Derivatives of thieno[2,3-d]pyrimidine and their using in treatment of fertility disorder

FIELD: organic chemistry, biology, pharmacy.

SUBSTANCE: invention relates to derivatives of thieno[2,3-d]pyrimidine of the general formula (I): or their pharmaceutically acceptable salts wherein R1 and R2 in common with nitrogen atom to which they are added form a ring comprising from 2 to 6 carbon atoms and optionally comprising one or more heteroatoms chosen from nitrogen (N), oxygen (O) and/or sulfur (S) atoms. Proposed compounds possess ability to activate both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and can be used in therapy in aims for regulating fertility. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 7 ex

 

The invention relates to compounds having agonist activity of hormones, glycoproteins, in particular, to compounds of the agonists of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition, the invention relates to the containing pharmaceutical compositions, as well as to the use of these compounds in medical therapy, in particular to regulate their fertility.

Gonadotropic hormones play a significant role in various body functions, including metabolism, temperature regulation and reproductive process. Gonadotropic pituitary hormones FSH and LH, for example, play a major role in stimulating the growth and maturation of follicles, whereas LH is associated with induzirovannom process of ovulation (Sharp, R. Clin. Endocrinol 33, 787-807, 1990; Dorrington and Armstwong, Recent Prog. Horm. Res 35, 301-342, 1979; Levy and other Human Reproduction 15, 2258-2265, 2000).

Currently LH used in the clinic in combination with FSH to stimulate (activity) of the ovaries, i.e. ovarian hyperstimulation for in vitro fertilization (IVF) and induction of ovulation in women with infertility associated with akouala (Insler, V., Int. J.Fertility 33, 85-97, 1988; Navot: and Rosenwaks, J.Vitro Fert. Embryo Transfer 5, 3-13, 1988), as well as with hypogonadism and male infertility.

Gonadotropic hormones act on specific types of gonadal cells to stimulate ovarian and testicular differential is eacii and steroidogeneza. The action of the pituitary and placental hormones mediated by specific receptors of the plasma membrane, which belong to a large group of G-proteinsathome receptors. They consist of single polypeptides with seven transmembrane domains and are able to interact with Gs-proteins, leading to activation of adenylcyclase.

Gonadotropic hormones intended for therapeutic purposes, can be isolated from human urine and have a low degree of purity (Morse and others, Amer. J. Reproduct. Immunol. and Microbiology 17, 143, 1988). Alternatively they can be obtained in the form of recombinant gonadotropins. In addition to the specified proteins gonadotropin receptors can be activated or deactivated synthetic compounds with low molecular weight. Bicyclic heteroaromatic compounds described in the patent WO 00/61586, in experiments in vitro and in vivo have shown that they are applicable as agonists LH.

In normal women, the secretion of pituitary LH and FSH is characterized by a surge in the middle of the cycle that precedes ovulation. Ovulation is characterized by three different physiological phenomena, that is, the maturation of the oocyte, the rupture of the follicle and luteinization. While the role of LH release in the development in vivo of these processes is undeniable, the role of the release of FSH is less clear. However, at present the time is shown, that FSH stimulates the maturation of the oocyte in vitro, inducing total cells produce a factor that positively overcomes latency meiosis induced by gipoksantin (Lu and others, Mol. Cell. Endocrinol. 164, 191-196, 2000). I believe that this factor is a Sterol (MAS), activating meiosis.

With ovulation stimulation, it is desirable to provide the effect of LH as the main component. In accordance with this invention found compounds, in particular, with excellent properties when applied to increase fertility. For these compounds LH-activity accompanied FSH activity.

Thus, the invention provides compounds with a low molecular weight, which in addition to LH activity unexpectedly also exhibit FSH activity. In General these compounds are thieno[2,3-d]pyrimidines, which are in the 4-position of the pyrimidine ring substituted phenyl group, which is in turn substituted in the meta-position.

The present invention presents derivatives of thieno[2,3-d]pyrimidine according to General formula I

or their pharmaceutically acceptable salts, where N(R1)R2 United (2-6C)geteroseksualnoe ring.

The most preferred compounds are: tert-butyl 5-amino-2-methylthio-4-(3-(2-(azetidin-1-yl)-acetamido)-phenyl)-Tien is[2,3-d]pyrimidine-6-carboxamide; tert-butyl 5-amino-2-methylthio-4-(3-(2-(morpholine-4-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide; tert-butyl 5-amino-2-methylthio-4-(3-(2-(thiomorpholine-4-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide; tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperidine-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide; tert-butyl 5-amino-2-methylthio-4-(3-(2-(pyrrolidin-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide and tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperazine-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide.

The term "United (2-6C)geteroseksualnoe ring" in the definition of formula I means that R1 and R2 together with the nitrogen atom to which they are attached, form a ring having 2-6 carbon atoms, possibly containing one or more heteroatoms selected from N, O and/or S. Examples of such rings are azetidin, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.

It is shown that the compounds of the above formula I are active agonist of LH and FSH. In the in vitro bioassay using Cho cells stably transfetsirovannyh receptors for LH and FSH person, accordingly, it was found that EC50in relation to the LH receptor is less than 5E-08, while in relation to the FSH-receptor EU50is less than E-05. Usually the activity of FSH ranges from about 1% activity agonistic stimulation of LH deprimere 10% agonistic stimulation of LH.

Additionally, the invention relates to pharmaceutical compositions containing the derivative thieno[2,3-d]pyrimidine or its salt of the General formula I.

Thus, the compounds of the invention can be used in therapy. An additional aspect of the invention is the use of the derivatives of thieno[2,3-d]pyrimidine of the General formula I for the preparation of medicaments for the regulation of fertility, more preferably, to stimulate ovulation. These connections apply to activate the receptor as LH and FSH. The compounds of this invention can therefore be used in methods of treatment of women with infertility problems (fertility).

