NZ205181A - 2-methyl-lyserg-8-yl ethers and thioethers,a method for their preparation and pharmaceutical compositions which contain them - Google Patents
2-methyl-lyserg-8-yl ethers and thioethers,a method for their preparation and pharmaceutical compositions which contain themInfo
- Publication number
- NZ205181A NZ205181A NZ205181A NZ20518183A NZ205181A NZ 205181 A NZ205181 A NZ 205181A NZ 205181 A NZ205181 A NZ 205181A NZ 20518183 A NZ20518183 A NZ 20518183A NZ 205181 A NZ205181 A NZ 205181A
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- acid addition
- addition salt
- methyl
- phenyl
- Prior art date
Links
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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Description
New Zealand Paient Spedficaiion for Paient Number £05181
2051 81
Priority Date(s): &.3.3P.
Complete Specification Filed:
Class: ..i. jJ.4&
Publication Date: ... .P.}???). P.O. Journal, No: ..J.P.KQ
NO
f 3 (.
W.\} A SA»
No,: Date:
NEW ZEALAND
PATENTS ACT, 1953
COMPLETE SPECIFICATION
ergot alkaloids
*/We, SANDOZ LTD., of 35 Lichtstrasse, CH-4002 Basle, Switzerland, a Swiss Body Corporate,
hereby declare the invention for which X / v/e pray that a patent may be granted tojrHKjfcus, and the method by which it is to be performed, to be particularly described in and by the following staternent:-
* ^ bv la)
5: SI
la
ERGOT ALKALOIDS
This invention relates to ergot alkaloids.
The present invention provides 2-methyl-lyserg-8-yl ethers and thioethers and acid addition salts hereinafter referred to as 5 compounds of the invention.
The compounds of the invention are substituted in the 2 and 8 positions of the ergoline nucleus and may be substituted in any other position. The compounds may exist in isomeric form, ePg. as 8R and 8S isomers.
The invention particularly provides compounds of formula I
CH0-X-R
I
3
m
205181
wherein X is -0- or -S-,
Rj is hydrogen, ((4-4) al kyl or phenyl,
P«2 is (Ci_3)a 1 kyl and
R3 is phenyl or pyridyl, unsubstituted
or monosubstituted or independently di- or tri-substituted by halogen of atomic number from 9 to 35, (Ci_4)alkyl or (C'i_4)alkoxy, or (Ci_4)alkyl,
and acid addition salts thereof.
A compound of the invention may be produced by a process 10 which includes the step of replacing the group Y in a corresponding 8-CH2-Y derivative wherein V is a leaving group with an ether or a thioether radical and recovering the compound as such or es an acid addition salt thereof.
In particular a compound of formula I or an acid addition salt may be produced by a process which includes the step of replacing the group Y in a compound of formula II
ch2-y
II
205181
-3- 1QQ-5QG3
wherein Rj and R2 are as defined above, and Y is a leaving group,
by a group of formula III
-xr3 III
wherein r3 and X are as defined above and recovering the compound of formula I as such or as an acid addition salt thereof.
The above process may be effected in conventional manner. Y may be for example halogen, e.g. chlorine or bromine, or a 10 group of formula -O-so2-R wherein R is lower alkyl or optionally substituted phenyl, containing e.g. up to 10 carbon atoms. Preferably Y is mesyloxy or tosyloxy.
Conveniently the reaction is effected in a solvent, e.g. an inert aprotic polar solvent such as an organic carboxylic acid 15 amide such as dimethyl formamide or hexamethylphosphoric tri-amide or acetonitile. If desired water, preferably in small quantities, may be present.
Suitable reaction temperatures may be elevated temperatures, e.g. from about 50 to about 100°C.
205 181
-4- 100-50G3
Conveniently the reaction is effected in en inert gas atmosphere, e.g. under nitrogen.
Preferably the radical of formula III is introduced by using a compound of formula IV
MXR3 IV
wherein X and R3 are as defined above and
M is hydrogen or preferably an alkali metal.
Conveniently an excess of used. For example from 2 to 10 mole of compound of formula II
a compound of formula III is Mol compound of formula III per may be used.
