Using belamcanda chinensis extract as estrogen-like organ-selective medicinal preparation without uterotropic effect
FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to using Belamcanda chinensis extract for preparing organ-selective medicinal preparation without uterotropic effect or with minimal such effect that is used as estrogen-like preparation. This preparation is used in selective treatment and/or prophylaxis of cardiovascular diseases, in particular, atherosclerosis and osteoporosis, climacteric disturbances, especially for prophylaxis or softening congestions of blood. Extract is used in manufacturing a medicinal preparation in ready formulation for selective treatment and/or prophylaxis of cardiovascular diseases, in particular atherosclerosis, and for selective treatment and/or prophylaxis of osteoporosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood. Extract promotes to effective prophylaxis and/or treatment of cardiovascular diseases, in particular, atherosclerosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood.
EFFECT: valuable medicinal properties of extract.
4 cl, 4 ex
The present invention relates to the use of extracts of Belamcanda chinensis as an active type of estrogen the body-selective drug.
Produced in the ovaries 17-β-estradiol (wherever estradiol no mentioned hereinafter, it is every time refers to the physiological 17-β-estradiol [hereinafter also referred to as E2]), in the body normally has the function of accelerating proliferation. In addition to the regulation of the female cycle, for example, he has a homeostatic effect on bone metabolism and prevents the formation of atherosclerotic plaques in vascular endothelium.
During menopause due to cessation of ovarian function is a decrease in the level of estradiol. This causes weakening of the processes of proliferation and in the hypothalamus leads to increased activity of the pulse generator GTUG (pulser gonadotropin releasing hormone is a timer in the hypothalamus and therefore beating periodic secretion of LH (luteinizing hormone) steroids affecting its amplitude and frequency). In the end, women in menopause stimulated secretion of LH entails the so-called "tides", which are felt as irritating.
In the absence of a sufficiently high level of estradiol in the blood activity of osteoclasts and, thus, destruction of bone mass Ave which has, accompanied by the increased risk of bone fractures. At the same time, there is a long-term risk of plaque formation in the vascular system and, therefore, increases the risk of heart attacks.
Extracts of Cimicifuga racemosa and Belamcanda chinensis is well known in folk medicine, as it can soften perimenopause and post-menopausal disorders. To date this is explained by the fact that the extracts of both herbal substances show an action that is similar to estrogen, with all its positive effects on many organs of the human body, especially the brain, ovaries, bone, vascular system. In turn, similar to the estrogen effect on the uterus, vagina, mammary gland and liver will be unfavorable.
In the patent DE 19652183 described the production of extracts from Cimicifuga racemosa for the treatment of estrogen-dependent tumors. According to the patent, on the basis of these extracts obtained therapeutic drugs that estrogen-like action and inhibiting the proliferation of tumor cells.
Known drugs on the basis of extracts from plants of the family Iridaceae, for example by obtaining alcoholic essences with subsequent extraction of the active ingredients ether, as described in JP 63-196522, for the treatment of peptic ulcer disease, or water, and JV is rtovyh extracts from Belamcanda chinensis based on the lowest and polyhydric alcohols, to prevent skin aging, as shown in JP 07-138179.
It is also known that one of the active ingredients of plant extracts of the family Iridaceae is techoriented, various compounds which were isolated from plants Belamcanda chinensis, is described in detail in JP 63-030417 for use in quality control of drugs.
Bad, however, that until now was not available medicine from medicinal plants Belamcanda chinensis, which could be used in body-selective prevention or treatment in cases of estrogen deficiency and which not would be adverse effects on the uterus, vagina and other organs.
Accordingly, the present invention, therefore, is to obtain herbal substances from Belamcanda chinensis with effects similar to estrogen, but those that were organ-selective, without the influence or with a weak effect on the uterus.
The problem is solved by obtaining a basis of these extracts Belamcanda chinensis similar to the estrogen the body-selective drug, no uterotrophic effect or with such, what at least can be neglected.
In experiments both in-vitro and in-vivo surprisingly it was found that the extracts obtained from Belamcanda chinensis, organic the solvents or supercritical CO 2the body is selectively affect the Central nervous system, skeletal system and the vascular system in the absence of effects on the uterus, i.e. in the absence of the so-called uterotrophic effect. The extracts used in accordance with the invention, therefore, suitable for the production of medicinal preparations in the finished prescription form for selective treatment and/or prevention of osteoporosis.
