Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/14—All rings being cycloaliphatic
  • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

Definitions

• Pulmonary hypertension is characterized by an abnormally high blood pressure in the lung vasculature. It is a progressive, lethal disease that leads to heart failure and can occur in the pulmonary artery, pulmonary vein, or pulmonary capillaries. Symptomatically patients experience shortness of breath, dizziness, fainting, and other symptoms, all of which are made worse by exertion. There are multiple causes, and can be of unknown origin, idiopathic, and can lead to hypertension in other systems, for example, portopulmonary hypertension in which patients have both portal and pulmonary hypertension.
• Pulmonary hypertension has been classified into five groups by the World Health Organization (WHO).
• Group I is called pulmonary arterial hypertension (PAH), and includes PAH that has no known cause (idiopathic), inherited PAH (i.e., familial PAH or FPAH), PAH that is caused by drugs or toxins, and PAH caused by conditions such as connective tissue diseases, HIV infection, liver disease, and congenital heart disease.
• Group II pulmonary hypertension is characterized as pulmonary hypertension associated with left heart disease.
• Group III pulmonary hypertension is characterized as PH associated with lung diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases, as well as PH associated with sleep-related breathing disorders (e.g., sleep apnea).
• Group IV PH is PH due to chronic thrombotic and/or embolic disease, e.g., PH caused by blood clots in the lungs or blood clotting disorders.
• Group V includes PH caused by other disorders or conditions, e.g., blood disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis), metabolic disorders (e.g., thyroid disease, glycogen storage disease).
• blood disorders e.g., polycythemia vera, essential thrombocythemia
• systemic disorders e.g., sarcoidosis, vasculitis
• metabolic disorders e.g., thyroid disease, glycogen storage disease.
• Pulmonary arterial hypertension afflicts approximately 200,000 people globally with approximately 30,000-40,000 of those patients in the United States. PAH patients experience constriction of pulmonary arteries which leads to high pulmonary arterial pressures, making it difficult for the heart to pump blood to the lungs. Patients suffer from shortness of breath and fatigue which often severely limits the ability to perform physical activity.
• the New York Heart Association has categorized PAH patients into four functional classes, used to rate the severity of the disease.
• Class I PAH patients as categorized by the NYHA, do not have a limitation of physical activity, as ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. Treatment is not needed for class I PAH patients.
• Class II PAH patients as categorized by the NYHA have a slight limitation on physical activity. These patients are comfortable at rest, but ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope.
• Class III PAH patients as categorized by the NYHA have a marked limitation of physical activity.
• class III PAH patients Although comfortable at rest, class III PAH patients experience undue dyspnoea or fatigue, chest pain or near syncope as a result of less than ordinary physical activity.
• Class IV PAH patients as categorized by the NYHA are unable to carry out any physical activity without symptoms.
• Class IV PAH patients might experience dyspnoea and/or fatigue at rest, and discomfort is increased by any physical activity. Signs of right heart failure are often manifested by class TV PAH patients.
• ERA endothelin receptor antagonist
• PDE-5 inhibitors indicated for the treatment of PAH include sildenafil (Revatio®), tadalafil (Adcirca®).
• Prostanoids indicated for the treatment of PAH include iloprost, epoprosentol and treprostinil (Remodulin®, Tyvaso®).
• the one approved guanylate cyclase stimulator is riociguat (Adempas®). Additionally, patients are often treated with combinations of the aforementioned compounds.
• Portopulmonary hypertension is defined by the coexistence of portal and pulmonary hypertension, and is a serious complication of liver disease.
• the diagnosis of portopulmonary hypertension is based on hemodynamic criteria: (1) portal hypertension and/or liver disease (clinical diagnosis-ascites/varices/splenomegaly), (2) mean pulmonary artery pressure > 25 mmHg at rest, (3) pulmonary vascular resistance > 240 dynes s/cm 5 , (4) pulmonary artery occlusion pressure ⁇ 15mmHg or transpulmonary gradient > 12 mmHg.
• PPH is a serious complication of liver disease, and is present in 0.25 to 4% of patients suffering from cirrhosis. Today, PPH is comorbid in 4-6% of those referred for a liver transplant.
• treprostinil prodrugs and treprostinil derivative prodrugs are provided herein, e.g., compounds of the Formulae (I), (II) or (III).
• the treprostinil or treprostinil derivative prodrug in one embodiment, comprises an ester or amide linkage to the prodrug moiety.
• One aspect of the invention relates to the synthesis of a carboxylic acid derivative of treprostinil.
• R2-OH is a linear or branched C5-C18 alkyl, a linear C2-C18 alkenyl or a branched C3-C18
• the acid catalyst in one embodiment is a resin or in some other solid form.
