Treprostinil fumaryldiketopiperidine prodrug

Abstract

The present invention provides novel treprostinil-based compounds, therapeutic methods using them, and methods for producing them. [Solution] This application provides novel compounds referred to as FDKP-treprostinyl compounds, which are treprostinyl compounds to which fumaryl 2,5-diketopiperazine is bonded, such as formula (5a) below. JPEG2026102863000037.jpg41154

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 036,561, filed on 9 June 2020, which is incorporated in its entirety by reference.

[0002] Technical field This application relates to prostacyclins in general, and more specifically to treprostinil prodrugs, as well as methods for producing and using such prodrugs. [Overview of the project]

[0003] summary One embodiment is a compound of formula 5a or 5b, or a pharmaceutically acceptable salt thereof, where R5 is H or a polymer carrier: [ka] [ka]

[0004] Another embodiment is a pharmaceutically acceptable batch containing the compound of the aforementioned embodiment having a purity of at least 90%. Another embodiment is a pharmaceutical composition containing the compound of the aforementioned embodiment.

[0005] Another embodiment is a method for producing an FDKP-treprostinyl compound, comprising: i) Treprostinil (1) [ka] The double-protected treprostinyl portion (2) [ka] to produce (where R1 is a carboxylic acid protecting group and where a) R2 is H and R3 is a hydroxyl protecting group or b) R2 is a hydroxyl protecting group and R3 is H); ii) reacting the doubly protected treprostinil moiety with a compound of formula (3)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0006] Another embodiment is a method of treating a treprostinil - treatable condition, comprising administering to a subject in need thereof a compound of the foregoing embodiments.

Mode for Carrying Out the Invention

[0007] Detailed Description As used in this specification and the claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Throughout this specification, unless otherwise indicated, the terms "comprise", "comprises", and "comprising" are used inclusively rather than exclusively. The term "or" is inclusive, unless modified, for example, by "any of". Thus, unless the context or explicit description dictates otherwise, the word "or" means any one member of a particular list and also includes any combination of members of that list. Except for examples or where otherwise indicated, all numbers expressing amounts of ingredients or reaction conditions used in this specification are to be understood as being modified in all instances by the term "about".

[0008] Headings are provided for convenience only and should not be construed as limiting the invention in any way. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. The specialized terms used in this specification are for the purpose of describing particular embodiments only and are not intended to limit the scope of the invention, which is defined only by the claims. To make the present disclosure more readily understood, certain terms are first defined. All additional definitions, including definitions of ranges, all numerical specifications, such as pH, temperature, time, concentration, molecular weight, are approximate and may vary by (+) or (-) 1, 5, or 10%. It should be understood that although not always explicitly stated, the term "about" is applied before all numerical specifications. Also, although not always explicitly stated, it should be understood that the reagents described in this specification are merely exemplary and that equivalents thereof are known in the art and are described throughout the detailed description.

[0009] "HPLC" refers to high performance liquid chromatography.

[0010] "NMR" refers to nuclear magnetic resonance.

[0011] "FDKP" refers to fumaryl 2,5-diketopiperazine or (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine.

[0012] "RRT" refers to relative retention time.

[0013] "TMSE" refers to trimethylsilylethyl ester.

[0014] "TMBDS" refers to tert-butyldimethylsilyl.

[0015] "EDCI" refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

[0016] "DMAP" refers to 4-dimethylaminopyridine.

[0017] "DMA" refers to N,N-dimethylacetamide.

[0018] "DMF" refers to N,N-dimethylformamide.

[0019] "TBAF" refers to tetra-n-butylammonium fluoride.

[0020] "THF" refers to tetrahydrofuran.

[0021] "LCMS" refers to liquid chromatography-mass spectrometry.

[0022] "IR" refers to infrared spectroscopy.

[0023] "TFA" refers to trifluoroacetic acid.

[0024] "DIEA" or "DIPEA" refers to N,N-diisopropylethylamine.

[0025] "DQF-COSY" refers to dual quantum filter correlation spectroscopy.

[0026] "ACN" refers to acetonitrile.

[0027] "HOBt" refers to hydroxybenzotriazole.

[0028] "DEPT-NMR" refers to distortion-free enhancement by polarization-transfer nuclear magnetic resonance.

[0029] The terms "protecting group" or "protective group" as used herein are known in the art and are described in TW Green, PGM Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999 (hereinafter "Greene, Protective Groups in Organic Synthesis"), the teachings relating to protecting groups of which are incorporated herein by reference in their entirety.

[0030] As used herein, “hydroxyl protecting group” or “hydroxyl protective group” refers to the generally understood definition of an alcohol or hydroxyl protecting group, as defined in TW Green, PGM Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999.

[0031] As used herein, the terms "carboxylic acid protecting group", "carboxyl protecting group", "carboxylic acid protective group", and "carboxyl protective group" refer to the generally understood definition of a carboxyl protecting group as defined in T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999.

[0032] As used herein, C 10 ~C n , for example C1~C 12 , C1~C8, or C1~C6, when used in front of a group, refers to a group containing m to n carbon atoms.

[0033] "Optionally substituted" refers to a group selected from that group and a substituted form of that group. The substituent can include any of the groups defined below. In one embodiment, the substituent is C1~C 10 or C1~C6 alkyl, substituted C1~C 10 or C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C6~C 10 aryl, C3~C8 cycloalkyl, C2~C 10 heterocyclyl, C1~C 10 heteroaryl, substituted C2~C6 alkenyl, substituted C2~C6 alkynyl, substituted C6~C 10 aryl, substituted C3~C8 cycloalkyl, substituted C2~C 10 heterocyclyl, substituted C1~C <000001​​​​"Medically acceptable salts" refer to salts of compounds that are suitable for medicinal use and are derived from a variety of organic and inorganic counterions well known in the art. Examples of medicatorially acceptable salts include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium when the compound contains an acidic functional group. When the molecule contains a basic functional group, salts of organic or inorganic acids, such as hydrochlorides, hydrobroms, tartrates, mesylates, acetates, maleates, and oxalates, are included. A teaching concerning medicatorially acceptable salts is incorporated herein by reference: Stahl and Wermuth, eds., “Handbook of Pharmaceutically Acceptable Salts,” (2002), Verlag Helvetica Chimica Acta, Zurich, Switzerland, which discusses various medicinal salts, their selection, preparation, and use.

