EP1746988A1 - Spiroderives pour le traitement de l'hypertension - Google Patents

Spiroderives pour le traitement de l'hypertension

Info

Publication number
EP1746988A1
EP1746988A1 EP04732165A EP04732165A EP1746988A1 EP 1746988 A1 EP1746988 A1 EP 1746988A1 EP 04732165 A EP04732165 A EP 04732165A EP 04732165 A EP04732165 A EP 04732165A EP 1746988 A1 EP1746988 A1 EP 1746988A1
Authority
EP
European Patent Office
Prior art keywords
medicament
ring
active ingredient
hypertension
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04732165A
Other languages
German (de)
English (en)
Inventor
Nadav Zamir
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Darley Pharmaceuticals Ltd
Original Assignee
Darley Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Darley Pharmaceuticals Ltd filed Critical Darley Pharmaceuticals Ltd
Publication of EP1746988A1 publication Critical patent/EP1746988A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes

Definitions

  • This invention relates to the treatment of hypertension. More specifically, the invention relates to a medicament for the treatment of hypertension
  • 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].
  • CHF congestive heart failure
  • 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.
  • ACE angiotensin-converting enzyme
  • 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].
  • cGMP Guanosine 3', 5 '-cyclic monophosphate
  • 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).
  • cGMP-dependent protein kinase PKG
  • 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).
  • 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.
  • 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.
  • the present invention concerns the use of a compound of the general formula I:
  • the compound of the general formula I also includes R and S (or '+' and '-') enantiomeric forms of said compound, as well as mixtures thereof.
  • 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.
  • 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.
  • 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.
  • blood pressure is considered normal or desired if the systolic blood is 130 mmHg or less and the diastolic blood pressure is
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • Fig. 2B depicts the changes in diastolic blood pressure.
  • 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.
  • the medicament When the medicament is administered intravenously, it may be in form of an infusion (e.g. continuously) or injection, such as bolus injection.
  • the medicament of the invention 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.
  • 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.
  • the medicaments of the present invention may be incorporated within a liposome prepared by any of the methods known in the art.
  • 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.
  • other active ingredients may be added. Such addition may for example exert a synergistic effect or reduce the side effects of each active ingredient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • BP blood pressure
  • HR heart rate
  • ECG electrocardiogram
  • 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
  • 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.
  • a third animal exhibited a profound drop in systemic blood pressure that lead to death within 15 minutes.
  • the two animals that survived showed minimal or no response of systemic blood pressure to both injections of Z-13-octadecenal.
  • Z-13-octadecenal is a potent toxic compound that its intravenous administration resulted in death of three out of five animals tested.
  • confluent SV-CISM-2 cells were washed with Ca 2+ - Mg 2+ 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 (l ⁇ M) 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.
  • TCA trichloroacetic acid
  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de 1,7-dioxaspiro[5.5]undécane pour la préparation d'un médicament destiné au traitement ou à la prévention de l'hypertension. L'invention concerne également une méthode destinée au traitement ou à la prévention de l'hypertension, selon le cas, à l'aide d'un médicament comprenant du 1,7 dioxaspiro[5.5]undécane en tant que principe actif.
EP04732165A 2004-05-11 2004-05-11 Spiroderives pour le traitement de l'hypertension Withdrawn EP1746988A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IL2004/000396 WO2005107739A1 (fr) 2004-05-11 2004-05-11 Spiroderives pour le traitement de l'hypertension

Publications (1)

Publication Number Publication Date
EP1746988A1 true EP1746988A1 (fr) 2007-01-31

Family

ID=34957456

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04732165A Withdrawn EP1746988A1 (fr) 2004-05-11 2004-05-11 Spiroderives pour le traitement de l'hypertension

Country Status (2)

Country Link
EP (1) EP1746988A1 (fr)
WO (1) WO2005107739A1 (fr)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3629287A (en) * 1968-10-01 1971-12-21 Cutter Lab 1 3-dioxolan-4-yl-alkyl amines
US3547951A (en) * 1969-06-17 1970-12-15 Waldo R Hardie 1,3-dioxolan-4-yl-alkyl guanidines
US3651090A (en) * 1969-12-17 1972-03-21 Cutter Lab 1 3-dioxolan-4-yl-alkyl guanidines
US4129659A (en) * 1977-08-08 1978-12-12 The University Of Miami Method for improving cardiovascular function with salinomycin
US4824959A (en) * 1988-02-18 1989-04-25 Bristol-Myers Company Intermediates for antihypercholesterolemic tetrazole compounds
HUT74450A (en) * 1993-12-27 1996-12-30 Eisai Co Ltd Anthranilic acid derivative and pharmaceutical compns. contg. such compds.
AU1929401A (en) * 1999-12-01 2001-06-12 Alydar Pharmaceuticals Ltd. Method for screening non-peptide, non-steroid inverterbrate pheromones, compositions containing the same and use of the compositions to treat diseases, conditions, and symptoms thereof
JP2004210648A (ja) * 2002-12-27 2004-07-29 Sumitomo Pharmaceut Co Ltd 新規マクロライド化合物及びその製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005107739A1 *

Also Published As

Publication number Publication date
WO2005107739A1 (fr) 2005-11-17

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