MXPA99009422A - Indazole amide compounds as serotoninergic agents - Google Patents

Abstract

A compound having general formula (I) wherein R1, R2, R3, R'3, R4, R5 and R6 have the meanings stated in the description, acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and pharmaceutically acceptable quaternary salts thereof.

Description

COMPOUNDS OF INDAZOL AMIDA AS SEROTONINÉRGIC AGENTS DESCRIPTION OF THE INVENTION The present invention relates to an indazole amide compound having a serotonergic action, a method for preparing the same and the pharmaceutical compositions containing the same. Among the many known families of serotonin receptors, 5HT receptors only in recent form have been identified in the urinary bladder, smooth muscle and cardiac and specific areas of the central nervous system. Compounds possessing agonistic, partially agonistic and agonistic actions against such receptors are of potential interest in the pharmacological treatment of gastrointestinal motility disorders, central nervous system disorders, urinary incontinence and cardiac arrhythmia. The action of these compounds is actually presented simulating or antagonizing the ability of serotonin to stimulate intestinal mobility through the action of enteric neurons, to modulate important brain processes such as training, memory and anxiety, to induce relaxation of the urinary bladder and increase the frequency of atrial contraction. At present, a family of indazole amide compounds has been found, which have affinity with 5HT4 receptors and which act as serotonin antagonists. Therefore, it is an object of the present invention to provide an indazole amide compound having the general formula: (I) wherein: R6 is selected from a group comprising cycloalkyl of 3 to 7 carbon atoms, a heterocyclic ring having from 5 to 6 members wherein from 1 to 4 members are heterogeneous atoms, equal or different from each other, selected from the group consists of N, O and S, dimethylaminoalkyl having 1 to 3 carbon atoms, methoxyalkyl of 1 to 3 carbon atoms, N-phenylamide, aminosulfonylmethyl, dihydroxyalkyl of 2 to 3 carbon atoms, aryl substituted by hydroxy; its acid addition salts with pharmaceutically acceptable organic and inorganic acids and their pharmaceutically acceptable quaternary salts. Preferred examples of aryl are phenyl, naphthyl and biphenyl. Preferred heterocyclic ring examples are thienyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazoyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, triazinyl, thiazolyl, tetrazolyl and thiadiazolyl. Typical examples of R6 are cyclopropyl, cyclohexyl, pyridinyl, tetrazolyl, morpholinyl, methoxymethyl, methoxypropyl, hydroxyphenyl, dimethylaminomethyl and aminosulfonylmethyl. It is a second object of the present invention to provide a process for preparing a compound of formula I, its acid addition salts with pharmaceutically acceptable organic and inorganic acids and their pharmaceutically acceptable quaternary salts, comprising: a) acylating a 4-aminomethylpiperidine of the formula: (ll) wherein: -P is a suitable protective group; through a halide of 1-alkyl-indazole-3-carboxylic acid of the formula: (III) wherein: X is halogen, to give a compound of the formula: (IV) b) deprotecting a compound of the formula (IV) to give a compound of the formula: (V) c) alkylating a compound of the formula (V) with a compound of the formula (VI) to give a compound of the formula (I) according to the following reaction scheme: (V) (VI) wherein: R6 has the meanings mentioned above, and Y is halogen, d) optionally forming an acid addition salt of an indazole amide compound of the formula (I) with a pharmaceutically acceptable organic or inorganic acid, or a quaternary salt pharmaceutically acceptable salt of an indazole amide compound of the formula (I). Typical examples of protecting groups (P) are benzyloxycarbonyl, benzyl, terbutoxycarbonyl and trimethylsilylethoxycarbonyl. Step a) is preferably carried out by reacting a compound of the formula (II) with a compound of the formula (III), wherein X is chlorine, in the presence of a suitable diluent and at a temperature of 0 to 140 ° C during a period from 0.5 to 20 hours. Preferably, the diluent is aprotic, polar or apolar. Even more preferably, it is aprotic apolar. Examples of suitable apolar aprotic diluents are aromatic hydrocarbons such as, for example, benzene, toluene and xylene. Examples of suitable polar aprotic diluents are dimethylformamide and dimethyl sulfoxide. Still most preferably, the reaction is carried out at a temperature of 15 to 40 ° C for a period of 1 to 14 hours. In turn, step b) is carried out according to techniques known to experts in the field of the protecting group (Theodora W. Greene and Peter GM Wuts, "Protective groups in organic synthesis", pp. 309-406, John Wiley & Sons, Inc., N. Y., 1991). In the case of benzyl and benzyloxycarbonyl, the deprotection of the protecting group is preferably carried out by catalytic hydrogenation. An example of a suitable catalyst is palladium on activated carbon. Preferably, the deprotection is carried out through hydrogenation in the presence of a suitable diluent such as, for example, a lower aliphatic alcohol, a lower aliphatic acid and mixtures thereof. An example of a preferred diluent is a mixture of ethyl alcohol / acetic acid. Step c) is preferably carried out with a compound of the formula (VI), wherein Y is chlorine or bromine in the presence of a suitable acid acceptor such as, for example, alkali carbonates and bicarbonates, lower trialkylamines and a suitable diluent such as, for example, aromatic hydrocarbons, dimethylformamide and lower aliphatic alcohols. Typical examples of preferred organic and inorganic acids for forming addition salts of the present invention (step d) are oxalic, maleic, tartaric, methanesulfonic, sulfuric, phosphoric, acidic bromide, and acid chloride. Methyl iodide is a typical example of a preferred compound for forming a quaternary pharmaceutically acceptable salt of the invention. The preparation of the aforementioned salts comprises the addition (step d) of a pharmaceutically acceptable organic or inorganic acid, or of methyl iodide to an indazole amide compound of the formula (I) contained in step c). The intermediaries of formulas (IV) and (V) are new. Therefore, they are a further object of the present invention. Alternatively, the indazole amide compound of the formula (I) can be prepared through the acylation of a suitable 4-aminomethylpiperidine with a compound of the formula (III).

