MXPA01003408A - Benzamide derivatives as thrombin inhibitors - Google Patents

Abstract

There are provided according to the invention novel compounds of formula (I), wherein R1 represents C1-4alkyl or C3-8cycloalkyl, R2 represents C1-4alkyl or C3-4alkenyl, R3 represents hydrogen, C1-3alkyl or halogen, and R4 represents C1-6alkyl, processes for preparing them, pharmaceutical formulations containing them and their use in therapy particularly as thrombin inhibitors.

Description

BENZAMIDE DERIVATIVES AS THROMBIN INHIBITORS This invention relates to a new class of chemical compounds and their use in medicine. In particular, the invention relates to new amide derivatives, to methods for their preparation, to pharmaceutical compositions containing them and to their use as thrombin inhibitors. The thrombin inhibitors have been previously described in International Patent Application No. WO 97/22589. Thrombin is a serine proteinase present in plasma and is formed by the conversion of its pro-thrombin precursor by the action of factor Xa. Thrombin plays a central role in the mechanism of blood coagulation by converting the soluble plasma protein, the fibrinogen, into insoluble fibrin. The insoluble fibrin matrix is required for the stabilization of the primary hemostatic plug. Very significant disease states are related to abnormal hemostasis. With respect to the coronary arterial vasculature, the formation REF .: 128564 Abnormal thrombi due to rupture of an established atherosclerotic plaque is the main cause of acute myocardial infarction and unstable angina. Both the treatment of an occlusive coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) are often accompanied by an acute thrombotic closure of the affected vessel that requires immediate resolution. With regard to the venous vasculature, a high percentage of patients who undergo major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected limb and predisposition to pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs both within vascular systems during septic shock, and in certain viral infections and cancer, and is characterized by the rapid consumption of coagulation factors and systemic coagulation that results in the formation of menopausal thrombi. life that are presented throughout the vasculature that leads to extended organ failure. Beyond its direct role in the formation of blood clots rich in fibrin, thrombin has been reported to have profound bioregulatory effects on a number of cellular components within the vasculature and blood, (Shu an, MA, Ann. Sci., 405: 349 (1986)). Inhibition of thrombin has been implicated as a potential treatment for a number of disease states. Thrombin inhibitors may be useful in the treatment of acute vascular diseases such as coronary thrombosis, stroke, pulmonary embolism, deep wound thrombosis, restenosis, atrial fibrillation, myocardial infarction, and unstable angina. They have been described as anticoagulant agents both in vivo and ex vivo and in edema and inflammation, whereby a low dose of thrombin inhibitor can reduce inflammatory responses mediated by thrombin of endothelial cells and platelets, without concomitant anticoagulant effects. Thrombin has been reported to contribute to the proliferation of fibroblasts of lung, and in this way, thrombin inhibitors could be used for the treatment of some fibrotic, lung diseases. Thrombin inhibitors have also been reported in the treatment of tumor metastasis, whereby the thrombin inhibitor prevents fibrin deposition and metastasis caused by the activation of the property of Factor X by the cis-proteinase-produced by certain tumor cells. They have been shown to inhibit neurite retraction and thus may have a potential in neurogenerative diseases such as Parkinson's and Alzheimer's disease. It has also been reported that they are used in conjunction with tro-bolic agents by allowing the use of lower doses of the thrombolytic agent. Other potential uses have been described in US 5,371,091 for the treatment of Kasabach Merritt syndrome and hemolytic uremic syndrome in EP 565897 for the prevention of fibrin deposits in the eye during ophthalmic surgery, and in DE4126277 for the treatment of osteoporosis.

In this manner, a new class of amide derivatives which act as thrombin inhibitors shown as formula (I) have been found. wherein ~ R1 represents alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 8 carbon atoms; R2 represents alkyl of 1 to 4 carbon atoms or alkenyl of 3 to 4 carbon atoms; R3 represents hydrogen, alkyl of 1 to 3 carbon atoms or halogen; R4 represents alkyl of 1 to 6 carbon atoms; and pharmaceutically acceptable derivatives or solvates thereof. With reference to the general formula (I), alkyl includes saturated hydrocarbon groups, both straight and branched chain, for example, methyl ethyl, and isopropyl; cycloalkyl includes saturated, cyclic hydrocarbon groups, for example cyclopentyl and cyclohexyl; alkenyl includes both straight and branched chain hydrocarbon groups containing a double bond, for example, propenyl, 2-methylpropenyl and butenyl. It will be appreciated that a compound of the formula (I) contains a chiral center at the position indicated by *. In this way, each compound within the formula (I) can exist in two isomeric, optical, different forms. The scope of the present invention is extended to cover the individual enantiomers of the compounds of the formula (I) and mixtures of enantiomers of the compounds of the formula (I) in any proportion, including racemic mixtures. In general, it is preferred to use a compound of the formula (I) in the form of a single, purified enantiomer, more preferably the (S) isomer. With reference to the general formula (I), R1 suitably represents propyl, isopropyl, butyl, cyclopentyl or cyclohexyl. RJ is preferably isopropyl. R2 is suitably methyl, ethyl, propyl isopropyl. R2 is preferably ethyl. R3 is suitably methyl or chloro. RJ is preferably methyl. R 4 is preferably methyl or ethyl. R 4 is preferably methyl. Suitable compounds of the general formula (I) for use according to the invention include: N-Ethyl-H-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; N, N-Diisopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; N-lsopropyl-3, N-dimethyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; 3, N-Dimethyl-N-propyl-5- [2S- (pyridin--ylamino) -propoxy] -benzamide; 3-Methyl-N, N-dipropyl-5- [2S- (pyridin--ylamino) -propoxy] -benzamide; N-Ethyl-3-methyl-N-propyl-5- [2S- (pyridin--ylamino) -propoxy] -benzamide; N-Butyl-3-methyl-N-propyl-5- [2S- (pyridin--ylamino) -propoxy] -benzamide; N-Cyclohexyl-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; N-Isopropyl-3-methyl-N-propyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; 3-Chloro-N-isopropyl-N-propyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; 3-Chloro-N, N-diisopropyl-5- [2- (pyridin--ylamino) -butoxy] -benzamide; and pharmaceutically acceptable derivatives or solvates thereof. Particular compounds of the general formula (I) for the use of the invention include: N-Ethyl-N-isopropyl-3-me thi-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; and pharmaceutically acceptable derivatives or solvates thereof. By a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, or a metabolically labile or stable derivative, for example, a derivative of an amine group, of a compound of the formula (I) or any other compound, which upon administration to the recipient, is capable of providing (either directly or indirectly) a compound of the formula (!) or an active metabolite or residue thereof. It will be appreciated by those skilled in the art that the compounds of the formula (I) can be modified to provide pharmaceutically acceptable derivatives thereof in any of the functional groups in the compounds of the formula (I). These derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teachings of Burger 's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice, which is incorporated herein by reference. Preferred pharmaceutically acceptable derivatives of the compounds of the formula (I) are pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts of the formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic acid, toluene-p-sul phonic, di-p-toluoyl-tartrate, sulfanilic, tartaric, acetic, citric, methanesulfonic, Formic, benzoic, malonic, naphthalene-2-sulphonic, and benzenesulfonic. Preferred pharmaceutically acceptable salts of the compounds of the formula (I) include the salt of toluene-p-sulphonic acid. Other acids such as oxalic acid, while in themselves are not pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in the preparation of compounds of the invention and their acid addition salts, pharmaceutically acceptable. The suitability of the compounds of formula (I) as thrombin inhibitors is exhibited by their ability to inhibit human thrombin in a chromogenic assay alpha- using Np-tosyl-gly-pro-lys p-nitroanilide as-the substrate chromogenic Additionally, the compounds of the formula (I) exhibit an effective anticoagulant activity in vitro "as indicated by the APTT assays described herein. Additionally, compounds of formula (I) exhibit anti activity thrombus effective tica as indicated in the model Derivation arteriovenous, described herein. In this way, the compounds of the formula (I) are useful in the treatment of clinical conditions susceptible to improvement by the administration of a thrombin inhibitor. These conditions include acute vascular diseases such as coronary thrombosis, seizure, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, restenosis, and atrial fibrillation; in inflammatory diseases mediated by edema and FAP such as respiratory distress syndrome in adults, septic shock, and reperfusion injury; the treatment of pulmonary fibrosis; the treatment of tumor metastasis; neurogenerative disease such as Parkinson's and Alzheimer's diseases; Viral infection; Kasabach Merritt syndrome; hemolytic uremic syndrome; arthritis; osteoporosis; as anticoagulants for blood extrapolation in, for example, dialysis, blood filtration, bypass, and storage of blood products; and in the lining of invasive devices such as prostheses, artificial valves and catheters in reducing the risk of trauma formation. Accordingly, the present invention provides a method of treating a mammal, including man, that suffers from conditions susceptible to improvement by a thrombin inhibitor, which method comprises administering to the subject an effective amount of a compound of the general formula ( I) or a pharmaceutically acceptable derivative thereof. References in this treatment specification include prophylactic treatment as well as relief of symptoms. In a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for use as a therapeutic agent for use in medicine, particularly human medicine.

