AU604512B2 - Octahydrobenzo(g)quinoline-3beta-carbonyl derivatives useful as dopamine receptor stimulating and prolactin secretion inhibiting agents - Google Patents

Description

I

I COMMONWEALT H OF 'AUSTRALIA PATENT ACT 1952 COMPLETE

SPECIFICATION

(ORIGINAL)

FOR OFFICE USE CLASS INT. CLASS Application Number: Lodged: 6 c o V etz 0 0 0 0 a it a* CV t V Complete Specification Lodged: Accepted: Published: Priority: Related Art-: a.r~ndn'ants l 1 i

L

z C V t C C Ct C r C S t C 'C 1 C CC C

C

NAME OF APPLICANT: JDDRESS OF APPLICANT: NAME(S) OF INVENTOR(S) SANDOZ LTD.

CH-4002 Basle,

SWITZERLAND.

Cyril MAHAIM, Christos PAPAGEORGIOU, Trevor James PETCHER ADDRESS FOR SERVICE: DAVIES COLLISON, Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: "Octahydrobenzo[g]quinoline-3 3-carbonyl-urea derivatives useful as dopamine receptor stimulating and prolactin secretion inhibiting agents".

The following statement is a full description of this invention, including the best method of performing it known to us /0 -1- 4 6~ 100-6965

-IA-

"Octahydrobenzo[gjquinolinie-3 p-carbonyl-urea derivatives useful as dopamine receptor stimulating and prolactin secretion inhlibiting agents".

This invention relates to octahydrobenzo[glquinolines.

The present invention provides a compound of formula I 11

H

I

ii

A~

66@0 06 66 6 0666 0 6006 6606 6 ~0 00 060000 o 6 6 66 0 6 60 66 o p 066 06 6 0 6 660 0? 6 0 660 0 60 0 0 to to 6 6 00 0 6(66 (C 0 C NCC; NH-R3 wherein is alkyl of 1 to 4 C-atoms, ally] or 2-propinyl, cine of groups and R 3 is alkyl of 1' to 4 C-atoms and the other of these groups and R 3 is a group of formula (CH 6 2 n R -7 wherein and R P independently of one another,

C

2

H

5 is 2 3 or 4, and R 5 independently of one another, hydroxy, methoxy, alkanoyloxy of 1 to or benzoyloxy, with the proviso that simultaneously be hydrogen, a ne C H 3 or are hydrogen, 4 C-atoms both cannot in free base form or in acid addition salt form, in (3R,4aR,lOaR) or (3S,4aS,l0aS) optical isomer form or in the form of a mixture of these isomers.

aT 100-6965 totC t C C rr c

SCC

C

tOf* C CC

CC

In the above formula, as well as in the following description and inthe claims, the formulae of the octahydrobenzo- [g]quinolines cover not just the single stereoisomer shown, but als.o optical antipodes thereof and mixtures of the optical isomers, e.g. racemates.

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

The compounds: of formula I may exist in the free base form or in acid addition salt form. The free base forms can be converted in conventional manner into their acid addition salt forms, and vice versa. Thus, the compounds of formula I may form acid addition salt forms, e.g. with inorganic acids such as hydrochloric acid or with organic acids such as maleic acid.

In formula I the following individual definitions and their combinations are preferred:- C t (CCC C r c R, is n-propyl or allyl

R

6 R is -(CH 2 )n-N 2 2)n- kis, especially -(CH2) -NC 3 2 "CH 3 alkyl, especially ethyl is OH or OCH 3 is hydrogen.

The present invention also provides a process for the production of .a compound of formula I 100-6965 wherein a) in order to produce a compound of formula I, wherein R 4 and R 5 independently of one another are hydrogen or |methoxy, with the proviso that both cannot simultaneously be hydrogen, a compound of-formula II 0000 0 oo 14

CO

N

/R2 H

H

o

II

wherein R4 and/or R5 are methoxy, is N-alkylated in 0 position 1, or :I t b) in order to produce a compound of formula I, wherein R 4 S and R 5 independently of one another, are hydrogen or hydroxy, with the proviso that both cannot simultane- St, ously be hydrogen, a compound of formula I, wherein R 4 and/or R 5 are methoxy,. undergoes ether cleavage, or c) in order to produce a compound of formula I, wherein R 4 and R 5 independently of one another, are hydrogen, alkanoyloxy of 1 to 4 C-atoms or benzoyloxy, with the proviso that both cannot simultaneously be hydrogen, a compound of formula I, wherein R4 and/or R 5 are hydroxy, is reacted with an alkanoic acid of 1 to 4 C-atoms or with benzoic acid or with a reactive derivative of such an ac'd and the compound of formula I is isolated in free base form or acid addition salt form.