Typical examples of pathological conditions that can benefit from treatment with a pharmaceutical composition according to this invention are all pathologies that respond to treatment with 5-HT4 receptor antagonists such as, for example, gastrointestinal disorders associated with high intestinal mobility, such such as IBS (irritable bowel syndrome), urinary incontinence and cardiac arrhythmias such as atrial fibrillation.

Preferably, the pharmaceutical compositions of the present invention will be prepared in suitable dosage forms comprising an effective dose of at least one compound of the formula (I) or a pharmaceutically acceptable acid salt thereof or a quaternary salt thereof and at least one pharmaceutically acceptable inert ingredient. Examples of suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; medicated creams, ointments and adhesive strips for topical administration; suppositories for rectal administration and sterile solutions for injectable, aerosol or ophthalmic administration. The dosage forms may also contain other conventional ingredients such as stabilizing agents, preservatives, surfactants, pH regulators, salts to adjust the osmotic pressure, emulsifiers, sweeteners, coloring agents, flavoring agents, and the like. When required by particular therapies, the pharmaceutical composition of the present invention may contain other pharmacologically active ingredients whose concomitant administration is therapeutically useful. The amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof can vary within a wide range, depending on known factors such as, for example, the type of disease to be treated, the severity of the disease, the body weight of the patient, the dosage form, the route of administration selected, the number of dosage forms administered per day and the effectiveness of the compound selected from formula (I). However, the optimum amount can easily and routinely be determined by one skilled in the art.

