NL8403874A - PYRAZOLOPYRIDINE DERIVATIVES, METHODS FOR THE PREPARATION THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE DERIVATIVES, THEIR USE AS PHARMACEUTICS. - Google Patents

Description

N.0. 32920

Pyrazolopyridine derivatives, methods of preparation thereof, pharmaceutical compositions containing these derivatives for use as pharmaceuticals.

The present invention relates to therapeutically suitable pyrazolopyridine derivatives, to processes for their preparation, to pharmaceutical compositions containing these derivatives and to their use as pharmaceuticals. The pyrazolopyridine derivatives are the compounds of the general formula 1, wherein R * is a carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group, R 1 represents a halogen atom, for example, fluorine, chlorine or bromine, or an alkyl, cyano, alkoxycarbonyl, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, -10 tro, hydroxy, alkoxy, aryloxy, aralkyl, trifluoromethyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, alfcanoyl, aroyl, or aryl group, or represents an amino group, which may be substituted with one or two groups selected from alkyl and aryl groups, and n represents 0, 1, 2, 3 or 4, preferably 1 or 2, and 15, if applicable, pharmaceutically acceptable salts thereof, b for example when R 1 and / or R 1 represents a carboxyl group, salts thereof, more particularly alkali metal salts, eg sodium salts, provided that: (i) R 1 is alkylcarbamoyl when n is 0, 20 (ii) R 2 * other then is a dialkylcarbamoyl group when η is 1 and R ^ is a methyl group, (iii) R ^ is different from a carboxyl or ethoxycarbonyl group when η is 1 and R ^ represents a methyl group in position 7 and (iv) R * then dimethylcarbamoyl is when (R) n represents a methoxy or tert-butyl group in position 5 or two methyl groups in positions 6 and 7.

When n represents 2, 3 or 4, the substituents R ^ may be the same or different. =

Aryl groups and parts within the definition of R 4 are preferably phenyl groups, which can carry one or more substituents selected from, for example, halogen atoms and alkyl, alkoxy, nitro and trifluoromethyl groups.

Alkyl groups and parts within the definitions of R ^ and R ^ can be straight or branched and contain up to 6 carbon atoms.

When the context allows, reference in the present description to the compounds of general formula 1 is intended to include reference to the aforementioned salts.

The compounds have valuable pharmacological properties, in particular properties indicative of utility in the treatment of arthritic diseases and related autoimmune diseases, such as rheumatoid arthritis, osteoarthritis, seronegative arthritis such as joint-stiffening spondylitis, psoriasis arthritis and enteropathic arthropathy, connective tissue diseases such as systemic lupus erythematosus and polymyotis and the tendency to reject grafts. In particular, laboratory tests have shown compounds of formula 10 1 to counteract the deterioration of joints in rodent limbs. These results are particularly important in that they contrast with compounds currently used in the treatment of arthritic diseases, which are primarily anti-inflammatories and do not have the ability to combat joint deterioration. Furthermore, the compounds of formula 1 are surprisingly remarkably better in their pharmacological properties compared to closely related compounds.

The beneficial properties of the compounds of formula 1 are enhanced by the fact that they have only a very low mammalian toxicity.

Preferred classes of compounds of formula 1 include those wherein βΛ is a dialkyl carbamoyl group containing up to 4 carbon atoms (eg, a dimethyl carbamoyl group) and those wherein a is alkyl (eg methyl, ethyl or tert-butyl), alkoxy (e.g. image represents methoxy), phenyl, cyano or alkoxycarbonyl (e.g. ethoxy-carbonyl) group.

Among compounds of formula 1, 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

35 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-phenylpyrazolo [1,5-a] pyridine, AI

5-cyano-3-methoxycarbonylpyrazolo [1,5-a] pyridine, AJ

40 3,5-bis (methoxycarbonyl) pyrazolo [1,5-a] pyridine, AK

8403874 • ft * 3

5-methoxypyrazolo [1 * 5-a] pyridine-3-carboxylic acid, AL

5-tert-butyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine, AM "

5-tert-butylpyrazolo [1,5-a] pyridine-3-carboxylic acid, AN

6.7-dimethylpyrazolo [1,5-a] pyridine-3-carboxylic acid, AO

5 5,7-dimethyl-3-methoxycarbonylpyrazolo [1,5-a] pyridine, AP

3-ethoxycarbonyl-5-phiethoxy-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-methoxycarbonylpyrazolo [1,5-a] pyridine, and AT

6.7-dimethyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine. AU

The connections AA, AB, AC, AE and AG are of exceptional importance.

