Therapeutic agent for treating hypertension

FIELD: medicine, pharmaceutics.

SUBSTANCE: agent for treating systemic hypertension contains as an active ingredient a compound presented by formula (1): or its pharmaceutically acceptable salt.

EFFECT: preparation of the new agent for treating systemic hypertension.

12 cl, 7 ex, 7 dwg

 

The technical field

The present invention relates to therapeutic tool for the treatment of hypertension (hereinafter may be referred to as "agent for the treatment of hypertension") and the means for reducing hypertension in patients with breast cancer in postmenopausal women.

The level of technology

Hypertension refers to an excessive increase in any of the following blood pressure: systolic blood pressure, that is, the maximum blood pressure, measured with the contraction of the heart when pumping blood into the arteries; and diastolic blood pressure, i.e. the minimum blood pressure measured when the heart expansion and filling with blood. According to the definition of the world Health Organization's (WTO) hypertension represents the maximum blood pressure (systolic blood pressure over 140 mm Hg or minimum blood pressure (diastolic blood pressure over 90 mm Hg (non-patent document 1). Distinguish the two types of hypertension: primary hypertension, for which there is any specific reason, and secondary hypertension caused by a specific reason. Primary hypertension, according to the report, 90% or more of all hypertensive cases. Primary hypertension, which often develops after with the front age and becomes chronic, is one of the first causes of death worldwide, because this condition is widespread, causes damage to major organs (e.g. brain, heart and kidney) and are closely associated with the flow of other arteriosclerotic diseases.

Commonly used for the treatment of hypertension include (1) calcium antagonists, (2) inhibitors of angiotensin-converting enzyme (3) antagonists angiotensin II receptor, (4) diuretics and (5) sympatholytic agent. However, each of these means for the treatment of hypertension causes side effects and may not be introduced to some patients. In this regard, there is a need in the treatment for hypertension, based on a new engine.

(7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol or pharmaceutically acceptable salt (see the following structural formula (1), a salt of citric acid compounds designated as "TAS-108"), has a strong affinity to the estrogen receptor (ER) and is known as an excellent therapeutic agent for the treatment of breast cancer (patent document 1 and non-patent document 2).

This compound is also used as a therapeutic agent for treating pulmonary hypertension or osteoporosis (see, for example, the patent to the side 1). Pulmonary hypertension is a disease which is difficult passage of blood through the narrowed peripheral arteriolar cavity blood vessels that carry blood from the heart to the lungs (i.e. pulmonary artery), which leads to an increase in blood pressure in the pulmonary arteries (pulmonary arterial pressure). Because the right ventricle of the heart, pumping blood into the pulmonary artery, can not withstand high pressure, constant high pulmonary arterial pressure causes the deterioration of the function of the right ventricle, which leads to failure of the right ventricle. Usually normal pulmonary arterial pressure is from 30 to 15 mm Hg (systolic), from 8 to 2 mm Hg (diastolic) and from 18 to 9 mm Hg (mean value). Therefore, pulmonary hypertension is a systolic pulmonary arterial pressure of 30 mm Hg or higher or mean pulmonary arterial pressure of 20 mm Hg or higher. According to statistics, in 2003 the Ministry of health, labour and welfare of Japan, in Japan the number of patients with primary pulmonary hypertension (see classification of pulmonary hypertension) increases from year to year and reportedly amounted to 637 in 2002. In contrast to systemic hypertension, pulmonary hypertension is often complicated by the different spacecraft is diopulmonary diseases. Pulmonary hypertension, which is not associated with such disease called primary pulmonary hypertension (PPH) and is defined as a specific disease (i.e. fatal disease). Thus, pulmonary hypertension is completely different from systemic hypertension in the sense of symptoms and definitions.

Selective modulators of estrogen receptor (SERM) are a class of chemically synthesized drugs, which are associated with oestrogen receptor α (ERα), and show how estrogenic (agonistic) activity and anti-estrogenic (antagonistic) activity of an organ-specific manner. Tamoxifen and raloxifene, which are typical SERM, exhibit agonistic activity against bone and lipid metabolism and antagonistic activity against the breast tissue. According to reports, these SERM can be used to regulate blood pressure (patent documents 2-4). However, recent studies have shown that the introduction of raloxifene, a typical SERM, patients with hypertension in postmenopausal women with systolic blood pressure 142±13 mm Hg was reduced only to 139±10 mm Hg (non-patent document 3).

