LU85690A1 - NOVEL PYRAZOLO (1,5-A) PYRIDINE DERIVATIVES, THEIR PREPARATION AND THE THERAPEUTIC COMPOSITIONS CONTAINING THEM - Google Patents

Description

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The present invention relates to new therapeutically active pyrazolopyridine derivatives, their methods of preparation and the pharmaceutical compositions containing them.

The pyrazolopyridine derivatives according to the invention are the compounds of general formula: a <Vs— I il (i)

"I N — N

V

in which R ^ represents a carboxy, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or dialkoylcarbamoyl radical, R £ represents a halogen atom such as fluorine, chlorine or bromine, or an alkyl, cyano, alkyloxycarbonyl, carboxy, carbamoyl radical, alkylcarbamoyl, dialcoylcarbamoyl, nitro, hydroxy, alkyloxy, aryloxy, aralkoyl, trifluoromethyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl or two-substituted radicals, arylsulphonyl or alkanoyl radical, arcanoyl or aroyl alkyl, arcanoyl or aroyl or aroyl or aroyl or aroyl or aroyl radical the alkyl and aryl radicals and n represents the number 0, 1, 2, 3 or 4, preferably 1 or 2, and, where appropriate, their pharmatically acceptable salts, for example when R ^ and / or R £ represent a carboxy radical , their salts, more especially the alkaline salts such as the sodium salt, provided that: i) R ^ is an alkylcarbamoyl radical when n is equal to zero, - ii) R ^ is different from a dialcoylcarba radical mean when n is equal to 1 and R ^ is a methyl radical, iii) R ^ is different from a carboxy or * ethoxycarbonyl radical when n is equal to 1 and represents a methyl radical in position 7.

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

The aryl radicals and aryl portions falling within the definition of // * * 2 are preferably phenyl radicals which may carry one or more substituents chosen from, for example, halogen atoms and the alkyl, alkyloxy, nitro and trifluoromethyl.

05 The alkyl radicals and alkyl portions falling within the definitions of Rj and R £ can be in straight or branched chain and contain up to 6 carbon atoms. When the context allows, it is understood that, when in the present description reference is made to the compounds of general formula (I), reference is also made to the salts mentioned above.

The products have remarkable pharmacological properties, in particular properties which make it possible to envisage a usefulness in the treatment of arthritic diseases and related anti-immune diseases such as rheumatoid arthritis, ortoreoarthritis, diseases of the seronegative arthritis type such as ankilosing spondylitis, psoriatic arthritis and enteropathic arthropathy, connective tissue disorders such as lupus erythematosus and polymyositis, and the tendency to reject transplants. In particular, in laboratory tests, the products of general formula (I) have been shown to be active in inhibiting deterioration of the limb joints in rodents. These results are particularly important because the products commonly used in the treatment of arthritic diseases are primarily anti-inflammatory drugs and do not have the capacity to inhibit deterioration of the joints. In addition, the products of general formula (I) surprisingly have pharmacological properties superior to those of products of close structure to which they are compared.

The beneficial properties of the products of general formula 30 (I) are reinforced by the fact that they exhibit only very low toxicity in mammals.

The preferred classes of compounds of formula (I) include those in which R ^ represents a dialkoylcarba-hub radical containing up to 4 carbon atoms (such as dimithylcarba- »3 hub) and those in which R2 represents an alkyl radical (such (methyl, ethyl or tert-butyl), alkyloxy (such as metho-xy), phenyl, cyano, or alkyloxycarbonyl (such as ethoxycarbonyl).

Q5 The compounds of general formula (I) which are particularly important are the following:

- 3-Ethoxycarbonyl-5-phenyl pyrazoloE1,5-a] pyridine AA

- 5-phenyl pyrazolo [1,5-a] pyridinecarboxylic acid-3 AB

"- (N, N-dimethylcarbamoyl) -3 phenyl-5 pyrazolo-

10 E1,5-a] pyridine AC

- 5.7-dimethyl acid pyrazolo [1,5-a] pyridinecarboxylic-3 AD

- Dimethyl-5.7 (N, îi-dimethylcarbamoyl) -3

pyrazolo [1,5-a] pyridine AE

- 5-methoxy-7 methyl acid pyrazolo [1,5-a] pyridine-

15 carboxylic-3 AF

- (N, N-dimethylcarbamoyl) -3 methoxy-5-methyl-7

pyrazolo [1,5-a] pyridine AG

- (N-propylcarbamoyl) -3 phenyl-5 pyrazolo [1,5-a]

pyridine AH

20 - (ïî, N-diethylcarbamoyl) -3-phenyl-5 pyrazolo [1,5-a]