The letters AA to AU are assigned to the compounds for later convenient reference in the description.

In the experiments, the compounds of formula 1, when administered twice orally to mice, each time at the dose listed in Table A, decreased by 50% the inhibition of migration of incubated mouse macrophage cells. This is a measure of the antagonism or reduction of lymphokine levels and is indicative of its usefulness in the treatment of arthritis patients.

Table A

Test Oral Dose Compound _ (mg / kg animal body weight) 25 AA_10______ AB_15_ AC_10_: _ AE _; _ 10_ AG _; _ lj5_ 30

The compounds of formula 1 are prepared using or adapting known methods, for example, as a feature of the present invention, methods described in the examples and reference examples below.

Therefore, according to a feature of the present invention, compounds of formula 1, wherein R 1 - represents a straight or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety (R 2 and n as defined above), are prepared by reaction of a solution of a compound of the general formula 2 (wherein 40 R 1 and n are as defined above and x V represents an anion, for example, an iodide or mesitylene sulfonate) in a. organic solvent, for example Ν, Ν-dimethylformamide, with a base, for example anhydrous potassium carbonate, followed by reaction with a compound of the general formula 3, wherein a straight or branched chain alkyl group containing 1 to 6 carbon atoms.

According to a feature of the invention, compounds of formula 1, wherein R 2 represents a carboxyl group (R 2 and n are as defined above) are prepared by the hydrolysis of compounds of formula 1, wherein R 2 represents a straight or branched chain alkoxycarbonyl group which contains 1 to 6 carbon atoms in the alkaxy moiety (R 1 and n are as defined above), for example, by treatment with an aqueous alkali, for example, an aqueous potassium hydroxide solution or an aqueous sodium hydroxide solution, followed by treatment with an aqueous acid, for example dilute hydrochloric acid.

According to a feature of the present invention, compounds of formula 1, wherein R * represents carbamoyl, alkyl carbamoyl or dialkyl carbamoyl, wherein the alkyl moieties are straight or branched and each contain 1 to 6 carbon atoms (R 1 and n are as defined above) nied) prepared from compounds of formula 1, wherein J 1 * represents a carboxyl group or a straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety (R 1 and n are as defined above), using or adapting known methods.

In one aspect, a compound of formula 1, wherein R 1 represents a carboxyl group (r 1 and n are as defined above) is converted, using or adapting known methods, to the corresponding acid halide or anhydride of the general formula 4 or 5 ( wherein a halogen atom represents, for example, chlorine and R 2 and n are as defined above) which is then reacted with a compound of the general formula 6, wherein R 1 and R 2 each represent a hydrogen atom or a straight or branched chain alkyl group, representing 1 to 6 carbon atoms. The reaction is preferably carried out in an organic solvent, for example ethanol, preferably below room temperature, for example at 0-10 ° C.

In another aspect, a compound of formula 1, wherein R ^ represents a straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety (R ^ and n are as defined above) is reacted directly with a compound * of the general formula 6 (R 4 and R 4 are as defined above), optionally in a solvent, for example ethanol, preferably in a sealed kettle.

According to a further feature of the present invention, compounds of formula 1 wherein R * is a straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety (R 1 and n are as defined above) are prepared by the esterification of compounds of formula 1, wherein R 1 represents a carboxyl group (R 1 and n are as defined above), by the use or adaptation of known methods of esterification of carboxylic acids, eg by reaction of a compound of formula 4 or 5 (wherein X 1, and n are as defined above), derived therefrom, with an alcohol of the general formula 7 wherein R® represents a straight or branched chain alkyl group containing 1 to 6 carbon atoms.

Compounds of formula 1 may also be prepared by conversion of other compounds of formula 1, by modification of the part or parts (R 1) n, for example as follows: (1) As a feature of the present invention, compounds of formula 1, wherein R 1 represents at least one straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety (R *, n and any other substituents R 2 are as defined above) and compounds of formula 1, wherein R 1 represents a carboxyl group (R 2, n and optionally other substituents R 2 are as defined above) interconverted using or adapting the above-described methods for the interconversion of compounds of formula 1, wherein R * represents an alkoxycarbonyl group and compounds of formula 1, wherein .R * represents a carboxyl group (R 1 and n are as defined above).

