GB2115811A - Ergot alkaloids - Google Patents

Ergot alkaloids Download PDF

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Publication number
GB2115811A
GB2115811A GB08304011A GB8304011A GB2115811A GB 2115811 A GB2115811 A GB 2115811A GB 08304011 A GB08304011 A GB 08304011A GB 8304011 A GB8304011 A GB 8304011A GB 2115811 A GB2115811 A GB 2115811A
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Prior art keywords
compound
acid addition
addition salts
methyl
ergoline
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GB2115811B (en
GB8304011D0 (en
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Georg Bolliger
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Sandoz AG
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/04—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
    • 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
    • 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
    • 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

Abstract

1-aryl ergot alkaloids and their acid addition salts thereof are indicated for use as an anti-parkinson agent, anti-depressant, neuroleptic, vigilance increasing agent or for the treatment of senile dementia. Aryl includes heteroaryl and may be substituted.

Description

SPECIFICATION Ergot alkaloids This invention relates to ergot alkaloids.
The present invention provides 1-aryl ergot alkaloids and their acid addition salts thereof.
The 1-aryl ergot alkaloids of the invention are hitherto unknown derivatives of ergot alkaloids, these latter alkaloids being preparable by chemical synthesis, or in some cases, also being found in nature or preparable by e.g. fermentation methods. They may be substituted. Additionally they may exist in the form of isomers e.g. 8R and 8S isomers.
The present invention particularly provides compounds of formula I
wherein Ar is an aryl group, either (i) R and R1 are each hydrogen and R2 is hydrogen or methoxy, or (ii) R is hydrogen and R, and R2 form together a single bond, or (iii) R and R1 together form a single bond and R2 is hydrogen or methoxy, R3 is hydrogen, carboxy, or a group--(CH2)n--X, wherein nis 1 or 2, X is hydrogen, hydroxy, cyano, carboxyl, or Y-R', wherein R' is alkyl(C1~4), phenyl or pyridyl, and Y is thio, oxy, or carbonyl, and R4 is alkyl(C1~3), or when Ra is carboxy, (CH2)nOH or (CH2)n--COOH additionally a physiologically hydrolysable ester thereof, and acid addition salts of the compound or ester.
The aryl group may be for example an optionally mono- or poly-substituted mono- or poly-cyclic, homo- or hetero-aromatic moiety. Substituents include for example, halogen, alkyl, hydroxy, acyloxy, trifluoromethyl, alkoxy, aryl, nitro, alkoxycarbonyl, acylamino or alkylamino groups.
Preferably the aryl group is an optionally substituted phenyl group, especially an unsubstituted phenyl group.
A group of compounds include compounds wherein Ar is phenyl or phenyl monosubstituted by halogen of atomic number 9 to 35, hydroxy, alkoxy(C1~4), alkyl(C1~4) or trifluoromethyl, or phenyl disubstituted independently by halogen of atomic number 9 to 35.
R3 may have the alpha or beta configuration when R is hydrogen. Preferably it has the beta configuration.
R1 and R2 are preferably together a bond.
R3 is preferably -CH2X. X is for example, hydroxy, cyano, or carboxyl and especially hydroxy.
R4 is preferably methyl.
The physiologically hydrolysable esters of the invention are esters which are split under physiological conditions to the corresponding ergot alcohols or acids.
Such esters include compounds of formula I wherein Ra is (CH2)n--O--CO--R", COOR", or (CH2)n--COOR", wherein R" is alkyl(C1~12), cycloalkyl(C3~,), pyridyl, phenyl or phenylalkyl(C7~12), or phenyl or phenylalkyl(C712) monosubstituted by alkyl (C1~4), phenyl or phenylalkyl(C,~12) mono- or independently di-substituted by halogen atomic number from 9 to 35 in the phenyl ring, or phenyl or phenylalkyl(C712) mono- or independently di- or tri-substituted by alkoxy(C1~4).