Typically, the amount of a compound of the formula (I) or a salt thereof in the pharmaceutical composition of this invention will be such as to ensure a administered dose level of 0001 to 50 mg / kg / day. The dosage forms of the composition Pharmaceutical according to this invention can be prepared according to methods that are known in the pharmaceutical chemistry and comprise mixing, granulation, compression, dilution, sterilization, and the like The following examples are intended to illustrate the present invention without limiting it in any way EXAMPLE 1 Preparation of 1-isopropyl-1 H-3-indazolcarbonyl chloride (III: X = C) a) 2-Methopropyl-1-α-soproptl-1 -1H-3-ndazole Carboxylate To a solution of 2-methypropyl-1H-3-nitrazol carboxylate (50g, 0 24 mole) in 300 ml of 1,2-d? Methoxy? -ethane was added a solution of isopropyl bromide (27.5 ml, 0.29 mole) in 100 ml of 1,2-d? Methoxy ethane and KOH (13.5 g, 024 mol) and the mixture was heated under reflux for 8 hours. After the solvent was removed, the residue was dissolved in 300 ml of toluene, and the solution thus obtained was washed with 100 ml of 1N NaOH, 2 x 100 ml of H2O and then dried and concentrated in vacuo. The residue was purified from the carboxylate isomer 2-methylpropyl-2-isopropyl-2H-3-indazole by flash chromatography (eluent, hexane: acetate ethyl = 95: 5) to give the title compound (23 g) as an oil. 1 H NMR (CDCl 3 d): 1.07 (d, J = 7 Hz, 6 H); 1.66 (d, J = 7Hz, 6H); 1.95-2.48 (m, 1H); 4.26 (d, J = 7Hz, 2H); 4.96 (heptet J = 7Hz, 1H); 7.15-7.70 (m, 3H); 8.03-8.33 (m, 1H). b) 1-isopropyl-1H-3-indazolecarboxylic acid A suspension of the compound of Example 1 a) (10 g, 0.4 moles) in 100 ml of 0.75 N NaOH was heated under reflux for 12 hours. The solution was then cooled, acidified with 40 ml of 6N HCl, the solid precipitate was filtered and recrystallized from 1: 1 hexane / ethyl acetate to give the title compound (5.5 g), p. F. 162-3 ° C (Harada H, and others, "Chem. Pharm. Bull", 43 (11), 1912-1930, 1995). H NMR (DMSO, d): 1.54 (d, J = 7Hz, 6H); 5.13 (heptet, J = 7Hz, 1H); 7.20-7.65 (m, 2H); 7.85 (d, J = 8Hz, 1H); 8.14 (d, J = 7Hz, 1H); 13.08 (broad s, 1H). c) 1-isopropyl-1 H-3-indazolecarbonyl chloride Thionyl chloride (4 ml, 0.054 mole) was added to a stirred solution of the compound of Example 1b) and the mixture was stirred under reflux for 2 hours. After removal of the solvent in vacuo, the residue was recrystallized from hexane to give 3.5 g of the title compound, mp 63-4 ° C Elemental Analysis for CHN CnHnCINaO% found 59 29 5 20 12 76% calculated 59 33 4 98 12 58 1 H NMR (CDCl 3, d), 1 69 (d, J = 7 Hz, 6 H), 500 (heptet, J = 7 Hz, 1 H), 7 20-7 70 (m, 3H), 8 03-8.33 (m, 1H) EXAMPLE 2 Preparation of N3-f M - (2-phenylethyl) -4- p -peridinylmethyl hydrochloride} -1-Isopropyl-1 H-3-indazolecarboxamide (AFR 306) [1 - (2-phenol? L) -1-p? Per? D? N? L] met? Lam? Na (3 g, 0 014 mol), prepared as described in EP-A-0 343307 , in 30 ml of toluene was dripped in a suspension of the compound of the compound of Example 1c) (3 g, 0 014 mol) in 30 ml of toluene After 3 hours at room temperature, the solid was filtered, dissolved in H2O , it was made basic with a 6N NaOH solution and extracted with 2 x 200 ml of CH2CI2. The solvent was removed by evaporation, the residue was purified on a column of S? O2 (eluent, CHCl3 MeOH = 95 5) and it was transformed to the corresponding hydrochloride The product obtained (2 g) was melted at 211-212 ° C Elemental Analysis for CHN Cl C25H33CIN40% found: 68.13 7.52 12.78 8.03 Calculated%: 68.09 7.54 12.70 8.04 1 H NMR (DMSO, d); 1.56 (d, J = 7Hz, 6H); 5.50-2.30 (m, 5H); 2.70- 3.90 (m, 10H); 5.10 (heptet, J = 7Hz, 1H); 7.05-7.63 (m, 7H); 7.81 (d, J = 8Hz, 1H); 8.21 (d, J = 8Hz, 1H); 8.47 (t, J = 6Hz, 1H); 11.05 (broad s, 1H). IR (KBr): vco 1652 cm "1.