The side chain in the 8 position in the compound of formula I may have the a or 6 configuration. Any alkyl or alkoxy radical has preferably 2 carbon atoms and especially 1 carbon atom. Halogen is preferably chlorine or bromine. X is preferably S.
is preferably hydrogen. r3 is conveniently unsubstituted pyridyl, preferably 2-pyridyl.
In one group of compounds X is -S-, R^ is hydrogen and r3 is 2-pyridyl.
20518 1
.mn co en
The compounds of the invention may be isolated and purified in conventional manner.
The compounds of the invention may be converted into acid addition salts in conventional manner and vice versa. A suitable 5 acid for salt formation includes hydrochloric acid.
The starting materials may be produced in conventional manner. For example compounds of formula II may be produced by reducing a compound of formula V
v
Compounds of formula V may be produced by reaction of a 10 compound of formula VI
ch2-y n-r.
2
VI
1
with 1,3-dithiane as described in the examples.
2 05 1 81
-6- 1QODGG3
Compounds of formula II may alternatively be produced from the known lysergic acid or 6-homologue thereof, reducing it to the alcohol and then replacing the hydroxyl group by the radical Y.
Insofar the prepration of any particular starting material 5 is not particularly described this is known or may be produced in conventional manner.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected. Optical rotations are at 20° and at the D line with the substance in ethanol/water 1:1 unless otherwise stated.
Abbreviations:
1 = optical rotation in pyridine
2 ~ Decomposition
3 = Hydrochloride
Nomenclature: lysergyl - 9,10-didehydro-6-methylergolin-83-yl-methyl.
205181
-7- 100-5003
EXAMPLE 1: 9,10-didehydro-2,6-dimethy1-83-(2-pyridylthio-methyl)ergoli ne a) 2-(l,3-dithian-2-yl)-lysergyl mesylate
2.9 ml sulfuryl chloride in 15 ml chloroform are added 5 dropwise to a solution of 4.2 g 1,3-dithiane in 100 ml chloroform at -30° within 30 minutes. After the temperature has risen to 20°, the mixture is stirred for 30 minutes at 20°. 7.5 g lysergyl mesylate in 100 ml chloroform are added at -10s. After the temperature has risen to 20°, the mixture is stirred for a 10 further 30 minutes at 20°. To work up the mixture is treated with ice/water, neutralised with 2N sodium carbonate and extracted with methylene chloride containing 10% isopropanol. The extracts are dried with sodium sulphate, filtered and concentrated. The resultant product is chromatographed on silicagel using methyene 15 chloride containing 2% methanol as eluant. to give the heading compound.
b) 2-methyl-lysergyl mesylate
100 nil of a suspension of Raney-Nickel in water is washed four times each with 100 ml dimethylformamide/acetone 1:4. The 20 washed Raney-Nickel is treated under argon with 115 ml dimethylformamide/acetone (1:4), and the stirred suspension is treated at room temperature with a solution of 4.3 g 2-(l,3-di-thian-2-yl)lysergyl mesylate in 80ml dimethylformamide/acetone (1:4). The mixture is stirred for 2 1/2 hours at room 25 temperature, filtered and the filter residue washed twice
205181
100 50G3
each time with 115 ml dimethylformamide/acetone (1:2). The filtrate is concentrated and dried up in a high vacuum to give the crude product which is chromatographed on 90 g silicagel with methylene chloride containing 2% methanol as eluant to give the 5 heading compound as a beige foam.
c) 9,10-d i dehydro-2,6-dimethyl -SB- (2-pyri dyl t h i ornethyl) -ergoline
A solution of 1.3 g 2-methyl-lysergyl mesylate and 2-mercap-topyridine in 20 ml dimethylformamide is treated with 4.5 ml 2N 10 sodium hydroxide and stirred at room temperature. The mixture is stirred with water and extracted with methylene chloride containing 10% isopropanol. The extracts are dried with sodium sulphate, filtered, concentrated and dried in a high vacuum. The crude product is chromatographed on 120 g silicagel with 15 chloroform containing 2% methanol and 0.1% concentrated ammonia to give the heading compound. M.pt. decomp. from 253°,[a] = + 58' (c = 0.37).
