GB2151623A - New pyrazolopyridine derivatives - Google Patents

Abstract

Pyrazolopyridine derivatives of the general formula: <IMAGE> wherein R<1> represents methoxy or tert-butyl and R<2> and R<3> both represent hydrogen, or R<1> represents hydrogen and R<2> and R<3> both represent methyl are new compounds which possess properties indicative of utility in the treatment of arthritic and related autoimmune disorders.

Description

SPECIFICATION New pyrazolopyridine derivatives This invention relates to new therapeutically useful pyrazolopyridine derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as pharmaceuticals.

The new pyrazolopyridine derivatives are the 3-(N,N-dimethylcarbamoyl)pyrazoloFi ,5-a]pyri- dines of the formula shown in Fig. I of the drawings assembled at the end of the present specification wherein R' represents a methoxy or tert-butyl group and R2 and R3 both represent hydrogen atoms, or else R1 represents a hydrogen atom and R2 and R3 both represent methyl groups, that is to say 3-(N, Ndimethylcarbamoyl)-5-methoxypyrazolo[l ,5-a]pyridine (compound A), 5-tert-butyl-3-( N, N-dimethylcarbamoyl)-pyrazolo[i , 5-a]pyridine (compound B), and 6, 7-dimethyl-3-(N, N-dimethylcarbamoyl)-pyrazolo[1 ,5-ajpyridine (compound C), shown in Figs. II, III, and IV respectively.

The letters A, B and C are assigned to the compounds for easy reference later in the specification.

The compounds have valuable pharmacological properties, in particular properties which are indicative of outstanding 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, the compounds 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, the compounds 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 Fig. I are enhanced by the fact that they have only very low mammalian toxicity.

In tests, compounds of the formula shown in Fig. 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 (mg/kg animal body weight) A 2.5 B 2 C 2 The compounds of the formula shown in Fig. I may be prepared by the application or adaptation of known methods.

Thus, as a feature of the present invention, the compounds of the formula shown in Fig. I are prepared by the reaction of an acid halide of the general formula shown in Fig. V (wherein R', R2 and R3 are as hereinbefore defined and X represents a halogen, e.g. chlorine, atom) with dimethylamine. Generally the reaction takes place in an organic solvent medium, e.g. a mixture of ethanol and dichloromethane, at temperatures from 0 C to room temperature, and in the presence of an excess of the dimethylamine.

Compounds of the formula shown in Fig. V may be obtained by the application or adaptation of known methods, for example methods described in the Reference Examples hereinafter.

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 the compounds of the formula shown in Fig. I and the Reference Examples illustrate the preparation of intermediates.

EXAMPLE 1 Compound A A stirred solution of 5-methoxypyrazolo[i ,5-a]pyridine-3-carbonyl chloride (0.929; prepared as described in Reference Example 2) in dry dichloromethane (14ml) was treated with a solution of dimethylamine in ethanol (33% w/v; 11 ml) at 2"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 recrystallised from cyclohexane, to give 3-(N,N-dimethylcarbamoyl)-5-methoxypyrazolot1,5-a]py- ridine (0.81g), in the form of yellow crystals, m.p. 127-129"C.

EXAMPLE 2 Compound B A stirred solution of 5-tert-butylpyrazolo[1,5-a]pyridine-3-carbonyl chloride (prepared as described in Reference Example 5 from 1 .6g of the parent carboxylic acid) in dry dichloromethane (20ml) was treated with a solution of dimethylamine in ethanol (33% w/v; 15ml). diluted with dichloromethane (2oil), at O'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 evaporated under vacuum, dissolved in dichloromethane and washed with water, and the organic solution was dried over magnesium sulphate and evaporated under reduced pressure.The resulting residue was recrystallised from hexane, to give 5-tert-butyl-3-(N,N- dimethylcarbamoyl)pyrazolo[1,5-a]pyridine (0.79), m.p. 126-129"C.