EXAMPLE 3 Preparation of N3f M - (phenylmethyl) -4-piperidinylmethyl) -1 -isopropyl I-1H-3-indazolecarboxamide (IV: P = -CH, C ^ HS) To a stirred solution of 1-isopropyl-1H-3-indazolcarbonyl chloride (52 g, 0.234 mol) in 300 ml of toluene was added dropwise a solution of [1- (phenylmethyl) -4-piperidinyl-methylamine, prepared as described in WO 94/10174, (47.7 g, 0.234 moles), in 200 ml of toluene. After 5 hours, the solvent was removed by evaporation under reduced pressure. The reaction mixture was treated with 2N NaOH, extracted with dichloromethane and concentrated in vacuo. The solid residue (95 g) was recrystallized? from 7: 3 hexane / ethyl acetate to provide the title compound as a white solid (45 g), m.p. 72-74 ° C.

Elemental Analysis for C H N C24H3oCIN4O% found: 73.78 7.87 14.35% calculated: 73.81 7.74 14.35 1H NMR (CDCl3, d); 1.59 (d, J = 7Hz, 6H); 1.10-2.25 (m, 7H); 2.80-3.15 (m, 2H); 3.27-3.60 (m, 4H); 4.86 (heptet, J = 7Hz, 1H); 7.00-7.60 (m, 9H); 8.27-8.52 (m, 1H). IR (KBr); vco 1641 cm "1.

EXAMPLE 4 Preparation of N3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide hydrochloride A suspension of the product of Example 3 (28 g, 0.076 mol) in 1500 ml of ethyl alcohol and 66 ml of glacial acetic acid was hydrogenated over 10% Pd-C (13.4 g) at 2.4605 kg / cm2. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water, treated with 5N NaOH and stirred for 2 hours at room temperature. The solid obtained was filtered (16.6 g) and converted to the corresponding hydrochloride (9.5 g), p. F. 211-214 ° C (decomposition). Elemental Analysis for H N C17H25CIN40. 1 / 2H2O% found: 58.82 7.68 16.36% calculated: 59.03 7.58 16.20 1 H NMR (DMSO, d); 1.55 (d, J = 7Hz, 6H); 1.31-2.18 (m, 5H); 2.58- 3.64 (m, 7H); 5.09 (heptet, J = 7Hz, 1H); 7.12-7.60 (m, 2H); 7.80 (d, J = 8Hz, 1H); 8.20 (d, J = 8Hz, 1H); 8.41 (t, J = 6Hz, 1H); 8.82-9.60 (m, 2H). IR (KBr); vco 1658 cm "1.

EXAMPLE 5 Preparation of N 3 - (f 1 - (4-phenylbutyl) -4-piperidininmethyl} -1-isopropyl-1 H -3-indazolecarboxamide oxalate (AFR603) (I: Rs = -Cp 2 Cp 2 fiHs) To a stirred suspension of the product of Example 4 as the free base (5.27 g, 15.6 mmol) in 20 ml of ethyl alcohol, K2CO3 (6.5 g: 50 mmol) and 4-phenylbromobutane ("Braun") were added., B-44. 2872, 1911) (3.6 g, 17.1 mmol). The reaction mixture was stirred at reflux for 10 hours. After removal of the solvent, the residue was partitioned between ethyl acetate and 1N HCl. The water phase was made basic with 2N NaOH, extracted with ethyl acetate and concentrated in vacuo. The solid was converted to the corresponding oxalate salt (2 g), p. F. 154-155 ° C. Elemental Analysis for C H N% found: 65.87 7.47 10.62% calculated: 65.52 7.39 10.54 1H NMR (DMSO, d); 1.55 (d.J = 7Hz, 6H); 1.31-2.18 (m, 5H); 2.30- 3.64 (m, 14H); 5.08 (heptet, J = 7Hz, 1H); 7.12-7.60 (m, 7H); 7.80 (d, J = 8Hz, 1H); 8.19 (d, J = 8Hz, 1H); 8.41 (t, J = 6Hz, 1H).

