FR2626177A1 - NOVEL ERGOLIN DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICINES - Google Patents

Abstract

The present invention relates to ergoline derivatives which are unsubstituted in position 8 and substituted in position 9, in the form of the free base or in the form of an acid addition salt. These compounds can be used as drugs.

Description

The subject of the present invention is new ergoline derivatives, their

preparation and

  their use as medicines.

  The invention relates in particular to ergoline derivatives which are unsubstituted in position 8 and substituted in position 9, in the form of the free base or

  in the form of an acid addition salt.

  These ergoline derivatives, hereinafter referred to as the new compounds, include the unsubstituted derivatives in position 8 and substituted in position 9 of all natural alkaloids and their derivatives obtained by synthesis containing the tetracyclic system of ergoline. They can carry at one or more of the positions 1, 2, 4, 5, 6, 7, 10, 12, 13 and 14 any of the groups usually found at these positions in the alkaloids of ergot and their derivatives, for example those described 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 can be in the form of racemates or in an optically active form, for example in the form of 9R or 9S isomers. The invention also relates to

  racemates as optically active forms.

  The new compounds can be in the form of free bases or in the form of acid addition salts. The invention relates to the basics

  free as well as acid addition salts.

  The substituent in position 9 is preferably

ment an aryl group.

  The aryl group can signify, for example, a homo- or heteroaromatic, monocyclic or polycyclic residue optionally carrying one or more substituents. Mention may be made, as substituents, of halogens and alkyl, hydroxy, acyloxy, trifluoromethyl, alkoxy, aryl, nitro groups,

  alkoxy carbonyl, acylamino and alkylamino.

  The aryl group preferably means an optionally substituted phenyl group, especially

an unsubstituted phenyl group.

  The invention relates in particular to the compounds of formula I H R2- g

2'.N-R1I

  H in which R1 signifies hydrogen or a C1-C4 alkyl group and R2 signifies a furannyl, phenyl or phenyl group carrying one or two substituents chosen from fluorine, chlorine, bromine and C1-C4 alkyl groups, trifluoromethyl and C1-C4 alkoxy, in the form of the free base or of an acid addition salt. According to usual practice in the literature, the above representation of the formula I includes the isomers having the configuration indicated, as well as their antipodes. The invention relates to the antipodes and the corresponding racemates of formula I. The alkyl or alkoxy groups preferably contain one or two carbon atoms, especially

a carbon atom.

  A group of compounds of formula I comprises the compounds in which R1 is as defined above and R2 signifies a furanyl, phenyl or phenyl group carrying one or two substituents chosen from fluorine, chlorine, bromine and alkyl groups in

C1-C4 and C1-C4 alkoxy.

  The invention also relates to a process for the preparation of the new compounds, a process in which a corresponding 2,3-dihydro-ergoline is oxidized and the resulting compound is recovered in the form of a free base

  or in the form of an acid addition salt.

  The invention relates in particular to a process for preparing the compounds of formula I and their acid addition salts, process according to which a compound of formula IIl H R2-- m-R1 I is oxidized in which R1 and R2 are as defined above and the resulting compound of formula I is recovered in the form of the free base or in the form of an acid addition salt. The oxidation of the compounds of formula II can be carried out according to the methods known in the chemistry of ergot alkaloids, for example by using a mild oxidizing agent such as

  manganese dioxide or benzene acid anhydride-

seleninic.

  The further processing of the reaction mixture

  nel obtained according to the above process and the purification

  tion of the compounds of formula I thus obtained, can

  be carried out according to known methods.

  The racemates can be separated according to known methods into their individual optically active components, for example by formation of acid addition salts with optically active acids,

  and fractional crystallization of diastereoiso-

  mothers. The optically pure compounds of formula I can also be obtained from products of

optically pure departure.

  Acid addition salts can be prepared according to known methods from bases

free and vice versa.

