IE913005A1

IE913005A1 - Indolonaphthyridines

Info

Publication number: IE913005A1
Application number: IE300591A
Authority: IE
Original assignee: Sandoz Ltd
Priority date: 1990-08-27
Filing date: 1991-08-26
Publication date: 1992-03-11
Also published as: NZ239547A; FI913991A0; AU646485B2; CA2049642A1; FI913991A; AU8271191A; HUT61548A; EP0473550A1; HU912693D0; KR920004386A; MX9100811A; CS262591A3; PT98778A; JPH04230685A; IL99294A0

Abstract

Indolonaphthyridines of the formula I in which R1, R2, R3, R4, R5, X and Y are as defined in the description, their preparation, and their use as therapeutic agents.

Description

The present invention relates to new 7a,8,9,10,ll,lla-hexahydro and 4,5,7a,8,9,10,11,lla-octahydro-7H-indolo[1,7-bc][2,6]— naphthyridines.

These compounds, hereinafter referred to as new compounds, are compounds of formula I wherein Rx is hydrogen, alkyl, alkylcarbonylalkyl, arylcarbonylalkyl, aralkyl or carbamoylalkyl optionally mono- or disubstituted by alkyl or aryl, 100-7683 R2 is as defined for Rx and may additionally be trifluoromethyl, alkoxy or alkylthio, R3, R4 and R5 independently are hydrogen, halogen, alkyl, alkoxy, alkylthio or tri fluoromethyl 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 11a) or more asymmetrical carbon atoms. The invention includes all resulting stereomers as well as their mixtures, e.g. the racemic mixtures of the enantiomers.

In position 7a and 11a 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 carbon atoms may be replaced by nitrogen.

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. 100-7683 An above-defined halogen is preferably fluorine or chlorine.

Rx is preferably alkyl, particularly methyl. R2, R3, R4 and R5 are preferably hydrogen. Preferably X and Y each are hydrogen.

The invention includes for example a group of compounds of formula I, wherein Rx is (Cx_4)alkyl and R2, R3, R4, R5, 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 Rx is (Cx_4)alkyl, R2, R3, R4 and R5 are each hydrogen 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,ll,llaoctahydro-7H-10-methyl-indolo[l,7-bcJ[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 N R R‘ Ia - 4 100-7683 wherein Ri, R2, R3, R4 and R5 are as defined above, replacing under reduction of the 7-oxo group the 10-ethoxycarbonyl group of a compound of formula II wherein R2, Rj, R4 and R5 are as defined above, by the group Ri, or b) for the production of a compound of formula Ib wherein Rx, R2, R3, R4 and R5 are as defined above, oxidating a compound of formula Ia, and recovering the thus obtained compound of formula I in free base or acid addition salt form. 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 Ia according to process b) may be carried out by known methods, for example using manganese oxide. 02/cobalt salts in methanol, palladium dichloride in triethylamine or benzene-selenic anhydride may also be used.

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.

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. (+)-[resp. (-)]-di-0,0'-p-toluoyl-D-(-)-[resp.

L_(+)]-tartaric acid, and fractional crystallisation of the diastereoisomeric acid addition salts. 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): 100-7633 100-7683 The 7a,8,9,10,ll,lla-hexahydro- and 4,5,7a,8,9,10,ll,lla-octahydro-7H-indolo[1,7-bcJ[2,6]naphthyridines and their physiologically acceptable acid addition salts, hereinafter referred to as compounds according to the invention, 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 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.

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 (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.

In the following examples, all temperatures are uncorrected and are in degrees Centigrade. 100-7683 EXAMPLE 1: cis-4,5,7a,8,9,10,11,lla-octahydro-7H-10-methylindolo|l,7-bc][2,6]naphthyridine 2.03 g (53.4 mmols) of lithium aluminium hydride (aluminium hydride can also be used) are placed at 0° in absolute tetrahydrofuran. A solution of 1.61 g (5.36 mmols) of cis-4,5,7a,8,9,10,11,lla-octahydro-7-oxo-7H-indolo[1,7-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 -20° and water is added in drops. The product is extracted with toluene. The toluene phase is dried and concentrated by evaporation, cis-4,5,7a,8,9,10,11,lla-octahydro-7H-10-methylindolo[1,7-bc](2,6]naphthyridine is obtained as a yellow oil. The crude 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,ll,lla-octahydro-7H-10methyl-indolo[1,7-bc][2,6]naphthyridine malonate is obtained with the melting point 158 - 159°.