[0035] "Pulmonary hypertension" refers to all forms of pulmonary hypertension, WHO Groups 1-5. Pulmonary arterial hypertension, also known as PAH, refers to WHO Group 1 pulmonary hypertension. PAH includes idiopathic, hereditary, drug- or toxin-induced, and persistent pulmonary hypertension (PPHN) in the neonatal period.

[0036] Generally, a pharmaceutically acceptable salt is one that substantially retains one or more of the desired pharmacological activities of the parent compound and is suitable for in vivo administration. Pharmacopoeciable salts include acid addition salts formed with inorganic or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, but are not limited to, hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, and phosphoric acid.

[0037] Organic acids suitable for producing pharmaceutically acceptable acid addition salts include, but are not limited to, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkyl sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, etc.), aryl sulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and others.

[0038] Medicinally acceptable salts also include those formed when acidic protons present in the parent compound are substituted with metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions) or ammonium ions (e.g., organic bases such as ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonium ions derived from ammonia).

[0039] Treprostinil, the active ingredient in Remodulin® (Treprostinil) Injection, Tyvaso® (Treprostinil) Inhalation Solution, and Orenitram® (Treprostinil) Extended-Release Tablets, is described in U.S. Patent No. 4,306,075. Methods for producing treprostinil and other prostacyclin derivatives are described, for example, in Moriarty, et al., J. Org. Chem. 2004, 69, 1890-1902, Drug of the Future, 2001, 26(4), 364-374. U.S. Patent Nos. 6,441,245, 6,528,688, 6,700,025, 6,809,223, 6,756,117, 8,461,393, 8,481,782; 8,242,305, 8,497,393, 8,940,930, 9,029,607, 9,156,786, and 9,388,154, 9,346,738; U.S. Patent Application Publication No. 2 Listed in publication numbers 012-0197041, 2013-0331593, 2014-0024856, 2015-0299091, 2015-0376106, 2016-0107973, 2015-0315114, 2016-0152548, and 2016-0175319; also listed in PCT publication numbers WO2016 / 0055819 and WO2016 / 081658.

[0040] The various uses and / or forms of treprostinil include, for example, U.S. Patent Nos. 5,153,222, 5,234,953, 6,521,212, 6,756,033, 6,803,386, 7,199,157, 6,054,486, 7,417,070, 7,384,978, 7,879,909, 8,563,614, 8,252,839, 8,536,363, 8,410,169, 8, No. 232,316, No. 8,609,728, No. 8,350,079, No. 8,349,892, No. 7,999,007, No. 8,658,694, No. 8,653,137, No. 9,029,607, No. 8,765,813 No. 9,050,311, No. 9,199,908, No. 9,278,901, No. 8,747,897, No. 9,358,240, No. 9,339,507, No. 9,255,064, No. 9,278,902, No. 9,278 ,903,9,758,465;9,422,223;9,878,972;9,624,156;US Patent Application Publications 2009-0036465, 2008-0200449, 2008-0280986, 2009-0124697, 2014-0275616, 2014-0275262, 2013-0184295, 2014-0323567, 2016-0030371, 2016- It is disclosed in publication numbers 0051505, 2016-0030355, 2016-0143868, 2015-0328232, 2015-0148414, 2016-0045470, 2016-0129087, 2017-0095432; 2018-0153847, and PCT publication numbers WO00 / 57701, WO20160105538, WO2016038532, and WO2018 / 058124.

[0041] Treprostinyl has the following chemical formula:

[0042] [ka]

[0043] The inventors of this invention have identified compounds of formula (5a) or (5b): [ka] [ka] Alternatively, treprostinyl prodrugs, which are pharmaceutically acceptable salts thereof, have been developed. In formulas (5a) and (5b), R5 is H or a polymer carrier, such as a polyethylene glycol (PEG) carrier, a fatty alcohol carrier, or a fatty amine carrier.

[0044] In some embodiments, polymer carriers such as PEG carriers may have an average molecular weight, such as a number-average molecular weight, ranging from about 200 to about 200,000. In some embodiments, polymer carriers such as PEG carriers may have an average molecular weight, such as a number-average molecular weight, ranging from about 200 to about 80,000. In some embodiments, the polymer carrier may be PEG1500, PEG4000, PEG5000, PEG8000, PEG10,000, PEG15,000, PEG20,000, and PEG25,000. In some embodiments, the polymer carrier may be PEG20,000.

[0045] In some embodiments, the fatty alcohol carrier is C1-C 20Contains alcohol. In some embodiments, the fatty alcohol carrier is saturated or unsaturated. In some embodiments, the fatty alcohol carrier is a saturated fatty alcohol carrier, e.g., 1-hexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol, etc. In some embodiments, the fatty alcohol carrier is an unsaturated fatty alcohol carrier, e.g., 10-undecen-1-ol, (Z)-9-octadecen-1-ol, (E)-9-octadecen-1-ol, (Z,Z)-9,12-octadecadien-1-ol, etc. Other fatty alcohols known in the art can be used, for example, those disclosed in K. Nowek et al., (2012) 'Fatty Alcohols' in Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA (which is incorporated herein in its entirety for teaching of fatty alcohols).