In a further aspect, the invention provides the use of a compound of the general formula (I) or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of a condition susceptible to improvement by a thrombin inhibitor. . While it is possible that, for use in therapy, a compound of the invention can be administered as the primary chemical, it is preferred to present the active ingredient as a pharmaceutical formulation. Thus, the invention further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative therein together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic ingredients and / or prophylactic . The compounds of the present invention may be used in combination with other antithrombotic drugs such as thromboxane receptor antagonists, prostacyclin mimetic compounds, phosphodiesterase inhibitors, fibrinogen antagonists, thrombolytic drugs such as tissue plasminogen activator and is treptokinase, non-steroidal anti-inflammatory drugs such as aspirin, and the like. In this manner, the compounds for use according to the present invention can be formulated for oral, buccal, parenteral, topical, rectal or transdermal administration, or in a form suitable for administration by inhalation or insufflation (either through of the mouth or nose). For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium acid phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or starch glycolate sodium); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as dispersing agents (eg, sorbitol syrup, cellulose derivatives or edible, hydrogenated fats); emulsifying agents (for example, lecitin or gum arabic); non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or vegetable oils, fractionated); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring agents, colorants or sweeteners, as appropriate.

Preparations for oral administration can be suitably formulated to give controlled release of the active compound. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. The compounds according to the present invention can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in a unit dose form, for example, in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents, such as suspending agents, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use.

The compounds according to the present invention can be formulated for topical administration by insufflation or inhalation. Examples of the types of preparation for topical administration include sprinklers or aerosols for use in an inhaler or insufflator, or a powder formulated for the use of an inhaler. Powders for external application can be formulated with the aid of any suitable powder base, for example, lactose, talc or starch. The spray compositions can be formulated as aqueous solutions or suspensions or as aerosols derived from pressurized containers, such as metered dose inhalers, with the use of a suitable propellant. The compounds with the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds can also be formulate as a deposit preparation. These long-term action formulations can be administered by implantation (eg, subcutaneously transcutaneously or intramuscularly), or by intramuscular injection. Thus, for example, the compounds according to the present invention 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. A proposed dose of the compounds according to the present invention for administration to the human (approximately 70 kg of body weight) is 0.1 mg to 1 g, preferably 1 mg to 500 mg of the active ingredient per unit dose, expressed as the weight of the free base. The unit dose can be administered, for example, from 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dose depending on the age and weight of the patient as well as the severity of the condition that is going to be treated. The precise dose and the route of administration will finally be at the discretion of the attending physician or veterinarian. The compounds of the invention can be prepared by any of the processes known in the art for the preparation of similar compounds. For example, according to a first process (A) wherein R1, R2, R3 and R4 are as previously defined, compounds of the formula (I) can be prepared by deprotection of a compound of the formula (II) ). wherein P1 represents a suitable protecting group such as tert-butoxycarbonyl, under suitable conditions, for example, acidic conditions for the removal of the tert-butoxycarbonyl group. According to a second process, (B), a compound of the formula (I) can be prepared with the reaction of a compound of the formula (III) with a compound of the formula (IV).

(III) (iv) wherein R7 represents hydrogen, and L represents hydroxyl. The coupling is conveniently carried out using the normal reagents such as diethyl azodicarboxylate, and triphenylphosphine in a suitable solvent such as toluene. According to a third process, (C), a compound of the formula (I) can be prepared by the reaction of a compound of the formula (III) with a compound of the formula (IV) wherein R7 represents hydrogen, and L represents a residual, suitable group, such as chlorine, in the presence of a suitable base, such as chlorine, in the presence of a suitable base, such as potassium carbonate. The coupling is conveniently carried out in a suitable solvent such as N, N-dimethylformamide, preferably at elevated temperature. According to a fourth process, (D), a compound of the formula (I) can be prepared from the reaction of the compounds of the formula (V) and the formula (VI).

(SAW) wherein R represents hydrogen. The reaction can conveniently be carried out in the presence of an activating agent or agents such as 1-hydroxybenzotriazole, 2- (IH-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyl-tetrahydroborate. iluronium, (TBTU) and a base such as ethyldiiopropylamine in a suitable solvent such as N, N-dimethylformamide. A compound of the formula can be prepared (II) by the reaction of a compound of the formula (III) with a compound of the formula (IV), wherein R7 represents P1, as defined above, and L represents hydroxyl or a suitable residual group such as 4-toluenesulfonate (tosylate). Where L represents hydroxyl, the coupling is conveniently carried out using conditions such as those used in a similar manner for the process of (B). Where L represents tosylate, the coupling is conveniently carried out in a suitable solvent, such as N, N-dimethylformamide, in the presence of a suitable base such as sodium hydride. A compound of the formula (II) can also be prepared by the reaction of the compounds of the formula (V) and the formula (VI) wherein R represents P1, as defined above, using suitably the process conditions ( D). The compounds of the formula (III) can be prepared from the compounds of the formula (VII). conveniently using boron tribromide in a suitable solvent such as dichloromethane. The compounds of the formula (III) can also be prepared from the compounds of the formula (IX).

