Therapeutic compound citric acid salt and pharmaceutical compositions based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a polymorphic modification of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one citrate. Invention describes 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one citrate of the formula:

. Also, invention describes a pharmaceutical composition possessing antagonistic activity with respect to serotonine-1D receptor (5-HT1D) comprising the compound by claim 1 and pharmaceutically acceptable carrier, and a method for treatment of hypertension, all forms of depression and other diseases in mammals comprising administration the therapeutically effective dose of compound by claim 1 in needing mammal. Invention provides citrate that is stable in solid state and compatible with excipients in preparing preparations of definite medicines.

EFFECT: improved and valuable pharmaceutical properties of salt.

12 cl, 5 dwg, 8 tbl, 1 ex

 

The present invention relates to polymorphic modifications citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl) benzylidene]thiomorpholine-3-one

and pharmaceutical compositions based on it.

The compound 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one is an antagonist of the serotonin receptor-1D (5-HT1D) and can be used in the treatment of a number of disorders, diseases and conditions of the Central nervous system. This connection, in particular, can be used in the treatment of hypertension, all forms of depression, depression of cancer patients, depressed patients with Parkinson's disease, depression patients after myocardial infarction, subsyndromal symptomatic depression, depression in infertile women, pediatric neuropsychiatric depression, major depressive disorder, single bouts of depression, recurrent depression, child depression, caused by poor circulation, postpartum depression, dysthymia; mild, moderate or severe forms of depression with atypical features, melancholic features, psychotic features, catatonic features, or without them; seasonal emotional disorder, geriatric depression, chronic depression; disorders of regulation in the state of depression or having the AI anxiety and depression; a mixed state of depression and anxiety; mood disorders, caused by any substance; and secondary mood disorders due to a General condition, bipolar disorder, bipolar disorder in phase oppression, disorder and General anxiety, phobias, agoraphobia, anxiety when communicating, sociophobia, simple phobias, disorders in the atomized state anxiety syndrome post-traumatic stress disorder when detached consciousness of personality, premature ejaculation, violations of the act of eating disorders associated with alcohol consumption, mental anorexia, neurogenic disorders, obesity, addiction to chemical drugs and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana and benzodiazepines; histamine headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder type of disorder panic type with agoraphobia, memory disorders, dementia, amnesia, and age-related decline in cognitive abilities (ARCD), Parkinson's disease, dementia in Parkinson's disease, parkinsonism caused by antipsychotics, tardive dyskinesia, endocrine disorders, hyperprolactinaemia, vasospasm, a narrowing of the blood vessels in cerebral vascular with the tees, cerebellar ataxia, disorders of the gastrointestinal tract, including changes in contractility and secretion, negative symptoms of schizophrenia, premenstrual syndrome, syndrome fibromyalgia, stress incontinence, syndrome Tourette, trichotillomania, kleptomania, male impotence, cancer, small cell lung cancer, chronic paroxysmal of hemicrania, headache associated with vascular disorders, autism, developing deep disorder, without diagnosis (NOS), disorders Asperger's, selective mutism, chronic motor or vocal TIC, somatization, insomnia, intermittent spasmodic disorder, Pyromania, pathological gambling addiction, disorders of the control of motivation, premenstrual dysphoria, attention deficit with hyperactivity disorder (ADHD) in mammals, particularly in humans. The citrate of the present invention can also be used in the form of pharmaceutical compositions in combination with an antidepressant (SRI), inhibiting re-uptake of serotonin, for the treatment of a number of specified conditions.

Compounds that are antagonists of the receptor serotonin-1D, including 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one, especially including its hydrochloric salt, specified in the application WO 8/14433, published April 9, 1998 (corresponding to the application U.S. Ser. No. 09/254999, filed September 8, 1997, 09/733346, filed December 8, 2000, and PCT/IB01/02139, filed November 12, 2001). In these applications covered in General the present application and incorporated herein in full by reference, indicated mainly pharmaceutically acceptable acid additive salts of these compounds.

The citrate of the present invention exhibits such properties, including stability in the solid state, and compatibility with fillers, for certain drugs drugs products that allow you to achieve advantages in comparison with the known salts of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one.

BRIEF DESCRIPTION of DRAWINGS

In Fig. 1 shows a recording device-recorder with differential scanning calorimetry (DSC) citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one.

In Fig. 2 presents the observed powder x-ray citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one. (Y is a linear number of signals per second; X represents a value of 2 teta, expressed in degrees.

In Fig. 3 presents the calculated powder x-ray citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]t is morpholin-3-one. (Y is a linear number of signals per second; X represents values of 2 theta, expressed in degrees.

In Fig. 4 shows the x-ray crystal structure of citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one.

In Fig. 5 shows the NMR13With a range of solid phase citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-it is defined using thecross-polarization during the rotation of the magic angle at C, NMR spectrometer (Bruker Avance DRX with a frequency of 500 MHz on the sensor with a clearance of 7 mm

The INVENTION

The present invention relates to a citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one. The citrate of the present invention is an anhydrous or nearly anhydrous polymorph.

The citrate of the present invention is also characterized by the main peaks in the x-ray,expressed in 2θ and the distance d, measured with copper radiation(within the specified error):

4,4
Angle 2(±0,2)The value of d (E) (±2)
13,06,8
17,45,1
18,0a 4.9
18,9the 4.7
20,0
of 21.24,2
22,24,0
24,03,7
27,13,3
32,42,8

Citrate according to the invention is characterized by the fact that it usually forms flakes. In addition, the citrate is also characterized by the fact that forms monoclinic crystals belonging to space groupPc.Citrate, in addition, is characterized by having a melting point/decomposition approximately 198 - 199°S, as determined by the method of differential scanning calorimetry (DSC).Next, citrate according to the invention is characterized by the fact that it has a solubility in water of 1.3 mg/ml, and has a naturalthe pH of the aqueous solution is equal 3,37. In addition, the absorption of citrate is 1,27% at a relative humidity of 90%.

