Derivatives of proline, suitable as inhibitors of elastase of human leukocytes

 

(57) Abstract:

Describes the new derivatives of Proline General formula I

< / BR>
or solvated form, or ketal, or Hemi-ketal as diastereomeric mixtures containing 50% or more diastereoisomer formula Ia

< / BR>
or solvated form, or Catala, or Hemi-Catala. The compounds are inhibitors of elastase of human leukocytes. 6 C. and 10 C.p. f-crystals, 8 ill.

The invention relates to new derivatives of Proline, and more specifically to individual forms new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL)- propyl]pyrrolidin-2-carboxamide, which are inhibitors of elastase of human leukocytes (ALC), also known as elastase human neutrophils (ANC), which are important, for example, as a means of research work in pharmacological, diagnostic and related studies and in the treatment of diseases of mammals, which also involved ALC. For example, ALC is the cause of the pathogenesis of acute respiratory distress syndrome (ARDS), rheumatoid arthritis, atherosclerosis, emphysema and other inflammatory diseases, including inflammatory diseases demonicheskiy bronchitis and cystic fibrosis. ALC is also the cause of some vascular diseases and associated States (and used in their treatment), with the participation of neutrophils, or who are involved in neutrophils, such as bleeding associated with acute leukemia, non-lymphocytic leukemia, and reperfusion injury associated with, for example, myocardial ischemia, and related conditions associated with coronary artery disease, such as angina and myocardial infarction, cerebrovascular ischemia such as transient cerebral blood flow or sudden impairment of cerebral circulation, peripheral obtenerse vascular disease, such as intermittent claudication and critical limb ischemia, venous insufficiency, such as venous hypertension, varicose veins and the formation of venous ulcers, as well as with weak States with reperfusion, such as conditions associated with reconstructive surgery on vessels, thrombolism and plastic surgery on the blood vessels. The invention relates also to methods for treating one or more of these disease States and to the use of one or more individual forms a new derived during the manufacture in addition, relates to pharmaceutical compositions containing one or more individual forms a new derivative as an active ingredient, and to methods for individual forms a new derivative, to new intermediate products used in the above methods, and a process for the production of these intermediate products.

Due to the obvious role of elastase of human leukocytes in recent years there has been considerable amount of research work aimed at the development of inhibitors of ALC. In U.S. patent 4910190 described a number of closely related structures peptidoglycan derived triptorelin, which are inhibitors of elastase of human leukocytes. Currently, applicants discovered that certain forms of new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL) propyl]pyrrolidin-2-carboxamide of the formula I (at the end of this description) are unexpectedly potent inhibitors of ALC.

According to one aspect of the invention features the compound (S)-1-[(S)-2-(methoxycarbonylamino)-3-methyl-butyryl]-N-[2 - methyl-1-(TRIFLUOROACETYL) propyl] pyrrolidin-2-carboxamide, or MES, both in the form diastereomeric mixture of (S)-1-[(S)-2- (methoxycarbonylamino)-3-methylbutyryl the but)-3-methylbutyryl]-N-[(R)-2 - methyl-1-(TRIFLUOROACETYL) propyl]pyrrolidin-2-carboxamide (or MES) and in the form of substantially or practically pure diastereoisomer (S)-1-[(S)-2-(methoxycarbonylamino)-3 - methylbutyryl] -N-[(S)-2-methyl-1-TRIFLUOROACETYL)propyl] pyrrolidin-2-carboxamide (or MES).

Note that the compound of formula I has three chiral center (indicated in the formula I as * and #) and, therefore, can exist in eight different stereometric forms or in the form of diastereomers a mixture of two or more of these forms. For example, the connection (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N- [2-methyl-1-(TRIFLUOROACETYL) propyl] pyrrolidin-2-carboxamide is a compound of formula 1, in which the two chiral center marked * have the S-configuration, and the third chiral center marked as # has a RS-configuration. Therefore, the connection is diastereomeric mixture containing diastereoisomer with chiral centers marked with * and #, with all the S-configuration, that is, (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N- [(S)- 2-methyl-1-(TRIFLUOROACETYL) propyl] pyrrolidin-2-carboxamide (hereinafter referred to as "SSS-diastereoisomer formula I, and which may also be represented as shown in formula Ia given in the end of the description, in depicting bold connection means a connection, protruding above the plane of the paper), and diastereoisomer with chiral centers marked with * has the S-configuration, and the center marked # having the R-configuration, that is, (S)-1-[(S)-2- (matoke "SSR-diastereoisomer formula (I), or their solvate. This diastereomer mixture includes, for example, a mixture containing approximately equal amounts of SSS and SSR-diastereoisomers, i.e. the ratio of SSS:SSR is about 1:1. For example, the received diastereomer mixtures containing SSS and SSR-diastereoisomer in the ratio of 53:47 and 47:53 (SSS:SSR). Individual forms of the compounds of formula I which are preferred, are diastereomer mixture that is enriched SSS-diastereoisomers, i.e. the ratio of SSS:SSR is more than 1:1. Particularly preferred form of connection is a substantially or practically pure SSS-diastereoisomer, i.e. SSS-diastereoisomer containing less than 5% (more specifically, less than 3% and preferably less than 2%) other diastereoisomers.

Note that SSS-diastereoisomer formula I may also form diastereomer mixture with one or more other forms of the formula I, for example, can be obtained (S)-1- [2-(methoxycarbonylamino)-3-methylbutyryl] -N-[(S)-2-methyl-1- (TRIFLUOROACETYL) propyl] pyrrolidin-2-carboxamid (diastereomeric mixture of SSS and RSS forms of formula (I) or (I-[(S)-2-(methoxycarbonylamino) -3-methylbutyryl] -N-[(S)-2-methyl-1- (TRIFLUOROACETYL) propyl] pyrrolidin-2-carboxamid (diastereomer the e about 50% or more SSS-diastereoisomer, together with one or more other possible diastereoisomers with different configurations at the chiral centers marked in the formula I as * and #, are therefore the following aspects of the present invention.