100-6965 Process a) may be effected in conventional manner for an N-alkylation process. It may take place, e.g. by means of a reaction with a compound of formula R 1 Z, wherein Z is a leaving group. Z preferably signifies Cl, Br, I or the acid group of an organic sulphonic acid, e.g. methanesulphonyloxy or p-toxyloxy. The reaction is preferably carried out in the presence of an acid-binding agent, e.g. Na 2

CO

3 or an o"0o. organic base.

The ether cleavage of process b) may take place in conveno tional manner, e.g. using reactive derivatives of the S° above-mentioned acids, preferably acid halides or acid o anhydrides.

The acylation of process c) may be effected in conventional 1 manner, e.g. using reactive derivatives of the above-mentioned oo oacids, preferably acid halides or acid anhydrides. I The starting compounds of formula II may be produced for o example as follows:- 1) a compound of formula III is isomerized in a basic Smedium to form a compound of formula IV,with simultaneously hydrolysis of the ester group to a carboxyl group:- II Iv l h~ N H H H, OCH3

OCH

2) a compound of formula IV is reacted with a carbodiimide of formula V N-- I, 100-6965 6

R

8 -N C N-(CH 2 )n-N V

R

7 wherein R 8 is alkyl of 1 to 4 C-atoms, to form a compound of formula VI 1 O IjR3 V

I

SCO-N

H stee OCH 3 StCC "cC This process may be carried out using processes which are known in general for the production of ureides from carboxylic acids and carbodi.imides.

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

If required, an organic base such as N-ethyl-diisopropylamine can be added. In this reaction there may be produced Sboth compounds of formula VI wherein R is

-(CH

2 )n' 1 6 and R 3 is alkyl, and those wherein R 2 is alkvl and R 3 is ~(CH n -n i P7 These two compounds can be separated from one another in conventional manner, e.g. by selective crystallisation or by chromatography.

3) the OCH 3 group in position 1 of a compound of formula VI is cleaved to produce a compound of formula II.

This cleavage may preferably take place by reduction, e.g.using zinc and acetic acid.

S- Al 100-6965 Compounds of formula II, IV, V and VII are new and form per se part of the invention.

Insofar as the production of any particular compound is not particularly described, e.g. compounds of formula III, these are known or may be produced in conventional manner or in analogous manner to those described n the literature l or those described in the examples.

a t Individual optical isomers may be produced from pure eve optically active starting materials, e.g. an optically S'P active compound of formula III.

Racemic mixtures may be separated into individual optical i isomers-, e.g. by using chromatography through supports I l c bearing optically active compounds.

i In the following examples all temperatures are given in degr Celsius and are uncorrected.

I t In the examples hereinafter the racemates are characterised i, with the name in the a/P system 3 ,4aa,10ap) followed by the designation (racemate).

A\ .i 100-6965 EXAMPLE 1: 1-ethyl-3-(3-dimethylaminopropyl)-3-(l-allyl-6methoxy-1 ,2,3,4,4aa,5 ,l0,1 0a -octahydrobenzo[gJ- 9yinol ine.-gc bn -ra(aeat 900 mg of 1-ethyl-3-(3-dimethylaminopropyl)-3-(6-methoxy- 1,2,3,4,4aa,5,l0,10a -octahydrobenzo~glquinoline-3 -carbofyl)-urea (racemate) are dissolved in 9 ml of dimethylforma- 00 a a00 mide, then mixed with 340 mg of Na 200O3 and 0.18 ml of allyl 0000bromide, and sti rred for 6 hours at room temperature. The Coco 0000 reaction mixture is then poured onto water and extracted 000004 with ethyl acetate.

00 0 o 0 0. 1 After drying and evaporation, the title compound is obtained 0 o is flash chromatographed over basic silica gel with CH C1 2 CH 3 0H 5% ammonia solution The dihydrochloride of the title compound obtained melts at 1850 (with foaming).

The starting material may be produced as follows:- C tC C a)0 g fl-meth~'axy-amtocroriyl-6-hxy12 ,234,a,5lla-ot- 4ac5,l0,10a octahydrobenzo[glquinoline (racemate), 40 ml of ethanol, 5 ml of water and 2.0 g of KOH are added together and refluxed overnight. In the morning, the mi xtur-e is concentrated, poured onto 2N HCl and the precipitated white solid is filtered off by suction. M~p.

of the title compound. ca. 2150C.

100 -6 965 b 1-ethyl-3-(3-dimethylafminopropyl)-3-(1-methoxy-6-methoxyl,2,3,4,4aa,5,l0,10afp-octahydrobenzo[glquinoline-3 carbon~jl: -urea 500mg of the end product of stage 323 mg of N-ethyl- N'-(3'-dimethylaminopropyl)-carbodiimide, 0,36 ml of Nethyliisopropylamine and 10 ml of tetrahydrofuran are 0 04 QQIV t'added together and boiled overnight under argon. In the t morning, the mixture is concentrated by evaporation. The colourless resinous residue is dissolved in CH 2 C1 2 and i s shaken twice with 2N NaOH, Subsequently, the CH Cl 2 solution is shakpn twice with 2n HCl, the acidic phase is rendered alkaline with conc. NaOH and extracted with CH C1 2 The organic phase is dried and concentrated by evaporation.

The residue obtained is a colourless resin which is dissolved in a little CH C1 2 and flash chromatographed with K CH Cl 2 4% CH OH. The isomer 3-ethyl-l-(3-dimethyiaminopropyl)-3-(I-methoxy-6-methoxy-1,2,3,4,4aa,5,10,loa -octa- V K hydrobenzotglquinoline-3p-carbonyl)-urea is obtained as the second product.

c) l-ethyl-3 -(3-dimethylaminopropyl)-3-(6-methoxy-l,2,3,4,- 4aa,5,10,10ap-octahydrobenzo~glquinoline-3 -carbonyl)urea (racemate 1.64 g of the end product of stage b) are suspended in 20 ml of acetic acid and 10 ml of water, and then 5.8 g of zinc dust are added in portions whilst stirring at room temperature, whereby an exothermic reaction is observed. After this addition, stirring continues for 6 hours at room temperature.

i-^ 100-6965 The mixture is subsequently filtered and washed with water and ethyl acetate. The filtrate is concentrated, mixed with NaHCO 3 solution and extracted with ethyl acetate. The organic phase is washed once with brine, dried and concentrated. The title compound is obtained.

0000 oe0o EXAMPLE 2: 1-ethyl-3-(3-dimethylaminopropyl)-3-(1-propyl-6o methoxy-1,2,3,4,4aa,5,10,10ap-octahydrobenzo[g]- 0 000000 coo* guinoline-3IB-carbong}-urearacemate 0 0 Soo The title compound is produced analogously to example 1.

M.p. of the dihydrochloride (foam) ca. 140 0 C with decomposition.

0 00 °0 0 EXAMPLE 3: 0 e The (3R,4aR,10aR) optical isomer of the title compound of 0 So00 example 1 is obtained from the corresponding (-)(3S,4aR,10aR) 0000 1-methoxy-3 -carboxy-6-methoxy-1 ,2,3,4,4aa,5 10,10a -octabo hydrobenzo[g]quino line.

000000 The compounds of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, have interesting pharmacological properties and are therefore indicated for use in therapy.

In particular, the compounds of formula I possess dopaminergic activity (dopamine receptor stimulating activity) and prolactin (PRL) secretion inhibiting activity. This activity may be demonstrated e.g. by the inhibition of basal prolactin secretion of male rats using the method of E.FlUckiger et al'. (Experientia 34, 1330, 1978). In this test, the compounds are shown to be active at doses of from about 0.005 to about 0.1 mg/kg s.c.

-MMM_

ii C- i II

C

t 100-6965 000, a O 0000 0 0 0000 0009 0 0 0 0 0 a0 00 0 0 00 00 0 0 o oo a 0 o00 Go i 0o o

,I

00 I 000 I 0 1 In addition, when administered perorally at doses of ca. 0.03 to 0.5 mg/kg poo. the compounds have long-lasting activity, e.g. when compared to bromocriptine.

The compound of example 1 is the preferred racemate compound. The 3R,4aR,1OaR isomer is the preferred isomer.

Because of their PRL secretion inhibiting activity, the compounds of formula I in free base form or in pharmaceutically acceptable acid addition salt form are indicated for use as prolactin secretion inhibitors, e.g. the treatment of illnesses in which a reduction of the PRL level is desired, e.g. in the treatment of galactorrhoea, in the treatment of PRL-dependent menstrual" disorders, e.g. amenorrhoea, to prevent lactation, and in the treatment of hyperprolactinemic hypogonadism of men and women, and in the treatment of prolactinomas. Because of their dopaminergic activity the compounds are also indicated for use in Morbus Parkinson.

The prolactin secretion inhibiting activity is the preferred indication.

An indicated daily dose is from about 0.5 to about 10 mg> conveniently administered once-a-day or if desired once up to 5 days.

Unit dosages may contain from about 0.5 to about 50 mg.

The compounds of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, may be administered enterally (for example as -11- 100-6965 tablets or capsules) or parenterally as injection solutions or suspensions). If desired they may also be j used in sustained release form.

The invention also provides pharmaceutical compositions which comprise a compound of formula I in free base form or pharmaceutically acceptable acid addition salt form in association with a pharmaceutical diluent or tablet.

SThese compositions, for example, a solution or a tablet,

S

c can be produced in conventional methods, using conven- "c tional adjuvants and carriers.

C c The invention also relates to the compounds of formula I in free base form or in pharmaceutically acceptable acid addition salt form for use in therapy, especially i ofor use as prolactin inhibitors and dopaminergic g agents, e.g. for any of the above indicated indications, oo

Claims (2)

1-A compound of formula I w h er ein is alkyl of 1 to 4 C-atoms, allyl or 2-propinyl, one of groups R 2 and R3is alkyl of 1, to 4 C-atoms and the other of these groups and R 3 is a group of formula 9 t C C at t I t A, (CH where in tC V I C t C and R 7 9 independently of one another, C 2 H i s 2 3 or 4 and independently of one another, hydroxy, methoxy, alkanoyloxy of 1 to or benzoyloxy, with the proviso that simultaneously be hydrogen, CH 3 or are hydrogen, 4 C-atoms both cannot in free base form or in .acid addition salt form, in (3R,4aR,lOaR) or (3S,4aS,lOaS) optical isomer form, or in the form of a mixture of these isomers. -13-

100-6965 AUSTRALIA 2. A compound of claim 1 in free base form or in acid addition salt form, in individual isomer form, in free base form or in acid addition salt form. 3. A compound of claim 2 in free base form or in acid addition salt form, having the configuration shown in claim 1. 4, An antipode of a compound of claim 3 in free base form or in acid addition salt form. A compound of claim 1 which is 1-ethyl-3-(3-dimethyl- aminopropyl)-3-(l-allyl-6-methoxy- ,2,3,4,4aa,5,10,l0aS- octahydrobenzo[g]-quinoline-3p-carbonyl)-urea in free base Sform or in acid addition salt form. 6. A compound of claim 5 in racemate form, 7, A compound of claim 5 in the form of the (3R,4aR,1OaR) isomer, 8. A compound of claim 1 which is 1-ethyl-3-(3-dimethyl- aminopropyl )-3-(1-propyl-6-methoxy-1 .2,3,4,4aa,,5;10,10a5- octahydrobenzo[g]-quinoline-3p-carbonyl)-urea in free base form or in acid addition salt form. t ®r -1JE -14- 9. A process for the production of a compound of formula I as defined in claim 1 wherein a) in order to produce a compound of formula I, wherein R 4 and R 5 independently of one another are hydrogen or methoxy, with the proviso that both cannot simultaneously be hydrogen, a compound of formula II R /R R CO-N 2 Q0 CO-HR 3 II wherein R 4 and/or R 5 are methoxy, is N-alkylated in position 1, or b) in order to produce a compound of formula I, wherein o R 4 and R 5 independently of one another, are "Getz hydrogen or hydroxy, with the proviso that both cannot simultaneously be hydrogen, 20 a compound of formula I, wherein R 4 and/or R 5 are methoxy, undergoes either cleavage, or c) in order to produce a compound of formula I, wherein R 4 and R 5 independently of one another, are hydrogen, alkanoyloxy of 1 to 4 C-atoms or 1 c benzoyloxy, with the proviso that both cannot S'simultaneously be hydrogen, a compound of formula I, wherein.R 4 and/or R 5 are hydroxy, is reacted with an alkanoic acid of 1 to 4 .a 30 C-atoms or with benzoic acid or with a reactive derivative of such an acid and the compound of i C formula I is isolated in free base form or acid SCfc addition salt form. 10. A pharmaceutical composition comprising a compound of claim 1 in free base form or pharmaceutically 41 7 -g o let03 ,dbl186170.spec,14 acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. 11. A method of inducing prolactin secretion inhibiting activity or dopaminergic receptor agonist activity in a subject which comprises administering a compound of claim 1 in free base form or pharmaceutically acceptable acid addition salt form to a subject in need of such treatment. 12. A compound of formula II 4a R -R 5 CO-N 2 1lO CO-NHR 3 i| t a compound of formula IV SH IV OCH3 H3 or a compound of formula VI 4 H R2 VI OCH 3 30 wherein R 2 and R 3 are as defined in claim 1 and wherein R4 and/or R5 are methoxy. DATED this 14th day of September, 1990 Sandoz Ltd. SBy Its Patent Attorneys 1 I DAVIES COLLISON 9009 -d51ieL034,dbl186170.spec,15