MXPA97005231A - Prolin derivatives useful as inhibitors of elastase leukocyte hum - Google Patents

Abstract

The present invention relates to particular forms of a 1-substituted N- [2-methyl-1- (trifluoroacetyl) propyl] pyrrolidine-2-carboxamide of the formula (I) which are inhibitors of human leukocyte elastase (HLE) ), also known as human neutrophil elastase (HNE) making them useful as long as such inhibition is desired, such as for research tool of pharmacological studies, diagnostic and related studies and in the treatment of diseases in mammals, which HLE is involved . The invention also includes pharmaceutical compositions containing such forms, processes for preparing the forms and intermediates useful in the synthesis of the forms

Description

PROLIN DERIVATIVES USEFUL AS ELASTASE INHIBITORS HUMAN LEUKOCYTE DESCRIPTION OF THE INVENTION The present invention relates to proline derivatives, and more particularly to particular forms of a 1-substituted-N- [2-methyl-1- (trifluoroacetyl) propy1] pyrrolidine-2-carboxamide derivative which are leukocyte elastase derivatives Human (HLE), also known as human neutrdfile elastase (HNE), which has a value, for example, as a research tool in pharmacological, diagnostic, and related studies in the treatment of conditions in mammals in which the HLE is involved. For example, HLE has been causally implicated in the pathogenesis of acute respiratory distress syndrome (ARDS), reu atoid arthritis, atherosclerosis, pulmonary emphysema and other inflamry conditions, including inflamry airway conditions characterized by increased and abnormal airway such such as acute and chronic bronchitis and cystic fibrosis. In addition, HLE has been causally implicated in certain vascular conditions and related conditions (and its therapy) in which the participation of neutrophils is involved or involved, for example, in the hemorrhage associated with acute non-lymphocytic leukemia, as well as in the reperfusion injury associated with, for example, myocardial ischemia and conditions associated with the coronary artery disease, such as angina and infarction, cerebrovascular ischemia such as transient ischemic attack and apoplectic attack, peripheral vascular occlusive disease, such as intermittent claudication and critical limb ischemia, venous insufficiency, such as venous hypertension, varicose veins and venous ulceration , as well as impaired reperfusion states, such as those associated with reconstructive vascular surgery, thrombolysis and angioplasty. The invention also relates to methods of treating one or more of these conditions of suffering - and the use of one or more of the particular forms of the novel derivative in the manufacture of a medicament for use in one or more of such conditions. The invention further relates to pharmaceutical compositions containing one or more of the particular forms of the novel derivative as an active ingredient, as well as to processes for the manufacture of the particular forms of the novel derivative, the novel intermediates useful in such processes and methods for the preparation of such intermediaries. Due to the obvious role of HLE, considerable significant effort has been made in recent years with respect to the development of HLE inhibitors. A number of structurally related peptidoyl trifluoromethane derivatives which are inhibitors are described in US Patent 4,910,190. of HLE. It has now been discovered that the particular forms of the novel 1-substituted-N- [2-methyl-l- (trifluoroacetyl) -propyl] -pyrrolidine-2-carboxamide derivative of the formula I (hereinafter set forth) they are unexpectedly potent inhibitors of HLE. According to one aspect of the invention, the compound (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-1- (trifluoroacetyl) propyl] is provided] pyrro-lidin-2-carboxamide, or a solvate thereof, both in the form of a diastereoisomeric mixture of (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(S ) -2-methyl-1- (trifluoroacetyl) propyl] pyrrolidine-2-carboxamide (or a solvate thereof), and (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N - [(R) -2-methyl-1- (trifluoroacetyl) propyl] -pyrrolidine-2-carboxamide (or a solvate thereof) and in the substantially or essentially pure diastereomeric form (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(S) -2-methyl-1- (trifluoroacetyDpropyl] pyrrolidine-2-carboxamide or a solvate thereof) It will be appreciated that a compound of formula I has the three chiral centers (identified by * and # in formula I) and can therefore exist in eight different forms and stereoisomeric, or as a diastereoisomeric mixture of two or more of these forms. For example, the compound (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-l-) trifluoroacetyl) propyl] pyrrolidine-2-carboxamide is a compound of the formula I in which two chiral centers identified by * have the configuration S and the third chiral center identified as # have the RS configuration. The compound is therefore a diastereomeric mixture comprising the diastereomer with the chiral centers marked * and #, all having the S configuration, ie, (S) -1- [(S) -2- (methoxycarbonylamino) -3- methylbutethyl] -N- [2-methyl-1-) trifluoro-acetyl) propyl] pyrrolidine-2-carboxamide (hereinafter referred to as the "SSS diastereomer" of formula I and which may be represented as shown in the formula the one in which a thickened ligature denotes a ligature that is projected from the plane of the paper) and the diastereomer with the chiral centers marked *, having the configuration S and those marked with #, having the configuration R, that is ( S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutryl] -N- [2-methyl-l-) trifluoroacetyl) propyl] pyrrolidine-2-carboxamide (hereinafter referred to as the "SSR dieystereoisomer" of formula I), or solvates thereof. Such a diastereomeric mixture includes, for example, a mixture containing approximately equal amounts of the SSS and SSR diastereomers, ie, the SSS: SSR ratio is about 1: 1. For example, diastereomeric mixtures comprise the diastereomers SSS and SSR in the ratios of 53:47 and 47:53 (SSS: SSR) have been * obtained. Particular forms of the compound of formula I that are preferred are diastereomeric mixtures that are enriched with the SSS diastereomer, for example, the ratio of SSS: SSR is greater than 1: 1. An especially preferred form of the compound is the substantial or essentially pure SSS diastereoisomer, i.e., the SSS diastereomer containing less than 5% (more particularly less than 3% and preferably less than 2%) of other diastereoisomers. It will be appreciated that the SSS diastereoisomer of formula I can also form a diastereomeric mixture with one or more other forms of formula I, for example, (S) -1- [2-methoxycarbonylamino-3-methylbutyryl] -N- [(S) -2-methyl-1- (trifluoroacetyl) propyl] pyrrolidine-2-carboxamide (a diastereoisomeric mixture of the SSS and RSS forms of Formula I) or 1- ([S-2-methyl-1- (trifluoroacetyl) propyl] pyrro-lidine-2-carboxamide (a diastereoisomeric mixture of the SSS and SRS forms of the formula I) can be obtained. Particular, and other diastereomeric mixtures containing about 50% or more of the SSS diastereomer together with one or more different possible diastereoisomers with different configurations at the chiral centers marked by * and # in formula I are therefore additional aspects of the present invention A diastereoisomeric mixture of the SSS and SSR diastereoisomers may exist in an amorphous non-crystalline form or a crystalline form, depending on the ratio of the SSS: SSR diastereoisomers present.A preferred diastereomeric mixture is one in which it can be isolated in crystalline form, which is particularly advantageous in the manufacture of the compound, or formulations thereof, at the levels of purity and uniformity required for the approval of the regulations. It will be appreciated that it is extremely difficult to obtain a compound that is an individual diastereomer completely free of the other diastereomeric forms, particularly a compound having three chiral centers. The present invention thus includes a crystalline form of the SSS diastereomer of formula I, or solvate thereof, which contains other possible diastereoisomers with different configurations at the chiral centers indicated by * and # in formula I. It has been found that a crystalline diastereoisomeric mixture of the SSS and SSR diastereoisomers of a hydrate thereof can be obtained to be substantially or essentially a diastereomeric mixture of the diastereomers SSS and SSR in the ratio (SSS: SSR) of 65:35 or more, for example, contains 35% or less of the SSR diastereoisomer. The present invention thus includes a crystalline form of the compound of formula I, or a solvate thereof, with a content of at least 65% of the SSS diastereomer. Preferably, the crystalline diastereoisomeric mixture has, for example, an SSS: SSR ratio that is 80:20 or higher, for example 95: 5 or higher, and especially 98.5: 1.5 or greater. An especially preferred form of the compound of the invention is the crystalline SSS diastereomer which is substantially or essentially pure, ie, contains less than 5% of other diastereoisomers, for example, less than 5% of the SSR diastereomer, preferably less than 3% of the SSR diastereoisomer, and more preferably less than 2% of the SSR diastereoisomer. A crystalline or amorphous diastereomeric mixture of the SSS and SSR forms, or the substantial or essentially pure SSS diastereomer, exists in a form that is substantially or substantially free of solvent (hereinafter referred to as the "ketone" form and as illustrated in the Formula for the pure SSS diastereoisomer) or as a solvated form, for example, hydrated, or 'as a mixture of the ketone and solvated (hydrated) forms. The hydrated form can exist, for example, as a gem diol of the trifluoroketone functionality, which is a compound of the formula Ib (hereinafter disclosed) for the substantial or essentially pure SSS diastereomer, or as a compound of the formula le (which is discussed hereinafter), or as a form incorporating a water molecule as part of the crystal lattice, or mixtures of such forms. The compounds of formula Ib or can, for example, be further hydrated. It will be appreciated that the degree of hydration of the diastereoisomeric mixture or the substantial or essentially pure SSS diastereomer can be expressed as a ratio of the hydrated forms to the ketone forms. For example, an amorphous non-crystalline diastereoisomeric mixture of the SSS and SSR forms has been isolated wherein the ratio of the hydrated form to the ketone form varies, for example, of about 30:70 (ie, enriched in the ketone form) to about 95: 5 or more (i.e., substantially or essentially in the hydrated form), including ratios such as about 50:50 and about 60:40. The crystalline forms have been obtained, for example, having an SSS: SSR ratio of about 95: 5 together with a hydrated: ketone ratio of about 80:20 and having an SSS: SSR ratio of about 65:35 or more (such as 98.5: 1.5) and are substantially or essentially in the hydrated form. The crystalline hydrates of the substantial or essentially pure SSS diastereomer containing approximately 4.1% (w / w) and 7.8% (w / w) of water have also been obtained. Such particular forms are additional aspects of the invention. It will be further understood that the present invention also encompasses any ketal or hemicetal (or mixtures thereof) of a diastereomeric mixture or of a form of the SSS diastereomer, or a solvate thereof, herein designated that is converted to gem-diol in live, for example, by hydrolysis or enzymatic cleavage (and where the residue is pharmaceutically acceptable). The present invention also includes any tautomer or pro-drug of the SSS diastereomer or a solvate thereof. It will be appreciated that the compound of formula Ib can be designated as the gem-diol form of the compound of the formula la or by means of the chemical name (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(S) -2-methyl-1- (2,2,2-trifluoro-1,1-dihydroxyethyl) -propyl] pyrrolidine-2-carboxamide. It will be appreciated that an alternative name for the compound of the formula la is N- [(1S) -1- ((2S) -2- [N- ((1S) -2-methyl-1- (2,2, 2 methyl-trifluoroacetyl) propyl) -carbamoyl] pyrrolidin-l-ylcarbonyl) -2-methylpropylcarbamate and an alternative name for the compound of the formula Ib is N - [((S) -1- ((2S) -2- [ N- ((S) -3,3-trifluoro-2,2-dihydroxy-l-isopropylpro-pyl) carbamoylpyrrolidin-1-yl-carbonyl) -2-methylpropyl] -carba-methyl ester.

