MXPA98010765A - Derivatives of acid piperidin acetico and its use in the treatment of tromboti disorders - Google Patents

Abstract

The present invention relates to the compounds of the formula (I) (See Formula) or to a physiologically functional salt, solvate, or derivative thereof, in which: it represents either CH2-CH2 or CH = CH, and represents a group (See Formula) R0 represents SO2Me or CONH2, and R1 represents SO2Me, to processes for their preparation, to pharmaceutical compositions containing such compounds and to their use in medicine, particularly in the treatment of thrombotic disorders

Description

] DERIVATIVES OF ACETIC PIPERID ACID AND ITS USE IN THE TREATMENT OF THROMBÓTIC DISORDERS FIELD OF THE INVENTION This invention relates to acetic acid derivatives, to processes for their aration, to pharmaceutical compositions containing such compounds and to their use in medicine.

BACKGROUND OF THE INVENTION It has been accepted extensively that the Gp Iib / IIIa glycoprotein complex is the binding site of fibrinogen on platelets mediating the adhesive function required for platelet aggregation and thrombus formation. We have now found a group of non-peptidic compounds which inhibit platelet aggregation dependent on blocked fibrinogen binding of fibrinogen to the Gp Ilb / IIIa complex of the putative fibrinogen receptor. The copending WO96 / 20196 and WO96 / 41803 applications, which were published after the priority date of the ent invention, describe compounds which act as inhibitors of fibrinogen-dependent platelet aggregation, the processes for their aration and their use in medicine. < -F .: 29125 DESCRIPTION OF THE INVENTION The ent invention therefore provides a compound of. formula (I) or a physiologically functional salt, solvate, or derivative thereof, wherein X reents either CH2-CH2 or CH = CH; And reents a group R ° reents S02Me or CONH2; and R1 reents S02Me. In a further aspect, the ent invention provides a compound of the formula (Ia) OR or a physiologically functional salt, solvate, or derivative thereof, wherein: X reents either CH2-CH2 or CH = CH. In a still further aspect, the ent invention provides a compound of the formula (Ib) or a physiologically functional salt, solvate, or derivative thereof, wherein: X reents either CH2-CH2 or CH = CH. In still yet another aspect, the ent invention provides a compound of the formula (le) or a physiologically functional salt, solvate, or derivative thereof, wherein: X reents either CH2-CH2 or CH = CH. Suitable compounds of the invention include: acid. { 4- [3-methanesulfonyl-5- (2-piperidin-4-yl-X £) -vi-t-M -) - indazol-1-yl] -piperidin-1-yl} -acetic; acid { 4- [3-methanesulfonyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic; and salts, solvates, and physiologically functional derivatives thereof. Additional suitable compounds of the invention include: acid. { 4- [3-carbamoyl-5- (2-piperidin-4-yl- (E) -vinyl) -indazol-1-yl] -piperidin-1-yl} -acétice-acid. { 4- [3-carbamoyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic; and salts, solvates, and physiologically functional derivatives thereof. Still further compounds of the invention include: acid. { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl- (E) -vinyl) -lH-indazol-3-yl] -piperidin-1-yl} -acetic; acid { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl-ethyl) -1 H -indazol-3-yl] -piperidin-1-yl} -acetic; and salts, solvates, and derivatives. of the same physiologically functional. A erred compound of the invention is the acid. { 4- [3-methanesulfonyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic or a physiologically functional salt, solvate or derivative thereof.

A further erred compound of the invention is the acid. { 4- [3-carbamoyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic or a salt, solvate, or physiologically functional derivative thereof. A still further erred compound of the invention is the acid. { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl-ethyl) -lH-indazol-3-yl] -piperidin-1-yl} -acetic or a salt, solvate, or physiologically functional derivative thereof. All references here after the "compounds of the formula (I)" or the "compounds of the ent invention" or the like, refer to the compound (s) of the formula (I) and the formulas (Ia) - (Ic) as described earlier, and their physiologically functional salts, solvates, or derivatives thereof. By the term "physiologically functional derivatives" is meant chemical derivatives of the compounds of the formula (I) which have the same physiological function as the free compounds of the formula (I), for example, which are convertible in the body to the same. According to the present invention, examples of the physiologically functional derivatives include the compounds of the formula (I) in which the carboxyl function has been modified, for example, as a carboxylic acid ester, such as an alkyl ether with C? _6. The salts and solvates of the compounds of the formula (I) which are suitable for use in medicine are those in which the negative ion or counterion or the associated solvent is pharmaceutically acceptable. However, salts and solvates having a counterion or pharmaceutically acceptable non-acceptable ion or an associated solvent are within the scope of the present invention, having use as intermediates in the preparation of the compounds of the formula (I) and their salts, pharmaceutically acceptable solvates, and physiologically acceptable derivatives. Suitable pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed with organic or inorganic acids (for example hydrochlorides, hydrobromides, sulfates, phosphates, benzoates, naphthoates, hydroxynaphthates, p-toluenesulfonates, methanesulfonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, gluconates, acetates, tricarbalylates, citrates, fumarates and maleates) and inorganic basic salts such as alkali metal salts (for example sodium salts). The hydrochloride salts of the compounds of the formula (I) are preferred for certain modes of administration. r salts of the compounds of the formula (I) include salts formed with trifluoroacetic acid. Suitable pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates. The term "alkyl" as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group . It is to be understood that the present invention embraces all isomers of the compounds of the formula (I) and its salts, solvates, and physiologically functional derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). By the term "pharmaceutically acceptable derivative" is meant a salt, solvate, or physiologically functional derivative of a compound of the formula (I) as defined herein above. The compounds of the formula (I) inhibit the aggregation of blood platelets as demonstrated by the studies carried out on washed and resuspended human platelets (HRP) using an optical aggregometer of the Born type (Born, GV, 1962, Nature, 194, 927-929).

In view of their fibrinogen antagonist activity, the compounds of formula (I) and their pharmaceutically acceptable derivatives are of interest for use in human and veterinary medicine, particularly in the treatment of thrombotic disorders. Particular examples of thrombotic disorders are known in the art and include occlusive vascular diseases such as myocardial infarction, cardiac events or fatalities, angina, temporal ischemic attacks and thrombotic attacks or attacks, arteriosclerosis, disease of the vessel walls, peripheral vascular disease, nephropathy, retinopathy, postoperative thrombosis, pulmonary embolism, deep vein thrombosis and retinal vein thrombosis. The compounds of formula (I) and their pharmaceutically acceptable derivatives are also of interest for use in the prophylactic treatment of peri-and post-operative complications following organ transplantation (particularly cardiac and renal), coronary artery bypass, peripheral artery bypass, angioplasty, thrombolysis and endarterectomy. The compounds of the formula (I) and their pharmaceutically acceptable derivatives may also be useful for the treatment of other conditions in which the glycoprotein Gp Ilb / IIIa complex or other integrin receptors are involved. Accordingly, for example, the compounds of the formula (I) and their pharmaceutically acceptable derivatives can enhance wound healing and be useful in the treatment of bone conditions caused or mediated by increased bone resorption. Particular examples of bone diseases are already known in the art and include osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastasis, periodental disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteopenia induced by immobilization and treatment of glucocorticoids. The compounds of formula (I) and their pharmaceutically acceptable derivatives may also be useful in the treatment of certain cancerous diseases, for example, to prevent or retard metastasis in cancer. According to a further aspect of the invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine, particularly for use in the treatment of thrombotic disorders. According to another aspect of the invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated through the glycoprotein GpIIb / IIIa complex or other integrin receptor. According to a further aspect of the invention, there is provided a method of treating a human or animal suffering from a condition which is mediated by the glycoprotein GpIIb / IIIa complex or another integrin receptor, which comprises administering to the subject or patient an effective amount of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof. According to a further aspect of the invention, there is provided the use of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment of thrombotic disorders. According to a further aspect of the invention, a method of treating a human or animal suffering from a thrombotic disorder is provided, such method comprises administering to the subject an effective amount of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof. It is to be understood that the reference to "treatment" includes both the treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise. It will be appreciated that the compounds of formula (I) and their pharmaceutically acceptable derivatives can be advantageously used in conjunction with one or more other therapeutic agents. Examples of suitable agents for adjunctive therapy include thrombolytic agents or any other compound that stimulates thrombolysis or fibrinolysis and cytotoxic drugs. It is to be understood that the present invention covers the use of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents. The compounds of the formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Accordingly, in another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in a conventional manner in mixed form with one or more physiologically acceptable carriers or excipients.

