WO1989010924A1

WO1989010924A1 - Indazole derivatives

Info

Publication number: WO1989010924A1
Application number: PCT/GB1989/000517
Authority: WO
Inventors: Roger Grayshan; Andrew Mckinnon French; Hamad Al-Khammees; Gareth Andrew De Boos
Original assignee: National Research Development Corporation
Priority date: 1988-05-12
Filing date: 1989-05-12
Publication date: 1989-11-16
Also published as: GB8811299D0; JPH03504242A

Abstract

A compound of formula (II), or a pharmaceutically acceptable acid additon salt thereof in which formula R1 represents a six membered heterocyclic ring A comprising one nitrogen atom and bound to the indazole ring system by carbon, the ring A being optionally substituted by one or more C1-C6 alkyl groups; R2 represents hydrogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy; R3 represents hydrogen, hydroxy, halogen, a C1-C6 alkyl or alkoxy group, or a group of formula -NO2, -CN, -CONH2 or -CONHR (R representing a C1-C3 alkyl group); R4, which may differ from R3, represents: hydrogen, hydroxy, halogen, a C1-C6 alkyl or alkoxy group, or a group of formula -NO2, -CN, -CONH2, or -CONHR (R representing a C1-C3 alkyl group); R5 represents hydrogen or halogen; X- represents an anionic moiety the nature of which is such that the compound of formula (II) is pharmaceutically acceptable and n is 1 or 2.

Description

INDAZOLE DERIVATIVES This invention relates to Indazole derivatives, and in particular to pyrazolo - and pyridazinoindazole derivatives, processes for their preparation and pharmaceutical compositions containing them. In Intensive efforts to find a bronchodilating agent for the treatment of asthma which is more satisfactory than the xanthine derivatives and beta-adrenoreceptor stimulants used at present, various indazole derivatives have been tested. The compound I, (2,3-dihydro-7-methyl-9-phenyl -1H-pyrazolo(1,2-a)Indazolium bromide) is said to be particularly promising

It has now been found that certain indazole derivatives have a bronchodilating activity which exceeds that of the demethylanalogue of compound I and, it is envisaged, will exceed that of Compound I per se. Accordingly, the present Invention comprises a compound of formula II or a pharmaceutically acceptable acid addition salt thereof:

in which formul a R₁ represents a six membered heterocyclic ring A compri si ng one ni trogen atom and bound to the i ndazol e ri ng system by carbon th ing A being optionally substituted by one or more C₁-C₆ alkyl gr oup s; R₂ represent hydrogen, hydroxy, C₁-C₆ alkyl or C₁-C₆ alkoxy,

R₃ represents hydrogen, hydroxy, halogen, a C₁-C₆ al kyl or alkoxy group, or a group of formula -NO₂, -CN,-CONH₂, or -CONHR (R representing a C₁-C₃ alkyl group);

R₄, which may differ from R₃, represents: hydrogen, hydroxy, halogen, a C₁-C₆ al kyl or al koxy group, or a group of formul a -NO₂, -CN,-CONH₂, or -CONHR (R representing a C₁-C₃alkyl group);

R₅ represents hydrogen or halogen,

X represents an anionic moiety the nature of which is such that the compound of formula II is pharmaceutically acceptable and n is 1 or 2.

In the compound II of the present invention, the nitrogen atom of ring A is preferably spaced from the carbon of the indazole ring system on which ring A is carried by three carbon atoms, that is the nitrogen of ring A is remotely located from the point of connection to the indazole ring system. Ring A may be aromatic, saturated or monounsaturated, in the latter case suitably adjacent the bond joining ring A to the indazole ring system as in the following case:

Compounds of the latter type are of particular interest. The nitrogen may be unsubstituted or carry a C₁-C₆ alkyl group, an acyl group of formula -COR' In which R' represents a C₁-C₆ alkyl group or a sul phonate group of formula -SO₂R", in which R" represents a C₁-C₃ alkyl or aryl group.

The substituent R₂ preferably represents hydrogen, hydroxy,

C₁-C₃ alkyl or alkoxy, X preferably represents halide and especially bromide, the substituent R₃: hydrogen, hydroxy, C₁- C₃ alkyl or alkoxy or halogen, the substituent R₄: hydrogen, hydroxy, C₁-C₃ alkyl or alkoxy or halogen and n is preferably one.

Typically X is an anionic moiety of one of the following acids: hydrochloric, hydrobromic, sulphuric, nitric, Isethlonic, phosphoric, maleic, salicyclic, p-toluenesulphonic, tartaric,citri, lactoblonic, formic, malonic, pantothenic, sucinic, naphthalene-2-sulphonic, benzenesulphonic, methanesulphonic, ethanesulphonic, sulphonic, carbonic, acetic and benzoic. When compound II is present in the form of an acid addition salt (in which case the compound is a double salt), the additional anion present is generally derived from one of the adds hereinbefore described, an add halide e.g. hydrobromide or hydrochlorlde being particularly preferred.