(IX) conveniently, by reaction with an acid chloride such as pivaloyl chloride, in the presence of a base such as triethylamine, in a suitable solvent such as toluene, followed by the reaction of the compounds of the formula (VI). The compounds of the formula (VII) can be prepared by the reaction of the compounds of the formula (VIII) and the formula (VI).

(Saw) conveniently according to the process conditions (D). Alternatively, the reaction of the compounds of the formula (VIII) and the formula (VI) can be carried out using oxalyl chloride in the presence of N, N-dimethylformamide in a suitable solvent such as tetrahydrofuran. The compounds of the formula (V) can be prepared by the oxidation of the aldehyde corresponding to the formula (X) wherein R7 represents hydrogen or P1. The conversion is effected by the treatment of the aldehyde with a suitable oxidizing agent such as sodium chlorite in the presence of sulfamic acid in a mixture of water and 1,4-dioxane.

The compounds of the formula (X) can be prepared from the compounds of the formula (XI) and (IV) where R7 represents hydrogen or P1 and L represents hydroxyl or a suitable residual group such as 4-toluensul fonate (tosylate), with the proviso that L is a suitable residual group, R7 preferably represents P1. Where L represents hydroxyl, the coupling is carried out using the normal reagents identical to those used in the process (B) Where L represents tosylate, the coupling is carried out in a suitable solvent such as N, N-di-ethylformamide in the presence of a suitable base such as sodium hydride. • The. compounds of the formula (V) can also be prepared from the compounds of the formula - (XII) wherein R7 represents hydrogen or P1 'and R8 represents a suitable protecting group such as alkyl, for example, methyl. The reaction is carried out using appropriate conditions such as lithium hydroxyl in 1,4-dioxane or aqueous sodium hydroxide in ethanol. The compounds of the formula (XII) can be prepared from the reaction of the compounds of the formula (XIII) and (IV) (XIII) (IV) wherein R7 represents hydrogen or P1, R8 represents a suitable protecting group such as alkyl, for example, methyl, and L represents hydroxyl or a group suitable residual such as 4-toluensul fonate (tosylate), with the proviso that L is a suitable residual group, R 'represents preferably P1, using the appropriate conditions similar to those used for the synthesis of the compounds of the formula (X). The compounds of the formula (IV), (VI), (VIII), (IX), (XI), and (XIII) are known in the art or can be prepared by the normal methods as described herein.

Biological assays I. Thrombin inhibitory activity. The compounds of the invention possess thrombin inhibitory activity as determined in vitro for their ability to inhibit human a-thrombin where a chromogenic assay, using N-p-tosyl-gly-pro-lys p-nitroanilide as the chromogenic substrate. All dilutions were made in a buffer consisting of: 50 mM HEPES, 150 mM NaCl, 5 mM CaCl 2, 0.1% PEG and pH 7.4. Briefly, the substrate (final concentration of 100 μM) was added to thrombin (final concentration of 1 nM) and the reaction was inspected for 10 minutes at 405 nm using a Bíotek EL340 plate reader; the test was carried out at room temperature. To obtain the IC50, the data was analyzed using KineticalcMR and processed using Activi tyBaseMR, to obtain the IC50 value. To determine the IC50 at zero and 15 minutes, the cojapuestos were pre-incubated with thrombin during these times before adding the chromogenic substrate.

II. Protocol for APTT The compounds of the invention possess anticoagulant activity as determined in vitro by their ability to extend the clotting time of human plasma, the activated, partial thromboplastin time (APTT). The citrated, mixed plasma (trisodium citrate at 0.38% w / v) was prepared from blood taken from healthy volunteers and stored at -70 ° C. The APTT tests were performed using a Trombotrack 4 from Nicomed. The actin reagent (a reconstituted extract of dehydrated rabbit brain, which also contains ellagic acid) was obtained from Baxter Healthcare Corporation USA. Briefly, the coded plasma was added to either the compound or distilled water followed by the addition of the actin reagent. These were then mixed for 2 minutes at 37 ° C before adding calcium chloride to start coagulation. The compounds extended the normal coagulation time, which is in the range of 30-35 seconds, to varying degrees depending on their concentrations. The degree of extension of the APTT was calculated by the ratio of the coagulation times in the presence of the compound. The concentration of the compound to extend the "normal" APTT by 1.5x was used as a criterion to compare the anticoagulant activities of the compounds.

Results The results below illustrate the thrombin inhibitory activity and the anti-coagulant activity of a range of compounds of the formula (I) using the biological methods described above: III. 'Protocol for the Arterio-Venous Derivation Model The compounds of the invention possess antithrombotic activity as determined in vivo for their ability to reduce thrombus formation in a rat arteriovenous shunt model. Anesthetized rats (Inactin 120 mg / kg i.p.) were prepared by the insertion of a shunt extracorporeal between the left carotid artery and the right jugular vein. The derivation consisted of two sections of 12 cm polythene tubing (Portex, 0.58 and 0.86 mm internal diameter, respectively) connected by 3 mm silicone rubber plugs (base diameter) (Jencons Scientific Ltd) to a length of 6 cm of polythene tubing (Portex, internal diameter of 3 mm). The pipeline was connected via holes; perforated through the center of each plug. An 8 cm piece of silk thread was held taut between the two plugs, passing through the central holes, so that it remained longitudinally oriented in the central portion of the branch. Prior to the placement of the cannula, the shunt was filled with 154 mM sodium chloride solution (saline). After placement of the cannula, a hemostatic clamp was left in place in the carotid artery to prevent blood flow through the shunt. The left carotid artery was also fitted with instruments' with an ultrasonic flow probe (Transonic Systems Inc., 0.5 mm) that was connected to a transonic flow meter (model T206) for the continuous display of the blood flow of the phasic carotid artery. The blood flow of the continuous carotid artery was acquired by a MI2 data acquisition system (Modular Instruments Ine.). After the placement of the cannula in the shunt, and a period of equilibrium, the protocol was started by the administration of the composite vehicle. The pre-treatment time was 30 minutes and the removal of the hemostatic clamp of the carotid artery was followed, thus allowing blood flow through the bypass. After 15 minutes the blood flow from the shunt, the arterial clamp was replaced, the shunt was removed, "and 0.5 ml of saline was slowly injected through the central portion of the shunt to remove free blood. and the associated thrombus was carefully removed and the weight of the thrombus determined.The coagulation parameters were calculated, including the time of activated partial thrombin (APTT) .The blood sample of 2 ml was taken by a direct cardiac punch and transferred to a tube that contains trisodium citrate (ratio 9: 1, final citrate concentration of 12.9 mM). The blood sample was mixed gently and transferred to eppendorf tubes and centrifuged at 10,000 g for 2 minutes. The plasma was decanted and stored at 4 ° C until the analysis. All tests were performed on an automated Sysmex CA5000 analyzer according to the instruction manual. Antithrombotic activity was assessed by a decrease in thrombus weight, an extension in occlusion time, and an increase in the area of the thrombus. blood flow, and the effects on the measured coagulation parameters were related. The invention is further illustrated by the following intermediates and examples.

