GB2214183A - Ergoline derivatives - Google Patents

Abstract

Ergoline derivatives unsubstituted in position 8 and substituted in position 9 are useful as dopaminergic agents. Preferred compounds are of formula I <IMAGE> Where R1 is H or alkey 1 and R2 angl. intermediates for these compounds are also claimed.

Description

ERGOLINE DERIVATIVES The present invention relates to new ergoline derivatives.

The invention provides ergoline derivatives unsubstituted in position 8 and substituted in position 9, in free base or acid addition salt form.

These ergoline derivatives, hereinafter referred to as new compounds, include the 8-unsubstituted, 9-substituted derivatives of all natural alkaloids and their synthetic derivatives containing the tetracyclic ergoline ring system. They may bear in one or more of the positions 1, 2, 4, 5, 6, 7, 10, 12, 13 and 14 any group usually found in these positions in the chemistry of ergot alkaloids, e.g. these disclosed in Ergot Alkaloids and Related Compounds, Handbook of Experimental Pharmacology, Vol. 49, Ed.

B. Berde and H.O. Schild, Berlin Heidelberg New York 1978. They may appear in racemic or optically active forms, e.g. as 9R or 9S isomers. The invention relates to both the racemates and the optically active forms.

The new compounds may be present in free base form or as acid addition salts. The invention relates to the free bases as well as to the acid addition salt forms.

The substituent in position 9 is preferably an aryl group.

The aryl group may be for example an optionally mono- or polysubstituted, 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.

The invention relates in particular to compounds of formula I,

wherein R1 is hydrogen or (C1,4)alkyl and R2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (C1,4)alkyl, trifluoromethyl or (C1,4)alkoxy, in free base or acid addition salt form.

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 and the corresponding racemates of formula I.

Any alkyl or alkoxy preferably has one or two carbon atoms and especially- one carbon atom.

A group of compounds of formula I includes compounds wherein R1 is as defined above and R2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (C1~4)alkyl or (C14 )alkoxy.

The present invention also relates to a process for the production of the new compounds, which includes the step of oxidizing a corresponding 2,3-dihydro-ergoline and recovering the resultant compound in free base or acid addition salt form.

The invention in particular relates to a process for the production of .a compound of formula I or an acid addition salt thereof, which includes the step of oxidizing a compound of formula II,

wherein R1 and R2 are as defined above and recovering the resultant compound of formula I in free base or acid addition salt form.

The oxidation of the compounds of formula II may take place in accordance with methods known from the chemistry of ergot alkaloids, e.g. using a mild oxidizing agent such as manganese dioxide or benzene selenium acid anhydride.

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 cristallisation 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 compounds of formula II may be produced in accordance with the following scheme, using known methods, e.g. as described in example 1 below:

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 invention also comprises the starting compounds of formulae II, III, IV, V and VI as defined above and their use as pharmaceuticals.

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.

In particular the compounds according to the invention exhibit dopaminergic activity in conventional tests. For example in rats lesioned unilaterally in the nigro-neostratal dopamine pathway by the effect of a 6-hydroxy-dopamine injection in the substantia nigra the compounds at doses of between about 1 and about 30 mg/kg p.o. or between about 0.3 and about 3 mg/kg s.c. or i.p., according to the method of U. Ungerstedt et al., Brain Res.

24, 485 (1970) and substantially the same as that described by J.M. Vigouret et al., Pharmacology 16 (Suppl. 1) 156 - 193 (1978), induce turning in the direction of the non-denerved side.

The compounds according to the invention are therefore useful as anti-parkinson agents.

The compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as preferred compounds, have particularly potent anti-parkinson activity.

The preferred compounds furthermore show activity in the following tests: In the observation test in the mouse the compounds at doses from 1 to 300 mg/kg p.o. provoke a prolongation of the wake phase and an increased reactivity to external stimuli.

In the sleep/wake cycle test in chronically implanted rats the compounds at doses from about 1 to about 100 mg/kg p.o. increase the REH sleep phase.

In the carbon-14 deoxyglucose rat test according to the principles of L. Sokoloff, Journal of Cerebral Blood Plow and Metabolism 1981, 1, 7 - 36, H.E. Savaki et al., Brain Research 1982, 233, 347 and J. Mc Culloch et al., Journal of Cerebral Blood Flow and Metabolism 1981, 1, 133 - 136], the compounds at doses from about 1 to 300 mg/kg p.o. alter the carbon-14 deoxyglucose uptake in particular areas of the brain, particularly in dopaminergic areas.

The preferred compounds are therefore useful for the treatment of primary degenerative dementia, particularly senile dementia of the Alzheimer type.