Moreover, these extracts are suitable for the production of medicinal preparations in the finished prescription form for selective treatment and/or prevention of cardiovascular diseases, particularly atherosclerosis.
Moreover, they are suitable for receiving drugs with a ready recipe for selective treatment and/or prevention of peri-menopausal and post-menopausal psychovegetative disorders such as, for example, the tides.
Moreover, it was found that the component techoriented, which was isolated from Belamcanda schinensis, essentially causing the same effect as that of the extract as a whole.
Apart from Belamcanda chinensis, this feature has been found in other Poaceae. Iridaceae, such as, for example, Iris germanica, I. tectorum, I. illyrica, I. dichotoma.
|Types||Belamcanda chinensis (Leman)DC.=|
|Pardanthus chinensis (L.) Ker-Gawler, and|
|Ixia chinensis L. (=Gemmingia chinensis|
To obtain extracts preferable to use rhizomes, stems, leaves and/or petals.
Fundamental phytochemicals description Belamcanda chinensis and its component parts is given in the dissertation of Ms. A.Nenninger (LMU Munchen, 1997), entitled "Phytochemische pharmakologische und Untersuchungen von Belamcanda sinensis, einer Arzneipflanze der TCM und anderer Irisarten".
With pharmaceutical preparations according to the invention were first derived medicinal substance from Belamcanda chinensis and other things. Iridaceae, which act as full antagonists of estrogen receptors in bone, cardiovascular system and brain.
Further advantages and features of the present invention will be clear from the description of the experimental data with reference to figures showing:
Figure 1: comparison of organic and aqueous phases Cimicifuga racemosa. Schedule replacement typical of the estrogen receptor in experiments on ligand binding. The concentration of the starting solution 17.66 mg/ml and then diluted 1:2, 1:4, etc. up to 1:64.
Figure 2: LH in serum before and 2 hours after intravenous introduction the Oia extract Belamcanda chinensis, E2 and filler. Extract Belamcanda chinensis has a similar ability to reduce elevated levels of LH in serum and E2.
Figure 3 influence of Cimicifuga racemosa and E2 on the weight of the uterus (Figa) and LH levels in the blood (Fig.3b) ovariectomised rats after a seven-day subcutaneous injection (mean +SV, n=8*, p<0.05 compared with cremophor as filler);
Figa) weight of the uterus;
Fig 3b) concentration of LH in the blood;
Figa) the influence of Cimicifuga racemosa and E2 have ovariectomised rats after a seven-day subcutaneous injection (mean +SV, n=8*, p<0.05 compared with cremophor as filler) on the expression of mRNA for E2-receptor α proptional area of the hypothalamus;
Fig.4b) expression of mRNA for IGF1 and C3 in the uterus ovariectomised rats after a seven-day subcutaneous injection
Figs) expression of mRNA for collagen 1 (Coll 1) and osteocalcin dice ovariectomised rats after 7 days of subcutaneous injection.
Experimental confirmation similar to the estrogen effects of Cimicifuga racemosa and Belamcanda chinensis
Such selective estrogen exposure has been demonstrated in stages in order for the series test systems of different complexity.
1. Experiments in vitro
1.1. In vitro experiments on Cimicifuga racemosa
Recognition of these patterns components antibodies directed against 1-β -estradiol (=E2) shown in vitro.
Extract of Cimicifuga racemosa evaporated above the rest. Substances having different polarity, enriched phase separation between dichloromethane and water. The affinity for binding to components of both phases was determined in vitro estrogenic receptors from the uterus of the pig. Cytosolic estrogen receptors of the uterus pigs were allocated in accordance with a conventional method and used in experiments on the substitution of ligands.
It was found that the estrogen-like structure, for example, from Cimicifuga racemosa, inherently hydrophilic and lipophilic, because they can extract from the extract of organic solvents. Substances present in organically extracted phase, had an affinity with antibodies ten times stronger than the substance remaining in the aqueous phase.
The differences between the two phases in the series of experiments with binding to receptors estradiol were even more. Affinity binding of substances to the estradiol should be high enough to provide a selectively-competitive interaction with the receptor estradiol free from cells of the drug. Within this test system the aqueous phase had no activity, whereas the organic phase had a very strong binding to the receptor.