205181
The following compounds of formula I having an 88 side chain are produced in analogous manner:-
Example Ri R2 R3 X M.pt. [a]
(c)
2 H C2H5 2-pyridyl S 2102 + 45° (0.435)
-r 5 3 CH3 C2H5 2-pyridyl S 1852 3 + 28° (0.33)
4 Phenyl CH3 2-pyridyl S 191-22 3 + 294° (0.85)
H CH3 p-methyl- S 205-82 + 22° (0.54)1
phenyl
6 H ch3 phenyl S 178-802 + 33° (0.76)1
7 H CH3 p-methyl- 0 173-52 + 39c (0.65)1
phenyl
8 H CH3 CH3 S 288-93 + 92° (0.5)
^ 9 H nC3H7 CH3 S 252-32 3
CH3 CH3 2-pyridyl S 188-923 +49° (0.59)
2 051gI
-10- *100 50G3 /UK
The compounds of the invention are pharmacologically active and are therefore indicated for ase as pharmaceuticals.
The compounds of the invention exhibit antagonistic effects on dopamine receptors as indicated in standard animal tests,
e.g. using the rat brain. Thus, the compounds lead on 5 administration p.o. of about 10 mg/kg to an increase of concentration of the dopamine metabolites,
3,4-dihydroxyphenyl-acetic acid (DOPAC) and homovallinic acid (HVA) in the striatum.
The biochemical parameters may be measured according to the 10 principles of F. Karoum et al., Europ. J. Pharmacol. £4, 311-318,
(1977) and H.R. Biirki et al., Psychopharmacology 227-237
(1978).
At the same doses the activity of tyrosine hydroxylase in vivo is increased according to the method of A.Carlson et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 163-168.
The compounds furthermore antagonise in vitro at about 1 mg/ml the apomorphine effect on electrically-stimulated acetylcholine release in striatum slices of the rat in accordance with the method of R.Markstein, J. Neural. Transmission _51, 39-59 20 (1981).
The compounds are therefore indicated for use as neuroleptics, especially for the treatment of schizophrenia.
2 0 5 1gl
-11- 400 5063
The compounds of the invention also exhibit serotonin agonist activity as indicated in standard animal tests.
For example, the compounds also increase at from about 0.1 to 0.5 mg/ml the electrically induced acetyl choline release in 5 the Hippocampus in the rat.
This is confirmed in the observation test over 6 hours on administration i.p. at from about 30 to about 50 mg/kg in rats or p.o. at from about 3 to about 10 mg/kg body weight in mice wherein the compounds induce a prolongation of the wake phase and 10 an increased reaction to external stimuli, in accordance with the principles described in J.M. Vigouret er. al., Pharmacology, J_6, (Suppl. 1), 1, 156-173 (1978).
The compounds are therefore indicated for use in dementia, especially senile dementia.
The compounds of the invention also exhibit anti-depressant activity as indicated in standard animal tests. For example in the 48 hour chronically implanted rat test effected according to H.Kleinlogel et al., Waking and Sleeping, 1980, 4_, 77-85, the compounds in p.o. administration of from about 3 to about 30 20 mg/kg, lead to a reduction of the paradoxical sleep phase without a significant rebound.
205181
-12- 100-5003
The compounds are therefore additionally .indicated for use as anti-depressants, especially for geriatrics.
The compounds also have a vasoconstricting activity as indicated by a noradrenaline potentiation in the method of 5 E.Mlil ler-Schweinitzer, Naunyn-Schrni edeberg1 s P»rch, Pharmacol.. 292, 113-118 (1976) in vitro on isolated strips of canine Arteria carotis externa at doses of from about 10~10 t0 m / litre.
The compounds are therefore of use as anti-migraine agents and for the treatment of tension headache.
Moreover, the compounds increase the local cerebral glucose utilisation in the sensomotor cortex, e.g. lateral Nucleus habenula, as indicated by the carbon-14-2-deoxyglucose autoradiographic technique with the rat brain on administration i.v. of from about 0.01 to about 0.1 mg/kg or p.o. 10 mg/kg of the 15 compounds [for method see e.g. L.Solokoff, Journal of Cerebral Blocd Flow and Metabolism, 1981, (1), 7-36; H.E. Savaki et al., Brain Research 1982, 233, 347-358, and J. McCulloch et al., Journal of Cerebral Blood Flow and Metabolism 1981, 1, 133-136.