The compounds of the formula (I) and their pharmaceutically acceptable derivatives can be formulated for administration in any suitable manner. The compounds, for example, can be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration. For oral administration, the pharmaceutical composition can take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. For transdermal administration, the pharmaceutical composition can be delivered in the form of a transdermal patch, such as a transdermal iontophoretic patch. In a preferred aspect, the present invention provides an iontophoretic delivery device (e.g., an iontophoretic patch) comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof, suitably a pharmaceutically acceptable salt thereof, for example, a hydrochloride salt. Iontophoretic devices and systems such as those known in the art, for example from, WO-A 9116946, WO-A 9116944, WO-A 9116943, WO-A 9115261, WO-A 9115260, WO-A 9115259, WO- A 9115258, WO-A 9115257, WO-A 9115250, WO-A 9109645, WO-A 9108795, WO-A 9004433, WO-A 9004432, WO-A 9003825, EP-A 254965, US 4717378, EP-A 252732 and GB-A 2239803, which are incorporated herein by reference. For parental administration, the pharmaceutical composition can be delivered as an injection or a continuous infusion (for example, intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. For administration by injection this may take the form of a unit dosage presentation or as a multiple dose presentation preferably with an added condom. Alternatively, for parenteral administration, the active ingredient may be in the powder form for reconstitution with a suitable vehicle. The compounds of the formula (I) and their pharmaceutically acceptable derivatives can also be formulated as a preparation for storage or storage. Such long-acting formulations can be administered by implant (for example subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. As stated above, the compounds of the formula (I) and their pharmaceutically acceptable derivatives can also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with an additional therapeutic agent, in particular a thrombolytic agent. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and therefore pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient, comprise a further aspect of the invention. The individual components of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of the formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound may differ from that when the compound is used alone. The appropriate doses will be readily appreciated by those skilled in the art. A daily dosage proposed of a compound of the formula (I) for the treatment of the human being is 0.01 mg / kg up to 30 mg / kg, which can be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and the route of administration. Therefore, for example, a daily dose of 0.1 mg / kg. up to 10 mg / kg., may be adequate for routine administration. The compounds of the formula (I) and the salts, solvates, and physiologically functional derivatives thereof can be prepared by any method known in the art for the preparation of the compounds of analogous structure, for example by the methods described below. Accordingly, according to a first process (A), the compounds of the formula (I) can be prepared by reacting a compound of the formula (II) or a protected derivative thereof, wherein Y is defined as for the formula (I) and R represents a separation group, for example, chlorine, bromine or iodine, or a group -OSO2CF3, with the compound of the formula ( III) or a protected derivative thereof, in the presence of a transition metal catalyst and at an elevated temperature. Suitable transition metal catalysts include palladium catalysts, such as a palladium catalyst and triarylphosphine. Suitable temperatures are from about 20 to about 160 ° C, such as 80 to 120 ° C, or the reflux temperature of the solvent. Conveniently the reaction is carried out in the presence of a base, such as a tertiary amine, and in a solvent, such as a polar solvent, for example N, N-dimethylformamide. According to another process (B) the compounds of the formula (I) can be prepared by interconversion, using other compounds of the formula (I) as precursors. For example, the compounds of the formula (I) in which X represents CH2-CH2 can be prepared from the corresponding compounds of the formula (I), or the protected derivatives thereof, in which X represents CH = CH by hydrogenation. The hydrogenation can be carried out in the presence of a transition metal catalyst, such as Raney Nickel, or a palladium, platinum or rhodium catalyst. Conveniently the reaction is carried out in a solvent, such as an alcohol (for example ethanol). Alternatively, the hydrogenation can be effected chemically, for example, using dimimide. Conveniently, the diimide is generated in situ from a suitable salt, such as dipotassium salt, diazenedicarboxylic acid, and the reaction is carried out in the presence of an acid, such as acetic acid, and a solvent, such as an alcohol ( for example methanol). As will be appreciated by those skilled in the art, it may be necessary or desirable at any stage in the processes described above to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.

Another process (c) for preparing the compounds of the formula (I) comprises therefore deprotecting a compound of the formula (IV) wherein X and Y are as defined for a compound of the formula (I), P 'is a carboxyl group or a protected carboxyl group and P "is hydrogen or an amino protecting group, provided that when P' is a group carboxyl, P "is not hydrogen and when P 'is hydrogen, P" is not a carboxyl group The compounds of formula (IV) can be prepared by processes (A) and (B) as described above, or by using any suitable methods, such as those described in the examples In a particular embodiment of the process (C), the compounds of the formula (I) can be prepared from protected carboxyl derivatives of the compounds of the formula (I), i.e. the compounds of the formula (IV) wherein P 'is a protected carboxyl group In a further embodiment of this process, the compounds of the formula (I) can be prepared from carboxyl and / or amino derivatives protected from the compounds of the formula (I), it is r the compounds of the formula (IV) wherein P "is an amino protecting group. The protecting groups used in the preparation of the compounds of the formula (I) can be used in a conventional manner. See, for example, those described in "Protective Groups in Organic Synthesis" by Theodora W. Green, second edition, (John Wiley and Sons, 1991), which also describes methods for the removal of such groups. Particular protected carboxyl groups include, for example, the carboxylic acid ester groups such as the alkyl or aralkyl esters of carboxylic acid, for example wherein the alkyl or aralkyl moiety of the ester function is methyl, ethyl, ter- butyl, methoxyphenyl, benzyl, diphenylmethyl, triphenylmethyl or p-nitrobenzyl. When the ester is an unbranched alkyl (for example methyl) the deprotection of the ester can be carried out under conditions of either basic hydrolysis, for example using lithium hydroxide, or acid hydrolysis, for example using hydrochloric acid. The tert-butyl ester and triphenylmethyl groups can be removed under acid hydrolysis conditions, using for example formic or trifluoroacetic acid at room temperature or using hydrochloric acid in acetic acid. The benzyl, diphenylmethyl and nitrobenzyl ester groups can be removed by hydrogenolysis in the presence of a metal catalyst (for example palladium). Particular amino protecting groups include, for example, aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N-benzyloxycarbonyl, t-butoxycarbonyl or trifluoroacetyl groups. The removal of the acyl groups can be carried out under standard conditions such as those referred to above. When a particular isomeric form of a compound of the formula (I) is desired, the required isomer can be conveniently separated using chromatography, high-resolution liquid (clar) preparative, applied to the final title compounds of the processes (A) to (C) previous or applied prior to any step of final checkout in the processes. The compounds of the formula (II) and (IV), or the protected derivatives thereof, can be prepared using any suitable methods, such as those described in the examples. Certain intermediates described above are novel compounds, and it is to be understood that all intermediates here form additional aspects of the present invention. The compounds of the formula (II), for example, the [4- (5-bromo-3-methanesulfonyl-indazol-1-yl) -piperidin-1-yl] -acetic acid tert-butyl ester, and the ester 5-bromo-l- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazole-3-carboxylic acid methyl ester, are key intermediates and represent a particular aspect of the present invention. The compounds of the formula (IV) are also an important aspect of the present invention and include the 4- tert-butyl ester. { 2- [1- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -3-methanesulfonyl-1H-indazol-5-yl] - (E) -vinyl} -piperidine-l-carboxylic acid 1- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -5- [2- (l-tert-butoxycarbonyl-piperidin-4-yl) - (E) - methyl ester vinyl] -lH-indazole-3-carboxylic acid, tert-butyl ester of 4-acid. { 2- [1- (1-tert-Butoxycarbonylmethyl-pi? Eridin-4-yl) -3-carbamoyl-lH-indazol-5-yl] - (E) -vinyl} -piperidine-1-carboxylic acid and 4- tert-butyl ester. { 2- [3- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -1-methanesulfonyl-lH-indazol-6-yl] - (E) -vinyl} -piperidin-l-carboxylic acid. Conveniently, the compounds of the invention are isolated following the working procedure as acid addition salts, for example trifluoroacetate or hydrochloride salts. The pharmaceutically acceptable acid addition salts of the compounds of the invention can be prepared from the corresponding trifluoroacetate salts by the exchange of ions using conventional means, for example by neutralization of the trifluoroacetate salt using a base such as sodium hydroxide. aqueous sodium, followed by the addition of a suitable organic or inorganic acid, for example, hydrochloric acid. Alternatively, acceptable acid addition salts. pharmaceutically they can be prepared directly by effecting deprotection with the appropriate organic or inorganic acid, for example, hydrochloric acid. The inorganic basic salts of the compounds of the invention can also be prepared from the corresponding trifluoroacetate salts by the addition of a suitable strong base such as sodium hydroxide. The solvates (for example the hydrates) of a compound of the invention can be formed during the working process of one of the process steps mentioned above. The following Examples illustrate the invention but do not limit the invention in any way. All temperatures are in ° C. Thin layer chromatography (c.c.d.) was carried out on silica plates. Preparative high-performance liquid chromatography (c.l.a.r.) was carried out, unless otherwise indicated, using a Dynamax column of 60A C18 8μM 25 cm x 41.4 mm d.i. eluted with a solvent mixture consisting of (i) 0.1% trifluoroacetic acid in water and (ii) acetonitrile, the eluent is expressed as the percentage of (ii) present in the solvent mixture, at a flow rate of 45 ml per minute. The c.l.a.r. Analytical was carried out unless otherwise indicated, using a Dynamax column 60A C18 8μM 25cm x 4.6mm d.i. eluted with a mixture of solvents consisting of (i) and (iii), 0.05% trifluoroacetic acid in acetonitrile, the eluent is expressed as the percentage of (iii) present in the solvent mixture, at a flow rate of 1. ml per minute. The following abbreviations are used: Me = methyl; Et = ethyl; THF = tetrahydrofuran; DMF = N, N-dimethylformamide; and RT = retention time of ciar.

