MXPA01011377A - Spray drying of thrombin inhibitors - Google Patents

Abstract

The invention relates to a method for producing thrombin inhibitors which have a constant weight and which are of formula (I), whereby n represents 0, 1, 2 and tautomers thereof, whereby an aqueous solution of the active substance is spray dried.

Description

DRYING DRYING OF THROMBIN INHIBITORS The invention relates to processes for the preparation of thrombin inhibitors of constant weight, specifically in spray drying of these inhibitors. The invention also relates to the novel salts of the thrombin inhibitors, the drugs comprising the latter and the use of these salts to produce drugs with antithrombotic effect.

The invention specifically relates to the novel salts of the general formula i, the preparation and use thereof, wherein the formula I has the following meaning: where n is 0, 1, 2, and the tautomers of these, The R configuration of the cyclohexylalanine and the S configuration of the dehydroproline are preferred, The preparation of the thrombin inhibitor I as acetate is described in WO 96/25426 (Example 93, page 128). With the isolation of the active substance on a RP column operated with acetic acid buffer (see the PCT application page 65, lines 25/26), the product is obtained in the form of the acetic acid salt, independently of its origin. The acetic acid salt is hygroscopic and forms different byproducts during storage.

Defined compounds of formula I are obtained by titrating acid solutions of the active substance with aqueous ammonia. During this, betaine of the substance -Active precipitates and can be obtained in pure form by filtration or centrifugation and drying. The hydrochlorides of the general formula I are obtained by adding stoichiometric amounts of HCl to betaine. Suitable solvents are water, Ci-Cß alcohols, Ci-C6 ethers, C-C6 esters, toluene, xylenes, DMF, DMSO, THF. The product is isolated by filtration or centrifugation and drying.

The active substance tends the irreversible adsorption of organic solvents. Organic solvent wastes are disadvantageous for pharmaceutical preparations. Isolation from water would be an attractive process. This does not give rise to products with constant weight because the active substance is highly hygroscopic. The degree of hygroscopicity depends on the relative humidity.

To determine the hygroscopicity, the samples of the anhydrous active substance are stored in desiccators in which a constant humidity is established by means of saturated saline solutions, at a constant temperature. The change in weight is determined by weighing at intervals of a few days. Obtaining weight is determined by the following formula: (weight after adsorption) - anhydrous weight Obtaining weight =; • • x 100 anhydrous weight An active substance dried under vacuum with n = 1 is shown in Table 1 below as an example of obtaining weight.

Table 1 The arrangement of a process chain in which the active substance is at a constant humidity from production to storage for pharmaceutical processing is extremely complicated.

An object of the present invention is to prepare an active substance of constant weight, which can be easily handled. It has surprisingly been found that with spray drying of active substance I, contrary to all other vacuum drying techniques, a constant residual moisture content can be established and thus have a constant weight during processing later.

The resulting amorphous form is also of pharmacological interest due to the effect of the crystallinity on the bioavailability.

The aqueous solution of the active substance to be dried is atomized by means of a two component nozzle. At the same time, a gas flow, preferably nitrogen, dries the dispersed droplets into amorphous solid particles. These solid particles are usually removed in a cyclone. The detached gas is filtered and passed to a purification tower.

The concentration of the solution to be dried is in the range from 5 to 40% by weight, preferably in the range from 15 to 25% by weight.

The temperature at the gas inlet is in the range of 80 to 150 ° C, preferably in the range of 110 to 130 ° C.

The outlet temperature of the gas is in the range of 30 to 70 ° C, preferably in the range of 50 to 60 ° C.

The atomizing gas pressure is in the range from 1.1 to 10 bar, preferably in the range of 2 to 5 bar.

The products prepared in this way are compact, and the pharmaceutical processing thereof is simple.

A product prepared in this way can be handled in the air without rapid change in its weight.

The spray dried products of the general formula I show a weight obtaining less than 1% after a few days even with a relative humidity of 75% after spray drying.

