carbon atoms. n is preferably 5.
A especially signifies oxygen, or nitrogen substituted by methyl or phenyl.
NRgR? preferably signifies amino, dimethylamino, 2o diethylamino or the 4-methyl-l-piperazinyl group.
Further, in accordance with the invention a compound of formula I may be obtained by a process comprising - 4 <1426 wherein X and R^ are as defined above, with the proviso that when P^ is methyl X is other than hydrogen, by exchanging the radical Z for a cyano group in a compound of formula II, wherein Z is a radical capable of being exchanged in a nucleophilic substitution reaction, and X and are as defined above, with the pro viso that whi hydrogen, or viso that when R^ is methyl X is other than - 5 h) producing a compound of formula lb, wherein X. R,, R and R, are as defined above, with the '' 1 3 4 proviso that when R^ is methyl and X is hydrogen NR^R^ is other than Ν,Ν-dimethylsulphamylamino, by acylating a compound of formula III, III wherein X, R^ and R^ are as defined above, with a reactive functional derivative of an acid R^OH, wherein R^ is as defined above, subject to the proviso defined above with respect to formula lb. - 6 41436 The reaction of a compound of formula II for obtaining a compound of formula la [process a)] and the reaction of a compound of formula III to obtain a compound of formula lb [process b)] may be effected in accordance with known methods.
The radical Z in the compounds of formula II may, for example, signify halogen such as chlorine or bromine, or an aliphatic or aromatic sulphonyloxy radical, preferably the mesyloxy or the g-tosyloxy radical. The reaction may, for example, be effected by reacting a compound of formula II with a cyano group donor, e.g. an alkali metal cyanide such as sodium or potassium cyanide.
The reaction is preferably effected in solution.
It is convenient to use aprotic solvents such as dimethyl formamide, hexamethylphosphoric acid triamide or acetonitrile, if necessary in admixture with a small portion of water.
The reaction is preferably effected with heating, e.g. to 50-100°C.
Process b) is an N-acylation process. The following reactive functional derivatives of R^OH may, for example, be used for the introduction of the radical R^ in a compound of formula III: for the introduction of the formyl radical the mixed anhydride of formic acid with acetic acid, for the introduction of the remaining radicals R^ a halide corresponding to the acid, e.g. the acid chloride or acid bromide, - 7 ~nd for the introduction of an alkanoyl radical the corresponding anhydrides [(alkanoyl)20].
Process b) is conveniently effected in solution. Suitable solvents are, for example, methylene chloride and dioxane. When an anhydride is used as acylating agent it is also possible to use an excess of anhydride as solvent.
The reaction is generally conveniently effected at a reaction temperature between -10°C and about room temperature. However, the N-formylation with the mixed anhydride of acetic acid and formic acid is conveniently effected at a slightly elevated temperature, e.g. 4O-6O°C.
Process b) is conveniently effected in the presence of a tertiary base such as triethylamine, or preferably in the presence of pyridine or a homologue thereof.
The compounds obtained in accordance with processes a) and b) may be obtained in the form of a base or in the form of acid addition salts thereof. Acid addition salt forms may be produced from the free bases in known manner 20 and vice versa.
The starting materials are known or may be produced in accordance with known methods, e.g. as described in the Examples.
In the following non-limitative Examples all tempera tures are indicated in degrees Centigrade. - 8 41436 EXAMPLE 1; 6-ethyl-Sa-cyano-methyl ergoline I 3.35 g (10 millimols) of 6-ethyl-8ra-mesyloxymethyl ergoline 1 are dissolved in 20 co of dimethyl formamide, and a solution of 3.25 g of potassium cyanide (50 millimols) in 4 cc of water is added. After standing at 80° for 48 hours, the reaction solution is poured into an excess of 2N sodium carbonate solution, the precipitate is filtered off, dried in the air and subsequently chromatographed on 150 g of aluminium oxide activity II-III. The title compound is eluted with 0.2% of methanol in methylene chloride and crystallizes from methanol (M.P.182°).
