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WO1991007175A1 - Emploi de s(-) atenolol optiquement pur dans le traitement de troubles cardiovasculaires - Google Patents

Emploi de s(-) atenolol optiquement pur dans le traitement de troubles cardiovasculaires Download PDF

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Publication number
WO1991007175A1
WO1991007175A1 PCT/US1990/006824 US9006824W WO9107175A1 WO 1991007175 A1 WO1991007175 A1 WO 1991007175A1 US 9006824 W US9006824 W US 9006824W WO 9107175 A1 WO9107175 A1 WO 9107175A1
Authority
WO
WIPO (PCT)
Prior art keywords
atenolol
beta
medicament
cardiovascular disorders
treatment
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.)
Ceased
Application number
PCT/US1990/006824
Other languages
English (en)
Inventor
Timothy J. Barberich
Robert L. Bratzler
James W. Young
William J. Louis
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.)
Sunovion Pharmaceuticals Inc
Original Assignee
Sepracor Inc
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 Sepracor Inc filed Critical Sepracor Inc
Publication of WO1991007175A1 publication Critical patent/WO1991007175A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • Atenolol is a drug belonging to the general class of compounds known as beta-blockers.
  • Beta-blockers include beta 1 - selective (cardio- selective) adrenoreceptor blocking agents, which are exemplified by such well-known commercial products such as Tenormin.
  • Atenolol is a potent cardiac regulator, which has both beta-blocking and ant ihyp ertens ive
  • the beta- adrenoreceptor blocking activity of atenolol is characterized by a reduction in resting and exercize heart rate and cardiac output, a reduction in the systolic and diastolic blood pressure at rest and on exercise, inhibition of isopronicol-induced tachycardia and reduction in reflex orthostatic tachycardia.
  • a significant beta-blocking effect of atenolol is apparent within one hour following oral administration of a single dose.
  • Atenolol generally
  • Atenolol is a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers. Enantiomers are organic compounds which differ only in that one isomer is a mirror image of the other and the mirror images cannot be superimposed. This phenomenon is known as chirality. Most biological molecules exist as enantiomers and exhibit
  • enantiomers can have profoundly different effects in biological systems: one enantiomer is often biologically active while the other has little or no biological activity at all.
  • the present invention relates to a method of treating cardiovascular disorders, including angina pectoris and hypertension, in an individual
  • the method is useful in treating cardiovascular disorders and in treating hypertension while reducing (decreasing or
  • the present method is useful for treating cardiac disorders, for example, associated with angina pectoris and/or hypertension.
  • Figure 1 is a graph showing the effects of various amounts of RS, R or S atenolol on
  • HR heart rate
  • DBP diastolic blood pressure
  • Figure 2 is a graph showing the effects of various amounts of RS, R or S atenolol on the resting heart rate in the pithed rat.
  • Figure 3 is a graph showing the effects of various amounts of propanolol (RS), or RS, R or S atenolol on the contractile tension of an isolated, electrically driven atrial muscle preparation.
  • RS propanolol
  • the present invention relies on the beta- blocking activity of the S (-) levorotatory
  • R and S refer to the configuration or relative positions of the chemical substituents that form the enantiomeric center.
  • S configuration is the levorotatory, or (-), enantiomer and the R configuration is, therefore, the detrorotatory, or (+), enantiomer.
  • S (-) - atenolol which is substantially free of its R(+) enantiomer, is administered alone, or in combination with other drugs in adjunctive treatment, to an individual suffering from a cardiovascular disorder, such as heart disease, angina or hypertension.
  • a cardiovascular disorder such as heart disease, angina or hypertension.
  • substantially free of the R(+) enantiomer means that the composition contains at least 90% by weight S (-) atenolol and 10% by weight or less of R(+) atenolol.
  • S (-) atenolol is
  • Racemic atenolol contains a mixture of the R (+) and S (-) enantiomers.
  • the S (-) enantiomer is the more active beta blocker of these enantiomers; it is the more pharmacologically effective form of
  • the S (-) enantiomer is about twice as potent as the racemic mixture; thus, a dose of the S enantiomer which is approximately one half that of the racemic mixture has the same beta blocking activity.
  • S (-) atenolol is
  • S (-) atenolol can be administered prophylactically to reduce the probability of occurrence of a heart attack.
  • the drug can be administered orally, by subcutaneous or other injection, intravenously, topically, parenterally, transdermally, rectally or via by sustained release methods, e.g., an implanted reservoir containing S (-) atenolol.
  • the form in which the drug will be administered e.g., powder, tablet, capsule, solution, emulsion
  • the quantity of the drug to be administered will be determined on an individual basis, and will be based at least in part on consideration of the individual's size, the severity of the symptoms to be treated and the result sought.
  • quantities of S (-) atenolol sufficient to reduce hypertension or regulate heart beat will be administered. For example, less than about 100 mg per day of S (-) atenolol (and, for example, less than 40 mg per day) is given in one dose or more doses to produce the desired effect.
  • pectoris may require up to about 200 mg per day; in such patients, 80 mg per day may be given.
  • a dose of about 20 to about 50 mg of S (-) atenolol (e.g., 20-40 mg) per day will be administered.
  • S (-) atenolol can be administered along with one or more other drugs.
  • other anti-hypertensive agents such as thiazide-type diuretics, calcium antagonists, hydralazine, prazosin, and alpha-methyl dopa, and, in some patients, angiotensin converting enzyme inhibitors, can be given with or in close temporal proximity to administration of S (-)
  • the two (or more) drugs S (-) atenolol and another drug can be administered in one composition or as two separate entities. For example, they can be administered in a single capsule, tablet, powder, liquid, etc. or as individual compounds.
  • the components included in a particular composition, in addition to S (-) atenolol and another drug or drugs, are determined primarily by the manner in which the composition is to be administered.
