Short-term action benzodiazepine salts and polymorphs thereof

FIELD: chemistry.

SUBSTANCE: invention describes novel, highly crystalline mono(benzenesulphonic acid)besylate salts and polymorphs of the compound of formula (I): , a pharmaceutical composition containing said compounds, methods of producing the salts and use thereof as medicinal agents, particularly for sedative or hypnotic, anxiolytic, muscle relaxation or anticonvulsant purposes.

EFFECT: improved method.

32 cl, 36 dwg, 22 tbl, 10 cl

 

This invention relates to salts of short-acting benzodiazepine, and to the use of these salts, in particular, in the quality of medicines for sedative or hypnotic, anxiolytic, muscle-relaxant or anticonvulsive purposes.

In European patent No. 1183243 describes the short-acting benzodiazepines, which include essential fragment of carboxylic acids and are inactivated by nonspecific esterases tissue. Predict that independent body mechanism of elimination is a characteristic of these benzodiazepines, providing a more predictable, replicable pharmacodynamic profile. These compounds are suitable for therapeutic purposes, including sedative-hypnotic, anxiolytic, muscle-relaxant and anticonvulsive goals. Connections are short-acting CNS-depressants, which are useful for intravenous administration in the following clinical circumstances: preoperational calming, anxiolytic and amnestic application in preoperational cases; conscious sedation during short-term diagnostic, surgical or endoscopic procedures; as a component for the induction and maintenance of General anesthesia, before and/or if it is accompanied by suggesting others anesthetic or analgesic agents; ICU sedation.

One of the compounds described in EP 1183243 (in the Example Ic-8, page 36)is methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propanoate shown in the formula (I) below:

While the basis of the formula (I) is stable when stored at 5°C, it is observed that the samples stored at 40°C/75% RH (open), dissolve, become in color from yellow to orange and show a marked decrease in the content of the original (see Example 1 below).

Currently, it has been unexpectedly found that the compound of formula (I) forms vysokobaricheskie mono(benzolsulfonat acid)besilate salt, which easily stand out from a number of pharmaceutically acceptable solvents and show good thermal stability, low hygroscopicity and high solubility.

In accordance with the invention is provided basilinna salt of the compounds of formula (I). Preferably the salt is a crystalline salt. Preferably a crystalline salt has a stoichiometry of 1:1 compound of formula (I):besilate. Preparation and characterization of polymorphic forms besylate salts described in the examples below.

According to the invention is provided crystalline polymorph besilate salt compounds is ormula (I) (denoted here besylate Form 1) which detects the nature of the powder x-ray diffraction (XRPD), which includes a characteristic peak at about 7,3, 7,8, 9,4, 12,1, 14,1, 14,4, 14,7 or 15.6 degrees two-theta.

Preferably the crystalline polymorph besilate Form 1 detects the character XRPD, which comprises characteristic peaks at about 7,3, 7,8, 9,4, 12,1, 14,1, 14,4, 14,7 or 15.6 degrees two-theta.

More preferably crystalline polymorph besilate Form 1 detects the character XRPD, which comprises characteristic peaks at 7,25 (10,60), 7,84 (72,60), 9,36 (12,10), 12,13 (32,50), 14,06 (48,50), 14,41 (74,30), 14,70 (50,70), 15,60 (26,90) [angle two theta degrees (percentage relative intensity)].

Preferably the crystalline polymorph Form 1 has an initial melting temperature differential scanning calorimetry (DSC) within 187-204°C, preferably about 191-192°C.

Crystal structure of Form 1 is decomposed with K (R factor 6.3). Form I has a stoichiometry 1:1 connection:besilate. Its crystallographic asymmetric unit contains two independent molecules of compound and two besilate molecules. Two independent molecules of compound are the only protonirovannymi in the imidazole ring. The crystal structure has the dimensions of a unit cell a = 7,6868 Å, b = 29,2607 Å, C = 12,3756 Å, α = 90°, β = 97,7880°, γ = 90°, and space group P21.Crystallizes the second structure is described in more detail in example 9, and crystallographic coordinates are given in Table 17. The length of the strips and corners to Form 2 are given, respectively, in Tables 19 and 20.

According to the invention is provided basilinna salt of the compounds of formula (I), which is a crystalline polymorphs, including crystals with dimensions of a single element a = 7,6868 Å, b = 29,2607 Å, c = 12,3756 Å, α = 90°, β = 97,7880°, γ = 90°.

According to the invention is also basilinna salt of the compounds of formula (I), which is a crystalline polymorphs having a crystalline structure defined by the structural coordinates shown in Table 17.

Further, according to the invention is provided basilinna salt of the compounds of formula (I) with the lengths of the strips and angles are shown in Tables 19 and 20, respectively.

Further, according to the invention is provided crystalline polymorph besilate salts of the compounds of formula (I) (denoted here Besylate Form 2), which shows the character (XRPD), which includes a characteristic peak at about 8,6, 10,5, 12,0, 13,1, 14,4 or 15.9 degrees two-theta.

Preferably the crystalline polymorph besilate Form 2 shows the nature of XRPD, which comprises characteristic peaks at about 8,6, 10,5, 12,0, 13,1, 14,4 or 15.9 degrees two-theta.

More preferably crystalline polymorph besilate Form 2 shows the nature of XRPD, which is characteristic includes the e peaks at 8,64 (17,60), 10,46 (21,00), 12,03 (22,80), 13,14 (27,70), 14,42 (11,20), 15,91 (100,00) [the angle 2θ° (% relative intensity)].

Preferably the crystalline polymorph besilate Form 2 has an initial melting temperature differential scanning calorimetry (DSC) in the range of 170-200°C., preferably about 180°C.

Crystal structure of Form 2 is decomposed with K (R factor of 3.8). Form 2 has a stoichiometry 1:1 connection:besilate. Its crystallographic asymmetric unit contains one molecule of the compound and one molecule besilate. The molecule of the compound is the only protonemal in the imidazole ring. The crystal structure has the dimensions of a unit cell a = 8,92130 Å, b = 11,1536 Å, C = 25,8345 Å, α = 90°, β = 90°, γ = 90°, and space group P212121.The crystal structure is described in more detail in example 10, and the crystallographic coordinates are given in Table 18. The length of the strips and corners to Form 2 are given, respectively, in Tables 21 and 22.

According to the invention is provided basilinna salt of the compounds of formula (I), which is a crystalline polymorphs, including crystals with dimensions of a single element a = 8,92130 Å, b = 11,1536 Å, C = 25,8345 Å, α = 90°, β = 90°, γ = 90°.

According to the invention is also basilinna salt of the compounds of formula (I), which is a crystalline polymorphs, is within a crystalline structure, defined by the structural coordinates shown in Table 18.

Further, according to the invention is provided basilinna salt of the compounds of formula (I) with the lengths of the strips and angles are shown in Tables 21 and 22, respectively.

Further, according to the invention is provided crystalline polymorph besilate salts of the compounds of formula (I) (denoted by Besylate Form 3), which shows the nature of the powder x-ray diffraction (XRPD), which includes a characteristic peak at about 7,6, 11,2, 12,4, 14,6, 15,2, 16,4 or 17.7 degrees two-theta.

Preferably the crystalline polymorph besilate Forms 3 shows the nature of XRPD, which comprises characteristic peaks at about 7,6, 11,2, 12,4, 14,6, 15,2, 16,4 and 17.7 degrees two-theta.

More preferably crystalline polymorph besilate Forms 3 shows the nature of XRPD, which comprises characteristic peaks at 7,61 (65,70), 11,19 (33,20), 12,38 (48,70), 14,63 (30,60), 15,18 (33,20), 16,40 (29,60), 17,68 (51,30) [the angle 2θ° (% relative intensity)].

Preferably the crystalline polymorph besilate Form 3 has an initial melting temperature differential scanning calorimetry (DSC) in the range of 195-205°C., preferably about 200-201°C.

Further, according to the invention is provided crystalline polymorph besilate salts of the compounds of formula (I) (denoted here Besylate Form 4), which is manifest in nature XRPD, which includes a characteristic peak at about 7,6, 10,8, 15,2, 15,9, or 22.0 degrees two-theta.

Preferably the crystalline polymorph besilate Forms 4 shows the nature of XRPD, which comprises characteristic peaks at about 7,6, 10,8, 15,2, 15,9 and 22.0 degrees two-theta.

Preferably the crystalline polymorph besilate Forms 4 shows the nature of XRPD, which comprises characteristic peaks at 7,62 (83,50), 10,75 (14,70), 15,17 (37,80), 15,85 (28,70), 22,03 (100) [the angle 2θ° (% relative intensity)].

Preferably the crystalline polymorph besilate Form 4 has an initial melting temperature differential scanning calorimetry (DSC) in the range of 180-185°C., preferably about 182°C.

On the basis of data clarity education, output, purity and chemical stability and solid forms, the preferred salt is besylate Form 1.

According to the invention is also a method of obtaining besilate salts of the compounds of formula (I), which includes the interaction of the free base of the compounds of formula (I) with benzosulfimide acid.

According to the invention is also a method of obtaining a salt of the invention, which includes contacting the free base of the compounds of formula (I) with benzosulfimide acid in solution, causing precipitate formation besilate salt. Preferably the method on which further includes a step precipitate.

The free base is preferably dissolved in toluene, ethanol, ethyl acetate, MtBE, dichloromethane (DCM), izopropilazette, ethyl formate, methanol or acetone. More preferably the free base is dissolved in toluene or ethyl acetate. Benzolsulfonat acid is preferably dissolved in ethanol.

Besylate Form 1 may be obtained by contacting the solution of the free base of the compounds of formula (I) in toluene, ethyl acetate, acetone, isopropylacetate or ethyl formate solution benzosulfimide acid in ethanol to precipitate the salt.

According to the invention is also basilinna salt of the compounds of formula (I), which can be obtained using the above method.

Besylate Form 2 can be obtained by contacting the solution of the free base of the compounds of formula (I) in methanol with a solution of benzosulfimide acid in ethanol to precipitate the salt. Preferably the mixture is cooled below ambient temperature (e.g., 4°C).

According to the invention is also basilinna salt of the compounds of formula (I)obtained as described above.

Besylate Form 3 may be obtained by using the persecution of the liquid, resulting in the crystallization of Form 1 from a mixture of ethyl acetate/ethanol (Form 1). Preference is sustained fashion, the liquid is cooled below ambient temperature (e.g., 4°C).

In one of the embodiments of besylate Form 3 may be obtained by the persecution of the solution of the filtrate separated from the precipitate formed by the contacting of the solution of the compounds of formula (I) in ethyl acetate with a solution of benzosulfimide acid in ethanol, crystalline salt besilate Form 1 of compound of formula (I) obtaining crystalline polymorph besilate Form 3.

According to the invention is also basilinna salt of the compounds of formula (I)obtained by using any of the methods described above.

Besylate Form 4 can be obtained by recrystallization besilate Form 1 from a mixture of isopropylacetate/ethanol, preferably 40% isopropylacetate/ethanol.

According to the invention is also basilinna salt of the compounds of formula (I), which may be as described above.

Salts according to the invention can also be obtained by crystallization besilate the compounds of formula (I) from a suitable solvent or mixture of suitable solvent/antibacterial or solvent/co-solvent. The solution or mixture, in appropriate cases, can be cooled and/or to evaporate to achieve crystallization.

The authors found that the crystallization of Form 2 is observed in extreme degrees or polarity (e.g., a mixture of acetonitrile:water), or solid (is-nonan), or both (dimethylsulfoxide:1,2-dichlorobenzene).

Examples of solvents for crystallization of Form 2 are: Nanan, methanol.

Examples of solvent mixtures/antibacterial for crystallization of Form 1 are: dimethyl/methyl isobutyl ketone; dimethylacetamide/tetrachlorethylene; acetonitrile/3-methylbutane-1-ol; acetonitrile/1,2-dichlorobenzene; acetonitrile/pentalateral; methanol/3-methylbutane-1-ol; methanol/methyl isobutyl ketone; 2,2,2-triptoreline/1,4-xylene; ethanol/methyl isobutyl ketone; ethanol/1,4-xylene; propane-1-ol/1,2-dichlorobenzene; propane-1-ol/tetrachlorethylene; propan-2-ol/1,2-dichlorobenzene; propane-2-ol/n-nonan; 2-methoxyethanol/water; 2-methoxyethanol/pentalateral; 2-methoxyethanol/1,4-xylene; tetrahydrofuran/water, tetrahydrofuran/3-methylbutane-1-ol; tetrahydrofuran/1,2-dichlorobenzene; tetrahydrofuran/ethyl acetate; tetrahydrofuran/1,3-xylene.

Examples of solvent mixtures/antibacterial for crystallization of Form 2 are: ethanol/ethyl acetate; ethanol/methyl isobutyl ketone; ethanol/p-cumene; dimethylsulfoxide/1,2-dichlorobenzene; acetonitrile/water, ethanol/1,2-dichlorobenzene; ethanol/tetrachlorethylene; tetrahydrofuran/1,2-dichlorobenzene; tetrahydrofuran/ethyl acetate.

According to a preferred embodiment of the form 1 is crystallized from 2-methoxyethanol/pistillata.

According to predpochtitel the WMD embodiment of the form 2 crystallized from ethanol/ethyl acetate.

According to a preferred embodiment of the form 2 crystallized from methanol/ethanol (preferably by cooling the solution besilate the compounds of formula (I) in a mixture of methanol/ethanol at a temperature below ambient temperature, for example, 4°C).