Abbreviations H .p .1. c. High Resolution Liquid Chromatography Rt Retention Time DIPEA N-Eti Idi isopropyl amine DMF N, N-Dimet ilformamide TBTU Tetrafluoroborate 2- (lH- benzo-triazol-1-yl) -1, 1, 3, 3-tetramethyluronium. DMAP 4-Dimethylaminopyridine br broad s singlet d doublet triplet m muí tiplete t .1. c. Thin layer chromatography Methods H.p.l.c. Analytical in a Hewlett Packard Series II 1090 liquid chromatograph using a C-18 Rainin Microsorb column (size 4.6 x 150 mm, catalog number 80-215-C) operating at a flow rate of 1.5 ml / min. The eluents were A: 0.1% trifluoroacetic acid / water, B: 0.05% trifluoroacetic acid / acetoni trilo.

Gradients System 1: 15-95% B in A for 15 min, Retention times are given for a wavelength (?) Of 254 nm unless otherwise indicated H.p.l.c. Preparation: System A: Supelcosil LC-ABZ column (size 21.2 mm x 25 cm or 21.2 mm x 10 cm) operating at 15 ml / min (the eluents were A: 0.1% trifluoroacetic acid / water, B: trifluoroacetic acid al 0.01% in acetonitrile / water at 95: 5) System B: Prochrom.50 mm column with 200 g of Sorbil C60 silica gel operating at 80 ml / min [the eluent was: dichloromethane (80), methanol (20), acetic acid (0.5) and ammonia (0.5)] Tlc It was carried out using silica Camlab (PolygramR SILG / UV254). The eluent was dichloromethane: ethanol: aqueous ammonia in the indicated ratio. The flash column chromatography was carried out on Merck silica gel (Merck 9385) or using Megabond Elut® SI cartridges (bound phase, normal, size 60 cc / 10 g) Intermediate 1 (S) -2- (2, 3, 5, 6-Tetrachloro-pyridin-4-ylamino) -propan-l-ol To a solution of pentachloropyridine (30 g) in 2-propanol (300 ml) was added DIPEA (18 ml), DMAP (0.8 g) and (S) - (+) -2-amino-1-propanol (18 g), and the reaction mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methanol and filtered to give the title compound as a white solid (18 g). Mass spectrum: Found: MH + 279.

Intermediate 2 (S) -2- (Pyridin-4-ylamino) -propan-1-ol A mixture of (S) -2- (2, 3, 5, β-tet racloro-pyridin-4-ylamino) -propan -1-ol (6 g), 10% palladium on carbon (3 g), potassium carbonate (14.3 g) and ethanol (110 ml) was stirred under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through Harbolite ™ and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (3.2 g) Mass spectrum: Found: MH + 153 Intermediate 3 3-Methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzoic acid A mixture of 3-methyl-5 [2S- (pyridin-4-ylamino) -propoxy] -methyl ester - Benzoic acid (9.5 g) and 2M sodium hydroxide solution (31.5 ml) in ethanol (100 ml) was heated at 60 ° C for 1 hour. On cooling, the reaction mixture was neutralized with 2M hydrochloric acid to pH 7 and concentrated under reduced pressure. The residue was subjected to flash column chromatography, eluting with dichloromethane: ethanol (4: 1), ethanol, and me tanol: formic acid (10: 1), to give an impure sample of the title compound of the title. The purification < Additional using Megabond flash chromatography, eluting with dichloromethane: ethanol (4: 1) and methanol, gave the title compound as a pale yellow solid (6.8 g) Mass spectrum; Found: MH + 287.

Intermediate 4 3-Met il-5- [2S- (pi ridin-4-ylamino) -propoxyl] -benzoic acid methyl ester (A :) A mixture of methyl 3-hydroxy-5-methylbenzoate1 (11.2 g), triphenylphosphine (17.7 g), (S) -2- (pyridin--ylamino) -propan-1-ol (10.3 g) and tetrahydrofuran (300 ml) was treated for 10 minutes with diethyl azodicarboxylate (10.6 ml) and the solution The resulting mixture was stirred at room temperature, under nitrogen for 72 hours. The reaction mixture was concentrated under reduced pressure and the crude product was subjected to flash column chromatography, eluting with dichloromethane: ethanol: aqueous ammonia (95: 5: 0.5), to give the title compound as a colorless oil (9.5 g ). Mass spectrum: Found: MH + 301. (B :) A mixture of methyl 3-hydroxy-5-methyl methylbenzoate 1 (8 g), tributylphosphine (11.9 ml), (S) -2- (pyridine-4 - ilamino) -propan-1-ol (4.9 g) and toluene (300 ml) was treated with 1,1 '- (azodicarbonyl) dipiperidine (12.1 g) and the resulting solution was stirred at room temperature, under nitrogen for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to flash column chromatography eluting with chloroform: methanol: aqueous ammonia (95: 5: 1) to give the title compound as an oil (13.3 g) Mass spectrum: Found: MH + 301.

Intermediate 5 Ethyl ester of 2 - (tert-Butoxycarboni 1-pyridin-4-yl-amino) -butyric acid To a solution of the tert-butyl ester of pyridin-4-yl-carbamic acid 2 (2 g) in dry DMF (25 g) ml) was added sodium hydride (60% dispersion in mineral oil 0.54 g) and ethyl 2-bromobutyl (1.7 ml). The mixture was stirred at room temperature for 18 hours. Water (25 ml) was added and the mixture was extracted with ethyl ether. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The crude product was subjected to flash column chromatography eluting with cyclohexane: ethyl acetate (4: 1)), to give the title compound as a colorless oil (0.332 g). Mass spectrum: Found: MHT 295.

Intermediate 6 2- (pyridin-4-ylamino) -butan-1-ol A stirred solution of 2- (tert-butoxycarbonyl-pyridin-4-ylamino) butyric acid ethyl ester (0.33 g) in ethanol (5 ml) treated with sodium borohydride (0.12 g) and stirring was continued for 18 hours. Water (1 ml) was added and the mixture was concentrated under reduced pressure. The residue was absorbed with silica and the resulting powder was loaded onto a flash column that was eluted with methanol: chloroform: aqueous ammonia (10: 89: 1). The title compound (0.168 g) was obtained as an oil after evaporation of the product containing the fractions. Mass spectrum: Found MH + 167.