Example 1 Synthesis of (4- [3-methanesulfonyl-5- (2-piperidin-4-yl- (E) -vinyl) -indazol-1-yl] -piperidin-1-yl] tris (trifluoroacetate). acetic acid (i) 5-Bromo-2-nitro-2H-indazole To the stirred acetic anhydride (410 ml) at -5 ° is added, by dripping, fuming nitric acid (8.5 ml). After 20 minutes, the solution is cooled to -15 ° and 5-bromoindazole (7.70 g) is added portionwise maintaining the temperature at -15 °. The mixture is stirred at -15 ° for 2 h, added to water cooled with ice (11), and stirred for an additional 2 h. The solid is collected by filtration and partitioned between diethyl ether and 5M aqueous sodium hydroxide. The aqueous layer is extracted with diethyl ether and the combined organic extracts are dried (Na2SO) and evaporated in vacuo to give the title compound as an orange solid (7.45 g). Mass spectrum m / z 243 (MH +) xRef: C. Dell'Erba et al., Tetrahedron, 1994, 50, 3529. (ii) 5-Bromo-3-methanesulfonyl-lH-indazole A mixture of 5-bromo-2-nitro-2H-indazole (3.12 g) and sodium methansulfinate (2.89 g) in DMF (20 ml) is stirred at 20 ° for 5 h. The mixture is concentrated in vacuo and the residue is partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with dichloromethane. The combined organic extracts are dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow solid (1.88 g). Mass spectrum m / z 294 (MNH4 +) (iii) 4- (5-Bromo-3-methanesulfonyl-indazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester A stirred mixture of 5-bromo-3-methanesulfonyl-1H-indazole (1.20 g), 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.58 g), potassium carbonate (1.81 g) and N, N-dimethylformamide (20 ml) is heated at 100 ° for 18 h. The cold mixture is concentrated in vacuo. The residue is purified by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate: cyclohexane 1: 5 to give the title compound as a creamy solid (1.37 g). Mass spectrum m / z 459 (MH +) 2Ref: EP-A-0 560 268 Al (iv) 5-Bromo-3-meta? sulfonyl-l-piperidin-4-yl-lH-indazole A solution of the 4- (5-bromo-3-methanesulfonyl-indazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (1.36 g) in trifluoroacetic acid (10 ml) is stirred at 20 ° for 1.5 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and 0.5M aqueous sodium hydroxide. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound as a creamy solid (0.90 g). Mass spectrum m / z 360 (MH +) (v) [4- (5-Bromo-3-methanesulfonyl-indazol-1-yl) -piperidin-1-yl] -acetic acid tert-butyl ester A mixture of 5-bromo-3-methanesulfonyl-l-? Iperidin-4-yl-lH-indazole (0.90 g), tert-butyl bromoacetate (0.390 ml) and sodium bicarbonate (0.380 g) in N, N- dimethylformamide (15.0 ml) is stirred at 20 ° for 20 hours. The mixture is concentrated in vacuo and the residue is partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane, and the combined organic layers are concentrated in vacuo. The residue is purified by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate-cyclohexane (gradient 1: 4 to 1: 3) to give the title compound as a creamy solid (0.870 g).

Mass spectrum m / z 474 (MH +) (vi) 4- Tertiary butyl ester. { 2- [l- (1-tert-Butoxycarbonylmethyl-piperidin-4-yl) -3-methanesulfonyl-lH-indazol-5-yl] - (E) -vinyl} -piperidine-l-carboxylic acid A stirred mixture of [4- (5-bromo-3-methanesulfonyl-indazol-1-yl) -piperidin-1-yl] -acetic acid tert-butyl ester (0.350 g), 4- tert-butyl ester vinyl-piperidine-l-carboxylic acid (0.177 g), triethylamine (0.320 ml), palladium (II) acetate (0.014 g), tri-o-tolylphosphine (0.037 g) and N, N-dimethylformamide (2.50 ml), heat at 110 ° under nitrogen for 16 hours. The cooled mixture is concentrated in vacuo and partitioned between ethyl acetate and aqueous sodium bicarbonate., saturated. The aqueous layer is extracted with ethyl acetate and the combined organic layers are concentrated in vacuo. The residue is purified by flash chromatography on silica gel (Merck 9385), eluting with dichloromethane: ethanol: 880 ammonia (80: 18: 2) to give the title compound as a white solid (0.270 g). Mass spectrum m / z 603 (MH *) 3Ref: PCT / EP95 / 05043 (vii) (4-T3-methanesulfonyl-5- (2-piperidin-4-yl- (E) -vinyl) trifluoroacetate salt -indazol-1-yl] -piperidin-l-yl.} -acetic The ter-butyl ester of the acid 4-. { 2- [1- (1-tert-Butoxycarbonylmethyl-piperidin-4-yl) -3-methanesulfonyl-1H-indazol-5-yl] - (E) -vinyl} -piperidine-l-carboxylic acid (0.270 g) is dissolved in trifluoroacetic acid (10 ml) and the mixture is stirred at 20 ° for 5 hours. The mixture is concentrated in vacuo, and the residue is purified by trituration with diethyl ether. The resulting solid is collected by filtration and dried in vacuo to give the title compound as a creamy solid (0.170 g).

Mass spectrum m / z 447 (MH +) Analysis: Found: C, 42.0; H, 3.9; N, 6.8; S, 3.9 C22H30N4O-.S.3.2CF3CO2H requires: C, 42.0; H, 4.1; N, 6.9; S, 3.95% Example 2 Synthesis of (4- [3-methanesulfonyl-5- (2-pi? Eridin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl] -acetic acid trifluoroacetate salt.

