WO2008019106A1 - Méthodes et compositions pour le traitement d'hypertension pulmonaire utilisant une combinaison d'un agent bloquant de canal calcium et un inhibiteur de phosphodiestérase - Google Patents

Méthodes et compositions pour le traitement d'hypertension pulmonaire utilisant une combinaison d'un agent bloquant de canal calcium et un inhibiteur de phosphodiestérase Download PDF

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Publication number
WO2008019106A1
WO2008019106A1 PCT/US2007/017410 US2007017410W WO2008019106A1 WO 2008019106 A1 WO2008019106 A1 WO 2008019106A1 US 2007017410 W US2007017410 W US 2007017410W WO 2008019106 A1 WO2008019106 A1 WO 2008019106A1
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Prior art keywords
calcium channel
channel blocker
phosphodiesterase inhibitor
pulmonary
pulmonary hypertension
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PCT/US2007/017410
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English (en)
Inventor
Jeff Bechard
Beth Allison
John K. Gibson
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Artesian Therapeutics, Inc.
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Publication of WO2008019106A1 publication Critical patent/WO2008019106A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is directed to the treatment of pulmonary hypertension.
  • the present invention includes methods of treating pulmonary hypertension using a combination of a calcium channel blocker and a phosphodiesterase inhibitor, as well as pharmaceutical compositions comprising a calcium channel blocker and a phosphodiesterase inhibitor, including, e.g., admixtures suitable for inhaled delivery.
  • Pulmonary hypertension is a complex, life-threatening disease for which there is no cure. Despite limited advances in therapy, pulmonary hypertension associated mortality remains high, with a mean survival of approximately 2.8 years from the onset of disease. Patients with pulmonary hypertension suffer shortness of breath, fatigue, temporary blackouts, chest pain, bluish skin color, a racing heart, and chest pain.
  • Pulmonary hypertension is characterized by abnormally high blood pressure in the blood vessels of the lungs. It generally begins when the lung's tiny arteries narrow or become blocked, causing increased resistance to blood flow and increased pressure within the arteries. As the pressure builds, the heart's right ventricle works harder to pump blood through the lungs, especially when increased flow is needed, as during exercise. Eventually, the heart weakens, and oftentimes fails completely. Heart failure is the leading cause of death in patients with pulmonary hypertension.
  • pulmonary hypertension falls into one of two categories; primary pulmonary hypertension, for which no underlying cause is identified, and secondary pulmonary hypertension, for which an underlying cause is identified.
  • Secondary pulmonary hypertension is the most common form of the disease, and may be caused by congenital heart defects, connective tissue disease (e.g., scleroderma), medications (e.g., the diet pill fen-phen), HIV infection, blood clots, liver disease, and chronic blood clots in the pulmonary artery, among others causes.
  • connective tissue disease e.g., scleroderma
  • medications e.g., the diet pill fen-phen
  • HIV infection e.g., the diet pill fen-phen
  • blood clots e.g., the diet pill fen-phen
  • liver disease e.g., chronic blood clots in the pulmonary artery, among others causes.
  • Pulmonary hypertension treatment is complex, controversial and potentially dangerous (Rubin L.J., Primary Pulmonary Hypertension, N. Engl. J.
  • pulmonary hypertension is treated with medications to lower the pressure in the lungs, making the heart work more efficiently.
  • Vasodilators, or drugs that dilate blood vessels, are often used in managing secondary pulmonary hypertension.
  • prostacyclins dilate the blood vessels in the lungs, and are commonly considered the most effective treatment for pulmonary hypertension.
  • a popular synthetic version is given intravenously via continuous infusion that requires a semi-permanent central venous catheter.
  • the delivery system may cause sepsis and thrombosis.
  • the drug is unstable, and must therefore be kept on ice during its continuous administration, 24 hours a day, 7 days a week. Interruption can be fatal.
  • Subcutaneously delivered prostacyclins have been developed, but they can be very painful.
  • Oral pills are also available, but drug stability is still an issue.
  • the present invention provides methods of treating or preventing pulmonary hypertension in a subject, comprising providing a phosphodiesterase inhibitor and a calcium channel blocker to the subject by inhalation or intranasally.
  • a composition comprising the phosphodiesterase inhibitor and the calcium channel blocker is provided to the subject.
  • a single dual pharmacophore molecule comprising the phosphodiesterase and the calcium channel blocker is provided to the subject.
  • the phosphodiesterase inhibitor and the calcium channel blocker are provided separately.
  • the phosphodiesterase inhibitor and the calcium channel blocker are administered simultaneously, while in another embodiment they are administered sequentially in any order.
  • the present invention provides a pharmaceutical composition comprising a calcium channel blocker and a phosphodiesterase inhibitor, wherein the composition is formulated for inhalation.
  • the present invention provides a drug delivery device adapted for nasal administration of a pharmaceutical composition, wherein the delivery device comprises a pharmaceutical composition comprising a calcium channel blocker and a phosphodiesterase inhibitor.
  • the calcium channel blocker is selected from the group consisting of: amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil, nisoldipine, nitrendipine, lacidipine, lercaninidipine, gallopimil, mibefradil, diltiazem, and isradipine.
  • the phosphodiesterase inhibitor is selected from the group consisting of sildenafil, tadafil, inoximone, pimobendan, vardenafil, milrinone, and amrinone.
  • Figure 1 is a graph showing decrease of pulmonary vascular resistance in anesthetized dogs following administration of a dual pharmacophore comprising calcium channel blocker and phosphodiesterase inhibitor moieties.
  • Alkyl refers to a saturated straight or branched chain hydrocarbon radical. Examples include without limitation methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkylene refers to a divalent alkyl radical.
  • Alkylthio refers to a sulfur substituted alkyl radical.
  • Alkenyl refers to an unsaturated straight or branched chain hydrocarbon radical comprising at least one carbon to carbon double bond. Examples include without limitation ethenyl, propenyl, iso-propenyl, butenyl, iso- butenyl, tert-butenyl, n-pentenyl and n-hexenyl.
  • Alkenylene refers to a divalent alkenyl radical.
