Heterodimer compositions and methods for treating eye disorders

Abstract

This specification describes a processable composition comprising at least one moiety that can be processed in free form. This specification also describes compositions and methods for treating eye diseases or disorders, including glaucoma, blepharitis, ocular inflammation, diabetic macular edema, posterior ocular inflammation, anterior ocular inflammation, macular degeneration (e.g., wet macular degeneration (AMD) or dry AMD), post-cataract surgery, and retinal vein occlusion. The compositions and methods include steroids and prostaglandins that demonstrate anti-inflammatory activity, intraocular pressure (IOP) reduction, and / or other desirable activities. The compositions are injected into the eye to provide therapeutic benefits to patients suffering from eye disorders.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 63 / 019,182, filed 1 May 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Prostaglandins (prostaglandin analogs) are state-of-the-art medications in the treatment of glaucoma and can be used to treat other eye disorders. In some cases, prostaglandins are useful in lowering intraocular pressure (IOP), a major risk factor in glaucoma. Typically, prostaglandins are formulated for ophthalmic use and delivered in the form of eye drops. However, frequent ocular administration of prostaglandins is often required to achieve efficacy. For example, once-daily administration of latanoprost has been reported to reduce IOP by an average of approximately 35%. [Overview of the project]

[0003] In some embodiments herein, a compound comprising a first radical (D1) and a second radical (D2) (e.g., having the formula D1-L-D2) is disclosed. In some examples, D1 is a treatable group (also referred herein as a treatable radical), L is a linker, and D2 is a drug (also referred herein as a drug radical). In some embodiments, L is a hydrolyzable linker or bond such that D1 and D2 are released (e.g., in their free, non-radical forms) when the compound of formula D1-L-D2 is administered (e.g., for ophthalmic purposes) (or when it is present in or otherwise exposed to an aqueous environment such as a buffer, tear solution, serum, etc.). In some examples, a compound containing other untreatable drugs (e.g., D2-L-D2 (e.g., D2-D2)) is obtained in a treatable form by linking group D1 to an activator D2 (e.g., an untreatable activator) via linker L (e.g., covalently) (e.g., D1-L-D2). In some cases, a drug (such as a prostaglandin) binds to a processable group (such as a steroid or other radical of a formula described herein, such as formula (I)). In some cases, the processable group D1 may or may not be processable on its own when in free form, but when combined with D2 (e.g., via a linker L), it yields a processable solid (e.g., at physiological temperature) (e.g., at temperatures above physiological temperature).

[0004] In one example herein, a platform is provided for providing compounds and implants (e.g., those with high drug content, low excipient content (e.g., those that typically require removal), and other benefits as described herein) that result in the long-term release of therapeutic agents (e.g., prostaglandins, steroids, beta-blockers, etc.) in biological and therapeutic applications, such as ocular (e.g., implant) administration.

[0005] In some cases, the compounds provided herein (e.g., unprocessable drugs such as prostaglandins, conjugated to processable radicals such as steroids, radicals, etc., via a linker, etc.) can be processed into forms (e.g., implants, coatings, or other bodies) that can be administered to an individual requiring administration (e.g., the eye of an individual). In some cases, such compounds can be processed without requiring additional excipients or materials (e.g., controlled-release polymers, extracellular matrix, or other components). In some cases, the absence or small amount of additional excipients or materials limits the impact on drug delivery while promoting high levels of drug delivery (e.g., small implants can have high amounts of drug).

[0006] In some cases, such compounds (or implants containing such compounds) are administered to an individual (e.g., implanted) so that sustained and / or otherwise controlled (e.g., topical) delivery of the drug is achieved. In some cases, the delivery of compounds (e.g., in the form of implants or coatings) facilitates the delivery of drug components or their radicals over long periods, such as weeks, months, or longer. In some cases, the compounds, formulations, and implants provided herein facilitate long-term drug delivery to individuals requiring delivery without requiring frequent dosing. For example, as discussed herein, prostaglandins are often formulated and administered as eye drops, such as those administered daily. In some cases, administration is required to maintain (e.g., optimize) therapeutic efficacy without requiring strict adherence to frequent dosing. However, in the case of the compounds provided herein, long-term delivery of such drugs can be achieved over periods of weeks, months, or longer with infrequent dosing (e.g., once or twice a year).

[0007] In some embodiments, group D1 is also an activator or active drug (e.g., its radical). In some embodiments, both D1 and D2 are effective in treating a single indication such that administration of the compound herein produces a combined therapeutic effect. For example, in some embodiments, D1 is a steroid and D2 is a prostaglandin. In some embodiments, such as in the treatment of glaucoma, the anti-inflammatory effect of the steroid and the intraocular pressure-lowering effect of the prostaglandin together exert a therapeutic effect. In some embodiments, such as when the compound is formulated as an implant or formulated together with an implant, D1 is anti-inflammatory (e.g., a steroid) to minimize the inflammatory response to the implant.

[0008] In some embodiments herein, compounds as described herein, compositions (e.g., pharmaceuticals) containing the compounds described herein, and methods for preparing and using the compounds provided herein are provided. In some embodiments, methods for using the compounds provided herein include methods for treating disorders of an individual requiring treatment, such as disorders treatable by drug D2 (e.g., in its free form). In some embodiments, methods for treatment provided herein include methods for treating eye disorders such as glaucoma. Disclosure of methods provided herein includes disclosure of pharmaceutical compositions containing (e.g., in an effective amount) the compounds provided herein for such use.

[0009] In one embodiment of this specification, a compound comprising a first radical and a second radical, wherein the first radical is of formula (I):

[0010] [ka] A compound containing the structure is provided.

[0011] In one embodiment,

[0012] [ka] is a single bond or a double bond. In some embodiments, R a , R b , and R c are each independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, and alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. In certain embodiments, any one of R a , R b , or R c combines with another one of R a , R b , or R c to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, X 1 , X 2 , X 3 , and X 4 are each independently selected from the group consisting of a bond and Q y , and Q is each independently -O-, -NR-, -S(R) x -, and -C(R) z- is selected from the group consisting of -. In some embodiments, y is 1 to 3. In some embodiments, x is independently 0 to 5. In some embodiments, z is independently 1 or 2 (e.g., depending on the degree of saturation). In some embodiments, m, n, and o are independently 0 to 6. In some embodiments, R is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, and thiol (e.g., alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are optionally substituted), or R is combined with another R to form an oxo. In some embodiments, the second radical is a therapeutically active agent (or drug). In some embodiments, the first radical (e.g., a steroid) is different from the second radical (e.g., a prostaglandin). In some embodiments, the first radical, the second radical, or both the first and second radicals are not steroids. In some embodiments herein, pharmaceutically acceptable salts or solvates of the compound of formula (I) are also provided.

[0013] In some embodiments, the second radical is a drug. In some embodiments, the drug is a prostaglandin. In some embodiments, the prostaglandin is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost acid, or any of the aforementioned fragments or radicals.

[0014] In some embodiments, X 1 Q1 is Q1. In some embodiments, X 2 is a bond. In some embodiments, X 3 Q2 is Q2. In some embodiments, X 4 Q1 is Q1. In some embodiments, X 1 and X4 These are Q1, respectively. In some embodiments, X 2 is a combination, X 3 Q is Q2. In some embodiments, Q is -C(R)1- or -C(R)2-. In some embodiments, X 1 and X 4 These are independently -C(R)1- or -C(R)2-. In some embodiments, X 2 is a combination, X 3 is -C(R)2C(R)2-, -C(R)C(R)2-, or -C(R)C(R)-. In some embodiments, X 1 and X 4 Each of these is -C(R)2-, and X 2 X is a combination, 3 is -C(R)2C(R)2- or -C(R)C(R)2-.

[0015] In some embodiments, R is independently hydrogen, halogen, alkyl, heteroalkyl, hydroxy, or amino (e.g., dihydroamino, alkylamino, or arylamino), or combines with another R to form an oxo. In some embodiments, R is independently hydrogen, halogen, alkyl, or hydroxy, or combines with another R to form an oxo. In some embodiments, R is independently hydrogen or halogen. In some embodiments, R is independently hydrogen or alkyl. In some embodiments, R is independently hydrogen or hydroxy. In some embodiments, R is independently hydrogen or combines with another R to form an oxo.

[0016] In some embodiments, the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol of R is optionally substituted. In some embodiments, R is R a , R b , or R cBy combining with one of the following, an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl is formed. In some embodiments, R is amino, and R a , R b , or R c By combining with one of the following, it forms an optionally substituted heterocycloalkyl. In some embodiments, R is amino, and R a or R c When combined with one of these, it forms a heterocycloalkyl with optional substitution.

[0017] In some embodiments of this specification, a compound comprising a first radical and a second radical, wherein the first radical is of formula (IA):

[0018] [ka] A compound containing the structure is provided.

[0019] In some embodiments,

[0020] [ka] is a single bond or a double bond. In some embodiments, R a , R b , and R c Each is independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, and alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. In some embodiments, m, n, and o are each independently 0 to 6. In some embodiments, R a , R b , or R c One of the following is R a , Rb , or R c By combining with another of these, they form substituted or unsubstituted cycloalkyl or heterocycloalkyl groups. In some embodiments, the second radical is a therapeutically active agent (or drug), and the first radical (e.g., a steroid) is different from the second radical (e.g., a prostaglandin). In some embodiments, the first radical, the second radical, or both the first and second radicals are not steroids. In some embodiments herein, pharmaceutically active salts or solvates of the compound of formula (IA) are also provided.

[0021] In some embodiments, both the first radical and the second radical have the structure of formula (I) or formula (IA). In some embodiments, the first radical has the structure of formula (I) or formula (IA), while the second radical does not have the structure of formula (I) or formula (IA). In some embodiments, the structure of formula (I) or formula (IA) has a melting temperature and / or glass transition temperature of at least 20°C (e.g., at least 25°C, at least 30°C, at least 37°C, at least 40°C, at least 50°C, at least 100°C, or higher) in its free form.

[0022] In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, R b Each of these is independently hydrogen, halogen, alkyl, heteroalkyl, hydroxy, amino (e.g., dihydroamino, alkylamino, or arylamino), or another R b It forms an oxo by becoming integrated with R b These are, independently, hydrogen, halogen, alkyl, hydroxyl, or another R b It forms an oxo together with R b Each is independently hydrogen or halogen. In some embodiments, R bEach is independently hydrogen or alkyl. In some embodiments, R b Each is independently hydrogen or hydroxyl. In some embodiments, R b Each is either hydrogen independently, or another R b It forms an oxo together with the other elements.

[0023] In some embodiments, R b The alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol of R is optionally substituted. In some embodiments, R b R a , R b , or R c By combining with one of these, an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl is formed. In some embodiments, R b It is an amino acid, R a or R c By combining with one of these, it forms an optionally substituted heterocycloalkyl. In some embodiments, R b It is an amino acid, R a or R c When combined with one of these, it forms an optionally substituted alkyl group.

[0024] In some embodiments, R c One of them is another R c By integrating with, it forms an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In some embodiments, R c One of them is another R c By integrating with, it forms an optionally substituted cycloalkyl. In some embodiments, R c One of them is another R cBy combining with, it forms a cycloalkyl group substituted with one or more substituents, each substituent selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, and alkyl, heteroalkyl, cycloalkyl, alkoxy, amino, thiol, or heterocycloalkyl may be optionally substituted.

