LU87439A1 - NOVEL ERGOLIN DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICINES - Google Patents

Description

8 — ί__2_Λ

y ή Q 9 GRAND DUCHY OF LUXEMBOURG

. ........ ~~~ ....... — ........... Minister of ..........., .... .. * _........... aqg | "..... 'of the Economy and the Middle Classes _ _ 3¾¾ Intellectual Property Service

Title issued .................................. [. gp LUXEMBOURG

Patent Application ............................................ .................................................. ................... (1) I. Request

The ..... company known as: SANDOZ SA. Lichtstrasse 35, CH-4002 Basel, Switzerland_ (2) - represented by Mr. Louis EMRINGER, lawyer, residing in Luxembourg, _____________ acting in his capacity as agent ______ ___ ____ --- ---------------------------------------------------------- ---------------------------------------------------------- ---------------------------------------------------------- ------------- (3) submitting) this twenty-four ...... jan viex ....... 1.9.fl.Q .-. Q. ^ F. ........................... (4) at ..... / tT / every hour, at the Ministry of the Economy and Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning:

New derivatives of Γ ergo line, their preparation and their use ....... (5) as ..... medicines ..................... .................................................. .................................................. .................................................. .................................................. .................................................. .......

2. description in French ...................._____________________________________________ of the invention in three copies: 3 .............. ............ / .. / .................................. ..drawing boards, in triplicate; 4. the receipt of the fees paid to the Luxembourg Registration Office on ..24 ........ January ........ 1.98.9 .....; 5. the delegation of power, dated ............... Sâlfe .________________________________________________________ on ^ ... 3 ^ „4yr.Viex .... J ... 9 .. 8.S ___________; 6. the successor document (authorization); 3 ^ ti3ô $ "tosncas8mHaint ± KtexpeHKaiMtitéxjexxHKdâ2lmaii0içxp [K ± ^ esi: imKmKHr (x> esK (sBm4: (6) claims (s) for the above patent application the priority of one (s) request (s) of (7) ) ....... Patent ......................................... .................................................. ................................... filed in (8) Federal Rep. .... . from Germany .......................

je (g) ...... January 26, 1988 ..................................... .................................................. .................................................. ............................................

under N ° (10) ........? ...... — ..... 9..Ë ....... iZ§,: ,,, 1 ... .................................................. .................................................. .................................................. .................................................. .................................................. ....

in the name of (ii) SAM.QZ .-. P.AIE.NI-.GMB ^ ....... LQ..r..r ... a..Q..b ....> ..AI..Le.mag does

elect (elect) domicile for him / her and, if designated, for his / her representative, in Luxembourg ..... 1.41 ...., .. x ... U. £ ....... AliißXJL

A den ....... 2652 ....... Luxembourg ................................ .................................................. .................................................. .................................................. .............................................. (12) soHicite (nt) the grant of a patent for the subject described and represented in the abovementioned appendices, with postponement of this grant to ................. six .. .................................................. .................................................. .................................................. .......................month. (13)

The depositor / agent: ............. JL · * .......... JïL · ...... mtA .......... .................................................. .................................................. .................................................. ........................... (14) IL-Pfocès de Dépôt

The above application for a patent for invention has been filed with the Ministry of the Economy and the Middle Classes, Intellectual Property Service ^ Luxembourg, on: ^ $ JA $ jggQ

λ ·· ·. ' \ · \ Pr. The Minister for the Economy and the Middle Classes, at ... UJ / ÂCL · heures \, p. d.

. · \? The head of the intellectual property department,

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EXPLANATIONS RELATING TO THE FORMÇÇÇÉÉPÔT. / T / V

- v- (1) if applicable '' Request for an addition certificate to the main orevet, to the main patent application No ..... 'f .. ./^ of ...... ...... ”- (2) enter the surname, first name, profession, / / Λ 1 * 7 \ address of the applicant. when the latter is an individual or the corporate name, legal form, address of the head office, when the applicant is a legal person - (3) enter C- ^ l * JJ the name, first name, address of the authorized representative, counsel in industrial property, with special powers, if applicable: "represented by ........... acting as an agent" - (4) date of filing in full - (5) title of the invention - (6) enter the names, first names, addresses of the inventors or the indication "(see) separate designation (will follow)", when the desi-A / j! Gnation is done or will be done in a separate document, or the indication "not to mention", when the inventor signs or signs a non-mention document to be attached to a designation X * 100-7266 I '' CLAIM OF PRIORITY i | - de the patent application

In the FEDERAL REPUBLIC OF GERMANY

From January 26, 1988

DESCRIPTIVE MEMORY

filed in support of an application for

PATENT

t at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: New derivatives of Vergoline, their preparation and their use as medicines.