Therapeutically applicable salts of compounds of formula I are salts in which the counterion pharmaceutically acceptable. However, additive salts with acids bases corresponding to the formula I, can find application, for example, upon receipt or purification of pharmaceutically acceptable compounds. All salts are pharmaceutically acceptable or not included in the scope of the invention.

Examples of the additive salts are salts, derivatives of such mineral acids as hydrochloric acid, phosphoric acid, sulfuric acid, preferably hydrochloric acid, and organic acids such as citric acid, tartaric acid, acetic acid, milk is acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid and the like.

Suitable routes of administration of compounds of the formula I or their pharmaceutically acceptable salts, are also related to their use as active ingredients, are intramuscular injections, subcutaneous injections, intravenous, or intraperitoneal injection, oral and intranasal administration. Preferably the compounds can be administered orally. The exact dose and mode of administration of the active ingredient or pharmaceutical composition will depend on therapeutic effect, which must be distinet (treatment of infertility, contraception), and can vary depending on the particular compound, the route of administration, the age and condition of the individual subject to whom the drug should be entered.

Usually parenteral administration requires lower doses than other routes of administration that are more dependent on adsorption. However, the human dose preferably contains 0,0001-25 mg per kg of body weight. The desired dose may be a single dose or multiple subdot, administered at appropriate intervals throughout the day. In the case of a recipient-women dose can be entered in the corresponding intervals of days of the menstrual cycle to support allikul or as a single dose for inducing ovulation. Dose and mode of administration, may be different for recipients of women and men.

In the case of introducing in vitro or ex vivo like IVF-introducing the compound of the invention should be used in the incubation medium at a concentration of about 0.01 to 5 mg/ml

This invention relates also to pharmaceutical compositions containing derivatives of thieno[2,3-d]pyrimidine of the formula I in a mixture with pharmaceutically acceptable excipients and possibly other therapeutic agents. The excipient must be "acceptable" in the sense of compatibility with other components of the composition and not to be harmful to the recipient.

Pharmaceutical compositions include those which are suitable for oral, rectal, nasal, local (including intradermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, transdermal, intramuscular, intravenous and intradermal) administration. The composition can be obtained by any method well known in the field of pharmacy, for example, using such methods as described in Gennaro and others, Remington''s Pharmaceutical Sciences (18th ed. Mack Publishing company, 1990, see especially part 8: Pharmaceutical Preparations and Their Manufacture).

These methods include the stage of combining the active ingredient with any auxiliary agent. Auxiliary agent and, also called additional components are conventional components (Gennaro, supra), as fillers, binders, diluents, disintegrant, lubricants, dyes, odorants and wetting agents.

Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets or capsules, or in the form of powder or granules, or in the form of a solution or suspension. The active ingredient may also be presented as a bolus or paste. The composition can also be prepared in the form of suppositories or enemas for rectal administration.

For parenteral administration suitable compositions are aqueous and non-aqueous sterile injection solutions. The compositions can be presented in the form of packaging for a single dose or repeated administration, for example, in the form of sealed bottles and vials and may be stored in a lyophilized condition requiring before use, only the addition of sterile liquid carrier, for example water.

Compositions or preparations suitable for nasal inhalation, can be finely ground powders or aerosols, which can be obtained by spray metered dose aerosol under pressure, by means of a spray or by injection.

Derivatives Tien is[2,3-d]pyrimidine of the invention can also be entered in the form of implantable pharmaceutical devices consisting of a core of active material Packed in the membrane, releasing its variable speed. These implants are used subcutaneously or topically, and they are able to release the active component is approximately constant speed for a relatively long period of time, for example, from weeks to years. Methods of obtaining implantable pharmaceutical devices, such as known in modern art, as described, for example in the European patent 0303306 (AKZO N.V.).

Thus, the compounds according to this invention can be used for the same clinical purposes as natural LH, with the advantage that they possess FSH activity, show the changed properties of stability and can be entered in various ways.

The compounds of this invention represented by formula (I)can usually be obtained by nucleophilic substitution of the halide (II), where Q=Cl or Br, with (cyclic secondary amines of the formula (III) in an appropriate solvent, such as N,N-dimethylformamide or THF (tetrahydrofuran) at room temperature in the presence of a tertiary base, such as N,N-diisopropylethylamine (DIPEA).

Derivatives of the formula (II), where Q=Cl or Br, can be obtained from the regioselective acylation derived meta-aniline is (V) acylchlorides type (IV), where Q=Cl or Br, in the presence of a tertiary base, such as N,N-diisopropylethylamine, in a suitable solvent such as dichloromethane or THF.

The compound (V) can be obtained well-known in the prior art to restore microfunction in derivative (VI) with an appropriate reducing agent such as tin chloride(II), in proton solvent such as ethanol, in the presence of hydrochloric acid at elevated temperature (J. Heilbron, J.Chem. Soc., 1279 (1940)).

Thienopyrimidine (VI) can be obtained by condensation of the carboxylic acid (VII) with tert-butylamine under the action of agent combinations, such as tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (TBTU) or hexaphosphate patrimonialization (PyBrOP) and a tertiary base, such as N,N-diisopropylethylamine.

Saponification complex ethyl ester (VIII) to the corresponding carboxylic acid (VII) proceeds in the presence of a base such as lithium hydroxide, potassium hydroxide or sodium hydroxide in aqueous dioxane at elevated temperature (80°to boil).

Bicyclic compound (VIII) is formed by substitution of the chloride (X) ethylmercaptan under the action of N,N-diisopropylethylamine with PEFC is blowing the circuit loop of the intermediate simple tiefer (IX) catalyzed by base. The specified type of education thieno[2,3-d]pyrimidine ring is described in: S.A. Abdel-Hady, M.A. Badawy, Y.A. Ibrahim, Sulfur Lett. 9, 101 (1989) and S. Tumkevicius, Liebigs Ann., 1703 (1995).

