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WO2000076544A1 - Derives de l'aminotetraline pour le traitement des maladies cardio-vasculaires - Google Patents

Derives de l'aminotetraline pour le traitement des maladies cardio-vasculaires Download PDF

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Publication number
WO2000076544A1
WO2000076544A1 PCT/EP2000/005231 EP0005231W WO0076544A1 WO 2000076544 A1 WO2000076544 A1 WO 2000076544A1 EP 0005231 W EP0005231 W EP 0005231W WO 0076544 A1 WO0076544 A1 WO 0076544A1
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WO
WIPO (PCT)
Prior art keywords
chf
therapy
administration
activity
left ventricular
Prior art date
Application number
PCT/EP2000/005231
Other languages
English (en)
Inventor
Stefano Bongrani
Roberta Razzetti
Maurizio Civelli
Alberto Umile
Paolo Chiesi
Original Assignee
Chiesi Farmaceutici S.P.A.
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
Priority claimed from PCT/EP1996/001060 external-priority patent/WO1996029065A2/fr
Priority to SI200030234T priority Critical patent/SI1183046T1/xx
Priority to IL14696200A priority patent/IL146962A0/xx
Priority to JP2001502876A priority patent/JP2003501483A/ja
Priority to DE60004996T priority patent/DE60004996T2/de
Priority to PL00352119A priority patent/PL352119A1/xx
Priority to US10/009,352 priority patent/US6576671B1/en
Priority to NZ515727A priority patent/NZ515727A/xx
Priority to EA200101159A priority patent/EA003830B1/ru
Application filed by Chiesi Farmaceutici S.P.A. filed Critical Chiesi Farmaceutici S.P.A.
Priority to CA002376715A priority patent/CA2376715A1/fr
Priority to EP00935184A priority patent/EP1183046B1/fr
Priority to SK1801-2001A priority patent/SK18012001A3/sk
Priority to AT00935184T priority patent/ATE248607T1/de
Priority to KR1020017015440A priority patent/KR20020005772A/ko
Priority to EEP200100663A priority patent/EE200100663A/xx
Priority to BR0012121-5A priority patent/BR0012121A/pt
Priority to DK00935184T priority patent/DK1183046T3/da
Priority to HU0201650A priority patent/HUP0201650A2/hu
Priority to MXPA01012638A priority patent/MXPA01012638A/es
Priority to AU50765/00A priority patent/AU766230B2/en
Publication of WO2000076544A1 publication Critical patent/WO2000076544A1/fr
Priority to NO20016000A priority patent/NO20016000L/no
Priority to HK02105724.0A priority patent/HK1044279B/zh