Diastereomeric mixture of SSS and SSR-diastereoisomers can exist in an amorphous, non-crystalline form or in crystalline form depending on the ratio of SSS: SSR present diastereoisomers. Preferred diastereomer mixture is a mixture that can be isolated in crystalline form, which is particularly suitable in the manufacture of the compounds or compositions based on it, with a degree of purity and homogeneity required for certification of a standard pattern. Note that it is extremely difficult to get a connection, representing the only diastereoisomer, completely free from other possible diastereomeric forms, in particular the connection that has three chiral center. Therefore, the present invention includes a crystalline form SSS-diastereoisomer formula I or its MES, which contains other possible diastereomeric forms with different configurations at the chiral centers marked in titomirov, or their hydrates, which is essentially or practically diastereomeric mixture of SSS and SSR-diastereoisomeric ratio (SSS:SSR) 65:35 or more, i.e., it contains 35% or less of the SSR-diastereoisomer. Therefore, the present invention includes a crystalline form of the compound of formula I or its MES with the content of the SSS-diastereoisomer at least 65%. Preferably the crystalline diastereomer mixture is, for example, the ratio of SSS:SSR, which is 80: 20 or more, such as 95:5 or more, and in particular to 98.5:1.5 or more. Particularly preferred form of the compounds according to the invention is a crystalline SSS-diastereoisomer, which is substantially or nearly pure, i.e. it contains less than 5% of other diastereoisomers, for example less than 5% of the SSR-diastereoisomer, preferably less than 3% of the SSR-diastereoisomer and more preferably less than 2% of the SSR-diastereoisomer.

Amorphous or crystalline diastereomeric mixture of SSS and SSR-form, or substantially or practically pure diastereoisomer, exists in a form that is essentially or substantially free from solvent (which is referred to below ketone form and which is illustrated by formula Ia for chionoi and solvated (hydrated) form. Hydrated form may exist, for example, in the form of a gem-diol trifurcating radical, i.e. the compounds of formula Ib (presented at the end of the description) for substantially or practically pure SSS-diastereoisomer, or in the form of the compounds of formula Ic (presented at the end of the description), or in a form that includes a water molecule as part of the crystal lattice, or a mixture of such forms. The compounds of formula Ib or Ic, in addition, can be, for example, hydrated.

Note that the degree of hydration diastereomeric mixture either substantially or practically pure SSS-diastereoisomer can be expressed as the ratio of the number of hydrated forms to the amount of ketone form. For example, the selected amorphous, noncrystalline diastereomeric mixture of SSS and SSR-forms, in which the ratio of the hydrated form to the ketone form is changed, for example, from about 30:70 (i.e., a mixture enriched ketone form) to about 95:5 or more (i.e. a mixture essentially or substantially hydrated form), including such ratios, as about 50:50 and 60:40. For example, were obtained crystalline forms, which are relevant SSS: SSR about 95:5 at the same time with respect to the hydrate:ketone of about 80:20, and quotational form. Were also obtained crystalline hydrates substantially or practically pure SSS-diastereoisomer containing approximately 4.1% (by weight) and 7.8% (by weight) of water. These individual forms are further aspects of the invention. In addition, note that the present invention also covers any ketal or hemiketal (or mixtures thereof) diastereomeric mixture or form SSS-diastereoisomer, or MES, against those who turn into a gem-diol in vivo, for example, by hydrolysis or enzymatic cleavage (and whose remainder is pharmaceutically acceptable). The present invention also includes any tautomer or prodrug SSS-diastereoisomer or MES.

Note that the compound of formula Ib may be referred to as a gem-diol form of the compounds of formula Ia or by chemical name (S)-1-[(S)-2- (methoxycarbonylamino)-3- (methylbutyryl)] -N-[(S)-2-methyl-1- (2,2,2-Cryptor-1,1-dihydroxyethyl) propyl]pyrrolidin-2 - carboxamid. It should also be noted that an alternative name for the compounds of formula Ia is methyl-N-[(1S)-1- ((2S)-2-[N-((1S)-2-methyl-1- (2,2,2-TRIFLUOROACETYL)-propyl) carbarnoyl]pyrrolidin-1-ylcarbonyl) -2-methylpropyl]-carbamate, and alternativefuel) carbarnoyl-pyrrolidin-1-ylcarbonyl) -2-methylpropyl]carbamate.

The melting point of the crystalline SSS-diastereoisomer containing SSR-diastereoisomer, usually depends on the level of content present SSR-diastereoisomer and on the degree of solvation (hydration). It can be determined using standard techniques, well known in the technology, for example using differential scanning calorimetry (DSC).

Preferably the crystalline SSS-diastereoisomer is in hydrated form. For example, were discovered hydrated form SSS-diastereoisomer that have such a positive property that they are not hygroscopic, such as form a and form B, which are described below. Thus, the preferred form SSS-diastereoisomer is a crystalline form containing less than 5% (preferably less than 3% and especially preferably less than 2%) of the SSR-diastereoisomer, and is substantially or nearly in hydrated form. It is established that such crystalline hydrated form, such as form A and form B have good biological suitability and good solubility in aqueous buffer, and both of these properties are positive.

Especially preferably is located in the hydrated form, has a powder x-ray, which consists of two main characteristic peak at about 2 = to 10.8 and 11.4o. This form (referred to in the present description form A) contains approximately 4.1% of water. Powder x-ray also includes relatively less intense characteristic peaks occurring at approximately 2 = 15,4, 16,8, 18,2, 18,6, 20,6, 21,6, 21,9, 22,8 and 25.0o. Range of powder x-ray diffraction (XDS) is a typical sample of this form is shown in Fig. 1 and 2, where Fig. 2 shows a less intense peaks in an enlarged scale. Additional physical data suggest that this crystalline form is essentially or substantially in the form of a diol of the formula Ib.

The following preferred crystalline form SSS-diastereoisomer formula I, when it is substantially or almost clean and is in a hydrated form has a powder x-ray that includes the main characteristic peak at approximately 2 = 7,2. This form (referred to in the present description form) contains approximately 7.8% by weight (for example, of 7.3 to 8.3% by weight) of water. Powder x-ray also includes relatively less intense characteristic peaks, vstrechka rays typical sample of this form is shown in Fig. 3. Additional physical data suggest that this crystalline form is substantially or almost monohydrate diol of formula Ib.

When he is essentially or substantially pure and substantially or practically free from solvent (i.e., is "ketone" form), SSS-diastereoisomer formula I has a powder x-ray that includes the main characteristic peak at approximately 2 = 12,1. This x-ray also includes relatively less intense peaks occurring at approximately 2 = 6,0, and 16,8 17,7o. Range XDS typical sample in the "ketone" form shown in Fig. 4.

