Treprostinyl derivatives, their compositions, and uses

Abstract

To provide treprostinil derivatives that can act as prodrugs of treprostinil.SOLUTION: The present invention discloses a compound of formula (I), or a pharmaceutically acceptable salt thereof or the like (where R1 and R2 are independently hydrogen, alkylcarbonyl, alkoxyalkylcarbonyl or the like, where, both R1 and R2 are not hydrogen, and neither -OR1 nor -OR2 form acetate, benzoate or the like).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefits of U.S. Patent Application No. 14 / 829,180 filed on 18 August 2015, and U.S. Patent Applications No. 14 / 742,544 and No. 14 / 742,579, both filed on 17 June 2015, the entire disclosures of each application are incorporated herein by reference for all purposes. [Background technology]

[0002] Background of this disclosure Pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH), is a potentially fatal condition characterized by increased pulmonary artery pressure and pulmonary vascular resistance. Several medications available to treat PH or PAH cannot be effectively administered orally for various reasons and are generally administered via subcutaneous, intravenous, or intramuscular routes. These routes of administration generally require intervention by a healthcare professional and can involve considerable discomfort and potential local trauma for the patient.

[0003] An example of such a drug is treprostinil. Treprostinil as a free acid exhibits an absolute oral bioavailability of less than 10% and has a very short systemic half-life due to significant metabolism. Treprostinil can be administered in inhalation form, but approximately 50% of PAH patients are unable to take inhaled treprostinil due to irritation. Treprostinil (also referred to herein as compound A) has the following structure: TIFF0007850537000001.tif30128 Treprostinyl can exist as a salt such as a sodium salt or a diethanolamine salt. [Overview of the project]

[0004] Summary of this disclosure In the present disclosure, treprostinil derivatives are described 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: TIFF0007850537000002.tif33128where R 1 and R 2 are each independently hydrogen, TIFF0007850537000003.tif51147and R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , j, m, and t are as described herein, provided that R 1 and R 2 are not both hydrogen; -OR 1 nor -OR 2 forms an acetate ester; -OR 1 nor -OR 2 forms a benzoate ester; -OR 1 nor -OR 2 forms a substituted cyclohexane ester; -OR 1 nor -OR 2 forms an ester with a (protected or unprotected) amino acid, peptide, or protein, or an ester thereof; The compound of formula (I) is not a homopolymer or heteropolymer of treprostinil, or does not contain more than two molecules or units of treprostinil.

[0005] In other embodiments, the treprostinil derivative has the structure of formula (II): TIFF0007850537000004.tif3412where -O-Z-CO2H is TIFF0007850537000005.tif9128, -O-heteroalkyl-CO2H, -O-cyclyl-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H, which may be substituted with -cyclyl-, -heteroalkyl-, R 7 , R 8 , and n are as described herein, however, -OZ-CO2H is Not TIFF0007850537000006.tif8128; -OZ-CO2H does not contain sugar.

[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, treprostinil derivatives are administered topically, for example, transdermally (e.g., by transdermal patches). [Modes for carrying out the invention]

[0007] Detailed explanation of this disclosure Various aspects of this disclosure are described herein, but it will be apparent to those skilled in the art that such aspects are provided only as examples. It will also be apparent to those skilled in the art that numerous modifications and changes, as well as variations and substitutions, of the aspects described herein will not depart from this disclosure. It will be understood that various alternative aspects of the aspects described herein may be used in implementing this disclosure. It will also be understood that any aspect of this disclosure may be combined with any one or more other aspects described herein that are not inconsistent with such aspect.

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

[0009] Furthermore, unless otherwise explicitly stated, in any method described or claimed herein that includes two or more acts or steps, 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, although it will be understood that this disclosure includes embodiments in which the order is thus limited.

[0010] Furthermore, if an aspect of this specification or claims is referred to as including one or more features, it will be understood that this disclosure also includes aspects consisting of or essentially comprising such features.

[0011] Furthermore, it will be understood that any aspect of this disclosure, for example, any aspect found in the prior art, may be explicitly excluded from the claims, regardless of whether or not specific exclusions are stated herein.

[0012] Headings are included herein for reference and to help locate specific sections. The headings are not intended to limit the scope of the aspects and concepts described in the sections under those headings, and such aspects and concepts may demonstrate applicability to other sections throughout the entire disclosure.

[0013] All patent and non-patent documents referenced herein are incorporated herein by reference to the same extent as each patent or non-patent document is specifically and individually directed to be incorporated herein by reference in its entirety.

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

[0015] The terms “approximately” or “about” mean an allowable error with respect to a particular value determined by those skilled in the art, and this error depends in part on how that value is measured or determined. In certain embodiments, the terms “approximately” or “about” mean within one standard deviation. In some embodiments, if no specific error limit is given (e.g., the standard deviation of the mean shown in a chart or table of data), the terms “approximately” or “about” mean a range encompassing the stated value, and similarly, a range encompassing rounding up or down to the stated value with significant figures taken into account. In certain embodiments, the terms “approximately” or “about” mean within 10% or 5% of a particular value. Whenever the terms “approximately” or “about” precede the first number in a series of numbers or a range of numbers, the terms “approximately” or “about” apply to each individual number in that series of numbers or range of numbers.

[0016] The terms "at least" when preceding the first number in a series of two or more numbers, or "greater than" when following the first number, always apply to each individual number in that series.

[0017] When the terms “less than” or “less than” appear after the first number in a sequence of two or more numbers, they always apply to each individual number in that sequence.

[0018] The term "pharmaceutically acceptable" means a substance (e.g., an active ingredient or excipient) that is suitable for use in contact with target tissues and organs without causing excessive irritation, allergic reactions, immunogenicity, or toxicity, that has a reasonable benefit-risk ratio, and that is effective for its intended use. Furthermore, a "pharmaceutically acceptable" excipient or carrier of a pharmaceutical composition is compatible with the other components of that composition.

[0019] The term "therapeutic dose" means the amount of a compound that, when administered to a subject, is sufficient to prevent or, to some extent, the onset of one or more symptoms of the medical condition being treated or associated with said condition. The term "therapeutic dose" also means the amount of a compound sufficient to induce a biological or medical response in a cell, tissue, organ, system, animal, or human being pursued by a researcher, veterinarian, physician, or clinician.

[0020] The terms “to treat,” “to treat,” and “treatment” include reducing or suppressing one or more symptoms associated with a medical condition or such condition, and reducing or eliminating one or more causes of such condition. References to “treatment” of a condition are intended to include prevention of such condition. The terms “to prevent,” “to prevent,” and “prevent” include preventing or delaying the onset of one or more symptoms associated with a medical condition or such condition, preventing a subject from contracting a condition, and reducing the risk of a subject contracting a condition. The term “medical condition” includes diseases and disorders.

[0021] The term "subject" means an animal, including but not limited to mammals such as primates (e.g., humans, chimpanzees, and monkeys), rodents (e.g., rats, mice, gerbils, and hamsters), rabbits (e.g., rabbits), pigs (e.g., pigs), horses (e.g., horses), dogs (e.g., dogs), and felines (e.g., cats). In this specification, the terms "subject" and "patient" are used interchangeably with respect to mammalian subjects, such as human subjects.

[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 alcohol [e.g., ethanol]) non-covalently bonded to the compound. A “hydrate” of a compound contains a stoichiometric or non-stoichiometric amount of water non-covalently bonded to the compound. A “clathrate” of a compound contains molecules of a substance (e.g., solvent) encapsulated within the crystalline structure of the compound. A “polymorph” of a compound is the crystalline form of the compound. In specific cases of this disclosure, the specific descriptions of “salt,” “solvate,” “hydrate,” “clathrate,” or “polymorph” of a compound shall not be construed as an intentional exclusion of any of these forms in other cases of this disclosure where the term “compound” is used without any description of any of these forms.

[0023] The terms "sugar" and "saccharides" are used interchangeably in this specification.

[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 group, where the alkyl group may be substituted with one or more substituents. In certain embodiments, the alkyl group may have 1 to 20 substituents (C 1~20 ), 1~10 pieces (C 1~10 ), or 1 to 6 (C 1~6 ) A linear saturated monovalent hydrocarbon group having carbon atoms, or 3 to 20 (C 3~20 ), 3~10 pieces (C 3~10 ), or 3-6 pieces (C 3~6 It is a branched saturated monovalent hydrocarbon group having ) carbon atoms. For example, "C 1~6 The term "alkyl" refers to a linear saturated monovalent hydrocarbon group consisting of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group consisting of 3 to 6 carbon atoms. 1~6 and branch C 3~6Alkyl groups are sometimes called "lower alkyl groups." Non-exclusive examples of alkyl groups include methyl, ethyl, propyl (including all isomers such as n-propyl and isopropyl), butyl (including all isomers such as n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including all isomers such as n-pentyl), and hexyl (including all isomers such as n-hexyl).

[0026] The terms "alkylene" and "-alkyl-" mean a divalent alkyl group which may be substituted with one or more substituents as described herein.

[0027] The term "heteroalkyl" means a linear or branched saturated monovalent hydrocarbon group containing one or more heteroatoms independently selected from O, N, and S. The terms "heteroalkylene" and "-heteroalkyl-" mean a divalent heteroalkyl group. Heteroalkyl and -heteroalkyl- groups may be substituted with one or more substituents as described herein. Examples of heteroalkyl and -heteroalkyl- groups include, but are not limited to, -(CH2)2-(O or S)-CH2CH3 and -(CH2)2-(O or S)-(CH2)2-.