(2) As another feature of the present invention, compounds of formula 1 wherein R 2 are a straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety (R 2, n and optionally other substituents R 2) as defined above) prepared by the hydrolysis of compounds of formula 1, wherein represents a cyano group (R 2, n and optionally other substituents R 2 are as defined above), for example by reaction with an aqueous alkali, for example a aqueous sodium hydroxide solution or aqueous potassium hydroxide solution, in the presence of the appropriate alcohol of formula 7 (R1 is as defined above, preferably methyl or ethyl).

The aforementioned salts of certain compounds of formula 8403874 I 6 1 are prepared by using or adapting methods known per se, for example by reacting the parent compound of formula 1 with an alkali metal hydroxide, carbonate or preferably hydrogen carbonate, in an aqueous or aqueous organic medium, followed by separation of the salt by methods known per se.

The term "known methods" as used herein is to be understood to mean methods which have hitherto been used or have been described in the literature.

The following examples illustrate the preparation of compounds of formula 1 and the reference examples illustrate the preparation of intermediates.

Example I Connection AA

A stirred solution of 1-amino-4-phenylpyridinium iodide (2.0 g) in anhydrous N, N-dimethylformamide (20 ml) was treated with anhydrous potassium carbonate (1.01 g) at room temperature, followed 30 minutes later by dropwise treatment with ethyl propanol (1.31 g). The mixture was stirred for an additional 1 hour and then it was poured into a mixture of ice and water (75 ml) and extracted with diethyl ether.

The ether extract was washed with water, dried over magnesium sulfate and evaporated to give a dark red residue. Part of this residue was triturated with petroleum ether (b.p. 40-60 ° C) and then subjected to silica gel chromatography, eluting with chloroform, followed by recrystallization from cyclohexane to give 3-ethoxycarbonyl-5-phenylpyrazolo [1,5- a] pyridine, in the form of white needles with a melting point of 96-97 ° C.

Example II

Compounds AB, * AC, AD, AE, AF, AG, AH and AI 30 A suspension of 3-ethoxycarbonyl-5-phenylpyrazolo [1,5-a] pyridine (1.0 g, prepared as described in Example I) in ethanol (5 ml) was treated with a solution of potassium hydroxide (0.4 g) in water (2 ml) and then refluxed for 45 minutes. The transparent solution was poured into water (50 ml) and washed with diethyl ether 35 (3 x 15 ml) and then the solution was acidified to a pH of 1 by treatment with concentrated hydrochloric acid. The resulting white precipitate was filtered off, washed with water and recrystallized from a mixture of Ν, Ν-dimethylformamide and water to give 5-phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid (0.45 g) in the form of 40 a white solid, mp 252-254 ° C (with decomposition).

8403874 • * 7

A suspension of 5-phenylpyrazolo [1,5-a] pyridine-3'-carboxylic acid (1.54 g, prepared as described above) in warm anhydrous methanol (40 ml) was dissolved with an potassium hydroxide (0.36 g) in anhydrous methanol (8 ml). The resulting transparent solution was evaporated to dryness under a third pressure and the residual solid was suspended in anhydrous toluene (50 ml). The stirred suspension was treated with oxalyl chloride (1.43 ml) 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 (0.9 g), which was used in the next step without further purification .

A stirred solution of 5-phenylpyrazolo [1,5-a] pyridine-3-carbonyl chloride (0.9 g) in dry dichloo methane (25 ml) was treated at 0 ° C with a solution of dimethylamine in ethanol (33 w / v%, 12 ml). When the addition was complete, the mixture was allowed to come to room temperature and the mixture was kept at room temperature overnight. The mixture was then washed with water and the organic solution was dried over magnesium sulfate and evaporated to dryness under a reduced pressure. The residue obtained was triturated with petroleum ether (boiling point 40-60 ° G) and recrystallized from a mixture of carbon tetrachloride and hexane to give 3- (N, N-dimethylcarbamoyl) -5-phenylpyrazolo [1,5 -a] pyridine (0.3 g) 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, which was used as the starting product, with the appropriate amounts of .5,7-dimethyl- 3-methoxycarbonylpyrazolo [1,5-a] pyridine and 3-ethoxycarbonyl-5-methoxy-7-methylpyrazolo [1,5-a] pyridine, each prepared as described in Example IX-30, the following compounds were prepared: 3-carboxy-5,7-dimethylpyrazoio [1,5-a] pyridine, melting point 167-170 ° G (with decomposition), 3-carboxy-5-methoxy-7-methylpyrazolo [1,5-a] pyridine, 5 7-dimethyl-3- (N, N-dimethylcarbamoyl) pyrazolo [1,5-a] pyridine, melting point 124-127 ° C (subjected to silica gel chromatography with ethyl acetate as eluent and recrystallized from cyclohexane) and 3 - (N, N-dimethylcarbamoyl) -5-methoxy-7-methylpyrazolo [1,5-a] pyridine, mp 126-129 ° C (recrystallized from hexane).