• the acid catalyst in one embodiment is sulfuric acid or sulfonic acid.
• Other acid catalysts in solid, e.g., a resin, or liquid form) include but are not limitied to hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrene solfonate, hyeteropoly acid, zeolites, metal oxides, and graphene oxygene diments, the treprostinil or treprostinil compound of the formula
• the Mitsunobu reaction can be used, where a mixture of triphenylphosphine (PPI1 3 ) and diisoporpyl azodicarboxylate (DIAD or its diethyl analogue, DEAD) convert an alcohol and carboxylic acid to the ester to form one of the carboxylic acid ester prodrugs provided herein.
• PPI1 3 triphenylphosphine
• DEAD diisoporpyl azodicarboxylate
• N, N'-dicyclohexylcarbodiimide (DCC) or N, N'- diisopropylcarbodiimide (DIC) is used in combination with 4-dimethylaminopyridine (DMAP) in an esterification reaction (sometimes referred to as Steglich esterification).
• Treprostinil amide derivatives (e.g., of the formula: ) can be manufactured according to well known protocols of amide functionalization of a carboxylic
• treprostinil or a compound of the formula
• NH 2 R2, R3, R4 and n are defined herein.
• Ri is NH, O or S
• R2 is H, a linear C5-C1 8 alkyl, branched C5-C1 8 alkyl, linear C2-C1 8 alkenyl, branched C3-C1 8 alkenyl, aryl; aryl-Ci-Cis alkyl; an amino acid or a peptide
• R3 is H, OH, O-alkyl or O-alkenyl
• R4 is an optionally substituted linear or branched C1-C15 alkyl, or an optionally substituted linear or branched C2-C15 alkenyl
• n is an integer from 0 to 5, with the proviso that the prostacyclin compound is not treprostinil.
• a method provided herein is used to manufacture a prostacyclin compound of Formula (II), or a pharmaceutically acceptable salt:
• Ri is NH, O or S
• R2 is a linear or branched C5-C18 alkyl, a linear C2-C18 alkenyl or a branched C3-C1 8 alkenyl, aryl, aryl-Ci-Cis alkyl, an amino acid or a peptide
• n is an integer from 0 to 5.
• a compound of Formula (I) and/or (II) is manufactured by a method described herein, wherein one or more hydrogen atoms is substituted with a deuterium.
• the present invention relates to an isotopologue of Formula (I) and/or (II), substituted with one or more deuterium atoms.
• the isotopologue of Formula (I) and/or (II) may be used to accurately determine the concentration of compounds of Formula (I) and/or (II) in biological fluids and to determine metabolic patterns of compounds of Formula (I) and/or (II) and its isotopologues.
• Yet another embodiment of the invention relates to a method for manufacturing the prostacyclin compound of Formula (III), or a pharmaceutically acceptable salt,: Formula (III), wherein Ri and R2 are defined above, and
• Figure 1 is an esterification scheme for an alkyl ester-TR prodrug compound provided herein.
• Figure 2 is a general scheme for synthesis of acylated treprostinil derivative prodrugs.
• alkyl refers to both a straight chain alkyl, wherein alkyl chain length is indicated by a range of numbers, and a branched alkyl, wherein a branching point in the chain exists, and the total number of carbons in the chain is indicated by a range of numbers.
• alkyl refers to an alkyl chain as defined above containing 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 carbons (i.e., Ce-Cie alkyl).
• alkenyl refers to a carbon chain containing one or more carbon-carbon double bonds.
• aryl refers to a cyclic hydrocarbon, where the ring is characterized by delocalized ⁇ electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated by a range of numbers.
• aryl refers to a cyclic hydrocarbon as described above containing 6, 7, 8, 9, or 10 ring atoms (i.e., Ce-Cw aryl). Examples of an aryl group include, but are not limited to, benzene, naphthalene, tetralin, indene, and indane.
• alkoxy refers to -O-(alkyl), wherein “alkyl” is as defined above.
• substituted in connection with a moiety as used herein refers to a further substituent which is attached to the moiety at any acceptable location on the moiety. Unless otherwise indicated, moieties can bond through a carbon, nitrogen, oxygen, sulfur, or any other acceptable atom.