Citrate according to the invention is also characterized by the fact that, being investigated by NMR13With in solids with cross-polarization and rotation under magic angle,detects the following main resonance peaks in the lower fields from 100 ppm (±0,1 ppm relative to the standard adamantane, when29 ppm):d 179,3, 177,0,171,6, 164,0, 151,0 and 144,1.

Another embodiment of the invention relates to pharmaceutical compositions containing citrate 4-(3,4-dichlorophenyl)-2-[2-(methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one and pharmaceutically acceptable carrier or excipient, in particular, compositions for use in the treatment of hypertension, all forms of depression, depression of cancer patients, depressed patients with Parkinson's disease, depression patients after myocardial infarction, subsyndromal symptomatic depression, depression in infertile women, pediatric neuropsychiatric depression, major depressive disorder, single bouts of depression, recurrent depression, child depression, caused by poor circulation, postpartum depression, dysthymia; mild, moderate or severe forms of depression with atypical features, melancholic features, psychotic features, catatonic features, or without them; seasonal emotional disorder, geriatric depression, chronic depression; disorders regulation at the state of depression or anxiety and depression; a mixed state of depression and anxiety; mood disorders, caused by any substance; and secondary mood disorders due to a General condition, bipolar disorder, bipolar disorder in phase oppression, disorder and General anxiety, phobias, agoraphobia, anxiety when communicating, sociophobia, simple phobias, disorders in the atomized state anxiety syndrome post traumatic stress disorder, RA the disorder when detached consciousness of personality premature ejaculation, violations of the act of eating disorders associated with alcohol consumption, mental anorexia, neurogenic disorders, obesity, addiction to chemical drugs and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana and benzodiazepines; histamine headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder type of disorder panic type with agoraphobia, memory disorders, dementia, amnesia, and age-related decline in cognitive abilities (ARCD), Parkinson's disease, dementia in Parkinson's disease, parkinsonism induced by neuroleptics, tardive dyskinesia, endocrine disorders, hyperprolactinaemia, vasospasm, a narrowing of the blood vessels in the cerebral vasculature, cerebellar ataxia, disorders of the gastrointestinal tract, including changes in contractility and secretion, negative symptoms of schizophrenia, premenstrual syndrome, syndrome fibromyalgia, stress incontinence, syndrome Tourette, trichotillomania, kleptomania, male impotence, cancer, small cell lunglung cancer, chronic paroxysmal of hemicrania, headache associated with vascular disorders, autism, developing deep disorder, without UTO is in diagnosis (NOS), disorders Asperger's, selective mutism, chronic motor or vocal TIC, somatization, insomnia, intermittent spasmodic disorder, Pyromania, pathological gambling addiction, disorders of the control of motivation, premenstrual dysphoria, attention deficit with hyperactivity disorder (ADHD) in mammals, particularly in humans.

The present invention also relates to methods for treating hypertension, all forms of depression, depression of cancer patients, depressed patients with Parkinson's disease, depression patients after myocardial infarction, subsyndromal symptomatic depression, depression in infertile women, pediatric neuropsychiatric depression, major depressive disorder, single bouts of depression, recurrent depression, child depression, caused by poor circulation, postpartum depression, dysthymia; mild, moderate or severe forms of depression with atypical features, melancholic features, psychotic features, catatonic features, or without them; seasonal emotional disorder, geriatric depression, chronic depression; disorders of regulation in the state of depression or anxiety and depression; a mixed state of depression and anxiety; mood disorders, due to the Kim-any substance; and secondary mood disorders due to a General condition, bipolar disorder, bipolar disorder in phase oppression, disorder and General anxiety, phobias, agoraphobia, anxiety when communicating, sociophobia, simple phobias, disorders in the atomized state anxiety syndrome post-traumatic stress disorder when detached consciousness of personality, premature ejaculation, violations of the act of eating disorders associated with alcohol consumption, mental anorexia, neurogenic disorders, obesity, addiction to chemical drugs and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana and benzodiazepines; histamine headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder type of disorder panic type with agoraphobia, memory disorders, dementia, amnesia, and age-related decline in cognitive abilities (ARCD), Parkinson's disease, dementia in Parkinson's disease, parkinsonism caused by antipsychotics, tardive dyskinesia, endocrine disorders, hyperprolactinaemia, vasospasm, a narrowing of the blood vessels in the cerebral vasculature, cerebellar ataxia, disorders of the gastrointestinal tract, including changes in contractile what sposobnosti and secretion, negative symptoms of schizophrenia, premenstrual syndrome, syndrome fibromyalgia, stress incontinence, syndrome Tourette, trichotillomania, kleptomania, male impotence, cancer, small cell lunglung cancer, chronic paroxysmal of hemicrania, headache associated with vascular disorders, autism, developing deep disorder, without diagnosis (NOS), disorders Asperger's, selective mutism, chronic motor or vocal TIC, somatization, insomnia, intermittent spasmodic disorder, Pyromania, pathological gambling addiction, disorders of the control of motivation, premenstrual dysphoria, attention deficit with hyperactivity disorder (ADHD) in mammals, particularly in humans, including the introduction of citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-Il)benzyliden]thiomorpholine-3-one person in it to the needy.

The invention relates also to a method for citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one, which includes stages:

(i) contacting 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one, dissolved in a suitable solvent, with citric acid;

and

(ii) collecting the formed crystals.

The preferred embodiment of the invention is such, where p is ghadami solvent selected from the group consisting of (C1-C6) Olkiluoto alcohol, (C1-C6) alkylation, or (C1-C6) Olkiluoto ether. More preferably, the suitable solvent is 2-propanol. Preferred is a method of the invention, when the stage of contacting (i) is carried out by contacting 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-it is in the form of a solution with citric acid solution. More preferably, when the stage of contacting (i) is carried out by adding solid citric acid to a solution of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one.