The results are presented in figure 1.
1.2. In vitro studies Belamcnda chinensis
According to the results of other studies it is known that extracts of Belamcanda chinensis also have components that are recognized by antibodies directed against the 17-β-estradiol, and contact with the receptor 17-β-estradiol (cf. Nenninger loc. cit.). Found that these extracts have similar estrogen different effects on different organ systems and, in particular, the lack of uterotrophic effect.
2. Experiments in vivo: a proof estrogenic effects on ovariectomized rat
The binding of E2 receptor very selectively; however, it is impossible to say, accelerated or inhibited subsequent processes inside the cell, i.e. whether the substance is an agonist or antagonist. This property can only be determined in a suitable cellular system or in the whole animal.
Ovariectomised rat is an established model of post-menopausal women, which stops the production of estradiol. As a result of external revenue 17-β-estradiol or substances, which are similar to estrogen exposure, there is a restoration of estrogen-sensitive anatomical and morphological parameters, such as the increasing weight of the uterus and distribution of dead skin cells, i.e. blascovich epithelial cells in the epithelium of the vagina, or hormonal changes, such as reducing the level of LH in the blood is bratanich animals.
All the following experiments were conducted on ovariectomised rats Sprague-Dawley (hereinafter, "RIA rat"), which has a weight of from 240 to 280,
2.1. A single application of Belamcanda chinensis
The manifestation of the action of the extract Belamcanda chinensis, acting by type of estradiol occurs very quickly. Even after a single intravenous introduction of filler, estradiol and extract Belamcanda chinensis RIA rat positively stops under the action of E2, and under the action of Belamcanda chinensis. When assessing the degree of improvement of the drug there was a significant decrease in the level of LH in the serum as compared with the previous levels, and in comparison with treated crematorium control animals. Cremator is an emulsifier based on polyethoxysiloxane derivatives of castor oil.
The results are presented in figure 2.
In the uterus of animals six hours after administration of the extract Belamcanda chinensis expression of uterine genes VEGF, IGF 1 and C3 did not change compared to control, whereas the introduction of estradiol caused a clear increase in gene expression of these three estrogen-regulated proteins. On constitutively expressed gene MDA none of these treatments had no significant influence.
These findings indicate that components of Belamcanda chinensis cause inhibition of the pulse generator GTUG in estrogenreceptor structures of the hypothalamus and, so, have estrogen-agonistic effect. While pituitary secretion of LH is significantly inhibited as components of Belamcanda chinensis, and estradiol. In contrast to estradiol, components Belamcanda chinensis have no uterotrophic activity. Estradiol significantly regulates the gene expression of VEGF, IGF 1 and C3 upwards - an action that is not observed in Belamcanda chinensis.
Conduct active experiments on the effect of IV injection of an extract of Belamcanda chinensis
24 rats (8 animals per group) under ether anesthesia the day before the experiment in implanted jugular vein catheter. On the day of the experiment took 6 blood samples with an interval of 10 minutes Immediately after selecting the sixth sample 62.5 mg (5%) extract of Belamcanda chinensis or 10 μg 17-β-estradiol (E2) or solution (5%) of cremophor in isotonic NaCl, 1 ml, respectively, was injected intravenously and for another 2 h with 10-minute intervals, taking blood samples. After 6 h after intravenous injection the animals were decapitated, took blood, cut out the ovaries, weighed and subjected to deep freezing in liquid nitrogen.
2.2. Single use lektoriranje
After a single injection lektoriranje determined its impact over time on the level of LH in the blood and is similar to estradiol immunoreactivity. Concentration lektoriranje in the blood of animals, opredelennaya through E2-RIA after 20 min, corresponds to about 100 equivalents picograms estradiol.
Techoriented initiating rapid decline in LH. The kinetics of reduction of LH, obtained under the action of lektoriranje up to 60 min after/in the introduction, is perfectly correlated with that of estradiol, but then does not lead to further reduction, and again slowly increases.