A group of compounds are those of formula I wherein R1 is hydrogen, R1 and R2 together from a bond, or R1 and R2 each are hydrogen, R3 is methyl, hydroxymethyl, cyanomethyl, carboxymethyl, alkoxymethyl(C2~5), alkoxyethyl (Cas), alkylthioethyl(C3-6), alkoxycarbonyloxyethyl (C4-7) or alkoxycarbonylethyl(C4-7), and R4 is methyl, and Ra has the beta configuration, and acid addition salts thereof.
The present invention also provides a process for the production of an 1 -aryl ergot alkaloid or an acid addition salt thereof which includes the steps of arylating a corresponding ergot alkaloid unsubstituted in the 1 position or a precursor thereof and obtaining the compound as such or as an acid addition salt thereof.
In particular the present invention provides a process for the production of a compound of formula I as defined above, an ester thereof or an acid addition salt of the compound or ester which includes the steps of arylating a compound of formula II
wherein Ar, R and R1 to R4 are as defined above, or when Ra is carboxy, (CH2)nOH or (CH2)nCOOH if desired in the form of a physiologically hydrolysable ester, or a precursor of the compound or ester, and obtaining the compound of formula I or ester as such or as an acid addition salt thereof.
The process of the invention may for example be effected in conventional manner from an Ullmann reaction. A preferred catalyst is copper powder.
An arylating agent such as that of formula Ill Ar-X Ill wherein Ar is as defined above, and X1 is chlorine, bromine or preferably iodine, may be used.
The reaction may be effected without a solvent or with an appropriate solvent such as pyridine, quinoline, toluene, nitrobenzene, dimethylsulphoxide or dimethylformamide. When a non-basic solvent is used e.g. potassium carbonate may be added.
Suitable reaction temperatures are a.g. from about 80 to about 2000 C. Preferably an inert gas such as nitrogen or argon is present.
The starting material e.g of formula II and their esters may be used in the form of precursors, e.g.
compounds which may be converted into e.g. a compound of formula II or an ester thereof. After the arylation reaction the product niay be converted into e.g. a compound of formula I or its ester or an acid addition salt. For example the compound of formula II may be temporarily protected.
The 1-aryl ergot alkaloids in free base form may be converted into acid addition salts in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid, sulphuric acid, maleic acid, fumaric acid and tartaric acid.
The 1-aryl ergot alkaloids of the invention may be isolated and purified in conventional manner.
The starting materials are known or may be produced in conventional manner.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
All optical rotations are at the D line.
Example 1 8p-hydroxymethyl-6-methyl-1 -phenyl-9,1 O-didehydro-ergoline( 1 -phenyl-lysergol) 5.7 g of copper powder and 3.3 g potassium carbonate in a sulphur vessel are treated with a solution of 5.1 g lysergol in 60 dimethylformamide and 4.5 g iodobenzene. The copper brown suspension is stirred for 5 hours at 1 700C under nitrogen and then cooled. The mixture is diluted with methylene chloride, and filtered through a filtering aid such as Hyflo. The filtrate is washed with 2 N soda solution three times. The organic phases are washed with water, treated with active charcoal, dried with sodium sulphate and concentrated to give the heading compound which is crystallized from ether/petroleum ether and then from methylene chloride/hexane to give white crystals. M.pt. 133 1360; [a]20=+1 9.1 0 (c=0.74 in chloroform).
The hydrogen maleate may be obtained in conventional manner. M.pt. 199-201 0 (decomp.); [cr32o=+880 (c=0.7 in dimethylformamide).
