Treprostinil derivatives and compositions and uses thereof

Abstract

Treprostinil derivatives that can act as prodrugs of treprostinil are provided. The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. TIFF2026021603000135.tif33128 (in the formula, R 1 and R 2 are independently hydrogen, alkylcarbonyl, alkoxyalkylcarbonyl, etc., provided that R 1 and R 2 Both -OR and -OR cannot be hydrogen. 1 and-OR 2 None of these compounds form acetate esters, benzoate esters, etc.)

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. patent application Ser. No. 14 / 829,180, filed Aug. 18, 2015, and U.S. patent application Ser. Nos. 14 / 742,544 and 14 / 742,579, both filed June 17, 2015, the entire disclosures of each of which are incorporated herein by reference for all purposes. [Background technology]

[0002] Background of the Disclosure Pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH), is a potentially fatal disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. Several drugs available for treating PH or PAH cannot be effectively administered orally for various reasons and are generally administered via subcutaneous, intravenous, or intramuscular routes. These administration routes generally require intervention by a medical professional and can involve significant patient discomfort and potential local trauma.

[0003] One example of such a drug is treprostinil. Treprostinil as a free acid exhibits an absolute oral bioavailability of less than 10% and a very short systemic half-life due to significant metabolism. Treprostinil can be administered in an inhaled form, but approximately 50% of PAH patients cannot take inhaled treprostinil due to irritation. Treprostinil (also referred to herein as Compound A) has the following structure: TIFF2026021603000001.tif30128 Treprostinil can exist as a salt, such as the sodium salt or the diethanolamine salt. Summary of the Invention

[0004] Summary of the Disclosure The present disclosure describes treprostinil derivatives that act as prodrugs and can increase the systemic availability of treprostinil. In some embodiments, the treprostinil derivative has the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof: TIFF2026021603000002.tif33128 formula, R 1 and R 2 are independently hydrogen, TIFF2026021603000003.tif51147, R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , j, m, and t are as described herein, except: R 1 and R 2 cannot both be hydrogen; -OR 1 Mo-OR 2 does not form acetate esters; -OR 1 Mo-OR 2 without forming benzoate esters; -OR 1 Mo-OR 2 does not form substituted cyclohexane esters; -OR 1 Mo-OR 2 does not form esters with or into (protected or unprotected) amino acids, peptides, or proteins; The compounds of formula (I) are not homopolymers or heteropolymers of treprostinil or contain more than one molecule or unit of treprostinil.

[0005] In other embodiments, the treprostinil derivative has the structure of formula (II): TIFF2026021603000004.tif34128In the formula, -OZ-CO2H is TIFF2026021603000005.tif9128, -O-heteroalkyl-CO2H, -O-cyclyl-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H, each of which may be substituted, -cyclyl-, -heteroalkyl-, R 7 , R 8 and n is as described herein, with the proviso that -OZ-CO2H instead of TIFF2026021603000006.tif8128; -OZ-CO2H does not contain a sugar moiety.

[0006] Treprostinil derivatives can be used to treat any condition that responds to treatment with treprostinil, including pulmonary hypertension (e.g., PAH). In some embodiments, the treprostinil derivative is administered locally, e.g., transdermally (e.g., via a transdermal patch). DETAILED DESCRIPTION OF THE INVENTION

[0007] Detailed Description of the Disclosure While various aspects of the present disclosure are described herein, it will be apparent to those skilled in the art that the aspects are presented by way of example only. Numerous modifications and variations, as well as variations and substitutions of the aspects described herein, will be apparent to those skilled in the art without departing from the present disclosure. It will be understood that various alternatives to the aspects described herein can be used to implement the present disclosure. It will also be understood that any aspect of the present disclosure may be combined with any one or more other aspects described herein that are not inconsistent with the aspect.

[0008] Where elements are presented in list form (e.g., in a Markush group), it will be understood that each possible subgroup of the elements is also disclosed, and that any one or more elements can be removed from the list or group.

[0009] Also, unless expressly indicated to the contrary, in any method described or claimed herein that includes two or more acts or steps, it will be understood that the order of the acts or steps of the method is not necessarily limited to the order in which the acts or steps of the method are described, but that the present disclosure encompasses embodiments in which the order is so limited.

[0010] Furthermore, generally, when an aspect in the specification or claims is referred to as comprising one or more features, it will be understood that the disclosure also encompasses aspects that consist of or consist essentially of those features.

[0011] It will also be understood that any aspect of the present disclosure, for example, any aspect found in the prior art, may be expressly excluded from the claims, regardless of whether a specific exclusion is set forth herein.

[0012] Headings are included herein for reference and to help locate particular sections. Headings are not intended to limit the scope of the aspects and concepts described in the section under that heading, and such aspects and concepts may have applicability in other sections throughout this disclosure.

[0013] All patent and non-patent literature cited in this specification is incorporated herein by reference in its entirety to the same extent as if each individual patent or non-patent literature was specifically and individually indicated to be incorporated herein by reference in its entirety.

[0014] I. definition As used in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" can include plural referents as well as singular referents, unless specifically stated otherwise.

[0015] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within one standard deviation. In some embodiments, when a specific error limit (e.g., standard deviation for a mean value shown in a chart or table of data) is not stated, the term "about" or "approximately" means a range that includes the stated value, and similarly, a range that is encompassed by rounding up or down the stated value, taking into account significant digits. In certain embodiments, the term "about" or "approximately" means within 10% or 5% of the particular value. Whenever the term "about" or "approximately" appears before the first number in a series of two or more numbers or a series of two or more numerical ranges, the term "about" or "approximately" applies to each single number in the series or range.

[0016] The term "at least" when preceding the first number in a series of two or more numbers, or "more than" when following the first number, always applies to every single number in the series.

[0017] The term "less than or equal to" or "less than," when followed after the first number in a series of two or more numbers, applies to each single number in the series.

[0018] The term "pharmaceutically acceptable" means a substance (e.g., an active ingredient or excipient) that is suitable for use in contact with the tissues and organs of a subject without undue irritation, allergic response, immunogenicity, and toxicity, commensurate with a reasonable benefit / risk ratio, and that is effective for its intended use. Also, a "pharmaceutically acceptable" excipient or carrier of a pharmaceutical composition is compatible with the other ingredients of the composition.

[0019] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to prevent or alleviate to some extent the occurrence of the medical condition being treated or one or more symptoms associated with that condition. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, organ, system, animal, or human that is sought by a researcher, veterinarian, physician, or clinician.

[0020] The terms "treat," "treating," and "treatment" include alleviating or arresting a medical condition or one or more symptoms associated with the condition, and alleviating or eradicating one or more causes of the condition. Reference to "treatment" of a condition is intended to include prevention of the condition. The terms "prevent," "preventing," and "prevention" include preventing or delaying the onset of a medical condition or one or more symptoms associated with the condition, preventing a subject from contracting a condition, and reducing a subject's risk of contracting a condition. The term "medical condition" includes diseases and disorders.

[0021] The term "subject" refers to animals, including, but not limited to, mammals such as primates (e.g., humans, chimpanzees, and monkeys), rodents (e.g., rats, mice, gerbils, and hamsters), lagomorphs (e.g., rabbits), porcines (e.g., pigs), equines (e.g., horses), canines (e.g., dogs), and felines (e.g., cats). As used herein, the terms "subject" and "patient" are used interchangeably in reference to a mammalian subject, such as a human subject.

[0022] The term "compound" encompasses salts, solvates, hydrates, clathrates, and polymorphs of the compound. A "solvate" of a compound contains a stoichiometric or non-stoichiometric amount of solvent (e.g., water, acetone, or an alcohol [e.g., ethanol]) non-covalently bound to the compound. A "hydrate" of a compound contains a stoichiometric or non-stoichiometric amount of water non-covalently bound to the compound. A "clathrate" of a compound contains molecules of a substance (e.g., a solvent) encapsulated in the crystalline structure of the compound. A "polymorph" of a compound is a crystalline form of the compound. The specific mention of a "salt," "solvate," "hydrate," "clathrate," or "polymorph" with respect to a compound in certain instances of this disclosure is not to be construed as an intentional exclusion of any of these forms in other instances of this disclosure where the term "compound" is used without mention of any of these forms.

[0023] The terms "sugar" and "saccharides" are used interchangeably herein.

[0024] The terms "halogen," "halide," and "halo" refer to fluorine, chlorine, bromine, and iodine.

[0025] The term "alkyl" means a linear or branched saturated monovalent hydrocarbon radical, where the alkyl group may be optionally substituted with one or more substituents. In certain embodiments, the alkyl group has 1 to 20 carbon atoms (C 1~20 ), 1~10 pieces (C 1~10 ), or 1 to 6 (C 1~6 ) or a linear saturated monovalent hydrocarbon group having 3 to 20 carbon atoms (C 3~20 ), 3~10 pieces (C 3~10 ), or 3 to 6 (C 3~6 ) is a branched saturated monovalent hydrocarbon group having carbon atoms. 1~6 The term "alkyl" means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. 1~6 and branch C 3~6An alkyl group is sometimes referred to as a “lower alkyl.” Non-limiting examples of alkyl groups include methyl, ethyl, propyl (including all isomeric forms such as n-propyl and isopropyl), butyl (including all isomeric forms such as n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including all isomeric forms such as n-pentyl), and hexyl (including all isomeric forms such as n-hexyl).

[0026] The terms "alkylene" and "-alkyl-" refer to a divalent alkyl group optionally substituted with one or more substituents described herein.

[0027] The term "heteroalkyl" means a linear or branched saturated monovalent hydrocarbon radical containing one or more heteroatoms independently selected from O, N, and S. The terms "heteroalkylene" and "-heteroalkyl-" refer to a divalent heteroalkyl radical. Heteroalkyl and -heteroalkyl- groups may be optionally substituted with one or more substituents described herein. Examples of heteroalkyl and -heteroalkyl- groups include, but are not limited to, -(CH)-(O or S)-CHCH and -(CH)-(O or S)-(CH)-.

[0028] The term "alkoxy" means an --O-alkyl group optionally substituted with one or more substituents as described herein.

[0029] The term "haloalkyl" means an alkyl group substituted with one or more halide atoms. Haloalkyl groups may be optionally substituted with one or more further substituents described herein.

[0030] The term "-alkylaryl" refers to an alkyl group substituted with one or more aryl groups. The -alkylaryl group may be optionally substituted with one or more further substituents as described herein.

[0031] The term "cycloalkyl" refers to a cyclic saturated bridged or unbridged monovalent hydrocarbon group, optionally substituted with one or more substituents described herein. In certain embodiments, a cycloalkyl group has 3 to 10 carbon atoms (C 3~10 ), or 3 to 8 (C 3~8 ), or 3 to 6 (C 3~6 ) carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, and adamantyl. The term "-cycloalkyl-" means a divalent cycloalkyl group optionally substituted with one or more substituents described herein.

[0032] The terms "heterocyclyl" and "heterocycle" refer to a monocyclic non-aromatic group or a polycyclic group containing at least one non-aromatic ring, wherein at least one non-aromatic ring contains one or more heteroatoms independently selected from O, N, and S. The non-aromatic ring(s) containing one or more heteroatoms can be attached to or fused to one or more saturated, partially unsaturated, or aromatic rings. In certain embodiments, a heterocyclyl or heterocyclic group has 3 to 15, or 3 to 12, or 3 to 10, or 3 to 8, or 3 to 6 ring atoms. In some embodiments, a heterocyclyl or heterocyclic group is a monocyclic, bicyclic, or tricyclic ring system that can include fused or bridged ring systems, and in which nitrogen or sulfur atoms can be oxidized or quaternized, and in which one or more rings can be fully saturated, partially saturated, or aromatic. The heterocyclyl or heterocyclic group may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound.Examples of heterocyclyl or heterocyclic groups include azepinyl, azetidinyl, aziridinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, β-carbolinyl, chromanyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, indolizinyl, isobenzotet Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl (oxolanyl), tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl (tetrahydrothiophenyl, thiolanyl), thiamorpholinyl (thiomorpholinyl), thiazolidinyl, and 1,3,5-trithianyl. The term "-heterocyclyl-" refers to a divalent heterocyclyl group. Heterocyclyl or heterocyclic groups, and -heterocyclyl- groups, may be substituted with one or more substituents as described herein.