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

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

[0031] The term "cycloalkyl" means a cyclic saturated crosslinked or uncrosslinked monovalent hydrocarbon group which may be substituted with one or more substituents as described herein. In certain embodiments, the cycloalkyl group has 3 to 10 (C 3~10 ), or 3 to 8 (C 3~8 ), or 3-6 pieces (C 3~6 It has a carbon atom. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, dekalinyl, and adamantyl. The term "-cycloalkyl-" means a divalent cycloalkyl group which may be substituted with one or more substituents as described herein.

[0032] The terms “heterocyclyl” and “heterocyclic” mean monocyclic non-aromatic groups or polycyclic groups containing at least one non-aromatic ring, where at least one non-aromatic ring contains one or more heteroatoms independently selected from O, N, and S. The non-aromatic ring containing one or more heteroatoms may be bonded to or fused to one or more saturated, partially unsaturated, or aromatic rings. In certain embodiments, the heterocyclyl group 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, the heterocyclyl group or heterocyclic group may include fused or bridging ring systems and may be monocyclic, bicyclic, or tricyclic ring systems in which the nitrogen or sulfur atom is oxidized, or the nitrogen atom is quaternized, and one or more rings may be fully saturated or partially saturated, or aromatic rings. A heterocyclyl group or heterocyclic group can bond to the main structure at any heteroatom or carbon atom that forms a stable compound.Examples of heterocyclyl or heterocyclic groups include azepinyl, azetidinyl, azilidinyl, benzodioxanyl, benzodioxolyl, benzofuranol, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, β-carbonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzoisothiadinyl, dihydrobenzoisooxazinyl, dihydrofuryl, dihydropyranyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, dithianyl, furanolyl, imidazolidinyl, imidazolinyl, indolinyl, indolinyl, isobenzoteto Examples include, but are not limited to, rahydrofuranil, isobenzotetrahydrothienyl, isochromanil, isoindlinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinyl, oxazolidinyl, oxyranil, piperazinyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranil (oxolanil), tetrahydroisoquinolinyl, tetrahydropyranil, tetrahydrothienyl (tetrahydrothiophenyl, thioranil), thiamorpholinyl (thiomorpholinyl), thiazolidinyl, and 1,3,5-trithianil. The term "-heterocyclyl-" means a divalent heterocyclyl group. The heterocyclyl group or heterocyclic group, and the -heterocyclyl- group, may be substituted with one or more substituents as described herein.

[0033] The term "aryl" means a monocyclic aromatic hydrocarbon group or a polycyclic group containing at least one aromatic hydrocarbon ring. In certain embodiments, the aryl group has 6 to 15, 6 to 12, or 6 to 10 ring atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, fluorenyl, azlenyl, anthryl, phenanthryl, biphenyl, and terphenyl. The aromatic hydrocarbon ring of the aryl group may 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-" means a divalent aryl group. The aryl and -aryl- groups may be substituted with one or more substituents as described herein.

[0034] The term "heteroaryl" means a monocyclic aromatic group or a polycyclic group containing at least one aromatic ring, where the at least one aromatic ring contains one or more heteroatoms independently selected from O, N, and S. The aromatic heterocycle may be bonded to or fused to one or more saturated rings, partially unsaturated rings, or aromatic rings, the latter of which may contain only carbon atoms or one or more heteroatoms. The heteroaryl group can bond to the main structure at any heteroatom or carbon atom that forms a stable compound. In certain embodiments, the heteroaryl group has 5 to 15, or 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, pyridadinyl, and triazinyl. Non-exclusive examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzothienyl (benzothiophenyl), quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzotriazolyl, indolidinyl, benzofuranil, isobenzofuranil, chromonyl, coumalinyl, sinnolinyl, quinazolinyl, quinoxalinyl, indazolyl, naphthilidinyl, phthalazinyl, quinazolinyl, purinyl, pyrrolopyridinyl, phlopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzoindolyl, dibenzofuranil, phenanthrollinyl, acridinyl, phenantridinyl, and xanthenyl. The term "-heteroaryl-" means a divalent heteroaryl group. Heteroaryl groups and -heteroaryl- groups may be substituted with one or more substituents as described herein.

[0035] Each group described herein (including, but not limited to, alkyl, heteroalkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, and heteroaryl) may be substituted with one or more substituents, either as a primary group or as a substituent. In certain embodiments, each group described herein may be a halide, cyano, nitro, hydroxyl, sulfhydryl (-SH), amino (-NH2), or -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 The substituents may be substituted with 1 to 6 substituents independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where R 11 In each case, independently, these are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 12 and R 13 In each case, independently, is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R 12 and R 13 Furthermore, the nitrogen atoms to which they are bonded form a heterocycle or heteroaryl ring.

[0036] II. stereoisomer It will be understood that this disclosure encompasses all possible diastereomers and all possible stereoisomers, including enantiomers and racemic mixtures of enantiomers, of the compounds described herein, and does not encompass only specific stereoisomers indicated by the illustrated structures or nomenclature. Some aspects of this disclosure relate to specific stereoisomers indicated by the illustrated structures or nomenclature. The specific use of phrases such as "or its stereoisomers" with respect to a compound in certain cases of this disclosure shall not be construed as an intentional exclusion of any other possible stereoisomers of the compound in other cases of this disclosure where the term "compound" is used without such phrases.

[0037] III. Treprostinyl derivatives This disclosure provides treprostinyl derivatives that can function as prodrugs of treprostinyl. In some embodiments, the treprostinyl derivative has formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof: TIFF0007850537000007.tif33128In formula, R 1 and R 2 Hydrogen, It is TIFF0007850537000008.tif50147, 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 In each case, independently, is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 4 and R 5 Furthermore, the carbon atoms to which they are bonded form a C3-C6 cycloalkyl ring; R 6 In each case, independently, hydrogen and R3 -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 These atoms, 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 a heterocycle or heteroaryl ring; j is an integer between 0 and 4, independently in each case; m is an integer between 1 and 10, independently in each case; t is an integer from 1 to 9, independently in each case; however, R 1 and R 2 It is not possible for both to be 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, nor does it form esters thereof; 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.

[0038] Treprostinyl derivatives of formula (I) are esters with (protected or unprotected) amino acids, peptides (e.g., dipeptides, tripeptides, tetrapeptides, or longer peptides), or proteins, or form esters thereof -OR 1 OR 2 or not having either. Furthermore, the compounds of formula (I) do not contain treprostinil linked to or conjugated to peptides (including polypeptides) or proteins. Furthermore, the compounds of formula (I) are independently described herein. R is TIFF0007850537000009.tif14128 1 and / or R 2 It does not contain treprostinil linked to or attached to any polymer other than those mentioned above.

[0039] The compounds of formula (I) do not contain treprostinil directly or indirectly bound to another molecular or monomeric unit of treprostinil. In some embodiments, the compounds of formula (I) do not contain treprostinil directly or indirectly bound 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 contain treprostinil directly or indirectly bound to prostacyclin (also known as prostaglandin I2 or epoprostenol) or its analogues (e.g., beraprost, cicaprost, or iloprost), or to another prostaglandin or its analogue. In further embodiments, the compounds of formula (I) do not contain treprostinil indirectly bound to another therapeutic agent by a linker containing a hydroxyl group and a carboxyl group (e.g., β-hydroxybutyrate, 6-hydroxyhexanoic acid, hydroxyl-polyethylene glycol-carboxylic acid, glycolic acid, or lactic acid).

[0040] In certain cases, R in TIFF0007850537000010.tif9128 3is not an alkyl substituted with a nitrogen-containing group, nor a cycloalkyl substituted with a carbonyl-containing group. In a further aspect, R in TIFF0007850537000011.tif9128 3 neither the alkyl group nor the cycloalkyl group is substituted. In yet a further aspect, R in TIFF0007850537000012.tif9128 3 none of the alkyl group, haloalkyl group, -alkylaryl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is substituted.

[0041] In a further aspect, R in TIFF0007850537000013.tif9128 3 is not alkyl, unsubstituted alkyl, or substituted alkyl. In some aspects, R in TIFF0007850537000014.tif9128 3 is not haloalkyl, unsubstituted haloalkyl, or substituted haloalkyl. In certain aspects, R in TIFF0007850537000015.tif9128 3 is not -alkylaryl, unsubstituted -alkylaryl, or substituted -alkylaryl. In a further aspect, R in TIFF0007850537000016.tif9128 3 is not cycloalkyl, unsubstituted cycloalkyl, or substituted cycloalkyl. In other aspects, R in TIFF0007850537000017.tif9128 3 is not heterocyclyl, unsubstituted heterocyclyl, or substituted heterocyclyl. In yet other aspects, R in TIFF0007850537000018.tif9128 3 is not aryl, unsubstituted aryl, or substituted aryl. In yet other aspects, R in TIFF0007850537000019.tif91283 is not heteroaryl, unsubstituted heteroaryl, or substituted heteroaryl.

[0042] In some embodiments, R in TIFF0007850537000020.tif9128 3 is not alkyl, unsubstituted alkyl, or substituted alkyl. In certain embodiments, R in TIFF0007850537000021.tif9128 3 is not haloalkyl, unsubstituted haloalkyl, or substituted haloalkyl. In further embodiments, R in TIFF0007850537000022.tif9128 3 is not -alkylaryl, unsubstituted -alkylaryl, or substituted -alkylaryl. In further embodiments, R in TIFF0007850537000023.tif9128 3 is not cycloalkyl, unsubstituted cycloalkyl, or substituted cycloalkyl. In other embodiments, R in TIFF0007850537000024.tif9128 3 is not heterocyclyl, unsubstituted heterocyclyl, or substituted heterocyclyl. In still further embodiments, R in TIFF0007850537000025.tif9128 3 is not aryl, unsubstituted aryl, or substituted aryl. In still further embodiments, R in TIFF0007850537000026.tif9128 3 is not heteroaryl, unsubstituted heteroaryl, or substituted heteroaryl.

