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WO2016037098A1 - Sacubitril deutérisé - Google Patents

Sacubitril deutérisé Download PDF

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Publication number
WO2016037098A1
WO2016037098A1 PCT/US2015/048626 US2015048626W WO2016037098A1 WO 2016037098 A1 WO2016037098 A1 WO 2016037098A1 US 2015048626 W US2015048626 W US 2015048626W WO 2016037098 A1 WO2016037098 A1 WO 2016037098A1
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Prior art keywords
ch2ch2
cd2cd2
cds
compound
chs
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English (en)
Inventor
Roger D. Tung
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Concert Pharmaceuticals Inc
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Concert Pharmaceuticals Inc
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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
    • C07C233/47—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 a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • 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

  • Heart failure is a disease in which the heart cannot pump enough blood to the body's organs, resulting in shortness of breath, fatigue and retention of fluids. Five million to six million Americans, and an estimated 26 million people globally, have heart failure, and it is the leading cause of hospitalization in the United States and Europe, according to a recent paper in the Journal of the American College of Cardiology.
  • Sacubitril also known as AHU377, and chemically as 5-(biphenyl-4-yl)-4(5)-(3- carboxypropionamido)-2(R)-methylbutyric acid ethyl ester, is an inhibitor of neprilysin, also known as enkephalinase or neutral endopeptidase (NEP). Sacubitril has been approved as part of a fixed dose combination with valsartan, an angiotensin II receptor antagonist, for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart faulure.
  • Sacubitril is described in US patent 5,217,996. Despite its promising activity, sacubitril is administered as a fixed dose combination with another active ingredient. The selection of a suitable fixed dose combination is often limited by the pharmacokinetics and pharmacodynamics of each active ingredient. For LCZ696, the pharmacokinetics and pharmacodynamics have been described by J. Gu, et al. J. Clin. Pharmacol. 2010; 50:401-414 (2010). It would be desirable to have new analogs of sacubitril with improved pharmacokinetic properties, especially new analogs that provide greater options for use with a second therapeutic agent.
  • This invention relates to deuterium substituted analogs of sacubitril and pharmaceutically acceptable salts thereof.
  • This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering sacubitril.
  • the invention also relates to compositions comprising a combination of a deuterated sacubitril analog and an angiotensin receptor antagonist. Such combinations are useful, for example, for treating patients with heart failure to reduce the risk of death from cardiovascular causes or hospitalization for heart failure.
  • the compounds of this invention are deuterium substituted analogs of sacubitril that are useful for treating subjects who had heart failure.
  • the compounds of this invention are useful when combined with an angiotensin receptor antagonist such as valsartan.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated specifically as “D” or “deuterium”
  • the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5%) deuterium incorporation).
  • isotopologue refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.
  • a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure.
  • the relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.
  • the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.
  • the invention also provides salts of the compounds of the invention.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid
  • salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate
  • the pharmaceutically acceptable salt may also be a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D
  • Substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • R 1 i is tionally substituted by one or more deuterium
  • R 2 is methyl, optionally substituted by one or more deuterium;
  • Z is -C(R 7 ) 2 C(R 8 )2-, wherein each R 7 and each R 8 are independently hydrogen or deuterium;
  • Each R 3 is independently hydrogen or deuterium;
  • Each R 4 is independently hydrogen or deuterium;
  • R 5 is hydrogen or deuterium;
  • R 6 is hydrogen or deuterium; provided that R 6 is deuterium when neither R 1 nor R 2 are substituted by deuterium and each of R 3 , R 4 , R 5 , R 7 and R 8 are hydrogen.
  • One embodiment relates to a compound of Formula I where R 2 is -CH3 or -CD3, each R 3 is the same, each R 4 is the same, each R 7 is the same and each R 8 is the same.
  • Z is -CH2CH2-; - CD2CD2S-CD2CH2-; or -CH2CD2-.
  • Z is -CH2CH2-; -CD2CD2-;- CD2CH2-; or -CH2CD2-
  • R 2 is -CH3 or -CD3
  • each R 3 is the same
  • each R 4 is the same
  • each R 7 is the same
  • each R 8 is the same.
  • R 1 groups are the following:
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • R 1 is R ! -c, which are referred to as compounds of Formula IV, or a pharmaceutically acceptable salt thereof, where Z, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as described above.
  • Another embodiment relates to compounds of Formula I where R 1 is R ! -d, which are referred to as compounds of Formula V, or a pharmaceutically acceptable salt thereof, where Z, R 2 , R 3 , R 4 , R 5 , and R 6 are as described above.
  • Examples of specific compounds of Formulae IV and V are those compounds of each formula where Z, R 2 , R 3 , R 4 , R 5 , and R 6 are as described in Tables 2a and 2b above.
  • the compounds and compositions of this invention may include small amounts of other stereoisomers.
  • the percentage of compounds having the (R) configuration at the 2 position is greater than 80%, greater than 90%, greater than 95% and greater than 99% and the percentage of compounds having the (S) configuration at the 4 position is greater than 80%, greater than 90%, greater than 95% and greater than 99%.
  • COX is a carboxyl or carboxyl derivatized in the form of a pharmaceutically acceptable ester or amide
  • X' is a leaving group suitable for condensing a carboxylic acid with an amine to form an amide.
  • Deuterated versions of the intermediate VI are readily available by methods known in the art.
  • compounds where Z is -CD2CD2- may be prepared from succinic acid using deuterium- hydrogen exchange reactions under acid or base catalysis in the presence of a deuterated solvent.
  • Suitable deuterated solvents include, for example, deuterium oxide, a deuterated alcohol such as EtOD or MeOD, or a combination thereof.
  • Compounds where Z is -CHD-CHD- can be prepared from fumaric acid by hydrogenation with deuterium.
  • Intermediate VI can be prepared by known methods where the percent incorporation of each deuterium is at least 90%, at least 95% and at least 99%.