[0025] In some embodiments, R (for example, of formula (I) or formula (IA)) a , R b , and R c Each of the groups is one or more optionally and independently selected from -OH, oxo, alkyl (e.g., alkenyl), heteroalkyl, cycloalkyl, or alkoxy, and the alkyl, heteroalkyl, cycloalkyl, or alkoxy groups are further optionally substituted. In some embodiments, R (e.g., of formula (I) or formula (IA)) a , R b , or R c Each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl group may be independently substituted or unsubstituted. In some embodiments, each group may be independently unsubstituted or substituted with one or more substituents as described herein. In specific embodiments, each group may be independently unsubstituted or substituted with one or more substituents, each substituent selected from the group consisting of -OH, oxo, alkyl, heteroalkyl, cycloalkyl, or alkoxy, and the alkyl, heteroalkyl, cycloalkyl, or alkoxy may be further optionally substituted.

[0026] In some embodiments, the substituted or unsubstituted cycloalkyl or heterocycloalkyl groups (e.g., of formula (I) or formula (IA)) are each optionally and independently substituted with one or more groups, each group being independently selected from -OH, oxo, alkyl (e.g., alkenyl, alkynyl), -S-alkyl, -NH-alkyl, halogen, heteroalkyl, cycloalkyl, or alkoxy, and the alkyl (e.g., -S-alkyl, -NH-alkyl), heteroalkyl, cycloalkyl, or alkoxy groups are further optionally substituted. In some embodiments, the substituted or unsubstituted cycloalkyl or heterocycloalkyl groups are independently substituted or unsubstituted. In some embodiments, each group is independently unsubstituted or substituted with any one or more substituents described herein. In specific embodiments, each group is either independently unsubstituted or substituted with one or more substituents, each substituent selected from the group consisting of -OH, oxo, alkyl (e.g., alkenyl, alkynyl), -S-alkyl, -NH-alkyl, halogen, heteroalkyl, cycloalkyl, or alkoxy, and alkyl (e.g., -S-alkyl, -NH-alkyl), heteroalkyl, cycloalkyl, or alkoxy may be further optionally substituted. In some embodiments, the cycloalkyl (e.g., of formula (I) or formula (IA)) is substituted with oxo, -OH, optionally substituted alkyl, or optionally substituted alkoxy. In some embodiments, the alkyl is substituted with one or more halogens, oxo, -OH, alkyl (e.g., alkenyl), -S-alkyl, -NH-alkyl, or alkoxy, and alkyl (e.g., -S-alkyl, -NH-alkyl) or alkoxy may be further optionally substituted. In some embodiments, the alkyl is methyl.

[0027] In some embodiments of this specification, a compound comprising a first radical and a second radical, wherein the first radical is of formula (IB):

[0028] [ka] Compounds are provided that include the structure of.

[0029] In some embodiments,

[0030] [Chemical Formula] is a single bond or a double bond. In some embodiments, R a , R b , R c , and R d are each independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, and the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted. In some embodiments, m, n, o, and p are each independently 0 to 6. In some embodiments, any one of R a , R b , R c , and R d combines with another one of R a , R b , R c , and R d to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, the second radical is a therapeutically active agent (or drug), and the first radical (e.g., steroid) is different from the second radical (e.g., prostaglandin). In some embodiments, the first radical, the second radical, or both the first radical and the second radical are not steroids. In certain embodiments herein, pharmaceutically acceptable salts or solvates of the compounds of formula (IB) are also provided.

[0031] In some embodiments, one of the rings B of formula (I), formula (IA), or formula (IB) is optionally substituted cycloalkyl. In some embodiments, one of the rings B of formula (I), formula (IA), or formula (IB) does not contain a heteroatom within the ring (e.g., ring B is optionally substituted cycloalkyl). In some embodiments, one of the rings B of formula (I), formula (IA), or formula (IB) contains only a single bond. In some embodiments, one of the rings B of formula (I), formula (IA), or formula (IB) contains at least one double bond. In some embodiments, one of the rings B of formula (I), formula (IA), or formula (IB) is bonded to at least one ring (e.g., ring A and / or ring C) which contains at least one double bond. In some embodiments, ring A contains at least one double bond. In some embodiments, ring C contains at least one double bond. In some embodiments, ring A and ring C each independently contain at least one double bond. In some embodiments, one of ring B of formula (I), formula (IA), or formula (IB) is bonded to at least one aromatic ring (e.g., ring A and / or ring C). In some embodiments, one of ring B of formula (I) or formula (IA) is aromatic. In some embodiments, one of ring A of formula (I) or formula (IA), ring B, and ring C are each aromatic.

[0032] In some embodiments, m is 4. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, o is 5. In some embodiments, o is 4. In some embodiments, o is 3. In some embodiments, o is 2. In some embodiments, o is 1. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0033] In some embodiments, R a , R b , R c , and R d are each independently selected from the group consisting of oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, and alkyl, heteroalkyl, cycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, or heterocycloalkyl is optionally substituted. In some embodiments, R a are each independently selected from -OH, oxo, halogen, alkyl, or alkoxy, and alkyl or alkoxy is optionally substituted. In some embodiments, R b are each independently selected from -OH, oxo, halogen, or optionally substituted alkyl. In some embodiments, R c are each independently selected from -OH, oxo, or optionally substituted alkyl. In some embodiments, R d are each independently selected from -OH, oxo, alkyl (e.g., alkenyl or alkynyl), heteroalkyl, or R d together form oxo, and alkyl or heteroalkyl is optionally substituted. In some embodiments, the substituted alkyl of R d is -COOH, -(C=O)alkyl, -(C=O)Oalkyl, -O(C=O)Oalkyl, -(C=O)Salkyl, and alkyl is optionally substituted by -OH or halogen. In some embodiments, one R d joins with another R d to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl.

[0034] In some embodiments, R a , Rb , R c , or R d One of the alkyl groups is a C1-C3 alkyl group. In some embodiments, R a , R b , R c , or R d Any one of the alkyl groups is substituted with an oxo, and further optionally selected with alkyl, hydroxy, halogen, heteroalkyl, alkoxy, or thioether, and further optionally substituted with alkyl, alkoxy, thioether, or heteroalkyl. In some embodiments, R a , R b , R c , or R d One of the alkoxy groups is a C1-C3 alkoxy.

[0035] In some embodiments, ring A is aromatic. In some embodiments, ring A contains at least one double bond. In some embodiments, ring A contains one double bond. In some embodiments, ring A contains two double bonds. In some embodiments, ring B contains at least one double bond. In some embodiments, ring B contains one double bond. In some embodiments, ring C contains one double bond. In some embodiments, ring D contains one double bond. In some embodiments, ring A contains at least one double bond, and rings B, C, and D each consist of single bonds. In some embodiments, ring A is aromatic, and rings B, C, and D each consist of single bonds. In some embodiments, ring A contains at least one double bond, and at least one of rings B, C, or D contains a double bond. In some embodiments, ring A contains at least one double bond, and ring B contains a double bond. In some embodiments, ring A contains at least one double bond, and ring C contains a double bond. In some embodiments, ring A contains at least one double bond, and ring D contains a double bond.

[0036] In some embodiments of this specification, a compound comprising a first radical and a second radical, wherein the first radical is of formula (IC):

[0037] [ka] A compound containing the structure is provided.

[0038] In some embodiments,

[0039] [ka] is a single bond or a double bond. In some embodiments, R a is hydrogen, -OH, or oxo. In some embodiments, R a’ Each is independently selected from hydrogen, -OH, halogen, C1-C3 alkyl, and alkoxy. In some embodiments, R a” R is either absent, hydrogen, or a C1-C3 alkyl group. In some embodiments, R b R is either absent or is hydrogen, a halogen, or a C1-C3 alkyl group. In some embodiments, R b’ is hydrogen, halogen, -OH, oxo, or C1-C3 alkyl. In some embodiments, R b” is hydrogen or -OH. In some embodiments, R c Each is independently hydrogen, -OH, oxo, or C1-C3 alkyl. In some embodiments, R c’ Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, R c” R is hydrogen, -OH, C1-C3 alkyl, or -C(=O)H. In some embodiments, R d These are independently hydrogen, -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or R dEach of these elements combines to form an oxo, and alkyl or heteroalkyl elements are optionally substituted. In some embodiments, R d’ R is hydrogen, -OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments, one R d R d’ In combination with the first radical, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, the first radical, the second radical, or both the first and second radicals are not steroids. In some embodiments, the second radical is a therapeutically active agent (or drug), and the first radical (e.g., a steroid) is different from the second radical (e.g., a prostaglandin). In some embodiments herein, pharmaceutically active salts or solvates of the compound of formula (IC) are also provided.

[0040] In some embodiments, one of the structures of formula (I), formula (IA), formula (IB), or formula (IC) consists of a single bond. In some embodiments, one of the structures of formula (I), formula (IA), formula (IB), or formula (IC) contains at least one double bond. In some embodiments, one of the structures of formula (I), formula (IA), formula (IB), or formula (IC) contains one double bond. In some embodiments, one of the structures of formula (I), formula (IA), formula (IB), or formula (IC) contains two double bonds. In some embodiments, one of the structures of formula (I), formula (IA), formula (IB), or formula (IC) contains three double bonds. In some embodiments, one of the structures of formula (I), formula (IA), formula (IB), or formula (IC) contains at least one aromatic ring. In some embodiments, one of the structures of formula (I), formula (IA), formula (IB), or formula (IC) includes one aromatic ring.

[0041] In some embodiments, R a is -OH. In some embodiments, R ais -OH and is bonded to a fully saturated cycloalkyl group. In some embodiments, R a is -OH and is bonded to the aryl group. In some embodiments, R a is an oxo. In some embodiments, R a It is an oxo and is adjacent to at least one double bond. In some embodiments, R a It is an oxo and adjacent to one double bond. In some embodiments, R a It is an oxo molecule and is adjacent to two double bonds.

[0042] In some embodiments, R a’ These are, independently, hydrogen or halogen (e.g., fluoro or chloro). In some embodiments, R a’ Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, R a’ Each is independently hydrogen or a C1-C3 alkoxy. In some embodiments, R a’ Each of them is bonded by a single bond. In some embodiments, R a’ Each of these is hydrogen. In some embodiments, at least one R a’ It is bonded to a double bond. In some embodiments, one R a’ It is bonded to a double bond. In some embodiments, R a’ Each is bonded to a double bond. In some embodiments, R a’ Each is independently hydrogen or a C1-C3 alkyl group and is bonded to a single bond. In some embodiments, R a’ Each is independently hydrogen or halogen, and one R a’ It is bonded to a double bond. In some embodiments, R a’ Each of these is a hydrogen atom, which is bonded to the single bond. In some embodiments, R a’ Each of these is a hydrogen atom, which is bonded to the double bond. In some embodiments, R a’ Each is bonded to an aryl group and is independently hydrogen or a C1-C3 alkoxy. In some embodiments, R a’It is hydrogen and is bonded to the aryl group.

[0043] In some embodiments, R a” It does not exist. In some embodiments, R a” is hydrogen. In some embodiments, R a” is a C1-C3 alkyl group. In some embodiments, R a is -OH or oxo, R a’ Each is independently hydrogen or a C1-C3 alkyl, and R a” is a C1-C3 alkyl group. In some embodiments, R a is -OH or oxo, R a’ Each is independently hydrogen or a C1-C3 alkoxy, and R a” is a C1-C3 alkyl group. In some embodiments, R a It is oxo, R a’ Each is independently hydrogen or halogen (e.g., fluoro or chloro), and R a” is a C1-C3 alkyl group (e.g., methyl). In some embodiments, R a It is oxo, R a’ Each is independently either hydrogen or a C1-C3 alkyl group (e.g., methyl), and R a” is a C1-C3 alkyl group (e.g., methyl). In some embodiments, R a It is oxo, R a’ is hydrogen, R a” is a C1-C3 alkyl group (e.g., methyl). In some embodiments, R a is -OH, and R a’ Each is independently hydrogen or a C1-C3 alkoxy (e.g., methoxy), and R a” It does not exist. In some embodiments, R a is -OH, and R a’ is hydrogen, R a” is a C1-C3 alkyl group (e.g., methyl). In some embodiments, R a R is -OH a’ Each of them is hydrogen, and R a” It does not exist.