The 6-ethyl-8a-mesyloxymethyl ergoline I, required as starting material may be obtained as follows: 8 (a) 100 g of 6-demethyl-6-ethyl-Z\ ' -lysergic acid methyl ester are dissolved in 900 cc of dimethyl . formamide while heating, dilution is effected with 1.5 litres of glacial acetic acid, and after the addition of 10 g of platinum oxide, hydrogenation is effected at +40-50° and normal pressure until the take up of hydrogen stops. The catalyst is filtered off and the filtrate is further hydrogenated under the above conditions after the addition of 5 g of platinum oxide. Working up is effected by filtering and evaporating the filtrate to dryness. The resulting resin is dissolved in 1.5 litres of methylene chloride containing 5% of methyl alcohol, the solution is stirred well with 20 g of active charcoal, - 9 4442® filtration is effected, after cooling well, it is slowly covered with a layer of one litre of 2N sodium carbonate solution and carefully shaken. The aqueous phase is again extracted twice with 500 co of methylene chloride. After drying the organic phase over sodium sulphate and concentrating to about 1/5 of the original volume, dilution with about 500 cc of ether and scratching are effected. After standing at 0° for 2 hours 6-demethyl-6-ethyl-9,10-dihydroisolysergic acid methyl ester I crystallizes. (b) 38 g of lithium aluminium hydride are suspended in 2.5 litres of absolute tetrahydrofuran under nitrogen, cooling is effected to 0°, and a solution of 200 g of the product of step a) in 2,5 litres of absolute tetrahydrofuran is added dropwise within 15 minutes while stirring vigorously. The reaction product is subsequently diluted with 2.5 litres of absolute tetrahydrofuran and stirred for a further 30 minutes. Working up is effected by the careful successive dropwise addition of 100 cc of ethyl acetate, 100 cc of methanol and 50 cc of water. Dilution is sub20 sequently effected with 2 litres of 30% methanol in methylene chloride and filtration is effected. The residue is again boiled out 4 times with 1 litre amounts of 30% methanol in methylene chloride. After concentration and crystallization from methanol,the combined filtrates yield 6-demethyl-625 ethyl-9,10-dihydro-isolysergol I. (c) 100 g of the product of step b) are suspended in 500 cc of absolute pyridine and 1.1 litres of absolute - 10 41436 acetonitrile, and a solution of 80 cc of methane-sulphochloride in 200 cc of absolute acetonitrile is added dropwise at 0° while stirring. After removing the cooling bath, the reaction mixture is stirred for a further hour at room temperature , whereby a yellowish precipitate results. Working up is effected by again cooling to 0° and adding a 2N ammonia solution until an alkaline reaction is obtained. After scratching, 6-ethyl-8a-methane-sulphonyloxymethyl ergoline I crystallizes.
The following compound of formula la is obtained in a manner analogous to that described in process a) above, by using the corresponding compound of formula II (Z = mesyloxy): Ex.Nr. XR1 M.P. 2 ClCH3 of the hydrochloride 267-268° EXAMPLE 3; 6-methyl8a-sulphamylan)lno ergoline I millimols of 6-methyl-8a-amino ergoline I are dissolved in a mixture of 200 cc of methylene chloride and 2o 25 cc of absolute pyridine, and a solution of 25 millimols of sulphamyl chloride in 25 cc of methylene chloride is added dropwise with stirring at room temperature. After stirring for 12 hdurs, working up is effected as described in Example 1. The orange red crude base is chromatographed on a 50-fold quantity of silica gel, to purify the title compound. - 11 The following compounds of formula lb are obtained in a manner analogous to that described in Example 3, by acylating the corresponding compounds of formula