In compounds of particular Interest both R₄ and R₅ represent hydrogen R₂ represent hydrogen or C₁-C₆ alkoxy and R₃ represents hydrogen, halogen, a C₁-C₃ alkyl group or a group of formula -NO₂, -CN, -CONH₂, or -CONHR (R representing a C₁-C₃ alkyl group).

The following compounds (and acid salts thereof e.g. hydrochlorldes) are of particular interest:

(1) 2,3-Dihydro-9(1-methyl-1,2,5,6 tetrahydro-4-pyridyl)-1-4-pyrazolo(1,2-a)indazolium bromide; (11) 2,3-dihydro-9(1-methyl)-4-pyridyl)-1-4-pyrazolo-(1,2a)-indazolium bromide; (iii)2,3-dihydro-9(l-methyl)-4-piperidyl)-1-4-pyrazolo-(1,2a)-indazolium bromide; (iv) 7-methyl-2,3-dihydro-9(1-methyl-1,2,5,6 tetrahydropyridyl)-1-4 pyrazolo(1,2-a)- indazolium bromide; (v) 7-methyl-2,3-dihydro-9(1- ethyl-1,2,5,6 tetrahydropyridyl)-1-4-pyrazolo(1,2-a) Indazolium bromide. In the compounds (iv) and (v) R₃ of formula II represents, of course, methyl.

The present invention further includes within a further aspect a compound of formula II or a pharmaceutically acceptable acid addition salt thereof for use in therapy and in particular for use in the treatment of prophylaxis of asthma. In a yet further aspect of the Invention an asthmatic subject is treated with a compound of formula II or a pharmaceutically acceptabl e add addition salt thereof in an amount effective to dilate the bronchi. The compound of formula II or a pharmaceutically acceptable add addition salt thereof Is generally administered in the form of a composition comprising a pharmaceutically acceptable diluent or carrier, typically orally, by injection or Inhalation and in unit dosage form. Although it i s envi saged that precise recommended doses will be established by trial, LD₅₀ values indicate that typically a dose of 50-100mg will be administered to human patients at least once and usually twi ce daily.

Compounds II according to the present Invention may be prepared from the corresponding indazole or acid addition salt thereof.

In accordance with a further aspect of the present invention, a process for the production of a compound II or a pharmaceutically acceptable add addition salt thereof comprises treating an indazole of formula III or an add addition salt thereof,

with a substituted alkane of formula Y-(CH₂)_n+2-Z wherein Y and Z which may be Identical or different, represent moieties capable of existence as anions in the presence of a reducing agent such as a hydride e.g. an alkali metal hydride whereby a compound of formula IV Is produced the counterion Y of which is, when necessary, subsequently replaced by a counterion X .

Treatment of compound III Is generally conducted in a solvent such as dimethyl formamide, the temperature generally being maintained at least initially below 0ºC. Subsequent heating to a temperature between ambient and 100ºC, typically 40-50ºC. may be required.

In a preferred procedure, after treatment of the indazole (or addition salt) with reducing agent, the reaction mixture is rendered acidic prior to cyclization.

In general Y & Z both represent chlorine or bromine and when a compound II is required in which X is other than chloride or bromide the compound IV is treated with a source of X , such as an ion exchange resin, so that Y is replaced by X .

In some cases it is possible to isolate an intermediate which is of formula V, or VI or is an add addition salt thereof. Such an Intermediate or a mixture of such Intermediates, on application of heat, preferably when in add solution yields the compound II or an addition salt thereof

The solution is preferably dilute and the solvent inert.

Compounds of formula II may be generated by following various routes of which those now shown in Sheets I, IA and II below are Illustrative. It will be appreciated that the routes outlined in these Sheets overlap considerably.

Reagents i ) 4-Pyridyl -carboxal dehyde/tetrahydrofuran . ii ) Jones' reagent/propanone. iii) 6M Hydrochloric add aq./ethanol. iv) Boron trichloride/dichloromethane/4-cyano-pyridine/ 1,1,2,2-tetrachloroethane; aluminium trichloride; hydrochloric acid aq. v) 10% Palladium-carbon/ethanol/hydrazine hydrate. vi)a) 10M Hydrochloric acid aq.; sodium nitrite aq.; sodium azide aq.; sodium bicarbonate aq.; hydrazine hydrate/ ethanol/ethanoic acid, b) 10M Hydrochloric add aq.; sodium nitrite aq.; sodium bisulphite aq. or c) 10M Hydrochloric acid aq.; sodium nitrite aq.; tin dichloride aq. vii) 1-Methyl-4-piperidone/2N phosphoric acid aq./ethanoic acid, viii) Iodomethane/ethyl ethanoate. ix) Borane-dimethyl sulphide/tetrahydrofuran; trimethyl amine N-oxide dihydrate. x) Sodium periodate/methanol aq. xi) Sodium borohydride/methanol. xii) 5M Hydrochloric acid aq./ethanol. xiii)a) 10M Hydrochloric acid aq.; sodium nitrite aq.; sodium azide aq.; sodium bicarbonate aq.; hydraziue hydrate/ ethanol/ethanoic acid. or b) 10M Hydrochloric acid aq.; sodium nitrite aq.; tin dichloride aq. xiv) Sodium hydride/dimethyl methanamide; 1,3-dibromopropane; 0.3MM hydrochloric acid aq./methanol; butanol/ heat.