• amino acid refers to both natural (genetically encoded) and non-natural (non-genetically encoded) amino acids, and moieties thereof. Of the twenty natural amino acids
• the 20 th amino acid, proline is also within the scope of the present invention, and has the Of the twenty natural amino acids, all but glycine is chiral, and both the D- and L- amino acid isomers, as well as mixtures thereof, are amenable for use with the prostacyclin compounds described herein. It is also noted that an amino acid moiety is encompassed by the term "amino acid.” For example, the amino acid moieties -CO- are encompassed by the term
• non-natural amino acids amenable for use with the present invention include ⁇ -alanine ( ⁇ -Ala); 2,3-diaminopropionic acid (Dpr); nipecotic acid (Nip); pipecolic acid (Pip); ornithine (Om); citrulline (Cit); t-butylalanine (t-BuA); 2-tbutylglycine (t-BuG); N-methylisoleucine (Melle); phenylglycine (PhG); cyclohexylalanine (ChA); norleucine (Nle); naphthylalanine (Nal); 4-chlorophenylalanine (Phe(4-Cl)); 2-fluorophenylalanine (Phe(2-F)); 3-fluorophen ylalanine (Phe(3-F)); 4-fluorophenylalanine (Phe( 4-F)); penicillamine (Pen); l,2,3,
• Non-genetically encoded amino acid residues include 3-aminopropionic acid; 4-aminobutyric acid; isonipecotic acid (Inp); aza-pipecolic acid (azPip); aza-proline (azPro); a-aminoisobutyric acid (Aib); ⁇ - aminohexanoic acid (Aha); ⁇ -aminovaleric acid (Ava); N-methylglycine (MeGly).
• a "peptide” is a polymer of amino acids (or moieties thereof) linked by a peptide bond.
• Peptides for use with the present invention comprise from about two to about fifteen amino acids, for example, two, three, four, five, six, seven, eight, nine or ten amino acids (or moieties thereof).
• salt or “salts” as used herein encompasses pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases.
• the nature of the salt is not critical, provided that it is pharmaceutically acceptable.
• Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
• Exemplary pharmaceutical salts are disclosed in Stahl, P.H., Wermuth, C.G., Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica Acta/Wiley-VCH: Zurich, 2002, the contents of which are hereby incorporated by reference in their entirety.
• inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
• Appropriate organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, -hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanes
• Suitable pharmaceutically acceptable salts of free acid-containing compounds disclosed herein include, without limitation, metallic salts and organic salts.
• Exemplary metallic salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other physiological acceptable metals.
• Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
• Exemplary organic salts can be made from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, for example, tromethamine, diethylamine, tetra-N-methylammonium, N,N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
• Methods are provided herein for the synthesis of treprostinil prodrugs, as well as treprostinil derivative prodrugs, for example prodrugs of Formulae (I), (II) and (III).
• the prodrugs find utility in the treatment of pulmonary hypertension, for example, pulmonary arterial hypertension and portopulmonary hypertension, as well as other indicaitons, as described in U.S. Patent Application Publication No. 2015/0148414, published May 28, 2015, the disclosure of which is incorporated by reference in its entirety for all purposes.
• the treprostinil derivative prodrug or treprostinil prodrug, or a composition comprising the same is effective when employed in a once-daily, twice-daily or three-times daily dosing regimen, for example, for the treatment of pulmonary arterial hypertension or portopulmonary hypertension in a patient in need thereof.
• the prostacyclin compound provided herein in one embodiment, can be administered less frequently than treprostinil, with equal or greater efficacy. Moreover, in one embodiment, the side effect profile of the compounds provided herein is less deleterious than the side effect profile resulting from treprostinil administration.
• One aspect of the invention relates to the synthesis of a carboxylic acid derivative of treprostinil.
• the R2 is a linear or branched C5-C1 8 alkyl, a linear C2-C1 8 alkenyl or a branched C3-C1 8
• R4 is an optionally substituted linear or branched C1-C 5 alkyl, or an optionally substituted linear or branched C2-C15 alkenyl; and n is an integer from 0 to 5.
• the purity of the final product will depend in part on the purity of the reagents employed in the esterification reaction, and/or the cleanup procedure after the reaction has completed. For example, a high purity alcohol will give a higher purity treprostinil ester derivative than a lower purity alcohol. Similarly, a higher purity product is obtained through clean-up procedures such as HPLC, diafiltration, etc.
• the acid catalyst in one embodiment is a resin or in some other solid form. However, in other embodiment, the acid catalyst is in liquid form.
• the acid catalyst in one embodiment is sulfuric acid or sulfonic acid.
• Other acid catalysts include but are not limited to hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrene solfonate, hyeteropoly acid, zeolites, metal oxides, and graphene oxygene.
• Acid catalyst resins e.g., sulfonic acid resin catalysts are available commercially, e.g., from Sigma-Aldrich, under the trade name AMBERLYST.
• Other resins are available commercially, e.g., from Purolite®, and are amenable for use with the methods described herein.
• n are defined above) and/or alcohol R2-OH is dissolved in a solvent prior to the esterification reaction.
• a solvent such as dioxane prior to the esterification reaction.