Proceeding in a similar manner again, replace the dimethylamine starting material with the appropriate amounts of propyl amine and diethylamine, respectively. 3- (N-propylcarbamoyl) -5-phenylpyrazolo [1,5 -a] pyridine, melting point 132-133eC (subjected to chromatography on silica gel with ethyl acetate as eluent) and 5- (N, N-diethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine, melting point 102 -103 ° C (subjected to silica gel chromatography using ethyl acetate as eluent) «

Example III Compound AJ

A cooled solution of 1-amino-4-cyanopyridinium mesitylene sulfonate (0.64 g, prepared as described in Reference Example 1) at 0 ° C in dry N, N-dimethylformamide (5 ml) was washed with anhydrous potassium carbonate (0 , 41 g) and methyl propanolate (0.34 g) and stirred at 0 ° C for 30 minutes and then at room temperature for 5 hours and stored at room temperature overnight. The solvent was removed under reduced pressure and the residue triturated with chloroform (25 ml). The insoluble product 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 (80 mg), m.p. 184-186 ° C.

Example IV Compound AK

A solution of 5-cyano-3-methoxycarbonylpyrazolo [1,5-a] pyridine 25 (25 mg, prepared as described in Example III) in methanol (3 ml) containing 5 drops of anhydrous sodium hydroxide solution (2N) was added heated to reflux for 3 hours and then evaporated to dryness under reduced pressure. The resulting residue was dissolved in water (3 ml) 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; NMR (in deuterated dimethyl sulfoxide) 3.90, 3.98, 7.52, 8.62, 8.66 and 9.04 ppm].

35 Example V Connection AL "

A suspension of 3-methoxycarbonyl-5-methoxypyrazolo [1,5-a] pyridine (1.89 g, prepared as described in Example IX) in methanol (21 ml) was dissolved with a solution of potassium hydroxide (1.56 g) in water (2.2 40 ml) and then heated under reflux for 100 minutes. The transparent solution was cooled and evaporated under reduced pressure, then in water (10 ml) dissolved and washed with diethyl ether and then acidified by treatment with dilute hydrochloric acid (2N), the white precipitate obtained was filtered off to give 5-methoxypyrazolo [1,5-a] pyridine-3-carboxylic acid (1 * 5 g) with a melting point of 228-229 ° C.

Example VI Compound AM

A stirred solution of 1-amino-4-tert-butylpyridinium iodide [10 g, prepared using methods described in J. Org. Chem., 1968, 33_ (5), 2062-2064] in anhydrous N, N-dimethylformamide (70 ml) was treated with anhydrous potassium carbonate (5 g) at room temperature, followed after 30 minutes by dropwise treatment with a solution of ethyl propoxide ( 10 g) in dimethylformamide (20 ml), lat 15 mixture was left overnight and then evaporated to dryness under reduced pressure and treated with water (250 ml) and extracted with diethyl ether. The ether extract was washed with water, dried over magnesium sulfate 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 (2.1 g) as a light orange solid [NMR (in deuterochloroform): 8.35 ppm (1H, doublet, J 7Hz), 8.28 ppm (1H, singlet), 8.0 ppm (1H, doublet, J 2Hz), 7.9 ppm (1H, doublet of doublets, J * 7Hz and 2Hz), 4.3ppm (2H, quartet, J * 7Hz), 1.4ppm (12H, multiplet)].

Example VII Compound AN

A suspension of 5-tert-butyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine (2.0 g, prepared as described in Example VI) in methanol (25 ml) was taken with a solution of potassium hydroxide (1.5 g) treated in water (5 ml) and then refluxed overnight.

The solvent was evaporated under reduced pressure and the residue was treated with water (25 ml) and washed with diethyl ether, then acidified by treatment with dilute hydrochloric acid (2N). The resulting white precipitate was filtered off and washed with water to give 5-t-butylpyrazolo [1,5-a] pyridine-3-carboxylic acid (1.6 g), mp 189-190 ° C (with decomposition).