When an anil ino precursor of an Intermediate of formula III has a plane of symmetry (which intersects the benzene nucleus as right angles) the bicyclic product therefrom generally consists of only one isomer. For example the compound 3,5-dimethylaniline is readily convertible Into the following compound:-

When however no such plane of symmetry exists, as in 2-methoxyaniline, a mixture of the following isomers is produced:

It has been found that a halogen substituent, suitably ortho to the -NH₂ group may be used to block the formation of an unwanted isomer from an anilino starting material and can be subsequently removed, if desired. This route isillustrated by the following conversion.

The present Invention is i l l ustrated by the fol lowi ng examples :-

Example 1

2.3-Dihvdro-9(1-Methyl-1,2,5,6-Tetrahvdro-4-Pyridyl) 1-4-Pyrazolo-(1,2-a)-Indazolium Bromide (Compound R77).

A. (±) (2-(2.2-Dimethyl propanami do)phenyl-pyri d-4-yl-methanol . Butyl lithium (32.Og; 0.5mol) in hexane was added dropwise to a solution of 2,2-dimethylpropanamidobenzene (45.0g; 0.25mol) in dry tetrahydrofuran (11) at 0°C under nitrogen and then, the mixture was stirred at this temperature for two hours. A solution of 4-pyridine-carboxaldehyde (26.7g) In tetrahydrofuran (300ml) was added dropwise. Following this addition, the reaction mi xture was sti rred for one hour at 0 ºC and then at ambient temperature overnight. After that, the reaction mixture was quenched with ice/water and the tetrahydrofuran was evaporated to a minimum volume. The aqueous solution was extracted with diethyl ether which was dried, filtered and the solvent evaporated to give a brown oil. Silica chromatography using petroleum ether: diethyl ether as elutlng solvent gave the product (41.8g; 58%) as a white solid, m.p. 154-156°C. i.r. 3597 (OH), 3340 (NH) and (C=O) 1664cm^-1 'H n.m.r. 9.30 (H, b, NH); 8.41-8.09 (2H, m, aromatic); 7.51-701 (6H, m, aromatic); 5.90-5.75 (1H, b, (CHOH); 1.04 (9H, s, (CH₃)₃) p.p.m.

B. (2-(2.2-Dimethylpropamido)phenyl)-4-pyridyl-methanone. Jones' reagent was added to a solution of 2-(2,2-dimethylpropanamido)phenyl-pyrid-4-yl-methanol (38.0g; 0.31mol) in propanone (400ml) at 0ºC until the solution was deep orange. The reaction mixture was allowed to stir for thirty minutes, then sulphur dioxide saturated propanone was added to destroy any excess of the reagent. Water was added and the product extracted with ethyl ethanoate. The extract was dried, filtered and the solvent evaporated to give a yellow oil (35. g; 95%). Purification by silica chromatography of a sample gave a small amount of the pure product as a pale yellow oil. i.r. 3310 (NH), 1683 (NHCO). and (CO) 1635cm^-1 n.m.r. 8.90-863 (2H, m, aromatic); 7.79-6.95 (6H, m, aromatic); 1.36 (9H, s, (CH₃)₃) p.p.m.

C. 2-Aminophenyl-4-pyridyl-methanone. (From (2-(2,2-dimethylpropanamido)-phenyl)-4-pyridylmethanone). To a stirred solution of (2-(2,2-dimethylpropanamido)-phenyl)-4-pyri dyl -methanone (32.Og; O.llmol) in ethanol (400ml), 10M aqueous hydrochloric acid (150ml) and water (100ml) were added. The reaction mixture was heated under refluc for twenty hours, then after cooling, it was poured Into water and basifi ed with 2M aqueous sodium hydroxide. The mixture was extracted with diethyl ether. After drying, filtering and evaporation of the solvent, a yellow crystalline solid was obtained (19.5g; 87%). m.p. 162-164°C. i.r. 3500, 3360 (NH₂) and (C=O) 1635cm^-1

Η n.m.r. 8.95-8.55 (2H, b, NH₂); 7.50-6.21 (8H, m, aromatic) p.p.m. 1³C n.m.r. (CD₃CO₂D) 106.5 (s); 153.4 (s); 151.4 (s); 147.9 (d); 136.5 (d); 134.9 (d); 124.6 (d); 118.3 (d);

116 (s); 116.3 (d) p.p.m.