EXAMPLE 3 Compound C A stirred solution of 6,7-dimethylpyrazolo[1 ,5-a]pyridine-3-carbonyl chloride (2.29; prepared as described in Reference Example 7) in dry dichloromethane (35ml) was treated with a solution of dimethylamine in ethanol (33% w/v; 26ml), diluted with dichloromethane (35ml), at O"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 recrystallised twice from cyclohexane, to give 6,7-dimethyl 3-(N,Ndimethylcarbamoyl)pyrazolo[1 ,5-a]pyridine (0.6g), m.p. 153-156oC.

REFERENCE EXAMPLE 1 A suspension of 3-methoxycarbonyl-5-methoxypyrazolo[1,5-a]pyridine [1 .89g; prepared by methods described in J. Org. Chem., 1968, 33(5), 2062-2064] 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 methoxypyrazoIo1 , 5-a]pyridine-3-carboxylic acid (1.5g), m.p. 228-229"C.

REFERENCE EXAMPLE 2 A suspension of 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (1.50g; prepared as described in Reference Example 1) in hot an hydros methanol (29ml) was treated with a solution of potassium hydroxide (0.499) in anhydrous methanol (6 ml). The resulting orange solution was evaporated to dryness under reduced pressure and the residual solid was suspended in anhydrous toluene (39ml). The stirred suspension was treated with oxalyl chloride (1.33ml) at room temperature, and after 30 minutes the mixture was treated with dry pyridine (6 drops) and stirred overnight.The mixture was filtered and the filtrate was evaporated under reduced pressure, to give 5-methoxypyrazolo[1 ,5-a]pyridine-3-carbonyl chloride (0.929), which was used in the next stage without further purification.

REFERENCE EXAMPLE 3 A stirred solution of 1-amino-4-tert-butylpyridinium iodide El Og; prepared by the application of methods described in J. Org. Chem., 1968, 33(5), 2062-2064] in anhydrous N,Ndimethylformamide (70ml) was treated with anhydrous potassium carbonate (5g) at room temperature followed, after 30 minutes, by treatment with a solution of ethyl propiolate (10g) 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 (2.1g) in the form of a pale orange solid [N.M.R. (in deuterochloroform): 8.35ppm (1 H, doublet, J = 7Hz), 8.28ppm (1 H, singlet), 8.0ppm (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)].

REFERENCE EXAMPLE 4 A suspension of 5-tert-butyl-3-ethoxy-carbonylpyrazolo(1 ,5-a]pyridine (2.09; prepared as described in Reference Example 3) 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-rert-butylpyrazolo [1,5-a]pyridine-3-carboxylic acid (1.6g), m.p. 189-190"C (with decomposition).

REFERENCE EXAMPLE 5 A suspension of 5-tert-butylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid (1.6g; prepared as described in Reference Example 4) in hot anhydrous methanol (40ml) was treated with a solution of potassium hydroxide (0.47g) in anhydrous methanol (8ml). The resulting clear solution was evaporated to dryness under reduced pressure and the residual solid was suspended in an hydros toluene (25my). The stirred suspension was treated with oxalyl chloride (2ml) at room temperature, and after 1 5 minutes the mixture was treated with dry pyridine (5 drops) and stirred for 2 hours.The mixture was filtered and the filtrate was evaporated under reduced pressure, to give 5-tert-butylpyrazolo[1 ,5-a]pyridine-3-carbonyl chloride, in the form of an oil which rapidly crystallised.

REFERENCE EXAMPLE 6 A suspension of 6,7-dimethyl-3-methoxycarbonylpyrazolo[1 ,5-a]pyridine [4.05g; prepared by methods described in J. Org. Chem., 1968, 33(5), 2062-2064] in methanol (45ml) was treated with a solution of potassium hydroxide (3.38g) in water (5ml) and then it was heated at reflux for 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-dimethylpyra zolo[1,5-a]pyridine-3-carboxylic acid (2.29g), m.p. 229-232"C (with decomposition).