pyridine AI

- Cyano-5 methoxycarbonyl-3 pyrazoloE1,5-a] pyridine AJ

- Bis (methoxycarbonyl) -3.5 pyrazoloE1.5-a] pyridine AK

- 5-methoxy acid pyrazoloEl, 5-a] pyridinecarboxylic-3 AL

25 - tert-Butyl-5 ethoxycarbonyl-3 pyrazoloE1,5-a] pyridine AM

* - Tert-butyl-5 pyrazoloE1,5-a] pyridinecarboxylic acid-3 AN

- 6,7 Dimethyl acid pyrazoloE1,5-a] pyridinecarboxylic-3 AO

- Dimethyl-5,7 methyloxycarbonyl-3 pyrazoloE1,5-a] -pyridine AP

- Ethoxycarbonyl-3 methyloxy-5-methyl-7 pyrazolo-

30 [1,5-a] pyridine AQ

- 3-methoxycarbonyl-5-methoxy pyrazolo [1,5-a] pyridine AR

- 5-methoxy-3-ethoxycarbonyl pyrazoloE1,5-a] pyridine AS

- Dimethyl-6,7 methoxycarbonyl-3 pyrazoloE1,5-a] pyridine AT

- Dimethyl-6,7 ethoxycarbonyl-3 pyrazoloE1,5-a] pyridine AU

Ù% 4 - (N, N-dimethylcarbamoyl) -3 5-methoxy pyrazolo [1,5-a]

pyridine AV

- tert-butyl-5 (N, N-dimethylcarbamoyl) -3 pyrazolo [1,5-a]

05 pyridine AW

- Dimethyl-6,7 (N, N-dimethylcarbamoyl) -3 pyrazolo [1,5-a]

pyridine AX

Compounds AA, AB, AC, AE, AG, AV, AW and AX are of "particular importance.

10 The letters AA to AX are assigned to the compounds to "facilitate later references in the description.

In the tests, the compounds of general formula (I) when administered twice orally to mice, each time at the dose indicated in table I, reduce the inhibition by about 50%. of the migration of inhibited mouse macrophage cells. This is a measure of the antagonism or reduction of lymphokine levels and is an indication of the usefulness of the products in the treatment of arthritis patients.

... ......—. ----- - - - - - ------- -

U

»5

TABLE I

! • ·: COMPOUND: ORAL DOSE:: TESTED: (mg / kg BODY WEIGHT OF ANIMAL); • · ·: AA: 10: 05: AB: 15: *: AC: 10:: AE: 10: • · ·: AG: 18: v · · • · ·: AV: 2.5: 10: AW: 3:: AX: 2:

The compounds of general formula (I) can be prepared by application or adaptation of the known methods, for example, as a characteristic of the present invention, the methods described in the examples and reference examples below.

Thus, according to a characteristic of the present invention, the compounds of general formula (I) in which R 1 represents an alkyloxycarbonyl radical in which the alkyl part contains 1 to 6 carbon atoms in a straight or branched chain and R 2 and n are defined as previously are prepared by the action of a solution of a compound of general formula: Ü

• V

6; Λ <yn— It. a “L N-NH„

Vf 2 (Xj) - in which and n are defined as above and represents an anion such as the iodide or mesitylenesulfonate ion, in a suitable organic solvent such as Ν, Ν-dimethylformamide, in the presence of a base such as anhydrous potassium carbonate, followed by the action of a compound of general formula: HC 3 C-COOR3 (III) in which represents an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain.

According to a characteristic of the present invention, the compounds of general formula (I) in which R ^ represents a carboxy radical and R3 and n are defined as above, are prepared by hydrolysis of the compounds of general formula (I) in which R ^ represents an alkyloxycarbonyl radical, the alkyl part of which contains 1 to 6 carbon atoms in a straight or branched chain and R £ and n are defined as above, for example by treatment with an aqueous alkali, such as an aqueous solution of sodium hydroxide or potassium hydroxide , followed by treatment with an aqueous acid such as dilute hydrochloric acid.

According to a characteristic of the present invention, the compounds of general formula (I) in which R 1 represents a carbamoyl, alkylcarbamoyl or dialkoylcarbamoyl radical in which the alkyl parts contain 1 to 6 carbon atoms in straight or branched chain and R2 and n are defined as above, are prepared from the compounds of general formula (I) in which R ^ represents a carboxy radical or an alkyloxycarbonyl radical in which the alkyl part contains 1 to 6 carbon atoms in straight or branched chain with application or adaptation of known methods.

50 According to one aspect of the invention, a compound of general formula (I) in which R ^ represents a carboxy radical and R3 and

U

Λ 7 η are defined as above is converted by application or adaptation of known methods to corresponding acid halide or to corresponding acid anhydride, of respective formulas (IV) and (V): p cox2 CO - 0 <aâ

05 (Vn I f] (Vn— I II

v-N V “N

L J 2 (IV) (V) in which X2 represents a halogen atom such as chlorine and R2 and n are defined as above, which compound is then reacted with a compound of general formula:: R.