The melting point of the crystalline SSS diastereomer containing the SSR diastereomer generally depends on the level of the SSR diastereomer present and the level of solvation (hydration). It can be determined by conventional processes well known in the art, for example, by differential scanning calorimetry (DSC). Preferably, the crystalline SSS diastereomer is in a hydrated form. For example, hydrated forms of the SSS diastereomer have been found to have an advantageous property because they are non-hygroscopic, e.g., Form A and Form B referred to hereafter. Therefore, a preferred form of the SSS diastereomer is a crystalline form containing less than 5% (preferably less than 3% and especially less than 2%) of the SSR diastereomer and substantially or essentially in a hydrated form. Such crystalline hydrated forms, for example Form A and Form B, have been found to possess good bioavailability and good solubility in aqueous buffers, both being advantageous properties. A particularly preferred crystalline form of the SSS diastereomer of the formula I, when substantially or essentially pure and in a hydrated form, has an X-ray powder diffraction pattern including two specific peaks greater than about 20 = 10.8 and 11.4 °. This form (mentioned here as Form A) contains approximately 4.1% water. The X-ray powder diffraction pattern also includes fewer relatively intense specific peaks occurring at approximately 20 == 15.4, 16.8, 18.2, 18.6, 20.6, 21.6, 21.9, 22.8, and 25.0 °. The X-ray powder diffraction (XDS) spectrum of a sample typical of this form is shown in Figures 1 and 2, below, in which Figure 2 shows the less intense peaks on an enlarged scale. Additional physical data suggests that this crystalline form is substantially or essentially in the form of the diol of formula Ib. A further preferred crystalline form of the SSS diastereomer of formula I, when substantially or essentially pure in a hydrated form, has an X-ray powder diffraction pattern that includes a specific peak greater than about 20 = 7.2 °. This form (mentioned here as Form B) contains approximately 7.8% w / w (for example, 7.3-8.3% w / w) of water. The X-ray powder diffraction pattern also includes fewer relatively intense specific peaks occurring at approximately 20 = 7.4, 9.0, 10.8, 11.3, 14.5, 15.9, 17.8, 18.1, 19.7, and 22.5 °. The XDS of a typical sample of this form is shown in Figure 3 below. Additional physical data suggests that this crystalline form is substantially or essentially the monohydrate of the diol of the formula Ib. When it is substantially or essentially pure and substantially or substantially solvent-free (ie, in the "ketone" form), the SSS diastereomer has an X-ray powder diffraction pattern that includes a specific peak greater than about 20 = 12.1. This pattern also includes fewer relatively intense peaks occurring at approximately 20 = 6.0, 16.8, and 17.7 °. The XDS of a typical sample of the "ketone" form is shown in Figure 4 below. X-ray powder diffraction spectra were determined, for example, using the Scintag XDS-2000 X-ray diffractometer, with an EC &G solid state photon detector, GLP (germanium) series operated by a Microvax computer and using Diffraction Control System software provided by Scintag Inc., Sunnydale, California, USA. The X-ray tube used was a Cu K-alpha, with a wavelength of 1.5406A at 45KV and 40mA. The receiving slots were fixed at 2 and 4 mm and the set of divergent slots at 0.5 and 0.2 mm with respect to the trajectory of the incident beam. The spectra were obtained in continuous scan mode with a rotary switch increment of 0.02. Each sample was exposed to 1 degree 2-theta per minute (execution time 38 minutes) and was collected from 2 to 40 degrees 2-theta, to produce a trace of separations against the intensity for this scale. For the diffraction analysis, the samples were packed in round aluminum alloy sample trays with a diameter of 25 mm and a depth of 2 mm. The powder sample was placed in the tray such that an excess amount of the volume of the tray is present and subsequently leveled to the edge of the tray with a glass microscope stage. Silicon of the NBS 640b type was used as an external standard. Alternatively, a D5000 X-ray diffractometer was used, recording the diffractogram in the? -? on the scale from 2 to 40 degrees 2-theta with 4 seconds of exposure per increment of 0.02 ° 2T. An infrared spectrum was obtained for a typical sample of form A. The infrared spectrum was obtained by the technique of solvent drainage well known in the art, from acetonitrile castings of a sample on a salt window for analysis for the direct transmission. The infrared spectrum was determined on the wave number scale from 4000 to 400 cm "1. The infrared spectrum is shown in Figure 5. The spectrum of Figure 5 includes sharp peaks of approximately 2968, 1762, 1721, 1690, 1632 , 1525, 1447, 1207 and 1154 crn-1.

