WO1994014441A1 - Utilisation d'une dihydropyridine enantiomere - Google Patents

Utilisation d'une dihydropyridine enantiomere Download PDF

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Publication number
WO1994014441A1
WO1994014441A1 PCT/SE1993/001071 SE9301071W WO9414441A1 WO 1994014441 A1 WO1994014441 A1 WO 1994014441A1 SE 9301071 W SE9301071 W SE 9301071W WO 9414441 A1 WO9414441 A1 WO 9414441A1
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WO
WIPO (PCT)
Prior art keywords
treatment
felodipine
pharmaceutical preparation
medicament
manufacture
Prior art date
Application number
PCT/SE1993/001071
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English (en)
Inventor
Bertil Bengt Samuelsson
Margareta Nordlander
Peter Thoren
Original Assignee
Aktiebolaget Astra
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 Aktiebolaget Astra filed Critical Aktiebolaget Astra
Priority to AU58253/94A priority Critical patent/AU5825394A/en
Publication of WO1994014441A1 publication Critical patent/WO1994014441A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the present invention relates to the use of an enantiomer selected from the group consisting of R(+) felodipine, R(+) nitrendipine and R(+) nimodipine for the manufacture of a medicament for the treatment of stroke; chronic neurodegenerative disorders; alcohol abstinence; chronic pain conditions and other situations when cerebral ischemia may be a hazard to the patient.
  • the invention also relates to a method for the treatment of stroke, chronic neruodegenerative disorders; alcohol abstinence; chronic pain conditions or cerebral ischemia and to a pharmaceutical preparation for use in the treatment of the same.
  • Calcium antagonists exert their effect by blockade of the L-type calcium channel in the sacrolemma of vascular and myocardial muscle and in the central nervous system.
  • Felodipine is more potent in inhibiting vascular calcium channels than myocardial calcium channels;
  • the vascular versus myocardial selectivity is about 10 times higher than that of nifedipine and about 100 times higher than that of verapamil (Ljung B., Drugs (1985) Suppl. 12, p. 46-58).
  • the high vascular selectivity will safeguard against untoward cardiac effects in doses causing vascular dilatation and blood pressure reduction.
  • Felodipine as an active compound having antihypertensive effect is described in European Patent No. 7293. It is marketed as an antihypertensive drug and has in 1992 been prescribed for 600 000 patient-years world-wide.
  • Nitrendipine and nimodipine as active compounds having antihypertensive effect are described in GB 1 358 951.
  • Isradipine as an active compound having antihypertensive effect is described in GB 2 037 766 and amlodipine as an active compound having antihypertensive effect is described in EP 89 167.
  • Felodipine given to hypertensive rats have shown to reduce the extent of neuronal necrosis observed after ligation of the middle cerebral artery but only in doses which reduce blood pressure. In states of low cerebral perfusion as in ischemia, it is unfavorable to lower blood pressure since it will further impair perfusion unless the arteries in the ischemic area can be further dilated, which is usually not the case. Felodipine thus does not seem ideal for the treatment of stroke and other states of cerebral ischemia.
  • dihydropyridines on the market used for treatment of cardiovascular diseases including felodipine contain one asymmetric carbon in the 4 position of the dihydropyridine ring and are racemates of the S and R enantiomers.
  • Experimental evaluation of the pharmacodynamic properties of the enantiomers has shown that one enantiomer, usually S, of several dihydropyridines (nitrendipine, isradipine, niguldipine, nimodipine, felodipine) is more potent than the other enantiomer in its inhibitory action on vascular smooth muscle activity.
  • the R enantiomers of felodipine, nitrendipine and nimodipine can be used as an agent to block neuronal calcium channels in doses triggering small blood pressure effects.
  • R(+) felodipine is used to block neuronal calcium channels. It has been found that the S(-) enantiomer of felodipine is about 13-25 times more potent in inducing an antihypertensive effect than the R(+) enantiomer.
  • the S(-) enantiomer of nitrendipine has been found to be about 10 times more potent than the R(+) enantiomer in reducing blood pressure in SHR rats (spontaneously hypertensive rats).
  • R(+) felodipine has the chemical name (4R)-4-(2,3-dichlorophenyl)-l,4- dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ester.
  • R(+) nitrendipine has the chemical name (4R)-l,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl methyl ester.
  • R(+) nimodipine has the chemical name (4R)-l,4-dihydro-2,6- dimethyl-4-(3- ⁇ trophenyl)-3,5-pyridinedicarboxylic acid 2- methoxyethyl 1-methylethyl ester.
  • All the above R enantiomers can be used in the manufacture of a medicament for the treatment of stroke; chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and AIDS-induced dementia; alcohol abstinence; chronic pain conditions and other situations when cerebral ischemia may be a hazard to the patient, such as multi infarct dementia.
  • chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and AIDS-induced dementia
  • alcohol abstinence chronic pain conditions and other situations when cerebral ischemia may be a hazard to the patient, such as multi infarct dementia.
  • R(+) felodipine can be synthesized according to Lamm et al. Tetrahedron Letters, Vol. 30, No. 46, pp 6423-6426, 1989; R(+) nitrendipine according to Eltze et al., Chirality, vol. 2, pp 233-240, (1990) and R(+) nimodipine according to Towart et al., Arzheim. Forsch./Drug Res., vol. 32, pp 338-349, (1982).
  • the enantiomers are usually administered orally, parenterally or rectally in a pharmaceutical preparation, which contains the active compound as free base in combination with a pharmaceutically acceptable carrier.
  • the carrier can be a solid, semisolid or liquid diluent or a capsule.
  • the carrier can provide modified release of the active drug.
  • the type of carrier will depend on the administration route.
  • a preparation to be administered orally in form of a tablet can include, in addition to the active drug, a solubilizer (e.g. a polyethoxylated fatty acid), a component which modifies the drug release (e.g. hydroxypropyl methyl cellulose), a filler (e.g. lactos), a binder (e.g. hydroxypropyl methyl cellulose) and a lubricant (e.g. sodium stearyl fumarate).
  • the tablets can be coated with a suspension of coloring pigments (e.g. iron oxide) and film forming agents (e.g. cellulose derivate).
  • An aqueous solution of the drug for parenteral use can include a co-solvent (e.g. polyethylene glycol).
  • the amount of active compound is between 0.1 and 99% by weight of the preparation, suitably between 0.5 and 20% by weight in preparations for injection and between 2 and 50% by weight in preparations for oral administration.
  • the daily dose of the active compound depends on individual needs (for example the patient's condition, body weight, age, sex etc.) as well as on the method of administration. Generally speaking, the oral dosage may range from 0.1 to 500 mg, preferably 1 to 50 mg, active compound per day.
  • the plasma concentration of S(-) felodipine at which blood pressure was reduced 20% was about 30 nmol/1 and the corresponding plasma concentration of R(+) felodipine was aroimd 800 nmol/1, a potency ratio at the effector level of about 25.
  • Experiment 2 Neuronal effects in vitro
  • the intracellular calcium concentration is very important in cellular homeostasis of all cells including neurons. Even brief periods of elevated calcium concentration will activate intracellular enzymes, which can degenerate the cell (See review by Siesjo & Bengtsson; J Cerebral Blood Flow and Metabolism, 1989, 9; 127-140).
  • the influx of calcium in neurons occurs basically by two mechanisms; a. the glutamate activated NMDA-channel and b. the voltage sensitive calcium L-channels. (Bertolino & Llinas, Annu Rev Pharmacol and Toxicol, 1992, 32; 399-421).
  • nifedipine (a dihydropyridine calcium antagonist) blocked the kainic acid induced toxi ⁇ ty with a pIC ⁇ Q of 10-20 ⁇ mol.
  • the authors speculate that the mechanism is related to blocking the calcium influx via L-channels, which are opened by the depolarization of the neurons.
  • This method to test the ability of felodipine and the R- and S- enantiomeres of felodipine to block neurotoxic effects of kainic acid i.e. the ability of the compounds to bind to neuronal L-channels.
  • LDH was normalized in percent of maximal release triggered by Triton.
  • the kainic acid exposure increase LDH release 3-5 fold. The most likely explanation for this is that kainic acid will depolarize the cultures and secondary to this an influx of calcium will occur via the L-channels. Treatment of the cultures with increasing doses of
  • Felodipine the R- and S-enantiomers of Felodipine will induce a dose related reduction of LDH release.
  • the maximal response is a reduction to about 20-25% of the release in the untreated cultures.
  • the pICt jQ for this inhibition was 5.13 ⁇ mol for felodipine-racemate and 5.21 ⁇ mol and 5.21 ⁇ mol for R- and S-felodipine respectively.
  • test data according to the invention shows that the R(+) and S(-) enantiomers of felodipine are equally potent in their ability to antagonize neuronal calcium channels. It also shows that the S(-) enantiomer is many times more potent than the R(+)enantiomer in inducing an antihypertensive effect.
  • R(+)enantiomer can be used as a specific agent to block neuronal calcium channels in doses triggening small blood pressure effects.
  • R(+)nitrendipine and R(+)nimodipin can be used for this purpose.
  • Sodium stearyl fumarate 10.5 g R(+) felodipine was dissolved in Myrj 51 and the solution obtained was mixed carefully with hydroxypropyl methylcellulose, cellulose and lactose. The mixture was granulated with ethanol and dried. Sodium stearyl fumarate was added as a lubricant and tablets containing 20 mg R(+)-felodipine were prepared by compression in a tabletting machine.
  • the drug was dissolved in ethanol, the propylene glycol was added and water was thereafter added to final volume.
  • the solution was sterilized by filtration and filled into sterile vessels, which were autoclaved.

