WO2010059967A2 - Inhibiteurs amides de rénine - Google Patents

Inhibiteurs amides de rénine Download PDF

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Publication number
WO2010059967A2
WO2010059967A2 PCT/US2009/065378 US2009065378W WO2010059967A2 WO 2010059967 A2 WO2010059967 A2 WO 2010059967A2 US 2009065378 W US2009065378 W US 2009065378W WO 2010059967 A2 WO2010059967 A2 WO 2010059967A2
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Prior art keywords
compound
recited
group
methoxy
methoxypropoxy
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PCT/US2009/065378
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English (en)
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WO2010059967A3 (fr
Inventor
Thomas G. Gant
Monouchehr Shahbaz
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Auspex Pharmaceuticals, Inc.
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Priority to EP09828307A priority Critical patent/EP2364292A4/fr
Publication of WO2010059967A2 publication Critical patent/WO2010059967A2/fr
Publication of WO2010059967A3 publication Critical patent/WO2010059967A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • new amide compounds, pharmaceutical compositions made thereof, and methods to inhibit renin activity in a subject are also provided for the treatment of disorders such as hypertension, atherosclerosis, cardiac disease, cardiac hypertrophy, cardiac failure, renal disease, renal failure, stroke, and myocardial infarction.
  • Aliskiren aliskiren fumarate, Rasilez, Tekturna, SPP- 100, CGP-60536, CGP-60536B, CGP-62198, CGP-62198A, CAS# 173334-57-1, and CAS# 173334- 58-2
  • (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2- isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide is a renin inhibitor.
  • Aliskiren is commonly prescribed for the treatment of hypertension, atherosclerosis, cardiac disease, cardiac hypertrophy, cardiac failure, and renal failure. (Drug Report for Aliskiren, Thomson Investigational Drug Database (Sept. 15, 2008)); and Jensen et al., Nature Rev. 2008, 7, 399-410). Aliskiren has also shown promise in treating stroke and myocardial infarction (Van Tassell et al., Ann. Pharmacother. 2007, 41, 456-464).
  • Aliskiren is subject to CYP3A4-mediated oxidative metabolism via O- demethylation of the aromatic methoxy group, O-demethylation at the 3-methoxy- propoxy side chain (followed by oxidation to the carboxylic acid), and complete dealkylation of the 3-methoxy-propoxy side chain to the phenol (Waldmeier et al., Drug Metab. Disp. 2007, 35, 1418-28).
  • Adverse effects associated with aliskiren administration include: elevated uric acid, gout, renal stones, rash, gastroesophageal reflux, dyspepsia, abdominal pain, diarrhea, dizziness, edema, angioedema, hypotension, headache, fatigue and nasopharyngitis (Drug Report for Aliskiren, Thomson Investigational Drug Database (Sept. 15, 2008)).
  • the animal body expresses various enzymes, such as the cytochrome P 450 enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
  • CYPs cytochrome P 450 enzymes
  • esterases proteases
  • reductases reductases
  • dehydrogenases dehydrogenases
  • monoamine oxidases monoamine oxidases
  • Such metabolic reactions frequently involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or a carbon-carbon (C-C) ⁇ -bond.
  • C-H carbon-hydrogen
  • C-O carbon-oxygen
  • C-C carbon-carbon
  • the resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term
  • the transition state in a reaction is a short lived state along the reaction pathway during which the original bonds have stretched to their limit.
  • the activation energy E 301 for a reaction is the energy required to reach the transition state of that reaction. Once the transition state is reached, the molecules can either revert to the original reactants, or form new bonds giving rise to reaction products.
  • a catalyst facilitates a reaction process by lowering the activation energy leading to a transition state. Enzymes are examples of biological catalysts.
  • Carbon-hydrogen bond strength is directly proportional to the absolute value of the ground- state vibrational energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium ( 1 H), a C-D bond is stronger than the corresponding C- 1 H bond. If a C- 1 H bond is broken during a rate-determining step in a chemical
  • DKIE Deuterium Kinetic Isotope Effect
  • Deuterium 2 H or D
  • Deuterium oxide looks and tastes like H 2 O, but has different physical properties.
  • the DKIE was used to decrease the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride.
  • this method may not be applicable to all drug classes.
  • deuterium incorporation can lead to metabolic switching.
  • Metabolic switching occurs when xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching is enabled by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites.
  • Aliskiren is a renin inhibitor.