[0044] In some embodiments, R b It does not exist. In some embodiments, R b is hydrogen. In some embodiments, R b is a halogen (e.g., fluoro or chloro). In some embodiments, R b’ is hydrogen. In some embodiments, R b’ is a halogen (e.g., fluoro or chloro). In some embodiments, R b’ is -OH. In some embodiments, R b’ is an oxo. In some embodiments, R b’ is a C1-C3 alkyl group (e.g., methyl). In some embodiments, R b’ R is hydrogen, a halogen (e.g., fluoro or chloro), or a C1-C3 alkyl (e.g., methyl), and is bonded to a single bond. In some embodiments, R b’ R is hydrogen or a C1-C3 alkyl group (e.g., methyl) and is bonded to the double bond. In some embodiments, R b” is hydrogen. In some embodiments, R b” It is -OH.

[0045] In some embodiments, R b R is hydrogen or halogen (e.g., fluoro or chloro), b’ R is hydrogen, halogen (e.g., fluoro or chloro), or C1-C3 alkyl (e.g., methyl), b” is hydrogen. In some embodiments, R b R is hydrogen or halogen (e.g., fluoro or chloro), b’ R is hydrogen or halogen (e.g., fluoro or chloro), b” is hydrogen. In some embodiments, R b is a halogen (e.g., fluoro or chloro), and R b’ is a halogen (e.g., fluoro or chloro), and R b”is hydrogen. In some embodiments, R b is a halogen (e.g., fluoro or chloro), and R b’ is hydrogen, R b” is hydrogen. In some embodiments, R b is hydrogen, R b’ is a halogen (e.g., fluoro or chloro), and R b” is hydrogen. In some embodiments, R b is hydrogen, R b’ is a C1-C3 alkyl group (e.g., methyl), and R b” is hydrogen. In some embodiments, R b is hydrogen, R b’ is hydrogen, R b” is -OH. In some embodiments, R b is hydrogen, R b’ It is oxo, R b” is hydrogen. In some embodiments, Rb, Rb', and R b” Each of these is hydrogen.

[0046] In some embodiments, R c Each is independently hydrogen or -OH. In some embodiments, R c Each is independently hydrogen or oxo. In some embodiments, R c Each of these is hydrogen. In some embodiments, R c’ Each of these is hydrogen. In some embodiments, R c’ Each of these is a C1-C3 alkyl group. In some embodiments, R c” is hydrogen. In some embodiments, R c” is a C1-C3 alkyl group. In some embodiments, R c” It is -C(=O)H.

[0047] In some embodiments, R c Each of them is hydrogen, and R c’ Each of them is hydrogen, and R c” is a C1-C3 alkyl group. In some embodiments, R cEach is independently hydrogen or -OH, and R c’ Each of them is hydrogen, and R c” is a C1-C3 alkyl group. In some embodiments, R c Each is independently a hydrogen or oxo, and R c’ Each of them is hydrogen, and R c” is a C1-C3 alkyl group. In some embodiments, R c Each is independently hydrogen or -OH, and R c’ Each of them is hydrogen, and R c” is -C(=O)H. In some embodiments, R c Each is independently hydrogen or -OH, and R c’ Each of these is a C1-C3 alkyl group, and R c” It is hydrogen.

[0048] In some embodiments, one R d It does not exist, R d’ and other R d It is bonded to the double bond. In some embodiments, R is bonded to the double bond. d’ and other R d These are hydrogen atoms, respectively.

[0049] In some embodiments, one R d It is hydrogen, and the other R d R is -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), or heteroalkyl, and the alkyl or heteroalkyl is optionally substituted. In some embodiments, one R d It is alkyl, and other R d R is -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), or heteroalkyl, and the alkyl or heteroalkyl is optionally substituted. In some embodiments, one R d is an alkoxy that is optionally substituted, and other R dR is -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), or heteroalkyl, and the alkyl or heteroalkyl is optionally substituted. In some embodiments, one R d is -OH, and the other R d R is a -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), or heteroalkyl, where the alkyl or heteroalkyl is optionally substituted. In some embodiments, R d Each is independently hydrogen or -OH. In some embodiments, R d Each of these is independently an optionally substituted alkyl or -OH group. In some embodiments, R d Each is independently -COOH or -OH. In some embodiments, R d Each is independently a -COOH or optionally substituted alkoxy. In some embodiments, R d Each of them combines to form an oxo. In some embodiments, R d These combine to form an optionally substituted alkenyl. In some embodiments, the alkenyl is substituted with -COOH and alkyl. In some embodiments, the alkyl includes a saturated or unsaturated carbon bond. In some embodiments, R d Each of these is independently an optionally substituted alkyl or hydrogen. In some embodiments, the alkyl consists of a saturated carbon bond. In some embodiments, the alkyl is substituted with C1-C3 alkyl and alkyl further substituted with -COOH. In some embodiments, the alkyl is substituted with C1-C3 alkyl and alkyl further substituted with -OH.

[0050] In some embodiments, R d’ is hydrogen. In some embodiments, R d’ is -OH. In some embodiments, R d’is a C1-C3 alkyl group (e.g., alkylene or alkenyl). In some embodiments, the C1-C3 alkyl group is methyl. In some embodiments, the C1-C3 alkyl group is CHCH. In some embodiments, R d’ It is a heteroalkyl. In some embodiments, the heteroalkyl is a -O(C=O)C1-C3 alkyl.

[0051] In some embodiments, one R d R d’ By integrating with, it forms an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In some embodiments, one R d R d’ By integrating with, it forms a heterocycloalkyl group substituted with one or more alkyl groups. In some embodiments, one R d is an optionally substituted alkyl, and other R d R d’ By combining with, it forms a heterocycloalkyl group substituted with one or more alkyl groups. In some embodiments, the alkyl group is substituted with oxo and -OH groups. In some embodiments, the alkyl group is substituted with an alkyl group further substituted with oxo and a halogen (e.g., fluoro or chloro). In some embodiments, the heterocycloalkyl group is optionally substituted with a dioxolane. In some embodiments, the optionally substituted dioxolane is 2,2-dimethyl-1,3-dioxolane. In some embodiments, the optionally substituted dioxolane is 1,4-dioxaspiron[4.4]nonane.

[0052] In some embodiments, R d Each is an alkyl group that is independently substituted with hydrogen or optionally substituted, and R d’ is hydrogen. In some embodiments, R d Each is an alkyl group that is independently substituted with hydrogen or optionally substituted, and R d’ is a C1-C3 alkyl group. In some embodiments, R dEach of these is an alkyl that is independently and arbitrarily substituted, and R d’ is hydrogen. In some embodiments, R d Each of these is an alkyl group independently of -OH or optionally substituted, and R d’ is hydrogen. In some embodiments, R d Each of these is an independently -COOH or optionally substituted alkoxy, and R d’ is hydrogen. In some embodiments, R d Each is an alkyl group independently substituted with -OH or optionally substituted, and R d’ is a C1-C3 alkyl group. In some embodiments, R d Each of these is an alkyl group independently of -OH or optionally substituted, and R d’ is -OH. In some embodiments, R d Each of these is an alkyl group independently of -OH or optionally substituted, and R d’ is an alkyl group (e.g., an alkenyl group). In some embodiments, R d Each is independently hydrogen or -OH, and R d’ is hydrogen. In some embodiments, R d Each of these is independently -OH or -COOH, and R d’ is hydrogen. In some embodiments, Rd and R d’ Each of these is hydrogen. In some embodiments, R d These are alkenils that have been substituted by any choice, and R d’ R is an optionally substituted alkoxy. In some embodiments, R d Each of them combines to form an oxo, R d’ is hydrogen. In some embodiments, one R d is an optionally substituted alkyl, and other R d R d’ By integrating with it, it forms a heterocycloalkyl group with optional substitutions.

[0053] In some embodiments, R d or R d’The alkyl or heteroalkyl is substituted with one or more of the group consisting of -SH, -OH, -COOH, oxo, halogen, amino (e.g., dihydroamino, alkylamino, or arylamino), alkyl (e.g., alkenyl, alkynyl), heteroalkyl, ester, amide, sulfonic acid, and sulfone. In some embodiments, one R d R d’ By integrating with it, it forms a substituted heterocycloalkyl group.

[0054] In some embodiments, R d The alkyl group is substituted with an alkyl group further substituted with oxo and hydroxyl groups. In some embodiments, R d The alkyl group is substituted with an alkyl group that is further substituted with an oxo group and a halogen (e.g., fluorine or chlorine). In some embodiments, R d The alkyl group is substituted with oxo and C1-C3 alkyl groups. In some embodiments, R d The alkyl group is substituted with an oxo group, and an alkyl group further substituted with an alkoxy group that is further substituted with an oxo group and a C1-C3 alkyl group. In some embodiments, R d The alkyl is substituted with alkyl, and alkyl further substituted with oxo, and amino further substituted with alkyl further substituted with sulfonic acid. In some embodiments, R d The alkyl is substituted with an oxo, and a thiol (e.g., thioether) further substituted with a C1-C3 alkyl that is further substituted with a halogen (e.g., fluorine or chlorine). In some embodiments, R d The alkyl group is substituted with -OH. In some embodiments, R d The alkyl is substituted with an oxo, and a hydroxyl (e.g., ether) further substituted with a C1-C3 alkyl that is further substituted with a halogen (e.g., fluorine or chlorine). In some embodiments, R d The alkoxy is substituted with alkoxy that is further substituted with oxo and aryl.

[0055] In some embodiments, the C1-C3 alkyl is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some embodiments, the C1-C3 alkyl is methyl. In some embodiments, the C1-C3 alkoxy is methoxy, ethoxy, propyoxy, or isopropoxy. In some embodiments, the C1-C3 alkyl is methoxy.

[0056] In some embodiments, the first radical and the second radical are linked by a linker (e.g., a bond). In some embodiments, the first radical is linked to the R of the first radical. a , R b , R c , or R d The first radical is bonded to the second radical via one of the following. In some embodiments, the first radical is R a , R b , R c , or R d R is bonded to the second radical via one of the following, and the first radical is bonded to the second radical. a , R b , R c , or R d This includes hydroxyl radicals (e.g., when combined with a linker or a second radical (where the linker is a bond), they form ethers), thiol radicals (e.g., when combined with a linker or a second radical (where the linker is a bond), they form thioethers), or carboxylate radicals (e.g., when combined with a linker or a second radical (where the linker is a bond), they form esters or carbonates). In some embodiments, the linkage between thiol radicals forms a thioester, disulfide, or thiocarbonate. In some embodiments, the linkage between carboxylate radicals forms an anhydride. In some embodiments, the first radical is R a , R b , R c , or R dR is bonded to the second radical via one of the following, and the first radical is bonded to the second radical. a , R b , R c , or R d It contains an amino radical (for example, when combined with a linker or a second radical (a linker is a bond), it forms an amide, carbamate, or thiocarbamate).

[0057] In some embodiments, R is used to bond the first radical to the second radical. a , R b , R c , or R d This includes a hydroxyl radical that forms an ether by combining with a linker or a second radical. In some embodiments, R is used to bond the first radical to the second radical. a , R b , R c , or R d This includes a thiol radical that forms a thioether by combining with a linker or a second radical. In some embodiments, R is used to bond the first radical to the second radical. a , R b , R c , or R d This includes a carboxylate radical that combines with a linker or a second radical to form an ester or carbonate.

