Method and composition for reducing blood pressure and treat congestive heart failure in a mammal

 

(57) Abstract:

The present invention can be used in veterinary medicine and relates to compositions and methods for lowering blood pressure and treat congestive heart failure in mammals. The invention relates to synergistic compositions comprising at least two therapeutic agent selected from the group consisting of a renin inhibitor, an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II, and inhibitors and antagonists are present in a quantity sufficient for synergistic therapeutic effect, such as lowering blood pressure and treat congestive heart failure in mammals. In addition, this invention relates to methods achieve a synergistic therapeutic effect as lowering blood pressure and treat congestive heart failure in mammals, and these methods include receiving these mammals (either sequentially or simultaneously), at least two therapeutic agents selected from the group consisting of a renin inhibitor, an inhibitor of the enzyme converting angiotensin I and antagonists and crystals, 3 table.

This invention relates to compositions and methods to achieve therapeutic effect as lowering blood pressure and treat congestive heart failure in mammals. More specifically, this invention relates to synergistic compositions comprising at least two therapeutic agent selected from the group consisting of a renin inhibitor, an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II, and inhibitors and antagonists are present in a quantity sufficient for synergistic therapeutic effect, such as lowering blood pressure and treat heart failure in mammals. In addition, this invention relates to methods achieve a synergistic therapeutic effect as lowering blood pressure and treat congestive heart failure in mammals, and these methods include receiving specified mammal (either sequentially or simultaneously), at least two therapeutic agents selected from the group consisting of a renin inhibitor, an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II, in a quantity sufficient to demonstrate the splitting effect of angiotensin on the renin enzyme, described in U.S. patent No. 4 814 342 and U.S. patent No. 4 895 834. Among other things such renin inhibitors useful for lowering blood pressure and in the treatment of congestive heart failure and also to achieve other therapeutic effects.

Examples of inhibitors of the enzyme converting angiotensin I is described in U.S. patent No. 4 046 889 and 4 374 829. Among the known inhibitors of the enzyme converting angiotensin I mentioned captopril, enalapril, lisinopril and ramipril. Such inhibitors of the enzyme converting angiotensin I ACE inhibitors are also useful in reducing blood pressure in mammals and in the treatment of congestive heart failure as well as to achieve other therapeutic effects.

Examples of antagonists of angiotensin II (AP antagonists described in U.S. patent No. 4 355 040, U.S. patent No. 4 880 804, European patent N 253 310, European patent No. 323 841 and European patent No. 324 377. Among the known AP antagonists mentioned Dup 753. Such antagonists, among others, are useful in reducing blood pressure in mammals and in the treatment of congestive heart failure.

The present study compares the effect of known inhibitors of renin H77 effect Aiy achieve the same effect, the renin inhibitor and ACE inhibitor operate by the same mechanism of recovery of angiotensin II. Another presents the study compares the hemodynamic effects of MK-422, ACE inhibitor and an inhibitor of renin and it is concluded that the reaction to the action of each is identical. Sweet C. S. and J. other Cardiovax Pharmacol 6: 1067 - 1075 (1984). Another study comparing the effect of the renin inhibitor H77 and ACE inhibitor captopril published Oldman AA and al in J. Cardiovax Pharmacol 6: 672 - 677 (1984). In this study reported that injection of captopril in infusion H77 gives a small additional hypotensive effect.

Until the present invention, described here, there were no reports about the use of a renin inhibitor with ACE inhibitor for achieving a synergistic effect on lowering blood pressure or any other synergistic therapeutic effect, such as treatment of congestive heart failure when using a certain amount of an inhibitor of renin and ACE inhibitor.

Furthermore, until the present invention no reports of the use or intention to use the renin inhibitor together with AP antagonist, ACE inhibitor, together with AP antagonist or inhibitor rent synergistic effect on lowering blood pressure or synergistic effect for the treatment of congestive heart failure.