D. 2-Azidophenyl-4-pyridyl-methanone.

10M Aqueous hydrochl ori c add (100ml) was added dropwise to a stirred solution of 2-aminophenyl-4-pyri dyl -methanone (18.0g; 91 mmol) in propanone (40ml) at 0ºC. After the addition of the add, the propanone was removed under reduced pressure and the solution cooled again to 0°C. A solution of sodium nitrite (7.5g; 109 mmol) in water (30ml) was then added to the reaction mixture followed after 30 minutes by the addition of a solution of sodium azide (14. Ig; 218 mmol) in water (40ml). The mixture was then stirred for a further 30 minutes, neutralised with 10% aqueous sodium bicarbonate solution and extracted with ethyl ethanoate. Solvent evaporation of the dried and filtered extract gave the crude product (16.5g; 81%). Purifi cation by silica chromatography of a sample gave a small amount of the pure product as a yellow oil. i.r. 2109 (N₃) and (C-O) 1675cm^-1 H n.m.r. 8.80-8.31 (2H, m, aromatic); 7.41-6.92 (6g, m, aromatic) p.p.m.

E. 3-(4-Pyridyl)-indazole.

(From 2-azidophenyl-4-pyridyl-methanone.) 2-Azidophenyl-4-pyridyl-methanone (15.0g; 67 mmol) in absolute ethanol (400ml) was refluxed for seven hours, with hydrazine hydrate (65ml; 1.5 mol) and glacial ethanoic acid (5 ml). The reaction mixture was cooled, neutralised with glacial ethanoic acid, water was added, and then it was extracted with ethyl ethanoate. The extract was dri ed , fi ltered and the sol vent evaporated to gi ve a whi te sol i d (7.1 g; 55%) whi ch was recrystal U sed from di ethyl ether to gi ve the pure product in the form of white needles, m.p. 187-189°C i.r. (NH) 3460cm^-1 Η n.m.r. 8.80-8.31 (H, b, NH); 8.10-6.91 (8H, m, aromatic) p.p.m.

F. l-Methyl-4-(indazol-3-yl)-pyridinium iodide Iodomethane (4.6g; 33 mmol) was added to a well stirred solution of 3-(4-pyridyl)-indazole (6.0g; 30.7 mmol) in ethyl ethanoate (100ml). The reaction mixture was heated under refl ux for four hours. The precipitate obtained was separated and the solvent was evaporated to a smaller volume from which further product was filtered off to give a total yield of the product (8.9g; 86%) as a brown solid, m.p. 230°C (decomp.).

'H n.m.r. 8.85(2H, complex d, pyridyl); 8.68(2H, complex d, pyri dyl ) ; 8.28 ( 1 H , d , C(5)-H) ; 7.43( 1 H , dd ,

C(6)-H); 7.55 (1H, dd, C(7)-H); 7,72 (1H, d, C(8)-H); 4.40(3H, s, NCH₃).

G. 3-(l-Methyl-l.2.5.6-tetrahvdro-pyrid-4yl)-indazole.

Sodium borohydride (0.45g) was added in small portions to a cooled and stirred solution of l-methyl-4-(indazol-3-yl)pyrldinlum iodide (2.1g; 6.2 mmol) in dry methanol (50ml). The reaction mixture was stirred at 0°C for one hour, then the solvent was evaporated. The residue was extracted into trichloro-methane and purified by silica chromatography to give the pure product as a white solid (1.2g; 92%). m.p. 158-159°C. i.r. 3462 (NH) and (N-CH₃) 2780cm^-1 Η n.m.r. 8.01-7.75 (1H, m, aromatic); 7.45-6.95 (3H, m, aromatic); 6.60-6.35 (1H, m, CH=C); 3.41-2.55 ( 6H , m, CH₂) ; 2.48 (3H , s , CH>) p . p .m.

¹³C n.m.r. (CD₃OD): 145.6 (s); 143. 1 (s); 130.9 (s); 127.5 (d); 124.1 (d); 122.2 (d); 122.0 (d); 121.3 (s); 111.3 (d); 55.2 (t); 52.8 (t); 45.5 (q); 28.0 (t) p.p.m.

H. 2.3-Dihydro-9-(l-methyl-1,2,5,6-tetrahydropyrid-4-yl)-1H- pyrazolo-(1,2-a)-indazol ium bromide hydrochloride. (R.77 acid salt)

Sodium hydride as a 60% dispersion in oil (210mg) was added to dimethyl methanamide (25ml) at 0º C with stirring under a nitrogen atmosphere. 3-d-Methyl-1,2,5,6-tetrahydropyrid-4-yl)-Indazole (1.10g; 5.16 mmol) dissolved in dimethyl methanamide (25ml) was added dropwise to the slurry over ten minutes. The reaction mixture was stirred at ambient temperature for thirty minutes before being cooled to 0°C. This mixture was added via a cannula needle dropwise over ten minutes to a solution of 1,3-dibromopropane (1.04g) In dimethyl methanamlde (15ml). After thirty minutes, the reaction mixture was allowed to reach ambient temperature and was stirred for three hours. The mixture was quenched on Ice water and extracted with trichloromethane. After drying over potassium carbonate and magnesium sulphate and filtering, the solvent was removed at ambient or lower temperature under partial vacuum. Silica chromatography provided the intermediate compound as the least polar product. This Intermediate pale yellow solid (385mg) was taken up in butanol (40ml) and 0.33M aqueous hydrochloric add (3.5ml) was added. After refluxlng for two hours, the solvent was removed by evaporation. The white solid so obtained was washed with a little trichloromethane and ethyl ethanoate, and then dried, to give 2,3-dihydro-9-(1-methyl-1,2,5,6-tetrahydro-pyrid-4-y1)-1Hpyrazolo-(1 ,2-a)-i ndazoli um bromide hydrochloride (340mg; 18%). m.p. >200ºC i.r. 3400 (NH) and 2740 (N-CH₃)cm^-1 m.a. m.s.

