Pharmaceutically acceptable thymodepressin salts and method of obtaining thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutically acceptable crystalline or amorphous salts of D-isoglutamyl-D-tryptophan, methods of their obtaining, pharmaceutical compositions, containing them, and their application for obtaining pharmaceutical compositions for treatment of different conditions and/or diseases. In particular claimed invention relates to potassium salt of D-isoglutamyl-D-tryptophan (1:1) and magnesium salt of D-isoglutamyl-D-tryptophan (2:1).

EFFECT: obtaining pharmaceutically acceptable crystalline or amorphous salts of D-isoglutamyl-D-tryptophan.

22 cl, 15 dwg, 13 ex

 

The SCOPE of the INVENTION

This invention relates to new crystalline and amorphous pharmaceutically acceptable salts D-isoglutamine-D-tryptophan. In particular, this invention relates to a potassium salt of D-isoglutamine-D-tryptophan (1:1), lithium salt of D-isoglutamine-D-tryptophan (1:1), the calcium salt of D-isoglutamine-D-tryptophan (2:1), magnesium salt (D-isoglutamine-D-tryptophan (2:1) and organic ammonium salts of D-isoglutamine-D-tryptophan (1:1), whose properties are improved compared to the amorphous D-isoglutamine-D-tryptophan, crystalline D-isoglutamine-D-tryptophan and disodium salt of D-isoglutamine-D-tryptophan. This invention also relates to methods of producing such new salts of D-isoglutamine-D-tryptophan.

BACKGROUND of the INVENTION

The compound D-isoglutamine-D-tryptophan (also known as H-D-iGlu-D-Trp-OH or thymodepressin) is a synthetic generegulatory dipeptide following formula:

Thymodepressin is a free dibasic acid, which is assigned a registration number® according to Chemical Abstracts Service (CAS) 186087-26-3. U.S. patent 5736519 reveals H-D-iGlu-D-Trp-OH and method thereof, in which the compound purified by ion exchange chromatography. The connection is an immunosuppressant and selectively inhibits the proliferation gemopoeticheskoi the cells-precursors and stimulates apoptosis of granulocytes and apoptosis of lymphocytes (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).

Thymodepressin currently sold in Russia in the form of a disodium salt of D-isoglutamine-D-tryptophan in the form of liquid preparation for injection and in the form for intranasal use for the treatment of psoriasis and atopic dermatitis. The solid form of the disodium salt of D-isoglutamine-D-tryptophan is an amorphous powder which is hygroscopic and difficult to handle. Molecular formula disodium salt of D-isoglutamine-D-tryptophan C16H17N3Na2O5. Its chemical structure is presented below:

and described in Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622.

When conducting research, the inventors have found that dried disodium salt of D-isoglutamine-D-tryptophan is extremely hygroscopic, within a few minutes turns into a gel in the air and is difficult to handle.

Powder or amorphous form of compound intended for pharmaceutical use may lead to production problems related to bulk density, hygroscopicity and variable water content, which cannot be adjusted by drying in vacuum. D-isoglutamine-D-tryptophan is a dipeptide, and drying the amorphous F. rmy at elevated temperature, for example, 80-100°C, in vacuum is not recommended. Thus, there are serious difficulties encountered in the course of the purification method disodium salt of D-isoglutamine-D-tryptophan and producing pure disodium salt on an industrial scale. Moreover, there is no published methods of its receipt.

Monosodium salt of D-isoglutamine-D-tryptophan identified by Chemical Abstracts Services (CAS) and are listed in the registers CAS REGISTRYSMunder the registration number CAS® 863988-88-9. However, there are no references which mentioned the matter, and, therefore, there are no published data regarding its identity, physical and/or chemical properties, characteristics or method of its production. Dried powder monosodium and disodium salts of peptide drugs cannot provide a controlled range of the bulk density of the powder to the recipe. It may require significant investment in technology dispersion of lyophilized material.

Thus, there is a need to develop alternative crystalline pharmaceutically acceptable salt of D-isoglutamine-D-tryptophan. Such crystalline salt in General can be cleaned easier in comparison with an amorphous shape and may have other preferred properties,for example, from the point of view of their specific crystalline forms, and/or characteristics of solubility, and/or lack of hygroscopicity, and/or characteristics of stability, including properties, thermal stability, and/or their ability to undergo oxidative decomposition.

BRIEF description of the INVENTION

The present invention was the development of a number of new stable, pharmaceutically acceptable salts of thymodepressin, suitable for pharmaceutical preparations.

Not all salts D-isoglutamine-D-tryptophan are chemically stable (e.g., amorphous disodium salt). However, the inventors have gained new stable metal and organic ammonium salts of D-isoglutamine-D-tryptophan (H-D-i-Glu-D-Trp-OH), which are the subject of the present invention.

In one aspect of the present invention offers new salt D-isoglutamine-D-tryptophan. Such new forms of salt are compounds of the formula I:

where M is chosen from the group consisting of lithium and potassium;

formula II:

where B is chosen from the group consisting of magnesium and calcium; and formula III:

where A is selected from the group consisting of tert-butylamine, Tris(hydroxymethyl)methylamine and methyl-(2,3,4,56-pentahydroxy)ammonium.

Specifically, the new salts of the formula I of the lithium cation or potassium replaces one hydrogen atom in the carboxyl fragment of compound D-isoglutamine-D-tryptophan. The inventors have found that the new salts of the formula I according to the present invention, where M represents potassium (i.e. monogalia Sol D-isoglutamine-D-tryptophan) may exist in various forms, in particular, amorphous or non-crystalline form, as well as in crystalline form. The inventors have also found that the new salts of the formula I according to the present invention, where M represents lithium (i.e., monolithian Sol D-isoglutamine-D-tryptophan) may exist in various forms, in particular, amorphous or non-crystalline form, as well as in crystalline form. Thus, this invention relates to monolithic and monoclinic salts D-isoglutamine-D-tryptophan in any of their forms.

In another aspect of the present invention offers new lithium salts and potassium salts of D-isoglutamine-D-tryptophan, the compounds of formula I.

In another aspect of the present invention features a crystalline potassium salt of D-isoglutamine-D-tryptophan, a compound of formula I.

In another aspect of the present invention features a crystalline lithium salt of D-isoglutamine-D-tryptophan, the compounds of formula I.

This invention is also relates to crystalline form of the magnesium salt of D-isoglutamine-D-tryptophan and semi-crystalline form of the calcium salt of D-isoglutamine-D-tryptophan, where the cation is calcium or magnesium replaces one hydrogen atom in the carboxyl fragment of compound D-isoglutamine-D-tryptophan. Calcium or magnesium salt of D-isoglutamine-D-tryptophan produced in the ratio 2:1, as illustrated by formula II.

The inventors have found that the magnesium salt of the present invention (i.e., a magnesium salt of thymodepressin [1:2]) exists in crystalline form, while the calcium salt of the present invention (i.e., calcium salt of thymodepressin [1:2]) is semi-crystalline with a percent crystallinity not greater than about 67%.

In another aspect, the present invention proposes a new crystalline magnesium salt of D-isoglutamine-D-tryptophan, a compound of formula II.

In another aspect of the present invention offers a calcium salt of D-isoglutamine-D-tryptophan, a compound of formula II.

This invention also relates to an organic amine salts of the formula III, where A is chosen from the group consisting of tert-butylamine, Tris(hydroxymethyl)methylamine and methyl-(2,3,4,5,6-pentahydroxy)-ammonium. The inventors have found that such salts of formula III are amorphous.

In another aspect, the present invention proposes a new tert-butylamine, Tris(hydroxymethyl)metromanila, methyl-(2,3,4,5,6-pentahydroxy)-ammonium is Sol D-isoglutamine-D-tryptophan, the compound of formula III.

In another aspect of the present invention proposes a method of obtaining salts of formulas I, II and III of the dipeptide D-isoglutamine-D-tryptophan.

In another aspect of the present invention proposes a method of obtaining the salts of D-isoglutamine-D-tryptophan (compound of formula I and II) in the salt exchange D-isoglutamine-D-tryptophan ammonium salt (1:1).

In an earlier patent application filed in Canada on November 28, 2006, the applicant discloses methods of obtaining D-isoglutamine-D-tryptophan and its monoammonium salt, a new stable crystalline form D-isoglutamine-D-tryptophan and its monoammonium salt. D-isoglutamine-D-tryptophan and its monoammonium salt used in the present invention, can be obtained using the method described in the above patent application.

In another aspect of the present invention features a pharmaceutical composition which comprises any of the new salts described above, and at least one pharmaceutically acceptable carrier.

The pharmaceutical composition can be obtained by combining any of the new salts described above, and at least one pharmaceutically acceptable carrier. In another aspect, the present invention proposes a method of creating a pharmaceutical composition that is part of any of the new salts, described above, and at least one pharmaceutically acceptable carrier.

In another aspect of the present invention features the use of any of the new salts described in this invention, with taking medicines for treatment of psoriasis in a subject in need of such treatment.

Another characteristic of the crystalline salts of the present invention is that they can also be used as intermediates in obtaining a non-crystalline salt in order to ensure the provision of non-crystalline salt with a level of purity and homogeneity, which are suitable for the preparation of the corresponding strict pharmaceutical requirements and specifications. Examples of these salts are the lithium salt, the sodium, potassium and ammonium salts. Methods of recrystallization in General remove impurities in the course of the way while cleaning the amorphous substance of peptide drugs requires preparative reversed-phase liquid chromatography high pressure, which is not economical.

Other and further advantages and features of the present invention will be obvious to experts in this field from the following detailed description, which is accompanied by relevant figures.

BRIEF DESCRIPTION of FIGURES

In the attached figures the x:

In Fig.1A presents a powder x-ray (XRPD) of potassium salt of D-isoglutamine-D-tryptophan (1:1).