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of 5,6-diisobutyroyloxy-2- methylaminotetralin in the preparation of pharmaceutical compositions for the therapy of cardiac disorders, particularly congestive heart failure.
  • the symptomatic therapy usually aims at reducing the workload of the decompensed heart and improving the mechanical function.
  • the therapy of congestive heart failure has to be directed to the improvement of the hemodynamic factors, on one hand, and to the pharmacological modulation of the neurohumoral system on the other.
  • Dopaminergic drugs appear as candidates to become established as drugs for heart failure in the majority of patients.
  • dopamine has peculiar characteristics, compared with the other medicaments, since it stimulates both dopaminergic and alpha and beta- adrenergic receptors.
  • DAj receptors smooth muscle of the vascular system
  • DA 2 receptors pre-synaptic position
  • the usefulness of dopamine in the treatment of heart failure is, however, restricted by it being inactive orally.
  • Analogously dobutamine a synthetic analogue of dopamine, can be used only intravenously.
  • Aminotetralin derivatives have been studied for a long time as dopamine structural analogues for any uses as medicaments.
  • CHF 1035 5,6-Diisobutyroyloxy-2-methylaminotetralin, hereinafter referred to as CHF 1035, has been described first in GB Pat. 2123410 among a series of aminotetralin derivatives disclosed as potential antibronchospastic due to their activity on adrenergic receptors. Both 5,6-dihydroxy-2-methylaminotetralin (hereinafter indicated with the experimental abbreviation CHF 1024) and CHF 1035 have been formerly characterized as compounds having prevailing selective activity on ⁇ 2 adrenergic receptors.
  • CHF 1024 and CHF 1035 in addition to the already known ⁇ 2 agonist activity, have remarkable peripheral DA 2 and ⁇ 2 presynaptic activities leading to a reduction of the sympathetic tone, which is elevated in heart failure patients.
  • CHF 1024 and CHF 1035 have a vasodilating activity due the combination of their effects on ⁇ 2 and ⁇ 2 and DA]/DA 2 receptors as well as a cardiac isotropic activity.
  • CHF 1024 and CHF 1035 have agonist activity on dopaminergic receptors and that they are selective for the presynaptic DA 2 ones.
  • ⁇ 2 adrenergic and DA 2 -dopaminergic activities of the compounds have been evaluated in binding tests (example 1 and 3), in isolated neuronally- stimulated rat vas deferens (example 2) and in rabbit rectococcygeus muscle (example 4).
  • cardiovascular effects of the compounds have been evaluated in vivo in anesthetized rats both after intravenous and intraduodenal administration (example 5 ) .
  • CHF 1024 and CHF 1035 were tested on human platelets and on rat cerebral cortex.
  • the antagonist [ H]-rauwolscine was used as marker of the receptor, being its binding reversible, saturable and specific.
  • CHF 1024 exhibited a significantly higher affinity than dopamine, 9 times in platelets and 15 times in cerebral cortex.
  • the affinity of CHF 1035 was similar to that of dopamine, utilized as reference compound.
  • CHF 1035 The lower affinity of CHF 1035 for the receptor is probably due to the esterification of the molecule.
  • IC 5 Q molar concentration of drug required for 50% inhibition of [ 3 H]-rauwolscine specific binding.
  • IC 50 value molar concentration of drug which induces 50% inhibition of the electrically induced contraction:
  • C.I. 95% Confidence Interval
  • the compounds CHF 1024 and CHF 1035 are about 20-70 times more potent than dopamine, respectively.
  • CHF 1024 for peripheral DA 2 dopaminergic receptors was tested on bovine adrenal cortex evaluating its effect on the interaction of [ ⁇ ](-)sulpiride with the specific binding sites of this system.
  • Dopamine has been employed as reference compound.
  • IC 50 concentration required for 50% inhibition of specific binding
  • the affinity of CHF 1024 for DA 2 receptors is 1 1 times higher than that of dopamine.
  • CHF 1024 and CHF 1035 on peripheral DA 2 dopaminergic receptors has been tested in the electrically stimulated rabbit rectococcygeus muscle.
  • Both compounds determined a dose-dependent inhibition of contraction induced by electrical stimulation and were approximately 3 times more potent than dopamine, utilized as reference compound.
  • mice Male albino rats (Sprague Dawley, 350-400 g) were anesthetized by sodium pentobarbital (60 mg/kg) and maintained by i.v. infusion (6 mg/h). The trachea was cannulated to facilitate spontaneous respiration and body temperature was maintained at 37 C Homoiothermic Blanket Control System
  • the right femoral artery was cannulated for arterial blood pressure measurement and left jugular vein or duodenum were cannulated for drug administration.
  • Mean arterial pressure and heart rate were continuously monitored by pressure transducer and medium gain amplifier triggered by the
  • CHF 1024 (0.23, 0.69 and 2.3 ⁇ g/kg/min) was administered by intravenous infusion for 30 min and cardiovascular parameters were recorded for further 30 min after discontinuation.
  • CHF 1035 was administered intraduodenally (1 mg/kg).
  • the response to CHF 3035 was determined in the absence and in the presence of the selective ⁇ 2 -adrenoceptor antagonist ICI 118.551 (0.2 mg/kg i.v.) and the selective DA 2 -dopaminergic antagonist domperidone (0 3 mg/kg i.v.) both alone and in combination.