The infrared spectrum was also obtained for a typical sample of Form A using a Nicolet 20SXC FTIR spectrometer. The spectrum was obtained using a dispersion of 2% of the sample in potassium bromide. The infrared spectrum is shown in Figure 6 below. The spectrum of Figure 6 includes sharp peaks of approximately 3402, 3321, 3252, 3060, 2967, 2878, 1699, 1674, 1629, 1535, 1532, 1446, 1271, 1258, 1249, 1175, 11521, 1118, 1089, 1029 , 1013, 1004, 635, 593 and 567 cm "1. Using similar conditions, an infrared spectrum was obtained for a typical sample of Form B. The infrared spectrum is shown in Figure 7 below. it includes sharp peaks of approximately 3428, 3304, 2971, 2875, 1708, 1682, 1637, 1556, 1518, 1470, 1449, 1428, 1316, 1310, 1277, 1265, 1236, 1196, 1175, 1144, 1120, 1081, 1036 , 1005, 928, 818, 790 and 727 cm "1. Using similar conditions, an infrared spectrum was obtained for a typical sample of the SSS diastereomer in the substantially "ketone" form. The infrared spectrum is shown in Figure 8. The spectrum of Figure 8 includes sharp peaks of approximately 3415, 3300, 2967, 2876, * 1764, 1723, 1711, 1695, 1686, 1634, 1527, 1445, 1356, 1286, 1234, 1213, 1139, 1105, 1061, 1020, 774, 732 and 671 cm "1. It will be understood that the 2T values of the X-ray powder diffraction patterns and the wavelengths of the infrared spectra may vary slightly from one machine to another and similarly the collected values should not be considered as absolute, for example, the two largest specific peaks that occurred at approximately 2T = 10.8 and 11.4 ° for a typical sample of Form A when a light diffractometer was used X Scintag XDS-2000 will occur approximately 2T = 10.6 and 11.2 ° respectively when a Siemens D5000 X-ray diffraction was used (with the less intense peaks also occurring at a proportionally lower relative 2T value). the hydroxyl groups of the forms of formula Ib or le (or a hydrate thereof) are acidic and such compounds can therefore form pharmaceutically acceptable crystalline salts, using conventional processes, for example, with bases that give physiologically acceptable cations , for example, alkali metal salts (such as sodium or potassium), alkaline earth metal salts or organic amine salts. The invention therefore includes pharmaceutically acceptable crystalline salts of the forms of formula Ib and IC or a hydrate thereof. The various forms of the compound of the formula I referred to in the foregoing, or solvates (hydrates) thereof, can be obtained, for example, by the following process, which are additional separate aspects of the invention. A non-crystalline (amorphous) diastereoisomeric mixture of the diastereomers SSS and SSR can be obtained by oxidation of the compound of the formula II with a suitable oxidation agent. A suitable oxidizing agent is known in the art for the conversion of a hydroxy group to a ketone group. Suitable oxidizing agents and conditions include, for example, the use of oxalyl chloride, dimethyl sulfoxide and a tertiary amine; the use of acetic anhydride and dimethyl sulfoxide; the use of chromium pyridine trioxide complex in dichloromethane; the use of hypervalent iodine reagent such as 1, 1, l-triacetoxy-2, 1-benzoxidol-3 (3H) -one with trifluoroacetic acid in dichloromethane; the use of excess dimethyl sulfoxide and a water-soluble carbodiimide in the presence of dichloroacetic acid; or an alkali metal alkali metal permanganate, such as potassium permanganate solution or alkaline aqueous sodium permanganate. Particularly suitable oxidation agents are the last two mentioned, especially the solution of potassium permanganate or aqueous alkaline sodium, for example a mixture of sodium hydroxide and potassium or sodium permanganate.

The compound of formula II can be obtained, for example, as shown in Schemes 1 and 2, using conventional processes, or as illustrated in the Examples. Steps (a) to (d) of Scheme 1 can be performed as described in U.S. Patent 5,194,588 or European Patent 189305. Step (e) -is carried out using conventional processes for the formation of a carbamate starting from a primary amine, for example, using a methyl halogenoformate, such as methyl chloroformate, in the presence of a suitable base such as triethylamine, or N-methylmorpholine, and in a suitable solvent or diluent, for example, a hydrocarbon chlorinated, (such as dichloromethane or chloroform) or an ethereal solvent (such as tetrahydrofuran or dioxane), and at a temperature on the scale of, for example, -10 ° C to 50 ° C, such as 0 ° C to 30 ° C. The reaction steps of Scheme 2 include conventional protection steps (step (10)), deprotection or selective deprotection (steps (1), (3), (6), (8), (9) and (12)) ), coupling (steps (4), (59; (13) and (14)) and carbamate formation (steps (2), (7) and (11)) well known in the art It will be appreciated that the diastereomeric mixtures of the SSS and RSS diastereoisomers and the SSS and SRS diastereoisomers can be obtained using analogous processes with an appropriate selection of L- or DL-valine or proline (or the protected derivatives thereof) as starting materials and using (2R, 3S ) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol in the appropriate coupling steps The substantial or essentially pure SSS diastereomer can be obtained, for example, by oxidation of (S) -1_ t (S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(S) -2-methyl-1- ((R) -2,2,2-trifluoro-1-hydroxyethyl) propyl] pyrrolidi- na-2-carboxamide (from the formula ula lía) with a suitable oxidation agent, such as one of the oxidation agents mentioned in the above. The starting alcohol can be obtained as shown in Scheme 2. The crystalline forms of the SSS diastereomer containing 35% or less of the SSR diastereomer can be obtained from a non-crystalline (amorphous) diastereomeric mixture of the diastereomers SSS and SSR, which contain the SSS and SSR diastereoisomers in approximately equal amounts (ie, a ratio of about 1: 1, typically 53:47 or 47:53) by crystallization from a suitable non-polar solvent, such as a mixture of methyl ether butyl and hexane, preferably, containing a small amount of water and optionally containing a small amount of hydrochloric acid, for example, 0-02 mole equivalents of 36% w / w hydrochloric acid and 1-2.1 mole equivalents of water. It has been found that it is preferable to add aqueous hydrochloric acid to the crystallization solvent when a non-crystalline diastereoisomeric mixture of the SSS: SSR ratio of 47:53 is used. To initiate crystallization, culture with the crystalline SSS diastereomer is preferred. The crystalline product is generally isolated as a mixture of the hydrated form and the ketone form, typically at a ratio of about 80:20 (hydrate: ketone) or higher. A hydrated form of a ketone mixture and the hydrated forms can be converted to the substantially or essentially "ketone" form by drying a vacuum oven (eg, about 50 ° C). However, such a ketone form is hygroscopic. The crystalline, substantially or essentially pure, forms of the SSS diastereomer can be obtained by repeated recrystallization or recrystallization of the crystalline forms of the SSS diastereomer containing the SSR diastereomer. Solvents or mixtures of solvents that can be used include, for example, butyl acetate, butyl acetate / hexane, acetone / water, acetone / hexane, acetone / petroleum fraction e.g. 100-120 ° C, 1,2-dimethoxyethane / hexane, 1,2-dimethoxyethane / water / hexane, ethyl acetate / water / hexane, ethyl acetate / hexane, water, dibutyl ether / hexane, dichloromethane / hexane, 1,2-dimethoxy-ethane / water, methanol / toluene, tert-butylmethyl ether / hexane, isopropanol / hexane and tetrahydrofuran / hexane. To obtain Form A, the first ten solvents or solvent mixtures mentioned in the above are preferred. Wet ethyl acetate / hexane is particularly useful for obtaining Form A. Particularly useful solvents or mixtures of the solvents to obtain Form B are 1,2-dimethoxyethane / water and water / methanol, although this form can also be obtained when ethyl acetate / water / hexane is used. When reference is made to hexane herein, it includes isomers of hexane (such as isohexane) or mixtures thereof. Substantially pure or essentially pure crystalline forms of the SSS diastereomer can also be obtained by crystallization of the substantial or essentially pure SSS diastereomer isolated in a non-crystalline form (eg, by oxidation of the compound of the formula Ilia), such as an oil, using solvents or mixtures of similar solvents, mentioned in the foregoing, especially a mixture of ethyl acetate, water and hexane. In addition, Form A can also be obtained from Form B by recrystallization, for example, as illustrated in Example 9. In addition to the crystalline "ketone" form (which is hygroscopic) it can be obtained from Form A , for example, as illustrated in Example 10. The preparation of a semicetal ketal from ketone is well known in the art. 3-Amino-4-methyl-1,1,1-trifluoro-2-pentanol can be obtained as described in U.S. Patent No. 4,910,190 or as illustrated in the Examples. A particularly advantageous process * for the manufacture of (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol, which is a further aspect of the present invention, comprises (as illustrated in Scheme 3): (1) the reaction of (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol or a salt thereof, with triphosgene or dimethyl carbonate in the presence of a suitable base to give (4RS, 5RS) -4-isopropyl-5-trifluoromethyloxazolidin-2-one; followed by (2) the reaction of (4RS, 5SR) -4-isopropyl-5-trifluoromethyloxazolidin-2-one, or an alkali metal salt thereof, with (-) - menthyl chloroformate. to give (4RS, 5SR ) -4-isopropyl-3- [(1R, 3R, 4S) -3-p-menthyloxycarbonyl] -5-trilyforomethyloxazolidin-2-one and the separation of the isomer (4S, 5R) -4-isopropyl-3- [( IR, 3R, 4S) -3-p-menthyloxycarbonyl] -5-trifluoromethyloxazolidin-2-one; followed by (3) the hydrolysis of the hydrolysis (4S, 5R) -4-isopropyl-3- [IR, 3R, 4S) -3-p.-menthyloxycarbonyl] -5-trifluoromethyloxyzolidin-2-one under basic conditions, to give (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol. In Step (1), a suitable base is an aqueous alkali metal hydroxide, for example, sodium or potassium hydroxide. The reaction is generally carried out in a suitable inert solvent or diluent, for example, a hydrocarbon such as toluene. The reaction is exothermic and thus the reaction is generally effected with external cooling by maintaining the temperature at about 0 ° C to 50 ° C, for example, at about room temperature. In step (2), the reaction is carried out in a suitable solvent or diluent, for example an ether solvent, such as tetrahydrofuran. Conveniently the oxazolidinone is converted to its alkali metal salt, for example, using butyllithium at about -78 ° C, before the addition of the (-) - menthyl chloroformate. During the operation, the desired (4S, 5R) isomer is crystallized from the mixture of the isomers and collected by filtration. In step (3), suitable conditions include, for example, the use of an aqueous solution of an alkali metal hydroxide (such as sodium or potassium hydroxide) in an ether solvent or diluent, such as dioxane, at a temperature on the scale of, for example, 60-130 ° C (such as 90-120 ° C). The utility of the compound of the invention can be demonstrated by standard tests and clinical studies, including those described in the following.

