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WO1993000081A1 - Nadolol s(-) optiquement pur utilise dans le traitement des troubles cardio-vasculaires - Google Patents

Nadolol s(-) optiquement pur utilise dans le traitement des troubles cardio-vasculaires Download PDF

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Publication number
WO1993000081A1
WO1993000081A1 PCT/US1992/005429 US9205429W WO9300081A1 WO 1993000081 A1 WO1993000081 A1 WO 1993000081A1 US 9205429 W US9205429 W US 9205429W WO 9300081 A1 WO9300081 A1 WO 9300081A1
Authority
WO
WIPO (PCT)
Prior art keywords
nadolol
beta
side effects
amount
undesirable side
Prior art date
Application number
PCT/US1992/005429
Other languages
English (en)
Inventor
James W. Young
Timothy J. Barberich
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 WO1993000081A1 publication Critical patent/WO1993000081A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame

Definitions

  • Nadolol is a drug belonging to the general class of compounds known as beta-blockers.
  • Beta-blockers are beta-selective adrenoreceptor blocking agents, and include well-known commercial products such as propanolol and atenolol.
  • Nadolol is a potent cardiac regulator with both antihypertensive and antianginal activity.
  • the beta-adrenoreceptor blocking activity of nadolol is characterized by a reduction in resting and exercise heart rate and cardiac output, a reduction in the systolic and diastolic blood pressure at rest and on exercise, inhibition of isoproterenol-induced tachycardia and reduction in reflex orthostatic tachycardia.
  • nadolol By blocking the positive chronotropic and inotropic effects of catecholamines and by decreasing blood pressure, nadolol generally reduces the oxygen requirements of the heart, at any given level of effort.
  • Nadolol is known to be a non-selective beta blocker. That is, it interacts strongly with both cardiac (beta-1 type) adrenoreceptors and with those adrenoreceptors in bronchial and vascular (beta-2 type) musculature. Because of the non-selectivity of nadolol, it is contraindicated in patients with bronchial asthma and other obstructive airways diseases.
  • Nadolol is not metabolized to a significant degree by the liver. It is excreted by the kidneys unchanged. Because the drug has an appreciable half-life (about 20-24 hours) it can be administered on a once-daily dosage basis. However, because of its relatively long half-life and excretion characteristics, dosage of nadolol must be adjusted with care in patients with impaired renal function.
  • Nadolol has been found to possess substantially less direct yocardial depressant activity than some other beta-blockers. For instance, it was found to exhibit about 1/2Oth the myocardial depressant effect of propranolol in experiments with anesthetized dogs.
  • Nadolol is a race ic mixture. That is, it is a mixture of optical isomers, called enantiomers.
  • Enantiomers are structurally similar compounds which differ only in that one isomer is a configurational mirror image of the other and the mirror images cannot be superimposed. This phenomenon is known as chirality. Most biological molecules exhibit chirality. Although structurally similar, enantiomers can have profoundly different effects in biological systems. Few studies have been conducted to investigate biological characteristics of the enantiomers of nadolol. Raxworthy et al. (Xenobiotica 1986, Vol. 16, No. l, pp.
  • the present invention relates to a method of treating cardiovascular disorders, including angina pectoris and hypertension, in an individual comprising administering to the individual a beta-blocking or antihypertensive amount of the levorotatory or S(-) enantiomer of nadolol , which is substantially free of the dextrorotatory or R(+) enantiomer.
  • the method is useful in treating cardiovascular disorders and in treating hypertension while reducing or avoiding undesirable side effects such as gastro-intestinal distress, dizziness, fatigue, as well as certain cardiovascular and central nervous system effects, and allergic reactions, which are due, at least in part, to the presence of the R(+) enantiomer.
  • beta-blocking drugs it is important to have a beta-blocking and antihypertensive composition which also minimizes these side effects.
  • a composition containing the S(-) isomer of nadolol is particularly useful because the S(-) isomer exhibits both these desired characteristics of treating cardiovascular disorders and, at the same time, reducing undesirable side effects.
  • the present method provides a safe, highly effective method for treating cardiac disorders associated with angina pectoris and/or hypertension.
  • the present invention relies on the beta-blocking activity of the levorotatory enantiomer of nadolol, referred to as S(-) nadolol, to provide enhanced beta-blocking activity (for example, as treatment for angina pectoris or hypertension) without many of the undesirable side effects associated with beta-blockers.
  • cardiovascular effects such as excessive bradycardia, impaired peripheral vascular circulation (for example typified by symptoms of the Raynaud type) , cardiac rhythm/conduction disturbances and/or atrioventricular block
  • central nervous system effects such as dizziness, fatigue, paresthesias, sedation and behavioral changes
  • respiratory effects such as bronchospasm
  • gastrointestinal effects such as nausea, diarrhea, constipation, and indigestion
  • miscellaneous effects such as impotence or decreased libido, headache, dry mouth, eyes or skin, and tinnitis
  • dermatological effects such as causing or aggravating certain forms of psoriasis or exanthema.
  • S(-)nadolol which is sub ⁇ stantially 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.
