AU638874B2 - Ergoline derivatives useful as dopamine antagonistic agents - Google Patents
Ergoline derivatives useful as dopamine antagonistic agents Download PDFInfo
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- AU638874B2 AU638874B2 AU86006/91A AU8600691A AU638874B2 AU 638874 B2 AU638874 B2 AU 638874B2 AU 86006/91 A AU86006/91 A AU 86006/91A AU 8600691 A AU8600691 A AU 8600691A AU 638874 B2 AU638874 B2 AU 638874B2
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- phenyl
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- free base
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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
-
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Ergoline derivatives of the formula I <IMAGE> in which R1, R2 and R3 are as defined in the description, their preparation and use as therapeutics.
Description
63 .4
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Sandoz Ltd.
S ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.
INVENTION TITLE: de.vc.Vv S UOsUl c da's, lCk0?Y Ox0.^ 0'0 The following statement is a full description of this invention, including the best method of performing it known to me/us:- 99 9.
*t9 la The present invention relates to new ergoline derivatives.
More particularly the invention provides compounds of formula I, 44 4 .5 wherein R, is hydrogen or (C 1 4 )alkyl,
R
2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (C 1 4 )alkyl, (C 1 4 alkoxy or trifluoromethyl and
R
3 is chlorine, %.ine or iodine, in free base or acid addition salt form.
2 100-7692 In accordance with usual practice in the literature, the above representation of formula I embraces the isomers with the configuration as indicated, as well as their antipodes. The invention covers both antipodes as well as their mixtures, e.g.
their racemic mixtures.
Any alkyl or alkoxy preferably has one or two carbon atoms and especially one.
R is preferably alkyl, particularly methyl.
R
2 is preferably phenyl, particularly unsubstituted phenyl.
R
3 is preferably chlorine.
The preferred compound is the (+)-[5R(5P,9c,10a)]-2-chloro- 6-methyl-9-phenyl-ergoline in free base or acid addition salt form.
The invention also provides a process for the production of a compound of formula I or an acid addition salt thereof, which includes the step of halogenating a compound of formula II,
H
*R
S2 H
N-R
'N R
(II)
HN H wherein RI and R 2 are as defined above and recovering the resultant compound of formula I in free base or acid addition salt form.
-3- 100-7692 The halogenation of the compounds of formula II may take place in accordance with methods well known from the chemistry of ergot alkaloids.
Working up of the reaction mixtures obtained according to the above process, and purification of the compounds of formula I thus obtained, may be effected in accordance with known methods.
The racemates may be separated into the individual optically active components, using known methods, e.g. formation of acid addition salts with optically active acids, and fractionated crystallisation of the diastereoisomeric acid addition salts.
Optically pure compounds of formula I may also be obtained from optically pure starting materials.
Acid addition salts can be produced from the free base forms in known manner, and vice versa.
The starting compounds of formula II may be produced in accordance with the following reaction scheme, using known methods, e.g. as described in the following example 1: Qieem 4 100-7692 1) H 2 N-R 1 2) R 2 C 1
VIII
tReduction Reduction Epimerisation
S
.3 H1 2 /ld Oxidation 5 100-7692 Insofar as the production of the starting products is not described, these are known or they may be produced by known processes or in analogous manner to known processes.
The new compounds in free base or pharmaceutically acceptable acid addition salt form, hereinafter referred to as compounds according to the invention, exhibit pharmacological activity and are, therefore, useful as pharmaceuticals.
S. The compounds according to the invention have in particular dopamine-antagonistic activity in vivo on the central nervous system, which is demonstrated in the following animal models: Using cerebral dialysis [method of A. Imperato and G. Di Chiara, European Journal of Pharmacology, 156 (1988) 385 393] on freely moving rats, a significant increase in dopamine release is established at doses of ca. 1 to 5 mg/kg i.p.
On the mouse, at doses of ca. 2 mg/kg s.c. or there was observed a significant inhibition of rearing induced by subcutaneous administration of 0.5 mg/kg apomorphine.