Holding: the HEL-rats had catheters placed in the external jugular vein under ether anesthesia 24 h before the start of the experiment in accordance with the methodology Harms & Ojega (Harms PG and Ojega SR: A rapid and simple procedure for chronic cannulation of the rat jugular vein. J. Appl. Physiol. (1974) 36: 391-392). The end of the tube was placed in a skin pocket on the neck. So when sampling blood does not need to touch the animals, the catheter is extended through silicone tubing. The catheter and the tube was washed with ringer's solution containing 50 IU (international units) of heparin/ml
Blood samples, each of 100 micrograms, selected animals with 10-minute intervals, and a selected amount reimbursed ringer's solution with heparin. Upon selection of the 6-th sample was injected intravenously at 1.0 ml of the appropriate test solution. Test solutions were used: 2% cremophor (= solution filler), techoriented 7 mg/ml filler, 17-β-estradiol 10 mcg/ml filler. Blood with 10 minute intervals were taken for 140 minutes
Blood samples, obtained in such the way, was placed in a vessel for reactions Eppendorf volume of 0.5 ml with 10 ml heparin-Losung (5000 international units/ml Liquemin), centrifuged for 10 min at 10000*g and the plasma was stored at -20°to conduct radioimmunological tests.
RIA for LH and prolactin based on anticigarette, control and iadarola drugs from firms NIH (Bethesda, Maryland, USA). The concentration of estradiol and cross-reacting isoflavones were measured using RIA from DPC, Bad Nauheim.
2.3. The effect of the extract Belamcanda chinensis after injection for 7 days
The effect of repeated administration of estradiol, extract Belamcanda chinensis and filler on the total weight, the weight of the uterus, hormonal levels and activation of genes of the uterus and bone was investigated at ovariectomised rats after daily subcutaneous injection for 7 days.
The average body weight of animals treated with cremophor and Belamcanda chinensis, did not differ, whereas animals treated with E2 were significantly easier. Also did not significantly differ mass mares animals treated with cremophor and Belamcanda chinensis, whereas those that received E2, more than tripled the weight of females.
Serum levels of LH in animals treated Belamcanda chinensis, has fallen slightly, but significantly compared to the control gramofonnyj fall under the action of estradiol was more pronounced.
In the fallopian extract mRNA of extras the diol was significantly increased gene expression of VEGF to 149% compared with controls after one week of injection. Under the action of the extract Belamcanda chinensis expression slightly, but unreliable, increased. Was not affected by expression is not estrogen-regulated essential genes, for example, cytochrome C oxidase (=SSC).
In the extract of the femoral head was determined the gene expression of collagen 1A1, osteocalcin, IGF1 and TGF β-mRNA. Estradiol, as well as Belamcanda chinensis, significantly inhibited the expression of all 4 genes, without affecting gene CSO.
The difference in action of estradiol and Belamcanda chinensis becomes pronounced after seven days of treatment. Extract Belamcanda chinensis is estradiol agonistic effect on pituitary secretion of LH by inhibiting the pulse generator GTUG and gene expression of four estrogen-regulated genes in the bone. In contrast, estrogenic effects on the uterus absent: none the weight of the uterus or estrogen-dependent VEGF gene is not exposed to an extract of Belamcanda chinensis. In contrast, estradiol causes swelling of the uterus and the activation of the VEGF gene.
Conducting subacute experiments on the effect of daily subcutaneous injection for 7 days:
8 animals from each experimental group (24 total) daily from 8:00 to 9:00) was subcutaneously injected 62.5 mg extract Belamcanda chinensis, 10 µg of estradiol or solvent (cremophor 5%, 1 ml), respectively. After 6 h after the last injection, animals were decapitated and each animal was selected as the aorta, the uterus, head of the left femur was cleaned and frozen in liquid nitrogen.
In the blood samples was determined by LH and estradiol immunoreactivity.
2.4. Repeated use of Cimicifuga racemosa
He previously 14 days after oophorectomy animal was subcutaneously injected corresponding to the test substance at doses of 62.5 mg Cimicifuga racemosa for the rat, or 8 µg of estradiol a rat once daily in the morning for 7 days. Both substances were dissolved in 5% cremophor, control animals received only the filler.
After decapitation of the animals brain, uterus and thigh analyzed for the regeneration of the mRNA. The concentration of LH in the blood of animals was determined using RIA. The expression of estrogen-regulated genes in these organs was determined using semi-quantitative analysis of RT-PCR.
The uterus of animals treated with estradiol were more than three times more weight than those of animals treated with Cimicifuga racemosa and filler, which essentially did not differ in their average values. This means that the components of Cimicifuga racemosa not affect the uterus of animals. The same applies for the vagina, where there is keratinization of epithelial tissues in animals treated with Cimicifuga racemosa and the filler, in direct contrast to animals receiving estradiol.