51 8 1
100 5063
The compounds of the invention are thus additionally indicated for use in the treatment of cerebral insufficiency.
For all the above indications an indicated daily dose is from about 1 to about 100 mg conveniently administered in didived doses 2 to 4 times a day in unit dosage form containing about 0.3 to about 50 mg, or in sustained release form.
205181
The present invention provides also a compound of the invention in pharmaceutically acceptable form for use as an antidepressant, neuroleptic, for the treatment of dementia, cerebral 10 insufficiency or migraine.
The preferred indication is senile dementia. The preferred compound is the compound of Example 1.
The compounds of the invention may be administered as such or as the pharmaceutically acceptable acid addition salt 15 thereof. Such acid addition salts exhibit the same order of activity as the free bases. The present invention provides accordingly a pharmaceutical composition 'which comprises a compound of the invention in a pharmaceutically acceptable form in association with a pharmaceutical carrier or diluent. Such 20 compositions may be formulated in conventional manner so as to be for example tablets or solutions.
205ISJ
Claims (25)
1. A process for the production of a 2-methyl-1yserg-8-yl ether or thioether or an acid addition salt thereof which includes the step of replacing the group Y in a correspondng 8-CH2Y 5 derivative wherein Y is a leaving group with an ether or a thioether radical and recovering the compound as such or as an acid addition salt thereof.
2. A process for the preparation of a compound of formula I I wherein X is -0- or -S- 10 R-[ is hydrogen, (Ci_4)alkyl or phenyl R2 is (C.j_3) al kyl and R3 is phenyl or pyridyl, unsubstituted or monosubstituted 15 or independently di- or tri-substituted by halogen of atomic number from 9 to 35, (C^-4) al kyl or (C-^ ..4) -alkoxy, or (Ci_4)alkyl or an acid addition salt thereof, -16- 2051 8 \ 100-5003 which includes the step of replacing the group Y in a compound of 5 Y is a leaving group, by a group of formula III -xr3 III wherein R3 and X are as defined above and recovering the compound of formula I as such or as an acid addition salt thereof. 10
3. A process for the preparation of a 2-methyl-lyserg-S-yl ether or thioether or an acid addition salt thereof substantially as hereinbefore described with reference to any one of the Examples.
4. A 2-methyl-lyserg-8-yl ether or thioether or an acid addition 15 salt thereof. 2 0 518 1 ■100-50G3-
5. A compound of formula I as defined in claim 2 or an acid addition salt thereof,
6. A compound of claim 5 wherein X is sulphur or an acid addition salt thereof. 5
7. A compound of claim 6 wherein R]_ is hydrogen, and R3 is 2-pyridyl or an acid addition salt thereof.
8. A compound of claim 5 wherein r3 is phenyl, unsubstituted or substituted by (Ci_4)alkyl, pyridyl or ((4.4)alkyl and the 8 side chain has the beta configuration or an acid addition salt 10 thereof.
9. 9,10-d i dehydro-2,6-di methyl-813-(2-pyri dy11hiomethy1)ergo line or an acid addition salt thereof.
10. A compound of cl^im 8 wherein R]_, R2, r3 and X are respectively H, C2H5, 2-pyridyl, S, or an acid addition salt 15 thereof.
11. A compound of claim 8 wherein R}, R2, r3 and X are respectively ch3, C2H5, 2-pyridyl, S, or an acid addition salt thereof. -18- 20 51 81 100-5063
12. A compound of claim 8 wherein Ri, R2, R3 and X are respectively phenyl, ch3. 2-pyridyl, S, or an acid addition salt thereof.
13. A compound of claim 8 wherein Ri, R2, r3 ana X are 5 respectively H, CH3, p-methyl-phenyl, S, or an acid addition salt thereof.
14. A compound of claim 8 wherein Ri, R2, R3 and X are respectively H, CH3, phenyl, S, or an acid addition salt thereof.
15. A compound of claim 8 wherein Rj, R2, R3 and X are 10 respectively H, ch3, p-methyl-phenyl, 0, or an acid addition salt thereof.
