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
  • A61K31/02—Halogenated hydrocarbons
  • A61K31/025—Halogenated hydrocarbons carbocyclic
  • A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
  • C07C25/18—Polycyclic aromatic halogenated hydrocarbons
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/41—Preparation of salts of carboxylic acids
  • C07C51/418—Preparation of metal complexes containing carboxylic acid moieties

Definitions

• This invention relates to methods for employing diphenylhalonium ion to elicit various pharmacological effects treating different types of cardiovascular dysfunction.
• diphenylhalonium ion has been found to be useful in stimulating guanylate cyclase activity, increasing the contractility of cardiac muscle and inhibiting the aggregation of blood platelet cells, each effect being desirable in ameliorating symptoms associated with particular pathological or pathogenic conditions.
• SNP Sodium nitroprusside
• SNP Sodium nitroprusside
• Prolonged administration of SNP can lead to symptoms of thiocyanate toxicity.
• Thyroid hormone insufficiency has also been reported during prolonged infusions of SNP.
• SNP has become the drug of choice for treating hypertensive crises, and is also widely used in the acute management of cardiac failure.
• the potent activity in vivo of SNP has been linked to the drug s ability to stimulate guanylate cyclase in most mammalian tissues.
• cyclic GMP guanosine 3',5'-cyclic phosphoric acid
• cyclic GMP guanosine monophosphate
• cardiac glycosides such as digitalis
• cardiac glycosides still play a principal role in the treatment of chronic heart failure, in part because they can be taken orally, unlike SNP , which must be administered intravenously.
• cardiac glycosides in addition to a comparatively narrow toxic-to-therapeutic ratio, cardiac glycosides also generally display a relatively weak inotropic effect. This deficiency in the pharmacological profile of cardiac glycosides has prompted an ongoing search for potent inotropic agents that can be employed in the managment of severe congestive heart failure. See Bairn et al, "Evaluation of a new bipyridine inotropic agent - Milrinone
• a single hemodynamic agent would combine SNP-like activity with inotropic activity, and would be suitable for administration by more than one route, e.g. , orally as well as intravenously.
• Such an agent would be extremely useful in treating heart failure, since it could act to increase the force of contraction of the failing ventricle while concomitantly decreasing the total peripheral resistance against which the weakened heart must work. See Cohn and Franciosa, "Vasodilator therapy of cardiac failure," NEW ENGL . J. MED. 297: 27-31, 254-58 (1977).
• the agent's SNP-like activity included elevating cGMP levels in blood platelets, the agent could also inhibit platelet aggregation, thereby ameliorating the atherosclerotic condition which is often present in patients with heart failure and to which platelet aggregation contributes.
• diphenylhalonium-based compounds While there is an extensive literature concerning candidates for therapeutic hemodynamic agents, there has apparently been no recognition in the art of pharmacological activity for diphenylhalonium-based compounds in this regard.
• One bivalent iodine compound, dipheyleneiodonium, and several of its derivatives have been identified as potent hypoglycemic agents, causing substantial , irreversible decreases of sugar levels in the blood of several animal species when administered orally in relatively low dosages.
• diphenyleneiodonium catalyzes an exchange of Cl- and OH- ions across biological membranes, and, independently, diminishes the rate of respiration in mitochondria by inhibiting the oxidation of NADH-linked substrates. Id.
• hypoglycemia-inducing activity of diphenyleneiodonium has been linked to the compound's ability to impair gluconeogenesis secondarily, via inhibition of mitochondrial NADH oxidation.
• Holland et al "Mechanism of action of the hypoglycemic agent diphenyleneiodonium," J BIOL. CHEM. 218:
• diphenyliodonium salts such as diphenyliodonium chloride (DIC)
• DIC diphenyliodonium chloride
• the sodium nitroprusside-like effect comprises stimulating guanylate cyclase activity and vasodilation, respectively.