[0043] In certain embodiments, R in any one of TIFF0007850537000027.tif14164 6 is not hydrogen. In some embodiments, R in any one of TIFF0007850537000028.tif141666 R in the description 3 is not alkyl, unsubstituted alkyl, or substituted alkyl. In further embodiments, R in any one of TIFF0007850537000029.tif14165 6 R in the description 3 is not a haloalkyl, unsubstituted haloalkyl, or substituted haloalkyl. In further embodiments, R in any one of TIFF0007850537000030.tif14165 6 R in the description 3 It is not an alkylaryl, unsubstituted alkylaryl, or substituted alkylaryl. In further embodiments, R in any one of TIFF0007850537000031.tif14164 6 R in the description 3 is not a cycloalkyl, unsubstituted cycloalkyl, or substituted cycloalkyl. In other embodiments, R in any one of TIFF0007850537000032.tif14165 6 R in the description 3 is not a heterocyclyl, an unsubstituted heterocyclyl, or a substituted heterocyclyl. In other embodiments, R in any one of TIFF0007850537000033.tif14165 6 R in the description 3 It is not an aryl, a non-substituted aryl, or a substituted aryl. In other embodiments, R in any one of TIFF0007850537000034.tif14166 6 R in the description 3 It is not a heteroaryl, unsubstituted heteroaryl, or substituted heteroaryl.

[0044] In some embodiments, j is 0, 1, or 2, independently in each case. In certain embodiments, j is 0. In further embodiments, m is an integer between 1 and 6, or between 1 and 3, independently in each case. In further embodiments, t is an integer between 1 and 5, or between 1 and 3, independently in each case.

[0045] In some embodiments, R 1 and R 2 Hydrogen, TIFF0007850537000035.tif14128, where R 4 , R 5 , R 6 , and m are as defined above, and k is an integer from 1 to 9 in each case, however R 1 and R 2 Both cannot be hydrogen. In certain embodiments, k is an integer between 1 and 5, or between 1 and 3, independently in each case.

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

[0047] In some embodiments, R 1 and R 2 Independently, hydrogen or TIFF0007850537000036.tif9128, however, R 1 and R 2 Both cannot be hydrogen. In certain embodiments, R 3 In each case, independently, R is a C2-C6 alkyl, a C3-C6 cycloalkyl, or a 3-6 membered heterocycline. In some embodiments, R 3 In each case, the elements are independently C2-C6 alkyl groups.

[0048] In a further embodiment, R 1 and R 2 Independently, hydrogen or TIFF0007850537000037.tif13128, however, R 1 and R 2 Both cannot be hydrogen. In some embodiments, R 4 and R 5 In each case, is hydrogen, and the α carbon atom (adjacent to the carbonyl group) may be substituted with a C1-C3 alkyl group, R 6 In each case, independently, is hydrogen or a C1-C6 alkyl group, and in each case, independently, is an integer from 1 to 6 or from 1 to 3. In certain embodiments, R 4 and R 5In each case, is hydrogen, and the α carbon atom may be substituted with a methyl group, R 6 In each case, is independently hydrogen or a C1-C3 alkyl group (e.g., methyl), and m is independently an integer between 1 and 6, or between 1 and 3, in each case.

[0049] In further embodiments, R 1 and R 2 Hydrogen, TIFF0007850537000038.tif13128, however, R 1 and R 2 Both cannot be hydrogen. In some embodiments, R 4 and R 5 In each case, is it hydrogen, or R 4 In each case, is hydrogen, and R 5 In each case, R is a C1-C3 alkyl group; 6 In each case, is independently hydrogen or a C1-C6 alkyl group; and in each case, is independently 0, 1, or 2. In certain embodiments, R 4 and R 5 In each case, is it hydrogen, or R 4 In each case, is hydrogen, and R 5 In each case, it is methyl; R 6 In each case, is independently hydrogen or a C1-C3 alkyl group (e.g., methyl); and in each case, is independently 0 or 1.

[0050] In a further embodiment, R 1 and R 2 Independently, hydrogen or TIFF0007850537000039.tif9128, however, R 1 and R 2 Both cannot be hydrogen. In some embodiments, R 3 In each case, R is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In certain embodiments, R 3In each case, these are independently C1-C3 alkyl or C1-C3 haloalkyl.

[0051] In other embodiments, R 1 and R 2 Independently, hydrogen or TIFF0007850537000040.tif10128, however, R 1 and R 2 Both cannot be hydrogen. In some embodiments, R 6 In each case, R is independently hydrogen or a C1-C6 alkyl group, and t is independently an integer from 1 to 5 or from 1 to 3 in each case. In certain embodiments, R 6 In each case, is independently hydrogen or a C1-C3 alkyl group (e.g., methyl), and t is independently an integer between 1 and 6, or between 1 and 3, in each case.

[0052] In other embodiments, R 1 and R 2 Independently, hydrogen or TIFF0007850537000041.tif10128, however, R 1 and R 2 Both cannot be hydrogen. In some embodiments, R 6 In each case, is independently hydrogen or a C1-C6 alkyl group, and j is independently 0, 1, or 2 in each case. In certain embodiments, R 6 In each case, is independently hydrogen or a C1-C3 alkyl group (e.g., methyl), and j is independently 0 or 1 in each case.

[0053] In a further embodiment, R 1 and R 2 Independently, hydrogen or TIFF0007850537000042.tif10128, however, R 1 and R 2 Both cannot be hydrogen. In some embodiments, R 9 and R 10In each case, it is either a C1-C6 alkyl group or R 9 and R 10 Furthermore, the nitrogen atoms to which they are bonded form a 3- to 6-membered heterocycle, and t is an integer between 1 and 5, or between 1 and 3, independently in each case. In certain embodiments, R 9 and R 10 In each case, is independently a C1-C3 alkyl group (e.g., methyl), and t is independently an integer between 1 and 6, or between 1 and 3, in each case.

[0054] In a further embodiment, R 1 and R 2 Hydrogen, TIFF0007850537000043.tif17128, however, R 1 and R 2 Both cannot be hydrogen. In some embodiments, R 6 In each case, R is independently hydrogen or a C1-C6 alkyl group. In certain embodiments, R 6 In each case, the element is independently a C1-C3 alkyl group (e.g., methyl).

[0055] In some embodiments, R 1 and R 2 They are independently selected from the following group: hydrogen, In formula TIFF0007850537000044.tif205166, each portion having a stereocenter adjacent to a carbonyl group or elsewhere may have a (R)-stereochemical configuration or a (S)-stereochemical configuration, and may be racemic at the stereocenter. However, R 1 and R 2 It is impossible for both to be hydrogen. In this disclosure, (1) R 2 is hydrogen, -OR 1 (2) R 1 is hydrogen, -OR 2(3) -OR 1 and -OR 2 Treprostinyl derivatives are specifically described, in which all of the above parts are derivatized at the same portion and at each of the above-mentioned parts (excluding hydrogen). In a particular embodiment, R 1 and R 2 They are independently selected from the following group: hydrogen, TIFF0007850537000045.tif27166 However, R 1 and R 2 It is impossible for both to be hydrogen.

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

[0057] In certain embodiments, the treprostinyl derivative of formula (I) is selected from the group consisting of the following: TIFF0007850537000046.tif30135TIFF0007850537000047.tif225136TIFF0007850537000048.tif209142TIFF0007850537000049.tif234142TIFF0007850537000050.tif158146 and their pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures).

[0058] In other embodiments, the treprostinyl derivative has formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof: TIFF0007850537000051.tif34128In formula, -OZ-CO2H is TIFF0007850537000052.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. Here, -Sicryl- is a -cycloalkyl-, -heterocyclyl-, -aryl-, or -heteroaryl-; R 7 and R 8 In each case, independently, is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 7 and R 8 Furthermore, the carbon atoms to which they are bonded form a C3-C6 cycloalkyl ring; n is an integer between 1 and 10; however, -OZ-CO2H is Not TIFF0007850537000053.tif8128; -OZ-CO2H does not contain sugar.

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

[0060] In certain embodiments, -OZ-CO2H is It is not TIFF0007850537000054.tif16128. In a further embodiment, if n is 1 or 2, R 7 and R 8 In each case, it is hydrogen.

[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-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H is not a -cycloalkyl-, unsubstituted -cycloalkyl-, or substituted -cycloalkyl-. In other embodiments, the -cyclyl- in -O-cyclyl-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H is not a -heterocyclyl-, unsubstituted -heterocyclyl-, or substituted -heterocyclyl-. In yet another embodiment, the -cyclyl- in -O-cyclyl-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H is not -aryl-, unsubstituted -aryl-, or substituted -aryl-. In yet another embodiment, the -cyclyl- in -O-cyclyl-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H is not -heteroaryl-, unsubstituted -heteroaryl-, or substituted -heteroaryl-.

[0063] In some embodiments, -OZ-CO2H is The file is TIFF0007850537000055.tif9128, however, -OZ-CO2H is It is not TIFF0007850537000056.tif8128. In certain aspects, R 7 and R 8 In each case, is hydrogen, and the carbon atom adjacent to the ester oxygen atom may be 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 8In each case, is hydrogen, and the carbon atom adjacent to the ester oxygen atom may be substituted with a C1-C3 alkyl (e.g., methyl) group, and n is an integer from 1 to 6, or from 1 to 3.