The vacuum-dried and freeze-dried products of the general formula I show a weight obtaining greater than 6% with a relative humidity of 75%.

Furthermore, a comparison of the storage stability of the salts I according to the invention with fumarate and acetate salts, surprisingly, shows that the active substances according to the invention are more stable with storage than the corresponding organic acid salts .

Table 2: Storage at 70 ° C, 1 bar in an open container. The data is the content of the active substance based on the content of the initial active substance in the open container in% of the areas by HPLC Table 3: Content of the active substance in% of the areas by HPLC of the active substance formula I n = l The compounds of the formula I are thrombin inhibitors and can be used for the following indications: - diseases whose pathomechanism is directly or indirectly based on the proteolytic effect of thrombin diseases whose pathomechanism is based on thrombin-dependent activation of receptors and signal transduction diseases associated with stimulation [e.g. by PAI-1, PDGF (platelet-derived growth factor), P-selectin, ICAM-11, tissue factor] or inhibition (e.g. NO synthesis in smooth muscle cells) of the Gene expression in body cells diseases based on the mitogenic effect of thrombin diseases based on a thrombin-dependent change in the contractility and permeability of epithelial cells (eg vascular endothelial cells) - thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial infarction or cerebral infarction , atrial fibrillation, bypass occlusion - disseminated intravascular coagulation (DIC) - reocclusion and to reduce the time of reperfusion with co-medication with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC, plasminogen activators of salivary glands of animals, and the recombinant and mutated forms of all these substances - the presence of early reocclusion and late restenosis after PTCA proliferation of thrombin-dependent smooth muscle cells accumulation of active thrombin in the CNS (for example in Alzheimer's disease) tumor growth, and to prevent adhesion and metastasis of tumor cells.

The novel compounds can be used in particular for the treatment and prophylaxis of thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarcts and unstable angina, also for the treatment of disseminated intravascular coagulation (DIC). . These may also be suitable for treatment in combination with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators to reduce the reperfusion time and prolong the reocclusion time.

Other preferred areas of use are the prevention of early thrombin-dependent reocclusion and late restenosis after percutaneous transluminal coronary angioplasty, the prevention of thrombin-induced smooth muscle cell proliferation, the prevention of active thrombin accumulation in the CNS ( for example in Alzheimer's disease), the control of tumors and the prevention of mechanisms that cause the adhesion and metastasis of tumor cells.

The novel compounds can also be used to coat artificial surfaces such as hemodialysis membranes and piping systems and lines needed for this, and oxygenators for extravascular circulation, stents and heart valves.

The novel compounds can also be used for diseases whose pathomechanism is directly or indirectly based on the proteolytic effect of the quininogenases, especially kallikrein, for example for inflammatory diseases such as asthma, pancreatitis, rhinitis, arthritis, urticaria and other internal inflammatory diseases.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intramuscularly, intravenously, intraperitoneally, rectally) in a traditional manner. The administration can also take place with vapors or rubbers through the nasopharyngeal space. The compounds in particular can be administered orally.

The dose depends on the age, condition and weight of the patient and the mode of administration. The daily dose of the active substance per person is usually between about 10 and 2000 mg in oral administration, and between about 1 and 200 mg in parenteral administration. This dose can be administered in 2 to 4 individual doses or once a day as a form of deposit.

The novel compounds can be used in the usual solid or liquid dosage forms, for example as coated or uncoated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These can be produced in a traditional way. The active substances for this purpose can be processed with conventional pharmaceutical excipients such as tablet binders, diluents, preservatives, tablet disintegrators, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, agents that reduce the rate of release, antioxidants and / or propellant gases (see H. Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way usually contain the active substance in an amount of 0.1 to 99% by weight.