Inhibition measurements: The potency of the compound of the invention (or a particular form thereof) to act as an inhibitor of human leukocyte elastase (HLE) on methoxy succinyl-alanyl-alanyl-prolyl-valine-p-nitroanilide of the weight peptide substrate low molecular weight, is determined as described in U.S. Patent 4,910,190. The potency of the compound is evaluated by obtaining a kinetic determination of the dissociation constant. K ^, of the complex formed from the interaction of the inhibitor with HLE. It was found that the compound of Example 1 has a K¿ of 36 nM. It was found that the compound of Example 2 has a K. ^ of 9 nM.

Acute Lung Damage Model: Animal models of emphysema include intratracheal (i.t.) administration of an elastolytic protease that causes a destructive, slowly progressive lesion of the lung. These injuries are usually evaluated from a few weeks to a few months after the initial damage. However, these proteases also induce an injury that is evident in the first few hours. The early lesion is first hemorrhagic, progresses to an inflammatory lesion at the end of the first 24 hours and ends in the first damage after the first week. To take advantage of this early injury, you can use the following model. First the hamsters are lightly anesthetized with Brevitál. It is then administered directly into the trachea brine regulated at its phosphate pH (PBS) of 7.4, either alone or containing human leukocyte elastase (HLE). Twenty-four hours later the animals are eliminated and the lungs are removed and the external tissue is carefully cut. After determination of the wet lung weight, the lungs are washed with PBS and the total washable red and white blood cells recovered are determined. The weights of the wet lung, the total washable white cells and the total washable red cells are raised in a dose-dependent manner after administration of HLE. Compounds that are effective elastase inhibitors can prevent or decrease the severity of the enzyme-induced injury resulting in lower wet lung weight and values for total washable cells, both white and red, with respect to the administration of HLE alone. Compounds can be evaluated by administering them intratracheally as solutions or suspensions in PBS, either with, or at various times before the stimulation of HLE (400 μg), or by dosing them intravenously or orally as solutions at various times before administration. stimulation of HlE (100 μg) to determine its usefulness to prevent HlE injury. A solution of the compound of the invention (or a particular form thereof) can be prepared in conventional manner using 10% polyethylene glycol 400 / PBS.