[0058] In some embodiments, the first radical has the structure of formula (I), formula (IA), formula (IB), or formula (IC), and the second radical does not have the structure of formula (I), formula (IA), formula (IB), or formula (IC). In some embodiments, the structure of formula (I), formula (IA), formula (IB), or formula (IC) has a melting temperature and / or glass transition temperature of at least 20°C (e.g., at least 25°C, at least 30°C, at least 37°C, at least 40°C, at least 50°C, at least 100°C, or higher) in its free form.

[0059] In some embodiments, both the first and second radicals consist of a three-membered ring system of formula (I), formula (IA), formula (IB), or formula (IC). In some embodiments, the first radical is a central nervous system (CNS) agent. In some embodiments, the radical of formula (I), formula (IA), formula (IB), or formula (IC) is a steroid, opioid agonist, opioid antagonist, adrenergic receptor antagonist (e.g., β-blockers, α-1 blockers), or serotonergic antagonist (e.g., serotonin 5-HT3 receptor antagonist). In some embodiments, the first radical is an anti-inflammatory agent, an antipsychotic (e.g., typical antipsychotics, atypical antipsychotics, schizophrenia agents, etc.). In some embodiments, the IOP-reducing agent is a β-blocker. In some embodiments, the β-blocker is timolol.

[0060] In some embodiments, the second radical is an intraocular pressure (IOP) lowering agent. In some embodiments, the first radical is an anti-inflammatory agent and the second radical is an IOP lowering agent. In some embodiments, the first radical is an IOP lowering steroid (e.g., Anecoltab) or a benign steroid (e.g., cholesterol) and the second radical is an IOP lowering agent. In some embodiments, the IOP lowering agent is a prostaglandin.

[0061] In some embodiments, the first radical is a solid in its free form (e.g., having a melting point of at least 30°C). In some embodiments, the second radical is a liquid in its free form (e.g., having a melting point below 30°C). In some embodiments, the first radical is a steroid (e.g., dexamethasone, anecoltab, etc.). In some embodiments, the steroid is a corticosteroid (e.g., a glucocorticoid or mineralocorticoid), a sex steroid, a neurosteroid, an aminosteroid, or a secosteroid. In some embodiments, the second radical is not a steroid (i.e., it does not have any of the structures of formula (I), formula (IA), formula (IB), or formula (IC)). In some embodiments, the first radical is a steroid and the second radical is a prostaglandin.

[0062] In some embodiments, the second radical is given by formula (II):

[0063] [ka] It has the structure of [the object].

[0064] In some embodiments,

[0065] [ka] is a single bond or a double bond. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 Each of these is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. In some embodiments, R1 , R 2 , R 3 , R 4 , or R 5 Any one of these combines to form an optionally substituted cycloalkyl or heterocycloalkyl. In some embodiments, X is -O-, -NR-, -S(R) a -, and -C(R) b - Selected from the group consisting of -. In some embodiments, a is independently 0 to 2. In some embodiments, b is independently 1 or 2. In some embodiments herein, pharmaceutically salts or solvates of the compound of formula (II) are also provided.

[0066] In some embodiments, X is S, -C(R)1-, or -C(R)2-. In some embodiments, X is S bonded to a single bond. In some embodiments, X is -CH- or -CH2-.

[0067] In some embodiments, R 4 R is an alkyl group substituted with one or more groups, each independently selected from -C(=O)OC1-C3 alkyl, -COOH, -CONH2, -CONHC1-C3 alkyl, and / or alkyl (e.g., alkylene or alkenyl). In some embodiments, R 4 R is an alkyl group substituted with -COOH. In some embodiments, R 4 is an alkyl group substituted with -C(=O)OC1-C3 alkyl. In some embodiments, R 4 is an alkyl group substituted with -CONH2. In some embodiments, R 4 is an alkyl group substituted with -CONHC1-C3 alkyl. In some embodiments, R 4 The alkyl group contains at least one double bond. In some embodiments, R 4 The alkyl group contains one double bond. In some embodiments, R 4 The alkyl group contains two double bonds. In some embodiments, the two double bonds form an allene.

[0068] In some embodiments, R 5 The alkyl group is substituted with one or more groups, each independently selected from halogens, -OH, oxo, alkyl (e.g., alkynyl), alkoxy, aryl, and aryloxy groups, where the alkyl (e.g., alkynyl), aryl, or aryloxy groups are optionally substituted. In some embodiments, the alkyl group is substituted with one or more groups, each independently selected from halogens, -OH, oxo, alkyl (e.g., alkynyl), aryl, or aryloxy groups, where the alkyl (e.g., alkynyl), aryl, or aryloxy groups are optionally substituted. In some embodiments, the aryl or aryloxy group is substituted with one or more halogen groups. In some embodiments, the aryl or aryloxy group is not substituted.

[0069] In some embodiments, the second radical is given by formula (IIA):

[0070] [ka] It has the structure of [the object].

[0071] In some embodiments,

[0072] [ka] Each of these is independently a single bond or a double bond. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5Each of these is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted.

[0073] In some embodiments, formula (IIA) contains three double bonds. In some embodiments, formula (IIA) contains two double bonds. In some embodiments, formula (IIA) contains one double bond.

[0074] In some embodiments, R 1 and R 3 Each is independently -OH or oxo. In some embodiments, R 1 It is oxo, R 2 is hydrogen, R 3 is -OH. In some embodiments, R 3 It is oxo, R 2 is hydrogen, R 1 is -OH. In some embodiments, R 1 and R 3 Each of them is -OH, and R 2 It is hydrogen.

[0075] In some embodiments, R 4 is -C(=O)OC1-C3 alkyl, -COOH, -CONH2, or -CONHC1-C3 alkyl. In some embodiments, R 4 is -COOH. In some embodiments, R 4 It is -CONH2.

[0076] In some embodiments, R 5 is an alkyl or aryloxy, and alkyl and aryloxy are optionally substituted. In some embodiments, R 5is alkyl. In some embodiments, alkyl is butyl or hexyl. In some embodiments, R 5 R is an alkyl group substituted with an optionally substituted aryl group or an alkyl group substituted with an optionally substituted alkyl group. In some embodiments, the alkyl group is substituted with an unsubstituted aryl group. In some embodiments, the alkyl group is substituted with an alkyl group (e.g., buta-2-yne). In some embodiments, R 5 is an unsubstituted aryloxy. In some embodiments, R 5 This is an aryloxy substituted with one or more alkyl (e.g., -CF3) or halo (fluoro or chloro) groups. In some embodiments, the aryloxy is substituted with -CF3.

[0077] In some embodiments, R 6 and R 6’ These are each fluoro. In some embodiments, R 6 is H or methyl, R 6’ is -OH. In some embodiments, R 6 H is R 6’ is -OH. In some embodiments, R 6 is methyl, and R 6’ is -OH. In some embodiments, R 6 and R 6’ These combine to form an oxo.

[0078] In some embodiments, R of formula (II) 3 and R 4 These combine to form optionally substituted cycloalkyl or heterocycloalkyl groups. In some embodiments, R of formula (II) 3 and R 4 These combine to form a heterocycloalkyl group substituted with optionally substituted alkyl groups (e.g., alkenyl groups). In some embodiments, R of formula (II) 3 and R 4These combine to form a heterocycloalkyl substituted with an alkyl (e.g., an alkenyl) substituted with -COOH or -C(=O)OC1-C3 alkyl. In some embodiments, the heterocycloalkyl is substituted with an alkyl further substituted with -COOH or -C(=O)OC1-C3 alkyl. In some embodiments, the heterocycloalkyl is substituted with an alkenyl further substituted with alkyl, and this alkyl is further substituted with -COOH or -C(=O)OC1-C3 alkyl. In some embodiments, the alkyl or alkenyl is substituted with -COOH.

[0079] In some embodiments, the second radical is given by formula (IIB):

[0080] [ka] It has the structure of [the object].

[0081] In some embodiments,

[0082] [ka] is a single bond or a double bond. In some embodiments, R 1 , R 2 , and R 5 Each of these is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. In some embodiments, R 6” is oxo or -OH. In some embodiments, Y 1 and Y 2Each is independently bonded or alkylene. In some embodiments, G is O or CH2. In some embodiments, g is 1 or 2. In some embodiments, R 10 is alkyl or H. In some embodiments herein, pharmaceutically active salts or solvates of the compound of formula (IIB) are also provided.

[0083] In some embodiments, G is O and Y 1 is a bond. In some embodiments, Y 2 g is methylene. In some embodiments, g is 1. In some embodiments, G is O and Y 1 is alkylene. In some embodiments, Y 2 This is a bond. In some embodiments, g is 2.

[0084] In some embodiments, R 1 is oxo or -OH. In some embodiments, R 1 is -OH. In some embodiments, R 1 is -OH, and R 2 is hydrogen. In some embodiments, R 6” is -OH. In some embodiments, R 5 is alkyl. In some embodiments, R 5 This is the substituted aryl.

[0085] In some embodiments, G is O and Y 1 Y is a combination, 2 is methylene, g is 1, R 1 is -OH, and R 2 is hydrogen, R 5 is alkyl, R 6” is -OH, and R 10 H is H. In some embodiments, G is O and Y 1 is methylene, Y 2 is a bond, g is 2, R 1 is -OH, and R 2 is hydrogen, R5 is a substituted aryl, R 6” is -OH, and R 10 It is H or C1-C3 alkyl.

[0086] In some embodiments, R 5 R is selected from one or more of the group consisting of -O-, -OH, halogen, alkyl (e.g., alkynyl), and aryl, and alkyl (e.g., alkynyl) and aryl are optionally substituted with one or more of alkyl (e.g., fluoroalkyl), halogen, and -OH. In some embodiments, R 5 is an optionally substituted aryl, or an optionally substituted -O-aryl. In some embodiments, R 5 R is an alkyl or aryloxy, and alkyl and optionally substituted aryloxy. In some embodiments, R 5 is alkyl. In some embodiments, alkyl is butyl or hexyl. In some embodiments, R 5 is an unsubstituted aryloxy. In some embodiments, the aryloxy is substituted with 1 or 2 -F. In some embodiments, R 5 R is either aryl or O-aryl and is not substituted. In some embodiments, R 5 The elements are aryl or O-aryl, each substituted with one or more halogens or haloalkyls (e.g., trifluoroalkyls, e.g., trifluoromethyl).

[0087] In some embodiments herein, a compound is provided comprising a first radical and a second radical, wherein the first radical has a structure of any one of formulas (I), (IA), (IB), or (IC), and the second radical has a structure of any one of formulas (II), (IIA), or (IIB). In some embodiments, the first radical (e.g., having a structure of any one of formulas (I), (IA), (IB), or (IC)) and the second radical (e.g., formula (II), (IIA), or (IIB)) are linked by a linker (e.g., a hydrolyzable linker). In some embodiments, the linker is a bond.

[0088] In some embodiments, compounds comprising steroids are provided herein. In some embodiments, compounds comprising prostaglandins are provided herein. In some embodiments, compounds comprising linkers (e.g., hydrolyzable linkers) are provided herein. In some embodiments, the linker is adjacent to the steroid and prostaglandin (e.g., by covalent bonds). In some embodiments herein, pharmaceutically salts or solvates of the compounds are also provided.

[0089] In some embodiments, this specification includes formula (III):

[0090] [ka] A compound having the structure is provided.

[0091] In some embodiments,

[0092] [ka] is a single bond or a double bond. In some embodiments, R a , R b , R c , and R dEach is independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, and alkyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are optionally substituted. In some embodiments, R a , R b , R c , and R d One of the following is R a , R b , R c , and R d By combining with another of these, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, m, n, o, and p are each independently 0 to 6. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 Each is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, where alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. In some embodiments, L is a linker. In some embodiments herein, pharmaceutically active salts or solvates of the compound of formula (III) are also provided.

[0093] In some embodiments, any optional substitution of any one of the bases of formula (III) is as provided elsewhere herein (for example, as in formula (IB) or formula (II)).

