IE58241B1 - A novel 8 alpha -acylaminoergoline - Google Patents
A novel 8 alpha -acylaminoergolineInfo
- Publication number
- IE58241B1 IE58241B1 IE358789A IE358789A IE58241B1 IE 58241 B1 IE58241 B1 IE 58241B1 IE 358789 A IE358789 A IE 358789A IE 358789 A IE358789 A IE 358789A IE 58241 B1 IE58241 B1 IE 58241B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- acid addition
- pharmaceutically acceptable
- addition salt
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000003176 neuroleptic agent Substances 0.000 claims description 5
- 230000000701 neuroleptic effect Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 230000028327 secretion Effects 0.000 description 17
- 102000003946 Prolactin Human genes 0.000 description 13
- 108010057464 Prolactin Proteins 0.000 description 13
- 229940097325 prolactin Drugs 0.000 description 13
- 230000000694 effects Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010998 test method Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960004046 apomorphine Drugs 0.000 description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 230000006651 lactation Effects 0.000 description 3
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- 206010017600 Galactorrhoea Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000007928 imidazolide derivatives Chemical class 0.000 description 2
- 231100000546 inhibition of ovulation Toxicity 0.000 description 2
- QXOFQMUQMXGKGQ-NORZTCDRSA-N n-[(6ar,9s,10ar)-5-chloro-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-2,2-dimethylpropanamide Chemical compound C1=CC([C@H]2C[C@@H](CN([C@@H]2C2)C)NC(=O)C(C)(C)C)=C3C2=C(Cl)NC3=C1 QXOFQMUQMXGKGQ-NORZTCDRSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 208000033830 Hot Flashes Diseases 0.000 description 1
- 206010060800 Hot flush Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- 206010036832 Prolactinoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000095 emetic effect Effects 0.000 description 1
- 230000012173 estrus Effects 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000035929 gnawing Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- ICTOYWQIZZRCHX-KVSKMBFKSA-N n-[(6ar,9s,10ar)-7-propyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-2,2-dimethylpropanamide Chemical compound C1=CC([C@H]2C[C@@H](CN([C@@H]2C2)CCC)NC(=O)C(C)(C)C)=C3C2=CNC3=C1 ICTOYWQIZZRCHX-KVSKMBFKSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000030153 prolactin-producing pituitary gland adenoma Diseases 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
The present invention relates to a novel 8a-acylamino-ergoline, processes for its production, pharmaceutical compositions containing it and its use as a pharmaceutical.
The 8a-ergolines comprises a major class of compounds possessing varying degrees and type of biological activity and potential therapeutic utility. Thus DOS 25 30 577 and 26 56 344 disclose a wide range of ergoline derivatives which are variously 8a-substituted. Amongst possible 8a-substituents embraced there are included numerous derivatised amino groupings including inter al. acylamino and related residues. The subject compounds are variously described as possessing dopaminergic and prolactin secretion inhibiting activity.
The present invention provides a novel 8a-acyl amino-ergo line, which has been found to possess especially interesting or advantageous biological activity or profile.
More particularly the present invention relates to the compound of formula I ,NH-COC(CH3)3 (I) HN-Cl as well as the acid addition salts thereof.
The present invention also provides a process for the production of the compound of formula I and its acid addition salts, which process comprises: a) reacting the compound of formula II H N- CH3 H NH.
(II) -3with the compound of formula III C(CH3)3COOH (III) or a reactive functional derivative thereof, or b) chlorinating the compound of formula la and recovering the obtained compound of formula I as such or as an acid addition salt thereof.
Process step a) may be carried out in accordance with standard procedures. Suitable reactive functional derivatives of the compound of formula III include e.g. the corresponding acyl halides, in particular chlorides, and imidazolides. Reaction with acylhalides is suitably effected in the presence of a base, such as triethylamine or HGnig-base. Reaction with imidazolides (obtained e.g. by reaction of the compound of formula III with Ν,Ν-carbonyldiimidazole) is suitably carried out in an inert solvent such as tetrahydrofuran or ethanol, e.g. at reflux temperature. Where compound of formula HI iSi employed as such, reaction may suitably be effected e.g. in the presence of propanephosphonic acid anhydride. -4Process step b) may also be carried out in accordance with known techniques, using standard chlorinating agents such as N-Cl-succinimide or sulphuryl chloride. The reaction is conveniently performed in the presence of an inert diluent or sovent such as methylene chloride or tetrahydrofuran.
The starting material of formula II may be produced analogously to the known compounds and in accordance with known procedures.
The starting material for step b) may be prepared in accordance with process step a).
The compound of formula I may be recovered from the initially obtained reaction medium as such (i.e. in free base form) or in acid addition salt form e.g. in the form of their pharmaceutically acceptable acid addition salts. Suitable pharmaceutically acceptable acid addition salts Include both such salts with inorganic acids, for example the hydrochloride salts, as well as such salts with organic acids, for example the oxalates and maleates.
