GB2153818A

GB2153818A - Pyrazolopyridine derivatives

Info

Publication number: GB2153818A
Application number: GB08431986A
Authority: GB
Inventors: Christopher Antony Ramsden; Libert Clinton Saunder; Peter James Warne; Barbara Joyce Broughton; Raymond Frederick Collins; Edward Lunt
Original assignee: May and Baker Ltd
Current assignee: May and Baker Ltd
Priority date: 1983-12-21
Filing date: 1984-12-19
Publication date: 1985-08-29
Also published as: ES542457A0; IT1178768B; LU85690A1; BE901336A; GB8334001D0; GB2153818B; NL8403874A; JPS60172979A; GR82507B; AU3690684A; GB8431986D0; ATA404684A; ES538957A0; IL73860A0; SE8406478D0; DK616784A; FI845022A0; FI845022L; FR2556723A1; ZA849903B

Abstract

Pyrazolopyridine derivatives of the formula: <IMAGE> wherein R<1> represents a carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group, R<2> represents a halogen atom or an alkyl, cyano, alkoxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, nitro, hydroxy, alkoxy, aryloxy, aralkyl, trifluoromethyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylthio, arylsulphinyl, arylsulphonyl, alkanoyl, aroyl or aryl group, or an amino group which may be substituted by one or two groups selected from alkyl and aryl groups, and n represents 0, 1, 2, 3 or 4, and salts thereof, with the provisos that:- (i) R<1> is alkylcarbamoyl when n is 0, (ii) R<1> is other than a dialkylcarbamoyl group when n is 1 and R<2> is a methyl group, (iii) R<1> is other than a carboxy or ethoxycarbonyl group when n is 1 and R<2> represents a methyl group in the 7-position, and (iv) R<1> is other than dimethylcarbamoyl when (R<1>)n represents a methoxy or tert-butyl group in the 5-position or two methyl groups in the 6-and 7-positions, are new compounds which possess properties indicative of utility in the treatment of arthritic and related autoimmune disorders. <IMAGE>

Description

SPECIFICATION Pyrazolopyridine derivatives This invention relates to therapeutically useful pyrazolopyridine derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use as pharmaceuticals.

The pyrazolopyridine derivatives are the compounds of the general formula shown in Figure I at the end of the present specification, wherein R1 represents a carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, group, R2 represents a halogen e.g. fluorine, chlorine or bromine, atom or an alkyl, cyano, alkoxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, nitro, hydroxy, alkoxy, aryloxy, aralkyl, trifluoromethyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylthio, arylsuiphinyl, arylsulphonyl, alkanoyl, aroyl or aryl group, or an amino group which may be substituted by one or two groups selected from alkyl and aryl groups, and n represents 0, 1,2,3 or4, preferably 1 or 2, and, when applicable, pharmaceutically acceptable salts thereof, for example when R1 and/or R2 represents a carboxy group, salts thereof, more especially alkali metal, e.g. sodium, salts, with the provisos that: (i) R1 is alkylcarbamoyl when n is0, (ii) R1 is other than a dialkylcarbamoyl group when n is 1 and R2 is a methyl group, (iii) R1 is other than a carboxy or ethoxycarbonyl group when n is 1 and R2 represents a methyl group in the 7-position, and (iv) R1 is other than dimethylcarbamoyl when (R1)n represents a methoxy or tert-butyl group in the 5-position or two methyl groups in the 6- and 7-positions.

When n represents 2, 3 or 4 the substituents R2 may be the same or different.

Aryl groups and moieties within the definition of R2 are preferably phenyl groups which may carry one or more substituents selected from, for example, halogen atoms and alkyl, alkoxy, nitro and trifluoromethyl groups.

Alkyl groups and moieties within the definitions of R1 and R2 may be straight or branched and may contain up to 6 carbon atoms.

Whenever the context so permits reference in this specification to the compounds of the general formula shown in Figure I is meant to include reference to the aforementioned salts.