[0064] In a further embodiment, -OZ-CO2H is TIFF0007850537000057.tif13128, where R 7 and R 8 As defined above, p is an integer from 1 to 9, and q is an integer from 0 to 8, however, -OZ-CO2H is It is not TIFF0007850537000058.tif8128. In certain embodiments, p is an integer between 1 and 5, or between 1 and 3, and q is an integer between 0 and 4, or between 0 and 2. In some embodiments, R 7 and R 8 In all cases, these are hydrogen atoms, and p is an integer from 1 to 5, or from 1 to 3 (or R 7 and R 8 (where is hydrogen in each case, and q is an integer between 0 and 4, or between 0 and 2). In this disclosure, R 7 and R 8 Treprostinyl derivatives are specifically described, where all are hydrogen atoms and p is one of 1, 2, 3, 4, 5, 6, 7, 8, and 9. In a further embodiment, -OZ-CO2H is The filename is TIFF0007850537000059.tif10128, where p is 2, 3, 4, or 5. In this disclosure, -OZ-CO2H is A treprostinyl derivative is specifically described, which is TIFF0007850537000060.tif10128, where p is one of 2, 3, 4, 5, 6, 7, 8, and 9, and the stereocenter bonded to the methyl group may have a (R)-stereochemical configuration or a (S)-stereochemical configuration and may be racemic at that position.

[0065] In a further embodiment, -OZ-CO2H is TIFF0007850537000061.tif12128, where the A ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and u is an integer from 0 to 9. In this disclosure, treprostinyl derivatives are specifically described in which the A ring is one of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and u is one of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9. In certain embodiments, -OZ-CO2H is The expression is TIFF0007850537000062.tif11128, where u is an integer from 0 to 9 or from 0 to 5. In addition, in this disclosure, -OZ-CO2H is A specific treprostinyl derivative is described, which is TIFF0007850537000063.tif11128 and where u is one of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9.

[0066] In other embodiments, -OZ-CO2H is -O-heteroalkyl-CO2H, and -O-heteroalkyl-CO2H is selected from the group consisting of: In formula TIFF0007850537000064.tif50163, r is one of 1, 2, and 3; Each portion having a stereocenter adjacent to the oxygen atom bonded to treprostinyl, and / or a stereocenter adjacent to the carboxyl group, may independently have either an (R)-stereochemical configuration or an (S)-stereochemical configuration, and may be racemic at its stereocenters. This disclosure specifically describes treprostinyl derivatives in which -OZ-CO2H is a part in the group. In certain embodiments, -OZ-CO2H is The filename is TIFF0007850537000065.tif9161, where r is 1, 2, or 3.

[0067] In a further embodiment, -OZ-CO2H is -O-cycloalkyl-CO2H, -O-CH2-cycloalkyl-CO2H, -O-cycloalkyl-CH2-CO2H, or -O-CH2-cycloalkyl-CH2-CO2H, where 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 These are 1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans). This disclosure specifically describes 64 treprostinyl derivatives in which -OZ-CO2H is a part of the group. In certain embodiments, -OZ-CO2H is selected from the group consisting of: In formula TIFF0007850537000066.tif24146, for each part, the two groups on the cycloalkyl ring can be cis or trans relative to each other.

[0068] In some embodiments, the treprostinyl derivative of formula (II) is selected from the group consisting of the following: TIFF0007850537000067.tif160138TIFF0007850537000068.tif204142TIFF0007850537000069.tif37136 and their pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures).

[0069] The treprostinyl derivatives described herein are available or usable in the form of pharmaceutically acceptable salts. Treprostinyl derivatives have a carboxyl group and can therefore 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 forming base addition salts include chloroprocaine, choline, cyclohexylamine, dibenzylamine, N,N'-dibenzylethylenediamine, 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 (e.g., a basic nitrogen atom), it can form an addition salt with an acid. Non-limiting examples of acids useful for forming acid addition salts include mineral acids (e.g., HCl, HBr, HI, nitric acid, phosphoric acid, and sulfuric acid), as well as organic acids such as carboxylic acids (e.g., acetic acid) and sulfonic acids (e.g., 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 treprostinyl compounds To remove foreign substances such as drugs, the animal's body produces cytochrome P 450Various enzymes, such as esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, are expressed, and these enzymes react with xenobiotics for renal excretion, converting them into highly polar intermediates or metabolites. Such metabolic reactions may involve the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) bonds or carbon-carbon (C=C) π bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacological, pharmacokinetic, and pharmacodynamic properties, as well as toxicity profiles, compared to the parent compound. In many drugs, such metabolic oxidation may be rapid, necessitating increased doses and / or increased frequency of administration, which may lead to increased side effects.

[0072] This disclosure provides treprostinyl isotope substitutions corresponding to the treprostinyl derivatives described herein, which are deuterated (deuterated) at one or more positions. In some embodiments, the treprostinyl derivative is deuterated at one or more positions in the parent treprostinyl structure, and therefore, when the derivative is converted to treprostinyl in vivo, the resulting active parent drug is deuterated at one or more positions.

[0073] Deuteration of treprostinyl compounds at one or more positions may result in any one, more, or all of the following benefits: (1) extension of half-life; (2) reduction of the dose and / or number of doses required to achieve the desired effect; (3) reduction of inter-subject variability in blood or plasma levels of the parent drug; (4) increased efficacy; (5) reduction of side effects due to a reduction in the amount of parent drug administered and / or reduction in the production of harmful metabolites; and (6) increased maximum tolerated dose.

[0074] In any one, more, or all of the available positions in a treprostinyl (Trp) compound, for example, hydrogen can be replaced with deuterium at any one, 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 hydroxyacetic acid group of Trp, or any combination thereof. In certain embodiments, the treprostinyl derivative is deuterated at any one, more, or all of the available positions in the cyclohexyl ring of Trp and / or the hydroxyacetic acid 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) treprostinyl derivative independently exhibits a deuterium enrichment of at least about 10%, 25%, 50%, 75%, 90%, 95%, or 98%. In particular embodiments, each deuterium-enriched position independently exhibits a deuterium enrichment of at least about 90%, 95%, or 98%.

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

[0077] The term "deuterium enrichment" refers to the proportion of a molecule in which deuterium is incorporated instead of hydrogen at a given position. 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 “deuterized” or “deuterated” used to describe a given position in a molecule, or the symbol “D” used to represent an element at a given position in a molecular diagram, mean that the particular position is deuterized beyond its natural distribution. 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%) of deuterium at a particular position. In certain embodiments, the deuterium enrichment is at least about 90%, 95%, or 98% of deuterium at a particular position.

[0079] V. Pharmaceutical composition Further aspects of this disclosure relate to a pharmaceutical composition comprising one or more treprostinil derivatives described herein, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or polymorph thereof, and one or more pharmaceutically acceptable excipients or carriers. The composition may contain further therapeutic agents.

[0080] Pharmacovigilant excipients and carriers include pharmaceutically acceptable substances, materials, and media. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption retarders, sweeteners, flavorings, colorants, stabilizers, preservatives, antioxidants, antimicrobial agents, antibacterial agents, antifungal agents, auxiliaries, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is well known in the art. For example, conventional media and carriers include, but are not limited to, oils (e.g., vegetable oils such as sesame oil), aqueous solvents (e.g., saline and phosphate-buffered saline [PBS]), and solvents (e.g., dimethyl sulfoxide [DMSO] and alcohols [such as ethanol and glycerin]). Except where any conventional excipient or carrier is incompatible with the active ingredient (with respect to the contents of a pharmaceutical composition, the term “active ingredient” encompasses prodrugs), this disclosure includes the use of conventional excipients and carriers in formulations containing treprostinil derivatives. See, for example, 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 formulation may depend on various factors, including the chosen 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 subarachnoid), intracavitary, intraperitoneal, and topical (including skin / supercutaneous, percutaneous, mucous membrane, transmucosal, intranasal [e.g., by nasal spray or nasal drop], intraocular [e.g., by eye drop], intrapulmonary [e.g., by inhalation], buccal, sublingual, rectal, and vaginal). Topical formulations may be designed to produce local or systemic therapeutic effects.

[0082] As an example, formulations of treprostinil derivatives suitable for oral administration may be presented, for example, as capsules (including push-fit capsules and soft capsules), cachets, or tablets; as powders or granules; or as boluses, licks, or pastes. For example, push-fit capsules may contain a mixture of the treprostinil derivative with, for example, a filler (e.g., lactose), a binder (e.g., starch), and a lubricant (e.g., talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the treprostinil derivative can be dissolved or suspended in a suitable liquid (e.g., fatty oil, liquid paraffin, or liquid polyethylene glycol), and a stabilizer may be added.

[0083] Furthermore, the oral administration composition can be formulated as a solution or suspension in aqueous and / or non-aqueous liquids, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A dispersible powder or granule of a treprostinil derivative can be mixed with any suitable combination of aqueous liquid, organic solvent, and / or oil and any suitable excipient (e.g., any combination of dispersants, wetting agents, suspending agents, emulsifiers, and / or preservatives) to form a solution, suspension, or emulsion.

[0084] Furthermore, 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. Further advantages of intravenous administration include the ability to directly deliver the therapeutic agent into the systemic circulation to achieve a rapid systemic effect, and the ability to deliver the therapeutic agent continuously and / or in large quantities as needed. Formulations for injection or infusion may be in the form of solutions, suspensions, or emulsions in oily or aqueous media, for example, and may contain excipients such as suspending agents, dispersants, and / or stabilizers. For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions may contain treprostinil derivatives together with excipients such as antioxidants, buffers, bacteriostatic agents, and solutes to make the formulation isotonic with the target blood. Aqueous or non-aqueous sterile suspensions may contain treprostinil derivatives together with excipients such as suspending agents and thickeners, and optionally stabilizers, and agents that increase the solubility of the treprostinil derivative to enable the preparation of higher concentration solutions or suspensions. As another example, sterile aqueous solutions for injection or infusion (e.g., subcutaneous or intravenous) may contain treprostinil derivatives, sodium chloride, buffers (e.g., sodium citrate), preservatives (e.g., m-cresol), and optionally bases (e.g., NaOH) and / or acids (e.g., HCl) to adjust the pH.