Preferably, when the stage contacting is carried out for from 1 to 24 hours, better if in the course of from 10 to 20 hours, and it includes stirring or mixing the resulting mixture. The preferred embodiment of this method is when the stage (i) is carried out at a temperature between room temperature and the boiling temperature of the solvent;more preferably, between room temperature and boiling point2-propanol, i.e. approximately at 80°S; most preferably, when the method is carried out at a temperature of between 30 and 60°C. Preferably, when the reaction mixture is allowed to cool to room temperature, after CA is adding citric acid to the finished and allowed to mix until the end of the reaction.

The present invention relates also to the citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one obtained by the method according to the invention.

Detailed description of the invention

the compound 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-it is an antagonist of the serotonin receptor-1D (5-HT1Dreceptor) and can be used to treat a variety of diseases, disorders and conditions of the CNS.Free base compound and its hydrochloric salt can be obtained by the method described in international patent publication no WO 98/14433 published April 9, 1998, incorporated herein by reference in full.

Citrate can be obtained in many different conditions. However, according to the present invention, the free base 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one, preferablydissolved in a suitable solvent to dissolve, after which citric acid is added to the solution thus prepared to receive the additive salt of citric acid according to the invention. Preferably, the suitable solvent is selected from the group comprising (C1-C6) alkilany alcohol, (C1-C6) alkylation, or (C1-C6) alkilany the property; more preferably, (C1-C6) alkilany alcohol; most preferably 2-propanol. Preferably, the method according to the invention is such that when the stage of contacting (i) is carried out by contacting 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one in the form of a solution with citric acid, or in solution or in the solid state.

Preferably, when the stage contacting is carried out for a period of time between 1 and 24 hours, preferably between 10 and 20 hours, including the stirring or mixing the resulting mixture. The preferred embodiment of the method is a method by which stage (i) is carried out at a temperature between room temperature and the boiling temperature of the solvent;more preferably,between room temperature and the boiling point of 2-propanol, i.e., about 80°S; most preferably, the method is carried out at a temperature of between 30 and 60°C. Preferably, if the reaction mixture is allowed to cool to room temperature after the addition of citric acid was completed, and allowed to mix until the end of the reaction.

Citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]thiomorpholine-3-it is only slightly hygroscopic and has a high solubility in water. Such feature is specific, in combination with its relative inertness to conventional fillers used in pharmaceutical preparations, make it highly suitable for use in pharmaceutical preparations.

Although usually all known additive, acid salts of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-she cristallini, most of these salts are so hygroscopic that are unsuitable for use in pharmaceutical preparations. The citrate of the present invention exhibits a water absorption of approximately 1,27% wt./wt. when exposed to a relative 90%humidity in a wet chamber.Solubility in watercitrate saltis 1.3 mg/ml at a pH of 3,37. In addition, citrate 4-(3,4-dichlorophenyl)-2-[2-(4 - methylpiperazin-1-yl)benzylidene]thiomorpholine-3-it shows high stabilnosti in the solid state, as in the light and at elevated temperatures, and high humidity.

Differential scanning calorimetry

Thermal behavior of solid citrate according to the invention was studied using differential scanning calorimetry (DSC). The curve obtained for the salt, as shown in Fig. 1. DSC thermograms were obtained on the instrument DSC 821e(STAReSestem) company Mettler Toledo. Typically, samples, weighing between 1 and 10 mg, prepared in corrugated aluminum alloy is niewyk crucible with a small point hole. The measurements were carried out at heating rate 5°C/min in the temperature range from 30 to 300°C.

As can be seen from figure 1, citrate detects a melting point of about 198-199°C. the person skilled in the art, however, will note that when measuring method DSK there is some degree of variability in the actual measurement of the initial and peak temperatures, depending on the heating rate, shape and purity of the crystal and other measurement parameters.

Powder x-ray

Powder x-ray citrate according to the invention were obtained on a diffractometer D 5000 Bruker (Bruker AXS, Madison, Wisconsin)equipped with a copper radiator CuKa,fixed slits (1,0, 1,0, 0.6 mm) and solid-state detector firms Kavex.Data were obtained by changing two theta (2) from 3.0 to 40.0 degrees when the step size 0.04 degrees and the time step, equal to 1.0 sec.

Powder x-ray diffraction citrateheldat the copper anode at a wavelength of 1, equal 1,54056, and a wavelength of 2, equal 1,54439 (relative intensity 0,500). The change interval 2 was between 3.0 and 40.0 degrees, when the step size is equal to 0.04 degrees, the size of the time step, equal to 1.00 seconds, the width of the smoothing component 0,300, and background 1.0.

The diffraction peaks at angles of diffraction (2), measured in the analysis of powder diffraction is ntgenovskih rays for a given salt, shown in Table 1. Relative intensity, however, can vary, depending on the size and morphology of the crystal. In fact, the measured powder x-ray is shown in figure 2.

Table 2 shows 2θ, distance d and the relative intensity and position of the peaks in the powder x-ray characteristic of citrate. The figures obtained by computer calculations.

Table 1

Powder x-ray citrate with intensities and peak positions of the diffraction bands
Angle

Value

d
Online.

(Rel.)
Angle

Value

d
Online.

(Rel.)
Angle

The value of d

E
Online.

(Rel.)
8,210,73,723,1a 3.913,632,42,818,6
11,57,7a 4.924,03,733,532,82,77,4
13,06,814,524,73,65,333,62,73,3
13,76,55,625,13,59,934,52,66,3
14,95,99,8 26,23,46,934,92,6the 4.7
16,3of 5.47,026,63,411,235,82,54,1
16,65,313,127,13,320,436,32,57,5
17,45,1100,027,73,26,236,82,44,3
18,0a 4.940,228,33,26,337,32,4the 5.7
18,9the 4.7the 17.329,63,010,7to 38.32,46,3
20,04,471,630,42,98,338,92,34,3
of 21.24,223,431,02,93,4
22,24,020,031,62,82,8
Table 2

The intensity and position of peaks characteristic of citrate with powder x-ray diffraction
Angle

The value of dOnline.