• Other solvents besides dioxane, or in combination with dioxane can also be used.
• acetonitrile (MeCN), ⁇ , ⁇ '-dimethylformamide (DMF), dichloromethane (DCM), or a combination thereof can be used.
• solvents are provided in Table 1 below.
• Carboxylic acid esterification reactions other than the ones described above are known to those of ordinary skill in the art and are amenable for use in manufacturing the treprostinil alkyl esters described herein.
• the Mitsunobu reaction can be used, where a mixture of triphenylphosphine (PPI1 3 ) and diisoporpyl azodicarboxylate (DIAD or its diethyl analogue, DEAD) convert an alcohol and carboxylic acid to the ester.
• PPI1 3 triphenylphosphine
• DEAD diisoporpyl azodicarboxylate
• the DIAD is reduced as it serves as the hydrogen acceptor
• the PPh 3 is oxidized to OPPh 3 .
• N, N'-dicyclohexylcarbodiimide (DCC) or N, N'- diisopropylcarbodiimide (DIC) is used in combination with 4-dimethylaminopyridine (DMAP) (additive) in an esterification reaction (sometimes referred to as Steglich esterification).
• DCC or DIC and the carboxylic acid (treprostinil or its non- esterified derivative) are able to form an O-acylisourea activated carboxylic acid intermediate.
• the alcohol is added to the activated compound to form the stable dicyclohexylurea and the ester.
• the treprostinil or its non-esterified derivative is first dissolved in solvent, e.g., one of the solvents described above, prior to performing the Steglich esterification.
• esterification reactions can be employed.
• l-[Bis (dimethylamino) methylene]- lH-l,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (HATU) or benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) can be used as a coupling reagent.
• HATU hydroxyaminophosphate
• PyBOP benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate
• These reagents can be used with or without an additive to facilitate the coupling.
• triethylamine can be used in some embodiments in conjunction with either HATU or PyBOP coupling reagents to form a treprostinil alkyl ester.
• the treprostinil or non-esterified treprostinil derivative can first be dissolved in solvent prior to performing the esterification reaction.
• an esterification of treprostinil or a treprostinil derivative proceeds through steps 1 through 5 of the reaction scheme set forth in Example 3 of PCT Publication No. WO 201 1/153363, incorporated by reference herein in its entirety for all purposes.
• Treprostinil amide derivatives (e.g., of the formula: ) can be manufactured according to protocols of amide functionalization of a carboxylic acid group.
• treprostinil or a compound of the formula (for example, dissolved in dioxane) is combined with HATU or PyBOP and alkylamine R2-NH2 R2, R3, R4 and n are defined above.
• DIPEA N,N-Diisopropylethylamine
• EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
• HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
• HOBt 1-Hydroxybenzotriazole hydrate
• MIBA 5-methoxy-2-iodophenylboronie acid
• PfpOH 2,2,3,3,3-Pentafluoro-l-propanol
• Ri is NH, O or S
• R2 is H, a linear C5-C1 8 alkyl, branched C5-C1 8 alkyl, linear C2-C1 8 alkenyl, branched C3-C1 8 alkenyl, aryl, aryl-Ci-Cis alkyl; an amino acid or a peptide;
• R4 is an optionally substituted linear or branched C1-C15 alkyl, or an optionally substituted linear or branched C2-C15 alkenyl;
• n is an integer from 0 to 5, with the proviso that the prostacyclin compound of Formula (I) is not treprostinil.
• a prostacyclin compound of Formula (I) is manufactured, wherein R 3 is OH and n is 0 or 1.
• R4 is an optionally substituted linear or branched C1-C 5 alkyl.
• Ri is NH or O.
• a prostacyclin compound of Formula (I) is manufactured, wherein Ri is NH, O or S; R2 is a linear C5-C1 8 alkyl, branched C5-C1 8 alkyl, linear C2-C1 8 alkenyl, branched C3-C18 alkenyl; R3 is H, OH or O-alkyl; R4 is an optionally substituted linear or branched C1-C15 alkyl, or an optionally substituted linear or branched C2-C15 alkenyl; and n is an integer from 0 to 5.
• Ri is NH or O and R2 is a linear C5-C1 8 alkyl or a branched C5-C1 8 alkyl.
• R2 is aryl or aryl-Ci-Cis alkyl; R 3 is OH and n is 0 or 1.
• R4 is an optionally substituted linear or branched C1-C15 alkyl.
• the present invention provides a method for manufacturing prostacyclin compound of Formula (I), wherein the compound is a compound of one Formulae (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt thereof:
• R4 is , with the proviso that the compound is not treprostinil, i.e., R2 and R5 cannot both be H.