  • **S(-) nadolol refers to the levorotatory isomer of cis-5-[3-[ (l,l-dimethylethyl)amino]-2- hydroxypropoxy]-1,2,3,4-tetrahydro-2,3- naphthalenediol.
  • the term "substantially free of the R(+) enantiomer" as used herein means that the composi ⁇ tion contains at least 90% by weight S(-) nadolol and 10% by weight or less of R(+) nadolol. Preferably, the composition contains at least 98% by weight of S(-) nadolol and 2% or less of R(+) nadolol.
  • Racemic nadolol i.e., a mixture of R(+) and S(-) enantiomers
  • the S(-)isomer has the desired antihypertensive and antianginal activities.
  • R(+) nadolol can induce significant side effects in some individuals.
  • S(-) nadolol is administered to an individual suffering from a cardiovascular disorder, such as angina pectoris or hypertension.
  • a cardiovascular disorder such as angina pectoris or hypertension.
  • S(-) nadolol is administered therapeutically to an individual to reduce or ameliorate hypertension or to reduce the symptoms of angina pectoris.
  • S(-) nadolol can be administered prophylactically to reduce the probability of occurrence of a heart attack or therapeutically after the occurrence of a heart attack.
  • the present method also has the advantage that it offers improved antihypertensive and antianginal therapy to patients with impaired renal function.
  • nadolol Since nadolol is excreted mainly by the kidneys, it tends to accumulate to an undesired extent in cases of renal failure, leading to an aggravation of any one or several of the above-mentioned side effects.
  • the presence of the undesired R(+) enantiomer of nadolol also places an unneeded burden on the kidney function of the patient since it must be excreted even though it contributes no desirable effect to the patient's benefit.
  • the present method also provides the unexpected benefit of reducing cardiac depressant effects of nadolol. Even though nadolol is known to possess lower myocardial depressant activity than propanolol, this characteristic is further reduced by use of the S(-) enantiomer in place of the racemic mixture. In some patients bradycardia (slowing of the heartbeat) and negative inotropic effects (weakening of the force of the heartbeat) can represent serious side effects and can lead to an increased risk of congestive heart failure or aggravation of an existing malady of this type.
  • R(+) nadolol is not useful in treating hypertension or angina pectoris, for example, it does contribute to the cardiac depressant effects of the drug.
  • Administration of S(-) nadolol essentially free of the contaminating R(+) enantiomer provides a significant reduction in the incidence or seriousness of such side effects.
  • the drug can be administered orally, by subcutaneous or other injection, intravenously, topically, parent- erally, transdermally, rectally or via sustained release methods, e.g., an implanted reservoir containing S(-) nadolol.
  • the form in which the drug will be administered (e.g., powder, tablet, capsule, solution, emulsion) will depend on the route by which it is administered.
  • 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(-) nadolol sufficient to reduce hypertension or reduce the symptoms of angina pectoris will be administered. For example, less than about 80 mg per day of S(-) nadolol (given in one dose or multiple doses) is usually sufficient to produce the desired effect. Some patients having hypertension, however, may require up to about 200 mg per day.
  • S(-) nadolol can be administered along with one or more other drugs.
  • other anti-hypertensive agents such as bendroflumethazide or other thiazide-type diuretics, hydralazine, prazosin, and alpha-methyl dopa
  • S(-) nadolol 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.
  • 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 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(-) nadolol alone or in combination with (an)other drug(s) , is administered to an individual periodically as necessary to reduce or ameliorate symptoms of the hypertension or angina pectoris being treated while reducing or avoiding undesirable side effects associated with beta-blockers, including cardiac, respiratory, central nervous system, gastro-intestinal, and allergic reactions.
  • beta-blockers including cardiac, respiratory, central nervous system, gastro-intestinal, and allergic reactions.
  • 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.
  • the invention is further illustrated by the following example. This example is not intended to be limiting of the invention in any way.
  • DMF Dry dimethylformamide
  • Potassium t-butoxide is then added to form a solution.
  • 1,2,3, -Tetrahydro-2R,3S,5- naphthalenetriol in dry DMF is then slowly added at 5-10 ⁇ C with vigorous stirring.
  • the resulting mixture is then warmed to room temperature and stirred for a number of hours before being cooled back to 5 C C with ice-water.
  • S-Glycidyl m-nitrobenzenesulfonate in DMF is then slowly added. After the addition, the mixture is stirred while allowing it to warm to room temperature. The reaction is then adjusted to neutral pH with NaH.PO..
  • the wet solid from the above reaction is added to water followed by t-butylamine.
  • the suspension is heated to reflux and stirred for a number of hours.
  • the reaction is followed by HPLC.
  • the reaction is then cooled to room temperature and the excess t-butylamine removed by distillation.
  • the resulting mixture is then saturated with NaCl.
  • a solution of NaOH is then added to make the mixture 2% in NaOH.
  • the mixture is stirred, then cooled to 5°C and filtered.
  • the solid is washed with water and dried in vacuo to give the title compound.