Method A The acid tris (trifluoroacetate). { 4- [3-methanesulfonyl-5- (2-piperidin-4-yl- (E) -vinyl) -indazol-1-yl] -piperidin-1-yl} -acetic (0.782 g) is hydrogenated at ambient temperature and pressure over 10% palladium on carbon (50% paste, 0.20 g) in water: 70:30 ethanol for 6 hours. The catalyst is removed by filtration and the solvent is evaporated in vacuo to give a yellow oil (0.577 g). Purification by preparative HPLC (10-75% gradient profile (ii) in 20 minutes, 250nM detection, RT 10.3 minutes) and trituration of the resulting gum with dry ether gave the title compound as a white solid (0.180 g) . Mass spectrum m / z 449 (MH +) Analysis Found: C, 44.6; H, 5.2; N 7.8; S, 4.3. C22H32N4O4S: 2.4CF3COOH requires: C, 44.6; H 4.8; N 7.8; S.4.4.

Method B (a) 4-Bromo- (2-methylthiomethyl) aniline The dimethyl sulfoxide (105 ml) was added dropwise to a stirred solution of N-chlorosuccinimide (139.7 g) in dichloromethane (3750 ml) in the range of 0 to -5 ° C and the resulting suspension was cooled to -20 °. C. To this is added dropwise a solution of 4-bromoaniline (150.0 g) in dichloromethane (300 ml), the suspension is stirred at -20 ° C and the reaction mixture is diluted with triethylamine (292 ml). The reaction mixture is stirred at room temperature for 58 hours, washed with water, 2N hydrochloric acid, 8% w / w aqueous sodium bicarbonate, dried (MgSO) and evaporated in vacuo to give the title compound as a pale yellow solid (162.0 g). Mass spectrum m / z 232. 9 (MH +) (b) 5-Bromo-3-methylsulfani1-lH-indazole The solution of sodium nitrite (48.4 g) in water (100 ml) is added dropwise to a stirred solution of 4-bromo- (2-methylthiomethyl) aniline (163.0 g) and fluoroboric acid (230 ml, 48% p). / p of aqueous solution) in water (815 ml) at 10-15 ° C. The resulting yellow suspension was stirred at room temperature for 1 hour, the solid was isolated by filtration, the solid was washed with water and diethyl ether and finally suspended in chloroform (4000 ml). The stirred suspension is treated with potassium acetate (138.0 g) and 18-Corona-6 (9.30 g) and stirred at room temperature for 2 hours. The reaction mixture is filtered and the filtrate washed with 2N sodium hydroxide, dried (MgSO) and evaporated in vacuo to give the title compound as a pale yellow solid (147.7 g). Mass spectrum m / z 243.9 (MH +) (c) 5-Bromo-3-methanesulfonyl-lH-indazole The Oxone® (182.2 g) is added in portions to a stirred suspension of 5-bromo-3-methylsulfanyl-1H-indazole (36.0 g) in methanol (450 ml) and water (135 ml). The reaction mixture is stirred at room temperature for 3 hours, concentrated in vacuo and the resulting oil is partitioned between ethyl acetate and water. The biphasic mixture is separated, and the aqueous phase is extracted with ethyl acetate, the combined organic extracts are washed with 8% w / w aqueous sodium bicarbonate and water, dried (MgSO 4) and evaporated in vacuo to give the title compound. title as a discolored white solid (38.8 g) • Mass spectrum m / z 293.9 (MNH4 +) (d) 4- [3-Methanesulfonyl-5-] tert-butyl ester. { l- (l-tert-butoxycarbonylmethyl-2-piperidin-4-yl-ethyl.} - lH-indazol-l-yl] -l-piperidine acetic A solution of the ter-butyl acid ester 4-. { 2- [l- (L-tert-butoxycarbonylmethyl-piperidin-4-yl) -3-methanesulfonyl-lH-indazol-5-yl] - (E) -vinyl} -l-piperidine acetic acid (77.0 g) in ethanol (760 ml) is added to a pre-hydrogenated suspension of 10% Pd / C (115.5 g) in ethanol (77 ml) and water (19 ml) and the stirred suspension The resultant was hydrogenated at room temperature for 26 hours. The reaction is filtered through hyflo, the residue is washed with ethanol and the combined filtrate is evaporated in vacuo to give a pale yellow oil which was purified by Biotage chromatography, eluting with ethyl acetate: cyclohexane (1: 1). ), to give the title compound as a gummy solid (46.8 g). Mass spectrum m / z 605.3 (MH +) (e) 4- [3-Methanesulfonyl-5- (2-piperidin-4-yl-ethyl) -lH-indazol-1-yl] -l-piperidine acetic acid dihydrochloride A solution of the 4- [3-methanesulfonyl-5-] tert-butyl ester. { 1- (1-tert-butoxycarbonylmethyl-2-piperidin-4-yl-ethyl)} -IH-indazol-1-yl] -l-piperidine acetic acid (25.0 g) in trifluoroacetic acid (250 ml) is stirred at room temperature for 4 hours. The reaction mixture is evaporated in vacuo and the residue is purified by preparative HPLC, eluting with water: acetonitrile: trifluoroacetic acid (gradient 90: 10: 0.1 to 25: 75: 0, 20 minutes, detection 260 nm, RT 13 minutes) , to give a white solid which is dissolved in 2N hydrochloric acid and evaporated in vacuo to give a white solid. The hydrochloric acid procedure is repeated twice. The white solid is triturated with acetone (100 ml) and the suspension is evaporated in vacuo. The solid is triturated again with acetone (100 ml), the suspension is stirred at room temperature for 0.5 hours and the solid is isolated by filtration, washed with acetone and dried in vacuo at 45 ° C to a constant weight to give the Compound the title as a white crystalline solid (10.03 g).