The starting material may be produced as follows: a) 2,3-dihydro-l-(4-pyridinylcarbonyl)-lH-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 20° 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 20°. Afterwards, the preparation is washed with ‘water, the organic phase is dried and concentrated by 100-7683 evaporation. 2,3-dihydro-l-(4-pyridinylcarbonyl)-lH-indole is obtained with a melting point of 127 - 128° (crystallisation from methylene chloride/ethanol/hexane). b) 4-(2>3-dihydro-lH-indol-l-yl-carbonyl)-l-methylpyridiniumiodide 224 g (1 mol) of 2,3-dihydro-l-(4-pyridinylcarbonyl)-lHindole 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-lHindol-l-yl-carbonyl)-l-methylpyridinium-iodide is obtained in the form of yellow crystals. It has a melting point of 242 243° (crystallisation acetone/ether). c) 2,3-dihydro-l-(l>2>3>6-tetrahydro-l-iaethyl-4-pyridinylcarbonyl)-lH-indole 308 g (0.84 mols) of 4-(2,3-dihydro-lH-indol-l-yl-carbonyl)1-methylpyridinium-iodide are suspended in ethanol. The solution is cooled to +10°. A mixture of 95.9 g (2.52 mols) of sodium borohydride in 960 ml of water and 96 ml of 30£ 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 organic phase is separated and the product is extracted therefrom with 2 n hydrochloric acid. The aqueous solution containing hydrochloric acid is rendered alkaline with 30X caustic soda, and the product is extracted with methylene chloride. The organic phase is dried 100-7683 and concentrated by evaporation. 2,3-dihydro-l-(l,2,3,6tetrahydro-l-methyl-4-pyridinylcarbonyl)-lH-indole is obtained with a melting point of 70 - 72° (crystallisation from ether/petroleum ether). d) 4-(2,3-dihydro-lH-indol-l-yl-carbonyl)-l,2,3,6-tetrahydro-1pyridine-carbamic acid ethyl ester 145.4 g (0.6 mols) of 2,3-dihydro-l-(l,2,3,6-tetrahydro-lmethyl-4-pyridinylcarbonyl)-lH-indole are placed in toluene. 156.6 ml of N-ethyldiisopropylamine are added and heated to 80°. At the same temperature, a solution of 196.8 ml (2.1 mols) of chloroformic acid ethyl ester in toluene is added to the reaction mixture in drops. The mixture is stirred for 2 hours at 80° and subsequently cooled to 0°. The preparation is mixed with water-ice and washed with 2 n hydrochloric acid. The toluene phase is separated, dried and concentrated by evaporation. 4-(2,3-dihydro-lH-indol-l-ylcarbonyl)-l,2,3,6-tetrahydro-l-pyridinecarbamic acid ethyl ester is obtained with a melting point of 112 - 113° (crystallisation from methyl-tert.butylether/ether). e) cis-4,5,7a,8,9,10,11,1la-octahydro-7-oxo-7H-indolo[1,7-be](2,6]naphthyridine-10-carbamic acid ethyl ester 2.0 g (6.7 mmols) of 4-(2,3-dihydro-lH-indol-l-yl-carbonyl)1,2,3,6-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 an interval of 12 hours, the dipping lamp is cleaned and the reaction solution is treated with 3 mol X active charcoal and filtered over Hyflo. After a total of 50 hours irradiation, the toluene is evaporated. The crude product is purified by column chromatoIE 913005 100-7683 graphy (silica gel) and the cis/trans diastereoisomers are thus separated. cis-4,5,7a,8,9,10,11,lla-octahydro-7-oxo-7Hindolo[1,7-bc](2,6]naphthyridine-10-carbamic acid ethyl ester is obtained as an oil.

IR(CH2C12) : r = 1665 cm [e-1] (amide C=0); 1690 cm [e-1] (carbamate C=0). 1H-NMR(D6-DMSO), 360 MHz : d (ppm) = 1.20 (t, J = 7.5 Hz; 3H, carbamate-CH3); 4.08 (q, J = 7.5 Hz; 2H, carbamate-CH2).

EXAMPLE 2; trans-4,5,7a,8,9,10,ll,lla-octahydro-7H-10-methylindolo]!,7-bc][2,6]naphthyridine Production corresponds to that of the cis-diastereoisomer (example 1). trans-4,5,7a,8,9,10,ll,lla-octahydro-7H-10-methylindolo[1,7-bc][2,6]naphthyridine is obtained with the melting point 102 - 103° (ether/hexane). As the malonate with the melting point 155 - 156° (acetone/methanol).