Acute Hemorrhagic Test: This assay depends on the monitoring only of the amount of hemorrhage in the lung after intratracheal administration of human neutrophil elastase (HNE). Hemorrhage is quantified by breaking down the erythrocytes recovered in the lung lavage fluid and comparing those with dilutions of all hamster blood. The screening protocol similar to that described in Fletcher et al., American Review of Respiratory Disease (1990), 141, 672-677, is as follows. Compounds that have been shown to be in vitro inhibitors of HNE are conveniently prepared for dosing as described above for the Acute Lung Injury Model. Male Syrian hamsters were slightly anesthetized (held for 16-18 hours before use), with Brevital sodium (30 mg / kg i.p.). The compounds are then dosed intravenously or orally to the hamsters at a fixed time, such as 30 or 90 minutes before the intratracheal administration of 50 μg / animal of HNE in 300 μl of phosphate brine (PBS) pH 7.4. Four hours after the administration of the enzyme, the animals were eliminated with an overdose of pentobarbital sodium, the thorax was opened and the lungs and the heart were removed and the lungs were cleaned of foreign material. The excised lungs were washed with three changes of 2 ml of PBS via a tracheal cannula. The recovered washings are combined, the volumes are recorded (approximately 5 ml) and the washings are stored at 4 ° C until they are tested. To calculate the amount of blood in each sample, the frozen washes and a complete hamster blood sample are sonified to break the erythrocytes and are diluted in an appropriate manner in individual wells of a 96-well microtiter plate. The optical densities (OD) of the rinsed washings and the blood samples were determined at 540 nm. They were determined (blood equivalents μl) / (wash mi) by comparing the optical densities of the test samples with the optical densities of the normal curve prepared from whole hamster blood. The total μl equivalents of blood recovered is determined by multiplying the wash volume recovered by (blood equivalents μl) / (wash mi) for each sample. The results were reported as% inhibition of HNE-induced hemorrhage with respect to the controls treated with PBS when the test compound is given at a specific dose and a specific time before the administration of HNE. It was found that ED50 for the compound of Example 1 is 4.5 mg / kg after oral dosing. It was found that ED50 for the compound of Example 2, is 1.9 mg / kg after oral dosing and 0.6 mg / kg after intravenous administration. No apparent toxicity was observed when the compound of the invention was administered in the aforementioned in vivo tests. It will be appreciated that the implications of a compound activity in the Acute Lung Injury or Acute Haemorrhagic Test model are not limited to emphysema, but rather, that the test demonstrates evidence of general in vivo inhibition of HLE. According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of the invention (or a particular form thereof) or a solvate thereof, and a pharmaceutically acceptable diluent or carrier. As noted in the above, another aspect of the invention is a method for using the compound of the invention (or a particular form thereof), or a solvate thereof, in the treatment of a condition or condition in a mammal, especially a human, in which HLE is involved, such as those referred to in the above and particularly acute and chronic bronchitis, pulmonary emphysema, reperfusion injury, adult respiratory distress syndrome, cystic fibrosis or peripheral vascular disease (such as limb ischemia) criticism or intermittent claudication). The compound of the present invention (or a particular form thereof) can be administered to a warm-blooded animal, particularly a human, which needs it for the treatment of a condition in which HLE is involved, in the form of a conventional pharmaceutical composition, for example as generally described in U.S. Patent 4,910,190. One mode of administration may be through a powder or liquid aerosol. In a powder aerosol, the compound of the invention (or a particular form thereof) can be administered in the same manner as cromolyn sodium through a turbo-inhaler device "Spinhaler" (registered trademark) obtained from Fisons Corp. of Bedford, Massachusets at a rate of approximately 0.1 to 50 mg per capsule, 1 to 8 capsules administered daily for an average human. Each capsule to be used in the turbo-inhaler contains the required amount of the compound of the invention (or the particular form thereof) with the remainder of the 20 mg capsule being a pharmaceutically acceptable carrier such as lactose. In a liquid aerosol, the compound of the invention (or a particular form thereof) can be administered using a nebulizer such as, for example, a nebulizer "Retec" (registered trademark), in which the solution is nebulized with compressed air . The aerosol can be administered, for example, at the rate of one to about eight times per day as follows: A nebulizer is filled with a solution of the compound (or a particular form thereof), for example 3.5 ml of the solution containing mg / ml; the solution in the nebulizer is nebulized with compressed air; and the patient breathes normally (tidal volume) for eight minutes with the nebulizer in his mouth. Alternatively, the mode of administration may be parenteral, including subcutaneous deposition by means of an osmotic or, preferably, oral pump. The compound of the invention (or a particular form thereof) can be formulated conventionally in an oral or parenteral dosage form by adjusting approximately 10 to 250 mg per unit dose with the conventional vehicle, excipient, binder, preservative, stabilizer, flavor or similar as it was called for the accepted pharmaceutical practice, for example as described in United States Patent 3,755,340. For parenteral administration, an intravenous, intramuscular or subcutaneous injection of 1 to 10 ml containing about 0.02 mg to 10 mg / kg of body weight of the compound of the invention (or a particular form thereof) is provided 3 or 4 times a day. day. The injection will contain the compound of the invention (or a particular form thereof) in a sterile aqueous isotonic solution or suspension optionally with a preservative such as phenol or a solubilizing agent such as ethylenediamine tetraacetic acid (EDTA). For parenteral administration or use in an aerosol, an aqueous formulation can be prepared, for example, by dissolving the compound (or a particular form thereof) in polyethylene glycol 400 / 5-10% phosphate buffered saline, followed by filtration. aseptic and sterile storage using standard procedures. In general, the compound of the invention (or a particular form thereof) will be administered to humans in a daily dose in the range of, for example, 5 to 100 mg of the compound (or a particular form thereof) by means of aerosol. or from 50 to 1000 mg intravenously or orally or a combination thereof. However, it will be readily understood that it may be necessary to vary the dose of the compound (or a particular form thereof) administered in accordance with known medical practice to take into account the nature and severity of the condition under treatment, concurrent therapy and age, weight and sex of the patient receiving the treatment. In a similar manner it will be understood that the generally equivalent amounts of a solvate (eg hydrated) form of the compound can also be used. The protocols for the administration of an HLE inhibitor and the evaluation of patients are described in the European Patent Applications with Publication Numbers 458535, 458536, 458537 and 463811 for the treatment or prevention of cystic fibrosis, ARDS, bronchitis and hemorrhage. associated with acute non-lymphocytic leukemia or its therapy, respectively; and the compound of the invention (or a particular form thereof) can be used similarly or preferably used by means of oral administration, for the treatment of those conditions and conditions either alone or in combination with another therapeutic agent indicated usually for the treatment of the particular condition. For the therapeutic or prophylactic treatment of vascular disease or related condition in a mammal in which neutrophils are involved or involved, a compound of the invention (or a particular form thereof) can be conveniently administered via an oral or parenteral route. , either alone or simultaneously or sequentially with another therapeutically active agent usually administered for the condition. The utility of the compound of the invention (or a particular form thereof) in such treatment of vascular conditions and related conditions can be demonstrated using the methods described in International Patent Application No. WO 92/22309. The various aspects of the invention will now be illustrated by means of the following non-limiting examples in which, unless stated otherwise: (i) temperatures are enriched Celsius (° C); the operations were carried out at room temperature, that is, at a temperature in the range of 18-25 ° C; (ii) the organic solutions were dried over anhydrous magnesium sulfate; the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascais, 4.5-30 mm Hg) with a bath temperature of up to 60 ° C; (iii) chromatography means "flash chromatography" (Still's method) are carried out in Merck Kieselgel (Article 9385 of E. Merck, Darmstadt, Germany), to the elution using both stages and gradients of ramp are represented by the term in parentheses "gradient" followed by the initial and final relationships of the solvent; thin-layer chromatography (TLC) was carried out on silica plates, for example 0.25 mm of silica gel GHLF plates (Article 21521 of Analtech, Newark, DE, USA); (iv) in general, the course of the reactions was followed by means of TLC and the reaction times given for illustration only; (v) the melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in the isolation of materials with different melting points in some preparations; (vi) the final products had satisfactory nuclear magnetic resonance (NMR) spectrum; and where they are examined, they were substantially pure by means of CLAP; (vii) the returns are given only for illustration and are not necessarily those which can be obtained through the development of the diligent process; the preparations were repeated if more than one material was required; (viii) when given, the NMR data are in the form of delta values for higher diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 250 MHz using DMSO-dg as solvent; conventional abbreviations were used for the signal form; for AB spectra the directly observed changes were reported; (ix) chemical symbols have their usual meaning; SI units and symbols were used; (x) the reduced pressures are given as absolute pressures in Pascals (Pa); high pressures are given as gauge pressures in bars; (xi) the solvent ratios are given in terms of volume: volume (v / v); (xii) mass spectra (EM) were cori fi ed with an electron energy of 70 volts of electrons in the chemical ionization mode using a direct exposure probe; where the ionization is indicated is effected by means of electron impact (IE) or fast atom bombardment (FAB); generally, only the peaks- which indicate the main mass were reported; and (xiii) CLAP was used to establish the ratio of SSS: SSR diastereoisomers of formula I in the isolated material, using an inverted phase SUPELCO LC-18, 25 cm x 4.6 mm column and water: acetonitrile (70: 30) as eluent. The flow rate was 1.0 ml / minute, the injection volume was 20 μl by means of valve and the detection wavelength was 205 nm. The retention time for the SSS diastereomer was approximately 9.9 minutes and that for the SSR diastereomer was approximately 11.7 minutes.

Example 1 1- (3-Dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (1.84 g) was added to a solution of (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N - [2-methyl-l- (2,2, 2-trifluoro-1-hydroxyethyl) propyl] pyrrolidine-2-carboxamide (0.41 g) were dissolved in dimethyl sulfoxide (DMSO, 5 ml) and toluene (5 ml), followed by the dropwise addition of dichloroacetic acid (0.32 ml). The resulting sulution is allowed to stir at 20 ° C for 2 hours. The solution is then poured into ethyl acetate (200 ml) and washed successively with 1M hydrochloric acid, water and brine. The organic solution is dried (MgSO 4) and concentrated under vacuum. The residue is purified by instantaneous chromatography (gradient elution: methanol: methylene chloride, 3:97 to 5:95) to give (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl ] -N- [2-methyl-l- (2,2,2-trifluoroacetyl) propyl] -pyrrolidine-2-carboxamide (0.27 g) as a white foam (as a mixture of the ketone and hydrated forms); CCF, Rf = 0.4 (methanol: dichloromethane, 2.5: 97.5); NMR-iH (DMSO / D20): 4.44 (m, 1H), 4.00 (m, 2H), 3.72 (m, 1H), 3.51 (m, 4H), 202-1.75 (m, 6H), 0.95-0.78 ( m, 12H); Analysis for C18H28F3N3 ° 5-H2 ° '3: Calculated: C, 50.42; H, 6.72; N, 9.80; Found: C, 50.31; H, 6.28; N, 9.56. The starting material of (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-1- (2,2,2-trifluoro-1-hydroxyethyl) propyl ] pyrrolidine-2-carboxamide is obtained as follows: Methyl chloroformate [0. 12 mi) is added to a solution of the (2RS, 3SR) -L-valyl-N- [3- (4-methyl-1.1.1-trifluoro-2-hydroxypentyl)] -L-prolinamide (obtained as described in U.S. Patent 5,194,588) (0.5 g ) and triethylamine (0.57 ml) in dichloromethane (13.6 ml) at 0 ° C. The solution is allowed to stir for 0.5 hour, and then it is poured into ethyl acetate (100 ml). The organic solution is washed successively with a solution of saturated aqueous sodium bicarbonate, water and brine. The solution is dried (MgSO 4) and concentrated under vacuum. The residue is purified by flash chromatography (gradient elution; methanol: methylene chloride, 5:95 to 7:93) to give (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-1- (2 , 2, 2-trifluoro-1-hydroxyethyl) propyl] pyrrolidine-2-carboxamide (0.51 g); TLC, (methanol: methylene chloride, 5:95); MS: m / z = 426 (M + 1).

