HU193727B - Process for producing pyrazolo/1,5-a/pyridine derivatives - Google Patents

Abstract

Pyrazolo- 1,5-a -pyradine derivs. of formula (I) and their salts are useful in the treatment of arthritic pains. In the formula R1 stands for carboxyl, alkoxy-carbonyl, carbamoyl, alkyl-carbamoyl or dialkyl-carbamoyl, R2 means halogen, alkyl, cyano, alkoxy-carbonyl, carboxyl, carbamoyl, alkyl-carbamoyl, dialkyl-carbamoyl, nitro, hydroxy, alkoxy, aryl-oxy, aralkyl, trifluoro-methyl, alkyl-thio, alkyl-sulfinyl, alkyl-sulfonyl, aryl-thio, aryl-sulfinyl, aryl-sulfonyl, alkanoyl, aroyl or aryl, or opt. a substd. amino gp., n is 0-4.

Description

The present invention relates to novel pharmaceutical pyrazole pyridine derivatives and to pharmaceutical compositions containing such compounds.

The pyrazolo-pyridine derivatives of the present invention are represented by formula (I)

R ^{1 is} carboxyl, alkoxycarbonyl, alkylcarbamoyl or dialkylcarbamoyl;

R ^{2 is} alkyl, cyano, alkoxycarbonyl, alkoxy or phenyl; and n is 0, 1, 2, preferably 1 or 2, with the proviso that

i) R ^{1 is an} alkylcarbamoyl group when n = 0;

ii) R ^{1 is different from} dialkylcarbamoyl when n = 1 and

R ^{2 is} methyl, and iii) other than R ^{1 is} carboxyl and ethoxycarbonyl if n = 1 and

R ² methyl group 7 -.

When n is 2, the substituents on R ² , other than alkyl, are different, R ^{2 is} 5-,

6- and / or 7-position.

^R1 and ^R2 can be alkyl groups and moieties are straight or branched chain groups, and having up to 4 carbon atoms.

Where the context so permits, reference is made herein to the salts of the compounds of formula (I).

The compounds exhibit valuable pharmacological properties, particularly those that are associated with arthritis disorders and related autoimmune disorders such as arthritis deformans, osteoarthritis, seronegative arthritis, vertebral anthylosis, psoriatic arthritis and enteropathic arthritis (e.g. polymyotics and their propensity to treat transplants). In particular, in laboratory tests, compounds of formula I inhibited the deterioration of joints in rodent limbs. These results are particularly important when compared to compounds currently used to treat arthritic disorders, which are primarily anti-inflammatory and are unable to prevent joint deterioration. Furthermore, the compounds of formula I are surprisingly far better than their very close compounds in terms of their pharmacological properties.

The beneficial effect of the compounds of formula I is further enhanced by the fact that they exhibit only very low toxicity.

Preferred groups of compounds of formula I include those wherein R ^{1 is a} dialkylcarbamoyl group having up to 4 carbon atoms (e.g., dimethylcarbamoyl) and those wherein R ^{2 is} alkyl (e.g., methyl, ethyl or methyl). tert-butyl), 2 alkoxy (e.g. methoxy), phenyl, cyano or alkoxycarbonyl (e.g. ethoxycarbonyl).

Particularly important compounds of formula I include: 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- (Ν, Ν-Diethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine Al

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

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

5-Methoxy-pyrazolo [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

5.7-Dimethyl-3-methoxycarbonyl-pyrazo [1,5-a] pyridine AP

3-Ethoxycarbonyl-5-methoxy-7-methylpyrazolo [1,5-a] pyridine AQ

3-methoxycarbonyl-5-methoxypyrazo [1,5-a] pyridine AR

5-Methoxy-3-ethoxycarbonylpyrazolo [1,5-a] pyridine AS

6.7-Dimethyl-3-methoxycarbonylpyrazolo [1,5-a] pyridine AT

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

3- (N, N-Dimethylcarbamoyl) -5-methoxy-pyrazolo [1,5-a] pyridine AV

5-tert-Butyl-3- (N, N-dimethylcarbamoyl) -pyrazolo [1,5-a] pyridine and AW

6.7-Dimethyl-3- (Ν, Ν-dimethylcarbamyl) -pyrazolo [1,5-a] pyridine AX.