Intermediate 7 3-Chloro-N, N-diisopropyl-5-methoxy-benzamide Oxalyl chloride (2.36 ml) was added dropwise to a solution of DMF (0.1 ml) and 3-chloro-5-methoxybenzoic acid (4.67 g) in anhydrous tetrahydrofuran (100 ml). After 1 hour, diisopropylamine (3.75 ml) and DIPEA (9.51 ml) were added and stirring was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was extracted with 1M hydrochloric acid, and saturated aqueous sodium carbonate and water. After drying the organic phase with brine and over sodium sulfate, the solvent was removed under reduced pressure to give the title compound as a brown solid (4.6 g). Mass spectrum: Found: MH + 270.

Intermediate 3-Chloro-5-hydroxy-N, N-diisopropyl-benzamide To a stirred solution of 3-chloro-N, N-diisopropyl-5-methoxy-benzamide (2.96 g) in anhydrous dichloromethane (30 ml) at -78 ° C a solution of boron tribromide in dichloromethane (40 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred for 19 hours. The The reaction mixture was cooled to -78 ° C and methanol (20 ml) was added. The reaction mixture was allowed to warm again to room temperature, stirred for 24 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with water and dried over brine, and over sodium sulfate. The crude product was purified by flash column chromatography, eluting with cyclohexane: ethyl acetate (1: 1), to give the title compound as a white solid (2.24 g) System 1 of H.p.l.c., Rt 11.1 min.

Intermediate 9 3-Chloro-5- [2S- (pyridin-4-ylamino) -propoxy] -benzoic acid methyl ester To a mixture of 3-chloro-5-hydroxy-benzoic acid methyl ester4 (4.5 g), triphenylphosphine (6.3 g), (S) -2- (pyridin--ylamino) -propan-1-ol (3.65 g) and tetrahydrofuran (100 ml) was treated for 10 minutes with diethyl azodicarboxylate (5.7 ml) and the solution The resultant was stirred at room temperature, under nitrogen for 96 hours. The reaction mixture was concentrated under reduced pressure and the crude product was subjected to flash column chromatography, eluting with dichloromethane: methanol: aqueous ammonia (97: 3: 0.3) to give the title compound as a colorless oil (1.5 g) Mass spectrum: Found: MH + 321 Intermediate 10 Acid 3-Chloro-5- [2 S- (pyridin-4-ylamino) -propoxy] benzoic acid 3-Chloro-5- [2S- (pyridin-4-ylamino) -propoxy] -benzoic acid methyl ester (1.47 g) in ethanol (15 ml) and 2M sodium hydroxide solution (4.6 ml) were heated at 60 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure and acidified with acetic acid pH 4. The resulting solution was hydrated with diethyl ether and a precipitated solid was completely filtered. The solid was stirred in water, and then filtered to give the title compound as a cream solid (1.1 g) Mass spectrum: Found: MH + 307 Intermediate 11 N- [(SS) -2-chloro-1-methylethyl] pyridine-amine hydrochloride The (S) -2- (Pyridin-1-ylamino) -propan-1-ol (15 g) was treated in dichloromethane (150 ml) with thionyl chloride (59 g) while maintaining the temperature at < 10 ° C, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (20.1 g) Mass spectrum: Found: MH + 171 Intermediate 12 N-Ethyl-3-hydroxy-N-isopropyl-5-methyl-benzamide A suspension cooled (<5 ° C) 3-hydroxy-5-methylbenzoic acid 1 (50 g) in triethylamine (100 g) and toluene (500 ml) under nitrogen was added pivaloyl chloride (97.2 ml) and the resulting mixture was stirred at 0-5 ° C for 2 hours. Ethyl isopropylamine (55.7 ml) was added, the reaction mixture was stirred at 0-5 ° C for 2 hours and allowed to reach room temperature. The mixture was washed twice with water and concentrated under reduced pressure to leave a dark oil. This oil was dissolved in ethanol (500 ml) and treated with a 5M solution of NaOH (100 g of NaOH in 500 ml of water) for 3 hours at room temperature. The ethanol was removed under reduced pressure and the resulting basic solution was diluted with water and extracted with toluene. The basic layer was acidified with acetic acid to pH 5 and the resulting aqueous mixture was extracted with dichloromethane. The combined organic extracts were washed with brine and concentrated under reduced pressure to give the title compound as an orange / brown solid (41 g). Mass spectrum: Found: MH + 222 Example 1 N-Ethyl-N-isopropyl-3-methyl-5- [2S (pyridin-4-ylamino) -propoxy] -benzamide To a solution of N-ethyl-3-hydroxy-N-isopropyl-5-met ilbenzamide (5 g) in DMF (50 ml) was added potassium carbonate (14.1 g). The mixture was heated to 4.5 ° C and N- [(SS) -2-chloro-1-methylethyl] pyridin-4-amine hydrochloride (9.4 g) was added in portions over 5 minutes. heated to 115-120 ° C and stirred at this temperature for 100 hours. After cooling to room temperature, water (100 ml) was added and the resulting slurry was extracted with dichloromethane. The combined organic phases were washed with 10% NaOH (10 g in 100 ml of water), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The oil was purified by flash column chromatography eluting with dichloromethane: methanol: aqueous ammonia (98: 1: 1) - (94: 5: 1), to give the title compound as a yellow oil (4.4 g) Mass spectrum : Found: MH + 356 XH-NMR d ppm (DMSO-d6) 8.04 (1 / 2AA 'BB', 2 H), 6.90 (brs, 1H) 6.72 (brs, 1H), 6.67 (brs, 1H), 6.58 ( 1 / 2AA'BB *, 2H), 4.45, 3.83 (2 x brs, 1H), 4.05-3.90 (m, 3H), 3.33 (m, 2H), 2.32 (s, 3H), 1.28 (d, 3H) , 1.30-1.05 (m, 9H).

The compound of Example 1 can also be prepared according to the following procedure.

N-Ethyl-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide A mixture of 3-met il-5- [2S- (pyridin-4-ylamino) acid -propoxy] benzoic (0.1 g), TBTU (0.225 g), DIPEA (0.5 ml) and N-ethisopropylamine (0.09 ml) in dry DMF (2 ml) was stirred at room temperature for 60 hours. The reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The combined organic fractions were dried with brine and magnesium sulfate, and concentrated under reduced pressure. The crude product was subjected to Megabond flash column chromatography eluting with dichloromethane: ethanol: aqueous ammonia (95: 5: 0.5), to give the title compound as a yellow oil (0.097 g). T.l.c. (95: 5: 0.5) Rf 0.3. Mass spectrum: Found: MH + 356.