The following examples are illustrative of the processes for the production of the subject compound : -5EXAMPLE 1: Preparation of 8a-benzoy1amino-6-n-propylergo!ine 1.4 ml benzoylchloride in 5 ml CH2CI2 are added drop-wise with stirring at 5 - 10 * C to a suspension of 3.0 g 8a-amino-6-npropylergoline in 100 ml CH2CI2 and 2.0 ml triethylamine. The obtained reaction mixture is stirred for 15 to 20 hours at 20 * C and then washed thoroughly 2 x with 25 ml 2N NaOH and H2O. The organic phase is dried over MgS04, filtered and evaporated. The residue (pale brown foam) is dissolved in ethanol, and crystallised as the hydrobromide by addition of equivalent amounts of HBr in acetic acid. M.P. on recrystallisation from C2H5OH/H2O (80 : 2) = 290 * with decomposition.
Analogously is obtained 2-chloro-6-methyl-8a-pivaloylamino-ergoline, m.p. 215-216°C.
EXAMPLE 2: Preparation of 2-chloro-6-n-propyl-8a-plvaloylamino-ergo1ine g silica gel are added to 2 g 6-n-propyl-8a-pivaloylaminoergoline (example 2) in 50 ml methylene chloride, pre-cooled to 0 * C. 0.503 ml sulfurylchloride are added drop-wise and the reaction mixture stirred for 4 hours. IN potassium carbonate solution is added, the mixture extracted with methylene chloride, dried over Na2S04 and concentrated. The residue is chromatographed on 50 g silica gel using toluene/ethylacetate (2 : 1) as eluant to yield the title compound. M.P. « 146 - 147 * C.
Analogously is obtained 2-chloro-6-methyl-8a-pivaloylamino-ergoline, m.p. 215-216 °C. -6The compound of formula I and its pharmaceutically acceptable acid addition salts possess pharmacological activity as can be shown in standard animal test methods, and are accordingly indicated for use as pharmaceuticals.
In particular the said compound and salts possess prolactin (PRL) secretion inhibiting activity as demonstrated e.g. by inhibition of basal prolactin secretion in male rats in the method described by Fliickiger et al, Experientia 34, 1330 (1970). Compounds of formula I exhibit activity in this test method at dosages of from 0.0005 to 0.5 mg/kg s.c..
In addition compound of formula I , and its pharmaceutically acceptable acid addition salts possess leutenising hormone (LH) secretion inhibiting activity as demonstrated by ovulation inhibition in the following test method (c.f. Marko et al., Life Sciences 33, 233 - 240 (1983)]: Female rats (200 - 250 g) of regular 4 day cycle receive test substance during pro-oestrus at ca. 13.00 and 16.00 hrs. The next morning they are sacrificed, the oviducts examined microscopically and the ova counted. Ovulation is deemed to be inhibited only if no ova are found. The average number of ova counted for each of a series of test animal groups receiving test substance at differing dosages is also recorded in order to permit determination of ΕΟςο values i.e. dosages at which 50 X ovulation inhibition is achieved.
Furthermore compound, of formula I and its' pharmaceutically acceptable acid addition salts, possess apomorphine antagonistic activity as demonstrated -7in the test method described by Jansson et al., Arz. Forsch. 10, 1003, (1960). Thus compound of formula I inhibitsapormorphine (10 mg/kg s.c.) induced, stereotyped gnawing over periods of several hours, at dosages of from 0.032 mg/kg s.c..
As will be appreciated, activity as PRL secretion inhibitors as demonstrable in the relevant test method described above is also demonstrative of dopamine agonist activity. Furthermore apomorphine antagonist activity as demonstrable ----:- in the relevant test method described above is also demonstrable of dopamine antagonist activity. Thus compound of . formula I. may be characterised as having a dual dopamine agonist/antagonist activity profile.
In view of its PRL secretion inhibiting activity, compound of formula I and its pharmaceutically acceptable acid addition salts are indicated for use as PRL secretion inhibitors, e.g. in the treatment of conditions or disorders for which reduction of prolactin levels is indicated, for example for the treatment of galactorrhoea including post-partum galactorrhoea, for the treatment of prolactin-dependent menstrual disorders including amenorrhea, for the inhibition of lactation including post-partum lactation and morbid lactation as well as for the treatment of hyperprolactinaemic hpyogonadlsm in males and females and of prolactinoma. Furthermore in view of concomitant dopamine agonist activity compound of formula I and its pharmaceutically acceptable acid addition salts are also indicated for use as dopamine agonists, e.g. for the treatment of Morbus Parkinson.
In view of its LH secretion Inhibiting activity compound of formula I —:-:—=-------- and its pharmaceutically acceptable acid addition salts are further -8indicated for use in the treatment of disorders having an aetiology associated with or modulated by LH secretion or having an aetiology in which the physiological regulation of LH secretion is implicated, for example in the treatment of prostate hypertrophy, in the treatment of menopausal syndrome, in particular post-menopausal hot flashes, as well as the treatment of mammaryand prostate-carcinoma.