Η n.m.r. 8.20-7.15(4H, m, aromatic);6.70-6.50(1H, m, CH-C); 4.94(2H, t, N-CH:) ;4.20-4.05(2H, m, N-CH:); 3.80-3.60(2H, m, N-CH₂) ;3.25-3.00(4H, m, 2 x CH:): 2.72(3H, s, N-CH₃) p.p.m.

Example 2:

2.3-Dihydro-9(1-Methyl-1,2,5,6-Tetrahvdro-4-Pyridyl)

1-4-Pyrazolo-( 1,2-a)-Indazolium Bromide (Compound R77).

The title compound was prepared as described in Example 1 except that compound C was prepared as follows from (2-amino-4-chlorophenyl)-4-pyridyl-methanone:

(2-Amino-4-chlorophenyl)-4- pyridyl-methanone (120mg; 0.52 mmpl), prepared according to the literature method, was dissolved in ethanol (15ml) at ambient temperature under nitrogen. Palladium 10% on carbon (70mg) was added and the mixture refluxed for thirty minutes. After cooling, the catalyst was removed by filtration through celi te and the solvent was removed by evaporation at reduced pressure. The residue was taken up in ethyl ethanoate (80ml), washed with water (15ml), dried over magnesium sulphate and filtered. Evaporation of the solvent gave the Impure product which was purified by flash chromatography on silica to give the pure product (80mg, 78%), Identical to that previously prepared (vide supra).

Example 3: 2,3-Dihydro-9(1-Methyl-1,2,5,6-Tetrahydro-4-Pyridyl)

1-4-Pyrazolo-(1,2-a)-Indazolium Bromide (Compound R77). The title compound was prepared as described in Example 1 except that compound E was prepared from 2-aminophenyl-4-pyridylmethanone using sodium bisulphite: 2-Aminophenyl-4-pyridyl-methanone (3.1g; 16 mmol) was dissolved in 10M aqueous hydrochloric acid (35ml) at 0ºC with stirring. Sodium nitrite (1.0g) in water (7.5ml) was added dropwlse over five minutes. After stirring for a further hour sodium bisulphite (10g) was added in portions. After stirring for thirty minutes at 0ºC and one hour at ambient temperature, the reaction was extracted with ethyl ethanoate (3 x 400ml), dried, filtered and the solvent removed under reduced pressure. Flash silica chromatography provide slightly impure indazole (630mg; 21%). Further silica chromatography provided pure material (480mg; 16%) identical to that previous prepared (vide supra).

Example 4:

2,3-Dihydro-9(1-Methyl-1,2,5,6-Tetrahydro-4-Pyridyl) 1-4-Pyrazolo-(1,2-a)-Indazolium Bromide (Compound R77). The title compound was prepared as described in Example 1 except that compound E was prepared from 2-aminophenyl-4-pyridylmethanone using tin dichloride:

2-Aminophenyl-4-pyridyl-methanone (4.9g; 25 mmol) was dissolved in 10M aqueous hydrochloric acid (30ml) at 0ºC under a nitrogen atmosphere. Sodium nitrite (2.0g) dissolved in water (8.5ml) was added dropwise over fifteen minutes. After stirring for a further hour, tin dichloride dihydrate (11g) in water (100ml) was added dropwise over fifteen minutes. After stirring for one hour at ambient temperature, the reaction mixture was cooled to 0ºC and saturated aqueous sodium carbonate was added dropwise until the mixture was basic. This was then evaporated to dryness, extracted Into methanol , filtered and the solvent evaporated. Flash silica chromatography provided the product (3.8g; 79%), which was identical to that previously prepared (vide supra).

Example 5:

2,3-Dihydro-9(1-Hethyl-1,2,5,6-Tetrahydro-4-Pyridyl) 1-4-Pyrazolo-(1,2-a)-Indazolium Bromide (Compound R77).