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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)
  • Hydrogenated Pyridines (AREA)

Abstract

Utilisation d'un énantiomère sélectioné dans le groupe formé par R(+) félodipine, R(+) nitrendipine et R(+) nimodipine pour fabriquer un médicament destiné au traitement des attaques, des toubles neurodégénératifs chroniques, de la privation d'alcool, des états de douleurs chroniques et d'autres situations dans lesquelles l'ishémie cérébrale peut être un risque pour le patient; et procédé de traitement et préparation pharmaceutique destinée à être utilisée dans ce traitement.
PCT/SE1993/001071 1992-12-22 1993-12-15 Utilisation d'une dihydropyridine enantiomere WO1994014441A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58253/94A AU5825394A (en) 1992-12-22 1993-12-15 Use of an enantiomeric dihydropyridine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9203857-9 1992-12-22
SE9203857A SE9203857D0 (sv) 1992-12-22 1992-12-22 Use of an enantiomeric dihydropyridine

Publications (1)

Publication Number Publication Date
WO1994014441A1 true WO1994014441A1 (fr) 1994-07-07

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PCT/SE1993/001071 WO1994014441A1 (fr) 1992-12-22 1993-12-15 Utilisation d'une dihydropyridine enantiomere

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AU (1) AU5825394A (fr)
IS (1) IS4109A (fr)
SE (1) SE9203857D0 (fr)
WO (1) WO1994014441A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1343501A1 (fr) * 2000-11-21 2003-09-17 Howard Zik Utilisation de bloqueurs du canal calcium a la 1,4-dihydropyridine pour traiter des atteintes neurologiques imputables au virus de l'herpes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2815578C2 (de) * 1978-04-11 1986-01-16 Bayer Ag, 5090 Leverkusen Neue pharmazeutische Verwendung von Nimodipin
EP0330924A2 (fr) * 1988-02-27 1989-09-06 Troponwerke GmbH & Co. KG Utilisation des dérivés de la 1,4-dihydropyridine dans le traitement de la dépendance à l'alcool
WO1992003137A1 (fr) * 1990-08-23 1992-03-05 The Children's Medical Center Corporation Traitement des demences, des myelopathies, des neuropathies peripheriques et des pertes de vision liees au sida
WO1992007564A2 (fr) * 1990-10-30 1992-05-14 The Wellcome Foundation Limited Procede de traitement des maladies demyelinisantes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2815578C2 (de) * 1978-04-11 1986-01-16 Bayer Ag, 5090 Leverkusen Neue pharmazeutische Verwendung von Nimodipin
EP0330924A2 (fr) * 1988-02-27 1989-09-06 Troponwerke GmbH & Co. KG Utilisation des dérivés de la 1,4-dihydropyridine dans le traitement de la dépendance à l'alcool
WO1992003137A1 (fr) * 1990-08-23 1992-03-05 The Children's Medical Center Corporation Traitement des demences, des myelopathies, des neuropathies peripheriques et des pertes de vision liees au sida
WO1992007564A2 (fr) * 1990-10-30 1992-05-14 The Wellcome Foundation Limited Procede de traitement des maladies demyelinisantes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 115, No. 5, 5 August 1991, (Columbus, Ohio, USA), ELTZE, MANFRID et al., "Stereoselective Inhibition of Thromboxane-Induced Coronary Vasoconstruction by 1,4-Dihydropyridine Calcium Channel Antagonists", page 49, the Abstract No. 41577e; & CHIRALITY, 1990, 2 (4), 233-240. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1343501A1 (fr) * 2000-11-21 2003-09-17 Howard Zik Utilisation de bloqueurs du canal calcium a la 1,4-dihydropyridine pour traiter des atteintes neurologiques imputables au virus de l'herpes
EP1343501A4 (fr) * 2000-11-21 2004-12-15 Howard Zik Utilisation de bloqueurs du canal calcium a la 1,4-dihydropyridine pour traiter des atteintes neurologiques imputables au virus de l'herpes

Also Published As

Publication number Publication date
SE9203857D0 (sv) 1992-12-22
IS4109A (is) 1994-06-23
AU5825394A (en) 1994-07-19

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