(Rel.)
13,06,814,5
17,45,1100,0
18,0a 4.940,2
18,9the 4.7the 17.3
20,04,471,6
of 21.24,223,4
22,24,020,0
24,03,733,5
27,13,320,4
32,42,818,6

X-ray analysis of the single crystal

The single crystal citrate according to the invention was obtained and studied using x-ray diffraction. Typical crystal was studied and the data set to 1Ewas received (the maximum value of sin /= 0,5) directo is the ETP R4RA/v, from Siemens. The atomic scattering factors were taken from International Tables for X-Ray Crystallography, Vol. 4, pp. 55, 99, 149 (Birmingham: Kynoch Press, 1974). According to the data obtained for single crystal and powder x-ray was calculated for comparison with the actually measured x-ray.

Structures were calculated using direct methods. Library of computer programs SHELXTLTM,provided by the company Bruker AXS, Inc., facilitated all necessary crystallographic calculations and visual representation of molecules (SHELXTLTMReference Manual, Version 5.1, Bruker AXS, Madison, WI 1997). The relevant crystal data collection and refinement are summarized in table 3.

The trial structure was obtained by direct methods and was refined by conventional methods. Positions of hydrogen atoms were calculated where possible. The hydrogen atoms Mamilov and the hydrogen atoms on the nitrogen and oxygen were localized differential Fourier method. The parameters of the hydrogen atom were taken into account in the calculations of the structural factor, but were not refined. All shifts,calculated in the final cycles of least-squares method, were less than 0.1 corresponding standard deviations. The final R value-index was 4,72%. The final difference Fouriernot found the absence or displacementthe electron density. The refined structure was is built using software package graphomania SHELXTL and shown in figure 4.

Table 4 causes the coordinates of the atoms (X104) and equivalent isotropic displacement (A2X103for this salt. Table 5 lists the observed bond length [A] and angles [about] for citrate. Table 6 shows the parameters of the anisotropic displacement (A2X103), allowing to calculate the exponential factor of the anisotropic displacement, which has the form-2p2[h2a*2U11+...+2hka*b*U12]. Finally, in table 7, below, lists the coordinates of hydrogen atoms (X104) and isotropic displacement (A2X104for this salt.

/tr> C(1X)-O(2X) 60(9)td align="center"> 14(6)td align="center"> H(13)

Powder x-ray was calculated according to the data of a single crystal obtained for citrate when using computer programs XFOG and XPOW, which is part of the library of computer programs SHELXTLTM.Calculated powder x-ray shown in Fig. 3.

NMR of solids

Citrate was characterized by NMR in solids. Approximately 300 mg of the sample was tightly Packed in a 7 mm ZrO the spinner.The NMR spectra of13Were obtained using cross - polarization while rotating under magic angle(CPMAS) at 295 K, the NMR spectrometer (Bruker Avance DRX, with a frequency of 500 MHz on the sensor with a clearance of 7 mm

The sample was rotated with a frequency of 15.0 kHz. The contact time when the cross-polarization was 1 MS. The total number of scans required for most of the samples amounted to 512, which led to the duration of the Desk around 30 minutes Spectra were compared with an external standard of adamantane, the highest field signal of a methyl group, d 29,5 MD.

The spectrum of the NMR13CCPMAScitrate is shown in Fig. 5. Samples of citrate was good enough to obtain high-quality spectra of solids. The resolution was good, and the sensitivity was acceptable.

The main resonance peaks in the spectrum of solid hydrocarbon citrate 4-(3,4-dichloro enyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]thiomorpholine-3-it is in the lower fields of 100 MT are shown in table 8.

Table 3

Data of the crystal structure and the measurement parameters for citrate
For citrate
Americasa formulaWith22H24N3OSC2+C6H7O7-
Weight according to the formula640,52
Temperature293(2)
Wavelength1,E
Crystallographic symmetryMonoclinic
Space groupRS
The size of the elementary cella=6,5940(10) E

b=15,257(2) E

c=15,099(2) E
α=90°

β=101,440(10)°

γ=90°
Volume1488,9(4) E3
Z2
Density (calculated)1,429 mg/m3
The absorption coefficient3,081 mm-1
F(000)668
The crystal size0,24x0,04x0,04 mm3
Total reflection 1707
Independent reflections1707[R(int)=0,0000]
Completeness for theta=49,98°100%
The absorption correctionNone
Method of refiningFull-fabric method of least squares on F2
Data/restrictions/

options
1707/0/391
Consent for F21,065
The final value of R-indices [l > 2sigma(l)]R1=0,0472,

wR2=0,1028
Absolute structure parameter-0,01(3)
The extinction coefficient0,0038(6)
Naibolshei. peak and cavity0,223 and -0,268 E. E.3
Table 4

The coordinates of the atoms (X10-4) and equivalent isotropic displacement (E2x 103for citrate. U(EQ)is defined as one third of the trace orthogonalizing tensor Uij)
XXU(EQ)
S(1X)16003502(2)840153(1)
Cl(1X)7950(8)4063(2)13244(3)83(1)
Cl(2)11404(8)2613(2)13403(3)73(1)
N(1)8720(15)1936(5)6037(6)42(2)
With(2)9164(19)2836(7)523(7) 50(3)
With(3)7216(19)3358(7)5475(7)48(3)
N(4)6189(14)3417(5)6246(5)37(2)
With(5)5665(19)2527(6)6513(7)44(3)
With(6)7568(18)1994(7)6786(6)41(3)
With(7)4480(17)4015(6)6160(6)34(3)
With(8)3464(19)4335(7)5318(7)45(3)
With(9)1780(20)4884(8)5270(8)57(4)
With(10)1145(19) 5140(7)6041(9)55(3)
With(11)2141(19)4849(7)6862(7)47(3)
With(12)3874(17)4282(6)6954(6)36(3)
With(13)5020(16)4044(6)7850(6)35(3)
With(14)4255(15)3731(6)8528(6)32(3)
(15)5686(18)3625(7)9400(7)41(3)
N(16)5221(14)3032(5)10007(5)38(2)
With(17)3520(20)2409(8)9721(10)77(4)
With(18) 1591(19)2834(8)9378(8)58(3)
With(19)6643(17)2904(7)code 10837(6)33(3)
With(20)8123(17)2257(7)10928(7)40(3)
With(21)9521(19)2151(7)11710(7)51(3)
With(22)9542(18)2713(7)12428(7)45(3)
With(23)8029(19)3353(7)12367(6)43(3)
With(24)6611(19)3453(7)11563(7)45(3)
O(25)7262(14)4069(6)9602(5)70(3)
10622(18)1388(7)6296(8)57(3)
(1X)10057(19)-243(7)3822(8)53(3)
O(2)11060(17)-820(6)3541(6)100(4)
O(3)10378(16)-38(6)4658(6)84(3)
With(4)8610(18)320(6)3209(6)40(3)
(5X)6358(19)214(6)3317(7)35(3)
O(6X)5754(14)-675(5)3152(5)52(2)
With(7)6105(16)491(8)4257(6) 39(3)
O(8X)5421(15)-95(6)4709(5)75(3)
O(9ץ)6600(14)1254(5)4507(5)55(2)
(10X)4897(18)794(7)2640(6)46(3)
(11X)4463(19)533(6)1651(6)32(2)
(12X)2826(13)708(5)1170(5)50(2)
On(H)5938(13)140(6)1372(5)64(3)
Table 5