  • the carbon-hydrogen bonds of aliskiren contain a naturally occurring distribution of hydrogen isotopes, namely 1 H or protium (about 99.9844%), 2 H or deuterium (about 0.0156%), and 3 H or tritium (in the range between about 0.5 and 67 tritium atoms per 10 protium atoms).
  • DKIE Deuterium Kinetic Isotope Effect
  • a medicine with a longer half-life may result in greater efficacy and cost savings.
  • Various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) decrease the number of doses needed to achieve a desired effect, (d) decrease the amount of a dose needed to achieve a desired effect, (e) increase the formation of active metabolites, if any are formed, (f) decrease the production of deleterious metabolites in specific tissues, and/or (g) create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not.
  • the deuteration approach has the strong potential to slow the metabolism of aliskiren and attenuate interpatient variability.
  • Novel compounds and pharmaceutical compositions certain of which have been found to inhibit renin have been discovered, together with methods of synthesizing and using the compounds, including methods for the treatment of renin-mediated disorders in a patient by administering the compounds as disclosed herein.
  • R 1 -R 53 are independently selected from the group consisting of hydrogen and deuterium; and at least one of R 1 -R 53 is deuterium.
  • said salt is a hemifumarate salt.
  • Certain compounds disclosed herein may possess useful renin inhibiting activity, and may be used in the treatment or prophylaxis of a disorder in which renin plays an active role.
  • certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions.
  • Certain embodiments provide methods for inhibiting renin activity.
  • Other embodiments provide methods for treating a renin-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention.
  • Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by inhibiting renin activity.
  • the compounds as disclosed herein may also contain less prevalent isotopes for other elements, including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen.
  • the compound disclosed herein may expose a patient to a maximum of about 0.000005% D 2 O or about 0.00001% DHO, assuming that all of the C-D bonds in the compound as disclosed herein are metabolized and released as D 2 O or DHO.
  • the levels of D 2 O shown to cause toxicity in animals is much greater than even the maximum limit of exposure caused by administration of the deuterium enriched compound as disclosed herein.
  • the deuterium-enriched compound disclosed herein should not cause any additional toxicity due to the formation of D 2 O or DHO upon drug metabolism.
  • the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half-life (Ty 2 ), lowering the maximum plasma concentration (C max ) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related toxicity, and/or lowering the probability of drug-drug interactions.
  • deuterium enrichment refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non- enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • deuterium when used to describe a given position in a molecule such as R 1 -R 53 or the symbol "D", when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium.
  • deuterium enrichment is no less than about 1%, in another no less than about 5%, in another no less than about 10%, in another no less than about 20%, in another no less than about 50%, in another no less than about 70%, in another no less than about 80%, in another no less than about 90%, or in another no less than about 98% of deuterium at the specified position.
  • isotopic enrichment refers to the percentage of incorporation of a less prevalent isotope of an element at a given position in a molecule in the place of the more prevalent isotope of the element.
  • non-isotopically enriched refers to a molecule in which the percentages of the various isotopes are substantially the same as the naturally occurring percentages.
  • Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S”, depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as D-isomers and L-isomers, and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
  • bond refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disease”, “syndrome”, and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.
  • treat are meant to include alleviating or abrogating a disorder or one or more of the symptoms associated with a disorder; or alleviating or eradicating the cause(s) of the disorder itself.
  • treatment of a disorder is intended to include prevention.
  • prevent refer to a method of delaying or precluding the onset of a disorder; and/or its attendant symptoms, barring a subject from acquiring a disorder or reducing a subject's risk of acquiring a disorder.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like.
  • a primate e.g., human, monkey, chimpanzee, gorilla, and the like
  • rodents e.g., rats, mice, gerbils, hamsters, ferrets, and the like
  • lagomorphs e.g., pig, miniature pig
  • swine e.g., pig, miniature pig
  • equine canine
  • feline feline
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the disorders described herein.
  • renin refers to a circulating enzyme that participates in the body's renin-angiotensin system (RAS).
  • RAS renin-angiotensin system
  • the renin-angiotensin system is one of the key regulators of electrolyte and fluid balance, and blood pressure. Renin initiates the RAS cascade by cleaving angiotensinogen, which is produced by the liver, to yield angiotensin I that is further converted into angiotensin II by angiotensin- converting enzyme (ACE), primarily within the capillaries of the lungs.
  • ACE angiotensin- converting enzyme
  • Angiotensin II increases blood pressure, by inducing blood vessels to constrict, increasing the secretion of ADH and aldosterone, and stimulating the hypothalamus to activate the thirst reflex.
  • Renin is secreted from juxtaglomerular cells of the afferent arterioles.