AA, AB, AC, AE, AG, AV, AW and AX are extremely important.

The compounds are designated AA-AX for ease of reference throughout the specification.

In the studies, the compounds of formula (I), when administered orally twice to mice, reduced the migration of incubated mouse macrophage cells by 50% in each case at the dose shown in Table I. This is the degree of antagonism or reduction in lymph levels and refers to its utility in the treatment of an arthritic patient.

-2193727

Table I

examined Oral dose (mg / animal compound kg body weight) AA 10 AB 15 AC 10 AE 10 BRANCH 18 AV 2.5 AW 2 AX 2 The (I) compounds of the general formula

because they can be prepared by methods or analogs such as those described in the Examples for the preparation of the final products and intermediates of the present invention.

Thus, in accordance with the present invention, compounds of formula (I) wherein R ^{1 in} the alkoxy moiety is a straight or branched alkoxycarbonyl group having ¹ to 4 carbon atoms (R ^f and n are as defined above) are prepared by wherein R ² and n are as defined above and Χ ^1θ anion such as iodide or mesitylene sulfonate ion is used in a suitable organic solvent, e.g. A solution of Ν, Ν-dimethylformamide is reacted with a base such as anhydrous potassium carbonate and then with a compound of formula III wherein R ^{3 is a C} 1-4 straight or branched alkyl group.

According to the present invention (I) Compounds of formula I wherein ^R1 is a carboxyl group (R ² and n are as defined above) is prepared by reacting a compound of formula (I) in which R 'is alkoxycarbonyl having 1-4 carbon atoms, straight or branched C alkoxycarbonyl group, for example, with an aqueous base such as aqueous potassium hydroxide solution or aqueous sodium hydroxide solution, followed by aqueous acid such as dilute hydrochloric acid.

The present invention provides compounds of formula I wherein R 'is an alkylcarbamoyl or dialkylcarbamoyl group and the alkyl moiety is a straight or branched C 1 -C 4 radical (R ² and n are as defined above) using known methods or analogs are prepared from compounds of formula I wherein R ^{1 is a} carboxyl group or a straight or branched alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety (R ² and n being as defined above).

In one method, the (I) compound wherein R ¹ carboxy group (R ² and n are as defined above), is converted to the corresponding (IV) to an acid halide of formula by the application or analogously to known methods ^(X2 halogen atom such as chlorine atom and R ² and n are as defined above) which is then reacted with a compound of formula VI, wherein R ⁴ and R ^{3 are each} hydrogen and one or both of them are C 1 -C 4 straight or branched alkyl. The reaction is preferably carried out in an organic solvent such as ethanol at a temperature below room temperature, such as 0-10 ° C.

Alternatively, a compound of formula (I) wherein R 'in the alkoxy moiety is a straight or branched alkoxycarbonyl group having from 1 to 4 carbon atoms (R 1 and n being as defined above) is a compound of formula (VI) wherein R ⁴ and R ⁵ are as defined above, optionally in a solvent such as ethanol, preferably in a sealed vessel.

In a further aspect of the invention, compounds of formula I wherein R ^{2 in} the alkoxy moiety is a linear or branched alkoxycarbonyl group (R ¹ , n and each other R ² are as defined above) are represented by (I). is prepared by hydrolysis of compounds of formula ( ^II) wherein R ^{2 is a} cyano group (R ¹ , n and each other R ² is as defined above), for example using an aqueous base such as aqueous sodium hydroxide or aqueous potassium hydroxide. in the presence of an alcohol of the general formula (R ^{6 -} (C 1 -C 4) alkyl, preferably methyl or ethyl).

As used herein, the term "known methods" refers to methods used or described so far in the literature.

The following examples illustrate the preparation of the compounds of formula I and the Roman numerals for the preparation of intermediates.