REFERENCE EXAMPLE 7 A suspension of 6,7-dimethylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid (2.0g; prepared as described in Reference Example 6) in hot an hydros methanol (40ml) was treated with a solution of potassium hydroxide (0.65g) in anhydrous methanol (8ml). The resulting solution was evaporated to dryness under reduced pressure and the residual solid was suspended in anhydrous toluene (53ml). The stirred suspension was treated with oxalyl chloride (1.79ml) at room temperature, and after 30 minutes the mixture was treated with dry pyridine (8 drops) and stirred overnight.The mixture was filtered and the filtrate was evaporated under reduced pressure, to give 6,7-dimethylpyrazolo[1 ,5-a]pyridine-3-carbonyl chloride (2.2g) in the form of a yellow crystalline solid, which was used in the next stage without further purification.

The present invention includes within its scope pharmaceutical compositions which comprise at least one of the compounds of the formula shown in Fig. I 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.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders, and granules. In such solid compositions the active compound or compounds is 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 per se 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 1 Omg) of compound of the formula shown in Fig. 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 Fig. 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 Fig. 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-methoxypyrazolo [1 ,5-a]pyridine 50mg potato starch 100mg magnesium stearate 2.5mg Aerosil 2.5mg COMPOSITION EXAMPLE 2 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: : 5-tert-butyl-3-(N, N-dimethylcarbamoyl) pyrazolo[1,5-a]pyridine 50mg potato starch 100mg magnesium stearate 2.5mg Aerosil 2.5mg COMPOSITION EXAMPLE 3 Capsules for oral administration were made up in the usual manner by filling No. 2 size gelatin capsules each with 155mug of the following composition: 6, 7-dimethyl-3-( N, N-dimethylcarbamoyl)- pyrazolo[1 ,5-a]pyridine 50mg potato starch 100mg magnesium stearate 2.5mg Aerosil 2.5mg

Claims (15)

1. A pyrazolopyridine derivative of the general formula:

wherein R1 represents a methoxy or tert-butyl group and R2 and R3 both represent hydrogen atoms, or R' represents a hydrogen atom and R2 and R3 both represent methyl groups.

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

3. A compound according to claim 1 which is 5-tert-butyl-3-(N,N-dimethylcarbamoyl)pyra zolo[1 ,5-a]pyridine.

4. A compound according to claim 1 which is 6,7-dimethyl-3.(N,N-dimethylcarbamoyl)pyra- zolo[1 ,5-a]pyridine.

5. A process for the preparation of a pyrazolopyridine as claimed in claim 1 which comprises reacting an acid halide of the general formula:

(wherein R', R2 and R3 are as defined in claim 1 and X represents a halogen atom) with dimethylamine.

6. A process according to claim 5 in which the reaction is carried out in an organic solvent medium at a temperature from O"C to room temperature and in the presence of an excess of dimethylamine.

7. A process according to claim 5 or 6 wherein X in the general formula depicted in claim 5 represents a chlorine atom.

8. Process according to claim 5 substantially as hereinbefore described in Example 1, 2 or 3.

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

10. A pharmaceutical composition according to claim 9 in which the pyrazolopyridine derivative is 3-( N, N-dimethylcarbamoyl)-5-methoxypyrazolo[ 1 ,5-a]pyridine.

11. A pharmaceutical composition according to claim 9 in which the pyrazolopyridine derivative is 5-tert-butyl-3-(N, N-dimethylcarbamoyl)pyrazolo[ 1 ,5-a]pyridine.

1 2. A pharmaceutical composition according to claim 9 in which the pyrazolopyridine derivative is 6, 7-dimethyl-3-( N, N-dimethylcarba moyl)pyrazolo[ 1 ,5-a]pyridine.

1 3. A pharmaceutical composition according to claim 9 substantially as hereinbefore described in Composition Example 1, 2 or 3.

14. A pyrazolopyridine derivative of the general formula shown in claim 1, wherein R1, R' and R3 are as defined in claim 1, for use in therapy.

15. A pyrazolopyridine derivative of the general formula shown in claim 1 wherein Rl, R and R3 are as defined in claim 1 for use in the treatment of arthritic disorders and related autoimmune disorders.