  • Alky ⁇ yl refers to an unsaturated straight or branched chain hydrocarbon radical comprising at least one carbon to carbon triple bond. Examples include without limitation ethynyl, propynyl, iso-propynyl, butynyl, iso- butynyl, tert-butynyl, pentynyl and hexynyl.
  • Alkynylene refers to a divalent alkynyl radical.
  • Cycloalkyl refers to a cyclic alkyl radical. Examples include without limitation cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Cycloalkenyl refers to a cyclic alkenyl radical. Examples include without limitation cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • Alkoxy refers to an alkyl group bonded through an oxygen linkage.
  • Alkenoxy refers to an alkenyl group bonded through an oxygen linkage.
  • Substituted phenyl refers to a phenyl that is substituted with one or more substituent(s).
  • substituents include without limitation Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, phenoxy, benzyloxy, hydroxy, carboxy, hydroperoxy, carbamido, carbamoyl, carbamyl, carbonyl, carbozoyl, amino, hydroxyamino, formamido, formyl, guanyl, cyano, cyanoamino, isocyano, isocyanato, diazo, azido, hydrazino, triazano, nitrilo, nitro, nitroso, isonitroso, nitrosamino, imino, nitrosimino, oxo, Ci-C 6 alkylthio,
  • Aryl refers to a cyclic aromatic hydrocarbon moiety having one or more closed ring(s). Examples include without limitation phenyl, benzyl, naphthyl, anthracenyl, phenanthracenyl and biphenyl.
  • Heteroaryl refers to a cyclic aromatic moiety having one or more closed rings with one or more heteroatom(s) (for example, sulfur, nitrogen or oxygen) in at least one ring. Examples include without limitation pyrryl, furanyl, thienyl, pyridinyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, benzofuranyl and benzothienyl.
  • Halo refers to a fluoro, chloro, bromo or iodo radical.
  • isosteres refer to elements, functional groups, substituents, molecules or ions having different molecular formulae but exhibiting similar or identical physical properties.
  • tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they have different molecular formulae.
  • two isosteric molecules have similar or identical volumes and shapes.
  • isosteric molecules should be isomorphic and able to co-crystallize.
  • Other physical properties that isosteric molecules usually share include boiling point, density, viscosity and thermal conductivity.
  • isosteres encompasses "bioisosteres.”
  • Bioisosteres are isosteres that, in addition to their physical similarities, share some common biological properties. Typically, bioisosteres interact with the same recognition site or produce broadly similar biological effects.
  • Effective amount refers to the amount required to produce a desired effect, for example: regulating calcium homeostasis; treating a disease, condition in which disregulation of calcium homeostasis is implicated; treating pulmonary hypertension, a cardiovascular disease, stroke, epilepsy, ophthalmic disorder or migraine; or inhibiting PDE (for example, PDE-3) or L-type calcium channels.
  • Metal refers to a substance produced by metabolism or by a metabolic process.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ or portion of the body.
  • Each carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and suitable for use with the patient.
  • Examples of materials that can serve as a pharmaceutically acceptable carrier include without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydro
  • “Pharmaceutically acceptable equivalent” includes, without limitation, pharmaceutically acceptable salts, hydrates, solvates, metabolites, prodrugs and isosteres. Many pharmaceutically acceptable equivalents are expected to have the same or similar in vitro or in vivo activity as the compounds of the invention.
  • “Pharmaceutically acceptable salt” refers to an acid or base salt of the inventive compounds, which salt possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable.
  • the salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexa ⁇ oate, hydrochloride hydrobromide, hydroiodide, 2- hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate
  • Examples of a base salt include without limitation ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
  • the basic nitrogen-containing groups can be quartemized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as phenethyl bromides.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides
  • Prodrug refers to a derivative of the inventive compounds that undergoes biotransformation, such as metabolism, before exhibiting its pharmacological effect(s).
  • the prodrug is formulated with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • the prodrug can be readily prepared from the inventive compounds using conventional methods, such as that described in BURGER'S MEDICINAL CHEMISTRY AND DRUG CHEMISTRY, Fifth Ed., Vol. 1 , pp. 172- 178, 949-982 (1995).
  • “Isomers” refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms.
  • Stepoisomers refer to isomers that differ only in the arrangement of the atoms in space.
  • Diastereoisomers refer to stereoisomers that are not mirror images of each other. Diastereoisomers occur in compounds having two or more asymmetric carbon atoms; thus, such compounds have 2 n optical isomers, where n is the number of asymmetric carbon atoms. “Enantiomers” refers to stereoisomers that are non-superimposable mirror images of one another.
  • Enantiomer-enriched refers to a mixture in which one enantiomer predominates.
  • Racemic refers to a mixture containing equal parts of individual ' enantiomers.
  • Non-racemic refers to a mixture containing unequal parts of individual enantiomers.
  • Animal refers to a living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Examples include, without limitation, members of the human, equine, porcine, bovine, murine, canine and feline species. In the case of a human, an
  • animal may also be referred to as a "patient.”
  • “Mammal” refers to a warm-blooded vertebrate animal.
  • Calcium homeostasis refers to the internal equilibrium of calcium in a cell.
  • Cardiovascular disease refers to a disease of the heart, blood vessels or circulation.
  • Heart failure refers to the pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues.
  • Consgestive heart failure refers to heart failure that results in the development of congestion and edema in the metabolizing tissues.
  • SA/AV node disturbance refers to an abnormal or irregular conduction and/or rhythm associated with the sinoatrial (SA) node and/or the atrioventricular (AV) node.
  • arrhythmia refers to abnormal heart rhythm. In arrhythmia, the heartbeats may be too slow, too fast, too irregular or too early. Examples of arrhythmia include, without limitation, bradycardia, fibrillation (atrial or ventricular) and premature contraction. "Hypertrophic subaortic stenosis” refers to enlargement of the heart muscle due to pressure overload in the left ventricle resulting from partial blockage of the aorta.
  • Angina refers to chest pain associated with partial or complete occlusion of one or more coronary arteries in the heart.
  • Treating refers to: (i) preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • the present invention is based on the discovery that treatment with a combination of a calcium channel blocker and a phosphodiesterase inhibitor reduces both pulmonary vascular resistance and pulmonary wedge pressure and is, therefore, useful in the treatment or prevention of pulmonary hypertension.