  • a composition to be administered orally in tablet form can include, in addition to the drugs, a filler (e.g., lactose), a binder (e.g., carboxymethyl cellulose, gum arabic, gelatin), an adjuvant, a flavoring agent, a coloring agent and a coating material (e.g., wax or a plasticizer).
  • a filler e.g., lactose
  • a binder e.g., carboxymethyl cellulose, gum arabic, gelatin
  • an adjuvant e.g., carboxymethyl cellulose, gum arabic, gelatin
  • composition to be administered in liquid form can include the combination of drugs and, optionally, an emulsifying agent, a flavoring agent and/or a coloring agent.
  • S (-) atenolol alone or in combination with another drug (s) is administered to an individual periodically as necessary to reduce or ameliorate symptoms of the hypertension or angina being treated while reducing or avoiding undesirable side effects associated with beta-blockers.
  • the length of time during which the drugs are administered and the dosage will depend on the disorder being treated, the type and severity of the symptoms, and the physical condition of the individual being treated.
  • m-Nitrobenzenesulfonyl chloride (426g, 1.92 mole) was added in portions while maintaining the temperature below 10°C. During addition, a white precipitate (Et 3 N-HCl) was formed. The mixture was stirred at RT for 22 hours. The mixture was then diluted with small volume of EtOAc and filtered. The solid residue was washed thoroughly with EtOAc. The filtrate was then concentrated to dryness to give a yellow oil which on standing and cooling became a solid. The solid was recrystallized twice from EtOAc/hexane until the optical rotation did not change.
  • the mixture was then filtered and the residual solid was washed thoroughly with small portions of DMF.
  • the combined filtrate was then concentrated to ca. one liter in volume.
  • the concentrate was placed in a 2 liter 3-neck round bottom flask equipped with a reflux condenser and a magnetic stir bar.
  • Rats weighing approximately 200-250 g were anaesthetised with halothane and the left carotid artery and left jugular vein was cnnulated and the trachea exposed and
  • isoprenaline 0.05 ⁇ g/kg was initially given three times at intervals of 10 minutes to establish control responses to heart rate.
  • test drug antagonist
  • isoprenaline 5 minutes later.
  • the protocol was repeated at intervals of 15 minutes using successively higher doses of antagonist.
  • the dose range was based on a logarithmic series, 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300, 1000, 3000 and 10, 000 ug/kg.
  • the method used to determine the pA 2 value was taken from the description of MacKay. To determine the ⁇ A 2 for inhibition of tachycardia the response to isoprenaline was first recorded alone, and then the response to isoprenaline in the presence of antagonist was recorded. The concentration of isoprenaline which produced 50% inhibition of the maximal response (the IC 50 ) was determined in the presence and absence of the antagonist and the dose ratio is defined as the difference between the log concentrations D 1 and D 2 . The pA 2 was then determined from the equation in MacKay using the dose ratio and molar concentration of the antagonist.
  • rat atria The results obtained in rat atria are shown in Table 1.
  • the R and S isomers were those supplied by Sepracor, Inc.
  • the racemic mixture was obtained either from Sigma, as a standard commercial preparation, or from a combination of equal amounts of the Sepracor isomers.
  • pA 2 values of the S-atenolol were of the order of 7.6 compared to values of 5.9-6.5 for the R-atenolol. This represents a relative potency for the S-isomer of 18-52 times that for the R.
  • the pA 2 of racemic atenolol obtained from either Sigma or Sepracor was of the order of 7.2-7.5 indicating a potency of 10-20 times greater than for the R-isomer alone but only 1.8 to 2.5 times less than the S-isomer.
  • beta-2 adrenoceptor preparations Two beta-2 adrenoceptor preparations were used. They were the isolated rat uterus and the isolated guinea pig trachea, again using isoprenaline as the agonist (Table 2). In the rat uterus the pA 2 values for S-atenolol were approximately 6 versus 4.7 for R-atenolol, and the racemic atenolol (from Sigma) was 5.8.
  • adrenoceptor antagonist activity a standard dose of isoprenaline was given, 0.05 ⁇ g/kg, producing a beta-1 mediated tachycardia, and the inhibition of this response by successive doses of the antagonist was assessed.
  • the ID 50 of the antagonist is the concentration that inhibits the isoprenaline tachycariac response by 50%.
  • the isoprenaline also produces a beta-2 adrenoceptor mediated fall in blood pressure.
  • both S and racemic atenolol inhibited the agonist effect of isoprenaline on heart rate in a dose- dependent way, but only inhibited the effect of isoprenaline on blood pressure at concentrations > 10,000 ⁇ g/kg indicating they both had significant beta-1 selectivity in this model.
  • the S isomer was 6 times more potent than the racemic and 90 times more potent than the R isomer. Again the S isomer was the most potent form in inhibiting the ability of isoprenaline to reduce blood pressure but the relative potency to the other forms could not be clearly established because
  • the pithed rat preparation was also used to assess the presence of agonist activity (ISA) in the stereoisomers of atenolol. This would be apparent as a dose-dependent increase in heart rate (beta-1) or a dose-dependent fall in blood pressure (beta-2) which would be blocked by propranolol. There was no evidence of either beta-1 or beta-2 ISA with any of the forms of atenolol studied.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le S(-) aténolol optiquement pur, lequel est exempt du R(+) énantiomère, constitue un agent bêta-bloquant puissant dans la régulation des pulsations cardiaques, soulageant les symptômes de l'angine de poitrine et réduisant la pression sanguine chez des individus. Un procédé est décrit, lequel utilise le S(-) énantiomère d'aténolol optiquement pur, afin de traiter des troubles cardiovasculaires, tout en réduisant les effets secondaires indésirables associés aux agents bêta-bloquants.
PCT/US1990/006824 1989-11-21 1990-11-21 Emploi de s(-) atenolol optiquement pur dans le traitement de troubles cardiovasculaires Ceased WO1991007175A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44003689A 1989-11-21 1989-11-21
US440,036 1989-11-21

