WO2005107739A1

WO2005107739A1 - Spiroderivatives for the treatment of hypertension

Info

Publication number: WO2005107739A1
Application number: PCT/IL2004/000396
Authority: WO
Inventors: Nadav Zamir
Original assignee: Darley Pharmaceuticals Ltd.
Priority date: 2004-05-11
Filing date: 2004-05-11
Publication date: 2005-11-17
Also published as: EP1746988A1

Abstract

The present invention relates to use of 1,7-dioxaspiro[5.5]undecane for the preparation of a medicament for the treatment or prevention of hypertension. The invention also provides a method for treatment or prevention of hypertension using a medicament comprising 1,7 dioxaspiro[5.5]undecane as an active ingredient, such that the hypertension is treated or prevented, as the case may be.

Description

SPIRODERIVATIVES FOR THE TREATMENT OF HYPERTENSION

FIELD OF THE INVENTION This invention relates to the treatment of hypertension. More specifically, the invention relates to a medicament for the treatment of hypertension

LIST OF REFERENCES The following references are considered to be pertinent for the purpose of understanding the background of the present invention: 1. WO 01/39766 2. Williams GH, 2001 Approach to the Patient with Hypertension in til Harrison's Principles of Internal Medicine, (1

Edition. Publisher McGraw-Hill Companies Inc., Editor: Braunwald E) pp 211 -214 3. Lucas KA, et al. 2000 Guanylyl Cyclases and Signalling by cyclyc GMP Pharmacol. Rev. 52:375-414 4. Ding et al. 1999. Activation of particulate guanylyl cyclase by endothelins in cultured SV-40 transformed cat iris sphincter smooth muscle cells. Life Sci. Vol: 64 pp. 161-174

BACKGROUND OF THE INVENTION Hypertension is the most common cardiovascular disease. It is defined as blood pressure higher than 140 mmHg systolic or 90 mmHg diastolic. Hypertension precedes development of congestive heart failure (CHF) in 91% of the cases and is a major risk factor for myocardial infarction and stroke [Williams, 2001]. Known antihypertensive drugs are classified according to their mechanism of action as diuretics, angiotensin-converting enzyme (ACE) inhibitors, alpha-adrenergic blockers, beta-adrenergic blockers, angiotensin II antagonists, calcium channel blockers and vasodilators. Each class of drugs has known side effects that sometimes prevents administration of the drugs to a given patient or class of patients. Moreover, of those with high blood pressure, 26.2 % are on medication but their hypertension is not adequately controlled and 14.8 % do not receive any medication for various reasons, mainly non compliance due to the drugs' side effects [Williams, 2001]. Thus, there is still and unmet need for new drugs with improved efficacy and reduced side effects. Many of the cardiac, vascular, and renal responses in hypertension are mediated by signal transduction involving the second messenger cGMP (Guanosine 3', 5 '-cyclic monophosphate) [Lucas, 2000]. Endogenous and exogenous compounds, e.g., natriuretic peptides, nitric oxide (NO), and nitrates, modulate vasodilatation and blood pressure by increasing the intracellular concentration of cGMP in vascular smooth muscle cells, causing activation of the cGMP-dependent protein kinase (PKG) (Lucas, 2000). There are several mechanisms that result in elevation of intracellular cGMP levels such as activation of soluble guanylyl cyclase, activation of particulate guanylyl cyclase and inhibition of cGMP - dependent phosphodiesterase ((PDE) type I and V). Semiochemicals-derived compounds such as Z-7-Tetradecenal, Z-13-Octadecenal, E,E-8,10-Dodecadienol, Z-11-Hexadecenyl- Acetate and l,7-Dioxaspiro[5.5]undecane were shown to elevate cGMP levels in vitro in cultured SV40 transformed cat iris sphincter smooth muscle (SV-CISM-2) (WO 01/39766). One of the problems in selecting an active ingredient for the reduction of blood pressure is that this reduction must be stringently controlled, since excessive lowering of blood pressure is also hazardous and may lead to death of the subject. Careful screening of potential active ingredients must be carried out to select only those that would lower systemic blood pressure with only acceptable side effects. SUMMARY OF THE INVENTION The present invention is based on the discovery that l,7-dioxaspiro[5.5]undecane lowered systemic blood pressure without causing discernible harm to the tested animals and without causing a detectable affect on heart contractility.