On the rat, at doses of ca. 1 to 10 mg/kg p.o. s.c. or ca. 0.1 to 1 mg/kg the compounds according to the invention inhibit the locomotor activity increase which was induced by administering 10 mg/kg p.o. of the D 1 -agonist (-)-(6aR,12bR)- 4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridine. In this test, the substance to be tested is applied one hour before the D 1 -agonist, and the locomotor activity is measured under red light using photoelectric cells.
The compounds according to the invention can therefore be used as dopamine-antagonists, e.g. in the treatment of schizophrenia.
6 100-7692 An indicated daily dosage is in the range from about 10 to 200 mg, especially about 40 to 160 mg, of a compound according to the invention, together with solid or liquid carriers or diluents.
In accordance with the foregoing, the present invention also provides a compound according to the invention, for use as a pharmaceutical, e.g. for thr treatment of schizophrenia.
The present invention furthermore provides a pharmaceutical composition comprising a compound according to the invention in association with at least one pharmaceutical carrier or diluent.
Such compositions may be manufactured in conventional manner.
In the following examples, all temperatures are uncorrected and are in degrees Centigrade.
7 100-7692 EXAMPLE 1: (+)-(5R(50,9x,10m) 1-2-chloro--6-methyl--9-phenylergoline a) (-)-(2aS)-l-benzoyl-4-methylamino-1, 2, 2a, 3-tetrahydro-benz- [c,dlindole 12 g of rethylamine are introduced at 0 50 into a solution of 20 g (73 mmol) of (+)-l-benzoyl-1,2,2a,3,4,5-hexahydro-4ketobenz[c,d]indole and 2 g of montmorillonite (K1O) catralyst in 200 ml of tetrahydrofuran. After stirring for 5 hour!s at 00, the solution is filtered, the solvent is concentrateA by evaporation and recrystallized from methylene chlor~Ae/ether.
The title compound thus obtained melts at 1630 (decormp.).
[MI [c 20 4 -540 (c I in methylene chloride).
b) ]-l-benzyl-2,3-dihydro-5, 10-didehydro-7-ox,- 6-me thyl-9-phenyl-ergoline 12.5 g (75 mmol' of cinnamic acid chloride, dissolved in ml of methylene chloride, are added in drops at -20* to a solution of 20.9 g (72 mmol) of the compound obtained under a) and 11 ml (130 mmol) of pyridine in 400 ml oi. methylene chloride. After stirring for 3T/ hours, the reaction solution is washed with water, 2 N hydrochloric acid and saturated
KHCO
3 After drying over magnesium sulphate, the yellow-brown oil is crystallized with acetone/pentane. 248 2500.
*MD2 ,A149.3* (c 1 in methylene chloride).
c) J-1-benzyi-2,3-dihydro-5, 10-didehydro-6-methyl-9phenyl-ergoline Aluminium hydride is produced by addii~g 10.1 g (100 mmal) of sulphuric acid in drops at -300 to a suspension of 7.8 g (200 mmol) of lithium aluminium hydride in 175 ml of tetra- 8 100-7692 hydrofuran. 17 g (41 mmol) of the compound obtained under b) are added in drops to this suspension at 15 200 over the course of 30 minutes. After stirring for 2 hours, 25 ml of saturated NazSO 4 solution and 10 ml of cone. NaOH are added in drops in succession at 00. After filtration and evaporation of the solvent, the residue is crystallized from ether/pentane, 144 1460.
[O]D
20 111.50 (c 1 in methylene chloride).
d) -1-benzyl-2,3-dihydro-6-methyl-9-phenylergoline 3.4 g of NaCNBH 3 are added at 00 to a solution of 14 g (35.6 mmol) of the compound obtained under c) and 50 mg of brom-cresol green in 450 ml of tetrahydrofuran/methanol The pH is maintained at 5 by adding 14 ml of 4.3 N hydrochloric acid in ethanol. After 2h hours, the solution is concentrated by evaporation, rendered alkaline with saturated
K
2 C0 3 and extracted with methylene chloride. After drying and evaporating, yellow crystals with a m.p. of 89 920 are obtained.