In Fig.1B presents an infrared spectrum with Fourier transform (FTIR) crystalline potassium salt of D-isoglutamine-D-tryptophan (1:1).

In Fig.1C presents FTIR spectrum of amorphous potassium salt of D-isoglutamine-D-tryptophan (1:1).

In Fig.2A presents the XRPD pattern of the lithium salt of D-isoglutamine-D-tryptophan (1:1).

In Fig.2B presents FTIR spectrum of crystalline lithium salt of D-isoglutamine-D-tryptophan (1:1).

In Fig.2C presents FTIR spectrum of amorphous lithium salt of D-isoglutamine-D-tryptophan (1:1).

In Fig.3A presents XRPD magnesium salt of D-isoglutamine-D-tryptophan (1:2).

In Fig.3B presents the FTIR spectrum of the magnesium salt of D-isoglutamine-D-tryptophan (1:2).

Fig.4A presents XRPD calcium salt of D-isoglutamine-D-tryptophan (1:2).

In Fig.4B presents XRPD calcium salt of D-isoglutamine-D-tryptophan (1:2).

In Fig.4C presents the FTIR spectrum of the calcium salt of D-isoglutamine-D-tryptophan (1:2) obtained by using a material with Fig.4A.

In Fig.5 shows a graph identify the composition of the dipeptide D-isoglutamine-D-tryptophan at different pH.

In Fig.6 shows the FTIR spectrum of the amorphous salt of tert-butylamine and D-isoglutamine-D-tryptophan (1:1).

In Fig.7 shows FTIR spectrum of amorphous mono-Tris(hydroxymethyl)aminomethane the salt D-isoglutamine-D-tryptophan (1:1).

In Fig.8 shows FTIR spectrum of amorphous mono-N-methyl-D-glutaminol salt D-isoglutamine-D-tryptophan (1:1).

A DETAILED DESCRIPTION of the PREFERRED VARIANTS of the INVENTION

As was mentioned above, this invention relates to new metal salts of D-isoglutamine-D-tryptophan and organic amine salts of D-isoglutamine-D-tryptophan.

The present invention D-isoglutamine-D-tryptophan is free dibasic acid

Chemistry of amino acids or simple dipeptides complicated by the fact that the group-NH2represents the basis and the group-CO2H is an acid. Thus, in aqueous solution ion H+moves from one end of the molecule to another to form zwitter-ion battery:

Zwitter ions simultaneously electrically charged and electrically neutral. They contain positive and negative charges, but the total charge on the molecule is zero. Although the formation of the salt is not linked to any theory, the amino acid fragment iGlu H-D-iGlu-D-Trp-OH exists in the form of zwitter-ion battery, and thus, there is only one group-CO2H, which remains available for the formation of salts, if only 1 EQ. monovalent metal hydroxide, 0.5 EQ. divalent metal hydroxide B(OH)2or one equivalent of the amine content of inorganic fillers is used to adjust the pH to neutral values. Examples of the monovalent metal hydroxides are sodium hydroxide, lithium hydroxide and potassium hydroxide. Examples of divalent metal hydroxides include calcium hydroxide and magnesium hydroxide.

If the salt of monovalent metal and H-D-iGlu-D-Trp-OH of formula I is represented in the format shown above, only one group of CO2H can communicate with one ion is monovalent metal with the formation of the salt of formula I. Examples of such monobasic salts of the present invention are potassium and lithium salt (1:1). Examples of divalent metal salts of the present invention are magnesium and calcium salts. Examples of the organic amine salts of the present invention are salts of tert-butylamine, Tris(hydroxymethyl)methylamine and methyl-(2,3,4,5,6-pentahydroxy)ammonium.

Although in the prior art freely uses the term "thymodepressin to designate as free dibasic D-isoglutamine-D-tryptophan and its disodium salt, within the context of the present invention, thymodepressin is a free dibasic acid D-isoglutamine-D-tryptophan with the molecular formula C16H19N3O5and the disodium salt is a compound with the molecular formula C16H17/sub> N3Na2O5. They are two different chemicals with different physicochemical properties.

In this invention monolithian or monogalia salt is formed by replacing one hydrogen atom of a carboxyl group, a metal ion, lithium or potassium, with the structure shown in formula I above. The specific structure is shown below:

Lithium salt of the formula I

Potassium salt of formula I

In this invention the magnesium or calcium salt is formed by replacing one hydrogen atom of a carboxyl group, a metal ion, magnesium or calcium, with the structure shown in formula II above. The term “calcium salt of D-isoglutamine-D-tryptophan (2:1)” in this description refers to Ca(D-isoglutamine-D-tryptophan)2. Similarly, the term “magnesium salt of D-isoglutamine-D-tryptophan (2:1)” refers here to Mg(D-isoglutamine-D-tryptophan)2. The specific structure is shown below:

Calcium salt of formula II

The magnesium salt of the formula II

In this invention, organic amine salts include salts of the peptide and organic amine. For example, tert-butylamine, N-methyl-D-glucamine and tromethamine are organic amines. Organic salt AMI is and the present invention is formed by replacing one hydrogen atom of the carboxyl group of an organic amine with the structure, shown in formula III above. For example, an organic amine salt formed from tert-butylamine and D-isoglutamine-D-tryptophan, in this description denotes a salt of D-isoglutamine-D-tryptophan tert-butylamine (1:1). The specific structure is shown below:

Organic amine salt of the present invention, formed from N-methyl-D-glutamine and D-isoglutamine-D-tryptophan, in this description denotes a salt of D-isoglutamine-D-tryptophan methyl-(2,3,4,5,6-pentahydroxy)ammonium (1:1). The specific structure is shown below:

Organic amine salt of the present invention, formed of tromethamine and D-isoglutamine-D-tryptophan, in this description denotes a salt of D-isoglutamine-D-tryptophan Tris(hydroxymethyl)methylamine (1:1). The specific structure is shown below:

Pharmaceutically acceptable salt of the drug substance is chemically stable and can be used in pharmaceutical compositions. In contrast to simple aromatic hydrocarbons, thymodepressin is a dipeptide with multiple functional groups. Dipeptide D-isoglutamine-D-tryptophan contains alpha-amino groups, two carboxyl groups and indolic nitrogen within one molecule. The ideal salt should be such, for the cat is Roy pH of a solution is close to 7 or is in the range of weakly basic pH. During the study, the inventors to develop a new salt-free from the shortcomings of the disodium salt of D-isoglutamine-D-tryptophan, used graphical determination of the composition (Fig.5) in order to determine the salt with an ideal pH of solution and solubility, which is acceptable for pharmaceutical preparations. Fig.5 is a graph showing the identification of the structure, H-D-iGlu-D-Trp-HE in the range of pH from 0 to 12, using experimentally derived values of pKa. In Fig.5, LH2= H-D-iGlu-D-Trp-OH, LH = salt of monocarboxylic acids, L = salt of dicarboxylic acid and LH3= acid additive salt of H-D-iGlu-D-Trp-OH. On the X-axis shows the value of the pH of the solution, while on the Y-axis shows the number of forms that are present at a particular value of pH. Based on practical experience of the inventors, they use 6 ml of water per gram of H-D-iGlu-D-Trp-OH, for the purposes of allocation, which corresponds to the concentration of a solution of 0.5 M

According to the graphic determination of the structure shown in Fig.5, pH to form dibasic acid is from about 2.7 to about 3 in solution. the pH of the solution to the metal salt of the formula I, where M represents potassium or lithium; dibasic salt of formula II, where a is a calcium or magnesium, is about 7.

Other salts, for example salts of the formula IV

where M is as defined above, and salts of formula V

where B is as defined above, and salts of formula VI

where A is as defined above, are new salt.

Disodium salt (formula IV, where M = Na) is less stable chemical form as a solid. It is extremely hygroscopic, and it is very difficult to weigh in the study formulations. In solution, in accordance with the graphical determination of the composition (Fig.5), the pH exceeds to 9.0, and the pH of the solution must be brought to values from about 7.0 to about 7.4 for in the manufacture of the drug.

As indicated above, the inventors have found that the potassium salt of formula I can exist in amorphous or non-crystalline form, as well as in crystalline form, depending on the conditions under which it was obtained, as described in more detail below. This invention relates to montalieu salt of thymodepressin in any of its forms.

In one embodiment, the present invention offers a potassium salt of formula I in amorphous form.

In another embodiment, the present invention offers a potassium salt of formula I in crystalline form.

In another embodiment of the present invention crystalline potassium Sol the formula I is characterized by a powder x-ray, obtained at λ=1,542 Å using a radiation source of Cu Kα, which contains peaks in the area of the following 2θ values- 9,91, 14,84, 15,81, 18,97, 19,76, 24,04, 24,36, 24,82, 25,48, 27,49, 27,94, 28,42, 30,82, 31,28, 31,69, 32,17, 34,35, 35,81 and 36,96°.

In another embodiment of the present invention the crystalline potassium salt of formula I is characterized by a powder x-ray, substantially similar to that shown in Fig.1A.

As indicated above, the inventors have determined that the lithium salt of the formula I can exist in amorphous or non-crystalline form, as well as in crystalline form, depending on the conditions under which it was obtained, as described in more detail below. This invention relates monolitavia salt of thymodepressin in any of its forms.

In one embodiment, the present invention proposes a lithium salt of formula I in amorphous form.

In another embodiment, the present invention proposes a lithium salt of formula I in crystalline form.

In another embodiment of the present invention crystalline lithium salt of formula I is characterized by a powder x-ray obtained at λ=1,542 Å using a radiation source of Cu Kα, which contains peaks in the area of the following 2θ values- 13,57, 15,53, 18,71, 20,11, 23,34, 24,1, 25,09, 27,31, 27,72, 28,39, 29,31, 30,19, 31,21, 32,06, 33,05, 33,62 and 37,41°.

In another embodiment of the present invention the crystal lit the Wake of the salt of formula I is characterized by a powder x-ray, substantially similar to the one shown in Fig.2A.