[0046] In some embodiments, R5 is a fatty amine support that generates a carboxyl group and an amide bond. In some embodiments, the fatty amine support is C1-C 20It contains an amine. In some embodiments, the fatty amine carrier is saturated or unsaturated. In some embodiments, the fatty amine carrier is a saturated fatty amine carrier, such as 1-hexaneamine, 1-heptanamine, 1-octanaamine, 1-nonanamine, 1-decaneamine, etc. In some embodiments, the fatty amine carrier is an unsaturated fatty amine carrier, such as 10-undecene-1-amine, (Z)-9-octadecene-1-10-undecene-1-amine, (E)-9-octadecene-1-10-undecene-1-amine, (Z,Z)-9,12-octadecadiene-1-10-undecene-1-amine, etc. Other fatty amines known in the art can be used as fatty amine supports, for example, those disclosed in K. Nowek et al., (2012) 'Fatty Alcohols' in Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA (which is incorporated herein in its entirety for teaching of fatty alcohols).

[0047] When administered to subjects such as humans, the prodrug undergoes in vivo biomodulation, such as chemical or enzymatic cleavage, to enable delivery of an effective amount of treprostinil to the subject.

[0048] Pharmaceutical composition Treprostinil prodrugs may be provided in the form of pharmaceutical compositions that may also include pharmaceutically acceptable carriers, excipients, binders, diluents, etc. Such pharmaceutical compositions can be manufactured by methods known in the art, particularly granulation, mixing, dissolution, encapsulation, lyophilization, emulsification, or wet grinding processes. The compositions may be in the form of granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, and liquids. The compositions can be formulated for many different routes of administration, for example, oral administration, transmucosal administration, rectal administration, transdermal or subcutaneous administration, and for subarachnoid, intravenous, intramuscular, intraperitoneal, intranasal, intraocular, or intracerebroventricular injection. Treprostinil prodrugs may be administered by injection or as a sustained-release formulation, for example, as a local administration rather than systemic administration, via any of the above routes.

[0049] In some embodiments, treprostinil prodrugs can be administered by inhalation. Treprostinil can be formulated for dry powder inhalation (DPI) using any suitable technology or formulation.

[0050] In one embodiment, the pharmaceutical composition may be a mixture of a treprostinil prodrug and a carrier such as sterile water. In some embodiments, the treprostinil prodrug is formulated for subcutaneous administration, and such formulation may or may not contain m-cresol or another preservative.

[0051] For oral, intraoral, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel caps, and caplets may be acceptable solid dosage forms. These can be prepared, for example, by mixing one or more treprostinil prodrugs or pharmaceutically acceptable salts thereof with at least one additive or excipient, such as starch or other excipients. Suitable additives or excipients may include sucrose, lactose, cellulose sugars, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitin, chitosan, pectin, tragacanth gum, acacia gum, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methylcellulose, hydroxypropyl methylcellulose, and / or polyvinylpyrrolidone. Optionally, the oral dosage form may contain other components to aid administration, such as inert diluents or lubricants, such as magnesium stearate; preservatives, such as parabens or sorbic acid; antioxidants, such as ascorbic acid, tocopherol, or cysteine; disintegrants, binders, thickeners, buffers, sweeteners, flavorings, or fragrances. Furthermore, dyes or pigments may be added for identification. The tablets can be further treated with suitable coating materials known in the art.

[0052] The liquid dosage form for oral administration is, Pharmaceutical preparations may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries, and liquids, which may contain inert diluents such as water. Pharmaceutical preparations can be prepared as liquid suspensions or solutions using sterile liquids, including oils, water, alcohols, and combinations thereof, although these are not particularly limited. Pharmaceutically appropriate surfactants, suspending agents, and emulsifiers may be added for oral or parenteral administration.

[0053] As described above, the suspension may contain oil. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. The suspension preparation may also contain fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. The suspension preparation may also contain alcohols, such as, but are not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as, but are not limited to, poly(ethylene glycol), petroleum hydrocarbons, such as mineral oil and petrolatum, and water can also be used in the suspension preparation.

[0054] Injectable dosage forms generally include aqueous or oily suspensions that can be prepared using appropriate dispersants or wetting agents and suspending agents. The injectable form may be in solution phase or in the form of a suspension prepared with a solvent or diluent. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic saline. Alternatively, sterile oils may be used as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile and includes natural or synthetic oils, fatty acids, monoglycerides, diglycerides, or triglycerides.

[0055] For injection, the pharmaceutical formulation may be a powder suitable for reconstitution with appropriate solutions as described above. Examples of these include, but are not limited to, lyophilized, tumble-dried, or spray-dried powders, amorphous powders, granules, precipitates, or particles. For injection, the formulation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability adjusters, and combinations thereof. Compounds can be formulated for parenteral administration by infusion, such as bolus injection or continuous infusion. Unit dosage forms for injection may be in ampoules or multi-dose containers. In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known and usable by those skilled in the art. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0056] Treprostinil prodrugs can be formulated into parenterally administered formulations, which may include sterile aqueous formulations of treprostinil prodrug or pharmaceutically acceptable salts thereof, and the formulations may be isotonic with the blood of the intended recipient. These formulations can be administered by subcutaneous injection, although administration may also be by intravenous, intramuscular, or intradermal injection. Such preparations can be conveniently prepared by mixing the compound with water or glycine or citrate buffer, sterilizing the resulting solution, and making it isotonic with blood. Injectable formulations may contain 0.1–5% w / v of treprostinil based on the weight of the prodrug and can be administered at a rate of 0.1 ml / min / kg. Alternatively, the prodrug may be administered at a rate of 0.625–50 ng / kg / min based on the weight of the treprostinil in the prodrug. Alternatively, the prodrug may be administered at a rate of 10–15 ng / kg / min based on the weight of the treprostinil in the prodrug.

[0057] In some embodiments, the concentration of treprostinil prodrug in formulations for parenteral administration, such as intravenous or subcutaneous injection (including continuous subcutaneous injection), may be 0.0005 to 30 mg / mL, or 0.0007 to 50 mg / mL, or 0.001 to 15 mg / mL, or any value or partial range within these ranges. Exemplary concentrations may include 0.1 mg / mL, 1 mg / mL, 2.5 mg / mL, 5 mg / mL, or 10 mg / mL.