The title compound was prepared as described in Example 1 except that compound E was prepared from (2-amino-5-chlorophenyl)-4-pyridyl-methanone as follows:

(2-Amino-5-chlorophenyl)-4-pyridyl-methanone (1.16g; 5.05 mmol) was dissolved in 10M aqueous hydrochloric acid (5ml) at 0°C with stirring and under a nitrogen atmosphere. Sodium nitrite (380mg) dissolved In water (1.5ml) was added dropwise over a period of about five minutes. After a further thirty minutes, sodium bisulphite (3.8g) dissolved in water (20ml) was added dropwise over ten minutes. The reaction mixture was stirred for thirty minutes at 0ºC and thirty minutes at ambient temperature. The solution was made alkaline with 2M aqueous sodium hydroxide and the extracted with ethyl ethanoate (3 x 100ml). The dark red coloured extract became golden brown coloured when dried over a mixture of potassium carbonate and magnesium sulphate. After filtering and evaporating the solvent, the Intermediate was obtained using radial chromatography on silica as a yellow oil, 5-chloro-3-(4-pyridyl)-indazole (450mg; 39%). i.r. (N-H) 2500-3300cm^-1

Η n.m.r. 8.71 (2H, complex d, pyridyl); 7.81 (2H, complex d, pyridyl); 7.99 (1H, dd, C(5)-H) 7.42 (2H, m, C(7)-H and C (8)-H) p.p.m. Repetition provided a larger quantity of this Intermediate, a portion of which (960mg; 4.2 mmol) was dissolved in ethanol (50ml) and hydrazine hydrate (12.5ml). After adding 10% palladium-carbon (500mg) under nitrogen, the reaction mixture was refluxed for ten minutes. The catalyst was removed by filtration then the volatiles were removed under reduced pressure. The residue was taken up in ethyl ethanoate (250ml), washed with water (50ml), dried over magnesium sulphate and filtered. Radial silica chromatography of the material, obtained by evaporation, provided pure product (550mg; 67%) as a white solid, identical to that previously prepared (vide supra).

Example 6:

2,3-Dihydro-9(1-metyyl)-4-piperidyl)-l-4-pyrazolo(1,2a)-indazolium bromide (compound R78)

A. 3-(1-Methyl-1,2,5,6-tetrahydro-4-pyridyl)-2-methylindole. 2-Methylindole (50g; 0.38 mol) dissolved in glacial ethanoic acid (11) was stirred at 70°C (oil bath) and 2N aqueous phosphoric acid (250ml) and 1-methyl-4-piperidone (93.8ml; 0.76 mol) were added. Stirring was continued at this temperature for two hours, after which the reaction was cooled to 0°C (ice:water) and a mixture of 0.88 ammonia:ice was added, with vigorous stirring, until no more brown precipitate formed. This precipitate was filtered off, lightly washed with water until neutral, dried, filtered and the solvent evaporated to give a brown solid (70.2g; 81%). Recrystallisation of a small sample gave the pure product in the form of off-white needles, from diethyl ether and petroleum ether. m.p. 138-140°C. i.r. 3472 (NH); 2788 (N-CH₃) cm^-1. H n.m.r. 1.46 (1H, b, NH); 2.27-3.23 (4H, m, aromatic); 4.29 (1H, b, CH); 6.59-7.82 (6H, m, CH₂); 7.57 (3H, s, N-CH₃); 7.72 (3H, s, indole CH₃) p.p.m. m.s. M⁺ 226.

B. 3-(4-(1-Methyl)-piperidyl)-2-methyl indol e. 3-(1-Methyl-1,2,5,6-tetrahydro-4-pyridyl)-2-methylindole

(68g; 0.30 mol) was reduced in portions. Vigorously stirred portions (4.0g) of starting material in a mixture of ethanol (160ml), water (200ml) and 10M aqueous hydrochloric acid (40ml) were hydrogenated over 5% palladium on carbon (0.4g; 10% by weight) at room temperature until the theoretical volume of hydrogen was consumed (400ml). The reaction mixtures were filtered through celite, neutralised with 10M aqueous sodium hydroxide and, under reduced pressure, evaporated almost to dryness and extracted with ethyl ethanoate. The extract was dried, filtered and evaporated to give a brown solid (65.2g;95%). Recrystallisation gave the pure product in the form of yellow crystals, from diethyl ether and petroleum ether. m.p. 166-168ºC. i.r. 3473 (NH); 2790 (N-CH₃) cm^-1 Η n.m.r. 1.91 (1H, b, NH); 2.15-3.22 (4H, m, aromatic); 6.76-8.52 (9H, m, CH/CH₂); 7.66 (6H, s, 2 x CH₃) p.p.m.

¹³C n.m.r. (CDCl₃): 135.3(s); 129.9(s); 127.5(s); 120.5(d); 119.1 (d); 118.7(d); 115.1 (s); 110.2(d); 56.9(t); 46.7(q); 34.0(d); 32.0(t) p.p.m.

C. (2-Ethanamidophenyl)-(4-(1-methyl)-piperidyl)-methanone. Sodium periodate (47g; 0.22 mol) in water (600ml) was added in aliquots to a stirred solution of 3-(4-(1-methyl)-piperidyl)-2-methyl indole (20g; 0.088 mol) in methanol (400ml) at room temperature and the white precipitate, which formed throughout the reaction, was periodically filtered off. After two days the solution was filtered and, under reduced pressure, evaporated almost to dryness. The reaction mixture was extracted with trichloromethane. The extract was dried, filtered and evaporated to give a brown oil (13.7g, 60%). Silica chromatography gave the pure product in the form of a yellow oil. i.r. 3253 (NH); 2793 (N-CH₃); 1690 (NHCOCH₃); 1648

(C=O) cm.^-1 Η n.m.r. 1.12-1.34 (1H, m, aromatic); 1.95-3.03 (3H, m, aromatic); 6.51-8.40 (9H, m, CH/CH₂); 7.67(3H, s,

N-CH₃); 7.77(3H, s, CH₃) p.p.m. 1³C n.m.r. (CD₃OD): 208.1 (s); 171.6(s)l 141.0(s);

135.2(d); 131.7(d); 124.5(d); 124.2(s); 122.8(d); 55.7(t); 46.1 (q); 44.9(d); 29.5(t); 24.9(q) p.p.m.