Suitable reaction conditions for the cyclization are sodium ethylate in ethanol or N,N-diisopropylethylamine in toluene/ethanol (1/1, vol/about.) at boiling point.

Need Chloramin (X) can be synthesized as known from the literature method, for example, as described A.A. Santilli, D.H. Kim and S.V.Wanser, J.Heterocycl. Chem. 8, 445, 1971. According to this method lactam (XI) is treated with POCl3at elevated temperature (80°to boil) with the formation of chloride (X). The addition of an appropriate solvent, for example dioxane, and/or adding or PCl5or N,N-dimethylaniline to the reaction mixture can lead to shorter reaction time and higher outputs chloride (X).

The path to the lactam (XI) provides multicomponent condensation ethylcyanoacrylate with 3-nitro-benzaldehyde and S-Methylisothiazolinone in ethanol under the action of a base such as potassium carbonate, at an elevated temperature (60°).

Related methods proposed in S. Kambe, K. Saito and H. Kishi, Synthesis, 287 (1979); A.M. Abd-Elfattah, S.M. Hussain and A.M. El-Reedy, Tetrahedron39, 3197 (1983); S.M. Hussain, A. A. El-Barbary, and S.A. Mansour, J.Heterocycl. Chem. 22, 169 (1985).

Methods for determining binding of the receptor in samples both in vitro and in vivo, to determine the biological activity of gonadotropic hormones are well known. Usually expressed receptor is introduced into contact with the compound to be tested, and measuring the binding, or stimulation or inhibition of a functional response.

To measure the functional response of selected DNA coderush gene receptor LH or FSH, preferably receptor human, Express in a suitable host cell. Such a cell can be a cell of the ovary of the Chinese hamster, but also other cells. Preferred mammalian cells (Jia and others, Mol. Endocrin., 5, 759-776, 1991).

How to create recombinant cell lines expressing LH or FSH, is well known in modern art (Sambrook and other, Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Receptor expression reaches the expression of DNA that encodes a target protein. Methods site-directed mutagenesis, ligation of additional sequences, PCR (PCR), and the creation of suitable expression systems are well known in the prior art. Part or all of the DNA encoding the desired protein can be produced synthetically using standard solid-phase metal is Dickey, it is preferable to include restriction sites to facilitate ligation. Suitable control elements for transcription and translation included coding sequences can be fused to the coding DNA sequences. As is well known, is now available expression systems that are compatible with a wide variety of hosts, including prokaryotic hosts, such as bacteria, and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, bird cages and the like.

Cells expressing the receptor is then contacted with the test compound to observe binding, or stimulation or inhibition of a functional response.

Alternatively, to measure the binding of the compounds may be used in the selected cell membrane containing the expressed receptor.

To measure the binding can be used radioactively or fluorescently labeled compounds. As reference compounds may be used in recombinant LH or FSH person. Alternatively, can be also carried out tests of competitive binding.

Another test is the screening of compounds agonist of LH or FSH by determining the stimulation of receptor-mediated accumulation of camp. So the m way this method provides for the expression of the receptor on the surface of the host cell and the effect on the cell of the test compounds. Then measure the amount of camp. The level of camp may be reduced or increased depending on inhibitory or stimulatory actions of the test compounds bind c receptor.

In addition to the direct measurement, for example, the level of camp in exposed cell can be used in cells, which in addition to the transfection of the receptor-encoding DNA, transliterowany a second DNA that encodes a gene-reporter, expression of which depends on the level of camp. These genes reporters can be induced or can be designed in such a way that they were connected in some new elements, sensitive to the camp. Typically, the gene expression of the reporter can be controlled by any sensor that is responsive to changes in the level of camp. Suitable genes reporters are, for example, LacZ, alkaline phosphatase, luciferase Firefly and fluorescense green protein. The principles of the specified sample TRANS-activation are well known in the prior art and described Stratowa, Ch, Himmler, and A Czernilofsky, A.P., Curr.Opin.Biotechnol. 6, 574 (1995).

For screening active compounds receptors for LH and FSH tested at 10-5M should show the activity of more than 20% of the maximum activity, when LH and FSH used as a reference. Another criterion may be the value of the EU50that should be <10-5M, preferably <10-7M.

A qualified professional determines that the desired value of the EU50depends on the test connection. For example, the connection with the EU50less than 10-5M is usually considered as a candidate for selection as a drug. Preferably the specified value below 10-7M. However, the connection that has higher EC50but is selective for a particular receptor may be an even better candidate.

Screening compounds agonist of LH receptors may also be effected through the use of assay cells mouse Leydig (Van Damme, M., Robersen, D. And Diczfalusy, E., Acta Endocrinol. 77: 655-671 (1974), Mannaerts, B., Kloosterboer, H., and Schuurs, A., Neuroendocrinology of reproduction. R.Rolland and others, Eds., Elsevier Science Publishers B.V., 49-58 (1987)). In the specified test the LH receptor-mediated formation of testosterone can be measured in the Leydig cell, isolated from male (male) mouse.

The activity of FSH agonist compounds may also be defined on the models of ex vivo using cultured murine follicle according Nayudu, P and Osborn, S. (J. Reproduction and Fertility 95, 349-362 (1992)). To do this, the mouse ovarian follicles were isolated and cultured in the presence of compounds of FSH agonists for inducere the project for the growth of the follicle. Measuring the diameter of follicles and estradiol in the culture medium shows the growth of the follicle.