  • compositions of the present invention may be administered topically, e.g., by inhalation, to the lungs, resulting in specificity for the pulmonary vasculature and conferring little or no systemic side effects.
  • Phosphodiesterase inhibition decreases pulmonary vascular resistance by elevating cytosolic cAMP/cGMP, resulting in vasodilation.
  • calcium channel blockade results in vasodilation and lowered pulmonary vascular resistance, albeit through a divergent mechanism involving inhibition of L-type calcium channels on vascular smooth muscle cells, resulting in reduction of intracellular calcium levels and ensuing smooth muscle relaxation.
  • PDE phosphodiesterase
  • calcium channel blockers have been used independently via oral administration to treat pulmonary hypertension.
  • calcium channel blockers require high dose levels, are only effective in approximately 20-25% of patients with pulmonary hypertension, and have adverse effects on systemic vascular resistance.
  • sildenafil requires high dose levels, and, although it demonstrates some selectivity for pulmonary vasculature, it is not devoid of unwanted systemic effects.
  • the combination of the pharmacological effects of phosphodiesterase inhibition and calcium channel blockade results in an additive or synergistic effect on pulmonary vascular resistance that is greater than either effect alone.
  • topical administration affords specificity for pulmonary vasculature, while reducing untoward systemic effects.
  • the present invention provides novel methods of treating or preventing pulmonary hypertension, which methods provide increased efficacy and reduced adverse systemic effects as compared to previous methods. In general, these methods comprise providing to a subject diagnosed with or at risk for developing pulmonary hypertension a combination of a calcium channel blocker and a phosphodiesterase (PDE) inhibitor.
  • PDE phosphodiesterase
  • PDE inhibitor and calcium channel blocker compounds are administered simultaneously as separate formulations, sequentially and in any order as separate formulations, simultaneously in a single formulation or as a combined admixture, or simultaneously as a single dual pharmacophore molecule.
  • the methods may further include providing two or more of either or both of a calcium channel blocker and/or PDE inhibitor.
  • the present invention includes a method of reducing or preventing pulmonary vascular resistance, comprising providing to a subject diagnosed with or at risk for pulmonary hypertension or pulmonary vascular resistance, a combination of a PDE inhibitor and a calcium channel blocker.
  • the present invention includes a method of treating or preventing heart failure, e.g., congestive heart failure, comprising providing to a subject diagnosed with or at risk for heart failure, a combination of a PDE inhibitor and a calcium channel blocker.
  • the methods of the present invention may be used in a variety of applications, including both human and veterinary treatment.
  • a subject may be a human or other animal, and in particular embodiments, a mammal.
  • the PDE inhibitor and calcium channel blocker are provided topically to the pulmonary vasculature, e.g., by nasal or oral delivery or inhalation or, more generally, via delivery to the lungs.
  • pulmonary hypertension examples include, but are not limited to, pulmonary arterial hypertension, pulmonary venuous hypertension, pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia, pulmonary hypertension due to chronic thrombotic and/or embolic disease, and pulmonary hypertension due to disorders directly affecting the pulmonary vasculature.
  • Pulmonary arterial hypertension includes, e.g., primary pulmonary hypertension and secondary pulmonary hypertension related to another disease or condition, such as e.g., collagen vascular disease, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, pregnancy, persistent pulmonary hypertension of the newborn, or drugs and toxins.
  • another disease or condition such as e.g., collagen vascular disease, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, pregnancy, persistent pulmonary hypertension of the newborn, or drugs and toxins.
  • Pulmonary venuous hypertension includes or is related to, e.g., left- sided atrial or ventricular heart disease, left-sided valvular heart disease, extrinsic compression of the central pulmonary veins, and pulmonary veno-occlusive disease.
  • Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia is caused primarily by diseases that effect the structure and function of the lungs, rather than heart or other organs. These include, e.g., chronic obstructive pulmonary disease, interstitial lung disease, sleep disordered breathing, alveolar hyperventilation disorders, chronic exposure to high altitude, neonatal lung disease, and alveolar capillary dysplasia.
  • Pulmonary hypertension due to chronic thrombotic and/or embolic disease is caused by blockages in the pulmonary blood vessels, such as, e.g., thromboembolic obstruction of proximal pulmonary artiers and obstruction of distal pulmonary arteries.
  • Pulmonary hypertension due to disorders directly affecting the pulmonary vasculature results from diseases and disorders that directly affect the pulmonary blood vessels, including, e.g., inflammatory diseases such as schistosomiasis and sarcoidosis, and pulmonary capillary haemangiomatosis.
  • Pulmonary hypertension is further associated with a number of cardiovascular diseases, lupus, and sclerodoma.
  • Combinations of the present invention may be administered according to any means known to an ordinarily skilled practitioner, and may be determined according to routine factors known in the arts.
  • embodiments of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular and intravenous), rectally, buccally
  • transdermal ⁇ including sublingual), transdermal ⁇ , or topically (e.g., intranasally, by inhalation).
  • an admixture or an intravenous admixture comprising a phosphodiesterase inhibitor and a calcium channel blocker is provided topically, e.g., by inhalation, orally, or intravenously.
  • administration a single dual pharmacophore molecule comprising a phosphodiesterase inhibitor moiety and a calcium channel blocker moiety, both of which are connected by a variable linker is provided topically, e.g., by inhalation, orally, or intravenously.
  • compositions disclosed herein may be delivered via oral administration.
  • the compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft-shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • compositions Comprising a Calcium Channel Blocker and a Phosphodiesterase Inhibitor
  • compositions of the present invention may be practiced using any calcium channel blocker and any phosphodiesterase inhibitor.
  • the present invention includes compositions comprising one or more calcium channel blockers and one or more phosphodiesterase inhibitors.
  • only one phosphodiesterase inhibitor and one calcium channel blocker is utilized, although the present invention contemplates that use of combinations comprising more than one of either or both of a PDE inhibitor and/or a calcium channel blocker.
  • a variety of each of these types of compounds are known and available in the art, and any may be used according to the present invention.