[0094] In some embodiments, this specification includes formula (IV):

[0095] [ka] A compound having the structure is provided.

[0096] In some embodiments,

[0097] [ka] is a single bond or a double bond. In some embodiments, R a is hydrogen, -OH, or oxo. In some embodiments, R a’ Each is independently selected from hydrogen, -OH, halogen, C1-C3 alkyl, and alkoxy. In some embodiments, R a” R is either absent, hydrogen, or a C1-C3 alkyl group. In some embodiments, R b R is either absent or is hydrogen, a halogen, or a C1-C3 alkyl group. In some embodiments, R b’ is hydrogen, halogen, -OH, oxo, or C1-C3 alkyl. In some embodiments, R b” is hydrogen or -OH. In some embodiments, R c Each is independently hydrogen, -OH, oxo, or C1-C3 alkyl. In some embodiments, R c’ Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, R c” R is hydrogen, -OH, C1-C3 alkyl, or -C(=O)H. In some embodiments, R d These are independently hydrogen, -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or R d Each of these elements combines to form an oxo, and alkyl or heteroalkyl elements are optionally substituted. In some embodiments, R d’ R is hydrogen, -OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments, one R d R d’By integrating with, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 Each of these is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. In some embodiments, R 6 and R 6’ These are, independently, hydrogen, halogen, alkyl, or R 6 and R 6’ These combine to form an oxo. In some embodiments herein, pharmaceutically active salts or solvates of the compound of formula (IV) are also provided.

[0098] In one embodiment, this specification includes formula (V):

[0099] [ka] A compound having the structure is provided.

[0100] In some embodiments,

[0101] [ka] is a single bond or a double bond. In some embodiments, R a is hydrogen, -OH, or oxo. In some embodiments, R a’ Each is independently selected from hydrogen, -OH, halogen, C1-C3 alkyl, and alkoxy. In some embodiments, R a” R is either absent, hydrogen, or a C1-C3 alkyl group. In some embodiments, R bR is either absent or is hydrogen, a halogen, or a C1-C3 alkyl group. In some embodiments, R b’ is hydrogen, halogen, -OH, oxo, or C1-C3 alkyl. In some embodiments, R b” is hydrogen or -OH. In some embodiments, R c Each is independently hydrogen, -OH, oxo, or C1-C3 alkyl. In some embodiments, R c’ Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, R c” R is hydrogen, -OH, C1-C3 alkyl, or -C(=O)H. In some embodiments, R d These are independently hydrogen, -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or R d Each of these elements combines to form an oxo, and alkyl or heteroalkyl elements are optionally substituted. In some embodiments, R d’ R is hydrogen, -OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments, one R d R d’ By integrating with, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments, R 1 , R 2 , and R 5 Each of these is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. In some embodiments, R 6” is oxo or -OH. In some embodiments, Y 1 and Y 2Each is independently bonded or alkylene. In some embodiments, G is O or CH2. In some embodiments, g is 1 or 2. In some embodiments, R 10 is alkyl or H. In some embodiments, L is a linker. In some embodiments herein, pharmaceutically active salts or solvates of the compound of formula (V) are also provided.

[0102] In some embodiments, one hydroxyl radical or carboxylate radical of formula (I), formula (IA), formula (IB), or formula (IC) is linked to another hydroxyl radical or carboxylate radical of formula (I), formula (IA), formula (IB), or formula (IC) via a linker. In some embodiments, one hydroxyl radical or carboxylate radical of formula (I), formula (IA), formula (IB), or formula (IC) is linked to one hydroxyl radical or carboxylate radical of formula (II), formula (IIA), or formula (IIB) via a linker. In some embodiments, one hydroxyl radical of formula (I), formula (IA), formula (IB), or formula (IC) is linked to one hydroxyl radical of formula (II), formula (IIA), or formula (IIB) via a linker. In some embodiments, one hydroxyl radical of formula (I), formula (IA), formula (IB), or formula (IC) is linked to one carboxylate radical of formula (II), formula (IIA), or formula (IIB) via a linker. In some embodiments, one carboxylate radical of formula (I), formula (IA), formula (IB), or formula (IC) is linked to one hydroxyl radical of formula (II), formula (IIA), or formula (IIB) via a linker. In some embodiments, one carboxylate radical of formula (I), formula (IA), formula (IB), or formula (IC) is linked to one carboxylate radical of formula (II), formula (IIA), or formula (IIB) via a linker. In some embodiments, the linker is a bond. In some embodiments, the linker is an oxo.

[0103] In some embodiments, R a , R a’ , R b , R b’ , R b” , R c , R c” , R d , or Rd’ One of these is an ester radical, a hydroxyl radical, or a carboxylate radical, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 One of these is an amide radical, a thiol radical, a hydroxyl radical, or a carboxylate radical. In some embodiments, R a , R a’ , R b , R b’ , R b” , R c , R c” , R d , or R d’ One of these is an ester radical, a hydroxyl radical, or a carboxylate radical, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 One of these is a hydroxyl radical or a carboxylate radical. In some embodiments, R a , R a’ , R b , R b’ , R b” , R c , R c” , R d , or R d’ Any of the radicals are linked by the linker R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 Adjacent to any of the radicals. In some embodiments, R a , R a’ , Rb , R b’ , R b” , R c , R c” , R d , or R d’ Any of the radicals are linked by the linker R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 Adjacent to any of the radicals. In some embodiments, R a , R b , R c , or R d Any of the radicals are linked by the linker R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 Adjacent to any of the radicals. In some embodiments, R d or R d’ Any of the radicals are linked by the linker R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 Adjacent to any of the radicals. In some embodiments, R d The radical is linked by the linker R 4 , R 6 , R 6’ , R 6” , or R 10 Adjacent to any of the radicals. In some embodiments, R d The radical is linked by the linker R 4 or R 10 Adjacent to the radical of R. In some embodiments, R d The radical is linked by the linker R 6 , R 6’ , or R 6” It is adjacent to any of the radicals. In some embodiments, the linker is an oxo. In some embodiments, the linker is a bond.

[0104] In some embodiments, the linker is bonded, alkyl, heteroalkyl, or alkoxy, and the alkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, heteroalkyl, or alkoxy is each independently substituted with one or more groups, each independently selected from the group consisting of -O-, -S-, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g., polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker is alkyl (alkylene), and the alkyl (alkylene) is substituted with one or more groups selected from -OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker is unsubstituted alkyl (alkylene). In some embodiments, the linker is heteroalkyl (heteroalkylene), and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl. In some embodiments, the linker is an unsubstituted heteroalkyl (heteroalkylene). In some embodiments, the linker is a bond.

[0105] In some embodiments, the linker comprises one or more linker groups, each independently selected from bonded, alkyl, cycloalkyl, heteroalkyl, or alkoxy groups, and the alkyl, cycloalkyl, heteroalkyl, or alkoxy groups are optionally substituted. In some embodiments, the linker is bonded, alkyl, cycloalkyl, heteroalkyl, or alkoxy, and the alkyl, cycloalkyl, heteroalkyl, or alkoxy groups are optionally substituted. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, or alkoxy groups are each independently substituted with one or more substituents, each independently selected from the group consisting of -O- (e.g., -OH), -S- (e.g., -SH), silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g., polyTHF), and optionally substituted cycloalkyl groups. In some embodiments, the linker comprises one or more linker groups, each independently selected from alkyl(alkylene) and cycloalkyl(cycloalkylene). In some embodiments, the linker is alkyl(alkylene) or cycloalkyl(cycloalkylene). In some embodiments, the alkyl(alkylene) or cycloalkyl(cycloalkylene) is unsubstituted or substituted with one or more substituents, each independently selected from the group consisting of -OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker comprises unsubstituted or substituted alkylene-cycloalkylene-alkylene.

[0106] In some embodiments, the linker comprises at least one oxo. In some embodiments, the linker is an oxo. In some embodiments, the linker comprises at least one carbamate. In some embodiments, the linker is a carbamate. In some embodiments, the linker comprises at least one ester. In some embodiments, the linker is an ester.

[0107] In some embodiments, the linker is oxo, -O-, -S-, unsubstituted alkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n It comprises one or more linker groups selected from, where n is 1 to 20. In some embodiments, the linker is a bond, an unsubstituted alkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n , and C=O(CH2CH2) n C=O(CH(CH3)C(=O)O) n And n is 1 to 20. In some embodiments, n is 1 to 10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0108] In some embodiments, the linker comprises one or more linker groups, each independently of the following: bond, -O-, -O(C=O)-, -O(C=O)-O-, -S-, unsubstituted alkylene, unsubstituted cycloalkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , and (CH(CH3)C(=O)O) n Selected from the group consisting of, where n is 1 to 20. In some embodiments, the linker is bonded, unsubstituted alkylene, unsubstituted alkylene-cycloalkylene-alkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n C=O(CH2CH2) n C=O(CH(CH3)C(=O)O) n And n is 1 to 20. In some embodiments, n is 1 to 10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0109] In some embodiments, the linker is hydrolyzed in a buffer. In some embodiments, the linker is hydrolyzably unstable. In some embodiments, the linker is hydrolyzed with water. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or esterase). In some embodiments, the enzyme is an esterase.

[0110] In some embodiments, the first radical is

[0111] [ka]

[0112] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0113] In some embodiments, the first radical is

[0114] [ka]

[0115] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0116] In some embodiments, the second radical is

[0117] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0118] In some embodiments, the second radical is

[0119] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0120] In some embodiments, the first radical is a hydroxyl radical. In some embodiments, the second radical is a hydroxyl radical. In some embodiments, the first radical is a carboxyl radical. In some embodiments, the second radical is a carboxyl radical.

[0121] In one embodiment, formula (VI) is used herein:

[0122] [ka] A compound having the structure is provided.

[0123] In some embodiments,

[0124] [ka] is a single bond or a double bond. In some embodiments, R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl, or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 7 is hydrogen, R 8 is methyl. In some embodiments, R 9 R is either absent or is hydrogen or hydroxyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 R is hydroxyl. In some embodiments, R 9It does not exist. In some embodiments, L is a linker. In some embodiments, L is a linker as described herein. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker groups, each independently selected from the group consisting of alkylene, cycloalkylene, and -O-. In some embodiments, PG is a prostaglandin radical. Also provided herein are pharmaceutically acceptable salts or solvates of the compound of formula (VI).

[0125] In some embodiments, the compounds provided herein are of formula (VI-A):

[0126] [ka] It has the structure of [the object].

[0127] In some embodiments,

[0128] [ka] is a single bond or a double bond. In some embodiments, R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl, or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 7 is hydrogen, R 8L is methyl. In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker groups, each independently selected from the group consisting of alkylene, cycloalkylene, or -O-. In some embodiments, PG is a prostaglandin radical. Also provided herein are pharmaceutically acceptable salts or solvates of compounds of formula (VI-A).

[0129] In some embodiments, the compounds provided herein are of formula (VI-B):

[0130] [ka] It has the structure of [the object].

[0131] In some embodiments,

[0132] [ka] is a single bond or a double bond. In some embodiments, R 7 is hydrogen or halogen. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl, or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 7 is hydrogen, R 8 is methyl. In some embodiments, R 9 R is either absent or is hydrogen or hydroxyl. In some embodiments, R 9is hydrogen. In some embodiments, R 9 R is hydroxyl. In some embodiments, R 9 It does not exist. In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker groups, each independently selected from the group consisting of alkylene, cycloalkylene, or -O-. In some embodiments, PG is a prostaglandin radical. Also provided in some embodiments herein are pharmaceutically acceptable salts or solvates of compounds of formula (VI-B).

[0133] In some embodiments, the compounds provided herein are of formula (VI-C):

[0134] [ka] It has the structure of [the object].