/ 4 HN (VI)

X

10 in which and R ,. represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain. Preferably, the reaction is carried out in an organic solvent such as ethanol, preferably below room temperature, for example between 0 and 10 ° C.

According to another aspect of the invention, a compound of general formula (I) in which R 1 represents an alkyl-xycarbonyl radical in which the alkyl part contains 116 carbon atoms in straight or branched chain and R 2 and n are defined as above is reacted directly with a compound of general formula (VI) in which R ^ and R ,. are defined as above, optionally in a solvent such as ethanol, preferably in sealed apparatus.

According to another characteristic of the present invention, the compounds of general formula (I) in which R 1 represents an alkyloxycarbonyl radical in which the alkyl part contains 1 to 6 carbon atoms in a straight or branched chain and R 2 and n are / 7 rnr 8 defined as above are prepared by esterification of compounds of general formula (I) in which represents a carboxy radical and R2 and n are defined as previously, by application or adaptation of known methods for esterifying a carboxylic acid, for example by action of a derivative of general formula (IV) or (V) in which X2, R2 and n are defined as above, with an alcohol of general formula:

RgOH (VII) in which Rg represents an alkyl radical containing 1 to 6 10 carbon atoms in a straight or branched chain.

The compounds of general formula (I) can also be prepared by conversion of other compounds of general formula (I), by modification of the entity or entities For example as follows: 1) According to a characteristic of the present invention, the compounds of general formula (I) in which R2 represents at least one alkyloxycarbonyl radical in which the alkyl part contains 1 to 6 carbon atoms in a straight or branched chain, R ^, n and any other substituent R2 being defined as above, and the compounds of general formula (I) in which R2 represents a carboxy radical, R ^, n and any other substituent R2 being defined as above, can be interconverted by application or adaptation of methods described above for the interconversion of compounds of general formula (I ) in which R ^ represents an alkyloxycarbonyl radical and of compounds of general formula (I) in which R ^ represents a carboxy radical, R2 and n being defined as above emment.

2) According to another characteristic of the present invention, the compounds of general formula (I) in which R2 represents an alkyloxycarbonyl radical, the alkyl part of which contains 1 to 6 carbon atoms in straight or branched chain, R ^, n and any other substituent R2 being defined as above, can be - prepared by hydrolysis of compounds of general formula (I) in which R2 represents a cyano radical, R ^, n and any other

If 9

V

killing R2 being defined as above, for example by the action of an aqueous alkali such as an aqueous solution of sodium hydroxide or potassium hydroxide, in the presence of an appropriate alcohol of general formula (VII) in which Rg is defined as above, of preferably Rg 05 being a methyl or ethyl radical.

The salts mentioned above for certain compounds of general formula (I) are prepared by application or adaptation of methods known per se, for example by reaction of the parent compound of general formula (I) with a hydroxide, a carbonate or preferably a bicarbonate of alkali metal, in an aqueous or hydro-organic medium, followed by the isolation of the salt by methods known per se.

By "known methods" as used in the present description is meant the methods already used or described in the literature.

The following examples illustrate the preparation of the compounds of general formula (I) and the reference examples illustrate the preparation of the intermediates.

EXAMPLE 1

20 AA compound

a stirred solution of 2 g of 1-amino-4-phenyl pyridinium iodide in 20 cm3 of Ν, Ν-dimethylformamide is treated with 1.01 g of anhydrous potassium carbonate at room temperature and then, after 30 minutes, with 1 , 31 g of ethyl propiolate which is added dropwise. The mixture is stirred for another hour then is thrown into 75 cm3 of a mixture of ice and water and extracted with diethyl ether. The ethereal extract is washed with water, dried over magnesium sulfate and evaporated. A dark red residue is thus obtained. Part of this residue is triturated with petroleum ether (m.p. 40-60 ° C) and then subjected to chromatography on silica gel, eluting with chloroform. The product is then recrystallized from cyclohexane. 3-ethoxycarbonyl-5-phenyl-pyrazolo [1,5-a] pyridine is thus obtained in the form of white needles, melting at 96-97 ° C.

k% 10 EXAMPLE 2

Compounds AB, AC, AD, AE, AF, AH and AI

t

A suspension of 1 g of 3-ethoxycarbonyl-5-phenyl pyrazolo [1,5-a] pyridine (prepared as described in Example 1) in 5 cm 3 05 of ethanol is treated with a solution of 0.4 g of potash in 2 cm3 of water and then heated to reflux for 45 minutes. The clear solution is thrown into 50 cm3 of water and washed with 3 times 15 cm3 of diethyl ether. The aqueous solution is then acidified to pH 1 with an aqueous solution of concentrated hydrochloric acid. The white precipitate obtained is separated by filtration, washed with water and recrystallized from a mixture of Ν, Ν-dimethylformamide and water. 0.45 g of 5-phenyl pyrazolo [1,5-a] pyridinecarboxylic-3 acid is thus obtained in the form of a white solid melting at 252-254eC (with decomposition).