According to a preferred embodiment of the form 3 is crystallized from a mixture of ethanol/ethyl acetate (appropriately by cooling the mixture at a temperature below ambient temperature, for example, 4°C).

According to a preferred embodiment of the form 4 is crystallized from a mixture of isopropylacetate/ethanol (preferably by cooling the solution besilate the compounds of formula (I) in a mixture of isopropylacetate/ethanol to ambient temperature).

According to the invention is also basilinna salt of the compounds of formula (I)obtained by any of the methods described above.

Methods of obtaining salts according to the invention are described in detail below in the examples.

Sol according to the invention can be used as a medicine, in particular for a sedative or hypnotic, anxiolytic purposes, as a muscle relaxant or anticonvulsive purposes.

Although the connection according to the invention can be introduced in the form of weight of active chemical substances, it is preferable that it is provided with a pharmaceutically priemel the th carrier, excipient or diluent in the form of pharmaceutical compositions. Media, excipient or diluent should be, of course, acceptable in the sense of compatibility with other ingredients of the composition and must not be harmful to the recipient.

Accordingly, the present invention provides a pharmaceutical composition comprising the salt according to the invention and a pharmaceutically acceptable carrier, excipient or diluent.

The pharmaceutical compositions according to the invention include in their number of compositions suitable for oral, rectal, topical, buccal (e.g., sublingual) and parenteral (e.g. subcutaneous, intramuscular, vnutricerepnogo or intravenous) administration.

Preferably the salt according to the invention is provided in the form of a pharmaceutical composition for parenteral administration, for example, via intravenous or intramuscular injection solution. When the pharmaceutical composition is a composition for parenteral administration, the composition may be aqueous or non-aqueous solution or mixture of liquids, which may contain bacteriostatic agents, antioxidants, buffers, or other pharmaceutically acceptable additives.

Preferred prescription form salts according to the invention is acidic water with the food with a pH of 2-4, or in an aqueous solution of cyclodextrin (CD). Cyclodextrins that can be used for these prescription forms, represent or anionic-charged sulphobutylether (SBE) derivatives of β-CD, especially SBE7-β-CD, sold under the trade name Captisol firm CyDex, Inc. (Critical Reviews in Therapeutic Drug Carrier Systems, 14(1), 1-104 (1997)), or hydroxypropyl CD s.

Additional preferred prescription form salts according to the invention is liofilizovannye form, containing in addition to salt, at least one of the following agents: ascorbic acid, citric acid, maleic, phosphoric acid, glycine, glycine hydrochloride, succinic, or tartaric acid. It is believed that these agents are useful as superyoshi, sintering or imaging agents. In some cases it may be beneficial inclusion in prescription form of sodium chloride, mannitol, polyvinylpyrrolidone, or other ingredients.

The preferred method of creating the prescription form (for example, acid buffer based or CD) may depend on the physico-chemical properties (e.g. water solubility, pKa and other) specific salt. Alternative salt can be represented in the form of liofilizirovannogo solids for personaline with water (for injection or dextrose or saline. Such prescription form is usually presented in the form IU the border dosage forms, such as capsules or injection device from time to time. They can also be represented in mnogochasovykh forms, such as the bubble, from which can be extracted corresponding dose. All such prescription form must be sterile.

According to the invention is provided a method of producing sedation or hypnosis the subject, which provides an introduction to the subject an effective sedative or hypnotic amount of salt according to the invention.

According to the invention is also a method of induction anxiolysis the subject, which includes an introduction to the subject an effective anxiolytic amount of salt according to the invention.

According to the invention additionally provides a method of inducing muscle relaxation in a subject, which includes an introduction to the subject an effective muscle-relaxante amount of salt according to the invention.

According to the invention additionally provides a method of treating convulsions in a subject, which includes an introduction to the subject an effective anticonvulsive amount of salt according to the invention.

According to the invention is also the use of sedative or hypnotic amount of salt according to the invention in the manufacture of a medicine for producerof the Oia, the subject has a sedative action or hypnosis.

According to the invention is also the salt of the invention for producing the subject has a sedative action or hypnosis.

According to the invention is also the use of anxiolytic amount of salt in the manufacture of a medicinal product for producing the subject anxiolysis.

According to the invention is also the salt of the invention for producing the subject anxiolysis.

According to the invention additionally provides the use of muscle-relaxing amount of salt of the invention in the manufacture of a medicinal product for producing the subject muscle relaxation.

According to the invention the following is a salt of the invention for producing the subject muscle relaxation.

According to the invention further provides the use of anticonvulsive amount of salt of the invention in the manufacture of drugs for the treatment of convulsions in the subject.

According to the invention is also the salt of the invention for the treatment of the subject convulsions.

Subject properly is a mammal, preferably human.

Suitable parenteral pharmaceutical preparation for introducing people preferably will contain about 0.1-20 mg/ml salt according to the invention in solution or multiple the number is and its for-parenteral multi-dose containers.

Intravenous administration may take the form of a bolus injection or, more suitably, a continuous infusion. Dosage for each subject may vary, but a suitable intravenous quantity or dosage of the salt according to the invention for receiving sedation or hypnosis in a mammal is 0.01-5.0 mg/kg of body weight, and more specifically 0.02 to 0.5 mg/kg of body weight, and the above doses are given per weight of salt, which is the active ingredient. Appropriate intravenous quantity or dose of salts according to the invention to obtain anxiolysis the mammal is 0.01-5.0 mg/kg of body weight, and more specifically 0.02 to 0.5 mg/kg of body weight, and the above doses are given per weight of salt, which is the active ingredient. Appropriate intravenous quantity or dose of salts according to the invention to obtain muscle relaxation in a mammal is 0.01-5.0 mg/kg of body weight, and more specifically 0.02 to 0.5 mg/kg of body weight, and the above doses are given per weight of salt, which is the active ingredient. Appropriate intravenous quantity or dose of salts according to the invention for treating convulsions in a mammal is 0.01-5.0 mg/kg of body weight, and more specifically 0.02 to 0.5 mg/kg of body weight, and the above doses are given per weight of salt, which is active and gradient.

Salts according to the invention are Central nervous system depressants short-term actions, which are useful for intravenous administration in the following clinical situations: preoperational calming, anxiolytic and amnestic application for preoperational cases; conscious sedation during short-term diagnostic, surgical or endoscopic procedures; as a component for the induction and maintenance of General anesthesia, before and/or if it is accompanied by the introduction of other anesthetic or analgesic agents; ICU sedation.

Preferred embodiments of the invention are described in the following examples with reference to the accompanying drawings, in which:

Figure 1 shows the graph content (% relative to initial) the compounds of formula (I) against temperature storage;

Figure 2 shows differential scanning calorimetry (DSC) LJC-039-081-1;

Figure 3 shows the DSC (DSC) LJC-039-081-1 (solid), covered LJC-039-081-2 (dashed);

Figure 4 shows DSC besylate forms (Form 1 - solid, 2 - dashed);

Figure 5 shows DSC besylate forms (Form 1 - solid Form of 3 - dotted points);

6 shows the chromatogram LJC-039-037-1 at T0and T4(and refer to the results in Table 10);

Fig.7 shows the XRPD compared LJC-039-037-1 (besilate salt) before and at the Le 4-week stability studies;

Figa shows a comparison of the XRPD besilate form 1 and Form 2;

Figv shows differential scanning calorimetry (DSC) overlay form 1 and Form 2;

Figa shows XRPD comparison besilate forms 1 and 3, and Figv shows overlay Forms 1 and 3;

Figure 10 shows the DSC (DSC) LJC-039-086-1 (besylate Form 4);

11 shows the results for besilate Form 1: (A) XRPD for 100 mg loading LJC-039-037-1; (B) DSC 100 mg loading LJC-039-037-1; (C) TGA to 100 mg loading LJC-039-037-1; D)1H NMR (NMR) for 100 mg loading LJC-039-037-1; (E) GVS 100 mg loading LJC-0390-037-1; (F) XPRD after GVS 100 mg loading LJC-039-037-1; (G) XRPD after stability at 40°C/75%RH (relative humidity) for a 100 mg loading LJC-039-037-1; (H) VT XRPD for 100 mg loading LJC-039-037-1; (I) microscopy in polarized light for a 100 mg loading LJC-039-037-1;

Fig shows the results for besilate Form 2: (A) XRPD for 100 mg loading LJC-039-067-8; (B) DSC 100 mg loading LJC-039-067-8; (C) DSC speed track load curve 2°C/min; D)1H NMR for LJC-039-067-8;

Fig shows the results for besilate Form 3: (A) XRPD for LJC-039-081-2 (2nd collection of liquids LJC-039-081-1); (B) DSC for LJC-039-081-2; (C) DSC for LJC-039-081-2 (tracking speed of the load curve 2°C/min); (D) TGA (TGA) for LJC-039-081-2; E)1H NMR for LJC-039-081-2; (F) GVS for LJC-039-081-2; (G) XRPD after GVS for LJC-039-081-2;

Fig shows the results for besilate Form 4: (A) XRPD for LJC-039-086-1; (B) DSC for LJC-039-086-1; C)1H NMR for LJC-039-086-1;

F. g shows HPLC chromatography release download besylate salts accompanied by detailed results reportedly Agilent ChemStation;

Fig shows chiral chromatography for LJC-039-081-1 and LJC-039-083-1;

Fig shows a sample image (field of view of approximately 4-8 mm diameter) solid forms observed during crystallization besilate the compounds of formula (I);

Fig shows the contents of the asymmetric links in the Form 1;

Fig shows the molecular structure determined using single-crystal x-ray diffraction of crystals besilate the compounds of formula (I), form 1, grown from a solution mixture of 2-methoxyethanol:pentalateral with atoms represented by thermal ellipsoids. Shows only the hydrogen atoms located in the crystal structure;

Fig shows the conformation or structure associated with two independent molecules in the Form 1;

Fig shows a comparison of the conformations assigned to one independent molecule in the Form of 1 (top), and the conformation of the Form 2 (bottom);

Fig shows a comparison of the conformations assigned to two independent besilate in the Form 1, a view in two different directions;

Fig shows a comparison of the conformations assigned to one independent besilate in the Form 1 (top), and the conformation of the Form 2 (bottom);

Fig shows the crystal structure determined using single-crystal x-ray diffraction of crystals besilate connection is ormula (I), grown from a solution mixture of 2-methoxyethanol:pentalateral view along the crystallographic a axis (a), (b-axis (b) and c axis (c);

Fig shows the approximate location of C-O<a 3.6 Å, C-C<a 3.6 Å, N-O,<a 3.5 Å to Form 1;

Fig shows the calculated powder diffraction pattern according to single crystal x-ray diffraction to Form 1;

Fig shows the crystal plate shape observed for the besilate of Form 2 of compound of formula (I);

Fig shows the contents of the asymmetric links in the Form 2;

Fig shows the molecular structure determined using single-crystal x-ray diffraction of crystals besilate Form 2 of compound of formula (I) atoms are represented by thermal ellipsoids. Shows only the hydrogen atoms have specific in the crystal structure;

Fig shows the conformation assigned independent molecule in the Form 2;

Fig shows the conformation assigned independent besylate in Form 2, in two different directions;

Fig shows the crystal structure determined using single-crystal x-ray diffraction of crystals besilate the compounds of formula (I) Form 2 view along the crystallographic a axis (a), (b-axis (b) and c axis (c);

Fig shows the approximate location of C-O<a 3.6 Å, C-C<a 3.6 Å and N-O<a 3.5 Å to Form 2

Fig shows the calculated powder diffraction pattern according to single crystal x-ray diffraction to Form 2;

Fig shows the tagging of nuclear centres for besilate the compounds of formula (I) Form 1; and

Fig shows the tagging of nuclear centres for besilate the compounds of formula (I) Form 2.

Example 1

The study of the stability of the compounds of formula (I) in the solid state

Method/Technology.Accurately weighed 2-mg samples of the compounds of formula (I), put them in a 4-ml glass vials with screw caps. The samples were tested at the beginning and after 34 days of storage at 5°C/Relative Humidity Environment (AMRH) Closed at 30°C/60% Relative Humidity (RH) Closed at 40°C/75% RH Open and at 60°C./AMRH Closed.

The samples were examined visually for the appearance. The value of the content of the compounds of formula (I) was determined using HPLC method in Table 1. Ratio % weight./weight. (%/W) measured relative to the standard samples of the compounds of formula (I) Batch U12438/79/1. The values % of the area was obtained by dividing the peak area of the compounds of formula (I) on the total peak area.

Table 1
Conditions for HPLC method
Column:
Phase=Phenomenex Luna C18(2)
Length×internal). Diameter =100×4.6 mm
The particle size =3 microns
Mobile phase:A = 1000:1 Water/Triperoxonane acid
B = 1000:0.5 Acetonitrile/Triperoxonane acid
Flow rate:1.0 ml/min
The temperature of the column:40ºC
GradientTime (min)%%
0,08020
20,02060
25,02060
25,18020
30,08020
The wavelength of detection:230 mm
The injected sample mass1.0 microgram, usually 1 ál injection of 1.0 mg
the compounds of formula (I)/ml in 60:40
Water/Acetonitrile
Retention timeThe compound of formula (I) eluted at approximately of 7.64 min

RESULTS

Appearance.Table 2 presents the results of the evaluation of the appearance.