[0085] In some embodiments, typical dosage forms of treprostinil derivatives are formulated as buccal or sublingual tablets or pills. Advantages of buccal or sublingual tablets or pills include avoidance of gastrointestinal absorption and first-pass metabolism, as well as rapid absorption into the systemic circulation. Buccal or sublingual tablets or pills can be designed to enable more rapid release of treprostinil derivatives for even faster uptake into the systemic circulation. Tablets or pills for buccal or sublingual use may contain, in addition to a therapeutically effective amount of 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), humectants (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), flavorings (e.g., spearmint flavoring), sweeteners (e.g., sucralose), and colorants (e.g., iron yellow).

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

[0087] Furthermore, treprostinil derivatives can be formulated for oral inhalation administration. Advantages of inhalation administration include avoiding first-pass metabolism, the ability to tailor the therapeutic agent to rapid delivery through the mucous membrane of the airways, or more selective deposition of the therapeutic agent in the stomach with fewer systemic side effects. In certain embodiments, the sterile aqueous solution for oral inhalation contains a treprostinil derivative, sodium chloride, a buffer (e.g., sodium citrate), possibly a preservative (e.g., m-cresol), and possibly a base (e.g., NaOH) and / or acid (e.g., HCl) to adjust the pH.

[0088] For delayed or sustained release of treprostinil derivatives, the composition can be formulated as a depot formulation that can be implanted or injected, for example, intramuscularly or subcutaneously, into a target. The depot formulation can be designed to deliver the treprostinil derivative over a relatively long period, for example, at least about 1 week, 2 weeks, 3 weeks, 1 month, 1.5 months, 2 months, or longer. For example, the treprostinil derivative can be formulated with a polymer material (e.g., polyethylene glycol [PEG], polylactic acid [PLA], or polyglycolic acid [PGA], or a copolymer thereof [e.g., PLGA]), with a hydrophobic material (e.g., as an emulsion in oil), and / or with an ion exchange resin, or as a poorly soluble derivative (e.g., a poorly soluble salt). As an example, the treprostinil derivative can be incorporated into or embedded in sustained-release microparticles composed of PLGA and formulated as a monthly depot formulation.

[0089] Furthermore, treprostinyl derivatives can be contained in or dispersed in the matrix material. The matrix material may contain 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, thereby increasing the stability of the compound while it is contained in the reservoir. Such “release systems” may be configured as transdermal or transmucosal patches and may contain excipients that can promote the release of the compound, such as water-swellable materials (e.g., hydrogels) that help to expel the compound from the reservoir. Examples of such release systems are described in U.S. Patents 4,144,317 and 5,797,898.

[0090] The release system can exhibit a time-regulated release profile (e.g., pulsed release) when temporal variation in plasma levels is desired, or a more continuous or consistent release profile when a constant plasma level is desired. Pulsed release can be achieved from individual reservoirs or multiple reservoirs. For example, if each reservoir provides only a single pulse, multiple pulses ("pulsed" release) can be achieved by releasing single pulses from multiple reservoirs at time intervals. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of the release system and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system that decomposes, elutes, or disperses compounds over a long period of time. Furthermore, it can be simulated as continuous release by releasing several pulses of a compound in succession ("digital" release). Active release systems can be used alone or in combination with passive release systems as described in U.S. Patent No. 5,797,898.

[0091] Pharmaceutical compositions can be prepared in any preferred manner known in the art, for example, by conventional processes such as mixing, dissolving, suspending, granulating, sugar-coating, wet grinding, emulsifying, encapsulating, or compressing.

[0092] This composition may be presented in a single-dose unit formulation. In the unit formulation, all active and non-active ingredients are combined in a suitable system, and the components do not need to be mixed to form the composition to be administered. The unit formulation may contain an effective amount or a suitable portion of the treprostinil derivative. Typical examples of unit formulations are tablets, capsules, or pills for oral administration.

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

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

[0095] VI. Topical composition containing a transdermal delivery system Topical formulations applied to the skin or mucous membranes may be useful for transdermal or transmucosal administration of therapeutic agents into the bloodstream for systemic distribution. Advantages of topical administration 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, greater homogenization of the plasma delivery or delivery profile of therapeutic agents, reduced frequency of administration, minimized or absent invasiveness, easier self-administration, and improved patient compliance. With respect to the contents of a pharmaceutical composition, the terms “therapeutic agent” or “drug” encompass prodrugs.

[0096] In general, and in addition to the disclosures relating to topical formulations described elsewhere in this specification, suitable compositions for topical administration include, but are not limited to, liquid or semi-liquid formulations such as sprays, gels, liniments, lotions, and oil-in-water or water-in-oil emulsions such as creams, foams, ointments, and pastes, as well as solutions or suspensions such as droplets (e.g., eye drops, nasal drops, and ear drops). In some embodiments, a topical composition comprises a therapeutic agent dissolved, dispersed, or suspended in a carrier. The carrier may be, for example, a solution, suspension, emulsion, ointment, or gel base, and may contain, for example, petrolatum, lanolin, wax (e.g., beeswax), mineral oil, long-chain alcohol, polyethylene glycol or polypropylene glycol, diluents (e.g., water and / or alcohol [e.g., ethanol or propylene glycol]), emulsifiers, stabilizers, or thickeners, or any combination thereof. A topical composition may include, for example, a transdermal patch, a microneedle patch, or a transdermal or transmucosal delivery device such as an ion electrophoresis device. Alternatively, topical formulations can be administered by means of this. Topical compositions can deliver drugs transdermally or transmucosally by concentration gradient (with or without the use of chemiosmotic enhancers) or by an active mechanism (e.g., ion electrophoresis or microneedles).

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

[0098] VII. Therapeutic use of treprostinil derivatives The treprostinil derivatives described herein are convertible to treprostinil in vivo and are therefore capable of acting as prodrugs of treprostinil. In some embodiments, the treprostinil derivative is slowly and partially converted to treprostinil in the blood or skin (e.g., when administered transdermally) (e.g., conversion rates of less than about 30%, less than about 20%, less than about 10%, or less than about 5%) and rapidly and substantially completely converted to treprostinil in the liver (e.g., conversion rates of at least about 70%, 80%, 90%, or 95%). In other embodiments, the treprostinil derivative is converted to a considerable amount (e.g., conversion rates of at least about 30%, 40%, 50%, or 60%) or substantially completely (e.g., conversion rates of at least about 70%, 80%, 90%, or 95%) in the blood. In yet another embodiment, the treprostinil derivative is administered transdermally and converted to treprostinil to some extent in the skin (e.g., conversion rates of less than about 30%, less than about 20%, or less than about 10%) without causing significant side effects, such as irritation, at the injection site. In yet another embodiment, the treprostinil derivative is at least about 50, 100, 500, or 1000 times (e.g., at least about 100 times) 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, portal pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, ischemic diseases (e.g., myocardial ischemia, ischemic stroke, peripheral vascular disease [including peripheral artery disease], ischemic limbs, Raynaud's phenomenon [including Raynaud's disease and Raynaud's syndrome], scleroderma [including systemic sclerosis], and renal failure), ischemic ulcers (e.g., finger ulcers), cardiovascular diseases (e.g., coronary artery disease), heart failure (e.g., congestive heart failure), conditions requiring anticoagulation (e.g., post-myocardial infarction and post-cardiac surgery) atherosclerosis (e.g., atherosclerosis), thrombotic microangiopathy, venous occlusion (e.g., central retinal vein occlusion), hypertension (e.g., pre-eclampsia), diabetic vascular disorders, extracorporeal circulation, inflammatory diseases (e.g., chronic obstructive pulmonary disease [COPD] and psoriasis), reproduction and childbirth, uncontrolled cell proliferation conditions (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 prostacyclin or treprostinil-responsive conditions selected from the group consisting of: Pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, asthma, congestive heart failure, peripheral vascular disease, severe intermittent claudication, atherosclerosis (e.g., atherosclerosis), ischemic lesions (e.g., peripheral ischemic skin lesions, e.g., lesions caused by Buerger's disease, Raynaud's phenomenon, Raynaud's disease, scleroderma, and systemic sclerosis), severe ischemic limbs, neuropathic foot ulcers (e.g., diabetic neuropathic foot ulcers), renal insufficiency and renal failure, immunosuppression, proliferative disorders (e.g., tumors and cancers of the head and neck, brain, lungs, liver, kidneys, pancreas, gastrointestinal tract [e.g., colon], prostate, and breast), and pain associated with each of the aforementioned conditions.

[0101] Treprostinil derivatives can be used in combination with additional therapeutic agents to treat any condition that responds to treatment with prostacyclin or treprostinil. As a non-limiting example, 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, to treat vascular (e.g., cardiovascular) disorders.