The starting material may be produced as follows: trans-4,5,73,8,9,10,11,lla-octahydro-7-oxo-7H-indolo[1,7-bc][2,6]naphthyridine-10-carbaaic acid ethyl ester Production corresponds to that of the cis-diastereoisomer (example 1 e). trans-4,5,7a,8,9,10,ll,lla-octahydro-7-oxo-7Hindolo[l,7-bc][2,6]naphthyridine-10-carbamic acid ethyl ester is obtained with a melting point of 132 - 133° (crystallisation from methyl-tert.butylether).

The following compounds of formula I are produced analogously to example 1: 100-7683 Example R config. m.p. of dihydrochloride 3 ethyl (+)-cis 280 - 281° 4 n-propyl (+)-cis 294 - 296° EXAMPLE 5: (+)-cis-4,5,73,8,9,10,11,lla-octahydro-7H-10-methy1indolo[l,7-bc][2,6jnaphthyridine 13.57 g (59 mmols) of (+/-)-cis-4,5,7a,8,9,10,ll,lla-octahydro7H-10-methyl-indolo[l,7-bc][2,6]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 until reaching a constant rotatory value [to obtain the (-)-enantiomer (example 6), the mother liquors are collected separately]. (-)-di-0,0'-p-toluyl-L-tartrate is obtained with a melting point of 158 - 159° and the rotatory value of -46° (c = 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,8,9,10,ll,llaoctahydro-7H-10-methyl-indolo[1,7-bc][2,6 Jnaphthyridine is obtained with the rotatory value + 132° (c = 0.5; methanol). The base crystallises as the malonate with the melting point 129 130° (crystallisation from acetone/ether) and the rotatory value +71° (c = 0.5; methanol). 100-7683 EXAMPLE 6: (-)-cis-4,5,7a,8,9,10,ll,lla-octahydro-7H-10-methylindolo[l,7-bc][2,6jnaphthyridine Preparation is from (+/-)-cis-4,5,7a,8,9,10,ll,lla-octahydro-7H10-methyl-indolo[l,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 5). (+)-di-0,0'-ptoluyl-D-tartrate is obtained with the melting point 160 - 161° (methanol/acetone) and the rotatory value +46° (c = 0.5, methanol). After release of the base, (-)-cis-4,5,7a,8,9,10,ll,lla-octahydro-7H-10-methyl-indolo[l,7-bc][2,6]naphthyridine is obtained with the rotatory value -130° (c = 0.5, methanol). The base crystallises as the malonate with the melting point 129 130° (acetone/ether) and the rotatory value -75° (c = 0.5, methanol).

EXAMPLE 7: cis-7a,8,9,10,11,lla-hexahydro-10-methyl-7H-indolo[1,7-bc][2,6]naphthyridine 200 mg (0.9 mmols) of cis-4,5,7a,8,9,10,11,lla-octahydro-7H-10methyl-indolo[l,7-bc][2,6Jnaphthyridine (example 1) are dissolved in methylene chloride. 2.00 g of manganese(IV)oxide (precipitated active) are added whilst stirring at 20°. 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,ll,lla-hexahydro-10-methyl-7H-indolo[1,7-bc][2,6]naphthyridine is obtained with the melting point 125 - 126°. 1H-NMR, 360 MHz (CDC13): d (ppm) = 2.31 (s; 3H, 10-N-CH3).

As the hydrogen fumarate, the compound has the melting point 127° (decomp.). 100-7683 EXAMPLE 8: trans-7a,8,9,10,ll,lla-hexahydro-10-methyl-7Hindolo[l,7-bc][2,6]naphthyridine Production corresponds to that of the cis-diastereoisomer (example 7). trans-7a,8,9,10,11,lla-hexahydro-10-methyl-7Hindolo[l,7-bc][2,6]naphthyridine is obtained with the melting point 143 - 145° (crystallisation from ethanol). 1H-NMR, 360 MHz(CDCl3): d (ppm) = 2.45 (s; 3H, 10-N-CH3); 6.44 (m; 1H, C-4-H).

The starting material may be produced as follows: a) trans-4,5,78,8,9,10,11,lla-octahydro-7-oxo-7H-indolo[l,7-bc][2,6]naphthyridine-10-carbamic acid ethyl ester Production corresponds to that of the cis-diastereoisomer (example 1 e). trans-4,5,7a,8,9,10,ll,lla-octahydro-7-oxo-7Hindolo[1,7-bc][2,6]naphthyridine-10-carbamic acid ethyl ester is obtained with a melting point of 132 - 133° (crystallisation from methyl-tert.butylether). b) t rans-4,5,7a,8,9,10,11,1la-oc tahydro-7H-10-me thyl-indolo[1,7-bc][2,6]naphthyridine Production corresponds to that of the cis-diastereoisomer (example 1). trans-4,5,7a,8,9,10,ll,lla-octahydro-7H-10methyl-indolo[l,7-bc][2,6]naphthyridine is obtained with a melting point of 102 - 103° (ether/hexane). As the malonate with a melting point of 155 - 156° (acetone/methanol).

