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WO2007053415A2 - Agents pour le traitement d’arythmies cardiaques - Google Patents

Agents pour le traitement d’arythmies cardiaques Download PDF

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Publication number
WO2007053415A2
WO2007053415A2 PCT/US2006/041749 US2006041749W WO2007053415A2 WO 2007053415 A2 WO2007053415 A2 WO 2007053415A2 US 2006041749 W US2006041749 W US 2006041749W WO 2007053415 A2 WO2007053415 A2 WO 2007053415A2
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substituted
unsubstituted
compound
subject
pharmaceutically acceptable
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WO2007053415A3 (fr
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Maurice Robert Cross
Derek Anthony Terrar
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Novartis Vaccines and Diagnostics Inc
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Novartis Vaccines and Diagnostics Inc
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    • 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
    • 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
    • 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
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P9/06—Antiarrhythmics

Definitions

  • This invention relates to methods of treating cardiac arrhythmias while minimizing undesirable side effects, comprising administration of dexrazoxane, analogs thereof, prodrugs thereof, metabolites thereof, or therapeutic dosage forms thereof.
  • Dexrazoxane is known to prevent cardiomyopathy in cancer patients receiving high doses of the anthracycline agent, doxorubicin. To date, the mechanism by which dexrazoxane exerts its cardioprotective effect is not fully understood; however, it is suggested that an active metabolite, ADR-925, chelates iron accumulated in the heart from doxorubicin administration. Although safe and useful in protection against damage from doxorubicin, there has yet to have been exploration into the use of dexrazoxane as a therapeutic agent or for use in preventing/treating myocardial conditions outside of anthracycline-associated ! toxicities.
  • MI post-myocardial infarction
  • VT ventricular tachycardia
  • VF ventricular fibrillation
  • ⁇ -blockers and calcium- channel blockers which are widely used to treat arrhythmias, can cause hypotension and have negative inotropic effects.
  • beta blockers class II agents
  • calcium antagonists class IV agents
  • class I agents are actually harmful.
  • Selective adenosine A 1 receptor modulators with a significant half -life are also being considered for amelioration of arrhythmias.
  • the benefit of class III drugs, which affect action potential duration (APD) is presently of great interest and being evaluated further in large clinical trials.
  • One drug in particular, amiodarone has shown positive responses, however, toxicity and even proarrhythmic effects have limited its use.
  • the invention relates to a method of treating cardiac arrhythmias in a mammal comprising administration of a therapeutically effective dose of dexrazoxane, and novel derivatives of dexrazoxane and their prodrugs.
  • the invention provides a method of treating a subject suffering from a cardiac arrhythmia comprising administering a compound of Formula (IA), (IB), (IC), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof:
  • X 1 and X 2 are independently selected form CH, N, S, or O; each R 1 is H, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 6-1O aryl, or substituted or unsubstituted heterocyclyl; each R 2 is H, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 6-10 ary
  • R 5 and R 6 are independently selected from H, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkenyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted heterocyclyl, with the proviso that if X 1 is O or S, R 5 is absent, or if X 2 is O or S, R 6 is absent; each m is independently 1, 2, or 3; each n is independently O, 1, or 2; and each p is independently 0, 1, or 2; wherein the cardiac arrhythmia is treated in the subject after administration of the compound of Formula (IA), (IB), (IC), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof.
  • the compound has the Formula (IA).
  • R 5 and R 6 are both H.
  • X 1 and X 2 are N and each n is 1.
  • each of R 3 and R 4 are appended to the adjacent (alpha) carbon to X 1 and
  • R 1 is unsubstituted C 1-6 alkyl and R 2 is H.
  • the compound has the Formula (IC), R 2 is unsubstituted C 1-6 alkyl and R 1 is H. ⁇ [0011] In another embodiment, the compound has the Formula (IB) or (IC) and each n and p is 1.
  • the compound is:
  • the compound is:
  • the compound is:
  • the compound is:
  • the prodrug of Formula (IA), (IB) or (IC) is administered to the subject.