The observed bond length [E] and angles [about] for citrate
S(1X)-C(14)1,758(10)C(15)-N(16)1,365(12)
S(1X)-C(18)1,794(11)N(16)-C(19)1,422(12)
C1(1X)-C(23)1,719(10)N(16)-C(17)1,470(13)
Cl(2)-C(22)1,727(10)C(17)-C(18)1,429(17)
N(1)-C(6)1,486(12)With(19)-(20)1,375(13)
N(1)-C(2)1,500(12)C(19)-C(24)1,385(14)
N(1)-C(26)1,493(13)C(20)-C(21)1,356(14)
C(2)-C(3)1,495(16)C(21)-C(22)1,380(14)
C(3)-N(4)1,461(12)C(22)-C(23)1,386(14)
N(4)-C(7)1,435(13)C(23)-C(24)1,386(14)
N(4)-C(5)1,478(12)there were 1,227(13)
C(5)-C(6)1,483(14)C(1X)-O(3X)1,278(13)
C(7)-C(8)to 1.402(13)C(1X)-C(4X)1,468(14)
C(7)-C(12)1,398(13)C(4X)-C(5X)1,534(15)
C(8)-C(9)at 1,384(16)C(5X)-O(6X)1,423(11)
C(9)-C(10)1,369(15)C(5X)-C(7X)1,522(14)
C(10)-C(11)1,357(14)C(5X)-C(10X)1,537(14)
C(11)-C(12)1,418(15)C(7X)-O(9X)1,247(12)
C(12)-C(13)1,458(13)C(7X)-O(8X)1,261(12)
C(13)-C(14)1,317(12)C(10X)-C(11X)1,517(13)
C(14)-C(15)1,470(14)C(11X)-O(12X)1,205(11)
C(15)-O(25)there were 1,227(12)C(11X)-O(13X)1,283(11)
C(14)-S(1X)-C(18)100,9(5)C(18)-C(17)-N(16)112,7(10)
C(6)-N(1)-C(2)110,3(8)C(17)-C(18)-S(1X)114,1(9)
C(6)-N(1)-C(26)111,3(8)C(20)-C(19)-C(24)118,5(9)
C(2)-N(1)-C(26)112,9(9)C(20)-C(19)-N(16)121,2(9)
N(1)-C(2)-C(3)110,8(9)C(24)-C(19)-N(16)to 120.3(9)
N(4)-C(3)-C(2)110,2(8)C(21)-C(20)-C(19)121,3(10)
C(7)-N(4)-C(3)116,6(8)C(20)-C(21)-C(22)120,6(10)
C(7)-N(4)-C(5)112,8(8)C(21)-C(22)-C(23)119,4(10)
C(3)-N(4)-C(5)109,3(8)C(21)-C(22)-Cl(2X)120,6(9)
N(4)-C(5)-C(6)110,4(9)C(23)-C(22)-Cl(2X)119,9(8)
C(5)-C(6)-N(1)to 110.7(8)C(24)-C(23)-C(22)119,2(9)
C(8)-C(7)-C(12)120,7(10)C(24)-C(23)-Cl(1X)119,1(9)
C(8)-C(7)-N(4)121,9(9)C(22)-C(23)-Cl(1X)to 121.6(8)
C(12)-C(7)-N(4)117,4(8)C(23)-C(24)-C(19)120,9(10)
C(9)-C(8)-C(7)119,6(10)O(2X)-C(1X)-O(3X)121,5(11)
C(1)-C(9)-C(8) to 120.3(10)O(2X)-C(1X)-C(4X)122,0(11)
C(11)-C(10)-C(9)120,6(11)O(3X)-C(1X)-C(4X)116,1(10)
C(10)-C(11)-C(12)to 121.6(11)C(1X)-C(4X)-C(5X)of 113.2(9)
C(7)-C(12)-C(11)117,1(9)O(6X)-C(5X)-C(7X)110,4(9)
C(7)-C(12)-C(13)122,6(10)O(6X)-C(5X)-C(4X)109,0(8)
C(11)-C(12)-C(13)120,2(9)C(7X)-C(5X)-C(4X)110,9(8)
C(14)-C(13)-C(12)127,1(9)O(6X)-C(5X)-C(10X)108,4(8)
C(13)-C(14)-C(15)117,4(9)C(7X)-C(5X)-C(10X)106,9(8)
C(13)-C(14)-S(1X)120,9(7)C(4X)-C(5X)-C(10X)111,1(8)
C(15-C(14)-S(1X) to 121.6(8)O(9X)-C(7X)-O(8X)to 126.8(9)
O(25)-C(15)-N(16)119,5(9)O(9X)-C(7X)-C(5X)118,0(10)
O(25)-C(15)-C(14)121,5(10)O(8X)-C(7X)-C(5X)115,2(10)
N(16)-C(15)-C(14)119,0(10)C(11X)-C(10X)-C(5X)118,4(8)
C(15)-N(16)-C(19)119,1(9)O(12X)-C(11X)-O(13X)123,6(9)
C(15)-N(16)-C(17)119,5(9)O(12X)-C(11X)-C(10X)120,4(9)
C(19)-N(16)-C(17)120,1(9)O(13X)-C(11X)-O(10X)116,0(9)
Table 6