[O]D
20 -39.90 (c 1 in methylene chloride).
e) (-)-[3S(50,9a,10a)]-1-benzyl-2,3-dihydro-6-methyl-9-phenylergoline A solution of 12 g (32 mmol) of the compound obtained under 8.5 g (32 mmol) of 18-Crown-6 and 3.6 g (32 mmol) of potassium-t.-butylate in 250 ml of abs, dimethyl sulphoxid, is stirred for 18 hours at room temperature. After dilution with 500 ml of ice water, extraction takes place 3 x with ethyl acetate and the organic phases are washed 1 x with water, dried over magnesium sulphate and concentrated by 9 100-7692 evaporation. The dark brown oil is recrystallized from acetone/pentane. 125 1270.
[a]D 2 0 -107.40 (c 1 in methylene chloride).
f) 9a,10)]-2,3-dihydro-6-methyl-9-phenyl-ergoline A solution of 6.0 g (15 mmol) of the compound obtained under 30 ml of 1 N hydrochloric acid and 500 mg of Pd catalyst in 100 ml of methanol is hydrogenated at room temperature. After filtration of the catalyst, the solution is mixed with 100 ml of 2 N sodium hydroxide and extracted with methylene chloride. After drying over magnesium sulphate, the organic phases are concentrated by evaporation.
The crystalline residue melts at 158 1600.
[]D
20 -86.6° (c 1 in methylene chloride).
g) (+)-[5R(9a,10a)]-6-methyl-9-phenyl-ergoline A solution of 4.5 g (14.8 mmol) of the compound obtained under 5.2 g (44.3 mmol) of indole and 2.8 g of benzeneselenic acid anhydride in 90 ml of tetrahydrofuran is stirred for 4 hours at room temperature. After concentration by evaporation, the residue is recrystallized from acetone/ether. M.p. 2900.
[a]D 2 0 31.00 (c 0.5 in pyridine).
h) 9a, 10a)]-2-chloro-6-methyl-9-phenyl-ergoline 1.76 ml of BF3.etherate are added at -100 to a suspension consisting of 2 g of (+)-[5R(50,9a,10a)]-6-methyl-9-phenylergoline in 30 ml of acetonitrile. 0.54 ml of sulphuryl chloride are added in drops at 0° to the homogeneous solution over the course of 5 minutes. After stirring for 30 minutes, working up is effected by adding 5 ml of 4 N sodium carbonate 10 100-7692 solution, extracting with ethyl acetate, drying over sodium sulphate, concentrating by evaporatienr and recrystallizing from methanol/acetone. from 2300 decomposition.
30.8' (c 0.5 in pyridine).
The followir3j enantiomer is obtained analogously to example 1: E~xample R, R 2
R
3 H-p. (base) rotation 2
C
3 p-Cl-phenyl CI 230-245* (decomp.) The following racemic forms are obtained analogously to example 1, but starting with (±)-l-benzoyl-1,2,2a,3,4,5-hexahydro-4-ke tobenz dlindole: Example R, R 2
R
3 M.p. (base) 3 CH 3 phenyl I Cl 262 2640 4 CH3 p-P-phenyi C1 251 2540
CH
3 p-CF 3 -phenyl C1 252 -2560 (decomp.) 6 CH 3 phenyl Br 246 -2480 7 CU 3 phenyl 1 2230 (decomp.)
Claims (9)
1. A compound of formula I H N-R 1 I H HNq R 3 wherein R, is hydrogen or (C 1 4 )alkyl, R 2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (C 1 4 )alkyl, (C 1 4 alkoxy or trifluoromethyl and R 3 is chlorine, bromine or iodine, in free base or acid addition salt form.