SUMMARY OF THE INVENTION The present invention is based on the discovery that l,7-dioxaspiro[5.5]undecane lowered systemic blood pressure without causing discernible harm to the tested animals and without causing a detectable affect on heart contractility. Thus, the present invention concerns the use of a compound of the general formula I:

wherein X represents, independently, an oxygen or a sulfur atom; each ring represents, independently, a saturated or unsaturated, five, six or seven-membered ring; each ring may, independently, be substituted with one or more substituents selected from =0 or compounds of the formula -RY, wherein R represents a valence bond or a linear or branched lower alkylene, lower alkenylene or lower alkynylene; and Y represents a hydrogen, a halide, -C(0)NZ₂, -C(0)-OZ or -OZ, wherein Z, which may be the same or different in -C(0)NZ₂, represents a hydrogen or a linear or branched lower alkyl, lower alkenyl or lower alkynyl; or when each ring in said compound of the general formula I is substituted with at least one of the above substituents, the two substituents, including the carbon atoms to which they are bonded, may form together a five, six or seven-membered ring which may be substituted with the group -RY, as defined above; The term "lower" is used herein to denote a C C₄ or C₂-C₄ containing group. The compound of the general formula I, according to the invention, also includes R and S (or '+' and '-') enantiomeric forms of said compound, as well as mixtures thereof. One example of enantiomer forms include the (R)-l,7-dioxaspiro[5.5]undecane form and the (S)-l,7-dioxaspiro[5.5]undecane analog form thereof. The mixture may be a racemic mixture or may contain the two stereoisomers at different quantities. A person skilled in the art of the invention would appreciate that the scope of the present invention comprises any compound of the general formula (I) as defined above that is known or expected by ones skilled in the art of the invention to have essentially the same properties and effects as l,7-dioxaspiro[5.5]undecane. Thus, according to a first aspect of the present invention use of a compound of the general formula (I) as defined above is provided for the preparation of a medicament for the treatment or prevention of hypertension. The term "treatment¹" in the present invention means administration of a medicament with the result that high blood pressure is reduced or cured. The reduction or curing as a result of treatment includes an effect on at least one parameter of hypertension, including systolic and/or diastolic blood pressure or any of the resulting effects known to be associated with hypertension. The term "prevention" in the present invention means administration of a medicament with the result that the subject's blood pressure (systolic and/or diastolic) is maintained within a desired range. Generally, blood pressure is considered normal or desired if the systolic blood is 130 mmHg or less and the diastolic blood pressure is

85mHg or less Categories of blood pressure are detailed in Table 1 [Williams, 2001]. Table 1 Classification of biood pressure for adults aged 18 years and older

However, for many patients other parameters may affect the desired blood pressure and thus it may be desirable to maintain it at a higher or lower pressure than the aforementioned. For example in some cases, such as some geriatric patients, the desirable blood pressure for the patient is that of mild hypertension (systolic 140-159 mmHg and diastolic 90-99 mmHg). According to another aspect, the present invention provides a method for the treatment of hypertension comprising administration to an individual an effective amount of a medicament comprising a compound of the general formula I as defined above as an active ingredient, such that the hypertension is treated. According to yet another aspect, the present invention provides a method for the prevention of hypertension comprising administration to an individual an effective amount of a medicament comprising a compound of the general formula I as defined above as an active ingredient, such that the blood pressure is maintained substantially within a desirable rate. In the context of this invention an individual's blood pressure is within a desirable range if the systolic and/or diastolic blood pressure is within the desired category as described in table 1 (e.g. normal blood pressure, high normal blood pressure, mild hypertension, etc). According to yet another aspect, the present invention provides a medicament for the treatment or prevention of hypertension comprising a compound of the general formula I as defined above as an effective ingredient and a pharmaceutically acceptable carrier. The "effective amount" for purposes herein is determined by such considerations as may be known in the art. The amount must be effective to achieve the desired therapeutic effect (i.e. treatment or prevention) as described above. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half life in the body, on undesired side effects, if any, on factors such as age, gender, family history, weight etc.