• R2 is m1 ' m2 or
• Ci-C alkenyl In even a further embodiment, R2 is m1 m2 and ml and m2 are both 4.
• R2 is m1 m2 and ml is 3 and m2 is 4, or ml is 2 and m2 is 3.
• R2 is H
• R 3 is OH
• R4 is
• ml and m2 are each independently an integer selected from 1 to 9 and each occurrence of R' is independently H, a linear or branched Ci-Cs alkyl, or a linear or branched Ci-Cs alkenyl.
• R' is independently H, a linear or branched Ci-Cs alkyl, or a linear or branched Ci-Cs alkenyl.
• ml and/or m2 is an integer from 2-9, the ml/m2 at the end of the carbon chain is CH 3 , while the remaining ml/m2 groups are CH 2 .
• a method for manufacturing a prostacyclin compound of one of Formula (la), (lb), (Ic) or (Id) wherein R 3 is OH, as provided in one of Formulae (la'), (lb'), (Ic') or (Id'):
• R' is independently H, a linear or branched -Cs alkyl, or a linear or branched
• R2 is
• Yet another embodiment of the invention relates to a method for manufacturing a prostacyclin compound of one of Formula (la”), (lb"), (Ic") or (Id”), or a pharmaceutically acceptable salt thereof:
• R2 is H, a linear or branched C5-C1 8 alkyl, linear C2-C1 8 alkenyl, branched C3-C1 8 alkenyl, aryl, aryl-Ci-Cis alkyl; an amino acid or a peptide; and
• R 3 is OH and R2 is 5-nonanyl, 4-heptyl, 4-octyl, 3-octyl, 2-dimethyl-l -propyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, 3-pentyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
• R 2 is decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
• R2 is a linear alkyl.
• R 2 is a linear C5-C1 8 alkyl or a branched C5-C1 8 alkyl.
• R2 is a linear C6-C1 8 alkyl or a branched C6-C1 8 alkyl.
• R2 is a linear C6-C14 alkyl, e.g., a linear Ce alkyl, Cs alkyl, C 10 alkyl, C 12 alkyl or C 14 alkyl.
• a compound of Formula (Ic") is provided wherein R2 is a linear C5-C1 8 alkyl; R 3 is OH and R5 is H.
• a compound of Formula (Ic") is provided wherein R 2 is a linear C6-C1 8 alkyl; R 3 is OH and R5 is H.
• a compound of Formula (Ic") is provided wherein R 2 is a linear C6-C1 6 alkyl; R 3 is OH and R5 is H.
• a compound of Formula (Ic") is provided wherein R2 is a linear Cs-Ci4 alkyl; R 3 is OH and R5 is OH.
• a method for manufacturing a prostacyclin compound of Formula (Ic") wherein R2 is a linear C5-C1 8 alkyl; R 3 is OH and R5 is H.
• a compound of Formula (Ic") is provided wherein R2 is a branched C6-C18 alkyl; R 3 is OH and R5 is H.
• a compound of Formula (Ic") is provided wherein R2 is a branched C6-C1 6 alkyl; R 3 is OH and R5 is H.
• a compound of Formula (Ic") is provided wherein R 2 is a branched Cs-Ci4 alkyl; R 3 is OH and R 5 is H.
• a method for manufacturing a prostacyclin compound of Formula (la"), (lb"), (Ic”) or (Id") is provided, wherein R 3 is OH, R 5 is H and R 2 is and ml and m2 are each independently an integer selected from
• a method for manufacturing a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is provided where R2 is a linear or branched C5-C1 8 alkyl.
• R2 is 5-nonanyl, 4-heptanyl, 4-octanyl, 3-octanyl, 2-dimethyl-l- propanyl, 3,3-dimethyl-l-butanyl, 2-ethyl-l-butanyl, 3-pentanyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
• a method for manufacturing a prostacyclin compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic") or (Id") is provided where R2 is a linear or branched C5-C18 alkyl. In even a further embodiment, R2 is a linear C5-C18
• R2 is , where ml and m2 are each independently an integer selected from 1 to 9 and each occurrence of R' is independently H, a linear or branched Ci-Cs alkyl, or a linear or branched Ci-Cs alkenyl.
• R 2 is a branched C5-C1 8 alkyl.
• R 2 is 5-nonanyl, 4-heptyl, 4-octyl, 3-octyl, 2-dimethyl-l -propyl, 3,3- dimethyl-1 -butyl, 2-ethyl-l -butyl, 3 -pentyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
• the prostacyclin compound manufactured by the methods provided herein has the following structure:
• Ri is NH, O or S.