  The compounds of formula II can be prepared according to the following scheme, using known methods, for example as described in example 1 below: "/ / / -t

2626 1 77

H

R2 '-. 0

1) H2N-R1

Nr

H H

N ,, 2)

il ciil

0 VII C 0 VI

Red. l

H H

R2 - H R2--

N-R.1-

N g HReduction R1

NTH H

IV V

Ep imeri sation H R2-- N -R1 H2 / Pd

N H

  N III When the preparation of the starting materials is not described, these are known or can be prepared according to known methods or

  analogous to known methods.

  The invention also includes the starting materials of formula II, III, IV, V and VI such as

  defined above and their use as a medicine

  ment. New compounds as free base or pharmaceutically acid addition salt

  acceptable, hereinafter referred to as the compounds of the invention

  tion, have interesting pharmacolo-

  gics and can therefore be used in therapy

as drugs.

  The compounds of the invention exert in particular a dopaminergic activity as appears from the conventional tests. This activity was demonstrated, for example, in the test carried out according to the method described by U. Ungerstedt et al., In Brain Res. 24, 485 (1970) modified by J.M. Vigouret et al., Pharmacology 16 (Suppl. 1) 156-193 (1978) on rats

  in which unilateral degeneration has been caused

  rale of the nigro-striated pathways by injection of 6-hydro-

  xy-dopamine in the substantia nigra. In this test, a rotation behavior contralateral to the lesion is observed, after administration of the compounds orally at doses of between approximately 1 and approximately

  mg / kg or subcutaneously or intra-

  peritoneal at doses between about 0.3 and

about 3 mg / kg.

  The compounds of the invention can therefore

  be used therapeutically as anti-

  Parkinson's. The compounds of formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as the preferred compounds, are

  particularly active as anti-parkinso- agents

  niens. The preferred compounds are also active in the following tests: In the observation test in mice, the compounds cause a prolongation of the waking state and an increase in the reactivity to external stimuli after administration by the oral route to

  doses between 1 and 300 mg / kg.

  In the sleep cycle trial - -

  Monitoring carried out in chronically implanted rats, the compounds increase the AMOR sleep phase, after oral administration at doses included

  between about 1 and about 100 mg / kg.

In the test at] 4C-de-

  soxyglucose performed in rats (according to the method described by L. Solokoff in Journal of Cerebral Blood Flow and Metabolism, 1981, 1, 7-36, by HE Savaki et al., in Brain Research 1982, 233, 347 and by J. Mc Culloch et al., In Journal of Cerebral Blood Flow

  and Metabolism 1981, 1, 133-136), the compounds modi-

  rely on the fixation of 14C-deoxyglucose in particular areas of the brain, in particular in dopaminergic areas, after oral administration at doses of between about 1 and

300 mg / kg.

  The preferred compounds of the invention are therefore indicated for use in therapy for the treatment of primary degenerative dementia, in particular

  particular of senile dementia of the Alzheimer type.

  Preferred compounds are also indicated.

  for use in therapy as an anti

  depressants, as appears from tests on ani-

  ailments, such as inhibition of catalepsy and

  ptosis caused by tetrabenazine in rats.

  To groups of 6 Sprague- strain rats

  Dawley we administer the test substance 30 minutes

  before tetrabenazine (10 mg / kg intraperitoneally

  neal). 40 minutes after administration of tetra-

  benazine, we assess the catalepsy of each rat by placing the forelegs on a wooden block 7 cm high. We measure the time during which the animal remains in this unnatural position, up to a maximum of 45 seconds. Immediately after determining catalepsy, the degree of ptosis is recorded on a 4-point scale. 1 means the absence of ptosis, while 4 indicates complete closure of the eyes. The values obtained for each eye separately are added so that the maximum possible total is 8. It is considered that the catalepsy caused by tetrabenazine is inhibited when a catalepsy equal to or less than 29 seconds is observed. Rats with a ptosis level of 3 are considered to be protected against ptosis caused by tetrabenazine. This process is repeated 60 minutes after

  administration of tetrabenazine. The antago-

  nists are expressed in percentages.

  In the above test, the preferred compounds

  res inhibit catalepsy and ptosis caused by

  tetrabenazine after intravenous administration

  peritoneal at doses between 5 and

mg / kg.