BRIEF DESCRIPTION OF THE DRAWINGS In order to understand the invention and to see how it may be carried out in practice, a preferred embodiment will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: Figure 1 is a graphic representation of the effect of two bolus injections of l,7-dioxaspiro[5.5]undecane on systemic blood pressure. Arrows indicate the times of bolus injections. Fig. 1A depicts the changes in systolic blood pressure, and Fig. IB depicts the changes in diastolic blood pressure. Figure 2 is a graphic representation of the effect of two bolus injections of Z-13-octadecenal on systemic blood pressure. Arrows indicate the times of bolus injections. Fig. 2 A depicts the changes in systolic blood pressure, and Fig. 2B depicts the changes in diastolic blood pressure.

DETAILED DESCRIPTION OF THE INVENTION According to a first aspect of the present invention use of a compound of the general formula (I) as defined above is provided for the preparation of a medicament for the treatment of hypertension. The medicament may be administered to an individual by one of a variety of administration modes, including, but not limited to oral, intravenous, intramuscular, transdermal, subcutaneous, topical, sublingual, rectal, nasal, and the like. Additionally, the medicament may be administered by inhalation. When the medicament is administered intravenously, it may be in form of an infusion (e.g. continuously) or injection, such as bolus injection. When the medicament of the invention is administered orally, it may be administered in the form of a tablet, a pill, a capsule (e.g. a gelatin capsule) a powder or a pellet. Where a liquid carrier is used, the oral preparation may be in the form of a syrup, emulsion, or soft gelatin capsule. Nasal administration may be by nasal insufflation or as an aerosol, and internal administration such as rectal administration may be by use of a suppository. Compositions for topical administration may be, for example, in the form of creams, ointments, lotions, solutions, gels and transdermal patches. The compound according to Formula (I) as defined above may be typically be administered with a pharmaceutically acceptable carrier which does not interfere with the efficacy of the active ingredient. The carrier may be selected from a large number of carriers known in the art and its nature will depend on the intended form of administration and indication for which the active ingredient is used. Tablets, pills and capsules containing the compound according to Formula (I) as defined above may also include conventional excipients such as lactose, starch, magnesium stearate, and the like. Suppositories may include excipients such as waxes and glycerol. Injectable solutions may comprise saline, buffering agents, dextrose, water, glycerol, ethanol and solvents such as propylene glycol, polyethylene glycol and ethanol. Such solutions may also comprise stabilizing agents and preservatives which are typically antimicrobial agents (such as chlorbutol, benzyl alcohol, sodium benzoate, ascorbic acid, and phenol) and antioxidants (such as butylated hydroxy toluene, propyl gallate, and sulfites). Enteric coatings, flavorings, and dyes and colorants may also be used. At times, the medicaments of the present invention may be incorporated within a liposome prepared by any of the methods known in the art. In addition, the medicaments containing the compound according to Formula (I) as defined above may be encapsulated in inert polymerized particles such as, for example, nano particles, microspheres, and microparticles known in the art. The medicament produced according to the invention may comprise the compound according to Formula (I) as defined above as the only active ingredient. Alternatively other active ingredients may be added. Such addition may for example exert a synergistic effect or reduce the side effects of each active ingredient. According to the present invention, the medicament comprising the compound according to Formula (I) as defined above may be administered separately or, alternatively, in combination with various other treatments administered to the patient for the same or different disease, condition or symptom thereof. In case of combination with other treatments administered to the patient, the method or medicament of the present invention may be administered at the same time with, before and/or after the other treatment or medicament. The effective amount of the compound according to Formula (I) as defined above administered for the treatment of Hypertension will be typically in the range of from about 0.1 to 200 mg/kg/day, or even from about 1.0 to 180 mg/kg/day. Lower dosage can be used also to obtain a transient short term effect. It would be appreciated that in the methods of the present invention, an individual that is to be subject of treatment should be identified. For treatment of hypertension, such subject would be manifesting hypertension (either occasionally or chronically). For the purpose of prevention of hypertension would be such that is considered likely to suffer from hypertension. A person skilled in the art of the invention would know what parameters may be indicative of such likelihood. For example this may be based on the individual's medical history (related to hypertension or any other medical condition or parameter) or that of the individual's family, the individual's occupation, etc. Prevention of hypertension in case of a hypertensive individual may also be the prevention of an increase of hypertension. In such case the desired rate may be hypertensive as well. According to yet another aspect, a medicament for the treatment or prevention of hypertension comprising the compound according to Formula (I) as defined above as an effective ingredient and a pharmaceutically acceptable carrier. This medicament may be used in the method of this invention and may be prepared and have any form as described in this application or known in the art. EXAMPLES Materials Anantin, L-NAME (N^G-nitro-L-arginine methyl ester) and IBMX (3-isobutyl- methylxanthine), were purchased from Sigma Chemicals Co. St.Louis, Mo, USA.