  • Juxtaglomerular cells can be activated by either: prostaglandins, which are released from the macula densa in response to the rate of fluid flow through the distal tubule; by decreases in renal perfusion pressure through stretch receptors in the vascular wall; and by nervous stimulation, mainly through beta-1 receptor activation.
  • Renin's primary function is therefore to maintain homoestasis by increasing blood pressure, thereby leading to restoration of perfusion pressure in the kidneys.
  • Renin can also bind to ATP6AP2. This renin/ ATP6AP2 complex increases the rate of conversion of angiotensinogen to angiotensin I by fourfold over that of soluble renin.
  • An over-active renin- angiotension system leads to vasoconstriction and retention of sodium and water, which in turn leads to hypertension.
  • renin-mediated disorder refers to a disorder that is characterized by abnormal renin activity, or normal renin activity that when inhibited leads to the amelioration of other abnormal biological processes.
  • a renin- mediated disorder may be completely or partially mediated by inhibiting renin activity.
  • a renin-mediated disorder is one in which inhibition of renin results in some effect on the underlying disorder e.g., administration of a renin inhibitor results in some improvement in at least some of the patients being treated.
  • renin inhibitor refers to the ability of a compound disclosed herein to alter the function of renin.
  • a renin inhibitor may block or reduce the activity of renin by forming a reversible or irreversible covalent bond between the inhibitor and renin or through formation of a noncovalently bound complex. Such inhibition may be manifest only in particular cell types or may be contingent on a particular biological event.
  • the term "renin inhibitor” also refers to altering the function of renin by decreasing the probability that a complex forms between renin and a natural substrate. In some embodiments, renin inhibition may be assessed using the methods described in Kelly et al., Diabetologia 2007, 50(11), 2398-2404.
  • inhibitors refers to altering the activity of renin by administering a renin inhibitor.
  • therapeutically acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, immunogenecity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • pharmaceutically acceptable carrier refers to a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • Each component must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenecity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • active ingredient refers to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.
  • drug refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.
  • release controlling excipient refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • nonrelease controlling excipient refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • prodrug refers to a compound functional derivative of the compound as disclosed herein and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci.
  • the compounds disclosed herein can exist as therapeutically acceptable salts.
  • pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds disclosed herein which are therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with a suitable acid or base.
  • Therapeutically acceptable salts include acid and basic addition salts.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)- camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, gluco
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-
  • compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g. , in Remington's Pharmaceutical Sciences.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc., New York, NY, 2002; Vol. 126).
  • compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • compounds may be delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 5 mg to 2 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the disorder being treated. Also, the route of administration may vary depending on the disorder and its severity.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disorder.
  • the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved disorder is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • Renin-mediated disorders include, but are not limited to, hypertension, atherosclerosis, cardiac disorders, cardiac hypertrophy, left ventricular hypertrophy, cardiac failure, renal disorders, renal failure, stroke, and myocardial infarction, and/or any disorder which can lessened, alleviated, or prevented by administering a renin inhibitor.
  • a method of treating a renin-mediated disorder comprises administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to affect: (1) decreased inter-individual variation in plasma levels of the compound or a metabolite thereof; (2) increased average plasma levels of the compound or decreased average plasma levels of at least one metabolite of the compound per dosage unit; (3) decreased inhibition of, and/or metabolism by at least one cytochrome P 450 or monoamine oxidase isoform in the subject; (4) decreased metabolism via at least one polymorphically-expressed cytochrome P 450 isoform in the subject; (5) at least one statistically-significantly improved disorder- control and/or disorder-eradication endpoint; (6) an improved clinical effect during the treatment of the disorder, (7) prevention of recurrence, or delay of decline or appearance, of abnormal alimentary or hepatic parameters as the primary clinical benefit, or (8) reduction or elimination
  • inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof is decreased; average plasma levels of the compound as disclosed herein are increased; average plasma levels of a metabolite of the compound as disclosed herein are decreased; inhibition of a cytochrome P 450 or monoamine oxidase isoform by a compound as disclosed herein is decreased; or metabolism of the compound as disclosed herein by at least one polymorphically-expressed cytochrome P 450 isoform is decreased; by greater than about 5%, greater than about 10%, greater than about 20%, greater than about
  • Plasma levels of the compound as disclosed herein, or metabolites thereof, may be measured using the methods described by Li et al., Rapid
  • cytochrome P 450 isoforms in a mammalian subject include, but are not limited to, CYPlAl, CYP1A2, CYPlBl, CYP2A6, CYP2A13,
  • CYPI lBl CYP11B2
  • CYP17 CYP19
  • CYP21 CYP24
  • CYP26A1 CYP26B1
  • CYP27A1, CYP27B1, CYP39, CYP46, and CYP51 are CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.