  Preferred compounds are therefore indicated

  for therapeutic use as an anti

  depressants. The preferred compounds also exert an anxiolytic activity as appears from the tests carried out on animals, for example in the test of

  4 plates described by C. Aron et al., Neuropharmaco-

  logy 10, 459-469 (1971). In this test, the preferred compounds have been found to be active after oral administration at doses between 10 and

mg / kg.

  Preferred compounds are therefore indicated

  for therapeutic use as an anxiol-

  ticks. The preferred compounds are also active as anti-obesity agents, as appears from the tests

  practiced on animals, for example by their ability

  to reduce the weight and consumption of food in dogs after administration of doses between 7 and 28 mg / kg / day, or by the activity that they exercise in mice in the competition trial

for access to food.

  In this last test, groups of 2 male OF-1 mice are forced to compete for 10 minutes for a single food pellet by depriving them of food 6 hours before placing them in a neutral cage. Because of this promiscuity, the tendency to eat animals is offset by the

  social behavior. One of the 2 mice receives the sub-

  trial stanza and the other receives placebo orally 1 hour before the trial. The frequencies and

  durations of social activities and periods of nutrition

  tion are recorded for both animals. The effects of the test substance are determined by calculating the average differences between the behavioral responses of animals treated with the substance

  and those treated with placebo (in groups).

  In all cases, 8 pairs of mice are used per treatment; the Wilcoxon test is used to judge the meanings of the effects within the groups (p <0.05). A separate group in which both partners receive the vehicle serves as a control group

  independent. We judge the differences between the results

  states of these mice and those of the groups subjected to

  the test, using the Mann-Whitney U test.

  In the above test, the preferred compounds

  res cause a reduction in dependent diet

  the dose after oral administration at doses between 3 and 30 mg / kg, while at the same doses the number of social interactions did not

changed significantly.

  The preferred compounds can therefore be

  used in therapy as anti-obesity agents.

  The preferred compounds also exert a cardiovascular activity as is apparent from the tests carried out on animals, for example in the test carried out in the anesthetized dog according to the protocol described by B. J. Clark, Postgrad. Med. J. 57 (suppl. 1),

  p. 45-54 (1981). In this test, the provo-

  decrease in blood pressure, increase in blood flow to the mesenteric artery, and decrease in vascular resistance of the mesenteric artery after administration

  intravenously at a dose of 0.3 mg / kg.

  Preferred compounds can therefore be used therapeutically for the treatment of hypertension, congestive heart failure

  and chronic renal failure.

  The various indications mentioned above

  above suggest that preferred compounds are equally

  useful for the treatment of schizophrenia

(negative symptoms).

  For all the above indications, the appropriate daily dose is between approximately mg and 200 mg of compound according to the invention, in combination with solid or liquid vehicles or diluents. The present invention also relates to a compound according to the invention, for use as a medicament, for example for the treatment of

  Parkinson's disease, primary degenerative dementia

  tive, depression, anxiety, obesity, hypertension, congestive heart failure,

  chronic kidney disease and schizo-

  phrenia. The present invention also relates to a pharmaceutical composition comprising a compound of the invention in combination with at least one pharmaceutically acceptable carrier or diluent. Such compositions can be prepared according to the

usual methods.

  The following examples illustrate the present invention without in any way limiting its scope. In these examples the temperatures are not corrected and

are indicated in degrees Celsius.

  EXAMPLE 1: (+) - [5R (50.9 =, 10 =] - 6-methyl-9-phenyl-

  ergoline or (+) - [5R, 9R, lOR] -6-methyl-9-phenyl-ergoline

  a) (-) - (2aS) -1-benzoyl-4-methylamino-1,2,2a, 3-

  tetrahydrobenzo [c, dl] indole At a temperature between 0 and 5, 12 g of methylamine are introduced into a solution of

  g (73 mMole) of (+) - l-benzoyl-1l, 2.2a, 3,4,5-

  hexahydro-4-oxobenzo [c, d] indole and 2 g montmo-

  rillonite (K10) in 200 ml of tetrahydrofuran.