• Ri is O or N
• one of the following compounds (5-nonanyl treprostinil (alkyl ester, 5C 9 -TR) or 5-nonanyl treprostinil (amide linked; 5C9-TR-A), is provided:
• R 2 is , where ml and m2 are each independently each an integer selected from 1 to 9 and each occurrence of R' is independently H, a linear or branched Ci-Cs alkyl, or a linear or branched Ci-Cs alkenyl.
• the compounds provided herein can include a symmetrical branched alkyl or an asymmetrical branched alkyl as the R2 moiety.
• R2 is therefore a symmetrical branched alkyl.
• R2 is an assymetrical branched alkyl when ml and m2 are different.
• the prostacyclin compound manufactured by the disclosed methods comprises an asymmetrical branched alkyl at the R2 position, such as, for example, 3-hexanyl (3Ce), 2-heptanyl (2C 7 ), 3-heptanyl (3C 7 ), 2-octanyl (2C 8 ), 3-octanyl (3C 8 ), or 4- octanyl (4C 8 ).
• an asymmetrical branched alkyl at the R2 position such as, for example, 3-hexanyl (3Ce), 2-heptanyl (2C 7 ), 3-heptanyl (3C 7 ), 2-octanyl (2C 8 ), 3-octanyl (3C 8 ), or 4- octanyl (4C 8 ).
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is manufactured by the disclosed methods, wherein R 2 is a branched alkyl selected from 2,2- diethyl-l-pentyl, 3-pentyl, 4-octyl, 5-nonanyl, 2-ethyl-l -butyl, 2-propyl-l-pentyl, 12-butyl-l- octyl, 2-dimethyl-l -propyl, and 3,3-dimethyl-l-butyl.
• a method for manufacturing a prostacyclin compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic') or (Id') is provided, wherein, R 2 is a linear or branched C5-C18 alkenyl.
• R2 is a linear C5-C1 8 alkenyl selected from pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl or octadecenyl.
• R3 is OH.
• R2 is a branched C5-C1 8 alkenyl selected from pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl or octadecenyl.
• R 3 is OH.
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is provided and R4 is is synthesized by one of the methods provided
• R4 is OH
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is is synthesized by one of the methods provided herein and R2 a linear C5-C18 alkyl, R 3 is OH and
• R2 is 5-nonanyl, 4-heptyl, 4- octanyl, 3-octanyl, 2-dimethyl-l -propyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, 3-pentyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is is synthesized by one of the methods provided herein and R2 hexyl, dodecyl, tetradecyl, hexadecyl, 5-nonanyl, 4-heptanyl, 4-octanyl, 3-o l, 3,3-dimethyl-l- butyl, 2-ethyl-l -butyl, 3-pentyl, R 3 is OH and R4
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is is synthesized by one of the methods provided herein and R2 hexyl, R 3 is OH and R4 is
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is is synthesized by one of the methods described herein and R2 hexyl, R3 is OH and R4 is
• a method for manufacturing a prostacyclin compound of Formula (la"), (lb"), (Ic”) or (Id") is provided and R 2 hexyl, R 3 is OH R4 is H.
• the prostacyclin compound is a compound of Formula (Ic").
• a prostacyclin compound of Formula (la), (lb"), (Ic") or (Id") is provided and R2 dodecyl, tetradecyl, pentadecyl or hexadecyl, R 3 is OH R4 is H.
• the compound is a compound of Formula (la").
• the compound is present in a lipid nanoparticle formulation as described in more detail below.
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herien, and R2 heptyl,
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herien, and R2 octyl, R 3 is OH and R4
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herien, and R2 nonyl, R3 is OH and R4 is
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herien, and
• R2 decyl
• R 3 is OH
• R4 is
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herien, and
• R2 undecyl, R 3 is OH and R4
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herien, and R2 dodecyl, R 3 is OH and R4
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is is synthesized by a method described herien, and R2 tridecyl, R 3 is OH and R4 is [0083]
• R 2 tetradecyl, R 3 is OH
• a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herein, and R2 pentadecyl, R3 is OH and R4 is
• Another embodiment of the invention concerns a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt is synthesized by a method described herien, wherein R 2 hexadecyl, R 3 is OH and R4 is
• Yet another embodiment of the invention concerns a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), a or pharmaceutically acceptable salt is synthesized by a method described herein, wherein R 2 heptadecyl, R 3 is OH and R4 is
• Yet another embodiment of the invention concerns a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt is synthesized by a method described herien, wherein R 2 octadecyl, R 3 is OH and R4 is
• a method for manufacturing a compound of Formula (I), (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt, wherein one or more hydrogen atoms is substituted with a deuterium.
• the present invention relates to an isotopologue of Formula (I), (la), (lb), (Ic) or (Id), substituted with one or more deuterium atoms.