16. A compound of claim 8 wherein Rj, Ro, R3 and X are respectively H, ch3, ch3, S, or an acid addition salt thereof.
17. A compound of claim 8 wherein Ri, R2, R3 and X are 15 respectively H, nC3H7, CH3, S, or an acid addition salt thereof.
18. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use as a pharmaceutical.
19. A compound of any one of claims 4 to 17 or a pharmaceutically 20 acceptable acid addition salt thereof for use as a neuroleptic. zosm -19-
20. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use in the treatment of cerebral insufficiency.
21. A compound of any one of claims 4 to 17 or a pharmaceutically 5 acceptable acid addition salt thereof for use against migraine.
22. A compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof for use as a vasoconstricting agent.
23. A compound of any one of claims 4 to 17 or a pharmaceutically 10 acceptable acid addition salt thereof for use against dementia.
24. A pharmaceutical composition comprising a compound of any one of claims 4 to 17 or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or d i1uent. 15
25. A compound of formula II as defined in claim 2. or Al & son AGLETS KCfl 7lii£ APPLICANTS
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH4772/82A CH649998A5 (en) | 1982-08-09 | 1982-08-09 | ERGOL DERIVATIVES, A METHOD FOR THEIR PRODUCTION AND HEALING AGENTS, CONTAINING THESE ERGOL DERIVATIVES AS AN ACTIVE SUBSTANCE. |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ205181A true NZ205181A (en) | 1986-07-11 |
Family
ID=4282273
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ205181A NZ205181A (en) | 1982-08-09 | 1983-08-08 | 2-methyl-lyserg-8-yl ethers and thioethers,a method for their preparation and pharmaceutical compositions which contain them |
Country Status (23)
Country | Link |
---|---|
JP (1) | JPS5948480A (en) |
AT (1) | AT383125B (en) |
AU (1) | AU563736B2 (en) |
BE (1) | BE897473A (en) |
CA (1) | CA1215972A (en) |
CH (1) | CH649998A5 (en) |
DE (1) | DE3327705A1 (en) |
DK (1) | DK361983A (en) |
ES (1) | ES524815A0 (en) |
FI (1) | FI73679C (en) |
FR (1) | FR2531433B1 (en) |
GB (1) | GB2125041B (en) |
GR (1) | GR78923B (en) |
HU (1) | HU187600B (en) |
IL (1) | IL69450A (en) |
IT (1) | IT1168961B (en) |
MY (1) | MY8700166A (en) |
NL (1) | NL8302776A (en) |
NZ (1) | NZ205181A (en) |
PH (1) | PH20385A (en) |
PT (1) | PT77168B (en) |
SE (1) | SE8304315L (en) |
ZA (1) | ZA835850B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4675322A (en) * | 1984-12-10 | 1987-06-23 | Eli Lilly And Company | 1-Substituted-6-n-propyl-8β-methylthio-methylergolines |
HU193782B (en) * | 1985-06-21 | 1987-11-30 | Richter Gedeon Vegyeszet | Process for producing 2-halogeno-nicergoline derivatives and acid additional salts thereof |
FR2589734B1 (en) * | 1985-11-13 | 1988-09-02 | Roussel Uclaf | USE OF ERGOLIN DERIVATIVES FOR OBTAINING A GERIATRIC MEDICINE |
US4798834A (en) * | 1987-08-31 | 1989-01-17 | Eli Lilly And Company | Optionally substituted (3β-9,10-didehydro-2,3-dihydro ergoline as serotonergic function enhancement |
DE3913756A1 (en) * | 1989-04-21 | 1990-10-25 | Schering Ag | 8 (BETA) SUBSTITUTED ERGOLINE, METHOD FOR THE PRODUCTION AND USE THEREOF |