Prepared in a similar manner using commercially available amines were: Example 2 N, N-Di i sopropi 1-3-met il-5- [2S- (pyridin-α-amino-propoxy] -benzamide T. l.c. (95: 5: 0.5) Rf 0.1 Mass Spectrum: Found: MH + 370 Example 3 N-Isopropyl-3, N-dimethyl-5- [2S- (pyridin-α-amino-propoxy] -benzamide T.1., C. (95: 5: 0.5) Rf 0.3 Mass spectrum: Found: MH + 342 Example 4 3, N-Dimethyl-N-propyl-5- [2S- (pyridin-4-ylamino-propoxy] -benzamide T.l.c. (95: 5: 0.5) Rf 0.3 Mass spectrum: Found: MH + 342 Example 5 3-Methyl-N, N-dipropyl-5- [2S- (pyridin-4-ylamino) propoxy] -benzamide T.l.c. (95: 5: 0.5) Rf 0.3 Mass spectrum: Found: MH + 370 Example 6 N-Ethyl-3-methyl-N-propyl-5 [2S- (pyridin-4-ylamino) propoxy] -benzamide T.l.c. (95: 5: 0.5) Rf 0.3 Mass spectrum: Found: MH + 356 Example 7 N-Butyl-3-methyl-N-propyl-5- [2S- (pyridin-4-ylamino) propoxy] -benzamide T.l.c. (95: 5: 0.5) Rf 0.3 Mass spectrum: Found: MH + 384 Example 8 N-Cyclohexyl-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide T.1. c. (95: 5: 0.5) Rf 0.3 Mass spectrum: Found: MH + 410 Example 9 N-Isopropyl-3-methyl-N-propi 1-5- [2S- (pyridin-4'-ylamino) -propoxy] -benzamide T.l.c. (100: 8: 1) Rf 0.3 Mass spectrum: Found: MH + 370 Example 3-Chloro-N- i sopropi-N-propyl-5 - [2 S - (pi ri din-4-ylamino) -propoxy] -benzamide A "mixture of 3-chloro-5-acid" - [2S- (pyridin-4-ylamino) -propoxy] -benzoic acid (0.1 g), TBTU (0.225 g), DIPEA (0.5 ml) and N-propyl-isopropy sheet (0.067 g) in dry DMF (2 ml) The mixture was poured into saturated aqueous sodium bicarbonate, extracted with ethyl acetate.The combined organic extracts were concentrated under reduced pressure and the residue was subjected to Megabond flash column chromatography, eluting with dichloromethane: methanol: aqueous ammonia (95: 5: 0.5) to give the title compound as a yellow oil (0.08 g) TLC (97: 3: 0.3) Rf 0.2 Mass spectrum: Found: MH + 390 Example 11 3-Chloro-N, N-dii-sopropyl-5- [2- (pyridin-4-ylamino) -butoxy] -benzamide hydrochloride A mixture of 3-chloro-5-hydroxy-N, N-diisopropyl-benzamide (0.05 g), 2 - (pyridin-4-) ilamino) -butan-1-ol (0.023 g), triphenylphosphine (0.04 g) and toluene (1 ml), was treated with diisopropyl azodicarboxylate (0.03 ml) and the resulting solution was stirred under nitrogen for 8 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography eluting with chloroform: methanol: aqueous ammonia (90: 10: 1), to give an impure sample of the title compound. This impure sample was subjected to H.p.l.c. preparation (system A) and the purified material was treated with 1M hydrogen chloride in ether and ethyl, to give the title compound as a gum (0.002 g) Mass spectrum: Found: MH + 404 Hplc system 1, Rt 11.1 min .

EXAMPLE 12 N-Ethyl-N-isopropyl-3-met-il-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide hydrochloride N-ethyl-N-isopropyl-3-methyl-5- [ 2S- (pyridin-4-ylamino) -propoxy] -benzamide (6.21 g) in 2M hydrochloric acid (35 ml) was stirred for 10 minutes, and then the mixture was concentrated under reduced pressure.

The residue was azeotroped with acetonitrile twice. This whole procedure was repeated to give the title compound as an amorphous powder (6.19 g). Mass spectrum: Found: MH + 356 System 1 of H.p.l.c., Rt 7.0 min.

The compound of Example 12 can also be prepared according to the following procedure.

N-Ethyl-N-isopropyl-3-met-il-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide hydrochloride A mixture of 1,1 '- (azodicarbonyl) -dipiperidine (10.3 g) and tributyl phosphine (10.3 g), in toluene (350 ml) was treated with (S) -2 (pyridin-4-ylamino) -propan-1-ol (4.1 g) and N-et il-3-hydroxy-N -isopropyl-5-methylbenzamide (12 g) and the resulting solution was stirred at 40 ° C under nitrogen for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a light brown oil which was partially purified by H.p.l.c. preparatory (system B). The resulting oil (21.17 g) was dissolved in dichloromethane and washed with aqueous ammonia solution, water and brine and then concentrated under reduced pressure to produce an oil (5.74 g) this oil was dissolved in tetrahydrofuran (50 ml), a mixture of methanol (0.52 ml) and acetyl chloride (1.12 g) was added. ml) and stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and the residue was azeotroped with diisopropyl ether to give the title compound as a white foam (3.7 g) Mass Spectrum: Found: MH + 356 X H-NMR d ppm (DMSO-d 6) 13.62. brs, 1H), 8.84 (brd, 1H) 8.22, 8.07 (brd, 2H), 7.02, 6.93 (2 x brd, 2H), 6.78 (brs, 1H), 6.68 (brs, 1H), 6.60 (brs, 1H) ), 4.40, 3.76 (brs, 1H), 4.22 (m, 1H), 4.06, 3.98 (ABX, 2H), 3.29, 3.12 (2 x brs, 2H), 2.27 (s, 3H), 1.28 (d, 3H) ), 1.25-1.00 (brm, 9H).

Example 13 N-Ethyl-N-isopropyl-3-met-il-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide 4-Methylbenzenesulfonate To a solution of N-ethyl-N-isopropyl-3 -methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide (3 g) in isopropyl alcohol (30 ml) was added acid p-toluenesulfonic acid (1.62 g) and the resulting solution was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to give a pale yellow oil which was redissolved in isopropyl alcohol (10 ml). The resulting solution was then added to diisopropyl ether (50 ml) which resulted in the title compound which was produced as a white crystalline solid (3.22 g). Mass spectrum: Found: MH + 356 XH-NMR d ppm (DMSO-d6) 13.09 (brs, 1H), 8.61 (brd, 1H), 8.23, 8.08 (2 x 1 / 2AA'BB ', 2H), 7.48 ( 1 / 2AA'BB ', 2H), 7.11 (1 / 2AA'BB', 2H), 7.03, 6.88 (2 x 1 / 2AA * BB ', 2H), 6.78 (brs, 1H), 6.68 (brs, 1H) ), 6.60 (brs, 1H), 4.40, 3.76 (2 x brs, 1H), 4.22 (m, 1H), 4.09, 3.97 (ABX, 2H), 3.29, 3.12 (2x brs, 2H), 2.28 (s, 6H) m 1.27 (d, 3H), 1.24-1.02 (m, 9H).