[0033] The term "aryl" refers to a monocyclic aromatic hydrocarbon group or a polycyclic group containing at least one aromatic hydrocarbon ring. In certain embodiments, aryl groups have 6 to 15, 6 to 12, or 6 to 10 ring atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, biphenyl, and terphenyl. The aromatic hydrocarbon ring of an aryl group can be bonded to or fused to one or more saturated, partially unsaturated, or aromatic rings, examples of which include dihydronaphthyl, indenyl, indanyl, and tetrahydronaphthyl (tetralinyl). The term "-aryl-" refers to a divalent aryl group. Aryl and -aryl- groups can be optionally substituted with one or more substituents described herein.

[0034] The term "heteroaryl" refers to a monocyclic aromatic group or a polycyclic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, N, and S. Aromatic heterocycles may be attached to or fused to one or more saturated, partially unsaturated, or aromatic rings, which may contain only carbon atoms or one or more heteroatoms. A heteroaryl group may be attached to the main structure at any heteroatom or carbon atom that results in a stable compound. In certain embodiments, heteroaryl groups have 5 to 15, 5 to 12, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Non-limiting examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzothienyl (benzothiophenyl), quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzotriazolyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indazolyl, naphthyridinyl, phthalazinyl, quinazolinyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzoindolyl, dibenzofuranyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. The term "-heteroaryl-" refers to a divalent heteroaryl group. Heteroaryl and -heteroaryl- groups may be optionally substituted with one or more substituents described herein.

[0035] Each group described herein (including, but not limited to, alkyl, heteroalkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, and heteroaryl), whether as a primary group or as a substituent, can be optionally substituted with one or more substituents. In certain embodiments, each group described herein can be substituted with any of halide, cyano, nitro, hydroxyl, sulfhydryl (-SH), amino (-NH), -OR, ... 11 , -SR 11 , -NR 12 R 13 , -C(=O)R 11 , -C(=O)OR 11 , -OC(=O)R 11 , -C(=O)NR 12 R 13 , -NR 11 C(=O)R 11 , alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein R 11 is, independently at each occurrence, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 12 and R 13 is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R 12 and R 13 and the nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring.

[0036] II. stereoisomer It will be understood that the present disclosure encompasses all possible stereoisomers, including all possible diastereomers and enantiomers, of the compounds described herein, and does not encompass only the specific stereoisomer depicted in the depicted structure or nomenclature. Some aspects of the present disclosure relate to the specific stereoisomer depicted in the depicted structure or nomenclature. The specific recitation of phrases such as "or a stereoisomer thereof" with respect to a compound in certain instances of the present disclosure is not to be construed as an intentional exclusion of any of the other possible stereoisomers of the compound in other instances of the present disclosure where the term "compound" is used without the recitation of phrases such as "or a stereoisomer thereof."

[0037] III. Treprostinil derivatives The present disclosure provides treprostinil derivatives that can function as prodrugs of treprostinil. In some embodiments, the treprostinil derivative has formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof: TIFF2026021603000007.tif33128 formula, R 1 and R 2 are independently hydrogen, TIFF2026021603000008.tif50147, where R 3 is, independently at each occurrence, alkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted; R 4 and R 5 is, independently in each occurrence, hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached form a C3-C6 cycloalkyl ring; R 6 is, independently in each occurrence, hydrogen, R3 , -C(=O)R 3 , -C(=O)OR 3 , or -C(=O)NR 9 R 10 or R 6 , and R 4 or R 5 form a heterocyclic ring together with the atoms to which they are attached; R 9 and R 10 is, independently at each occurrence, hydrogen, alkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 9 and R 10 and the nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring; j is, independently in each occurrence, an integer from 0 to 4; m is, independently in each occurrence, an integer from 1 to 10; t is, independently in each occurrence, an integer from 1 to 9; however, R 1 and R 2 cannot both be hydrogen; -OR 1 Mo-OR 2 does not form acetate esters; -OR 1 Mo-OR 2 without forming benzoate esters; -OR 1 Mo-OR 2 does not form substituted cyclohexane esters; -OR 1 Mo-OR 2 does not form esters with or into (protected or unprotected) amino acids, peptides, or proteins; The compounds of formula (I) are not homopolymers or heteropolymers of treprostinil or contain more than one molecule or unit of treprostinil.

[0038] The treprostinil derivatives of formula (I) may be esters with (protected or unprotected) amino acids, peptides (e.g., dipeptides, tripeptides, tetrapeptides, or longer peptides), or proteins, or may form esters thereof -OR 1 -OR 2 , or both. Furthermore, compounds of formula (I) do not include treprostinil linked or bound to a peptide (including polypeptide) or protein. Furthermore, compounds of formula (I) do not independently have any of the treprostinils described herein. TIFF2026021603000009.tif14128 1 and / or R 2 The present invention does not include treprostinil linked or attached to a polymer other than .

[0039] The compounds of Formula (I) do not include treprostinil bound directly or indirectly to another molecule or monomer unit of treprostinil. In some embodiments, the compounds of Formula (I) do not include treprostinil bound directly or indirectly to another therapeutic agent (e.g., a therapeutic agent containing at least one carboxyl group and at least one hydroxyl group). In certain embodiments, the compounds of Formula (I) do not include treprostinil bound directly or indirectly to prostacyclin (also known as prostaglandin I2 or epoprostenol) or an analog thereof (e.g., beraprost, cicaprost, or iloprost), or to another prostaglandin or an analog thereof. In further embodiments, the compounds of Formula (I) do not include treprostinil bound indirectly to another therapeutic agent via a linker containing a hydroxyl group and a carboxyl group (e.g., β-hydroxybutyric acid, 6-hydroxyhexanoic acid, hydroxyl-polyethylene glycol-carboxylic acid, glycolic acid, or lactic acid).

[0040] In certain embodiments, R in TIFF2026021603000010.tif9128 3is not an alkyl substituted with a nitrogen-containing group or a cycloalkyl substituted with a carbonyl-containing group. R in TIFF2026021603000011.tif9128 3 In yet a further aspect, neither the alkyl nor the cycloalkyl group of R in TIFF2026021603000012.tif9128 3 None of the alkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is substituted.

[0041] In a further aspect, R in TIFF2026021603000013.tif9128 3 is not alkyl, unsubstituted alkyl, or substituted alkyl. R in TIFF2026021603000014.tif9128 3 is not haloalkyl, unsubstituted haloalkyl, or substituted haloalkyl. R in TIFF2026021603000015.tif9128 3 is not -alkylaryl, unsubstituted -alkylaryl, or substituted -alkylaryl. R in TIFF2026021603000016.tif9128 3 is not cycloalkyl, unsubstituted cycloalkyl, or substituted cycloalkyl. R in TIFF2026021603000017.tif9128 3 is not heterocyclyl, unsubstituted heterocyclyl, or substituted heterocyclyl. R in TIFF2026021603000018.tif9128 3 is not aryl, unsubstituted aryl, or substituted aryl. R in TIFF2026021603000019.tif91283 is not heteroaryl, unsubstituted heteroaryl, or substituted heteroaryl.

[0042] In some embodiments, R in TIFF2026021603000020.tif9128 3 is not alkyl, unsubstituted alkyl, or substituted alkyl. R in TIFF2026021603000021.tif9128 3 is not haloalkyl, unsubstituted haloalkyl, or substituted haloalkyl. R in TIFF2026021603000022.tif9128 3 is not -alkylaryl, unsubstituted -alkylaryl, or substituted -alkylaryl. R in TIFF2026021603000023.tif9128 3 is not cycloalkyl, unsubstituted cycloalkyl, or substituted cycloalkyl. R in TIFF2026021603000024.tif9128 3 is not heterocyclyl, unsubstituted heterocyclyl, or substituted heterocyclyl. R in TIFF2026021603000025.tif9128 3 is not aryl, unsubstituted aryl, or substituted aryl. R in TIFF2026021603000026.tif9128 3 is not heteroaryl, unsubstituted heteroaryl, or substituted heteroaryl.

[0043] In certain embodiments, R in any one of TIFF2026021603000027.tif14164 6 is not hydrogen. R in any one of TIFF2026021603000028.tif141666 R in the description of 3 is not alkyl, unsubstituted alkyl, or substituted alkyl. R in any one of TIFF2026021603000029.tif14165 6 R in the description of 3 is not haloalkyl, unsubstituted haloalkyl, or substituted haloalkyl. R in any one of TIFF2026021603000030.tif14165 6 R in the description of 3 is not -alkylaryl, unsubstituted -alkylaryl, or substituted -alkylaryl. R in any one of TIFF2026021603000031.tif14164 6 R in the description of 3 is not cycloalkyl, unsubstituted cycloalkyl, or substituted cycloalkyl. R in any one of TIFF2026021603000032.tif14165 6 R in the description of 3 is not heterocyclyl, unsubstituted heterocyclyl, or substituted heterocyclyl. R in any one of TIFF2026021603000033.tif14165 6 R in the description of 3 is not aryl, unsubstituted aryl, or substituted aryl. R in any one of TIFF2026021603000034.tif14166 6 R in the description of 3 is not heteroaryl, unsubstituted heteroaryl, or substituted heteroaryl.

[0044] In some embodiments, j is, independently at each occurrence, 0, 1, or 2. In certain embodiments, j is 0. In further embodiments, m is, independently at each occurrence, an integer from 1 to 6, or from 1 to 3. In further embodiments, t is, independently at each occurrence, an integer from 1 to 5, or from 1 to 3.

[0045] In some embodiments, R 1 and R 2 are independently hydrogen, TIFF2026021603000035.tif14128, where R 4 , R 5 , R 6 and m are as defined above, and k is, independently in each occurrence, an integer from 1 to 9, with the proviso that R 1 and R 2 and n are not both hydrogen. In certain embodiments, k is, independently in each occurrence, an integer from 1 to 5, or from 1 to 3.

[0046] In a further aspect, R 3 is, independently in each occurrence, C1-C6 alkyl; R 4 and R 5 is, independently in each occurrence, hydrogen or C1-C3 alkyl, or R 4 and R 5 and the carbon atoms to which they are attached form a cyclopropyl ring; R 6 is, independently in each occurrence, hydrogen or R 3 and;R 9 and R 10 is, independently in each occurrence, C1-C6 alkyl; or R 9 and R 10 and the nitrogen atom to which they are attached form a 3- to 6-membered heterocycle; j is, independently in each occurrence, 0 or 1; m is, independently in each occurrence, 1 or 2; and t is, independently in each occurrence, 1 or 2. In certain embodiments, R 3is, independently at each occurrence, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl; R 4 and R 5 is independently in each occurrence hydrogen, methyl, ethyl, propyl, or isopropyl; R 6 is, independently in each occurrence, hydrogen or R 3 and;R 9 and R 10 is, independently in each occurrence, C1-C3 alkyl; j is 0; m is 1; and t is 1.

[0047] In some embodiments, R 1 and R 2 are independently hydrogen or TIFF2026021603000036.tif9128, but R 1 and R 2 and R cannot both be hydrogen. 3 is, independently at each occurrence, C2-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl. 3 is independently in each occurrence C2-C6 alkyl.

[0048] In a further aspect, R 1 and R 2 are independently hydrogen or TIFF2026021603000037.tif13128, but R 1 and R 2 In some embodiments, R 4 and R 5 is hydrogen in each case, the α carbon atom (adjacent to the carbonyl group) may be substituted with a C1-C3 alkyl group, and R 6 is, independently in each occurrence, hydrogen or C1-C6 alkyl, and m is, independently in each occurrence, an integer from 1 to 6, or from 1 to 3. In certain embodiments, R 4 and R 5is hydrogen in each case, the α carbon atom may be substituted with a methyl group, R 6 is, independently in each occurrence, hydrogen or C1-C3 alkyl (e.g., methyl), and m is, independently in each occurrence, an integer from 1 to 6, or from 1 to 3.