A suspension of 1.54 g of 5-phenyl pyrazolo [1,5-a] v pyridinecarboxylic-3 acid (prepared as described above) in 40 cm3 of boiling anhydrous methanol is treated with a solution of 0.36 g of potassium hydroxide in 8 cm3 of anhydrous methanol. The clear solution obtained is evaporated to dryness under reduced pressure and the solid obtained is suspended in 50 cm3 of anhydrous toluene. The stirred suspension is treated with 1.43 cm3 of oxalyl chloride at room temperature and, after 30 minutes, the mixture is treated with 4 drops of anhydrous pyridine and then stirred overnight. The mixture is filtered and the filtrate is evaporated under reduced pressure. 0.9 g of 5-phenyl pyrazolo [1,5-a] pyridinecarboxylic-3-chloride is thus obtained, which is used without further purification in the subsequent syntheses.

A stirred solution of 0.9 g of 5-phenyl pyrazolo [1,5-a] pyridinecarboxylic-3 chloride in 25 cm3 of dichloromethane is treated at 0 ° C with 12 cm3 of a 33% solution (weight / volume) of dimethylamine in ethanol. When the addition is complete, the mixture is allowed to return to ambient temperature and kept at ambient temperature overnight. The mixture is then washed with water and the organic solution is dried over λ 11 magnesium sulfate and concentrated to dryness under reduced pressure. The residue obtained is triturated with petroleum ether (m.p .: 40-60 ° C) then recrystallized from a mixture of carbon tetrachloride and hexane. 0.3 g of (N, N-dimethylcarbamoyl) -3 phenyl-5 05 pyrazolo [1,5-a] pyridine is thus obtained in the form of a white solid, melting at 88-90 ° C.

By operating in an analogous manner, but replacing the 3-etho-xycarbonyl-5-phenyl-pyrazolo [1,5-a] pyridine, used as raw material, by the appropriate amounts of dimethyl-5,7 10-methoxycarbonyl-3 pyrazolo [ 1,5-a] pyridine and 3-ethoxycarbonyl-5-methoxy-7-methyl pyrazolo [1,5-a] pyridine, prepared as described in Example 9, were prepared respectively: - 5-dimethyl acid , 7 pyrazolo [1,5-a] pyridinecarboxy-lique-3 melting at 167-170 ° C (with decomposition), 15 - 5-methoxy-methyl-7 pyrazolo [1,5-a] pyridine, 'v dimethyl-5.7 (N, N-dimethylcarbamoyl) -3 pyrazolo [1,5-a] pyridine melting at 124-127 ° C (provided that they have been chromatographed on silica gel, eluting with acetate ethyl and to have been recrystallized from cyclohexane), and 20 - la (N, N-dimethylcarbamoyl) -3 5-methoxy-7-methyl-pyrazolo [1,5-a] pyridine, melting at 126-129 ° C (after recrystallization from hexane).

By again operating in an analogous manner but by replacing dimethylamine, used as raw material, by the appropriate amounts of propylamine and of diethylamine, the following were prepared respectively: - (N-propylcarbamoyl) -3 phenyl-5 pyrazolo [1, 5-a] pyridine melting at 132-133 ° C (after chromatography on silica gel, eluting with ethyl acetate).

30 - (N, N-diethylcarbamoyl) -3-phenyl-5 pyrazolo [1,5-a] pyridine, melting at 102-103 ° C (after chromatography on silica gel eluting with ethyl acetate) .

♦ 12 λ EXAMPLE 3

Compound_AJ

/

A solution cooled to 0 ° C. of 0.64 g of mesitylene sulfonate of 1-amino-4 cyano pyridinium (prepared as described in Example 05 of reference 1) in 5 cm3 of anhydrous Ν, Ν-dimethylformamide is treated with 0.41 g of anhydrous potassium carbonate and 0.34 g of methyl propiolate then stirred at 0 ° C for 30 minutes at room temperature for 5 hours and left to stand overnight at room temperature. The solvent is removed in vacuo and the residue is triturated with 25 cm3 of chloroform. The insoluble material is removed by filtration. The filtrate is evaporated to dryness and the residue is subjected to chromatography under medium pressure, eluting with ethyl acetate. 80 mg of 3-cyano-3-methoxycarbonyl pyrazolo [1,5-a] pyridine, melting at 184-186 ° C., are thus obtained.

h 15 EXAMPLE 4

Compound_AK

A solution of 25 mg of cyano-5 methoxycarbonyl-3 pyrazo-lo [1,5-a] pyridine (prepared as described in Example 3) in 3 cm3 of methanol containing 5 drops of a 2N aqueous sodium hydroxide solution 20 is heated at reflux for 3 hours and then evaporated to dryness under vacuum. The residue obtained is dissolved in 3 cm3 of water and the solution is acidified with an aqueous solution of concentrated hydrochloric acid. The precipitate formed is separated by filtration and subjected to chromatography under medium pressure, eluting with chloroform - 25 me. The bis- (methoxycarbonyl) -3.5 pyrazolo [1,5-a] pyridine is thus obtained:

Mass spectrum: 234

Spectrum of R.M.N. (Deuterated dimethyl sulfoxide): δ = 3.90; 3.98; 7.52; 8.62; 8.66 and 9.04 p.p.m.