The compounds have valuable pharmacological properties, in particular properties which are indicative of utility in the treatment of arthritic disorders and related autoimmune disorders, such as rheumatoid arthritis, osteoarthritis, seronegative arthritides such as ankylosing spondylitis, psoriatic arthritis and enteropathic arthropathy, connective tissue disorders such as systemic lupus erythematosus and polymyotis, and the tendency to rejection of transplants. In particular, in laboratory tests, compounds of the formula shown in Figure I have have been shown to inhibit the deterioration of joints in rodents' limbs. These results are particularly important when contrasted with compounds currently employed in the treatment of arthritic disorders, which are primarily antiinflammatories and do not possess the said ability to inhibit joint deterioration.Furthermore, compounds of the formula shown in Figure I surprisingly are markedly superior in their pharmacological properties when compared with closely related compounds.

The beneficial properties of the compounds of the formula shown in Figure I are enhanced by the fact that they have only very low mammalian toxicity.

Preferred classes of compounds of the formula shown in Figure I include those wherein R1 represents a dialkylcarbamoyl group containing up to 4 carbon atoms (e.g. a dimethylcarbamoyl group) and those wherein R2 represents an alkyl (e.g. methyl, ethyl or tert-butyl), alkoxy (e.g. methoxy), phenyl, cyano or alkoxycarbonyl (e.g. ethoxycarbonyl) group.

Compounds of the formula shown in Figure I which are particularly important include the following: 3-ethoxycarbonyl-5-phenylpyrazolo[1 ,5-a] pyridine; AA 5-phenylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid; AB 3-(N,N-dimethylcarbamoyl)-5-phenylpyrazolo[1 ,5-a]pyridine; AC 3-carboxy-5,7-dimethylpyrazolo[1 ,5-a]pyridine; AD 5,7-dimethyl-3-(N,N-dimethylcarbamoyl)pyrazolo[1,5-a]pyridine; AE 3-carboxy-5-methoxy-7-methylpyrazolo[1,5-a]pyridine; AF 3-(N,N-dimethylcarbamoyl)-5-methoxy-7-methylpyrazolo[1,5-a]pyridine; AG 3-(N-propylcarbamoyl)-5-phenylpyrazolo[1 ,5-a]pyridine;; AH 3-(N,N-diethylcarbamoyl)-5-phenyl pyrazolo[l ,5-a]pyridine; Al 5-cyano-3-methoxycarbonylpyrazolo[1 ,5-a] pyridine; AJ 3,5-bis(methoxycarbonyl)pyrazolo[1 ,5-ajpyridine; AK 5-methoxypyrazolo[1 ,5-a]pyridine-3-carboxylic acid; AL 5-tert-butyl-3-ethoxycarbonyl pyrazolo[1 ,5-a]pyridine; AM 5-tert-butyl pyrazolo[1 ,5-ajpyridine-3-carboxylic acid; AN 6,7-dimethyl pyrazolo[1 ,5-ajpyridine-3-carboxylic acid;AO 5,7-dimethyl-3-methoxycarbonylpyrazolo[1 ,5-a]pyridine; AP 3-ethoxycarbonyl-5-methoxy-7-methylpyrazolo[1 ,5-a] pyridine; AQ 3-methoxycarbonyl-5-methoxypyrazolo [1,5-a] pyridine; AR 5-methoxy-3-ethoxycarbonylpyrazolo[1,5-a]pyridine; AS 6,7-dimethyl-3-methoxycarbonyipyrazolo[1 ,5-a] pyridine; and AT 6,7-dimethyl-3-ethoxycarbonyl pyrazolo[1 ,5-a]pyridine AU Compounds AA, AB, AC, AE and AG are of outstanding importance.

The letters AA to AU are assigned to the compounds for easy reference later in the specification.

In tests, compounds of the formula shown in Figure I when twice administered orally to mice, each time at the dose shown in the following Table I, reduced by 50% the inhibition of migration of incubated mouse macrophage cells. This is a measure of antagonism or reduction of the levels of lymphokines and is indicative of utility in the treatment of arthritic patients.

TABLE I Test Oral dose Compound (mglkg animal body weight) AA 10 AB 15 AC 10 AE 10 AG 18 The compounds of the formula shown in Figure I are prepared by the application or adaptation of known methods, for example, as a feature of the present invention, methods described in the Examples and Reference Examples hereinafter.

Thus, according to a feature of the present invention, compounds of the formula shown in Figure I wherein R1 represents a straight or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety (R2 and n being as hereinbefore defined) are prepared by the reaction of a solution of a compound of the general formula shown in Figure II (wherein R2 and n are as hereinbefore defined and X1 represents an anion, e.g. an iodide or mesitylenesulphonate ion) in a suitable organic solvent, e.g.