Table 2
General data appearance the compounds of formula (I)
Storage conditionsTimeAppearance
days
CT (room temperature)originalCreamy light yellow powder
5C/AMRH Closed34Creamy light yellow powder
30C/60% RH Closed34Creamy light yellow powder
40C/75% RH Open34Blurring yellow mass on the bottom of the bubble
60C/AMRH Closed34Blurring from dark yellow to orange mass on the bottom of the bubble

Content (% V/V) the compounds of formula (I).Value content % V/V (see Table 3) show significant variability in order to determine R the differences between the initial value and the values measured after 34 days of storage at 5°C./AMRH Closed at 30°C/60% RH or Closed at 40°C/75% RH Open. Average % in/in particular for samples stored 34 days at 60°C./AMRH Closed, shows 10% in/decrease from the initial values.

The content of the compounds of formula (I) (% area).The content of the compounds of formula (I) (% area) (see Table 3 and Figure 1) shows no significant change after 34 days of storage at 5°C./AMRH Closed, but steadily decreases with increasing temperature for samples stored at 30°C/60% RH Closed at 40°C/75% RH Open or at 60°C./AMRH Closed. The major degradation peaks are observed at RRT of 0.68, 0.87 for and RRT 0,90, but chromatogram, which are relatively complex even when the initial condition (23 peak), also show many new small degradant peaks (for example, 7 peaks during storage at 30°C/60% RH Closed; 13-20 peaks when stored at 60°C./AMRH Closed). These observations suggest multiple ways degradation. Degradant when RRT 0,68 experimentally determined as the product of the hydrolysis of ester (the free acid of compounds of formula (I)). It is the most predominant for products stored at 40°C/75% RH Open, as would be expected for products of hydrolysis.

Table 3
Aggregated data HPLC of the compounds of formula (I)
Storage conditionsTimeThe content of the compounds of formula (I)% With respect to the initial % of the area Avg.
days%/% square
CT (room temperature)original100,595,14Avg = 94,81
CT (room temperature)original104,194,47
5C/AMRH Closed #1134102,695,30/td> 100,52
30C/60% RH Closed #113494,794,2099,36
40C/75% RH Open #134105,493,4598,57
40C/75% RH Open #234100,393,3998,50
60C/AMRH Closed #134for 93.487,77to 92.57
60C/AMRH Closed #234to 91.187,77to 92.57

Note

1. Because of an error in the setting device sequence (sequencing machine) automatic probabilit had only one sample.

CONCLUSIONS

The compound of formula (I) is stable, as for appearance and content during storage, at least for 34 days at 5°C./AMRH Closed. No changes in appearance are not observed during storage at 30°C/60% RH Closed, but there was approximately 0.6% decrease in the content of the compounds of formula (I) relative to the initial % of the area. Samples stored at 40°C/75% RH Open or 60°C./AMRH Closed, radigales, the color became yellow to orange, and they showed a marked reduction (1.5 to 8%) content of the compounds of formula (I) with respect to the original. The major degradation peaks are observed at RRT of 0.68, 0.87 for and RRT 0,90 along with numerous smaller peaks, suggesting the multiple paths of destruction. Sample, collapsing when RRT 0,68 experimentally identified as a product of ester hydrolysis. These results indicate that the compound of formula (I) must be kept refrigerated or frozen to save for a long time.

Example 2

The solubility of the compounds of formula (I) were determined in a wide range of organic solvents. Data solubility are shown in Table 4 below.

Table 4SolventMin. the desired solvent/mg/mlMethanol446Ethanol324Propane-2-ol454Acetone214Toluene460The ethyl acetate218Tetrahydrofuran311Acetonitrile362

The data clearly show that the compound of formula (I) has a high solubility in common organic solvents. Preferred solvents are ethanol and toluene.

As for the RCA, was measured two main centers of the free base of the compound. However, the main center of the pyridine ring had a record of the RCA 1,99. Measurements showed that the RCA main center of the imidazole ring was 4,53.

To obtain besilate salts of the compounds of formula (I) used benzosulfimide acid. Experiments were performed with 20 mg scale using 6 volumes of the extract solvent. All reactions were carried out at ambient temperature with acids loaded in the form of ready-made solutions in ethanol (1M) or in the form of solids, depending on the solubility.

Isolated solids showed a significant shift of the peaks in the analysis1H NMR, confirming the formation of salts. Analysis using X-ray Powder Diffraction (XRPD) showed that salt has a crystalline appearance. Table 5 summarizes the selected form of salt.

Table 5
RecordSolSolventID
1besylatetolueneLJC-039-009-7

Salt was subsequently stored at 40°C/75% RH for two weeks, then were subjected to analyses XRDP and HPLC chemical purity to assess the stability of the materials. Salt kept the same powder character after exposure to the action of moisture and also maintained a high chemical purity, confirming improved stability.

From the results of the T1purity of the individual salts (table 6 below) you can see that basilinna salt of toluene showed the highest levels of purity before and after stability studies.

Table 6
Brief description of cleanliness before and after storage at 40°C/75% RH for one week
RecordSolIDThe purity of the T0/%The purity of the T1/%
1besylateLJC-039-009-795,995,9

The results presented above show that the form besilate salt showed a high purity and good stability results.

Example 3

Zoom besilate salt to 100 mg was performed on the basis of the data of Example 2. It was found that toluene is the preferred solvent for separation besylate salts.

Basilinna salt of the compounds of formula (I)

The increase in the scale up to 50 mg of the input material was performed in order to confirm whether or not the process to rise, and in order to confirm that the selected material had the same crystalline form (Form 1), observed in the previous experiment on a smaller scale. As soon as the analysis of confirmation is erdil, what salt is Form 1 and that the properties are what you expected, spent another zoom with 100 mg of the input material, in order to conduct a full description and to submit a sample for analysis of stability for 4 weeks at 40°C/75% RH. Both reactions in an enlarged scale was carried out in toluene with benzosulfimide acid added in the form of a solution in ethanol (1M).

Besilate experimental procedure

The free base of the compounds of formula (I) (100 mg, loading 704-17) was loaded into a test tube and when the ambient temperature was added toluene (600 ml). To the solution was added benzosulfimide acid (250 μl, 1M in ethanol) and the reaction mixture was stirred for 15 minutes, and then the solution was precipitated solid, which was filtered, washed with toluene and dried in a drying Cabinet at 40°C in vacuum. Analysis by XRPD showed that the solid has the same powder structure, as well as other manufactured besilate, and analysis1H NMR confirmed the formation of a salt according expressive peak axes.

Table 7
RecordIDSolGVS absorption-distribution/% The beginning of the melt-ing/°CTGA weight loss/%Dissolve remote mg/mlChemical purity %Chiral purity % E.E.
1LJC-039-037-1besylate2,0201,3a 4.98,3to 97.194,4

The enantiomeric excess for LJC-039-037-1 was only 94,4, so the result was compared with another load besilate (LJC-039-081-1), which was dedicated in identical conditions. The enantiomeric excess of the load amounted to 99.1%.

Optimization of process

To improve further outputs besilate salt (Form 1) was subjected to screening four solvent (isopropylacetate, ethyl formate, methanol and acetone). In General spent eight 100 mg scale reactions in these solvents with the appropriate acid, added as a ready solution in ethanol for comparison with previous experiments.

The compound of formula (I) (download 704-38, 100 mg) was dissolved in solvent (600 μl) at ambient temperature. Added acid (250 μl, 1M ready solution in ethanol) and all of the reaction mixture was left of stativ for 48 hours at ambient conditions. The results are presented in Table 8.

Table 8
The results of experiments optimization process
The entry in the tableReference number in your lab bookSolSolventXRPDOutput/%Purity/% squarePurity after 40°C/75% RH for 4 weeks
1LJC-039-067-2besylateacetoneForm 13898,498,1
2LJC-039-067-4besylateiPrOAcForm 17997,795,9
3LJC-039-067-6besylateethyl formateForm 140 98,698,3
4LJC-039-067-8besylateMeOHSingle crystals, Form 2Not recorded98,1Not recorded

All reactions, except education besilate in methanol showed the Form 1. The reaction in methanol was carried out at 4°C. the Obtained data confirmed anhydrous, besilate 1:1 and the powder material structure confirmed the presence of a new form (Form 2).

From the study it was concluded that solvents, such as isopropylacetate, increase the purity of the salt, however, reduce its allocation. Due to the fact that the previous choice of solvent (ethyl acetate) gave a high yield of the salt with high purity, it was decided to use the acetate to end experiments on a larger scale.

Besilate (Form 1) 1 g zoom

Conducted education 1 g besilate salt. When this is successfully received 950 mg (70% yield) of the substance of the Form 1. Fluids were intensely colored (yellow) and therefore was tetrafluoride crystals, a small amount of Form 1, to facilitate the selection. The liquid was kept at 4°C for 16 hours. The obtained solid substance was shown the new sample powder (Form 3). The solid was analyzed using thermal analysis and XRPD with variable temperature to confirm that it was or not valid polymorpha or MES. The interpretation of the results of the analysis allowed us to conclude that it is not a MES, according to analysis1H NMR, and DSC analysis showed two endothermic event identified by the study on the microscope with a heating table (Figure 3). It was interpreted that the seed crystals of Form 1 melts at 187°C, and Form 3 is melted at 200°C. the Reason why the Form 1 were not identified using XRPD, is that this technique is less sensitive than microscopy.

Form 3 is deposited in the sediment at a lower temperature than Form 1.

The characterization was performed on the polymorphs to infer the relationships between them.

Table 9
Thermal data besylate forms
RecordIDFormThe beginning of the melting point/°CΔH/Jg-1
1LJC-039-081-11201 56
2LJC-039-067-8218073
3LJC-039-081-21, 3187, 2007,6, 37

Lower the melting point of a small number of the Form 1, presented in the form of LJC-039-081-2, can potentially be attributed to a lower purity (97,2% compared with 97.9% of the LJC-039-081-1).

Figure 4 shows DSC data besylate forms 1 (solid line) and 2 (dotted line).

Figure 5 shows DSC data besylate forms 1 (solid line) and 2 (dashed dot line).

Example 4

Stability studies of salt

Table 10
Summary table of pureness salt after 4 weeks of stability studies
Sample IDSolT0T1T2T3T4
LJC-039-037-1besylate to 97.197,397,496,796,7

Crystalline samples besilate was kept at 40°C/75% RH in General within four weeks, and every seven days samples were taken for HPLC analysis. HPLC purity besilate remained stable up to T3when she reached 96,7%. This value, however, remained constant up to T4.

The HPLC chromatogram for the form besilate salt represented at 6 in time from zero and up to four weeks.

It is suspected that the dominant peak before the peak of the initial compounds is the result of pollution, since λmaxdoes not correspond to λmaxpeak source. He is also missing in the profile of impurities of the T1T2T3and T4.

From powder structures of salts before and after study on the humidity, you can see that any change in the form of no.

Fig.7 shows the XRPD comparison LJC-039-037-1 (besilate salt) before and after 4 weeks of stability studies.

Example 5

The study of polymorphism

To determine the propensity besylate salts to demonstrate polymorphism, carried out the experiment of aging using thirty solvents (fifteen undiluted plus their parallel 2.5% aqueous dissolve the s). The solid is suspended in different solvents (see Table 11) within one week cycle heating/cooling from ambient temperature to 60°C. After one week suspension is evaporated and the solids were analyzed using XRPD and HPLC.

• the original HPLC purity of 97.7%

Table 11
The results of the study of polymorphism besilate (LJC-039-058-2)
RecordSolventXRPD after 1 weekHPLC purity/% square
1acetoneForm 197,5
2THFForm 197,6
3IPAamorphous substanceto 97.1
4MtBEForm 197,7
5DCMamorphous substance 97,4
6EtOHoilnot analyzed
7MEKForm 197,2
81,4-DioxaneForm 197,2
9iPrOAcForm 197,5
10DMFoilnot analyzed
11MeCNForm 194,3
12nBuOHoilnot analyzed
13nPrOHoilnot analyzed
14MIBKForm 197,7
15MeOHoil not analyzed
16a 2.5% aqueous solution of acetoneForm 196,8
17a 2.5% aqueous solution of THFamorphous substance93,3
18a 2.5% aqueous solution of IPAForm 176,1
19a 2.5% aqueous solution of MtBEoilnot analyzed
20a 2.5% aqueous solution of DCMForm 197,4
21a 2.5% aqueous solution of EtOHoilnot analyzed
22a 2.5% aqueous solution of MEKForm 193,9
23a 2.5% aqueous solution of 1,4-DioxaneForm 186
24a 2.5% aqueous solution iPrOc oilnot analyzed
25a 2.5% aqueous solution of DMFoilnot analyzed
26a 2.5% aqueous solution of MeCNForm 193,3
27a 2.5% aqueous solution nBuOHoilnot analyzed
28a 2.5% aqueous solution nPrOHoilnot analyzed
29a 2.5% aqueous solution of MIBKForm 197,3
30a 2.5% aqueous solution of MeOHoilnot analyzed

The study of the maturation using besilate salt found no new forms. The results of the index of cleanliness after aging show that those substances that are suspended in acetonitrile, aqueous THF, aqueous IPA, water MEK, aqueous dioxane and aqueous solution of acetonitrile, rasla is Alice. This implies that basilinna salt (Form 1) has a good stability of undiluted solution in organic solvents at high temperatures.

The study of new forms besilate

Although the results of the study maturation was not seen any new forms besilate salt, a new form was observed when the crystals were grown in methanol. Single crystals obtained from methanol, were grown in order to obtain the powder structure. It turned out that this structure differs from Form 1. Repeat the experiment was performed in order to obtain an additional supply of Form 2. In contrast to the possibility of evaporation of the solvent, giving, thus, Form 1, select the Form 2 was from liquids only when precipitation for 16 hours. Interestingly, attended by two features: needle crystals and blocks. Both showed the same powder structure as the needles that were used for structure determination single crystals.

