LU87047A1 - NOVEL DERIVATIVES OF OCTAHYDROBENZO (G) QUINOLEENE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Description

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,,; B7T4 y GRAND-DUCHÉ DE LUXEMBOURG

; Hic * \ et N, Minister of \ 8 NO Y "133? '' Economics and Classes Movennes _ ..... i BfCiS Intellectual Property Service

TlttC dellVre_J ëg | LUXEMBOURG

Patent Application a. \.

7 ........... ....... ..........._ ........... -................... ............... .................. (U

I. Request

The so-called company: SANDOZS. A., Lichtstrasse 35, CH-4002 Basel, Switzerland (2) represented by Mr. Louis EMRINGER, lawyer, residing in Luxembourg, acting in his capacity as agent (31 dcposetntice di x; - hui t .. no v em br e. .... 1900 -q uat re-vi ngt-sept (41 at ........... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning:

New aerives oe 1: octahyGroLenzo [g3quinoleene, their (?) ..... preparation and use ...... as medicines 2. description in language ^ ran.Çaise .......... ........ of the invention in three copies: 3. // drawing boards, in three copies: 4. receipt of the fees paid to the Registration Office in Luxembourg, November 13, 1987; 5. the delegation of power, dated from Basel on November 10, 1987; 6. the successor document (authorization); déetaKe (BriagaaaiunaMKtaxaspBH3gfeakàdecBBQE5dàgtoatiaaxgggdgteKhimagBtHMEM ^ "KgK (6) asserts! ntl for the above patent application the priority of one (s) application (s) of (7) patent filed (s) SK (8'l) 'Germany i ^ g ^ 21 November 1986 under the N "(10) p 36 39 855.1 aunomde (ll) S ^ DOZ-PATENT-GMBH, Humboldtstr. 3, D-7850 Lörrach, Germany elects (elects) domicile for him ( it) and, if appointed, for its representative, at Luxembourg 141, rue Albert Und in 2652 Luxembourg seeks (s) the grant of a patent for the subject described and represented in the abovementioned appendices, with adjournment of this delivery to S1X ... .. month. (13)

The depositor / agent: J *. Λ, î Π4> —Ht - Deposit Minutes

The aforementioned patent application has been filed with the Ministry of the Economy and the Middle Classes. Intelleçjndîf ^ Eïhi ^ {nbourg Property Service. dated: | o 1g * 7 ... S \: λ, ί Σ- '·'> · Pr. the Minister of Economy and the Middle Classes.

" à A i ....... heures f S qjfei - '<zK \ £' (, 1 p. d.

s N1- /: -> i. r \ \ ^ ï'p-j /> / The head of the intellectual property department.

V "'. / / 1 / CO'f I) üïïï_ / y * f EXPLANATIONS RELATIVE TO FORMVLAlRE'ÔÊTïÉFÔT] / \“' ù.f? L- (2) s ti yaheu "Request for cenificar d ademon at hrevei principal . to the main patent application Να ... ΙΛ \ ι .. '\ Z u. ^ T: ·. no. prtnorr. pr.Mt · *. ·, ..- ti yfV ^ i ut addressed to the applicant, when CälUi-Cl a partlcuîstroule ^ denammatitMi social, form uiriduiut. adre ^ e du siece "<; i.âÉ îorvtmi? te .a-ttimû-ju · ev l.- t η> "" τη · .nc ~ r ".

’100-6965 CLAIMING THE PRIORITY of the patent application In the Federal Republic of Germany November 21, 1986 DESCRIPTION OF THE MEMORANDUM filed in support of an application for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: New derivatives of octahydrobenzo [g] quinoline, their preparation and their use as medicaments

The subject of the present invention is new derivatives of octahydrobenzo [g] quinoline, their preparation and their use as medicaments.