N,N-dimethylformamide, with a base, e.g. anhydrous potassium carbonate, followed by reaction with a compound of the general formula: H-C=-C-COOR3 Ill wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms.

According to a feature of the present invention, compounds of the formula shown in Figure I wherein R represents a carboxy group (R2 and n being as hereinbefore defined) are prepared by the hydrolysis of compounds of the formula shown in Figure I wherein R1 represents a straight- or branched-chain i alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety (R2 and n being as hereinbefore defined), for example by treatment with an aqueous alkali, e.g. aqueous potassium hydroxide solution or aqueous sodium hydroxide solution, followed by treatment with an aqueous acid, e.g. dilute hydrochloric acid.

According to a feature of the present invention, compounds of the formula shown in Figure I wherein R1 I represents carbamoyl, alkylcarbamoyl or dialkylcarbamoyl wherein the alkyl moieties are straight or branched and each contain from 1 to 6 carbon atoms (R2 and n being as hereinbefore defined) are prepared from compounds of the formula shown in Figure I wherein R1 represents a carboxy group or a straight- or branched-chain aikoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety (R2 and n being as hereinbefore defined) by the application or adaptation of known methods.

According to one aspect, a compound of the formula shown in Figure I wherein R1 represents a carboxy group (R2 and n being as hereinbefore defined) is converted by the application or adaptation of known methods to the corresponding acid halide or acid anhydride of the general formulae shown in Figure IV and Figure V respectively (wherein X2 represents a halogen, e.g. chlorine, atom and R2 and n are as hereinbefore defined), which is then reacted with a compound of the general formula: NHR4R5 VI wherein R4 and R5 each represent a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms. The reaction is preferably carried out in an organic solvent, e.g. ethanol, preferably i below room temperature, e.g. at 0-10"C.

According to another aspect, a compound of the formula shown in Figure I wherein R1 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety (R2 and n being as hereinbefore defined) is reacted direct with a compound of the general formula VI (R4 and R5 being as hereinbefore defined), optionally in a solvent, e.g. ethanol, preferably in a sealed vessel.

According to a further feature of the present invention, compounds of the formula shown in Figure I wherein R1 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety (R2 and n being as hereinbefore defined) are prepared by the esterification of compounds of the formula shown in Figure I wherein R1 represents a carboxy group (R2 and n being as hereinbefore defined), by the application or adaptation of known methods of esterification of carboxylic acids, e.g. by reaction of a compound of formula IV or V (wherein X2, R2 and n are as hereinbefore defined), derived therefrom, with an alcohol of the general formula: RETCH Vll wherein Re represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms.

Compounds of the formula shown in Figure I may also be prepared by conversion of other compounds of the formula shown in Figure I, by modification of the moiety or moieties (R2)n, for example as follows: (1 ) As a feature of the present invention, compounds of the formula shown in Figure I wherein R2 represents at least one straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety (R', n and any other substituents R2 being as hereinbefore defined) and compounds of the formula shown in Figure I wherein R2 represents a carboxy group (R1, n and any other substituents R2 being as hereinbefore defined) are interconverted by the application or adaptation of methods described herein before for the interconversion of compounds of the formula shown in Figure I wherein R1 represents an alkoxycarbonyl group and compounds of the formula shown in Figure I wherein R represents a carboxy group (R2 and n being as hereinbefore defined).

(2) As a further feature of the present invention, compounds of the formula shown in Figure I wherein R2 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety (R1, n and any other substituents R2 being as hereinbefore defined) are prepared by the hydrolysis of compounds of the formula shown in Figure I wherein R2 represents a cyano group (R1, n and any other substituents R2 being as hereinbefore defined), for example by reaction with aqueous alkali, e.g.

aqueous sodium hydroxide solution or aqueous sodium hydroxide solution, in the presence of the appropriate alcohol of formula VII (R6 being as hereinbefore defined, preferably methyl or ethyl).

The aforementioned salts of certain compounds of the formula shown in Figure I are prepared by the application or adaptation of methods known per se, for example by reaction of the parent compound of the formula shown in Figure 1 with an alkali metal hydroxide, carbonate or, preferably, bicarbonate, in an aqueous or aqueous-organic medium, followed by isolation of the salt by methods known perse.