Spectra, powder x-ray diffraction was determined, for example, using x-ray diffractometer Scintag XDS-2000 solid state detector of photons EC& G series GLP (germanium), managed by the Microvax computer, and using software Diffraction Management System supplied by the company Scintag Inc., Sunnydale, California, USA. Used x-ray tube was a tube Cu K-alpha wavelength at 45 kV and 40 mA. Receiving slit were set at a distance of 2 and 4 mm, and the slit engaged divergence, were installed at a distance of 0.2 and 0.5 mm attributed the chopper and increment of 0.02. Each sample exhibited at a speed of 1 degree of angle 2-theta per minute (slew time was 38 minutes) and took the readings from 2 to 40 degrees 2-theta with obtaining the curve of the lattice parameter depending on the intensity for that interval.

For carrying out diffraction analysis, the samples were Packed in round cups for samples of aluminum alloy with a diameter of 25 mm and a height of 2 mm, a Powder sample was placed in a Cup so that the substance was found to be in excess compared with the volume of the Cup, and then leveled on the edge of the Cup with the help of slides microscope. As an external standard used silicon type NBS 640b.

Alternatively, used x-ray diffractometer Siemens D5000, recording the diffraction pattern in mode in the range from 2 to 40 degrees 2-theta, with an exposure of 4 seconds per increment 2 0.02o.

For a typical sample of form a was obtained infrared spectrum. The infrared spectrum was obtained using the methods of casting solvent, well-known in the technology of the combined acetonitrile fills the sample in a salt box for analysis by direct transmission. The infrared spectrum was determined in the range is their peaks at approximately 2968, 1762, 1721, 1690, 1632, 1525, 1447, 1207 and 1154 cm-1.

The infrared spectrum was also obtained for a typical sample form using a spectrometer Nicolet 20SXC FTIR. The spectrum was obtained using 2% of the variance of the sample in potassium bromide. The infrared spectrum shown in Fig. 6. Spectrum in Fig. 6 includes sharp peaks at approximately 3402, 3321, 3252, 3060, 2967, 2878, 1699, 1674, 1629, 1535, 1532, 1446, 1271, 1258, 1249, 1175, 1152, 1118, 1089, 1029, 1013, 1004, 635, 593 and 567 cm-1. Using similar conditions was obtained infrared spectrum for a typical sample form C. the Infrared spectrum shown in Fig. 7. Spectrum in Fig. 7 includes sharp peaks at 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 was obtained infrared spectrum for a typical sample SSS-diastereoisomer in a substantially "ketone" form. The infrared spectrum shown in Fig. 8. Spectrum in Fig. 8 includes sharp peaks at approximately 3415, 3300, 2967, 2876, 1764, 1723, 1711, 1695, 1686, 1634, 1527, 1445, 1356, 1286, 1234, 1213, 1139, 1105, 1061, 1020, 774, 774, 732 and 671 cm-1.

Note that the value 2 for powder x-ray wavelengths of infrared spectra can slightly vary from one device to another, and the characteristic-specific peak which occur in about 2 = to 10.8 and 11.4ofor a typical sample forms And in the case of using x-ray diffractometer Scintag XDS-2000 meet at about 2 = to 10.6 and 11.2oaccordingly, in the case of using x-ray diffractometer Siemens D-5000 (with less intense peaks also occur at a proportionally lower relative values of 2).

Note that the hydrogen atoms of hydroxyl groups form, having the formula Ib or Ic (or its hydrate), are acid and that, therefore, such compounds can form crystalline farmatsevticheskii acceptable salt using standard techniques, for example, bases, giving a physiologically acceptable cations, such as salts of alkali metal (such as sodium or potassium), alkaline earth metal or organic amine. Therefore, the invention includes a crystalline pharmaceutically acceptable salt forms of the formula Ib and Ic, or their hydrates.

Different forms of the compounds of formula I or their solvate (hydrate) can be obtained, for example, by the following processes, which are, then, some aspects of the invention.

Noncrystalline (AMO who redstavlena at the end of the description) with a suitable oxidizing agent.

Suitable oxidising agent is a known technology oxidant for the conversion of the hydroxyl group in the ketone group. Suitable oxidizing agents and conditions include, for example, the use of oxalicacid, dimethyl sulfoxide and tertiary amine; using acetic anhydride and dimethyl sulfoxide; using pyridine complex with chromium trioxide in dichloromethane; the use of a reagent containing hypervalent iodine, such as 1,1,1-triacetoxy-2.1-benzoxazol-3(3H)-he triperoxonane acid in dichloromethane; the use of an excess of dimethyl sulfoxide and water-soluble carbodiimide in the presence of dichloracetic acid; or permangante alkali metal in the alkali aqueous solution such as an alkaline aqueous solution of potassium permanganate or sodium permanganate. Particularly suitable oxidizing agents are the last two of these, in particular alkaline aqueous solution of potassium permanganate or sodium, for example a mixture of sodium hydroxide and potassium permanganate or sodium.

The compound of formula II can be obtained, for example, as shown in schemes 1 and 2 given in the end of the description, using standard methods or as illustrated in PR is 5. Stage (e) is conducted using the standard methods of obtaining carbamate from primary amine, for example, using methylvalerate, such as methylchloroform, in the presence of a suitable base, such as triethylamine or N-methylmorpholine, and in a suitable solvent or diluent, for example a chlorinated hydrocarbon (such as dichloromethane or chloroform) or solvent type simple ether (such as tetrahydrofuran or dioxane) at temperatures of, for example, in the range -10oC to 50oC, for example from 0oC to 30oC. the reaction according to scheme 2 include standard protection phase (stage (10)), unprotect or selective removal protection (stage(1), (3), (6), (8), (9) and (12)), combinations (phase(4), (5), (13) and (14)) and the formation of carbamate (stage (2), (7) and (11)), is well known in the technology.

Note that diastereomeric mixture of SSS and RSS diastereoisomers and SSS and SRS-diastereoisomers can be obtained using similar techniques with an appropriate choice of L - or DL-valine or Proline (or their protected derivatives) as a source of nutrients and using (2R, 3S)-3-amino-4-methyl-1,1,1-Cryptor-2-pentanol at appropriate stages of the combination.