  • Examples of monoamine oxidase isoforms in a mammalian subject include, but are not limited to, MAO A , and MAO B -
  • the inhibition of the MAO A isoform is measured by the method of Weyler et al., /.
  • Examples of polymorphically-expressed cytochrome P 450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
  • liver microsomes cytochrome P 450 isoforms
  • monoamine oxidase isoforms are measured by the methods described herein.
  • Examples of improved disorder-control and/or disorder-eradication endpoints or improved clinical effects include, but are not limited to, left ventricular hypertrophy, reduced mean sitting systolic blood pressure, reduced mean sitting diastolic blood pressure, reduced brain naturietic peptide levels, reduced proteinuria, reduction of blood pressure, reduced mean urinary albumin excretion rate, reduced early morning urinary albumin creatinine ratio, reduced plasma renin activity, and preservation of organ function in diabetic patients.
  • hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase ("ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP,” “ ⁇ -GTP,” or “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5'- nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in "Diagnostic and Laboratory Test Reference", 4 th edition, Mosby, 1999. These assays are run by accredited laboratories according to standard protocol.
  • certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the compounds disclosed herein may also be combined or used in combination with other agents useful in the treatment of renin-mediated disorders. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • Such other agents, adjuvants, or drugs may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound as disclosed herein. When a compound as disclosed herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound disclosed herein may be utilized, but is not required.
  • the compounds disclosed herein can be combined with one or more adrenergic receptor antagonists, angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, anti-arrhythmics, anticoagulants, antiplatelet agents, beta-1 adrenergic receptor antagonists, calcium channel blockers, fibrates, platelet aggregation inhibitors, HMG-CoA reductase inhibitors, and diuretics.
  • adrenergic receptor antagonists angiotensin II receptor antagonists, angiotensin-converting enzyme inhibitors, anti-arrhythmics, anticoagulants, antiplatelet agents, beta-1 adrenergic receptor antagonists, calcium channel blockers, fibrates, platelet aggregation inhibitors, HMG-CoA reductase inhibitors, and diuretics.
  • the compounds disclosed herein can be combined with one or more adrenergic receptor antagonists, including, but not limited to, atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol, doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline, bucindolol, carvedilol, and labetalol.
  • adrenergic receptor antagonists including, but not limited to, atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol, doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline, bucindolo
  • the compounds disclosed herein can be combined with one or more angiotensin II receptor antagonists, including, but not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, molsidomin, and pentaerythritol tetranitrate.
  • angiotensin II receptor antagonists including, but not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, molsidomin, and pentaerythritol tetranitrate
  • the compounds disclosed herein can be combined with one or more angiotensin-converting enzyme inhibitors, including, but not limited to, captopril, enalapril, lisinopril, perindopril, ramipril, quinapril, benazepril, cilazapril, fosinopril, trandolapril, spirapril, delapril, moexipril, temocapril, zofenopril, and imidapril.
  • angiotensin-converting enzyme inhibitors including, but not limited to, captopril, enalapril, lisinopril, perindopril, ramipril, quinapril, benazepril, cilazapril, fosinopril, trandolapril, spirapril, delapril, moexipril, temocapril, zofenopri
  • the compounds disclosed herein can be combined with one or more anti-arrhythmics, including, but not limited to quinidine, procainamide, disopyramide, sparteine, ajmaline, prajmaline, lorajmine, lidocaine, mexiletine, tocainide, aprindine, propafenone, flecainide, lorcainide, encainide, amiodarone, bretylium tosilate, bunaftine, dofetilide, ibutilidem, moracizine, and cibenzoline.
  • one or more anti-arrhythmics including, but not limited to quinidine, procainamide, disopyramide, sparteine, ajmaline, prajmaline, lorajmine, lidocaine, mexiletine, tocainide, aprindine, propafenone, flecainide, lorcainide, encainide, ami
  • the compounds provided herein can be combined with one or more anticoagulants, including, but not limited to, acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximalagatran.
  • anticoagulants including, but not limited to, acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximalagatran.
  • the compounds provided herein can be combined with one or more antiplatelet agents, including, but not limited to, abciximab, cilostazol, clopidogrel, dipyridamole, ticlopidine, and tirofibin.
  • antiplatelet agents including, but not limited to, abciximab, cilostazol, clopidogrel, dipyridamole, ticlopidine, and tirofibin.