The invention relates in particular to the compounds of

5 formula I

r4

r2 I

s Γ O 1 nCO-NH-R3 10 H, R1 in which

R1 represents a C1-C4 alkyl, allyl or 2-propynyl group, one of the symbols R2 and R3 represents a C1-C4 alkyl group and the other a group of formula - (Ci,) in which R6 and R7 signify, independently of one another, CH3 or C2H5 and n signify 2, 3 or 4, and R4 and R5 signify, independently of one another, hydrogen or a hydroxy or methoxy group, C1-C4 alkanoyloxy or benzoyloxy, R4 and R5 which cannot simultaneously mean hydrogen, in the form of the free base, of an acid addition salt, of optical isomer (3R, 4aR, 10aR) or ( 3S, 4aS, 10aS) or as a mixture of these isomers.

In the above formula as well as in the description and the claims, the formulas of the octahydrobenzo [g] quino-30 leines cover not only the indicated stereoisomer, but also its optical antipodes and mixtures of optical isomers, for example racemics.

2

The preferred optical isomers are the isomers (3R, 4aR, 10aR).

The compounds of formula I can be in the form of a free base or an acid addition salt. The free bases 5 can be transformed according to the usual methods into their acid addition salts, and vice versa. The compounds of formula I can therefore form acid addition salts, for example with mineral acids such as hydrochloric acid, or with organic acids such as maleic acid.

10 In formula I, the symbols preferably have the following meanings, taken individually or in combination:

R1 signifies an n-propyl or allyl group, R2 signifies ~ (CHg) n “N especially 15 N R7 ch3 R3 signifies an alkyl group, especially an ethyl group, R4 signifies OH or OCH3, R5 signifies hydrogen.

The invention also relates to a process for the preparation of the compounds of formula I, process according to which

a) to prepare a compound of formula I, in which R4 and R5 signify, independently of one another, hydrogen or a methoxy group, R4 and R5 not being able to signify simultaneously hydrogen, is alkylated on the nitrogen in position 1 a compound of formula II

R.v / n.

^ η * CO-N 2

F Ο I 1 1 xco-nhr3 II

30 H H

in which R'4 and / or R'5 signify a methoxy group, or 3 b) to prepare a compound of formula I, in which R4 and R5 signify, independently of one another, hydrogen or a group hydroxy, R4 and R5 cannot simultaneously signify hydrogen, the ether groups are split into a compound of formula I, in which R4 and / or R5 signify a methoxy group or c) to prepare a compound of formula I, in which R4 and R5 mean, independently of one another, hydrogen, a (4-C4 or benzoyloxy) alkanoyloxy group, R4 and R5 being unable to simultaneously signify hydrogen, a compound of formula I is reacted, in which R4 and / or R5 signify a hydroxy group, with a C1-C4 alkanoic acid or benzoic acid, or with a reactive derivative of such an acid, and the compound of formula I is isolated in the form of the free base or an acid addition salt.

Process a) can be carried out conventionally for alkylation on nitrogen. It can be carried out, for example, by reaction with a compound of formula RiZ, in which Z signifies an eliminable group. Z preferably means Cl, Br, I or the acid residue of an organic sulfonic acid, for example a methanesulfonyloxy or p-tosyloxy group. The reaction is preferably carried out in the presence of an acid-binding agent, for example Na2CO3 or an organic base.

The cleavage of the ether groups according to method b) can be carried out according to conventional methods, for example using hydrobromic acid or boron tribromide.

The acylation of process c) can be carried out according to conventional methods, for example using reactive derivatives of the acids indicated above, preferably acid halides or acid anhydrides.

I * 4

The starting materials of formula II can be prepared, for example as follows: 1) A compound of formula III is isomerized in basic medium to form a compound of formula IV, with simultaneous hydrolysis of the ester group into a carboxy group: O · * Γ H f4

Vv ^ v- cooc ^ _ ^ 'C00h 10 H · ^ ° ^ Η3 och ^

III 'IV

2) A compound of formula IV is reacted with a carbodiimide of formula V

15 VN s c - N- (CH2) n-N ^ 6 y R7

wherein Rg represents a C1-C4 alkyl group, to form a compound of formula VI

20. N e / R.

R5 V CQ ~ N

Υλ] T · Vco-nhr, U 1 1 3 vi «s 25 This process can be carried out according to known methods for the preparation of ureides from carboxylic acids and carbodiimides.