The parameters of the anisotropic displacement (E2X103for citrate. The exponential factor of the anisotropic displacement takes the form

-2π2[h2a*2U11+...+2hka*b*U12]
U11 U22U33U23U13U12
S(1X)40(2)76(2)39(2)6(2)2(1)-14(2)
Cl(1X)128(3)69(2)46(2)-17(2)1(2)24(2)
Cl(2)81(2)82(2)47(2)7(2)-13(2)13(2)
N(1)53(6)44(6)30(5)-11(4)10(5)-16(5)
With(2)53(8)57(8)46(7)-9(6)28(6)-22(7)
With(3)56(8)56(7)35(6)1(5)16(6) -14(6)
N(4)45(6)45(6)23(5)-1(4)12(4)-2(5)
With(5)61(8)39(6)36(6)15(5)24(6)-7(6)
With(6)63(8)41(6)22(6)2(5)17(6)-2(6)
With(7)43(7)37(6)21(6)3(5)4(5)-23(6)
With(8)51(8)49(7)33(7)6(5)6(6)-15(7)
With(9)64(10)52(7)45(8)22(6)-15(7)-17(8)
With(10)49(9)43(7)66(9) 11(7)-5(7)-1(6)
With(11)55(8)46(7)36(7)10(5)-1(6)4(6)
With(12)47(7)27(6)33(7)6(5)5(5)-9(6)
With(13)38(7)43(6)24(6)0(5)6(5)-4(5)
With(14)35(6)39(6)19(5)-6(5)2(5)-12(5)
(15)35(7)51(7)38(7)-5(6)5(6)-8(6)
N(16)53(6)28(5)30(5)6(4)-1(5)-8(5)
With(17)77(10)58(8) 78(9)22(7)-26(8)-39(8)
With(18)46(8)56(8)71(8)18(7)7(7)-22(7)
With(19)39(7)35(6)22(6)5(5)-2(5)-1(6)
With(20)51(8)41(7)29(6)-1(5)9(6)7(6)
With(21)61(8)50(7)45(7)10(6)22(7)19(6)
With(22)49(8)45(7)39(7)18(6)3(6)19(6)
With(23)70(8)47(7)14(6)-2(5)12(6)1(7)
With(24)35(7)41(7)-2(6)13(7)1(6)
O(25)60(6)104(7)39(4)29(4)-6(4)-35(6)
With(26)57(9)55(7)60(8)-12(6)14(7)2(7)
(1X)54(8)41(7)61(9)-9(6)2(7)4(7)
O(2)106(9)93(7)87(7)-21(6)-13(6)43(7)
About(3)99(8)107(7)33(5)-7(5)-21(5)52(6)
With(4)53(8)30(6)34(6)-1(5)4(6)
(5X)49(8)31(6)24(5)1(5)7(5)3(6)
On(6X)71(6)43(5)40(5)-4(3)8(4)-5(4)
With(7)38(7)62(8)15(6)-7(6)-2(5)9(6)
O(8X)106(8)108(7)18(4)-7(4)29(5)-51(6)
On(9ץ)75(6)51(5)34(4)-18(4)0(4)10(5)
(10X)54(8)60(7)23(6)-4(5)9(5)18(6)
(11X)40(7)33(6)27(6) 10(5)13(6)6(6)
(12X)43(5)75(5)28(4)-12(4)-7(4)15(4)
On(H)68(6)104(7)19(4)9(4)5(4)44(5)
Table 7

The coordinates of the hydrogen atoms (x 104) and isotropic displacement (E2x 103for citrate
XZU(EQ)
H(1X)7880(190)1710(70)5570(80)80
H(2A)98142789520280
H(2B)101183134619980
H(3A)753839425290 80
H(3B)62983082497180
H(5A)47532246601180
H(5B)49442564701380
H(6A)71991410695280
H(6B)84452258731080
H(8)39234179479680
H(9)10655080471180
H(10)235518600280
H(11)16755026737780
64474120795380
H(17A)38592028a 9,25780
H(17B)337320451023280
H(18A)12353198985180
H(18B)5242391922680
H(20)816718861044480
H(21)1047316951176480
H(24)562338951151280
H(26A)114221595685980
H(26B 114321429583580
H(-26 C)10234789636180
H(3XX)11700(300)-220(100)5150(100)140(60)
H(4XA)8699184259180
H(4XB)9020927332180
H(6XX)6600(200)-1000(80)3490(80)80
H(10A)3582822283480
H(10B)54651382268380
H(13X)5480(180)190(70)610(80)80
Table 8

The main resonance peaks citrate obtained by NMR13C in solids (relative to the benchmark adamantane, 29,MD)
13C
179,3
177,0
171,6
164,0
151,0
144,1

Citrate according to the invention (hereinafter referred to as "active salt can be injected or oral, percutaneous (for example, when using the patch)through the nose,sublingual, rectal, parenteral, or locally.Percutaneous and oral administration is preferable. Active salt is most preferably administered in the range of dosages from about 0.01 mg to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day, in single or fractional doses, although variations will necessarily occur depending upon the weight and condition of the patient under treatment, and, in particular, from the selected route of administration. However, the level of dosage in the range of from about 0.001 mg to about 10 mg per 1 kg of body weight per day is most desirable for use. Modifications, however, may be appropriate, depending on the weight and condition of the people is th, being treated and its individual response to the specified medication, as well as from selected pharmaceutical product and time period and interval within which produce this introduction. In some instances, dosage levels, is less than the lower limit of the above range may be more appropriate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first broken up into several small doses for administration throughout the day.