Patent document 1: WO 99/33859

Patent document 2: patent GB No. 2374412

Patent documents is 3: WO 2001/26651

Patent document 4: JP-A-2002-531496

Non-patent document 1: J. Hypertens., 1999; 17: 151-183

Non-patent document 2: Proceedings of the American Association for Cancer Research Annual Meeting, (March, 2001) Vol. 42, pp. 270

Non-patent document 3: J. Cardiol., 2004; 94: 1453-1456

DISCLOSURE of INVENTION

Objectives of the invention

The aim of the present invention is to provide a means for the treatment of hypertension, based on a new mechanism, which shows excellent hypotensive effect in patients with hypertension and no effect on patients with normal pressure.

Means of solving the problem

The author of the present invention have studied therapeutic effects of TAS-108 in hypertension, which in fact does not show agonistic activity against receptor α estrogen, but shows potent antagonistic activity against him, and the result was unexpectedly found that the TAS-108 significantly reduces blood pressure in patients with hypertension in postmenopausal women who have typical SERM does not actually cause a hypotensive action and only reduce blood pressure in patients with normal pressure. The present invention has been accomplished based on these findings.

Thus, the present invention provides a means for treating hypertension containing as the active component is enta (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol, represented by the following formula (1):

or its pharmaceutically acceptable salt.

The present invention also provides a means to reduce hypertension (hereinafter may be called as "reducing hypertension agent") in patients with breast cancer in postmenopausal women, where the product contains, as an active ingredient, a compound represented by the formula (1), or its pharmaceutically acceptable salt.

The present invention also provides a method of treating hypertension or a method of reducing hypertension in patients with breast cancer in postmenopausal women, characterized in that the method comprises introducing the compound represented by formula (1), or its pharmaceutically acceptable salt to the individual in need.

The present invention also provides the use of compounds represented by formula (1), or its pharmaceutically acceptable salts for the production of tools for the treatment of hypertension or means for reducing hypertension in patients with breast cancer in postmenopausal women.

The results of the invention

The treatment for hypertension according to the present invention significantly reduces high systolic blood pressure of 140 mm Hg or more, up to a normal level. In addition, the creation for the treatment of hypertension can reduce the blood pressure of the patient with diastolic blood pressure, constituting more than 90 mm Hg, to a normal level. When this drug for treatment of hypertension modestly reduces blood pressure in patients with systolic blood pressure, amounting to 140 mm Hg or below. This hypotensive effect is especially pronounced among postmenopausal women; in particular, patients with breast cancer in postmenopausal women.

Brief description of figures

Figure 1 shows the change in average blood pressure in four patients with hypertension with systolic blood pressure 140 mm Hg or higher.

Figure 2 shows the change in blood pressure of the patient with hypertension with systolic blood pressure 140 mm Hg or higher.

Figure 3 shows the change in blood pressure of the patient with hypertension with systolic blood pressure 140 mm Hg or higher.

Figure 4 shows the change in blood pressure in individuals with normal pressure with systolic blood pressure below 140 mm Hg

Figure 5 shows the change in average blood pressure with the introduction of TAS-108.

Figure 6 shows the change in heart rate with the introduction of TAS-108.

7 shows the change in average blood pressure during the introduction of raloxifene.

The best way of carrying out the invention

The compound represented by formula (1), or its headlights is asepticheski acceptable salt, used according to the present invention can be obtained, for example, by the method described in patent document 1.

Pharmaceutically acceptable salt of the compound of the present invention is not specifically limited, provided that the use of the usual well-known salts. Pharmaceutically acceptable salt preferably is an acid additive salt. Examples of acids used to prepare the acid additive salts include organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid and salicylic acid; and inorganic acids such as hydrochloric acid, bromatologia acid, sulfuric acid, nitric acid and phosphoric acid. Preferred among them are organic acids and most preferred citric acid. In particular, a salt of citric acid compounds designated as "TAS-108".

As described in the examples below, the compound represented by formula (1), or its pharmaceutically acceptable salt smart is raising blood pressure in patients with hypertension with systolic blood pressure, components 140 mm Hg or more, up to the normal systolic pressure less than 140 mm Hg in Addition, the compound or its pharmaceutically acceptable salt reduces blood pressure in patients with diastolic blood pressure of 90 mm Hg, to a normal diastolic pressure less than 90 mm Hg When this compound or its pharmaceutically acceptable salt does not reduce blood pressure in patients with normal systolic blood pressure less than 140 mm Hg Is hypotensive effect is ensured for a long period of time. Thus, the pharmaceutical agent according to the present invention can be used as a therapeutic agent for the treatment of systemic hypertension (e.g., primary hypertension).