The following compounds may be made in analogous manner: Example 2 8p-hydroxymethyl-6-methyl-1 -phenyl- ergoline( 1 -phenyl)9,1 O-dihydrolysergol) M.pt. 200--202 ; [a]20 9350 (c=0.73 in chloroform).
Example 3 8ss-cyanomethyl-6-methyl-l -phenyl-9, 1 0-didehydro-ergoline M.pt. 164--167 ; [α]20=+41.7 (c=0.63 in chloroform).
Example 4 1 -phenyl-6-methyl-9,1 O-didehydro-ergoline-8P-acetic acid (1 -phenyl-homo-lysergic-acid) M.pt. 2700 (decomp.).
Example 5 8-hydroxymethyl-6-methyl-1 -phenyl-8,9-didehydro-ergoline-(1-phenyl-elymoclavine) M.pt. 140--143 ; [α]20=-118.0 (c=0.58 in chloroform).
Example 6 9,1 O-didehydro-8P-hydroxymethyl-6-methyl-l -(4-chlorophenyl)-ergoline M.pt. 201--202 ; (decomp.); [a]20=+12.80 (c=0.5 in chloroform).
Example 7 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(3,4-dichlorophenyl)-ergoline M.pt. 107 (decomp.); [α]20=-1 0.30 (c=0.5 in dimethylformamide).
Example 8 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(4-methoxyphenyl)-ergoline M.pt. (160--161 (decomp.); [α]20=+41.5 (c=0.7 in chloroform).
Example 9 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(4-fluorophenyl)-ergoline M.pt. 200--201 (decomp.); [α]20=-5.5 (c=0.5 in dimethylformamide).
Example 10 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(2-methoxyphenyl)-ergoline M.pt. 155--157 (decomp.); [α]20=+18.2 (c=0.5 in dimethylformamide).
Example 11 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(2-fluorophenyl)-ergoline M.pt. 141--144 (decomp.); [α]20=+13 (c=0.5 in dimethylformamide).
Example 12 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(4-methylphenyl)-ergoline M.pt. 202--203 (decomp.); [α]20=-1.2 (c=0.5 in dimethylformamide).
Example 13 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(4-trifluoromethylphenyl)-ergoline M.pt. 151--152 (decomp.); [α]20=-7.3 (c=0.5 in dimethylformamide).
Example 14 9,1 O-didehydro-8P-hydroxymethyl-6-methyl-(3 chloro-phenyl)-ergoline M.pt. 170--172 ; [α]20=-6.0 (c=0.45 in dimethylformamide).
Example 15 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(3-methoxy-phenyl)-ergoline M.pt. 160--162 ; [α]20=-2.8 (c=0.5 in dimethylformamide).
Example 16 8p-acetoxymethyl-9, 1 O-didehydro-6-methyl-1 -phenyl-ergoline Hydrogen fumarate: M.pt. 190--194 ; (decomp.); [a]20=+9.00 (c=0.5 in dimethylformamide) Example 17 9,10-didehydro-6-methyl-8ss-nicotinoyloxymethyl-1-phenyl-ergoline M.pt. 135--138 ; (decomp.); [α]20=+20.0 (c=0.5 in dimethylformamide).
Example 18 9,10-didehydro-6-methyl-1-phenyl-8ss-trimethylacetoxymethyl-ergoline M.pt. 130--133 ; [α]20=+14.0 (c=0.7 in dimethylformamide).
Example 19 9,1 O-didehydro-6.8P-dimethyl-l -phenyl-ergoline Hydrochloride: M.pt. 282--285 ; (decomp.); [a]20=+ 1090 (c=0.5 in dimethylformamide).
Example 20 9,1 O-didehydro-8P-hydroxymethyl-6-propyi-l -phenyl-ergoline Hydrochloride: M.pt. 27O2730; (decomp.); [a]20=+680 (c=1.0 in dimethylformamide).
Example 21 8P-methoxycarbonyl-l -phenyl- methylergoline M.pt. 155--157 ; [a]2O=91 .80 (c=0.55 in chloroform).
Example 22 1 -phenyl-6-methyl-ergoline M.pt. 247--243 ; [a]20--46 80 (c=0.77 in DMF).
Example 23 9,10-didehydro-6-methyl-1-phenyl-8ss-(2-pyridylthiomethyl)ergoline M.pt. 107--109 ; [α]20=-20.0 (c=0.4 in chloroform).
Example 24 8a-cyanomethyl-6-methyl-1 -phenyl-ergoline M.pt. 147--149 ; [a120=-99.O0 (c=0.94 in chloroform).
Example 25 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(3-hydroxyphenyl)ergoline M.pt. 201--203 (decomp.); [α]20=+1.0 (c=0.5 in dimethylformamide).
Example 26 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(4-hydroxyphenyl)ergoline M.pt. 186--190 (decomp.); [α]20=+5.0 (c=0.55 in dimethylformamide).
The 1 -aryl ergot alkaloids and their pharmaceutically acceptable acid addition salts thereof, hereinafter called the pharmaceutical compounds of the invention, are pharmacologically active and are therefore indicated for use as pharmaceuticals.