It is preferable to allow the compounds of formula IV and V to react together under reflux for several hours in an inert solvent, for example tetrahydrofuran.

If necessary, an organic base such as N-ethyl-diisopropylamine can be added. In this reaction, the compound of formula VI is formed in which

y D

f * 2 signifies - (ch „) -N 6 and R3 signifies an alkyl group 2 n 's _ 7 5, and that of formula VI in which R2 signifies an alkyl group and R3 signifies a group“ (CH,) -M "1 n V.

10 7

These two compounds can be separated from one another according to the usual methods, for example by selective crystallization or by chromatography.

3) The OCH3 group is split in position 1 of a compound of formula VI

To prepare a compound of formula II.

This cleavage can be carried out by reduction, for example using zinc and acetic acid.

The compounds of formula II and VI are new and also form part of the invention.

When the preparation of a particular compound is not described, for example the compounds of formula III, these are known or can be obtained according to known methods or in a manner analogous to the methods described in the literature or in the examples .

The individual optical isomers can be obtained from optically active starting materials, for example the optically active compounds of formula III.

The racemic mixtures can be split into their individual optical isomers, for example by chromatography on supports carrying optically active compounds.

The following examples illustrate the present invention without in any way limiting its scope. All temperatures are given in degrees Celsius and are not corrected. In these examples, the racemates are designated according to the α / β system (for example 3β, 35 4aoi, 10aß) followed by the designation (racemic).

6 EXAMPLE 1: 1-ethyl-3- (3-dimethylaminopropyl) -3- (1-allyl-6-methoxy-1, 2,3,4,4aa, 5,10 JOaß-octah.ydrobenzoCqlquinoleine-Sß-carbonyO- urea (racemic)

900 mg of 1-ethyl-3- (3-dimethylaminopropyl) -5 3- (6-methoxy-1,2,3,4,4aa, 5,10,10aß-octahydrobenzo [g] quinoline-3B-carbonyl) are dissolved. ) -urea (racemic) in 9 ml of dimethylformamide, 340 mg of Na2CO3 and 0.18 ml of allyl bromide are added, and the mixture is stirred for 6 hours at room temperature. The reaction mixture is then poured into water and extracted with ethyl acetate.

After drying and evaporation, the title compound is obtained in the form of a brown resin. It is dissolved in a little CH2Cl2 and subjected to rapid chromatography on a column of basic silica gel with a CH2Cl2 / O mixture of 5% CH3OH / 5% ammonia (a 25¾). The dihydrochloride of the title compound obtained melts at 185 ° (foam).

The starting material can be prepared as follows: a) l-methoxy-33-carboxy-6-methox.yl, 2,3,4,4aot, 5,10, lOaß-octahydro-benzo [q] quinoline (racemic) A mixture of 2.0 g of l-methoxy-3 "-methoxycarbonyl -6-methoxy-l, 2,3,4,4aa, 5,10,10aß-octahydrobenzo [g] quinoline is heated at reflux overnight. (racemic), 40 ml of ethanol, 5 ml of water and 2.0 g of KOH. The following morning, the mixture is concentrated, it is poured into 2N HCl and the white solid which is precipitated is filtered off: 25 ° F = approximately 215 °.

b) 1-ethyl-3- (3-dimeth.ylami nopropyl) -3- (1-methoxy-6-methoxy-1, 2,3,4,4aa, 5,10,10aB-octahydrobenzoCg3quinoline-38-carbonyl) -urea (racemic)

Is heated under reflux under argon overnight 500 mg of the compound of step a), 323 mg of N-ethyl-N '- (3'-dimethyl-aminopropyl) -carbodiimide, 0.36 ml of N-ethyldiisopropylamine and 10 ml of tetrahydrofuran. The next morning, the mixture is evaporated. The colorless resinous residue is dissolved in CH2Cl2 and stirred twice with 2N NaOH. The CH2Cl2 solution is then stirred twice with 2N HCl and the acid phase is calcified or separated with concentrated NaOH and extracted with CH2Cl2 * The organic phase is dried and evaporated. The residue obtained is a colorless resin which is dissolved in a little CH2Cl2 and which is subjected to rapid column chromatography with CH2Cl2 at 4% CH3OH.