[0135] In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker groups, each independently selected from the group consisting of alkylene, cycloalkylene, or -O-. In some embodiments, PG is a prostaglandin radical. Also provided herein are pharmaceutically acceptable salts or solvates of compounds of formula (VI-B).

[0136] In one embodiment, formula (VII) is used herein:

[0137] [ka] A compound having a prostaglandin (PG) radical is provided.

[0138] In some embodiments,

[0139] [ka] is a single bond or a double bond. In some embodiments, G is OH and Y 1 is hydrogen. In some embodiments, G is Y 1 By becoming one with, it forms -O-CH2-. In some embodiments, Y 2 is a bond or -CH2-. In some embodiments, g is 1 or 2. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 11 は-OR 13 or -NR 13’ R 13” In some embodiments, R 13 , R 13’ , and R 13” Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, u is 0 to 5. In some embodiments, R 6 and R 6’ These are each fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 ∫F is F, and u is 2. In some embodiments, CF3 and u are 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is -NHCH2CH3. In some embodiments, R 11 It is -OCH2(CH3)2.

[0140] In some embodiments, the prostaglandin (PG) radical provided herein is of formula (VII-A):

[0141] [ka] It has.

[0142] In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 11 は-OR 13 or -NR 13’ R 13” In some embodiments, R 13 , R 13’ , and R 13” Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, u is 0 to 5. In some embodiments, R 6 and R 6’ Each is independently fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 is F and u is 2. In some embodiments, CF3 and u are 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is -NHCH2CH3. In some embodiments, R 11It is -OCH2(CH3)2.

[0143] In some embodiments, the prostaglandin (PG) radical is represented by formula (VII-B):

[0144] [ka] It has.

[0145] In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 11 は-OR 13 or -NR 13’ R 13” In some embodiments, R 13 , R 13’ , and R 13” Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, u is 0 to 5. In some embodiments, R 6 and R 6’ Each is independently fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 is F and u is 2. In some embodiments, CF3 and u are 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is -NHCH2CH3. In some embodiments, R 11It is -OCH2(CH3)2.

[0146] In some embodiments, a radical (e.g., a PG radical) is bonded to a linker (e.g., L) provided herein. In some embodiments, the PG radical is bonded to a linker (e.g., L), and the linker is further bonded to a steroid radical (e.g., one provided herein). In some embodiments, R 11 R is a radical (e.g., a hydroxyl radical or an amino radical) that is bonded to a linker (e.g., a linker radical) provided herein (e.g., another linker radical is further bonded to a steroid radical provided herein). In some embodiments, R 6 or R 6’ This is a radical (e.g., a hydroxyl radical) that is bonded to a linker (e.g., a linker radical) provided herein (for example, another linker radical is further bonded to a steroid radical provided herein).

[0147] In one embodiment, formula (VIII) is used herein:

[0148] [ka] A compound having the structure is provided.

[0149] In some embodiments,

[0150] [ka] is a single or double bond. In some embodiments, L is a linker. In some embodiments, A is a steroid radical. In some embodiments, G is OH and Y 1 is hydrogen. In some embodiments, G is Y 1 By becoming one with, it forms -O-CH2-. In some embodiments, Y2 is a bond or -CH2-. In some embodiments, g is 1 or 2. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 11 は-OR 13 or -NR 13’ R 13” In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, R 13 , R 13’ , and R 13” Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, u is 0 to 5. In some embodiments, R 6 and R 6’ Each is independently fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12 is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is -NHCH2CH3. In some embodiments, R 11 is -OCH2(CH3)2. In some embodiments herein, pharmaceutically acceptable salts or solvates of the compound of formula (VIII) are also provided.

[0151] In one embodiment, formula (VIII-A) is used herein:

[0152] [ka] A compound having the structure is provided.

[0153] In some embodiments, L is a linker. In some embodiments, A is a steroid radical. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each of these is independently hydrogen, halogen, or OH, and R 11 は-OR 13 or -NR 13’ R 13” In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, R 13 , R 13’ , and R 13” Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, u is 0 to 5. In some embodiments, R 6 and R 6’ Each is independently fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12 is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is -NHCH2CH3. In some embodiments, R 11is -OCH2(CH3)2. In some embodiments herein, pharmaceutically acceptable salts or solvates of the compound of formula (VIII-A) are also provided.

[0154] In one embodiment, formula (VIII-B) is used herein:

[0155] [ka] A compound having the structure is provided.

[0156] In some embodiments, L is a linker. In some embodiments, A is a steroid radical. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 11 は-OR 13 or -NR 13’ R 13” In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, R 13 , R 13’ , and R 13” Each is independently hydrogen or a C1-C3 alkyl group. In some embodiments, u is 0 to 5. In some embodiments, R 6 and R 6’ Each is independently fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12is CF3 and u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, R 11 is OH. In some embodiments, R 11 is -NHCH2CH3. In some embodiments, R 11 is -OCH2(CH3)2. In some embodiments herein, pharmaceutically acceptable salts or solvates of the compound of formula (VIII-B) are also provided.

[0157] In some embodiments, R 11 is a radical (e.g., a hydroxyl radical or an amino radical) that is bonded to L. In some embodiments, R 6 or R 6’ L is a radical (e.g., a hydroxyl radical) bonded to L. In some embodiments, L is a bond. In some embodiments, L comprises one or more linker groups, each independently selected from the group consisting of alkylene, cycloalkylene, or -O-.

[0158] In one embodiment, A is

[0159] [ka] It has the structure of [the object].

[0160] In some embodiments,

[0161] [ka] is a single bond or a double bond. In some embodiments, R 7 is hydrogen or halogen. In some embodiments, R 8 is hydrogen or a C1-C4 alkyl group. In some embodiments, R9 R is either absent or is hydrogen or hydroxyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl, or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 9 It is a hydroxyl group.

[0162] In one embodiment, A is

[0163] [ka] It has the structure of [the object].

[0164] In some embodiments,

[0165] [ka] is a single bond or a double bond. In some embodiments, R 7 is hydrogen or halogen. In some embodiments, R 8 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 9 R is either absent or is hydrogen or hydroxyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl, or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 It is methyl.

[0166] In one embodiment, A is

[0167] [ka] It has the structure of [the object].

[0168] In some embodiments,

[0169] [ka] is a single bond or a double bond. In some embodiments, R 7 is hydrogen or halogen. In some embodiments, R 8 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 9 R is either absent or is hydrogen or hydroxyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is fluoro. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is methyl, ethyl, propyl, or butyl. In some embodiments, R 8 is methyl, ethyl, or butyl. In some embodiments, R 8 is methyl. In some embodiments, R 9 It is a hydroxyl group.

[0170] In one embodiment, A is

[0171] [ka] It has the structure of [the object].

[0172] In one embodiment, formula (IX) is used herein:

[0173] [ka] A compound having the structure is provided.

[0174] In one embodiment,

[0175] [ka] Each of these is independently a single bond or a double bond. In some embodiments, G is OH and Y 1 is hydrogen. In some embodiments, G is Y 1 By becoming one with, it forms -O-CH2-. In some embodiments, Y 2 is a bond or -CH2-. In some embodiments, g is 1 or 2. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, u is 0 to 5. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, R 6 and R 6’ These are each fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12∫ CF3, where u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. Also provided herein are pharmaceutically acceptable salts or solvates of the compound of formula (IX).

[0176] In one embodiment, formula (X) is used herein:

[0177] [ka] A compound having the structure is provided.

[0178] In one embodiment,

[0179] [ka] Each is independently a single bond or a double bond. In some embodiments, L is a linker. In some embodiments, L is a bond. In some embodiments, L is -(C=O)- or -O-(C=O)-. In some embodiments, G is OH and Y 1 is hydrogen. In some embodiments, G is Y 1 By becoming one with, it forms -O-CH2-. In some embodiments, Y 2 is a bond or -CH2-. In some embodiments, g is 1 or 2. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’ Each is independently hydrogen, halogen, or OH. In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, u is 0 to 5. In some embodiments, Z is -O- or -CH2-. In some embodiments, R 6 and R 6’Each is independently hydrogen, halogen, or OH. In some embodiments, R 12 Each is independently a halogen or a haloalkyl. In some embodiments, R 6 and R 6’ Each is independently fluoro. In some embodiments, R 6 OH is R 6’ is hydrogen. In some embodiments, Z is -O-. In some embodiments, Z is -CH2-. In some embodiments, R 12 is F and u is 2. In some embodiments, R 12 ∫ CF3, where u is 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. Also provided in some embodiments herein are pharmaceutically acceptable salts or solvates of the compound of formula (X).

[0180] In some embodiments, the compounds provided herein include a steroid bonded to a second agent (e.g., a prostaglandin) via an optional linker (e.g., travoprost-anecoltab) to form a heteroalkyl bond (e.g., an ester, a carbonate, etc.), thereby releasing the steroid and / or the second agent in their free forms upon cleavage of the heteroalkyl bond (e.g., hydrolysis). In some embodiments, a steroid radical provided herein (e.g., a first radical) (e.g., a hydroxyl radical (e.g., anecoltab desacetate radical)) is bonded to an optional linker or a second radical provided herein (e.g., a prostaglandin radical) (e.g., a hydroxyl radical, a carboxylic acid radical, etc.) to form the compounds provided herein.

[0181] In some embodiments, the Specified Information provides pharmaceutical compositions comprising any of the compounds provided herein, such as formula (I), formula (IA), formula (IB), formula (IC), formula (II), formula (IIA), formula (IIB), formula (III), formula (IV), formula (V), formula (VI), formula (VI-A), formula (VI-B), formula (VI-C), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), formula (IX), or formula (X), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient. Another embodiment provides a pharmaceutical composition suitable for ocular administration. Another embodiment provides a pharmaceutical composition suitable for intraocular administration. In some embodiments, intraocular administration is administration to the eye, such as intraocular, intraocular, intravitreous, suprachoroidal, punctal, posterior, or subconjunctival.

[0182] Another embodiment provides a pharmaceutical composition suitable for subcutaneous administration. Another embodiment provides a pharmaceutical composition suitable for intrathecal administration.

[0183] Another embodiment provides a pharmaceutical implant or article comprising any of the compounds provided herein, such as formula (I), formula (IA), formula (IB), formula (IC), formula (II), formula (IIA), formula (IIB), formula (III), formula (IV), or formula (V), or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the implant or article contains at least 50% by weight (at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 98% by weight, etc.) of the compound and / or a pharmaceutically acceptable salt thereof. In some examples, the article or implant provided herein contains at least 50% by weight of the compound provided herein. In some examples, the article or implant provided herein contains at least 70% by weight of the compound provided herein. In some examples, the article or implant provided herein contains at least 90% by weight of the compound provided herein. In some examples, the article or implant provided herein contains at least 95% by weight of the compound provided herein. In some examples, the article or implant provided herein contains at least 99% by weight of the compound provided herein. In some examples, the article or implant provided herein contains additional components, e.g., up to 20% by weight, 15% by weight, 10% by weight, 5% by weight, 1% by weight, 0.1% by weight, 0.01% by weight or less of additional components. In some embodiments, the articles or implants provided herein contain up to 5% by weight (e.g., up to 1% by weight, up to 0.1% by weight, or less) of a first radical in free form (e.g., a steroid (such as those described herein)), a second radical in free form (e.g., a prostaglandin (such as those described herein)), or a combination thereof (e.g., as impurities such as residues resulting from the manufacturing process of those provided herein). In some embodiments, the articles or implants provided herein contain up to 5% by weight (e.g., up to 1% by weight, up to 0.1% by weight, or less) of impurities such as residues resulting from the manufacturing process of those provided herein. In some embodiments, the articles or implants provided herein contain up to 5% by weight (e.g., up to 1% by weight, up to 0.1% by weight, or less) of a steroid (as described herein).