[ I] cGMP RIA kit was purchased from Amersham, Arlington Heights, IL, USA. Reagents for cell cultures were purchased from GIBCO Life Technologies, Grand Island, NY, USA. All other chemicals were likewise fine laboratory grade chemicals purchased periodically from established manufacturers. l,7-dioxaspiro[5.5]undecane and Z-13-octadecenal were dissolved in ethanol and diluted with saline prior to intravenous administration.

In-vivo procedures Compounds that were shown to be able to elevate cGMP levels in cultured smooth muscle cells (WO 01/39766) were tested for their ability to lower blood pressure of normotensive rats. These were l,7-dioxaspiro[5.5]undecane and another compound termed Z-13-octadecenal. Both compounds showed comparable ability to elevate cGMP levels in smooth cultured muscle cells (WO 01/39766). 1. Rat strain and Experimental preparations Male Sprague-Dawley rats, weighing 250-350 grams were anaesthetized with mixture of Ketamine (90mg/Kg body weight) and Xylazine (lOmg/Kg body weight) in a single bolus injection. The rats' chest was shaven; and the rats were secured in supine position. Anaesthetized rats were intubated with 18G catheter, connected to a ventilator [Harvard Apparatus] and ventilated with a room air (volume: 2ml, rate: 70 per min). The left femoral vein was cannulated for drug administration, which is standardized to injections of 0.2 ml/100 grams body weight over a period of 0.5-1 minutes. For measurement of hemodynamic parameters [blood pressure (BP), heart rate (HR)] a cannula was inserted retrogradely into the left carotid artery. The tip of the catheter was positioned close to the origin of the subclavian artery. 2. Continuous Monitoring of ECG and Hemodynamic parameters For continuous monitoring of blood pressure (systolic and diastolic pressure) and heart rate, the catheter was connected to a pressure transducer [Grass instrument co., Quincy, Mass. USA]. To monitor the ECG (electrocardiogram): two electrodes were connected to the animal's arms and one electrode was connected to its left leg. The monitoring system was calibrated at the beginning of each experiment. Recording all the steps of the calibration. ECG and hemodynamic parameters were recorded continuously during the whole experiment. Monitoring rate (speed of paper) was at 5 mm/sec. At different times (stabilization, after injections, blood pressure changes, etc.,) the monitoring rate was changed to 25 mm/sec. In addition routinely, every 5 minutes the monitoring rate was changed to 25 mm/sec. for 15 sec. ECG recordings were obtained at the same times as hemodynamic measurements. 3. Test compound administration When stable hemodynamic conditions were achieved for at least 20 minutes (baseline control values), a test compound (l,7-dioxaspiro[5.5]undecane or Z-13-octadecenal) was administrated twice. The test compound was administered by bolus injection intravenously at different doses (2,4,6,8 mg/Kg body weight). Each dose was administrated twice in the same manner. The second dose was given after the hemodynamic parameters were recovered (or stabilized) following the first injection. 4. Results

Effect of 1, 7-dioxaspiro[5.5]undecane on Systemic Blood Pressure and ECG of normotensive anesthetized Rats The effect of l,7-dioxaspiro[5.5]undecane (at different doses, and multiple dosing) on systemic blood pressure is shown in Figure 1. As can be seen in Figure 1A bolus injection of l,7-dioxaspiro[5.5]undecane