EXAMPLE 6 Preparation of N3- (M-2-cyclohexylethyl) -4-piperidinemethyl) -1-isopropyl-1H-3-indazolecarboxamide hydrochloride (AFR604) Following the procedure of Example 5, N3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (4.42 g) and (2-bromoethyl) -cyclohexane ("JACS", 48, 1089-1093, 1926) (4.63 g), gave the title compound (2.5 g), p. F. 244-246 ° C (decomposition). Elemental Analysis for C H N CI "C25H39N4O. 1/2 H2O% found: 65.51 9.05 12.57 7.89 Calculated%: 68.09 7.54 12.70 7.77 1 H NMR (DMSO, d); 1.55 (d, J = 7Hz, 6H); 0.68-2.18 (m, 17H); 2.63-3.70 (m, 10H); 5.09 (heptet, J = 7Hz, 1H); 7.12-7.60 (m, 2H); 7.80 (d, J = 8Hz, 1H); 8.20 (d, J = 8Hz, 1H); 8.41 (t, J = 6Hz, 1H); 10.70 (s broad 1H). IR (KBr): vco 1656 cm "1.

EXAMPLE 7 Preparation of N3 - ((1-F3- (dimethylamino) propyl-4-piperidinyl) methyl) -1-isopropyl-1H-3-indazolecarboxamide dimaleate (AFR606) fl: RR = -CH, NC, Hfi ) Following the procedure of Example 5, N3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (3 g) and N- (3-chloropropyl) -N, N-dimethylamine hydrochloride (580 mg) gave the title compound (950 mg), p. F. 155-156 ° C. Elemental Analysis for C H N C3oH43N509. 1/2 H2O% found: 57.83 7.01 11.11% calculated: 57.50 7.08 11.18 1H NMR (DMSO, d); 1.55 (d, J = 7Hz, 6H); 1.68-2.28 (m, 17H); 2.81 (s, 6H); 2.75-3.75 (m, 11H); 5.09 (heptet, J = 7Hz, 1H); 7.12-7.60 (m, 2H); 7.81 (d, J = 8Hz, 1H); 8.20 (d, J = 8Hz, 1H); 8.45 (t, J = 6Hz, 1H).

EXAMPLE 8 Preparation of N3- (f 1 -f2- (4-morpholinyl) ethyl-4-piperidinyl-1-methyl) -1-isopropyl-1H-3-indazolecarboxamide dihydrochloride (AFR607) (I: Rfi = CH NO) Following the procedure of Example 5, N3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (3 g) and 4- (2-chloroethyl) -morpholine (3.42 g) gave the title compound (3.4 g), p.