As indicated above, the inventors have found that the magnesium salt of the formula II exists in a crystalline form.

In another embodiment, the present invention features a magnesium salt of formula II in crystalline form.

In another embodiment of the present invention crystalline magnesium salt of the formula II, which is characterized by a powder x-ray obtained at λ=1,542 Å using a radiation source of Cu Kα, which contains peaks in the area of the following 2θ values- 12,2, 13,74, 14,84, 16,16, 17,96, 18,52, 18,94, 19,49, 21,05, 21,56, 22,56, 23,36, 24,12, 26,27, 27,65, 28,42, 29,14, 30,55, 31,77, 32,62, 33,26, 35,05, 36,34, 37,22 and 38,05°.

In another embodiment of the present invention crystalline magnesium salt of formula II is characterized by a powder x-ray, substantially similar to that shown in Fig.3A.

The percentage of crystallinity of thymodepressin calcium or the calcium salt of the formula II according to the present invention is below approximately 67%, more preferably below about 50%, and most preferably below about 25%.

In another embodiment, the present invention proposes a calcium salt of formula II with a degree of crystallinity below about 67%.

The total crystallinity, as measured by powder x-ray diffraction analysis, to ensure Ecevit additional useful information for pharmaceutical materials which contain any amorphous material formed during the synthesis procedure. It is also a valuable indicator from the point of view of monitoring long-term changes in crystalline materials. Not being associated with any structural and compositional characteristics, the indicator "percent crystallinity" may be an appropriate indicator of the strength of a particular material as a function of time. The method of determining percent crystallinity of the compounds of the present invention described in the example below. Typical examples of XRPD calcium salt of D-isoglutamine-D-tryptophan is shown in Fig.4A and 4B.

In another embodiment, the present invention offers a salt of tert-butylamine formula III, as shown below:

In another embodiment, the present invention offers a salt of Tris(hydroxymethyl)methylamine formula III, as shown below:

In another embodiment, the present invention proposes salt of methyl-(2,3,4,5,6-pentahydroxy)ammonium of the formula III, as shown below:

In another embodiment, the present invention proposes a method of receiving lithium or potassium salt of the formula I, which comprises (a) interaction of D-isoglutamine-D-tryptophan in water with lithium hydroxide or potassium; (b) the concentration of the licensing solution before formation of the oil and adding isopropanol with stirring to precipitate salts; separation of the resulting sludge; drying the product under vacuum to obtain a metal salt of formula I, where M represents lithium or potassium.

In another embodiment, the present invention proposes a method of obtaining sodium salt of formula IV, which comprises (a) interaction of D-isoglutamine-D-tryptophan in water with sodium hydroxide; (b) the concentration of the solution before formation of the oil and adding isopropanol with stirring to precipitate salt; separating the resulting sludge; drying the product under vacuum to obtain a metal salt of formula IV, where M represents sodium.

In particular, a salt of a metal carboxylate of the formula I is formed by the interaction of a mixture of H-D-iGlu-D-Trp-OH with a metal hydroxide in amount less than about 1 EQ., for example, potassium hydroxide or lithium hydroxide, and the pH correction using the same metal hydroxide to approximately 7,0. Evaporation of solvent gives an oil which is treated with isopropanol to precipitate the solid salt. Salt produce by conventional means and dried in vacuum to obtain the product of formula I.

In another embodiment, the present invention proposes a method of obtaining calcium salt of the formula II, which comprises (a) interaction of D-isoglutamine-D-tryptophan in water with calcium hydroxide; (b) concentration under stirring to precipitate with the Lee; the Department received the precipitate and drying the product under vacuum to obtain a metal salt of formula II, where In represents the calcium.

In particular, the calcium salt is obtained by mixing the dipeptide H-D-iGlu-D-Trp-OH with calcium hydroxide, preferably approximately 0,48-0,49 EQ. calcium hydroxide in 1 EQ. H-D-iGlu-D-Trp-OH, when the temperature of the ice bath with stirring for several hours, preferably from about 2.5 to about 4 hours, to obtain the solution. The preferred amount of water is approximately 12.5 ml of water per 1 gram of H-D-iGlu-D-Trp-OH. the pH of the solution was brought to about 6 using a saturated solution of Ca(OH)2and insoluble particles were filtered off. The filtrate was evaporated up to a level of from about 14 to about 16% of the initial volume. Under stirring over a period of from about 14 to about 18 hours at room temperature, a solid substance was filtered. Calcium salt was dried in vacuum.

In another embodiment, the present invention proposes a method of obtaining magnesium salts of the formula II, which comprises (a) interaction of D-isoglutamine-D-tryptophan with ethoxide magnesium in isopropanol; (b) concentrating the solution to obtain a solid substance; mixing the solution with water; filtering off insoluble h is STIC; dilution of the filtrate with water under stirring to precipitate salt; separating the obtained precipitate and drying in vacuum salt of formula II where B is magnesium.

In particular, the magnesium salt is produced by adding H-D-iGlu-D-Trp-OH to a mixture of ethoxide magnesium in isopropanol at a temperature of the ice bath, it is preferable to use approximately 0,48-0,49 EQ. ethoxide magnesium 1 EQ. H-D-iGlu-D-Trp-OH. The mixture is stirred for a period of from about 3 to about 10 hours, preferably from about 4 to about 5 hours. the pH of the solution was checked by taking a sample and mixing it with a few drops of water. Added additional ethoxide magnesium, preferably from approximately 0.1 to approximately 0,12 EQ. ethoxide magnesium, and was stirred for a period of from about 10 to about 18 hours, preferably for a period of from about 14 to about 16 hours. the pH of the solution was checked by taking a sample and mixing it with a few drops of water, the pH was approximately 7,0. The solution was evaporated under reduced pressure to obtain a solid substance, which dissolves in water. Insoluble particles were filtered off, and the filtrate was evaporated to obtain a solid substance. The solid was stirred with water to form a suspension, and then stirred in t is the increase in the period from approximately 3 to approximately 6 hours with sediment. The magnesium salt was filtered and dried in vacuum.

In another embodiment, the present invention proposes a method of obtaining organic amine salt of formula III, which comprises (a) interaction of D-isoglutamine-D-tryptophan with an organic amine in water, where the organic amine is a tert-butylamine, or N-methylglucamine, or tromethamine; and (b) the concentration of the solution, joint evaporation with isopropanol; adding acetone to precipitate salt; separating the obtained precipitate, and drying the product under vacuum to obtain an organic ammonium salt of the formula III, where A represents a tert-butylamine or Tris(hydroxymethyl)matrimony or methyl-(2,3,4,5,6-pentahydroxy)ammonium.

In particular, the compound of formula III, where the counterion is an organic amine, was obtained by mixing an organic amine with H-D-iGlu-D-Trp-OH in water at ambient temperature, stirring the mixture over a period of time from about 12 to about 18 hours. The solvent was evaporated together with isopropanol and evaporated in vacuum to obtain solid, which was stirred with acetone and filtered. Examples of organic amines selected from the group consisting of Tris(hydroxymethyl)aminomethane, N-methylglucamine and tert-butylamine.

In another embodiment of the present invention proposed the Xia way salt exchange to obtain a salt of D-isoglutamine-D-tryptophan, which includes (a) the interaction of the ammonium salt represented by the formula VII

in aqueous solution with about 1 EQ. metal hydroxide represented by MOH, where M is potassium or lithium; and (b) evaporating the solvent to obtain solid, which was stirred with water and isopropanol to obtain the compounds of formula I, where M represents potassium or lithium.

In another embodiment, the present invention proposes a method salt exchange to obtain a salt of D-isoglutamine-D-tryptophan, which includes (a) the interaction of the ammonium salt represented by the formula VII, in aqueous solution with about 0.5 EQ. metal hydroxide B(OH)2where B is a calcium or magnesium; (b) evaporating the solvent to obtain solid, which was stirred with water and isopropanol to obtain the compounds of formula II where a is a calcium or magnesium.

The compound of the formula I can be obtained salt exchange. Stable ammonium salt of H-D-iGlu-D-Trp-OH is used as the starting material. Below is a typical way to obtain the compounds of formula I. a Solution of H-D-iGlu-D-Trp-OH, ammonium salt (1:1) is stirred with a metal hydroxide in water and stirred for a period from about 15 minutes to approximately 2 hours and the owls, preferably, during the period from about 15 minutes to about 45 minutes. The solvent is removed by evaporation and the remaining liquid is stirred with isopropanol to obtain precipitate. The hydroxide of a metal selected from the group consisting of lithium hydroxide and potassium hydroxide. Powder x-ray D-isoglutamine-D-tryptophan potassium salt (1:1) and D-isoglutamine-D-tryptophan, lithium salt (1:1) show that they are crystalline substance.

If a solution of H-D-iGlu-D-Trp-OH, ammonium salt (1:1) is mixed with a metal hydroxide in water, followed by stirring for a period from about 15 minutes to about 2 hours, preferably over a period of time from about 15 minutes to about 45 minutes, and then dried by freeze drying, the material thus obtained is amorphous. The amorphous form of sodium, potassium or lithium salt of H-D-iGlu-D-Trp-OH can be obtained by this method.

The compound of formula II can be obtained by exchange of the ammonium salt with calcium hydroxide or magnesium hydroxide. For example, a suspension of H-D-iGlu-D-Trp-OH and a metal hydroxide in water, for example, calcium hydroxide or magnesium hydroxide, heated to approximately 50-65°C for a period of from about 1 to about 4 hours. The solvent is removed what pariwana. The remaining liquid is stirred with isopropanol to precipitate H-D-iGlu-D-Trp-OH, metal salt (2:1). If the metal is magnesium, the obtained metal salt of H-D-iGlu-D-Trp-OH magnesium (2:1) is a crystalline, as evidenced by powder x-ray. If the metal is calcium, a dedicated H-D-iGlu-D-Trp-OH calcium (2:1) is semi-crystalline substance, with a degree of crystallinity less than about 67%.