Example 1

Compound AA

To a solution of 2.0 g of 1-amino-4-phenylpyridinium iodide in 20 ml of anhydrous Ν, dimet-dimethylformamide was added with stirring 1.01 g of potassium carbonate at room temperature, and after 30 minutes, 1.31 g of ethyl propiolate. drip it. The mixture was stirred for an additional 1 hour and then poured into a mixture of water (75 ml) and ice and extracted with diethyl ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to give a dark red residue. A portion of this residue was triturated with hot petroleum ether at 40-60 ° C and then chromatographed on silica gel using chloroform as eluent followed by recrystallization from cyclohexane to give 3-ethoxycarbonyl-5-phenylpyrazolo melting at 96-97 ° C. [1,5-a] pyridine J is obtained in the form of white needles.

Example 2

AB, AC, AD, AE, AF, AG, AH and Al

To a suspension of 1.0 g of 3-ethoxycarbonyl-5-phenylpyrazolo [1,5-a] pyridine prepared in Example 1 in 5 ml of ethanol was added 0.4 g of potassium hydroxide in 2 ml of water, and the mixture is refluxed for 45 minutes. The clear solution was poured into 50 ml of water, extracted 3 times with 15 ml of diethyl ether and acidified to pH 1 with concentrated hydrochloric acid. The resulting white precipitate was filtered off and washed with water 3

-3193727 and recrystallized from Ν, Ν-dimethylformamide / water. 0.45 g of 5-phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid, m.p. 252-254 DEG C., is obtained in the form of a white solid.

1.54 g of the 5-phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid prepared above are suspended in 40 ml of hot anhydrous methanol and a solution of 0.36 g of potassium hydroxide in 8 ml of anhydrous methanol is added. The resulting clear solution was evaporated to dryness under reduced pressure and the residual solid suspended in anhydrous toluene (50 mL). Oxalyl chloride (1.43 mL) was added to the suspension with stirring at room temperature, and after 30 minutes, 4 drops of pyridine were added and stirred overnight. After filtration, the filtrate was concentrated under reduced pressure to give 0.9 g of 5-phenylpyrazolo [1,5-a] pyridine-3-carbonyl chloride which was used in the next step without purification.

0.9 g of 5-phenylpyrazolo [1,5-a] pyridine-3-carbonyl chloride is dissolved in 25 ml of dry dichloromethane and 12 ml of 33% w / v ethanol dimethyl at 0 ° C. amine solution. After the addition was complete, the mixture was allowed to warm to room temperature and kept at room temperature overnight. The reaction solution was washed with water and the organic solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with hot petroleum ether at 40-60 ° C and then recrystallized from a mixture of carbon tetrachloride and hexane to give 0.3 g of 3- (N, N-dimethylcarbamoyl) -5-phenyl- (m.p. 88-90 ° C). pyrazolo [1,5-a] pyridine was obtained as a white solid.

In a similar manner, but using the starting material 3-ethoxycarbonyl-5-phenylpyrazolo [1,5-a] pyridine as an appropriate amount of 5,7-dimethyl-3-methoxycarbonylpyrazolo [1,5-a] ] pyridine and 3-ethoxycarbonyl-5-methoxy-7-methylpyrazolo [1,5-a] pyridine, both prepared as in Example 9, give the following compounds:

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. 124-127 ° C (silica gel chromatography, eluting with ethyl acetate and recrystallizing from cyclohexane);

3- (N, N-dimethylcarbamoyl) -5-methoxy-7-methylpyrazolo [1,5-a] pyridine, m.p. 126-129 ° C (recrystallized from cyclohexane).

Again, the following compounds were prepared in a similar manner, but substituted with the corresponding amounts of dimethylamine used as starting material:

3- (N-propylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine, m.p. 132-133 ° C (silica gel chromatographed on silica gel using ethyl acetate as eluent) and

3- (N, N-diethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine, m.p. 102-103 ° C (silica gel chromatography, using ethyl acetate as eluent);

Example 3

Compound AJ

To a solution of 0.64 g of 1-amino-4-cyanopyridinium mesitylene sulfonate prepared in Example 1 in 5 ml of dry Ν, Ν-dimethylformamide cooled to 0 ° C was treated with 0.41 g of potassium carbonate and 0. Methyl propiolate (34 g) was added and the mixture was stirred at 0 ° C for 30 minutes, then at room temperature for 5 hours and allowed to stand overnight at room temperature. The solvent was removed in vacuo and the residue was triturated with 25 ml of chloroform. The insoluble material is filtered off. The filtrate is evaporated to dryness and the residue is chromatographed under medium pressure using 1-acetate as eluant to give 80 mg of 5-cyano-3-methoxycarbonylpyrazolo [1,5-a] pyridine, m.p. 184-186 ° C.