F. 266-267 ° C (decomposition). Elemental Analysis for C H N CI "C23H37CI2N5O2. 1/2 H2O% found: 55.74 7.61 13.96 14.12% calculated: 55.75 7.73 14.13 14.31 1 H NMR (DMSO, d); 1.55 (d, J = 7Hz, 6H); 1.30-2.25 (m, 5H); 2.75-4.30 (m, 19H); 5.09 (heptet, J = 7Hz, 1H); 7.12-7.60 (m, 2H); 7.81 (d, J = 8Hz, 1H); 8.20 (d, J = 8Hz, 1H); 8.45 (t, J = 6Hz, 1H); 10.80 (s broad 1H); 10.60 (s broad, 1H). IR (KBr): vco 1652 cm \ EXAMPLE 9 Preparation of N 3 -f (1-f 2-rmethylsulphonyl) -ann-inletyl-4-piperidinyl) methyH-1-isopropyl-1H-3-indazolecarboxamine hydrochloride (AFR703) (I: Rfi = CHTSCNH-) Following the procedure of Example 5, N3- (4-piperidinylmethyl) -1-isopropyl-1H-3-indazolecarboxamide (5g) N- (2-bromoethyl) -methanesulfonamide (WO 93/18036) (3g) gave the compound of the title (1.5 g), pf 186-187 ° C (decomposition) Elemental Analysis for CHNS CI "C20H32CIN4O3S.% Found: 52.15 7.22 15.30 6.98 7.77% calculated: 52.45 7.04 15.29 7.00 7.74 1H NMR (DMSO, d), 1.55 (d, J = 7Hz, 6H) 1.40-2.30 (m, 5H), 3.00 (s, 3H), 2.75-3.80 (m, 10H), 5.09 (heptet, J = 7Hz, 1H), 7.12-7.70 (m, 3H), 7.80 (d, J = 8Hz, 1H), 8.20 (d, J = 8Hz, 1H), 8.45 (t, J = 6Hz, 1H), 10.73 (s broad 1H), IR (KBr): vco 1651 cm "1.

EXAMPLE 10 Preparation of N3- (. {1-r2-pyridinyl) etM14-piperidinHmethyl) -1-isopropyl-1H-3-indazolecarboxamide hydrochloride (AFR605) (I: Rfi = CSHN) To a stirred suspension of the product of Example 4, as free base (10 g, 33.3 mmol), 2-vinylpyridine (3.6 g, 34 mmol), 2 ml of glacial acetic acid and 2.5 ml of water were added. After 16 hours at 95 ° C, the reaction mixture was made basic with 2N NaOH, extracted with ethyl acetate and concentrated in vacuo. The residue was purified through flash silica gel chromatography with CHCl3: MeOH = 97: 3 as eluent to produce a solid which was converted to the hydrochloride salt (5 g), p. F. 122-123 ° C (decomposition). Elementary Analysis for C H N CI " C25H39N40. 1/2 H2O% found: 62.80 7.42 15.18 7.78 Calculated%: 62.66 7.45 15.22 7.71 1 H NMR (DMSO, d); 1.55 (d, J = 7Hz, 6H); 1.68-2.30 (m, 5H); 2.80-3.78 (m, 12H); 5.10 (heptet, J = 7Hz, 1H); 7.12-7.60 (m, 4H); 7.68-8.00 (m, 2H), 8.21 (d, J = 7Hz, 1H); 8.33-8.70 (m, 2H); 11.05 (s broad 1 HOUR). IR (KBr): vco 1644 cm "1.

TEST 1 Antagonistic Action of the 5-HT4 Receptor The antagonistic action of the compounds of the formula (I) was evaluated by testing the influence of the compound under evaluation on the serotonin-induced relaxation of the rat oesophageal tunica pre-contracted with carbachol according to the method described by J.

D. Gale et al., In "BR J. Pharmacol.", 1 J_ 332-338, (1994). All tested compounds of the invention showed pA2 > 8. The specific values for AFR 603- AFR 604, AFR 605, AFR 606 and AFR 306 are shown in Table 1 below.

TABLE 1 Compound pA2 s.e. AFR 603 9.12 1.42 AFR 604 8.19 0.99 AFR 605 10.8 1.90 AFR 306 9.36 0.38 s. e = error is nd ar.

Claims (6)

1. - A compound that has the general formula: ( wherein: R6 is selected from a group comprising cycloalkyl of 3 to 7 carbon atoms, a heterocyclic ring having from 5 to 6 members wherein from 1 to 4 members are heterogeneous atoms, equal or different from each other, selected from the group consists of N, O and S, dimethylaminoalkyl having 1 to 3 carbon atoms, methoxyalkyl of 1 to 3 carbon atoms, N-phenylamide, aminosulfonylmethyl, dihydroxyalkyl of 2 to 3 carbon atoms, aryl substituted by hydroxy; its acid addition salts with pharmaceutically acceptable organic and inorganic acids and their pharmaceutically acceptable quaternary salts.