Example 2 A solution of potassium permanganate (16.6 g) in water (100 ml) is added dropwise to a 0 ° C solution of (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl ] -N- [(S) -2-methyl-1- ((R) -2,2, 2-trifluoro-1-hydroxyethyl) propyl] pyrrolidine-2-carboxamide (15 g) in tert-butyl alcohol (175 ml), water (100 ml) and 0.6 M sodium hydroxide solution (175 ml). The solution is stirred for 2 hours and then quenched by the addition of methanol (70 ml), followed by stirring for 1 hour. The mixture is filtered through diatomaceous earth and the filtrate is made acidic at pH 2 using 1M hydrochloric acid and saturated with sodium chloride. The product is extracted into ether (5 x 100 mL) and the solvent is removed under vacuum. The resulting oil is chromatographed (methanol: dichloromethane 5:95) and the solvent is removed to give an oil. Hexane (40 mL) is added to a stirred solution of the oil in ethyl acetate (which had been subjected to water presaturation) (40 mL) and stirring is continued for 24 hours during which time a crystalline solid formed . Another portion of hexane (40 mL) is added and the solid is collected and dried under vacuum (40 ° C) to give (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] - N- [(S) -2-methyl-1- (2,2,2-trifluoroacetyl) propyl] pyrrolidine-2-carboxamide (9.45 g) as a white crystalline solid (as substantially or essentially Form A), NMR- 1H (300 MHz, DMSO / D20): 4.42 (m, 1H), 4.02 (d, 1H), 3.73 (m, 1H), 3.59 (m, 1H), 3.54 (s, 3H), 2.23 (, 1H) , 2.00-1.76 (m, 6H), 0.91 (m, 6H), 0.85 (d, 3H), 0.80 (d, 3H); Analysis for C18H28F3N3 ° 5-H20: Calculated: C, 48.97; H, 6.85; N, 9.51; Found: C, 49.02, H, 6.80; N, 9.66; (XDS shown in Figure 1).

The starting material of (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(S) -2-methyl-1-. { (R) - (2,2,2-trifluoro-1-hydroxyethyl) propyl] pyrrolidine-2-carboxamide was obtained as follows: (i) The N- [(phenylmethoxy) -carbonyl] -l-butyl ester -valil-L-proline (905 g) is dissolved in ethanol (4 liters) and palladium on charcoal 10% (20 g) is added. The reaction mixture is stirred under a nitrogen atmosphere (3.52 kg / cm2 (50 psi)) for 12 hours and then the catalyst is removed by filtration through diatomaceous earth. The filtrate is concentrated under vacuum and the residue is re-evaporated twice from toluene (1 liter) to give the tert-butyl ester of L-Valyl-L-Proline as an oil (628 g); TLC, Rf = 0.2, acetone: hexane (20:80); MS: m / z = 271 (M + 1). (ii) A solution of sodium carbonate (110.5 g) in water (1.5 liters) and tert-butyl ether of L-Valyl-L-Proline in tetrahydrofuran (THF, 1 liter) are combined and cooled to 0 ° C. The rocking is diluted with ether (400 ml) and methyl chloroformate (39.4 g) is added in drops. The reaction mixture is then allowed to warm to room temperature for 2 hours. The layers are separated and the organic phase is washed twice with 1M hydrochloric acid, followed by saturated aqueous sodium bicarbonate solution and brine. The aqueous phase is extracted with ether. All the organic phases are combined and dried (MgSO4) and the solvent is removed to give the N- (methoxycarbonyl) -L-valyl-L-proline tert-butyl ester (125.9 g); NMR-1H (300 MHz, DMSO / d4-trifluoroacetic acid): 4.23 (dd, 1H), 4.06 (d, 1H), 3.78 (m, 1H), 3.57 (m, 1H), 3.55 (s, 3H), 2.16 (m, 1H), 1.95 (m, 3H), 1.80 (m, 1H), 1.42 (s, 9H), 0.94 (m, 6H); MS: m / z = 329 (M + 1). (iii) To a solution of the tert-butyl ester of N- [methoxycarbonyl] -L-valyl-L-proline (813 g) in toluene (3 liters) is added an ion exchange resin Amberlust-15 (190 g) . The reaction is heated to 120 ° C to distill the water present in the resin by means of a water / toluene azeotrope. Approximately 400 ml of the distillate was collected. The heating is then continued at reflux for 1.5 hours. The reaction is cooled to 60 ° C and the resin is removed by filtration. The filtrate is extracted with 1M NaOH (2.5 liters) followed by aqueous sodium bicarbonate solution, saturated. The combined basic extracts are extracted with a mixture of THF / ethyl acetate (1: 1, 1 liter) and then cooled in an ice bath. The aqueous solution is made acidic at pH 1.5 using cold 3M hydrochloric acid (1 liter) and extracted twice with THF / ethyl acetate (1: 1, 1.5 liters and 1 liter). The extracts are combined and washed with brine, dried (MgSO4) and the solvent is removed by evaporation. The resulting material is dissolved in ether (1 liter) and left to crystallize at 0 ° C for 48 hours.

The resulting solid is collected by filtration, washed with cold ether and dried under vacuum to give N- [methoxycarbonyl] -L-valityl-L-proline (373 g), NMR - ^ - H (300 MHz, DMSO) 12.4 (s, 1H), 7.37 (d, 1H), 4.25 (dd, 1H), 4.00 (t, 1H), 3.79 (m, 1H), 3.55 (m, 1H), 3.51 (s, 3H) , 2.11 (m, 1H), 1.85 (m, 4H), 0.91 (d, 3H), 0.87 (d, 3H); MS m / z = 273 (M + l). (iv) N-Methylmorpholine (8.5 ml) is added to a solution of N- (methoxycarbonyl) -L-valyl-L-proline (12.5 g) in THF (150 ml) and the solution is cooled to -15 ° C in an ice / acetone bath. The isobutyl chloroformate (6.6 ml) is added dropwise and the mixture is stirred for 1 hour. A second portion of N-methylmorpholine (8.5 ml) is added, followed by the hemioxalate salt of (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol (10 g). The reaction mixture is then allowed to stir for 12 hours while allowing it to warm to room temperature. The reaction mixture is diluted with ether (500 ml) and washed successively with saturated aqueous sodium bicarbonate solution, 1 M HCl and brine. The aqueous layers are extracted with ether and all the organic phases are combined and dried (MgSO4). The solution is filtered and the solvent is removed by evaporation. The resulting material is filtered through a silica gel using ether as the eluent. The ether fractions containing the product are combined and the solvent is removed by evaporation. The product is dried under vacuum to give (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(S) -2-methyl-1- (R) - (2 , 2,2-trifluoro-1-hydroxyethyl) propyl] pyrrolidine-2-carboxamide (16.1 g); NMR - ^ - H (300 MHz, DMSO): 7.61 (d, 1H), 7.28 (d, 1H), 6.44 (d, 1H), 4.44 (m, 1H), 4.05 (m, 1H), 3.98 (m , 1H), 3.75 (m, 2H), 3.55 (m, 1H), 3.50 (s, 3H), 1.83 (m, 6H), 0.90 (d, 3H), 0.86 (d, .3H); MS: m / z = 426. The hemioxalate salt of (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol used in step (iv) is obtained as follows: (i) Triphosgene (23) is added. g) in a portion for a well-stirred mixture of the hemioxalate salt of (2RS, 3SR) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol (50 g) in toluene (250 ml) and the 2M sodium hydroxide solution (350 ml). The reaction begins to be exothermic and is placed in an ice bath. After 0.5 hours the reaction is heated to 25 ° C and the TLC indicates a substantial amount of an unreacted amine present. The pH of the solution is readjusted to approximately 12 using 50% sodium hydroxide solution. An additional portion of triphosgene (8 g) is added and the solution is stirred for 1 hour. The pH of the reaction mixture is lowered to pH 7 using 1M hydrochloric acid and extracted twice with ether. The combined ether layers are washed with water, brine and dried (MgSO4). The solvent is removed by evaporation to give an oil, which crystallizes to rest. The resulting solid is collected by filtration and washed with ether hexane (1: 1) to give 27 g of (4RS), 5SR) -4-isopropyl-5-trifluoromethyl-oxazolidin-2-one as a white solid, m.p. 71-72 ° C; NMR - ^ - H (300 MHz, DMSO): 8.45 (s, 1H), 5.11 (m, 1H), 3.61 (m, 1H), 1.72 (m, 1H), 0.86 (d, 6H). (ii) n-Butyllithium (20 mL of a 10M solution in hexane) is added to a solution of (4RS) .5SR) -4-isopropyl-5-trifluoromethyloxazolidin-2-one (35.8 g) in THF (600) mi) at -78 ° C, followed by stirring for 0.5 hours. The chloroformate of (-) - menthyl (41 ml, freshly distilled) was followed by continuing stirring at -78 ° C for 0.5 hour. The solution is heated to 25 ° C and the reaction is stopped by the addition of saturated aqueous sodium bicarbonate solution. The product is extracted into ether and washed with water and brine. The solution is dried (MgSO4) and the solvent is removed under vacuum. The resulting oil is recrystallized to rest to give a solid which is collected by filtration. The solid is washed with ether: hexane (1: 1) and dried to give (4S, 5R) -4-isopropyl-3- [(IR, 3R, 4S) -3-jD-menthyloxycarbonyl] -5-trifluoromethyloxane -zolidin-2-one (23.15 g); p.f. 138-140 ° C; 1 H-NMR (300 MHz, DMSO): 5.51 (dd, 1H), 4.68 (m, 1H), 4.26 (m, 1H), 2.27 (m, 1H), 1.94 (d, 1H), 1.78 (m, 1H) ), 1.62 (d, 2H), 1.42 (m, 2H), 1.01 (dd, 2H), 0.95-0.84 (, 24H), 0.71 (d, 3H); 19FRMN (376.5 MHz, DMSO): -76.9910; 99% d.e. (Another crop of 4.3 g (99% d.e.) is obtained from the mother liquor). [Note: the (4R, 5S) isomer has m.p. 80-82 ° C and 19FRMN (376.5 MHz, DMSO): - 77.0019. (iii) A solution of (4S, 5R) -4-isopropyl-3- [(IR, 3R, 4S) -3-p-menthyloxycarbonyl] -5-trifluoromethyloxazo-lidin-2-one (27 g) in dioxane ( 70 ml) and 50% potassium hydroxide solution (80 ml) is heated at 100 ° C for 2 days. The reaction is cooled, diluted with ether (400 ml) and the organic layer separated. The pH of the aqueous solution is adjusted to 9 (in approximately original form 14) using 6M hydrochloric acid. The aqueous layer is extracted 3 times with ether (300 mi) The organic phases are combined, dried (MgSO 4) and added to a well-stirred solution of oxalic acid dihydrate (4.5 g) in acetonitrile (100 ml). The solid which is precipitated is collected by filtration, washed with ether and dried under vacuum (60 ° C) to give 15.9 g of white solid. The solid is triturated with ether (300 ml), collected by filtration and dried to give (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol isolated as its salt hemioxalate (13.4 g, 88% yield) as a white solid, mp 184-186 ° C; I-NMR (300 MHz, DMSO): 5.71 (broad s, 3H), 4.08 (ddd, 1H), 2.88 (m, 1H), 1.81 (m, 1H), 0.92 (m, 6H); Analysis for CgH12F3NO. C2H204 0.5: Calculated: C, 38.89; H, 6.06; N, 6.48; Found: C, 38.75; H, 5.95; N, 6.47. The (2RS.3SR) -3-amino-s4-methyl-1,1,1-trifluoro-2-pentanol used in step (i) is obtained as described in U.S. Patent 4,910,190.