Example 4

A solution of 5 mg of 5-cyano-3-methoxycarbonylpyrazolo [1,5-a] pyridine in 3 ml of methanol, prepared as in Example 3, is heated with 5 drops of 2N aqueous sodium hydroxide solution for 3 hours. , then evaporate to dryness in vacuo. The resulting residue was dissolved in 3 ml of water and acidified with concentrated hydrochloric acid. The precipitate was filtered off and chromatographed under medium pressure using chloroform as eluent to give 3,5-bis (methoxycarbonyl) pyrazolo [1,5-a] pyridine (mass spectrum 234; NMR spectrum (in deuterated dimethyl sulfoxide) 3). 90, 3.98, 7.52, 8.62, 8.66 and 9.04 ppm).

Example 5

Compound AL

1.89 g of 3-methoxycarbonyl-5-methoxypyrazolo [1,5-a] pyridine prepared in Example 9 are suspended in 21 ml of methanol and then 1.56 g of potassium hydroxide in 2.2 ml of water are added. and boil for 100 minutes. The clear solution was cooled, concentrated in vacuo, dissolved in water (10 mL), washed with diethyl ether and acidified with 2N hydrochloric acid. The white precipitate was filtered off to give 1.5 g of 5-methoxy-pyrazolo [1,5-a] pyridine-3-carboxylic acid, m.p.

Example 6

Compound AM g, J. Org. Chem. 1968, 33 (5), 2062-2064 To a solution of l-amino-4-tert-butylpyridinium iodide prepared in 70 ml of anhydrous Ν, Ν-dimethylformamide was added 5 g of anhydrous potassium carbonate. at room temperature and then 30 minutes later, 10 g of ethyl propiolate dissolved in 20 ml of dimethylformamide are added dropwise to 4193727. The mixture was allowed to stand overnight and then concentrated in vacuo. Water (250 mL) was added and the mixture was extracted with diethyl ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to give a dark residue. The residue was chromatographed on silica gel under medium pressure using chloroform as eluent to give 2.1 g of 5-tert-butyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine as a pale orange solid (NMR (in deuterochloroform)). ppm: 8.35 (1H, d, J = 7Hz), 8.28 (1H, s), 8.0 (1H, d, J = 2Hz), 7.9 (1H, dd, J = 7) Hz, 2Hz); 4.3 (2H, q, J = 7Hz); 1.4 (12H, m)).

Example 7

Compound AN

To a suspension of 2.0 g of 5-tert-butyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine obtained in Example 6 in 25 ml of methanol was added 1.5 g of potassium hydroxide in water and boil overnight. The solvent was evaporated in vacuo and to the residue was added water (25 ml), washed with diethyl ether and acidified with 2N hydrochloric acid. The resulting white precipitate was filtered off and washed with water to give Ι.θ g of 5-tert-butylpyrazolo [1,5-a] pyridine-3-carboxylic acid, m.p. 189-190 ° C.

Example 8

Compound AO

To a suspension of 4.05 g of 6,7-dimethyl-3-methoxycarbonylpyrazolo [1,5-a] pyridine prepared in Example 9 in 45 ml of methanol was added 3.38 g of potassium hydroxide in 5 ml of water and Bring to the boil for 100 minutes. The clear solution was cooled, evaporated to dryness in vacuo, then dissolved in water, extracted with diethyl ether and acidified with 2N hydrochloric acid. The resulting precipitate was filtered off to isolate 2.29 g of 6,7-dimethylpyrazolo [1,5-a] pyridine-3-carboxylic acid, m.p. 229232 ° C.

