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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

• 11-substituted 5,ll-dihydro-6H-pyrido[2,3-b] [1,4] benzodiazepin-6-ones such as 11-aminoacetyl- 5,ll-dihydro-6H-pyrido[2,3-6] [1,4] benzodiazepin-6- ones or the non-toxic pharmacologically acceptable salts thereof, are tricyclic compounds having the structural formula
• R.. is hydrogen or alkyl of 1 to 4 carbon atoms
• R 2 is hydrogen chlorine or methyl
• R_ and R . are each alkyl of 1 to 5 carbon atoms or, together with each other and the nitrogen atom to which they are attached, camphidino, pyrrolidino, morpholino, piperidino, methyl-piperidino, ethyl-piperidino, piperazino, N 1 -methyl-piperazino, N'-ethyl- piperazino, N'-hydroxyethyl-piperazino, N'-benzyl- piperazino, N'-methylbenzyl-piperazino or hexamethyle- neimino.
• Pirenzepine is an antimuscarinic agent which has been demonstrated to be an effective inhibitor of gastric secretion and is currently available in Europe as an anti-ulcer medication. It is thought to specifically antagonize a subtype of muscarinic receptors; it inhibits gastric secretion but not other muscarinic activities (i.e., gastric emptying, esophageal motility) and neither mydriasis nor tachy ⁇ cardia occur with its administration. It has been reported to be relatively ineffective (compared to atropine) in smooth muscle preparations from the intestine and vasculature. Grass, and Skorodin (Am. Rev. Respir. Dis.
• piren ⁇ zepine to inhibit vagally-induced bronchoconstric ⁇ tion in mammals.
• the compounds of the present invention, and specifically pirenzepine have the advantage of atropine of being able to be adminis ⁇ tered orally without concurrent side effects due to selectivity for a receptor subtype which appears to be limited to the vagal bronchoconstructive pathway (and the vagal secretary pathway in the stomach) .
• compounds of the present invention are better choices of antimuscarinic agents for airways obstruc ⁇ tive disease because they are potent inhibitors of vagally - induced bronchoconstriction and can be given orally without crossing the blood brain barrier or causing other side effects.
• Pulmonary resistance was calculated from raw data signals of transpulmonary pressure, volume, and flow using a Z80 CPU computer.
• a saline filled polyethylene catheter was placed in the thoracic aorta, threaded via the femoral artery in order to measure phasic aortic pressure and heart rate.
• the animals were paralyzed with succinyl- choline and mechanically ventilated.
• the cervical vagus nerve was isolated bilaterally and transected.
• the distal cut ends of the cervical vagi were electrically stimulated simultaneously for 1 minute duration (40 Hz frequency, 0.3 msec pulse duration, 10 volts intensity) , and the maximum increase in pulmonary resistance and decrease in heart rate determined. Two stimulations were performed 3 minutes apart. Intravenous infusions of antagonist drug, either atropine or pirenzepine, were given in 5 increasing concentrations and vagal stimulation repeated. Stimulations were performed at 6 and 9 minutes after each drug infusion was begun. Six animals received atropine and 6 animals pirenzepine. For each dose of antagonist drug, the percent inhibi ⁇ tion of the change in pulmonary resistance or heart rate induced by vagal stimulation was determined and an inhibition curve constructed. The dose of drug required to antagonize by 50% the effect of vagal stimulation on pulmonary resistance and heart rate (IC 50) was calculated from the curves. The results appear in the following table:
• pirenzepine shows a differential inhibitory activity, with a 42-fold greater inhibitory activity on bronchoconstriction as compared to the decrease in heart rate.
• Ml pirenzepine sensitive

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• Health & Medical Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1986
  • 1986-03-31 EP EP19860902624 patent/EP0218678A1/de active Pending
  • 1986-03-31 WO PCT/US1986/000644 patent/WO1986006278A1/en not_active Application Discontinuation

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