The preferred compounds furthermore have anti-depressant activity as indicated by animal tests, e.g. by the inhibition of tetrabenazine-induced catalepsy and ptosis in the rat.

Groups of 6 rats of a Sprague-Dawley derivation receive the test substance 30 minutes before tetrabenazine (10 mg/kg i.p.).

40 Minutes after tetrabenazine the catalepsy of each rat is estimated by placing the forepaws on a 7 cm high wooden block.

The time for which the animals remain in this unnatural position is measured, up to a maximum of 45 seconds. Immediately after determining the catalepsy, the degree of ptosis is scored on a 4-point scale. No ptosis is represented by 1 whereas a score of 4 indicates complete eye-closure. The values from the separately scored eyes are added, so that the maximum score possible is 8.

If a catalepsy of 29 seconds or less is observed, the tetrabenazine-induced catalepsy is said to be antagonised. Rats with a ptosis score of less than 3 are said to be protected against the ptotic effect of tetrabenazine. This procedure is repeated 60 minutes after tetrabenazine. The antagonistic effects are expressed as percentages.

In the above test the preferred compounds inhibit the tetrabenazine-induced catalepsy and ptosis upon administering doses of 5 to 50 mg/kg i.p.

The preferred compounds are therefore useful as antidepressants.

The preferred compounds furthermore have anxiolytic activity as indicated by animal tests, e.g. by the four plates test according to C. Aron et al., Neuropharmacology 10, 459 - 469 (1971). In this test the preferred compounds show activity upon administering doses of 10 to 100 mg/kg p.o.

The preferred compounds are therefore useful as anxiolytics.

The preferred compounds furthermore have anti-obesity activity as indicated by animal tests, e.g. by their ability to decrease body weight and food consumption in the dog upon administering doses of 7 to 28 mg/kg/day, or their activity in the Competitive Feeding Situation Test.

In this test, pairs of male OF-l mice are forced to compete over 10 minutes for a single food pellet by depriving them of food for 6 hours prior to placing both mice in a neutral cage. Because of the close proximity between the mice, the tendency to eat is competitively offset by the tendency to interact socially. One partner receives the drug and the other receives the placebo by the oral route, 1 hour before testing. Frequencies and durations of social activities and eating bouts are recorded for both animals. Drug effects are determined by calculating the mean differences between the behavioural responses of drugged and placebo-treated partners (within groups). In all cases 8 pairs of mice/treatment are tested, the Wilcoxon sign rank test being used to judge significances of effects within groups (p < 0.05, 2-tailed).A separate group in which both partners receive the vehicle serves as an independent control. Differences between the scores of these mice and the test groups are judged using the Mann-Whitney U test (i.e. across group comparisons).

In the above test the preferred compounds induced a dosedependent reduction of eating upon administering doses of 3 to 30 mg/kg p.o., whereas at the same dosages the number of social interactions did not change significantly.

The preferred compounds are therefore useful as anti-obesity agents.

The preferred compounds furthermore exhibit cardio-vascular activity as indicated by animal tests, e.g. in the anaesthetized dog according to B.J. Clark, Postgrad. Med. J. 57 (suppl. 1), p. 45 - 54 (1981). In this test the compounds decrease the blood pressure, increase the mesenteric artery blood flow and decrease the mesenteric vascular resistance upon administration of 0.3 mg/kg i.v.

The preferred compounds are therefore useful for the treatment of hypertension, congestive heart failure and chronic renal failure.

The various indications mentioned above suggest that the preferred compounds are also useful in schizophrenics (negative symptoms).

For all above mentioned indications, an indicated daily dosage is in the range from about 20 mg to about 200 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 the treatment of Parkinson's disease, primary degenerative dementia, depression, anxiety, obesity, hypertension, congestive cardiac failure, chronic renal failure and schizophrenia.

The present invention further provides pharmaceutical compositions 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.

The present invention furthermore provides a method for the treatment of Parkinson's disease, primary degenerative dementia, depression, anxiety, obesity, hypertension, congestive cardiac failure, chronic renal failure or schizophrenia, which comprises administering a therapeutically effective amount of a compound according to the invention in pharmaceutically acceptable form to a subject in need of such treatment.

In the following examples, all temperatures are uncorrected and are in degrees Centigrade.