The treatment for hypertension according to the present invention is intended for administration to patients with systemic hypertension. Therapeutic agent preferably is designed to introduce patients with primary hypertension, and more preferably women in postmenopause (in particular, patients with breast cancer in postmenopausal women).

As you know, QOL (quality of life) of patients with breast cancer often unsatisfactory. For example, the risk of associated diseases increased the W after menopause (for example, symptoms of hypertension due to increased blood pressure, hyperlipidemia due to the increased concentration of cholesterol in the blood and osteoporosis by reducing bone density) (see Treat Endocrinol. 2004; 3 (5): 289-307). The pharmaceutical agent of the present invention is also used as a means to reduce hypertension (risk factor) in patients with breast cancer in postmenopausal women. The pharmaceutical agent of the present invention is useful for applications, with the introduction of pharmaceuticals to a patient with breast cancer before or after menopause, systolic blood pressure is maintained at a normal level of less than 140 mm Hg and diastolic blood pressure is maintained at a normal level which is less than 90 mm Hg

The pharmaceutical agent of the present invention can be prepared in various dosage forms. Such dosage forms can be, for example, oral drugs, injections, rectal suppositories or preparations for external use (e.g., ointments or patches)that can be obtained in the usual ways to get dosage forms known to the person skilled in the art. Oral solid product (for example, tablets, coated tablets, granules, parasecoli capsules) can be prepared by adding to the active ingredient of the filler and, if necessary, additives such as a binder, baking powder, grease, dye, sweetener or flavoring, and then performing a normal process operations. Oral liquid product (e.g., oral solution or syrup) can be prepared by adding to the active ingredient additives such as sweetening agents, buffer, stabilizer or flavoring, and then performing a normal process operations. Injection (subcutaneous injection, intramuscular injection or intravenous injection) can be prepared by adding to the active ingredient component, regulating pH, buffer, stabilizer, means regulating toychest, local anesthetic means or the like, and then performing a normal process operations. Rectal suppository can be prepared by adding to the active ingredient excipient and, if necessary, additives such as surfactant, and then performing a normal process operations. Ointment (for example, in the form of a paste, cream or gel) is prepared in the usual way by mixing, if necessary, the active ingredient with commonly used additives, such as base, stabilizer, moisturizer, or preservative. Examples of bases that can be used flucytosine vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, and bentonite. Examples of preservatives that can be used include methyl-p-hydroxybenzoate, ethyl-p-hydroxybenzoate and propyl-p-hydroxybenzoate. The patch can be prepared by applying on a commonly used substrate of the above-mentioned ointment, cream, gel or paste or the like in the usual ways. Examples of appropriate substrates include woven and non-woven fabrics made of cotton, staple fiber and chemical fiber; and film and foam sheets, made of soft vinyl chloride, polyethylene and polyurethane.

The amount of compounds represented by formula (1), or its pharmaceutically acceptable salt included in any of the above forms of the product of a single dose varies depending on, for example, symptoms of the patient, in need thereof, or the product form. In the General case, preferably, the amount of the compound or its pharmaceutically acceptable salt in a single dose is from about 5 to about 1000 mg (oral contraceptives), from about 0.1 to about 500 mg (for injection) and from about 5 to about 1000 mg for suppositories or external drug).

Daily dose of a compound represented by the formula (1), or its pharmaceutically PR is acceptable salt, which is included in any of the above dosage forms depends on the symptom, etc. of the patient, in need thereof, and cannot be determined uniquely. However, in General, the daily dose is preferably from about 0.1 to about 5000 mg.

EXAMPLES

Below the present invention will be described in more detail with reference to examples of the preparations and Examples. However, the present invention is not limited to these examples.

Example 1 drug - Pills

TAS-10850 mg
Corn starch50 mg
Microcrystalline cellulose50 mg
Hydroxypropylcellulose15 mg
Lactose47 mg
Talc2 mg
Magnesium stearate2 mg
Ethylcellulose30 mg
Unsaturated glycerides2 mg
The titanium dioxide is 2 mg

Prepared tablets (tablets of 250 mg) with the above composition in the usual way.

Example preparation of 2 - Granules

TAS-108300 mg
Lactose540 mg
Corn starch100 mg
Hydroxypropylcellulose50 mg
Talc10 mg

Prepared pellets (1000 mg per package) with the above composition in the usual way.