A full analysis was carried out on the Form 2. It was concluded that it is indeed polymorph, as these single crystals confirmed anhydrous, besilate 1:1.

On Figa shows a comparison of the XRPD besilate Forms 1 and 2. There is an obvious difference between Form 1 (trace 1) and Form 2 (trace 2). As what you can see two characters or structures of powder, both forms are very different. Thermal analysis was carried out to compare the melting points of the two forms and recorded measurements of thermodynamic solubility.

On FIGU shown overlapping Forms 1 and 2. Forms 1 and 2 show one endothermic (melting).

Form 3 is identified when liquids LGC-039-081-1 (1 g reaction in an enlarged scale) stood second collection. The analysis was carried out to determine whether it is a MES, and as a form vzaimoprevrascheny.

On Figa shows a comparison of the XRPD besilate Forms 1 and 3. Figv shows overlapping Forms 1 and 3.

Form 1 shows one endothermic (melting), while Form 3 shows two results. Microscopy hot stage Form 3 clearly shows two melting in the range of 20°With each other. Accepted without evidence that there is a small amount of the lower melting polymorph, as it is not picked up when XRPD at variable temperature, which is a less sensitive technique. It is quite possible that the first endothermic result is of the Form 1, which was used for the priming fluid, of which stood out the Form 3.

Data solubility show that all three forms have very similar solubility in water at pH 3 to about 7.8 to 8.3 mg/ml

Bezila the Naya salt Form 4

Released party besilate salt Form 1 (LJC-039-083-1) was of high purity (97,6%), but contained a small amount of impurities are transferred from the free base (0,78%, to 11.9 min at room temp.). This impurity was observed in the DSC experiment, showing an endothermic transition (beginning at 130°C). Confirmed peak with figure λ., not associated with an indicator of the main peak.

Took 100 mg of a sample to try recrystallization from a mixture of 40% isopropylacetate/ethanol. Recrystallization was carried out traditionally by dissolving the salt in a minimum amount of hot solvent, and then slow cooling to ambient temperature, to obtain the precipitate. The dried solid was analysed by XRPD, which pointed to a new form, and with the help of thermal analysis and1H NMR confirmed that it is polymorpha, not MES. Figure 10 shows the DSC LJC-039-086-1.

Screening of salt showed that the compound of formula (I) forms many salts in the corresponding interval of the RCA, and they easily stand out from a number of solvents. According to the complete characterization of the salts was determined that besylate salts have good stability, with regard to humidity. The result came to the conclusion that there are two polymorphic forms besilate. Form 3 is obtained from the second the first collection LJC-039-081-1 liquids after seed Form 1. Form 4 was observed after recrystallization was carried out Form 1 from a mixture of 40% isopropylacetate/ethanol.

The full analysis is shown below figure 11-14.

Experimental procedures for Examples 2-5

Example 2

The compound of formula (I) (5 mg/well) were dissolved in a solvent1(1Ethanol, toluene, and acetonitrile) (30 μl) in HPLC vessels. To the solution were added benzolsulfonat acid to (11.4 μl, 1M in ethanol), and the reaction mixture stood overnight at ambient conditions. Those vessels that contained solid material was subjected to drying at 40°C under vacuum, and those who remained with substances in the form of solutions, was subjected to concentration by evaporation, and then was treated with heptane. Substances that are precipitated, dried, as mentioned, but those who samakovlis were stored at 4°C.

Besylate Form 1 zoom

The compound of formula (I) (100 mg) was dissolved in ethyl acetate (600 ml) and was added to benzolsulfonat acid (250 μl, 1M in ethanol). Instantly occurred deposition, and the reaction mixture is stirred for 24 hours at ambient conditions. The solid is filtered, rinsed with ethyl acetate and dried in an oven at 40°C under vacuum for 16 hours.

Methods of analysis

The differential is Naya scanning calorimetry (DSC)

Data DSC was going on TA instrument Q1000, equipped with a 50-position avtopromsborka. Calibration standard energy and temperature was the Indies. The samples were heated at a rate of 10°C/min at a temperature of between 25 and 350°C. Above the samples was supported by purging with nitrogen at 30 ml/min

Unless otherwise stated, were used samples between 0.5 and 3 mg, and all samples were held in a perforated pins aluminum pan.

Thermogravimetric analysis (TGA)

TGA data were collected on a TA instrument Q500 TGA, calibrated by Alumel, and passed with the speed of scanning 10°C/minute. Above samples was supported by purging with nitrogen at 60 ml/min

Unless otherwise noted, usually in a pre-tared platinum crucible was loaded 5-10 mg samples.

NMR

All spectra were collected on Bruker 400 MHz, equipped prosobonia. The sample or samples were prepared ind6-DMSO unless otherwise stated.

XRPD (Powder x-ray diffraction)

Bruker AXS C2 GADDS Diffractometer

Characters powder x-ray diffraction for samples was determined on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for autoprobing positioning and a HiStar detector 2-dimensional space. X-ray optics soteitis one Gobel multilayer mirrors in combination with a collimator with pin holes of 0.3 mm

The divergence of the beam, i.e. the effective size of the x-ray beam on the sample was approximately 4 mm was Used θ-θ continuous scan with distance from the sample to the detector 20 cm which gives an effective 2θ interval 3,2-29,8°. A typical exposure time of the sample was 120 seconds.

Samples for work in the environmental conditions were prepared as flat plate specimens using powder without grinding. To obtain a flat surface approximately 1-2 mg of sample was slightly merged on a glass slide. The samples subjected to the run in an environment that was placed on a silicon wafer with a thermally conductive connection. The sample is then heated to the appropriate temperature at a rate of about 20°C./minute and subsequently before he started the data collection, was kept isothermal for about 1 minute.

Analysis purity:

Chemical method

Analysis of purity was performed on an Agilent HP1100:
Method:A gradient Reversed phase
Duration method/min:34
Column: Phenomenex Gemini C18 5 μm to 2.0×50 mm) (accessory cartridge Phenomenex Gemini auxiliary Chuck 2×4 mm)
The column temperature/°C:40
Injection/µl:5
The flow rate ml/min:0,8
Detection:UV
Wavelength/nm:255 (band width 90 nm),
240 (width 80 nm),
254 (bandwidth 8 nm)
Phase A:2 mmol of NH4HCO3(brought to rn solution of NH3)
Phase:acetonitrile

Temporary table:
Time/min%A%B
09010
251090
28,81090
2990 10
349010

Chiral method:

Analysis of purity was performed on a Gilson system HPLC:
Method:Isocrotonic, Normal phase
Duration method/min:50
Column:Diacel Chrialcel OJ-H (5 μm) of 4.6×250 mm (Auxiliary cartridge Diacel Chrialcel OJ-H analytical auxiliary Chuck 5 μm to 4.0×10 mm)
The column temperature/°C:40
Injection/µl:10
The flow rate ml/min:1,0
Detection:UV
Wavelength/nm:225 (detector with single wavelength)
Phase A:hexane
Phase:ethanol

Temporary table:
Time/min%A%B
0937

Research gravimetric vapor sorption (GVS)

All samples were transported in sorption analyzer moisture Hiden IGASorp working with CFRSorp software. Sample sizes were typically 10 mg Adsorption-desorption isotherm moisture was carried out, as shown below (2 scanner, giving 1 full cycle). All samples were loaded/unloaded at normal room temperature and humidity (40% RH, 25°C). All samples were analyzed using XRPD after GVS analysis. Standard isotherm was carried out at 25°C at 10% relative humidity in the range 0-90% relative importance of the range, unless otherwise noted.

Scan 1Scan 2
AdsorptionDesorptionAdsorption
408510
507520
606 30
704540
8035
9025
15
5
0

Solubility

Solubility was measured by using a suspension of a sufficient number of connections in 0.25 ml of solvent (water), with a maximum final concentration of 10 mg/ml of the original free-form connections. The suspension was balanced at 25°C for 24 hours and then test the pH and filtration through glass fiber With a 96-well plate. The filtrate was then diluted to h. Quantitative analysis was performed using HPLC with reference to the standard, dissolved in DMSO at approximately 0.1 mg/ml was Injectibles different volumes of the standard, in experiments with diluted and undiluted. The solubility was calculated by integrating the peak area detected at the same time hold the project, that and the peak maximum in injectioni standard. If the filter plate has sufficient solids, XRPD is usually checked on the phase changes, the formation of hydrate, amorphization, crystallization, etc.

Table:
Time/min% Phase A% Phase B
0,0955
1,08020
2,3595
3,3595
3,5955
4,4955

Determination of the pKa

The definition of the RCA was performed on the instrument Sirius GlpKa Annex D-PAS. Measurement was performed using potentiometric titration in mixtures of MeOH:H2O at 25°C. Title the environment was ion fortress, brought with 0,15 M KCl. The values found in mixtures of MeOH:H2O, extrapair is Alice to 0% co-solvent through extrapolation Yasuda-Shediovsky.

Microscopy with a heating table

Microscopy with a heating table was analyzed using a Leica LM/DM polarized microscope, combined with a Mettler-Toledo MTFP82HT heating table in a temperature range of 25-350°C With a typical heat-up rates in the range of 10-20°C/min, a Small amount of sample was dispersibles on a glass slide with individual particles, as can be more divided. The samples were examined under conditions of normal cross-polarized light (in combination with λ false color filter) with a ×20 objective lens.

Chiral method for purity
The installation system
Pump:Gilson 322 binary pump
Detector:Gilson 152 UV/Vis
Autoparametric:Gilson 233XL hour + Gilson 402 pump dual syringe
Column oven:Phenomenex Termasphere TS-130
Software:Gilson Unipoint LC software
Column: Daicel Chiralcel OJ-H, 5 μm, a 4.6×250 mm
Auxiliary column:Daicel Chiralcel OJ-H analytical auxiliary cartridge, 5 microns, of 4.6×10 mm
Conditions of HPLC
Channel A:Hexane (93%)
Channel:Ethanol (7%)
Flow rate:1.0 ml/min
Wavelength detector:225 nm
The temperature of the column:40°C
Time pass:50,0 min

Conditions sample

Approximately 0.2 mg of sample was dissolved in the appropriate volume mixture of hexane:ethanol 1:1 V/V (v/v), giving 0.2 mg/ml. This solution was closed with a lid and placed in a vortex mixer at high speed for a period of ~15 seconds. If at this point remained solid, then the sample vessel was subjected to sonication for approximately 10 seconds, followed by additional processing in a vortex mixer for 10-15 seconds. 10 µl injectibles on the HPLC system. The samples were injectibles twice after the original is through a double injection of a mixture of hexane:ethanol 1:1 V/V as the blind experience.

Example 5

An example of pharmacological tests

Estimated anaesthetic and sedative effects besilate salt Form 1 of the present invention. Basilinna (benzosulfimide acid) salt was dissolved in physiological solution for introducing a test composition to the animal. The test composition was injected into mice, placed in individual Plexiglas cages (20×10×10 cm). Mice were injected with intravenous or media, or the test substance. Recorded latent period before falling asleep and duration of anesthesia (maximum: 90 minutes after administration of the test substance). To anesthesia indicates the loss of the installation reflex (bringing the body in normal position) (LRR). Test the installation reflex was performed as soon as the animals seemed to be subjected to the action of sedatives, approximately every 20-30 seconds. When adjusting reflex was absent, we measured the duration of the loss of the installation reflex test return installation reflex approximately every 20-30 seconds after that. Researched eight mice per group and were performed blind experience. The results of the study are given in the table below.

TREATMENT (mg/kg) CCThe number of mice
with LRR
Latency to LRR (min)The duration of LRR (##) (min)
mean ± standard error (#)mean ± standard error (#)p value :
Media0-0,0±0,0-
CNS 7056X besilate (20,4)2-1,7±1,3 NS0,1441
CNS 7056X besilate (27,2)5 +3,0±0,24,9±1,6 *0,0106
CNS 7056X besilate (34)6 ++1,8±0,26,0±1,9 **0,0038
CNS 7056X besilate (40,8)6 ++1,6±0,57,3±2,5 **0,0038
Mann-Whitney U experience: NS = insignificant, * = p<0,05; ** = p<0,01
Fisher's exact experience (number of mice with LRR); no indication = not significant; + = p<0,05; ++ = p<0,01
(#): not calculated, the EU and n< 3
(##): max = 90 minutes after injection

The results in the table above show that basilinna salt Form 1 has on animals short latency before losing installation of reflex and, consequently, a short time prior to anesthesia induction. In addition, the mouse quickly recover from anesthesia, as indicated by the short duration of the losing installation of reflex. Thus, this connection can provide the fast induction and recovery from anesthesia.

Example 6

Additional conditions for crystallization of Forms 2, 3 and 4

Additional conditions were tested in an attempt to reproduce reported earlier crystallization of Forms 2, 3 and 4. However, the extent reported, were significantly reduced and methodology accordingly modified as described below.

Form 2

5 mg solids were dissolved in 25 μl of methanol was added 10 μl of ethanol; the solution is then cooled at 4°C for 3 days.

Form 3

Attempts were made in three versions:

1. 5 mg solids were dissolved in 25 μl of ethanol was added 120 μl of ethyl acetate; the solution is then cooled at 4°C for 3 days.

2. 10,1 mg solids were dissolved in 300 μl of ethanol was added 120 μl of ethyl acetate; the solution is then cooled at 4°C during the course the e 3 days.

3. 2.5 mg solids were dissolved in 50 μl of ethanol milanesiana vessel was added 100 μl of ethyl acetate; the solution is then cooled at 4°C for 3 days.