  • Calcium channel blockers typically affect L-type voltage-sensitive calcium channels in the cellular plasma membrane, blocking the movement of calcium into cells of the heart and the blood vessels. As a result, intracellular calcium levels remain low upon stimulation, thereby relaxing vascular smooth muscle cells, dilating the blood vessels, and decreasing total peripheral resistance. The heart remains responsive to sympathetic nervous system stimulation, allowing more effective maintenance of lowered blood pressure. Calcium channel blocking agents have been used in subjects with hypertension, including subjects with pulmonary hypertension.
  • calcium channel blockers are represented by the five structurally divergent families, including the benzothiazepines, bihydropyridines, phenylalkylamines, diarylaminopropylamine ethers, benzimidazole-substituted tetralines.
  • calcium channel blockers include, but are not limited to, amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil, nisoldipine, nitrendipine, lacidipine, lercaninidipine, gallopimil, mibefradil, diltiazem, isradipine, or combinations thereof.
  • Phosphodiesterase Inhibitors include, but are not limited to, amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil, nisoldipine, nitrendipine, lacidipine, lercaninidipine, gallopimil, mibefradil
  • Phosphodiesterase (PDE) inhibitors inhibit one or more of the PDE enzyme subtypes, including PDEi-PDEn.
  • PDEi-PDEn Phosphodiesterase
  • Members of the PDE family target a variety of biochemical pathways, and vary with respect to their tissue, cellular and subcellular distribution.
  • some PDE enzymes degrade the cyclic nucleotides cAMP and cGMP, which are common regulators of ion channel conductance and play a role in relaxing smooth muscles.
  • PDE inhibitors prevent cGMP/cAMP degradation, encouraging relaxation of vascular smooth muscles in blood vessels, and leading to vasodilation and increased blood flow.
  • PDE inhibitor-mediated vasodilation decreases pulmonary vascular resistance in subjects with hypertension-related problems, including subjects with pulmonary hypertension in particular.
  • PDE inhibitors are commonly categorized into specific subtypes, or families (see, W. J. Thompson, Pharmac. Ther. (1991) 51: 13-33; and J. P. Hall, Br J. CHn. Pharmac. (1993) 35: 1-7).
  • embodiments of the present invention include, but are not limited to, the families of PDEi inhibitors (e.g., Ca ⁇ /Calmodulin-activatable), PDE 2 inhibitors (e.g., cGMP activatable), PDE 3 inhibitors (e.g., cGMP inhibitable), PDE 4 inhibitors (e.g., cAMP-specific), and PDE 5 inhibitors (e.g., cGMP-specific).
  • the PDE inhibitor component is either specific for a particular PDE, or possesses combined inhibition (e.g., PDE 3 /PDE5 or PDE 3 /PDE4 inhibition).
  • PDEi inhibitors include, but are not limited to, calmodulin antagonists (e.g., phenothiazines, W-7, CGS 9343B), vinpocetine (TCV-3B), HA-558, 8-methoxymethyl-3-isobutyl-1-methylxanthine, KW-6 (isoquinoline derivative, 8-methylamino-3-isobutyl-1-methylxantine (MIMAX), and dibenzoquinazoline diones (dihydroisoquinoline derivative), or combinations thereof.
  • calmodulin antagonists e.g., phenothiazines, W-7, CGS 9343B
  • TCV-3B vinpocetine
  • HA-558 8-methoxymethyl-3-isobutyl-1-methylxanthine
  • KW-6 isoquinoline derivative, 8-methylamino-3-isobutyl-1-methylxantine (MIMAX)
  • dibenzoquinazoline diones
  • PDE 2 inhibitors include, but are not limited to, trequinsin, oxindole (2), and erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), and ND7001(Neuro3D), or combinations thereof.
  • PDE 3 inhibitors include, but are not limited to, milrinone, amrinone, motapizone, cilostazol, indolidan, cilostamide, lixazinone, Y-590, imazodan, SKF 94120, quazinone, IC 153, 110, cilostazol, bemorandan, siguazodan, adibendan, olprinone, enoximone, pimobendan, saterinone, and sulmazole, or combinations thereof.
  • PDE 4 inhibitor embodiments include, but are not limited to, those that fall generally into one of six chemical structural classes: rolipram-like, xanthines, nitraquazones, benzofurans, naphthalenes, and quinolines.
  • Representative examples of rolipram-like analogs include imidazolidinones and pyrrolizidinone mimetics of rolipram and Ro 20-1724, as well as benzamide derivatives of rolipram such as RP 73401 (Rhone-Poulenc Rorer).
  • xanthine analogs include denbufylline and arofylline; nitraquazone analogs include CP- 77,059 (Pfizer) and a series of pyrid[2,3d]pyridazin-5-ones; benzofuran analogs include BAY 19-8004 and EP-685479 (Bayer); napthalene analogs include T-440 (Tanabe Seiyaku); and quinoline analogs include SDZ-ISQ-844 (Novartis).
  • PDE 4 inhibitors may also include cilomilast, roflumilast, and pumafentrine, cipamfylline, atizoram, darbufelone, and arofylline, or combinations thereof.
  • PDE 5 inhibitors include, but are not limited to, sildenafil, tadafil, zaprinast, vardenafil, dipyridamole, pyrazolopyrimidinones, griseolic acid derivatives, 4-aryl-1-isoquinolinone derivatives, 1 ,7- and 2,7-naphthyridine derivatives, 2-phenylpurinones, phenylpyridone derivatives, pyrimidi ⁇ es, pyrimidopyrimidines, purines, quinazolines, phenylpyrimidinones, imidazoquinoxalinones or aza analogues thereof, phenylpyridones, 4-bromo-5-(pyridylmethylamino)-6-[3-(4- chlorophenyl)propoxy]-3(2H)pyridazinone, 1-[4-[(1 ,3-benzodioxol-5- yl-
  • furazlocillin cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1- b]purin-4-one, 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate, 4-bromo- 5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone, 1- methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1 ,6-dihydro-7 H- pyrazolo(4,3-d)pyrimidin-7-one, and 1-[4[(1 ,3-benzodioxol-5-ylmethyl)amino]-6- chloro-2-quinazolinyl]4-piperidi necarbox
  • PDE3/PDE4 inhibitors include, but are not limited to, theophylline, isobutylmethylxanthine, AH-21-132, Org-30029 (Organon), Org-20241 (Organon), Org-9731 (Organon), zardaverine, vinpocetine, EHNA (MEP-1), milrinone, siguazodan, zaprinast, SK+F 96231 , tolafentrine, filaminast, roflumilast, pumafentrine, cipamfylline, atizoram, darbufelone, and arofylline or combinations thereof.