For measurement of LH activity of the compounds in vivo can be studied the induction of ovulation in immature mice. In the specified test immature female mouse was first introduced FSH isolated from urine, and after about 48 hours the connection agonist of LH. Animals were killed after administration of the agonist of LH and under the microscope estimated the number of eggs in the fallopian tubes.

For measurement of FSH activity of the compounds in vivo immature female mice were treated with 0, 8, 24 and 32 hours connection-agonist FSH to induce the growth of the follicle. After 52 hours after the start of the experiment, the animals were injected hCG to induce ovulation. Animals were killed 72 hours after the start of the experiment and under the microscope estimated the number of eggs in the fallopian tubes. Additionally it was determined the mass of the ovary.

The compounds of this invention can be used clinically in those schemes (treatment), where now use LH or hCG. They provide for the replacement of LH in patients with hypogonadism hypogonadism in both men and women, the introduction in the middle of the cycle to induce ovulation (OI) or regulation hyperstimulation (SLEEP) or stimulation of the yellow body.

The following examples illustrate the invention and should not be interpreted as og is anichini of the invention.

EXAMPLES

Example 1

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(azetidin-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

(a). 5-Cyano-4-(3-nitrophenyl)-2-methylthio-6-oxopyrimidine

A mixture of sulfate S-methylisothiazoline (69,0 g), 3-nitrobenzaldehyde (75,0 g), ethylcyanoacrylate (56,0 ml) and potassium carbonate (72.5 g) in .EtOH (1500 ml) was stirred at 60°16 hours the Reaction mixture was cooled to 0°in an ice bath. The resulting precipitate was filtered, washed .EtOH and dissolved in hot water (100°). The solution was cooled to room temperature, acidified 2 N. HCl to pH 2 and was cooled to 0°in an ice bath. The resulting precipitate was filtered and washed with ice water. Residual water from the precipitate was removed by sovpadeniem with 1,4-dioxane.

Output: 54,0 mg

MS-ESI (mass spectrum (electrospray ionization): [M+H]+=289,0

TLC (thin layer chromatography): Rf=of 0.3, silica gel, DCM (dichloromethane)/Meon=9/1 (about./vol.).

(b). 6-Chloro-5-cyano-4-(3-nitrophenyl)-2-methylthiopyrimidin

POCl3(100 ml) was added to a stirred solution of 5-cyano-4-(3-nitrophenyl)-2-methylthio-6-oxopyrimidine (example 1(a)of 25.0 g) in dry 1,4-dioxane (300 ml). After 3 h at 90°the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (100 ml) and the resulting solution was cooled to 0°S: gently priba the Lyali the icy water. The resulting precipitate was filtered and washed with water. Residual water from the precipitate was removed by sovpadeniem with 1,4-dioxane.

Output: 26,0 g

MS-ESI: [M+H]+=307,0

TLC: Rf=of 0.5, silica gel, heptane/EtOAc=3/2 (about./vol.).

(C). Ethyl-5-cyano-4-(3-nitrophenyl)-2-methylthio-6-(ethoxycarbonylmethyl)-pyrimidine

DIPEA (15.7 ml) was added to a stirred solution of ethyl-2-mercaptoacetate (9,3 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthiopyrimidine (example 1(b), 26,0 g) in a mixture of EtOH and DCM (250 ml). After 1 h at room temperature, to the mixture was added 0.1 G. aq. HCl (500 ml) and then was extracted with DCM (3 x 500 ml), dried (MgSO4) and concentrated under reduced pressure.

Output: 28,0 g

MS-ESI: [M+H]+=RUR 390.4

TLC: Rf=of 0.5, silica gel, heptane/EtOAc=3/2 (about./vol.).

(d). Ethyl ester of 5-amino-4-(3-nitrophenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid

A mixture of ethyl-5-cyano-4-(3-nitrophenyl)-2-methylthio-6-(ethoxycarbonylmethyl)-pyrimidine (example 1(C)of 28.0 g) and DIPEA (30 ml) in a mixture of toluene (150 ml) and EtOH (150 ml) was stirred at boiling point (100° (C) 16 h the Mixture was then cooled to room temperature and concentrated under reduced pressure. Residual DIPEA was removed by sovpadeniem with toluene.

Output: 28,0 g

MS-ESI: [M+H]+=391,2

TLC: Rf=0.6, silica gel, heptane/EtOAc=3/2 (about./vol.).

(e). Ethyl ester of 5-amino-4-(3-AMINOPHENYL)-2-methylthio-thieno[2,3-d]pyrimi the in-6-carboxylic acid

EtOH (440 ml) was added to a mixture of ethyl ester of 5-amino-4-(3-nitrophenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 1(d)of 28.0 g), conc. aq. HCl (15 ml) and tin chloride(II) (41,0 g) in 1,4-dioxane (400 ml). The mixture was stirred at 90°16 h the Mixture was then cooled to room temperature and concentrated under reduced pressure. The residue is suspended in EtOAc (1000 ml) was added 4 n aq. NaOH to pH 10-11. The mixture is vigorously stirred, the organic layer was separated, dried (MgSO4) and concentrated under reduced pressure.

Output: 21,0 g

MS-ESI: [M+H]+=361,0

TLC: Rf=0.6, silica gel, heptane/EtOAc=3/2 (about./vol.).

(f). 5-Amino-4-(3-AMINOPHENYL)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid

Potassium hydroxide (32,4 g) was added to a solution of ethyl ester of 5-amino-4-(3-AMINOPHENYL)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 1(e), or 21.0 g) in a mixture of 1,4-dioxane (300 ml) and water (100 ml). After 16 h at 90°the mixture was cooled to 10°and with vigorous stirring was added 2 n aq. citric acid (300 ml). The resulting precipitate was filtered, washed with water (180 ml) and dried in vacuum.

Yield: 14.0 g

MS-ESI: [M+H]+=333,0

TLC: Rf=of 0.5, silica gel, DCM/MeOH=9/1 (about./vol.).