Analysis found: Q 46 9- H 6 8- N 9 9 C22H32N4O S.2HCI.2H2O requires: C, 47.3; H, 6.8; N, 10.0% Example 3 Synthesis of (4- [3-carbamoyl-5- (2-piperidin-4-yl- (E) -vinyl) -indazol-l-yl] -piperidin-l-yl} -acetic acid trifluoroacetate (a) 5-Bromo-l- (1-tert-butoxycarbonyl-piperidin-4-yl) -lH-indazole-3-carboxylic acid methyl ester The methyl ester of 5-bromo-lH-indazole-3-carboxylic acid4 (35.8 g) in dry THF (400 ml) containing the 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (40.9 g, 153 mmoles) is treated with potassium t-butoxide (15.75 g, 140 mmol) and stirred at reflux under nitrogen for 24 hours. When it is cooled, the mixture is evaporated in vacuo and the residue is treated with saturated aqueous ammonium chloride (400 ml). The mixture is extracted with ethyl acetate and the combined, dried organic extracts (Na2SO4) are evaporated in vacuo over silica gel. The resulting silica is applied as a plug to a flash column of silica gel, eluting with cyclohexane: ethyl acetate (gradient 19: 1 to 3: 1) to give first an isomer followed by the title product ( 22.8 g). C.c.d. Si02 (cyclohexane: EtOAc, 7: 3), Rf 0.29. Ref4 G.A. Bistrocchi et al., Drugs. Ed. Sci., 1981, 36, 315. (b) Bis (trifluoroacetate) of 5-bromo-1-piperidin-4-yl-lH-indazc -3-carboxylic acid methyl ester Trifluoroacetic acid (100 ml) is added to the methyl ester of 5-bromo-l- (1-tert-butoxycarbonyl-piperidin-4-yl) -lH-indazole-3-carboxylic acid (22.75 g) at 23 ° C for 1 minute. After 1 hour, the mixture is evaporated in vacuo and co-evaporated with dichloromethane to give the title product (28.05 g) as a pale yellow solid. C.c.d. Si02 (CH2Cl2: EtOH: 880NH3, 89: 10: 1), Rf 0.18. (c) 5-Bromo-l- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazole-3-carboxylic acid methyl ester A solution of the bis (trifluoroacetate) of 5-bromo-l-piperidin-4-yl-lH-indazole-3-carboxylic acid methyl ester (28.05 g) and tert-butyl bromoacetate (7.3 ml) in DMF (500 ml) treated with diisopropylethylamine (25.9 ml) under nitrogen with shaking at 23 ° and maintained or preserved for 4 days. Additional tert-butyl bromoacetate (1.4 ml) is added, followed by diisopropylethylamine (5.0 ml) and stirring is continued for 2 hours. The mixture is evaporated in vacuo, treated with saturated, aqueous sodium bicarbonate (400 ml), and extracted with ethyl acetate. The dried organic extracts (Na2SO4), combined, are evaporated in vacuo and the residue is crystallized from ethyl acetate to give the title product (13.43 g). C.c.d. Si02 (Cyclohexane: EtOAc, 7: 3) Rf 0.17 (d) L- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -5- [2- (1-tert-butoxycarbonyl-piperidin-4-methyl ester -yl) - (E) -vinyl] -lH-indazole-3-carboxylic acid A mixture of 5-bromo-1- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazole-3-carboxylic acid methyl ester (13.43 g), 4-vinyl-piperidine tert-butyl ester -1-carboxylic acid (6.90 g), palladium (II) acetate (666 mg), tri-o-tolylphosphine (1.81 g), (triethylamine (12.4 ml, 89.1 mmol), and DMF (200 ml) is stirred at 120 Under nitrogen for 15 hours.When cooled, the mixture is evaporated in vacuo, treated with saturated aqueous sodium bicarbonate (200 ml), and extracted with ethyl acetate.The dry organic extracts (Na2SO4), combined, evaporate in vacuo and the residue is purified by flash chromatography on silica gel.The gradual elution with dichloromethane: ethanol: 880 ammonia (gradient 989: 10: 1 to 978: 20: 2) gives the title compound as a colored foam dim orange (8.94 g) Ccd SiO2 (CH2Cl2: EtOH: 880NH3, 978: 20: 2) Rf 0.14. (e) 4- Tertiary butyl ester. { 2-fl- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -3-carbamoyl-lH-indazol-5-yl] - (E) -vinyl} -piperidine-l-carboxylic acid l- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -5- [2- (1-tert-butoxycarbonyl-piperidin-4-yl) - (E) - methyl ester vinyl] -lH-indazole-3-carboxylic acid (600 mg) in methanol (20 ml) saturated with ammonia is heated at 80 ° for 50 hours. The cold solution is evaporated in vacuo and the residue is purified by flash chromatography on silica gel. Gradual elution with dichloromethane: tanol: 0.88 ammonia (gradient 989: 10: 1 to 967: 30: 3) afforded the title compound as a white foam (373 mg). C.c.d. Si02 (CH2Cl2: EtOH: 880NH3, 978: 20: 2) Rf 0.08. (f) (4- [3-Carbamoyl-5- (2-piperidin-4-yl- (E) -vinyl) -methiazol-1-yl] -piperidin-1-yl} -acetic acid trifluoroacetate A solution of 4- tertiary butyl ester. { 2- [l- (L-tert-butoxycarbonylmethyl-piperidin-4-yl) -3-carbamoyl-lH-indazol-5-yl] - (E) -vinyl} -piperidine-l-carboxylic acid (292 mg) in trifluoroacetic acid (6 ml) is maintained at 23 ° for 2 h. The solution is evaporated in vacuo, coevaporated with water (3 ml), and triturated with diethyl ether to give the title product as a white solid (311 mg). Mass spectrum m / z 412 (MH +).

Analysis found: C.45.0; H, 4.8; N.9.4. C22H29N5? 3'2.8CF3CO2H requires: C.45.4; H.4.4; N, 9.6%. Example 4 f Synthesis of acid trifluoroacetate. { 4-f3-carbamoyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic Method A A solution of acid trifluoroacetate. { 4- [3-carbamoyl-5- (2-piperidin-4-yl- (E) -vinyl) -indazol-1-yl] -piperidin-1-yl} Acetic acid (100 mg) in water (40 ml) is added to a suspension of 10% palladium prehydrogenated on activated carbon (70 mg) in water (10 ml) and stirred under hydrogen for 4 hours. The catalyst is removed by filtration, washed, and the filtrate is treated with trifluoroacetic acid (2 drops). The solution is evaporated in vacuo, and the residue is triturated with ether to give the title product as fine white crystals (74 mg). Mass spectrum, m / z 414.1 (MH +) CLAR Analytical RT 9.2 min. Analysis found: 45 7 - 1-1 49 - N 9 9 C22H31 N5? 3.2.65 CF3CO2H requires: C, 45.8; H, 4.7; N, 9.8%.

Method B (a) 5-bromo-3-formyl-lH-indazole A solution of 5-bromoindole (100 g) and sodium nitrite (350 g) in 1,4-dioxane (3.5 1) and water (18 vol.) Is acidified to pH 2.5 by the gradual addition of 3N hydrochloric acid (18). 1) for 0.5 h at 20-25 °. The mixture is stirred for 0.75 h and then extracted with ethyl acetate. The combined organic extracts are diluted with ethyl acetate (11) and washed with water. The combined water washings were extracted with ethyl acetate. The organic layer is washed with water, combined with the main organic extract and evaporated to give a black-dark brown solid. This solid was triturated with ethyl acetate (200 ml) for 1 h, filtered and the filter cake washed with ethyl acetate and dried to give the title compound as a red-brown solid (60.8 g) . Mass spectrum m / z 223, 225 [M-H +] ~ (b) 5-Bromo-3-cyano-lH-indazole A suspension of 5-bromo-3-formyl-lH-indazole (143 g) is heated to 65-70 ° in a solution of hydroxylamine-O-sulfonic acid (93.4) in water (1.4 1) for 16 h. The mixture is cooled to 20 ° for 1 h, filtered and the filter cake washed with water and dried at 45 ° C to give a solid (146 g). This solid is refluxed in toluene (3.65 1) for 1 h and filtered at 90 ° C. The filtrate is reheated to give a solution, stirred and cooled to 10 °. The suspension is filtered, the filter cake is washed with toluene and dried to give the title compound as a pale brown solid (111 g). Mass spectrum m / z 220, 222 [M-H +] ~ (c) 4- (5-Bromo-3-cyano-lH-indazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester A suspension of 5-bromo-3-cyano-lH-indazole (111 g), l-tert-butoxycarbonyl-4-methylsulfonyl-piperidine (168 g) and potassium carbonate (193 g) in DMF (1.1 1) is heated at 105-110 ° for 6 hours, evaporated to dryness and The orange residue is partitioned between dichloromethane and water. The aqueous phase is extracted again with dichloromethane, the combined organic substances are washed with water and evaporated to an orange residue (130 g). This residue is triturated with a mixture of cyclohexane and ethyl acetate (6: 1, 1.04 1) for 1 h and filtered. The filter cake is washed with a mixture of cyclohexane and ethyl acetate and dried to give the title compound as a pale yellow powder (125 g). Mass spectrum m / z 405, 407 [MH +] (d) 5-Bromo-l-piperidin-4-yl-lH-indazol-3-carboxamide The 4- (5-bromo-3-cyano-lH-indazol-1-yl) -piperidine-1-carboxylic acid tert-butyl ester (62 g) is added in portions over 1 h at 20-30 ° to sulfuric acid conc. (620 g) and the suspension is stirred for 2 h. The mixture is poured onto ice (1.24 kg), basified to pH 12 with 5N sodium hydroxide (2.44 1) at 20-30 ° for 1.5 h, diluted with water (300 ml) and filtered. The filter cake is washed with water and dried to give the title compound as a colorless white solid (51.5 g). Mass spectrum m / z 323, 325 [MH +] (e) 4- (5-Bromo-3-aminocarbonyl-lH-indazol-1-yl) -1-piperidine acetic acid tert-butyl ester The tert-butyl bromoacetate (60.4 g) is carefully added to a solution of 5-bromo-l-piperidin-4-yl-lH-indazole-3-carboxamide (100 g) and triethylamine (43.3 ml) in DMF (1 g). 1) at 20-30 ° and the mixture is stirred for 2 h. Water (1.5 1) is added by dripping for 1 h to the mixture at < 25 °, the suspension is stirred for 1 h and filtered. The filter cake is washed with water and dried to give the title compound as a faint yellow solid (121 g). Mass spectrum m / z 437, 439 [MH +] (f) 4- Tertiary butyl ester. { 2- [3-aminocarbonyl-l- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-5-yl] - (E) -vinyl} -piperidin-l-carboxylic acid.