-T * û (

i K I

X

Λ 13 EXAMPLE 5

Compound AL

A suspension of 1.89 g of 3-methoxycarbonyl-5-methoxy-pyrazolo [1,5-a] pyridine (prepared as described in Example 9) in 05 21 cm 3 of methanol is treated with a solution of 1.56 g of potassium hydroxide in 2.2 cm3 of water and the mixture is then heated under reflux for 1 hour 40 minutes. The clear solution obtained is cooled and evaporated to dryness under vacuum. The residue is taken up with 10 cm3 of water; the solution is washed with diethyl ether then. Acidified with a 2N aqueous hydrochloric acid solution. The white precipitate obtained is separated by filtration. 1.5 g of 5-methoxy pyrazolo [1,5-a] pyridinecarboxylic-3 acid are thus obtained, melting at 228-229 ° C.

EXAMPLE 6

15 AM compound

A stirred solution of 10 g of 1-amino tert-butyl-4 pyridinium iodide [prepared by application of methods described in J.

Org. Chem. (1968), 33 ^ (5), 2062-2064] in 70 cm3 of N, N-dimethyl-formamide is treated with 5 g of anhydrous potassium carbonate at room temperature. After 30 minutes, a solution of 10 g of ethyl propiolate in 20 cm3 of dimethylformamide is added dropwise. The mixture is left to stand overnight and is then evaporated under vacuum. The residue is taken up in 250 cm3 of water and extracted with diethyl ether. The ether extract is washed with water, dried over magnesium sulfate and the ether is evaporated. A dark residue is obtained. This residue is subjected to chromatography on silica gel, eluting with chloroform. 2.1 g of tert-butyl-5-ethoxycarbonyl-3 pyrazolo [1,5-a] pyridine are thus obtained in the form of a pale orange solid.

30 Spectrum of R.M.N. (in D2O): 8.35 ppm (1H, doublet, J = 7 Hz) 8.28 ppm (1H, singlet), 8.0 ppm (1H, doublet J = 2Hz), 7.9 ppm (1H, doublet doublets, J = 7Hz and 2Hz), 4.3 ppm (2H, quartet, J = 7 Hz), 1.4 ppm (12H, multiplet).

il 14 „EXAMPLE 7

Compound AN

A suspension of 2 g of tert-butyl-5-ethoxycarbonyl-3 pyrazolo [1,5-a] pyridine (prepared as described in example 6) in 05 25 cm3 of methanol is treated with a solution of 1.5 g of potassium hydroxide in 5 cm3 of water and the mixture is heated at reflux overnight. The solvent is evaporated under vacuum and the residue is taken up with 25 cm3 of water. The solution is washed with diethyl ether and is then acidified with a 2N aqueous hydrochloric acid solution. The white precipitate obtained is separated by filtration and washed with water. 1.6 g of tert-butyl-5 pyrazolo [1,5-a] pyridine-carboxylic-3-acid are thus obtained, melting at 189-190 ° C (with decomposition).

EXAMPLE 8

Compound AO

A suspension of 4.05 g of 6,7-dimethyl-3-methoxycarbonyl pyrazolo [1,5-a] pyridine (prepared as described in Example 9) in 45 cm3 of methanol is treated with a solution of 3.38 g of potassium hydroxide in 5 cm3 of water and the mixture is heated to reflux for 1 hour 40 minutes. The clear solution obtained is cooled and evaporated in vacuo. The residue is dissolved in water; the solution is washed with diethyl ether and then acidified with a 2N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration. 2.29 g of 6.7-dimethyl pyrazolo [1,5-a] pyridinecarboxylic-3 acid are thus obtained, melting at 229-232 ° C (with decomposition).

* EXAMPLE 9

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

By operating in a similar manner to that described above and to that described in J. Org. Chem., (1968), 33_ (5), 2062-30 2064 and using the corresponding raw materials, were prepared: - dimethyl-5,7 methoxycarbonyl-3 pyrazolo [1,5-a] pyridine, boiling at 116-146 ° C at 0.2 mmHg, 15% - 3-ethoxycarbonyl-5-methoxy-7-methyl-pyrazolo [1,5-a] v pyridine.