  • Another embodiment of the invention provides a method of treating a subject suffering from a cardiac arrhythmia comprising administering a prodrug of a compound of Formula (IB):
  • X 1 and X 2 are independently selected form CH, N, S, or O; each R 1 is H, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 6-1O aryl, or substituted or unsubstituted heterocyclyl; each R 2 is H, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 6-10 ary
  • the compound of Formula IB is:
  • the prodrug has the Formula (IA) or
  • the prodrug that is administered to the subject is a compound listed in Table 1.
  • the myocardial' action potential duration (APD) decreases in the subject.
  • the QT interval is maintained or decreased in the subject.
  • the compound or a pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrug thereof does not decrease contractility in the subject.
  • the compound is not co-administered nor used in conjunction with an anthracycline compound.
  • the compound is not co-administered nor used in conjunction with doxorubicin.
  • the subject has minimal myelosuppresion after administration of the compound, tautomer, stereoisomer or prodrug thereof.
  • the cardiac arrhythmia is a ventricular or supraventricular arrhythmia.
  • the cardiac arrhythmia is a ventricular tachyarrhythmia.
  • the cardiac arrhythmia is re-entrant tachyarrhythmia.
  • the subject is suffering from congestive heart failure (CHF).
  • CHF congestive heart failure
  • the compound is administered after an ischemic insult.
  • the compound contacts a cell or tissue in the subject's heart.
  • the compound of Formula (IA) is administered to the subject and a compound of Formula (IB) or (IC) contacts the cell or tissue in the subject's heart.
  • the compound that contacts the cell is:
  • composition comprising:
  • a pharmaceutical composition comprising:
  • a pharmaceutical composition comprising:
  • a compound comprising:
  • Another embodiment provides, a compound, comprising:
  • Another embodiment provides, a compound, comprising:
  • Another embodiment provides, a method of treating a subject suffering from cardiac arrhythmia comprising: administering to the subject,an effective amount of the compound or pharmaceutical composition of any one of preceding compounds.
  • Another embodiment provides, a prodrug of a compound of Formula (IB):
  • X 1 and X 2 are independently selected form CH, N, S, or O; each R 1 is H, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 6-I0 aryl, or substituted or unsubstituted heterocyclyl; each R 2 is H, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 6-10 ary
  • R 1 and R 2 are taken together to form a 3-7 membered substituted or unsubstituted carbocyclyl or heterocyclyl group; each n is independently 0, 1, or 2; and each p is independently 0, 1, or 2; wherein the cardiac arrhythmia is treated in the subject after contacting the compound of Formula (IB) with a cell and/or tissue in the subject; wherein the prodrug is not dexrazoxane.
  • the compound is:
  • Another embodiment provides, a method of preventing or treating cardiomyopathy comprising: administering to the subject an effective amount of any one of the preceding compounds or a prodrug of any one of the preceding compounds.
  • the cardiomyopathy is from administration of an anticancer agent, particularly anfhracycline, more particularly ' doxorubicin.
  • the prodrug is listed in Table 1, excluding Example 1.
  • composition comprising human serum from a patient suffering from a cardiac arrhythmia and a compound having the following structure:
  • the present invention also encompasses pharmaceutical compositions of each of the compounds described herein.
  • the compositions of the present invention may be administered or used in conjunction with an adjuvant.
  • Methods of manufacturing the compositions described herein are provided and contemplated to fall within the scope of the invention, as is the use of the compositions in methods for manufacturing medicaments for use in the methods of the invention.
  • Figure 1 Effects of Dexrazoxane on developed tension in guinea pig whole hearts.
  • Figure 2 Effects of Dexrazoxane on unloaded cell shortening in single ventricular myocytes.
  • FIG. 6 Mean data for the peak amplitude of action potential driven unloaded cell shortening (UCS) measured in single ventricular myocytes is shown.
  • UCS action potential driven unloaded cell shortening
  • Figure 8 Effects of Dexrazoxane on APDg 0 in single ventricular myocytes.
  • Figure 8 shows typical action potential records taken from a single ventricular myocytes under control conditions and in the presence of dexrazoxane (10 ⁇ M) superfused for 10 minutes, 20 minutes and 30 minutes. Dexrazoxane (under these conditions) shortened action potential duration.