[0058] In some embodiments, formulations of treprostinil prodrugs for parenteral administration, such as intravenous or subcutaneous injection (including continuous subcutaneous injection), can be prepared by mixing the prodrug with a vehicle such as a buffer. In certain embodiments, the vehicle may be a phosphate-containing vehicle, i.e., at least one phosphate, which may be, for example, a dibasic phosphate, such as dibasic sodium phosphate or dibasic potassium phosphate, or a tribasic phosphate, such as tribasic sodium phosphate or tribasic potassium phosphate. In certain embodiments, the vehicle may also contain a chloride salt, which may be a halogen salt, such as sodium chloride or potassium chloride. The tonicity of the vehicle can be adjusted using a halogen salt such as sodium chloride. In certain embodiments, it may be preferable that the phosphate and the halogen salt have the same cation. For example, if the phosphate is sodium phosphate, such as tribasic sodium phosphate or tribasic sodium phosphate, the halogen salt may be a halogen salt such as sodium chloride. Similarly, if the phosphate is potassium phosphate, such as tribasic potassium phosphate or tribasic potassium phosphate, the halogen salt may be a potassium halogen salt such as potassium chloride. The solvent in the vehicle may include water. In certain embodiments, water may be the sole solvent in the vehicle. In even more specific embodiments, the vehicle may contain one or more additional solvents in addition to water. In some embodiments, the additional solvent may be a preservative such as m-cresol.

[0059] Preferably, the vehicle is isotonic with the blood of a patient, such as a human. The term isotonic may mean that the osmotic pressure and ion concentration of the vehicle match those of a patient, such as a human. Non-limiting examples of the vehicle include phosphate-buffered saline, which is an aqueous salt solution containing disodium hydrogen phosphate, sodium chloride, and in some formulations, potassium chloride and potassium dihydrogen phosphate. Other examples may include a vehicle containing 20 mM dibasic sodium phosphate along with 125 mM sodium chloride, and a vehicle containing 15 mM tribasic sodium phosphate, 125 mM sodium chloride, and 0.3% w / w m-cresol.

[0060] Treatment method Treprostinil prodrugs can be used to treat diseases or conditions treatable with treprostinil, i.e., diseases or conditions for which treprostinil is known to be effective. In some embodiments, such conditions may be pulmonary hypertension. In some embodiments, treprostinil prodrugs can be used to treat pulmonary arterial hypertension (PAH). In some embodiments, treprostinil prodrugs can be used to treat one or more of WHO Group 1-5 pulmonary hypertensions. Similarly, the treprostinil prodrugs described herein can be used to treat any disease or condition for which treprostinil is indicated or useful. Treprostinil prodrugs can be administered as a single therapeutic agent or in addition to other active substances containing treprostinil.

[0061] In some embodiments, a method is provided for treating a disease or condition, comprising administering a compound (e.g., a prodrug) or composition disclosed herein to a subject. In some embodiments, the disease or condition is one or more selected from pulmonary hypertension, congestive heart failure, peripheral vascular disease, Raynaud's phenomenon, scleroderma, renal failure, peripheral neuropathy, finger ulcers, intermittent claudication, ischemic limb disease, peripheral ischemic lesions, pulmonary fibrosis, and asthma. In some embodiments, the disease is pulmonary hypertension.

[0062] Administration can be carried out via the above routes, or, for example, orally, intravenously, intra-arterially, intramuscularly, intranasally, rectally, vaginally, or subcutaneously. In some embodiments, the composition is administered by injection. In some embodiments, administration is carried out orally. In some embodiments, administration is carried out subcutaneously.

[0063] The subject to be treated may be a human, dog, cat, bird, non-human primate, cattle, or horse. In a preferred embodiment, the subject is a human.

[0064] In some embodiments, a method is provided for treating a disease or condition, the method comprising administering a prodrug of treprostinil to a subject, wherein the prodrug is converted to a metabolite, which comprises, is essentially, or may comprise treprostinil.

[0065] Treprostinil prodrugs can be administered in effective doses to subjects such as humans.

[0066] The term “effective dose” may mean the amount of treprostinil prodrug that may be required to treat a disease or condition such as pulmonary hypertension. In some embodiments, the effective dose of treprostinil prodrug may be the same as or similar to the effective dose of treprostinil for treating the same disease or condition. In some embodiments, the effective dose of treprostinil prodrug may be different from the effective dose of treprostinil for treating the same disease or condition. A person skilled in the art may determine the “effective dose” of treprostinil prodrug based, for example, the disease or condition in question, the amount of treprostinil known to treat, improve, or prevent the disease or condition, and the rate at which the prodrug is converted to treprostinil in vivo.

[0067] Manufacturing method FDKP-treprostinyl prodrugs can be prepared from a double-protected treprostinyl moiety having two of the three hydroxyl groups of the treprostinyl moiety, which is protected by a hydroxyl protecting group.

[0068] [ka]

[0069] The double-protected treprostinyl moiety can be produced from unprotected treprostinyl, i.e., the compound of formula (1), using, for example, the method disclosed in Greene, Protective Groups in Organic Synthesis (which is incorporated herein by reference in its entirety).

[0070] To produce a cyclopentyl ring FDKP-treprostinyl prodrug, the double-protected treprostinyl moiety may be the compound of formula (2a), and to produce a side-chain FDKP-treprostinyl prodrug, the double-protected treprostinyl moiety may be the compound of formula (2b).

[0071] [ka]

[0072] [ka]

[0073] In some embodiments, in the double-protected treprostinyl moiety, R1 and R2 (or R3) are protecting groups. R1 and R2 (or R3) may be the same or different. In some embodiments, R1 may be a silyl carboxylic acid protecting group or a benzyl carboxylic acid protecting group. Silyl carboxylic acid protecting groups may be, for example, trimethylsilyl, triethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or phenyldimethylsilyl. Benzyl carboxylic acid protecting groups may be unsubstituted benzyl or substituted benzyl groups, i.e., benzyl groups substituted at one or more meta, ortho, or para positions with one or more substituents independently selected from the group consisting of -NO2, -CN, halogens (e.g., -F, -Cl, -Br, or -I), (C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkoxy. In some embodiments, R2 (or R3) may be a silyl hydroxyl protecting group, such as trimethylsilyl, triethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or phenyldimethylsilyl.