(8mg/Kg body weight) caused after 30 minutes a reduction in systolic blood pressure that ranged between 10-30% (average 18.1%). Additional bolus injection of l,7-dioxaspiro[5.5]undecane at the same dose caused after 30 minutes a greater reduction in systolic blood pressure that ranged between 15-42% (average 28.3%). Similarly, as shown in Figure IB, l,7-dioxaspiro[5.5]undecane (8mg/Kg body weight) caused after 30 minutes a reduction in diastolic blood pressure that ranged between 7-32% (average 20.5%). Additional bolus injection of l,7-dioxaspiro[5.5]undecane at the same dose caused after 30 minutes a greater reduction in diastolic blood pressure that ranged between 15-53% (average 36.5%). The effect of l,7-dioxaspiro[5.5]undecane on systemic blood pressure at lower doses was measured as well. Single and double dose of l,7-dioxaspiro[5.5]undecane at 2mg/Kg body weight had no effect on systemic blood pressure of anesthetized normotensive rats. Single dose of l,7-dioxaspiro[5.5]undecane at 4mg/Kg body weight had a mild hypotensive effect that last for about 15 minutes on systemic blood pressure of anesthetized normotensive rats. This hypotensive effect was more pronounced after the second injection of the same dose. l,7-dioxaspiro[5.5]undecane after single and double dosage of 2-8 mg/Kg body weight i.v. (intravenous) bolus injections had no effect on heart contractility was evidenced by ECG monitoring during the experiments, (data not shown). Thus it seems that l,7-dioxaspiro[5.5]undecane exerts its vasodilatory effect via reduction in total peripheral resistance (TPR).

Effect of Z-13-octadecenal on Systemic Blood Pressure of normotensive Rats As can be seen in Figure 2, bolus injection of 8-mg/Kg body weight

Z-13-octadecenal caused an uncontrolled reduction in blood pressure in three out of five animals tested. The hypotensive/toxic effect was rapid and profound and lead to death of two animals within 15 minutes after the first injection of Z-13-octadecenal. After the second injection of Z-13-octadecenal a third animal exhibited a profound drop in systemic blood pressure that lead to death within 15 minutes. Interestingly, the two animals that survived showed minimal or no response of systemic blood pressure to both injections of Z-13-octadecenal. Bolus injection of 4-mg/Kg body weight Z-13-octadecenal caused no reduction in blood pressure in two animal tested, in single and double dose administration, (data not shown) Thus it is concluded that Z-13-octadecenal is a potent toxic compound that its intravenous administration resulted in death of three out of five animals tested.

In-vitro methods The mechanism by which l,7-dioxaspiro[5.5]undecane elevates intracellular cGMP was elucidated as follows: 1. Cell culture Cat iris sphincter smooth muscle (SV-CISM-2) cells were maintained in Dulbecco's modified Eagle medium (DMEM), supplemented with 10% fetal calf serum (FCS) and 50μg/ml gentamicin (culture medium) as described by Ding et al. 1999.(Life Sci. Vol: 64 pp. 161-174) To initiate subculture, confluent SV-CISM-2 cells were washed with Ca²⁺ - Mg²⁺ free Dulbecco's phosphate buffered salt solution (PBS) and treated with 0.05% trypsin in 0.5mM EDTA for 3 minutes at 37°C. This was followed by addition of culture medium, and the cell suspension was centrifuged at 200g for 5 minutes. The pelleted cells were suspended in culture medium and seeded in 6-well plates for the cGMP assay. 2. cGMP Assay Confluent cells, in 6-well plates were washed once with DMEM and incubated in 2ml DMEM for 15 minutes at 37°C. IBMX (0.1 mM) was added and incubated for additional 10 minutes. The tested agent was then added and incubations continued for 10 minutes. Anantin (lμM) or L-NAME (0.1 mM) were added along with IBMX, 10 minutes prior to addition of the tested compound. Reactions were stopped by replacing the medium with 1ml ice-cold 5% trichloroacetic acid (TCA) (W/V). The obtained samples were homogenized, centrifuged and the supernatants were extracted with anhydrous diethylether. A 100 μl portion of the supernatant from each sample was taken; and after appropriate dilutions cGMP was assayed by radioimmunoassay RIA as described by the aforementioned Ding et al. 1999. 3. Determination of protein Protein content was determinate by the method of Lowry with bovine serum albumin as standard as described in the aforementioned Ding et al. 1999. 4. Data The data are presented as mean ± SEM of three separate experiments with triplicate incubations for each data point. 5. Results L-Arginine analogue (L-NAME), an NO synthase inhibitor, was used to test the involvement of soluble guanylyl cyclase. Anantin, a specific membranal guanylyl cyclase antagonist, was used to examine the role of this enzyme in l,7-dioxaspiro[5.5]undecane action. The experiments with l,7-dioxaspiro[5.5]undecane were preformed in presence of IBMX thus excluding PDE inhibition by l,7-dioxaspiro[5.5]undecane as a mechanism for cGMP elevation. The levels of cGMP were measured, and the results of different treatments are depicted in Table 1.