Example VIII Compound AO

40 A suspension of 6,7-dimethyl-3-methoxycarbonylpyrazolo [1,5-a] py] 8403874 4 ridin (4.05 g, prepared as described in Example IX) in methanol (45 ml) was dissolved of potassium hydroxide (3.38 g) in water (5 ml) and then refluxed for 100 minutes. The transparent solution was cooled and evaporated under reduced pressure, then dissolved in water and washed with diethyl ether, then acidified by treatment with dilute hydrochloric acid (2N). The precipitate obtained was filtered to give 6,7-dimethylpyrazolo [1,5-a] pyridine-3-carboxylic acid (2.29 g), mp 229-232 ° C (with decomposition).

Example IX

Connections AP, AQ, AR, AS, AT and AU

By proceeding in a similar manner as before and in J. Org. Chem., 1968, 33 (5), 2062-2064, and prepared using the appropriate starting products: 5,7-dimethyl-3-methoxycarbonylpyrazolo [1,5-a] pyridine, bp 116-146 ° C / 0.027 kPa, 3-ethoxycarbonyl-5-methoxy-7-methylpyrazolo [1,5-a] pyridine [NMR (in deuterochloroform): 8.25 ppm (1H, singlet), 7.3 ppm (1H, doublet, J = 2Hz), 6.4ppm (1H, doublet, J = 2Hz), 4.35ppm (2H, quartet, J = 7Hz), 3.9ppm (3H, singlet), 2.7ppm (3H , singlet), 1.4 ppm (3H, triplet, J = 7Hz)], 3-methoxycarbonyl-5-methoxypyrazolo [1,5-a] pyridine, mp 98-100 ° C (from cyclohexane), 5-methoxy- 3-ethoxycarbonylpyrazolo [1,5-a] pyridine, mp 109-110 ° C, 6.7-dimethyl-3-methoxycarbonylpyrazolo [1,5-a] pyridine, boiling 110-134 ° C / 0.0067 kPa and.

6.7-dimethyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine, bp 140-145 ° C / 0.067 kPa.

30 Reference example 1

A solution of 4-cyanopyridine (1.82 g) in dichloromethane (20 ml) was treated with a solution of mesitylene sulfonylhydroxylamine (3.7 g) in dichloromethane (40 ml) for 15 minutes at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes and then diluted with diethyl ether (30ml). The white solid that formed was filtered off and washed well with diethyl ether to give 1-amino-4-cyanopyridinium mesitylene sulfonate (3.6 g) mp 136-138 ° C.

The present also includes pharmaceutical compositions containing at least one compound of formula 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or coating. In clinical practice, the compositions of the 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 suitable means of administering some of the compounds of formula 1.

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, as is normal practice, contain additional substances other than inert diluents, for example lubricants, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions and elixirs containing commonly used inert diluents such as water and liquid paraffin in the art. In addition to intenable diluents, such compositions may also contain additives such as wetting and suspending agents, sweeteners, flavors, perfumes and preservatives.

The compositions of 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 extenders.

Solid compositions for rectal administration include suppositories, which are formulated in known manner and contain the active compound or compounds.

Compositions of the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or slurry media are propylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain additives such as preservatives, wetting, emulsifying and dispersing agents. For example, they can be sterilized by filtration through a bacteria retaining filter, by incorporation of sterilizing agents into the compositions, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved immediately before use in a sterile injectable medium. Like the more common intravenous and intramuscular routes, the compositions can 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 fats, paraffin or other waxes or lacquers or creams to be applied topically, for example to the skin area around an affected joint for arthritis also belong to the invention.

The percentage of active ingredients in the compositions of the invention may be varied, it being necessary that they will form such a ratio that an appropriate dosage for the desired effect will be achieved. Obviously, different unit dosage forms can be administered at about the same time. In general, the compositions should contain 0.1 to 80% by weight of active ingredient, especially in tablet form »

The dose used depends on the desired effect, the route of administration and the duration of the treatment. In the adult, the doses are generally between 0.01 and 100 mg (preferably between 0.1 and 10 mg, more particularly between 1 and 10 mg) of the compound of formula 1 per kg of body weight per day.

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

The compounds of formula '1 can be administered every day or, depending on the wishes of the practicing physician, less often, eg weekly.