[0049] In still a further aspect, R 1 and R 2 are independently hydrogen, TIFF2026021603000038.tif13128, but R 1 and R 2 In some embodiments, R 4 and R 5 is hydrogen in each case, or R 4 is hydrogen in each case, and R 5 is in each occurrence C1-C3 alkyl; R 6 is, independently at each occurrence, hydrogen or C1-C6 alkyl; and j is, independently at each occurrence, 0, 1, or 2. In certain embodiments, R 4 and R 5 is hydrogen in each case, or R 4 is hydrogen in each case, and R 5 is in each case methyl; R 6 is, independently at each occurrence, hydrogen or C1-C3 alkyl (e.g., methyl); and j is, independently at each occurrence, 0 or 1.

[0050] In a further aspect, R 1 and R 2 are independently hydrogen or TIFF2026021603000039.tif9128, but R 1 and R 2 In some embodiments, R 3 is, independently at each occurrence, C1-C6 alkyl or C1-C6 haloalkyl. 3is independently in each occurrence C1-C3 alkyl or C1-C3 haloalkyl.

[0051] In other embodiments, R 1 and R 2 are independently hydrogen or TIFF2026021603000040.tif10128, but R 1 and R 2 In some embodiments, R 6 is, independently in each occurrence, hydrogen or C1-C6 alkyl, and t is, independently in each occurrence, an integer from 1 to 5, or from 1 to 3. In certain embodiments, R 6 is independently in each occurrence hydrogen or C1-C3 alkyl (e.g., methyl), and t is independently in each occurrence an integer from 1 to 6, or from 1 to 3.

[0052] In still other embodiments, R 1 and R 2 are independently hydrogen or TIFF2026021603000041.tif10128, but R 1 and R 2 In some embodiments, R 6 is, independently at each occurrence, hydrogen or C1-C6 alkyl, and j is, independently at each occurrence, 0, 1, or 2. In certain embodiments, R 6 is, independently in each occurrence, hydrogen or C1-C3 alkyl (e.g., methyl), and j is, independently in each occurrence, 0 or 1.

[0053] In a further aspect, R 1 and R 2 are independently hydrogen or TIFF2026021603000042.tif10128, but R 1 and R 2 In some embodiments, R 9 and R 10is, independently in each occurrence, C1-C6 alkyl; or R 9 and R 10 and the nitrogen atom to which they are attached form a 3- to 6-membered heterocycle, and t, in each occurrence, is independently an integer from 1 to 5, or from 1 to 3. In certain embodiments, R 9 and R 10 is, independently in each occurrence, C1-C3 alkyl (e.g., methyl), and t is, independently in each occurrence, an integer from 1 to 6, or 1 to 3.

[0054] In a further aspect, R 1 and R 2 are independently hydrogen, TIFF2026021603000043.tif17128, but R 1 and R 2 In some embodiments, R 6 is, independently at each occurrence, hydrogen or C1-C6 alkyl. In certain embodiments, R 6 is, independently in each occurrence, C1-C3 alkyl (e.g., methyl).

[0055] In some embodiments, R 1 and R 2 is independently selected from the group consisting of: hydrogen, TIFF2026021603000044.tif205166 In the formula, each moiety having a stereocenter adjacent to the carbonyl group or elsewhere may have either the (R)-stereochemical configuration or the (S)-stereochemical configuration, or may be racemic at that stereocenter. However, R 1 and R 2 cannot both be hydrogen. In this disclosure, (1) R 2 is hydrogen, -OR 1 is derivatized with each moiety (except hydrogen) in the group; (2) R 1 is hydrogen, -OR 2is derivatized with each moiety (except hydrogen) in the group; and (3) -OR 1 AND-OR 2 Specifically described are treprostinil derivatives in which R are both derivatized with the same moiety and with each moiety in the group (except hydrogen). 1 and R 2 is independently selected from the group consisting of: hydrogen, TIFF2026021603000045.tif27166However, R 1 and R 2 cannot both be hydrogen.

[0056] In some embodiments, -OR 1 AND-OR 2 and R are both derivatized [Formula (Ic)] and may be derivatized with the same group. 2 is hydrogen, -OR 1 is derivatized [Formula (Ia)]. In yet another embodiment, R 1 is hydrogen, -OR 2 is the derivatized [formula (Ib)].

[0057] In certain embodiments, the treprostinil derivative of formula (I) is selected from the group consisting of: TIFF2026021603000046.tif30135TIFF2026021603000047.tif225136TIFF2026021603000048.tif209142TIFF2026021603000049.tif234142TIFF2026021603000050.tif158146 and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof.

[0058] In other embodiments, the treprostinil derivative has the formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof: TIFF2026021603000051.tif34128In formula, -OZ-CO2H TIFF2026021603000052.tif9128, -O-heteroalkyl-COH, -O-cyclyl-COH, -O-CH-cyclyl-COH, -O-cyclyl-CH-COH, or -O-CH-cyclyl-CH-COH, each of which is optionally substituted; where: -cyclyl- is -cycloalkyl-, -heterocyclyl-, -aryl-, or -heteroaryl-; R 7 and R 8 is, independently in each occurrence, hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 7 and R 8 and the carbon atoms to which they are attached form a C3-C6 cycloalkyl ring; where n is an integer between 1 and 10; however, -OZ-CO2H instead of TIFF2026021603000053.tif8128; -OZ-CO2H does not contain a sugar moiety.

[0059] In some embodiments, n is an integer from 1 to 6, or from 1 to 3. In other embodiments, n is an integer from 3 to 10, or from 3 to 6. In further embodiments, R 7 and R 8 is hydrogen in each occurrence, and n is an integer from 1 to 10, or from 1 to 6, or from 1 to 3.

[0060] In certain embodiments, -OZ-COH is In a further embodiment, when n is 1 or 2, R 7 and R 8 is hydrogen in each case.

[0061] In some embodiments, -OZ-CO2H does not contain a -heterocyclyl- group or a substituted -heterocyclyl- group.

[0062] In further embodiments, the -cyclyl- in -O-cyclyl-COH, -O-CH-cyclyl-COH, -O-cyclyl-CH-COH, or -O-CH-cyclyl-CH-COH is not -cycloalkyl-, unsubstituted cycloalkyl-, or substituted cycloalkyl-. In other embodiments, the -cyclyl- in -O-cyclyl-COH, -O-CH-cyclyl-COH, -O-cyclyl-CH-COH, or -O-CH-cyclyl-CH-COH is not -heterocyclyl-, unsubstituted heterocyclyl-, or substituted heterocyclyl-. In still other embodiments, the -cyclyl- in -O-cyclyl-COH, -O-CH-cyclyl-COH, -O-cyclyl-CH-COH, or -O-CH-cyclyl-CH-COH is not -aryl-, unsubstituted aryl-, or substituted aryl-. In still other embodiments, the -cyclyl- in -O-cyclyl-COH, -O-CH-cyclyl-COH, -O-cyclyl-CH-COH, or -O-CH-cyclyl-CH-COH is not -heteroaryl-, unsubstituted heteroaryl-, or substituted heteroaryl-.

[0063] In some embodiments, -OZ-CO2H is TIFF2026021603000055.tif9128, except for -OZ-CO2H TIFF2026021603000056.tif8128. In certain embodiments, R 7 and R 8 is hydrogen in each occurrence, the carbon atom adjacent to the ester oxygen atom is optionally substituted with a C1-C6 alkyl group, and n is an integer from 1 to 6, or from 1 to 3. In some embodiments, R 7 and R 8is hydrogen in each occurrence, the carbon atom adjacent to the ester oxygen atom may be substituted with a C1-C3 alkyl (eg, methyl) group, and n is an integer of 1 to 6, or 1 to 3.

[0064] In a further aspect, -OZ-COH is TIFF2026021603000057.tif13128, where R 7 and R 8 is as defined above, p is an integer of 1 to 9, and q is an integer of 0 to 8, with the proviso that -OZ-CO2H is TIFF2026021603000058.tif8128. In certain embodiments, p is an integer from 1 to 5, or from 1 to 3, and q is an integer from 0 to 4, or from 0 to 2. In some embodiments, R 7 and R 8 are all hydrogen, and p is an integer of 1 to 5 or 1 to 3 (or R 7 and R 8 is hydrogen in each occurrence, and q is an integer from 0 to 4, or from 0 to 2. 7 and R 8 Specifically described are treprostinil derivatives in which each is hydrogen and p is any of 1, 2, 3, 4, 5, 6, 7, 8, and 9. In a further embodiment, -OZ-CO2H is TIFF2026021603000059.tif10128, where p is 2, 3, 4, or 5. In this disclosure, -OZ-CO2H is TIFF2026021603000060.tif10128, where p is any of 2, 3, 4, 5, 6, 7, 8, and 9, and the stereocenter attached to the methyl group may have an (R)-stereochemical configuration or an (S)-stereochemical configuration, or may be racemic at that position.

[0065] In a further aspect, -OZ-COH is TIFF2026021603000061.tif12128, wherein the A ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and u is an integer from 0 to 9. The present disclosure specifically describes treprostinil derivatives in which the A ring is any of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and u is any of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9. In certain embodiments, -OZ-CO2H is TIFF2026021603000062.tif11128, where u is an integer of 0 to 9 or 0 to 5. In addition, in the present disclosure, -OZ-CO2H TIFF2026021603000063.tif11128, and u is any of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9. Treprostinil derivatives are specifically described.

[0066] In other embodiments, -OZ-COH is -O-heteroalkyl-COH, wherein -O-heteroalkyl-COH is selected from the group consisting of: TIFF2026021603000064.tif50163where r is 1, 2, or 3; Each moiety having a stereocenter adjacent to the oxygen atom bound to treprostinil and / or a stereocenter adjacent to the carboxyl group may independently have either the (R)-stereochemical configuration or the (S)-stereochemical configuration and may be racemic at that(their) stereocenter(s). The present disclosure specifically describes treprostinil derivatives in which -OZ-CO2H is a moiety in the above group. In certain embodiments, -OZ-CO2H is TIFF2026021603000065.tif9161, where r is 1, 2, or 3.

[0067] In a further aspect, -OZ-COH is -O-cycloalkyl-COH, -O-CH-cycloalkyl-COH, -O-cycloalkyl-CH-COH, or -O-CH-cycloalkyl-CH-COH, and for each of said moieties, -cycloalkyl- is 1,2-cyclopropyl (cis or trans); or 1,3-cyclobutyl (cis or trans) or 1,2-cyclobutyl (cis or trans); or 1,3-cyclopentyl (cis or trans) or 1,2-cyclopentyl (cis or trans); or It is 1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans). The present disclosure specifically describes 64 treprostinil derivatives, where -OZ-CO2H is a moiety in the group. In certain embodiments, -OZ-CO2H is selected from the group consisting of: TIFF2026021603000066.tif24146wherein for each moiety, the two groups on the cycloalkyl ring can be cis or trans relative to each other.

[0068] In some embodiments, the treprostinil derivative of formula (II) is selected from the group consisting of: TIFF2026021603000067.tif160138TIFF2026021603000068.tif204142TIFF2026021603000069.tif37136 and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof.

[0069] The treprostinil derivatives described herein can exist or be used in the form of pharmaceutically acceptable salts. Treprostinil derivatives have a carboxyl group, and therefore can form addition salts with bases. Pharmaceutically acceptable base addition salts can be formed with, for example, metals (e.g., alkali metals or alkaline earth metals) or amines (e.g., organic amines). Examples of metals useful as cations include, but are not limited to, alkali metals (e.g., lithium, sodium, potassium, and cesium), alkaline earth metals (e.g., magnesium, calcium, and barium), aluminum, and zinc. Metal cations can be obtained as inorganic bases, such as hydroxides, carbonates, and bicarbonates. Non-limiting examples of organic amines useful for the formation of base addition salts include chloroprocaine, choline, cyclohexylamine, dibenzylamine, N,N'-dibenzylethylene-diamine, dicyclohexylamine, diethanolamine, ethylenediamine, N-ethylpiperidine, histidine, isopropylamine, N-methylglucamine, procaine, pyrazine, triethylamine, trimethylamine, and tromethamine.