  • the antagonists were administered 10 min before the i.d. drug administration.
  • Intravenous administration of CHF 1024 induced a dose-dependent reduction in mean arterial pressure which persists even after infusion discontinuation.
  • n number of animals
  • hypotensive response was characterized by a rapid and marked fall (peak effect of about 45% reduction from basal value at 5 min after administration) followed by a slow recovery (about 20% reduction from basal value is still present 2 hours after administration).
  • PCWP pulmonary capillary wedge pressure
  • CJ cardiac index
  • the evaluations were carried out by catheterization of the right heart (Swan-Ganz catheter), measuring the hemodynamic parameters of the tested medicament before administration or "pre-dose” (PD) and for the 300 subsequent minutes after the administration or "after-dose” (AD), every 20 minutes for the first 2 hours, then every 60 minutes.
  • noradrenaline (NE) pg/ml
  • adrenalin (E) pg/ml
  • the general hemodynamic effect CHF 1035 can be ascribed to the peripheral vasodilating activity of the medicament, both arterial and venous.
  • This evident activity on peripheral receptors could have induced a neurohumoral hyper-reactivity, with a consequent increase in noradrenaline and adrenalin plasmatic levels, which is an undesired reaction in a pathological subject.
  • CHF 1035 is capable of inducing systemic vasodilation without inducing any reflected increase in catecholamines plasmatic levels.
  • the vasodilating activity of the compound derives from its receptor properties, particularly from the activity on pre-synaptic DA 2 and ⁇ 2 receptors, the stimulation of which can inhibit the catecholamine release, as it is well known.
  • congestive heart failure is one of the most common causes of death and disability in industrialized nations and is among the syndromes most commonly encountered in clinical practice, affecting nearly 4 million persons in the USA and 14 million individuals in Europe.
  • the current pharmacological treatment of the condition includes diuretics, angiotensin converting enzyme (ACE) inhibitors and digitalis.
  • ACE angiotensin converting enzyme
  • CHF 1035 improves the clinical condition and the exercise capacity of patients with congestive heart failure when used as add-on therapy to baseline therapy with diuretics or with diuretics and ACE- inhibitors and/or with diuretics and digitalis.
  • CHF 1030 as added therapy have been evaluated in patients suffering from NYHA class II-III congestive heart failure due to mild hypertension, or coronary disease, or chronic cardiomyopathy who were on diuretics or diuretics and an angiotensin-converting enzyme inhibitor.
  • the study therapy was started by patients on day 1 and proceeded until day 28 of the study.
  • CHF 1035 improved the functional and clinical condition of patients, compared to placebo.
  • This improvement was ostensible in terms of the NYHA functional class, exercise performance, and symptoms and signs of pulmonary and systemic congestion, central haemodynamic alterations, and decreased regional/organ blood flows. For the evaluation of clinical condition, more than 60 symptoms or signs were evaluated.
  • CCSs clinical compound scorings
  • the pulmonary congestion appeared as the most important determinant of the functional status in congestive heart failure and was the most sensitive CCS to CHF 1035 add-on therapy.
  • CHF 1035 increases diuresis without affecting natriuresis and kaliuresis.
  • CHF 1035 is the diisobutyroyl ester of 5,6-dihydroxy-2- methylaminotetralin, which is referred to as CHF 1024.
  • CHF 1035 is transformed by the plasma and tissue esterases into the pharmacologically active desesterified form, which is also included within the present invention.
  • CHF 1035 can be advantageously used as pro-drug for the preparation of pharmaceutical compositions for the therapy of cardiac disorders and in particular for congestive cardiac failure.
  • the daily dose of the active ingredient can vary from 1- 100 mg and preferably ranges from 2.5-20 mg.
  • the administration can be performed by any route, preferably by the oral route.
  • the compound can be formulated in solid or liquid preparations, preferably in tablets, using the additives and excipients of common use in pharmaceutical technique.
  • transdermal systems which are adhesive matrixes that can be applied to the skin containing a suitable concentration of the active ingredient, which can gradually be released thus entering the blood circulation.
  • MI Myocardial infarction
  • Delapril was dissolved in drinking water at the final concentration of 0.043 mg/ml.
  • the delapril solutions were prepared freshly every third day and their concentration adjusted to body weight every 15 days to obtain an average dose of 6 mg-kg " ' -day " .
  • CHF 1024 was administered continuously for four weeks through osmotic minipumps implanted subcutaneously behind the neck. Concentrated solutions of CHF 1024 were dissolved in 10% ascorbic acid in distilled water at a final concentration of 40 mM (mean delivery rate 0.33 mg-kg ⁇ -day "1 ).
  • Morphometric bidimensional and three-dimensional analyzes of the LV were done according to a method previously described (1) and ampliated for three-dimensional evaluations (2).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