By the term "known methods" as used in this specification is meant methods heretofore used or described in the literature.

The following Examples illustrate the preparation of compounds of the formula shown in Figure I and the Reference Examples illustrate the preparation of intermediates.

EXAMPLE 1 CompoundAA A stirred solution of 1-amino-4-phenyl-pyridinium iodide (2.09) in anhydrous N,N-dimethylformamide (20ml) was treated with anhydrous potassium carbonate (1.01 g) at room temperature followed, after 30 minutes, by treatment with ethyl propiolate (1.319) dropwise. The mixture was stirred for a further period of 1 hour and then it was poured into a mixture of ice and water (75ml) and extracted with diethyl ether. The ethereal extract was washed with water, dried over magnesium sulphate and evaporated, to give a dark red residue.A portion of this residue was triturated with petroleum ether (b.p. 40-60"C), and then it was subjected to chromatography on silica gel, eluting with chloroform, followed by recrystallisation from cyclohexane, to give 3-ethoxycarbonyl-5-phenylpyrazolo[1,5-ajpyridine, in the form of white needles, m.p.

96-97"C.

EXAMPLE 2 CompoundsAB, AC, AD, AE, AF, AG, AHandAl A suspension of 3-ethoxycarbonyl-5-phenyl-pyrazolo[1 ,5-a]pyridine (1.0g; prepared as described in Example 1) in ethanol (5ml) was treated with a solution of potassium hydroxide (0.49) in water (2ml) and then it was heated at reflux for 45 minutes. The clear solution was poured into water (50ml) and washed with diethyl ether (3 x 15ml) and then it was then acidified to pH1 by treatment with concentrated hydrochloric acid. The resulting white precipitate was filtered off, washed with water, and recrystallised from a mixture of N,N-dimethylformamide and water, to give 5-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.45g), in the form of a white solid, m.p.252-254"C (with decomposition).

A suspension of 5-phenylpyrazolo[1 ,5.a]-pyridine-3-carboxylic acid (1.549; prepared as described above) in hot anhydrous methanol (40ml) was treated with a solution of potassium hydroxide (0.369) in anhydrous methanol (8ml). The resulting clear solution was evaporated to dryness under reduced pressure and the residual solid was suspended in anhydrous toluene (50ml). The stirred suspension was treated with oxalyl chloride (1.43ml) at room temperature, and after 30 minutes the mixture was treated with dry pyridine (4 drops) and stirred overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure, to give 5-phenylpyrazolo[1 ,5,-a]pyridine-3-carbonyl chloride (0.9g), which was used in the next stage without further purification.

A stirred solution of 5-phenylpyrazolo[1,5-a]pyridine-3-carbonyl chloride (0.9g) in dry dichloromethane (25ml) was treated with a solution of dimethylamine in ethanol (33% w/v; 12ml) at 0 C. When the addition was complete, the mixture was allowed to warm to room temperature and it was maintained at room temperature overnight. The mixture was then washed with water and the organic solution was dried over magnesium sulphate and evaporated under reduced pressure. The resulting residue was triturated with petroleum ether (b.p. 40-60"C) and recrystallised from a mixture of carbon tetrachloride and hexane, to give 3-(N,N-dimethylcarbamoyl)-5-phenylpyrazolo[1,5-a]-pyridine (0.39) in the form of a white solid, m.p.

88-90"C.

By proceeding in a similar manner, but replacing the 3-ethoxycarbonyl-5-phenylpyrazolo[1,5-a]pyridine, used as a starting material, by the appropriate quantities of 5,7-dimethyl-3-methoxy-carbonylpyrazolo[1 ,5- a]pyridine, and 3-ethoxycarbonyl-5-methoxy-7-methylpyrazolo[1 ,5-a]pyridine,respectively, each prepared as described in Example 9, there were prepared:: 3-carboxy-5,7-dimethylpyrazolo]1,5-a]pyridine, m.p. 167-170"C (with decomposition); 3-carboxy-5-methoxy-7-methylpyrazolo[1 ,5-a]pyridine; 5,7-dimethyl-3-(N,N-dimethylcarbamoyl)pyrazolo[1,5-a]pyridine, m.p. 124-1 27"C (subjected to chromatog raphy on silica gel with ethyl acetate as eluent and recrystallised from cyclohexane); and 3-(N,N-dimethylcarba moyl)-5-methoxy-7-methyl-pyrazolo[1 5-a] pyridine, m.p. 126-1 290C (recrystallised from hexane).