  • the compounds disclosed herein can be combined with one or more of beta- 1 adrenergic receptor antagonists, including, but not limited to betaxolol, alprenolol, oxprenolol, pindolol, propranolol, timolol, sotalol, nadolol, mepindolol, carteolol, tertatolol, bopindolol, bupranolol, penbutolol, cloranolol, practolol, metoprolol, atenolol, acebutolol, bevantolol, bisoprolol, celiprolol, esmolol, epanolol, s-atenolol, nebivolol, talinolol, labetalol, and carvedilol
  • the compounds disclosed herein can be combined with one or more calcium channel blockers, including, but not limited to amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nhisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine, mibefradil, verapamil, gallopamil, diltiazem, fendiline, bepridil, lidoflazine, and perhexiline.
  • calcium channel blockers including, but not limited to amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nhisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barni
  • the compounds provided herein can be combined with one or more fibrates, including, but not limited to, clofibrate, bezafibrate, aluminium clofibrate, gemfibrozil, fenofibrate, simfibrate, ronifibrate, ciprofibrate, etofibrate, and clofibride.
  • fibrates including, but not limited to, clofibrate, bezafibrate, aluminium clofibrate, gemfibrozil, fenofibrate, simfibrate, ronifibrate, ciprofibrate, etofibrate, and clofibride.
  • the compounds disclosed herein can be combined with one or more platelet aggregation inhibitors, including, but not limited to acetylsalicylic acid/aspirin, aloxiprin, ditazole, carbasalate calcium, cloricromen, dipyridamole, indobufen, picotamide, triflusal, clopidogrel, ticlopidine, prasugrel, beraprost, prostacyclin, iloprost, and treprostinil.
  • platelet aggregation inhibitors including, but not limited to acetylsalicylic acid/aspirin, aloxiprin, ditazole, carbasalate calcium, cloricromen, dipyridamole, indobufen, picotamide, triflusal, clopidogrel, ticlopidine, prasugrel, beraprost, prostacyclin, iloprost, and treprostinil.
  • the compounds disclosed herein can be combined with one or more HMG-CoA reductase inhibitors, including, but not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.
  • HMG-CoA reductase inhibitors including, but not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.
  • the compounds disclosed herein can be combined with one or more diuretics, including, but not limited to, bendroflumethiazide, hydroflumethiazide, hydrochlorothiazide, chlorothiazide, polythiazide, trichlormethiazide, cyclopenthiazide, methyclothiazide, cyclothiazide, mebutizide, quinethazone, clopamide, chlortalidone, mefruside, clofenamide, metolazone, meticrane, xipamide, indapamide, clorexolone, fenquizone, mersalyl, theobromine, cicletanine, furosemide, bumetanide, piretanide, torasemide, etacrynic acid, tienilic acid, muzolimine, etozolin, spironolactone, potassium canrenoate, canren
  • the compounds disclosed herein can also be administered in combination with other classes of compounds, including, but not limited to, norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane
  • metformin glucosidase inhibitors
  • glucosidase inhibitors e.g., acarbose
  • insulins meglitinides (e.g., repaglinide)
  • meglitinides e.g., repaglinide
  • sulfonylureas e.g., glimepiride, glyburide, and glipizide
  • thiozolidinediones e.g.
  • certain embodiments provide methods for treating renin-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder.
  • certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of renin-mediated disorders.
  • Isotopic hydrogen can be introduced into a compound as disclosed herein by synthetic techniques that employ deuterated reagents, whereby incorporation rates are pre-determined; and/or by exchange techniques, wherein incorporation rates are determined by equilibrium conditions, and may be highly variable depending on the reaction conditions.
  • Synthetic techniques where tritium or deuterium is directly and specifically inserted by tritiated or deuterated reagents of known isotopic content, may yield high tritium or deuterium abundance, but can be limited by the chemistry required.
  • Exchange techniques on the other hand, may yield lower tritium or deuterium incorporation, often with the isotope being distributed over many sites on the molecule.
  • the compounds as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or following procedures similar to those described in the Example section herein and routine modifications thereof, and/or procedures found in Lindsay et al., /. Org. Chem. 2006, 71(13), 4766-77; Dondoni et al., Tet. Lett. 2001, 42, 4819-23; Sandham et al., Tet. Lett. 2000, 41, 10091-94; Dong et al., Tet. Lett.
  • Compound 1 is reacted with an appropriate reducing agent, such as hydrogen gas and an appropriate catalyst, such as palladium on carbon, in an appropriate solvent, such as methanol, to give compound 2.