Crystalline form SSS-diastereoisomer containing 35% or less of the SSR-diastereoisomer, can be obtained from non-crystalline (amorphous) diastereomeric mixture of SSS and SSR-diastereoisomer containing SSS and SSR-diastereoisomer in approximately equal amounts (i.e. a ratio of about 1: 1, typically 53:47 47:53), by crystallization from a suitable non-polar solvent such as a mixture of tert-butyl simple ether and hexane, preferably containing a small amount of water and optionally containing a small amount of hydrochloric acid, for example, 0-0,2 molar equivalent of 36% hydrochloric acid, and 1-2,1 molar equivalent of water. It is established, that is preferred to add the aqueous hydrochloric acid to the solvent from which the crystallization is carried out, in the case when using non-crystalline diastereomer mixture with the ratio of SSS:SSR, constituting 47: 53. To initiate crystal is the product is usually provided in the form of a mixture of hydrated and ketone forms, usually a ratio of about 80:20 (hydrate:ketone) or more. Hydrated form, or a mixture of ketone and hydrated forms can be converted into a substantially or practically "ketone" form by drying in a vacuum oven (for example, at a temperature of about 50oC). However, this ketone form is hygroscopic.

Significantly or substantially pure crystalline form SSS-diastereoisomer can be obtained by recrystallization or by repeated recrystallization of the crystalline forms of the SSS-diastereoisomer containing SSR-diastereoisomer. Solvents or solvent mixtures that can be used for this purpose include, for example, butyl acetate, butyl acetate/hexane, acetone/water, acetone/hexane, acetone/oil fraction with a boiling point 100-120oC, 1,2-dimethoxyethan/hexane, 1,2-dimethoxyethane/water/hexane, ethyl acetate/water/hexane, ethyl acetate/hexane, water, disutility ether/hexane, dichloromethane/hexane, 1,2-dimethoxyethane/water, methanol/toluene, methyl tert-butyl ether/hexane, isopropanol/hexane and tetrahydrofuran/hexane. In order for A preferred are the first ten solvents or mixtures of solvents of the above. Particularly suitable restore the form can also be obtained when using a mixture of ethyl acetate/water/hexane. The concept of "hexane" when it is used in the present work, include the isomers of hexane (such as isohexane) or mixtures thereof.

Significantly or substantially pure crystalline form SSS-diastereoisomer can also be obtained by crystallization of substantially or practically pure SSS-diastereoisomer allocated in non-crystalline form (for example, by oxidation of compounds of formula IIa), such as oil, solvents or mixtures of solvents, such as those described above, especially a mixture of ethyl acetate, water and hexane.

In addition, form A can be obtained from the form by recrystallization, for example, as shown in example 9. In addition, crystalline ketone form (which is hygroscopic) can be obtained from the form And, for example, as shown in example 10.

Getting Catala or Hemi-ketela of the ketone is well known in the technology.

3-amino-4-methyl-1,1,1 - Cryptor-2-pentanol can be obtained as described in U.S. patent N 4910190 or as shown in the examples.

Especially convenient is the way to obtain (2R,3S)-3-amino-4-methyl-1,1,1-Cryptor-2-pentanol, which is the next aspect of the invention is 1,1,1-Cryptor-2-pentanol or its salt with triphosgene or dimethylcarbonate in the presence of a suitable base to obtain (4RS,5SR)-4-isopropyl-5-triftormetilfosfinov-2-it; followed

(2) the interaction of (4RS,5SR)-4-isopropyl-5 - trifluoromethyl-oxazolidin-2, or its salt with an alkaline metal (-)-methylchloroform with the receipt of (4RS,5SR)-4-isopropyl-3- [(1R,3R,4S)-3-p-Menthyl-oxycarbonyl]-5-trifluoromethyl - oxazolidin-2-it, and release isomer (4S,5R)-4-isopropyl-3- [(1R, 3R,4S)-3-p-Menthyl-oxycarbonyl]-5-Cryptor - methyloxazolidine-2-he; the next

(3) hydrolysis of isomer (4S, 5R)-4-isopropyl-3-[(1R,3R,4S)-3-p-methyloxycarbonyl]-5 - triftormetilfosfinov-2-he in an alkaline medium to obtain (2R,3S)-3-amino-4-methyl-1,1,1-Cryptor-2-pentanol.

At the stage (1) with a suitable base is an aqueous solution of alkali metal hydroxide, for example sodium hydroxide or potassium. The reaction is in General carried out in a suitable inert solvent or diluent, for example a hydrocarbon, such as toluene. The reaction is exothermic and, therefore, the reaction generally is carried out in conditions of external cooling to maintain a temperature of about from 0oC to 50oC, for example at approximately ambient temperature.

At stage (2) the reaction is carried out in a suitable solvent or diluent, for example in a solvent, having the essential character, such as tetrahydrofur metal, for example, using utility at a temperature of about -78oC. processing the desired (4S,5R)-isomer is crystallized from a mixture of isomers and is collected by filtration.

At stage (3) suitable conditions include, for example, using an aqueous solution of alkali metal hydroxide (such as potassium hydroxide or sodium) in a solvent or diluent essential character, such as dioxane, at a temperature in the range of, for example, 60-130oC (such as for example 90-120oC).

The usefulness of the compounds according to the invention can be demonstrated using standard tests and clinical studies, including those described below.

Quantitative measurements of the braking

The ability of compounds according to the invention (or a separate form) to act as an inhibitor of elastase of human leukocytes (ALC) on the peptide substrate methoxy-succinyl-alanyl-alanyl-prolyl-valine-p - nitroanilide with low molecular weight was determined as described in U.S. patent 4910190. The ability of the compounds was evaluated by obtaining the kinetic evaluation of the dissociation constants, Kicomplex formed by the interaction of the inhibitor with the RA 2 has Kiequal to 9 nm.

Model of lung damage in the acute form

Models of emphysema in animals included intratracheal (i.t.) introduction alactolyticus proteases to induce a slowly progressive lung damage of a destructive nature. Usually this defeat was evaluated in a time interval of several weeks to several months after the initial hemorrhage. However, these proteases also cause the lesion, which appears in the first few hours. Early defeat in the beginning is hemorrhagic, progresses in inflammatory lesions by the end of the first 24 hours and is eliminated within the first weeks after the hemorrhage. To take advantage of this early lesions may be used in the next model.