First, 3-ethyl-1- (3-dimethylaminopropyl) - 3- (1-methoxy-6-methoxy-1,2,3,4,4aa, 5,10,10aß-octahydrobenzo [g] quinoline) is obtained. -3B-carbonyl) -urea isomer and then the title compound.

C) l-eth.y1-3- (3-dimethylaminoprop.yl) -3- (6-methox.yl, 2,3,4,4a ", 5,10, lQaß-octah.ydrobenzoCq] quinoleine-3ß -carbonyl) -uree (racemic)

1.64 g of the compound of step b) are suspended in 20 ml of acetic acid and 10 ml of water and 5.8 g of zinc powder is added in portions, with stirring at room temperature. ; The reaction is exothermic. After this addition, the mixture is further stirred for 6 hours at room temperature. The mixture is then filtered and washed with water and ethyl acetate. The filtrate is concentrated, mixed with NaHCO3 solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried and concentrated. The title compound is obtained.

EXAMPLE 2 1-ethyl-3- (3-dimethylaminopropyl) -3- (1-propyl-6-methoxy-1,2,3,4,4a ", 5,10,10aB-octahydrobenzo [q] quinoline-3B -carbony1) -urea (racemic) Using a procedure analogous to that described in Example 1, the title compound is obtained. The dihydrochloride (foam) melts at 140 ° (decomposition).

EXAMPLE 3:

The optical isomer (3R, 4aR, 10aR) of the title compound of Example 1 is obtained from (-) (3S, 4aR, 10aR) -1-methoxy-3B-carboxy-6-methoxy- 1,2,3,4,4aa, 5,10,10aB-octahydrobenzo [g] quinoline.

The compounds of formula I, in the form of the free base or of a pharmaceutically acceptable acid addition salt, are distinguished by interesting pharmacological properties and can therefore be used therapeutically as medicaments.

t 1 8

The compounds of formula I exercise in particular a dopaminergic activity (stimulating activity of dopaminergic receptors) and an activity inhibiting the secretion of prolactin. This activity can be demonstrated, for example, by inhibiting the secretion of basal prolactin in male rats according to the protocol of E. Flückiger et al., (Experientia 34, 1330, 1978). In this test, the compounds are active at doses of between about 0.005 and about 0.1 mg / kg after administration subcutaneously.

In addition, when administered orally at doses of about 0.03 to 0.5 mg / kg, the compounds have longer lasting activity, compared for example to that of bromocriptine.

The compound of Example 1 is the preferred racemic. The 3R, 4aR, 10aR isomer is the preferred isomer.

Due to their inhibitory activity against prolactin secretion, the compounds of formula I, in the form of a free base or a pharmaceutically acceptable acid addition salt, can be used therapeutically as inhibitors of secretion of prolactin. prolactin, for example for the treatment of diseases requiring a reduction in the level of prolactin, for example for the treatment of galactorrhea, menstrual disorders dependent on prolactin, for example amenorrhea, for the inhibition of lactation, for the treatment of hyperprolactinemic hypogonadism in men and women and for the treatment of prolactinemia. Due to their dopaminergic activity, the compounds of formula I are also indicated for the treatment of Parkinson's disease.

The preferred therapeutic indication is the inhibition of prolactin secretion.

The indicated daily dose is between approximately 0.5 and approximately 10 mg, advantageously administered once a day or, if necessary, once every 5 days.

9

Unit doses may contain from about 0.5 to about 50 mg of active substance.

The invention also relates to a compound of formula I, in the form of a free base or a pharmaceutically acceptable acid addition salt of pharma-5, for use as a medicament, especially as a prolactin inhibitor and dopaminergic agent, for example for one of the indications mentioned above.

The compounds of formula I in the form of the free base or of a pharmaceutically acceptable acid addition salt can be administered enterally (for example in the form of tablets or capsules) or parenterally (for example under form of injectable solutions or suspensions). If necessary, they can also be used in a sustained release form.