  • Compounds comprising both a phosphodiesterase inhibitor moiety and a calcium channel blocker moiety may be used according to the methods and compositions of the present invention, including, e.g., compounds possessing inhibitory activity against PDE-3 and L-type calcium channels, of the general formula
  • Y is a dihydropyridine L-type calcium channel blocker moiety
  • L is a linking group; and X is a PDE-3 inhibitory moiety.
  • dihydropyridine L-type calcium channel blockers examples include without limitation:
  • R 1 and R 4 are independently hydrogen, halo, nitro, cyano, trifluoromethyl, amino, -NR 5 R 6 , Ci-C 4 alkoxy, C 1 -C 4 alkylthio, Ci-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, wherein one or more — CH 2 — group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O— , -S-, — SO2— and/or -NR 5 -, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R 5 and R 6 are independently hydrogen, Ci-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -Ce alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted
  • R 2 and R 3 are independently -COOR 7 , nitro, cyano ortrifluoromethyl
  • R 7 is Ci-Ce alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Ci-C 4 alkoxy Or -NR 5 R 6 ;
  • L is a direct bond, C1-C1 2 alkylene, C 2 -Ci 2 alkenylene or C 2 -Ci 2 alkynylene, wherein one or more -CH 2 - group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O- -S-, -SO 2 - and/or -NR 5 -, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); and
  • X is a moiety of formula A, B, C, D, E, F 1 G 1 H, I 1 J, K, L, M. N 1 O 1 P or Q
  • each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, -NR 5 R 6 , Ci-C 4 alkoxy, C 1 -C 4 alkylthio, -COOR 7 , Ci-Ci 2 alkyl C 2 -C 12 alkenyl or C 2 -C12 alkynyl, wherein one or more — CH 2 — group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with — O— , -S-, — SO2— and/or — NR 5 -, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s).
  • R 1 and R 4 are each Ci-C 4 alkyl
  • R 2 and R 3 are each -COOR 7
  • L is a direct bond
  • X is a moiety of formula A or P.
  • Examples of compounds of formula I include without limitation:
  • R 2 , R 3 , R 4 , L and X are as defined above; and Ar is an aryl or heteroaryl that is optionally substituted in 1 to 3 position(s) with hailo, nitro, cyano, trifluoromethyl, amino, -NR 5 R 6 , Ci-C 4 alkoxy, Ci-C 4 alkylthio, -COQR 7 , Ci-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, wherein one or more -CH 2 - grou ⁇ (s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with — O-, -S-, — SO 2 - and/or -NR 5 -, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s).
  • Ar is an aryl or heteroaryl that is optionally
  • R 2 when R 2 is — COOCH2CH 3 , R 3 is cyano, R 4 is methyl, L is methylene, X is a moiety of formula A 1 each R is hydrogen, and Ar is trifluoromethylphenyl, then L is not connected to the nitrogen atom of A; when R 2 and R 3 are each cyano, R 4 is amino, L is -SCH 2 -, X is a moiety of formula P, and each R is hydrogen, then Ar is not fluorophenyl; and when R 2 is -COOCH 2 CH 3 , R 3 is -COOCH 3 , R 4 is methyl, X is a moiety of formula P, each R is hydrogen, and Ar is chlorophenyl, then L is not -CH 2 OCH 2 CH 2 -, -CH 2 OCH 2 CH 2 NHCO- or -CH 2 OCH 2 CH 2 NCH 3 CO-.
  • R 2 and R 3 are each -COOR 7 , R 4 is C 1 -C4 alkyl, X is a moiety of formula A, and Ar is phenyl that is optionally substituted in 1 to 3 position(s).
  • Examples of compounds of formula Il include without limitation:
  • Another embodiment of the present invention encompasses a compound of formula III or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein:
  • R 1 , R 3 , R 4 , L, X and Ar are as defined above.
  • R 1 and R 4 are each methyl
  • R 3 is -COOCH 3 , aad X is a moiety of formula A or O, then L is not alkyl substituted with —COO- connected directly to the pyridine ring.
  • R 1 and R 4 are each Ci-C 4 alkyl, R 3 is -COOR 7 , X is a moiety of formula E, and Ar is phenyl that is optionally substituted in 1 to 3 position(s).
  • Examples of compounds of formula III include without limitation:
  • variable substituent Every variable substituent is defined independently at each occurrence. Thus, the definition of a variable substituent in one part of a formula is independent of its definition(s) elsewhere in that formula and of its def ⁇ nition(s) in other formulas.
  • inventive compounds may possess one or more asymmetric carbon center(s), they may be capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures of optical isomers.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes. One such process entails formation of diastereoisomeric salts by treatment with an optically active acid or base, then separation of the mixture of diastereoisomers by crystallization, followed by liberation of the optically active bases from the salts.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • a different process for separating optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available process involves synthesis of covalent diastereoisomeric molecules, for example, esters, amides, acetals and ketals, by reacting the inventive compounds with an optically active acid in an activated form, an optically active diol or an optically active isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • optically active compounds of this invention likewise can be obtained by utilizing optically active starting materials.
  • the compounds of this invention encompass individual optical isomers as well as racemic and non-racemic mixtures. In some non-racemic mixtures, the R configuration may be enriched while in other non-racemic mixtures, the S configuration may be enriched.
  • Particular embodiments of the present invention include formulations, or admixtures, comprising one or more PDE inhibitors (PDEi) and one or more calcium channel blockers (CCB), and possibly a pharmaceutically acceptable carrier.