In view of its apomorphine antagonistic activity compound of formula I and its pharmaceutically acceptable acid addition salts are indicated for use as neuroleptic agents, for example for the treatment of schizophrenia.
It will be further appreciated that the subject compound and its pharmaceutically acceptable acid addtion salts will be of particular interest in relation to their indicated utility as a PRL secretion Inhibitor , having regard to the reduced likelihood of undesirable side-effects (e.g. emetic activity) occurring at endocrinologically active dosages.
For the above uses, the dosage required will of course vary depending on e.g. the mode of administration, the particular condition to be treated and the effect desired.
However an indicated daily dosage is in the range of: -91) from about 0.05 to about 5.0 mg for use in PRL secretion inhibi tion; 2) from about 1 to about 10 mg for use in LH secretion inhibition; and 3) from about 1 to about 40 mg, for neuroleptic use, of compound of formula I, conveniently administered in divided doses of 2 to 4x/day in unit dosage form or in sustained release form. Suitable unit dosage forms accordingly comprise: 1) from about 0.01 to about 2.5 mg; 2) from about 0.25 to about 5.0 mg; and 3) from about 0.25 to about 20.0 mg, (according to intended utility) of compound of formula I together with one or more pharmaceutically acceptable diluents or carriers therefore.
The compound of formula I may be administered as such or in the form of its pharmaceutically acceptable acid addition salts.
Such salts exhibit the same order of activity as the free bases.
The compound of formula I may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of tablets or capsules, or parenterally e.g. in the form of injectible solutions or suspensions.
In accordance with the foregoing the present Invention also provides: 1) A pharmaceutical composition comprising the compound of formula I I as hereinbefore defined or a pharmaceutically acceptable -10acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier therefor; 2) The conpouid of formula I as hereinbefore defined or pharmaceutically acceptable acid addition salt thereof for use as a pharmaceutical, i.e. for use in therapy, for example: for use as an PRL secretion inhibitor or for use as a dopamine agonist; or for use as an LH secretion inhibitor; or for use as a neuroleptic; and especially for use in any of the specific indications hereinbefore recited in relation to such use; as well as 3) A method of 3.1. a inhibiting PRL secretion; 3.1. b treating Morbus Parkinson; 3.2 inhibiting LH secretion; or 3.3 effecting neuroleptic treatment, e.g. for treating any of specific conditions hereinbefore recited in relation to such treatment, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of the compound of formula I as hereinbefore defined or a pharmaceutically acceptable acid addition salt thereof.
Claims (9)
1. The compound of formula I or acid addition salt thereof.
2. Process for the production of the compound of formula I as de fined in claim 1 or acid addition salt thereof, which process comprises: a) reacting a compound of formula II with the compound of formula III C(CH 3 ) 3 COOH (III) or b) chlorinating the compound of formula Ia -12Η ,Ί -CH 3 Ή HN-“-H H NH-COC( CH 3 J 3 (Ia) and recovering the obtained compound of formula I as such or as an acid addition salt thereof.·
3. . The compound of formula I, whenever produced by a process according to claim 2.
4. A pharmaceutical composition comprising the compound as defined in claim 1 or pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier therefor.
5. The compound as defined in claim 1 or pharmaceutically acceptable acid addition salt thereof, for use as a pharmaceutical.
6. The compound as defined in claim 1 or pharmaceutically acceptable acid addition salt thereof, for use as a neuroleptic.
7. A process for the production of the compound of formula I as defined in claim 1 substantially as described herein with reference to the Example.
8. A compound of formula I as defined in claim 1 whenever prepared by a process as claimed in claim 7.
9. A pharmaceutical composition comprising a compound according to claim 8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3400853 | 1984-01-12 | ||
| IE6485A IE58228B1 (en) | 1984-01-12 | 1985-01-10 | Novel 8 alpha -acylaminoergolines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE58241B1 true IE58241B1 (en) | 1993-08-11 |
Family
ID=25817521
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE358789A IE58241B1 (en) | 1984-01-12 | 1985-01-10 | A novel 8 alpha -acylaminoergoline |
| IE358689A IE58240B1 (en) | 1984-01-12 | 1985-01-10 | A novel 8 -acylaminoergoline |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE358689A IE58240B1 (en) | 1984-01-12 | 1985-01-10 | A novel 8 -acylaminoergoline |
Country Status (1)
| Country | Link |
|---|---|
| IE (2) | IE58241B1 (en) |
-
1985
- 1985-01-10 IE IE358789A patent/IE58241B1/en not_active IP Right Cessation
- 1985-01-10 IE IE358689A patent/IE58240B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE58240B1 (en) | 1993-08-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |