AU646485B2 - Indolonaphthyridines, their production and use - Google Patents

Indolonaphthyridines, their production and use Download PDF

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AU646485B2
AU646485B2 AU82711/91A AU8271191A AU646485B2 AU 646485 B2 AU646485 B2 AU 646485B2 AU 82711/91 A AU82711/91 A AU 82711/91A AU 8271191 A AU8271191 A AU 8271191A AU 646485 B2 AU646485 B2 AU 646485B2
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alkyl
hydrogen
acid addition
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Joachim Nozulak
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Sandoz AG
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Description

46L
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Sandoz Ltd.
-DRESS FOR SERVICE: 0 0S0gS~ 0 0* 0e 0
S.
0*
S
S SO
S
SS*@ SO S S 5.5.
S S *5 0
US
S 0@ S S 5550 a 0
S.
DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.
INVEN4TION TITLE: "Indolonaplithyridines, their production and use".
The following statement is a full description of this invention, including the best method of performing it known to me/us:- -la The present invention relates to new 7 a,8,9,1Q,11,lla-hexahydro and 4 5 ,7a,8,9,1O,11,lla-octahydro-7H-indolofl,7-bcj [2,6Jnaphthyridines.
These compounds, hereinafter referred to as new compounds, are compounds of formula I
U
U U U. 0 0S
U.
U.
0* 0*UU
U
UO U UO U
U.
U.
U
OUUU
*0 U
U.
0* x y wherein R, is hydrogen, alkyl, alkylcarbonylalkyl, arylcarbonylalkyl, aralkyl or carbamoylalkyl optionally mono- or disubstituted by alkyl or aryl, 2 100-7683
R
2 is as defined for RI and may additionally be trifluoromethyl, alkoxy or alkylthio,
R
3
R
4 and R 5 independently are hydrogen, halogen, alkyl, alkoxy, alkylthio or trifluoromethyl and X and Y are each hydrogen or form together a single bond, in free base or acid addition salt form.
Depending on the substituents the new compounds may present two (in position 7a and lla) or more asymmetrical carbon atoms. The invention includes all resulting stereomers as well as their mixtures, e.g. the racemic mixtures of the enantiomers.
*9* SSo. In position 7a and lla the configuration of the new compounds may be cis or trans.
Any alkyl, alkoxy or alkylthio group as well as any alkyl moiety in an alkylcarbonylalkyl, arylcarbonylalkyl, aralkyl or optionally substituted carbamoylalkyl group of a new compound contains 1 to 4 carbon atoms.
An aryl moiety in an arylcarbonylakyl, aralkyl or arylcarbamoylalkyl group is a five or six membered, saturated, unsaturated or aromatic carbocyclic ring optionally mono-, di- or trisubstituted by above-defined alkyl, alkoxy or alkylthio, wherein one or two *o* carbon atoms may be replaced by nitrogen.
ef Halogen is fluorine, chlorine, bromine or iodine.
Insofar as above-defined alkyl, alkoxy or alkylthio groups are present in the new compounds, these preferably have one or two carbon atoms and especially signify methyl, methoxy or methylthio.
3 100-7683 An above-defined halogen is preferably fluorine or chlorine.
RI is preferably alkyl, particularly methyl. R 2
R
3
R
4 and R are preferably hydrogen. Preferably X and Y each are hydrogen.
The invention includes for example a group of compounds of formula I, wherein RL is (Ci- 4 )alkyl and R 2
R
3
R
4 Rs, X and Y are each hydrogen, in free base or acid addition salt form.
The invention also includes a group of compounds of formula I, wherein R 1 is (C 1 4 )alkyl, R 2
R
3
R
4 and R 5 are each hydrogen I and X and Y together form a single bond, in free base form or acid addition salt form.
The preferred compound is the (+)-cis-4,5,7a,8,9,10,11,11aoctahydro-7H-10-methyl-indolo[1,7-bc][2,6]naphthyridine in free base or acid addition salt form.
The present invention also provides a process for the production of a compound of formula I or an acid addition salt thereof, which includes the step of a for the production of a compound of formula Ia
R
99 9 N R go Ia I
I
4 100-7 683 wherein R 1
R
2
R
3
R
4 and R 5 are as defined above, replacing under reduction of the 7-oxo group the lO-ethoxycarbonyl group of a compound of formula II 0 0 000000 0 0 0*0 0 Ot o .0 0 0 00 R 4 R wherein R 2
R
3
R
4 and R 5 are as
R
1 or 0I defined above, by the group b) for the production of a compound of formula lb SO 00 0 *000 0* OS 0 0* 0 0 00 00 0 6 00 0 00 00 wherein R 1
R
2
R
3
R
4 and R 5 a compound of formula Ia, are as defined above, oxidating and recovering the thus obtained compound of formula I in free base or acid additinri salt form.
5 100-7683 The reaction according to process a) may take place by known methods.
To introduce a methyl group, the ethoxycarbonyl group can be reduced in known manner, e.g. using aluminium hydride or complex aluminium hydrides such as lithium aluminium hydride.
To introduce a higher alkyl or a substituted alkyl group, the ethoxycarbonyl group can be firstly cleaved and the amine obtained can then be alkylated.
Oxidation of the compounds of formula la according to process b) may be carried out by known methods, for example using manganese oxide. 0 2 /cobalt salts in methanol, palladium dichloride in triethylamine or benzene-selenic anhydride may also be used.
S*
Working up of the obtained reaction mixtures and purification of the compounds of formula I thus obtained may take place in accordance with known methods.
Acid addition salts may be produced in known manner from the free bases, and vice versa.
SS
The process according to the invention may be effected using starting products in the form of individual, optically active isomers or mixtures thereof, especially the racemates thereof, thus resulting in the corresponding end products.
The racemates can be split into individual, optically active components, whereby known methods are employed, e.g. via transient acid addition salt formation with optically active acids, e.g. (-)]-di-O,0'-p-toluoyl-D-(-)-[resp.
L-(+)]-tartaric acid, and fracticnal crystallisation of the diastereoisomeric acid addition salts.
6 100-7683 The starting compounds of formula II may be produced by commencing with isonicotinic acid chloride (known from Beilstein 4, vol. 22/1, page 526) and indoline (known from Beilstein 4, vol. 20/4, page 2896) or with deriatives thereof which can be produced according to known methods, in accordance with the following reaction scheme, e.g. as described in example 1 under a) to e): &fe* &*see0 68S 7- 100-763
H
R R R 3
R
R 3 z 4 V
I
-*of 0.
too to N NaBH~ 4
IV
IClr 2 Et 1. hy' 2. Diaster.trennung 8 100-7683 The 7a,8,9,10,11,lla-hexahydro- and 4,5,7a,8,9,10,11,11a-octahydro-7H-indolo[l,7-bc][2,6]naphthyridines and their physiologically acceptable acid addition salts, hereinafter referred to as compounds according to the inventio' exhibit interesting pharmacological activities in animal tests and are, therefore, useful as pharmaceuticals.
In particular, the compounds according to the invention have an antagonist effect at the central 5HT-1C receptors.
The compounds according to the invention have a potent binding affinity to central 5HT-1C receptors as e.g. measured according 9 0 to the method disclosed by D. Hoyer et al., Eur. J. Pharm., 118, 13 23 (1985). The compound of Example 5 has a pKD value of 7.8.
9* The compounds according to the invention antagonise the hypolocomotion induced in rats by administration of m-chlorophenylpiperazine (mCPP) according to the method disclosed by G. A. Kennett and G. Curzon, Br. J. Pharmacol., 94, 137 147 9 (1988). In this test the compounds according to the invention counteract the mCPP reduced locomotion after administration at dosages of from about 0.5 to 30 mg/kg p.o.
The compounds according to the invention are therefore useful for the prophylactic treatment of migraine or for the treatment of disorders e.g. anxiety, depression, schizophrenia, autism, obsessive compulsive disorders, panic attacks, priapism, bulimia and situations of increased intracranial pressure.
An indicated daily dosage is in the range from about 0.5 to about 300 mg of a compound according to the invention, together with solid or liquid carriers or diluents.
9 100-7683 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 prophylactic treatment of migraine or for the treatment of disorders e.g. anxiety, depression, schizophrenia, autism, obsessive compulsive disorders, panic attacks, priapism, bulimia and situations of increased intracranial pressure.
The present invention furthermore provides a pharmaceutical composition 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.
o, In the following examples, all temperatures are uncorrected and Sare in degrees Centigrade.
go
SO
0O o 10 100-7683 EXAMPLE 1: cis-4,5,7a,8,9,10,11,lla-octahydro-7H-10-methylindolo[1,7-bc][2,6]naphthyridine 2.03 g (53.4 mmols) of lithium aluminium hydride (aluminium hydride can also be used) are placed at 00 in absolute tetrahyatofuran. A solution of 1.61 g (5.36 mmols) of cis-4,5,7a,8,9,- 10,11,lla-octahydro-7-oxo-7H-indolo[l,7-bc][2,6]naphthyridine-10carbamic acid ethyl ester in absolute tetrahydrofuran is subsequently added in drops. The reaction mixture is refluxed for three hours and subsequently left to stand for 12 hours at room temperature. Afterwards, the reaction solution is cooled to -200 and water is added in drops. The product is extracted wih toluene. The toluene phase is dried and concentrated by Sevaporation. cis-4,5,7a,8,9,,10,lla-octahydro-7H-10-methyl- Sindolo[l,7-bc][2,6]naphthyridine is obtained as a yellow oil. The *s cruud product is dissolved in acetone and mixed with the equivalent quantity of malonic acid. After crystallisation from methanol/acetone, the cis-4,5,7a,8,9,10,1,lla-octahydro-7H-10methyl-indolo[l,7-bc][2,6]naphthyridine malonate is obtained with the melting point 158 1590.
The starting material may be produced as follows: a) 2,3-dihydro-l-(4-pyridinylcarbonyl)-1H-indole 327 g (2.05 mols) of isonicotinic acid chloride hydrochloride are placed in methylene chloride (the hydrochloride is prepared by reacting isonicotinic acid hydrochloride in thionyl chloride according to a conventional process). To the solution are added in drops at 200 532 ml (3.69 mols) of triethylamine, followed by 206 ml (1.84 mols) of indoline dissolved in methylene chloride. The mixture is stirred for 16 hours at 200. Afterwards, the preparation is washed with water, the organic phase is dried and concentrate by 11 100-7683 evaporation. 2,3-dihydro-l-(4-pyridinylcarbonyl)-1H-indole is obtained with a melting point of 127 1280 (crystallisation from methylene chloride/ethanol/hexane).
b) 4-(2,3-dihydro-lH-indol-1-yl-carbonyl)-l-methylpyridiniumiodide 224 g (1 mol) of 2,3-dihydro-l-(4-pyridinylcarbonyl)-1Hindole are suspended in acetone. The suspension is heated to reflux, and 137.6 ml (2.21 mols) of methyl iodide are added in drops. After 45 minutes, a further 68.8 ml (1.1 mols) of methyl iodide are added. The reaction mixture is refluxed for a further 2 hours. Afterwards, the crystallised product is filtered off, washed with ether and dried. 4-(2,3-dihydro-1Hindol-l-yl-carbonyl)-l-methylpyridinium-iodide is obtained in the form of yellow crystals. It has a melting point of 242 2430 (crystallisation acetone/ether).
c) 2,3-dihydro-l-(1,2,3,6-tetrahydro-l-methyl-4-pyridinyls* carbonyl)-lH-indole 308 g (0.84 mols) of 4-(2,3-dihydro-H1-indol-l-yl-carbonyl)- 1-methylpyridinium-iodide are suspended in ethanol. The solution is cooled to +100. A mixture of 95.9 g (2.52 mols) of sodium borohydride in 960 ml of water and 96 ml of caustic soda is added in drops whilst stirring intensely.
Stirring subsequently continues for 2 hours at room temperature. Afterwards, the reaction mixture is concentrated on a rotary evaporator. The residue is mixed with ice water and methylene chloride. The orga phase is separated and the product is extracted therefrom with 2 n hydrochloric acid. The aqueous solution containing hydrochloric acid is rendered alkaline with 30% caustic soda, and the product is extracted with methylene chloride. The organic phase is dried 12 100-7683 and concentrated by evaporation. 2,3--dihydro-1-(1,2,3,6tetrahydro-1-methyl-4-pyridinylcarbonyl)-1H-indole is obtained with a melting point of 70 720 (crystallisation from ether/petroleum ether).
d) 4-(2 ,3-dihydro-lH-indol-1-yl-carbonyl)-1 6-tetrahydro-lpyridine-carbamic acid ethyl ester 145.4 g (0.6 mols) of 2,3-dihydro-l-kl,2,3,6-tetrahydro-lmethyl-4-pyridinylcarbonyl)-fl-indole are placed in toluene.
156.6 ml of N-ethyldiisopropylamine are added and heated to 800. At the same temperature, a solution of 196.8 ml mols) of chloroformic acid ethyl ester in toluene is added to the reaction mixture in drops. The mixture is stirred for 2 hours at 800 and subsequently cooled to 00. The preparation is mixed with water-ice and washed with 2 n hydrochloric acid. The toluene phase is separated, dried and concentrated by evaporatioa. 3-dihydro-1H-indol-1-ylcarbonyl)-1,2,31,6-tetrahydro.-l-pyridinecarbamic acid ethyl ester is obtained with a melting point of 112 -1l3* ~:.(crystallisation from methyl-tert.butylether/ether).
cis-4,5,7a,8,9,10,11,lla-octahydro-7-oxo-7H-indololl,7-bcj-, [2,61naphthyridine-10-carbaaic acid ethyl ester 0: 2.0 g (6.7 mmols) of 4-(2,3--dihydro-11-indol-1-yl-carbomyl)- ,2,3,6-tetrahydro-l-pyridinecarbamic acid ethyl ester in toluene are irradiated under argon, whilst stirring, with a 400 watt mercury high-pressure lamp. The reaction vessel is cooled under running water. After ar. interval of 12 hours, the dipping lamp is cleaned and the reaction solution is treated with 3 mol active charcoal and filtered over Hyflo.
After a total of 50 hours irradiation, the toluene is evaporated. The crude product is purified by column chromato- 13 100-7683 graphy (silica gel) and the cis/trans diastereoisomers are thus separated. cis- 4 ,5,7a,8,9,10,1l,lla-octahydro-7-oxo-71indolo[l,7-bcl[2,6]naphthyridine-10-carbamic acid ethyl ester is obtained as an oil.
IR(CH
2 C1 2 r 1665 cm [e-11 (amide 1690 cm [~e-11 (carbamate C=0).
1H-NMR(D6-DMSO), 360 MHz d (ppm) 1.20 J 7.5 Hz; 3H, carbamate-0H3); 4.08 J -7.5 Hz; 2H, carbamate-CH2).
S
.0*0 OS 0 XML 2:00(xape1) trans-4,5, 7a,8,9, 10, 11,lla-octahydro-7H-10-methylindoloil, doo[ 7-bcJ 6lnisptaiinedwtthme in poi 100 -rodctio cor eonds tothat of the cis-diatereoisotemltn 00.
so 0 (eaml 1) trans-4,5,7a,8 ,9,10,l1,llataydr i2ndolol,7-bci26n -arthyiin ais otainedsth hemltn Poutio 102 rre103 nd(ether hae) As the malonaateewih hmeltn eaml Ie.trans-4,5,7a,8,9, 10,11, lla-octahydro-7-oxo-7H-idl[,7b- [2 nlo[thyridi,naphhyidie-0arbauic acid ethyl ester i Th Pr odu ing coeponds tof thtofl the pis dusedeoisogoer t example 1:e.tas457,,,011laothdo--x-H 14 100-7683 Example RI config. rn.p. of dihydrochioride 3 ethyl 280 2810 4 n-propyl 294 2960 EXAMPLE 5: 7a,8,9,lO, 11, lla-octahydro-7H-10-methylindolo[11,7-bc][12,61 naplithyridine 13.57 g (59 mmols) of (+/-)-cis-4,5,7a,8,9,1Q,11,lla-octahydro- 0 a 7H-10-methyl-indolo[1,7-bc][12,6]naphthyridine (for preparation :see example 1) are dissolved in acetone. This solution is mixed with 23.92 g (59 mmols) of (-)-di-0,0'-p-toluyl-L-tartaric acid monohydrate in acetone. The solution is concentrated, mixed with ether and the crystallised salt is filtered off and washed with acetone/ether. The salt is recrystallised from ethanol/acetone see*&:until reaching a constant rotatory value [to obtain the a 6 (-)-enantiomer (example the mother liquors are collected 000:0 00 separately]. (-)-di-O,0'-p-toluyl-L-tartrate is obtained with a as melting point of 158 1590 and the rotatory value of -461 (c= 0e 0.5, methanol). The base is released from the crystallisate having constant rotatory value by adding ice/conc. ammonia solution and methylene chloride. (+)-cis-4,5,7a,8,9,l0,11,lla- *00* octahydro-7H-10-methyl-indolo[1,7-bc] [2,6]naphthyridine is .:obtained with the rotatory value 1320 (c 0.5; methanol). The base crystallises as the malonate with the melting point 129 (crystallisation from acetone/ether) and the rotatory value +71* (c 0.5; methanol).
15 100-7683 EXAMPLE 6: 4 ,5,7a,8,9,10,11,lla-octahydro-7-10-methyl.
indolo [1,7-bc] (2,61 naphthyridine Preparation is from (+/-)-cis-4,5,7a,8,9,1O,11,lla-octahydro-7H- 10-methyl-indolo[1,7-bc] [2,6]naphthyridine (example 1) or from the collected mother liquors of (+)-enantiomer production, using (+)-di-0,0'-p-toluyl-D-tartaric acid. The process is analogous to the preparation of the (+)-enantiomer (example toluyl-D-tartrate is obtained with the melting point 160 1610 (methamol/acetoaie) and the rotatory value +460 (c methanol). After release of the base, (-)-cis-4,5,7a,8,9,10,11,lla-octahydro-7H-10-methyl-indolo[1,7-bc] [2,6]naphthyridine is obtained with the rotatory value -13QO (c 0.5, methanol). The base crystallises as the malonate with the melting point 129 1300 (acetone/ether) and the rotatory value -75* (c S. methanol).
EXAMPLE 7: cis-7a,8,9,10,11,lla-hexahydro-10-uaethyl-7H-indolo- [2,61naphthyridine '200 mg (0.9 mmols) of cis-4,5,7a,8,9,10,11,lla-octahydro-7H-10- 0 00methyl-indolo[1,7-bc] 12,6]naphthyridine (example 1) are dissolved so in methylene chloride. 2.00 g of manganese(IV)oxide (precipitated active) are added whilst stirring at 200. Stirring is effected for 4 hours at room temperature, the reaction mixture is subsequently filtered over Hyflo and the methylene chloride filtrate is concentrated by evaporation. After crystallisation from ether, cis-7a,8,9,10,l1,11a-iiexahydro-10-methyl-7H-indolo- 11,7-bc][2,6]naphthyridine is obtained with the melting point 125 1260.
1H-NMR, 360 MHz (CDCl3): d (ppm) 2.31 3H, 10-N-CH3).
As the hydrogen fumarate, the compound has the melting point 1270 (decomp.).
16 6 -100-768 3 EXAMPLE 8: trans-7a, 8,9,10,11, lla-hexahydro-l0-methyl-71indolo[1,7-bcJ [2,6]naphthyridine Production corresponds to that of the cis-diastereoisomer (example trans-7a,8,9,10,11,lla-hexahydro-10-methyl-71indolo[1,7-bc]l2,6]naphthyridine is obtained with the melting point 143 1450 (crystallisation from ethanol).
1H-NMR, 360 MHz(CDCl3): d (ppm) =2.45 3H, 10-N-0H3); 6.44 (in; 1H1, C-4-H).
The starting material mybe prdcda olows: a) trans-4,5,7a,8,9, 10,11, lla-octahydro-7-oxo-7H-indolo[1, 7-bc]- 6]naphthyridine-10-carbamic acid ethyl ester S**Production corresponds to that of the cis-dlastereoisomer (example 1 trans-4,5,7a,8,9,10,11,lla-octahydro-7-oxo-7Hindolo[1,7-bcJ (2,6]naphthyridine-10-carbamic acid ethyl ester is obtained with a melting point of 132 1330 (crystallisation from methyl-tert utylether).
b) trans-4,5,7a,8,9, 10,11, lla-octa hydro-7H-1O-uethyl-indolo- [1,7-bel [2,6Jnaphthyridine Production corresponds to that of the cis-diastereoisomer (example trans-4,5,7a,8,9,l0,ll,lla-octahydro-7H-10- *methyl-indolo[1,7-bc][2,6]naphthyridine is obtained with a melting point of 102 1030 (ether/hexane). As the malonate with a melting point of 155 1560 (acetone/methanol).
The following compounds of formula I, wherein R 2
R
4
R
5 X and Y are hydrogen, are produced analogously to example 7: 17 100-7682 Example R, R 3 conf ig. M. P.
9 ethyl R 156-158* (hydrogen maleinate) n-propyl H 105-1070 (hydrogen maleinate) 11 methyl 2-Cl (±)-trans 3240 (detomp.) (hydrochloride) EXAMPLE 12: (-)-cis-7a,8,9,1O,i,lla-hexahydro-1O-methyl-7Blindolol 1,7-bc] 6]naphthyridine 16.10 g (71 mmols) of (+/-)-cis-7a,B,9,10,11,lla-hexahydro-10methyl-7H-indololl,7-bcl (2,6]naphthyridine (for production see example 7) are dissolved in acetone. This solution is mixed with 28.80 g (71 mmols) of (-)-di-0,0'-p-toluyl-L.-tartaric acid monohydrate (in acetone). The solution is concentrated, mixed with ether and the crystallised salt is filtered off and washed with acetone/methanol. The salt is recrystallised from methylene chloride/methanol until reaching a constant rotatory value. (The mother liquors are collected separately, see example 13). The 4 00 base is released from the crystallisate having constant rotatory 0e value by adding ice/conc. ammonia solution and methylene chloride.
(-)-cis-7a,8,9,1Q,11,Ila-hexahydro-10-methyl-7Ef-indolo[L,7-bcl- [2,6]naphthyridine is obtai'ied with the melting point 99 1000 and the rotatory value [c 0 .5 0 (c =0,25, CH 2 Cl 2 18 100-7683 EXAMPLE 13: (+)-eis-7a,8,9,10,11,la-hexahyro-10-methyl-7..
indolo[1,7-bc] [2,6]naphthyridine Preparation is from (+/-)-cis-7a,8,9,10,11,lla-hexahydro-10methyl-711-indolo[1,7-bc] [2,6]naphthyridine (example 7) or from the collected mother liquors of (-)-enantiomer production, using (+)-di-0,0'-p-toluyl-D-tartaric acid. The process is analogous to the preparation of the (-)-enantiomer (example 12). After release of the base, (+)-cis-7a,8,9,10,l1,lla-hexahydro-10-methyl-7Hindolo[l,7-bc][2,6)naphthyridine is obtained with the melting Osseo:point 101 1020 (ether/hexane) and with the rotatory value .Co* [OC]20 49O (c =0,25, CH 2
CI
2
D
C. 0,

Claims (9)

1. A process for the production of a compound of formula I R F 1 N 11aoR2 *R3 .a R R X Y wherein R 1 is hydrogen, alkyl, alkylcarbonylalkyl, arylcarbonyl- alkyl, aralkyl or carbamoylalkyl optionally mono- or disubstituted by alkyl or aryl, R 2 is as defined for R 1 and may additionally be trifluoro- methyl, alkoxy or alkylthio, R 3 R 4 and R 5 independently are hydrogen, halogen, alkyl, alkoxy, alkylthio or trifluoromethyl and X and Y are each hydrogen or form together a single bond, or an acid addition salt thereof, which includes the step of 20 Case 100-7683 a for the producz.ion of a compound of formula Ia wherein R 1 R 2 R. 3 R 4 and R 5 are as defined above, replacing under reduction of the 7-oxo group the 1O-ethoxycarbonyl group of a compound of formula II S S. S S. S S S S. wherein R 2 R 3 R 4 and R 5 are as group R 1 or defined above, by the b) for the production of a compound of frnrmula lb 21 Case 100-7683 wherein R 1 R 2 R 3 R 4 and R 5 are as defined above, oxidating a compound of formula la as defined above, and recovering the thus obtained compound of formula Ia or Ib in free base or acid addition salt form.
2. A compound of formula I in free base or acid addition salt form, whenever produced by a process of claim 1.
3. A compound of formula I in free base or acid addition salt form, as defined in claim 1.
4. A compcund of claim 3 wherein R 1 is (C1- 4 )alkyl and R 2 R 3 R 4 R
5 X and Y are each hydrogen. A compound of claim 3 wherein R 1 is (C 1 -4)alkyl, R2, R 3 R4 S and R5 are each hydrogen and X and Y together form a single bond.
6. A compound of claim 3 which is the -cis-4,5,7a, 8,9,10,11,11a-octahydro-7H-10-methyl- indolo[l,7-bc] 2,6]naphthyridine in free base or acid addition salt form.
7. A pharmaceutical composition comprising a compound according to any one of claims 2 to 6 in physiologically acceptable form, in association with a pharmaceutical carrier or diluent. -22-
8. A method for the prophylactic treatment of migraine or the treatment of anxiety, depression, schizophrenia, autism, obsessive compulsive disorders, panic attacks, priapism, bulimia and situations of increased intracranial pressure which comprises administering a therapeutically effective amount of a compound according to any one of claims 2 to 6 to a subject in need thereof.
9. Processes for the production of compounds of formula I or compounds of formula I whenever produced by such processes, substantially as hereinbefore described with reference to the Examples. DATED this 2nd day of December, 1993 Candoz Ltd. S' By Its Patent Attorneys 20 DAVIES COLLISON CAVE S i 931202,p:\oper\dab,8271 1.spe,22 Abstract of the disclosure 7a,8,9, 10,11, ila-hexahydro and 4,5,7a,8,9,10,11, lia-octahydro- 7H-indolo[1,7-bc][2,6]naphthyridines of formula I sa 4 S S .6~S6t 4* 4 *ue~. £5 S £5 a. £4 I x y wherein R 1 R 2 R 3 R 4 R 5 X and Y are as defined in the description, have an antagonist effect at the central receptors. 4 a b 4
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DE4027018A DE4027018A1 (en) 1990-08-27 1990-08-27 New octa:hydro-indolo-naphthyridine derivs.
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DE19904027015 DE4027015A1 (en) 1990-08-27 1990-08-27 New octa:hydro-indolo-naphthyridine derivs.

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