• a composition is provided which is capable of supplying diphenylhalonium ion in vivo for use in inhibiting blood platelet aggregation.
• FIGURE 1 shows the dose-related effect of diphenyliodonium hexaf luorophosphate (DIFP) and SNP, respectively on soluble guanylate cyclase activity.
• DIFP diphenyliodonium hexaf luorophosphate
• SNP soluble guanylate cyclase activity.
• FIGURE 2 depicts the cumulative dose-response of DIFP for three cardiovascular parameters in the anesthetized dog. Increasing amounts of DIFP were injected (i.v.) at the times indicated by the arrows to produce cumulative doses of 0.1, 0.4, 1.4, 4.4 mg/kg.
• FIGURE 3 shows the effect of DIFP on myocardial contractility in the anesthetized dog.
• FIGURE 4 shows the comparison of the cardiovascular effects of DIFP and SNP in the dog.
• SNP was administered as a 60-minute infusion ( 10 ⁇ g/kg/min) and DIFP was given as a bolus (1 mg/kg i.v.) at time zero.
• Values are group means
• the DPHO ion can be complexed, in accordance with the present invention, with an anion derived from a nontoxic, pharmaceutically acceptable inorganic or organic acid.
• the anion could be, for example, chloride, bromide, phosphate, hexafluorophosphate, iodide, dichloroiodate, hydroxide, sulfate, bisulfate, edisylate, nitrate, benzenesulfonate, methanesulfonate, tosylate, acetate, haloacetate, halosulfonate, propionate, benzoate, fumarate, maleate, lactate, citrate, picrate and tartrate. Because of their relative toxicity, fluoroborate, hexafluoroarsenate, and benzesulfonate salts are not recommended for use in humans .
• DPHO-based compounds can also be given intravenously, intramuscularly or subcutaneously since they are generally soluble, in therapeutically effective concentrations, in standard physiological solutions. Since DPHO-based compounds are generally light-sensitive, their preparation for parenteral administration should take into account a probable, gradual loss of efficacy in solution upon exposure to light. For example, a particular compound could be packaged as an anhydrous powder in a light-resistant glass vial and dissolved just prior to use in sterile buffered saline.
• a DPHO-based compound could be combined in a lanolin-petrolatum base as an ointment and packaged, for example, in a tube or in an application patch containing a premeasured dose.
• an ointment once applied, would be covered by an occlusive cellophane or paper dressing to enhance adsorption.
• the ointment would be applied to body skin covered by clothing to decrease the chance of photodecomposition.
• a DPHO-based compound can be combined in light-resistant gelatin capsules with an inert bulk filling agent, such as talc or kaolin.
• a DPHO-based compound can be combined in tablet form with a suitable filler and a binder which permits rapid dissolution of the tablet when the tablet is placed on the buccal mucose.
• a nonvolatile fixing agent polyethylene glycol 4000, can be added to stabilize the DPHO-based tablet formulation.
• carbohydrate-based fillers like lactose and starch 1500 should be avoided, since the halonium moiety may react with carbohydrates.
• DHPO ion can stimulate guanylate cyclase activity, and thereby elevate cyclic GMP levels, in approximately the same concentation range (about 10 to 10 M) as does SNP.
• the effect of DPHO ion on cyclic GMP levels is reflected in its ability to relax systemic vessels, thereby reducing arterial blood pressure and total peripheral resistance.
• DPHO ion can also inhibit blood platelet aggregation, possibly because of its SNP-like effect on guanylate cyclase activity.
• DPHO ion acts as an inotropic agent, increasing the contractility of cardiac muscle and, hence, the force of myocardial contractions.
• DPHO vasodilating dose
• MAP mean systemic arterial pressure
• CO cardiac output
• stroke volume stroke volume and the velocity of left ventricular contraction, normalized to peak left ventricular pressure, are all enhanced after DPHO treatment, while pulmonary arterial pressure and pulmonary vascular resistance are relatively unaffected.