[0074] The double-protected treprostinyl moiety can react with an FDKP moiety, such as the compound of formula (3), to produce a double-protected FDKP-treprostinyl compound, which may be a double-protected FDKP-treprostinyl compound of formula (4a) or (4b).

[0075] [ka]

[0076] [ka]

[0077] [ka] In the FDKP section, R5 can be H.

[0078] The coupling reaction between the FDKP moiety and the double-protected treprostinyl moiety may be carried out in the presence of a carbodiimide, which may be a water-soluble carbodiimide such as EDCI. The reaction between the FDKP moiety and the double-protected treprostinyl moiety may be carried out in the presence of a nucleophile, which may be a pyridine compound such as DMAP. In some embodiments, the nucleophile such as DMAP may be used together with an organic base such as DIPEA or triethylamine. The nucleophile such as DMAP may be present alone or together with an organic base in a polar solvent such as DMA or DMF. The reaction between the FDKP moiety and the double-protected treprostinyl moiety may be carried out in the presence of a coupling reagent selected from Table 1 below.

[0079] In a compound of formula (5a) or (5b), where R5 is a polymer carrier, a fatty alcohol carrier, or a fatty amine carrier, the compound may be produced from a coupling reaction of a compound of formula (5a) or (5b), where R5 is H and a polymer, fatty acid, or fatty amine. In some embodiments, the coupling is a dicyclohexylcarbodiimide (DCC) coupling or a coupling carried out using reagents selected from Table 1 below. [Table 1]

[0080] The double-protected FDKP-treprostinyl moiety can be deprotected to produce an unprotected FDKP-treprostinyl compound of formula (5a) or (5b).

[0081] [ka]

[0082] [ka]

[0083] In some embodiments, deprotection of the double-protected FDKP-treprostinyl compound of formula 4a(4b) can be carried out in a single step by cleaving the protecting groups at R1 and R2(R3) in one step and substituting them with hydrogen. For example, if the protecting groups at R1 and R2(R3) are of the same type, deprotection of the double-protected FDKP-treprostinyl compound of formula 4a(4b) can be carried out in a single step. For example, if both the protecting groups at R1 and R2(R3) are silyl protecting groups, and they may be the same or different, deprotection of the double-protected FDKP-treprostinyl compound of formula 4a(4b) can be carried out in a single step using an acid or a silyl ester or ether cleaving agent that is a fluoride such as tetra-n-butylammonium fluoride.

[0084] Furthermore, in some embodiments, the deprotection of the double-protected FDKP-treprostinyl compound of formula 4a(4b) can be carried out in two steps: one is the cleavage of the carboxyl protecting group at R1, and the other is the cleavage of the hydroxyl protecting group at R2(R3). In some embodiments, the cleavage may be carried out first with respect to R1 and then with respect to R2(R3). In some other embodiments, the cleavage may be carried out first with respect to R2(R3) and then with respect to R1. For example, if R1 is a benzyl carboxylic acid protecting group and R2 (or R3) is a silyl hydroxyl protecting group, such as trimethylsilyl, triethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl, phenyldimethylsilyl, the benzyl carboxylic acid protecting group can be cleaved at R1 to produce a single-protected FDKP-treprostinyl compound of formula (6a) or (6b):

[0085] [ka] [ka]

[0086] The cleavage of the benzylcarboxylic acid protecting group at R1 can be carried out using chemoselective benzyl cleavage agents, such as trimethyltin hydroxide, barium hydroxide, barium carbonate, cesium hydroxide, cesium carbonate, other alkali metal hydroxides and carbonates, tributyltin hydroxide, tetramethylammonium hydroxide, or tetrabutylammonium hydroxide.

[0087] Next, the unprotected FDKP-treprostinyl compound of formula (5a) or (5b) can be produced from the single protected FDKP-treprostinyl compound of formula (6a) or (6b). In some embodiments, the unprotected FDKP-treprostinyl compound of formula (5a) or (5b) can be produced from the single protected FDKP-treprostinyl compound of formula (6a) or (6b) by cleaving the silyl ether hydroxyl protecting group at R2 or R3 using an acid or a silyl ether cleaving agent which may be a fluoride such as tetra-n-butylammonium fluoride. In some other embodiments, the unprotected FDKP-treprostinyl compound of formula (5a) or (5b) may be produced from the single-protected FDKP-treprostinyl compound of formula (6a) or (6b) by simply storing the single-protected FDKP-treprostinyl compound of formula (6a) or (6b) for a long period of time, for example, at least 10 hours, or at least 12 hours, or at least 14 hours, or at least 16 hours, or at least 18 hours, to enable the cleavage of the silyl hydroxyl protecting group at R2 or R3 using an acid or a silyl ether cleaving agent which may be a fluoride such as tetra-n-butylammonium fluoride. For example, in some embodiments, storing a single-protected FDKP-treprostinyl compound of formula (6a) or (6b) in trifluoroacetic acid (TFA) at low concentrations, for example, from about 0.005% to about 0.2%, or from about 0.01% to about 0.1%, for an extended period, e.g., at least 10 hours, or at least 12 hours, or at least 14 hours, or at least 16 hours, or at least 18 hours, allows for the cleavage of the silyl ether hydroxyl protecting group at R2 or R3.

[0088] The FDKP-treprostinyl compound of formula (5a) or (5b) can be produced in batches with a purity of at least 90%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 98.5%. In some embodiments, the batch group has a purity of at least 90%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 98.5%.

[0089] In some embodiments, a batch of the compound of formula (5a) may not substantially contain the compound of formula (5b). In some embodiments, a batch of the compound of formula (5b) may not substantially contain the compound of formula (5a). For example, in some embodiments, a batch of the compound of formula (5a) may contain less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, less than 0.3%, or less than 0.1% of the compound of formula (5b). Similarly, in some embodiments, a batch of the compound of formula (5b) may contain less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, less than 0.3%, or less than 0.1% of the compound of formula (5a).