[0185] In some embodiments, the implant or article, when implanted or otherwise administered to an individual (i.e., placed in an aqueous medium (e.g., aqueous buffer), serum, or other physiological medium at a physiological temperature such as 37°C), releases (e.g., active) groups from itself. In some examples, the released (e.g., active) groups are free forms of a first radical and / or a second radical. In some examples, the (e.g., active) groups released from the compound are active fragments or metabolites of the first and / or second radicals. In some embodiments, the implant or article is subjected to surface erosion to release the compound, the first radical, and / or the second radical (or (e.g., active) fragment or its radical). In some embodiments, the first and second radicals are released from the pharmaceutical implant or article in near zero order in solution (e.g., buffer, serum, biological environment, in vivo, etc.). In some embodiments, the first and second radicals (or their (e.g., active) fragments or metabolites) are released. 10 ga t 50 It is released from the medical implant or article at a rate of more than 1 / 10 of the normal rate, in 100% bovine serum at 37°C, or in phosphate-buffered saline (PBS) at 37°C.

[0186] In some embodiments, pharmaceutical compositions are provided comprising a compound having the structure of any one of formulas (I), (IA), (IB), (IC), (II), (IIA), (IIB), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, or any of the compounds provided herein. In some embodiments, the composition comprises any of formulas (I), (IA), (IB), (IC), (II), (IIA), (IIB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X) The invention further comprises in some amounts any of the free forms of any of the radicals provided herein, or combinations thereof, such as a free form of a radical having any one of the structures (e.g., a steroid) (where the free form is the above-mentioned structure, and the free form (e.g., its -COO- or -O-) has a negative charge (e.g., as -O-) or H (e.g., as -OH) rather than being connected to a linker and / or other (first or second) radical).In some embodiments, the compositions provided herein include the compounds provided herein and the free form of a radical having any one of the structures of formula (I), formula (IA), formula (IB), formula (IC), formula (II), formula (IIA), formula (IIB), formula (IC), formula (II), formula (IIA), formula (IIB), formula (III), formula (IV), formula (V), formula (VI), formula (VI-A), formula (VI-B), formula (VI-C), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), formula (IX), or formula (X). The ratio (e.g., by weight or mole) of any free form of a radical provided herein, or a combination thereof (where the free form is the structure described above, and the free form (e.g., its -COO- or -O-) has a negative charge (e.g., as -O-) or H (e.g., as -OH) rather than being conjugated to a linker and / or other (first or second) radicals, is about 1:99 to about 100:0 (e.g., the amount of the free form of the radical to the total amount of the free form of the radical with the conjugate is between 0% (by weight or mole) and 99%). In some embodiments, the relative amount of the free form of the radical is 0% to about 50%, such as 0% to about 20%, 0% to about 10%, about 0.1% to about 10%, about 0.1% to about 5%, less than 5%, less than 2.5%, less than 2%, etc. (the percentage is by weight / weight or mole / moles).Furthermore, in some examples, the compounds provided herein, when administered to an individual (e.g., intraocularly, subcutaneously, or intrathecally), are formulas (I), (IA), (IB), (IC), (II), (IIA), (IIB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VI II) Releasing a free form of any of the radicals provided herein, or a combination thereof, such as a free form of the structure of a compound having any one of the structures of formula (VIII-A), formula (VIII-B), formula (IX), or formula (X) (wherein the free form (e.g., its -CO- or -O-) has a negative charge (e.g., as -O-) or H (e.g., as -OH) rather than being connected to a linker and / or other (first or second) radical.

[0187] In one embodiment, a method is provided for treating an eye disease or disorder in a patient requiring treatment, comprising the step of administering to the patient a composition comprising any compound provided herein, such as a compound having the structure of any one of formulas (I), (IA), (IB), (IC), (II), (IIA), (IIB), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof. Another embodiment provides a method in which the eye disease or disorder is glaucoma. Another embodiment provides a method in which the eye disease or disorder is selected from the group consisting of ocular inflammation, diabetic macular edema, posterior segment inflammation, anterior segment inflammation, macular degeneration (e.g., wet macular degeneration (AMD)), post-cataract surgery, and retinal vein occlusion.

[0188] In one embodiment, the Specified provides a method for treating a medical indication or disorder (e.g., a disease and / or disorder of the eye or nervous system), comprising the step of administering a therapeutically effective amount of a compound or composition provided herein. In some embodiments, a composition provided herein (for example, used in a method provided herein) comprises a therapeutically effective amount of a compound provided herein (for example, in a concentration effective to treat an eye disease or disorder in an individual requiring treatment), the method comprising the step of administering to an individual a compound having any one structure of formula (I), formula (IA), formula (IB), formula (IC), formula (II), formula (IIA), formula (IIB), formula (III), formula (IV), formula (V), formula (VI), formula (VI-A), formula (VI-B), formula (VI-C), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), formula (IX), or formula (X), a pharmaceutically acceptable salt, an implant, an article, or a composition. In some embodiments, compositions provided herein (e.g., used in methods provided herein) contain the compounds provided herein in therapeutically effective amounts (e.g., in concentrations effective to treat glaucoma, inflammation, and / or reduce intraocular pressure in the eye). In some embodiments, compositions provided herein (e.g., pharmaceutical and / or ophthalmic) contain the compounds provided herein in amounts from about 0.1% to about 10% by weight. [Brief explanation of the drawing]

[0189] The novel features of the present invention will be described in detail with the appended claims. The features and advantages of the present invention will be better understood by referring to the following detailed description illustrating exemplary embodiments in which the principles of the present invention are used, and to the following appended drawings (also referred to herein as “Figure” and “FIG.”).

[0190] [Figure 1]This figure shows the chemical structures of prodrug esters and pharmacovigilant active ingredients for prostaglandins exemplified herein (e.g., travaprost (Figure 1A) and travoprost acid (Figure 1B), respectively) and steroids (e.g., anecoltab acetate (Figure 1C) and anecoltab deacetate (Figure 1D), respectively). [Figure 2A] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (travoprost-anecoltab, compound 1) exemplified herein. [Figure 2B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (travoprost-anecoltab, compound 1) as exemplified herein. [Figure 2C] This figure shows the drug release profile of compound 1 (pellet) in fetal bovine serum (FBS) over a 15-day period. [Figure 2D] This figure shows the progression of the surface erosion drug release profile in the pellet of compound 1 in FBS over 15 days. [Figure 3A] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (travoprost-dexamethasone, compound 2) exemplified herein. [Figure 3B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (travoprost-dexamethasone, compound 2) as exemplified herein. [Figure 3C] This figure shows the drug release profile of compound 2 (pellet) in phosphate-buffered saline (PBS) over a 30-day period. [Figure 3D] This figure shows the progression of the drug release profile (e.g., surface erosion) and swelling profile (e.g., surface erosion) of compound 2 pellets in PBS over 30 days. [Figure 4] This figure shows the chemical structures of prodrug esters and pharmacokinetic active ingredients for prostaglandins exemplified herein (e.g., latanoprost (Figure 4A) and latanoprostic acid (Figure 4B), respectively). [Figure 5A]This figure shows the chemical structure of the steroid-prostaglandin heterodimer (latanoprost-dexamethasone, compound 3) exemplified herein. [Figure 5B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (latanoprost-dexamethasone, compound 3) as exemplified herein. [Figure 5C] This figure shows the drug release profile of compound 3 (pellet) in fetal bovine serum (FBS) over a 30-day period. [Figure 5D] This figure shows the progression of the drug release profile (e.g., surface erosion) and swelling profile (e.g., surface erosion) of compound 3 pellets in FBS over 30 days. [Figure 6A] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (latanoprost-estrone, compound 4) exemplified herein. [Figure 6B] This figure shows the drug release profile of compound 4 (coated on a polymer substrate) in fetal bovine serum (FBS) over an 8-day period. [Figure 6C] This figure shows the progression of surface coating drug release in compound 4 in FBS over a 7-day period. [Figure 7A] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (bimatoprost-anecoltab, compound 5) exemplified herein. [Figure 7B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (bimatoprost-anecoltab, compound 5) as exemplified herein. [Figure 7C] This figure shows the drug release profile of compound 5 (pellet) in fetal bovine serum (FBS) over a 25-day period. [Figure 7D] This figure shows the progression of the drug release profile (e.g., surface erosion) in the pellet of compound 5 in FBS over 28 days. [Figure 8A]This figure shows the chemical structure of the steroid-prostaglandin heterodimer (latanoprost-anecoltab, compound 6) exemplified herein. [Figure 8B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (latanoprost-anecoltab, compound 6) as exemplified herein. [Figure 8C] This figure shows the drug release profiles of latanoprost acid (●) and anecoltab desacetate (○) (pellets) in fetal bovine serum (FBS) over a 30-day period. [Figure 8D] This figure shows the progression of the drug release profile (e.g., surface erosion) in the pellet of compound 6 in FBS over 28 days. [Figure 9A] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (tafluprost-anecoltab, compound 7) exemplified herein. [Figure 9B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (tafluprost-anecoltab, compound 7) as exemplified herein. [Figure 9C] This figure shows the drug release profile of compound 7 (pellet) in fetal bovine serum (FBS) over a 30-day period. [Figure 9D] This figure shows the progression of the drug release profile (e.g., surface erosion) in the pellet of compound 7 in FBS over 28 days. [Figure 10A] This figure shows an extruded rod of a steroid-prostaglandin heterodimer (bimatoprost-anecoltab, compound 5) as exemplified herein. [Figure 10B] This figure shows the drug release profile of compound 5 (extruded rod) in fetal bovine serum (FBS) over a 30-day period. [Figure 10C] This figure shows the progression of the drug release profile (e.g., surface erosion) of compound 5 in an extruded rod in FBS over 30 days. [Figure 11A]This figure shows an extruded rod of a steroid-prostaglandin heterodimer (travoprost-anecoltab, compound 1) as exemplified herein. [Figure 11B] This figure shows the drug release profile of compound 1 (extruded rod) in fetal bovine serum (FBS) over a 30-day period. [Figure 12A] This figure shows an extruded rod of a steroid-prostaglandin heterodimer (latanoprost-anecoltab, compound 6) as exemplified herein. [Figure 12B] This figure shows the drug release profile of compound 6 (extruded rod) in fetal bovine serum (FBS) over a 70-day period. [Figure 12C] This figure shows the progression of the drug release profile (e.g., surface erosion) of compound 6 in an extruded rod in FBS over 70 days. [Figure 13A] This figure shows an extruded rod of a steroid-prostaglandin heterodimer (tafluprost-anecoltab, compound 7) as exemplified herein. [Figure 13B] This figure shows the drug release profile of compound 7 (extruded rod) in fetal bovine serum (FBS) over a 100-day period. [Figure 13C] This figure shows the progression of the drug release profile (e.g., surface erosion) of compound 7 in an extruded rod in FBS over 100 days. [Figure 14] This figure shows the extruded rods of the steroid-prostaglandin heterodimer (bimatoprost-anecoltab, compound 5) exemplified herein in the eye of a rabbit. [Figure 15A] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (travoprost-cyclohexanedimethanol-anecoltab, compound 8) exemplified herein. [Figure 15B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (travoprost-cyclohexanedimethanol-anecoltab, compound 8) as exemplified herein. [Figure 15C]This figure shows the drug release profile of compound 8 (pellet) in fetal bovine serum (FBS) over an 8-day period. [Figure 16] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (travoprost-naltrexone, compound 9) exemplified herein. [Figure 17] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (timolol-deoxycholic acid, compound 10) exemplified herein. [Figure 18] This figure shows the purity of compound 5 before (pre-sterilization) or after sterilization of compound 5 in ethylene oxide or by gamma rays or E-beam. [Figure 19A] This figure shows the chemical structure of the steroid-prostaglandin heterodimer (bimatoprost(C15)-anecoltab, compound 11) exemplified herein. [Figure 19B] This figure shows a heat-treated pellet of a steroid-prostaglandin heterodimer (bimatoprost (C15)-anecoltab, compound 11) as exemplified herein. [Modes for carrying out the invention]

[0191] Specific definition As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context makes it clear. For example, a reference to “drug” includes multiple such drugs, and a reference to “cell” includes one or more cells (or more cells), and their equivalents known to those skilled in the art. When ranges relating to physical properties such as molecular weight, or chemical properties such as chemical formulas are used herein, all combinations of ranges and specific embodiments within them, and subcombinations, are intended to be inclusive. When referring to a number or range of numbers, the term “about” means that the number or range of numbers referred to is an approximation within the range of experimental variation (or statistical experimental error), and therefore the number or range of numbers may vary by 1% to 15% of the explicitly stated number or range of numbers. The term “comprising” (and related terms such as “comprise,” “comprises,” “having,” or “including”) is not intended to exclude, in other specific embodiments, that any embodiment of any of the compounds, compositions, methods, or processes described herein may consist of or substantially consist of the described features.