• DPHO pharmaco logic properties of DPHO evidence a utility for DPHO-based compounds in treating both systemic hypertension and chronic or acute left ventricular heart failure.
• DPHO resembles N,N-di-n-propyldopamine and N-n-propyl-N-n-butyl dopamine, both of which dopamine derivatives have been identified as therapeutically useful vasodilators. Fennell et al ,
• DIFP is readily substituted at the bis-4 positions. Substitution at one or both of the 4-positions would make less likely the possibility that a benzyl moiety would be among the metabolic products of a DPHO-based compound. For example, modification to the bis-4-methyl form (metabolic product comprising a toluene moiety) should be considered for human applications.
• either or both 4-positions of the DHPO ion can be substituted by ethyl, butyl, t-butyl, methoxy, ethoxy, amino, -CH 3 SO 2 , carboxyl, methylcarboxyl and/or ethylcarboxyl.
• [ 3 H]-cGMP was assayed using a crude soluble preparation from rat lung, as adapted from the methods of Garbers and Murad,
• the cyclase reaction consisted of 25 mM TRIS-HCl (pH 7.6) containing isobutylmethylxanthine (3 mM) , creatine kinase (33 units/ml) , creatine phosphate (20 mM) , MnCl 2 (3 mM) , dithioreitol (5 mM) , cGMP (1 mM) , [ 3 H]-GTP (0.75 mM, 2.5 x
• the tubes were frozen in dry ice/acetone, thawed and centrifuged (2500 x g, 15 minutes) to precipitate unreacted [ 3 H]-GTP.
• the H-cGMP in the supernatant was isolated by ion-exchange column chromatography using polyethylenimine cellulose (Sigma Chemical Co. , St. Louis, MO) , as taught by Garbers and Murad, supra, and counted by liquid scintillation spectrometry at an efficiency of about 38%.
• Catheters were placed from the femoral arteries retrograde into the left ventricle and mid-abdominal aorta to measure left ventricular and systemic arterial pressures, respectively.
• a Swan-Ganz thermister-tipped pulmonary artery catheter (American Edwards Laboratories, Santa Anna,
• CA intraveneous
• SNP was given by continuous infusion to obtain a sustained reduction in MAP.
• Cardiac output was measured with an American Edwards 9520 A cardiac output computer using thermal dilution technique. Ten mis of ice-cold (1-5o C) 5% dextrose in water was injected as a bolus in the right ventricle on two occasions within 2 minutes, and the values averaged for the calculation of the CO.
• the abdominal aortic catheter was connected to a Hewlett Packard transducer, and blood pressure was recorded on a Hewlett Packard 77588 polygraph.
• Maximum left ventricular (IV dP/dt) and left ventricular pressure (LVP), as well as left ventricular end diastolic pressure (LVEDP) were measured via the catheter inserted into the left ventricle through the right femoral artery.
• Cardiac contractility was measured as max dP/dt, or as max dP/dt divided by LVP at max dP/dt .
• Lead a VF electrocardiogram was monitored continuously and 5000 units of heparin were administered to avoid clotting.
• total peripheral vascular resistance TPR dynes ⁇ sec ⁇ cm -5 ) was calculated (as mean aortic pressure/CO x 80).
• Cardiac output (measured by thermal dilution) was transiently reduced during the injection period (Figure 2C) , but subsequently rose by the end of the injection period and reached maximum value at 70 min.
• the rate of ventricular contraction (dP/dt) normalized for left ventricular pressure, increased steadily after administration of DIFP ( Figure 3 ) , indicating an increase in myocardial. contractility.

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• 1984
  • 1984-11-06 EP EP19840904265 patent/EP0161305A1/de not_active Withdrawn
  • 1984-11-06 AU AU36154/84A patent/AU3615484A/en not_active Abandoned
  • 1984-11-06 WO PCT/US1984/001802 patent/WO1985002174A1/en unknown

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