EXAMPLE 14 N-Ethyl-N-isopropyl-3-methyl-5-yl [2 S- (pyridin-4-ylamino) -propoxy] -benzamide 2-hydroxybenzoate To a solution of N-ethyl-N-isopropyl- 3-methyl-5- [2S-pyridin-4-ylamino) -propoxy] -benzamide (0.65 g) in toluene (3.2 ml) was added a solution of salicylic acid (0.25 g) in tetrahydrofuran (1.2 ml) and the resulting solution was stirred at room temperature for two hours. The solution was cooled to 0 ° C and diluted with diisopropyl ether (5 ml); the crystallization did not occur. The solution was then concentrated under reduced pressure to give the title compound as a foam (1.0 g) Mass spectrum: Found: MH + 356 XH-NMR d ppm (CDC1) 8.02 (brd, 2H), 7.95 (dd, 1H) , 7.61 (brd, 1H), 7.31 (dt, 1H), 6.91 (brd, 1H), 6.80 (dt, 1H), 6.70 (brs, 1H), 6.66 / brd, 2H), 6.56 (brs, 1H), 4.59, 3.92 (2 x brs, 1H), 4.07-3.82 (3 xm, 3H), 3.38.3.20 (2 x brs, 2H), 2.30 (s, 3H), 1.35 (d, 3H), 1.26 (brt, 3H), 1.13 (brd, 6H).

Example 15 (2R, 3R) -2, 3-dihydroxybutanedioate of N-ethyl-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide To a solution of N-et il-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide (0.65 g) in tetrahydrofuran (3.2 ml) was added a solution of L-tartaric acid (0.28 g) in methanol (5 ml). No crystallization occurred at room temperature. The reaction mixture was concentrated under reduced pressure to give a colorless gum which was then dissolved in a minimum amount of isopropyl alcohol and added to excess diisopropyl ether (250 ml). The resulting solution was stirred at room temperature for 2 days and filtered to give the title compound as a white solid (0.82 g) Mass spectrum: Found: MH + 356 XH-NMR d ppm (DMSO-d6) 8.12 (1 / 2AA'BB ', 2H), 7.97 (d, 1H), 6.83 (1 / 2AA'BB', 2H), 6.79 (brs, 1H), 6.68 (brs, 1H), 6.61 (brs, 1H), 4.40, 3.76 (2 x brs, 1H), 4.12 (m, 1H), 4.04 (s + ABX, 3H), 3.98 (ABX, 1H), 3.28, 3.13 (2 x brs, 2H), 2.28 (s, 3H), 1.27 (d, 3H), 1.24-1.00 (m, 9H).

Example 16 N-Ethyl-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide 4-aminobenzenesulfonate To a solution of N-et-il-N-isopropyl-3 -methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide (0.65 g) in tetrahydrofuran (3.2 ml) was added a slurry of sulphanilic acid (0.32 g) in water (5 ml). The resulting clear solution was stirred at room temperature for 2.5 hours then concentrated under reduced pressure. The residue was dissolved in diisopropyl ether (30 ml) and after 2 days was filtered to give the title compound as a white powder (0.86 g). Mass spectrum: Found: MH + 356 1H-NMR d ppm (DMSO-d6) 13.1 (brs, 1H), 8.61 (brd, 1H), 8.23, 8.08 (2 x 1 / 2AA'BB ', 2H), 7.30 ( 1 / 2AA'BB ', 2H), 7.03, 6.88 (2 x 1 / 2AA'BB', 2H), 6.78 (brs, 1H), 6.68 (brs, 1H), 6.60 (brs, 1H), 6.54 (1 / 2AA'BB ', 2H), 6.02 (brs, 2H), 4.40, 3.76 (2 x brs, 1H), 4.23 (m, 1H), 4.09, 3.97 (ABX, 2H), 3.29, 3.12 (2 x brs , 2H), 2.28 (s, 3H, 1.28 (d, 3H), 1.24-1.00 (m, 9H).

References 1) Turner, FA; Gearien, JE, J. Org Chem., 1959, 1952. 2) Kelly, TA; McNeil, DW, Terahedron Lett., 1994, 35 (48), 9003. 3) Sargent, MV, J. Chem. Soc. Perkin Trans 1, 1982, 1095. 4) Kimio, T, Sumió, S. Masaru, 0, He terocycles, 1985, 23 (6), 1483.

The compounds of the formula (I) can be included in the pharmaceutical formulations, the details of these formulations are given below TABLETS FOR ORAL ADMINISTRATION A. Direct Compression The active ingredient was sieved and mixed with the excipients. The resulting mixture was compressed into tablets using a tablet machine equipped with punches of suitable diameter. A rotating machine can also be used for forming tablets.

Tablets of various concentrations can be prepared for example by altering the ratio of the active ingredient to lactose or the compression weight using suitable punches.

B. Wet granulation Formulation (i) The active ingredient was screened through a suitable screen and mixed with lactose, starch and pregelatinized corn starch. Suitable volumes of purified water were added and the powders were granulated. After drying, the granules were selected and mixed with the magnesium stearate. The granules were then compressed into tablets using diameter punches suitable. The water used for the granulation does not appear in the final product. A rotating machine can also be used for forming tablets. Tablets of various concentrations can be prepared for example by altering the ratio of the active ingredient to lactose or the weight of understanding and using suitable punches.

Formulation (ii * Water does not appear in the final product. The typical interval 100-140 g per kg of mixture.

The active ingredient and the lactose were mixed together, and granulated by the addition of the purified water. The granules obtained after mixing were dried and passed through a screen, and the resulting granules were then mixed with other tablet core excipients. The mixture was compressed into tablets. A rotating machine can also be used for forming tablets. Tablets of various concentrations can be prepared, for example by altering the ratio 2 of the active ingredient lactose or the compression weight and using suitable punches. The tablets can be film coated with suitable film-forming materials such as hydroxypropylmethylcellulose, Q preferably incorporating pigments into the formulation, using standard techniques. Alternatively, the tablets may be sugar coated, or enteric coated.

++ Water does not appear in the final product COMPRESSION COATED TABLET The active ingredient can also be formulated as a tablet core using conventional excipients such as fillers, binders, disintegrants and lubricants, and these cores are then compressed into an outer tablet (compression coated) using Conventional excipients such COJEO a hydrophilic polymer independent of pH-independent filler, binders, disintegrants and lubricants. This outer coating may also contain the active ingredient. Compression of both the core and the outer compression liner can be achieved using conventional tabletting machinery. This dosage form can be designed to control the release of the active ingredient as required.

EFFERVESCENT TABLET Lemon flavor 0.5 Pure alcohol for c. s granulation The active ingredient, anhydrous monosodium citrate, sodium bicarbonate and spores were mixed together and granulated by the addition of a solution of the polyvinylpyrrolidone in alcohol. The granules obtained after mixing were dried and passed through a sieve and the resulting granules were then mixed with the sodium benzoate and the flavors. The granulated material was compressed into tablets using punches of suitable diameter. A rotating machine can also be used for forming tablets.