DE10212564B4 (en) * | 2002-03-12 | 2007-04-19 | Neurobiotec Gmbh | 1-Allyl ergot alkaloid derivatives and their use for the prophylaxis and treatment of migraine |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE41533B1 (en) * | 1974-03-14 | 1980-01-30 | Sandoz Ltd | Thiomethyl ergolene derivatives |
US3901894A (en) * | 1974-06-06 | 1975-08-26 | Lilly Co Eli | 8-thiomethylergolines |
US3959288A (en) * | 1974-12-13 | 1976-05-25 | Eli Lilly And Company | 8-Oxymethylergolines and process therefor |
US4166182A (en) * | 1978-02-08 | 1979-08-28 | Eli Lilly And Company | 6-n-propyl-8-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 |
-
1982
- 1982-08-09 CH CH4772/82A patent/CH649998A5/en not_active IP Right Cessation
-
1983
- 1983-08-01 DE DE19833327705 patent/DE3327705A1/en not_active Withdrawn
- 1983-08-02 FI FI832789A patent/FI73679C/en not_active IP Right Cessation
- 1983-08-04 FR FR8313018A patent/FR2531433B1/en not_active Expired
- 1983-08-05 GB GB08321222A patent/GB2125041B/en not_active Expired
- 1983-08-05 NL NL8302776A patent/NL8302776A/en not_active Application Discontinuation
- 1983-08-05 BE BE1/10847A patent/BE897473A/en not_active IP Right Cessation
- 1983-08-08 JP JP58144843A patent/JPS5948480A/en active Pending
- 1983-08-08 DK DK361983A patent/DK361983A/en unknown
- 1983-08-08 IL IL69450A patent/IL69450A/en unknown
- 1983-08-08 NZ NZ205181A patent/NZ205181A/en unknown
- 1983-08-08 HU HU832798A patent/HU187600B/en unknown
- 1983-08-08 GR GR72165A patent/GR78923B/el unknown
- 1983-08-08 AT AT0286383A patent/AT383125B/en not_active IP Right Cessation
- 1983-08-08 ES ES524815A patent/ES524815A0/en active Granted
- 1983-08-08 PT PT77168A patent/PT77168B/en unknown
- 1983-08-08 SE SE8304315A patent/SE8304315L/en not_active Application Discontinuation
- 1983-08-08 CA CA000434064A patent/CA1215972A/en not_active Expired
- 1983-08-08 AU AU17672/83A patent/AU563736B2/en not_active Expired - Fee Related
- 1983-08-09 IT IT22490/83A patent/IT1168961B/en active
- 1983-08-09 ZA ZA835850A patent/ZA835850B/en unknown
- 1983-08-09 PH PH29378A patent/PH20385A/en unknown
-
1987
- 1987-12-30 MY MY166/87A patent/MY8700166A/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA835850B (en) | 1985-03-27 |
CA1215972A (en) | 1986-12-30 |
JPS5948480A (en) | 1984-03-19 |
AT383125B (en) | 1987-05-25 |
FI832789A0 (en) | 1983-08-02 |
GB2125041A (en) | 1984-02-29 |
FR2531433B1 (en) | 1985-10-18 |
IL69450A (en) | 1986-10-31 |
HU187600B (en) | 1986-01-28 |
SE8304315D0 (en) | 1983-08-08 |
AU1767283A (en) | 1984-02-16 |
PH20385A (en) | 1986-12-08 |
ES8502992A1 (en) | 1985-02-01 |
IT8322490A0 (en) | 1983-08-09 |
DE3327705A1 (en) | 1984-02-09 |
PT77168B (en) | 1986-03-27 |
CH649998A5 (en) | 1985-06-28 |
BE897473A (en) | 1984-02-06 |
GB8321222D0 (en) | 1983-09-07 |
MY8700166A (en) | 1987-12-31 |
DK361983A (en) | 1984-02-10 |
IL69450A0 (en) | 1983-11-30 |
FR2531433A1 (en) | 1984-02-10 |
ATA286383A (en) | 1986-10-15 |
ES524815A0 (en) | 1985-02-01 |
AU563736B2 (en) | 1987-07-23 |
SE8304315L (en) | 1984-02-10 |
FI73679C (en) | 1987-11-09 |
FI73679B (en) | 1987-07-31 |
GB2125041B (en) | 1986-04-23 |
DK361983D0 (en) | 1983-08-08 |
FI832789A (en) | 1984-02-10 |
GR78923B (en) | 1984-10-02 |
NL8302776A (en) | 1984-03-01 |
IT1168961B (en) | 1987-05-20 |
PT77168A (en) | 1983-09-01 |
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