  • PDEi PDE inhibitors
  • CCB calcium channel blockers
  • Formulations, or admixtures, of the present invention typically comprise an amount of each component that is sufficient to achieve a therapeutic or prophylactic effect upon administration to a subject at a prescribed dosage.
  • Formulations, or admixtures may be in any form, e.g., solid, liquid, gaseous, aerosolized, etc.
  • the PDEi and CCB components in an admixture may comprise any combination
  • each PDEi or CCB component in an admixture can vary with respect to the other component, depending on the effective amount of any given component, and/or the additive or synergistic effects resulting from the combination of the two components.
  • each separate PDEi and CCB component can be present in the admixture at an effective ratio with respect to the other component.
  • the effective amount of each component can be calculated by such variables as mass, mass per volume, molarity, weight percentage, or the like, and the corresponding effective ratio can be determined therefrom.
  • each separate active component can be present in the admixture at an effective molar ratio with respect to the other.
  • the effective molar ratio may be based on the actual effective amount of each component, e.g., (XmM PDEi) or (XmM CCB), wherein XmM reflects for example the molar concentration of the given component, and may be represented by the formulas (XmM PDEi/XmM CCB) or (XmM CCB/XmM PDEi).
  • the effective molar ratio with respect to the above-recited formulas is recited in the following non-limiting examples: (0.001 :1), (0.005:1), (0.01 :1), (0.02:1), (0.04:1), (0.06:1), (0.08:1), (0.1 :1), (0.2:1), (0.3/1), (0.4:1), (0.5:1), (0.6:1), (0.7:1), (0.8:1), (0.9:1), (1:1), (1.1 :1), (1.2:1), (1.3:1), (1.4:1), (1.5:1), (1.6:1), (1.7:1), (1.8:1), (1.9:1), (2:1 ), (3:1), (4:1), (5:1), (6:1), (8:1), (10:1), (15:1), (20:1), (30:1), (40:1), (50:1).
  • compositions for use in accordance with the present invention may be formulated in any manner known to the ordinarily skilled artisan, and may comprise one or more PDE inhibitor (PDEi) components, one or more calcium channel blocker (CCB) components, and a carrier.
  • PDEi PDE inhibitor
  • CCB calcium channel blocker
  • the PDEi and CCB components may be formulated as separate compounds, as a combined admixture, or as a single dual pharmacophore molecule.
  • the PDE inhibitor may be varied, e.g., using representative examples described herein, or it may be specific to a particular PDE ⁇ e.g., PDE 1 , PDE 2 , PDE 3 , PDE 4 , or PDE 5 ), or it may have mixed inhibition (e.g., PDE 3 /PDE 5 , PDE3/PDE4), or any combination thereof.
  • the calcium channel blocker component can also be varied, e.g., using representative examples described herein, e.g., amlopidine, verapimil, nifedipine, diltiazem, etc., or it may be a combination thereof.
  • the linker between the PDE inhibitor and calcium channel blocker components can also be varied to alter physiochemical properties, e.g., stability, solubility, size, etc.
  • pharmaceutical compositions of the present invention are formulated so as to provide extended release or enhanced stability of one or more compounds.
  • compositions may be formulation in lipid emulsions, liposomes, or polymeric matrixes.
  • embodiments of the present invention are formulated so as to comprise an amount of each component that is sufficient to achieve a therapeutic or prophylactic effect upon administration to a subject at a prescribed dosage.
  • each component will depend upon the particular PDEi or CCB component chosen, as each individual drug within the family of PDEi and CCB components has its own prescribed effective dosage range known to those skilled in the art.
  • the actual effective amount will also depend on the condition being treated, the route of administration, the drug treatment used to treat the condition, the medical history of the patient, and the additive or synergistic effects resulting from the combination of the two components. Determination of the effective amount is well within the capabilities of those skilled in the art.
  • the effective amount for use in humans can be determined from animal models. For example, a dose for humans can be formulated to achieve circulating concentrations that have been found to be effective in animals.
  • an effective amount of an active component is from about 0.0001 mg to about 500 mg active agent per kilogram body weight of a patient, from about 0.001 to about 250 mg active agent per kilogram body weight of the patient, from about 0.01 mg to about 100 mg active agent per kilogram body weight of the patient, from about 0.5 mg to about 50 mg active agent per kilogram body weight of the patient, or from about 1 mg to about 15 mg active agent per kilogram body weight of the patient.
  • a pharmaceutical formulation of an active agent comprises an amount from about 0.0001 wt. % to about 10 wt. %, from about 0.001 wt.
  • Embodiments of the present invention may be administered by any route known to an ordinarily skilled artisan. The selection of the most appropriate delivery route will vary, and may be influenced by the pharmacological properties of the selected calcium channel blocker and phosphodiesterase inhibitor, the nature and severity of the condition being treated, and the physical condition of the recipient.
  • the pharmaceutical compositions of the present invention comprise one or more excipients and may be in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like (see, e.g., Mathiowitz et ai. Nature 1997 Mar 27;386(6623):410-4; Hwang et ai, Crit Rev Ther Drug Carrier Syst 1998;15(3):243-84; U. S. Patent 5,641,515; U. S. Patent 5,580,579 and U. S. Patent 5,792,451).
  • Tablets, troches, pills, capsules and the like may also contain any of a variety of additional components, for example, a binder, such as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, cornstarch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compounds may be incorporated into sustained-release preparation and formulations.
  • Such approaches are well known to the skilled artisan, some of which are further described, for example, in U. S. Patent 5,543,158, U. S. Patent 5,641 ,515 and U. S. Patent 5,399,363.
  • solutions of the active compounds as free-base or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations generally will contain a preservative to prevent the growth of microorganisms.
  • Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U. S. Patent 5,466,468).
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils.
  • a coating such as lecithin
  • surfactants for example
  • microorganisms can be facilitated by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thir ⁇ erosal, and the like.
  • various antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thir ⁇ erosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • compositions disclosed herein are formulated in a neutral or salt form.
  • Illustrative pharmaceutically- acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the carriers may further comprise any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
  • solvents dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the formulation may be delivered topically, e.g., by intranasal sprays, inhalation, and/or other aerosol delivery vehicles.