III with the acid chloride: Ex.Nr. XR1R3R4 M.P. 4 HCH3 HCO2C2H5 1 frow.1200 (dec.) (base) ' (a]‘° = -29° j (o = 0,35; dinethyl formamide) 10 5 HCH3 HCO2CH3 of the hydrochloride: 279-280° I 6 HCH3 H COC(CH3)3 of the base: 199-200° 7 HCH3 H 117-119° 15 8 HCH3 H so2nh-c(ch3 9 10 H HCH3 CK3 H H vQ /~y S0--N NCI a EXAMPLE 11: 6-methyl-8ct-formylamino erqoline I 2.41 g (10 millimols) of 6-methyl-8oc-amino ergoline 20 I are dissolved in 5 cc of formic acid, and 5 cc of acetic anhydride are added dropwise at 50-60° while stirring. After stirring for one hour, gas evolution stops; cooling is subsequently effected to 0°, and the reaction mixture is carefully neutralized with 4N potassium hydroxide solution, and extraction is effected with chloroform containing methanol. - 12 41423 After drying and concentrating the organic phases by evaporation, the title compound crystallizes from ethanol, and is obtained in pure form after recrystallization from methylene chloride/ethanol. 2Ω [a]p = +23° (c = 0.3, pyridine).
EXAMPLE 12: 6-methyl-8«-pivaloylamino ergoline I The process is effected in a manner analogous to that described in Example 6, except that pivalic acid anhydride is used in place of pivalic acid chloride as acylating agent, whereby the title compound, having a M.P. of 199 to 200°, is obtained.
The compounds of formula I exhibit pharmacological activity. In particular, the compounds· exhibit central dopaminergic stimulant activity, as indicated in standard tests, for example according to the principles of U.Ungerstedt Acta Physiol. Scand.Suppl. (1971) 367, 69-93, by an induction of contralateral turning in rats lesioned unilaterally in the substantia nigra by 6-hydroxydopamine and by an induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test: Rats, 180-222 g, are placed in Perspex (Registered Trade Mark) cylinders of 30 cm diameter on a wire grid floor After 30 minutes to allow acclimatisation to the cage, the rats are injected with the compound under investigation.
The behaviour of the rats is observed for 2 minutes at 30 minute intervals for 2 hours and then at 60 minute intervals for a total of up to 7 hours. The degree of stereotyped behaviour observed is assessed using a scoring system based on that described by Costall, Naylor and Olley [Euro.J. Pharmac. 18, 83-94 (1972)].
The scores and criteria are as follows : 1. Intermittent sniffing 2. Persistent sniffing, occasional licking 3. Licking, occasional biting 4. Intense and persistent biting - 14 41436 The compounds are, therefore, indicated for use as central dopaminergic stimulant agents, for example, for treating Morbus Parkinson. For this use an indicated dose from 0.5 to 100 mg, especially 1 - 50 mg, conveniently administered in divided doses 2 t6 4 times a day in unit dosage form containing from 0.1 to 50 mg, or in sustained release form.
The compounds additionally exhibit prolactin secretion inhibition activity as indicated in standard tests , for example, in rats by an inhibition of ovum implantion as follows : The compound under investigation is administered to female rats 5 days after coitus and shown to be sperm positive according to the vaginal smear test. The rats are sacrificed on day 12 and their uteri are examined by means of the Salewski reaction for proof that the nidations process has been interrupted [Arch.exp.Path.Pharm. 247, 367 (1967)].
The compounds are, therefore, indicated for use as prolactin secretion inhibitor agents. For this use an indicated daily dose is 0.05 to 10 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.01 to 5 mg, or in sustained release form.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner, so as to be, for example, a solution or a tablet.
In one group of compounds of formula I as defined above R2 is CH2«CN. In another group of compounds R2 is -NHR, wherein R is formyl, alkanoyl, alkoxycarbonyl or wherein R^ and R^ are alkyl or together are "''CH2^n'"' wherein n is frorn 3 to 5.
In yet another group of compounds X is H, is CH^ and R3 is H.