• the isotopologue of Formula (I), (la), (lb), (Ic) or (Id) may be used to accurately determine the concentration of compounds of Formula (I), (la), (lb), (Ic) or (Id) in biological fluids and to determine metabolic patterns of compounds of Formula (I), (la), (lb), (Ic) or (Id) and its isotopologues.
• Ri is NH, O or S
• R2 is a linear or branched C5-C1 8 alkyl, a linear C2-C1 8 alkenyl or a branched C3-C1 8 alkenyl, aryl, aryl-Ci-Cis alkyl, an amino acid or a peptide;
• n is an integer from 0 to 5.
• the method comprises manufacturing a prostacyclin compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Ri is NH, O or S; R2 is a linear or branched C5-C1 8 alkyl, a linear C2-C1 8 alkenyl or a branched C3-C1 8 alkenyl; and n is an integer from 0 to 5. In a further embodiment, n is 1 and Ri is NH or O.
• the method comprises manufacturing a prostacyclin compound of Formula (II), wherein the prostacyclin compound is a compound of formula (Ila), (lib), (lie) or (lid), or a pharmaceutically acceptable salt thereof:
• Formula (lie) Formula (lid) wherein R2 is a linear or branched C5-C1 8 alkyl, a linear C2-C1 8 alkenyl or a branched C3-C1 8 alkenyl, aryl, aryl-Ci-Cis alkyl, an amino acid or a peptide.
• R2 is a linear or branched C5-C1 8 alkyl, a linear C2-C1 8 alkenyl or a branched C3-C1 8 alkenyl, aryl, aryl-Ci-Cis alkyl, an amino acid or a peptide.
• a compound of formula (Ila), (lib), (lie) or (lid) is provided wherein R 2 is a linear or branched C5-C1 8 alkyl, a linear C2-C1 8 alkenyl or a branched C3-C1 8 alkenyl.
• a compound of Formula (II), (Ila), (lib), (lie) or (lid) wherein one or more hydrogen atoms is substituted with a deuterium. Accordingly, in one embodiment, the present invention relates to an isotopologue of Formula (II), (Ila), (lib), (lie) or (lid), substituted with one or more deuterium atoms.
• the isotopologue of Formula (II), (Ila), (lib), (lie) or (lid) may be used to accurately determine the concentration of compounds of Formula (II), (Ila), (lib), (lie) or (lid) in biological fluids and to determine metabolic patterns of compounds of Formula (II), (Ila), (lib), (lie) or (lid) and its isotopologues.
• the invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions, as set forth herein.
• the method comprises manufacturing a prostacyclin compound of Formula (lie).
• R2 is a linear C5-C1 8 alkyl or a branched C5-C1 8 alkyl.
• R2 is a linear C6-C1 8 alkyl.
• R2 is a linear C6-C1 0 alkyl.
• R2 is a hexyl, heptyl or octyl.
• R2 linear C 5 -Cis alk l
• R 2 branched C 5 -Ci 8 alkyl
• R2 linear C6 alkyl
• R 2 branched C6 alkyl
• R2 linear C6-C18 alkyl
• R 2 branched C6-Cis alkyl
• R2 linear C7 alkyl
• R2 branched C7 alkyl
• R2 linear C 7 -Cis alkyl
• R 2 branched C 7 -Ci 8 alkyl
• R2 linear C ⁇ alkyl
• R 2 branched C ⁇ alkyl
• R2 linear Cj-Cis alkyl
• R 2 branched C 8 -Ci 8 alkyl
• R2 linear Cg alkyl
• R 2 branched Cg alkyl
• R2 linear Cg-Cis alkyl
• R 2 branched Cg-Cis alkyl
• R2 linear C10 alkyl
• R 2 branched Qo alkyl
• R2 linear Cio-Cis alkyl
• R 2 branched Cio-Cis alkyl
• R2 linear Cn alkyl
• R 2 branched Cn alkyl
• R2 linear C5-C12 alkyl
• R 2 branched C5-C12 alkyl
• R2 linear C12 alkyl
• R 2 branched C12 alkyl
• R2 linear C6-C10 alkyl
• R 2 branched C 6 -Ci 0 alkyl
• R2 linear C13 alkyl
• R 2 branched C13 alkyl
• Yet another embodiment of the invention relates to a method for manufacturing a prostacyclin compound of Formula (III), or a pharmaceutically acceptable salt thereof:
• the manufacturing methods provide prostacyclin compounds that contain a chiral moiety at one or more of the R 2 , R5 and/or Re positions.
• the moiety at position R 2 in one embodiment, is a chiral moiety and comprises either the R isomer, the S isomer, or a mixture thereof.
• An optical isomer at position R 2 , R5 and/or Re can also be classified with the D/L nomenclature.