X *

The present invention relates to new ergoline derivatives, their preparation and their use as medicaments.

The invention relates in particular to ergoline derivatives which are unsubstituted in position 8 and substituted in position 9, in the form of a 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 Fharmacology, Vol. 49, Ed. B. Berde and H.0. 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 relates both to racemates and to 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 free bases as well as acid addition salts.

The substituent in position 9 is preferably an aryl group.

The aryl group can signify, for example, a homo- or hetero-aromatic, monocyclic or polycyclic residue optionally carrying one or more substituents. As substituents, mention may be made, for example, of halogens and alkyl, hydroxy, “” 2 acyloxy, trifluoromethyl, alkoxy, aryl, nitro, alkoxy-carbonyl, acylamino and alkylamino groups.

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

2 9 a.m.

ywkLN-Ri

C XU 1 I

HN-ü in which

Rx signifies hydrogen or a C 1 -C 4 alkyl group and R 2 signifies a furannyl, phenyl or phenyl group carrying one or two substituents chosen from fluorine, chlorine, bromine and C 1 -C 4 alkyl, trifluoromethyl and alkoxy groups in C 1 -C 4, in the form of a free base or of an acid addition salt.

According to usual practice in the literature, the above representation of formula I includes 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 t * 3 the compounds in which R 1 is as defined above and R 2 signifies a furannyl, phenyl or phenyl group carrying one or two substituents chosen from fluorine, chlorine, bromine and the groups C1-C4 alkyl 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 addition salt. acid.

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 II is oxidized

H

VTÎÏ CXv 11

Hn- »H

in which R 1 and R 2 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 methods known in the chemistry of ergot alkaloids, for example by using a mild oxidizing agent such as manganese dioxide or the anhydride of benzene-seleninic acid.

The subsequent treatment of the reaction mixture obtained according to the above process and the purification 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 forming acid addition salts with optically active acids, and fractional crystallization of the diastereoisomeric salts. The optically pure compounds of formula I can also be obtained from optically pure starting materials.

The acid addition salts can be prepared according to known methods from free bases 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: -., R X "X_ J l 5

H

fffj ^ 1} H2N-R1 fï ^ f ^ 1

fl L_rH - * fl W

0 VII C1 0 VI

Red.

y

H H

AÙ * R1 | H Reduction | oj> - qj> IV v

Epimerization y

H

lï N-rt [ιΎΤT vpd fl 1 |> h *

N — J

III

* \ 6

When the preparation of the starting materials is not described, these are known or can be prepared according to known methods or in a similar manner to known methods.

The invention also includes the starting materials of formula II, III, IV, V and VI as defined above and their use as medicaments.

The new compounds in the form of the free base or of a pharmaceutically acceptable acid addition salt, hereinafter referred to as the compounds of the invention, have advantageous pharmacological properties and can therefore be used in therapy as medicaments.

The compounds of the invention exert in particular a dopaminergic activity as appears from the conventional tests. This activity was evidenced 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 JM Vigouret et al., Pharmacology _16 (Suppl. 1) 156-193 (1978) in rats in which unilateral degeneration of the nigro-striated pathways was caused by injection of 6-hydro-xy-dopamine into the substantia nigra. rotational behavior contralateral to the lesion, after administration of the compounds orally at doses between about 1 and about 30 mg / kg or subcutaneously or intraperitoneally at doses between about 0.3 and about 3 mg / kg.

The compounds of the invention can therefore be used in therapy as antiparkinsonian agents.

The compounds of formula I and their pharmaceutically acceptable acid addition salts,

Jt X

7 hereinafter designated the preferred compounds, are particularly active as anti-parkinsonian agents.

The preferred compounds are also active in the following tests:

In the observational test in mice, the compounds cause a prolongation of the waking state and an increase in the reactivity to external stimuli after oral administration at doses between 1 and 300 mg / kg.