  • Figure 9. Effects of Dexrazoxane on APD 90 and QT interval.
  • Figure 10. Effects of Dexrazoxane on heart rate variability in stable
  • the present invention provides compositions with equivalent efficacy and , ,. . desired pharmacological properties of amiodarone, yet without the associated • toxicities and without decreased contractility.
  • dexrazoxane or a pharmaceutically acceptable salt, derivative, tautomer, stereoisomer, or metabolite thereof to the treatment of cardiac arrhythmias is evidenced by the evaluation of the thermodynamic properties of the compound, e.g., measuring its partition coefficient between water and octanol, evaluation of its kinetics of elimination by measuring its stability in buffer and in human plasma, and evaluation of its safety and physiological properties in humans and animal preparations. More specifically, dexrazoxane can be used for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure.
  • compositions comprising dexrazoxane have many advantages over the currently available antiarrhythmic agents such as amiodarone. These advantages include: proven safety profiles, rapid onset of action, increased efficacy, decreased toxicities, new dosing regimens permitting long term exposure and greater propensity for adherence, lower potential for drug interactions, and simultaneous reduction in potential metal ion/topoisomerase associated toxicities.
  • the subject compounds have properties similar to those of amiodarone, but provide further advantages. More specifically, the subject compounds are Class El agents with efficacy comparable or surpassing amiodarone, having a structure such that the drug can be readily metabolized to a polar, water-soluble composition which can be eliminated by the lddneys. This is a definite advantage over amiodarone, which has a fairly arduous elimination process. This increased elimination and decreased toxicity makes antiarrhythmic therapy using dexrazoxahe or compositions comprising the subject compounds easier to manage.
  • novel compounds can be included in a composition comprising a second active ingredient.
  • the second active ingredient can be useful for concurrent or synergistic treatment of arrhythmia or for the treatment of an unrelated condition which can be present with or result from arrhythmia or other cardiomyopathy.
  • These Compounds, and compositions thereof may include additional compounds known to be useful for the treatment of cardiac arrhythmias, cardioprotective agents, antibiotics, antiviral agents, or thrombolytic agents ,(e.g., streptokinase, tissue plasminogen activator, or recombinant tissue plasminogen activator).
  • the compounds and compositions of the invention can have particular usefulness for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure (CHF).
  • CHF congestive heart failure
  • Post- myocardial infarction patients can also benefit from the administration of the subject compounds and compositions; thus, methods of treating post-myocardial infarction patients are also provided by the subject invention.
  • Cardioprotective agents include vasodilators and beta blockers described for use in patients with coronary insufficiency (such as those of U.S. Pat. No. 5,175,187 or others known to the skilled artisan).
  • Other cardioprotective agents include known anti-hypertensive agents, e.g., (S)- l-[6-amino-2-[[hydroxy(4- phenylbutyl)phosphinyl]oxyl]-L-proline (U.S. Pat. No. 4,962,095) and zofenopril (U.S. Pat. No. 4,931,464).
  • Additional cardioprotective agents include, but are not limited to, aspirin, heparin, warfalin, digitalis, digitoxin, nitroglycerin, isosorbide dinitrate, hydralazine, nitroprusside, captopril, enalapril, and lisinopril.
  • the compounds and compositions also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways.
  • Compounds and compositions of the invention are also useful for the treatment of ventricular and supra-ventricular arrhythmias, including atrial fibrillation and flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained and non-sustained ventricular tachycardia (VT), and ventricular fibrillation (VF).
  • arrhythmias which may be treated by the compounds of the instant invention include: narrow QRS tachycardia (atrial, intra- /para- A-V node, or accessory pathway),ventricular tachycardia, and ventricular arrhythmias in cardiomyopathy.
  • an effective amount of a compound to treat cardiac arrhythmias may be an amount necessary to resume a regular heart beat, or to positively affect a.mechanism associated with irregularity, such as sodium channel blockage, beta ⁇ blocking or modulating adrenergic receptors, APD modulating, decreasing QT intervals, or calcium channel antagonism.