Examples Example N- ((hydroxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline 6-amidino-3-picolinyl amide (betaine) 90 g (0.116 mol) of the compound N-boc-N - ((t-butoxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline 6-amidino-3-picolinyl amide N-acetyl- ( S) -cysteinate, which is described in Example 3 of WO 98/09950, 360 g of water and 44.56 g (38% concentration, 0.464 mol) of hydrochloric acid were heated at 65 ° C for two hours. Cooling to room temperature was followed by extraction once with ethyl acetate, and the phases were separated and the pH was adjusted to 8.2 with 105 g of a 25% aqueous solution of ammonia, this precipitated the product, then stirred for one hour, it was filtered with suction, washed with ice water and then dried in an oven with vacuum. There were obtained 41.66 g (0.091 mol, 79%) of N- ((hydroxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline 6-amidino-3-picolinyl amide as a colorless solid. 2nd Example N- ((hydroxy-carbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline hydrochloride 6-amidino-3-picolinyl amide 29. 4 kg (88% pure, 57 mol) of N- ((hydroxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline 6-amidino-3-picolinyl amide in 100 kg of water were mixed with 5.45 kg (38% concentration, 57 mol) of hydrochloric acid, were clarified by filtration and spray dried. 27.1 kg (93% purity, 51 mol, 89%) of N- ((hydroxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline hydrochloride 6-amidino-3-picolinyl amide were obtained. in the form of a colorless powder. 3rd Example N- ((hydroxycarbonyl) ethylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline 6-amidino-3-picolinyl amide dihydrochloride 3. 2 g (6.1 mmol) of N- ((hydroxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline hydrochloride 6-amidino-3-picolinyl amide were introduced into 40 ml of water and then of addition of 6.1 g of 1 molar hydrochloric acid, the solution was dried by freezing. 3.25 g (6.1 mol, 100%) of N- ((hydroxycarbonyl) methylene) - (R) -cyclohexylalanyl- (S) -3,4-dehydroproline dihydrochloride of 6-amidino-3-picolinyl amide were obtained as a powder colorless.

Claims (1)

1. CLAIMS A process for the preparation of constant weight thrombin inhibitors, of formula I: where n is 0, 1, 2, and the tautomers of these wherein an aqueous solution of the active substance is spray-dried. The process as claimed in claim 1, wherein the concentration of the solution to be dried is in the range between 5 and 40% by weight. The process as claimed in any of claims 1 or 2, wherein the gas inlet temperature is in the range between 30 ° C and 70 ° C. A compound of the formula I: where n is 0, 1, 2, the stereoisomer tautomers thereof. The compound as claimed in claim 4 in amorphous form. A medicament containing a compound of the formula I as claimed in claim 4 or 5 in addition to the usual carriers and excipients. The use of a compound of formula I as claimed in claim 4 or 5 to produce medicaments for the treatment or prophylaxis of: diseases whose pathomechanism is directly or indirectly based on the proteolytic effect of thrombin • diseases whose pathomechanism is based on the thrombin-dependent activation of the receptors and the signal transduction • diseases associated with stimulation [e.g. by PAI-1, PDGF (platelet-derived growth factor), P-selectin, ICAM-11, tissue factor] or inhibition (e.g., NO synthesis in smooth muscle cells) the expression of genes in body cells • diseases based on the mitogenic effect of thrombin diseases based on a thrombin-dependent change in the contractility and permeability of epithelial cells (eg, vascular endothelial cells) • thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarction, atrial fibrillation, bypass occlusion disseminated intravascular coagulation (DIC) • reocclusion and to reduce the time of reperfusion with co-medication with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC, plasminogen activators of the salivary glands of animals, and recombinant forms and mutated of all these substances • the presence of early reocclusion and late restenosis after PTCA proliferation of thrombin-dependent smooth muscle cells • accumulation of active thrombin in the CNS (for example in Alzheimer's disease) • Tumor growth, and to prevent adhesion and metastasis of tumor cells. The compound of formula I as claimed in claim 4 or 5 for coating surfaces.