(g). Tert-butyl 5-amino-4-(3-AMINOPHENYL)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxamide

TBTU (16.1 g) was added to a solution of 5-amino-4-(3-Amin is phenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 1(f), 14.0 g), DIPEA (17,4 ml) and tert-butylamine (7,3 g) in DCM/DMF (dimethylformamide) (1/1, vol/about., 250 ml). After 3 h at room temperature the mixture was washed a feast upon. aq. NaHCO3(3*100 ml)of 0.1 n aq. HCl (100 ml) and water (100 ml). The organic layer was concentrated under reduced pressure. The crude product was purified by crystallization from warm .EtOH (300 ml).

Output: 10,5 g

MS-ESI: [M+H]+=388,2

HPLC (high performance liquid chromatography): Rt=30,72 min, Luna C-18(2), 5 μm, 250*2.0 mm, detection at UV=210 nm, column temperature=40°C, flow rate 0.25 ml/min, eluent water/ACN/Meon=90/9,5/0,5 to 0/95/5, the running time=50 minutes

(h). Tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamide)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

Bromocatechol (615 mg) was added to a solution of tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 1(g), 1.08 g) and DIPEA (2,43 ml) in dry DCM (20 ml). After 3 h at room temperature the mixture was diluted with DCM, washed the feast upon. aq. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by chromatographytandem on silica gel, using as eluent heptane/EtOAc=3/2 (about./vol.).

Output: 910 mg

MS-ESI: [M+H]+=510,2

TLC: Rf=of 0.3, silica gel, heptane/EtOAc=3/2 (about./about.)

(i). Tert-butyl 5-amino-2-methylthio-4-(3-(2-(azetidin-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

Tre the-butyl-5-amino-4-(3-(2-bromoacetamide)-phenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxamide (example 1(h), 91 mg) was added to a solution of hydrochloride of azetidine (120 mg) and N,N-diisopropylethylamine (0.25 ml) in DCM (5 ml). After 16 h at room temperature the mixture was washed a feast upon. aq. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified HPLC using a column Luna C-18, gradient elution: 0.1% aq. TFA (triperoxonane acid)+10% aq. ACN/ACN=90/10 to 10/90 over 30 minutes the Connection specified in the title, then liofilizirovanny from water with 0.1% TFA.

Yield: 56 mg (salt with TFA)

MS-ESI: [M+H]+=485,2

HPLC: Rt=13,45 min, column Luna C-18(2), 3 ám, 100 x 2.0 mm, detection at UV=210 nm, column temperature=40°C, flow rate 0.25 ml/min, eluent a phosphate buffer solution of 50 mm pH 2,1/water/ACN=10/70/20 to 10/10/80 (about./vol.), the running time=20 minutes

Example 2

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(morpholine-4-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

Morpholine (5.0 ml) was added to a solution of tert-butyl 5-amino-4-(3-(2-bromoacetamide)phenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxamide (example 1(h), 1.0 g) in THF (50 ml). After 16 h at room temperature the mixture was concentrated under reduced pressure. The residue was purified column chromatography on silica gel using DCM/MeOH=9/1 as eluent. The crude product was further purified HPLC using a column Luna C-18, gradient elution: 0.1% of .TFA/water/ACN=3/97/0 to 3/7/90 30 min. Chi is the existence of a connection, specified in the title, liofilizirovanny of a mixture of 0.1% aq. TFA and water.

Yield: 215 mg (salt with TFA)

MS-ESI: [M+H]+=515,2

HPLC: Rt=vs. 20.62 min, Luna C-18(2), 5 μm, 150*2 mm, detection at UV=210 nm, column temperature=40°C, flow rate=0.25 ml/min, eluent a phosphate buffer solution of 50 mm pH 2,1/water/ACN/MeOH=from 10/72/17/1 to 10/18/68/4 (about./vol.), the running time=40 minutes

Example 3

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(thiomorpholine-4-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

Thiomorpholine (2,16 ml) was added to a solution of tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamide)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1(h)of 1.09 g) in DCM (50 ml). After 16 h at room temperature the mixture was diluted with DCM, washed the feast upon. aq. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified HPLC using a column Luna C-18, gradient elution: 0.1% of .TFA+10% aq. ACN/ACN=from 100/0 to 10/90 30 min. Net connection specified in the title, liofilizirovanny of water, acidified with 1 n aq. HCl.

Output: 816 mg

MS-ESI: [M+H]+=531,WASH: Rt=14,72 min, column Luna C-18(2), 3 μm, 100*2 mm, detection at UV=210 nm+254 nm, column temperature=40°C, flow rate=0.25 ml/min, eluent a phosphate buffer solution of 50 mm pH 2,1/water/ACN/MeOH=from 10/72/17/1 to 10/18/68/4 (about./vol.), the running time=20 minutes

Example 4

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperidine-1-yl)-acetamido)-the dryer is l)-thieno[2,3-d]pyrimidine-6-carboxamide

Piperidine (3.0 ml) was added to a solution of tert-butyl 5-amino-4-(3-(2-bromoacetamide)-phenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxamide (example 1(h), 1.0 g) in CH2Cl2(50 ml). After 16 h at room temperature the mixture was concentrated under reduced pressure. The residue was purified column chromatography on silica gel using DCM/MeOH=9/1 as eluent. The crude product was further purified HPLC using a column Luna C-18, gradient elution: 0.1% of .TFA/ACN=from 100/0 to 10/90 30 min. Net connection specified in the title, liofilizirovanny of a mixture of 0.1% aq. TFA and water.