The present invention relates to methods and compositions useful for achieving such a synergistic therapeutic effects as lowering blood pressure in mammals, in need, and to treat congestive heart failure in mammals. More specifically, this invention relates to methods of lowering blood pressure in mammals, in need, including reception of the specified mammal in a quantity of at least two therapeutic agents selected from the group consisting of a renin inhibitor, an inhibitor of the enzyme converting angiotensin I, and antagonists of angiotensin II. This invention also relates to compositions useful for receiving mammal in need of some number of at least two therapeutic agents selected from the group consisting of a renin inhibitor, an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II. This invention also relates to methods of treatment of congestive heart failure in mammals, which include the reception of these mammals a number of at least two therapeutic agents selected from the group consisting of an inhibitor Reny herein, the term "synergistic" means, the effect achieved by the methods and compositions of the present invention, more than the sum of effects from methods and compositions comprising the inhibitors and antagonists of the present invention separately and in the amount used in these methods and compositions.

In accordance with one aspect of this invention it is now possible to achieve a synergistic therapeutic effect in a mammal using such a large number of renin inhibitor and ACE inhibitor, which, if you enter one drug, are not able to give this effect, and this effect is more than the sum of the effects achieved by each inhibitor separately. Preferred therapeutic effects obtained in accordance with this aspect of the present invention, are low blood pressure and treat congestive heart failure in need of mammals. Take a renin inhibitor and ACE inhibitor can sequentially or simultaneously, preferably simultaneously receiving. When serial reception, the renin inhibitor can be applied before and after ACE inhibitor, but it is preferable to take the renin inhibitor to ACE inhibitor.

In accordance with another aspect of this from the TBE renin inhibitor and an AII antagonist, which separate reception are not able to give this effect, and this effect is more than the sum of the effects achieved with separate reception inhibitor and antagonist. Preferred therapeutic effect achieved in accordance with the present invention is the lowering of blood pressure and treatment of congestive heart failure in need of mammals. Take a renin inhibitor and an AII antagonist can sequentially or simultaneously, preferably simultaneously receiving. In the case of serial reception, the renin inhibitor can be applied before or after AII antagonist, it is preferable to take the renin inhibitor to AII antagonist.

In accordance with another aspect of the invention it is now possible to achieve a synergistic therapeutic effect in a mammal with so many ACE inhibitor and an AII antagonist which separate reception are not able to give this effect, and this effect is greater than the sum of the effects achieved with separate reception inhibitor and antagonist. Preferred therapeutic effect achieved in accordance with this aspect of the invention is the lowering of blood pressure and treatment of congestive heart condition is on, or simultaneously, the preferred simultaneous reception. In the case of consistent application of the ACE inhibitor can be taken before or after AII antagonist, it is preferable to apply the ACE inhibitor to AII antagonist.

In accordance with another aspect of the invention it is now possible to achieve a synergistic therapeutic effect in a mammal with the high number of renin inhibitor, an ACE inhibitor and an AII antagonist which separate reception are not able to give the above effect, and this effect is more than the sum of the effects achieved with separate reception inhibitor and antagonist. Preferred therapeutic effect achieved in accordance with this aspect of the invention is the lowering of blood pressure and treatment of congestive heart failure in need of mammals. Take a renin inhibitor, an ACE inhibitor and an AII antagonist can sequentially or simultaneously, any two of them or all three. The preferred simultaneous reception of all three components. When serial reception inhibitors and antagonist can be applied in any order. However, when serial reception preferable to apply the inhibitor of renin to ACE inhibitor, which, in turn, taking renin inhibitor, and/or ACE inhibitor, and/or AII antagonist, the present invention provides a particularly useful means of achieving a therapeutic effect in reducing blood pressure and treat congestive heart failure with less than a therapeutic level of a renin inhibitor, and/or ACE inhibitor, and/or AII antagonist. Therefore, when using this invention may minimally reduce the potential side effects associated with the use of large therapeutic doses of renin inhibitor, an ACE inhibitor and/or AII antagonist, and to achieve a therapeutic effect in reducing blood pressure or treatment of congestive heart failure.