D. (2-Aminophenyl)-(4-(1-methyl)-piperidyl)-methanone

2-(Ethanamidophenyl)-(4-(1-methyl)-piperndyl)-methanone was converted Into the title compound by following a standard add hydrolysis procedure.

E. (2-Azidophenyl)-(4-(1-methyl)-piperidyl)-methanone .

(2-Aminophenyl)-(4-(l-methyl)-piperidyl)-methanone (16.4g; 75 mmol) was dissolved with a little warming in 10M aqueous hydrochloric add (200ml) and stirred at 0ºC (ice/water). Sodium nitrite (6.75g; 0.98 mol) in water (50ml) was added dropwise. After thirty minutes sodium azide (12.7g; 0.196 mol) in water (100ml) was also added dropwise, and stirring was continued for a further thirty minutes. The reaction was neutralised by pouring it slowly onto a vigorously stirred mixture of ethyl ethanoate and 2M aqueous sodium hydroxide. The ethyl ethanoate was separated and, after further extracting the aqueous portion with ethyl ethanoate, the organic portions were combined, washed with water until neutral, dried, filtered and evaporated to give a brown oil (13.2g, 72%). Silica chromatography of a small sample gave the pure product in the form of a yellow oil. i .r. 2791 (N-CH₃); 2127 (N₃); 1683 (C=O) cm^-1 Η n.m.r. 2.32-3.05 (4H, m, aromatic); 6.54-8.35 (9H, m,

CH/CH₂) ; 7.71 (3H , s , CH₃) p . p.m.

F. 3-(4(1-Methyl)piperidyl)-indazole.

(From (2-azidophenyl)-(4-(l-methyl)-piperidyl)-methanone.) (2-Azido phenyl)-(4-(l-methyl)-piperldyl)-methanone (16.5g; 68 mmol) in ethanol (400ml) was refluxed with hydrazine hydrate (65.5ml; 1.35 mol) and glacial ethanoic acid (10ml) for one day. The reaction was neutralised with glacial ethanoic acid, and after adding water, evaporating off most of the ethanol under reduced pressure and slight basification of the remaining solution, extraction with trichloromethane, drying, filtering and evaporating gave a brown solid (6.0g; 41%). Silica chromatography of a small sample gave the pure product as a yellow solid. m.p. 159-161ºC. i.r. 3472 (NH); 2792 (N-CH,) cm^-1 H n.m.r. 8.01-6.90 (4H, m, aromatic); 3.44-1 .87 (9H, m,

CH/CH₂); 2.37 (3H, s, CH₃) p.p.m. m.s. M±215; M±-CH₃200.

G. 2,3-Dihydro-9(1-methyl-4-piperidyl)-l-4-pyrazolo1 ,2a)-i ndazol i um bromide (Compound R78). 3-(4-(l-Methyl)piperidyl)-indazole is converted into the title compound (R78) by a procedure similar to that described in Example 1 H.

Example 7:

2 , 3-Di hydro-9(1-methyl-4-pi peri dyl )-l-4-pyrazolo- 1 ,2a)-i ndazol ium bromi de (Compound R78) .

The ti tle compound was prepared as descri bed in Exampl e 6 except that compound F was prepared from 3-(1-Methyl-1,2,5,6tetrahydro-pyrid-4-yl)-indazole as follows:

3-(1-Methyl-1,2,5,6-tetrahydro-pyrid-4yl)-indazole (1.0; 4.6 mmol) was dissolved in tetrahydrofuran (20ml) at 0ºC (ice/water) followed by the addition of trimethylamine N-oxide dihydrate (1.4g; 13 mmol). The reaction mixture was refluxed for five hours, then the solvent was evaporated and the res idue was dissolved in diglyme (15ml). After refluxing for one hour, the solvent was evaporated to give a yellow oil (0.4g, 45%). Purification by silica chromatography gave the product as a yellow solid, Identical to the product prepared previously (vide supra).

Example 8:

2,3-Dihydro-9(1-methyl-4-piperidyl)-l-4-pyrazolo1 ,2a)-indazolium bromide (Compound R78).