A mixture of 4- (5-bromo-3-aminocarbonyl-lH-indazol-1-yl) -1-piperidine acetic acid tert-butyl ester (120 g), 4- (E) - tert-butyl ester vinyl-piperidine-1-carboxylic (60.8 g), triethylamine (114.6 ml), tri-ortho-tolylphosphine (16.7 g), palladium acetate (6.2 g) and adjuvant for filter harbolite J2 (60 g) is heated to 105- 110 ° in DMF (2.4 1) for 14 h. The mixture is cooled to ca. 35 °, mineral coal (30 g) is added and the mixture is stirred for 1 h at ca. 35 ° before cooling to room temperature. The mixture is filtered and the filter pad washed with N, N-dimethylformamide and cyclohexane. The combined filtrates are diluted with water (240 ml), the phases are separated and the N, N-dimethylformamide / water extract is washed with cyclohexane and concentrated to a red gum: The gum is stirred in water (600 ml) during 1 h, additional water (1.8 ml) is added and the suspension is stirred for 0.5 h and filtered. The filter cake is washed with water and dried to give the title compound (153 g) as a yellow-orange solid. Mass spectrum m / z 568 [MH +] (g) 4- Tertiary butyl ester. { 2- [3-aminocarbonyl-l- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-5-yl] -ethyl} -piperidin-l-carboxylic acid. i A 10% palladium-carbon catalyst (73.5 g) is added to a solution of 4- tert-butyl ester. { 2- [3-aminocarbonyl-1- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-5-yl] - (E) -vinyl} -piperidine-l-carboxylic acid (147 g) in tetrahydrofuran (2.94 1) and stirred under an atmosphere of hydrogen at room temperature for 5 h. A second charge of 10% palladium-charcoal catalyst (73.5 g) and tetrahydrofuran (200 ml) is added and the suspension is stirred under hydrogen for an additional 18 h before a third catalyst charge (73.5 g) and Tetrahydrofuran (200 ml) is added and the suspension is stirred under hydrogen for another 20 h. The mixture is filtered, washed with tetrahydrofuran and evaporated to a thick black oil. This oil is purified by Biotage chromatography on silica gel eluting with ethyl acetate-cyclohexane (1: 1) and then ethyl acetate to give the title compound as white crystals (32.65 g). Mass spectrum m / z 570 [MH +] (h) (4- [3-Carbamoyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl] -acetic acid trifluoroacetate The ter-butyl ester of the acid 4-. { 2- [3-aminocarbonyl-1- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-5-yl] -ethyl} -piperidine-1-carboxylic acid (32.65 g) is added in two equal portions to trifluoroacetic acid (330 ml) and the solution is stirred at room temperature for 3 hours. The mixture is concentrated to a weight of 100 g and purified by preparative CIAR (Kromsil C8, 10 μm, reverse phase) eluting with water-acetonitrile-trifluoroacetic acid, 90: 10: 0. l% v / v (A) and water- acetonitrile, 25:75 (B) to give a white solid (26 g). The solid (23.6 g) is dissolved in water of CLAR grade (60 ml) and adjusted to pH 10 with an 880 ammonia solution (20 ml) added at 20-30 ° for 0.5 h. The milky white suspension is stirred at 20 ° for 1.5 h and filtered. The filter cake is washed with water with suction under vacuum for 10 minutes between each wash, dried at 40 ° for 18 h and allowed to equilibrate under ambient conditions for 4 h to give the title compound as a white powder (12.05 g) .

Mass spectrum m / z 414 [MH +] Example 5 Synthesis of (4- [1-methanesulfonyl-6- (2-piperidin-4-yl- (E) -vinyl) -lH-indazol-3-yl] -piperidin-1-yl} -acetic acid (a) l- [4- (2,4-dibromo-benzoyl) -piperidin-l-yl3-ethanone The 1,3-dibromobenzene (65 ml) is added to a stirred mixture of 1-acetyl-piperidine-4-carbonyl chloride hydrochloride (21.8 g) and aluminum chloride (III) (34.5 g) and the mixture is heated to 95-100 ° during 1. 5 h. When it is cooled, the mixture is poured into an ice-water mixture (50 ml) and extracted with ethyl acetate. The dried organic extracts (Na2SO4), combined, are evaporated in vacuo and the residue is purified by flash chromatography on silica gel (Merck 9385). Gradual elution with ether-ethanol (gradient 99: 1 to 90:10) gave the title compound as an orange oil (16.7 g). C.c.d. Si02 (Et20-EtOH, 9: 1) Rf = 0.23 Ref5 EP-A-0 428 437 (b) (2,4-dibromo-phenyl) -piperidin-4-yl-methanone hydrochloride A stirred mixture of l- [4- (2,4-dibromo-benzoyl) -piperidin-1-yl] -ethanone (11.00 g) and aqueous 5M hydrochloric acid (60 ml) is heated under reflux under nitrogen for 7 h. The mixture is evaporated in vacuo to give the title compound as a white solid (10.8 g). C.c.d. Si02 (CH2Cl2-EtOH-880NH3, 89: 10: 1) Rf = 0.17 (c) (2,4-Dibromo-phenyl) -piperidin-4-yl-methylene-hydrazine A stirred solution of (2,4-dibromo-phenyl) -piperidin-4-yl-methanone hydrochloride (7.04 g), hydrazine (6.0 ml), and ethanol (150 ml) is heated under reflux under nitrogen for 16 h. The cooled solution is evaporated in vacuo, treated with aqueous IMM sodium carbonate (50 ml), extracted with ether, and the dried organic extracts (Na2SO4), combined, are evaporated in vacuo. The residue is purified by flash chromatography (Merck 9385) eluting with dichloromethane-ethanol-880 ammonia (gradient 89: 10: 1 to 835: 150: 15) to give the title compound as a creamy solid (5.71 g).