  After stirring for 5 hours at 0, the

  solution, the solvent is evaporated and recrystallized

  read the residue in a mixture of methylene chloride and ether. The title compound thus obtained melts at 163 (decomp). [a] 20D = - 154 (c = 1

in methylene chloride).

  b) (-) - [3S, (9g)] - 1-benzoyl-2,3-dihydro-5,10-didehydro-

  7-oxo-6-methyl-9-phenyl-ergoline To a solution of 20.9 g (72 mMole) of the compound obtained under a) and 11 ml (130 mMole) of pyridine in 400 ml of methylene chloride, we add dropwise to -20 12.5 g (75 mMole) of cinnamyl chloride, dissolved in 60 ml of methylene chloride. After stirring for 3.5 hours, the reaction solution is washed with water, 2N hydrochloric acid and a saturated solution of KHCO3. After drying over magnesium sulfate, the oil is crystallized

  yellow-brown with a mixture of acetone and pentane.

  F - 248-250. [a] 20D - 149.3 (c - 1 in du

methylene chloride).

  c) (+) - [3S (9a)] - 1-benzoyl-2,3-dihydro-5,10-didehydro-

  6-methyl-9-phenyl-ergoline Aluminum hydride is prepared by dropwise addition of 10.1 g (100 mMole) of sulfuric acid to a suspension of 7.8 g (200 mMole) of lithium aluminum hydride in

  ml of tetrahydrofuran at -30. To this suspension

  After adding, drop by drop at a temperature between 15 and 20 and for minutes, 17 g (41 mMole) of the compound obtained under b). After stirring for 2 hours, 25 ml of a saturated Na2SO4 solution are added dropwise to 0 and then 10 ml of concentrated NaOH. After

  filtration and evaporation of the solvent, crystal-

  read the residue in a mixture of ether and pentane. F - 144-146. [a] 20D = 111.50 (c = 1 in

methylene chloride).

  d) (-) - [3S (50,9c, 10)] - 1-benzoyl-2,3-dihydro-6-methyl-

  9-phenyl-ergoline At 0 3.4 g of NaCNBH3 are added to a solution of 14 g (35.6 mMole) of the compound obtained under c) and 50 mg of bromocresol green in 450 ml of a mixture of tetrahydrofuran and methanol (2: 1). The pH is maintained at 5 by addition of 14 ml of 4.3N ethanolic hydrochloric acid. After 2.5 hours, the solution is evaporated, made alkaline with a saturated solution of K2CO3 and extracted with methylene chloride. After drying and evaporation, yellow crystals are obtained. F - 89-92. [a] 20D - -39.9 (c - 1 in

methylene chloride).

  e) (-) - [3S (50,9a, 10O)] - l-benzoyl-2,3-dihydro-6-

  methyl-9-phenyl-ergoline For 18 hours, a solution of 12 g (32 mMole) of the compound obtained under d) is stirred at room temperature, 8.5 g (32 mMole) of 18-Crown-6 and 3.6 g (32 mMole) of potassium tert.-butoxide in 250 ml of anhydrous dimethyl sulfoxide. After dilution with 500 ml of ice water, the solution is extracted 3 times with ethyl acetate, the organic phases are washed once with water, they are dried over magnesium sulphate and they are evaporated. Dark brown oil is recrystallized from

  a mixture of acetone and pentane. F = 125-127.

  [a] 2o0D - -107.4 (c - 1 in methylene chloride).

  f) (-) - [3S (50.9m, 10a)] - 2,3-dihydro-6-methyl-9-phenyl-

  ergoline At room temperature, 6.0 g (15 mMol) of the compound obtained under e) are hydrogenated in 30 ml of 1N hydrochloric acid and 100 ml of methanol in the presence of 500 mg of palladium catalyst (10%). After filtration of the catalyst, the solution is mixed with 100 ml of 2N sodium hydroxide and extracted with methylene chloride. After drying over magnesium sulfate, the organic phases are evaporated. The crystalline residue melts at 158-160. [C] 20D - -86.6 (c = 1 in chloride

methylene).

  g) (+) - [SR (5.9a, 10oa)] - 6-methyl-9-phenyl-ergoline For 4 hours a solution of 4.5 g (14.8 mMol) of the compound is stirred at room temperature obtained under f), 5.2 g (44.3 mMole) of indole and 2.8 g of benzene seleninic anhydride in 90 ml of tetrahydrofuran. After evaporation, the residue is crystallized from a mixture of acetone

and ether. F -> 290.