The title compound was prepared as described in Example 6 except that compound F was prepared from (2-aminophenyl)-(4-(lmethyl)-piperidyl)-methanone as follows:

(2-Aminophenyl )-(4- 1 methyl)-piperidyl)-methanone (3. lg, 14.2 mmol) was dissolved in 10M aqueous hydrochloric acid at 0ºC with stirring. After fifteen minutes, sodium nitrite (1.30g) in water (5.5ml) was added dropwise over a period of fifteen minutes. After stirring for one hour, tin dichloride trihydrate (7.5g) in water (60ml) was added dropwise over fifteen minutes. The reaction mixture was then allowed to reach ambient temperature. After two hours, the reaction was made basic with saturated aqueous sodium carbonate and then extracted with trichloromethane. After drying and filtering, the solvent was evaporated to give 3-(1-methyl-4-piperidyl)-indazole (1.2g). Evaporation of the aqueous phase, extraction into methanol and flash chromatography on silica provided more of the Indazole (1.0g: total 2.2g; 72%). The physical properties of the compound prepared in this fashion were Identical to those of the material obtained by the alternative methods, (vide supra).

Claims

CLAIMS 1. A compound of formula II or a pharmaceutically acceptable add addition salt thereof:

in which formula R₁ represents a six membered heterocyclic ring A comprising one nitrogen atom and bound to the Indazole ring system by carbon, the ring A being optionally substituted by one or more C₁-C₆ alkyl groups;

R₂ represent hydrogen, hydroxy, C₁-C₆ alkyl or C₁-C₆ alkoxy,

R₃ represents hydrogen, hydroxy, halogen, a C₁-C₆ alkyl or alkoxy group, or a group of formula -NO₂, -CN,-CONH₂, or -CONHR (R representing a C₁-C₃ alkyl group);

R₄, which may differ from R₃, represents: hydrogen, hydroxy, halogen, a C₁-C₆alkyl or alkoxy group, or a group of formula -NO₂, -CN,-CONH₂, or -CONHR (R representing a C₁-C₃ alkyl group);

R₅ represents hydrogen or halogen, X represents an anionic moiety the nature of which is such that the compound of formula II is pharmaceutically acceptable and n is 1 or 2.

2. A compound according to Claim 1, in which the nitrogen atom of ring A is spaced by three carbon atoms from the carbon of the

Indazole ring system on which ring A is carried.

3. A compound according to any preceding Claim, in which R₁ has the formula:

4. A compound according to Claim 3, in which the nitrogen of group R₁ carries a C₁-C₆ alkyl group.

5. A compound according to any preceding claim, in which R₂ represents hydrogen, hydroxy, C₁-C₃ alkyl or alkoxy.

6. A compound according to any preceding claim, in which X- represents halide.

7. A compound according to any preceding claim, in which R₃ represents hydrogen, hydroxy, C₁-C₃ alkyl or alkoxy or halogen.

8. A compound according to any preceding claim, in which R₄ represents hydrogen, hydroxy, C₁-C₃ alkyl or alkoxy or halogen.

9. A compound according to any preceding claim, in which n is one.

10. A compound according to any preceding claim, i n which R₄ and R₅ represent hydrogen.

11. A compound according to any preceding claim, in which R₂ represents hydrogen or C₁-C₆ alkoxy.

12. A compound which is: (i) 2,3-Dihydro-9(1-methyl-1,2,5,6 tetrahydro-4-pyridyl)-1-4-pyrazolo(1,2-a) i ndazol i urn bromlde ; ( i i ) 2 , 3-di hydro-9-(1-methyl )-4-pyridyl )-1-4-pyrazolo-(1 ,2a)Indazolium bromide; (iii) 2,3-dihydro-9-(1-methyl)-4-piperidyl)1-4-pyrazolo-(1,2a)-indazolium bromide; (iv) 7-methyl-2,3dihydro-9(1-methyl-1,2,5,6 tetrahydropyridyl)-1-4 pyrazolo(1,2-a)-indazolium bromide or (v) 7-methyl-2,3-dihydro-9(1ethyl-1,2,5,6 tetrahydropyridyl)-1-4-pyrazolo(l,2-a) Indazolium bromide or an add addition salt of such a compound.

13. A compound according to any preceding claim for use in therapy.

14. A method for the treatment or prophylaxis of asthma in which an asthmatic subject is treated with a compound according to any of Claims 1 to 12 in an amount effective to dilate the bronchi of the subject.

15. A composition for the treatment or prophylaxis of asthma which comprises a compound according to any of Claims 1 to 12 together with an inert carrier or diluent.

16. A process for the production of a compound II or a pharmaceutically acceptable add addition salt thereof comprises treating an indazole of formula III or an add addition salt thereof,

with a substituted alkane of formula Y-(CH₂)_n+2-Z wherein Y and Z which may be identical or different, represent moieties capable of existence as anions in the presence of a reducing agent such as a hydride e.g. an alkali metal hydride whereby a compound of formula IV is produced the counterlon Y of which is, when necessary, subsequently replaced by a counterlon X-.

17. An indazole of formula III or an add addition salt thereof hereinbefore described.

18. An Intermediate of formula IV or an add addition salt thereof hereinbefore described.

19. An Intermediate of formula V or VI or an add addition salt thereof hereinbefore described.