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

[0103] Pulmonary hypertension is an elevated blood pressure in the pulmonary vascular system, including the pulmonary arteries, pulmonary veins, and pulmonary capillaries. Therefore, pulmonary hypertension encompasses pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH) (e.g., congestive heart failure). More broadly, pulmonary hypertension includes: WHO Group I - Pulmonary artery 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 anemia]), 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, impaired alveolar hypoventilation, chronic exposure to high altitude, and developmental abnormalities; WHO Group IV - Chronic thromboembolic pulmonary hypertension (CTEPH); and WHO Group V - Pulmonary hypertension with unknown multifactorial mechanisms, including hematological 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 disorders), and other causes (e.g., tumor obstruction, fibrous mediastinitis, and chronic renal failure on dialysis).

[0104] For example, the effective daily dose and frequency of administration of treprostinil derivatives for treating pulmonary hypertension may depend on various factors, including the type of pulmonary hypertension, the severity of the condition, the mode of administration, the patient's age, weight, general health, sex, and diet, as well as the patient's response to treatment, and can be determined by the treating physician. In certain embodiments, the effective daily dose of treprostinil derivatives may be approximately 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 may be administered as a single dose or in divided doses. In further embodiments, the effective daily dose of treprostinil derivatives may be approximately 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, treprostinil derivatives are administered in single or multiple doses daily (including once, twice, three times, or more times daily), every two days, every three days, weekly, every two weeks, every three weeks, monthly, every six weeks, every two months, or every three weeks, or at a frequency deemed appropriate by the treating physician. In certain embodiments, treprostinil derivatives are administered for at least approximately one week, two weeks, or three weeks. In further embodiments, treprostinil derivatives are administered based on a chronic administration regimen. In certain embodiments, a therapeutically effective dose of treprostinil derivative is administered for at least approximately one month, one and a half months, two months, three months, four months, five months, six months, one year, or longer.

[0106] Treprostinil derivatives may be administered by any preferred route. Potential routes of administration of treprostinil derivatives include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary, and subarachnoid), intracavitary, intraperitoneal, and topical (including skin / supercutaneous, transdermal, mucous membrane, transmucosal, intranasal [e.g., by nasal spray or nasal drop], intraocular [e.g., by eye drop], intrapulmonary [e.g., by inhalation], buccal, sublingual, rectal, and vaginal). In some embodiments, treprostinil derivatives are administered topically (e.g., skin, transdermal, mucous membrane, transmucosal, intranasal, intrapulmonary [e.g., by inhalation], or sublingual). In certain embodiments, treprostinil derivatives are administered transdermally (e.g., by transdermal patch). In other embodiments, treprostinil derivatives are 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 (including, for example, by subcutaneous or intravenous injection or infusion).

[0107] In some embodiments, treprostinil derivatives are used to treat PAH. In certain embodiments, treprostinil derivatives are administered transdermally (e.g., by a transdermal patch). In further embodiments, additional therapeutic agents are used in combination with treprostinil derivatives to treat PAH. The additional therapeutic agents may be administered simultaneously with or immediately following (before or after) the administration of the treprostinil derivative. When administered simultaneously with the treprostinil derivative, the additional therapeutic agents may be contained in the same composition as the treprostinil derivative or in separate compositions.

[0108] In certain embodiments, further therapeutic agents for the treatment of PAH are selected from the following group: Prostaglandins and prostanoids (e.g., prostacyclin [prostaglandin I2] and its analogs, e.g., beraprost, cicaprost, and iloprost), other prostacyclin receptor agonists (e.g., selexipag and ACT-333679 [MRE-269]), calcium channel blockers (CCBs) (e.g., dihydropyridine CCBs [e.g., amlodipine and nifedipine] and non-dihydropyridine CCBs [e.g., diltiazem]), endothelin receptors (e.g., ET A and / or ET B Vasoactive agents (e.g., vasodilators), including but not limited to ) antagonists (e.g., ambrisentan, bosentan, sitaxentan, and Actelion-1), 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., synaciguat and riociguat), and their analogues, derivatives, and salts; Diuretics including, but not limited to, thiazide diuretics (e.g., bendroflumethiazide, chlorothiazide, epitizide, and hydrochlorothiazide), thiazide-like diuretics (e.g., chlorthalidone, indapamide, and metrazone), and their analogs, derivatives, and salts; Anticoagulants including, but not limited to, vitamin K antagonists (e.g., asenocumarol, atromentin, coumarin, phenindione, fenprocumon, and warfarin), direct thrombin inhibitors (e.g., argatroban, dabigatran, hirudin, repirudin, 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 hydraparinux), others (e.g., antithrombin, batroxobin, and hementin), and their analogs, derivatives, fragments, and salts; and Cardiac glycosides (e.g., digoxin, acetyldigoxin, and digoxigenin) as well as other types of therapeutic agents, including but not limited to oxygen therapy.

[0109] VII. Synthesis of treprostinyl derivatives R 2 is hydrogen, -OR 1The preparation of treprostinyl (Trp) derivatives of formula (I), obtained by derivatization of treprostinyl (Trp), can be carried out by reacting a Trp compound (e.g., compound C in the examples) that is appropriately protected at the octylhydroxyl and carboxyl groups with a carboxylic acid or a pre-prepared activated carbonyl compound (e.g., an acid chloride) in the presence of an activator (e.g., EDC, DCC, DIC, BOP-Cl, BOP reagent, HATU, HBTU, or CDI). The coupling reaction may include reaction-promoting additives (e.g., DMAP, HOSu, HOBT, or HOAT) and may also include non-nucleophilic or nucleophilic bases (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 activators, 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 A bis-protected Trp compound derivatized in the above formula can be deprotected using reagents and conditions known in the art to obtain a Trp derivative of formula (I). For example, P. Wuts and T. Greene, Greene's Protective Groups in Organic Synthesis, 4 th See Ed., John Wiley and Sons (2006).

[0110] R 1 is hydrogen, -OR 2The Trp derivative of formula (I), obtained by derivatization of , can be prepared by appropriately protecting the cyclopentyl hydroxyl group of compound C, deprotecting the octyl hydroxyl group without deprotecting the cyclopentyl hydroxyl group or carboxyl group, reacting the octyl hydroxyl group with an activated carbonyl compound (prepared in advance or in situ), and then deprotecting the cyclopentyl hydroxyl group and carboxyl group. -OR 1 and -OR 2 Preparation of Trp derivatives of formula (I) derivatized with different groups is described herein for compound C-OR 1 Derivatize the octylhydroxyl group and deprotect it, -OR 2 This can be done by derivatizing and deprotecting the carboxyl group. -OR 1 and -OR 2 The preparation of Trp derivatives of formula (I) derivatized with the same group involves deprotecting the octylhydroxyl group of compound C and the -OR as described herein. 1 and -OR 2 This can be done by derivatizing the compound and deprotecting the carboxyl group.

[0111] The Trp derivative of formula (II) can be prepared by reacting a Trp compound appropriately protected at the octylhydroxyl group (e.g., compound B in the example) with an alcohol in which the carboxyl group is appropriately protected, in the presence of an activator described herein, thereby deprotecting the octylhydroxyl group and the carboxyl group.

[0112] The synthesis of typical treprostinyl derivatives is described in the examples.