The compositions of this invention include a number of renin inhibitor, or ACE inhibitor or AII antagonist or inhibitor of renin and ACE inhibitor, or an inhibitor of renin and AII antagonist or ACE inhibitor and an AII antagonist or a renin inhibitor, an ACE inhibitor and an AII antagonist, and pharmaceutically suitable diluent or carrier. The number of renin inhibitor, an ACE inhibitor and an AII antagonist in such compositions is such that each of them separately in such quantity cannot provide this level terapevticheskoj is accordance with the invention a number of renin inhibitor, useful for receiving mammal in combination with the compositions of the present invention, including an ACE inhibitor or AII antagonist or ACE inhibitor, and AII antagonist.

Compositions of the present invention, including an ACE inhibitor, useful for receiving mammal in combination with the compositions of the present invention, comprising a renin inhibitor or AII antagonist or a renin inhibitor, and AII antagonist.

Compositions of the present invention, including an ACE inhibitor, useful for receiving mammal in combination with the compositions of the present invention, comprising a renin inhibitor or AII antagonist or a renin inhibitor, and AII antagonist.

Compositions of the present invention, including AII antagonist, useful for receiving mammal in combination with the compositions of the present invention, comprising a renin inhibitor, or ACE inhibitor, or an inhibitor of renin and ACE inhibitor.

A particular advantage of the present invention is that the compositions may include fewer renin inhibitor, and/or ACE inhibitor, and/or AII antagonist than is required for the compositions containing only a renin inhibitor, or only ACE inhibitor, or only AII Anta is tagonist, relevant to the present invention are compositions with reduced side effects, which may depend on the number of renin inhibitor, and/or ACE inhibitor, and/or AII antagonist required to achieve the same therapeutic effect, as for the compositions of this invention.

The present invention is not limited in any way to any specific inhibitors of renin and/or ACE inhibitors, and/or AII antagonists, applicable to all known renin inhibitors, ACE inhibitors and AII antagonists, as well as those that are being developed and will be opened. The synergistic effect of the present invention produces no special renin inhibitor, or ACE inhibitor or AII antagonist, and joint use of a renin inhibitor and ACE inhibitor, or an inhibitor of renin and AII antagonist or ACE inhibitor and an AII antagonist, as described in the invention. However, the preferred renin inhibitors for use in the methods and compositions of the invention are [-R[-R*-S*(S*S*)]-- [[2-[2-(4-morpholine-1-carboxamido)-1-oxo-3-phenyl-propyl]amino]- 3-methylthio-1-oxo-propyl amino cyclohexanebutyrate acid, isopropyl ester, preferred ACE-inhibitorresistant is Dup 753. Particularly preferred ACE inhibitors for use in the methods and compositions of the present invention are captopril, enalapril.

As discussed above, by applying this invention, it is now possible to achieve the desired therapeutic effect with less of a renin inhibitor, and/or ACE inhibitor, and/or AII antagonist than before. The desired therapeutic effect of this invention is (but is not limited to the lowering of blood pressure and/or treatment of congestive heart failure in mammals. Prior to this invention it was known that to achieve the desired therapeutic effect requires a certain amount of ACE inhibitor or AII antagonist or a renin inhibitor. Now to achieve the specified therapeutic effect in accordance with the invention require fewer renin inhibitor in combination with a number of ACE inhibitor and/or AII antagonist, the amount of which or which is less than that required for the desired therapeutic effect, as a result of this synergistic therapeutic effect is equal to or exceeds the achieved therapeutic effect. In addition, in accordance with this and is in a joint application with AII antagonist and/or a renin inhibitor, the number of which is smaller than required for a specific therapeutic effect, as a result of this synergistic therapeutic effect is equal to or exceeds the specified therapeutic effect. In addition, a synergistic therapeutic effect is achieved when using the methods and compositions of the present invention, more than the sum of the effects achieved when using the methods and compositions separate application or renin inhibitor, or ACE inhibitor or AII antagonist in an amount equal to the amount used in the methods and compositions of the invention.