[0090] The amount of the compound of formula (5a) or (5b) in a batch may be, for example, at least 0.1 g, at least 0.3 g, at least 0.5 g, at least 0.8 g, at least 1 g, at least 1.2 g, at least 1.5 g, at least 2 g, at least 3 g, at least 4 g, or at least 5 g.

[0091] The embodiments described herein are not limited to those described below, but are further illustrated by the following examples. [Examples]

[0092] Treprostinyl prodrugs containing (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) were synthesized. Specifically, FDKP-treprostinylcyclopentyl ring esters and FDKP-treprostinyl side chain esters were synthesized as shown in Scheme 1 and Scheme 2, respectively.

[0093] Scheme 1: Synthesis of FDKP-treprostinylcyclopentyl ring ester (6) [ka]

[0094] Scheme 2: Synthesis of FDKP-treprostinyl side chain ester (9) [ka]

[0095] FDKP-treprostinyl ester: The diprotected treprostinyl moiety, the side-chain TBDMS treprostinyl TMSE ester (1, R=TMSE), was coupled with (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) (3) in the presence of EDCI.HCl and DMAP in DMA or DMF to obtain mono-TBDMS FDKP treprostinyl TMSE cyclopentyl ring ester (4, R=TMSE) in moderate yield after chromatographic separation using a reverse-phase pre-packed column with water and acetonitrile. Desilylation of the TMSE and TBDMS groups from 4 using TBAF in THF yielded a small amount of the desired product, FDKP treprostinyl cyclopentyl ring ester (6), along with the FDKP cleavage product, i.e., treprostinyl. To overcome FDKP cleavage during desilylation, the protecting group TMSE was replaced with a benzyl group under acid protection. The benzyl-protected acid, side-chain TBDMS treprostinyl benzyl ester (2, R=benzyl), was used in the coupling reaction. Side-chain TBDMS treprostinyl benzyl ester (2) was coupled with FDKP, and after reverse-phase column chromatography, TBDMS FDKP treprostinyl benzylcyclopentyl ring ester (5, R=benzyl) was produced in moderate yield, and LC-MS and... 1 Confirmation was made by 1H NMR. Chemoselective debenzylation of the crude product (5, R=benzyl) with trimethyltin hydroxide in 1,2-dichloroethane yielded the corresponding acid (5, R=H). Traces of FDKP cleavage products were present. Purification of the crude acid by reverse-phase column using 0.05% trifluoroacetic acid (TFA) in water and acetonitrile yielded the desired FDKP-treprostinylcyclopentyl ring ester (6). Due to the weakly acidic nature of the 0.05% TFA solution, desilylation of TBDMS occurred while the combined fraction was stored overnight in a refrigerator. This avoided the extra chemical step required to cleave the TBDMS group to obtain the final compound 6. Lyophilization of the combined fraction yielded the pure FDKP-treprostinylcyclopentyl ring ester (6) as an off-white solid, and IR, 1The compounds were characterized by 1H NMR and LC-MS. Under similar reaction conditions, cyclopentyl TBDMS treprostinyl benzyl ester (7) was also coupled with FDKP (2) to obtain TBDMS FDKP-treprostinyl benzyl side-chain ring ester (3). Chemoselective debenzylation of the crude product (8) with trimethyltin hydroxide followed by desilylation in reverse-phase column chromatography yielded FDKP-treprostinyl side-chain ester (9) in moderate yield, and IR... 1 The samples were characterized by 1H NMR and LC-MS.

[0096] Synthesis method:

[0097] We attempted to couple diprotected treprostinil (1 or 2) with (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) (3) using various coupling reagents.

[0098] EDCI, HCl, DMAP, DIEA in N,N-dimethylacetamide (DMA)

[0099] EDCI,HCl, and DMAP in DMA or N,N-dimethylformamide (DMF)

[0100] O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurulinum tetrafluoroborate (TBTU) and DBU in DMA

[0101] 2-chloro-1-methylpyridinium iodide (CMPI) and triethylamine in DMA

[0102] EDCI, HCl, DMAP, HOBt, DIPEA in DMA

[0103] Solid-supported EDCI and solid-supported DMAP in DMF.

[0104] The coupling reaction of diprotected treprostinyl (1 or 2) with FDKP (3) using EDCI·HCl in DMF or DMA, or DMAP, yielded the desired coupling product (4 or 5), while other reagents did not work (Schemes 1 and 2). Compound (4) was purified by reversed-phase column chromatography using acetonitrile and water as the mobile phase. Attempting to cleave TBDMS and TMSE from compound (4) using tetrabutylammonium fluoride (TBAF) yielded a small amount of the target compound (6) along with treprostinyl (due to cleavage of the ester bond), and similar results were observed when compound (5) was used. Subsequently, TBAF was replaced with trimethyltin hydroxide to perform chemoselective cleavage of the benzyl ester from compound (3b) to obtain the corresponding acid. When trimethyltin hydroxide was used, hydrolysis of the ester bond between FDKP and the treprostinyl moiety was minimal. The crude acid after benzyl ester hydrolysis was purified by reverse-phase column chromatography using 0.05% ACN in water / 0.05% TFA in ACN to obtain TBDMS FDKP-treprostinyl-cyclopentyl ring ester, a precursor of compound (6). The desired product was detected by LC-MS. During storage of the purified product, cleavage of the TBDMS group occurred, generating the final product (6). Lyophilization of the combined pure fraction yielded FDKP-treprostinyl-cyclopentyl ring ester (6) as an off-white solid. Pure compound (6) was IR, 1 The samples were characterized by 1H NMR, DQF-COSY, and LC-MS.

[0105] Following the successful synthesis of FDKP-treprostinyl-cyclopentyl ring ester (6), FDKP-treprostinyl-side chain ester (9) was synthesized using diprotected treprostinyl (7) and FDKP (3) under similar reaction conditions, as shown in Scheme 2. Pure FDKP-treprostinyl-side chain ester (9) was IR, 1 The samples were characterized by 1H NMR, DQF-COSY, and LC-MS.