  • compounds of Formula I may be prepared where each of R 6 and R 7 have deuterium incorporation that is at least 90%, at least 95% and at least 99%.
  • Intermediate VIII is an amino acid that can be prepared by known methods for preparing a-amino acids such as a Strecker synthesis. Such methods are amenable to incorporation of deuterium at high levels of isotopic purity.
  • the amino acid VII can be prepared a Strecker synthesis from the corresponding aldehyde XI:
  • Protecting group chemistry known in the art leads to protected amino ester VIII-2, which can then be converted to triflate VIII- 3, and coupled under transition-metal catalyzed conditions with boronic acid VIII-4 to afford protected biphenyl amino esters VIII-5, which can be deprotected under standard conditions to give intermediates VHI-a through VHI-d.
  • R 85 , R 86 , R 87 , R 88 H
  • R 85 , R 86 , R 87 , R 88 D
  • Compounds having deuterium at R 4 can be prepared from intermediate XI or a precursor thereof where R 4 is hydrogen by hydrogen-deuterium exchange reactions in deuterated solvents as described above.
  • Compounds having deuterium at R 6 can be prepared from the analogous carboxylic acid or ester by reduction to the aldehyde using a deuterated reducing agent. These methods may provide high levels of deuterium incorporation where the percent incorporation of each deuterium at R 4 or at R 6 is at least
  • compounds of Formula I-V may be prepared where each R 4 and R 6 have deuterium incorporation that is at least 90%, at least 95% and at least 99%.
  • the starting aldehyde (XI) may be obtained where R 1 is a biphenyl moiety that is optionally substituted with deuterium, and in particular where the phenyl rings of the biphenyl are independently perdeuterated.
  • step (b) above other Wittig reagents may be used in place of intermediate IX and may be prepared where R 2 is a methyl group or a deuterated methyl group having deuterium incorporation of at least 90%, at least 95% and at least 99% at each deuterium of the R 2 group.
  • the invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I-V (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., including any of the formulae herein
  • the carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene -polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil -in- water liquid emulsion; a water-in-oil liquid emulsion;
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti -oxidants, 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.
  • the formulations may be presented in unit- dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • a composition of this invention further comprises a second therapeutic agent.
  • the second therapeutic agent may be selected from any angiotensin II receptor antagonist, also known as an angiotensin receptor blocker or ARB.
  • ARB has a high affinity for the type I angiotensin receptor.
  • Suitable ARBs include valsartan, losartan, irbesartan, olmersartan, telmisartan and candesartan.
  • the compound of the present invention is present in an effective amount.
  • the term "effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.
  • the amount of compound of Formula I-V administered is in the range of 10 mg to 400 mg per day, 20 mg to 300 mg per day, 25 mg to 200 mg per day, 30 mg to 200 mg per day, 40 mg to 200 mg per day or 50 to 200 mg per day.
  • the compound may be administered once per day or twice per day.
  • the molar ratio of compound of Formula I-V to the ARB will be in the range of 1 :2, 5 :8, 3 :4, 7:8, or 1 : 1.
  • the amount of compound of Formula I-V administered is in the range of 10 mg to 400 mg per day, 20 mg to 300 mg per day, 25 mg to 200 mg per day, 30 mg to 200 mg per day, 40 mg to 200 mg per day and 50 to 200 mg per day.
  • the compound may be administered in combination with an ARB such as valsartan once per day or twice per day.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co- usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
  • the invention provides a method of inhibiting the activity of neprilysin or neutral endopeptidase (NEP) in a cell, in vitro or in vivo, comprising contacting the cell with one or more compounds of Formula I-V herein, or a
  • the invention provides a method of treating a disease that is beneficially treated by LCZ696 in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention and, in particular a combination of a compound of this invention with a suitable ARB.
  • the compounds of this invention are useful for treating subjects who have had heart failure.
  • the compound is administered to reduce the risk of death or the need for hospitalization due to cardiovascular causes in said subjects.
  • the compounds of this invention are also useful for treating hypertension, renal insufficiency including edema and salt retention, pulmonary edema and congestive heart failure.
  • any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof one or more second therapeutic agents.
  • the second therapeutic agent may be selected from any angiotensin II receptor antagonist, also known as an angiotensin receptor blocker or ARB.
  • ARB has a high affinity for the type I angiotensin receptor. Examples of suitable ARBs include valsartan, losartan, irbesartan, olmersartan, telmisartan and candesartan.
  • the invention also relates to method of treating a subject who had heart failure by administering a compound of Formula I-V in combination with an angiotensin receptor antagonist.
  • the amount of compound of Formula I-V administered is in the range of 10 mg to 400 mg per day, 20 mg to 300 mg per day, 25 mg to 200 mg per day, 30 mg to 200 mg per day, 40 mg to 200 mg per day or 50 to 200 mg per day.
  • the compound may be administered once per day or twice per day.
  • the compound of Formula I-V and the ARB are administered in a molar ratio that is in the range of 1 :2, 5 :8, 3 :4, 7:8, or 1 : 1.
  • the invention provides the use of a compound of Formula I- V alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment in a subject of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I-V for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCb), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.
  • 7.5 mM stock solutions of test compounds are prepared in DMSO.
  • the 7.5 mM stock solutions are diluted to 12.5-50 ⁇ in acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 .
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ , aliquot of the 12.5-50 ⁇ test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 ⁇ test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl 2 .
  • the reaction mixtures are incubated at 37 °C, and 50 ⁇ , aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow- well 96-well plates which contain 50 ⁇ ⁇ of ice-cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 °C for 20 minutes after which 100 ⁇ ⁇ of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.
  • Supematants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart of the compound of Formula I-V and the positive control, 7-ethoxycoumarin (1 ⁇ ). Testing is done in triplicate. [60] Data analysis: The in vitro ti/ 2 s for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship,