In the sleep / wake cycle trial in chronically implanted rats, the compounds increase the AMOR sleep phase after oral administration at doses between about 1 and about 100 mg / kg. ...

_., at ^ C-de-

In the soxyglucose test carried out 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 modify the binding of 1 ^ c-deoxyglucose in particular areas of the brain, in particular in areas dopaminergic, after oral administration at doses 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 senile dementia of the Alzheimer type.

The preferred compounds are also indicated for therapeutic use as antidepressants, as has been shown in animal trials, for example the inhibition of catalepsy and ptosis caused by tetrabenazine in rats.

Groups of 6 Sprague-Dawley rats are administered the test substance 30 minutes before tetrabenazine (10 mg / kg intraperitoneally). 40 minutes after the administration of tetra-benazine, the catalepsy of each rat is evaluated 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 antagonistic effects are expressed in percentages.

In the above test, the preferred compounds inhibit catalepsy and ptosis caused by tetrabenazine after intraperitoneal administration at doses between 5 and 50 mg / kg.

The preferred compounds are therefore indicated for use in therapy as antidepressants.

The preferred compounds also exert an anxiolytic activity as appears from the tests carried out on animals, for example in the 4-plate test described by C. Aron et al., Neuropharmaco- K 19 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 100 mg / kg.

The preferred compounds are therefore indicated for use in therapy as anxiolytics.

The preferred compounds are also active as anti-obesity agents, as appears from the tests carried out on animals, for example by their ability to reduce the weight and the consumption of food in dogs after administration of doses of between 7 and 28 mg / kg / day, or by the activity 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 social behavior. One of the 2 mice receives the test substance and the other receives the oral placebo, 1 hour before the test. The frequencies and durations of social activities and feeding periods are recorded for the two 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 the two partners receive the vehicle serves as an independent control group r ι 10. The differences between the results of these mice and those of the test groups are judged using the Mann-Whitney U test.

In the above test, the preferred compounds cause a dose-dependent reduction in diet after oral administration at doses between 3 and 30 mg / kg, while at the same doses the number of social interactions has 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. J57 (suppl. 1), p. 45-54 (1981). In this test, the compounds cause a decrease in blood pressure, an increase in the blood flow of the mesenteric artery and a decrease in the 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 suggest that the preferred compounds are also useful for the treatment of schizophrenia (negative symptoms).

For all the above indications, the appropriate daily dose is between approximately 20 mg and 200 mg of compound according to the invention, in combination with solid or liquid vehicles or diluents.

I "11

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, depression, anxiety, obesity, hypertension, congestive heart failure, chronic renal failure and schizophrenia.

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 li (+) - [5r (5p, 9 ", 10"] - 6-methyl-9-phenyl-ergoline or (+) - [5R, 9R, 10R] -6-methyl-9-phenyl-erqoline a ) (-) - (2aS) -1-benzoyl-4-methylamino-1,2,2a, 3-tetrahydrobenzolc # d] indole At a temperature between 0 and 5 °, 12 g of methylamine are introduced into a solution of 20 g (73 mMole) of (+) - l-benzoyl-l, 2,2a, 3,4,5-hexahydro-4-oxobenzo [c, d] indole and 2 g of montmo-rillonite (K10) in 200 ml tetrahydrofuran. After stirring for 5 hours at 0 °, the solution is filtered, the solvent is evaporated and the residue is recrystallized from a mixture of methylene chloride and ether. The title compound thus obtained melts at 163 ° (decomp), [ot] 20D = - 154 ° (c = 1 in methylene chloride).

9 X

12 b) (-) - [3S, (9α)] - l-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, 12.5 g (75 mMole) of cinnamyl chloride are added dropwise at -20 ° , 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 KHC03. After drying over magnesium sulphate, the yellow-brown oil is crystallized with a mixture of acetone and pentane. F - 248-250 °. [a] 2 0 D - 149.3 ° (c = 1 in methylene chloride).

c) (+) - [3S (9a)] - 1-benzoyl-2,3-dihydro-5,10-didehydro- 6-methyl-9-phenyl-e rgoline

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 175 ml of tetrahydrofuran at -30 °. To this suspension, 17 g (41 mMole) of the compound obtained under b) are added dropwise at a temperature between 15 and 20 ° and for 30 minutes. After stirring for 2 hours, 25 ml of a saturated Na 2 SO 4 solution are added dropwise at 0 ° and then 10 ml of concentrated NaOH. After filtration and evaporation of the solvent, the residue is crystallized from a mixture of ether and pentane. F = 144-146 °. [a] 20D = 111.5 ° (c = 1 in methylene chloride).