C. c. d. Si02 (CH2Cl2-EtOH-880 NH3, 78: 20: 2) Rf = 0.13 (minor) and Rf = 0. 16 (higher) (d) 6-Bromo-3-piperidin-4-yl-lH-indazole hydrochloride A stirred mixture of (2,4-dibromo-phenyl) -piperidin-4-yl-methylene-hydrazine (5.64 g), sodium hydride (1.25 g, 60% dispersion in oil), and dry DMF (150 ml) it is heated at 105 ° under nitrogen for 6.5 h. Additional sodium hydride (200 mg) is added and heating is continued for 2 h. The mixture is evaporated in vacuo, acidified to pH 1 by the addition of aqueous 2M hydrochloric acid, and then basified to pH 8 by the addition of aqueous IMM sodium carbonate. The mixture is extracted with ether, and the dried organic extracts (Na 2 SO), combined, are evaporated in vacuo. The residue is purified by flash chromatography (Merck 9385), eluting with dichloromethane-ethanol-880 ammonia (gradient 89: 10: 1 to 78: 20: 2) to give the title compound as a creamy yellow solid (2.50 g. ). C.c.d. Si02 (CH2Cl2-EtOH-880NH3, 78: 20: 2) Rf = 0.6. (e) [4- (6-Bromo-lH-indazol-3-yl) -piperidin-l-yl] -acetic acid tert-butyl ester A mixture of 6-bromo-3-piperidin-4-yl-lH-indazole hydrochloride (500 mg), tert-butyl bromoacetate (0.29 ml), sodium bicarbonate (150 mg, 1.87 mmol), and DMF (10 ml) stir at 23 ° under nitrogen for 18 hours. The mixture is evaporated in vacuo, treated with saturated aqueous sodium bicarbonate (25 ml), and extracted with ethyl acetate (50 ml). The dried organic layer (Na2SO4) was evaporated in vacuo over silica gel (Merck 7734). Purification by flash chromatography (Merck 9385), eluting with dichloromethane-ethanol-880 ammonia (gradient 967: 30: 3 to 945: 50: 5) afforded the title compound as fine white crystals (347 mg). C.c.d. Si02 (CH2Cl2-EtOH-880 NH3, 945: 50: 5) Rf = 0.27 (f) 4- Tertiary butyl ester. { 2- [3- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-6-yl] - (E) -vinyl} -piperidin-l-carboxyl A mixture of [4- (6-bromo-lH-indazol-3-yl) -piperidin-1-yl] -acetic acid tert-butyl ester (1.34 g), 4-vinyl-piperidine tert-butyl ester -l-carboxylic acid (0.75 g), triethylamine (1.4 ml), palladium acetate (ii) (0.050 g) and tri (o-tolyl) phosphine (0.210 g) in DMF (60 ml) is stirred at 120 ° under nitrogen for 16 h. The mixture is evaporated in vacuo and purified by flash chromatography (Merck 9385), eluting with ethyl acetate: cyclohexane: triethylamine (50: 50: 2 to 100: 0: 2), to give the title compound as a yellow solid. (1.18 g). C.c.d. Si02 (CH2Cl2: EtOH: 880 NH3 95: 5: 0.5) Rf = 0.32 J Ester ter-butyl of acid 4-. { 2- [3- (1-tert-Butoxycarbonylmethyl-piperidin-4-yl) -1-methanesulfonyl-1H-indazol-6-yl] - (E) -vinyl} -piperidine-l-carboxylic acid A solution of 4- tertiary butyl ester. { 2- [3- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -1 H -indazol-6-yl] - (E) -vinyl} -piperidine-l-carboxylic acid (0.211 g) in DMF (10 ml) is treated with sodium hydride (60% dispersion in oil, 0.019 g) and stirred for 0.5 h at 23 ° C under nitrogen. Methanesulfonyl chloride (0.03 ml) is added and the mixture is stirred for an additional 40 hours. The solvent is evaporated in vacuo and the residue is partitioned between water (20 ml) and ethyl acetate. The extracts are dried (Na2SO4), evaporated in vacuo, and purified by flash chromatography on silica gel, eluting with cyclohexanone: ether: triethylamine 50: 50: 2, to give the title compound as a colorless gum (0.141 g ). Mass spectrum m / z 603 (MH +). (h) Acid trifluoroacetate. { 4- [l-Methanesulfonyl-6l- (2-piperidin-4-yl- (E) -vinyl-lH-indazol-3-yl] -piperidin-1-yl} -acetic acid The ter-butyl ester of the acid 4-. { 2- [3- (1-tert-Butoxycarbonylmethyl-piperidin-4-yl) -1-methanesulfonyl-lH-indazol-6-yl] - (E) -vinyl} -piperidine-l-carboxylic acid (0.138 g) is treated with trifluoroacetic acid (3 ml) and stirred at 22 ° C for 2 h. The solvent is evaporated in vacuo, and the residue is purified by preparative HPLC (gradient profile 20-70% (ii) in 18 minutes, Rf 12.5 min.). Triturate with ether to give the title compound as a white crystalline solid (0.114 g). Mass spectrum m / z 447.2 (MH +) Analysis Found: C.44.5; H.4.7; N.7.7. C22H3oN4? 4S.2.4C2HF3? 2 requires: C, 44.7; H.4.5; N, 7.8%.

Example 6 Synthesis of the acid. { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl-ethyl) -lH-indazol-3-yl] -piperidin-1-yl} -acetic Method A A solution of acid trifluoroacetate. { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl- (E) -vinyl) -1 H -indazol-3-yl] -piperidin-1-yl} -acetic (690 mg) in water (90 ml) is added to a stirred suspension of 10% palladium on carbon (600 mg) in water (30 ml) and the mixture is stirred at 23 ° under nitrogen for 6 h. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. to give. the title compound as fine white crystals (420 mg). Mass spectrum m / z 449 (MH +) Analysis Found: C, 42.6; H, 4.9; N, 7.2. C22H32N4O4S.3C2HF3O2.0.3C4H1oO requires: C, 42.4; H, 4.6; N, 6.8%.

Method B (a) 4- Tertiary butyl ester. { 2- [L-methanesulfonyl-3- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-6-yl] -ethyl} -piperidine-l-carboxylic acid The methanesulfonyl chloride (7.0 ml) is added dropwise to a stirred solution of the 4-tert-butyl ester. { 2- [3- (l-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-6-yl] -ethyl} -piperidine-l-carboxylic acid (40.1 g), and 4-N, N-dimethylaminopyridine (0.96 g) in pyridine (280 ml) at room temperature. The resulting coffee solution is stirred at room temperature for 18 h, diluted with water (400 ml) and extracted with dichloromethane (400 ml). The combined organic extracts are evaporated in vacuo, the brown residue is diluted with ethanol (400 ml) and evaporated in vacuo to give a brown oil. The oil is triturated with ethanol (400 ml) and evaporated in vacuo to almost 200 ml to give a suspension. The resulting solid is isolated by filtration, washed with ethanol and dried in vacuo at 45 ° C to give the title compound as a colorless white solid (37.6 g). Mass spectrum m / z 605 (MH +) (b) Acid (4- [1-methanesulfonyl-6- (2-piperidin-4-yl-ethyl) -lH-indazol-3-yl] -piperidin-1-yl} -acetic acid A solution of 4- tertiary butyl ester. { 2- [L-methanesulfonyl-3- (1-tert-butoxycarbonylmethyl-piperidin-4-yl) -lH-indazol-6-yl] -ethyl} -piperidine-l-carboxylic acid (20 g) in 5N hydrochloric acid (200 ml), is stirred at room temperature for 5 h. The reaction mixture is neutralized with saturated potassium carbonate (300 ml) and extracted with isopropanol. The combined organic extracts are evaporated in vacuo to give an oil which is diluted with ethanol (300 ml) and concentrated by rotary evaporation to give a white solid. The colorless white solid is purified by flash chromatography (Merck 9385) eluting with ethanol: dichloromethane: 0.88 ammonia (gradient: 15: 3: 1 to 15: 3: 1.5) to give the title compound as a white solid (10.1 g) . Analysis found: C, 56.3; H.7.7; N, 11.0% (C22H32N4O4S.0.80 H2O.0.83 C2H6?) X 0.984 wants; c, 55.8; H.7.6; N.11.1% Example 7 - Tablets a) Compound of the invention 5.0 mg Lactose 95.0 mg Microcrystalline cellulose 90.0 mg Crosslinked polyvinylpyrrolidone 8.0 mg Magnesium stearate 2.0 mg Compression weight 200.0 mg The compound of the invention, the microcrystalline cellulose, the lactose and the cross-linked polyvinylpyrrolidone are screened through a sieve of 500 microns and combined in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and combined with the active mixture. The mixture is compressed into tablets using suitable punches. b) Compound of the invention 5.0 mg Lactose 165.0 mg Pregelatinized starch 20.0 mg Crosslinked polyvinylpyrrolidone 8.0 mg Magnesium stearate 2.0 mg Compression weight 200.0 mg The compound of the invention, the lactose and the pregelatinized starch are combined together and granulated with water. The wet mass is dried and ground. The magnesium stearate and the crosslinked polyvinylpyrrolidone are sieved through a 250 micron sieve and combined with the granules. The resulting mixture is compressed using punches for suitable tablets.

Example 8 - Capsules a) Compound of the invention 5.0 mg Pregelatinized starch 193.0 mg Magnesium stearate 2.0 mg Filling weight 200.0 mg The compound of the invention and the pregelatinized starch are screened through a mesh sieve of 500 microns, combined together and lubricated with magnesium stearate, (sieved through a sieve of 250 microns). The mixture is filled into hard gelatin capsules of an appropriate size. b) Compound of the invention 5.0 mg Lactose 177.0 mg Polyvinylpyrrolidone 8.0 mg Crosslinked polyvinylpyrrolidone 8.0 mg Magnesium stearate 2.0 mg Filling weight 200.0 mg The composition of the invention and the lactose are combined together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and ground. The magnesium stearate and the crosslinked polyvinylpyrrolidine are screened through a 250 micron sieve and combined with the granules. The resulting mixture is filled into hard gelatin capsules of a suitable size.