In the practice of the methods of this invention, comprising the simultaneous or sequential in any order) the reception of two or more components (a renin inhibitor, and/or ACE inhibitor, and/or AII antagonist) can be applied orally, transbukkalno, parenteral, by inhalation, rectally or locally. Preferred oral administration. And even more preferred oral coadministration. Used here, the term "parenterale" includes subcutaneous, intravenous, intramuscular and vnutrigrudne injection and infusion, but is not limited to this. When serial reception of the renin inhibitor is 2">

The pharmaceutical compositions of the present invention include compositions consisting of or from a renin inhibitor, or ACE inhibitor or AII antagonist in an amount less than necessary to achieve the desired therapeutic effect, together with a pharmaceutically suitable diluent or carrier, and a composition consisting of two or more components (inhibitor of renin, ACE inhibitors, AII antagonist), each of which is present in amount less than that required to achieve the desired therapeutic effect, separate reception, together with a pharmaceutically suitable diluent or carrier.

Compounds of the present invention can be administered orally in the form of various dosage forms, for example, they can be prepared with various pharmaceutically suitable inert carriers in the form of tablets, capsules, pellets, pastilles, solid candles, powders, sprays, aqueous suspensions, elixirs, syrups and the like forms. Such carriers include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents, etc. in Addition, such pharmaceutical forms for oral administration can be sweetened and/or to give them opredelennogo invention is in such forms for oral administration range from about 0.5% to 90% by weight of the entire composition, i.e. a quantity sufficient to provide the required dose. Other suitable dosage forms of the compounds of the present invention include, but are not limited to) recipes for controlled release of drugs and devices, well known to experts.

For oral administration can be applied to tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate, together with various disintegrators such as starch, preferably potato or corn starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, as fillers in soft and hard gelatin capsules can also be used such lubricate as magnesium stearate, sodium lauryl sulphate and talc or compositions of similar type, including lactose, or milk sugar along with high-molecular glycols. If oral intake is required aqueous suspensions and/or elixirs, the main active ingredient in them can be combined with various sweetening or gives taste agents, painted materials or dyes and, the EU is a combination.

Although the oral route of administration of the compounds of the present invention are preferred, they can be taken and dropped.

For receiving parenteral use, solutions of the compounds in sesame oil, or oil of groundnuts, or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding pharmaceutically suitable salts. Optionally, in such aqueous solutions add a buffer or liquid diluent isotonic with the basic salt solution, or glucose. Such special aqueous solutions are suitable for intravenous, intramuscular or subcutaneous injection. In this regard, apply sterile water environment quickly get the standard methods, well known to specialists. For example, distilled water is usually used as a liquid diluent, and the final preparation is passed through a suitable bacterial filter, for example a glass filter (sintereel glass filter), or diatomaceous earth (diatomaccous-earth), or a porcelain filter (unglazed porcelain filter). Preferred filters of this type are the filters Bercefeld, Chemberland and Asbestos Disk-Metal Seitz, in which the liquid is drawn into a sterile container using a pump. Upon receipt of such solutions for injection Neobee through the skin, may include, for example, solutions, lotions, ointments, creams, gels, suppositories, shape, releasing the drug at a certain speed, and the ways to use them. Such forms, including a particular compound or compounds may also contain ethanol, water, enhancing the penetration means and inert media, such as the materials forming the gel, mineral oil, emulsifying agents, benzyl alcohol and the like. Special compositions that enhance passage through the skin, are disclosed in European patent N 271 983 and presented in the name of the continuation of this invention, the conclusions included in the present invention as references.

Necessary to achieve the desired therapeutic effect dosage renin inhibitor, and/or ACE inhibitor, and/or AII antagonist is the task of the practitioner, using the advantages disclosed in the invention. Interval dose for presents specific inhibitors of renin is from 0,250 mg/kg to 1.4 mg/kg (intravenous) and from 40 to 1200 mg/day (orally). Interval dose for the specific ACE inhibitors ranges from 40 to 450 mg/day (oral) and 20 mg/day (parenteral). Interval dose, not only for the mg/kg (oral) and 3 mg/kg (intravenously). The dosage corresponding to the present invention, can be varied depending on the needs of the patient, severity of the conditions and terms of acceptance. In addition, the prescribed dose can be split and take smaller portions throughout the day. The dose or dose that gives an optimal synergistic effect, pick, coordinating pharmacokinetic properties, such as the amount of input and T, therapeutic agent of the present invention, so that therapeutic window of each agent maximum overlap. This dosage is quickly determined by experts on the basis of the disclosed material.