  • Methods for delivering formulations topically to the lungs via nasal aerosol sprays have been described, e.g., in U. S. Patent 5,756,353 and U. S. Patent 5,804,212, the entire contents of which are herein incorporated by reference.
  • Methods for delivering both dry and liquid aerosolized formulations topically to the lungs via oral and other inhalation devices have also been described, e.g., in U.S. Patent 5,775,320, U.S. Patent 7,059,321 , U.S. Patent 5,404,871, the entire contents of which are herein incorporated by reference.
  • penetrants e.g. , surfactant acids
  • penetrants e.g. , surfactant acids
  • illustrative transmucosal drug delivery in the form of a polytetrafluoroetheylene support matrix is described in U. S. Patent 5,780,045, the entire contents of which are herein incorporated by reference.
  • Other materials such as preservatives, salts to achieve isotonicity, buffers, and the like, may be added to intranasal and inhalation formulations.
  • the present invention further includes medical devices useful for practicing the methods of the present invention, including, e.g., inhalation delivery devices, that comprises both a PDE inhibitor and a calcium channel blocker (or a dual pharmacophore). These may be adapted for either nasal or oral inhalation and include, e.g., nebulizers.
  • inhalation delivery devices that comprises both a PDE inhibitor and a calcium channel blocker (or a dual pharmacophore).
  • these may be adapted for either nasal or oral inhalation and include, e.g., nebulizers.
  • PVR Pulmonary vascular resistance
  • PAP is pulmonary trunk mean pressure (mm.Hg); RAP is right atrium mean pressure (mmHg), and CO is cardiac output (l/min).
  • PVR did not change after the 0.2 mg/kg dose of Compound 8 when compared to vehicle. PVR appeared to decrease with each additional escalating dose of Compound 8. PVR decreased slightly after dosing with 0.2 mg/kg of the S-enantiomer of Compound 8 when compared to vehicle. PVR remained decreased through the 2.0 mg/kg dose of the S-enantiomer of Compound 8 before increasing after the 6.0 mg/kg dose. In addition, Compound 8 reduced vascular resistance and pulmonary wedge pressure.
  • Anesthesia is induced in rabbits with ketamine (35 mg/kg) and xylazine (5 mg/kg), via an intramuscular injection into Biceps Femoris. Anesthesia is monitored by the absence of a pedal reflex. In addition, a pulse oximeter is used to monitor oxygen level in the blood. The animals are shaved at the neck and leg area (groin), and ECG leads (Lead II) are attached to assure sinus rhythm and normal heart rate. Tracheotomy is performed on the anesthetized animal. The animals are ventilated with 95% O 2 /5% CO 2 (tidal volume 5-7 ml/kg; frequency 45 /min) + isoflurane (maintained at 1.0 to 1.25% at 1.5 L/min).
  • rabbits are initially anesthetized with a mixture of ketamine (7 mg/kg) and xylazine (2.1 mg/kg), followed by a constant intravenous infusion of ketamine (80 mg/kg/h) and xylazine (25 mg/kg/h).
  • a 4 F catheter is inserted into the pulmonary artery via the right external jugular vein.
  • a direct cut down to the left femoral artery allows for blood pressure monitoring, and a 3.0 Fr Millar catheter is inserted into the left carotid artery for left ventricular pressure monitoring.
  • a 3.0 Fr catheter is inserted into the left external jugular vein for i.v. drug administration (10 ⁇ g/kg/min - 1000 ⁇ g/kg/min for 10 min).
  • the cannulae is flushed with heparin sodium (1000 U/ml).
  • test compounds are inhaled from a nebulizer via the inspiratory limb of the ventilation system (0.25-1.0 mg/ml given at a rate of 0.25-0.3 ml/min for 10 min).
  • the animals are covered with a sheet and monitored for 30 minutes before test compound infusion or inhalation.
  • Body temperature is maintained at 37 0 C with a heating pad and monitored using a rectal thermometer.
  • U46619 a thromboxane mimetic
  • U46619 is continually infused (0.5-2 ⁇ g/kg) to increase the pulmonary artery pressure from ⁇ 13 to ⁇ 26 mm Hg within 20 minutes.
  • Hemodynamic parameters are monitored during the infusion or inhalation of ascending doses of reference and test compounds. Blood samples are drawn from the left femoral artery during control conditions and at the end of each dose (6X1 ml_). Dose response curves are developed over 2-3 hours, after which the animals are euthanized by an intravenous injection of sodium pentobarbital (150 mg/kg i.v.).

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Abstract

La présente invention a pour objet des méthodes nouvelles pour traiter une hypertension pulmonaire. En particulier, la présente invention comprend des méthodes pour traiter une hypertension pulmonaire qui utilise en combinaison un agent bloquant de canal calcium et un inhibiteur de la phosphodiestérase, ainsi que des compositions pharmaceutiques qui comprennent un agent bloquant de canal calcium et un inhibiteur de la phosphodiestérase, y compris, par exemple, des mélanges appropriés à une administration par inhalation.