LH levels of animals treated filler, remained high, however,was significantly decreased under the action of estradiol, and Cimicifuga racemosa.
The results are presented on Figa) and 3b).
|The weight of the uterus (raw)||Cremophor (control)||Cimicifuga racemosa||E2|
|The number of animals||8||8||8|
|Average values (mg)||185.6||192.3||702.1|
|Concentrations of LH in the blood||Cremophor (control||Cimicifuga racemosa||E2|
|The number of animals||8||8||8|
|Mean values (ng/ml)||16.9||12.5||7.83|
As another marker of estrogenic effect was measured activation mRNA estrogen-stimulated protein. In this work, measurements were performed on tissues from the uterus, bone (badrena) and proptional zone of the hypothalamus.
In the hypothalamus as Cimicifuga racemosa, and E2 stimulated Express the mRNA for oestrogen receptor α (Figa). Bone Cimicifuga racemosa also behaves like estrogen and reduces by analogy with estradiol expression of mRNA for bone-specific collagen 1 and for genes osteocalcin (Figure 4 b).
On the contrary, did not observe any influence of Cimicifuga racemosa on estrogen-regulated genes in the uterus. Only estradiol increases mRNA for IGF and complementary factor C3 (Figs).
These findings prove that the components of Cimicifuga racemosa selectively affect different organs: the extract acts estrogenopodobnoe on the hypothalamus (the expression of E2 receptor and the release of LH) and on the bone, which is proved by the expression of genes for collagen 1 and osteocalcin. However, in contrast to estradiol, Cimicifuga racemosa does not affect the uterus, as manifested no effect on the weight of the uterus and gene expression IFG1 and C3.
Experiments performed in vivo and in vitro demonstrated that extracts of Cimicifuga racemosa and Belamcanda chinensis have similar estrogen action. It was found that the extracts of these medicinal substances are organ-selective Central nervous system, bones and blood vessels, but not in the uterus and, therefore, perfectly suitable for the prevention and treatment of estrogen deficiency without negative effects on the endometrium.
Identical effects were achieved using lektoriranje contained in Belamcanda chinensis.
the thus, the for the first time became available drugs with effects similar to estrogen, but no uterotrophic effect.
Such drugs can be used for the treatment and/or prevention of cardiovascular diseases, especially atherosclerosis, osteoporosis, peri - and post-menopausal psychovegetative disorders such as, for example, the tides.
Famous oral, intravenous and subcutaneous methods of use.
1. The use of an extract of Belamcanda Chinensis to obtain body-selective drug, no uterotrophic effect or with such, what at least can be neglected, as a drug that is similar to estrogen.
2. The use according to claim 1, characterized in that the extract is used for the production of a medicinal product in finished form for selective treatment and/or prevention of cardiovascular diseases, particularly atherosclerosis.
3. The use according to claim 1, characterized in that the extract is used for the production of a medicinal product in finished form for selective treatment and/or prevention of osteoporosis.
4. The use according to claim 1, characterized in that the extract is used for the production of a medicinal product in finished form for selective treatment and/or prevention of menopausal disorders, in particular to prevent the whether mitigation of the tides.
FIELD: medicine, neurology.
SUBSTANCE: the present innovation deals with treating cerebral vascular diseases accompanied with psychic disorders. For this purpose one should introduce homeopathic preparations named Cerebrum compositum and Hepar compositum per 2.2 ml every other day for 20 d intramuscularly, and beginning since the 11th d one should additionally prescribe Vertigohel preparation per 10 drops thrice daily for 10 d. The innovation suggested provides decreased different psychotic and unpsychotic depressive syndromes that considerably improves quality of life in this category of patients.
EFFECT: higher efficiency of therapy.
FIELD: medicine, cardiology, pharmacy.
SUBSTANCE: invention proposes applying moxonidine as an active component in preparing pharmaceutical compositions designated for treatment of injuries of heart muscle caused by infarction. Indicated compositions promote to prophylaxis in the infarction progression and to treatment of its complications also.
EFFECT: valuable medicinal properties of composition.
3 cl, 1 tbl, 1 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.
EFFECT: improved preparing method, valuable biochemical and medicinal properties.