In particular the pharmaceutical compounds of the invention exhibit anti-parkinson activity as indicated in standard tests. For example, the compounds induce, in rats, contralateral turning to nigrostriatal lesion on administration i.p. of from about 1 to about 3 mg/kg animal body weight according to the method of U. Ungerstedt, Acta physiol. scand. suppl. 387, 69-93 (1971).
The compounds are therefore indicated for use as anti-parkinson agents.
The pharmaceutical compounds of the invention also influence biogenic amine metabolism in particular inhibit turnover of serotonin and cause an increase in noradrenaline and dopamine turnover in the brain as indicated in standard animal tests, e.g. using the rat brain. Thus the compounds induce a reduction in the 5-hydroxyindoleacetic acid concentration (5-HIAA) in the cortex and in the Hippocampus on administration of about 10 mg/kg s.c. The compounds lead on administration s.c. of about 50 mg/kg to an increase of concentration of the dopamine metabolites, 3,4- dihydroxyphenylacetic acid (DOPAC) and homovallinic acid (HVA).
The compounds additionally lead on administration s.c. of about 50 mg/kg to an increase in concentration of the noradrenaline metabolite 4-hydroxy-3-methoxyphenylethylene glycol (MHPG- SO4) in the Hypothalamus and in the Pons/Medulla region indicating a increase in oradrenaline metabolism.
The biochemical parameters may be measured according to the principles of F. Karoum et al., Europ. J. Pharmacol. 44,311-318 (1977); B. H. C. Westrink et a., Europ. J. Pharmacol. 42, 179190 (1977) and H. R. Biirki et al., Psychopharmacology 57,227-237(1978).
On the basis of the action of the compounds on serotonin and noradrenaline turnover, and the action of the compounds in the above Ungerstedt test, the pharmacological compounds of the invention are indicated for use as anti-depressants, especially for geriatrics.
On the basis of the action of the compounds on dopamine turnover the compounds are also indicated for use as neuroleptics.
The pharmaceutical compounds of the invention are also serotoninergic agents as indicated in standard animal tests. For example in the sleep/wake cycle test in the cat, the compounds in p.o.
administration of from about 3 to about 10 mg/kg, lead to a reduction of the paradoxical sleep phase without significant influence in the classical sleep phase and lead to a prolongation of the wake phase.
The compounds are therefore additionally indicated for use as vigilance increasing agents.
On the basis of their action on biogenic amine turnover in the brain, in the Ungerstedt test and in the sleep/wake test, the compounds are also indicated for use in senile dementia, especially in the early stages thereof.
The present invention accordingly also provides a 1-aryl ergot alkaloid or a pharmaceutically acceptable acid addition salt thereof for use as an anti-parkinson agent, anti-depressant, neuroleptic or vigilance increasing agent or for the treatment of senile dementia.
As indicated daily dosage of the pharmaceutical compounds of the invention for all these indications is from about 0.5 to about 100 mg, e.g. 5 to 100 mg, conveniently administered in divided doses of 2 to 4 times a day in unit dosage form containing from about 0.1 to about 50 mg of the compounds or in sustained release form.
The preferred indication is senile dementia. The preferred compound is the compound of Example 1.
The 1-aryl ergot alkaloids may be administered as such or as the pharmaceutically acceptable acid addition salts thereof. Such acid addition salts exhibit the same order of activity as the free base forms of the 1-aryl ergot alkaloids. The present invention provides accordingly a pharmaceutical composition which comprises a 1-aryl ergot alkaloid or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be for example tablets or solutions.