By again proceeding in a simiiar manner, but replacing the dimethylamine, used as a starting material, by the appropriate quantities of propylamine and diethylamine respectively, there were prepared: 3-(N-propylcarbamoyl)-5-phenylpyrazolo[1 ,5-a]pyridine, m.p. 132-1 33"C (subjected to chromatography on silica gel with ethyl acetate as eluent); and 3-(N,N-diethylcarbamoyl)-5-phenylpyrazolo[1 ,5-a]pyridine m.p. 102-1 03'C (subjected to chromatography on silica gel with ethyl acetate as eluent).

EXAMPLE 3 CompoundAJ A cooled solution of 1-amino-4-cyano-pyridinium mesitylenesulphonate (0.64g; prepared as described in Reference Example 1) at OOC in dry N,N-dimethylformamide (5ml) was treated with anhydrous potassium carbonate (0.419) and methyl propiolate (0.349) and stirred at 0 C for 30 minutes and then at room temperature for 5 hours, and left to stand at room temperature overnight. The solvent was removed under vacuum and the residue was triturated with chloroform (25ml). The insoluble material was filtered off. The filtrate was evaporated to dryness and the resulting residue was subjected to medium pressure chromatography, eluting with ethyl acetate, to give 5-cyano-3-methoxycarbonylpyrazolo[1 ,5-a]-pyridine (80mg), m.p. 184-186"C.

EXAMPLE 4 CompoundAK A solution of 5-cyano-3-methoxycarbonyipyrazolo[l ,5-a]pyridine (25mg; prepared as described in Example 3) in methanol (3ml) containing 5 drops of aqueous sodium hydroxide solution (2N) was heated at reflux for 3 hours, and was then evaporated to dryness under vacuum. The resulting residue was dissolved in water (3ml) and acidified by treatment with concentrated hydrochloric acid. The precipitate was filtered off and subjected to medium pressure chromatography, eluting with chloroform, to give 3,5 bis(methoxycarbonyl)pyrazolo[1,5-a]pyridine [mass spectrum 234; N.M.R. (in deuterated dimethylsulphoxide) 3.90,3.98,7.52, 8.62,8.66 and 9.04ppm].

EXAMPLE 5 CompoundAL A suspension of 3-methoxycarbonyl-5-methoxypyrazolo[1 ,5-a]pyridine (1.899; prepared as described in Example 9) in methanol (21 ml) was treated with a solution of potassium hydroxide (1.56g) in water (2.2ml) and then it was heated at reflux for 100 minutes. The clear solution was cooled and evaporated under vacuum and then dissolved in water (1 Oml) and washed with diethyl ether and then it was acidified by treatment with dilute hydrochloric acid (2N). The resulting white precipitate was filtered off, to give 5-methoxypyrazolo[1 ,5-a]pyridine-3-carboxylic acid (1.5g), m.p. 228-229"C.

EXAMPLE 6 Compound AM A stirred solution of 1-amino-4-tert-butyl-pyridinium iodide [10g; prepared by the application of methods described in J. Org. Chem., 1968,33(5), 2062-2064] in anhydrous N,N-dimethylformamide (70ml) was treated with anhydrous potassium carbonate (5g) at room temperature followed, after 30 minutes, by treatment with a solution of ethyl propiolate (lOg) in dimethylformamide (20ml), dropwise. The mixture was left to stand overnight and then it was evaporated under vacuum and treated with water (250ml) and extracted with diethyl ether. The ethereal extract was washed with water, dried over magnesium sulphate and evaporated, to give a dark residue.This residue was subjected to medium pressure chromatography on silica gel, eluting with chloroform, to give 5-tert-butyl-3-ethoxycarbonylpyrazolo[1 ,5-a]pyridine (2.19) in the form of a pale orange solid [N.M.R. (in deuterochloroform): 8.35ppm (1H, doublet,J = 7Hz), 8.28ppm (1H, singlet), 8.Oppm (1 H, doublet, J = 2Hz), 7.9ppm (1 H, doublet of doublets, J = 7Hz and 2Hz), 4.3ppm (2H, quartet, J = 7Hz), 1.4ppm (12H, multiplet)].