14N-NMR is a useful technique features monoammonium salt of thymodepressin. Metal salts of formulas I and II, obtained as indicated above, substantially free from ammonium salts, as evidenced by the absence of signal NH4+according to the14N-NMR.

The inventors have used a graphical method to determine the composition (Fig.5) in order to calculate the pH range for the salt form of the dipeptide H-D-iGlu-D-Trp-OH. As shown in Fig.5, the salt of formula I, or II, or III predominates at pH values from about 6 to about 8 and makes them ideal candidates for use of the drug or administration of the pharmaceutical composition. It is particularly suitable for liquid preparations, sublingual tablets, nasal drops and sprays.

APPLICATION AND INTRODUCTION

Potassium, lithium, calcium, with magnesium and D-isoglutamine-D-tryptophan and organic amine salts and D-isoglutamine-D-tryptophan of the present invention can be incorporated into pharmaceutical compositions for administration to a subject in a therapeutically active amount of and in a biologically compatible form suitable for administration in vivo, i.e. in the form of peptides to the introduction, in which therapeutic effect superior to any toxic effects.

In accordance with the graphical method of determining the composition, as shown in Fig.5, the predominant forms at neutral pH values are monocarboxylate form of thymodepressin, that is, the monosodium salt of the dipeptide D-isoglutamine-D-tryptophan, if the counterion is a sodium. The disodium salt of D-isoglutamine-D-tryptophan is extremely hygroscopic, and it is very difficult to measure.

Amorphous or crystalline form salts of the present invention are ideal candidates for replacement of the disodium salt in the manufacture of various drugs suitable for treatment of such conditions and/or diseases for which treatment is used, thymodepressin, for example, psoriasis. The introduction of new crystalline and amorphous salts of the present invention, as described herein, may be implemented by any of the conventional routes of administration of therapeutic drugs with systemic activity. These methods include dosage forms for oral, parenteral and other types of systemic or local application or application in the form of an aerosol.

In may the STI from the intended method of administration of the composition for application can be in the form of solid, semi-solid or liquid dosage forms such as tablets, suppositories, pills, capsules, powders, liquids, aerosols, suspensions, etc., preferably in dosage forms suitable for a single administration of precise dosages. The composition will contain at least one conventional pharmaceutical carrier or excipient and crystalline thymodepressin or its pharmaceutically acceptable monoammonium salt, and may additionally include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.,

For solid compositions can be used in conventional non-toxic solid carriers include, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharinate, talc, cellulose, glucose, sucrose, magnesium carbonate, etc., pharmaceutical grade. The active compound, as defined above, can be entered into a suppository using, for example, polyalkylene glycols, such as propylene glycol, as the carrier. Suitable for pharmaceutical injection liquid compositions can, for example, be obtained by dissolving, dispersing, etc., active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as water, saline, aqueous glucose solution, the glycerin, canal etc., with the formation of this way of solution or suspension. Optionally, the pharmaceutical composition for injection may also contain minor amounts of nontoxic auxiliary substances, such as moisturizing or emulsifying means, bothersome tools and so on, for example, sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, the triethanolamine oleate, etc., the Actual methods for such dosage forms are known or will be apparent to a person skilled in the industry; for example, see Remington: The Science and Practice of Pharmacy, 21stEdition, 2006, Part 5, Pharmaceutical Manufacturing, Chapters 37, 39, 41-47 and 50, pp.702-719, 745-775, 802-938 and 1000-1017 (formerly known as Remington''s Pharmaceutical Sciences), David B. Troy (Ed.), Lipincott Williams & Wilkins, Baltimore, Maryland. The composition or formulation for administration in any case will contain the number of active(s) connection(s) in an amount effective for alleviating symptoms in a subject in need of treatment.

Parenteral administration is generally characterized by injection, subcutaneous, intramuscular or intravenous. The injection means can be introduced into traditional forms, such as liquid solutions or suspensions, solid forms suitable for the manufacture of a solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for instance, water, salt is actor, dextrose, glycerol, ethanol, etc., in Addition, optionally, the pharmaceutical composition for injection may also contain minor amounts of nontoxic auxiliary substances, such as moisturizing or emulsifying means, pH bothersome tools, etc., such as sodium acetate, sorbitan monolaurate, the triethanolamine oleate, etc.,

For salts of the present invention preferably oral or nasal (bronchial) introduction, depending on the nature of the disorder to be treated.

For oral administration of pharmaceutically acceptable non-toxic composition was prepared by connecting any of the commonly used excipients, pharmaceutical grade, such as mannitol, lactose, starch, magnesium stearate, sodium saccharinate, talc, cellulose, glucose, sucrose, magnesium carbonate, etc., Such compositions can be in the form of solutions, suspensions, tablets, pills, capsules, powders, formulations of slow release, etc., Such compositions can contain from approximately 1% to approximately 95% active ingredient, preferably from about 25% to about 70%.

Oral and nasal introduction into the lungs can also be carried out using aerosol dosage forms. For aerosol injection active ingredient FAV is preferably supplied in finely powdered form together with a surface-active agent and a propellant. Typical percentages of the active ingredients is from about 0.01 to about 20% by weight, preferably from about 0.04% to approximately 1.0%.

Surfactants usually must be non-toxic, and preferably soluble in the propellant. A typical example of such tools are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as Caproic, Caprylic, lauric, palmitic, stearic, linoleic, linolenic, alasaarela and oleic acid, with aliphatic polyhydric alcohol or its cyclic anhydride such as ethylene glycol, glycerin, erythritol, arabitol, mannitol, sorbitol anhydride hexitol derived from sorbitol (esters sorbitan present on the market under the name SPANS®) and polyoxyethylene and polyoxypropylene derivatives of these esters. Can be used mixed ethers, such as mixed or natural glycerides. Preferred surface-active agents are the oleates or sorbitan, for example, present on the market under the name ARLACEL® C (sorbitan sesquioleate), SPAN® 80 (sorbitan monooleate) and SPAN® 85 (sorbitan trioleate). The content of the surfactant may range from about 0.1% to about 20% by weight of the composition, a preference for the equipment, from about 0.25% to about 5%.

The remainder of the composition is typically a conventional propellant. Liquefied propellants are normally gaseous at ambient conditions and are condensed under pressure. Among suitable liquefied propellants - lower alkanes containing up to five carbon atoms, such as butane and propane; and, preferably, fluorinated or ferroresonance alkanes, such as those present on the market under the name FREON®. A mixture of the above components can also be used.

Upon receipt of the aerosol container equipped with a suitable valve, fill in the appropriate propellant containing finely ground active ingredient and a surfactant. Thus, the ingredients contained at high pressure to release upon actuation of the valve.

For local administration, such compositions contain an effective amount of compounds of this class in a mixture with at least one pharmaceutically acceptable non-toxic carrier. Suitable for the composition interval ranges from approximately 0.1% to approximately 10% of the active ingredient; the remainder of the composition is a native; preferably, from about 1% to about 2% active ingredient. The concentration of the active ingredient farmacevticheskih compositions, suitable for local use will vary depending on the activity of the specific compound that is used in accordance with the present condition and subject to be treated. Suitable carriers or solvents medicines for local use of these compounds include creams, ointments, lotions, emulsions, solutions, etc.

For example, suitable ointment for topical application of the compounds according to this invention contains from about 15 to about 45% of saturated fatty alcohol containing 16 to 24 carbon atoms, such as cetyl alcohol, stearyl alcohol, beganovic alcohol, etc., and from about 45 to about 85% by weight of a glycol solvent such as propylene glycol, polyethylene glycol, dipropyleneglycol and mixtures of these components. The ointment may also contain from about 0 to about 15% by weight of a plasticizer such as polyethylene glycol, 1,2,6-hexanetriol, sorbitol, glycerin, etc.; from about 0 to about 15% by weight of binders, such as saturated fatty acids containing from 16 to 24 carbon atoms, for example, stearic acid, palmitic acid, Bekenova acid, amides of fatty acids, for example, oleamide, palmitate, stearate, beginnig and esters of fatty acids, sod is readie 16-24 carbon atoms, such as sorbitol monostearate, polyethylene-glycol monostearate, polypropylenglycol or appropriate monoether other fatty acids, such as oleic acid and palmitic acid; and from about 0 to about 20% by weight of tools that enhance penetration, such as dimethyl sulfoxide or dimethylacetamide.

Therapeutically active amount of the salts of the present invention may vary in accordance with such factors as the pathological condition, age, sex and body weight of the individual. The treatment regimen may be adjusted to provide the optimum therapeutic response. In General, the scheme of daily introduction should include a dose in the range of from about 1 to about 200 mg of the peptide.

The following are examples of typical formulations, which in no way limit the context to obtain a variety of pharmaceutical compositions of the present invention:

153
IngredientsQuantity per tablet (mg)
The active ingredient25
Lactose, spray dried20
Corn starch
Magnesium stearate2

The above ingredients are thoroughly mixed and pressed into tablets with a single line.

IngredientsQuantity per tablet (mg)
The active ingredient100
Lactose, spray dried148
Magnesium stearate2

The above ingredients are mixed and introduced into hard gelatin capsule.

IngredientsQuantity per tablet (mg)
The active ingredient200
Lactose145
Corn starch50
Magnesium stearate5

The above ingredients are mixed and pressed into tablets with a single line.

The ingredient is Quantity per tablet (mg)
The active ingredient108
Lactose15
Corn starch25
Magnesium stearate2

The above ingredients are mixed and introduced into hard gelatin capsule.

IngredientsQuantity per tablet (mg)
The active ingredient150
Lactose92

The above ingredients are mixed and introduced into hard gelatin capsule.