Publications (1)

Publication Number Publication Date
WO1991007175A1 true WO1991007175A1 (fr) 1991-05-30

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PCT/US1990/006824 Ceased WO1991007175A1 (fr) 1989-11-21 1990-11-21 Emploi de s(-) atenolol optiquement pur dans le traitement de troubles cardiovasculaires

Country Status (5)

Country Link
EP (1) EP0519925A1 (fr)
JP (1) JPH05503510A (fr)
AU (1) AU643487B2 (fr)
CA (1) CA2069404A1 (fr)
WO (1) WO1991007175A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1013275A3 (fr) * 1991-11-26 2001-01-10 Sepracor, Inc. Procédés et compositions destinés à traiter l'hypertension, l'angine de poitrine et d'autres troubles à l'aide de (-) amlodipine optiquement pure
EP1022025A3 (fr) * 1991-06-26 2002-06-05 Sepracor, Inc. Methodes et compositions pour le traitement des vomissements, de la nausee et d'autres troubles faisant appel a l'ondansetron optiquement pur R(+)
US6548082B1 (en) 1999-03-01 2003-04-15 Sepracor Inc. Methods for treating apnea and apnea disorders using optically pure R(+) ondansetron
EP1121111B1 (fr) * 1998-10-15 2010-02-10 Imperial Innovations Limited Compositions pour traiter la perte de poids