[0070] If a compound has a basic atom or functional group (for example, a basic nitrogen atom), the compound can form an addition salt with an acid.Non-limiting examples of acids useful for forming acid addition salts include mineral acids (for example, HCl, HBr, HI, nitric acid, phosphoric acid, and sulfuric acid), and organic acids such as carboxylic acids (for example, acetic acid) and sulfonic acids (for example, ethanesulfonic acid).Pharmaceutically acceptable salts are described in detail in Handbook of Pharmaceutical Salts, Properties, Selection and Use, P. Stahl and C. Wermuth, Eds., Wiley-VCH (2011).

[0071] IV. Deuterated Treprostinil Compounds To remove foreign substances such as drugs, animal bodies produce cytochrome P 450They express a variety of enzymes, including enzymes such as esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with xenobiotics to convert them into highly polar intermediates or metabolites for renal excretion. Such metabolic reactions can involve the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) bonds or carbon-carbon (C=C) π bonds. The resulting metabolites can be stable or unstable under physiological conditions and can have substantially different pharmacological, pharmacokinetic, and pharmacodynamic properties, as well as toxicity profiles, compared to the parent compound. For many drugs, such metabolic oxidation can be rapid, resulting in the need for increased dosage and / or more frequent administration, which can result in increased side effects.

[0072] The present disclosure provides treprostinil isotope substitutes corresponding to the treprostinil derivatives described herein that are deuterium-enriched (deuterated) at one or more positions. In some embodiments, the treprostinil derivatives are deuterated at one or more positions in the parent treprostinil structure, such that when the derivative is converted to treprostinil in vivo, the resulting active parent drug is deuterated at one or more positions.

[0073] Deuteration of treprostinil compounds at one or more positions may exhibit any one or more, or all of the following advantages: (1) increased half-life; (2) reduced dosage and / or less frequent administration required to achieve a desired effect; (3) reduced inter-subject variability in blood or plasma levels of the parent drug; (4) increased efficacy; (5) reduced side effects due to reduced amounts of parent drug administered and / or reduced production of harmful metabolites; and (6) increased maximum tolerated dose.

[0074] In any one or more or all of the available positions in the treprostinil (Trp) compound, for example, in any one or more or all of the available positions in the phenyl ring of Trp, the cyclohexyl ring of Trp, the cyclopentyl ring of Trp, the octyl chain of Trp, or the hydroxyacetate group of Trp, or any combination thereof, hydrogen can be replaced with deuterium.In certain embodiments, the treprostinil derivative is deuterated in any one or more or all of the available positions in the cyclohexyl ring of Trp and / or the hydroxyacetate group of Trp.In some embodiments, at least one available position exhibits a deuterium enrichment of at least about 10%, 25%, 50%, 75%, 90%, 95%, or 98%.In certain embodiments, at least one available position exhibits a deuterium enrichment of at least about 90%, 95%, or 98%.

[0075] In further embodiments, each position in the deuterium-enriched (or deuterated) treprostinil derivative independently exhibits a deuterium enrichment of at least about 10%, 25%, 50%, 75%, 90%, 95%, or 98%. In certain embodiments, each deuterium-enriched position independently exhibits a deuterium enrichment of at least about 90%, 95%, or 98%.

[0076] Deuterated treprostinil derivatives are 13 C or 14 C and oxygen 17 O or 18 It may also contain low abundance isotopes of other elements, including but not limited to O.

[0077] The term "deuterium enrichment" refers to the percentage of deuterium incorporated into a molecule at a given position instead of hydrogen. For example, a deuterium enrichment of 10% at a given position means that 10% of the molecules in a given sample contain deuterium at that position. Since the natural distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a molecule synthesized using non-deuterium-enriched starting materials or reagents is approximately 0.0156%. Deuterium enrichment can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0078] The terms "deuterated" or "deuterated," when used to describe a given position in a molecule, or the symbol "D," when used to represent an element at a given position in a molecular structure diagram, mean that the particular position is enriched in deuterium beyond the natural distribution of deuterium. In some embodiments, the deuterium enrichment is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% (e.g., at least about 50%) deuterium at the particular position. In certain embodiments, the deuterium enrichment is at least about 90%, 95%, or 98% deuterium at the particular position.

[0079] V. Pharmaceutical Compositions A further aspect of the present disclosure relates to a pharmaceutical composition comprising one or more treprostinil derivatives described herein, or pharmaceutically acceptable salts, solvates, hydrates, clathrates, or polymorphs thereof, and one or more pharmaceutically acceptable excipients or carriers. The composition may also contain an additional therapeutic agent.

[0080] Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials, and vehicles.Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, solvents, isotonicity adjusters, buffers, pH adjusters, absorption retardants, sweeteners, flavorings, colorings, stabilizers, preservatives, antioxidants, antibacterial agents, antibacterial agents, antifungal agents, adjuvants, encapsulating materials, and coating materials.The use of such excipients in pharmaceutical preparations is known in the art.For example, conventional vehicles and carriers include, but are not limited to, oils (for example, vegetable oils such as sesame oil), aqueous solvents (for example, saline and phosphate buffered saline [PBS]), and solvents (for example, dimethyl sulfoxide [DMSO] and alcohol [such as ethanol and glycerin]). Except insofar as any conventional excipient or carrier is incompatible with the active ingredient (with respect to the contents of a pharmaceutical composition, the term "active ingredient" includes a prodrug), the present disclosure encompasses the use of conventional excipients and carriers in formulations containing treprostinil derivatives. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania

[2005] ); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton, Florida

[2004] ).

[0081] Appropriate formulations may depend on various factors, such as the selected route of administration. Potential routes of administration for pharmaceutical compositions containing treprostinil derivatives include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), intracavity, intraperitoneal, and topical (including cutaneous / epcutaneous, transdermal, mucosal, transmucosal, intranasal (e.g., via nasal spray or nasal drops), intraocular (e.g., via eye drops), intrapulmonary (e.g., via inhalation), buccal, sublingual, rectal, and vaginal). Topical formulations may be designed to produce a local or systemic therapeutic effect.

[0082] For example, the formulation of treprostinil derivative suitable for oral administration can be presented as, for example, capsules (including push-fit capsules and soft capsules), cachets, or tablets; as powders or granules; or as bolus tablets, electuaries, or pastes.For example, push-fit capsules can contain a mixture of treprostinil derivatives with, for example, fillers (e.g., lactose), binders (e.g., starch), and lubricants (e.g., talc or magnesium stearate), and optionally stabilizers.For soft capsules, the treprostinil derivative can be dissolved or suspended in a suitable liquid (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol), and stabilizers can be added.

[0083] The composition for oral administration can also be formulated as a solution or suspension in an aqueous liquid and / or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A dispersible powder or granules of the treprostinil derivative can be mixed with any suitable combination of an aqueous liquid, an organic solvent, and / or an oil and any suitable excipient (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent, and / or a preservative) to form a solution, suspension, or emulsion.

[0084] In addition, treprostinil derivatives can be formulated for parenteral administration by injection or infusion to avoid gastrointestinal absorption and first-pass metabolism.An exemplary parenteral route is intravenous.An additional advantage of intravenous administration is that the therapeutic agent is directly administered into the systemic circulation to achieve rapid systemic effects, and the therapeutic agent can be administered continuously and / or in large amounts as needed.The preparation for injection or infusion can be in the form of a solution, suspension, or emulsion in an oily or aqueous medium, and can contain excipients such as suspending agents, dispersing agents, and / or stabilizers.For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain treprostinil derivatives together with excipients such as antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with the subject's blood. Aqueous or non-aqueous sterile suspensions may contain the treprostinil derivative together with excipients such as suspending agents and thickening agents, and optionally stabilizers and agents that increase the solubility of the treprostinil derivative to allow for the preparation of more concentrated solutions or suspensions. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneous or intravenous) may contain the treprostinil derivative, sodium chloride, a buffer (e.g., sodium citrate), a preservative (e.g., m-cresol), and optionally a base (e.g., NaOH) and / or an acid (e.g., HCl) to adjust the pH.

[0085] In some embodiments, the typical dosage form of treprostinil derivative is formulated as buccal or sublingual tablets or pills.The advantages of buccal or sublingual tablets or pills include avoiding gastrointestinal absorption and first-pass metabolism, and rapid absorption into systemic circulation.Buccal or sublingual tablets or pills can be designed to realize the rapid release of treprostinil derivatives, so that treprostinil derivatives are more rapidly absorbed into systemic circulation. Buccal or sublingual tablets or pills may contain, in addition to a therapeutically effective amount of a treprostinil derivative, suitable excipients, including, but not limited to, any combination of fillers and diluents (e.g., mannitol and sorbitol), binders (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavors (e.g., spearmint flavor), sweeteners (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).

[0086] Furthermore, treprostinil derivatives can be formulated for intranasal administration.Intranasal administration avoids gastrointestinal absorption and first-pass metabolism.Intranasal formulations can contain treprostinil derivatives together with excipients such as solubility enhancers (e.g., propylene glycol), humectants (e.g., mannitol or sorbitol), buffers and water, and optionally preservatives (e.g., benzalkonium chloride), mucoadhesives (e.g., hydroxyethylcellulose), and / or penetration enhancers.

[0087] Furthermore, treprostinil derivatives can be formulated for oral inhalation administration.The advantages of inhalation administration include avoiding first-pass metabolism and adjusting the therapeutic agent for rapid delivery through the mucous membrane of the respiratory tract, or more selectively depositing the therapeutic agent in the stomach with fewer systemic side effects.In certain embodiments, the sterile aqueous solution for oral inhalation contains treprostinil derivatives, sodium chloride, a buffer (for example, sodium citrate), optionally a preservative (for example, m-cresol), and optionally a base (for example, NaOH) and / or an acid (for example, HCl) for adjusting pH.

[0088] For delayed or sustained release of treprostinil derivative, the composition can be formulated as a depot that can be implanted or injected into the subject, for example, intramuscularly or subcutaneously.Depot preparations can be designed to deliver treprostinil derivatives for a relatively long period, for example, at least about 1 week, 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months or more.For example, treprostinil derivatives can be formulated with polymer materials (for example, polyethylene glycol [PEG], polylactic acid [PLA], or polyglycolic acid [PGA], or their copolymers [for example, PLGA]), with hydrophobic materials (for example, as an emulsion in oil), and / or with ion exchange resins, or as poorly soluble derivatives (for example, poorly soluble salts).For example, treprostinil derivatives can be incorporated into or embedded in sustained-release microparticles made of PLGA, and formulated as a monthly depot preparation.

[0089] Alternatively, the treprostinil derivative can be contained or dispersed in a matrix material. The matrix material can include a polymer (e.g., ethylene-vinyl acetate) that controls the release of the compound, for example, by controlling the dissolution and / or dispersion of the compound from the reservoir, and can increase the stability of the compound while it is contained in the reservoir. Such a "release system" can be configured as a transdermal or transmucosal patch and can contain an excipient that can promote the release of the compound, for example, a water-swellable material (e.g., a hydrogel) that helps expel the compound from the reservoir. Examples of such release systems are described in U.S. Patent Nos. 4,144,317 and 5,797,898.

[0090] Release systems can exhibit timed release profiles (e.g., pulsed release) when time-varying plasma levels are desired, or more continuous or consistent release profiles when constant plasma levels are desired. Pulsed release can be achieved from individual reservoirs or from multiple reservoirs. For example, if each reservoir provides only a single pulse, multiple pulses ("pulsed" release) can be achieved by staggering the release of a single pulse from each of the multiple reservoirs. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of release systems and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system through which the compound degrades, elutes, or diffuses over an extended period of time. Furthermore, continuous release can be simulated by releasing several pulses of compound in rapid succession ("digital" release). Active release systems can be used alone or in combination with passive release systems, as described in U.S. Pat. No. 5,797,898.

[0091] The pharmaceutical compositions can be manufactured in any suitable manner known in the art, for example, by means of conventional mixing, dissolving, suspending, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0092] The composition can be presented in a unit dosage form as a single dose.In the unit dosage form, all active ingredients and inactive ingredients are combined in a suitable system, and the ingredients do not need to be mixed to form a composition to be administered.The unit dosage form can contain an effective amount or an appropriate fraction thereof of the treprostinil derivative.Representative examples of the unit dosage form are tablets, capsules, or pills for oral intake.