- Spectrum of R. Μ. N. (in CDCÎ ^): 8.25 ppm (1H, singlet), 7.3 ppm (1H, doublet, J = 2Hz) 05 6.4 ppm (1H, doublet, J = 2Hz), 4.35 ppm (2H, quartet, J = 7Hz), 3.9 ppm (3Hz singlet), 2.7 ppm (3H, singlet), 1.4 ppm (3H, triplet, J = 7Hz), - 3-methoxycarbonyl methoxy- 5 pyrazolo [1,5-a] pyridine, melting at 98-100 ° C (recrystallized from cyclohexane), 10 - methoxy-5-ethoxycarbonyl-3 pyrazolo [1,5-a] pyridine, melting at 109-110 ° C, - 6,7-dimethyl-3-methoxycarbonyl pyrazolo [1,5-a] pyridine, boiling at 110-134 ° C under 0.5 mmHg and - 6,7-dimethyl-3-ethoxycarbonyl pyrazolo [1,5 -a] 15 pyridine, boiling at 140-145 ° C under 0.5 mmHg.

* EXAMPLE 10

AV compound

A stirred solution of 0.92 g of 5-methoxy pyrazolo [1,5-a] pyridinecarboxylic acid-3 chloride (prepared as described in reference example 2) in 14 cm3 of dichloromethane is treated with 2 ° C with 11 cm3 of a 33% solution (weight / volume) of dimethylamine in ethanol. When the addition is complete, the mixture is allowed to return to room temperature and is then kept at room temperature overnight. The mixture is then washed with water and the organic solution is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is recrystallized from cyclohexane. 0.81 g of (N, N-dimethylcarbamoyl) -3-5-methoxy-pyrazolo [1,5-a] pyridine is thus obtained in the form of yellow crystals, melting at 127-129 ° C.

30 EXAMPLE 11

'' AW compound

A stirred solution of 5-tert-butyl pyrazolo [1,5-a] pyridinecarboxylic acid-3 chloride (prepared from 1.6 g a /

X

16 of corresponding acid as described in reference example 5) in r 20 cm3 of dichloromethane is treated at 0 ° C with 15 cm3 of a 33% solution (weight / volume) of dimethylamine in ethanol, diluted with 20 cm3 of dichloromethane. When the addition is complete, the mixture is allowed to return to room temperature and then is kept at room temperature overnight. The mixture is then concentrated to dryness under reduced pressure, dissolved in dichloromethane, washed with water and the organic solution is dried over magnesium sulfate and evaporated under reduced pressure.

The residue obtained is recrystallized from hexane. 0.7 g of tert-butyl-5 (N, N-dimethylcarbamoyl) -3 pyrazolo [1,5-a] pyridine is thus obtained, melting at 126 ° -129 ° C.

EXAMPLE 12

Compound AX

15 pounds A stirred solution of 2.2 g of 6,7-dimethyl pyrazolo [1,5-a] pyridinecarboxylic-3-chloride (prepared as described in Reference Example 7) in 35 cm3 of anhydrous dichloromethane is treated at 0 ° C with 26 cm3 of a 33% solution (weight / volume) of dimathylamine in ethanol diluted with 35 cm3 of dichloromethane. When the addition is complete, the mixture is allowed to return to room temperature and is then kept at room temperature overnight. The mixture is then washed with water and the organic solution is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is recrystallized twice from cyclohexane. 0.6 g of dimethyl-6.7 (N, N-dimethylcarbamoyl) -3 pyrazolo [1,5-a] pyridine, melting at 153-156 ° C., is thus obtained.

REFERENCE EXAMPLE 1

A solution of 1.82 g of 4-cyano-pyridine in 20 cm 3 of dichloromethane is treated in 15 minutes at 0 ° C. with a solution of 3.7 g of mesitylenesulfonylhydroxylamine in 40 cm 3 of dichloromethane. The reaction mixture is stirred at room temperature for 30 minutes and then is diluted with 30 cm3 of diethyl ether.

ή * 17

The white solid which forms is separated by filtration and washed thoroughly with diethyl ether. 3.6 g of amino-1-cyano-4-cyano-pyridinium mesitylenesulfonate are thus obtained, melting at 136-138 ° C.

05 REFERENCE 2 EXAMPLE

A suspension of 1.50 g of 5-methoxy-pyrazolo [1,5-a] pyridinecarboxylic-3 acid (prepared as described in Example 5) in 29 cm3 of boiling anhydrous methanol is treated with a solution of 0.49 g of potassium hydroxide in 6 cm3 of anhydrous methanol. The orange solution obtained is evaporated to dryness under reduced pressure and the solid residue is suspended in 39 cm3 of anhydrous toluene. The suspension is stirred and treated with 1.33 cm 3 of oxalyl chloride at room temperature. After 30 minutes, the mixture is treated with 6 drops of anhydrous pyridine and stirred overnight. The mixture is then filtered and the filtrate is evaporated to dryness under reduced pressure. 0.92 g of chloride of 5-methoxy-pyrazolo [1,5-a] pyridinecarboxylic-3-acid is thus obtained, which is used directly in the subsequent synthesis without further purification.