Active salt can be entered by itself or in compositions with pharmaceutically acceptable carriers or diluents, one of the methods previously outlined. In more detail, the active salt can be introduced in the form of a dosage form, characterized by a great variety, for example, they can be combined together with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermalpatches,biscuits, lozenges, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments-suspensionsaqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media,various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be appropriately podkosheny and/or flavored. Typically, the active salt is present in such dosage forms at concentration range from about 5.0 to about 70% of the mass.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various leavening agents,such as starch (preferably grain, potato or tapioca starch), alginic acid and certain complex silicates, together with substances,linking granules,such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as stearinovokisly salt of magnesium, sodium lauryl sulphate and talc, can be used for pelletizing. Solid compositions of a similar type may also be used as fillers in gelatin capsules;preferred materials in this connection also include lactose or milk sugar, as well as polyethylene glycol of high molecular weight. When aqueous suspensions and/or elixirs are intended for oral administration, the active ingredient may be combined with various sweetening or flavoring Agay is Tami, dyes and, if desired, emulsifying or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations.

For parenteral administration may be used a solution of an active salt or sesame or peanut oil or in aqueous propylene glycol. Aqueous solutions should be suitably buffered(the preferred pH value above 8),if necessary and the liquid diluent first make isotonic.Such aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. Preparation of all these solutions under sterile conditions is readily attainable standard pharmaceutical techniques well known to specialists in this field.

You can also enter active salt locally, and this can be done using creams, patches, jellies, gels, pastes, ointments and the like, in accordance with conventional pharmaceutical practice.

Example

The following example illustrates the method and the connection according to the invention. It should, however, be aware that this invention is not limited to this particular example.

Citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]thiomorpholine-3-one

B1-liter round-bottom flask, fitted in the upper part with a mechanical stirrer, a free base 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one (30,14 g; 0,067 mol; obtained by the method described in international patent publication no WO 98/14433) was dissolved in 525 ml of 2-propanol. The solution was stirred and heated to 50°C. Citric acid (16.2 g; 0,084 mol) was added in portions to the resulting clear solution, and the reaction mixture was left to cool and granulomatosawhenroom temperaturewithin 18 hours. A sample of the precipitated solids were examined by the method DSK to verify whether unreacted free base prior to collection of a white crystalline solid product. After filtration of the solid product was washed with 2-propanol (100 ml) and dried at 45°With vacuum while blowing with nitrogen. Specified in the header citrate was obtained with a yield of 94% (40.6 g; 0,063 mol).

1. Citrate 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)benzylidene]thiomorpholine-3-one of formula

2. The compound according to claim 1, having an x-ray is essentially characterized by the peak on the x-ray measured with copper radiation at size 2θ about 17,4.

3. The compound according to claim 1, having an x-ray is essentially characterized by a peak at x-ray is, measured with copper radiation at size 2θ about 20,4.

4. The compound according to claim 1, having an x-ray is essentially characterized by peaks on the x-ray measured with copper radiation at units 2θ about 17.4 and 20,0.

5. The compound according to claim 1, having an x-ray is essentially characterized by the following main peaks on the x-ray measured with copper radiation, expressed in 2θ and the distance d:

Angle 2θ (±0,2)The value of d (Å)(±2)
13,06,8
17,45,1
18,0a 4.9
18,9the 4.7
20,04,4
of 21.24,2
22,24,0
24,03,7
27,13,3
32,42,8

6. The compound according to claim 1, characterized by the starting point melting/decomposition at 198-199°C.

7. The compound according to claim 1, characterized in the study by NMR13With in solids with cross-polarization and rotation under magic angle as the main resonant peak: δ 179,3.

8. The compound according to claim 1, characterized in the study by NMR13With solid ones the Ah with cross-polarization and rotation under magic angle as the main resonant peak: δ 177,0.

9. The compound according to claim 1, characterized in the study by NMR13With in solids with cross-polarization and rotation under magic angle as the main resonant peak: δ 171,6.

10. The compound according to claim 1, characterized in the study by NMR13With in solids with cross-polarization and rotation under magic angle following main resonant peaks: δ 179,3, 177,0, 171,6, 164,0, 144,1.

11. Pharmaceutical composition having antagonistic activity against receptor serotonin-1D (5-HT1D)containing the compound according to claim 1 and a pharmaceutically acceptable carrier.

12. A method of treating hypertension, all forms of depression, depression of cancer patients, depressed patients with Parkinson's disease, depression patients after myocardial infarction, subsyndromal symptomatic depression, depression in infertile women, pediatric neuropsychiatric depression, major depressive disorder, single bouts of depression, recurrent depression, child depression, caused by poor circulation, postpartum depression, dysthymia; mild, moderate or severe forms of depression with atypical features, melancholic features, psychotic features, catatonic features, or without them; seasonal emotional disorder, senile de is ressie, chronic depression; disorders of regulation in the state of depression or anxiety and depression; a mixed state of depression and anxiety; mood disorders, caused by any substance, and secondary mood disorders due to a General condition, bipolar disorder, bipolar disorder in phase oppression, disorder and General anxiety, phobias, agoraphobia, anxiety when communicating, sociophobia, simple phobias, disorders in the atomized state anxiety syndrome post-traumatic stress disorder when detached consciousness of personality, premature ejaculation, violations of the act of eating disorders associated with alcohol consumption, nervously-mental anorexia, neurogenic disorders, obesity, addiction to chemical drugs and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana and benzodiazepines; histamine headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder type of disorder panic type with agoraphobia, memory disorders, dementia, amnesia, and age-related decline in cognitive abilities (ARCD), Parkinson's disease, dementia in Parkinson's disease, parkinsonism induced by neuroleptics, the late is th dyskinesia, endocrine disorders, hyperprolactinaemia, vasospasm, a narrowing of the blood vessels in the cerebral vasculature, cerebellar ataxia, disorders of the gastrointestinal tract, including changes in contractility and secretion, negative symptoms of schizophrenia, premenstrual syndrome, syndrome fibromyalgia, stress incontinence, syndrome Tourette, trichotillomania, kleptomania, male impotence, cancer, small cell lung cancer, chronic paroxysmal of hemicrania, headache associated with vascular disorders, autism, developing deep disorder, without diagnosis (NOS), disorders Asperger's, chronic motor or vocal TIC, somatization, insomnia, intermittent spasmodic disorder, Pyromania, pathological addiction to azartnym games, disorders of the control of motivation, premenstrual dysphoria, attention deficit with hyperactivity disorder (ADHD) in mammals, including the introduction in need of treatment a therapeutically effective amount of a compound according to claim 1.