[0093] Alternatively, the composition may be presented as a kit, in which the active ingredient, excipient, and carrier (e.g., solvent) are provided in two or more separate containers (e.g., ampoules, vials, tubes, bottles, or syringes) that must be combined to form the administered composition. The kit may include instructions for storing, preparing, and administering the composition (e.g., an intravenous solution).

[0094] In some embodiments, the kit comprises a treprostinil derivative or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or polymorph thereof and instructions for administering the compound to treat a condition responsive to treatment with treprostinil (e.g., pulmonary hypertension such as pulmonary arterial hypertension). In certain embodiments, the compound is contained within, incorporated into, or supplied by a device or system configured for transdermal delivery of the compound (e.g., a transdermal patch).

[0095] VI. Topical Compositions Comprising Transdermal Delivery Systems Topical formulations applied to the skin or mucosa can be useful for transdermal or transmucosal administration of therapeutic agents into the blood for systemic distribution. Advantages of topical administration can include avoidance of gastrointestinal absorption and first-pass metabolism, delivery of therapeutic agents with short half-lives and low oral bioavailability, improved controlled and sustained release of therapeutic agents, more uniform plasma administration or delivery profiles of therapeutic agents, reduced administration frequency of therapeutic agents, minimal or no invasiveness, ease of self-administration, and improved patient compliance. With respect to the contents of pharmaceutical compositions, the term "therapeutic agent" or "drug" encompasses prodrugs.

[0096] In general, and in addition to the disclosure regarding topical formulations elsewhere herein, compositions suitable for topical administration include, but are not limited to, liquid or semi-liquid formulations such as sprays, gels, liniments, lotions, oil-in-water or water-in-oil emulsions, such as creams, foams, ointments, and pastes, as well as solutions or suspensions, such as drops (e.g., eye drops, nose drops, and ear drops). In some embodiments, the topical composition comprises a therapeutic agent dissolved, dispersed, or suspended in a carrier. The carrier can be in the form of, for example, a solution, suspension, emulsion, ointment, or gel base, and can contain, for example, petrolatum, lanolin, wax (e.g., beeswax), mineral oil, long-chain alcohol, polyethylene glycol or polypropylene glycol, diluent (e.g., water and / or alcohol [e.g., ethanol or propylene glycol]), emulsifier, stabilizer, or thickener, or any combination thereof. The topical composition can comprise a transdermal or transmucosal delivery device, such as, for example, a transdermal patch, a microneedle patch, or an iontophoresis device. Alternatively, topical formulations can be administered thereby. Topical compositions can deliver drugs transdermally or transmucosally by concentration gradient (with or without the use of chemical penetration enhancers) or activation mechanisms (e.g., iontophoresis or microneedles).

[0097] In some embodiments, the treprostinil derivatives described herein are administered transdermally. In certain embodiments, the topical composition (e.g., a transdermal delivery system) contains a chemical penetration enhancer (e.g., a surfactant [e.g., sodium laureth sulfate], optionally in combination with an aromatic compound [e.g., phenylpiperazine]) that promotes transport of the treprostinil derivative through the skin into the systemic circulation. In further embodiments, the treprostinil derivative is administered via a transdermal patch. In certain embodiments, the transdermal patch comprises an impermeable backing membrane or backing layer, a drug reservoir, a semipermeable membrane that may serve as a rate-limiting or rate-controlling diffusion barrier, and a skin-contact adhesive layer. The semipermeable membrane may be composed of, for example, a suitable polymeric material (e.g., cellulose nitrate or acetate, polyisobutene, polypropylene, polyvinyl acetate, or polycarbonate). Transdermal drug delivery systems, including patches, can be designed to achieve controlled and extended release of drug for periods of up to, for example, about one week or longer. International Publication No. 1993 / 003696 and U.S. Patent Nos. 3,598,122; 4,144,317; 4,201,211; 4,262,003, and 4,379,454 describe various transdermal drug delivery systems, including patches, that can deliver controlled amounts of drugs for extended periods ranging from several hours to several days. Such systems can be modified for transdermal delivery of treprostinil derivatives.

[0098] VII. Therapeutic Uses of Treprostinil Derivatives The treprostinil derivatives described herein can be converted to treprostinil in vivo and therefore can act as prodrugs of treprostinil. In some embodiments, the treprostinil derivative is converted to treprostinil slowly and to a small extent (e.g., less than about 30%, less than about 20%, less than about 10%, or less than about 5%) in the blood or skin (e.g., when administered transdermally), and is converted to treprostinil rapidly and substantially completely (e.g., at least about 70%, 80%, 90%, or 95% conversion) in the liver. In other embodiments, the treprostinil derivative is converted to treprostinil to a significant extent (e.g., at least about 30%, 40%, 50%, or 60% conversion) or substantially completely (e.g., at least about 70%, 80%, 90%, or 95% conversion) in the blood. In yet other embodiments, the treprostinil derivative is administered transdermally and is converted to treprostinil in the skin to some extent (e.g., less than about 30%, less than about 20%, or less than about 10% conversion) and does not cause a significant amount of side effects, such as irritation, at the administration site. In further embodiments, the treprostinil derivative is at least about 50-fold, 100-fold, 500-fold, or 1000-fold (e.g., at least about 100-fold) less effective than treprostinil in stimulating prostacyclin receptors.

[0099] Treprostinil, a prostacyclin (prostaglandin I2) analog, exhibits various prostacyclin-like effects. For example, treprostinil can promote vasodilation, inhibit platelet activation and platelet aggregation, inhibit thrombus formation, stimulate thrombolysis, inhibit atherogenesis, inhibit cell proliferation, inhibit angiogenesis, promote endothelial cell membrane remodeling, reduce inflammation, and provide cytoprotection. As prodrugs of treprostinil, the treprostinil derivatives described herein can be used to treat a wide variety of conditions, including, but not limited to: Pulmonary hypertension, portopulmonary hypertension, pulmonary fibrosis, interstitial lung disease, ischemic disease (e.g., myocardial ischemia, ischemic stroke, peripheral vascular disease [including peripheral arterial disease], limb ischemia, Raynaud's phenomenon [including Raynaud's disease and Raynaud's syndrome], scleroderma [including systemic sclerosis], and renal insufficiency), ischemic ulcers (e.g., digital ulcers), cardiovascular disease (e.g., coronary artery disease), heart failure (e.g., congestive heart failure), conditions requiring anticoagulation (e.g., post-myocardial infarction and post-cardiac surgery) , atherogenesis (e.g., atherosclerosis), thrombotic microangiopathy, venous occlusion (e.g., central retinal vein occlusion), hypertension (e.g., preeclampsia), diabetic vasculopathy, extracorporeal circulation, inflammatory diseases (e.g., chronic obstructive pulmonary disease [COPD] and psoriasis), reproduction and childbirth, conditions of unregulated cell proliferation (e.g., tumors and cancer), cell / tissue preservation, and other therapeutic areas where treatment with prostacyclin or treprostinil may be beneficial.

[0100] In some embodiments, one or more treprostinil derivatives, or pharmaceutically acceptable salts, solvates, hydrates, clathrates, or polymorphs thereof, are used to treat a condition that responds to prostacyclin or treprostinil selected from the group consisting of: Pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, asthma, congestive heart failure, peripheral vascular disease, severe intermittent claudication, atherogenesis (e.g., atherosclerosis), ischemic lesions (e.g., peripheral ischemic skin lesions, such as Buerger's disease, Raynaud's phenomenon, Raynaud's disease, scleroderma, and lesions caused by systemic sclerosis), critical limb ischemia, neuropathic foot ulcers (e.g., diabetic neuropathic foot ulcers), renal insufficiency and failure, immunosuppression, proliferative disorders (e.g., tumors and cancers, such as those of the head and neck, brain, lung, liver, kidney, pancreas, gastrointestinal tract (e.g., colon), prostate, and breast), and pain associated with each of the foregoing conditions.

[0101] To treat any condition that responds to treatment with prostacyclin or treprostinil, treprostinil derivatives can be used in combination with additional therapeutic agents. As a non-limiting example, to treat vascular (e.g., cardiovascular) disorders, treprostinil derivatives can be used in combination with vascular (e.g., cardiovascular) therapeutic agents such as antiplatelet agents, phosphodiesterase inhibitors, calcium channel blockers, or endothelial antagonists, or any combination thereof.

[0102] In some embodiments, the treprostinil derivatives described herein are used to treat pulmonary hypertension. To treat pulmonary hypertension, additional therapeutic agents (e.g., vasoactive agents, diuretics, anticoagulants, or cardiac glycosides, or any combination thereof) may be administered. In certain embodiments, the pulmonary hypertension is pulmonary arterial hypertension.

[0103] Pulmonary hypertension is elevated blood pressure in the pulmonary vasculature, including the pulmonary arteries, veins, and capillaries. Thus, pulmonary hypertension encompasses pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH) (e.g., congestive heart failure). More broadly, pulmonary hypertension encompasses: WHO Group I - Pulmonary arterial hypertension, including idiopathic PAH, hereditary PAH (e.g., BMPR2, ALK1, and endoglin [with or without hereditary hemorrhagic telangiectasia]), drug-induced and toxin-induced PAH, PAH associated with various conditions (e.g., connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and chronic hemolytic anemia [e.g., sickle cell disease]), persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease (PVOD), and pulmonary capillary hemangiomatosis (PCH); WHO group II - pulmonary hypertension due to left heart disease, including systolic dysfunction, diastolic dysfunction, and valvular heart disease; WHO Group III - pulmonary hypertension due to lung disease and / or hypoxia, including chronic obstructive pulmonary disease (COPD), interstitial lung disease, other lung diseases with mixed restrictive and obstructive disorders, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, and developmental abnormalities; WHO Group IV - chronic thromboembolic pulmonary hypertension (CTEPH); and WHO Group V - Pulmonary hypertension with an unknown multifactorial mechanism, including hematologic disorders (e.g., myeloproliferative disorders and splenectomy), systemic diseases (e.g., sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, and vasculitis), metabolic disorders (e.g., glycogen storage disease, Gaucher disease, and thyroid disease), and other causes (e.g., tumor obstruction, fibrosing mediastinitis, and dialysis-stage chronic renal failure).

[0104] For example, the therapeutically effective amount and frequency of administration of a treprostinil derivative for treating pulmonary hypertension can depend on various factors, including the type of pulmonary hypertension, the severity of the condition, the mode of administration, the subject's age, weight, general health, sex, and diet, and the subject's response to treatment, and can be determined by the treating physician. In certain embodiments, the effective daily dose of the treprostinil derivative is about 0.1-100 mg, 0.1-50 mg, 0.5-50 mg, 0.5-25 mg, 0.5-10 mg, 1-10 mg, or 1-5 mg, or a dose deemed appropriate by the treating physician, and can be administered in single or divided doses. In further embodiments, the effective daily dose of the treprostinil derivative is about 0.001-2 mg / kg body weight, 0.005-1 mg / kg body weight, 0.01-0.5 mg / kg body weight, or 0.01-0.1 mg / kg body weight, or a dose deemed appropriate by the treating physician.

[0105] In some embodiments, the treprostinil derivative is administered in a single dose or multiple doses daily (including once, twice, three times, or more daily), every other day, every third day, every week, every two weeks, every three weeks, every month, every six weeks, every two months, or every three weeks, or as frequently as deemed appropriate by the treating physician.In certain embodiments, the treprostinil derivative is administered for at least about 1 week, 2 weeks, or 3 weeks.In further embodiments, the treprostinil derivative is administered according to a chronic administration regimen.In certain embodiments, the therapeutically effective amount of the treprostinil derivative is administered for at least about 1 month, 1.5 months, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, or more.