Claims (5)

WHAT WE CLAIM IS: 1. To 4 carbon atoms,mono- to tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosubstituted by halogen or alkoxy, of 1 to 4 carbon atoms, or a group NRgR?, wherein each of 20 Rg and R? is, independently hydrogen or alkyl of 1 to 4 - 17 carbon atoms, or R. and R_ together are one of the groups (CH.) or ο 7 z n (CH 2 ) 2 -A-(CH 2 ) 2 , wherein 5 n is a number from 3 to 7, and A is oxygen; sulphur; or-nitrogen substituted by alkyl of 1 to 4 carbon atoms or phenyl, with the proviso that when R^ is methyl and X is hydrogen, then R 2 is other than cyanomethyl and other than N,N-dime10 thylsulphamoylamino, which comprises a) producing a compound of formula la, wherein X and R are as defined above, with the proviso that when R^ is methyl X is other than hydrogen, by exchanging 15 the radical Z for a cyano group in a compound of formula II, - 18 41426 wherein Z is a radical capable of being exchanged in a nucleophilic substitution reaction, and X and are as defined above, with the proviso that when R^ is methyl X is other than hydrogen, 5 or b) producing a compound of formula lb, wherein X, R^, R^ and R^ are as defined above, with the proviso that when R^ is methyl and X is hydrogen 1 0 other than Ν,Ν-dimethyl-sulphamoylamino by acylating a 10 compound of formula III, - 19 III wherein X, R^ and Rg are as defined above, with a reactive functional derivative of an acid R^OH, wherein R^ is as defined above, subject to the proviso defined above with respect to formula lb. 5 2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Examples.
1. A process for the production of a compound of formula I, wherein X is hydrogen, chlorine or bromine, 5 R^ is methyl or ethyl, and r 2 is CHj-CN, or a group NR^R^, wherein Rj is hydrogen or alkyl of 1 to 4 carbon atoms , and R^ is formyl, alkanoyl of
2. To 5 carbon atoms in the 10 aggregate thereof, alkoxycarbonyl of 2 to 5 carbon atoms in the aggregate thereof, mono- to trihalogenalkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by halogen in a position other than a to the 15 oxygen, or the radical SO 2 Rg, wherein Rg is alkyl of
3. A compound of formula I, whenever produced by a process according to claim 1 or 2. 10
4. A compound of formula I, as defined in claim 1. 5. A compound of claim 4, wherein Rg is -CHg.CN. 6. A compound of claim 4, wherein Rg is -NRgR^, wherein Rg and R^ are as defined in claim 1. 7. A compound of claim 4, wherein Rg is -NHR, wherein R is 15 formyl or alkanoyl or alkoxycarbonyl as defined in_claim 1 / R 3 8. A compound of claim 4, Wherein R. is -NHSO-N _, II K 4 wherein R^ and R 4 are alkyl of 1 to 4 carbon atoms or together - [CHg] -, wherein n is from 3 to 5. 9. A compound of claim 4, wherein X is hydrogen. 20 10. A compound of claim 4, wherein X is chlorine. - 20 41436 11. A compound of claim 4, wherein X is bromine. 12. A compound of claim 4, wherein R^ is methyl. 13. · A compound of claim 4, wherein R^ is ethyl. 14. A compound of claim 4, wherein R, is formyl or alkanoyl, alkoxycarbonyl or halogenalkoxycarbonyl as defined in claim 1. 15. A compound of claim 4, wherein R^ is SO 2 Rg. 16. A compound of claim 15, wherein Rg is NRgR^. 17. 6-methyl-8a-formylamino ergoline I. 18. 6-methyl-8a-pivaloylamino ergoline I. 19. The compound of claim 5, wherein X is Cl and R^ is ch 3 . 20. The compound of claim 5, wherein X is H and R^ is C 2 H 521. A compound of claim 4, wherein X is H, R^ is CH^ and R 3 is H. 22. The compound Of claim 21, wherein R 4 is co 2 c 2 h 5. 23. The compound of claim 21, wherein R 4 is co 2 ch 3 . 24. The compound of claim 21, wherein R 4 is COC(CH 3 ) 3 . 25. The compound of claim 21, wherein R 4 is CO 2 CH 2 CC1 3· 26. The compound of claim 21, wherein R 4 is so 2 nh 2 . 27. The compound of claim 21, wherein R 4 is SO NH-C(CH-) 28. The compound of claim 21, wherein R 4 is r~”\ so 2 - N 29. The compound of claim 21, wherein E 4 is j / SO -l/ NCH. 2 \_/ 3 - 21 30. A compound according to any one of claims 4 to 29 in free base form. 31. A compound according to any one of claims 4 to 29 in acid addition salt form,
5. 32. A pharmaceutical composition comprising a compound according to any one of claims 4 to 29 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
IE1596/75A 1974-07-19 1975-07-17 8 -substituted ergoline i derivatives IE41426B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
IE2047/78A IE41427B1 (en) 1974-07-19 1975-07-17 6-methyl-8 -cyanomethylergoline i
IE2048/78A IE41428B1 (en) 1974-07-19 1975-07-17 6-methyl-8 -n,n-dimethyl sulphamoylaminoergoline i