The invention also relates to pharmaceutical compositions comprising, as active substance, a compound of formula I, in the form of the free base or of a pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable diluent or vehicle. These compositions can be in the form of solutions or tablets and can be prepared according to the usual methods using the usual adjuvants and vehicles.

Claims (11)

1. The compounds of formula I "4 c R2 j O I J S CO-NH-R3 R1 in which 10 Ri represents a C1-C4 alkyl, allyl or 2-propynyl group, one of the symbols R2 and R3 represents a C1-C4 alkyl group and the other a group of formula - (CH,) -H ^ R6 2 n v._ 15 * "in which R6 and R7 mean, independently of one another, CH3 or C2H5 and n means 2, 3 or 4, and R4 and R5 mean, independently of the other, hydrogen or hydroxy, methoxy, C1-C4 alkanoyloxy or benzoyloxy, R4 and R5 cannot simultaneously mean hydrogen, in the form of the free base, of an acid addition salt, d optical isomer (3R, 4aR, lOaR) or (3S, 4aS, lOaS) or in the form of a mixture of these isomers. 2. L-ethyl-3- (3-dimethylaminopropyl) -3- (l-allyl- 6-methoxy-l, 2,3,4,4aa, 5,10,10aß-octahydrobenzo [g] -quinoleine-3ß -carbonyl) -uree, in the form of a free base or an acid addition salt. 3. A compound according to claim 2, characterized in that it is in the form of a raclmic. 11 4. A compound according to claim 2, characterized in that it is in the form of an isomer (3R, 4aR, 10aR). 5. L-ethyl-3- (3-dimethylaminopropyl) -3- (l-propyl-6-methoxy-1,2,3,4,4aa, 5,10,10aß-octahydrobenzo [g] quinoline-33- carbonyl) -urea, in the form of a free base or an acid addition salt. 6. A process for the preparation of the compounds of formula I specified in claim 1, characterized in that a) for preparing a compound of formula I, in which R4 and R5 signify, independently of one another, hydrogen or a methoxy group, R4 and R5 cannot simultaneously signify hydrogen, a compound of formula II * CO-N ^ R2 15 0) 1 ^ CO-NH ^ II HH in which the alkyl in position 1 R'4 and / or R'5 signify a methoxy group, or b) to prepare a compound of formula I, in which R4 and R5 signify, independently of one another, hydrogen or a hydroxy group, Since R4 and R5 cannot simultaneously signify hydrogen, the ether groups are split into a compound of formula I, in which R4 and / or R5 signify a methoxy group, or c) to prepare a compound of formula I, in which R4 and R5 mean, independently of one another, hydrogen, a C1-C4 alkanoyloxy or benzoyloxy group, R4 and R5 which cannot signify whether simultaneously with hydrogen, a compound of formula I is reacted, in which R4 and / or R5 signify a hydroxy group, with a C1-C4 alkanoic acid or benzoic acid, or with a reactive derivative of such a acid, “ä” 12 and the compounds of formula I are isolated in the form of the free base or of an acid addition salt. 7. A compound according to any one of claims 1 to 5, in the form of a free base or a pharmaceutically acceptable acid addition salt, for use as a medicament. 8. A pharmaceutical composition, characterized in that it comprises, as active substance, a compound according to any one of claims 1 to 5, in the form of the free base or of a pharmaceutically acceptable acid addition salt, in combination with a pharmaceutically acceptable carrier or diluent. 9. The use of a compound according to any one of claims 1 to 5, in the form of a free base or a pharmaceutically acceptable acid addition salt, for the preparation of a medicament having inhibitory activity against prolactin secretion and stimulating activity of dopaminergic receptors. 10. The compounds corresponding to the following formulas II and VI 20 Q 11 ^ CO-NHRj II H H 25 ”. • Γ4 H C0 "N O T T ^ *“ * 3 VI H, 30 °° Β3. In which Rg, R3, R'4 and R5 have the meanings given in claims 1 and 8.