[0113] IX. Typical examples The following aspects of this disclosure are shown only as examples. 1. Compounds of formula (I), or their pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, or stereoisomers: TIFF0007850537000070.tif33128In formula, R 1and R 2 Hydrogen, It is TIFF0007850537000071.tif51147, 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 In each case, independently, is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 4 and R 5 Furthermore, the carbon atoms to which they are bonded form a C3-C6 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 These atoms, 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 a heterocycle or heteroaryl ring; j is an integer between 0 and 4, independently in each case; m is an integer between 1 and 10, independently in each case; t is an integer from 1 to 9, independently in each case; however, R 1 and R 2 It is not possible for both to be 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. 2. R in TIFF0007850537000072.tif9128 3 The compound according to Embodiment 1, but which is not an alkyl group substituted with a nitrogen-containing group, or a cycloalkyl group substituted with a carbonyl-containing group. 3. R in TIFF0007850537000073.tif9128 3 The compound according to embodiment 1, wherein neither alkyl group nor cycloalkyl group, nor any alkyl group, haloalkyl group, -alkylaryl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is substituted. 4. j is independently 0, 1, or 2 in each case. The compound according to any one of the above embodiments. 5. The compound according to any one of the above embodiments, wherein m is an integer from 1 to 6 independently in each case, and / or t is an integer from 1 to 5 independently in each case. 6. R 1 and R 2 Hydrogen, It is TIFF0007850537000074.tif14128, and here R 4 , R 5, R 6 , and m are as defined above; and k is an integer from 1 to 9, independently of each case; However, R 1 and R 2 It is not possible for both to be hydrogen. The compound according to any one of the above embodiments. 7. The compound according to embodiment 6, wherein k is an integer from 1 to 5, independently in each case. 8. R 3 However, in each case independently, they are C1-C6 alkyl groups; R 4 and R 5 However, in each case independently, it is either hydrogen or a C1-C3 alkyl group, 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, it is either C1-C6 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 compound according to any one of the above embodiments. 9. R 3 However, in each case independently, these are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl; R 4 and R 5 However, in each case, it is independently hydrogen, methyl, ethyl, propyl, or isopropyl; R 6which, in each case independently, is hydrogen or R 3 is; R<00003​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Compounds according to any one of the above embodiments, selected from the group consisting of TIFF0007850537000077.tif30136TIFF0007850537000078.tif225136TIFF0007850537000079.tif209142TIFF0007850537000080.tif235142TIFF0007850537000081.tif158146, as well as pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 17. Compounds selected from the group consisting of TIFF0007850537000082.tif30136TIFF0007850537000083.tif225136TIFF0007850537000084.tif209142TIFF0007850537000085.tif234142TIFF0007850537000086.tif158146, as well as pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 18. Compounds of formula (II), or their pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, or stereoisomers: TIFF0007850537000087.tif34128In formula, -OZ-CO2H is TIFF0007850537000088.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. Here, -Sicryl- is a -cycloalkyl-, -heterocyclyl-, -aryl-, or -heteroaryl-; R 7 and R 8 In each case, independently, is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 7 and R8 Furthermore, the carbon atoms to which they are bonded form a C3-C6 cycloalkyl ring; n is an integer between 1 and 10; however, -OZ-CO2H is Not TIFF0007850537000089.tif8128; and -OZ-CO2H does not contain sugar. 19. The compound according to embodiment 18, wherein n is an integer from 1 to 6. 20. The compound according to embodiment 18, wherein n is an integer from 3 to 10 or from 3 to 6. 21. -OZ-CO2H The compound described in embodiment 18, not TIFF0007850537000090.tif16128. 22. If n is 1 or 2, R 7 and R 8 The compound according to embodiment 18, wherein in each case, is hydrogen. 23. R 7 and R 8 The compound according to embodiment 18, wherein n is hydrogen in each case, and n is an integer from 1 to 10 or from 1 to 6. 24. The compound according to embodiment 18, wherein -OZ-CO2H does not contain a heterocyclyl group or a substituted heterocyclyl group. 25. -OZ-CO2H It is TIFF0007850537000091.tif13128, and here R 7 and R 8 As defined above; p is an integer from 1 to 9; and q is an integer between 0 and 8; However, -OZ-CO2H It is not TIFF0007850537000092.tif8128. The compound described in Embodiment 18. 26. The compound according to embodiment 25, wherein p is an integer from 1 to 5 and q is an integer from 0 to 4. 27. R 7and R 8 All of them are hydrogen, and p is an integer from 1 to 5, or from 1 to 3 (or R 7 and R 8 The compound according to embodiment 25 or 26 (where is hydrogen in each case and q is an integer from 0 to 4 or from 0 to 2). 28. -OZ-CO2H The compound according to embodiment 25 or 26, wherein the compound is TIFF0007850537000093.tif9128 and p is 2, 3, 4, or 5. 29. -OZ-CO2H is -O-heteroalkyl-CO2H, and -O-heteroalkyl-CO2H is A compound according to embodiment 18, selected from the group consisting of TIFF0007850537000094.tif50163, wherein r is one of 1, 2, and 3 in the formula. 30. -OZ-CO2H The compound according to embodiment 29, wherein the code is TIFF0007850537000095.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 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 It is 1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans). The compound described in Embodiment 18. 32. -OZ-CO2H A compound according to embodiment 31, selected from the group consisting of TIFF0007850537000096.tif24146. 33. Compounds according to any one of embodiments 18 to 32, selected from the group consisting of TIFF0007850537000097.tif160138TIFF0007850537000098.tif204141TIFF0007850537000099.tif37136, as well as pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 34. Compounds according to embodiment 33, selected from the group consisting of TIFF0007850537000100.tif118138, as well as pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 35. Compounds selected from the group consisting of TIFF0007850537000101.tif201138TIFF0007850537000102.tif202141, as well as pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 36. Compounds according to embodiment 35, selected from the group consisting of TIFF0007850537000103.tif119138, as well as pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers (including enantiomers and racemic mixtures) thereof. 37. A pharmaceutical composition comprising a compound described in any one of embodiments 1 to 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 according to embodiment 37, wherein the compound is the compound described in embodiment 17 or 35, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 39. The composition according to embodiment 38, wherein the compound is the compound according to embodiment 17 or 36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 40. The composition according to any one of embodiments 37 to 39, which is formulated or formulated for transdermal delivery of the compound. 41. The composition according to embodiment 40, which is formulated 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 of treatment a therapeutically effective amount of the compound according to any one of embodiments 1 to 36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 43. The method according to embodiment 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., atherosclerotic arteriosclerosis), ischemic lesions (e.g., peripheral ischemic lesions on the skin, e.g., lesions caused by Buerger's disease, Raynaud's phenomenon, Raynaud's disease, scleroderma, and systemic sclerosis), severe ischemic limbs, neuropathic foot ulcers (e.g., diabetic neuropathic foot ulcers), renal insufficiency and renal 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 foregoing conditions. 44. The method according to embodiment 43, wherein the medical condition is pulmonary hypertension. 45. The method according to embodiment 44, wherein the medical condition is pulmonary arterial hypertension. 46. The method according to any one of embodiments 42 to 45, wherein the compound is the compound according to embodiment 17 or 35, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 47. The method according to embodiment 46, wherein the compound is the compound according to embodiment 17 or 3, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof. 48. The method according to any one of embodiments 42 to 47, wherein the route of administration of the compound includes oral, parenteral (e.g., intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary, or subarachnoid), intracavitary, intraperitoneal, or topical (e.g., skin / supercutaneous, percutaneous, mucous membrane, transmucosa, intranasal [e.g. by nasal spray or nasal drop], intraocular [e.g. by eye drop], intrapulmonary [e.g. by inhalation], buccal, sublingual, rectal, or vaginal), or any combination thereof. 49. The method according to embodiment 48, wherein the compound is administered transdermally, for example, by a transdermal patch. 50. The aforementioned medical condition is pulmonary hypertension; The compound is the compound described in Embodiment 17 or 35, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof; The compound is administered transdermally (for example, by a transdermal patch), The method according to any one of embodiments 42 to 49. 51. The method according to any one of embodiments 42 to 50, further comprising the step of administering an additional therapeutic agent. 52. The method according to embodiment 51, wherein the further therapeutic agent comprises a vasoactive agent, a diuretic, an anticoagulant, or a cardiac glycoside, or any combination thereof. 53. A compound described in any one of embodiments 1 to 36, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof; and Instructions for administering the compound to treat medical conditions that respond to treatment with treprostinil. A kit that includes this. 54. The kit according to embodiment 53, wherein the compound is contained in or incorporated into an apparatus or system configured for transdermal delivery (e.g., a transdermal patch). 55. The kit according to embodiment 53 or 54, wherein the medical condition is pulmonary hypertension (e.g., pulmonary artery hypertension). [Examples]

[0114] X. Examples The following examples are intended solely to illustrate the present 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 treprostinil derivatives. The results are shown in Table 1.

[0116] (Test 1) The human liver microsome stability assay was performed by incubating a 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 NADPH production system (7.8 mg of glucose-6-phosphate, 1.7 mg of NADPH, and 6 units of 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 the reaction was stopped with an internal standard-containing stop solution. An uncofactored control was prepared at 45 minutes. After incubation, the samples were analyzed by LC-MS / MS. Intrinsic clearance was calculated using the peak area ratio of the analyte to the internal standard. Intrinsic clearance (CL) int The elimination rate constant was determined by nonlinear regression from the first-order elimination rate constant. The time course of treprostinil (compound A), the active drug, was monitored by LC-MS / MS analysis.

[0117] (Test 2) The human plasma stability assay was performed by incubating a 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 the reaction was stopped with an internal standard-containing stop solution. After incubation, the samples were analyzed by LC-MS / MS. The half-life was calculated using the peak area ratio of the analyte to the internal standard. The time-dependent formation of compound A, the active drug, was monitored by LC-MS / MS analysis.

[0118] (Test 3) The human skin homogenate stability assay was performed in the same manner as the human liver microsome stability assay, by incubating a 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 NADPH production system (7.8 mg of glucose-6-phosphate, 1.7 mg of NADPH, and 6 units of 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 the reaction was stopped with an internal standard-containing stop solution. An uncofactored control was prepared at 45 minutes. After incubation, the samples were analyzed by LC-MS / MS. Intrinsic clearance was calculated using the peak area ratio of the analyte to the internal standard. Intrinsic clearance (CL) int The ) was determined by nonlinear regression from the first-order disappearance rate constant. The time-dependent formation of compound A, the active drug, was monitored by LC-MS / MS analysis.

[0119] The results (half-lives) of the three stability assays described above are shown in Table 1. In Table 1, the codes for the half-lives of the test compounds in the assays are 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, diffusion area 0.64 cm 2The assay was performed using a vertical Franz diffusion cell with a volume of 7.5 mL. The assay was carried out at 32°C under continuous agitation. Thermally separated human cadaver epidermis, stored at -20°C after the thermal exfoliation procedure, was used in the assay. After thawing the human epidermis, it was placed in the diffusion cell. The test compound was applied to the skin, and the diffusion cell was closed with a screw cap. Complete medium or receptor medium was replaced with fresh medium at various time intervals. Using a portion of the collected medium, the cumulative skin permeability of the test compound at 72 hours was calculated. 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 specific donor, four (N = 4) replicate tests were performed.

[0122] The results of the skin permeability assay are shown in Table 1 above. In Table 1, the codes for the cumulative skin permeability of the test compounds at 72 hours after being tested on human epidermis from specific donors are as follows: + = Low to moderate skin permeability ++ = Moderate skin permeability +++ = High skin permeability ++++ = Very high skin permeability

[0123] Synthesis of treprostinyl derivatives Representative synthesis methods for the compounds of formulas (I) and (II) are shown below.