Form 4

Attempts were made in three versions:

1. Pre-heated (70°C) mixture of isopropylacetate:ethanol (40%:60% V/V) was added to 5 mg of heated solids in 20 μl aliquot up until the solid did not dissolve (in total 60 μl of a mixture of solvent); the solution is then left to slowly cool to ambient temperature in thermostatic water bath initially at 70°C for a period of hours.

2. 5 mg solids were dissolved in 180 μl of preheated (50°C) mixture solvent isopropylacetate:ethanol (40%:60% V/V), and the solution was given the opportunity to slowly cool to ambient temperature in thermostatic water bath (initially at 50°C) over a period of hours.

3. 5 mg of a solid substance was dissolved in 100 μl of preheated (50°C) mixture solvent isopropylacetate:ethanol (40%:60% V/V) in milanesiana vessel, and the solution was given the opportunity to slowly cool to ambient temperature in thermostatic water bath (initially at 50°C) over a period of hours.

Each of the stages of crystallization gave a solid material zinc steel sheet, stong and plasminogen the character, in this Form 4 were given an acicular material.

Example 7

Description besilate the compounds of formula (I)

Besilate the compounds of formula (I) is chiral, and believe that he has one enantiomeric form below, i.e. is the S-enantiomer (consistent with defined later structures of crystals):

Heterocyclic structure contains imidazole ring basic nitrogen (pKa of about 5), and in pyridinium ring more weakly basic nitrogen (pKa approximately 2). Imidazole nitrogen usually is protonated in the presence of strongly acidic besilate (pKa approximately minus 0.6) in aqueous solution, and peredelnyj nitrogen potentially also protonated under the conditions of excess besilate.

It is expected that the neutral form of the free base (i.e. deprotonirovannoi) connection is somewhat lipophilic (logPthe octanol/waterapproximately 4,0), and thus obviously prefers several lipophilic environment compared to water. Moreover, she probably saves the degree of lipophilicity, even when monoprotonated (logDthe octanol/waterapproximately 2 at pH 3), although the effect besilate of counterion probably enhances this trend due to its hydrophilicity. Stepanopoulos further reduced in the case deprotonirovannoi form (logD the octanol/waterapproximately 0.6 at pH 0).

This compound also has an excess of hydrogen bond acceptors and, therefore, will be the best way to partnerstvovat with giving hydrogen bonding solvents. Thus, it is expected that this compound would prefer the solubilization in some polar organic solvents, such as alcohols, especially those that provide partially lipophilic, giving hydrogen bond environment. This is confirmed by experimental evidence (details about the used solvents are given in Example 8):

2-ethoxyethanol
SolventThe observed solubility (mg/ml)
Formamid350
Water2
The sulfoxide500
Dimethylacetamide200
1,2-ethanediol60
Dimethylformamide300
Acetonitrile>20
Methanol400
20
2,2,2-triptoreline1000
Formamid100
Acetone2
Propane-1-ol15
Propane-2-ol4,8
2-methoxyethanol167
Hexaferrite-2-ol>700
Dichloromethane<<0,3
Tetrahydrofuran2,5
Methylbenzoate2
The ethyl acetate0,2
Chloroform<<0,4
1,4-dioxane1
Soluble (>5 mg/ml), partially soluble (2.5-5 mg/ml), partially insoluble (0.5 to 2.5 mg/ml), insoluble (<0.5 mg/ml)
These values are approximate, but experimentally confirmed.

These results clearly demonstrate the good solubility of the compounds in a wide range of polar organic solvents. In particular, 2,2,2-triptorelin and hexaferrite-2-ol are both defined as a very good solvent for this connection. This is consistent with the discussion above judgments, both solvent are strong hydrogen bond donors. Similarly, significantly more lipophilic solvents are defined as poor solvents and hence as a potential antibacterial for crystallization.

Example 8

Crystallization besilate the compounds of formula (I)

Describe the various conditions that can lead to obtaining a crystalline material besilate the compounds of formula (I) Forms 1 and 2. It is considered that the conditions of crystallization, which includes as components of the solvent are alcohols or acetonitrile, with their respective compatible antibacterially or cosolvent, provide the most promising conditions for obtaining useful crystalline material. First of all use the crystallization with the use of binary solvent mixtures/antibacterial. Crystallization was performed using slow evaporation of insufficiently saturated solutions of the compounds in the solvent mixtures/antibacterial, ambient and low (4°C) temperature. Crystallization is usually observed within 3-5 days.

When the allowed number is the primary objective of the sample, all conditions of crystallization was carried out twice on a glass tablet 96-well format, and used one half of each tablet to duplicate the conditions on the other half of the tablet. Cross contamination between wells is reduced to a minimum, depending on the design. All of the test conditions were reproducible in at least two-fold repetition, with the majority giving the solid material, were suitable for further analysis.

In all cases, the equipment that was in contact with samples and environments for crystallization, were thoroughly cleaned by a variety of solvents and reagents, before you washed in ethanol and subjected to drying by blowing with the use of rich viparyayah nitrogen.

Used solvents of high quality from industrial suppliers, as described in Table 12.

Table 12
SolventSet playerNo. cat.no partyGradePurity
1,2-dichlorobenzeneRomilH177 E558470SpS>99.8%of
1,4-xyleneFluka95682429739/1puriss p.a.>99%
1,4-dioxaneRomilH297H540480SpS>99.9%of
2,2,2-triptorelineRomilH860M538412SpS>99.9%of
acetonitrileRomilH049D531490SpS>99.9%of
dimethylacetamideRomilH249B540480SpS>99.9%of
the sulfoxideRomilH280W530480SpS>99.9%of
ethanol RomilH314O533480SpS>99.8%of
the ethyl acetateRomilH346T533480SpS>99.9%of
methyl isobutyl ketoneRomilH446M539430SpS>99.9%of
n-nonanRomilH568O558450SpS>99.9%of
pentalateralFluka4602213248/1puriss p.a.>98.5%of
propane-1-olRomilH624G531460SpS>99.9%of
propane-2-olRomilH625O530480SpS>99.9%of
tetrachlorethyleneRomilH702W536450SpS>99.9%of
tetrahydrofuranRomilH718B532470SpS>99.9%of
acetoneRomilH031E559470SpS>99.9%of
chloroformRomilH135B554470SpS>99.9%of
dichloromethaneRomil- H202 projectorO554460SpS>99.9%of
dimethylformamideRomilH253T546460SpS>99.9%of
formamidRomilH351Q537480 BioPure>99.9%of
hexaferrite-2-olRomilH359H559470SpS>99.9%of
methylbenzoateFluka12460417868/1purum>98%
waterRomilH950D537480SpS>99.9%of

Visual analysis of the resulting crystalline morphology of the materials was achieved by using a binocular microscope (approximately 10×-40× magnification) with attached digital camera, using as noise and reflected light, depending on what is appropriate.

The visual characteristics of the solid material is summarized below in Table 14. Observed prevalence sheet or layered/plate morphological form or in the form of unique crystals, or in the form of spherical entities. Among them there was almost no morphological differences between cristallization conducted at ambient temperature and pri°C, except with ethanol as solvent, when the tendency of growth of spherical entities and interface type decreased with lowered temperature. It is noticeable that the use of antibacterial can significantly improve the quality of the crystalline material.

Examples of the observed images of the crystalline material presented on Fig. As illustrated in this figure, acetonitrile has a tendency to give growth areas, usually visible as a consequence of poor education centers of crystallization, and hence the growth from the surfaces of the crystals of poor quality. In contrast, 2-methoxyethanol tends to give the unusual crystals leaf/needle-like morphology.

It seems that the Form 1 is generally preferable to crystallize it in many conditions. However, it is noticed that the Form 2 was also observed in several conditions of crystallization, including small-scale similar methods of obtaining Forms 3 and 4 (described in Example 6). Form 2 is observed in conditions when there are extreme values or polarity (acetonitrile:water), or solid (n-nonan), or both (dimethylsulfoxid:1,2-dichlorobenzene). Usually crystals of Form 2 were notable for their superior quality and obviously well-formed plate/layered features.

Determine the cell Defrag the AI of x-rays in single crystal

To provide supporting evidence generated by the crystal form was determined by the basic parameters of a number of crystals of suitable quality using x-ray diffraction single crystal. Basic parameters of single crystal was determined using a diffractometer Carr CCD with Mo radiation, the crystal was mounted on a glass fiber with oil and kept at 260 K. the Parameters for the Form 1 and Form 2 are defined as shown in Table 13.

Table 13
Basic parameters defined for crystals besilate the compounds of formula (I)
Form 1Form 2
The state of the crystals
Solvent2-methoxyethanolethanol
Antibacterial/
The co-solvent
pentalateralthe ethyl acetate
Morphology of crystalsneedleplate
The crystal size (mm)0,8×0,04×0,020,7×0,3×0,25
Colorcolorlesscolorless
Crystal structure
Systemmonoclinicorthorhombic
A single element a (Å)7,6868(1)8,92130(10)
b (Å)29,2607(5)11,1536(2)
c (Å)12,3756(3)25,8345(4)
α (°)9090
β (°)97,7880(8)90
γ (°)9090
Volume (Å3)2757,86(9)2570,65(7)

The results of crystallization under the conditions of Mesa solvent/co-solvent and solvent/antibacterial for besilate the compounds of formula (I) with the results of a single element by x-ray diffraction single crystal are shown in Table 14.

Table 14
The results of experimental crystallization under the conditions
mixtures of the solvent/co-solvent and solvent/antibacterial for the compounds of formula (I) with the results of a single element x-ray diffraction single crystal (the results of x-ray radiation
for crystallization in environmental conditions
if not specified otherwise).
The observed crystalsX-rays
SolventWith/antibacterial
(and conditions)
FormForm (Number and
feature crystals)
methanolethanol (4°C, 3 days)Blade(blade) and plate2 (6-ugolin.,blade)
ethanolethyl acetate (at 4°C, 3 days)blade and plate2(4 plates)
ethanol the ethyl acetateblade and plate2(6 plates)
isopropylacetateethanol(70°C→20°C)blades, plates and needles2(2-plate)
isopropylacetateethanol(50°C→20°C)blade and plate2 (6-Pollet-HN, 2 plates, 2 blade)
ethanolmethylisobutylketone (at 4°C, 3 days, milanesiana vials)table plate2(3 plates)
ethanolp-cYmen
(at 4°C, 3 days, milanesiana vials)
plate and tableteers. the layer.2(table 2)
Noonanno (milanesiana vials)blade and plate2(plate)
the sulfoxide1,2-dichlorobenzenefused tree blade one huge tableteers. plate2(table)
dimethylacetamidemethyl isobutyl ketoneplate fragments1(blade)
dimethylacetamidetetrachlorethylenefused blade1(2 blade)
acetonitrilewaterinterface2(table 2)
acetonitrile3-methylbutane-1-oltriangular plates, fragments and dendrites1(blade)
acetonitrile1,2-dichlorobenzenespherolite blade1(2 blade)
acetonitrilepentalateralspherolite blade1(blade)
methanolnothe interface plate 2(plate)
methanol3-methylbutane-1-oltriangular plate
and fragments
1(2 blade)
methanolmethyl isobutyl ketonefragments
and blade
1(blade)
2,2,2-triptoreline1,2-dichlorobenzeneinterface and opaque and translucent blade1(trance, blade)
2,2,2-triptoreline1,4-xyleneplate fragments1 (sferic., plate)
ethanolmethyl isobutyl ketonethe front end plate(5°C:tab-personal and plate)1(interface),2(table)
ethanol1,2-dichlorobenzenethe front end plate(5°C:igol-striated crystals)2(plate)
ethanol tetrachlorethyleneinterface (5°C: hexagonal cablecompany
plate)
2(blade 4°C)
ethanol1,4-xyleneinterface blade1(blade)
propane-1-olnoplate fragments1(plate)
propane-1-ol1,2-dichlorobenzeneinterface1(blade)
propane-1-oltetrachlorethyleneplate fragments and interface1(blade)
propane-2-ol1,2-dichlorobenzenefan-shaped needle tree and crystals1(blade)
propane-2-oln-nonanblade, needle crystals and spherolite needle crystals1(needle crystals is Art.)
2-methoxyethanolwaterblade1(2 blade)
2-methoxyethanolpentalateralneedle crystals1(blade)
2-methoxyethanol1,4-xyleneblade and needle crystals1(blade)
2-methoxyethanoln-nonanblade and tree crystals1(blade)
tetrahydrofuranwaterplate1(plate)
tetrahydrofuran3-methylbutane-1-olfused blade1(plate)
tetrahydrofuran1,2-dichlorobenzeneprismatic table, slices, powder2(table 3)
tetrahydrofuranthe ethyl acetatetree crystals, interface2(plate 4°C)
tetrahydrofuranisopropylacetatefused plate and accreted blade1(plate)
tetrahydrofuran1,3-xylenefused blade1(blade)
1,4-dioxanepentalateraltriangular plates, some spherulites1(2 trapolin. plate)
1,4-dioxane1,4-xyleneblade1(blade)

Managed to determine the full crystal structure x-ray diffraction on a single crystal for different crystals of suitable quality and get the full structure for Forms 1 and 2. The structure of these crystals are reported in Examples 9 and 10.

Example 9

Crystal structure of Form 1

Crystals besilate connection forms the crystals (I), grown from a solution mixture of 2-methoxyethanol:pentalateral, which have the form of needles, depicted on Fig.