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2927538B1 (fr) * 2008-02-14 2010-02-19 Servier Lab Association d'un inhibiteur du courant if sinusal et d'un beta-bloquant.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256586A1 (fr) * 1986-07-28 1988-02-24 Gist-Brocades N.V. Procédé pour la préparation d'esters de l'acide 4-(2,3-époxypropoxy)phénylacétique et de l'acide 4-(2-hydroxy-3-isopropylamino-propoxy)phénylacétique et/ou aténolol en forme stéréospécifique

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62245353A (ja) * 1986-04-18 1987-10-26 Hitachi Ltd Ｅｅｐｒｏｍのデ−タ書換え防止回路
JPS62271031A (ja) * 1986-05-20 1987-11-25 Fujitsu Ltd 記憶デ−タ保護方式

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256586A1 (fr) * 1986-07-28 1988-02-24 Gist-Brocades N.V. Procédé pour la préparation d'esters de l'acide 4-(2,3-époxypropoxy)phénylacétique et de l'acide 4-(2-hydroxy-3-isopropylamino-propoxy)phénylacétique et/ou aténolol en forme stéréospécifique

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
J.E.F. REYNOLDS ET AL.: "MARTINDALE, THE EXTRA PHARMACOPOEIA, 28TH EDITION" December 1982, THE PHARMACEUTICAL PRESS, LONDON, GB see pages 1324 - 1338 *
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY vol. 12, no. 2, August 1988, NEW YORK, US pages 208 - 217; T.J. RIMELE ET AL.: "COMPARISON OF THE BETA-ADRENORECEPTOR AFFINITY AND SELECTIVITY OF CETAMOLOL, ATENOLOL, BETAXOLOL AND ICI-118551" see page 212, column 1 - column 2 see pages 213 - 216, column 1 *
JOURNAL OF PHARMACY & PHARMACOLOGY vol. 40, no. 9, September 1988, LONDON, GB pages 609 - 612; N. EL TAYAR ET AL.: "INFLUENCE OF LIPOPHILICITY AND CHIRALITY ON THE SELECTIVITY OF LIGANDS FOR BETA1- AND BETA2-ADRENORECEPTORS" see the whole document *
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS vol. 247, no. 3, December 1988, BALTIMORE, US pages 958 - 964; J.G. WEBB ET AL.: "STEREOSELECTIVE SECRETION OF ATENOLOL FROM PC12 CELLS" see abstract see pages 961 - 963; figure 8 *
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS vol. 250, no. 3, September 1989, BALTIMORE, US pages 759 - 763; A.A. PEARSON ET AL.: "A STEREOSELECTIVE CENTRAL HYPOTENSIVE ACTION OF ATENOLOL" see abstract see pages 761 - 763; figures 1-5 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1022025A3 (fr) * 1991-06-26 2002-06-05 Sepracor, Inc. Methodes et compositions pour le traitement des vomissements, de la nausee et d'autres troubles faisant appel a l'ondansetron optiquement pur R(+)
EP1013275A3 (fr) * 1991-11-26 2001-01-10 Sepracor, Inc. Procédés et compositions destinés à traiter l'hypertension, l'angine de poitrine et d'autres troubles à l'aide de (-) amlodipine optiquement pure
EP1121111B1 (fr) * 1998-10-15 2010-02-10 Imperial Innovations Limited Compositions pour traiter la perte de poids
US6548082B1 (en) 1999-03-01 2003-04-15 Sepracor Inc. Methods for treating apnea and apnea disorders using optically pure R(+) ondansetron
US6649183B2 (en) 1999-03-01 2003-11-18 Sepracor Inc. Methods for treating apnea and apnea disorders using optically pure R(+) ondansetron

Also Published As

Publication number Publication date
AU643487B2 (en) 1993-11-18
CA2069404A1 (fr) 1991-05-22
JPH05503510A (ja) 1993-06-10
EP0519925A1 (fr) 1992-12-30
AU6893391A (en) 1991-06-13

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