[0106] The treprostinil derivative may be administered by any suitable route. Potential administration routes for the treprostinil derivative include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary, and intrathecal), intracavity, intraperitoneal, and topical (including cutaneous / epcutaneous, transdermal, mucosal, transmucosal, intranasal (e.g., via nasal spray or nasal drops), intraocular (e.g., via eye drops), intrapulmonary (e.g., via inhalation), buccal, sublingual, rectal, and intravaginal). In some embodiments, the treprostinil derivative is administered topically (e.g., cutaneous, transdermal, mucosal, transmucosal, intranasal, intrapulmonary (e.g., via inhalation), or sublingual). In certain embodiments, the treprostinil derivative is administered transdermally (e.g., via a transdermal patch). In other embodiments, the treprostinil derivative is administered by inhalation (e.g., oral inhalation). In a further embodiment, the treprostinil derivative is administered orally. In a further embodiment, the treprostinil derivative is administered parenterally (e.g., subcutaneously or intravenously, including by injection or infusion).

[0107] In some embodiments, the treprostinil derivative is used to treat PAH. In certain embodiments, the treprostinil derivative is administered transdermally (e.g., by a transdermal patch). In further embodiments, an additional therapeutic agent is used in combination with the treprostinil derivative to treat PAH. The additional therapeutic agent can be administered simultaneously with the administration of the treprostinil derivative or sequentially therewith (before or after). When administered simultaneously with the treprostinil derivative, the additional therapeutic agent can be contained in the same composition as the treprostinil derivative, or can be contained in a separate composition.

[0108] In certain embodiments, the additional therapeutic agent for the treatment of PAH is selected from the group consisting of: Prostaglandins and prostanoids (e.g., prostacyclin [prostaglandin I2] and its analogs, such as beraprost, cicaprost, and iloprost), other prostacyclin receptor agonists (e.g., selexipag and ACT-333679 [MRE-269]), calcium channel blockers (CCBs) (e.g., dihydropyridine-type CCBs [e.g., amlodipine and nifedipine] and non-dihydropyridine CCBs [e.g., diltiazem]), endothelin receptors (e.g., ET A and / or E.T. B vasoactive agents (e.g., vasodilators), including, but not limited to, phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, benzamidenafil, dynafil, lodenafil, mirodenafil, sildenafil, tadalafil, udenafil, vardenafil, dipyridamole, icariin, papaverine, propentofylline, zaprinast, and T-1032), soluble guanylate cyclase activators (e.g., cinaciguat and riociguat), and analogs, derivatives, and salts thereof; Diuretics, including but not limited to thiazide diuretics (e.g., bendroflumethiazide, chlorothiazide, epitizide, and hydrochlorothiazide), thiazide-like diuretics (e.g., chlorthalidone, indapamide, and metolazone), and analogs, derivatives, and salts thereof; Anticoagulants, including, but not limited to, vitamin K antagonists (e.g., acenocoumarol, atromentin, coumarin, phenindione, phenprocoumon, and warfarin), direct thrombin inhibitors (e.g., argatroban, dabigatran, hirudin, lepirudin, and bivalirudin), direct factor Xa inhibitors (e.g., apixaban, betrixaban, darexaban, edoxaban, eribaxaban, letaxaban, and rivaroxaban), heparin and its derivatives (e.g., unfractionated heparin, low molecular weight heparin, fondaparinux, and idraparinux), others (e.g., antithrombin, batroxobin, and hementin), and analogs, derivatives, fragments, and salts thereof; and Other types of therapeutic agents include, but are not limited to, cardiac glycosides (eg, digoxin, acetyldigoxin, and digoxigenin) and oxygen therapy.

[0109] VII. Synthesis of Treprostinil Derivatives R 2 is hydrogen, -OR 1The preparation of a treprostinil (Trp) derivative of Formula (I) derivatized with octyl hydroxyl and carboxyl groups of a Trp compound (e.g., Compound C in the Examples) can be carried out by reacting a Trp compound appropriately protected at the octyl hydroxyl and carboxyl groups with, for example, a carboxylic acid in the presence of an activating agent (e.g., EDC, DCC, DIC, BOP-Cl, BOP reagent, HATU, HBTU, or CDI) or a pre-prepared activated carbonyl compound (e.g., an acid chloride). The coupling reaction may include an additive (e.g., DMAP, HOSu, HOBT, or HOAT) to promote the reaction, and may also include a non-nucleophilic or nucleophilic base (e.g., TEA, DIPEA, N-methylmorpholine, pyridine, or imidazole). The coupling reaction can be carried out in a suitable solvent or solvent mixture (e.g., DCM, DMF, THF, dioxane, ethyl acetate, or acetonitrile, or any combination thereof). Coupling conditions and reagents, including activating agents, additives, and bases, are described, for example, in Handbook of Reagents for Organic Synthesis: Activating Agents and Protecting Groups, A. Pearson and W. Roush, Eds., John Wiley and Sons (1999). -OR 1 The bis-protected Trp compound derivatized in the formula (I) can be deprotected using reagents and conditions known in the art to give the Trp derivative of formula (I). See, for example, P. Wuts and T. Greene, Greene's Protective Groups in Organic Synthesis, 4 th Ed., John Wiley and Sons (2006).

[0110] R 1 is hydrogen, -OR 2The preparation of the Trp derivative of formula (I) derivatized with -OR can be carried out by appropriately protecting the cyclopentyl hydroxyl group of compound C, deprotecting the octyl hydroxyl group without deprotecting the cyclopentyl hydroxyl group or the carboxyl group, reacting the octyl hydroxyl group with an activated carbonyl compound (prepared or prepared in situ), and deprotecting the cyclopentyl hydroxyl group and the carboxyl group. 1 AND-OR 2 The preparation of Trp derivatives of formula (I) in which -OR is derivatized with different groups can be carried out by the method of the compound C described herein. 1 Derivatization of -OR 2 This can be achieved by derivatizing -OR and deprotecting the carboxyl group. 1 AND-OR 2 The preparation of Trp derivatives of formula (I) derivatized with the same group can be carried out by deprotecting the octyl hydroxyl group of compound C and then reacting with -OR as described herein. 1 AND-OR 2 and deprotecting the carboxyl group.

[0111] The Trp derivative of formula (II) can be prepared by reacting a Trp compound suitably protected at the octyl hydroxyl group (e.g., compound B in the Examples) with an alcohol suitably protected at its carboxyl group in the presence of an activating agent as described herein, followed by deprotection of the octyl hydroxyl group and the carboxyl group.

[0112] The synthesis of representative treprostinil derivatives is described in the Examples.

[0113] IX. Representative aspects The following aspects of the present disclosure are provided by way of example only. 1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof: TIFF2026021603000070.tif33128In formula, R 1and R 2 are independently hydrogen, TIFF2026021603000071.tif51147, where R 3 is, independently at each occurrence, alkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted; R 4 and R 5 is, independently in each occurrence, hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached form a C3-C6 cycloalkyl ring; R 6 is, independently in each occurrence, hydrogen, R 3 , -C(=O)R 3 , -C(=O)OR 3 , or -C(=O)NR 9 R 10 or R 6 , and R 4 or R 5 form a heterocyclic ring together with the atoms to which they are attached; R 9 and R 10 is, independently at each occurrence, hydrogen, alkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 9 and R 10 and the nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring; j is, independently in each occurrence, an integer from 0 to 4; m is, independently in each occurrence, an integer from 1 to 10; t is, independently in each occurrence, an integer from 1 to 9; however, R 1 and R 2 cannot both be hydrogen; -OR 1 Mo-OR 2 does not form acetate esters; -OR 1 Mo-OR 2 without forming benzoate esters; -OR 1 Mo-OR 2 does not form substituted cyclohexane esters; -OR 1 Mo-OR 2 does not form esters with (protected or unprotected) amino acids, peptides, or proteins, or esters thereof; and The compounds of formula (I) are not homopolymers or heteropolymers of treprostinil or contain more than one molecule or unit of treprostinil. 2. R in TIFF2026021603000072.tif9128 3 is not an alkyl substituted with a nitrogen-containing group or a cycloalkyl substituted with a carbonyl-containing group. 3. R in TIFF2026021603000073.tif9128 3 or any of the alkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is not substituted. 4. j is, independently in each occurrence, 0, 1, or 2. The compound of any one of the preceding embodiments. 5. The compound of any one of the previous embodiments, wherein m is, independently in each occurrence, an integer from 1 to 6, and / or t is, independently in each occurrence, an integer from 1 to 5. 6. R 1 and R 2 are independently hydrogen, TIFF2026021603000074.tif14128, where R 4 , R 5, R 6 and m is as defined above; and k is, independently in each occurrence, an integer from 1 to 9; However, R 1 and R 2 cannot both be hydrogen, A compound according to any one of the preceding aspects. 7. The compound according to embodiment 6, wherein k is, independently in each occurrence, an integer from 1 to 5. 8. R 3 is, independently in each occurrence, C1-C6 alkyl; R 4 and R 5 is, independently in each occurrence, hydrogen or C1-C3 alkyl, or R 4 and R 5 and the carbon atoms to which they are attached form a cyclopropyl ring; R 6 is, independently in each occurrence, hydrogen or R 3 and; R 9 and R 10 is, independently in each occurrence, C1-C6 alkyl; or R 9 and R 10 and the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic ring; j is, independently in each occurrence, 0 or 1; m is, independently in each occurrence, 1 or 2; t is, independently in each occurrence, 1 or 2; A compound according to any one of the preceding aspects. 9. R 3 is, independently in each occurrence, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl; R 4 and R 5 is independently in each occurrence hydrogen, methyl, ethyl, propyl, or isopropyl; R 6is, independently in each occurrence, hydrogen or R 3 and; R 9 and R 10 is, independently in each occurrence, C1-C3 alkyl; j is 0; m is 1; t is 1, 9. The compound of embodiment 8. 10. R 1 and R 2 became independent, hydrogen, TIFF2026021603000075.tif207167, provided that R 1 and R 2

[0023] The compound of any one of the preceding embodiments, wherein both are not hydrogen. 11. R 1 and R 2 became independent, hydrogen, TIFF2026021603000076.tif26165, provided that R 1 and R 2 and n is 0 or 1. The compound according to embodiment 10, wherein both are not hydrogen. 12. -OR 1 AND -OR 2 and wherein both are derivatized [Formula (Ic)], optionally derivatized with the same group. 13. -OR 1 AND -OR 2 12. The compound according to any one of aspects 1 to 11, wherein none of 14. R 2 is hydrogen, -OR 1 is derivatized [Formula (Ia)]. 15. R 1 is hydrogen, -OR 2 is derivatized [Formula (Ib)]. 16. TIFF2026021603000077.tif30136TIFF2026021603000078.tif225136TIFF2026021603000079.tif209142TIFF2026021603000080.tif235142TIFF2026021603000081.tif158146, and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 17. TIFF2026021603000082.tif30136TIFF2026021603000083.tif225136TIFF2026021603000084.tif209142TIFF2026021603000085.tif234142TIFF2026021603000086.tif158146, and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 18. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof: TIFF2026021603000087.tif34128 formula, -OZ-CO2H TIFF2026021603000088.tif9128, -O-heteroalkyl-COH, -O-cyclyl-COH, -O-CH-cyclyl-COH, -O-cyclyl-CH-COH, or -O-CH-cyclyl-CH-COH, each of which is optionally substituted; where: -cyclyl- is -cycloalkyl-, -heterocyclyl-, -aryl-, or -heteroaryl-; R 7 and R 8 is, independently in each occurrence, hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 7 and R8 and the carbon atoms to which they are attached form a C3-C6 cycloalkyl ring; where n is an integer between 1 and 10; however, -OZ-CO2H not TIFF2026021603000089.tif8128; and -OZ-CO2H does not contain a sugar moiety. 19. The compound of embodiment 18, wherein n is an integer from 1 to 6. 20. The compound of embodiment 18, wherein n is an integer from 3 to 10, or from 3 to 6. 21.-OZ-CO2H The compound of embodiment 18, which is not TIFF2026021603000090.tif16128. 22. If n is 1 or 2, R 7 and R 8