 

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21 cl, 5 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with treating disorders chosen out of the group consisting of mitochondrial encephalomyopathy along with lactic academia and shock-like attacks (MELAS), neurogenic muscular fatigue, ataxia, retenitis pigmentosa/maternally inherited Li syndrome (NARP/MILS), syndrome of mitochondrial ataxia, relapsing infections, aphasia, hypouricemia/hypomyelination, attacks and aciduria of dicarbonic acids (MARIAHS), renal canalicular acidosis, Li syndrome, refractory epilepsy with deteriorations during infection, syndrome of multiple deletions mitochondrial DNA (mtDNA) and deficiency of cytochrome c-oxidase (COX, complex IV). Moreover, one should introduce efficient quantity of 2',3',5'-tri-O-acetyl-1-beta-D-uridine (triacetyluridine) for a patients who has such a disorder or with the risk for appearance of such a disorder. The innovation enables to either decrease or remove the symptoms of the diseases mentioned due to correcting the processes in synthetic pathway of pyrimidine.

EFFECT: higher efficiency of therapy.

19 cl, 5 ex, 1 tbl

FIELD: medicine, psychiatry, neurology.

SUBSTANCE: the present innovation deals with treating affected amnestic functions in women after uterine and adnexal extirpation. For this purpose, after a 7-d-long introduction of estradiol as suppositories at curative dosage of 8-20 mcg/kg body weight patients should be additionally injected with galanthamine intramuscularly once daily for 7-10 d at the dosage 5 mg, moreover, decreasing the number of estradiol injections up to once/3 d. The innovation suggested provides high antiamnestic effect at decreased dosage of preparations due to their agonistic action.

EFFECT: higher efficiency of therapy.

FIELD: pharmacy.

SUBSTANCE: invention relates to a granulated pharmaceutical composition comprising granulated material and erythritol. Granulated material comprises a medicinal substance of unpleasant taste and wax. Also, invention relates to a pharmaceutical product for oral using that comprises the indicated granulated composition. The composition masks unpleasant taste of a medicinal agent and provides good feeling in oral using. The granulated composition can be swallowed easily by elderly humans, children and patients suffering with dysphagia. Except for, the product is useful for administration by using a tube.

EFFECT: improved and valuable properties of composition.

15 cl, 5 tbl, 6 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to using movalis as a frigoprotecting agent in cold trauma on background of alcoholic intoxication. Movalis is a highly active anti-inflammatory, power analgesic preparation under condition of alcoholic-cold trauma and doesn't show stomach complications. Prescription of movalis can be recommended in therapeutic doses to patients who work under condition of low temperatures.

EFFECT: improved and valuable medicinal properties of agent.

2 tbl, 3 dwg

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that are able to modulate the pharmacological response of one or some opioid receptors taken among ORL-1 and μ-receptors. Invention describes a compound of the formula (I): wherein W represents hydrogen atom, (C1-C10)-alkyl, (C1-C4)-alkyl-SO2N(V1)2, cyano-(C1-C10)-alkyl, (C1-C4)-alkyl-CON(V1)2, -NH2-SO2-(C1-C4)-alkyl-, (C1-C4)-alkyl-COOV1 wherein all V1 represent (C1-C6)-alkyl; Q represents a 6-membered aromatic group; n represents a whole number from 0 to 3; n' represents a whole number 0 or 1; A, B and C represent hydrogen atom; Z is taken among the group including a bond, linear or branched (C1-C6)-alkylene; R1 is taken among the group including hydrogen atom, (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C2-C10)-alkylene, (C3-C12)-cycloalkylamino-group, benzyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl wherein indicated alkyl, cycloalkyl, alkenyl, (C3-C12)-cycloalkylamino-group or benzyl are optionally substituted with substitutes taken among the group including (C1-C10)-alkyl, phenyl, benzyl, benzyloxy-group wherein indicated phenyl, benzyl and benzyloxy-group are substituted optionally with (C1-C10)-alkyl and indicated (C3-C12)-cycloalkyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl are substituted optionally with 1-3 substitutes taken among the group including (C1-C10)-alkyl and benzyl wherein indicated benzyl is substituted optionally with (C1-C10)-alkyl; R2 represents hydrogen atom and under condition that when n' = 0 then ZR1 doesn't means hydrogen atom (H), or to its pharmaceutically acceptable salt or solvate. Also, the invention describes a pharmaceutical composition based on thereof. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 5 tbl, 8 ex

FIELD: medicine, obstetrics.

SUBSTANCE: one should conduct antibacterial therapy 3 mo before planned pregnancy consisting of preparations of tetracyclinic group or macrolides in combination with nystatin and metronidasol to continue it since the first day of menstrual cycle and, also, it is necessary to perform correction of vaginal biocenosis, and about 3-4 wk after therapy carried out for 2 next mo before planned pregnancy starting, also, since the first day of menstrual cycle - metabolic therapy; At the onset of pregnancy one should conduct courses for preventing placental deficiency dealing with introduction of preparations that improve uterine-placental circulation, and preparations that improve rheological properties of blood and vitamin-metabolic therapy or the same preparations, and additionally - introduction of macrolides ad viferon rectally in case of activation of chlamydial infection. The present innovation enables to sanitize uterine cavity, improve uterine-placental circulation, restoration of placental tissue structure that, in its turn favors the birth of healthy generation.

EFFECT: higher efficiency of prophylaxis.

1 cl, 9 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethacyzine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 5 ex, 2 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested preparation contains ethmozine, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.

EFFECT: higher efficiency of application.

7 cl, 1 dwg, 7 ex, 2 tbl

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