A synergistic effect in reducing blood pressure when the joint introduction of a renin inhibitor and ACE inhibitor demonstrated as described below.

Use the renin inhibitor (RI) isopropyl ester [-R[-R*-S*(S*S*)]-- [[2-[[2-(4-morpholine-1-carboxamido)-1-oxo-3-phenyl-propyl] -amino] - 3-methylthio-1-oxo-propyl]amino]-cyclohexanemethanol acid, described in U.S. patent No. 4 814 342. Use the ACE inhibitor captopril. Guinea pigs Male Hartley weighing from 250 to 300 g were obtained from Charles River Laboratories, Lakevierv, new Jersey. Guinea pigs were allowed to acclimate for at least two weeks is Ali injection of Furosemide (furosemide, hasix2 mg/kg, intramuscularly) for three consecutive days. At least 24 hours before the experiment, animals were subjected to anesthesia with xylazine (xylazine Rompun10 mg/kg, subcutaneously) and ketamine (ketamine, vatalar80 mg/kg, intramuscularly) implanted cannula into the aorta via the right carotid artery, using aseptic technique, to directly change the values of arterial pressure (MAP). Also put a cannula (PE-50) into the left jugular vein for intravenous administration of the compounds. Both catheter output in the shoulder on the side of the animal and washed with a solution of dextrose, reduce blood clotting. To prevent blood clots each cannula filled with heparin with a concentration of 1000 IU/ml After surgery the animals give antibacterial trimethoprim/sulfamethoxazole (Di-Irem30 mg/kg, subcutaneously). Animals allowed to recover with water and put on butatriene food. On the day of each experiment Guinea pig give additional injection of furosemide (6 mg/kg, intramuscularly) to speed up the output of sodium and placed in a sound-proof vented box with a glass wall to watch. Values arteria the th gauge. The amount of blood pressure, heart rate were continuously recorded on the oscilloscope Grass Model 7D. The blood pressure value receive approximately every 20 seconds using your computer, the IBM PS/2 model 30 with program calculate the magnitude of blood pressure from the integrated spectrum. Get values corresponding period of at least an hour before and 2 hours (usually 4 hours) after administration of the drug. Intravenous check the connection, and then 250 ml of dextrose, reduce blood clotting.

For the quantitative determination of the baseline response to each medication get waves of response to dose for renin inhibitor (RI) of 0.3 - 3.0 mg/kg, intravenously, and captopril: 0.03 to 1.0 mg/kg, intravenously (n = 4 - 8). In experiments with the joint introduction of inhibitor captopril renin and first give a renin inhibitor, and is followed immediately by captopril. The dose together renin inhibitor and an inhibitor of the enzyme converting angiotensin chosen on the basis of the effects caused by reduction of pressure. Therefore, the contribution to the effect of each medication can be quantitatively determined by integrating and compare with the expected effect to determine vladenie in table I the values of changes in arterial blood pressure ( map) for various jointly entered doses of renin inhibitor (RI) and ACE inhibitor, see below AOC-MAR region above the graph of the response, the dose is calculated for each component using the method of line.

As shown in table I, the joint introduction of a renin inhibitor and ACE inhibitor results in a synergistic effect, significantly higher amount of effects achieved for each inhibitor separately.

The data of table I are obtained to calculate the AOC-MAR as averages MAR for all animals for each dose.

When analyzed the data of table I to calculate AOC-MAR averaged square of the graph of response to dose, found that AOC-MAR to 0.5 mg/kg RI + 0.05 mg/kg of captopril accidentally reflects data that is based only on three of the six animals. In the following table II shows the data AOC-MAR for the experiments presented in table I, and the data are now the results of the determination of the area above the graph of response to dose for each animal and the dose averaged AOC-MAR accurate to the standard deviation. In addition, data for the 0.5 mg/kg RI + 0.05 mg/kg of captopril reflect the results for all six animals received such a dose. The area above the graph of the response, the dose is calculated using the method of the ladder inhibitor results in a synergistic effect, significantly higher amount of effects achieved for each inhibitor separately.