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Abstract

La présente invention concerne des analogues substitués deutérisés de sacubitril et leurs sels pharmaceutiquement acceptables. L'invention porte en outre sur des compositions comprenant un composé de l'invention, et sur l'utilisation de ces compositions dans des méthodes de traitement de maladies et de troubles pris en charge de manière bénéfique par l'administration de sacubitil. L'invention concerne également des compositions comprenant une combinaison d'un analogue de sacubitril deutérisé et d'un antagoniste du récepteur de l'angiotensine. Ces combinaisons sont utiles, par exemple, pour traiter des patients souffrant d'insuffisance cardiaque afin de réduire le risque de décès dû à des causes cardio-vasculaires ou les hospitalisations dues à une insuffisance cardiaque.
PCT/US2015/048626 2014-09-04 2015-09-04 Sacubitril deutérisé Ceased WO2016037098A1 (fr)

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US62/046,061 2014-09-04

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017009784A1 (fr) 2015-07-14 2017-01-19 Cadila Healthcare Limited Formes à l'état solide de sel de trisodium du complexe valsartan/sacubitril et de sacubitril
CN106966926A (zh) * 2017-04-01 2017-07-21 沧州那瑞化学科技有限公司 一种lcz696中间体的制备方法
WO2017152755A1 (fr) * 2016-03-10 2017-09-14 深圳市塔吉瑞生物医药有限公司 Composé biphényle substitué et composition pharmaceutique correspondante
CN109400493A (zh) * 2017-08-15 2019-03-01 成都博腾药业有限公司 沙库比曲及其中间体的制备方法
WO2020210914A1 (fr) * 2019-04-18 2020-10-22 Val-Chum, Limited Partnership Composés marqués et leur utilisation pour l'imagerie et/ou leur utilisation pour le diagnostic d'affections ou de maladies

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Publication number Priority date Publication date Assignee Title
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
WO2003059345A1 (fr) * 2002-01-17 2003-07-24 Novartis Ag Compositions pharmaceutiques a base de valsartan et d'inhibiteurs nep
US20090326066A1 (en) 2006-09-13 2009-12-31 Novartis Ag Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors
US20120016151A1 (en) 2009-01-13 2012-01-19 Zhu Guoliang Process for manufacture and resolution of 2-acylamino-3-diphenylpropanoic acid
WO2012065958A1 (fr) * 2010-11-16 2012-05-24 Novartis Ag Procédé de traitement d'une néphropathie induite par les produits de contraste

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2017152755A1 (fr) * 2016-03-10 2017-09-14 深圳市塔吉瑞生物医药有限公司 Composé biphényle substitué et composition pharmaceutique correspondante
CN106966926A (zh) * 2017-04-01 2017-07-21 沧州那瑞化学科技有限公司 一种lcz696中间体的制备方法
CN106966926B (zh) * 2017-04-01 2018-10-19 沧州那瑞化学科技有限公司 一种lcz696中间体的制备方法
CN109400493A (zh) * 2017-08-15 2019-03-01 成都博腾药业有限公司 沙库比曲及其中间体的制备方法
WO2020210914A1 (fr) * 2019-04-18 2020-10-22 Val-Chum, Limited Partnership Composés marqués et leur utilisation pour l'imagerie et/ou leur utilisation pour le diagnostic d'affections ou de maladies

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