Claims (33)

Claims
1. A process for the production of an 1 -aryl ergot alkaloid or an acid addition salt thereof which includes the steps of arylating a corresponding ergot alkaloid unsubstituted in the 1 position or a precursor thereof and obtaining the compound as such or as an acid addition salt thereof.
2. A process for the production of a compound of formula
wherein Ar is an aryl group, either (i) R and R1 are each hydrogen and R2 is hydrogen or methoxy, or (ii) R is hydrogen and R, and R2 form together a single bond, or (iii) R and R together form a single bond and R2 is hydrogen or methoxy, Ra is hydrogen, carboxy or a group (CH2)nN, wherein n is 1 or 2, X is hydrogen, hydroxy, cyano, carboxyl, or Y-R', wherein R' is alkyl(C,~4), phenyl or pyridyl, and Y is thio, oxy or carbonyl, and R4 is alkyl(C~3), or when Ra is carboxyl, (CH2)nOH or (CH2)nCOOH additionally in the form of a physiologically hydrolysable ester, or acid addition salts of the compound or ester, which includes the steps of arylating a compound of formula Il
wherein AR, R and R1 to R4 are as defined above, or when Ra is carboxy, (CH2)nOH or (CH2)nCOOH if desired in the form of a physiologically hydrolysable ester, or a precursor of the compound or ester, and obtaining the compound of formula I or ester as such or as an acid addition salt thereof.
3. A process for the production of 1 -aryl ergot alkaloid or an acid addition salt thereof substantially as hereinbefore described with reference to any one of the examples.
4. A 1 -aryl ergot alkaloid or an acid addition salt thereof whenever produced by a process as claimed in claim 1, 2 or 3.
5. 1 -aryl ergo alkaloids and their acid addition salts.
6. A compound of formula I or ester as defined in claim 2 and their acid addition salts.
7. A compound of claim 6, wherein Ar is polycyclic heteroaryl substituted by up to 2 substituents, and acid addition salts thereof.
8. A compound of formula I as defined in claim 2 wherein R is hydrogen, R, and R2 together from a bond, or R1 and R2 each are hydrogen, Ra is methyl, hydroxymethyl, cyanomethyl, carboxy-methyl, aIkoxymethyl(C2), alkoxyethyl(C3~6), alkylthioethyl(C3~8), alkoxycarbonyloxyethyl(C4-7) or alkoxycarbonyIethyI(C47), and R4 is methyl, and Ra has the beta configuration, and acid addition salts thereof.
9. A compound of claim 5 which is 8p-hydroxymethyl-6-methyl-1 -phenyl-9,1 0-didehydro ergoline and acid addition salts thereof.
10. A compound of claim 5 which is 8p-hydroxymethyl-6-methyl-1 -phenyl-ergoline and acid addition salts thereof.
11. A compound of claim 5 which is 8ss-cyanomethyl-6-methyl-1-phenyl-9,10-didehydro- ergoline and acid addition salts thereof.
12. A compound of claim 5 which is 1 -phenyl-6-methyl-9, 1 O-didehydro-ergoline-8P-acetic acid and acid addition salts thereof.
13. A compound of claim 5 which is 8-hydroxymethyl-6-methyl-1 -phenyl-8,9-didehydro-ergoline and acid addition salts thereof.
14. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1 -(4 chlorophenyl)-ergoline and acid addition salts thereof.
15. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1 -(3,4dichlorophenyl)-ergoline and acid addition salts thereof.
16. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(4 methoxyphenyl)-ergoline and acid addition salts thereof.
17. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(4 fluorophenyl)-ergoline and acid addition salts thereof.
18. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1 -(2 methoxyphenyl)-ergoline and acid addition salts thereof.
19. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1 -(2 fluorophenyl)-ergoline and acid addition salts thereof.
20. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1 -(4 methylphenyl)-ergoline and acid addition salts thereof.
21. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1 -(4 trifluoromethylphenyl)-ergoline and acid addition salts thereof.
22. A compound of claim 5 which is 9,1 O-didehydro-8P-hydroxymethyl-6-methyl- l-(3-chloro- phenyl)-ergoline and acid addition salts thereof.
23. A compound of claim 5 which is 9,10-didehydro-8p-hydroxymethyl-6-methyl-1-(3-methoxy- phenyl)ergoline and acid addition salts thereof.
24. A compound of claim 5 which is 8ss-acetoxymethyl-9,10-didehydro-6-methyl-1 -phenyl ergoline and acid addition salts thereof.
25. A compound of claim 5 which is 9,10-didehydro-6-methyl-8ss-nicotinoyloxymethyl-1 -phenyl ergoline and acid addition salts thereof.
26. A compound of claim 5 which is 9,10-didehydro-6-methyl-1 -phenyl-8/3- trimethylacetoxymethyl-ergoline and acid addition salts thereof.
27. A compound of claim 5 which is 9,1 O-didehydro-6,8p-dimethylphenyl-ergoline and acid addition salts thereof.
28. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-nor-6-propyl-1 phenyl-ergoline and acid addition salts thereof.
29. A compound of claim 5 which is 8ss-methoxycarbonyl-1-phenyl-6-methyl-ergoline and acid addition salts thereof.
30. A compound of claim 5 which is 1 -phenyl-6-methyl-ergoline and acid addition salts thereof.
31. A compound of claim 5 which is 9,10-didehydro-6-methyl-1-phenyl-8ss-(2-pyridyl- thiomethyl)-ergoline and acid addition salts thereof.
32. A compound of claim 6, wherein Ar is phenyl, or phenyl monosubstituted by halogen of atomic of number 9 to 35, alkoxy(C1~4), alkyl(C1~4) or trifluoromethyl or phenyl disubstituted independently by halogen of atomic number of 9 to 35, and acid addition salts thereof.
33. A compound, ester of any one of claims 4 to 35 or a pharmaceutically acceptable acid addition salt thereof for use as an anti-parkinson agent, anti-depressant, neuroleptic or vigilance increasing agent or for the treatment of senile dementia.
33. A compound of claim 5 which is 8α-cyanomethyl-6-methyl-1-phenyl-ergoline and acid addition salts thereof.
34. A compound of formula I as defined in claim 2, wherein Ra is (CH2)n--O--CO--R', COOR", or (CH2)nCOOR", wherein R" is alkyl(C1~12), cycloalkyl(C3-7), pyridyl, phenyl or phenyIalkyI(C712), phenyl or phenylalkyl(C712) monosubstituted by alkyl(C1~4), phenyl or phenylalkyl(C~12) mono- or independently di-substituted by halogen of atomic number of from 9 to 35 in the phenyl ring, or phenyl or phenylaIkyl(C712) mono- or independently di- or tri-substituted by alkoxy(C14), and acid addition salts thereof.
34. A compound of claim 5 which is 9,10-didehydro-8ss-hydroxymethyl-6-methyl-1-(3- hydroxyphenyl)-ergoline and acid addition salts thereof.
35. A compound of claim 5 which is 9,1 O-didehydro-8-hydrnxymethyl-6-methyl-1 -(4- hydroxyphenyl)-ergoline and acid addition salts thereof.
36. A pharmaceutical composition which comprises a compound or ester of any one of claims 4 to 35 or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically carrier or diluent.
37. A compound, ester of any one of claims 4 to 35 or a pharmaceutically acceptable acid salt thereof for use as a pharmaceutical.
GB08304011A 1982-02-17 1983-02-14 Ergot alkaloids Expired GB2115811B (en)