Example 3 Using an oxidation procedure similar to that described in Example 2, but using (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-1- ( 2,2,2-trifluoro-l-hydroxyethyl) propyl] -pyrrolidine-2-carboxamide and adding the potassium permanganate solution at 5-10 ° C and after stirring at 10 ° C for one hour before the treatment with methanol, were obtained (after lifting by extraction in tert-butyl methyl ether, followed by washing with brine and concentration in vacuo) (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl ] -N- [2-methyl-1- (2,2,2-trifluoroacetyl) propyl] -pyrrolidine-2-carboxamide as a gum (in 75% yield); SSS relationship: SSR 53:47; hydrate: ketone 1: 1; NMR - ^ - H similar to that of the product of Example 1. [Using a similar procedure, but adding the potassium permanganate solution at room temperature instead of 5-10 ° C, the product was obtained in a ratio of SSS: SSR of 47:53].

The starting material (S) -1- [(S.) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-1- (2,2,2-trifluoro-1-hydroxyethyl) propyl] -pyrrolidine-2-carboxamide is obtained as an oil (in 55% yield) using an analogous procedure to that described in Example 2, part (iv), but using 3-amino-4-methyl-1, 1, 1-trifluoro-2-pentanol (as a mixture of diastereoisomers), itself obtained as described in USP 4,910,190 or as follows: (i) A solution of urea (72 g) in DMF (810 ml) is added to nitrite sodium (90 g), stirred for 10 minutes and then cooled to 15 ° C. Isobutyl iodide is added (97.2 ml) for 30 minutes and the reaction mixture is allowed to stir at room temperature for 20 hours. The mixture is re-cooled to 15 ° C and water (810 ml) is slowly added. The mixture is stirred for 5 minutes at room temperature and then extracted twice with butyl-tert-butyl ester. The combined organic extracts are washed twice with 20% aqueous sodium thiosulfate solution and concentrated under vacuum to give 2-methyl-1-nitropropane (39 g), which is used without further purification. (ii) 3A moly sieves (27.04 g) were heated at 120 ° C under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in tert-butyl butyl ether (420 ml). The mixture is stirred for 5 minutes, potassium carbonate (64.5 g) is added and the mixture is stirred for another 30 minutes. The mixture is cooled to 15 ° C and fluoral hydrate (22.0 g) is added for 30 minutes. The reaction mixture is stirred at room temperature for 16 hours, then cooled to 15 ° C and water (270 ml) is added. After stirring for 5 minutes at room temperature, the organic phase is separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. The solvent is then removed by evaporation under reduced pressure at a temperature below 40 ° C and the azeotropic oil is dried with isopropyl alcohol at a temperature below 50 ° C to give the 4-methyl-3-nitro- 1, 1, 1-trifluoro-2-pentanol (21.3 g) as an oil, which is used without further purification. (iii) A solution of 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (17.1 g) in isopropanol (115 ml) and acetic acid (0.43 ml) are hydrogenated on palladium in carbon on a 10% (2.4 g) at a pressure of 3.5 bar until the incorporation of hydrogen is complete. The catalyst is removed by filtration through diatomaceous earth and the filter cake is washed with isopropanol. The filtrate is evaporated under vacuum until no additional isopropanol is distilled and the residue is dissolved in acetonitrile (40 ml). A solution of oxalic acid (3.94 g) in acetonitrile (80 ml) is added with stirring and the mixture is cooled to 5 ° C. The product which is crystallized is collected by filtration, washed with cold acetonitrile and dried at 50 ° C to give 3-amino-4-methyl-1,1,1-trifluoro-2-pentanol as its oxalate salt (9.08 g).

Example 4 Hexane (13 ml) is added to a solution of (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-1- (2,2, -trifluoroacetyl) propyl] -pyrrolidine-2 -carboxamide (0.85 g); SSS: SSR 53:47; hydrate: ketone 1: 1) in tert-butyl methyl ether (8.5 ml) until you give the nebulosity. The solution is then heated to give a clear solution, cultured with the substantially pure crystalline SSS diastereomer and allowed to stand. A white crystallized solid which is collected by filtration to give (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(S) -2-methyl-1- (2,2,2-trifluoroacetyl) -propyl] -pyrrolidine-2-carboxamide as a crystalline solid in 30% yield, SSS: SSR 95: 5; hydrate: ketone 80:20; NMR similar to that of the product of Example 2.

Example 5 Using a procedure similar to that described in Example 4, but starting with a diastereoisomeric mixture of SSS: SSR 53:47 (1.73 g) and hydrate: ketone 95: 5, but adding 36% hydrochloric acid w / w (0.06 ml) and water (0.04 ml) to the crystallization solvent before the addition of hexane, the crystalline SSS diastereomer was obtained in a yield of 22% with SSS: SSR 98.5: 1.5 and substantially or essentially in a hydrated form.

Example 6 Using a procedure similar to that described in Example 5, but excluding hydrochloric acid, a crystalline diastereoisomeric mixture was obtained with SSS: SSR 65:35 and substantially or essentially in a hydrated form.

Example 7 Using a procedure similar to that described in Example 5, but starting with a diastereoisomeric mixture of SSS: SSR 47:53 and hydrate: ketone 60:40, the SSS crystalline diastereomer was obtained in 18% with SSS: SSR 98.5: 1.5 and substantially or essentially in a hydrated form.