REFERENCE EXAMPLE 3 A suspension of 1.6 g of 5-tert-butyl pyrazolo [1,5-a] pyridinecarboxylic-3 acid (prepared as described in Example 7) in 40 cm3 of boiling anhydrous methanol is treated with a solution of 0.47 g of potassium hydroxide in 8 cm3 of anhydrous methanol. The clear solution obtained is evaporated to dryness under reduced pressure and the residual solid is suspended in 25 cm3 of toluene. The suspension is stirred and treated with 2 cm3 of oxalyl chloride at room temperature. After 15 minutes, 5 drops of anhydrous pyridine are added to the reaction mixture and the mixture is left to stir for 2 hours. The mixture is filtered and the filtrate is evaporated under reduced pressure. The chloride of tert-butyl-5 ^ pyrazolo [1,5-a] pyridinecarboxylic-3-acid is thus obtained in the form of an oil which crystallizes rapidly.

iJ

18 REFERENCE EXAMPLE 4: A suspension of 2 g of 6,7-dimethyl pyrazolo [1,5-a] pyridinecarboxylic-3 acid (prepared as described in Example 8) in 40 cm3 of boiling anhydrous methanol is treated with a solution of 0.65 g of potassium hydroxide in 8 cm3 of anhydrous methanol. The solution obtained is evaporated to dryness under reduced pressure and the solid residue is suspended in 53 cm3 of anhydrous toluene.

The suspension is stirred and treated with 1.79 cm 3 of oxa-lyl chloride at room temperature, then after 30 minutes, the mixture is treated with 8 drops of pyridine and stirred overnight. The mixture is then filtered and the filtrate is evaporated to dryness under reduced pressure.

2.2 g of 6.7-dimethyl pyrazolo [1,5-a] pyridinecarboxylic-3-chloride are thus obtained in the form of a yellow crystalline solid, which is used directly in the subsequent synthesis without 15 further purification.

The present invention encompasses in its field pharmaceutical compositions which contain at least one of the compounds of general formula (I) or one of its pharmaceutically acceptable salts), in association with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of the present invention can be administered by oral, rectal or parenteral route, for example by intravenous route, or more particularly by topical or intraarticular route.

The aqueous solutions and the compositions which contain them are particularly suitable as a means of administration to some of the compounds of general formula (I).

Solid compositions for oral administration include tablets, pills, powders and granules.

In such compositions, the active compound (s) are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid or lactose.

These compositions may also contain, as is common practice, additional substances other than inert diluents, for example lubricants such as magnesium stearate.

r f I.

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Liquid compositions for oral administration 'm Ί include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs t t containing inert diluents commonly used in the art, such as water and paraffin oil. In addition to inert diluents, these compositions may contain adjuvants, such as wetting agents, suspending agents, sweetening, flavoring agents, perfumes and preservatives. The compositions according to the invention for oral administration also include the capsules of ingestible material, such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.

Solid compositions for rectal administration include suppositories formulated in a manner known per se and containing the active product (s).

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The preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of solvents or non-aqueous suspension media include propylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants. These compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents, by irradiation or by heating. They can also be produced in the form of sterile solid compositions which can be dissolved extemporaneously in a sterile injectable medium. These compositions can be administered both intraarticularly and by the usual intravenous and intramuscular routes.

Also included in the present invention are the compositions in the form of solutions or suspensions, possibly containing additives as indicated above, in vegetable or other fats, paraffin or other waxes, lacquers. 20 or creams intended to be applied locally, for example on the? X area of skin surrounding a joint to remove arthritis.

The percentage of active ingredient in the compositions 05 according to the invention can vary, but it is necessary that it constitutes a proportion such that a suitable dosage is obtained in order to obtain the desired effect. Of course, several unit dosage forms can be administered at about the same time. Generally, the compositions must contain between 0.1 and 80% by weight of active ingredient, especially when it comes to tablets.

The dose to be used depends on the desired effect, the route of administration and the duration of treatment. In adults, the doses are generally between 0.01 and 100 mg (preferably between 0.1 and 10 mg and more especially between 1 and 10 mg) of compound of general formula (I) per kilo of body weight and by .î * ^ day.

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

The compounds of general formula (I) can be administered daily or less often, for example weekly, according to the wishes of the attending physician.

The following composition examples illustrate the pharmaceutical compositions according to the present invention.

COMPOSITION EXAMPLE 1

Capsules for oral administration are prepared in the usual manner by filling gelatin capsules No. 2 v 30 each containing 155 mg of the following composition: ç - (N, N-dimethylcarbamoyl) -3 phenyl-5 pyrazolo [1,5 -a] pyridine ........................................... 50 mg ( kl 21 - potato starch ........................... 100 mg § - magnesium stearate ........ ...................... 2.5 mg "- aerosil ..................... ....................... 2.5 mg of the analogous compositions can be prepared using 05 other compounds of general formula (I) EXAMPLE of COMPOSITION 2

An aqueous solution is prepared in the usual manner from: - (N, N-dimethylcarbamoyl) -3-5-methoxy-methyl-7 10 pyrazolo [1,5-a] pyridine ........... ............... 2 g - distilled water .............................. ........ qsp100 cm3

Analogous compositions can be prepared using other compounds of general formula (I).