Output: 851 mg (salt with TFA)

MS-ESI: [M+H]+=513,2

HPLC: Rt=37,3 min, Luna C-18(2), 5 μm, 150*2 mm, detection at UV=210 nm, column temperature=40°C, flow rate=0.25 ml/min, eluent a phosphate buffer solution of 50 mm pH 2,1/water/ACN=20/60/20 to 20/0/80 (about./vol.), the running time=40 minutes

Example 5

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(pyrrolidin-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

Pyrrolidine (3.0 ml) was added to a solution of tert-butyl 5-amino-4-(3-(2-bromoacetamide)-phenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxamide (example 1(h), 1.0 g) in CH2Cl2(50 ml). After 16 h at room temperature the mixture was concentrated under reduced pressure. The residue was purified column chromatography on silica gel using DCM/MeOH=9/1 as eluent. The crude product facilities is but purified HPLC, using column Luna C-18, gradient elution: 0.1% of .TFA/ACN=from 100/0 to 10/90 30 min. Net connection specified in the title, liofilizirovanny of a mixture of 0.1% aq. TFA and water.

Output: 616 mg (salt with TFA)

MS-ESI: [M+H]+=499,2

HPLC: Rt=37,5 min, Luna C-18(2), 5 μm, 150*2 mm, detection at UV=210 nm, column temperature=40°C, flow rate=0.25 ml/min, eluent a phosphate buffer solution of 50 mm pH 2,1/water/ACN=20/60/20 to 20/0/80 (about./vol.), the running time=40 minutes

Example 6

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperidine-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

Piperazine (2.5 g) was added to a solution of tert-butyl 5-amino-4-(3-(2-bromoacetamide)-phenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxamide (example 1(h), 1.0 g) in CH2Cl2(50 ml). After 16 h at room temperature the mixture was concentrated under reduced pressure. The residue was purified column chromatography on silica gel using DCM/MeOH=7/1 as eluent. The crude product was further purified HPLC using a column Luna C-18, gradient elution: 0.1% of .TFA/ACN=from 100/0 to 10/90 30 min. Net connection specified in the title, liofilizirovanny of a mixture of 0.1% aq. TFA and water.

Output: 766 mg (salt with TFA)

MS-ESI: [M+H]+=514,4

HPLC: Rt=33,7 min, Luna C-18(2), 5 μm, 150*2 mm, detection at UV=210 nm, column temperature=40°C, flow rate=0.25 ml/min, eluent a phosphate buffer solution of 50 mm pH 2,1/water/ACN=2060/20 to 20/0/80 (about./vol.), the running time=40 minutes

Example 7

The biological activity of SNO-LH and SNO-FSH in vitro

LH-agonistic activity of the compounds was determined on cells Chinese hamster ovary (Cho)stably transfected receptors in human and cotransfection sensitive element of camp (CRE)/promoter directing the expression of a gene-reporter luciferase Firefly. The binding of ligand to Gs-associated LH-receptor increases camp, which, in turn, induces an increased transactivation construction of luciferase reporter. The luciferase signal was quantified using luminescence. For test compounds were calculated value EU50(concentration of test compound that causes 50% of maximal stimulation). For this purpose was used the software GraphPad PRISM, version 3.0 (GraphPad software Inc., SanDiego).

In this way was tested FSH-agonistic activity of compounds on cells SNO, transfected with the gene-reporter luciferase and FSH receptor of human rights. The results are shown in the table.

Biological activity in vivo

For measuring the activity of compounds are agonists of the receptor LH/FSH studied the induction of ovulation in immature mice. In this sample of immature female mice were injected FSH isolated from urine (Humegon of 12.5 IU/animal). After about 48 hours the animals were injected with the compound is an agonist of LH/FSH at a dose of 50 mg/kg Animals were killed 24 hours after administration of the agonist of LH/FSH and under a microscope to determine the number of eggs in the fallopian tubes. The results are shown in the table.

Example No.NameEC50 CHO

LHR (M)
EC50 CHO

FSHR (M)
The number of tested animalsThe number of ova (50 mg/kg r.o.)
1Tert-butyl 5-amino-2-methylthio-4-(3-(2-(azetidin-1-yl)-acetamido)-phenyl)-thieno-[2,3-d]pyrimidine-6-carboxamide3,86E-094,62E-07151,6
2Tert-butyl 5-amino-2-methylthio-4-(3-(2-(morpholine-4-yl)-acetamido)-phenyl)-thieno-[2,3-d]pyrimidine-6-carboxamide2,24TH-094,E-08109,3
3Tert-butyl 5-amino-2-methylthio-4-(3-(2-(thiomorpholine-4-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide8,E-091,E-061019,8
4Tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperidine-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide6,E-092,E-07
5Tert-butyl 5-amino-2-methylthio-4-(3-(2-(pyrrolidin-1-yl)-acetamido)-phenyl)-Tien is[2,3-d]pyrimidine-6-carboxamide 6,E-094,80E-07
6Tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperazine-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide3,E-091,50 PPM-07

1. Derivatives of thieno[2,3-d]pyrimidine of the General formula I

or their pharmaceutically acceptable salts, where R1 and R2 together with the nitrogen atom to which they are attached, form a ring having from 2 to 6 carbon atoms, optionally containing one or more heteroatoms selected from N, O and/or S.

2. A compound selected from the group comprising tert-butyl-5-amino-2-methylthio-4-(3-(2-(azetidin-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide; tert-butyl 5-amino-2-methylthio-4-(3-(2-morpholine-4-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide; tert-butyl-5-amino-2-methylthio-4-(3-(2-(thiomorpholine-4-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide; tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperidine-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide; tert-butyl 5-amino-2-methylthio-4-(3-(2-(pyrrolidin-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide or tert-butyl 5-amino-2-methylthio-4-(3-(2-(piperazine-1-yl)-acetamido)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide.