Selected single crystal acicular shape (size approximately 0.8×0,04×0.02 mm) and determined its basic parameters at 260 K, and then at 190 K. At lower temperatures between 260-190 To there was no transition. The analyzed structure is given here for the data at 190 K, the parameters of the crystal and x-ray diffraction cleaning are given in Table 15.

Table 15
Data are grown in a mixture of 2-methoxyethanol:pentalateral crystals besilate the compounds of formula (I), Form 1
The state of the crystals
CodeCNS7056 besylate
Solvent2-methoxyethanol
Antibacterial/co-solventpentalateral
Morphology of crystalsneedle
The crystal size (mm)0,8×0,04×0,02
Colorbest is to maintain
Crystal structure
FormulaC54H50Br2N8O10S2
Weight formula1194,98
Systemmonoclinic
Space groupP 21
A single element a (Å)7,6868(1)
b (Å)29,2607(5)
c (Å)12,3756(3)
α (°)90
β (°)97,7880(8)
γ (°)90
Volume (Å3)2757,86(9)
Z (number of molecules in the cell)2
Z' (No. of molecules in asymmetric unit)2
Density (g cm3)1,439
Adsorption µ [MoKα](mm-1)1,610
F(000)1224
A set of Data
Temperature (K)190
Devicediffractometer Kappa CCD
Scan typeω
Type adsorption correctionmultiresource
No. of measured reflections9868
No. of independent reflections9848
θ min/max (°)1,80/27,49
h min/max-9/9
k min/max-37/36
l min/max-15/15
Clean
CleanupF
l/σ(I) Off3
No. of used reflectionsof 6,821
No. of options686
R factor (%)6,34
Rw factor (%)6,39
S1,00
Δρ(minimum) Å-3-0,8
Δρ(maximum) Å-30,8
Max. for example. error0,0005
Print option0,027(11)

The contents of the asymmetric link shown in Fig. It consists of two independent molecules connection and two independent counterions besilate. Each connection has a protonated imidazole nitrogen.

Flack “Enantiopole” parameter was defined as 0.03 in(1), and, thus, depicted here, the stereochemistry of the structures completely installed and is consistent with the implied connection stereochemistry:

Crystallographic coordinates and other relevant data are given in the form of a SHELX file in Table 17.

Conformational disorder can be represented (in first approximation) "thermal ellipsoids" atomic positions, as shown in Fig. You can see that the main area of confusion lies in methyl groups and besilate.

The difference between the two independent molecules is the result mainly of ester chains, as shown in Fig. One molecule has an ester chain, which is coplanar with the imidazole ring, while the other molecule has an ester chain, which is orthogonal.

The conformation of the ester chain is different from the conformation adopted in the Form 2 (Fig). Orthogonal conformation observed in the Form 1 has the greatest similarity to the conformation found in the Form 2.

Two independent besilate have crossed conformation (Fig). The bond lengths shows no significant differences.

One besilate adopts the conformation observed for besilate in the form 2 (Fig).

Split the crystal structure viewed along the crystallographic axes a, b and C, illustrated in Figa, b and C, respectively. Fig summarizes the shortest contacts observed in the crystal packing.

Each connection interacts with two independent besilate. In particular, a short distance (type hydrogen bonds) are set is moved between one oxygen atom of one besilate and protonated nitrogen of the imidazole ring compounds. The second independent connection interacts similarly, but with the second independent basicatom.

Other close contacts (C-O, H-O) are observed between compounds and besilate mainly close imidazole and peredelnogo rings. Some close contacts are also observed between the two compounds (Br-N, C-C, O-H) and by two besilate (O-N contacts), but for the latter to a lesser extent.

Using a specific experimental crystal structure calculated nature of powder diffraction to Form 1 using CrystalDiffract® (CrysralDiffract is a registered trademark of the firm CrystalMaker Ltd) and is depicted on Fig. Given the nature of the powder corresponds to the experimental nature of the powder reported for a Form 1.

Example 10

Crystal structure of Form 2

Crystal Form 2 besilate the compounds of formula (I)which is in the form of plates, shown on Fig.

Selected single crystal plate (size approximately 0.7×0,30×0.25 mm) and determined its basic parameters at 260 K, and then at 190 K. At lower temperatures between 260-190 To there was no transition. The analyzed structure is given here for the data at 190 K, the parameters of the crystal and x-ray diffraction cleaning are given in Table 16.

Table 16
Data are grown in a mixture of ethanol:ethyl acetate crystals besilate the compounds of formula (I), Form 2.
The state of the crystals
CodeCNS7056 besylate
Solventethanol
Antibacterial/co-solventthe ethyl acetate
Morphology of crystalsplate
The crystal size (mm)0,7×0,30×0,25
Colorcolorless
Crystal structure
FormulaC27H25Br1N4O5S1
Weight formula597,49
SystemOrthorhombic
Space groupP 21212 1
A single element a (Å)8,92130(10)
b (Å)11,1526(2)
c (Å)25,8345(4)
α (°)90
β (°)90
γ (°)90
Volume (Å3)2570,65(7)
Z (number of molecules in the cell)4
Z' (No. of molecules in asymmetric unit)1
Density (g cm3)1,544
Adsorption µ [MoKα](mm-1)1,727
F(000)1224
A set of data
Temperature (K)190
Devicediffractometer Kappa CCD
Scan typeω
Type adsorption correctionmulti-scan
No. of measured reflections5750
No. of independent reflections5727
θ min/max (°)5,15/27,48
h min/max-11/11
k min/max-14/14
l min/max-33/33
Clean
CleanupF
l/σ(I) off3
No. of used reflections4067
No. of options344
R factor (%)3,85
Rw factor (%)3,66
S1,12
Δρ(minimum) Å-3and-0.6
Δρ(maximum) Å-30,5
Max. for example. error0,0003
Print option0,011(9)

The contents of the asymmetric link shown in Fig. It consists of one independent molecule compounds and one independent besilate. The compound is protonated imidazole nitrogen.

Flack “Enantiopole” parameter was defined as 0,011(9), and, thus, depicted here, the stereochemistry of the structures completely installed and is consistent with the implied connection stereochemistry. Crystallographic coordinates and other relevant data are given in the form of a SHELX file in Table 18.

Conformational disorder can be represented (in first approximation) “thermal ellipsoids” atomic positions, as shown in Fig. You can see that the main area of confusion lies in besilate.

As discussed above, the conformation of the ester chain in the Form of 2, depicted on Fig differs from the conformation adopted in the Form of 1.

However, the conformation besilate is similar to the conformation observed for one of besilate in the Form 1 (Fig).

The structure of the split crystal viewed along the crystallographic axes a, b and C, the sludge is astronuats on Figa, b and C, respectively, and Fig summarizes the shortest contacts observed in the crystal packing. A connection establishes a short contact (type hydrogen bonds with one oxygen atom besilate through its protonated imidazole nitrogen of the ring. Other short contacts (C-C, C-O, H-O) are observed between Union and basicatom on the imidazole ring.

Some close contacts are also observed between the two compounds (Br-S, C-C, O-C, O-H), most of which through the ester chain. Among besylate no close contacts.

Using a specific experimental crystal structure calculated nature of powder diffraction to Form 2 using CrystalDiffract® (Fig). Given the nature of the powder corresponds to the experimental nature of the powder reported for Form 2.

Table 17
Crystallographic coordinates and other relevant data are given in the table in the form of a SHELX file for besilate Form 1 of Compound of formula (I).

Table 18
Crystallographic coordinates and other relevant data are given in the table in the form of a SHELX file for besilate Form 2 of Compound of formula (I)

td align="center"> C89 1,500(9)Å
Table 19
The bond length for besilate Form 1 of Compound of formula (I)
S80O811,454(5)ÅS80O821,468(5)Å
S80O831,432(6)ÅS80C841,784(7)Å
C84C851,376(12)ÅC841,318(12)Å
C85C861,408(14)ÅC85H8510,927Å
C86C871,360(16)ÅC86H8610,936Å
C87C881,310(15)ÅC87H8710,934Å
C88C891,386(14)ÅC88H8810,935Å
C89H8910,932ÅS90O911,459(5)Å
S90O921,454(6)ÅS90O93 1,431(5)Å
S90C941,793(8)ÅC94C951,383(11)Å
C94C991,354(11)ÅC95C961,356(13)Å
C95H9510,938ÅC96C971,428(17)Å
C96H9610,934ÅC97C981,323(15)Å
C97H9710,924ÅC98C991,409(13)Å
C98H9810,927ÅC99H9910,924Å
Br1C21,886(6)ÅC2C31,382(9)Å
C2C71,381(9)ÅC3C41,358(10)Å
C3H310,928ÅC4C51,388(9)Å
C4H410,937ÅC5C61,398(9)Å
C5N181,454(8)ÅC6C7KZT 1,394(9)Å
C6C81,498(9)ÅC7H710,926Å
C8C9C8N151,274(8)Å
C9N10up 1.343(9)ÅC9C141,386(9)Å
N10C111,345(10)ÅC11C121,379(11)Å
C11H1110,933ÅC12C131,375(11)Å
C12H1210,927ÅC13C141,351(10)Å
C13H1310,918ÅC14H1410,921Å
N15C161,492(9)ÅC16C171,500(9)Å
C16C231,511(9)ÅC16H1610,988Å
C17N181,352(8)ÅC17N211,315(8)Å
N18C191,400(8)ÅC19C201,344(9)Å
C19C221,496(9)ÅC20N211,376(8)Å
C20H2010,927ÅN21H2111,000Å
C22H2210,958Å C22H2220,950Å
C22H2230,953ÅC23C241,536(11)Å
C23H2310,962ÅC23H2320,969Å
C24C251,470(11)ÅC24H2410,971Å
C24H2420,962ÅC25O261,202(10)Å
C25O271,354(10)ÅO27C281,445(10)Å
C28H2811,000ÅC28 H2821,000Å

C28H2831,000ÅBr51C521,886(7)Å
C52C531,366(11)ÅC52C571,412(10)Å
C53C541,404(11)ÅC53H5310,927Å
C54C551,383(10)ÅC54H5410,921Å
C55C561,414(9)ÅC55N681,427(9)Å
C56C571,396(9)Å C581,489(9)Å
C57H5710,925ÅC58C591,530(10)Å
C58N651,254(8)ÅC59N601.314 GC(9)Å
C59C641,391(10)ÅN60C611,372(10)Å
C61C621,386(14)ÅC61H6110,918Å
C62C631,355(15)ÅC62H6210,928Å
C63C641,378(13)ÅC63 H6310,932Å
C64H6410,917ÅN65C66of 1.485(8)Å
C66C671,474(9)ÅC66C731,516(10)Å
C66H6610,982ÅC67N681,354(9)Å
C67N711,334(8)ÅN68C691,406(9)Å
C69C70up 1.343(11)ÅC69C721,484(12)Å
C70N711,366(10)ÅC70H701 0,925Å
N71H7111,000ÅC72H7210,964Å
C72H7220,958ÅC72H7230,965Å
C73C741,535(10)ÅC73H7310,975Å
C73H7320,967ÅC74C751,493(12)Å
C74H7410,972ÅC74H7420,977Å
C75O761,185(9)ÅC75O771,360(9)Å
O77C781,440(11)ÅC78H7810,965Å
C78H7820,966ÅC78H7830,960Å

Table 20
The angles for besilate Form 1 of Compound of formula (I)
O81S80O82111,0(3)°O81S80O83112,9(4)°
O82S80O83to 114.4(4)°O81S80C84105,5(3)°
O82S80C841062(3)° O83S80C84to 106.0(4)°

C96
S80C84C85117,7(6)°S80C84C89123,6(7)°
C85C84C89118,3(8)°C84C85C86120,0(9)°
C84C85H851119,626°C86C85H851120,377°
C85C86C87118,1(10)°C85C86H861120,636°
C87C86H861121,303°C86C87C88the level of 121.8(10)°
C86C87H871119,251°C88C87H871118,984°
C87C88C89119,3(10)°C87C88H881120,392°
C89C88H881120,264°C84C89C88122,5(10)°
C84C89H891118,485°C88C89H891 119,061°
O91S90O92111,7(3)°O91S90O93112,8(4)°
O92S90O93113,5(3)°O91S90C94104,5(3)°
O92S90C94105,7(3)°O93S90C94108,0(3)°
S90C94C95120,6(6)°S90C94C99120,1(6)°
C95C94C99119,3(8)°C94C95to 121.6(9)°
C94C95H951118,566°C96C95H951119,820°
C95C96C97118,4(10)°C95C96H961119,911°
C97C96H961121,695°C96C97C98119,9(8)°
C96C97H971119,699°C98C97H971120,397°
C97C98C99120,8(9)°C97 C98H981119,080°
C99C98H981120,094°C94C99C98119,9(9)°
C94C99H991119,276°C98C99H991120,819°
Br1C2C3to 121.0(5)°Br1C2C7118,5(5)°
C3C2C7of 120.5(5)°C2C3C4119,7(6)°
C2C3H31120,203° C4C3H31120,109°
C3C4C5120,6(6)°C3C4H41120,600°
C5C4H41118,766°C4C5C6120,6(6)°
C4C5N18119,6(5)°C6C5N18to 119.8(6)°
C5C6C7117,8(6)°C5C6C8123,3(6)°
C7C6C8 118,8(6)°C2C7C6120,6(6)°
C2C7H71119,721°C6C7H71119,679°