On peut traiter le dysfonctionnement du ventricule gauche par un procédé consistant à administrer souffrant d'un remodelage du ventricule gauche une quantité à effet thérapeutique de 5,6-dihydéroxy-2-méthylaminotétraline, ou de 5,6-diisobutyroyl-oxy-2-méthyl-aminotétraline, l'un de leurs sels pharmacocompatibles, associés à un inhibiteur de l'enzyme de conversion de l'angiotensine.
PCT/EP2000/005231 1996-03-13 2000-06-07 Derives de l'aminotetraline pour le traitement des maladies cardio-vasculaires WO2000076544A1 (fr)

Priority Applications (21)

Application Number Priority Date Filing Date Title
AU50765/00A AU766230B2 (en) 1999-06-09 2000-06-07 Aminotetralin derivative for the therapy of cardiovascular diseases
EP00935184A EP1183046B1 (fr) 1999-06-09 2000-06-07 Derives de l'aminotetraline pour le traitement des maladies cardio-vasculaires
JP2001502876A JP2003501483A (ja) 1999-06-09 2000-06-07 心血管系疾患の治療のためのアミノテトラリン誘導体
DE60004996T DE60004996T2 (de) 1999-06-09 2000-06-07 Aminotetralin derivate zur therapie der kardiovaskulären erkrankungen
PL00352119A PL352119A1 (en) 1999-06-09 2000-06-07 Derivatives of aminotetraline for treatment of cardiovascular diseases
US10/009,352 US6576671B1 (en) 1999-06-09 2000-06-07 Aminotetralin derivatives for the therapy of cardiovascular diseases
NZ515727A NZ515727A (en) 1999-06-09 2000-06-07 Aminotetralin derivative for the therapy of cardiovascular diseases
AT00935184T ATE248607T1 (de) 1999-06-09 2000-06-07 Aminotetralin derivate zur therapie der kardiovaskulären erkrankungen
IL14696200A IL146962A0 (en) 1999-06-09 2000-06-07 Aminotetralin derivatives for the therapy of cardiovascular diseases
CA002376715A CA2376715A1 (fr) 1999-06-09 2000-06-07 Derives de l'aminotetraline pour le traitement des maladies cardio-vasculaires
SK1801-2001A SK18012001A3 (sk) 1999-06-09 2000-06-07 Použitie 5,6-dihydroxy-2-metylaminotetralínu alebo 5,6-diizobutyroyloxy-2-metylaminotetralínu
SI200030234T SI1183046T1 (en) 1999-06-09 2000-06-07 Aminotetralin derivative for the therapy of cardiovascular diseases
EA200101159A EA003830B1 (ru) 1999-06-09 2000-06-07 Производное аминотетралина для терапии сердечно-сосудистых заболеваний
KR1020017015440A KR20020005772A (ko) 1999-06-09 2000-06-07 심장혈관질환의 치료를 위한 아미노테트랄린추출물
EEP200100663A EE200100663A (et) 1999-06-09 2000-06-07 Aminotetraliini derivaat kardiovaskulaarsete haiguste raviks
BR0012121-5A BR0012121A (pt) 1999-06-09 2000-06-07 Derivado de aminotetralina para terapia de doenças cardiovasculares
DK00935184T DK1183046T3 (da) 1999-06-09 2000-06-07 Aminotetralin-derivat til behandlingen af cardiovaskulære sygdomme
HU0201650A HUP0201650A2 (hu) 1999-06-09 2000-06-07 Amino-tetralin-származékok alkalmazása szív- és érrendszeri betegségek gyógykezelésére használható gyógyszerek előállítására
MXPA01012638A MXPA01012638A (es) 1999-06-09 2000-06-07 Derivados de aminotetralina para la terapia de enfermedades cardiovasculares.
NO20016000A NO20016000L (no) 1999-06-09 2001-12-07 Aminotetralin-derivat for terapien av kardiovaskul¶re sykdommer
HK02105724.0A HK1044279B (zh) 1999-06-09 2002-08-06 治療心血管疾病用的氨基四氫化萘衍生物

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/EP1996/001060 WO1996029065A2 (fr) 1995-03-17 1996-03-13 Derive d'aminotetraline pour la therapie des maladies cardio-vasculaires
US09/328,434 US6103760A (en) 1995-03-17 1999-06-09 Aminotetralin derivative for the therapy of cardiovascular diseases
US09/328,434 1999-06-09

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/328,434 Continuation US6103760A (en) 1995-03-17 1999-06-09 Aminotetralin derivative for the therapy of cardiovascular diseases

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/009,352 A-371-Of-International US6576671B1 (en) 1999-06-09 2000-06-07 Aminotetralin derivatives for the therapy of cardiovascular diseases
US10/411,313 Division US20030207944A1 (en) 1999-06-09 2003-04-11 Aminotetralin derivative for the therapy of cardiovascular diseases

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WO2000076544A1 true WO2000076544A1 (fr) 2000-12-21

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PCT/EP2000/005231 WO2000076544A1 (fr) 1996-03-13 2000-06-07 Derives de l'aminotetraline pour le traitement des maladies cardio-vasculaires

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1500392A1 (fr) * 2003-07-24 2005-01-26 CHIESI FARMACEUTICI S.p.A. Dérivés d'aminotétraline comme médicament pour le traitement et la prévention du dysfonctionnement myocardique ischémique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029065A2 (fr) * 1995-03-17 1996-09-26 Chiesi Farmaceutici S.P.A. Derive d'aminotetraline pour la therapie des maladies cardio-vasculaires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029065A2 (fr) * 1995-03-17 1996-09-26 Chiesi Farmaceutici S.P.A. Derive d'aminotetraline pour la therapie des maladies cardio-vasculaires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S.MASSON E.A.: "Effects od DA2/alpha2 agonist and a beta-1 blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodeling in an experimental model of left ventricular dysfunction after coronary artery occlusion", JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, vol. 34, no. 3, 1999, pages 321 - 326, XP000953084 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1500392A1 (fr) * 2003-07-24 2005-01-26 CHIESI FARMACEUTICI S.p.A. Dérivés d'aminotétraline comme médicament pour le traitement et la prévention du dysfonctionnement myocardique ischémique

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