The present invention provides a method for the treatment of arthritic diseases and related autoimmune diseases in humans, which administer to the patient an amount of a compound or compounds of formula 1 sufficient to combat such a disease, includes.

The following composition examples illustrate pharmaceutical compositions of the present invention. Composition example 1

Capsules for oral administration were prepared in the usual manner 40 by filling gelatin capsules No. 2 each with 155 mg of the 3403874 3

«I

^ c 13 following composition: 3- (N, N-dimethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine 50 mg potato starch 100 mg 5 magnesium stearate 2.5 mg

Aerosil 2.5 mg

Similar compositions can be prepared using other compounds of formula 1.

10 Composition example 2

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

Similar compositions can be prepared using other compounds of formula 1.

S 4 0 3 8 7 4

Claims (23)

A pyrazolopyridine derivative of the general formula 1, wherein R * represents a carboxyl, alkoxycarbonyl, carbamoyl, alkyl carbamoyl or dialkyl carbamoyl group, a balogen atom or an alkyl, cyano, alkoxycarbonyl, carboxyl, carbamoyl, alkyl carbamoyl -, dialkylcarbamoyl, nitro, hydroxy, alkoxy, aryloxy, aralkyl, trifluoromethyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, alkanoyl, aroyl, or aryl group or represents an amino group, which may be substituted with one or two alkyl and / or aryl groups and represents n, 1, 2, 3 or 4 and pharmaceutically acceptable salts thereof, provided that: (i) R 1 is alkylcarbamoyl when n is 0, (ii) R ^ - is other than a dialkylcarbamoyl group when η is 1 and R ^ is a methyl group, 15 (iii) R ^ "is other than a carboxyl or ethoxycarbonyl group when η is 1 and R ^ is represents methyl group in position 7 and (iv) R ^ is other than dimethylcarbamoyl when (R *) n is a methoxy or tert.butyl group in position 5 or two methyl groups in positions 6 and 7. 2o A compound according to claim 1, characterized in that η represents 1, 2, 3 or 4. Compound according to claim 2, characterized in that η represents 1 or 2. 4. A compound according to claim 1, 2 or 3, characterized in that aryl groups and parts within the definition of R 1 are phenyl groups, which may contain one or more substituents selected from balogen atoms and alkyl, alkoxy, nitro- and trifluoromethyl groups. . Compound according to one or more of the preceding claims, characterized in that R 1 represents a dialkyl carbamoyl group containing at most 4 carbon atoms. Compound according to one or more of the preceding claims, characterized in that R * * represents a dimethylcarbamoyl group. 7. A compound according to any one or more of the preceding claims, characterized in that R 1 represents an alkyl carbamoyl, dialkyl carbamoyl, carboxyoxy or alkoxycarbonyl group and R 1 represents an alkyl, alkoxy, phenyl, cyano or represents alkoxycarbonyl group. 8. 3-Ethoxycarbonyl-5-phenylpyrazolo [1,5-a] pyridine. 9. 5-Phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid. 10. 3- (N, N-dimethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine. 11,5,7-Dimethyl-3- (N, N-dimethylcarbamoyl) pyrazolo [1,5-a] pyridine. 8403874 v * 12. 3- (N, N-dimethylcarbamoyl) -5-methoxy-7-methylpyrazolo [1,5-a] pyridine. The compound of claim 1, previously identified as one of the compounds AD, AF and AH to AU. Process for preparing a pyrazolopyridine derivative according to claim 1, wherein R * * represents a straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety, characterized in that a solution of a compound is used of the general formula 2, wherein and n are as defined in claim 1 and represents an anion, in an organic solvent, react with a base, followed by reaction with a compound of the general formula 3, wherein R 1 is an alkyl group straight or branched chain chain containing 1 to 6 carbon atoms. 15. Process according to claim 14, characterized in that X ”is an iodide or mesitylene sulfonate. 