The following compounds of formula I, wherein R2, R4, Rs, X and Y are hydrogen, are produced analogously to example 7: 100-7683 Example Ri r3 config. m.p. 9 ethyl H (±)-cis 156-158° (hydrogen maleinate) 10 n-propyl H (±)-cis 105-107° (hydrogen maleinate) 11 methyl 2-C1 (±)-trans 324° (decomp.) (hydrochloride) EXAMPLE 12: (-)-013-73,8,9,10,11,1la-hexahydro-10-methyl-7Hindolo[l,7-bc][2,6]naphthyridine 16.10 g (71 mmols) of (+/-)-cis-7a,8,9,10,ll,lla-hexahydro-10methyl-7H-indolo[1,7-bc][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 base is released from the crystallisate having constant rotatory value by adding ice/conc. ammonia solution and methylene chloride. (-)-cis-7a,8,9,10,11,1la-hexahydro-10-methyl-7H-indolo[1,7-bc][2,6]naphthyridine is obtained with the melting point 99 - 100° and the rotatory value [a]20 = -50° (c = 0,25, CH2CI2)· D 100-7683 EXAMPLE 13: (+)-cis-7a,8,9>10,ll,lla-hexahydro-10-methyl-7Hindolo[1,7-bc][2,6jnaphthyridine Preparation is from (+/-)-cis-7a,8,9,10,11,lla-hexahydro-10methyl-7H-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,8,9,10,11,lla-hexahydro-10-methyl-7Hindolo[l,7-bc][2,6]naphthyridine is obtained with the melting point 101 - 102° (ether/hexane) and with the rotatory value [a]20 = +49° (c = 0,25, CH2C12).

D 100-7683

Claims

1. A 4,5,7a,8,9,10,ll,lla-octahydro-7H-indolo[l,7-bc][2,6]naphthyridine in free base or physiologically acceptable acid addition salt form.

2. A process for the production of a compound of formula I wherein R x is hydrogen, alkyl, alkylcarbonylalkyl, arylcarbonylalkyl, aralkyl or carbamoylalkyl optionally mono- or disubstituted by alkyl or aryl, R 2 is as defined for R t 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, or an acid addition salt thereof, which includes the step of - 20 100-7683 wherein R x , R 2 , R 3 , R 4 and R 5 are as defined above, replacing under reduction of the 7-oxo group the 10-ethoxycarbonyl group of a compound of formula II wherein R 2 , R 3 , R 4 and R 5 are as defined above, by the group Ri, or 100-7683 b) for the production of a compound of formula Ib wherein R x , R 2 , R 3 , R 4 and R5 are as defined above, oxidating a compound of formula Ia, and recovering the thus obtained compound of formula I in free base or acid addition salt form.

3. A compound of formula I in free base or acid addition salt form, whenever produced by a process of claim 2.

4. A compound of formula I in free base or acid addition salt form, as defined in claim 2.

5. A compound of claim 4 wherein R x is (C x _ 4 )alkyl and R 2 , R 3 , R 4 , R 5 , X and Y are each hydrogen.

6. A compound of claim 4 wherein R x is (C x _ 4 )alkyl, R 2 , R 3 , R 4 and R 5 are each hydrogen and X and Y together form a single bond. 100-7683

7. A compound of claim 4 which is the (+)-cis-4,5,7a,8,9,10,11,lla-octahydro-7H-10-methylindolo[l,7-bc][2,6]naphthyridine in free base or acid addition salt form.

8. A compound of any one of claims 3 to 7 in physiologically acceptable form for use as a pharmaceutical.

9. A compound of any one of claims 3 to 7 in physiologically acceptable form, for use in the prophylactic treatment of migraine or in the treatment of anxiety, depression, schizophrenia, autism, obsessive compulsive disorders, panic attacks, priapism, bulimia and situations of increased intracranial pressure.

10. A pharmaceutical composition comprising a compound according to any one of claims 3 to 7 in physiologically acceptable form, in association with a pharmaceutical carrier or diluent.

11. A process for the production of a comoound of formula I substantially as hereinbefore described by way of Example.