Injectable, buffered to pH around 7, get with the subsequent ingredients:

Ingredients
The active ingredient0.2 g
KH2PO42 ml
KOH (1 n solution)required
the number to pH 7
Water (distilled, sterile)required
the number to 20 ml

Injectable, buffered to pH around 7, get with the subsequent ingredients:

Ingredients
The active ingredient0.01 g
Water (distilled, sterile)required
the quantity up to 1 ml
NaOH (0,2 ad)required
the number to pH 7

Suspension for oral use are the following composition:

Ingredients
The active ingredient0.1 g
Fumaric acid0.5 g
Methylparaben2.0 g
Granulated sugar0.1 g
Sorbitol (70% solution)25,5 g
Veegum® K (Vanderbilt Co.) is 12.85 g
Flavor1.0 g
Dyesa 0.035 ml
Distilled waterthe required amount to 100 ml

The product for local use:

IngredientsGrams
Active connection0,2-2
SPAN 602
TWEEN 602
Mineral oil5
Vaseline10
Methylparaben0,15
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
Distilled waterthe required amount to 100 ml

All of the above ingredients, except water, are combined and heated to approximately 45°C with stirring. Then d is billaut sufficient amount of water with a temperature of approximately 45°C with vigorous stirring for emulsification of the ingredients and then add the required amount of water to 100 g

Below the invention is explained in detail with reference to Examples, but the invention is in no way limited to them.

This invention features a pharmaceutical composition that contains lithium or potassium salt of formula I in any of its forms, and one or more pharmaceutically acceptable auxiliary substances.

This invention also features a pharmaceutical composition that contains calcium or magnesium salt of the formula II in any of its forms, and one or more pharmaceutically acceptable auxiliary substances.

The present invention further provides a pharmaceutical composition that contains an organic amine salt of the formula III in any of its forms, and one or more pharmaceutically acceptable auxiliary substances.

Further details of the preferred variants of the present invention is illustrated in the following examples, which should be interpreted as non-restrictive relative appended claims.

EXAMPLES

Example 1:

Obtaining potassium salt of D-isoglutamine-D-tryptophan (1:1) from D-isoglutamine-D-tryptophan and potassium hydroxide

In a round bottom flask of 100 ml equipped with a magnetic stirrer, were placed 5 ml of potassium hydroxide solution (0.5 n). The solution was cooled to 0°C in an ice bath, and thereto is obavljale solid H-D-iGlu-D-Trp-OH (1,00 g, 3 mmol). The mixture was stirred and simultaneously the pH of the solution was brought to approximately 6,0, adding a few drops of potassium hydroxide solution (0.5 n). The solution was filtered to remove particles of a solid substance. The filtrate was evaporated until dry with a bath temperature of approximately 30°C to obtain a solid substance. After drying in vacuum at room temperature during the night was getting salt in quantitative yield and purity HPLC (% peak area) of 98.3%. Method HPLC; column: XTerra MS C18; 5 μm, a 4.6×250 mm; mobile phase: A = water phase: 4 mm Tris, 2 mm EDTA, pH 7,4; B = organic phase: CH3CN; gradient: B%: 0 min 5%, 15 min 55%, 30 min 55%, 32 min 5%, 35 min 5% a; flow rate: 1 ml/min; volume of injection: 5 ál; λ: 222, 254, 282, 450 nm; retention time of product: 6,41 minutes the XRPD Pattern of this crystalline material is shown in Fig.1A; the water content according to the analysis by the method of Karl Fischer was 0.7%; UV (water, c = 23,8 μm, λmaxnm): 221 (ε 33270), 280 (ε 5417); MS (ratio of mass and charge): 372,0 [M]+, 334,2 [C16H20N3O5]+, 187,9 (100%). FTIR spectrum (KBr) shown in Fig.1B.

Example 2:

A. Obtaining montalieu salt D-isoglutamine-D-tryptophan (1:1) of monoammonium salt D-isoglutamine-D-tryptophan (1:1)

A solution of H-D-iGlu-D-Trp-OH, monoammonium salt (1:1), (1.66 g, of 4.05 mmol) and potassium hydroxide (253 mg, 4,50 mmol) in water (20 ml) was stirred at to matnog temperature for 15 minutes the pH of the solution was about 9. The reaction mixture was evaporated under reduced pressure to a volume of approximately 1 ml After cooling to room temperature was added isopropanol until the sludge solids. The resulting suspension was stirred at room temperature for 15 min, then filtered. The solid was washed with isopropanol (2×20 ml) and ethyl acetate (20 ml), then dried under vacuum in an oven with a temperature of 42°C, soaking at this temperature over night. Got the solid is nearly white (1,49 g, yield 99%). The water content according to the analysis by the method of Karl Fischer was 2.5%. Data analysis (sample XRPD, FTIR and MS spectra) similar to that described in Example 1.

B. Obtain the amorphous form of the potassium salt of D-isoglutamine-D-tryptophan (1:1) of monoammonium salt D-isoglutamine-D-tryptophan (1:1).

A solution of H-D-iGlu-D-Trp-HE, monoammonium salt (1:1), (517 mg, of 1.40 mmol) and potassium hydroxide (82 mg, of 1.46 mmol) in water (10 ml) was stirred at room temperature for 30 minutes. The resulting mixture was dried freeze drying over night. The product was obtained as a solid substance is almost white with a quantitative yield. Sample XRPD spectrum confirmed that the material is amorphous.1H NMR (D2O) δ: of 7.69 (d, J=7.9 Hz, 1H), of 7.48 (d, J=8,2 Hz, 1H), 7.23 percent (t, J=7,6 Hz, 1H), 7,2 (s, 1H), 7,16 (t, J=7,4 Hz, 1H), 4,59 (DD, J=8,7, 4.8 Hz, 1H), 3,51 (DD, J=6,8, 5.8 Hz, 1H), 3,38 (DD, J=14,8, 4.8 Hz, 1H), 3,11 (DD, J=14,8, 8,8 Hz, 1H), 2,20-2,49 (m, 2H) and 1.85-of 1.94 (m, 2H);13C NMR (D2O) δ: 181,4, 177,0, 176,6, 138,8, 129,9, 126,9, 124,5, 121,9, 121,4, 114,5, 113,2, 58,6, 57,0, 34,6 (CH2), 30,2 (CH2and 29,3 (CH2); the water content according to the analysis by the method of Karl Fischer amounted to 5.4%; FTIR spectrum (KBr) shown in Fig.1C; MS (ratio of mass and charge): 371,7 [M]+, 334,2 [C16H20N3O5]+, 187,9 (100%); HPLC purity (% peak area): 99,8%, retention time: 5,04 min; HPLC: column Waters Symmetry C18, a 3.9×150 mm, 5 μm; mobile phase: 0.035% of lO4pH 2/CH3CN, 85:15 isocratic, flow rate: 1 ml/min; λ: 220, 254, 280 nm.

Example 3:

A. Obtaining lithium salt of D-isoglutamine-D-tryptophan (1:1) of monoammonium salt D-isoglutamine-D-tryptophan (1:1) and lithium hydroxide monohydrate

A solution of H-D-iGlu-D-Trp-OH, monoammonium salt (1:1), (1.40 g, of 3.80 mmol) and lithium hydroxide monohydrate (159 mg, of 3.80 mmol) in water (20 ml) was stirred at room temperature for 20 minutes the pH was approximately 9. The reaction mixture is evaporated under reduced pressure to a volume of solvent approximately 2 ml. After cooling to room temperature was added isopropanol to sediment solids. The resulting suspension was stirred at room temperature for 20 min, ZAT is filtered. The solid was washed with isopropanol (2×20 ml) and ethyl acetate (20 ml), then dried under vacuum in an oven with a temperature of 42°C during the night. The product was obtained as a solid substance is almost white with a quantitative yield. The XRPD pattern of this crystalline material is shown in Fig.2A. The water content according to the analysis by the method of Karl Fischer 10.7 percent. MC (the ratio of mass and charge): 340,1 [M+1]+, 334,3 [C16H20N3O5]+, 187,9 (100%). FTIR spectrum (KBr) shown in Fig.2B.

B. a Solution of H-D-iGlu-D-Trp-OH, monoammonium salt (1:1), (480 mg, of 1.30 mmol) and lithium hydroxide monohydrate (57 mg, of 1.36 mmol) in water (10 ml) was stirred at room temperature for 30 minutes the mixture was dried freeze drying over night. The product was obtained as a solid substance is almost white with a quantitative yield. Sample XRPD confirmed that the material is amorphous.1H NMR (D2O) δ: of 7.69 (d, J=7.8 Hz, 1H), 7,50 (d, J=8,2 Hz, 1H), 7.23 percent (t, J=7,1 Hz, 1H), 7,22 (s, 1H), 7,16 (t, J=7.5 Hz, 1H), 4,57 (DD, J=8,7, 4.8 Hz, 1H), 3,36-of 3.43 (m, overlapping t and DD, 2H), 3,12 (DD, J=14,7, and 8.7 Hz, 1H), of 2.20 to 2.35 (m, 2H) and 1,78-of 1.92 (m, 2H);13C NMR (D2O) δ: 181,4, 178,1, 176,7, 138,8, 129,9, 126,9, 124,5, 121,9, 121,4, 114,5, 113,2, 58,6, 57,1, 34,7 (CH2), 30,2 (CH2and 29,3 (CH2); FTIR spectrum (KBr) shown in Fig.2C; the water content according to the analysis by the method of Karl Fischer stood at 11.5%. Range of MS similar to that described in the Application is e 3A; the HPLC purity (% peak area): 99,8%, retention time: 5,10 minutes was Used for the HPLC conditions described in Example 2B.