EXAMPLE 7 CompoundAN A suspension of 5-tert-butyl-3-ethoxy-carbonylpyrazolo[1,5-a]pyridine (2.09; prepared as described in Example 6) in methanol (25ml) was treated with a solution of potassium hydroxide (1.5g) in water (5ml) and then it was heated at reflux overnight. The solvent was evaporated under vacuum and the residue was treated with water (25ml) and washed with diethyl ether and then it was acidified by treatment with dilute hydrochloric acid (2N). The resulting white precipitate was filtered off and washed with water, to give 5-tert-butylpyrazolo[1 ,5-ajpyridine-3-carboxylic acid (1 .69), m.p. 189-1 90"C (with decomposition).

EXAMPLE 8 CompoundAO A suspension of 6,7-dimethyl-3-methoxycarbonylpyrazolo[1,5-a]pyridine (4.059; prepared as described in Example 9) in methanol (45ml) was treated with a solution of potassium hydroxide (3.389) in water (5ml) and then it was heated at reflux four 100 minutes. The clear solution was cooled and evaporated under vacuum and then dissolved in water and washed with diethyl ether and then it was acidified by treatment with dilute hydrochloric acid (2N). The resulting precipitate was filtered off, to give 6,7-dimethylpyrazolo[1 ,5-a] pyridine- 3-carboxylic acid (2.299), m.p. 229-232"C (with decomposition).

EXAMPLE 9 Compounds AP, AO, AR, AS, A Tand A U By proceeding in a manner similar to that described heretofore and in J. Org. Chem. 1968,33(5), 2062-2064, and using the appropriate starting materials, there were prepared: 5,7-dimethyl-3-methoxycarbonylpyrazolo[l ,5-a]pyridine, b.p. 116-146"C/0.2mmHg; 3-ethoxycarbonyl-5-methoxy-7-methylpyrazolo[1 ,5-a]pyridine [N.M.R. (in deuterochloroform): 8.25ppm (1 H, singlet), 7.3ppm (1 H, doublet, J = 2Hz), 6.4ppm (1 H, doublet, J = 2Hz), 4.35ppm (2H, quartet, J= 7Hz), 3.9ppm (3H,singlet),2.7ppm (3H, singlet), 1.4ppm triplet, J = 7Hz)]; 3-methoxycarbonyl-5-methoxypyrazolo[l pyridine, m.p.98-100 C (from cyclohexane); 5-methoxy-3-ethoxycarbonylpyrazolo[1 ,5-a]pyndine, m.p.109-110 C; 6,7-dimethyl-3-methoxycarbonylpyrazolo[1 ,5-a]pyridine, b.p. 1 1 0-1 34"C/0.05m m Hg; and 6,7-dimethyl-3-ethoxycarbonylpyrazolo[l ,5-a]pyridine, b.p. 140-145"C/0.5mmHg.

REFERENCE EXAMPLE 1 A solution of 4-cyanopyridine (1.829) in dichloromethane (20my) was treated at 0 C with a solution of mesitylenesulphonylhydroxylamine (3.79) in dichloromethane (40ml) during 15 minutes. The reaction mixture was stirred at room temperature for 30 minutes and was then diluted with diethyl ether (30my). The white solid which formed was filtered off and washed well with diethyl ether, to give 1-amino-4cyanopyridinium mesitylenesulphonate (3.69), m.p. 136-138"C.

The present invention includes within its scope pharmaceutical compositions which comprise at least one compound of the formula shown in Figure I, or pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or coating. In clinical practice the compositions of the present invention will normally be administered orally or rectally, or parenterally, for example intravenously, intramuscularly or, more particularly, topically or intraarticularly.

Aqueous solutions, and compositions containing them, are particularly convenient means of administering some of the compounds of the formula shown in Figure I.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid compositions the active compound or compounds are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.

The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing the active compounds with or without the addition of diluents or excipients.

Solid compositions for rectal administration include suppositories formulated in manner known perse and containing the active compound or compounds.

Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or suspending media are propylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, by irradiation, or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in a sterile injectable medium immediately before use. As well as the more customary intravenous and intramuscular routes, the compositions may be administered by intraarticular injection.