[0106] experiment:

[0107] Synthesis of TBDMS FDKP-treprostinyl TMSE cyclopentyl ring ester (4, R=TMSE):

[0108] To a solution of TBDMS-treprostinyl TMSE ester (1, R=TMSE) (0.50 g) in N,N-dimethylacetamide (DMA) (14 mL), (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) (3) (0.44 g), EDCI.HCl (0.24 g), and DMAP (0.30 g) were added at room temperature under argon. The suspension reaction mixture was stirred and heated to 100°C. The reaction mixture became clear and light brown, and was heated at 100°C overnight. Heating of the reaction mixture was stopped, and then evaporated under vacuum to remove DMA and other organic volatiles. The crude product was pulverized with toluene (75 mL) and the toluene-soluble product was decanted (this was repeated two more times). The toluene-insoluble product was dried under vacuum to obtain a light brown solid (0.61 g). The crude product was subjected to chromatography using a reverse pre-packed column with a mixture of water and acetonitrile to obtain TBDMS treprostinyl TMSE cyclopentyl FDKP ester (4, R=TMSE) (0.015 g), which was confirmed by LC-MS.

[0109] Synthesis of FDKP-treprostinylcyclopentyl ring ester (6):

[0110] A solution of FDKP-treprostinyl TMSE cyclopentyl ring ester (4, R=TMSE) (0.013 g) in dimethyl sulfoxide (0.75 mL) was mixed with a solution of tetrabutylammonium fluoride (TBAF) (1.0 M in THF (0.12 mL)) at room temperature under argon. The reaction mixture was stirred overnight at room temperature. After 22 hours, the reaction mixture was checked by LC-MS and showed the desired molecular weight of FDKP-treprostinyl cyclopentyl ring ester (6) along with the FDKP cleavage product, i.e., treprostinyl.

[0111] Synthesis of TBDMS FDKP-treprostinylbenzylcyclopentyl ring ester (5, R=benzyl):

[0112] To a solution of mono-TBDMS-treprostinylbenzyl ester (6, R=benzyl) (3.17 g) in N,N-dimethylformamide (DMF) (90 mL), (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) (3) (2.89 g), EDCI.HCl (1.54 g), and DMAP (1.54 g) were added at room temperature under argon. The suspension reaction mixture was stirred and heated to 100°C. The reaction mixture turned brown and turbid, and was heated at 100°C overnight. After 16 hours, the reaction mixture was checked for the desired product by LC-MS. Under similar reaction conditions, two further batches of coupling reactions were carried out with 0.61 g of TBDMS-treprostinylbenzyl ester (2, R=benzyl) and 0.55 g of (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP)(3), and checked by LC-MS. These three batches were combined based on the LC-MS data. The reaction mixture was evaporated under vacuum to remove DMF and other organic volatile substances to obtain a dark brown viscous liquid (18.37 g). The crude product was pulverized with dichloromethane (3 × 100 mL) and filtered. The dichloromethane-insoluble product (brown solid) was discarded, and the dichloromethane-soluble product was concentrated under vacuum to obtain a brown viscous semi-solid product (14.59 g). The crude product was pulverized with toluene (3 × 100 mL) and filtered. The toluene-soluble product (7.02 g after toluene evaporation) was discarded. The toluene-insoluble product was dried under vacuum to obtain a brown semi-solid (5.02 g). The crude product (5.0 g) was subjected to chromatography using a silica gel (188 g) column (230-400 mesh) with methanol (0-100%) in dichloromethane to obtain TBDMS FDKP-treprostinylbenzylcyclopentyl ring ester (5, R=benzyl) (2.26 g), which was confirmed by LC-MS. The purified product contained a small amount of DMAP, which could be removed in the next step.1.0 g of this purified product was further purified by chromatography on a reverse-phase pre-packed column using a mixture of water and acetonitrile containing 0.05% trifluoroacetic acid to obtain pure TBDMS FDKP-treprostinylbenzylcyclopentyl ring ester (5, R=benzyl) (0.085 g), which was confirmed by LC-MS.

[0113] Synthesis of FDKP treprostinyl cyclopentyl ring ester (14):

[0114] To a solution of crude mono-TBDMS FDKP treprostinyl benzylcyclopentyl ring ester (13, R=benzyl) (1.04 g) in 1,2-dichloroethane (25 mL), trimethyltin hydroxide (1.46 g) was added at room temperature under argon. The reaction mixture was heated overnight at 60 °C. After 19 hours, the reaction was checked by LC-MS and found to be complete. The reaction mixture was evaporated under vacuum to obtain a bright orange solid (2.91 g). The crude product (1.45 g) was further purified by chromatography on a reverse-phase pre-packed column using a mixture of water and acetonitrile containing 0.05% trifluoroacetic acid to obtain a pure fraction. After checking the LC-MS of the selected fractions, these fractions were combined. The combined fraction was stored in a refrigerator overnight. After 18 hours, the TBDMS group was completely cleaved and confirmed by LC-MS. The remaining crude product (1.45 g) was similarly purified. Next, both purified products were combined and freeze-dried to obtain the off-white FDKP-treprostinylcyclopentyl ring ester (6) as a white solid (0.212 g), and IR was performed. 1 The samples were characterized by 1H NMR and LC-MS.