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Claims (14)

22 1. New derivative of pyrazolo [1,5-a] pyridine, / "characterized in that it corresponds to the general formula: M (RJ --- (I) x 5— * 05 in which represents a carboxy radical , alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, R £ represents a halogen atom, or an alkyl, cyano, alkyloxycarbonyl, carboxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, nitro, hydroxy, alkyloxy, aryloxy, aralkyl, trifluoromethyl, alcoythio 10 alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl, arylsulphonyl, alkanoyl, aroyl or aryl, or an amino radical which may be substituted by one or two radicals chosen from the radicals alkyl and aryl and n represents the number 0, 1, 2 , 3 or 4, and where appropriate their pharmaceutically acceptable salts, provided that: i) R ^ is an alkylcarbamoyl radical when n is equal to zero, ii) R ^ is different from a dialcoylcarbamoyl radical when n is equal to 1 and R ^ is a methyl radical, Iii) Rj is different from a carboxy or ethoxycarbonyl radical when n is equal to 1 and R ^ represents a methyl radical in position 7, and 2. A derivative according to claim 1, characterized in that it is 3-ethoxycarbonyl-5-phenyl pyrazolo [1,5-a] pyri-dine. 3. A derivative according to claim 1, characterized in that it is 5-phenyl acid pyrazolo [1,5-a] pyridinecarboxy- x. lique-3. 4. Derivative according to claim 1, characterized in that it is (N, N-dimethylcarbamoyl) -3-phenyl-5 pyrazolo [1,5-a] pyridine. / kA ψ 23 5. Derivative according to claim 1, characterized in that it is dimethyl-5,7 (N, N-dimethylcarbamoyl) -3 pyrazolo [1,5-a] pyridine. 6. A derivative according to claim 1, characterized in that it is (N, N-dimethylcarbamoyl) -3 5-methyloxy-7-methyl-pyrazolo [1,5-a] pyridine. 7. A derivative according to claim 1, characterized in that it is (N, N-dimethylcarbamoyl) -3-5-methoxy pyrazolo [1,5-a] pyridine. 8 - A derivative according to claim 1, characterized in that it is tert-butyl-5 (N, N-dimethylcarbamoyl) -3 pyrazolo [1,5-a] pyridine. 9. A derivative according to claim 1, characterized in that it is dimethyl-6,7 (N, N-dimethylcarbamoyl) -3 pyrazolo 15 [1., 5-a]. 10. Process for the preparation of a derivative according to claim 1, in the formula of which represents an alkyloxycarbonyl radical, the alkyl part of which contains 1 to 6 carbon atoms in a straight or branched chain, characterized in that reacting is carried out. a solution of a compound of general formula: <Vir- {0U2 v (n) in which R ^ and n are defined as in claim 1 and * represents an anion, in an organic solvent with a base, followed by the reaction of a compound of general formula: H - C = C - C00R3 - (III) in which R ^ represents an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain, then isolates the "product obtained. 11. Process for the preparation of a derivative according to claim 1 in the formula of which R 1 represents a carboxy radical, characterized in that a derivative according to claim 1 is hydrolyzed in the formula 1 from which R ^ represents an alkyloxycarbonyl radical, the alkyl part of which contains 1 to 6 carbon atoms in straight or branched chain, then isolates the product obtained. 12. Process for the preparation of a derivative according to claim 1, in the formula of which represents a carbamoyl, alkylcarbamoyl or dialkoylcarbamoyl radical in which the alkyl portions contain 1 to 6 carbon atoms in straight or branched chain, characterized in that: A ) An acid halide or an acid anhydride of formula (IV) or (V) is reacted "C0X2 CO-- AA AÂ 0 (Vn I (Vn-- I; V ~ N V- · 2 v - - * (IV) (V) in which R2 and n are defined as in claim 1 and X2 represents a halogen atom, with a compound of general formula: R / / 4 15 HN ^ (VI) R5 in which R ^ and Rj. represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain and isolate the product obtained, or else B) A derivative according to claim 1 is reacted in the formula of which R ^ represents an alkyloxycarbonyl radical, the alkyl part of which contains 1 to 6 carbon atoms in a straight or branched chain with a compound of general formula (VI), in which R 1 and R 3 ,. are defined as above, optionally in a solvent. 25 13 - Process for the preparation of a derivative according to claim 1 in the formula of which R ^ represents at least one radical f / U V., »# Ί» i t r f% l I »9l '\ a *