IE44206B1 - Acylated 6-methyl-8a-amino-ergoline i compounds - Google Patents
Acylated 6-methyl-8a-amino-ergoline i compoundsInfo
- Publication number
- IE44206B1 IE44206B1 IE2861/76A IE286176A IE44206B1 IE 44206 B1 IE44206 B1 IE 44206B1 IE 2861/76 A IE2861/76 A IE 2861/76A IE 286176 A IE286176 A IE 286176A IE 44206 B1 IE44206 B1 IE 44206B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- compounds
- formula
- sog
- amino
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 37
- KGUBZNRUCSWDAU-ZKYQVNSYSA-N (6ar,9s,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-amine Chemical class C1=CC([C@H]2C[C@H](N)CN([C@@H]2C2)C)=C3C2=CNC3=C1 KGUBZNRUCSWDAU-ZKYQVNSYSA-N 0.000 title claims 2
- 239000002253 acid Substances 0.000 claims description 6
- 150000003839 salts Chemical group 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 241000700159 Rattus Species 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 5
- 230000037396 body weight Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 102000003946 Prolactin Human genes 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 229940097325 prolactin Drugs 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- JEWKYOIHXAZUTF-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;hydrochloride Chemical compound Cl.OC(=O)C(O)C(O)C(O)=O JEWKYOIHXAZUTF-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920005439 Perspex® Polymers 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 229940125688 antiparkinson agent Drugs 0.000 description 1
- QTCANKDTWWSCMR-UHFFFAOYSA-N costic aldehyde Natural products C1CCC(=C)C2CC(C(=C)C=O)CCC21C QTCANKDTWWSCMR-UHFFFAOYSA-N 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical class C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000011121 vaginal smear Methods 0.000 description 1
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
- C07D457/10—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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
Description
The present invention relates to ergolines.
Our Patent Specification No. 41426 discloses a class of compounds of formula I. It has now been found that certain compounds of this class not specifically disclosed therein, have particularly interesting properties.
The present invention provides compounds of formula I, 4 2 0 6 wherein R^ and R2 are:-NH-S02-N(Et), H -NH-S02-3-pyridyl H -NH-S02-pheny1 H -nh-so2-cf3 H -NH-SO2-Me H, or -NH-SO2-N(CH3)2 Br A compound of formula I may be produced by acylating 6-methyl-8a-amino-ergo1ine I.
The compounds of formula I may be produced in analogous manner to that disclosed in the above patent.
Free base forms of the compounds of formula I may be converted into the acid addition salt forms in conventional manner and vice versa.
The starting materials are known or may be produced in known manner.
The compounds of formula I exhibit pharmacological activity in animals. In particular, the compounds of formula I exhibit central dopaminergic stimulant activity, as indicated by 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 on i.p. administration of from 1 to 40 mg/kg animal body weight and by an induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test:3 Rats, 180-222 g, are placed in Perspex (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 Costal!, Naylor and Olleyjjluro J. Pharmac, J8, 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 In this test the compounds are administered i.p. at from 1 to 40 mg/kg animal body weight.
The compounds are therefore indicated for use as anti Parkinson agents.
An indicated daily dose is from 0.5 to 100 mg conveniently administered in divided doses 2 to 4 times a day in unit dosage form, containing from 20 0.1 to 50 mg of the compounds, or in sustained release form.
The Example 1 compound shows interesting activity.
Additionally, the compounds exhibit prolactin secretion inhibition activity, for example, in rats by the inhibition of ovum implantation as follows:4 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 |J\rch. exp. Path. Pharm. 247, 367 (1967)J .
The compounds are administered s.c. at fromo.olto 3 mg/kg animal body weight.
For the above-mentioned use the dosage will, of course, vary depending on the compound employed, mode of administration and therapy desired.
However, in general, satisfactory results are obtained when administered at a daily dosage of from 0.001 mg to 3 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammal, the total daily dosage is in the range from 0.05 to 10 mg, and dosage forms suitable for oral administration comprise from 0.01 mg to 5 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
The compounds are therefore indicated for use as prolactin secretion inhibitors. An indicated daily dose is from 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 of the compounds, 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 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 the following Examples all temperatures are in degrees Centigrade.
EXAMPLE In a manner analogous to that disclosed in Examples 3 to 12 of our above-mentioned Patent Specification No. 41426, the following compounds of formula I may be produced, wherein 5R1 r2 M.Pt. π 20 W D (c in DMF) /C2H5 —nh-so2-n C2^5 H 201-202° 1 * 3 218-220° 4 -57° -27° (0.3) (0.4)5 -nh-so2 . 262-266° 1 -59° (0.5) —nh-so2 H 199-201° 1 -55° (0.5) —NH-S02-CF3 H 206-208° 1 -45° (0.45) lo —NH-SOn-CH, H 219-220° 1 -69° (0.5) (decomp.) -so2-n /CH3 CH, Bp 253-256' (decomp.) +7° (0.5) ^base hydrochloride + 1 mol H20 hydrogen tartrate hydrochloride in pyridine instead of DMF
Claims (10)
1.I. A process for the production of a compound of formula I, wherein R-j and Rg are:-NH-SOg-N(Et) 2 H -NH-SOg-3-pyridyl H -NH-SOg-phenyl H -nh-so 2 -cf 3 H -NH-SOg-Me H, or -NH-S0g-N(CH 3 ) 2 Br which comprises acylating 6-methyl-8a-amino-ergoline I.