Example 9

AP, AQ, AR, AS, AT and AU

To date, and J. Org. Chem. 1968, 35 (5), 2062-2064 and using the appropriate starting materials, the following compounds were prepared:

5,7-dimethyl-3-methoxycarbonylpyrazolo [1,5-a] pyridine, m.p. 116-146 ° C / 26.66 Pa; 3-ethoxycarbonyl-5-methoxy-7-methylpyrazolo [1,5-a] pyridine (NMR (in deuterochloroform), ppm: 8.25 (1H, s); 7.3 (1H, d, J = 2Hz, 6.4 (1H, d, J = 2Hz), 4.35 (2H, q, J = 7Hz), 3.9 (3H, s), 2.7 (3H, s); 1.4 (3H, t, J = 7Hz));

3-methoxycarbonyl-5-methoxypyrazolo [1,5-a] pyridine, m.p. 98-100 ° C (from cyclohexane); 5-methoxy-3-ethoxycarbonylpyrazolo [1,5-a] pyridine, m.p. 109-110 ° C;

6.7-Dimethyl 1-3-methoxycarbonylpyrazolo [1,5-a] pyridine, b.p. 110-134 ° C / 6.66 Pa; and

6.7-Di-methyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine, b.p. 140-145 ° C / 66.6 Pa.

Example 10

Compound AV

0.92 g, a. To a solution of 5-methoxy-pyrazolo [1,5-a] pyridirole-3-carbonyl chloride prepared in Example 10a in 14 mL of dry dichloromethane was stirred with 11 mL of 33% by volume of dimethylamine in ethanol. is added at 2 ° C. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to stand overnight. After washing with water, the organic solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from cyclohexane to give 0.81 g of 3- (N, N-dimethylcarbamoyl) -5-methoxypyrazolo [1,5-a] pyridine, m.p. 27-129 ° C.

Example 11

Compound AW

1.6 g of the corresponding carboxylic acid are obtained as described in Annex III. To a solution of 5-tert-butylpyrazolo [1,5-a] pyridine-3-carbonyl chloride prepared in Example 1 with 20 mL of dry dichloromethane was stirred with 15 mL of 33% v / v 20 mL of dichloromethane. ethanolic dimethylamine solution diluted with methane was added at 0 ° C. After the addition was complete, the mixture was allowed to warm to room temperature and allowed to stand overnight. The reaction solution was concentrated in vacuo, dissolved in dichloromethane, washed with water and the organic solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from hexane to give 0.7 g of 5-tert-butyl-3- (Ν, Ν-dimethylcarbamoyl) pyrazolo [1,5-a] pyridine, m.p.

Example 12

Compound AX

2.2 g, a IV. To a solution of 6,7-dimethylpyrazole [1,5-a] pyridine-3-carbonyl chloride prepared in example 1d in 35 ml of dry dichloromethane was added 26 ml of 35% v / v diluted with 35 ml of dichloromethane with stirring. A solution of dimethylamine in ethanol was added at 0 ° C. After the addition was complete, the mixture was allowed to warm to room temperature and maintained at this temperature overnight. The mixture was washed with water and the organic solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized twice from cyclohexane to give 0.6 g of 6,7-dimethyl-3- (N, N-dimethylcarbamoyl) -pyrazolo [1,5-a] pyridine, m.p. 153156 ° C.

Production of intermediates

Example I

Dissolve 1.82 g of 4-cyanopyridine in 20 ml of dichloromethane and at 0 ° C 3.7 g of mesitylenesulfonylhydroxylamine in 40 ml of dichloromethane.

Add -5193727 nasal solution over 15 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then diluted with diethyl ether (30 mL). The resulting white solid was filtered off and washed thoroughly with diethyl ether to give 3.6 g of 1-amino-4-cyanopyridinium mesitylene sulfonate, m.p. 136138 ° C.

II. example

To a suspension of 1.50 g of 5-methoxy-pyrazolo [1,5-a] pyridine-3-carboxylic acid prepared in Example 5 in 29 ml of hot anhydrous methanol was added 0.49 g of potassium hydroxide in 6 ml of anhydrous methanol. The orange solution was evaporated to dryness under reduced pressure and the residual solid was suspended in 39 ml of anhydrous toluene. Oxalyl chloride (1.33 ml) was added to the suspension with stirring at room temperature, then 30 minutes later, 6 drops of dry pyridine were added and stirred overnight. After filtration, the filtrate was concentrated under reduced pressure to give 0.92 g of 5-methoxypyrazolo [1,5-a] pyridine-3-carbonyl chloride which was used in the next reaction without further purification.