Hamsters initially slightly anaesthetize using brevital (Brevital). Then directly into the trachea injected with saline phosphate buffer (PBS) with a pH of 7.4, either by itself or containing the elastase of human leukocytes (ELC). Twenty-four hour animal killed and the lungs were removed and carefully cut off the extraneous tissue. After determining the mass of raw their lungs (lungs), washed with PBS and determine about what elih cells. Masses of light crude, the total number lowairway red cells and the total number lowairway white cells increase depending on the dose, the subsequent introduction of ALC. Compounds that are effective inhibitors of elastase, can prevent or reduce the severity caused by enzyme destruction, leading to lower weight raw light and reducing the total number lowairway cells, both Reds and whites in relation to the introduction of only one of ALC. To evaluate compounds by their introduction vnutritrahealno in the form of solutions or suspensions in physiological solution with phosphate buffer, either simultaneously or at different points in time with the test introduction of ALC (400 mcg), or dosed by intravenous injection or orally in the form of solutions at different points in time before the test introduction of ALC (100 μg) to determine their usefulness in preventing induced ALC defeat. A solution of the compounds according to the invention (or a separate form) can be conveniently prepared using 10% polyethylene glycol 400 in PBS.

Test for bleeding in the acute form

This test is based on of the elastase of human neutrophils (ANC). Quantitative characterization of bleeding is determined by the destruction of red blood cells separated from the used washing liquid after lung lavage, and the comparison with the dilution of whole blood hamster. Inspection procedure similar to the procedure described in Fletcher et al., American Review of Respiratory Disease (1990), 141, 672-677, consists in the following. Connections which have shown that they are inhibitors of an in vitro, convenient way to prepare for the dosed introduction as described above for the model of lung damage in the acute form. Male Syrian hamsters (starving for 16-128 hours before use) slightly anaesthetize using brevital-sodium (30 mg/kg intraperitoneally). Then make dosed introduction hamsters compounds intravenously or orally for a specified time, such as 30 or 90 minutes prior to intratracheal administration of an in 300 μl of saline phosphate buffer with a pH of 7.4, 50 ug/animal. Four hours after administration of the enzyme animals killed using excessive dose pentobarbital-sodium, open the chest and remove the heart and lungs and clear light from the side of the material. Then light washed three shifts of 2 ml PBS che the preserve at 4oC until analyzed. To calculate the amount of blood in each sample thawing and rinsing the sample of whole blood hamster treated with ultrasound to destroy red blood cells, and appropriately diluted in separate wells of 96-hole tiralongo microplate. The optical density of the leaching and blood samples exposed to destruction of erythrocytes, determined at 540 nm. Relations (ál equivalent of blood)/(ml rinse) is determined by comparing the optical density of the test samples with an optical density calibration curve derived from whole blood of hamsters. The total number of allocated equivalents blood ál determined by multiplying the amount of leaching on the ratio (μl equivalents blood)/(ml rinse) for each sample. The results are given as % inhibition caused by an bleeding in comparison to the control samples treated with saline phosphate buffer for the test compounds, taken in a certain amount and a certain time of the introduction before the introduction of ANC. It was found that the compounds according to example 1 ED50(effective dose that provides braking by 50%) is 4.5 mg/kg of peroral the orally dosed introduction and 0.6 mg/kg intravenously dosed introduction.

Was not observed obvious toxicity in cases when the connection according to the invention was administered in the above in vivo tests.

It should be understood that the conclusions about the activity of compounds in models of lung damage in the acute form, or in the test bleeding in the acute form is not limited to emphysema, but rather that the test gives evidence of a General inhibition of ALC in vivo.

According to the following features of the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds according to the invention (or some form) or MES and a pharmaceutically acceptable diluent or carrier. As noted above, another feature of the invention is a method of using compounds according to the invention (or some form) or MES in the treatment of diseases or conditions of a mammal, in particular humans, which also involved ELC, such as diseases or conditions described above and, in particular, acute and chronic bronchitis, emphysema, reperfusion injury, respiratory distress syndrome in adults, cystic fibrosis, or peripheral vascular disease (takyu (or separate form) may be given a warm-blooded animal, in particular person, which (who) needs treatment, which involved ELC, in the form of a standard pharmaceutical composition, for example, as generally described in U.S. patent 4910190. One way of introduction can be performed by a powder or liquid aerosol. In the form of powder aerosol compound according to the invention (or a separate form) can be entered in the same way that cromolyn-sodium, through the device type turbomaster "Spinhaler" (trademark), manufactured by Fisons Corp. of Bedford, Massachusets, with a rate of about 0.1 to 50 mg per capsule, and the average person is entered from 1 to 8 capsules per day. Each capsule designed for use in turbomaster contains the required number of compounds according to the invention (or a separate form), and the rest of the content by mass of 20 mg per capsule represents a pharmaceutically acceptable carrier, such as lactose. In the form of liquid aerosol compound according to the invention (or a separate form) can be entered using a spray (aerosol inhaler), such as, for example, spray Retec" (trademark), in which the slurry is sprayed with compressed air. Aerosol IOC fill with a solution of the compound (or its separate forms), for example, 3.5 ml of a solution containing 10 mg/ml; solution in the spray is sprayed with compressed air; and the patient is breathing normally (tidal volume) for eight minutes with spray in the mouth.

In an alternative embodiment, the mode of administration can be parenteral, including subcutaneous deposition, by means of an osmotic pump or preferably orally. The connection according to the invention (or a separate form) can be conveniently prepared in the form of oral or parenteral dosage form by mixing from about 10 to 250 mg per unit dosage form with standard media, excipient, binder, preservative, stabilizer, flavoring agent or the like are provided conventional pharmaceutical practice, for example as described in U.S. patent 3755340. For parenteral administration should be intravenous, intramuscular or subcutaneous injection amount from 1 to 10 ml, containing from about 0.02 mg to 10 mg per kg of body weight of the compounds according to the invention (or a separate form), 3 or 4 times a day. Injection should contain the compound according to the invention (or a separate form) in water issadora, such as ethylenediaminetetraacetic acid (adtc). For parenteral administration or use in an aerosol can be prepared aqueous composition, for example, by dissolving the compound (or its separate form) in 5-10% polyethylene glycol 400 in physiological solution with phosphate buffer, followed by aseptic filtration and storage under sterile conditions using standard techniques.