3. Pharmaceutical compositions the Oia, with the ability to activate the receptor LH and FSH and derivative containing thieno[2,3-d]pyrimidine according to claim 1 and 2, or its pharmaceutically acceptable salt or MES in a mixture with a pharmaceutically acceptable auxiliary substance.

4. The use of FSH and LH-receptors.through derivatives of thieno[2,3-d]pyrimidine according to claims 1 and 2 or pharmaceutically acceptable salt or solvate for the manufacture of drugs for the regulation of fertility.

5. A method of treatment of disorders of fertility in patients in need, by introducing an effective amount of FSH and LH-receptors.through derivatives of thieno[2,3-d]pyrimidine according to claims 1 and 2.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1): wherein each R1 and R2 represents independently (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C3-C6)-cycloalkyl wherein each of them can be substituted possibly with halogen atom in the amount from 1 to 3; R3 represents isoxyzolydine-2-ylcarbonyl or tetrahydroisoxazine-2-ylcarbonyl wherein each ring is substituted possibly with one hydroxy-group; Q represents -CO- or -C(R4)(R5)- (wherein R4 represents hydrogen atom or (C1-C4)-alkyl, and R5 represents hydrogen atom or hydroxy-group); Ar represents 5-10-membered aromatic ring system wherein up to 4 ring atoms can be represented by heteroatoms chosen independently from nitrogen, oxygen and sulfur atoms and wherein this ring system is substituted possibly with one or more substitute. Proposed compounds can be used for modulation of autoimmune disease. Also, invention describes methods for synthesis of compounds of the formula (1) and pharmaceutical composition based on compounds of the formula (1).

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 44 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes glycine-substituted thieno[2,3-D]-pyrimidines of the formula (I): wherein X represents oxygen atom (O) or H,H; A represents sulfur atom (S), -NH, -N(R6), O or a bond; R1 represents (C1-C4)-alkyl, (C2-C4)-alkenyl, unsubstituted or substituted phenyl, thienyl, pyridyl; R2 represents hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-(C2-C4)-alkyl or hydroxy-(C2-C4)-alkyl; R3 and R4 are chosen independently from H, (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl; R5 represents H or (C1-C4)-alkyl, and R6 represents (C1-C4)-alkyl. Compound possess agonistic activity with respect to glycoprotein hormone, in particular, to compounds possessing agonist activity with respect to luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Also, invention describes pharmaceutical compositions containing such compounds and using these compounds in medicinal therapy, in particular, for fertilization control.

EFFECT: valuable biological and medicinal properties of compounds.

11 cl, 1 tbl, 27 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I):

wherein R1 means hydrogen atom; R2 means phenyl or phenyl mono- or di-substituted substituted with the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, perfluoro-(lower)-alkyl; R3 and R4 in common with carbon atoms to which they are bound form phenyl optionally and independently mono-, di- or tri-substituted with halogen atom or perfluoro-(lower)-alkyl, or form 5-, 6- or 7-membered saturated cycle optionally comprising heteroatom chosen from oxygen (O) and sulfur (S) atom and optionally and independently mono-substituted with (lower)-alkyl wherein indicated saturated cycle is condensed in ortho-position with 5-membered aromatic cycle optionally comprising S atom as a heteroatom, or with phenyl optionally and independently mono- di-substituted with the group: halogen atom, (lower)-alkyl, perfluoro-(lower)-alkyl or (lower)-alkoxy-group, and their pharmaceutically acceptable salts. Also, invention describes a method for synthesis of compounds, a pharmaceutical composition and using compounds for treatment and/or prophylaxis of DPP-IV-associated diseases. Compounds are used in treatment of such diseases as diabetes mellitus being first of all non-insulin dependent diabetes mellitus and damaged tolerance to glucose.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 39 ex

FIELD: agriculture, organic chemistry.

SUBSTANCE: invention relates to application of 2-[N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno[2,3-b]pyridine of formula as stimulator of sunflower growth.

EFFECT: stimulation of sunflower seed germination; increased sunflower productivity.

2 tbl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with the method of applying compositions containing trans-clomiphen and cis-clomiphen in the ratio by weight being above or equal 71/29 for increasing the level of testosterone in blood serum in male mammalian. Application of practically pure trans-clomiphen according to the present innovation provides increased level of testosterone both at the decrease and at sufficient content of this hormone, in case of necessity or desirability of such an increase for a mammalian, at decreased number of side effects as a result of clomiphen-based therapy.

EFFECT: higher efficiency of therapy.

4 cl, 3 dwg, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves prescribing walking in terrain in combination with biologically active additive «Phytopan M» received as herbal tea. Walking is done in the terrain having slope angle from 0 to 6° during 1.5-3 h individually dosing loading power taking into account heart beat rate frequency increment value measured during 1 min.

EFFECT: enhanced effectiveness of treatment course; improved microcirculation and a lymph drainage of small pelvis organs.

1 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes glycine-substituted thieno[2,3-D]-pyrimidines of the formula (I): wherein X represents oxygen atom (O) or H,H; A represents sulfur atom (S), -NH, -N(R6), O or a bond; R1 represents (C1-C4)-alkyl, (C2-C4)-alkenyl, unsubstituted or substituted phenyl, thienyl, pyridyl; R2 represents hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-(C2-C4)-alkyl or hydroxy-(C2-C4)-alkyl; R3 and R4 are chosen independently from H, (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl; R5 represents H or (C1-C4)-alkyl, and R6 represents (C1-C4)-alkyl. Compound possess agonistic activity with respect to glycoprotein hormone, in particular, to compounds possessing agonist activity with respect to luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Also, invention describes pharmaceutical compositions containing such compounds and using these compounds in medicinal therapy, in particular, for fertilization control.

EFFECT: valuable biological and medicinal properties of compounds.

11 cl, 1 tbl, 27 ex

FIELD: organic chemistry, steroids, biology.