Example preparation of 3 Capsules

TAS-108100 mg
Lactose30 mg
Corn starch50 mg
Microcrystalline cellulose10 mg
Magnesium stearate3 mg

Prepared capsules (capsules 193 mg) with the above composition in the usual way.

Example 4 drug Injection

TAS-108100 mg
Sodium chloride3.5 mg
Distilled water for injectionAppropriate amount (2 ml per ampoule)

Was prepared by injection with the above composition in the usual way.

The example of the drug 5 - Suppositories

TAS-108300 mg
Witepsol W-35 (registered trademark, a mixture of mono-, di - and triglycerides of saturated fatty acids (lauric acid to stearic acid), the product Dinamite Nobel)1400 mg

Prepared suppositories with the above composition in the usual way.

Example 1

Method. TAS-108 (40 mg, 80 mg or 120 mg) was administered orally to patients with breast cancer in postmenopausal women (age: 50-78) once daily after Breakfast for eight weeks. Blood pressure was measured in sitting position before the introduction of the first day of the introduction and in two weeks, four weeks and eight weeks after the start of injection.

Results. Four of the patients with breast cancer (15 patients) was established hypertension, that is, the systolic (the maximum) blood pressure 140 mm Hg or higher or diastolic (minimum) blood pressure 90 mm Hg or higher, measured before the introduction of the first day of the introduction. All four patients with hypertension systolic or diastolic blood pressure was reduced to the range of normal pressure after two to four weeks after the beginning of the introduction of TAS-108 (see Fig.1-3). In particular, the typical patient with hypertension (figure 2) systolic blood pressure was reduced by approximately 40 mm Hg (i.e. from 180 mm Hg to 138 mm Hg) after four weeks after the start of the introduction of TAS-108, that is, TAS-108 showed a significant anti-hypertensive effect. While the remaining 11 patients with breast cancer with normal blood pressure measured at the first day of introduction, did not observe any significant changes in blood pressure with the introduction of TAS-108 (see figure 4).

As shown, upon the occurrence of menopausal women experience a significant change in blood pressure, lipid metabolism, bone metabolism, etc. that closely associated with cardiovascular lesions. In accordance with the foregoing data TAS-108 selectively enhances the difference between the values of blood pressure in patients with hypertension in postmenopausal women and has no effect on the blood pressure of patients with normal blood pressure, which shows that TAS-108, expected to show the daily introduction of a superior therapeutic effect in patients with hypertension, particularly in patients with hypertension in postmenopausal women.

Example 2

Method. TAS-108 (100 mg) was administered devotionalism rats with spontaneous hypertension (SHR) once a day for seven days. Prior to the recent introduction of the investigational medicinal product and after 30 minutes, one hour, two hours and four hours after the last injection measured blood pressure at a constant heart rate of invasive automatic device for measuring blood pressure in rats/mice (BP-97A, product Softron) using the tail cuff (J. Lab. Clin. Med. 1971; 78: 957-962). As a comparison was administered at a dose of 100 mg once a day for seven days as a control solvent of 0.5% HPMC) or raloxifene.

Results. The percentage increase/decrease in blood pressure after the last injection of the investigational medicinal product was calculated by the blood pressure measured before the last administration of a medicinal product, and thus obtained values were compared with each other. In all rats, which were injected TAS-108 (100 mg), blood pressure was reduced after one or two hours after administration of the drug. More specifically, the mean blood pressure was reduced by 28.6% and diastolicheskoe the e blood pressure was decreased by 46.9%, and the maximum percentage reduction in blood pressure was observed two hours after injection (figure 5). During the course of the introduction did not observe significant changes in heart rate (6). However with the introduction of solvent or raloxifene at a dose of 100 mg during the course of the measurements did not observe significant changes in systolic blood pressure average blood pressure, diastolic blood pressure or heart rate (Fig.7).

Hypertension is considered a risk factor, for example, with heart disease, cerebrovascular disease, or diabetic nephropathy, and various therapeutic drugs from hypertension were investigated (Can. J. Cardiol. 2006; 22 (7): 565-571, Can. J. Cardiol. 2006; 22 (7): 583-593). Up to the present time have researched and used the usual therapeutic agent for the treatment of hypertension, including calcium antagonists, such as nifedipine, inhibitors of angiotensin-converting enzyme inhibitors angiotensin receptor. Medicines, providing a powerful anti-hypertensive effect (e.g., nifedipine), as is known, can cause patients side effects that cause reflex tachycardia. In this regard, attempts were made preparations for the treatment of hypertension in the product form with prolongirovannogo or develop a drug, which does not provide rapid hypotensive effect and regulates blood pressure gradually and prolongirovanne (Clin. Exp. Hypertens. A. 1984; 6 (8): 1485-1497, Blood Press Suppl. 1998; 1: 5-8).