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH998374A CH605936A5 (en) 1974-07-19 1974-07-19 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs
CH1103174A CH605938A5 (en) 1974-08-13 1974-08-13 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs

Publications (2)

Publication Number Publication Date
IE41426L IE41426L (en) 1976-01-19
IE41426B1 true IE41426B1 (en) 1980-01-02

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ES (1) ES439548A1 (en)
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GB1573621A (en) * 1976-01-02 1980-08-28 Sandoz Ltd Acylated 6-methyl-8a-amino-ergoline i compounds
DE2656344A1 (en) * 1975-12-23 1977-07-07 Sandoz Ag ERGOLIN DERIVATIVES, THEIR USE AND MANUFACTURING
IT1064473B (en) * 1976-11-24 1985-02-18 Simes 8-BETA-AMINOMETHYLERGOLINE DERIVATIVES ON SULFAMOIL
WO1982000463A1 (en) * 1980-07-25 1982-02-18 Ag Sandoz Ergoline derivatives,method for their preparation,pharmaceutical compositions containing them and their therapeutic application
BE889713A (en) * 1980-07-25 1982-01-25 Sandoz Sa NEW ERGOLIN DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS
CH644606A5 (en) * 1980-09-23 1984-08-15 Sandoz Ag METHOD FOR ISOMERIZING 9,10-DIHYDROLYSE ENERGY DERIVATIVES.
DE3101535A1 (en) * 1981-01-14 1982-08-12 Schering Ag, 1000 Berlin Und 4619 Bergkamen NEW (2-HALOGEN-ERGOLINYL) -N'.N'-DIETHYL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT
JPS58174081A (en) * 1982-04-05 1983-10-13 Mitsubishi Heavy Ind Ltd Ventilator for engine room of ship
CH664568A5 (en) * 1984-01-12 1988-03-15 Sandoz Ag 8-ALPHA ACYLAMINE OERGOLINE.
HU195810B (en) * 1984-12-24 1988-07-28 Sandoz Ag Process for preparing new 8alpha-acyl-amino-ergoline derivatives and pharmaceutical compositions containing such compounds
HUT45248A (en) * 1986-01-24 1988-06-28 Sandoz Ag Process for producing 8alpha-(acylamino)-ergoline derivatives and pharmaceuticals comprising such compounds
AT392945B (en) * 1988-06-27 1991-07-10 Gerhard Mader Ges M B H Ing STORAGE AND TRANSPORTATION CONTAINERS FOR Bulk goods and loose materials
DE4033496A1 (en) * 1990-10-20 1992-04-23 Sandoz Ag NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND USE

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US3218323A (en) * 1965-11-16 Esters of i,g-dimethyl-b-ergolenyl carbamic acid
FR1360618A (en) * 1963-06-17 1964-05-08 Sandoz Sa New urethanes of the lysergic series and their preparation
BE712054A (en) * 1967-03-16 1968-07-15
NL6818658A (en) * 1968-01-18 1969-07-22
AR206772A1 (en) * 1972-07-21 1976-08-23 Lilly Co Eli PROCEDURE TO PREPARE A NEW D-2-HALO-6-METHYL-8-CYANE (CARBOXAMIDE) METHYL ERGOLINE

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FR2282889B1 (en) 1979-08-10
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PH16594A (en) 1983-11-22
MY8100215A (en) 1981-12-31
HK56880A (en) 1980-10-16
FR2282889A1 (en) 1976-03-26
ES439548A1 (en) 1977-06-16
DK313175A (en) 1976-01-20
DE2530577A1 (en) 1976-01-29
IL47735A (en) 1979-11-30
FI61188C (en) 1982-06-10
DK143902C (en) 1982-04-13
GB1517971A (en) 1978-07-19
DE2530577C2 (en) 1990-11-08
DK145542C (en) 1983-05-02
AU505314B2 (en) 1979-11-15
GB1517973A (en) 1978-07-19
IL47735A0 (en) 1975-10-15
JPS5134199A (en) 1976-03-23
DD118635A5 (en) 1976-03-12
AU8316275A (en) 1977-01-20
FI61188B (en) 1982-02-26
NL7508416A (en) 1976-01-21
DK145542B (en) 1982-12-06
IE41426L (en) 1976-01-19
GB1517972A (en) 1978-07-19
MY8100217A (en) 1981-12-31
CA1073452A (en) 1980-03-11
HK56980A (en) 1980-10-16
FI752011A (en) 1976-01-20
DK298980A (en) 1980-07-10

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