Usually the connection according to the invention (or a separate form) can be administered to the human at a daily dose in the range of, for example, from 5 to 100 mg of the compound (or its separate form) in the form of an aerosol, or from 50 to 1000 mg intravenously or orally, or in combination. However, it is clear that it may be necessary to change the dose of the compound (or its separate form) in accordance with well known medical practice, taking into account the nature and severity of the disease, the treatment of which is associated with therapy and the age, weight and sex of the patient treated. At the same time it should be considered that can be used is usually an equivalent amount of solvated (for example, hydrated forms of the compounds. The order of introduction of the inhibitor ALC and OC is 11 for the treatment or prevention of cystic fibrosis, acute respiratory distress syndrome, bronchitis, and bleeding associated with acute leukemia, non

for leukemia, or therapy, respectively; and a connection according to the invention (or a separate form) can be used in a similar way, or preferably be used by oral administration for the treatment of these diseases and conditions either alone or in combination with another therapeutic agent, usually indicated for the treatment of a specific condition. For therapeutic treatment or prevention in a mammal of a vascular disease or a related condition involving neutrophils or which involved the neutrophils, the connection according to the invention (or a separate form) can be conveniently administered orally or parenterally or by itself, either simultaneously or sequentially with other therapeutically active means, usually entered in this condition. The usefulness of the compounds according to the invention (or a separate form) treatment of vascular diseases and related conditions can be demonstrated using the techniques described in International Patent Application, Publication N provide examples in which, unless otherwise specified:

(1) temperatures are given in degrees Celsius (oC); operations were carried out at room temperature or ambient temperature, i.e. at temperatures in the range of 18-25oC;

(2) organic solvents were dried over anhydrous magnesium sulfate; evaporation of solvent was performed using a rotary evaporator under reduced pressure (600-4000 PA; a 4.5-30 mm RT.CT.) with a bath temperature of up to 60oC;

(3) chromatography means flash chromatography (method of Steele (Still)) conducted on the sorbent Merck Kieselgel (Art 9835 from E. Merck, Darmstadt, Germany), elution, which was used as the stepped and sloping gradients indicated by the bracketed term "gradient", followed by the initial and final ratios of solvents; thin-layer chromatography (TLC) was performed on plates with silica gel, for example on the GHLF plates with a layer of silica gel in 0.25 mm (Art 21521 from Analtech, Newark, DE, USA);< / BR>
(4) usually over the course of the reaction was followed by thin layer chromatography, and reaction times are given for illustration only;

(5) melting points are uncorrected, and the designation (decomp. indicates decomposition; the melting temperature of aleuritic to selection in some preparations of substances with different melting temperatures;

(6) final products had satisfactory spectra of nuclear magnetic resonance (NMR); and in cases where they were investigated using liquid chromatography high resolution, was substantially pure;

(7) the outputs are given for illustration only and are not binding values for the outputs, which can be obtained by careful design of the process; if you wanted more substance, its preparation was repeated; the

(8) NMR data, when they are presented in the form of Delta values for major diagnostic protons, given in parts per million (million-1) relative to tetramethylsilane was (TMS) as the built-in standard determined at 250 MHz using DMSO-d6as a solvent; use standard abbreviations for waveforms; spectra AB are directly observed shifts;

(9) chemical symbols have their usual meanings; used units and symbols SI;

(10) reduced pressures are given as absolute pressures in Pascals (PA); elevated pressures are given as gauge pressure in Pascals (PA);

(11) the ratio of solvents are given as ratios of volume/volume (V/V);

(12) survey of mass spectra is direct exposure; moreover indicated ionization was induced by electron impact (EI) or fast atom bombardment (FAB); usually given only peaks that indicate the mass of the substance source; and

(13) to set the ratio of SSS:SSR diastereoisomers formula I in the selected substance used liquid chromatography high resolution using column 25 cm x 4.6 mm reversed-phase SUPELCO LC-18 and a mixture of water:acetonitrile (70:30) as eluent. The flow rate was 0.1 ml/min, and the total input was 20 µl using the valve, and the wavelength of detection was 205 nm. The delay time for the SSS-diastereoisomer was about 9.9 minutes, and the delay time for the SSR-diastereoisomer was about 11.7 minutes.

Example 1

Hydrochloride of 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide (1.84 g) was added to a solution of (S)-1-[(S)-2- (methoxy-carbylamine) -3-methylbutyryl]-N-[2-methyl-1-(2,2,2 - Cryptor-1-hydroxyethyl) propyl]pyrrolidin-2-carboxamide (0,41 g), dissolved in dimethyl sulfoxide (DMSO; 5 ml) and toluene (5 ml), then was added dropwise dichloracetic acid (0,32 ml). The resulting solution was stirred at 20oC for 2 hours. Then the solution was poured into ethyl acetate (200 ml) and then washed 1 the Residue was purified using flash chromatography (gradient elution; methanol: methylene chloride from 3:97 to 5:95) to obtain (S)-1-[(S)-2-(methoxycarbonylamino)-3 - methylbutyryl]-N-[2-methyl-1- (2,2,2-TRIFLUOROACETYL) propyl] pyrrolidin-2-carboxamide (0.27 g) as a white foam (mixture of ketone and hydrated forms); TLC, Rf=0,4 (methanol:dichloromethane to 2.5: 97,5);1H NMR (DMSO/D2O): of 4.44 (m, 1H), 4.00 points (m, 2H), and 3.72 (m, 1H), 3,51 (m, 4H), 2,02 is 1.75 (m, 6H), 0.95 to-0,78 (m, 12H); elemental analysis for C18H28F3N3O50.5 C2H2O4: calculated: C 38,89; H the 6.06; N 6,48; found: C 38,75; H 5,95; N 6,47.

(2RS), (3SR)-3-Amino-4-methyl-1,1,1-Cryptor-2-pentanol used in stage (1), obtained as described in U.S. patent 4910190.

Example 3

Using the method of oxidation, similar to the method described in example 2, but using (S)-1-[(S)-2- (methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2 - Cryptor-1-hydroxyethyl)propyl]pyrrolidin-2-carboxamide and adding potassium permanganate solution at 5-10oC, followed by stirring at 10oC for one hour before treatment with methanol was obtained after treatment with the extraction tert-butylmethylamine ether followed by washing with salt solution and evaporation in vacuum) (S)-1-[(S)-2-(methoxycarbonylamino)- 3-methylbutyryl] -N-[2-methyl 53:47; the ratio of the hydrate:ketone 1:1; range1H NMR similar range of product from example 1. [Using similar techniques, but with the addition of the potassium permanganate solution at ambient temperature instead of 5-10oC received the product with a ratio of SSS:SSR, constituting 47:53.]