  • the effective amount may vary, depending, for example, upon the arrhythmic condition treated, weight of the subject and severity of the disease. One of skill in the art can readily determine the effective amount empirically without undue experimentation.
  • a "subject” or “patient” is meant to describe a human or vertebrate animal including a dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, monkey, owl, rat, squirrel, slender loris, and mouse.
  • the compounds of the present invention can be used in the form of salts as in "pharmaceutically acceptable salts" derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2- napthalenesulfonate, oxalate, pamoate, pe
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such
  • metabolite refers to a compound that is rapidly transformed in vivo from the parent compound, for example by hydrolysis in blood.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound, for example by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. Prodrugs as described in U.S. Patent No.
  • 6,284,772 for example may be used as well 'as those described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology, Bernard Testa et al., 2003 and The Organic Chemistry of Drug Design and Drug Action [Chapter 8], Richard Silverman?.2004: ⁇ ; Additional prodrugs are described herein, particularly in the Examples section, such as Table 1.
  • alkyl refers to substituted and unsubstituted alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • C 1-6 alkyl has the same meaning as alkyl, except that it is limited to alkyl groups of six carbons or less.
  • C 1 I 6 alkyl also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 C(CH 3 ) S , -CH(CH 3 )CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH(CH 3 )CH(CH
  • C 1-6 alkyl further includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and such rings substituted with straight and branched chain alkyl groups as defined above.
  • the phrase alkyl also includes polycyclic alkyl groups such as, but not limited to, adamantyl norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as defined above.
  • aryl refers to Substituted and unsubstituted aryl- groups that do not contain heteroatoms.
  • C 6-10 aryl has the same meaning as aryl, except that it is limited to aryl groups of six to ten carbons atoms.
  • aryl includes, but is not limited to, groups such as phenyl, biphenyl, and naphthyl by way of example.
  • Aryl groups also include those in which one of the aromatic carbons is bonded to an alkyl, alkenyl, or alkynyl group as defined herein.
  • aryl includes, but is not limited to tolyl, and hydroxyphenyl among others.
  • alkenyl refers to straight chain, branched chain, and cyclic groups such as those described with respect to alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • C 2-6 alkenyl has the same meaning as alkenyl, except that it is limited to alkenyl groups of two to six carbons.
  • the phrase "C 1-6 alkenyl" indicates that the double bond may be the point of attachment of the alkenyl group.
  • alkynyl refers to straight and branched chain groups such as those described with respect to alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms.
  • alkoxy refers to groups having the formula -O-alkyl, wherein the point of attachment is the oxy group and the alkyl group is as defined above.
  • C 1-6 alkoxy has the same meaning as alkoxy, except that it is limited to alkoxy groups having from one to six carbon atoms.
  • aryloxy refers to groups having the formula -O-aryl, wherein the point of attachment is the oxy group and the dryl group is as defined above.
  • C 6-1O aryloxy has the same meaning as aryloxy, except that it is limited to aryloxy groups of six to ten carbon atoms.
  • heterocyclyl refers to both aromatic and nonaromatic ring compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, quinuclidyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-1,2,3- triazolyl etc.), tetrazolyl, (e.g.
  • saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms such as, but not limited to furanyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g.
  • unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.
  • unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to.2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl.
  • Heterocyclyl group also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones).
  • heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1,1 -dioxide.
  • Preferred heterocyclyl groups contain 5 or 6 ring members.
  • More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazo ⁇ e, isoxazole, furan, and tetrahydrofuran.
  • Heterocyclyl also refers to those groups as defined above in which one of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5- chlorobenzthiazolyl, 1-methyl piperazinyl, and 2-chloropyridyl among others. Heterocyclyl groups are those limited to having 2 to 15 carbon atoms and as many as 6 additional heteroatoms as described above. More preferred heterocyclyl groups have from 3 to 5 carbon atoms and as many as 2 heteroatoms. Most preferred heterocyclyl groups include piperidinyl, pyrrolidinyl, azetidinyl, and aziridinyl groups.