H161
C6C8C9117,5(5)°C6C8N15126,6(6)°
C9C8N15115,9(6)°C8C9N10USD 114.9(6)°
C8C9C14121,2(6)°N10C9C14123,9(6)°
C9N10C11115,5(6)°N10C11C12to 124.4(7)°
N10C11H111118,526°C12C11H111117,061°
C11C12C13117,4(7)°C11C12H121121,279°
C13C12H121121,289°C12C13C14to 120.4(6)°
C12C13H131119,499°C14C13H131 120,125°
C9C14C13118,3(6)°C9C14H141120,274°
C13C14H141121,419°C8N15C16118,0(5)°
N15C16C17105,9(5)°N15C16C23109,4(5)°
C17C16C23to 112.4(5)°N15C16H161110,723°
C17C16H161109,539°C23C16108,851°
C16C17N18the 122.7(6)°C16C17N21130,3(6)°
N18C17N21106,5(5)°C5N18C17123,1(5)°
C5N18C19127,0(5)°C17N18C19109,8(5)°
N18C19C20105,2(5)°N18C19C22125,3(6)°
C20C19C22129,4(6)°C19 C20N21108,0(5)°
C19C20H201126,017°N21C20H201126,026°
C17N21C20110,5(5)°C17N21H211124,840°
C20N21H211124,681°C19C22H221109,508°
C19C22H222109,778°H221C22H222108,808°
C19C22H223110,905° H221C22H223108,786°
H222C22H223109,018°C16C23C24112,3(6)°
C16C23H231109,392°C24C23H231108,812°
C16C23H232108,378°C24C23H232109,105°
H231C23H232108,825°C23C24C25114,3(7)°
C23C24H241 109,968°C25C24H241110,030°
C23C24H242108,195°C25C24H242105,346°
H241C24H242108,752°C24C25O26126,4(7)°

C58 112,017°
C24C25O27109,4(7)°O26C25O27123,9(7)°
C25O27C28115,2(7)°O27C28H281109,674°
O27C28H282109,261°H281C28H282109,475°
O27C28H283109,465°H281C28H283109,476°
H282C28H283109,476°Br51C52C53119,3(6)°
Br51C52C57119,0(5)°C53C52C57121,7(7)°
C52C53C54118,9(7)°C52C53H531 120,141°
C54C53H531120,985°C53C54C55119,8(7)°
C53C54H541120,227°C55C54H541120,000°
C54C55C56122,1(6)°C54C55N68119,4(6)°
C56C55N68118,5(6)°C55C56C57117,2(6)°
C55C56C58of 123.2(6)°C57C56119,5(6)°
C52C57C56120,2(7)°C52C57H571119,709°
C56C57H571120,138°C56C58C59116,5(6)°
C56C58N65a 126.7(6)°C59C58N65116,8(6)°
C58C59N60116,3(6)°C58C59C64118,5(7)°
N60C59C64125,0(7)°C59 N60C61116,1(7)°
N60C61C62121,7(8)°N60C61H611119,342°
C62C61H611118,993°C61C62C63120,6(8)°
C61C62H621120,029°C63C62H621119,353°
C62C63C64118,4(9)°C62C63H631120,452°
C64C63H631121,124° C59C64C63118,1(8)°
C59C64H641120,844°C63C64H641121,057°
C58N65C66118,2(6)°N65C66C67105,4(5)°
N65C66C73109,7(5)°C67C66C73111,5(6)°
N65C66H661109,122°C67C66H661108,890°
C73C66H661C66C67N68the level of 121.8(6)°
C66C67N71130,3(7)°N68C67N71107,4(6)°
C55N68C67122,5(6)°C55N68C69128,7(6)°
C67N68C69108,7(6)°N68C69C70105,5(6)°

N68C69C72124,0(7)°C70C69C72130,5(7)°
C69C70N71109,1(6)°C69C70H701125,444°
N71C70H701125,502°C67N71C70109,2(6)°
C67N71H711125,400°C70N71H711125,366°
C69C72H721110,667°C69C72H722109,838°
H721C72H722108,539°C69C72H723 110,831°
H721C72H723108,455°H722C72H723108,445°
C66C73C74111,0(6)°C66C73H731108,535°
C74C73H731110,248°C66C73H732110,751°
C74C73H732108,249°H731C73H732108,042°
C73C74C75to 112.4(6)°C73C74 H741108,496°
C75C74H741109,125°C73C74H742108,155°
C75C74H742108,578°H741C74H742110,035°
C74C75O76126,2(7)°C74C75O77to 110.7(7)°
O76C75O77123,0(7)°C75O77C78115,6(7)°
O77C78H781109,214° O77C78H782109,848°
H781C78H782109,923°O77C78H783109,687°
H781C78H783109,026°H782C78H783109,127°

Table 21
The bond length for besilate Form 2 of Compound of formula (I)
Br1C21,892(3)ÅC2C31,387(5)Å
C2C71,383(5)ÅC3C4 1,371(5)Å
C3H310,938ÅC4C51,392(5)Å
C4H410,921ÅC5C61,406(4)Å
C5N181,428(4)ÅC6C71,395(5)Å
C6C81,497(4)ÅC7H710,924Å
C8C91,497(4)ÅC8N151,276(4)Å
C9N101,338(4)ÅC9C141,395(5)Å
N10C111,345(4)ÅC11C121,378(5)Å
C11H1110,935ÅC12C131,370(5)Å
C12H1210,948ÅC13C141,382(5)Å

C13H1310,936ÅC14H1410,934Å
N15C161,478(4)ÅC16C171,487(5)Å
C16C231,527(5)ÅC16H1610,976Å
C17N181,346(4)ÅC17N211,320(4)Å
N18C191,391(4)ÅC19C201,342(5)Å
C19C221,494(5)ÅC20N211,378(5)Å
C20H2010,912ÅN21H2110,854Å
C22H2210,965ÅC22H2220,966Å
C22H2230,960ÅC23C241,534(5)Å
C2 H2310,969ÅC23H2320,981Å
C24C251,478(5)ÅC24H2410,960Å
C24H2420,988ÅC25O261,201(4)Å
C25O271,342(4)ÅO27C281,451(5)Å
C28H2810,964ÅC28H2820,965Å
C28H2830,962ÅS80O811,431(3)Å
S80O82 1,447(3)ÅS80O831,430(3)Å
S80C841,774(4)ÅC84C851,400(7)Å
C84C891,369(7)ÅC85C861,380(7)Å
C85H8510,932ÅC86C871,342(13)Å
C86H8610,943ÅC87C881,410(13)Å
C87H8710,934ÅC88C891,433(10)Å
C88H881 0,925ÅC89H8910,940Å

N18
Table 22
The angles for besilate Form 2 of Compound of formula (I)
Br1C2C3119,3(3)°Br1C2C7118,9(3)°
C3C2C7the level of 121.8(3)°C2C3C4119,0(3)°
C2C3H31120,033°C4C3H31120,959°
C3C4C5to 120.3(3)° C3C4H41119,485°
C5C4H41120,261°C4C5C6to 121.0(3)°
C4C5N18118,9(3)°C6C5N18120,1(3)°
C5C6C7118,2(3)°C5C6C8122,3(3)°
C7C6C8119,5(3)°C2C7C6119,7(3)°
C2C7H71C6C7H71119,874°
C6C8C9117,7(3)°C6C8N15to 124.4(3)°
C9C8N15to 117.9(3)°C8C9N10116,6(3)°
C8C9C14120,0(3)°N10C9C14123,4(3)°
C9N10C11of 116.7(3)°N10C11C12123,7(3)°
N10C11 H111117,041°C12C11H111119,278°
C11C12C13118,8(3)°C11C12H121120,443°
C13C12H121120,783°C12C13C14119,3(3)°
C12C13H131120,694°C14C13H131119,952°
C9C14C13118,1(3)°C9C14H141120,942°
C13 C14H141120,983°C8N15C16117,6(3)°
N15C16C17105,7(3)°N15C16C23110,8(3)°
C17C16C23by 115.7(3)°N15C16H161107,681°
C17C16H161107,726°C23C16H161108,910°
C16C17N18120,7(3)°C16C17N21131,2(3)°
C17N21108,0(3)°C5N18C17122,3(3)°
C5N18C19of 128.6(3)°C17N18C19109,0(3)°
N18C19C20105,7(3)°N18C19C22124,9(3)°
C20C19C22to 129.3(3)°C19C20N21108,6(3)°
C19C20H201127,007°N21C20H201 124,433°
C17N21C20108,7(3)°C17N21H211125,926°
C20N21H211125,351°C19C22H221110,223°
C19C22H222109,368°H221C22H222108,664°
C19C22H223111,184°H221C22H223109,452°
H222C22H223107,885°C16C23 C24107,9(3)°
C16C23H231107,712°C24C23H231110,073°
C16C23H232111,123°C24C23H232109,430°
H231C23H232110,583°C23C24C25118,8(3)°
C23C24H241107,661°C25C24H241104,516°
C23C24H242109,365° C25C24H242106,503°

H241C24H242109,671°C24C25O26123,3(3)°
C24C25O27to 114.4(3)°O26C25O27122,4(3)°
C25O27C28the 115.2(3)°O27C28H281108,952°
O27C28H282110,269°H281C28H282109,738°
O27C28 H283108,681°H281C28H283110,225°
H282C28H283108,963°O81S80O82111,9(2)°
O81S80O83or 115.1(2)°O82S80O83of 111.2(3)°
O81S80C84106,30(18)°O82S80C84104,5(2)°
O83S80C84107,0(2)°S80C84C85117,6(4)°
S8 C84C89122,1(4)°C85C84C89120,2(5)°
C84C85C86to 121.6(6)°C84C85H851119,148°
C86C85H851119,275°C85C86C87117,5(8)°
C85C86H861121,859°C87C86H861120,606°
C86C87C88124,9(7)°C86C87H871 117,763°
C88C87H871117,376°C87C88C89116,0(7)°
C87C88H881122,592°C89C88H881121,435°
C84C89C88119,8(8)°C84C89H891120,080°
C88C89H891120,078°

1. Basilinna salt of the compounds of formula (I)

2. Salt according to claim 1, which is a crystalline salt.

3. Basilinna salt according to claim 2, which is crystallic the ski polymorph Form 1, which manifests the nature of the powder x-ray diffraction (XRPD), including characteristic peaks at about 7,3, 7,8, 9,4, 12,1, 14,1, 14,4, 14,7 and 15.6 degrees two-theta.

4. Basilinna salt according to claim 2 or 3, which is a crystalline polymorph Form 1, including crystals with dimensions of the unit cell, a=7,6868 Å, b=29,2607 Å, C=12,3756 Å, α=90°, β=97,7880°, γ=90°.

5. Basilinna salt according to claim 2 or 3, which is a crystalline polymorph Form 1 having a crystal structure defined by the structural coordinates shown in the Table below:





6. Basilinna salt according to claim 2 or 3, which is a crystalline polymorph Form 1 having a crystal structure with lengths of strips and angles shown in the following Tables:
The length of the stripes:


Corners:

7. Basilinna salt according to claim 2, which is a crystalline polymorph Form 2, which shows the character of XRPD, including characteristic which peaks at about 8,6, 10,5, 12,0, 13,1 and 15.9 degrees two-theta.

8. Basilinna salt according to claim 2, which is a crystalline polymorph Form 2, including crystals with dimensions of the unit cell, a=8,92130 Å, b=11,1536 Å, C=25,8345 Å, α=90°, β=90°, γ=90°.

9. Basilinna salt according to claim 2, which is a crystalline polymorph Form 2 having a crystal structure defined by the structural coordinates shown in the Table below:



10. Basilinna salt according to claim 2, which is a crystalline polymorph Form 2 having a crystal structure with lengths of strips and angles shown in the following Tables:
The length of the stripes:

Corners

11. Basilinna salt according to claim 2, which is a crystalline polymorph besilate salt Form 3 the compounds of formula (I), which manifests the nature of the powder x-ray diffraction (XRPD), including characteristic peaks at 7,6, 11,2, 12,4, 14,6, 15,2, 16,4 and 17.7 degrees two-theta.

12. Basilinna salt according to claim 2, which is a crystalline polymorph besilate salt forms of 4 compounds of formula (I), which manifests the nature of XRPD, on the expectation by typical peaks at about 7.6, 10,8, 15,2, 15,9 and 22.0 degrees two-theta.

13. Pharmaceutical composition for the production of the subject sedation, hypnosis, anxiolysis, muscle relaxation or treat convulsions containing salt according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier, excipient or diluent.

14. Salt according to claim 1 for use as a drug to produce the subject sedation, hypnosis, anxiolysis, muscle relaxation or treat convulsions.

15. The use of sedative or hypnotic amount of salt according to any one of claims 1 to 12 for medicines for producing the subject sedation or hypnosis.

16. The use of anxiolytic amount of salt according to any one of claims 1 to 12 for medicines for producing the subject anxiolysis.

17. Application musicmarketing amount of salt according to any one of claims 1 to 12 for medicines for producing the subject muscle relaxation.

18. The use of anticonvulsive amount of salt according to any one of claims 1 to 12 to obtain drugs for the treatment of the subject convulsions.

19. The method of obtaining salt according to claim 1, including the interaction of the free base of the compounds of formula (I) with benzosulfimide acid.

20. The method according to claim 19, which includes contacting free the warping with benzosulfimide acid in solution, causing precipitate formation besilate salt.

21. The method according to claim 20, which further includes a sludge separation.

22. The method according to claim 20 or 21 to obtain a crystalline salt besilate Form 1, in which the free base is dissolved in toluene or ethyl acetate.