2. A compound of claim 1 wherein R 1 R 2 and R 3 are respectively CH 3 p-Cl-phenyl and Cl; CH 3 phenyl and Cl; CH 3 p-F-phenyl and Cl; CH 3 P-CF 3 -phenyl and Cl; CH 3 phenyl and Br; or CH 3 pheiiyl and 1, in free base or acid addition salt form.
3. A compound of claim 1 which is the 2-chloro-6-methyl-9-phenyl-ergoline in free base or acid addition salt form. -12-
4. A method for the treatment of schizophrenia which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 3 to a patient in need thereof.
A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 in pharmaceutically acceptable form, in association with a pharmaceutical carrier or diluent.
6. A process for the production of a compound of claim 1, which includes the step Jf halogenating a compound of formula II H (II) wherein R, and R 2 are as defined in claim 1, and recovering the resultant compound of formula I in free base or acid addition salt form.
7. A compound of formula I in free base or acid addition salt form, as defined in claim 1, whenever produced by the process of claim 6.
8. Compounds of formula I or processes for their production, substantially as hereinbefore described with reference to the Example. S S *SO,
9 DATED this 14th day of April, 1993 Sandoz Ltd. By Its Patent Attorneys DAVIES COLLISON CAVE 1'I 930414,p:\oper\dab86006.spc,12
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4033496A DE4033496A1 (en) | 1990-10-20 | 1990-10-20 | NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND USE |
| DE4033496 | 1990-10-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8600691A AU8600691A (en) | 1992-04-30 |
| AU638874B2 true AU638874B2 (en) | 1993-07-08 |
Family
ID=6416775
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU86006/91A Ceased AU638874B2 (en) | 1990-10-20 | 1991-10-18 | Ergoline derivatives useful as dopamine antagonistic agents |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0483063B1 (en) |
| JP (1) | JPH04257583A (en) |
| KR (1) | KR920008038A (en) |
| AT (1) | ATE111099T1 (en) |
| AU (1) | AU638874B2 (en) |
| CA (1) | CA2053712A1 (en) |
| CZ (1) | CZ279954B6 (en) |
| DE (2) | DE4033496A1 (en) |
| DK (1) | DK0483063T3 (en) |
| ES (1) | ES2059097T3 (en) |
| FI (1) | FI914942A (en) |
| HU (1) | HU210805B (en) |
| IE (1) | IE913663A1 (en) |
| IL (1) | IL99782A (en) |
| MX (1) | MX9101659A (en) |
| MY (1) | MY131110A (en) |
| NZ (1) | NZ240280A (en) |
| PT (1) | PT99286A (en) |
| RO (1) | RO106992B1 (en) |
| ZA (1) | ZA918346B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20110071014A (en) | 2008-10-17 | 2011-06-27 | 위스콘신 얼럼나이 리서어치 화운데이션 | Method of making biologically active alpha-beta peptides |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1120688A (en) * | 1987-02-03 | 1988-08-04 | Farmitalia Carlo Erba S.R.L. | - 8-heterocyclo-ergoline derivatives useful in the treatment of extrapyramidal syndromes |
| AU2872489A (en) * | 1988-01-26 | 1989-07-27 | Sandoz Ltd. | Ergoline derivatives-unsubstituted in position 8, substitutedin position |
| AU7078891A (en) * | 1990-01-25 | 1991-08-21 | Farmitalia Carlo Erba S.R.L. | Process for preparing ergoline derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1517971A (en) * | 1974-07-19 | 1978-07-19 | Sandoz Ltd | 8alpha-substituted ergoline i derivatives |