  • substitution groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, thioamido, amidino, , imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, heterocyclyl, aryl, haloalkyl, alkoxy, alkoxyalkyl-, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkylthio, aminoalkyl, alkylamino, cyanoalkyl, and the like.
  • one preferred "substituted C 1-6 alkyl” is tertbutanol.
  • Another preferred substituted C 1-6 alkyl is tertbutanol.
  • Another preferred substituted C 1-6 alkyl is tertbutanol.
  • the substitution group can itself be substituted one time.
  • an alkoxy substituent of an alkyl group may be substituted with a halogen, and oxo group, an aryl group, or the like.
  • the group substituted onto the substitution group can be carboxyl, halo, nitro, oxo, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, aminocarbonyl, -SR, thioamido, -SO 3 H, -SO 2 R or cycloalkyl, where R is typically hydrogen, hydroxyl or C 1-6 alkyl.
  • substituted substituent includes a straight chain group
  • the substitution can occur either within the chain (e.g., 2-hydroxypropyl, 2- aminobutyl, and the like) or at the chain terminus (e.g., 2-hydroxyethyl, 3- cyanopropyl, and the like).
  • Substituted substituents can be straight chain, branched or cyclic arrangements of covalently bonded carbon atoms or heteroatoms.
  • Dexrazoxane, metabolites, prodrugs, or derivatives thereof of formula I may exhibit the phenomenon of tautomerism, and the formula drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses antiarrhythmic activity and is not to be limited merely to any one tautomeric form utilized within the formula drawings.
  • Dexrazoxane, metabolites, prodrugs, or derivatives thereof of formula I also may exist in solvated as well as unsolvated forms such as, for example, hydrated forms.
  • the invention encompasses both solvated and unsolvated forms which possess activity.
  • the compounds of this invention can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents.
  • the compounds, or pharmaceutically acceptable salts thereof, of the present invention, in the described dosages are administered orally, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously. They are preferably administered intravenously, for example reconstituted in an aqueous solution.
  • the amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
  • dexrazoxane is currently formulated as a lyophilized acid salt of hydrochloride acid.
  • the acid salt is unstable in aqueous solution and so is lyophilized for stability.
  • dexrazoxane is dissolved in 0.1 M HCl at a concentration of 20 mg/ml and placed into vials. The vials are partially stoppered and loaded on the shelves of a lyophilization chamber. Compounding and vial-filling processes are carried out at ambient temperature. The solutions are frozen and the chamber evacuated until lyophilization is complete.
  • the solution occupies less than the full vial volume to optimize lyophilization time and to allow for expansion of the solution upon freezing.
  • the vials are then supplied to clinics in 250 mg or 500 mg doses. When needed, dexrazoxane is reconstituted in the clinic. A current recommended dose is 2g for an adult human. Thus, preparing a dose for injection previously required pooling four 500 mg doses.
  • Dexrazoxane is subject to decomposition in aqueous solutions. Because of this, the time span from compounding to beginning of freezing in the lyophilizer must not exceed 7 hours without significant decomposition. Lyophilized dexrazoxane is stable for extended periods of time, on the order of 12 months without significant decomposition. Reconstituted dexrazoxane is stable for about 6 hours at room temperature.
  • the solubility of dexrazoxane in water at 25 0 C is about 10 mg/ml water.
  • Dexrazoxane (ICRF-187) and its racemate, razoxane (ICRF- 159) are sparingly soluble in 0.1 N HCl, slightly soluble in polar solvents such as ethanol and methanol and practically insoluble in non-polar, organic solvents [Repta, Baltezor and Bansal, J. Pharm Sci. 65 (1976) 238-242].
  • the solubility of dexrazoxane increases as pH decreases. Formulating dexrazoxane as a salt of hydrochloric acid improves its solubility.
  • Solubility of hydrochloric acid as high as 35 mg/ml in 0.1 N HCl at 25 0 C has been reported (U.S. Patent No. 4,963,551), though therapeutic concentrations around 20-25 mg/ml are preferred (see U.S. Patent No. 5,760,039, hereby incorporated by reference).