23. The method according to claim 20, in which benzosulfimide acid dissolved in ethanol.

24. The method according to claim 20, to obtain a crystalline salt besilate Form 1 on any of PP-6, which includes the contacting of the solution of the free base of the compounds of formula (I) in toluene, ethyl acetate, acetone, isopropylacetate or ethyl formate solution benzosulfimide acid in ethanol, causing the formation of salts.

25. The method according to claim 20, to obtain a crystalline salt besilate Form 2 according to any one of claims 7 to 10, which comprises the contacting of the solution of the free base of the compounds of formula (I) in methanol with a solution of benzosulfimide acid in ethanol, causing the formation of salts.

26. A method of obtaining a crystalline salt besilate Form 3 to claim 11, which includes the persecution of the solution of the filtrate separated from the precipitate formed by the contacting of the solution of the compounds of formula (I) in ethyl acetate with a solution of benzosulfimide acid in ethanol, crystalline salt besilate Form 1 of compound of formula (I).

27. The method of obtaining crystallizes the Oh besilate salt forms of 4 to 12, which includes the recrystallization of the crystalline salt besilate Form 1 of compound of formula (I) from a mixture of 40% isopropylacetate/ethanol.

28. A method of obtaining a crystalline salt besilate Form 1 or Form 2 according to any one of claim 2 to 10, which includes crystallization besilate the compounds of formula (I) from a solvent or from a mixture of a suitable solvent/antibacterial or solvent/co-solvent.

29. Method of producing sedation or hypnosis in a subject comprising administration to the subject an effective sedative or hypnotic amount of salt according to any one of claims 1 to 12.

30. The method of induction anxiolysis the subject, including an introduction to the subject an effective anxiolytic amount of salt according to any one of claims 1 to 12.

31. Method of inducing muscle relaxation in a subject comprising administration to the subject an effective musicmarketing amount of salt according to any one of claims 1 to 12.

32. A method of treating convulsions in a subject comprising administration to the subject an effective anticonvulsive amount of salt according to any one of claims 1 to 12.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel derivatives of hexahydro pyrazino [2,1-c][1,2,4]triazine of general formula (III) (values of radicals are given in invention formula), their pharmaceutically acceptable salts and application of said compounds for obtaining medication for treatment and prevention of acute myeloid leukemia.

EFFECT: obtaining medication for treatment and prevention of acute myeloid leukemia

3 cl, 3 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted tetrahydropyrrolopyrazines of general formula I, wherein R1, R2 and R3 in each case independently mean hydrogen or groups R1 and R2 or R2 and R3 form a common cycle ; R4 and R5 in each case independently mean H; R6 means branched or unbranched saturated, unsubstituted C1-6-alkyl, or unsubstituted heteroaryl wherein heteroaryl is a 5- or 6-member aromatic residue containing 1 heteroatom specified in a group consisting of N, O and S, or means phenyl wherein phenyl is unsubstituted or single-substituted or double-substituted by 1 or 2 substitutes which in each case are independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, and , or means unsubstituted phenyl attached through C1-3-alkyl chain; R4a, R5a and R6a in each case independently mean H; R7 means (CH2)tC(=O)R8, wherein t is equal to 1, (C=O)(CH2)mNR11R12, wherein m is equal to 1 or 2, C(=O)(CH2)n(C=O)R8, wherein n is equal to 1, 2 or 3, (CH2)sNHC(=O)R8, wherein s is equal to 1 or 2; R8 means NR9R10 or saturated, branched or unbranched, unsubstituted C1-6-alkyl; wherein R9 and R10 in each case independently mean H, saturated, branched or unbranched, unsubstituted C1-6-alkyl, or unsubstituted or saturated C3-8-cycloalkyl, or phenyl, or phenyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein phenyl in each case is unsaturated or single or double saturated by 1 or 2 substitutes which independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, pyridyl, and , or unsubstituted heteroaryl attached through C1-3-alkyl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which are specified in a group consisting of O and S, wherein the alkyl chain is saturated, branched or unbranched, or heterocyclyl, or heterocyclyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein heterocyclyl in each case is saturated, unsubstituted or single substituted by benzyl, and heterocyclyl contains cycloalkyl containing 5 to 6 atoms in a cycle wherein 1 or 2 carbon atoms are substituted by 1 or 2 heteroatoms which are specified in a group consisting of N; or both groups R9 and R10 mean (CH2)3-6, CH2CH2OCH2CH2 or CH2CH2NR14CH2CH2; wherein R14 means phenyl or phenyl attached through C1-3-alkyl wherein phenyl in each case is unsaturated or single substituted by a substitute whih is specified in a group consisting of F, Cl, Br, I, O-C1-6-alkyl, and , or R14 means C(=O)R13; wherein R13 means saturated and unbranched C1-6-alkyl or means phenyl condensed with heteroaryl wherein heteroaryl is a 6-member aromatic residue 1 heteroatom of which is specified in a group consisting of N; R11 and R12 in each case independently mean H, saturated, branched or unbranched C1-6-alkyl, or unsubstituted, saturated C3-8-cycloalkyl, C(=O)R20 or S(=O)2R13; wherein R20 means NR21NR22, or R20 means saturated, branched or unbranched C1-6-alkyl, or means saturated C3-8-cycloalkyl, unsubstituted or single substituted by phenyl, or means unsaturated heteroaryl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which is specified in a group consisting of O, or means phenyl wherein phenyl is unsubstituted or single substituted by C1-6-alkyl or means phenyl attached through C1-6-alkyl which is unsubstituted or single substituted by a substitute specified in a group consisting of F, Cl, Br, I and CF3, wherein the alkyl chain is saturated or unsaturated, branched or unbranched; wherein R21 and R22 in each case independently mean H or saturated, branched or unbranched, unsubstituted C1-6-alkyl; in the form of bases and salts of physiologically acceptable acids. The invention also refers to methods for preparing them, to drug preparations for treating disorders or diseases related with at least partially KCNQ2/3 K+ canals containing such compounds.

EFFECT: there are prepared new compounds and based drug preparations which can find application in medicine for managing pain, epilepsy, migraine, panic conditions and urinary incontinence.

17 cl, 2 tbl, 91 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new bicyclic heterocyclic derivatives of general formula wherein radicals and symbols are specified in the patent claim. Said compounds are FGFR receptor (fibroblast growth factor receptor) inhibitors. The invention also refers to a method for preparing a preferential group of compounds of formula (I), to a pharmaceutical composition containing said compounds, and to the use of said compounds for treating diseases, e.g. cancer.

EFFECT: preparing the new bicyclic heterocyclic derivatives.

22 cl, 16 tbl, 422 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel bicyclic heterocyclic derivatives, which are compounds of formula where values of X1-X5, A, B, R1, R2, q are given in claim 1, as well as pharmaceutical compositions containing said compounds, and use of said compounds to treat cancer.

EFFECT: high efficiency of treatment.

22 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: described are novel azolo[1,2,4,5]tetrazine derivatives of general formula I, where Het=3,5-dimethylpyrazol-1-yl, X=N, R=cyclopropylmethylthio or pentylthio; or Het=3,5-dimethylpyrazol-1-yl, X=CH, R=isopropylthil; or Het=imidazol-1-yl, X=CH, R=H, and use of said compounds and additionally compounds of general formula (I), where Het=3,5-dimethylpyrazol-1-yl, X=N, K=cyclopentylthio; or Het=3,5-dimethylpyrazol-1-yl, X=CH, R=H or phenylthio based on disclosed activity as inhibitors of protein kinase PknA, PknB Mycobacterium tuberculosis when treating tuberculosis patients.

EFFECT: high efficiency of treatment.

2 cl, 2 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: stable fat emulsion contains prostaglandin as an active ingredient and phospholipids containing phosphatidylcholine and phosphatidyl glycerol in mass ratio 85:15 to 99.7:0.3. The fat emulsion under the invention and its active ingredient (prostaglandin) possess physical and chemical stability thereby increasing shelf life to approximately two years, and/or extended range of storage temperature to 10°C as compared with a commercially available fat prostaglandin emulsion.

EFFECT: fat emulsion under the invention enables satisfactory effectiveness even in the introduction of a low amount.

25 cl, 10 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a group of inventions involving a method and a pharmaceutical composition for reducing cardiotoxicity and/or improved survival rate after antracycline chemotherapy. A therapeutically effective amount of a pharmaceutical composition containing a compound representing V2 selective vasopressin antagonist as an active ingredient, or its pharmaceutically acceptable salt as an active ingredient is introduced simultaneously with or before the introduction of antracycline in a patient in need thereof.

EFFECT: invention provides reduced cardiotoxicity of antracyclines in reduced side effects ensured by a decreased level of serum vasopressin the abnormal content of which is typical for the patients suffering cancer, and which in turn is of paramount importance in developing congestive heart failure.

15 cl, 5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

FIELD: medicine.

SUBSTANCE: to reduce tachycardia in such patients used is ivabradin (coraxan) in dose 5-7.5 mg for 7-14 days with further supporting course in dose 5 mg to the moment of when preoperative reparation is finished.

EFFECT: application of ivabradin in preoperative period in case of manifest thyrotoxicosis instead of traditional beta-adrenoblockers makes it possible to weaken sympathetic impact on sinus node and increase chronotropic myocardium reserve, avoiding at the same time undesirable cardioplegic effects, characteristic of beta-adrenoblockers.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for prevention or treatment of inflammatory intestinal diseases (IID), which contains 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triasolo[4,5-c][1]-benzazepine, or its prodrug, preferably 2-(1-isopropoxycarbonyloxy-2-methypropyl)-7,8-dimethoxy-4(5H), 10-dioxi-2H-1,2,3-triasolo[4,5-c] [1]benzazepine, or its pharmaceutically acceptable salt; respective method of prevention or IID treatment and application of said compounds for manufacturing preventive or therapeutic substance against IID. Demonstrated is efficiency of claimed pharmaceutical composition, more powerful than sulfasalazine and prednisolon with respect to said purpose, in combination with high safety. Shown are few side effects of compounds, absence of inhibition of IL-2, IL-4, IL-5, IFN-gamma, absence of weight gain restraint resulting from treatment.

EFFECT: pharmaceutical composition in accordance with claimed invention can demonstrate powerful preventive and therapeutic action, even in case of severe form of disease with resistance to conventional therapeutic agents.

28 cl, 3 dwg, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 11-(piperazin-1-yl) dibenzo[b,f[1,4]oxazapine compounds of general formula specified below wherein the radicals are presented in the description, to their pharmaceutically acceptable salts and pharmaceutical compositions. There are also described methods for preparing said compounds.

EFFECT: compounds may be used for treating disorders, such as schizophrenia, resistant schizophrenia, bipolar disorder, psychotic depression, resistant depression, depressive conditions related to schizophrenia, treating resistant OCD, autism, senile dementia, psychotic dementia, L-DOPA-induced psychotic disorder, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleeping disorders.

39 cl, 25 ex, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of combination of (a) 13,14-dihydro-15-keta-16,16-dihalogen-derivative of prostaglandin, represented by formula (II) and (b) inhibitor of H+, K+-ATPase, which represents compound of general formula (II) in combination with pharmaceutically acceptable excipient for manufacturing pharmaceutical composition (demonstrating synergistic effect in treatment of gastrointestinal disorders), for treatment of gastrointestinal diseases and corresponding treatment method and synergistic pharmaceutical composition of the same purpose.

EFFECT: demonstrated is synergism of combination of 13,14-dihydro-15-keto-16,16-difluoroprostaglandin E1 in combination with omeprazole or lansoprazole in reduction of gastric ulcer dimensions.

15 cl, 1 dwg, 5 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely addictology, and deals with relief of alcohol abstinence syndrome by blockade of benzodiazepine receptors. For this purpose anexate is introduced intravenously. Introduction is performed twice in strict succession through fixed 3 hours in dose 0.5 mg, reaching complete reduction of main clinical manifestations of alcohol abstinence syndrome. Duration of each introduction is 3-5 minutes.

EFFECT: method ensures increase of treatment efficiency and reduction of terms of relieving psychoneurologic and somato-vegetative manifestations of alcohol abstinence.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to dentistry, and can be used in complex treatment of periodontitis. For this purpose fully used is general and local treatment with application of surgical benefits, occlusion rehabilitation, splinting and prosthetics of teeth, physical means and chemical therapeutic preparations, with additional application of daily subcutaneous injection of 1% nivalin solution.

EFFECT: method makes it possible in efficient way to restore integrity of nervous fibres in zone of periodontium recovery and optimise periodontium tissues to functional loads due to increase of sensitivity of postsynaptic membrane to acetylcholine and facilitation of cholinergic transmission in amplification and prolongation of endogenous acetylcholine action.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to homogenous pharmaceutical composition for treatment of inflammatory disorders, which contains mixture of steroid anti-inflammatory or anti-histamine active ingredient in pharmaceutically acceptable water carrier with liposome. As steroid anti-inflammatory ingredient used is budesonide or fluticasone or their pharmaceutically acceptable salt, and antihistamine preparation is represented by azelastine or its pharmaceutically acceptable salt, concentration of active ingredient in water carrier is, in fact, equal inside and outside liposomic structures and varies ±20% when concentration of active ingredient inside and outside liposomic structures is compared. Polar lipid is swellable in water and represents phospholipid or glycosphingolipid. Invention also relates to method of composition obtaining, which lies in joint mixing of polar lipid, water phase and said active ingredient and mixture homogenising. Invention also relates to method of treating inflammatory disorders, including introduction of claimed composition to individuum, suffering from or sensitive to said disorders.

EFFECT: invention ensures reduction of irritation, for instance, in case of nasal introduction of composition.

52 cl, 9 ex

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

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