Example 8 The product of Example 2 (5 g) is dissolved in 1,2-dimethoxyethane (DME; 6 ml) with slight heating. Water (5 ml) is carefully added to the solution to give a clear solution. The solution is allowed to cool to room temperature, cultivated with substantially pure crystalline SSS diastereoisomer and allowed to stand for 16 hours. The crystalline mass that has formed at the bottom of the container was carefully broken and collected by vacuum filtration. The crystalline product is washed with a mixture of DME and water and allowed to dry in a stream of air for 16 hours to give the crystalline SSS diastereoisomer (which then contains less than 2% of the diastereomer SSR) as substantially or essentially in Form B, with a water content of 7.3% w / w; (EDS spectrum shown in Figure 3). [Using a similar procedure using the recrystallized Form A as the initial material, Form B was obtained, which has a water content of 7.7% P / Pl • Example 9 The product of Example 8 (4.78 g) is dissolved in ethyl acetate (14.7 ml) with heating at 60 ° C under an inert atmosphere. Hexane (22 ml) is slowly added and the solution allowed to cool to 22 ° C. The crystalline product is collected by filtration and washed with hexane (10 ml), then allowed to dry in a stream of air to give the crystalline SSS diastereomer (which then contains less than 2% diastereomer SSR) as substantially or essentially in Form A, with a water content of 4.1% p / p Example 10 The product of Example 2 (1 g) is dissolved in cyclohexane (20 ml) and the solution is distilled at atmospheric pressure at 80 ° C to reduce the volume to 7 ml. The clear solution is then allowed to cool to 24 ° C. The solid is suspended, collected by means of suction filtration carried out under a stream of dry nitrogen and dried in a desiccator under vacuum in the presence of phosphorus pentoxide. The SSS critalino distereoisomers were then obtained (which then contains less than 2% of the SSR diastereoisomer) in substantially or essentially the "ketone" form; (XDS spectrum shown in Figure 4).

Chemical formulas Scheme I (R. a.lßul \ (3) 1 (e) CBZ - benzyloxycarbonyl Suitable conditions include: (a) DMF, 1-hydroxybenztriazole, Et3N, dicyclohexyl-carbodiimide, 0 ° C at room temperature (b) R = fcBu: trifluoroacetic acid, CH2C12, 0 ° C at room temperature R = Me: methanol / Aqueous NaOH, room temperature (c) ißuO.CO.Cl, N-methylmorpholine, THF, -35 ° C at 0 ° C, followed by aminoalcohol (d) H2, 10% Pd-C, EtOH (e) CH3O .CO.Cl, Et3N, CH2C12, 0 ° C Scheme 2 . { 10) »v» W ° COjSi (Mß). Y? CO.H The appropriate conditions for Scheme 2 include: Stages (1), (8), (9): as for Stage (d) of Scheme 1; Steps (2), (7), (11): MeOCOCl, Et3N or N-methylmorpholino, CH2C12 or THF, 0 ° C to 30 ° C; Steps (3), (6): trifluoroacetic acid, CH2C12, 0 ° C at room temperature; Stages (4), (5): as for Stage (a) of Scheme 1; Step (10): Me3SiCl, THF, N-methylmorpholine, 0-30 ° C; Step (12): aqueous acid hydrolysis; Stages (13), (14): as for Stage (c) of Scheme 1 Scheme 3 (1) (3) H OHCFI

Claims (16)

1. A compound of the formula I or a solvate thereof, or a ketal or semichetal thereof as a diastereoisomeric mixture, characterized in that it comprises 50% or more of the diastereoisomer of the formula or a solvate thereof or a ketal or semicetal thereof.

2. The compound according to claim 1, characterized in that it is the compound (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [2-methyl-l- (trifluoroacetyl) propyl] pyrrolidine-2-carboxamide or a solvate thereof, both in the form of a diastereomeric mixture of (S) -1- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [(3_) -2-methyl-1- (trifluoroacetyl) propyl] -pyrrolidine-2-carboxamide or a solvate thereof and (S) -l- [(S) -2- (methoxycarbonylamino) -3-methylbutyryl] -N- [ (R) -2-methyl-1- (trifluoroacetyl) propyl] pyrrolidine-2-carboxamide or a solvate thereof and in the form of the substantially or essentially pure diastereomer (S) -1- [(S) -2- (methoxycarbonylamino ) -3-methylbutyryl] -N- [(S) -2-methyl-1- (trifluoroacetyl) propyl] pyrrolidine-2 -carboxamide of the formula la or a solvate thereof.

3. The compound, solvate, ketal or semichetal according to claim 1 or 2, characterized in that it is in a crystalline form.

4. The compound or solvate according to any preceding claim, characterized in that it is in the form of the substantially or essentially pure diastereomer of the formula la or a hydrated form thereof.

5. The compound or solvate according to any preceding claim, characterized in that it is in the form of the substantially or essentially pure diastereomer of the formula Ib or a hydrated form thereof, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4, characterized in that it is crystalline, is in a hydrated form and has an X-ray powder diffraction pattern that includes specific peaks of approximately 2-theta = 10.8, 11.4, 21.6 and 21.9 degrees.

7. The compound according to claim 4, characterized in that it is crystalline, is in a hydrated form and has an X-ray powder diffraction pattern that includes specific peaks of approximately 2-theta = 7.2, 7.4, 9.0, 9.2, 10.8, 11.3, 14.5, 15.9, 17.8, 19.7 and 22.5 degrees.

8. A pharmaceutical composition characterized in that it comprises a compound, solvate, ketal, semicetal or pharmaceutically acceptable salt according to any preceding claim, together with a pharmaceutically acceptable diluent or carrier.

9. A process for the manufacture of a compound according to claim 1, or a solvate form thereof, which is characterized in that it comprises the oxidation of a compound of the formula II with a suitable oxidation agent.

10. A process according to claim 9, characterized in that a compound of the formula It is used as an initial material.

11. A process according to claim 10, followed by the formation of crystals from a solution of the product in a solvent, characterized in that it is selected from butyl acetate, a mixture of butyl acetate and hexane, a mixture of acetone and water, a mixture of acetone and hexane, a mixture of acetone and petroleum ether, eg 100-120 ° C, a mixture of 1,2-dimethoxyethane and hexane, a mixture of 1,2-dimethoxyethane, water and hexane, a mixture of ethyl acetate and hexane, a mixture of ethyl acetate, hexane and water, water, a mixture of dibutyl ether and hexane, a mixture of dichloromethane and hexane, a mixture of methanol and toluene, a mixture of tert-butyl methyl ether and hexane, a mixture of isopropanol and hexane and a mixture of tetrahydrofuran and hexane.

12. A process for preparing a compound according to claim 6 or claim 7, characterized in that it comprises forming crystals from a substantially pure or essentially diastereomeric solution of the formula la in a hydrated form in a solvent selected from butyl acetate, a mixture of butyl acetate and hexane, a mixture of acetone and water, a mixture of acetone and hexane, a mixture of acetone and petroleum ether, e.g. 100-120 ° C, a mixture of 1,2-dimethoxyethane and hexane, a mixture of 1,2-dimethoxyethane, water and hexane, a mixture of ethyl acetate and hexane, a mixture of ethyl acetate, hexane and water, and water.

13. A compound obtainable by means of the process according to claim 11 or 12.

14. A compound of formula II or lia.

15. A process for the manufacture of the intermediate (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol, or a salt thereof, characterized in that it comprises (i) the reaction of (4RS, 5SR) -4-isopropyl-5-trifluoromethyloxazolidin-2-one, or an alkali metal salt thereof, with (-) -methyl chloroformate to give (4RS, 5SR) -4 -isopropyl-3- [(1R, 3R, 4S) -3-p.-menthyloxycarbonyl] -5-trifluoromethyloxazolidin-2-one; (ii) separation of the isomer (4RS.5SR) -4-isopropyl-3 - [(IR, 3R, 4S) -3-p-menthyloxycarbonyl] -5-trifluoro-methyl-oxazolidin-2-one; and (iii) hydrolysing the isomer (4RS, 5SR) -4-isopropyl-3- [(IR, 3R, 4S) -3-p.-menthyloxycarbonyl] -5-trifluoromethyl-oxazolidin-2-one under basic conditions to give (2R, 3S) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol.

16. A method of administering a compound according to claim 1, or a solvate thereof, to a human in need thereof for treatment of a condition or condition in which human leukocyte elastase is involved.