  • a 20 mg/ml solution is known to be used commercially.
  • the concentration of dexrazoxane in the bulk solutions may also be quantified in terms of dexrazoxane molarity.
  • a 35 mg/ml solution of dexrazoxane in 0.01' N HCl is a 0.13 M dexrazoxane (the molecular weight of dexrazoxane being 268.28 g/mol).
  • Therapeutic and prophylactic application of the subject compounds, and compositions comprising them can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art. Further, the compounds of the invention have use as starting materials or intermediates for the preparation of other useful compounds and compositions. The compounds of the invention are useful for various non-therapeutic and therapeutic purposes. It is apparent from the testing that the compounds of the invention have effective antiarrhythmic activity. Specifically, they are useful in regulating cardiac arrhythmia, including atrial fibrillation, in animals and humans.
  • compositions containing compounds of the invention as active ingredients arc useful in prophylactic or therapeutic treatment of cardiac arrhythmias in humans or other mammals.
  • the dosage administered will be dependent upon the response desired; the type of host involved; its age, health, weight, kind of concurrent treatment, if any; frequency of treatment; therapeutic ratio and like considerations.
  • dexrazoxane can be present in the new compositions for use dermally, intranasally, bronchially, intramuscularly, intravaginally, intravenously, or orally in a concentration of from about 0.01 to about 50% w/w of the composition, and especially from about 0.1 to about 30% w/w of the composition.
  • the novel compound is present in a composition from about 1 to about 10% and, most preferably, the novel composition comprises about 5% novel compound.
  • compositions of the invention are advantageously used in a variety of forms, e.g., tablets, ointments, capsules, pills, powders, aerosols, granules, and oral solutions or suspensions and the like containing the indicated suitable quantities of the active ingredient.
  • Such compositions are referred to herein and in the accompanying claims generically as "pharmaceutical compositions.”
  • they can be in unit dosage form, namely, in physically discrete units suitable as unitary dosages for human or animal subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic or prophylactic effect in association with one or more pharmaceutically acceptable other ⁇ ngredients, e.g., diluent or carrier.
  • the active ingredients can be packaged in pressurized aerosol containers with a propellant, e.g., carbon dioxide, nitrogen, propane, etc. with the usual adjuvants such as cosolvents, wetting agents, 'etc. >
  • a propellant e.g., carbon dioxide, nitrogen, propane, etc.
  • adjuvants such as cosolvents, wetting agents, 'etc. >
  • the active ingredient can be .mixed with a diluent vehicle such as cocoa butter, viscous polyethylene glycols, hydrogenated oils, and such mixtures can be emulsified if desired.
  • a diluent vehicle such as cocoa butter, viscous polyethylene glycols, hydrogenated oils, and such mixtures can be emulsified if desired.
  • compositions comprise, as an inactive ingredient, an effective amount of one or more non-toxic, pharmaceutically acceptable ingredient(s).
  • ingredients for use in the compositions include ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, calcium carbonate, talc, flour, and equivalent non-toxic carriers and diluents.
  • adjuvants may be administered in conjunction with the compositions described herein for treatment of cardiac arrhythmias.
  • Myocytes were isolated enzymatically from guinea-pig ventricle as previously described (Powell et al, 1980; Mitchell et al, 1984). Briefly, male guinea-pigs were killed by cervical dislocation following stunning. Myocytes were isolated after perfusion of the heart with a physiological salt solution containing reduced calcium and 0.8 mg/mL of collagenase Type 1 (Worthington Biochemicals). Cells were stored at room temperature in Dulbecco's MEM (Life Technologies, Scotland) and used for electrophysiological investigation on the day of preparation.
  • Action potentials were recorded from single guinea-pig ventricular myocytes using the standard control conditions and criteria as adopted by CCTT Ltd. (see http://www.cctt.ltd.uk/apl.htm). Briefly, action potentials were recorded using conventional glass microelectrodes filled with 1 M KMeS 04 and 10 mM KCl. Electrode resistances were in the range of 40 to ⁇ M ⁇ . An Axoclamp 2B (Axon Instruments Inc) amplifier was used for electrical recording. Action potentials were continuously stimulated by application of a brief (1-2 ms) current stimuli applied via the intracellular microelectrode in 'bridge' mode.