In accordance with the above findings TAS-108 has a powerful hypotensive effect in rats with spontaneous hypertension, which represent a model for primary hypertension, but does not cause reflex tachycardia (i.e. side effects); TAS-108 provides hypotensive effect, which is characterized by a decrease in diastolic blood pressure, and raloxifene (i.e. typical SERM) does not exert a hypotensive effect, which confirms that, unlike the case with typical SERM, TAS-108 daily introduction will demonstrate excellent therapeutic effect on hypertension.

1. Therapeutic agent for the treatment of systemic hypertension, containing as the active ingredient (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol represented by formula (1):

or its pharmaceutically acceptable salt.

2. Therapeutic agent according to claim 1, which is intended to introduce the woman in postmenopausal women.

3. Therapeutic agent according to claim 1, which is intended for administration to a patient with breast cancer in postmenopausal women.

4. The tool is La reduction of systemic hypertension in patients with breast cancer in postmenopausal women, containing as the active ingredient (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol represented by formula (1):

or its pharmaceutically acceptable salt.

5. Treatment of systemic hypertension, characterized in that the method comprises the introduction of (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol represented by formula (1):

or its pharmaceutically acceptable salt to a subject in need of it.

6. The method according to claim 5, which is carried out in women in postmenopausal women.

7. The method according to claim 5, which is carried out in a patient with breast cancer in postmenopausal women.

8. The way to reduce systemic hypertension, characterized in that the method comprises the introduction of (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol represented by formula (1):

or its pharmaceutically acceptable salt to a patient with breast cancer in postmenopausal women.

9. The use of (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol represented by formula (1):

or its pharmaceutically acceptable salt for the manufacture of tools for the treatment of systemic hypertension.

10. Application pop, which is performed by women in postmenopause.

11. The use according to claim 9, which is performed by the patient with breast cancer in postmenopausal women.

12. The use of (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol represented by formula (1):

or its pharmaceutically acceptable salt for the manufacture of tools for the reduction of systemic hypertension in patients with breast cancer in postmenopausal women.



 

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FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood microvesicle level in impaired glucose tolerance. That is ensured by graduated physical activity, and administration of metformin 500 mg twice a day. The therapeutic course is at least 5 weeks.

EFFECT: offered combination of therapeutic modalities enables normalising the blood microvesicle level in a relatively short time that promotes prevention of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gerontology, endocrinology, and can be used for pathologically raised biological age reduction in the patients with abdominal obesity. That is ensured by prescription of efficient graduated static and dynamic physical activity, daily swimming in a pool for not less than 30 minutes a day, and also administration of metformin in dosage 850 mg twice a day. The therapeutic course is 7 weeks.

EFFECT: offered combination of the modalities enables to adjust the biological and chronological ages that improves quality of life in the case patients.

2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, and can be used for normalisation of adenosine diphosphate and adenosine triphosphate thrombocyte secretion activity in the patients with arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day in the morning.

EFFECT: combination of therapeutic modalities enables rapid normalisation of adenosine diphosphate and adenosine triphosphate thrombocyte secretion activity that promotes prevention of thrombotic complications in the case patients.

9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood α2 antiplasmin concentration in arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day at regular hours in the morning. The therapeutic course is 1 months.

EFFECT: offered combination of therapeutic modalities enables normalising the blood α2 antiplasmin level in a relatively short time that promotes prevention of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, namely to ophthalmology, and can be used for improvement of medication transportation to tissue of posterior eye segment by means of mucoadhesive substance in treatment of eye diseases. For this purpose efficient amount of solid composition, containing selected medication and mucoadhesive substance, is introduced into conjunctival sac. Used is mucoadhesive substance, whose adhesive strength constitutes from 200 to 1000 g.

EFFECT: group of inventions ensures efficient treatment of posterior eye segment diseases due to creation of conditions for long and high substance concentration in respective eye tissues.

13 cl, 8 dwg, 1 tbl, 13 ex

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