2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to the Example. 5
3. A compound of formula I, whenever produced by a process according to claim 1 or 2.
4. A compound of formula I, as defined in claim 1.
5. A compound of claim 4, wherein R-| and Rg are respectively • C 2^5 -NH-SOg-N, and H. C 2 H 5 10
6. A compound of claim 4, wherein R-| and Rg are respectively —NH-SO Z and H.
7. A compound of claim 4, wherein R-j and Rg are respectively 15 —NH-SOg and H. 4420 6
8. A compound of claim 4, wherein R-| and R 2 are respectively -NH-S0 2 -CF 3 and H.
9. A compound of claim 4, wherein R^ and R 2 are respectively -NH-S0 2 -CH 3 and H. 5 10. A compound of claim 4, wherein R-j and Rg are respectively ,CH„ -so 2 -n x and Br. CH„ 11. A compound according to any one of claims 3 to 10 in free base form. 12. A compound according to any one of claims 3 to 10 in acid addition salt form.
10. 13. A pharmaceutical composition comprising a compound according to any one of claims 3 to 10 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB48/76A GB1573621A (en) | 1976-01-02 | 1976-01-02 | Acylated 6-methyl-8a-amino-ergoline i compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE44206L IE44206L (en) | 1977-07-02 |
| IE44206B1 true IE44206B1 (en) | 1981-09-09 |
Family
ID=9697467
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2861/76A IE44206B1 (en) | 1976-01-02 | 1976-12-31 | Acylated 6-methyl-8a-amino-ergoline i compounds |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS604833B2 (en) |
| AU (2) | AU2104177A (en) |
| BE (1) | BE850050R (en) |
| DE (1) | DE2657770A1 (en) |
| FR (1) | FR2337135A2 (en) |
| GB (1) | GB1573621A (en) |
| HK (1) | HK30484A (en) |
| IE (1) | IE44206B1 (en) |
| IL (1) | IL51194A (en) |
| MY (1) | MY8500136A (en) |
| NL (1) | NL7614522A (en) |
| PH (1) | PH14106A (en) |
| SG (1) | SG79283G (en) |
| ZA (1) | ZA767715B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1982000463A1 (en) * | 1980-07-25 | 1982-02-18 | Ag Sandoz | Ergoline derivatives,method for their preparation,pharmaceutical compositions containing them and their therapeutic application |
| GB2112382B (en) * | 1981-11-06 | 1985-03-06 | Erba Farmitalia | Ergoline derivatives |
| DE3151912A1 (en) * | 1981-12-23 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW ERGOLIN AMINO DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| NL8400333A (en) * | 1983-02-16 | 1984-09-17 | Sandoz Ag | MOTHER-CHALK CALOIDS, THEIR PREPARATION AND THEIR USE. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2515100A1 (en) * | 1974-04-16 | 1975-11-06 | Sandoz Ag | PROCESS FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS |
| GB1517971A (en) * | 1974-07-19 | 1978-07-19 | Sandoz Ltd | 8alpha-substituted ergoline i derivatives |
-
1976
- 1976-01-02 GB GB48/76A patent/GB1573621A/en not_active Expired
- 1976-12-20 DE DE19762657770 patent/DE2657770A1/en not_active Ceased
- 1976-12-29 NL NL7614522A patent/NL7614522A/en not_active Application Discontinuation
- 1976-12-29 PH PH19306A patent/PH14106A/en unknown
- 1976-12-30 ZA ZA00767715A patent/ZA767715B/en unknown
- 1976-12-31 IL IL51194A patent/IL51194A/en unknown
- 1976-12-31 BE BE173804A patent/BE850050R/en not_active IP Right Cessation
- 1976-12-31 IE IE2861/76A patent/IE44206B1/en unknown
-
1977
- 1977-01-01 JP JP52000205A patent/JPS604833B2/en not_active Expired
- 1977-01-03 FR FR7700022A patent/FR2337135A2/en active Granted
- 1977-01-04 AU AU21041/77A patent/AU2104177A/en not_active Ceased
- 1977-01-04 AU AU21041/77A patent/AU513821B2/en not_active Ceased
-
1983
- 1983-12-14 SG SG792/83A patent/SG79283G/en unknown
-
1984
- 1984-04-05 HK HK304/84A patent/HK30484A/en unknown
-
1985
- 1985-12-30 MY MY136/85A patent/MY8500136A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2104177A (en) | 1978-07-13 |
| SG79283G (en) | 1984-08-03 |
| IL51194A (en) | 1980-03-31 |
| BE850050R (en) | 1977-06-30 |
| IE44206L (en) | 1977-07-02 |
| ZA767715B (en) | 1978-08-30 |
| FR2337135A2 (en) | 1977-07-29 |
| PH14106A (en) | 1981-02-24 |
| GB1573621A (en) | 1980-08-28 |
| NL7614522A (en) | 1977-07-05 |
| FR2337135B2 (en) | 1979-09-14 |
| MY8500136A (en) | 1985-12-31 |
| DE2657770A1 (en) | 1977-07-14 |
| IL51194A0 (en) | 1977-02-28 |
| JPS5285196A (en) | 1977-07-15 |
| JPS604833B2 (en) | 1985-02-06 |
| AU513821B2 (en) | 1981-01-08 |
| HK30484A (en) | 1984-04-13 |
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