Example 4:

Obtaining the lithium salt of D-isoglutamine-D-tryptophan (1:1) from D-isoglutamine-D-tryptophan and lithium hydroxide monohydrate

A. In a round bottom flask of 100 ml equipped with a magnetic stir bar was dissolved lithium hydroxide monohydrate (for 125.8 mg, 2,99 mmol) in 10 ml of water. The solution was cooled to 0°C using an ice bath. H-D-iGlu-D-Trp-OH (1,00 g, 3 mmol) suspended in solution. The solid slowly dissolved over 2.5 hours with the formation of transparent pale pink solution. After an additional 30 minutes of stirring the mixture was heated to room temperature. The solution was filtered and carefully evaporated to a volume of approximately 4 ml was Slowly added isopropanol (25 ml) prior to the formation of solids. The solution was filtered and the solid was divided into two equal parts.

B. One part of the solid substance obtained by the method And washed with isopropanol (2×15 ml). The solid is first air-dried and then dried in vacuum oven (35°C) during the night. The water content according to the analysis by the method of Karl Fischer amounted to 10.6%. The XRPD pattern and MC and FTIR (KBr) spectra of this compound is similar to the one described in Example 3A.

C. the Second part of the solids washed isopr what panolam (2×15 ml), then ethyl acetate (2×10 ml). The solid is first air-dried and then dried in vacuum oven (35°C) during the night. Sample XRPD and FTIR (KBr) spectrum of this compound is similar to the one described in Example 3A.

The combined output of material obtained by procedures B and C, is 0.99 g (yield of 97.6%).

Example 5:

Obtaining a magnesium salt of D-isoglutamine-D-tryptophan (1:2) from D-isoglutamine-D-tryptophan

In a round bottom flask of 100 ml equipped with a magnetic stirrer, was placed atoxic magnesium (Aldrich, 98%, 0,206 g of 1.76 mmol) and isopropanol (15 ml). The solution was cooled to 0°C in an ice bath was added solid H-D-iGlu-D-Trp-OH (1.20 g, of 3.60 mmol). The white suspension was stirred at room temperature for 4 hours. 2-3 drops of the reaction mixture was placed in a test tube and add a few drops of demineralized water. The mixture was shaken with the formation of a transparent solution. the pH of the solution was 4.0 to 4.5. To the reaction mixture was added atoxic magnesium (Aldrich, 98%, 0,050 g, 0.43 mmol). The mixture was stirred at room temperature overnight. 2-3 drops of white suspension was placed in a test tube and add a few drops of demineralized water. The mixture was shaken to obtain a transparent solution. the pH of the solution was approximately 7,0. The mixture is evaporated to the dry state at a bath temperature of 30°C with the formation of solid substances is white. The residue was dissolved in 15 ml of demineralized water to obtain a yellow solution. The latter was filtered to remove particles of a solid substance. The filtrate is evaporated to the dry state at a bath temperature of 30°C to obtain a solid substance. The solid is suspended in demineralised water (20 ml) and the mixture was stirred for 3 hours. A solid substance was separated by means of filtration and washed with ice-cold demineralized water (2×6 ml). The solid is first dried in air and then placed in a vacuum oven at 42°C, soaking at this temperature over night. Thus, 0.88 g (yield 72%, HPLC purity [% area peak]: 99,1%) of product was obtained. Used HPLC method described in Example 1. The retention time for this product was to 6.39 min Sample XRPD spectrum of this crystalline material is shown in Fig.3A. The water content according to the analysis by the method of Karl Fischer amounted to 12.2%. MS (ratio of mass and charge): 689,3 [M]+, 334,2 [C16H20N3O5]+187,9 (100%). UV (water, c = 11,7 μm, λmaxnm): 221 (ε 57906), 280 (ε 9449). FTIR spectrum (KBr) shown in Fig.3B.

Example 6:

Obtaining a magnesium salt of D-isoglutamine-D-tryptophan (1:2) of monoammonium salt D-isoglutamine-D-tryptophan (1:1)

A suspension of D-isoglutamine-D-tryptophan, monoammonium salt (1:1), (1,53 g, 4,15 mmol) hydroxide magnesium in H 2O (20 ml) was heated at 55-60°C, soaking at this temperature for 3 hours. The resulting yellowish suspension is evaporated under reduced pressure to a volume of approximately 1-2 ml was Then added isopropanol (30 ml). The suspension was stirred for 20 min at room temperature, then was filtered. The solid is washed successively with isopropanol (2×20 ml) and ethyl acetate (20 ml), then dried in a vacuum oven at 42°C, soaking at this temperature over night. Received solid yellow (1.5 g). The water content according to the analysis by the method of Karl Fischer was 8.8%. Data analysis (sample XRPD and FTIR and MS spectra) similar to that described in Example 5.

Example 7:

Getting the calcium salt of D-isoglutamine-D-tryptophan (1:2) from D-isoglutamine-D-tryptophan (1:1) and calcium hydroxide

In a round bottom flask of 100 ml equipped with a magnetic stirrer, were placed calcium hydroxide (Aldrich, 99.99% of, less than 3% calcium carbonate, 0,2603 g, 3,51 mmol) and demineralized water (30 ml). The turbid solution was cooled to 0°C in an ice bath, was added solid H-D-iGlu-D-Trp-OH (2,404 g, 7.2 mmol). The mixture was stirred for 2.5 hours with the formation of clear, slightly pink solution. the pH of the solution was brought to 6.0 by adding a saturated solution of calcium hydroxide. The solution was filtered to remove the hour is CI solids. The filtrate was divided into two equal volumes (about 20 ml each): Solution a and Solution B.

The solution was evaporated using a rotary evaporator to a volume of approximately 4-5 ml using a water bath with a temperature of approximately 30°C. the Solution remains clear. The obtained concentrated solution was intensively stirred at room temperature for 17 hours to obtain a solid substance. A solid substance was separated by filtration and washed with ice-cold demineralized water (3×6 ml). The solid is first dried, freeze drying, and then dried in a vacuum oven at 40°C, soaking at this temperature during the night with obtaining solids 0,70 g (55%, HPLC purity according to the % peak area: 97,7%). Used HPLC method described in Example 1. The retention time for this product was to 6.39 min Sample XRPD spectrum of this material is shown in Fig.4A. The water content according to the analysis by the method of Karl Fischer amounted to 5.4%. MS (ratio of mass and charge): 705,6 [M+1]+, 334,2 [C16H20N3O5]+, 187,9 (100%). UV (water, C=10.8 microns, λmaxnm): 221 (ε 61014), 280 (ε 9943). FTIR spectrum (KBr) shown in Fig.4C.

The solution was evaporated until dry. Added demineralized water (6 ml) and the mixture was stirred for 16 hours. The insoluble solid was filtered and su is or under high vacuum at 35°C for 48 hours (0,53 g). The XRPD pattern similar to the one shown in Fig.4A.

Example 8:

Getting the calcium salt of D-isoglutamine-D-tryptophan (1:2) of monoammonium salt D-isoglutamine-D-tryptophan (1:1) and calcium hydroxide

Suspension by monoammonium salt (1:1) D-isoglutamine-D-tryptophan, (1,49 g 4,06 mmol) and calcium hydroxide (150 mg, 2.03 mmol) in water (20 ml) was heated to a temperature of 55-60°C, soaking at this temperature for 1 hour. The resulting solution was evaporated under reduced pressure to a volume of approximately 1-2 ml) was Added isopropanol (30 ml). The suspension was stirred for 20 min at room temperature, then filtered. The solid is washed successively with isopropanol (2×20 ml) and ethyl acetate (20 ml), then dried in an oven at a temperature of 42°C, soaking at this temperature over night. Got the solid is nearly white (1.45 g). The XRPD pattern of this semi-crystalline material is shown in Fig.4B. This material has a lower degree of crystallinity than the material of Example 7. The water content according to the analysis by the method of Karl Fischer amounted to 6.2%. MS (ratio of mass and charge): 705,4 [M+1]+, 334,2 [C16H20N3O5]+, 187,9 (100%).

Example 9:

Determination of percent crystallinity of the calcium salt of D-iGlu-D-Trp by the method of powder x-ray diffraction analysis

In common with Epen crystallinity, measured by XRPD technique, provides additional useful information for pharmaceutical materials that contain any amorphous material formed during synthesis. She is also a suitable indicator from the point of view of monitoring long-term changes in crystalline materials. Not being associated with any structural and compositional properties, the indicator "percent crystallinity" may be an appropriate indicator of the strength of a particular material as a function of time.

The percentage of crystallinity is usually measured as the ratio between the part of the diffraction of the crystalline part of the sample, ICand full diffraction of the same sample, IC+B. The values of ICcan be obtained after appropriate subtraction of the diffuse part of the background, IB.

For such analyses, the diffraction is measured as the total area under the curve:

- solid sample obtained in the synthesis (data can be adjusted aerial dispersion) - ITOTAL,

only peaks (ICafter subtraction of the background correction with regard to air scattering),

- only basis with a correction taking into account aerial dispersion (IB).

where Ttotal=Ic+Ib.

It should be noted that this measurement is e is recommended as the standard for it is very difficult (almost impossible) to compare inter-laboratory results. Each diffractometer has its own zoom level of the background and the peak height and area under the curve depending on a number of instrumental factors, but also factors in the sample preparation.

The approach described above is possible for the most part diffractometers "point detector", in which the detector moves with synchronized speed, 2 times greater than the velocity of the sample, in order to ensure a constant ratio θ/2 θ.

However, in this study, due to the technical problems of diffraction system "point detector" D5000, all samples were analyzed on the D8 system, equipped with a 2D detector area, and the above approach could not be applied. Therefore, there has been developed another technique of measuring the crystallinity of the samples are analyzed on such a system. Selected only the narrow part of the 2D diffraction image with a single peak in the center and the neighboring area, which will be measured in the background.

Samples obtained in Example 8 demonstrate the % crystallinity of approximately 18-20%, while the samples obtained by the method of Example 7, demonstrate the range of % crystallinity approximately 25-50%. The percentage of crystallinity of the sample can be improved if the sample dissolve the ü in the water. Insoluble particles were filtered off and the solid substance was given slowly to precipitate out of solution.