d) (-) - [3S (5ß, 9a, 10ß)] - 1-benzoyl-2,3-dihydro-6-methyl-9-phenyl-ergoline At 0 °, 3.4 g of NaCNBH3 are added to a * * 13 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, 10a)] - 1-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 ambient temperature, 8.5 g (32 mMole) of 18-Crown-6 and 3.6 g (32 mMole) of tert .-potassium butylate in 250 ml of anhydrous dimethylsulfoxide. 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. The dark brown oil is recrystallized from a mixture of acetone and pentane. F = 125-127 °.

[a] 20D - -107.4 ° (c - 1 in methylene chloride).

f) (-) - [3S (5β, 9α, 10α)] - 2,3-dihydro-6-methyl-9-phenyl-ergoline At room temperature, hydrogenate 6.0 g (15 mMole) of the compound obtained under e) in 30 ml of IN 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 t * 14 drying over magnesium sulfate, the organic phases are evaporated. The crystalline residue melts at 158-160 °. [a] 20D = -86.6 ° (c * 1 in methylene chloride).

g) (+) - [5R (5β, 9α, 10α)] - 6-methyl-9-phenyl-ergoline

For 4 hours, a solution of 4.5 g (14.8 mMole) of the compound obtained under f), 5.2 g (44.3 mMole) of indole and 2.8 g of anhydride of l are stirred at ambient temperature. benzene seleninic acid in 90 ml of tetrahydrofuran. After evaporation, the residue is crystallized from a mixture of acetone and ether. F *> 290 °.

[a] 20d * 31.0 ° (c = 0.5 in pyridine).

The following racemates are prepared in a similar manner to that described in Example 1, but using the (+) - 1-benzoyl-1,2,2a, 3,4,5-hexahydro-4-oxobenzo [c, d ]-indole:

Example Rj ^ (base) 2 CH3 Phinyl 266 - 267 ° 3 CH3 p-Cl-phenyl 263 - 265 0 (decomp.) 4 CH2-CH2-CH3 Phenyie 227 - 228 0 5 ch3 Furannyle 250 - 252 0 6 CH3 3, 4-diOMe-Phényie 241 - 243 0 7 H Phényie 237 - 238 0 8 CH3 pF-phenyle 277 - 282 0 (decomp.) 9 CH3 p-CFj-phenyle 240 - 243 0 (décomp.)

The following enantiomers are prepared analogously to that described in Example 1, but using the appropriate enantiomer of 1-benzoyl-T * 15 1r 2,2a, 3,4,5-hexahydro-4-oxobenzo [c , d] -indole: E-xample R] F (Rotation oase 10 CH3 Phenyle> 300 0 11 CH3 pF-phenyle decomp, from-260 ° + 12 ch3 pF-phenyle cecomp. from g7Cf 7

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 of an acid addition salt. 2. A compound of formula IH R2 "ÎTl | Vij 1 HN- in which Ri signifies hydrogen or a Cx-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. 3. A compound according to claim 2, characterized in that R 1 signifies hydrogen or a C 1 -C 4 alkyl group and R 2 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 groups, in the form of the free base or of an acid addition salt. 4. A compound according to claim 2, s Ο »17 characterized in that Rj signifies a methyl group and R2 signifies a phenyl group. 5. La (+.) -_ [5R, 9R, 1 OR] _- 6-methyl-9-phenyl-ergoline, in the form of a free base or in the form of an 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 is oxidized H il HN- »H wherein R 1 and R 2 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 an acid addition salt. „8. A compound according to any one of claims 1 to 5, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, for use as a medicament. 9. A pharmaceutical composition, characterized in that it comprises a compound according to V "" · 18 any one of claims 1 to 5, in the form of a free base or in the form of a pharmaceutically acid addition salt acceptable, in combination with a pharmaceutically acceptable carrier or diluent. 10. A compound of formula II, III, IV, V and vi H "" U oS> Cu® IV v v-fY _ ^ N-R,. OSS II 0 VI formulas in which Ri and R2 have the meanings given in claim 2. 1. k - »I * 19 11. A compound according to claim 10, for use as a medicament.