CAPILLATE FORMULATIONS FILLED WITH LIQUID FOR ORAL ADMINISTRATION Liquid formulations were prepared by slowly adding the active ingredient to the other ingredients with constant mixing.

The liquid formulations were filled into gelatin capsules, the size of the capsule that was used and the filling agent that determines the possible weight / volume of filling and hence the dose of the active ingredient per capsule.

CAPSULES FILLED WITH POWDER p / p Active ingredient 24.5 Lactose 75.0 Magnesium stearate 0.5 The active ingredient was sieved and mixed with excipients. The mixture was filled into capsules of Hard gelatin using proper machinery. The dose is determined by the weight of the filling and the size of the capsule.

SYRUP The hydroxypropyl methylcellulose was dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The solution The resulting mixture was adjusted to volume and mixed with syrup, clarified by filtration.

SUSPENSION The aluminum monostearate was dispersed in approximately 90% of the fractionated coconut oil. The resulting suspension was heated to 115 ° C while stirring and then cooled. The sweetening agent, flavor and color were added and the active ingredient was dispersed properly. The suspension was brought to the volume with the remaining fractionated coconut oil and mixed.

SUBLINGUAL TABLET The active ingredient was screened through a suitable screen, mixed with the excipients and compressed using suitable punches. Tablets of various concentrations can be prepared by altering either the ratio of the active ingredient to the excipients or the compression weight and using suitable punches. For the formation of tablets, a rotating machine can also be used.

SUPPOSITORY FOR RECTAL ADMINISTRATION A registered trademark of Adeps Solidus Ph Eur A suspension of the active ingredient in molten Witepsol was prepared by filling using suitable machinery, in suppository molds of a size of 1 g.

PARi INJECTION 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 dilution of the active ingredient using diluted acid or dilute alkali or by the emission of suitable buffer salts. Antioxidants and metal chelating salts may also be included. The solution is clarified, brought to the final volume with water and the pH is remeasured and adjusted if necessary.

The solution can be packaged for injection, for example filling and sealing in vials or syringes. The vials, flasks or syringes can be filled septically (for example, the solution can be sterilized by filtration and filled in sterile vials under aseptic conditions) and / or thermally 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, closed by melting the glass and sterilized thermally.

FOR INHALATION Inhalation cartridges The active ingredient was micronized in a fluid energy mill at a fine particle size range before being mixed with the normal tablet-forming grade of lactose in a high-energy mixer. The powder mixture was filled into number 3 hard gelatin capsules in a suitable encapsulation shell. The content of the cartridges was administered using a powder inhaler, such as the Glaxo Rotahaler.

Pressurized Dosage Spray Measure The active ingredient was micronized in a fluid energy mill in a range of fine particle size. The oleic acid was mixed with before a temperature of 10-15 ° C and the micronized drug was mixed in the solution with a high-cut mixer. The suspension was dosed in aluminum aerosol cans and suitable dosing valves were attached to distribute 85 mg of suspension in the cans and dichlorodifluoromethane was filled in the canisters through the valves.

NASAL SPRAY The active ingredient and sodium chloride were dissolved in a portion of the water and the solution was brought to volume with the water and the solution was thoroughly mixed.

The pH can be adjusted to facilitate the solution of the active ingredient, using alkali acid and / or subsequently adjusted if necessary taking into account the pH for optimum stability. 5 > Alternatively, suitable buffer salts can be used. The solution can be preserved with, for example, benzalkonium chloride, and phenylethyl alcohol, for a multi-dose nasal spray. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. 8b

Claims (10)

CLAIMS Having described the invention as above, property is claimed as contained in the following:

1. A compound of the formula (I) characterized in that R1 represents alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 8 carbon atoms; R2 represents alkyl of 1 to 4 carbon atoms or alkenyl of 3 to 4 carbon atoms; R3 represents hydrogen, alkyl of 1 to 3 carbon atoms or halogen; R4 represents alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable derivative or solvate thereof.

2. A compound according to claim 1, characterized in that R3 represents methyl, or a pharmaceutically acceptable derivative or solvate thereof.

3. A compound according to claim 1 or claim 2, characterized in that R4 represents methyl, or a pharmaceutically acceptable derivative or solvate thereof.

4. A compound selected from: N-Ethyl-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; N, N-Diisopropyl-3-met il-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; N-Isopropyl-3, N-dimethyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; 3, N-Dimethyl-N-propyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; 3-Methyl-N, N-dipropyl-5- [2 S- (pyridin-4-ylamino) -propoxy] -benzamide; N-Et i 1-3-methyl-N-propyl-5- [2S- (pyridin--ylamino) -propoxy] -benzamide; N-Butyl-3-methyl-N-propyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; N-Cyclohexyl-N-isopropyl-3-met-il-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; N-Isopropyl-3-methyl-N-propyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; 3-Chloro-N-isopropyl-N-propyl-5- [2S- (pyridin-4-ylamino) -propoxy] -benzamide; 3-Chloro-N, N-diisopropyl-5- [2- (pyridin-4-ylamino) -butoxy] -benzamide; or a pharmaceutically acceptable derivative or solvate thereof.

5. The compound: 4-methexylbenzene fonate N-ethyl-N-isopropyl-3-methyl-5- [2S- (pyridin-4-ylamino) propyloxy] benzamide, or a pharmaceutically acceptable derivative or solvate thereof.

6. A method of treatment and / or prophylaxis of a mammal, including a human, suffering from conditions susceptible to improvement by a thrombin inhibitor, characterized in that the method comprises administering to the subject an effective amount of a compound with any of the claims 1-5, or a pharmaceutically acceptable derivative or solvate thereof.

7. A compound according to any of claims 1-5, or a pharmaceutically acceptable derivative or solvate thereof, for use in therapy. A compound according to any of claims 1-5, or a pharmaceutically acceptable derivative or solvate thereof, for the manufacture of a medicament for the treatment of a condition susceptible to improvement by a thrombin inhibitor. 9. A pharmaceutical formulation comprising a compound of any of claims 1-5, or a pharmaceutically acceptable derivative or solvate thereof, together with one or more pharmaceutically acceptable carriers therefor. 10. A process for preparing a compound of the formula (I), characterized in that the process comprises any of: (A) deprotection of a compound of the formula (II), wherein P1 represents a suitable protecting group; (B) reacting a compound of the formula (III) with a compound of the formula (IV) (III) (IV) wherein R7 represents hydrogen, and L represents hydroxyl; (C) reacting a compound of the formula (III) with a compound of the formula (IV) wherein R7 represents hydrogen, and L represents a suitable residual group, in the presence of a base; or (D) reacting a compound of the formula (V) with a compound of the formula (VI), V) (VI) wherein R7 represents hydrogen, in the presence of an activating agent or agents and a base.