All samples were measured to calculate their crystallinity using a narrow range of 21-25° strongest reflection at 13°. The background subtracted as linear and used empirical correlation coefficient of 2.5.

As mentioned above, the results thus obtained for the crystallinity of semi-crystalline samples should not be taken as absolute. None of the specimens of this structural type has no crystalline order, high enough to be considered as an absolute reference. In Examples 7 and 8 received calcium salt of thymodepressin (1:2) with different percentage of crystallinity.

Example 10:

Obtaining mono-tert-butylamine salt D-isoglutamine-D-tryptophan (1:1) from D-isoglutamine-D-tryptophan and tert-butylamine

A. To a suspension of D-iGlu-D-Trp (1,00 g, 3.00 mmol) in 25 ml of demineralized water was added 0.7 ml (2,22 EQ.) tert-butylamine at room temperature. The reaction mixture remained clear, and the pH of the solution was about 9. After stirring at room temperature for 1 hour was added isopropanol and volatile materials were removed in vacuo. The remaining solid is suspended in acetone and separated using vacuum fil the radio. The solid was dried in vacuum at 40°C during the night with the receipt of 1.16 g (yield 95%) of monosol amine.1H NMR confirmed that the product is oneadditional salt. Sample XRPD confirmed that the material is amorphous.1H NMR (D2O) δ: 7,71 (d, J=8.6 Hz, 1H), 7,39 (d, J=8,1 Hz, 1H), 7,13-7,16 (m, 2H), 7,07 (t, J=7,6 Hz, 1H), 4,48 (DD, J=8,3, a 4.9 Hz, 1H), 3,44 (t, J=6,4 Hz, 1H), or 3.28 (DD, J=14,8, a 4.7 Hz, 1H), to 3.02 (DD, J=14,7, to 8.7 Hz, 1H), 2,18-of 2.26 (m, 2H), 1,76-of 1.97 (m, 2H) and 1.26 (s, 9H).14N-NMR (D2O) δ (M. D.): 40,2 (user.) and 56.3 (C), *NH4NO3used as an external standard with the installation of the reference signal level 20,689 M. D. the water Content according to the analysis by the method of Karl Fischer was equal to 4.0%. MS (ratio of mass and charge): 407,3 [M+1]+(weak), 334,2 [C16H20N3O5]+, 187,9 (100%). The IR spectrum shown in Fig.6. UV (water, c = 34,8 μm, λmaxnm): 220 (ε 31067), 280 (ε 5112).

C. To a suspension of D-iGlu-D-Trp (1,00 g, 3.00 mmol) in 25 ml of demineralized water were added at 0.31 ml (1.0 EQ.) tert-butylamine at room temperature (RT). The reaction mixture remained clear, and the pH of the solution was about 9. After stirring at room temperature for 1 hour was added isopropanol and volatile materials were removed in vacuo. The remaining solid is suspended in acetone and the solid was separated by vacuum filtration. Solid substances which has been dried in vacuum at 40°C during the night with the receipt of 1.16 g (yield 95%) of the amine salt. Data analysis for this connection (XRPD,1H NMR, MC, FTIR) similar to that described in Example 10A above.

Example 11:

Getting salt monotis(hydroxymethyl)aminomethane D-isoglutamine-D-tryptophan (1:1) from D-isoglutamine-D-tryptophan and Tris(hydroxymethyl)aminomethane (TRIS)

To a suspension of D-iGlu-D-Trp (1,00 g, 3.00 mmol) in 20 ml of demineralized water was added a solution of 363 mg (1.0 EQ.) Tris(hydroxymethyl)aminomethane (TRIS) in 15 ml of demineralized water at room temperature. The reaction mixture remained clear, and the pH of the solution was about 7. After stirring at room temperature overnight was added isopropanol and volatile materials were removed in vacuo. Attempts to recrystallized connection using a mixture of isopropanol/water or methanol/diethyl ether were unsuccessful. The remaining solid is suspended in acetone and stirred at room temperature for 1 hour, the solid was separated by vacuum filtration. The solid was dried in vacuum at 40°C during the night with the receipt of 1.33 g of product (yield of 97.5%).1H NMR (D2O) δ: to 7.61 (d, J=7.9 Hz, 1H), 7,41 (d, J=8,1 Hz, 1H), 7,14-7,17 (m, 2H), was 7.08 (t, J=7,4 Hz, 1H), 4,48 (DD, J=8,5, 4.8 Hz, 1H), 3,64 (s, 6H), of 3.46 (t, J=6.0 Hz, 1H), or 3.28 (DD, J=14,8, a 4.7 Hz, 1H), to 3.02 (DD, J=14,7, and 8.7 Hz, 1H), 2,17-of 2.28 (m, 2H) and 1,74-1,90 (m, 2H). The water content according to the analysis by the method of Karl-Fischer who was 3.3%. MS (ratio of mass and charge): 454,9 [M+1]+(weak), 334,0 [C16H20N3O5]+, 187,9 (100%). The IR spectrum shown in Fig.7; UV (water, c = 36,4 μm, λmaxnm): 220 (ε 28373), 280 (ε 4537).

Example 12:

Obtaining mono-N-methyl-D-glutaminol salt D-isoglutamine-D-tryptophan (1:1) from D-isoglutamine-D-tryptophan and N-methyl-D-glucamine

To a suspension of D-iGlu-D-Trp (1,00 g, 3 mmol) in 20 ml of demineralized water was added to the solution 586 mg (1.0 EQ.) N-methyl-D-glucamine in 15 ml of demineralized water at room temperature. The reaction mixture was stirred over weekend at room temperature. The reaction mixture remained clear, and the pH of the solution was about 7. Added isopropanol and volatile materials were removed in vacuo. The remaining solid is suspended in acetone and the solid was separated by vacuum filtration. The solid was dried in vacuum at 40°C overnight to obtain a product with a quantitative yield. Sample XRPD confirmed that the material is amorphous.1H NMR (D2O) δ: to 7.61 (d, J=7.9 Hz, 1H), 7,41 (d, J=8,1 Hz, 1H), 7,15-to 7.18 (m, 2H), was 7.08 (t, J=7.5 Hz, 1H), 4,47 (DD, J=8,6, and 4.8 Hz, 1H), 3,99-was 4.02 (m, 1H), 3,70 of 3.75 (m, 2H), 3,65-3,68 (m, 1H), 3,54-of 3.60 (m, 2H), of 3.45 (t, J=6.2 Hz, 1H), 3.27 to (DD, J=14,8, a 4.7 Hz, 1H), 3,02-3,13 (m, 3H), 2,68 (s, 3H), 2,19-of 2.26 (m, 2H) and 1.75-of 1.95 (m, 2H).14N NMR (D2O) δ (M. D.): 29,6 and 39.2 (user. overlay), *NH4NO3riminal as an external standard with the installation of the reference signal level 20,689 M. D. The water content according to the analysis by the method of Karl Fischer amounted to 3.1%. MS (ratio of mass and charge): 529,5 [M+1]+, 334,2 [C16H20N3O5]+, 187,9 (100%). The IR spectrum shown in Fig.8. UV (water, c = 41,2 μm, λmaxnm): 220 (ε 27341), 280 (ε 4419).

Example 13:

An example of the method for obtaining D-isoglutamine-D-tryptophan, monoammonium salt (1:1) of H-D-iGlu-D-Trp-OH

H-D-iGlu-D-Trp-OH (1 g) was mixed with ammonium hydroxide (0.55 M, 6 ml). The mixture was stirred; the pH of the mixture is about 4.5. The ammonium hydroxide solution (0.55 M) was added dropwise until then, until the pH reaches 7,0-7,5. Volatile materials were removed in vacuo and the remaining oil was mixed with isopropanol. Formed a white precipitate. After 2 hours of solid ammonium salt was separated by vacuum filtration. The solid was dried to constant weight (1 g) in high vacuum for 12 hours to obtain D-isoglutamine-D-tryptophan, ammonium salt (1:1).

Although the preferred variants of the invention described herein, the experts in this field will be understood that they can be implemented variations without departing from the spirit of the invention or of the context of the attached claims.

1. Pharmaceutically acceptable salt of D-isoglutamine-D-tryptophan formula I:

where M represents potassium and where salt is Cree is a metallic form, which is characterized by peaks in the powder x-ray in the area of the following values 2-θ: 9,91, 14,84, 15,81, 18,97, 19,76, 24,04, 24,36, 24,82, 25,48, 27,49, 27,94, 28,42, 30,82, 31,28, 31,69, 32,17, 34,35, 35,81 and 36,96°.

2. Pharmaceutically acceptable salt p. 1, which is characterized by a powder x-ray shown in Fig.1A.

3. Pharmaceutically acceptable salt of D-isoglutamine-D-tryptophan formula I:

where M represents potassium and where salt is in amorphous form, which is characterized by an infrared spectrum with Fourier transform (FTIR), shown in Fig.1C.

4. Pharmaceutically acceptable salt of D-isoglutamine-D-tryptophan formula II:

where B represents magnesium and where salt is in crystalline form characterized by peaks in the powder x-ray in the area of the following values 2-θ: 12,2, 13,74, 14,84, 16,16, 17,96, 18,52, 18,94, 19,49, 21,05, 21,56, 22,56, 23,36, 24,12, 26,27, 27,65, 28,42, 29,14, 30,55, 31,77, 32,62, 33,26, 35,05, 36,34, 37,22 and 38,05°.