Table 2 The mechanism of l,7-dioxaspiro[5.5]undecane stimulating cGMP production in-vitro

As seen in Table 1, l,7-dioxaspiro[5.5]undecane increased cGMP concentration by 2.36 times. l,7-dioxaspiro[5.5]undecane did not elevate cGMP via activation of membranal guanylyl cyclase since anantin (a specific membranal guanylyl cyclase antagonist) had no inhibitory effect on cGMP formation when tested together with l,7-dioxaspiro[5.5]undecane. On the other hand the NO-synthase inhibitor, L-NAME, attenuated l,7-dioxaspiro[5.5]undecane stimulatory effect on cGMP production. The chemical nature of l,7-dioxaspiro[5.5]undecane indicates that this molecule cannot be a NO donor, there is no nitrogen atom in the molecular structure. Based on the above information it is understood that l,7-dioxaspiro[5.5]undecane may exert its action at least in part, via activation of soluble guanylyl cyclase.

Claims

CLAIMS:

1. Use of a compound of the general formula I:

wherein X represents, independently, an oxygen or a sulfur atom; each ring represents, independently, a saturated or unsaturated five, six or seven-membered ring; each ring may, independently, be substituted with one or more substituents selected from =0 or compounds of the formula -RY, wherein R represents a valence bond or a linear or branched lower alkylene, lower alkenylene or lower alkynylene; and Y represents a hydrogen, a halide, -C(0)NZ₂, - C(0)-OZ or -OZ, wherein Z, which may be the same or different in -C(0)NZ₂, represents a hydrogen or a linear or branched lower alkyl, lower alkenyl or lower alkynyl; or when each ring in said compound of the general formula I is substituted with at least one of the above substituents, the two substituents, including the carbon atoms to which they are bonded, may form together a five, six or seven-membered ring which may be substituted with the group -RY, as defined above; for the preparation of a medicament for the treatment or prevention of hypertension.

2. The use of Claim 1, wherein the amount of the compound of the general formula I is in the range of from about 0.1 to 200 mg/kg/day, or even from about 1.0 to 180 mg/kg/day.

3. The use of anyone of Claims 1 to 2, wherein the medicament is for intravenous injection.

4. The use of anyone of Claims 1 to 3, wherein the medicament exerts its action, at least in part, via activation of soluble guanylyl cyclase.

5. The use according to anyone of Claims 1 to 4, wherein the compound of the general formula I is l,7-dioxaspiro[5.5]undecane.

6. A method for the reduction of hypertension comprising administration to an individual an effective amount of a medicament comprising a compound of the general formula I:

wherein X represents, independently, an oxygen or a sulfur atom; each ring represents, independently, a saturated or unsaturated five, six or seven-membered ring; each ring may, independently, be substituted with one or more substituents selected from =0 or compounds of the formula -RY, wherein R represents a valence bond or a linear or branched lower alkylene, lower alkenylene or lower alkynylene; and Y represents a hydrogen, a halide, -C(0)NZ₂, - C(0)-OZ or -OZ, wherein Z, which may be the same or different in -C(0)NZ₂, represents a hydrogen or a linear or branched lower alkyl, lower alkenyl or lower alkynyl; or when each ring in said compound of the general formula I is substituted with at least one of the above substituents, the two substituents, including the carbon atoms to which they are bonded, may form together a five, six or seven-membered ring which may be substituted with the group -RY, as defined above; as an active ingredient, such that the hypertension is treated.