Compositions in the form of solutions or suspensions, if desired together with additives as described above, in vegetable or other greases, paraffin or other waxes or lacquers or creams, to be applied topically, for example to the skin area around an affected joint to relieve arthritis, are also included in the invention.

The percentage of active ingredients in the compositions of the invention may be varied, it being necessary that they should constitute a proportion such that a suitable dosage for the desired effect shall be obtained. Obviously several unit dosage forms may be administered at about the same time. Generally the compositions should contain 0.1% to 80% by weight of active ingredient, especially when in tablet form.

The dose employed depends upon the desired effect, the route of administration and the duration of the treatment. In the adult, the doses are generally between 0.01 and 100mg (preferably between 0.1 and 1 Omg, more especially between 1 and 10mug) of compound of the formula shown in Figure I per kg body weight per day.

For example, suitable daily doses for an adult weighing approximately 80kg could be 8-50mg intravenously, 50-200mg intramuscularly, 20-100mg intraarticularly, and 250-800mg orally or topically.

The compounds of the formula shown in Figure I may be administered each day or, according to the wishes of the medical practitioner, less often, e.g weekly.

The present invention provides a method of treating arthritic disorders and related autoimmune disorders in man which comprises administering to the patient an amount of a compound or compounds of the formula shown in Figure I sufficient to combat such a disorder.

The following Composition Examples illustrate pharmaceutical compositions according to the present invention.

COMPOSITION EXAMPLE 1 Capsules for oral administration were made up in the usual manner by filling No. 2 size gelatin capsules each with 155mg of the following composition: 3-(N-N-dimethylcarbamoyl)-5-phenylpyrazolo [1,5-a]pyridine 50mg potato starch 100mg magnesium stearate 2 .5mg Aerosil 2. 5mg Similar compositions can be prepared by the use of other compounds of the formula shown in Figure I.

COMPOSITION EXAMPLE 2 An aqueous solution was prepared in the usual manner from 3-(N-N-dimethylcarbamoyl)-5-methoxy-7-methylpyrazolo[1 ,5-a]pyridine (2g) and water (100ml).

Similar compositions can be prepared by the use of other compounds of the formula shown in Figure I.

R1 (R2) FIG.I n MNN.

(R2) (x1)0 FIGIl cox2 (R2) FIG. IV b FIG. IV (R )D < > t13(R2 n FIG.V

Claims

1. A pyrazolopyridine derivative of the general formula: R (R2) wherein R1 represents a carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group, R2 represents a halogen atom or an alkyl, cyano, alkoxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, nitro, hydroxy, alkoxy, aryloxy, aralkyl, trifluoromethyl, alkylthio, alkylsulphinyl, alkylsul phonyl, arylthio, arylsulphinyl, arylsulphonyl, alkanoyl, aroyl or aryl group, or an amino group which may be substituted by one or two groups selected from alkyl and aryl groups, and n represents 0,1,2,3 or 4, and pharmaceutically acceptable salts thereof, with the provisos that:: (i) R1 is alkylcarbamoyl when n is O, (ii) R1 is other than a dialkylcarbamoyl group when n is 1 and R2 is a methyl group, (iii) R1 is other than a carboxy or ethoxycarbonyl group when n is 1 and R2 represents a methyl group in the 7-position, and (iv) R1 is other than dimethylcarbamoyl when (R1)n represents a methoxy or tert-butyl group in the 5-position or two methyl groups in the 6- and 7-positions.

2. A compound according to claim 1 wherein n represents 1,2,3 or 4.

3. A compound according to claim 1 wherein n represents 1 or 2.

4. A compound according to claim 1, 2 or 3 wherein aryl groups and moieties within the definition of R2 are phenyl groups which may carry one or more substituents selected from halogen atoms and alkyl, alkoxy, nitro and trifluoromethyl groups.

5. A compound according to any one of the preceding claims wherein R1 represents a dialkylcarbamoyl group containing-up to 4 carbon atoms.

6. A compound according to any one of the preceding claims wherein R' represents a dimethylcarbamoyl group.

7. A compound according to any one of the preceding claims wherein R1 represents an alkylcarbamoyl, dialkylcarbamoyl, carboxy or alkoxycarbonyl group and R2 represents an alkyl, alkoxy, phenyl, cyano or alkoxycarbonyl group.