5. Pharmaceutically acceptable salt p. 4, which is characterized by a powder x-ray shown in Fig.3A.

6. Method of producing metal salts of D-isoglutamine-D-tryptophan formula I:

where M represents potassium, and where the salt is in crystalline form characterized by peaks in the powder is th radiograph in the field the following values 2-θ: to 9.91, 14,84, 15,81, 18,97, 19,76, 24,04, 24,36, 24,82, 25,48, 27,49, 27,94, 28,42, 30,82, 31,28, 31,69, 32,17, 34,35, 35,81 and 36,96° or characterized by powder x-ray shown in Fig.1A, and the method includes
(a) interaction of D-isoglutamine-D-tryptophan with potassium hydroxide in water to obtain a solution;
(b) concentrating the solution until the formation of the oil;
(c) adding isopropanol to the oil while stirring to precipitate the salt to obtain a precipitate;
(d) separating the resulting sludge; and
(e) drying the product under vacuum obtaining potassium salts of formula I.

7. Method of producing metal salts of D-isoglutamine-D-tryptophan formula II:

where In represents magnesium and where salt is in crystalline form characterized by peaks in the powder x-ray in the area of the following values 2-θ:12,2, 13,74, 14,84, 16,16, 17,96, 18,52, 18,94, 19,49, 21,05, 21,56, 22,56, 23,36, 24,12, 26,27, 27,65, 28,42, 29,14, 30,55, 31,77, 32,62, 33,26, 35,05, 36,34, 37,22 and 38,05° or characterized by powder x-ray shown in Fig.3A, and the method includes
(a) interaction of D-isoglutamine-D-tryptophan with ethoxide magnesium in isopropanol to obtain a solution;
(b) concentrating the solution to obtain a solid substance;
(c) mixing the solids with water;
(d) separating the insoluble particle filtering with obtaining f is ltrate;
(e) dilution of the filtrate with water with stirring to precipitate the product;
(f) separating the product; and
(g) drying the product under vacuum obtaining metallic magnesium salt of formula II.

8. The salt exchange method for obtaining a pharmaceutically acceptable salt of D-isoglutamine-D-tryptophan represented by the General formula I:

where M represents potassium, and where the salt is in crystalline form characterized by peaks in the powder x-ray in the area of the following values 2-θ: 9,91, 14,84, 15,81, 18,97, 19,76, 24,04, 24,36, 24,82, 25,48, 27,49, 27,94, 28,42, 30,82, 31,28, 31,69, 32,17, 34,35, 35,81 and 36,96° or characterized by powder x-ray shown in Fig.1A, and the method includes
(a) the interaction of the ammonium salt represented by the formula VII:

in aqueous solution with 1 EQ. metal hydroxide represented by the MES, where M is as defined above;
(b) evaporating the solvent to obtain a solid substance; and
(c) mixing the solids with water and isopropanol to obtain pharmaceutically acceptable salts of formula I.

9. The salt exchange method for obtaining a pharmaceutically acceptable salt of D-isoglutamine-D-tryptophan represented by the General formula I:

where M represents potassium and g the e Sol is in amorphous form, which is characterized by an infrared spectrum with Fourier transform (FTIR), shown in Fig.1C, and the method includes
(a) the interaction of the ammonium salt represented by the formula VII:

in aqueous solution with 1 EQ. metal hydroxide represented by the MES, where M is as defined above;
(b) stirring the solution for 30 minutes; and
(c) freeze drying the solution to obtain pharmaceutically acceptable salts of formula I.

10. The salt exchange method for obtaining a pharmaceutically acceptable salt of D-isoglutamine-D-tryptophan represented by the General formula II:

where In represents magnesium and where salt is in crystalline form characterized by peaks in the powder x-ray in the area of the following values 2-θ: 12,2, 13,74, 14,84, 16,16, 17,96, 18,52, 18,94, 19,49, 21,05, 21,56, 22,56, 23,36, 24,12, 26,27, 27,65, 28,42, 29,14, 30,55, 31,77, 32,62, 33,26, 35,05, 36,34, 37,22 and 38,05° or characterized by powder x-ray shown in Fig.3A, and the method includes
(a) the interaction of the ammonium salt represented by the formula VII:

in aqueous solution with about 0.5 EQ. metal hydroxide IN(OH)2where In is the same as defined above;
(b) evaporating the solvent to obtain the solid substances is TBA; and
(c) mixing the solids with water and isopropanol to obtain pharmaceutically acceptable salts of formula II.

11. Pharmaceutical composition having properties immunosuppressant containing a therapeutically effective amount of pharmaceutically acceptable salt according to any one of paragraphs.1-5 and at least one auxiliary substance.

12. A method of obtaining a pharmaceutical composition comprising combining pharmaceutically acceptable salt according to any one of paragraphs.1-5 with at least one pharmaceutically acceptable carrier.

13. Applying an effective amount of pharmaceutically acceptable salt according to any one of paragraphs.1-5 as an immunosuppressant.

14. Applying an effective amount of pharmaceutically acceptable salt according to any one of paragraphs.1-5 as a tool against psoriasis.

15. Applying an effective amount of pharmaceutically acceptable salt according to any one of paragraphs.1-5 as a means for the treatment of atopic dermatitis.

16. Applying an effective amount of pharmaceutically acceptable salt according to any one of paragraphs.1-5 as a selective inhibitor of proliferation of hematopoietic cells-precursors.

17. Applying an effective amount of pharmaceutically acceptable salt according to any one of paragraphs.1-5 as a stimulator of apoptosis of granulocytes and lymphocyte apoptosis.

18. Application of the effective amount of the pharmaceutical composition according to p. 11 for the treatment of psoriasis in need in this patient.

19. The effective amount of the pharmaceutical composition according to p. 11 for the treatment of immune diseases in need of this patient.

20. The effective amount of the pharmaceutical composition according to p. 11 for the treatment of atopic dermatitis in need in this patient.

21. The effective amount of the pharmaceutical composition according to p. 11 for selective inhibition of proliferation of hematopoietic cells-precursors in need in this patient.

22. The effective amount of the pharmaceutical composition according to p. 11 for stimulating apoptosis of granulocytes and lymphocyte apoptosis in need in this patient.



 

Same patents:

FIELD: food industry.

SUBSTANCE: invention relates to fodder additives containing dipeptides or their salts; one amino acid residue of dipeptide is represented by DL-methionine residue; the other amino acid residue of dipeptide is represented by amino acid in L-configuration chosen from the group including lysine, threonine, tryptophan, histidine, valine, leucine, isoleucine, phenylalanine, arginine, cysteine and cystine.

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31 cl, 17 dwg, 10 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds, which can be used as inhibitors of protease of hepatitis C virus, pharmaceutical compositions, containing the said compounds, and methods of their application.

EFFECT: obtaining compounds which can be used as inhibitors of protease of hepatitis C virus.

41 cl, 10 dwg, 7 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds, which can be used as inhibitors of protease of hepatitis C virus, to pharmaceutical compositions, which contain said compounds, and to methods of their application for treatment of diseases mediated by protease of hepatitis C virus.

EFFECT: obtaining compounds, which can be used as inhibitors of protease of hepatitis C virus.

37 cl, 22 dwg, 7 tbl, 34 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention described the macrocyclic compounds of formula wherein the radical values are presented in the patent claim. The above compounds are serine protease inhibitors wherein serine protease is hepatitis C virus (HCV) NS3 protease. This invention also discloses pharmaceutical compositions having antiviral activity against HCV, containing the claimed compounds, and one or more pharmaceutically acceptable carriers, as well as a method for preparing these compositions. The present invention describes a method of inhibiting the hepatitis C virus replication in a host, and a method of inhibiting activity of hepatitis C virus serine protease.

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69 cl, 39 ex, 8 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

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13 cl, 1 tbl, 17 ex

FIELD: medicine, pharmaceutics.

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8 cl, 4 tbl, 18 ex

FIELD: chemistry.

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51 cl, 14 ex, 8 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

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10 cl, 1 tbl, 124 ex

FIELD: medicine, pharmaceutics.

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42 cl, 4 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing lipodipeptides based on L-glutamic acid or L-glutamine and L-ornithine, L-lysine or L-arginine. L-glutamic acid or L-glutamine derivatives esterified with fatty alcohol residues are obtained by fusing an amino acid with a corresponding alcohol in the presence of a strongly acidic ion-exchange resin in H+ form. Amino groups of L-ornithine, L-lysine or L-arginine are protected and then activated with carboxyl groups. Further, a reaction takes place between esterified derivatives of L-glutamic acid or L-glutamine and the protected derivatives of L-ornithine, L-lysine or L-arginine to form lipodipeptides. The protective groups are then removed.

EFFECT: invention simplifies the process at the esterification step, reduces reaction temperature and reaction time to 2 hours.

3 ex

FIELD: biotechnology.

SUBSTANCE: invention also relates to a nutritional composition comprising herbs and/or spices obtained from plants belonging to Labiatae, "miso" or tomato, the method of preparing a food product comprising the step of adding the agent for imparting Kokumi to food ingredients, food product obtained using the said method, and the method of enhancing taste and/or odour of the food product using the agent for imparting Kokumi.

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20 cl, 1 dwg, 6 tbl, 4 ex

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14 cl, 1 dwg, 10 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing pure crystalline D-isoglutamyl-D-trytophan which involves a step of removing protection from essentially pure N-tert-butoxycarbonyl-D-isoglutamyl-D-tryptophan or diester thereof to yield essentially pure D-isoglutamyl-D- tryptophan. An amorphous ammonium alt of D-isoglutamyl-D- tryptophan (1:1) is also disclosed. Also disclosed is a method of producing a pure monoammonium salt of D-isoglutamyl-D-tryptophan from essentially pure N-tert-butoxycarbonyl-D- isoglutamyl-D-tryptophan. Disclosed is a compound H-D-Glu-(γ-D-Trp-OR2)-α-OR1 and pharmaceutically acceptable acid addition salts thereof. Disclosed is a solid pharmaceutical composition and use thereof as an immunodepressant or anti-psoriasis agent.

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51 cl, 14 ex, 8 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

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42 cl, 4 ex, 9 dwg

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FIELD: chemistry.

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48 cl, 5 tbl, 833 ex

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EFFECT: high bactericidal activity of the compounds.

13 cl, 22 tbl, 281 ex

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