2. A compound according to claim 1, characterized in that the heterocyclic rings are thienyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazoyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furazanyl, pyrrolinyl, imidizole, inyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morphinyl, triazinyl, thiazolyl, tetrazolyl and thiadiazolyl.

3. A compound according to claim 1, wherein R6 is selected from the group consisting of cyclopropyl, cyclohexyl, pyridinyl, tetrazolyl, morpholinyl, methoxymethyl, methoxypropyl, hydroxyphenyl, dimethylaminomethyl, and aminosulfonylmethyl.

4. A compound according to claim 1, wherein R6 is cyclohexyl.

5. A compound according to claim 1, wherein R6 is pyridinyl.

6. A compound according to claim 1, wherein R6 is dimethylaminomethyl. 7 - A compound according to claim 1, wherein R6 is morpholinyl. 8. A compound according to claim 1, wherein R6 is aminosulfonylmethyl. 9. A process for preparing a compound of the formula (I), acid addition salts thereof with pharmaceutically acceptable organic and inorganic acids and their pharmaceutically acceptable quaternary salts, comprising: a) acylating a 4-aminomethylpiperidine of the formula : (II) wherein: -P is a suitable protecting group; through a halide of 1-alkyl-indazole-3-carboxylic acid of the formula: (lll) wherein: X is halogen, to give a compound of the formula: (IV) b) deprotecting a compound of the formula (IV) to give a compound of the formula: (V) c) alkylating a compound of the formula (V) with a compound of the formula (VI) to give a compound of the formula (I) according to the following reaction scheme (V) (VI) wherein R6 has the above-mentioned meanings, and Y is halogen, d) optionally forming an acid addition salt of an indazole amide compound of the formula (I) with a pharmaceutically acceptable organic or inorganic acid or a pharmaceutically acceptable quaternary salt of an indazole amide compound of the formula (I) - A process according to claim 9, wherein P is selected from the group comprising benzyloxycarbonyl, benzyl, terbutoxycarbonyl, tpmethylsilylethoxycarbonyl 11 - A process of agreement with claims 9 or 10, wherein step a) is carried out by reacting a compound of the formula (II) with a compound of the formula (III), wherein X is chlorine, in the presence of a diluent at a temperature of 0 to 140 ° C for a period of 0.5 to 20 hours. 12. A process according to claim 10, wherein P is benzyl or benzyloxycarbonyl, step b) is carried out through catalytic hydrogenation. 13. A process according to any of the preceding claims, from 9 to 11, wherein when, in a compound of the formula (VI), Y is chlorine or bromine, step c) is carried out in the presence of an acid acceptor and in the presence of a diluent. 14. A process according to claim 9, wherein the methyl iodide forms a pharmaceutically acceptable quaternary salt of a compound of the formula (I), step d). 15. An intermediate compound having the general formula: (IV) wherein: P is selected from the group comprising benzyloxycarbonyl, terbutoxycarbonyl and trimethylsilylethoxycarbonyl. 16. A pharmaceutical composition, wherein said composition comprises an effective dose of at least one compound of the formula: (0 wherein: R6 is selected from a group comprising cycloalkyl of 3 to 7 carbon atoms, a heterocyclic ring having from 5 to 6 members wherein from 1 to 4 members are heterogeneous atoms, equal or different from each other, selected from the group consists of N, O and S, dimethylaminoalkyl having 1 to 3 carbon atoms, methoxyalkyl of 1 to 3 carbon atoms, N-phenylamide, aminosulfonylmethyl, dihydroxyalkyl of 2 to 3 carbon atoms, aryl substituted by hydroxy; its acid addition salts with pharmaceutically acceptable organic and inorganic acids and their pharmaceutically acceptable quaternary salts.