  • Action potential recording criteria amplitude and resting potential
  • Resting potential was measured over a 5-10 ms period before the stimulus artefact and values for the resting potential falling between -75 to -85 mV were taken as normal.
  • Action potential amplitude was measured following the stimulus artefact and values falling between 110 to 130 mV were taken as normal.
  • AU data are presented as mean ⁇ SEM. The effect of dexrazoxane on action potential characteristics was assessed using Student's t-test (MicroSoft Excel) and P ⁇ 0.05 was taken to indicate statistical significance.
  • Action potential duration was measured from the peak amplitude of the action potential to 90 % repolarisation level (APDg 0 ), and values for APDg 0 falling between 150 to 300 ms were taken as normal. Parameters measured in this study were action potential duration at 40, and 90% repolarisation levels (APD 40 and APD 90 ) using Clampfit 9.0.
  • APD 4O and APDg 0 values were calculated in the absence (control) and presence of a drug.
  • APDg 0-4O mS As an index of 'Triangulation' APDg 0 - APD 40 , (APDg 0-4O mS) in the absence (APDg 0-40 control) and presence of dexrazoxane (APDg O-40 drag) were calculated. This was normalised to the starting (control) APDg 0 to express APDg 0-40 duration as a % of control APDg 0 . Calculations were made for each cell individually; the values for each drug concentration were then averaged.
  • FIG. 3 Mean data showing the effect of dexrazoxane (10 ⁇ M) on action potential duration (APD90) is shown in Figure 3.
  • Bath solution was prepared daily.
  • the composition of the bath solution was (mM): NaCl 125; NaHCO 3 25; KCl 5.4; CaCl 2 1.8; MgCl 2 1.0; NaH 2 PO 4 1.2;
  • test substance (dexrazoxane) was made up as a stock solution in H 2 O
  • test substance perfusion solution (10-1M) and then diluted into the bath solution to prepare the test substance perfusion solution. This was done daily.
  • the initial test concentration for dexrazoxane was 10 ⁇ M.
  • Bipolar epicardial electrodes are placed on the inferior vena cava and right atrium for atrial pacing, recording local atrial activation, and for measurement of atrial excitation threshold (AET) and atrial relative (ARRP at 2x AET) and effective refractory periods (AERP at 10x AET). Bipolar electrodes also are sutured to the left ventricle for measurement of ventricular excitation threshold (VET) and ventricular relative (VRRP at 2x VET) and effective refractory periods (VERP at 10x VET).
  • AET atrial excitation threshold
  • ARRP at 2x AET
  • AERP effective refractory periods
  • cardiac electrophysiologic parameters also are measured before dexrazoxane administration and at the termination of the study: AH interval, an index of AV nodal conduction; HV interval, an index of His-ventricular conduction time; P-A interval, an index of intra-atrial conduction; and H-EG interval, an index of ventricular conduction; and paced ECG QT interval.
  • AV nodal functional refractory period (AVNFRP) and SA conduction time (SACT) are determined by the introduction of atrial extrastimuli during sinus rhythm, and the monitoring of ventricular response.
  • Dexrazoxane is administered as cumulative i.v. doses of 1, 3 and 10 mg/kg, with each dose administered as an intravenous bolus in a vehicle of PEG- 200. Additionally, ADR-925 is administered in equal amounts, in order to determine the active moiety of dexrazoxane.
  • Sustained atrial flutter is initiated in three dogs by electrical burst pacing (6-20 Hz) of the atria; atrial rates range from 440-530 cycles/min.
  • Intravenous bolus administration of PEG-200 vehicle alone has no effect on the atrial arrhythmia in all three animals.
  • Animals are implanted with a 25 mg pellet of DOCA and maintained on the 1% saline as their drinking fluid.
  • the animals are anesthetized with Avertin (tribromoethanol, 2.5%), and prepared for the recording of blood pressure and the EKG.