  [c] 20D = 31.0 (c = 0.5 in pyridine).

  The following racemates are prepared in a similar manner to that described in Example 1, but in

  using the (+) - l-benzoyl-l, 2,2a, 3,4,5-hexahydro-4-

  oxobenzo [c, d] -indole: Example RIz F (base) 2 CH3 Phenyl 266 - 267 3 CH3 p-Cl-phenyl 263 - 265 (decomp.) 4 CH2-CH2-CH3Phenyl 227 - 228 o CH3 Furannyl 250 - 252 6 CH3 3,4-diOMe-Phenyl 241 - 243 7 H Phenyl 237 - 238 O 8 CH3 pF-phenyl 277 - 282 O (decomp.) 9 CH3 p-CF3-phenyl 240 243 (decomp.) The following enantiomers are prepared analogously to that described in Example 1, but in

  using the appropriate enantiomer of 1-benzoyl-

  1,2,2a, 3,4,5-hexahydro-4-oxobenzo [c, d] -indole: Example R1 R | F (jase Rotation CH3 Phenyl> 300 o 11 CH3 p-F-phenyl decomp. From 260 +

  12 CH3 p-F-phenyl dCcomp. from i É7 [-

Claims (11)

  1. An ergoline derivative, characterized in that it is unsubstituted in position 8 and substituted in position 9, in the form of the free base or in the form an acid addition salt.   2. A compound of formula IH R2-- N-RI HN-- in which R1 signifies hydrogen or a C1-C4 alkyl group and R2 signifies a furannyl, phenyl or phenyl group bearing one or two substituents chosen from fluorine , chlorine, bromine and C1-C4 alkyl, and C1-C4 alkoxy, in the form of the free base or an acid addition salt. 3. A compound according to claim 2, characterized in that R1 signifies hydrogen or a C1-C4 alkyl group and R2 signifies a furannyl, phenyl or phenyl group carrying one or two substituents chosen from fluorine, chlorine, bromine and C1-C4 alkyl and C1-C4 alkoxy, in the form of the free base or an acid addition salt. 4. A compound according to claim 2, characterized in that RI signifies a methyl group and R2 signifies a phenyl group.   5. La (+) - [5R, 9R, lOR] -6-methyl-9-phenyl-   ergoline, as a free base or as a acid addition salt.   6. A process for the preparation of ergoline derivatives unsubstituted in position 8 and substituted in position 9 and their acid addition salts, characterized in that a corresponding 2,3-dihydro-ergoline is oxidized and the resulting compound is recovered in the form of a free base or in the form of an acid addition salt. 7. A process for the preparation of a compound of formula I as defined in claim 2, and of its acid addition salts, characterized in that a compound of formula II H R2 is oxidized X2N-RI II   H in which R1 and R2 are as specified in claim 2, and the resulting compound of formula I is recovered in the form of the free base or in the form of a acid addition salt.   8. A compound according to any one of   claims 1 to 5, in free base form or under   form of a pharmaceutically acid addition salt   acceptable, for use as a medicine.   9. A pharmaceutical composition, characterized in that it comprises a compound according to   any one of claims 1 to 5, in the form   free base or in the form of a pharmaceutically acceptable acid addition salt, in combination with a   pharmaceutically acceptable vehicle or diluent.   10. A compound of formula II, III, IV, V and VI H H H R R22 - H 2-R, -R R -R1 IIH Iz II H N IV V H R2-- H N-R N- C'-j II 0 VI   formulas in which R, and R2 have the   meanings given in claim 2.   11. A compound according to claim 10,   for use as a medicine.