| CH641802A5 (en) * | 1978-05-23 | 1984-03-15 | Lilly Industries Ltd | PROCESS FOR THE PREPARATION OF ISOQUINOLEIN DERIVATIVES. |
| HU196394B (en) * | 1986-06-27 | 1988-11-28 | Richter Gedeon Vegyeszet | Process for preparing 2-halogenated ergoline derivatives |
-
1990
- 1990-10-20 DE DE4033496A patent/DE4033496A1/en not_active Withdrawn
-
1991
- 1991-10-10 HU HU913212A patent/HU210805B/en not_active IP Right Cessation
- 1991-10-16 MY MYPI91001908A patent/MY131110A/en unknown
- 1991-10-17 DE DE59102829T patent/DE59102829D1/en not_active Expired - Fee Related
- 1991-10-17 ES ES91810800T patent/ES2059097T3/en not_active Expired - Lifetime
- 1991-10-17 DK DK91810800.2T patent/DK0483063T3/en active
- 1991-10-17 AT AT91810800T patent/ATE111099T1/en not_active IP Right Cessation
- 1991-10-17 EP EP91810800A patent/EP0483063B1/en not_active Expired - Lifetime
- 1991-10-17 CZ CS913153A patent/CZ279954B6/en unknown
- 1991-10-18 CA CA002053712A patent/CA2053712A1/en not_active Abandoned
- 1991-10-18 PT PT99286A patent/PT99286A/en not_active Application Discontinuation
- 1991-10-18 MX MX9101659A patent/MX9101659A/en unknown
- 1991-10-18 IL IL9978291A patent/IL99782A/en not_active IP Right Cessation
- 1991-10-18 AU AU86006/91A patent/AU638874B2/en not_active Ceased
- 1991-10-18 NZ NZ240280A patent/NZ240280A/en unknown
- 1991-10-18 FI FI914942A patent/FI914942A/en not_active Application Discontinuation
- 1991-10-18 JP JP3270854A patent/JPH04257583A/en active Pending
- 1991-10-18 IE IE366391A patent/IE913663A1/en unknown
- 1991-10-18 ZA ZA918346A patent/ZA918346B/en unknown
- 1991-10-19 KR KR1019910018481A patent/KR920008038A/en not_active Application Discontinuation
-
1992
- 1992-02-13 RO RO9200149A patent/RO106992B1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1120688A (en) * | 1987-02-03 | 1988-08-04 | Farmitalia Carlo Erba S.R.L. | - 8-heterocyclo-ergoline derivatives useful in the treatment of extrapyramidal syndromes |
| AU2872489A (en) * | 1988-01-26 | 1989-07-27 | Sandoz Ltd. | Ergoline derivatives-unsubstituted in position 8, substitutedin position |
| AU7078891A (en) * | 1990-01-25 | 1991-08-21 | Farmitalia Carlo Erba S.R.L. | Process for preparing ergoline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| FI914942A0 (en) | 1991-10-18 |
| HU913212D0 (en) | 1992-01-28 |
| DE59102829D1 (en) | 1994-10-13 |
| PT99286A (en) | 1992-08-31 |
| KR920008038A (en) | 1992-05-27 |
| FI914942A (en) | 1992-04-21 |
| MY131110A (en) | 2007-07-31 |
| MX9101659A (en) | 1994-01-31 |
| DE4033496A1 (en) | 1992-04-23 |
| CS315391A3 (en) | 1992-05-13 |
| IL99782A0 (en) | 1992-08-18 |
| JPH04257583A (en) | 1992-09-11 |
| EP0483063B1 (en) | 1994-09-07 |
| ATE111099T1 (en) | 1994-09-15 |
| ZA918346B (en) | 1993-04-19 |
| CA2053712A1 (en) | 1992-04-21 |
| HUT60495A (en) | 1992-09-28 |
| CZ279954B6 (en) | 1995-09-13 |
| DK0483063T3 (en) | 1994-11-14 |
| ES2059097T3 (en) | 1994-11-01 |
| NZ240280A (en) | 1993-09-27 |
| IL99782A (en) | 1995-05-26 |
| HU210805B (en) | 1995-07-28 |
| EP0483063A1 (en) | 1992-04-29 |
| IE913663A1 (en) | 1992-04-22 |
| AU8600691A (en) | 1992-04-30 |
| RO106992B1 (en) | 1993-08-30 |
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