  • Avertin tribromoethanol, 2.5%)
  • the animal's left jugular vein is also cannulated with PE-50 tubing.
  • the tubings are filled with saline and exteriorized dorsally between the animal's shoulders.
  • Isoproterenol a proarrhythmic agent
  • a diamino alkane such as diaminoethane, diaminocyclobutane, or propane- 1,2-diamine
  • tetra-acetic acid, and formamide are heated at HO 0 C together under reduced pressure for 1-2 hours. The heat is then raised to 15O 0 C and stirred for 2-3 additional hours. The reaction is cooled, filtered and then washed with ethanol.
  • Compounds with variable terminal rings are synthesized as follows: the nitrogen-containing heterocyclyl with the desired terminal ring structure (such as l,3-dimethylpiperazine-2,6-dione or morpholin-2-one) are added to a solution containing an alkyldihalide (such as 1,2-dichloropropane) in THF and the solution is heated until complete. Final compounds are identified by GC or LCMS and purified by column chromatography.
  • an alkyldihalide such as 1,2-dichloropropane
  • Dexrazoxane is' efficiently removed from the reaction mixture by loading 500 ⁇ l of the mixture on a Sep-PakPlus C 18 cartridge (Waters, Mississauga, ON, Canada) and elutingwith 2% (v/v) methanol at a flow rate of 1 ml/min. Although dexrazoxane is highly retained on the cartridge, B, C, and ADR-925 eluted together and are collected at elution volumes between 1.5 and 2.5 ml. HPLC analysis confirmed that dexrazoxane is not detectable in this fraction.
  • This 1-ml fraction, pH 6, is loaded on three Sep-Pak Accell Plus QMA (Waters) ion exchange cartridges connected in series and eluted with 2% (v/v) methanol at a flow rate of 5 ml/min.
  • Fractions containing B are collected at elution volumes between 3 and 4.5 ml, and those containing C between 5 and 9 ml.
  • the B fraction contains less than 0.1 mol% and 0.01 mol% of C and ADR-925, respectively.
  • the C fraction contains less than 0.1 mol% B and 0.05 mol% of ADR-925, respectively.
  • Prodrugs of the compositions of the present invention are provided in Table 1.

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Abstract

La présente invention concerne un procédé pour le traitement d'un sujet atteint d'une arythmie cardiaque qui comprend la mise en contact d'une quantité efficace de dexrazoxane ou d'un sel, d'un analogue, d'un tautomère ou d'un stéréoisomère pharmaceutiquement acceptable de celle-ci avec une cellule.
PCT/US2006/041749 2005-11-01 2006-10-24 Agents pour le traitement d’arythmies cardiaques Ceased WO2007053415A2 (fr)

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US8455641B2 (en) * 2006-11-24 2013-06-04 Cyathus Exquirere Pharmaforschungs Gmbh Method for producing 4,4′-(propane-1,2-diyl)-dipiperazine-2,6-dione

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US4895840A (en) * 1987-06-10 1990-01-23 A. H. Robins Company, Incorporated N-(aryl-,aryloxy-,arylthio-arylsulfinyl-and arylsulfonyl-)alkyl-N,N'-(or n'n')alkylaminoalkyl ureas and cyanoguanidines
US5242901A (en) * 1988-01-27 1993-09-07 New York University Reduction of anthracycline induced cardiotoxicity
GB8916071D0 (en) * 1989-07-13 1989-08-31 Creighton Andrew M Pharmaceutical compositions
US6638970B2 (en) * 2000-02-22 2003-10-28 Cv Therapeutics, Inc. Substituted alkylene diamine compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455641B2 (en) * 2006-11-24 2013-06-04 Cyathus Exquirere Pharmaforschungs Gmbh Method for producing 4,4′-(propane-1,2-diyl)-dipiperazine-2,6-dione
AT504621B1 (de) * 2006-11-24 2014-08-15 Cyathus Exquirere Pharmaforschungsgmbh Neues verfahren zur herstellung von 4,4'-(1-methyl -1,2-ethandiyl)-bis-(2,6-piperazindion)

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