Conventional procedures described above, are obtained and are presented in table III the values of the changes in blood pressure, expressed in the form AOC-MAR, for different doses of the ACE inhibitor is captopril, AII antagonist DUP 753 (losartan) and ACE inhibitor captopril + AII antagonist 753 (losartan). In the experiment with the joint receiving captopril and DUP 753 (losartan) first give captopril, and is followed immediately by DUP 753 (losartan). Dose jointly given captopril and DUP 753 determined on the basis of the maximum effect to reduce pressure in case of separate administration. In table II, EPA-MAR are average values of the area above the graph of response to dose for each animal depending on the dose. The area above the plots of the response, the dose is calculated using the method of line.

Table III shows that the combined use of ACE inhibitor and an AII antagonist results in a synergistic effect greater amount of effects achieved for ACE inhibitor and an AII antagonist separately.

1. The way to reduce blood pressure or treatment of congestive heart failure in a mammal, vkluchaiut at least two selected from the group consisting of a renin inhibitor, an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II.

2. The method according to p. 1, characterized in that a certain amount of a renin inhibitor and an inhibitor of the enzyme converting angiotensin I is injected into the body of the mammal at the same time.

3. The method according to p. 2, characterized in that as a renin inhibitor used [-R[-R*, -S*(S*,S*)]--hydroxy-- [[2-[[2-(4-morpholine-1-carboxamido)-1-oxo-3-phenylpropyl] amino] -3-methylthio-1-oxopropyl]-amino]cyclohexanemethanol acid, and by inhibiting the conversion of angiotensin I use captopril, or enalapril, or lisinopril or ramipril.

4. The method according to p. 1, characterized in that the inhibitor of the enzyme converting angiotensin I is a captopril, enalapril, lisinopril or ramipril and antagonist of angiotensin II is a losartan.

5. Pharmaceutical composition for lowering blood pressure or treating congestive heart failure in a mammal, comprising the medicinal substance and a suitable pharmaceutical diluent or carrier, characterized in that the quality of medicinal substances it includes a certain amount of time of conversion of angiotensin I and antagonist of angiotensin II.

6. The composition according to p. 5, characterized in that as a renin inhibitor, it includes [-R[-R*, -(S*, S*)]-hydroxy-- [[2-[[2-(4-morpholine-1-carboxamido)-1-oxo-3-phenylpropyl]amino]-3-methylthio-1-oxopropyl]amino]cyclohexanemethanol acid as an inhibitor of the enzyme converting angiotensin I - captopril, or enalapril, or lisinopril or ramipril, and as an antagonist of angiotensin II losartan.

7. Medicine to lower blood pressure or treat congestive heart failure in a mammal, consisting of two pharmaceutical compositions, including pharmaceutical substances, characterized in that the quality of drugs second pharmaceutical composition includes a quantity of a renin inhibitor or an inhibitor of the enzyme converting angiotensin I or antagonist of angiotensin II, or a certain amount of a renin inhibitor and an inhibitor of the enzyme converting angiotensin I, or a certain amount of an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II, or a certain amount of a renin inhibitor and an antagonist of angiotensin II, and the first pharmaceutical composition as medicinal substances includes defined is giotensin I and antagonist of angiotensin II and optionally pharmaceutically suitable diluent or carrier, provided what drug is the first pharmaceutical composition is not contained in the second pharmaceutical composition.

8. Medicine to lower blood pressure or treat congestive heart failure in a mammal, consisting of two pharmaceutical compositions, including pharmaceutical substances, characterized in that the quality of drugs second pharmaceutical composition includes a quantity of medicinal substance selected from a renin inhibitor, an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II, and the first pharmaceutical composition as a medicinal substance includes a quantity of a renin inhibitor and an inhibitor of the enzyme converting angiotensin I, or a certain amount of an inhibitor of the enzyme converting angiotensin I and antagonist of angiotensin II, or a certain amount of a renin inhibitor and an antagonist of angiotensin II and optionally pharmaceutically suitable diluent or carrier, provided that the medicinal substance, the second pharmaceutical composition is not contained in the first pharmaceutical composition.