The original substance (S)-1-[(S)-2-(methoxycarbonylamino)-3 - methylbutyryl] -N-[2-methyl-1-(2,2,2-Cryptor-1-hydroxy-ethyl) propyl] pyrrolidin-2-carboxamide was obtained as oil (yield 55%) when using a technique similar to the method described in example 2, part (4), but using 3-amino-4 - methyl-1,1,1-Cryptor-2-pentanol (in the form of a mixture of diastereoisomers), which, in turn, obtained as described in U.S. patent 4910190 or as follows.

(1) a Solution of urea (72 g) in dimethylformamide (810 ml) was added sodium nitrite (90 g), was stirred for 10 minutes and then cooled to 15oC. for 30 minutes was added isobutylated (97,2 ml) and the reaction mixture was allowed to mix at ambient temperature for 20 hours. The mixture was again cooled to 15oC and slowly added water (810 ml). The mixture was stirred for 5 minutes at ambient temperature and then was extracted twice methyl-tre is perivale in vacuum to obtain 2-methyl-1-nitropropane (39 g), which was used without further purification.

(2) Molecular sieve (27,04 g) was heated at 120oC in vacuum for 20 hours and was added to a solution of 2-methyl-1-nitropropane (13,0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, was added potassium carbonate (64,5 g) and the mixture was stirred for further 30 minutes. The mixture was cooled to 15oC for 30 minutes was added Fluorinert (22,0 g). The reaction mixture was stirred at ambient temperature for 16 hours, then was cooled to 15oC and was added water (270 ml). After stirring for 5 minutes at ambient temperature the organic phase was separated and washed with 10% aqueous potassium carbonate solution, a 2 M solution of hydrochloric acid and water. Then the solvent was removed by evaporation under reduced pressure at a temperature below 40oC and oil drove in the form of anhydrous azeotrope with isopropyl alcohol at a temperature below the 50oC to obtain 4-methyl-3-nitro-1,1,1 - Cryptor-2-pentanol (21,3 g) in the form of oil, which was used without further purification.

(3) a Solution of 4-methyl-3-nitro-1,1,1 - Cryptor-2-pentanol (17.1 g) in isopropanol (115 ml) and acetic acid (0,43 ml) was first made on 10% fell by filtration through diatomaceous earth and the filter cake was washed with isopropanol. The filtrate was evaporated in vacuum until the isopropanol was no longer distilled, and the residue was dissolved in acetonitrile (40 ml). Was added with stirring a solution of oxalic acid (3.94 g) in acetonitrile (80 ml) and the mixture was cooled at 5oC. the Product which crystallized was collected by filtration, washed with cold acetonitrile and dried at 50oC to obtain 4-methyl-3-nitro-1,1,1-Cryptor-2-pentanol in the form of its salt with oxalic acid (oxalate) (remaining 9.08 g).

Example 4

Hexane (13 ml) was added to a solution of (S)-1-[(S)-2- (methoxycarbonylamino)-3-methylbutyryl] -N-[2-methyl-1-(2,2,2 - TRIFLUOROACETYL)propyl]pyrrolidin-2-carboxamide (0.85 grams; SSS:SSR 53:47; hydrate:ketone 1: 1) in tert-butylmethylether ether (8.5 ml) up until continued blushing. Then the solution was heated to obtain a clear solution, making seed substantially pure crystalline SSS-diastereoisomer and allowed to settle. Crystallized solid is white, which was collected by filtration to obtain (S)-1-[(S)-2- (methoxycarbonyl-amino)-3 - methylbutyryl]-N-[(S)-2-methyl-1-(2,2,2-TRIFLUOROACETYL) propyl] pyrrolidin-2-carboxamide in the form of a crystalline solid with a yield of 30%, SSS: SSR 95:5; hydrate:ketone 80:20; SPCE, described in example 4, but based on diastereomeric mixture of SSS:SSR 53:47 (1.73 g) and hydrate:ketone 95:5 and adding to the solvent from which the crystallization is carried out, 36% (mass) hydrochloric acid (0.06 ml) and water (0.04 ml) before the addition of hexane, was obtained with the yield 22% crystalline SSS-diastereoisomer with SSS:SSR of 98.5:1.5 and substantially or nearly in hydrated form.

Example 6

Using a method similar to the method described in example 5, but excluding hydrochloric acid, was obtained crystalline diastereomeric mixture of SSS:SSR 65:35 and which is substantially or nearly in hydrated form.

Example 7

Using a method similar to the method described in example 5, but from diastereomeric mixture of SSS:SSR 47:53 and hydrate:ketone 60:40, was obtained with the yield 18% crystalline SSS-diastereoisomer with SSS:SSR of 98.5:1.5 and being substantially or nearly in hydrated form.

Example 8

The product from example 2 (5 g) was dissolved in 1,2 - dimethoxyethane (6 ml) under low heat. To the solution was carefully added water (5 ml) to obtain a transparent solution. The solution was allowed to cool to ambient temperature, making seed substantially pure crystalline SSS-diastereoisomer and gave otstorili using vacuum filtration. The crystalline product was washed with a mixture of 1,2-dimethoxyethane and water and allowed to dry in a current of air for 16 hours to obtain crystalline SSS-diastereoisomer (containing less than 2% of the SSR-diastereoisomer) as essentially or substantially of the form B with a water content of 7.3% mass; (range of x-ray diffraction shown in Fig. 3). [Using a similar technique, but using as the starting material recrystallized form A received form B with a water content of 7.7% of the mass.]

Example 9

The product from example 8 (4,78 g) was dissolved in ethyl acetate (14.7 ml) by heating to 60oC in an inert atmosphere. Was slowly added hexane (22 ml) and the solution was allowed to cool to 22oC. the Crystalline product was collected by filtration and washed with hexane (10 ml), then allowed to dry in air flow with obtaining crystalline substantially pure SSS-diastereoisomer (containing less than 2% of the SSR-diastereoisomer) as essentially or practically forms a water content of 4.1% mass.

Example 10

The product from example 2 (1 g) was dissolved in cyclohexane (20 ml) and the solution was distilled at atmospheric pressure at 80oC, reducing the volume to 7 ml Then transparent solution first pressure, held in a current of dry nitrogen, and dried in a desiccator under vacuum in the presence of phosphorus pentoxide. Thus was obtained a crystalline SSS-diastereoisomer (containing less than 2% of the SSR-diastereoisomer) as essentially or practically "ketone" form; (range of x-ray diffraction shown in Fig. 4).