[0124] Synthesis of {2-hydroxy-1-[3-(tetrahydropyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxy}benzyl acetate (compound C) A solution of {2-hydroxy-1-[3-(tetrahydropyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-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)phosphinate chloride (BOP-Cl) (7.8 g, 30.7 mmol) at 0 °C and stirred at room temperature (RT) for 2 hours. 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 obtain 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]naphthalene-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 hours. The reaction mixture was diluted with MTBE, washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. THP-protected methoxyacetic acid was dissolved in MeOH (4 mL) and treated with pyridinium p-toluenesulfonate (PPTS) (catalyst) and stirred at 50°C for 2 hours. The reaction mixture was concentrated, the residue was dissolved in MTBE (20 mL), washed with water, then brine to obtain crude THP-deprotected methoxyacetic acid. The crude product was incorporated into dioxane (5 mL) with 10% Pd / C (18 mg) and hydrogenated under a hydrogen atmosphere to obtain crude compound Ia-8 (64 mg) as an oily substance. MS: m / z 485 [M+Na] +

[0126] The following compounds were synthesized using the same procedure as described above. TIFF0007850537000107.tif63133

[0127] Example 4. Synthesis of [2-(2-hydroxyacetoxy)-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-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 hours. The reaction mixture was diluted with MTBE, washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. THP-protected benzyloxyacetic acid was dissolved in MeOH (4 mL), treated with PPTS (catalyst), and stirred at 50°C for 2 hours. The reaction mixture was concentrated, the residue was dissolved in MTBE (20 mL), washed with water, then brine to obtain crude THP-deprotected benzyloxyacetic acid. The crude product was incorporated into dioxane (5 mL) with 10% Pd / C (24 mg) and hydrogenated under a hydrogen atmosphere to obtain crude compound Ia-7 (56 mg) as an oily substance. 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]naphthalene-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 hours. Next, the reaction mixture was added to MeOH (2 mL) at 0°C and stirred for a further 1 hour. 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 (catalyst), and stirred at 50°C for 2 hours. The reaction mixture was concentrated, the residue was dissolved in MTBE (20 mL), and washed with water, then brine, to obtain crude THP-deprotected methyl carbonate. The crude product was incorporated into dioxane (5 mL) with 10% Pd / C (28 mg) and hydrogenated under a hydrogen atmosphere to obtain crude compound Ia-10 (83 mg) as an oily substance. MS: m / z 471 [M+Na] +

[0129] The following compounds were synthesized using the same procedure as described above. TIFF0007850537000110.tif30128

[0130] Synthesis of [2-benzyloxycarbonyloxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxy]benzyl acetate (compound D) 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 hours. The reaction mixture was diluted with MTBE, washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. Benzyl carbonate was dissolved in MeOH (4 mL), treated with PPTS (catalyst), and stirred at 50°C for 2 hours. The reaction mixture was concentrated, the residue was dissolved in MTBE (20 mL), washed with water, then brine to obtain 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]naphthalene-5-yloxy}acetic acid (compound Ib-8) 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 at 0°C for 1 hour under nitrogen. The reaction mixture was diluted with MTBE, washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography. Methoxyacetic acid was incorporated into dioxane (5 mL) with 10% Pd / C (16 mg) and hydrogenated under a hydrogen atmosphere to obtain crude compound Ib-8 (43 mg) as an oil. MS: m / z 485 [M+Na] +

[0132] The following compounds were synthesized using the same procedure as described above. TIFF0007850537000113.tif79139

[0133] Example 7. Synthesis of 3-{2-[2-hydroxy-1-(3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-5-yloxy]acetoxy}propionic acid (Compound II-4) TIFF0007850537000114.tif64128 Compound B (120 mg, 0.25 mmol), benzyl 3-hydroxypropionate (54 mg, 0.30 mmol), and trimethylamine (140 μL, 1.0 mmol) were mixed in a DCM (4 mL) solution with BOP-Cl (95 mg, 0.38 mmol). The reaction mixture was stirred under nitrogen at room temperature for 16 hours, diluted with MTBE, washed with brine, dried over sodium sulfate, concentrated into an oil, and purified by silica gel chromatography. An ethanol solution of THP-protected diester (4 mL) was treated with PPTS (50 mg), stirred at 50°C for 4 hours, concentrated into an oil, and purified by silica gel chromatography. A dioxane solution of THP-deprotected diester (5 mL) was treated with wet 5% Pd / C (20 mg) and stirred under a hydrogen balloon for 24 hours. The reaction mixture was filtered and concentrated to obtain crude compound II-4. MS: m / z 485 [M+Na] +

[0134] The following compounds were synthesized using the same procedure as described above. TIFF0007850537000115.tif37128

[0135] While specific embodiments are illustrated and described, it will be understood that various modifications are possible and envisioned herein. It will also be understood that this disclosure is not limited to the specific examples shown herein. The descriptions and illustrations of embodiments and examples of this disclosure herein are not intended to be constrained. Furthermore, it will be understood that not all aspects of this disclosure are limited to the specific descriptions, structures, or relative proportions described herein, which may depend on various conditions and variations. Various modifications and variations of the form and details of embodiments and examples of this disclosure will be apparent to those skilled in the art. Therefore, it will be assumed that this disclosure also covers all such modifications, variations, and equivalents.

Claims

1. Compounds of formula (I), or their pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers: During the ceremony, R 1 and R 2 Hydrogen, And here R 3 In each case, these are independently alkyl, haloalkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and they may be substituted with 1 to 6 substituents independently selected from the group consisting of halide, cyano, nitro, hydroxyl, -SH, -NH2, -OR11, -SR11, -NR12R13, -C(=O)R11, -C(=O)OR11, -OC(=O)R11, -C(=O)NR12R13, -NR11C(=O)R11, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Here R 11 is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl in each case; and R12 and R13 are, independently in each case, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R12 and R13, and the nitrogen atoms to which they are bonded, form a heterocycle or heteroaryl ring; R 4 and R 5 are, independently in each case, hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached form a C 3 -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 is not -OC(=O)R 3a (where R 3a is methyl, phenyl, or substituted cyclohexyl); -OR 1 mo-OR 2 It does not form esters with (protected or unprotected) amino acids, peptides, or proteins; and The compound of formula (I) does not contain two or more molecules 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. 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 between 1 and 9, independently in each case. The compound according to claim 1.

3. 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 compound according to claim 1 or 2.

4. R 1 and R 2 They became independent, hydrogen, The group is selected from the group consisting of, however, R 1 and R 2 The compound according to any one of claims 1 to 3, wherein both are not hydrogen.

5. R 2 A compound according to any one of claims 1 to 4, wherein R is hydrogen and R 1 is not hydrogen.

6. R 1 A compound according to any one of claims 1 to 4, wherein R2 is hydrogen and R2 is not hydrogen.

7. The compound according to any one of claims 1 to 4, wherein both R1 and R2 are not hydrogen, and -OR1 and -OR2 are the same group.

8. Compounds of formula (II), or their pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers: During the ceremony, -OZ-CO 2 Hは ,-O-(C 1-10 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 H is present, and each of these may be substituted with 1 to 6 substituents independently selected from the group consisting of halide, cyano, nitro, hydroxyl, -SH, -NH2, -OR11, -SR11, -NR12R13, -C(=O)R11, -C(=O)OR11, -OC(=O)R11, -C(=O)NR12R13, -NR11C(=O)R11, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Here R 11 is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl in each case; and R12 and R13 are, independently in each case, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R12 and R13, and the nitrogen atoms to which they are bonded, form a heterocycle or heteroaryl ring; Here, -Sicryl- is -cycloalkyl-, -heterocyclyl-, -aryl-, or -heteroaryl-; -(C1-10 heteroalkyl)- is a linear saturated divalent hydrocarbon group having 1 to 10 carbon atoms, or a branched saturated divalent hydrocarbon group having 3 to 10 carbon atoms, and containing one or more heteroatoms independently selected from O, N, and S; R 7 and R 8 In each case, independently, hydrogen and C 1 ~C 6 Alkyl, or C 3 ~C 6 It is either cycloalkyl or R 7 and R 8 Furthermore, the carbon atoms to which they are bonded are C 3 ~C 6 Forming a 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.

9. -OZ-CO 2 Hが Rather; or, If n is 1 or 2, R 7 and R 8 In each case, it is hydrogen. The compound according to claim 8.

10. R 7 and R 8 is hydrogen in each case, and n is an integer of 1 to 10 or 1 to 6, the compound according to claim 8.

11. -OZ-CO 2 Hが And here R 7 and R 8 This is as defined in claim 8; p is an integer from 1 to 9; and q is an integer between 0 and 8; The compound according to claim 8.

12. -OZ-CO 2 Hが The compound according to claim 11, wherein p is 2, 3, 4, or 5.

13. -O-Z-CO 2 H is optionally -O-(C 1-10 heteroalkyl)-CO 2 H, and optionally -O-(C 1-10 heteroalkyl)-CO 2 H is A compound according to claim 8, selected from the group consisting of, where r is one of 1, 2, and 3.

14. -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 compound according to claim 8.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers.

16. The pharmaceutical composition according to claim 15, which is configured or formulated for transdermal delivery of the compound.

17. The pharmaceutical composition according to claim 16, which is configured or formulated for transdermal delivery of the compound by a transdermal patch.

18. A composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, for use in the treatment of a medical condition responding to treatment with treprostinil.

19. The composition for use according to claim 18, wherein the medical condition is selected from the group consisting of pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, asthma, cardiovascular disease, congestive heart failure, peripheral vascular disease, severe intermittent claudication, atherosclerosis, ischemic disease, ischemic lesions, severe ischemic limb, ischemic ulcer, neuropathic foot ulcer, renal insufficiency and renal failure, inflammatory disease, proliferative disorders, and pain associated with each of the conditions.

20. The composition for use according to claim 18 or 19, wherein the medical condition is pulmonary artery hypertension.

21. A composition for use according to any one of claims 18 to 20, formulated for transdermal administration of the compound.

22. A composition for use according to claim 21, formulated for transdermal administration of the compound by a transdermal patch.

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