7. The method of Claim 6, wherein the amount of the active ingredient is in the range of from about 0.1 to 200 mg/kg/day.

8. The method of Claim 7, wherein the amount of the active ingredient is in the range of from about 1.0 to 180 mg/kg/day.

9. The method of Claim 6, wherein the medicament injected intravenously.

10. The method of Claim 6, wherein the medicament exerts its action, at least in part via activation of soluble guanylyl cyclase.

11. The method of Claim 6, wherein the active ingredient is 1 ,7-dioxaspiro[5.5]undecane.

12. A method for the prevention of hypertension comprising administration to an individual an effective amount of a medicament comprising a compound of the general formula I:

wherein X represents, independently, an oxygen or a sulfur atom; each ring represents, independently, a saturated or unsaturated five, six or seven-membered ring; each ring may, independently, be substituted with one or more substituents selected from =0 or compounds of the formula -RY, wherein R represents a valence bond or a linear or branched lower alkylene, lower alkenylene or lower alkynylene; and Y represents a hydrogen, a halide, -C(0)NZ₂, - C(0)-OZ or -OZ, wherein Z, which may be the same or different in -C(0)NZ₂, represents a hydrogen or a linear or branched lower alkyl, lower alkenyl or lower alkynyl; or when each ring in said compound of the general formula I is substituted with at least one of the above substituents, the two substituents, including the carbon atoms to which they are bonded, may form together a five, six or seven-membered ring which may be substituted with the group -RY, as defined above; as an active ingredient, such that the blood pressure is maintained substantially within a desirable rate.

13. The method of Claim 12, wherein the amount of the active ingredient is in the range of from about 0.1 to 200 mg/kg/day.

14. The method of Claim 13, wherein the amount of the active ingredient is in the range of from about 1.0 to 180 mg/kg/day.

15. The method of Claim 12, wherein the medicament injected intravenously.

16. The method of Claim 12, wherein the medicament exerts its action, at least in part via activation of soluble guanylyl cyclase.

17. The method of Claim 12, wherein the active ingredient is 1 ,7-dioxaspiro[5.5]undecane.

18. A method for the reduction of hypertension comprising administration to an individual an effective amount of a medicament comprising l,7-dioxasipro[5.5]undecane as an active ingredient, such that the hypertension is treated.

19. A method for the prevention of hypertension comprising administration to an individual an effective amount of a medicament comprising l,7-dioxasipro[5.5]undecane as an active ingredient, such that the blood pressure is maintained substantially within a desirable rate.

20. A medicament for the treatment or prevention of hypertension comprising a compound of the general formula I:

wherein X represents, independently, an oxygen or a sulfur atom; each ring represents, independently, a saturated or unsaturated five, six or seven-membered ring; ring may, independently, be substituted with one or more substituents selected from =0 or compounds of the formula -RY, wherein R represents a valence bond or a linear or branched lower alkylene, lower alkenylene or lower alkynylene; and Y represents a hydrogen, a halide, -C(0)NZ₂, - C(0)-OZ or -OZ, wherein Z, which may be the same or different in -C(0)NZ₂, represents a hydrogen or a linear or branched lower alkyl, lower alkenyl or lower alkynyl; or when each ring in said compound of the general formula I is substituted with at least one of the above substituents, the two substituents, including the carbon atoms to which they are bonded, may form together a five, six or seven-membered ring which may be substituted with the group -RY, as defined above; as an effective ingredient and a pharmaceutically acceptable carrier.

21. The medicament of Claim 20, wherein the amount of the active ingredient is in the range of from about 0.1 to 200 mg/kg/day.

22. The medicament of Claim 21, wherein the amount of the active ingredient is in the range of from about 1.0 to 180 mg/kg/day.

23. The medicament of anyone of Claims 20 to 21, wherein the medicament is for intravenous injection.

24. The medicament of anyone of Claims 20 to 23, wherein the medicament exerts its action, at least in part via activation of soluble guanylyl cyclase.

25. The medicament of anyone of Claims 20 to 24, wherein the active ingredient is l,7-dioxaspiro[5.5]undecane.