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WO2009136176A1 (en) * 2008-05-08 2009-11-12 E-Therapeutics Plc Compositions and methods for the treatment of fibromyalgia

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US4734501A (en) * 1985-10-01 1988-03-29 Eli Lilly And Company N-alkylation of dihydrolysergic acid

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009136176A1 (en) * 2008-05-08 2009-11-12 E-Therapeutics Plc Compositions and methods for the treatment of fibromyalgia

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NO830482L (en) 1983-08-18
SE8300865D0 (en) 1983-02-16
DK66483D0 (en) 1983-02-15
IT1197578B (en) 1988-12-06
FI830462L (en) 1983-08-18
FR2521562A1 (en) 1983-08-19
CS236786B2 (en) 1985-05-15
PL240608A1 (en) 1984-10-08
GB2115811B (en) 1985-08-14
FR2521562B1 (en) 1985-10-25
JPS58152884A (en) 1983-09-10
ES519811A0 (en) 1984-08-16
ZA831089B (en) 1984-09-26
PT76242A (en) 1983-03-01
DD209458A5 (en) 1984-05-09
IT8347734A0 (en) 1983-02-17
NL8300558A (en) 1983-09-16
DE3304361A1 (en) 1983-08-25
GR79562B (en) 1984-10-30
SE8300865L (en) 1983-08-18
BE895898A (en) 1983-08-16
AU1142083A (en) 1983-08-25
PT76242B (en) 1986-01-10
DK66483A (en) 1983-08-18
GB8304011D0 (en) 1983-03-16
FI830462A0 (en) 1983-02-10

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