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  • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le nadolol S(-) optiquement pur, ne contenant pratiquement pas d'énantiomère R(+), est un puissant β-bloquant qui permet de soulager les symptômes de l'angine de poitrine et de l'hypertension chez l'homme. Un procédé est décrit dans lequel on utilise l'énantiomère S(-) optiquement pur de nadolol pour traiter les troubles cardio-vasculaires tout en réduisant les effets secondaires indésirables associés à l'administration du médicament racémique.
PCT/US1992/005429 1991-06-28 1992-06-25 Nadolol s(-) optiquement pur utilise dans le traitement des troubles cardio-vasculaires WO1993000081A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US72296091A 1991-06-28 1991-06-28
US722,960 1991-06-28

Publications (1)

Publication Number Publication Date
WO1993000081A1 true WO1993000081A1 (fr) 1993-01-07

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075856A3 (fr) * 2003-02-24 2005-03-31 Novacardia Inc Methode de traitement d'une maladie au moyen d'un antagoniste du recepteur de l'adenosine a1
US7579331B2 (en) 2003-04-25 2009-08-25 Novacardia, Inc. Method of improved diuresis in individuals with impaired renal function
EP2983657A4 (fr) * 2013-04-05 2016-11-23 Numedii Inc Traitement de troubles gastro-intestinaux et d'autres troubles
WO2023250334A1 (fr) * 2022-06-21 2023-12-28 Curasen Therapeutics, Inc. Compositions et méthodes impliquant des composés isolés
WO2023250332A1 (fr) * 2022-06-21 2023-12-28 Curasen Therapeutics, Inc. Compositions et méthodes impliquant des composés isolés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1464950A (en) * 1973-05-03 1977-02-16 Squibb & Sons Inc Naphthalene derivatives
EP0105996A1 (fr) * 1982-10-15 1984-04-25 Merck & Co. Inc. Compositions ophtalmiques pour le traitement de la pression intraoculaire élevée
EP0165450A2 (fr) * 1984-05-23 1985-12-27 Bayer Ag Associations de nifédipine et procédé pour leurs préparations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1464950A (en) * 1973-05-03 1977-02-16 Squibb & Sons Inc Naphthalene derivatives
EP0105996A1 (fr) * 1982-10-15 1984-04-25 Merck & Co. Inc. Compositions ophtalmiques pour le traitement de la pression intraoculaire élevée
EP0165450A2 (fr) * 1984-05-23 1985-12-27 Bayer Ag Associations de nifédipine et procédé pour leurs préparations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Chromatography, vol. 539, no. 1, 8 February 1991, Elsevier Science Publishers B.V., (Amsterdam, NL), C.R. LEE et al.: "Liquid and high-pressure carbon dioxide chromatography of beta-blockers", pages 55-69, see abstract and introduction, pages 55-56, line 9 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075856A3 (fr) * 2003-02-24 2005-03-31 Novacardia Inc Methode de traitement d'une maladie au moyen d'un antagoniste du recepteur de l'adenosine a1
JP2006518765A (ja) * 2003-02-24 2006-08-17 ノヴァカーディア，インク． アデノシンａ１受容体アンタゴニストを使って疾患を処置する方法
US7579331B2 (en) 2003-04-25 2009-08-25 Novacardia, Inc. Method of improved diuresis in individuals with impaired renal function
EP2983657A4 (fr) * 2013-04-05 2016-11-23 Numedii Inc Traitement de troubles gastro-intestinaux et d'autres troubles
WO2023250334A1 (fr) * 2022-06-21 2023-12-28 Curasen Therapeutics, Inc. Compositions et méthodes impliquant des composés isolés
WO2023250332A1 (fr) * 2022-06-21 2023-12-28 Curasen Therapeutics, Inc. Compositions et méthodes impliquant des composés isolés

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AU2297192A (en) 1993-01-25

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