  • an appropriate chlorinating agent such as phosgene
  • an appropriate solvent such as N,N-dimethylformamide
  • compound 3 is reacted with (+)-pseudoephedrine in the presence of an appropriate base, such as sodium hydroxide, in an appropriate solvent, such as an appropriate mixture of toluene and water, to give compound 4.
  • Compound 4 is reacted with compound 5 in the presence of an appropriate catalyst, such as lithium chloride, in the presence of an appropriate base, such as lithium diisopropylamide, in an appropriate solvent, such as tetrahydrofuran, to give compound 6.
  • an appropriate reducing agent such as an ammonia-borane complex
  • an appropriate base such as n-butyllithium
  • an appropriate solvent such as tetrahydrofuran
  • compound 7 is reacted with an appropriate chlorinating agent, such as phosphorous oxychloride, in an appropriate solvent, such as an appropriate mixture of N,N-dimethylformamide and toluene, to give compound 8.
  • Compound 8 is reacted with compound 9, in the presence of an appropriate base, such as n-butyllithium, in an appropriate solvent, such as tetrahydrofuran, to give compound 10.
  • Compound 10 is reacted with an appropriate acid, such as hydrochloric acid, in an appropriate solvent, such as an appropriate mixture of water and acetonitrile, to give compound 11.
  • Compound 11 is reacted with an appropriate protecting agent, such as benzyl chloroformate, in the presence of an appropriate base, such as pyridine, in an appropriate solvent, such as dichloromethane, to give compound 12.
  • Compound 12 is reacted with an appropriate base, such as sodium hydroxide, in an appropriate solvent, such as an appropriate mixture of tetrahydrofuran, water, and and methanol, to give compound 13.
  • Compound 13 is reacted with 4-mercaptopyridine in the presence of an appropriate coupling agent, such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, in an appropriate solvent, such as dichloromethane, to give compound 14.
  • Compound 14 is reacted with compound 15 in the presence of an appropriate catalyst, such as samarium (II) iodide, in an appropriate solvent, such as tert-butanol, to give compound 16.
  • an appropriate catalyst such as samarium (II) iodide
  • Compound 16 is reacted with an appropriate reducing agent, such as lithium B-isopinocampheyl-9- borabicyclo[3.3.1]nonyl hydride, in an appropriate solvent, such as tetrahydrofuran, to give compound 17.
  • an appropriate reducing agent such as lithium B-isopinocampheyl-9- borabicyclo[3.3.1]nonyl hydride
  • an appropriate solvent such as tetrahydrofuran
  • Compound 17 is reacted with compound 18 in the presence of an appropriate base, such as lithium bis-(trimethylsilyl)amide, in an appropriate solvent, such as tetrahydrofuran, to give compound 19.
  • Compound 19 is reacted with an appropriate dehydrating agent, such as phosphorus pentachloride, in an appropriate solvent, such as dichloromethane, to give compound 20.
  • Compound 20 is reacted with an appropriate reducing agent, such as hydrogen gas and an appropriate catalyst, such as palladium on carbon, in an appropriate solvent, such as ethanol, to give compound 21.
  • Compound 21 is reacted with an appropriate protecting agent, such as di-tert-butyldicarbonate, in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as tetrahydrofuran, to give compound 22.
  • Compound 23 is reacted compound 24 (wherein X is an appropriate leaving group, such as iodine), in the presence of an appropriate base, such as sodium ethoxide, in an appropriate solvent, such as N,N- dimethylformamide, to give compound 25.
  • Compound 25 is reacted with an appropriate reducing agent, such as lithium aluminium hydride, in an appropriate solvent, such as diethyl ether, to give compound 26.
  • Compound 22 is reacted with compound 26 in the presence of an appropriate catalyst, such as 2-hydroxypyridine, in the presence of an appropriate base, such as triethylamine, to give compound 27.
  • Compound 27 is treated with an appropriate deprotecting reagent, such as a mixture of trimethylsilyl chloride and phenol, in an appropriate solvent, such as dichloromethane, to give compound 28 of Formula I.
  • Deuterium can be incorporated to different positions synthetically, according to the synthetic procedures as shown in Scheme I, by using appropriate deuterated intermediates.
  • To introduce deuterium at one or more positions of Ri-Ri 6 and Ri S1 compound 1 with the corresponding deuterium substitutions can be used.
  • To introduce deuterium at one or more positions of Ri 9 - R 25 compound 5 with the corresponding deuterium substitutions can be used.
  • To introduce deuterium at one or more positions of R 2 6-R 2 7, trideuteroborane- ammonia complex may used.