EXAMPLE 1: (+)-15R(569aloa)l-6-methyl-9-phenyl-ergoline or (+)-l5R,9R,lOR]-6-ethyl-9-phenyl-ergoline a) (-)-(2aS)-l-benzoyl-4-iethylamino-1,2,2a, 3-tetrahydro- benz[c,d]indole 12 g of methylamine are introduced at O - 5 to a solution of 20 g (73 mMol) of (+)-1-benzoyl-1,2,2a,3,4,5-hexahydro 4-ketobenz[c,d]indole and 2 g of montmorillonite (K10) catalyst in 200 ml of tetrahydrofuran. After stirring for 5 hours at O , the solution is filtered, the solvent is concentrated by evaporation and recrystallised from methylene chloride/ether. The title compound thus obtained melts at 163 (decomp.). [2O = - 154 (c = 1 in methylene D chloride).

b) (-)-13S(9a)]-l-benzoyl-2,3-dihydro-5,10-didehydro-7-oXo- 6-methyl-9-phenyl-ergoline 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 of methylene chloride is added in drops at - 20 0 12.5 g (75 mMol) of cinnamic acid chloride, dissolved in 60 ml of methylene chloride. After stirring for 3 X hours, the reaction solution is washed with water, 2 N hydrochloric acid and saturated KHC03. After drying with magnesium sulphate, the yellow-brown oil is crystallised with acetone/pentane.

M.p.: 248 - 250 0. [a]20 = 149.30 (c = 1 in methylene D chloride).

c) (+)-[3S(9a)]-1-benzoyl-2,3-dihydro-5,10-didehydro-6-methyl- 9-phenyl-ergoline Aluminium hydride is produced by adding 10.1 g (100 mMol) of sulphuric acid in drops to a suspension of 7.8 g (200 mMol) of lithium aluminium hydride in 175 ml of tetrahydrofuran at - 30 . 17 g (41 mMol) of the compound obtained under b) are added to this suspension in drops at 15 - 20 over the course of 30 minutes. After stirring for 2 hours, 25 ml of saturated Na2S04 solution and 10 ml of conc. NaOH are added in drops at O O in succession. After filtration and evapo ration of the solvent, the residue is crystallised from ether/pentane. M.p.: 144 - 146 . [a]20 = 111.5 (c 1 1 in D methylene chloride).

d) (-)-[3S(5ss,9a,10ss)-1-benzoyl-2,3-dihydro-6-methyl-9-phenyl- ergoline 3.4 g of NaCNBH3 are added at O O to a solution of 14 g (35.6 mMol) of the compound obtained under c) and 50 mg of cresol bromide green in 450 ml of tetrahydrofuran/methanol (2 : 1). The pH is kept at 5 by adding 14 ml of 4.3 N hydro chloric acid in ethanol. After 2 i hours, the solution is concentrated by evaporation, rendered alkaline with saturated K2C03 and extracted with methylene chloride. After drying and concentrating by evaporation, yellow crystals are obtained with amp. of 89 - 920. [a]20 = - 3990 (c = 1 in D methylene chloride).

e) (-)-[3S(5ss,9&alpha;,10&alpha;)]-1-benzoyl-2,3-dihydro-6-methyl-9-phenyl- ergoline A solution of 12 g (32 mMol) of the compound obtained under d), 8.5 g (32 mMol) of 18-Crown-6 and 3.6 g (32 mMol) of potassium-t.-butylate in 250 ml of absolute dimethyl sulphoxide is stirred for 18 hours at room temperature. After diluting with 500 ml of ice water, the solution is extracted 3 times with ethyl acetate and the organic phases are washed once with water, dried over magnesium sulphate and con centrated by evaporation. The dark brown oil is re crystallised from acetone/pentane. M.p.: 125 - 127 . lay20 = D - 107.4 (c = 1 in methylene chloride).

f) (-)-[3S(56,9a,10a)l-2,3-dihydro-6-methyl-9-phenyl-ergoline A solution of 6.0 g (15 mMol) of the compound obtained under e), 30 ml of 1 N hydrochloric acid and 500 mg of Pd catalyst (10 %) in 100 ml of methanol is hydrogenated at room tempe rature. 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 - 160 o. [a]20 = - 86.6 , D (c = 1 in methylene chloride).

g) (+)-[5R(5, 9a, 1o j-6-methyl-9-phenyl-ergoline A solution of 4.5 g (14.8 mMol) of the compound obtained under f), 5.2 g (44.3 mMol) of indole and 2.8 g of benzene selenious anhydride in 90 ml of tetrahydrofuran is stirred for 4 hours at room temperatur. After concentrating by evaporation, the residue is crystallised from acetone/ether.

M.p. > 2900. [a]20 = 31.0 0 (c = 0.5 in pyridine).