III. example

To a suspension of 1.6 g of 5-tert-butylpyrazolo [1,5-a] pyridine-3-carboxylic acid prepared in Example 7 in 40 ml of hot anhydrous methanol was added 0.47 g of potassium hydroxide in 8 ml of anhydrous methanol. solution. The clear solution was evaporated to dryness under reduced pressure and the resulting solid was suspended in anhydrous toluene (25 mL). To the suspension was added 2 ml of oxalyl chloride at room temperature with stirring, 15 minutes later, 5 drops of dry pyridine and stirred for 2 hours. After filtration, the filtrate was concentrated under reduced pressure to give 5-tert-butylpyrazolo [1,5-a] pyridine-3-carbonyl chloride as an oil which crystallizes rapidly.

ARC. example

To a suspension of 2.0 g of 6,7-dimethylpyrazolo [1,5-a] pyridine-3-carboxylic acid prepared in Example 8 in 40 ml of hot anhydrous methanol was dissolved 0.65 g of potassium hydroxide in 8 ml of anhydrous methanol. We are added. The resulting solution was evaporated to dryness under reduced pressure and the residual solid suspended in anhydrous toluene (53 mL). Oxalyl chloride (1.79 mL) was added to the slurry with stirring at room temperature, then 30 minutes later, 8 drops of dry pyridine were added and stirred overnight. After filtration, the filtrate was concentrated under reduced pressure to give 2.2 g of 6,7-dimethylpyrazolo [1,5-a] pyridine-3-carbonyl chloride as a yellow crystalline solid which was used in the next reaction without purification. .

The present invention also provides pharmaceutical compositions comprising at least one compound of general formula (I) in association with a pharmaceutically acceptable carrier or coating. In clinical practice, the compositions of the invention are generally administered orally, rectally or parenterally, for example, intravenously, intramuscularly, or more preferably topically or intraarticularly.

Some of the compounds of formula (I) are particularly conveniently administered in the form of aqueous solutions and compositions containing them.

Solid compositions suitable for oral administration include compressed tablets, pills, dispersible powders and granules. Such solid formulations are prepared by mixing the active compound or compounds with at least one inert diluent such as calcium carbonate, potato starch, alginic acid or lactose. In addition to inert diluents, it is common practice for the composition to include other substances such as lubricants such as magnesium stearate. Liquid preparations 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. In addition to the inert diluent, such compositions may also contain adjuvants such as wetting or suspending agents, sweetening, flavoring, perfuming, and preservative agents.

Oral formulations of the invention include capsules made of absorbable materials, such as gelatin, containing the active compounds with or without a diluent or excipient.

Solid compositions suitable for rectal administration include suppositories, which may be prepared in a manner known per se, containing one or more active compounds.

Formulations of this invention suitable for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solvents or suspending agents include propylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying and dispersing agents. They may be sterilized, for example, by weaving through a bacterial impermeable filter, incorporating a sterilizing agent, irradiation or heating. They may also be prepared in the form of sterile solid compositions which are dissolved in a sterile injectable medium immediately prior to use. In addition to the more common intravenous and intramuscular routes, the compositions may also be administered by intra-articular injection.

The present invention includes those prepared in the form of a solution or suspension

-6193727 formulations containing the active ingredient, if desired together with the additives described above, in vegetable or other fats, paraffin or other waxes or lacquers or creams, which may be applied topically, for example to the skin around the affected joint, to treat arthritis.

The percentage of active ingredient in the compositions of the present invention may vary, it being important that it be present in an amount that is necessary to achieve the desired effect at a suitable dose. Obviously, many dosage unit forms may be administered at the same time. Generally, the formulations will contain between 0.1% and 80% of the active ingredient, especially in the case of tablets.