[0037] 19. The compound according to embodiment 18, wherein each occurrence is hydrogen. 23. R 7 and R 8 is hydrogen at each occurrence; and n is an integer from 1 to 10 or from 1 to 6. 24. The compound of embodiment 18, wherein —OZ—CO2H does not comprise a -heterocyclyl- group or a substituted-heterocyclyl- group. 25.-OZ-CO2H TIFF2026021603000091.tif13128, where R 7 and R 8 is as defined above; p is an integer from 1 to 9; and where q is an integer between 0 and 8; However, -OZ-CO2H Not TIFF2026021603000092.tif8128, 19. The compound of embodiment 18. 26. The compound according to aspect 25, wherein p is an integer from 1 to 5 and q is an integer from 0 to 4. 27. R 7and R 8 are all hydrogen atoms, and p is an integer of 1 to 5 or 1 to 3 (or R 7 and R 8 is hydrogen in each occurrence, and q is an integer from 0 to 4, or 0 to 2. 28.-OZ-CO2H 27. The compound of embodiment 25 or 26, wherein the formula is TIFF2026021603000093.tif9128 and p is 2, 3, 4, or 5. 29. -OZ-CO2H is -O-heteroalkyl-CO2H and -O-heteroalkyl-CO2H is TIFF2026021603000094.tif50163, wherein r is 1, 2, or 3. 30.-OZ-CO2H TIFF2026021603000095.tif9160, and r is 1, 2, or 3. 31. -OZ-CO2H is -O-cycloalkyl-CO2H, -O-CH2-cycloalkyl-CO2H, -O-cycloalkyl-CH2-CO2H, or -O-CH2-cycloalkyl-CH2-CO2H, and for each of said moieties, -cycloalkyl- is 1,2-cyclopropyl (cis or trans); or 1,3-cyclobutyl (cis or trans) or 1,2-cyclobutyl (cis or trans); or 1,3-cyclopentyl (cis or trans) or 1,2-cyclopentyl (cis or trans); or 1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans); 19. The compound of embodiment 18. 32.-OZ-CO2H 32. The compound of embodiment 31, selected from the group consisting of: TIFF2026021603000096.tif24146. 33. TIFF2026021603000097.tif160138TIFF2026021603000098.tif204141TIFF2026021603000099.tif37136, and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 34. TIFF2026021603000100.tif118138, and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 35. A compound selected from the group consisting of TIFF2026021603000101.tif201138TIFF2026021603000102.tif202141, and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 36. TIFF2026021603000103.tif119138, and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 37. A pharmaceutical composition comprising a compound according to any one of aspects 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers. 38. The composition of aspect 37, wherein the compound is a compound of aspect 17 or 35, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 39. The composition of aspect 38, wherein the compound is a compound of aspect 17 or 36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 40. The composition of any one of aspects 37-39, wherein the composition is configured or formulated for transdermal delivery of the compound. 41. The composition of aspect 40, which is configured or formulated as a transdermal patch. 42. A method of treating a medical condition responsive to treatment with treprostinil, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 43. The method of aspect 42, wherein the medical condition is selected from the group consisting of pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, asthma, congestive heart failure, peripheral vascular disease, severe intermittent claudication, atherogenesis (e.g., atherosclerosis), ischemic lesions (e.g., peripheral ischemic lesions on the skin, e.g., Buerger's disease, Raynaud's phenomenon, Raynaud's disease, scleroderma, and lesions caused by systemic sclerosis), critical limb ischemia, neuropathic foot ulcers (e.g., diabetic neuropathic foot ulcers), renal insufficiency and failure, immunosuppression, proliferative disorders (e.g., tumors and cancers, e.g., tumors and cancers of the head and neck, brain, lung, liver, kidney, pancreas, gastrointestinal tract [e.g., colon], prostate, and breast), and pain associated with each of the conditions. 44. The method of aspect 43, wherein the medical condition is pulmonary hypertension. 45. The method of aspect 44, wherein the medical condition is pulmonary arterial hypertension. 46. ​​The method of any one of aspects 42 to 45, wherein the compound is a compound of aspect 17 or 35, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 47. The method of aspect 46, wherein the compound is a compound of aspect 17 or 36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 48. The method of any one of aspects 42-47, wherein the route of administration of the compound comprises oral, parenteral (e.g., intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary, or intrathecal), intracavitary, intraperitoneal, or topical (e.g., cutaneous / epcutaneous, transdermal, mucosal, transmucosal, intranasal (e.g., via nasal spray or nasal drops), intraocular (e.g., via eye drops), pulmonary (e.g., via inhalation), buccal, sublingual, rectal, or vaginal), or any combination thereof. 49. The method of embodiment 48, wherein the compound is administered transdermally, for example, by a transdermal patch. 50. The medical condition is pulmonary arterial hypertension; the compound is a compound of aspect 17 or 35, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof; the compound is administered transdermally (e.g., by a transdermal patch); A method according to any one of aspects 42 to 49. 51. The method of any one of aspects 42-50, further comprising administering an additional therapeutic agent. 52. The method of embodiment 51, wherein the additional therapeutic agent comprises a vasoactive agent, a diuretic, an anticoagulant, or a cardiac glycoside, or any combination thereof. 53. A compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof; and Instructions for administering treprostinil to treat a medical condition that responds to treatment with said compound Includes a kit. 54. The kit of embodiment 53, wherein the compound is contained in or incorporated into a device or system configured for transdermal delivery (e.g., a transdermal patch). 55. The kit of aspect 53 or 54, wherein the medical condition is pulmonary hypertension (e.g., pulmonary arterial hypertension). [Example]

[0114] X. Example The following examples are intended only to illustrate the invention. Other procedures, methodologies, assays, conditions, and reagents may be used, as appropriate.

[0115] Biological assays of treprostinil derivatives Example 1. Stability assay of treprostinil derivatives The following three stability assays were performed on the treprostinil derivatives, and the results are shown in Table 1.

[0116] (Test 1) Human liver microsome stability assays were performed by incubating 0.5 μM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing 0.5 mg of microsomal protein and 50 μL of an NADPH-generating system (7.8 mg glucose 6-phosphate, 1.7 mg NADPH, and 6 units glucose 6-phosphate dehydrogenase per mL in 2% w / v sodium bicarbonate) at 37°C for up to 45 minutes. Aliquots were taken at 0, 5, 15, 30, and 45 minutes and quenched with an internal standard-containing stop solution. A no-cofactor control was prepared at 45 minutes. After incubation, samples were analyzed by LC-MS / MS. The peak area ratio of the analyte to the internal standard was used to calculate intrinsic clearance (CL). int ) was determined by nonlinear regression from the first-order elimination rate constant. The time course of the active drug, treprostinil (Compound A), was monitored by LC-MS / MS analysis.

[0117] (Test 2) Human plasma stability assays were performed by incubating 0.5 μM test compound in heparinized human plasma at 37° C. for up to 120 minutes. Aliquots were taken at 0, 5, 15, 30, 60, 120, and 240 minutes and quenched with an internal standard-containing stop solution. After incubation, samples were analyzed by LC-MS / MS. The peak area ratio of the analyte to the internal standard was used to calculate half-life. The formation of the active drug, Compound A, over time was monitored by LC-MS / MS analysis.

[0118] (Test 3) Human skin homogenate stability assays were performed similarly to the human liver microsome stability assays by incubating 0.5 μM test compound in 50 mM potassium phosphate buffer (pH 7.4) containing 0.5 mg of human skin homogenate protein and 50 μL of an NADPH-generating system (7.8 mg glucose 6-phosphate, 1.7 mg NADPH, and 6 units glucose 6-phosphate dehydrogenase per mL in 2% w / v sodium bicarbonate) at 37°C for up to 45 minutes. Aliquots were taken at 0, 5, 15, 30, and 45 minutes and quenched with an internal standard-containing stop solution. A no-cofactor control was prepared at 45 minutes. After incubation, samples were analyzed by LC-MS / MS. The peak area ratio of the analyte to the internal standard was used to calculate intrinsic clearance (CL). int ) was determined by nonlinear regression from the first-order elimination rate constant. The formation of the active drug, Compound A, over time was monitored by LC-MS / MS analysis.

[0119] The results (half-lives) of the above three stability assays are shown in Table 1. In Table 1, the half-lives of the test compounds in the assays are coded as follows: A = Less than 15 minutes B = 15~30 minutes C = 31~60 minutes D = more than 60 minutes

[0120] [Table 1]

[0121] Example 2. Skin permeability assay of treprostinil derivatives (Test 4) Skin permeability assay was performed using a diffusion area of ​​0.64 cm 2The assay was performed using a vertical Franz diffusion cell with a volume of 7.5 mL. The assay was performed at 32°C under continuous stirring. Heat-isolated human cadaver epidermis stored at -20°C after a thermal stripping procedure was used in the assay. The human epidermis was thawed and then mounted on the diffusion cell. The test compound was applied to the skin, and the diffusion cell was closed with a screw cap. The complete medium or receptor medium was replaced with fresh medium at various time intervals. A portion of the collected medium was used to calculate the cumulative skin permeability of the test compound at 72 hours. The skin permeability of various test compounds was evaluated using human epidermis from different donors. For each test compound tested on human epidermis from a particular donor, four replicates (N = 4) were performed.

[0122] The results of the skin permeation assay are shown above in Table 1. In Table 1, the cumulative skin permeation at 72 hours for test compounds tested on human epidermis from a particular donor is coded as follows: + = Low to moderate skin permeability ++ = moderate skin penetration +++ = High skin permeability ++++ = Very high skin permeability

[0123] Synthesis of Treprostinil Derivatives A representative synthesis of compounds of formula (I) and (II) is shown below.

[0124] Synthesis of {2-hydroxy-1-[3-(tetrahydropyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}acetic acid benzyl ester (compound C) A solution of {2-hydroxy-1-[3-(tetrahydropyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}acetic acid (Compound B) (2 g, 4.21 mmol), benzyl alcohol (2.47 g, 22.9 mmol), and triethylamine (7.2 g, 71.3 mmol) in dichloromethane (DCM) (20 mL) was treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) (7.8 g, 30.7 mmol) at 0 °C and stirred at room temperature (RT) for 2 h. The reaction mixture was diluted with methyl tert-butyl ether (MTBE), washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound C. MS: m / z 587 [M+Na] +

[0125] Example 3. Synthesis of [1-(3-hydroxyoctyl)-2-(2-methoxyacetoxy)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]acetic acid (Compound Ia-8) A solution of compound C (90 mg, 0.15 mmol), NEt3 (70 μL, 0.5 mmol), and 4-dimethylaminopyridine (DMAP) (1 crystal) in DCM (2 mL) was treated with methoxyacetyl chloride (21 μL, 0.22 mmol) and stirred under nitrogen at room temperature for 12 h. The reaction mixture was diluted with MTBE, washed with water and then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The THP-protected methoxyacetate was dissolved in MeOH (4 mL), treated with pyridinium paratoluenesulfonate (PPTS) (catalyst), and stirred at 50 °C for 2 h. The reaction mixture was concentrated, and the residue was dissolved in MTBE (20 mL) and washed with water and then brine to give the crude THP-deprotected methoxyacetate. The crude product was taken up in dioxane (5 mL) with 10% Pd / C (18 mg) and hydrogenated under a hydrogen atmosphere to give crude compound Ia-8 (64 mg) as an oil. MS: m / z 485 [M+Na] +

[0126] The following compounds were synthesized using procedures similar to those described above: TIFF2026021603000107.tif63133

[0127] Example 4. Synthesis of [2-(2-hydroxyacetoxy)-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]acetic acid (Compound Ia-7) A solution of compound C (100 mg, 0.177 mmol), NEt3 (77 μL, 0.55 mmol), and DMAP (1 crystal) in DCM (2 mL) was treated with benzyloxyacetyl chloride (65 mg, 0.22 mmol) and stirred under nitrogen at room temperature for 12 h. The reaction mixture was diluted with MTBE, washed with water and then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The THP-protected benzyloxyacetate was dissolved in MeOH (4 mL), treated with PPTS (catalytic), and stirred at 50 °C for 2 h. The reaction mixture was concentrated, and the residue was dissolved in MTBE (20 mL) and washed with water and then brine to give the crude THP-deprotected benzyloxyacetate. The crude product was taken up in dioxane (5 mL) with 10% Pd / C (24 mg) and hydrogenated under a hydrogen atmosphere to give crude compound Ia-7 (56 mg) as an oil. MS: m / z 471 [M+Na] +