16. Process according to claim 14 or 15, characterized in that organisch, Ν-dimethylformamide is used as organic solvent and anhydrous potassium carbonate as base. 17. Process for preparing a pyrazolopyridine derivative according to claim 1, wherein R * represents a carboxyl group, characterized in that a compound of the general formula 1, wherein R 1 represents a straight or branched chain alkoxycarbonyl group, which 1 contains, represents, hydrolyses up to 6 carbon atoms in the alkoxy moiety. A process for preparing a pyrazolopyridine derivative according to claim 1, wherein R * * represents a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group, wherein the alkyl moieties are straight or branched and each contain 1 to 6 carbon atoms, characterized that one (A) is a corresponding acid halide or anhydride of the general formula 4 or 5, wherein R 1 and n are as defined in claim 1 and X 1 represents a halogen atom, reacts with a compound of the general formula 6, wherein R 4 and R 4 each represent a hydrogen atom or a straight or branched chain alkyl group containing 1 to 6 carbon atoms, or (B) a compound of the general formula 1 according to claim 1, wherein in R 3 represents a straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety, optionally converted into a solvent with a compound of the general formula 6, wherein R ^ and R ^ are as defined above. 19. Process according to claim 18 (A), characterized in that the reaction is carried out in an organic solvent below room temperature. Process according to claim 18 (B), characterized in that the reaction is carried out in a closed kettle. A process for preparing a pyrazolopyridine derivative according to claim 1, wherein R * * represents an alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety, characterized in that the esterification of a corresponding compound with the algenic formula 1, which represents a carboxyl group, according to known methods. A process for preparing a pyrazolopyridine derivative according to claim 1, (A) wherein R 1 represents at least one straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety, from a corresponding compound of formula 1, wherein R ^ represents a carboxyl group, according to known methods for the conversion of a carboxyl group into an alkoxycarbonyl group, (B) in which R1 represents a carboxyl group, from a corresponding compound of formula 1, wherein R1 represents a straight or branched chain alkoxycarbonyl group, containing 1 to 6 carbon atoms in the alkoxy moiety, according to known methods for the conversion of an alkoxycarbonyl group to a carboxyl group, (C) wherein R 1 is a straight or branched chain alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy moiety, from a corresponding compound of formula 1, wherein R 1 represents a cyano group 25, according to known methods for the conversion of a cyano group to an alkoxycarbonyl group. A compound according to claim 1 prepared by a method according to any one or more of claims 14 to 22. 24. Pharmaceutical composition, characterized in that the composition as active ingredient contains a pyrazolopyridine derivative according to claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutical carrier or coating. = Pharmaceutical composition according to claim 24, characterized in that the active ingredient composition contains a pyrazolopyridine derivative according to one or more of claims 8 to 12. The pyrazolopyridine derivative of the general formula according to claim 1, wherein R 1, R 1, and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof, for therapeutic use. 27. Pyrazolopyridine derivative of the general formula according to claim 8403874 v * r * clusion 1, wherein R 1, R 1 and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of arthritic diseases and related automobile -immune diseases. 11. H-t I- 84033/4 3 · «** IMederlandschOctrooibureau Ir .F.vanderBeek DrsP.deJorig! Ir A. D. Baarslag DrsD. H. Serlui-Koarts Anne read DrsC.H.J. van Soest IrG.J.SIot DrsJ.J. Hagen IrJ.J. Brammeijer DrsJ. BJKlijberg MrlrD.Hijmans IrF.Valdhuijsen "IrA.PIaisier IrLH.GMBauwens IrH.G.Leonhardt Ir CJA Soutendam Ir FHJF Janssen ^ _ IrLC.deBruiin Ir F. Kraag ·" ......... DrsA.vanGrafhorst IrJ.HMCoppens B. y 1 YY 1 IrB.Hijmans MrG. Chest At the Patent Office 1 V F E B1985 Rijswijk Your ref: Our ref. The Hague Johan de Wittlaan 15 @ 514541 * Kl / MJ-c 19.02.1985 Subject: Patent application no. 84.03874 in the name of. May & Baker Limited Term Response: - Regarding notified patent application, Agent requests and authorizes you to make the following corrections. a) page 1, line 24 M (Rl) n "becomes ·" (R2) n "b) page 6, line 18" ethylpropanol "becomes" ethylpropionate "c) page 8, line 13" methylpropoxide "becomes" methyl propionate "d) page 9, line 14" ethyl propoxide "becomes" ethyl propionate "e) page 14, line 17" (R1) n "becomes * (R2) n". The Agent, Λ / 7 Drs J.B.J. Klijberg, 8403874 5A1-83 Ί ν ί. 1 R1 (r2) d a. L · »2)„ - Γ I® (χ1) ® ^ νη, L2 H-CSC-COOR3 4 2 - C03T (r2) s - & _ 0 = c — 0 — G = 0 ^ - € ό Ó3 ~ <*% £. 2. NHR4R5 r6OH 84 03 87 4