The dose used will depend on the desired effect, the route of administration and the duration of treatment. For adults, the dosage will generally range from 0.01 to 100 mg, preferably from 0.1 to 10 mg, most preferably from 1 to 10 mg / kg body weight / day.

The daily dose for an adult weighing about 80 kg may be 8-50 mg intravenously, 50-200 mg intramuscularly, 20-100 mg intra-articularly, and 250-800 mg orally or topically.

The compounds of formula (I) may be administered daily or less frequently, e.g. weekly, as practiced by the practitioner.

The invention also relates to a method of treating arthritis disorders and related autoimmune disorders, comprising administering to a patient an amount of a compound of formula (I) or a compound of formula (I) which is useful for treating the disorder.

The following formulation examples illustrate the compositions of the present invention.

1. Preparation Example

Capsules for oral administration are prepared by filling gelatin capsule # 2 with 155 mg of the following composition;

3- (N, N-Dimethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine 50 mg potato starch 100 mg magnesium stearate 2.5 mg

Aerosil 2.5 mg

Similar formulations may be prepared using other compounds of formula (I).

Example 2 Preparation

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

Similar formulations may be prepared using other compounds of formula (I).

Claims (19)

A process for the preparation of pyrazolo [1,5-a] pyridine derivatives of the general formula (I) - in this formula R ¹ is carboxyl, the alkyl moieties being C 1 -C 4 alkoxycarbonyl, alkylcarbamoyl or dialkylcarbamoyl; R ^{2 is C} 1 -C 4 alkyl, cyano, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxy or phenyl in the alkoxy moiety, and is in the 5-, 6- and / or 7-position; n is 0,1 or 2, and when n is 2, R ^2, other than alkyl, has the same meaning, provided that i) R ^{1 is an} alkylcarbamoyl group when n = 0; ii) other than R ¹ dialkylcarbamoyl if n = I and R ^{2 are} methyl; and iii) other than R ¹ carboxyl and ethoxycarbonyl when n = 1 and R ^{2 is} prepared at the 7-position of the methyl group, characterized in that: a) for the preparation of compounds of the formula I in which R in the alkoxy moiety is a C 1 -C 4 alkoxycarbonyl group, R ² and na are compounds of the formula II in which R ² and π are It is as defined above and the anion X ¹ - in an aprotic organic solvent, an inorganic base and a compound of formula (III): - wherein R ³ in the C1-4 alkyl group - is reacted, or b) ^R1 is the alkyl part has from 1 to 4 carbon atoms, compounds of formula alkyl-carbamoyl or dialkylcarbamoyl group (I) in the preparation of - R ² and n are as defined above - (IV) an acid halide of the formula: - wherein R ² and n is as defined above and X ^{2 is} halogen, with a compound of formula VI, wherein R ⁴ and R ^{5 are C} 1 -C 4 alkyl, or one of them is hydrogen; For the preparation of compounds of formula I wherein R ¹ is carboxyl, as defined for R ² and na, wherein R 1 is C 1 -C 4 alkoxycarbonyl, R ² and na are as defined above. hydrolyzing; ^R1 is the alkyl parts C1-4alkyl carbamoyl, or compounds of formula (I) containing a dialkyl carbamoyl group of formula - R ² and n are as defined above - to obtain a compound (I) compound wherein R ¹ is alkoxycarbonyl having 1 to 4 carbon atoms, an alkoxycarbonyl group, R ² and n are as defined above, (VI) as defined above - is reacted with - R ⁴ and R ⁵ are as defined above; The general formula (I) for R ² in the alkoxy moiety containing a C 1-4 alkoxycarbonyl group Compounds -7193727 general formula - R 'and n are as defined above - for preparing a compound of formula (I) ^R2 is cyano formula - R ¹ and n are as defined above - the cyano group of (VII) in the presence of alcohols of the formula - R ⁶ 1-4 hydrolyzed by C alk alk alk alkyl. 2. A method according to any of claim 1 for preparing a compound (I) of formula in which is used as defined, n is 1 or 2, R ¹ and R ² in claim 1, characterized in that correspondingly substituted starting materials. A process for the preparation of a compound of formula (I) according to claim 1 or claim 2 wherein R ^{1 is a} dialkylcarbamoyl group having up to 4 carbon atoms, R ² and n are as defined above, wherein the appropriately substituted starting materials are used. . 4. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein R ¹ is dimethylcarbamoyl, wherein R ² and n are as defined above, wherein the starting materials are suitably substituted. The process for the preparation of 3-ethoxycarbonyl-5-phenylpyrazolo [1,5-a] pyridine according to claim 1, wherein the starting materials are suitably substituted. 6. A process for the preparation of 5-phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid according to claim 1, wherein the starting materials are suitably substituted. A process for the preparation of 3- (N, N-dimethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine according to claim 1 wherein the starting materials are suitably substituted. The process for the preparation of 5,7-dimethyl-3- (Ν, Ν-dimethylcarbamoyl) -pyrazolo [1,5-a] pyridine according to claim 1, wherein the starting materials are suitably substituted. 9. A process according to claim 1 for the preparation of 3- (N, N-dimethylcarbamoyl) -5-methoxy-7-methyl-1-pyrazolo], 5-a] pyridine, wherein the appropriately substituted starting material is materials are used. 10. A process according to claim 1 for the preparation of 3- (N, N-dimethyl-1-carbamoyl) -5-methoxy-pyrazolo [1,5-a] pyridine, wherein the starting materials are suitably substituted. 11. A process according to claim 1 for the preparation of 5-tert-butyl-3- (Ν, Ν-dimethylcarbamoyl) pyrazolo [1,5-a] pyridine, wherein the starting materials are suitably substituted. The process for the preparation of 6,7-dimethyl-3- (il, Ν-dimethylcarbamoyl) -pyrazolo [1,5-a] pyridine according to claim 1, characterized in that the appropriately substituted starting material is 5 compounds are used. The process of claim 1, 5,7-dimethylpyrazolo [1,5-a] pyridine-3-carboxylic acid, 3- (N-propylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine and 6,7-dimethyl-3-ethoxycarbonylpyrazolo [1,5-a] pyridine, characterized in that appropriately substituted starting materials are used. 14. The process of claim 1, wherein the compound of formula II is wherein Χ * θ is an iodide or mesitylene sulfonate ion, R ² and n are as defined in claim 1. Process (a) according to Claim 1, characterized in that the solvent is N, N-dimethylformamide and the base is anhydrous potassium carbonate. Process b) according to claim 1, characterized in that the reaction is carried out in an organic solvent at a temperature below room temperature. 25 ° C. 17. A process for the preparation of a compound of formula (I) wherein R ¹ , R ² and n are as defined in claim 1 as an active ingredient. 30, characterized in that the method according to claims 1-16. The compound of formula (I) obtained by the process of any one of claims 1 to 6 is mixed with a pharmaceutical carrier or diluent to form a pharmaceutical preparation. The process according to claim 17, wherein the active ingredient is 3-ethoxycarbonyl-5-phenylpyrazolo [1,5-a] pyridine, 5-phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid, 3- (Ν, Ν-dimethylcarbamoyl) -5-phenylpyrazolo [1,5-a] pyridine, 5,7-dimethyl-3- (N, N-dimethylcarbamoyl) pyrazolo [1,5- containing a] pyridine or 3- (Ν, Ν-dimethylcarbamoyl) -5-methoxy-7-methylpyrazolo [1,5-a] pyridine 45 for the preparation of a pharmaceutical composition. The active ingredient of the process of any one of claims 1 to 7 is mixed with a pharmaceutical carrier or diluent to form a pharmaceutical composition. 19. The process according to claim 17, wherein the active ingredient is 3- (N, N-dimethylcarbamoyl) -5-methoxypyrazolo [1,5-a] pyridine, 5-tert-butyl-3- (Ν, Ν-dimethyl-) carbamoyl) pyrazolo [1,5-a] pyridine or 6,7-dimethyl-3- ((, Ν-dimethylcarbamoyl) pyrazolo [1,5-a] pyridine, characterized in that: 1-16. The active ingredient produced by the process of any one of claims 1 to 10 is mixed with a pharmaceutical carrier or diluent to form a pharmaceutical composition.