PCT/US2007/017410 2006-08-04 2007-08-03 Méthodes et compositions pour le traitement d'hypertension pulmonaire utilisant une combinaison d'un agent bloquant de canal calcium et un inhibiteur de phosphodiestérase WO2008019106A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009115235A1 (fr) * 2008-03-20 2009-09-24 Bayer Schering Pharma Aktiengesellschaft Inhibiteurs de la phosphodiestérase pour le traitement de l’hypertension pulmonaire
CN104349778A (zh) * 2012-04-11 2015-02-11 简·布卢门施泰因 在失血和贫血治疗中用于防止血管活性的组合物
WO2018208723A1 (fr) * 2017-05-09 2018-11-15 Cardix Therapeutics LLC Compositions pharmaceutiques et méthodes de traitement de maladies cardiovasculaires
EP3283067A4 (fr) * 2015-04-14 2018-12-05 Milestone Pharmaceuticals Inc. Sels très hydrosolubles d'un inhibiteur des canaux calciques à base de phénylalkylamine à action courte et leurs utilisations
TWI657825B (zh) * 2018-04-04 2019-05-01 美進醫藥公司 治療心血管疾病的組合藥物及其製備和使用方法
US20210154177A1 (en) * 2017-11-06 2021-05-27 Stalicla S.A. Pharmaceutical composition for the treatment of autism
US11806314B2 (en) 2013-12-09 2023-11-07 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto
US11999694B2 (en) 2021-10-29 2024-06-04 Sensorium Therapeutics, Inc. Delivery of therapeutic alkaloid compounds

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000199A1 (fr) * 1998-06-26 2000-01-06 Nastech Pharmaceutical Company, Inc. Administration intranasale de citrate de sildenafil
DE19834506A1 (de) * 1998-07-31 2000-02-03 Hexal Ag Transmucosales therapeutisches System zur Anwendung von Sildenafil
US20040265238A1 (en) * 2003-06-27 2004-12-30 Imtiaz Chaudry Inhalable formulations for treating pulmonary hypertension and methods of using same
WO2005046676A1 (fr) * 2003-11-12 2005-05-26 University Of South Carolina Traitement ou prevention de troubles cardio-vasculaires et respiratoires a l'aide de nouveaux inhibiteurs de la phosphodiesterase specifiques de amp cyclique substitue-
US20050239867A1 (en) * 2004-04-23 2005-10-27 Zeldis Jerome B Methods of using and compositions comprising PDE4 modulators for the treatment and management of pulmonary hypertension
WO2006023944A2 (fr) * 2004-08-23 2006-03-02 Mannkind Corporation Administration pulmonaire d'inhibiteurs de phosphodiesterase de type 5

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000199A1 (fr) * 1998-06-26 2000-01-06 Nastech Pharmaceutical Company, Inc. Administration intranasale de citrate de sildenafil
DE19834506A1 (de) * 1998-07-31 2000-02-03 Hexal Ag Transmucosales therapeutisches System zur Anwendung von Sildenafil
US20040265238A1 (en) * 2003-06-27 2004-12-30 Imtiaz Chaudry Inhalable formulations for treating pulmonary hypertension and methods of using same
WO2005046676A1 (fr) * 2003-11-12 2005-05-26 University Of South Carolina Traitement ou prevention de troubles cardio-vasculaires et respiratoires a l'aide de nouveaux inhibiteurs de la phosphodiesterase specifiques de amp cyclique substitue-
US20050239867A1 (en) * 2004-04-23 2005-10-27 Zeldis Jerome B Methods of using and compositions comprising PDE4 modulators for the treatment and management of pulmonary hypertension
WO2006023944A2 (fr) * 2004-08-23 2006-03-02 Mannkind Corporation Administration pulmonaire d'inhibiteurs de phosphodiesterase de type 5

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009115235A1 (fr) * 2008-03-20 2009-09-24 Bayer Schering Pharma Aktiengesellschaft Inhibiteurs de la phosphodiestérase pour le traitement de l’hypertension pulmonaire
CN104349778A (zh) * 2012-04-11 2015-02-11 简·布卢门施泰因 在失血和贫血治疗中用于防止血管活性的组合物
EP2836215A4 (fr) * 2012-04-11 2016-06-08 Jan Blumenstein Composition pour la prévention de la vasoactivité dans le traitement d'une hémorragie et de l'anémie
US11806314B2 (en) 2013-12-09 2023-11-07 Respira Therapeutics, Inc. PDE5 inhibitor powder formulations and methods relating thereto
RU2731918C2 (ru) * 2015-04-14 2020-09-09 Майлстоун Фармасьютикалз Инк. Хорошо растворимые в воде соли фенилалкиламина - быстродействующего блокатора кальциевых каналов и их применение
EP3689344A1 (fr) * 2015-04-14 2020-08-05 Milestone Pharmaceuticals Inc. Sels hautement solubles dans l'eau d'un agent bloquant les canaux calciques à base de phénylalkylamine à brève durée d'action et leurs utilisations
EP3283067A4 (fr) * 2015-04-14 2018-12-05 Milestone Pharmaceuticals Inc. Sels très hydrosolubles d'un inhibiteur des canaux calciques à base de phénylalkylamine à action courte et leurs utilisations
AU2016249030B2 (en) * 2015-04-14 2020-08-27 Milestone Pharmaceuticals Inc. Highly water-soluble salts of a short acting phenylalkylamine calcium channel blocker and uses thereof
KR102197429B1 (ko) 2017-05-09 2020-12-31 카딕스 세러퓨틱스 엘엘씨 심혈관 질환의 치료를 위한 약학 조성물 및 방법
RU2715419C1 (ru) * 2017-05-09 2020-02-28 КАРДИКС ТЕРАПЕУТИКС ЭлЭлСи Фармацевтические составы и способы лечения сердечно-сосудистых заболеваний
KR20190075984A (ko) * 2017-05-09 2019-07-01 카딕스 세러퓨틱스 엘엘씨 심혈관 질환의 치료를 위한 약학 조성물 및 방법
CN109890366A (zh) * 2017-05-09 2019-06-14 美进医药公司 治疗心血管疾病的组合药物及其制备和使用方法
CN109890366B (zh) * 2017-05-09 2020-12-25 美进医药公司 治疗心血管疾病的组合药物及其制备和使用方法
US11266651B2 (en) 2017-05-09 2022-03-08 CARDIX Therapeutics, LLC Pharmaceutical compositions and methods of treating cardiovascular diseases
WO2018208723A1 (fr) * 2017-05-09 2018-11-15 Cardix Therapeutics LLC Compositions pharmaceutiques et méthodes de traitement de maladies cardiovasculaires
US20210154177A1 (en) * 2017-11-06 2021-05-27 Stalicla S.A. Pharmaceutical composition for the treatment of autism
WO2019194866A1 (fr) * 2018-04-04 2019-10-10 Cardix Therapeutics LLC Compositions pharmaceutiques deutérées et méthodes de traitement de maladies cardiovasculaires
TWI657825B (zh) * 2018-04-04 2019-05-01 美進醫藥公司 治療心血管疾病的組合藥物及其製備和使用方法
US11999694B2 (en) 2021-10-29 2024-06-04 Sensorium Therapeutics, Inc. Delivery of therapeutic alkaloid compounds

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