8. A compound according to claim 1 which is 3-ethoxycarbonyl-5-phenylpyrazolo[1 ,5-a]pyridine.

9. A compound according to claim 1 which is 5-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid.

10. A compound according to claim 1 which is 3-(N-N-dimethylcarbamoyl)-5-phenylpyrazolo[1,5- a]pyridine.

11. A compound according to claim 1 which is 5,7-dimethyl-3-(N,N-dimethylcarbamoyl)pyrazolo[1 5- a]pyridine.

12. A compound according to claim 1 which is 3-(N,N-dimethylcarbamoyl)-5-methoxy-7 methyl pyrazolo[1 ,5-a]pyridine.

13. A compound according to claim 1 hereinbefore identified as one of Compounds AD, AF and AH to AU.

14. A process for the preparation of a pyrazolopyridine derivative as claimed in claim 1, in which R1 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety, which comprises the reaction of a solution of a compound of the general formula:

(wherein R2 and n are as defined in claim 1 and X' represents an anion) in an organic solvent with a base, followed by reaction with a compound of the general formula: H-C=-C-COOR3 wherein R3 represents a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms.

15. A process according to claim 14 in which X- is an iodide or mesitylenesulphonate ion.

16. A process according to claim 14 or 15 in which the organic solvent is N,N-dimethylformamide and the base is anhydrous potassium carbonate.

17. A process for the preparation of a pyrazolopyridine derivative as claimed in claim 1 in which R1 represents a carboxy group which comprises the hydrolysis of a compound of general formula I depicted in claim 1 wherein R1 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety.

18. A process for the preparation of a pyrazolopyridine derivative as claimed in claim 1 in which R' represents a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group wherein the alkyl moieties are straight or branched and each contain from 1 to 6 carbon atoms, which comprises: (A) the reaction of a corresponding acid halide or acid anhydride of the general formula:

(wherein R2 and n are as defined in claim 1 and X2 represents a halogen atom) with a compound of the general formula:: NHR4R5 VI (wherein R4 and R5 each represent a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms) or (B) the reaction of a compound of general formula I depicted in claim 1, wherein R1 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety, with a compound of general formula VI, wherein R4 and R5 are as hereinbefore defined, optionally in a solvent.

19. Process according to claim 18 (A) in which the reaction is carried out in an organic solvent below room temperature.

20. Process according to claim 18 (B) in which the reaction is carried out in a sealed vessel.

21. A process for the preparation of a pyrazolopyridine derivative as claimed in claim 1 in which R' represents an alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety which comprises the esterification by known methods of a corresponding compound of general formula I wherein R1 represents a carboxy group.

22. A process for the preparation of a pyrazolopyridine derivative as claimed in claim 1, (A) wherein R2 represents at least one straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety, from a corresponding compound of formula I in which R2 represents a carboxy group, by known methods for the conversion of a carboxy group to an alkoxycarbonyl group; (B) wherein R2 represents a carboxy group from a corresponding compound of formula I in which R2 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety by known methods for the conversion of an alkoxycarbonyl group to a carboxy group;; (C) wherein R2 represents a straight- or branched-chain alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety from a corresponding compound of formula I, wherein R2 represents a cyano group by known methods for the conversion of a cyano group to an alkoxycarbonyl group.

23. A process for the preparation of pyrazolopyridine derivatives as claimed in claim 1 substantially as hereinbefore described in any one of Examples 1 to 9.

24. A compound according to claim 1 when prepared by a process claimed in any one of claims 14 to 23.

25. A pharmaceutical composition which comprises, as active ingredient, a pyrazolopyridine derivative as claimed in claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutical carrier or coating.

26. A pharmaceutical composition according to claim 25 which comprises, as active ingredient, a pyrazolopyridine derivative as claimed in any one of claims 8 to 12.

27. A pharmaceutical composition according to claim 25 substantially as hereinbefore described in Composition Example 1 or 2.

28. A pyrazolopyridine derivative of the general formula shown in claim 1, wherein R1, R2 and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

29. A pyrazolopyridine derivative of the general formula shown in claim 1, wherein R1, R2 and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of arthritic disorders and related autoimmune disorders.