• R2 is an amino acid or an amino acid moiety
• the amino acid or amino acid moiety can be the D-isomer, L-isomer, or a mixture thereof.
• one or more of the R2, 5 and/or I3 ⁇ 4 moieties is the R isomer or S isomer.
• one or more of the R2, R5 and/or R ⁇ moieties provided herein comprise a mixture of R and S moieties.
• the "R isomer” or “S isomer” as used herein refers to an enantiomerically pure isomer.
• An “enantiomerically pure isomer” has at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure R- or S- isomer or when using the D/L nomenclature, D- or L-isomer.
• a racemic compound is a compound having a mixture in equal amounts of both enantiomers.
• Treprostinil compounds derivatized with alkyl groups at the carboxylic acid moiety were prepared. Specifically, treprostinil was derivatized at the carboxylic acid moiety with C 2 , C3, C 4 , C5, Ce, Cs, Cio, C12, Ci6, and C 18 alkyl chains (i.e., R2 in Formula (A), below, is C 2 , C3, C 4 , C5, Ce, Cs, Cio, C12, Ci 6 or C 18 alkyl) to make treprostinil alkyl esters of various ester chain lengths.
• Treprostinil can be synthesized, for example, by the methods disclosed in U.S. Patent Nos.
• Treprostinil acid was dissolved in anhydrous dioxane/alcohol at a concentration 10 mg/mL (typically 4 mL).
• Alcohol (R2-OH) added was appropriate to make corresponding chain length at the R2 group.
• the alcohol was ethanol.
• the molar amount of alcohol in the solvent was ten times the molar amount of treprostinil.
• Table 5 were s nthesized by the method of scheme 2.
• R 2 (C 3 )
• R 2 (C 2 )
• a general diagram for synthesis of the alkyl ester of treprostinil is shown in Scheme I, below as well as Figure 1.
• the alcohol can be modified based on the desired alkyl ester chain length (e.g., C5-C18 alkyl esters of even or odd chain length, straight chain or branched).
• Other reaction conditions used to synthesize treprostinil ester prodrugs are provided in Table 6, below.
• DCC N,N'-Dicyclohexylcarbodiimide
• HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid Hexafluorophosphate;
• Treprostinil or treprostinil ester derivatives are acylated as follows.
• Example 1 The compound of Example 1 (0.05 mol) or treprostinil is dissolved in 10 mL of dichloromethane at 0 °C.
• Dimethylaminopyridine is added (20 mol%), and then a solution of an acyl chloride R(CO)Cl (2.1 equivalents) at 0 °C (wherein R is R5 or R 6 as described herein) is added to the compound of Example 1 or treprostinil.
• the solution is allowed to stir and warm to 23 °C over 1 hour.
• the reaction is monitored by thin layer chromatography, and when no further change is observed, the reaction is quenched with aHC0 3 (sat), and the quenched mixture is extracted with dichloromethane (3 x 10 mL).
• the combined organic extracts are dried over anhydrous sodium sulfate, and the solvent is removed under vacuum to afford the crude product. Purification is effected by column chromatography on silica gel with 2% methanol in dichlor
• R 2 can be selected such that the R2 group can be selectively removed after acylation of the secondary hydroxyl functionalities.
• protecting group strategies are well known to those skilled in the art, and are described in, e.g., Peter G.M. Wutes and Theodora W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, Wiley (2006), which is incorporated herein by reference in its entirety for all purposes. An exemplary scheme of such a process is shown below:
• the organic layers were combined and solvent was removed using a gentle stream of warmed 2 gas and gentle heat to yield a thick colorless oil.
• the crude material was dissolved in 20% "PrOH/Hexanes, passed through a 0.45 ⁇ syringe filter, and submitted to preparatory HPLC purification. Solvent was removed from the purified material using a gentle stream of warmed 2 gas and gentle heat to yield a thick colorless oil.
• the pure material was suspended in ethyl lactate for storage and was submitted to analytical HPLC for concentration determination.
• Ci 6 -TR-OAc 73% overall yield.
• the compound was also characterized by
• Treprostinil is available commercially, and can be synthesized, for example, by the methods disclosed in U.S. Patent Nos. 6,765, 117 and 8,497,393. Synthesis of prostaglandin derivatives is described in U.S. Patent No. 4,668,814. The disclosures of U.S. Patent Nos. 6,765, 117; 8,497,393 and 4,668,814 are each incorporated by reference in their entireties for all purposes.
• C 6 -TR-A and C 12 -TR-A were characterized by NMR spectroscopy.
• Patents, patent applications, patent application publications, journal articles and protocols referenced herein are incorporated by reference in their entireties, for all purposes.

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