[0128] Example 5. Synthesis of [1-(3-hydroxyoctyl)-2-methoxycarbonyloxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]acetic acid (Compound Ia-10) A solution of compound C (160 mg, 0.28 mmol) and NEt3 (798 μL, 2.8 mmol) in DCM (2 mL) was treated with phosgene solution (906 μL, 1.4 mmol, 0.5 M in toluene) at 0 °C, and the resulting mixture was stirred under nitrogen at 0 °C for 0.5 h. The reaction mixture was then added to MeOH (2 mL) at 0 °C and stirred for an additional 1 h. The solvent was removed, and the residue was purified by silica gel chromatography. The THP-protected methyl carbonate was dissolved in MeOH (4 mL), treated with PPTS (catalytic), and stirred at 50 °C for 2 h. The reaction mixture was concentrated, and the residue was dissolved in MTBE (20 mL) and washed with water and then brine to give the crude THP-deprotected methyl carbonate. The crude product was taken up in dioxane (5 mL) with 10% Pd / C (28 mg) and hydrogenated under a hydrogen atmosphere to give crude compound Ia-10 (83 mg) as an oil. MS: m / z 471 [M+Na] +

[0129] The following compounds were synthesized using procedures similar to those described above: TIFF2026021603000110.tif30128

[0130] Synthesis of [2-benzyloxycarbonyloxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]acetic acid benzyl ester (compound D) TIFF2026021603000111.tif26148 A solution of compound C (100 mg, 0.177 mmol), NEt3 (77 μL, 0.55 mmol), and DMAP (1 crystal) in DCM (2 mL) was treated with N-(benzyloxycarbonyloxy)succinimide (84 mg, 0.34 mmol) and stirred under nitrogen at room temperature for 24 h. The reaction mixture was diluted with MTBE, washed with water and then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The benzyl carbonate was dissolved in MeOH (4 mL), treated with PPTS (catalytic), and stirred at 50 °C for 2 h. The reaction mixture was concentrated, and the residue was dissolved in MTBE (20 mL) and washed with water and then brine to give crude compound D (110 mg) as an oil.

[0131] Example 6. Synthesis of {2-hydroxy-1-[3-(2-methoxyacetoxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}acetic acid (Compound Ib-8) TIFF2026021603000112.tif30152 A solution of compound D (70 mg, 0.11 mmol), NEt3 (75 μL, 0.52 mmol), and DMAP (1 crystal) in DCM (2 mL) was treated with methoxyacetyl chloride (21 μL, 0.22 mmol) and stirred under nitrogen at 0 °C for 1 h. The reaction mixture was diluted with MTBE, washed with water and then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The methoxyacetate was taken up in dioxane (5 mL) with 10% Pd / C (16 mg) and hydrogenated under a hydrogen atmosphere to give crude compound Ib-8 (43 mg) as an oil. MS: m / z 485 [M+Na] +

[0132] The following compounds were synthesized using procedures similar to those described above: TIFF2026021603000113.tif79139

[0133] Example 7. Synthesis of 3-{2-[2-hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]acetoxy}propionic acid (Compound II-4) To a solution of compound B (120 mg, 0.25 mmol), benzyl 3-hydroxypropionate (54 mg, 0.30 mmol), and trimethylamine (140 μL, 1.0 mmol) in DCM (4 mL) was added BOP-Cl (95 mg, 0.38 mmol). The reaction mixture was stirred under nitrogen at room temperature for 16 h, diluted with MTBE, washed with brine, dried over sodium sulfate, and concentrated to an oil, which was purified by silica gel chromatography. A solution of the THP-protected diester in ethanol (4 mL) was treated with PPTS (50 mg), stirred at 50 °C for 4 h, concentrated to an oil, and purified by silica gel chromatography. A solution of the THP-deprotected diester in dioxane (5 mL) was treated with wet 5% Pd / C (20 mg) and stirred under a hydrogen balloon for 24 h. The reaction mixture was filtered and concentrated to give crude compound II-4. MS: m / z 485 [M+Na] +

[0134] The following compounds were synthesized using procedures similar to those described above: TIFF2026021603000115.tif37128

[0135] While particular embodiments have been illustrated and described, it will be understood that various modifications can be made to the embodiments and are contemplated herein. It will also be understood that the present disclosure is not limited to the specific examples shown herein. The descriptions and illustrations of the embodiments and examples of the present disclosure herein are not intended to be construed in a limiting sense. Furthermore, it will be understood that all aspects of the present disclosure are not limited to the specific descriptions, configurations, or relative ratios set forth herein, which may depend on various conditions and variables. Various modifications and variations in form and details of the embodiments and examples of the present disclosure will be apparent to those skilled in the art. It is therefore contemplated that the present disclosure will cover all such modifications, variations, and equivalents.

Claims

1. A transdermal patch containing the compound of formula (I) below, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof: During the ceremony, R 1 and R 2 Hydrogen, And here R 3 In each case, independently, these are alkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and they may each be substituted; R 4 and R 5 are, in each case independently, hydrogen, C 1 to C 6 alkyl, or C 3 to C 6 cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached form a C 3 to C 6 cycloalkyl ring; R 6 In each case, independently, hydrogen and R 3 -C(=O)R 3 , -C(=O)OR 3 , or -C(=O)NR 9 R 10 Is it; or, R 6 , and R 4 or R 5 They, together with the atoms to which they are bonded, form a heterocycle; R 9 and R 10 In each case, independently, is hydrogen, alkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or, R 9 and R 10 Furthermore, the nitrogen atoms to which they are bonded form heterocyclic or heteroaryl rings; j is an integer between 0 and 4, independently in each case; m is an integer between 1 and 10, independently of the others; t is an integer from 1 to 9, independently in each case; however, R 1 and R 2 It is not the case that both are hydrogen; -OR 1 mo-OR 2 It does not form acetate esters; -OR 1 mo-OR 2 It does not form benzoic acid esters; -OR 1 mo-OR 2 It does not form substituted cyclohexane esters; -OR 1 mo-OR 2 It does not ester with (protected or unprotected) amino acids, peptides, or proteins, or form esters thereof; and The compound of formula (I) is neither a homopolymer nor a heteropolymer of treprostinyl, nor does it contain two or more molecules or units of treprostinyl; and, The compound of formula (I) is R 1 and / or R 2 but, It does not contain polymers, except when j is an integer up to 4.

2. Regarding the compound of formula (I), R 1 and R 2 Hydrogen, And here R 4 , R 5 , R 6 , and m are as defined in claim 1; and k is an integer from 1 to 9, independently of the others in each case; However, R 1 and R 2 It is not possible for both to be hydrogen. The transdermal patch according to claim 1.

3. Regarding the compound of formula (I), R 3 However, in each case independently, C 1 ~C 6 It is alkyl; R 4 and R 5 However, in each case independently, hydrogen or C 1 ~C 3 It is alkyl, or R 4 and R 5 Furthermore, the carbon atoms to which they are bonded form a cyclopropyl ring; R 6 However, in each case independently, hydrogen or R 3 And; R 9 and R 10 However, in each case independently, C 1 ~C 6 It is alkyl, or R 9 and R 10 Furthermore, the nitrogen atoms to which they are bonded form a 3- to 6-membered heterocycle; j is either 0 or 1, independently in each case; m is either 1 or 2, independently in each case; t is either 1 or 2 in each case independently. The transdermal patch according to claim 1 or 2.

4. Regarding the compound of formula (I), R 1 and R 2 They became independent, hydrogen, The group is selected from the group consisting of, however, R 1 and R 2 A transdermal patch according to any one of claims 1 to 3, wherein both are not hydrogen.

5. Regarding the compound of formula (I), R 2 is hydrogen, -OR 1 A transdermal patch according to any one of claims 1 to 4, wherein the compound is derivatized.

6. Regarding the compound of formula (I), R 1 is hydrogen, -OR 2 A transdermal patch according to any one of claims 1 to 4, wherein the compound is derivatized.

7. -OR 1 and -OR 2 The transdermal patch according to any one of claims 1 to 4, wherein both are derivatized and may be derivatized with the same group.

8. The compound of formula (I) The transdermal patch according to claim 1, comprising a compound selected from the group consisting of, as well as pharmaceutically acceptable salts, solvates, hydrates, and stereoisomers thereof.

9. A transdermal patch according to any one of claims 1 to 8, further comprising a chemopreservative.

10. A transdermal patch containing the compound of formula (II) below, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof: During the ceremony, -OZ-CO 2 Hは ,-O-(C 1 ~C 10 Heteroalkyl)-CO 2 H,-O-cyclyl-CO 2 H, -O-CH 2 -Cykrill-CO 2 H,-O-cyclyl-CH 2 -CO 2 H, or -O-CH 2 -Cykrill-CH 2 -CO 2 These are H, and they may each be substituted. Here, -Sicryl- is -cycloalkyl-, -heterocyclyl-, -aryl-, or -heteroaryl-; R 7 and R 8 are, independently in each case, hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, or R 7 and R 8 and the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl ring; n is an integer between 1 and 10; however, -OZ-CO 2 Hは Not; and -OZ-CO 2 H does not contain the sugar portion.

11. Regarding the compound of formula (II), R 7 and R 8 are each hydrogen in each case, and n is an integer of 1 to 10 or 1 to 6, the transdermal patch according to claim 10.

12. Regarding the compound of formula (II), -OZ-CO 2 Hが And here R 7 and R 8 This is as defined in claim 10; p is an integer from 1 to 9; and q is an integer between 0 and 8; However, -OZ-CO 2 H isn't it, The transdermal patch according to claim 10.

13. Regarding the compound of formula (II), -OZ-CO 2 Hが The transdermal patch according to claim 12, wherein p is 2, 3, 4, or 5.

14. Regarding the compound of formula (II), -OZ-CO 2 H is -O-(C 1 ~C 10 Heteroalkyl)-CO 2 H is -O-(C 1 ~C 10 Heteroalkyl)-CO 2 H A transdermal patch according to claim 10, selected from the group consisting of, where r is one of 1, 2, and 3.

15. Regarding the compound of formula (II), -OZ-CO 2 H is -O-cycloalkyl-CO 2 H, -O-CH 2 -Cycloalkyl-CO 2 H,-O-cycloalkyl-CH 2 -CO 2 H, or -O-CH 2 -Cycloalkyl-CH 2 -CO 2 H is H, and for each of the above parts, -cycloalkyl- is 1,2-Cyclopropyl (cis or trans); or 1,3-cyclobutyl (cis or trans) or 1,2-cyclobutyl (cis or trans); or 1,3-cyclopentyl (cis or trans) or 1,2-cyclopentyl (cis or trans); or 1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans) The transdermal patch according to claim 10.

16. The compound of formula (I) The transdermal patch according to claim 10, comprising a compound selected from the group consisting of, as well as pharmaceutically acceptable salts, solvates, hydrates, and stereoisomers (including enantiomers and racemic mixtures) thereof.

17. A transdermal patch according to any one of claims 10 to 16, further comprising a chemopreservative.

18. A transdermal patch according to any one of claims 1 to 17, further comprising a drug reservoir and a semipermeable membrane.

19. A transdermal patch according to any one of claims 1 to 17, further comprising a drug / polymer matrix.

20. A transdermal patch according to any one of claims 1 to 17, for use in the treatment of a medical condition that responds to treatment with treprostinil.

21. The transdermal patch according to claim 20, wherein the medical condition is selected from the group consisting of pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, asthma, congestive heart failure, peripheral vascular disease, severe intermittent claudication, atherosclerosis, ischemic lesions, severe limb ischemia, neuropathic foot ulcers, renal dysfunction and renal failure, immunosuppression, proliferative disorders, and pain associated with each of the conditions.

22. The transdermal patch according to claim 21, wherein the aforementioned medical condition is pulmonary hypertension, for example, pulmonary artery hypertension.

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