  • compound 9 with the corresponding deuterium substitutions can be used.
  • lithium B-isopinocampheyl- ⁇ -borabicycloP.S.lJnonyl deuteride can be used.
  • compound 15 with the corresponding deuterium substitutions can be used.
  • deuterium gas can be used.
  • compound 18 with the corresponding deuterium substitutions can be used.
  • compound 24 with the corresponding deuterium substitutions can be used.
  • lithium aluminum deuteride can be used.
  • Deuterium can be incorporated to various positions having an exchangeable proton, such as the amide N-Hs, the amine N-Hs, and the hydroxy O- Hs, via proton-deuterium equilibrium exchange.
  • an exchangeable proton such as the amide N-Hs, the amine N-Hs, and the hydroxy O- Hs
  • these protons may be replaced with deuterium selectively or non- selectively through a proton-deuterium exchange method known in the art.
  • Compound 29 is reacted with compound 30 (wherein X is an appropriate leaving group, such as iodide) in the presence of an appropriate base, such as potassium carbonate, in an appropriate solvent, such as N,N-dimethylformamide, to give compound 31.
  • Compound 31 is reacted with compound 32 in the presence of an appropriate hydroxyl activating agent, such as a combination of diisopropyl azodicarboxylate and an appropriate phosphine, such as triphenylphosphine, in an appropriate solvent, such as tetrahydrofuran, to afford compound 33.
  • Compound 33 is reacted with compound 34 at an elevated temperature and under an inert atmosphere to give compound 35.
  • Compound 35 is reacted with compound 36 in an appropriate solvent, such as tetrahydrofuran, to afford compound 37.
  • Compound 37 is treated with an appropriate oxidizing agent, such as chromium trioxide, in an appropriate solvent, such as an appropriate mixture of acetic acid and water, to give compound 38.
  • Compound 39 is treated with an appropriate base, such as n- butyllithium, in an appropriate solvent, such as tetrahydrofuran, to give a lithiated intermediate which is then reacted with compound 40 in an appropriate solvent, such as tetrahydrofuran, to afford compound 41.
  • Compound 41 is treated with an appropriate base, such as lithium bis(trimethylsilyl)amine, in an appropriate solvent, such as tetrahydrofuran, to give a lithiated intermediate which is then reacted with compound 42 in an appropriate solvent, such as tetrahydrofuran, to give compound 43.
  • Compound 38 is treated with an appropriate base, such as lithium bis(trimethylsilyl)amine, in an appropriate solvent, such as tetrahydrofuran, to give a lithiated intermediate which is then reacted with compound 43 in an appropriate solvent, such as tetrahydrofuran, to give compound 44.
  • Compound 44 is treated with an appropriate chiral auxiliary removal agent, such as a combination of lithium hydroxide and hydrogen peroxide, in an appropriate solvent, such as an appropriate mixture of tetrahyrdofuran and water, to give compound 45.
  • Compound 45 is reacted with compound 46 in the presence of an appropriate peptide coupling reagent, such as a combination of Ni-((ethylimino)methylene)-N 3 ,N 3 - dimethylpropane-l,3-diamine hydrochloride and lH-benzo[d][l,2,3]triazol-l-ol,an appropriate base, such as diisopropylethylamine, in an appropriate solvent, such as tetrahydrofuran, to give compound 47.
  • an appropriate peptide coupling reagent such as a combination of Ni-((ethylimino)methylene)-N 3 ,N 3 - dimethylpropane-l,3-diamine hydroch
  • Compound 47 is resolved by using an appropriate resolving method, such as chiral preparative high performance liquid chromatography ( ⁇ PLC), to give compound 48.
  • Compound 48 is treated with an appropriate reducing reagent, such as sodium borohydride, in an appropriate solvent, such as methanol, to give compound 49.
  • Compound 49 is reacted with an appropriate reducing agent, such as triethylsilane, in the presence of an appropriate acid, such as trifluoroacetic acid, in an appropriate solvent, such as 1,2- dichloroethane, to afford compound 50.
  • an appropriate reducing agent such as triethylsilane
  • Compound 50 is reacted with an appropriate brominating reagent, such as N-bromosuccinimide, in the presence of an appropriate acid, such as acetic acid, in an appropriate solvent, such as an appropriate mixture of tetrahydrofuran and water, to give compound 51.
  • an appropriate brominating reagent such as N-bromosuccinimide
  • an appropriate acid such as acetic acid
  • an appropriate solvent such as an appropriate mixture of tetrahydrofuran and water
  • Compound 51 is reacted with sodium azide in an appropriate solvent, such as 1,3- dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, to afford compound 52.