 

Same patents:

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis
The invention relates to physiologically active compounds and relates amidoalkylation and method of production thereof

The invention relates to a new compound is a sodium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid of formula (I), which is antioxidant and anti-ischemic activity and may find application in medicine

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

The invention relates to a new compound - monoethanolammonium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid f-crystals (I), which is antioxidant and anti-ischemic activity and may find application in medicine

The invention relates to medicine, the inhibitor of intimal hypertrophy, containing as the active ingredient oxindole derivative represented by formula I, or its salt, where R represents a hydrogen atom, phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a phenyl group, which may be substituted, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a hydrogen atom, a lower alkyl group, benzyl group or benzosulfimide group which may be substituted, or acyl group,axially group, lower alkoxycarbonyl group, phenylcarbamoyl group which may be substituted, or triptorelin group represents CH or N; n represents an integer from 0 to 4, inclusive, that indicates the number of substituents and double dotted/solid line represents a simple bond or double bond, which has an excellent inhibitory action against intimal hypertrophy, and used as an agent for prevention (treatment) attenuation of proliferative vascular diseases such as restenosis after RTSA, arteriosclerosis, peripheral embolism and angia, use oxendolone derived to obtain an inhibitor of intimal hypertrophy, compositions for inhibiting intimal hypertrophy and method of prevention and treatment of intimal hypertrophy

The invention relates to medicine, particularly cardiology, and for slowing the progression of corneoscleral

The invention relates to pharmacology, in particular ORGANOMETALLIC compounds possessing biological activity, which can find application in drug development for the prevention and treatment of coronary heart disease
The invention relates to physiologically active compounds and relates amidoalkylation and method of production thereof

Pharmaceutical drug // 2146522
The invention relates to a combined preparation

The invention relates to a new compound is a sodium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid of formula (I), which is antioxidant and anti-ischemic activity and may find application in medicine

The invention relates to new nitrates alcohols of General formula (I), where R', R", n, m are presented in the claims, the way they are received by means of nitration of 3-(acylaminoalkyl)-tetrahydro-1,3-oksazolov and-oxazino

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

The invention relates to a new compound - monoethanolammonium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid f-crystals (I), which is antioxidant and anti-ischemic activity and may find application in medicine

The invention relates to medicine, the inhibitor of intimal hypertrophy, containing as the active ingredient oxindole derivative represented by formula I, or its salt, where R represents a hydrogen atom, phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino or halogen atom, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxyl group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a phenyl group, which may be substituted, or pyridyloxy group which may be substituted by a lower alkyl group, lower alkoxygroup, lower alkylaminocarbonyl, hydroxy-group, amino group, lower alkylamino, a halogen atom, a lower alkoxycarbonyl group or a carboxyl group, a represents a hydrogen atom, a lower alkyl group, benzyl group or benzosulfimide group which may be substituted, or acyl group,axially group, lower alkoxycarbonyl group, phenylcarbamoyl group which may be substituted, or triptorelin group represents CH or N; n represents an integer from 0 to 4, inclusive, that indicates the number of substituents and double dotted/solid line represents a simple bond or double bond, which has an excellent inhibitory action against intimal hypertrophy, and used as an agent for prevention (treatment) attenuation of proliferative vascular diseases such as restenosis after RTSA, arteriosclerosis, peripheral embolism and angia, use oxendolone derived to obtain an inhibitor of intimal hypertrophy, compositions for inhibiting intimal hypertrophy and method of prevention and treatment of intimal hypertrophy

The invention relates to medicine, particularly cardiology, and for slowing the progression of corneoscleral

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

The invention relates to pharmaceutical compositions containing as active ingredient a derivative of triazine following General formula I or its MES, or its salt and a derivative of triazine

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts
Up!