D The following racemates are produced analogously to example 1, but using (+)-l-benzoyl-1,2,2a,3,4,5-hexahydro-4-ketobenz[c,d]- indole:

Example R1 R2 Np. (base) CH3 Phenyl 266 - 267 3 CH3 p-Cl-phenyl 263 - 265 (decomp.) 4 CH2-CH2-CH3 Phenyl 227 - 228 5 CH3 Furanyl 250 - 252 6 CH3 3,4-diOMe-Phenyl 241 - 243 7 H Phenyl 237 - 238 8 CH3 p-F-phenyl 277 - 282 (decomp.) CH3 p-CF3-phenyl 240 - 243 (decomp.) The following enantiomers are produced analogously to example 1, using the appropriate enantiomer of 1-benzoyl-1,2,2a,3,4,5-hexa- hydro-4-ketobenz[c,d]indole:

Example R1 R2 Np. (base) Rotation 10 CH3 Phenyl > 300 11 CH3 p-F-phenyl from 260 decomp. + 12 CH3 p-F-phenyl from 270 decomp.

Claims (35)

1. WHAT WE CLAIM IS: 1. An ergoline derivative unsubstituted in position 8 and substituted in position 9, in free base or acid addition salt form.
2. 2. A compound of formula I,

   wherein R1 is hydrogen or (C1-4)alkyl and R2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (C14)alkyl, trifluoro methyl or (C14)alkoxy, in free base or acid addition salt form.
3. 3. A compound of claim 2 wherein R1 is hydrogen or (C14)alkyl and R2 is furanyl, phenyl or phenyl mono- or disubstituted by fluorine, chlorine, bromine, (C14)alkyl or (C1-4)alkoxy.
4. 4. A compound of claim 2 wherein R1 is methyl and R2 is phenyl.
5. 5. A compound of claim 2 wherein R1 is methyl and R2 is p-chlorophenyl.
6. 6. A compound of claim 2 wherein R1 is n-propyl and R2 is phenyl.
7. 7. A compound of claim 2 wherein R1 is methyl and R2 is furanyl.
8. 8. A compound of claim 2 wherein R1 is methyl and R2 is 3, 4-dimethoxyphenyl.
9. 9. A compound of claim 2 wherein R1 is hydrogen and R2 is phenyl.
10. 10. A compound of claim 2 wherein R1 is methyl and R2 is p-fluorophenyl.
11. 11. A compound of claim 2 wherein R1 is methyl and R2 is p-trifluoromethylphenyl.
12. 12. A compound of claim 2 wherein R1 is methyl and R2 is phenyl, in form of the (+)-isomer.
13. 13. A compound of claim 2 wherein R1 is methyl and R2 is phenyl, in form of the (-)-isomer.
14. 14. A compound of claim 2 wherein R1 is methyl and R2 is p-fluorophenyl, in form of the (+)-isomer.
15. 15. A compound of claim 2 wherein R1 is methyl and R2 is p-fluorophenyl, in form of the (-)-isomer.
16. 16. A compound according to any one of claims 1 to 15, for use as a pharmaceutical.
17. 17. A compound according to any one of claims 1 to 15, for use in the treatment of Parkinson's disease.
18. 18. A compound according to any one of claims 2 to 15, for use in the treatment of primary degenerative dementia.
19. 19. A compound according to any one of claims 2 to 15, for use in the treatment of senile dementia of the Alzheimer type.
20. 20. A compound according to any one of claims 2 to 15, for use in the treatment of depression.
21. 21. A compound according to any one of claims 2 to 15, for use in the treatment of anxiety.
22. 22. A compound according to any one of claims 2 to 15, for use in the treatment of obesity.
23. 23. A compound according to any one of claims 2 to 15, for use in the treatment of hypertension.
24. 24. A compound according to any one of claims 2 to 15, for use in the treatment of congestive heart failure.
25. 25. A compound according to any one of claims 2 to 15, for use in the treatment of chronic renal failure.
26. 26. A compound according to any one of claims 2 to 15, for use in the treatment of schizophrenia.
27. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, in association with a pharma ceutical carrier or diluent.
28. 28. A process for the production of an ergoline derivative unsubstituted in position 8 and substituted in position 9, in free base or acid addition salt form, which includes the step of oxidizing a corresponding 2,3-dihydro-ergoline and recovering the resultant compound in free base or acid addition salt form.
29. 29. A process for the production of a compound of claim 2, which includes the step of oxidizing a compound of formula II,

    wherein R1 and R2 are as defined in claim 2, and recovering the resultant compound of formula I in free base or acid addition salt form.
30. 30. A compound of formula II as defined in claim 29.
31. 31. A compound of formula III as defined in the description.
32. 32. A compound of formula IV as defined in the description.
33. 33. A compound of formula V as defined in the description.
34. 34. A compound of formula VI as defined in the description.
35. 35. A compound of any one of claims 30 to 34 for use as a pharmaceutical.