  • Compound 52 is resolved with an an appropriate resolving method, such as chiral preparative ⁇ PLC, to give compound 53.
  • Compound 53 is reacted with an appropriate catalyst, such as pyridine-2-ol, and then reacted with compound 54 in the presence of an appropriate base, such as triethylamine, to give compound 55.
  • Compound 55 is treated with an appropriate reducing agent, such as hydrogen gas, in the presence of an appropriate catalyst, such as palladium on carbon, in an appropriate solvent, such as methanol, to give compound 56 of Formula I.
  • an appropriate reducing agent such as hydrogen gas
  • an appropriate catalyst such as palladium on carbon
  • an appropriate solvent such as methanol
  • compound 32 with the corresponding deuterium substitutions can be used.
  • compound 29 with the corresponding deuterium substitutions can be used.
  • compound 30 with the corresponding deuterium substitutions can be used.
  • sodium borodeuteride can be used.
  • triethylsilane with the corresponding deuterium substitutions can be used.
  • compound 36 with the corresponding deuterium substitutions can be used.
  • compound 42 with the corresponding deuterium substitutions can be used.
  • compound 40 with the corresponding deuterium substitutions can be used.
  • compound 54 with the corresponding deuterium substitutions can be used.
  • Deuterium can be incorporated to various positions having an exchangeable proton, such as the amide N-Hs, the amine N-Hs, and the hydroxy O- Hs, via proton-deuterium equilibrium exchange.
  • an exchangeable proton such as the amide N-Hs, the amine N-Hs, and the hydroxy O- Hs
  • these protons may be replaced with deuterium selectively or non- selectively through a proton-deuterium exchange method known in the art.
  • the invention is further illustrated by the following examples. All IUPAC names were generated using CambridgeSoft's ChemDraw 10.0.
  • l-(4-Methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-l-one At about 0 0 C, l-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-l-ol (56.4 g, 200 mmol, 1.00 equiv) was added dropwise to a stirred solution of chromium trioxide (30 g, 300 mmol, 1.50 equiv) in acetic acid / water (100 mL / 1000 mL). The resulting solution was stirred at ambient temperature for about 16 hours, and then was concentrated in vacuo.
  • Liver microsomal stability assays were conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% NaHC ⁇ 3 (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM MgCl 2 ).
  • Test compounds were prepared as solutions in 20% acetonitrile-water (20 ⁇ M stock solutions) and added to the assay mixture (final assay concentration 1 ⁇ M). Final concentration of acetonitrile in the assay should be ⁇ 1%.
  • the reactions were incubated at 37 0 C.
  • other isotopically-enriched compounds that have yet to be tested in this assay are expected to have an improvement in degradation half life of at least 15%; at least 20%; at least 30%; at least 40%; at least 50%; at least 60%; at least 70%; at least 80%; at least 90%; at least 100%; at least 150%; or at least 200%.
  • the degradation half-lives of Examples 1-3 (aliskiren, aliskiren- ⁇ , aliskiren-J ⁇ ) are shown in Table 1. Results of in vitro human liver microsomal (HLM) stabilit assay
  • the cytochrome P 450 enzymes are expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, CA).
  • reaction is stopped by the addition of an appropriate solvent (e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3 minutes. The supernatant is analyzed by HPLC/MS/MS.
  • an appropriate solvent e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid

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Abstract

La présente invention concerne de nouveaux inhibiteurs amides de rénine, des compositions pharmaceutiques de ceux-ci, et des procédés d’utilisation de ceux-ci.
PCT/US2009/065378 2008-11-20 2009-11-20 Inhibiteurs amides de rénine WO2010059967A2 (fr)

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EP2551260A1 (fr) 2011-07-28 2013-01-30 Chemo Ibérica, S.A. Procédé chimique pour l'ouverture de composés cycliques
WO2013144979A1 (fr) * 2012-03-28 2013-10-03 Maylan Laboratories Ltd Procédé pour la préparation d'aliskirène
US8883857B2 (en) 2012-12-07 2014-11-11 Baylor College Of Medicine Small molecule xanthine oxidase inhibitors and methods of use
CN110483250A (zh) * 2019-09-05 2019-11-22 青岛科技大学 一种卡巴匹林钙母液连续化乙醇回收及水杨酸脱除工艺

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US20080132555A1 (en) * 2006-11-28 2008-06-05 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted phenyltetrazoles
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US20090082458A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched aliskiren

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