[0115] Synthesis of mono-TBDMS FDKP-treprostinylbenzyl side chain ester (8):

[0116] To a solution of TBDMS-treprostinyl benzyl ester (7) (5.57 g) in N,N-dimethylformamide (DMF) (150 mL), (E)-3,6-bis[4-(N-carbonyl)-2-propenyl)amidobutyl]-2,5-diketopiperazine (FDKP) (3) (5.08 g), EDCI.HCl (2.69 g), and DMAP (3.43 g) were added at room temperature under argon. The suspension reaction mixture was stirred and heated to 100°C. The reaction mixture turned brown and turbid, and was heated at 100°C overnight. After 16 hours, the reaction mixture was checked for the desired product by LC-MS. The reaction mixture was evaporated under vacuum to remove DMF and other organic volatile substances, yielding a brown viscous liquid (22.86 g). The crude product was pulverized with dichloromethane (3 × 100 mL) and filtered. The dichloromethane-insoluble product (brown solid) was discarded, and the dichloromethane-soluble product was concentrated under vacuum to obtain a brown viscous liquid product (17.33 g). The crude product was ground with toluene (200 mL) and filtered. The toluene-soluble product (semi-solid product after toluene evaporation, 9.30 g) was discarded. The toluene-insoluble product was dried under vacuum to obtain a brown foamy solid (7.73 g). LC-MS of this crude product showed the desired TBDMS FDKP treprostinyl benzyl side chain ester (8) (7.73 g) as the main product. The crude product was used in the next step without further purification.

[0117] Synthesis of FDKP-treprostinyl side chain ester (9):

[0118] To a solution of crude mono-TBDMS FDKP treprostinyl benzyl side chain ester (8) (2.45 g) in 1,2-dichloroethane (100 mL), trimethyltin hydroxide (3.44 g) was added at room temperature under argon. The reaction mixture was heated overnight at 60 °C. After 17 hours, the reaction mixture was checked by LC-MS and found to be complete. The reaction mixture was cooled to room temperature. The dichloroethane layer was decanted from a brownish viscous liquid (rubbery). The dichloroethane layer was evaporated under vacuum to obtain a light brownish viscous liquid (4.48 g). LC-MS of this product showed that there was almost no product. The rubbery brown product was dried under high vacuum to obtain a foamy brown solid (1.02 g), which contained a large amount of the desired product. The crude product (1.0 g) was purified by chromatography on a reverse-phase pre-packed column using a mixture of water and acetonitrile containing 0.05% trifluoroacetic acid to obtain a pure fraction. After checking the LC-MS of the selected fractions, these fractions were combined. The combined fractions were stored in a refrigerator overnight. After 16 hours, the TBDMS group was completely cleaved and confirmed by LC-MS. The purified products were combined and freeze-dried to obtain off-white FDKP-treprostinyl side-chain ester (9) as an off-white solid (0.195 g), and IR was performed. 1 Characterization was performed by 1H NMR and LC-MS, and the purity was found to be 98.85% by HPLC.

[0119] While the above refers to certain preferred embodiments, it will be understood that the present invention is not limited thereto. Those skilled in the art will notice that various modifications can be made to the disclosed embodiments, and that such modifications are intended to fall within the scope of the present invention.

[0120] All publications, patent applications, and patents cited herein are incorporated herein by reference in their entirety.

Claims

1. Compounds of the following formula 5a or 5b: 【Chemistry 1】 【Chemistry 2】 or a pharmaceutically acceptable salt thereof (In the formula R ５ (is H).

2. The compound according to claim 1, wherein the compound is the compound of formula 5a.

3. The compound according to claim 1, wherein the compound is the compound of formula 5b.

4. R ５ The compound according to claim 1, wherein is H.

5. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable excipient.

6. A method for producing an FDKP-treprostinyl compound, i) Treprostinil (1) 【Transformation 3】 The double-protected treprostinyl portion (2) 【Chemistry 4】 To generate (in the formula, R １ is a carboxylic acid protecting group, and a) R ２ H is R ３ is a hydroxyl protecting group, or b) R ２ R is a hydroxyl protecting group, ３ (is H); ii) The double-protected treprostinyl moiety is a compound of the following formula (3) 【Transformation 5】 (wherein, R ４ is H, and R ５ is H) is reacted to obtain a double-protected FDKP-treprostinil compound having the following formula (4a) or (4b) 【Transformation 6】 【Transformation 7】 To generate; and iii) Deprotecting the double-protected FDKP-treprostinyl compound to obtain an FDKP-treprostinyl compound having the following formula (5a) or (5b) 【Transformation 8】 【Chemistry 9】 To generate, Methods that include...

7. R １ The method according to claim 6, wherein is a silylcarboxylic acid protecting group or a substituted or unsubstituted benzylcarboxylic acid protecting group.

8. R １ The method according to claim 7, wherein the protecting group is a silylcarboxylic acid selected from trimethylsilyl, triethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and phenyldimethylsilyl.

9. R １ The method according to claim 7, wherein is a substituted or unsubstituted benzylcarboxylic acid protecting group.

10. R ２ H is R ３ The method according to claim 6, wherein is a hydroxyl protecting group, the double-protected FDKP-treprostinyl compound has formula (4b), and the FDKP-treprostinyl compound has formula (5b).

11. R ３ H is R ２ The method according to claim 6, wherein is a hydroxyl protecting group, the double-protected FDKP-treprostinyl compound has formula (4a), and the FDKP-treprostinyl compound has formula (5a).

12. The method according to claim 6, wherein the reaction of the double-protected treprostinyl moiety with the compound of formula (3) is carried out in the presence of a carbodiimide and a nucleophile in a polar solvent.

13. The method according to claim 12, wherein the reaction is carried out in the presence of an organic base.

14. The deprotection deprotects the double-protected FDKP-treprostinyl compound to a single-protected FDKP-treprostinyl compound of the following formula (6a) or (6b): 【Chemistry 10】 【Chemistry 11】 The method according to claim 9, which includes generating a

15. The method according to claim 14, wherein the deprotection of a double-protected FDKP-treprostinyl compound to produce a single-protected FDKP-treprostinyl compound is carried out in the presence of a chemoselective benzyl cleavage agent.

16. The method according to claim 6, wherein the purity of the FDKP-treprostinyl compound is at least 90%.

17. A pharmaceutical composition for treating a treprostinil-treated condition, comprising the compound described in claim 1.

18. The pharmaceutical composition according to claim 17, wherein the aforementioned condition is pulmonary hypertension.

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