10 cl, 6 tbl, 337 ex
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
21 cl, 70 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.
EFFECT: improved and valuable properties of formulation.
3 cl, 1 tbl, 1 ex
FIELD: organic chemistry, chemical technology, biochemistry.
SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):
eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):
wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):
wherein R1, R2 and R4 have above given values.
EFFECT: valuable medicinal and biochemical properties of compounds.
6 cl, 4 tbl, 5 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to applying compounds of the general formula (1):
as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):
. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.
EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.
3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex
SUBSTANCE: the suggested pharmaceutical composition at delayed release contains fluvastatin or its pharmaceutically acceptable salt hydroxypropylmethylcellulose and nonionic hydrophilic polymer. The latter is being hydroxyethylcellulose at average molecular weight ranged 90000-1300000 or hydroxypropylcellulose at average molecular weight ranged 370000-1500000 or polyethylenoxide at average molecular weight ranged 100000-500000. The suggested pharmaceutical composition is necessary to obtain peroral medicinal remedy for decreasing cholesterol level in plasma, it, also, provides the supply of fluvastatin into the body during prolonged period of time, for example, for more than 6 h and enables to minimize the possibility for premature release or "discharge" of considerable fluvastatin quantities.
EFFECT: higher efficiency.
21 cl, 6 dwg, 5 ex, 5 tbl
SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.
EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):
as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).
EFFECT: valuable medicinal and pharmacological properties of compounds.
9 cl, 1 tbl, 15 sch, 22 ex
FIELD: organic chemistry, vitamins, medicine, pharmacy.
SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.
EFFECT: valuable medicinal properties of compounds.
13 cl, 3 sch, 3 tbl, 6 ex
FIELD: medicine, chemical-pharmaceutical industry.
SUBSTANCE: invention relates to new applying EP4 receptors agonist for treatment and/or prophylaxis of diseases associated with loss of osseous mass. Agonists of EP4 receptors show high effectiveness in treatment of diseases associated with loss of osseous mass, among the, as osteoporosis of different genesis. Agonists of EP4 receptors involve prostaglandin skeleton base.
EFFECT: valuable medicinal properties of pharmaceutical composition.
16 cl, 3 tbl, 5 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):
wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.
EFFECT: valuable medicinal properties of compounds.
11 cl, 4 sch, 1 tbl, 34 ex
SUBSTANCE: on should apply the suggested compound of formula 1 for treating and/or preventing osteoporosis and related osseous diseases.
EFFECT: higher efficiency of therapy and prophylaxis.
7 cl, 2 dwg, 21 ex, 6 tbl
FIELD: organic synthesis.
SUBSTANCE: invention provides compounds of general formula I:
in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.
EFFECT: increased choice of estrogen receptor modulators.
19 cl, 7 tbl, 11 ex
SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.
EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.
41 cl, 13 dwg, 4 tbl
FIELD: medicine, therapy.
SUBSTANCE: simultaneously for 20 d one should prescribe calcium D3 two times daily in the morning and in the evening per 1 tablet or Beresh Plus drops. The quantity of drops for daily intake is equal to patients body weight in kg and they should be introduced in three stages during meals by drinking them up with sufficient amount of water. Application of the suggested method optimizes calcium exchange in patients with osteoporosis, enables to achieve earlier and more stable results in normalization of calcium content in bones by preventing, thus, osteoporotic fractures.
EFFECT: higher efficiency of pharmacological correction.
FIELD: organic synthesis.
SUBSTANCE: invention provides compounds of general formula I:
, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.
EFFECT: increased choice of cysteine protease inhibitors.
34 cl, 1 tbl, 13 ex
FIELD: medicine, gynecology, pharmacy.
SUBSTANCE: invention relates to a method for supporting amenorrhea in women subjecting the constant progestin therapy providing to induce endometrial atrophy and to avoid significant unfavorable adverse effects that accompanying administration of progesin usually. Invention provides the complete amenorrhea without intermittent bleeding or secretion of small blood amount from vagina and without significant unfavorable adverse effects as can be occur in other methods. The curative effect is attained due to the constant intravaginal administration of progestin in water-insoluble, water-swelling cross-linked polymer based on polycarboxylic acid.
EFFECT: improved supporting method, valuable medicinal properties of composition.
7 cl, 3 dwg, 2 ex