Example 9 - Syrup a) Compound of the invention 5.0 mg Hydroxypropyl Methylcellulose 45.0 mg Propyl hydroxybenzoate 1.5 mg Butyl hydroxybenzoate 0.75 mg Saccharin sodium 5.0 mg Sorbitol solution 1.0 ml Suitable shock absorbers cs Example 9 (Cont.) Suitable seasoning agents cs Purified water up to 10 ml The hydroxypropyl methylcellulose is dispersed in a portion of warm purified water together with the hydroxybenzoates and the solution is allowed to cool to room temperature. Saccharin sodium, flavorings and sorbitol solution are added to the volumetric solution. The compound of the invention is dissolved in a portion of the remaining water and added to the volumetric solution. Suitable buffers can be added to control the pH in the region of maximum stability. The solution is made up to the volume, filtered and filled into suitable containers.

Example 10 - Injection Formulation % p / v Compound of the invention 1.00 Water for injections B.P. up to 100.00 The sodium chloride can be added to adjust the tonicity of the solution and the pH can be adjusted to that of maximum stability and / or to facilitate the solution of the compound of the invention using an alkali or dilute acid or by the addition of salts suitable shock absorbers. Antioxidants and metal chelating salts can also be included. The solution is clarified, it is made up to its final volume with water and the pH is remeasured and adjusted if necessary, to provide 10 mg / ml of the compound of the formula (I). The solution can be packaged for injection, for example by filling and sealing in ampoules, ampoules or syringes. Ampoules, ampoules or syringes can be filled aseptically (for example the solution can be sterilized by filtration and filled in sterile ampoules under aseptic conditions) and / or terminally sterilized (for example by heating in an autoclave using one of the acceptable cycles) . The solution can be packed under an inert nitrogen atmosphere. Preferably the solution is filled in ampoules, sealed by melting the glass and terminally sterilized. Additional sterile formulations are prepared in a similar manner, containing 0.5, 2.0 and 5% w / v of the compound of the formula (I), to respectively provide 5, 20 and 50 mg / ml of the compound of the formula (I).

Biological Data 1. Test of Human Washed Platelets The inhibition of platelet aggregation by the compounds of the invention is determined according to the following procedure. Whole blood with citrate (1 part 3.8% w / v trisodium citrate, 9 parts blood) was obtained from volunteers, free of medication for at least 10 days prior to donation. The blood is treated with aspirin (O.lmM) and prostacyclin (0: 06μM) prior to centrifugation (1400 g, 4 minutes, 20 ° C). The platelet-rich plasma (PRP) supernatant was isolated and further centrifuged (1400 g, 10 minutes, 20 ° C) to pellet the platelets. The supernatant is discarded and the platelet groupings or pills are resuspended in a physiological salt solution (5mM HEPES, 12mM NaHCO3, 140mM NaCl, 0.74mM KH2P0, 5.6mM D-Glucose and 2.82mM KCl) adjusted to pH 6.4 . This platelet suspension was centrifuged (1400 g, 8 minutes, 20 ° C) and the resulting platelet pool or pill is resuspended in physiological saline solution adjusted to pH 7 4. The resulting washed platelet preparation is diluted to give a final platelet count of 3 x 108/1. The purified human fibrinogen (Knight, L.C. et al., 1981 Thromb.Haemostasis, 46, (3), 593-596), Ca2 + and Mg2 + were added again to the preparation of washed platelets to give the final concentrations of 0.5 mg / ml, 1 mM and 0.5 mM respectively. The addition of the platelets was quantified using a turbido-etric method. The test compounds were incubated with the washed platelets (37 ° C) for 5 minutes prior to the addition of 1 μM of the platelet secretory agonist U-46619 (a stable thromboxane A2-mimetic). The inhibitory potency of the test compounds is expressed as an IC50 value, which is defined as the concentration of the compound required to inhibit the aggregation of platelets by 50%. The following IC50 values were obtained for the compounds of the invention: Table 1 It is noted that in relation to this date, the best method known by the applicant to carry out the present invention, is the conventional one for the manufacture of the objects or products to which it refers. Having described the invention as above, the content of the following is claimed as property:

Claims (13)

1. A compound of the formula (I) or a physiologically functional salt, solvate, or derivative thereof, characterized in that: X represents either CH2-CH2 or CH = CH; And represents a group R ° represent -acS02Me or C0NH2; .and R1 represents S02Me.
2. 2 . A compound according to claim, of the formula (la) or a physiologically functional salt, solvate, or derivative thereof, characterized in that X represents either CH2-CH2 or CH = CH.
3. 3. A compound according to claim 1, of the formula (Ib) or a physiologically functional salt, solvate, or derivative thereof, characterized in that X represents either CH2-CH2 or CH = CH.
4. 4. A compound according to claim 1, of the formula (le) or a physiologically functional salt, solvate, or derivative thereof, characterized in that X represents either CH2-CH2 or CH = CH.
5. 5. The acid { 4- [3-methanesulfonyl-5- (2-piperidin-4-yl- (E) -vinyl) -indazol-1-yl] -piperidin-1-yl} -acetic. the acid. { 4- [3-methanesulfonyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic; the acid. { 4- [3-carbamoyl-5- (2-piperidin-4-yl- (E) -vinyl) -indazol-1-yl] -piperidin-1-yl} -acetic; the acid. { 4- [3-carbamoyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic; the acid. { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl- (E) -vinyl) -lH-indazol-3-yl] -piperidin-1-yl} -acetic; the acid. { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl-ethyl) -1H-indazol-3-yl] -piperidin-1-yl} -acetic; and physiologically functional salts, solvates, and derivatives thereof.
6. 6. The acid { 4- [3-methanesulfonyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic; the acid. { 4- [3-carbamoyl-5- (2-piperidin-4-yl-ethyl) -indazol-1-yl] -piperidin-1-yl} -acetic; the acid. { 4- [1-methanesulfonyl-6- (2-piperidin-4-yl-ethyl) -1H-indazol-3-yl] -piperidin-1-yl} -acetic; or a physiologically functional salt, solvate, or derivative thereof.
7. 7. A compound according to any of claims 1-6, characterized in that it is a salt of the hydrochloride.
8. 8. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1 to 7, or a pharmaceutically acceptable derivative thereof, mixed with one or more physiologically acceptable carriers or excipients.
9. 9. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable derivative thereof, characterized in that it is used in human or veterinary medicine.
10. 10. The use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable derivative thereof, in the manufacture of a therapeutic agent for the treatment of thrombotic disorders.
11. 11. A method of treating a human or animal patient suffering from a condition which is mediated through the glycoprotein GpIIb / IIIa complex or other integrin receptor, characterized in that it comprises administering to the subject an effective amount of a compound in accordance with any of claims 1 to 7, or a pharmaceutically acceptable derivative thereof.
12. 12. A method according to claim 11, characterized in that the condition is a thrombotic disorder.
13. 13. A process for the preparation of a compound according to any of claims 1 to 7, characterized in that it comprises: (A) the reaction of a compound of the formula (II) or a protected derivative thereof, wherein Y is as defined for a compound of the formula (I) and R represents a separation group, with a compound of the formula (III) (III) or a protected derivative thereof; or (B) the interconversion using a compound of the formula (I) or a protected derivative thereof as a precursor; I (C) deprotection of a compound of the formula (IV), wherein X and Y are as defined for a compound of the formula (D, P 'is a carboxyl group or a protected carboxyl group and P "is hydrogen or an amino protecting group, provided that when P' is a carboxyl group , P "is not hydrogen, when P 'is a hydrogen, P" is not a carboxyl group, and / or optionally converting the resulting compound of the formula (I) to a pharmaceutically acceptable derivative thereof.