SUBSTANCE: invention relates to steroid compounds of the general formula (X):

wherein in fragment of the formula XA:

each bond between C6 and C7, between C7 and C8, between C8 and C9, between C8 and C14 and between C14 and C15 is a single or double bond under condition that each atom C6, C7, C8, C9, C14 and C15 is bound with adjacent C-atom by a single bond or one double bond; CR3 means -CHOH; A means methylene or ethylene group; R4 and R4' mean (C1-C4)-alkyl, hydrogen atom (H); R20 means (C1-C4)-alkyl; R23 and R23' mean in common piperidine-1-yl, morpholine-4-yl, pyrrolidine-1-yl, piperazinyl possibly substituted with -OH, benzene, pyridine, pyrimidine, phenyl, alkoxycarbonyl group, or R23 means H and R23' means substituted alkyl. These compounds can be used for stimulation of meiosis in human oocytes. In proposed compounds steroid differs specifically as nitrogen atom of amino-group is bound with C17-atom of steroid skeleton by spacer A.

EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

FIELD: medicine, gynecology.

SUBSTANCE: invention relates to a method for rehabilitation of women after medicinal artificial abortion. Method involves prescription of the preparation "Multi-tabs-intensiv" in the first 24 h after expulsion of fetus in the dose 1 tablet for 1 month and additional administration of the preparation "Djufaston" from 16-th to 25-th days in the dose 10 mg, 2 times per a day. Method provides the full-value recovery of endometrium in I-II phases of cycle after medicinal artificial abortion under conditions of blocking receptors to progesterone at the level of uterus as target-organ and recovery of physiological menstrual cycle.

EFFECT: improved method for rehabilitation.

1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to anhydrous, antifungal, lubricating gel compositions comprising polyhydric alcohol, gelatinizing agent and an antifungal azole compound, and to a method for treatment of a patient with fungal infections comprising administration of indicated composition in a patient. Compositions shows the excellent warming and lubricating effect after its applying on skin and mucosal tissues and provides the effective treatment of fungal infections.

EFFECT: improved and valuable properties of compositions.

21 cl, 2 tbl, 11 dwg, 9 ex

FIELD: medicine, gynecology.

SUBSTANCE: patients should be suggested to take radon procedures as baths, gynecolopgical irrigations, microenemas, laserotherapy in autoresonance mode at altering frequency of laser apparatus independently against frequency characteristics of human body, at wave length of 0.89 mcm, power of 10 W onto area of uterine projection in case of genital endometriosis and uterine myoma at exposure of 15 min and onto mammary glands in case of diffuse proliferative mastopathies. Impact fields should be chosen by sectors ranged 10-16 per 10-15 sec for each impact field. Local therapy should be conducted about 2.5-3 h after taking radon procedures successively, not earlier. The first stage - baths with malavit at 1:5 dilution at exposure of 15 min. The second stage - after removing the solution out of vagina it is necessary to introduce malavit gel at a tampon for 4-6 h. The whole therapy should be carried out together with internal intake of mineral water 30-60 min before meals thrice daily per 3.5 mg/kg body weight. The innovation enables to achieve prolonged remission, normalize hormonal level in blood and duration of the second phase of the cycle and decrease cholesterol level in blood.

EFFECT: higher efficiency of correction.

1 dwg, 4 ex

FIELD: medicine, gynecology.

SUBSTANCE: as a suggested preparation one should apply dried defibrinated or non-defibrinated blood of Siberian stags or spotted deer. The preparation suggested should be prescribed perorally per 25 mg (1 capsule) twice daily, therapy course corresponds to 25-35 d. Application of this preparation in women at normal level of gonadotropins, positive gestagen-test, with no hyperandrogenia and hyperprolactinemia at the absence of menstrual cycle of more than 3 mo provides the onset of menstruations at stable positive effect. After carrying out 3 therapeutic courses no relapses had been observed.

EFFECT: higher efficiency for regulating menstrual cycle.

3 cl, 2 ex, 3 tbl

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with composition for fertilization in vitro and the system for its delivering (device). The composition suggested contains steroid at the quantity of below 5% (weight/weight), that is: 4.4-dimethyl-5α-cholesta-8.14.24-trien-3β-ol, hemisuccinate of 4.4-dimethyl-5α-cholest-8.14.24-trien-3β-ol; 5α-cholest-8.14-dien-3β-ol; hemisuccinate of 5α-cholest-8.14-dien-3β-ol; (20S)-cholest-5-en-3, 20-diol; N-(methionine)amide of 3β-hydroxy-4.4-dimethyl-5α-chol-8.14-dien-24-oic acid or cholest-5-en-16β-ol, and, also, additive (water-soluble protein or phosphoglyceride). Delivering system has got either one foramen or one cavity that contains the composition mentioned as a solid product or solution. The composition of sterols contains no constituents negatively affecting oocytes and could be dissolved in aqueous medium without physical impact (that is, heating, mixing or ultrasound treatment).

EFFECT: higher efficiency of fertilization in vitro.

8 cl, 5 ex, 3 tbl

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to dihydropyrimidine compounds of the formula (I*): their enantiomers, diastereoisomers and pharmaceutically acceptable salts wherein X1, X2 and X3 in common with atoms to which they are added form ring of the formula: or ; R1 represents hydrogen atom; R2, R3*, R4, R5, R6 and R7 have values given in cl. 1 of the invention claim. Also, invention relates to separate dihydropyrimidine compounds. Proposed compounds are inhibitors of calcium channel function being especially inhibitors of Kv1 subfamily of potential-overlapping K+-channels and especially inhibitors of Kv 1.5 that associated with super-rapid activating delayed cleaning K+-flow of Ikur and can be used in treatment of arrhythmia and Ikur-associated diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 589 ex

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