1. Derivatives of Proline of the formula I

< / BR>
or solvated form, or ketal, or Hemi-ketal as diastereomeric mixtures containing 50% or more diastereoisomer formula Ia

< / BR>
or solvated form, or Catala, or Hemi-Catala.

2. Derivatives of Proline under item 1, which represent the connection (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(TRIFLUOROACETYL)propyl] pyrrolidin-2-carboxamide or MES, as diastereomeric mixture of (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(TRIFLUOROACETYL)propyl] pyrrolidin-2-carboxamide or its MES and (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl] -N-[(R)-2-methyl-1-(TRIFLUOROACETYL)propyl] pyrrolidin-2-carboxamide or its MES, and in the form of substantially or practically pure diastereoisomer (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(thrift ketal under item 1 or 2 in crystalline form.

4. Connection or MES according to any one of the preceding paragraphs as substantially or practically pure diastereoisomer formula Ia or its hydrated form.

5. Derivatives of Proline according to any one of the preceding paragraphs as substantially or practically pure diastereoisomer formula Ib

< / BR>
or its hydrated form, or its pharmaceutically acceptable salt.

6. Derivatives of Proline under item 4, which are crystalline, are in hydrated form and have a powder x-ray, including characteristic peaks at about 2-theta = 10,8, 11,4, 15,4, to 21.6 and 21.9o.

7. Derived Proline under item 4, which is crystalline, is in hydrated form and has a powder x-ray, including characteristic peaks at about 2-theta= 7,2, 7,4, 9,0, 9,2, 10,8, 11,3, 14,5, 15,9, 17,8, 19,7 and 22.5o.

8. The method of obtaining the derivative of Proline under item 1 or solvated form, which consists in the oxidation of compounds of formula II

a suitable oxidizing agent.

9. The method according to p. 8, where the original product is the compound of formula IIa

< / BR>
10. The method according to p. 9 followed by the formation of the crystal is on and water mixture of acetone and hexane, a mixture of acetone and petroleum ether with a boiling point of 100 to 120oC, 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, mixtures dibutylamino ether and hexane, a mixture of dichloromethane and hexane, a mixture of methanol and toluene, a mixture of methyl tert-butyl ether and hexane, a mixture of isopropanol and hexane and a mixture of tetrahydrofuran and hexane.

11. A method of obtaining a connection on p. 6 or 7, which is the formation of crystals from a solution substantially or practically pure diastereoisomer formula Ia in 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 with a boiling point of 100 to 120oC, 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.

12. Connection on p. 6 or 7, which is obtained by the formation of crystals from a solution substantially or practically pure diastereoisomer formula Ia in hydrated form in a solvent selected from Butinge ether with a boiling point of 100 120oC, 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. Connection on p. 1, which is obtained by oxidation of compounds of formula II

< / BR>
a suitable oxidizing agent, followed by the formation of crystals of the product 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 with a boiling point of 100 to 120oC, 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, mixtures dibutylamino ether and hexane, a mixture of dichloromethane and hexane, a mixture of methanol and toluene, a mixture of isopropanol and hexane and a mixture of tetrahydrofuran and hexane.

14. The compound of formula II or IIa

< / BR>
< / BR>
15. The method of obtaining the intermediate product (2R, 3S)-3-amino-4-methyl-1,1,1-Cryptor-2-pentanol, or its salt, which consists in: (1) the interaction of (4RS, 5SR)-4-isopropyl-5-triftormetilfosfinov-2, or its salt with an alkaline metal (-)-methylchloroform with the receipt of (4RS, 5SR)-4-isopropyl-3-[(1R, 3R, 4S] -3-p-Menthyl-axicorp referencelocation-2-he and (3) hydrolysis of isomer (4S, 5R)-4-isopropyl-3-[(1R, 3R, 4S)-3-p-methyloxycarbonyl]-5-triftormetilfosfinov-2-he in an alkaline medium to obtain (2R, 3S)-3-amino-4-methyl-1,1,1-Cryptor-2-pentanol.

16. Method of inhibiting elastase of human leukocytes by introducing a connection on p. 1 or MES.

 

Same patents:

The invention relates to medicine, namely to methods of producing biologically active substances that have immunoregulatory properties, and may find application in medicine, veterinary medicine and experimental biochemistry

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to medicine

The invention relates to new nitrogen-containing heterocyclic compounds which possess valuable biological properties, in particular derived cycloalkane-indole-azaindole, mixtures of their isomers, or individual isomers and their pharmaceutically acceptable salts, derivatives of carboxylic acid as starting compounds and pharmaceutical compositions inhibiting the release associated with apolipoprotein B - 100 lipoproteins

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula II, where R1, R2are primocane C1-6alkyl group; R4represents unsubstituted phenyl; R5and R8represent hydrogen; R6represents methoxy or bromo; R7arepresents methoxy, hydroxy or trifluoromethyl; R9and R10represent hydrogen, salts, solvate or physiologically functional derivatives, and method of production thereof

The invention relates to new substituted 4-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazoles and 4-(2,3-dihydro-1H-inden-1-yl)-1H-imidazoles and their additive salts, to processes for their preparation and to pharmaceutical compositions based on them

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic insufficiency of cerebral blood circulation, transient cerebral ischemia, cerebral stroke, multi-infarct dementia, atherosclerosis of cerebral vessels, encephalopathy, mental and neurological disorders associated with cerebrovascular insufficiency; in ophthalmology: vascular diseases of the retina and/or choroid, degenerative changes of yellow spots, secondary glaucoma; teatree: age-related vascular or toxic depressions hearing, dizziness labyrinth of origin, as well as vazovegetative symptoms of menopausal syndrome

The invention relates to medicine, in particular to pharmacology and therapeutics

The invention relates to medicine, in particular to pharmacology, and in particular to methods of obtaining medicines on the basis of active metabolites peptide

protease" target="_blank">

The invention relates to a series of new analogues of amino acids which exhibit selective inhibition of the enzyme that converts the enzyme interleukin-1, to compositions containing the new analogues of amino acids, and to methods of using them for medicinal purposes

The invention relates to medicine, namely to methods of producing biologically active substances that have immunoregulatory properties, and may find application in medicine, veterinary medicine and experimental biochemistry
Up!