[0192] "Amino" represents a -NH2 radical (dihydroamino). "Alkylamino" represents an amino group substituted with one or more alkyl groups as defined herein. "Arylamino" represents an amino group substituted with one or more aryl groups as defined herein.

[0193] "Cyano" represents the -CN radical.

[0194] "Nitro" represents the -NO2 radical.

[0195] "Oxa" represents -O- (radical).

[0196] "Oxo" represents the O radical.

[0197] "Thioxo" represents the S radical.

[0198] "Imino" represents the NH radical.

[0199] "Oxymo" represents the N-OH radical.

[0200] "Hydrazino" represents the N-NH2 radical.

[0201] "Hydrogen" represents the "H" radical.

[0202] "Alkyl" generally refers to linear or branched hydrocarbon chain radicals consisting only of carbon and hydrogen atoms, such as having 1 to 15 carbon atoms (e.g., C1-C 15 This represents an alkyl group. Unless otherwise specified, alkyl groups are either saturated or unsaturated (e.g., alkenyls containing at least one carbon-carbon double bond, or alkynyls containing at least one carbon-carbon triple bond). Unless otherwise specified, disclosures of “alkyl” provided herein are intended to include separate listings of saturated “alkyl” or unsaturated alkyl groups (alkenyls, alkynyls). Alkyl groups as described herein are generally monovalent, but may also be divalent (they may also be referred to herein as “alkylene” or “alkylenylene” or alkynylene groups). In some embodiments, an alkyl group has 1 to 13 carbon atoms (e.g., C1-C1). 13It contains alkyl. In one embodiment, the alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In another embodiment, the alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In another embodiment, the alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In another embodiment, the alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In another embodiment, the alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In another embodiment, the alkyl contains 1 carbon atom (e.g., C1 alkyl). In another embodiment, the alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15 In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is bonded to the remainder of the molecule by a single bond. Typically, each alkyl group is independently substituted or unsubstituted. Unless otherwise specified, each “alkyl” listed herein includes a specific and explicit listing of unsaturated “alkyl” groups. Similarly, unless otherwise specified herein, alkyl groups are substituents of the following types: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR a -OC(O)-N(R a )2, -N(R a )C(O)Ra , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2(t is 1 or 2) is arbitrarily replaced by one or more of these, R a Each of these is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0203] "Alkoxy" refers to a radical bonded via the oxygen atom of a -O-alkyl group, where alkyl is an alkyl chain as defined above.

[0204] "Alkenyl" represents a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In some embodiments, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 4 carbon atoms. The alkenyl is optionally substituted as described for the "alkyl" group.

[0205] "Alkynyl" represents a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. In some embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 4 carbon atoms. The alkenyl is optionally substituted as described for the "alkyl" group.

[0206] "Alkylene" or "alkylene chain" generally refers to a straight or branched divalent alkyl group having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, i-propylene, n-butylene, etc. Unless otherwise specified herein, alkylene chains are optionally substituted as described herein for alkyl groups.

[0207] The term “article” as used herein generally refers to a pharmaceutical composition that is machined, molded, heat-treated, emulsion-treated, electrospinned, electrosprayed, blow-molded, or extruded to form fibers, fiber meshes, woven fabrics, nonwoven fabrics, films, surface coatings, pellets, cylindrical bodies, rods, fine particles, nanoparticles, or other molded articles.

[0208] "Aryl" represents a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon consisting of 5 to 18 carbon atoms, and at least one of the plurality of rings in the ring system is completely unsaturated, that is, contains a cyclic delocalized (4n + 2)π - electron system in accordance with Hückel's theory. Examples of the ring system from which the aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, naphthalene. Unless otherwise specified herein, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include an aryl radical optionally substituted by one or more substituents, and the one or more substituents are independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R<00​​a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2), selected from, and R a is, independently of each other, hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), and R b is, independently of each other, a direct bond, or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, the above substituents are each unsubstituted.

[0209] "Aralkyl" or "aryl-alkyl" is the formula -R c - Represents the aryl radical, R c These are alkylene chains, such as methylene and ethylene, as defined above. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for the aryl group.

[0210] "Carbocyclyl" or "cycloalkyl" represents a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including a system of fused or bridging rings, and having 3 to 15 carbon atoms. In some embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. The remainder of the molecule is bonded by single bonds. Carbocyclyls or cycloalkyls can be saturated (containing only CC bonds) or unsaturated (containing one or more double or triple bonds). Examples of saturated cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also called "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclyl radicals include adamantyl, norbornyl (bicyclo[2.2.1]heptanyl), norborneyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified herein, the term "carbocykrill" is intended to include a carbocykrill radical optionally substituted with one or more substituents, one or more of which may be alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralquinyl, optionally substituted carbocykrill, optionally substituted carbocykrillalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(Ra )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R aEach is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, and R c These are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0211] "Carbocyclylalkyl" is a compound of the formula -R c - Represents the radical of carbocyclyl, R c This is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

[0212] "Carbocyclyl alkenyl" is represented by formula -R c - Represents the radical of carbocyclyl, R c This is an alkenylene chain as defined above. The alkenylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0213] "Carbocyclic alkynyl" refers to a radical of the formula -R c -carbocyclic, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclic radical are optionally substituted as defined above.

[0214] "Carbocyclic alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-R c -carbocyclic, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic radical are optionally substituted as defined above.

[0215] "Halo" or "halogen" refers to a substituent of bromo, chloro, fluoro, or iodo.

[0216] "Fluoroalkyl" refers to an alkyl radical as defined above, which alkyl radical is substituted by one or more fluoro radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0217] The term “heteroalkyl” refers to an alkyl group as defined above, where one or more of the alkyl backbone carbon atoms are substituted with heteroatoms (with an appropriate number of substituents or valencies, e.g., -CH2- may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, where carbon is substituted with nitrogen, oxygen, selenium, or other suitable heteroatoms. In some examples, each substituted carbon atom is independently substituted with oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -NS(aryl)-, or with another substituent as intended herein), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-). In some embodiments, the heteroalkyl is bonded to the rest of the molecule at the carbon atoms of the heteroalkyl. In some embodiments, the heteroalkyl is bonded to the rest of the molecule at the heteroatoms of the heteroalkyl. In some embodiments, the heteroalkyl is C1-C 18 It is a heteroalkyl. In some embodiments, the heteroalkyl is C1-C 12 The heteroalkyl group is a heteroalkyl group. In some embodiments, the heteroalkyl group is a C1-C6 heteroalkyl group. In some embodiments, the heteroalkyl group is a C1-C4 heteroalkyl group. Typical heteroalkyl groups include, but are not limited to, -OCH2OMe or -CH2CH2OMe. In some embodiments, as defined herein, the heteroalkyl group includes alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl groups. Unless otherwise specified herein, the heteroalkyl group is optionally substituted with alkyl groups as defined above.

[0218] "Heteroalkylene" refers to a divalent heteroalkyl group, as defined above, which links one part of a molecule to another part. Unless otherwise specified, heteroalkylenes are optionally substituted with alkyl groups as defined above.

[0219] "Heterocyclyl" represents a stable 3-18 membered non-aromatic ring radical containing 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, optionally including fused or bridging ring systems. Heteroatoms in heterocyclyl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl radicals are partially or completely saturated. Heterocyclyls are bonded to the remainder of the molecule by atoms on any of the rings. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specified herein, the term “heterocyclyl” is intended to include heterocyclyl radicals as defined above, which are optionally substituted by one or more substituents, which include alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralquinyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b-OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R aEach is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, and R c These are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0220] An "N-heterocyclyl" or "N-bonded heterocyclyl" represents a heterocyclyl radical as defined above, containing at least one nitrogen atom, where the bond site of the heterocyclyl radical to the rest of the molecule is via the nitrogen atom in the heterocyclyl radical. N-heterocyclyl radicals are optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0221] A "C-heterocyclyl" or "C-bonded heterocyclyl" represents a heterocyclyl radical as defined above, containing at least one heteroatom, where the bond site of the heterocyclyl radical to the rest of the molecule is via a carbon atom in the heterocyclyl radical. C-heterocyclyl radicals are optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl.

[0222] "Heterocyclylalkyl" is a compound of formulas -R c - Represents the radical of a heterocycline, R c This is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, this heterocyclyl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for the heterocyclyl group.

[0223] "Heterocyclylalkoxy" is a formula -OR c - Represents a radical bonded via the oxygen atom of a heterocycline, R c This is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, this heterocyclyl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for the heterocyclyl group.

[0224] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2- to 17 carbon atoms and 1- to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one of the rings is completely unsaturated, i.e., contains a delocalized (4n+2)π-electron system of the ring according to Hückel's theory. Heteroaryls include fused ring systems or bridging ring systems. Heteroatoms in heteroaryl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryls are bonded to the remainder of the molecule via any of the atoms of the ring. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinyl, carbazolyl, sinnolinyl, cyclopenta[d]pyrimidinyl, and 6,7-dihydro-5H-s Clopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]sinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexa Hydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido(p yrido)[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyrimidinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,Examples include, but are not limited to, [3-d]pyridinyl and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term “heteroaryl” is intended to include heteroaryl radicals as defined above, which are optionally substituted with one or more substituents, and which include alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -Rb -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R a Each is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, R c These are linear or branched alkylene or alkenylene chains, and unless otherwise specified, the substituents described above are not substituted.

[0225] "N-heteroaryl" represents a heteroaryl radical as defined above, containing at least one nitrogen atom, where the bond site of the heteroaryl radical to the rest of the molecule is via the nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for the heteroaryl radical.

[0226] "C-heteroaryl" represents a heteroaryl radical as defined above, where the bond site of the heteroaryl radical to the rest of the molecule is via a carbon atom in the heteroaryl radical. The C-heteroaryl radical can be optionally substituted for the heteroaryl radical as described above.

[0227] "Heteroarylalkyl" is a compound of the formula -R c - Represents a heteroaryl radical, R c This is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, this heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for the heteroaryl group.

[0228] "Heteroarylalkoxy" is a formula -OR c - Represents a radical bonded via the oxygen atom of a heteroaryl group, R c This is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, this heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for the heteroaryl group.

[0229] In some embodiments, the compounds disclosed herein contain one or more chiral centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined as (R) or (S) from an absolute stereochemical standpoint. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by this disclosure. Where the compounds described herein contain an alkene double bond, and unless otherwise specified, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomers are also intended to be included. The term “geometric isomer” refers to the E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-isomers, meta-isomers, and para-isomers around a benzene ring.

[0230] Typically, optionally substituted groups are either independently substituted or unsubstituted. Each list of optionally substituted groups provided herein includes, unless otherwise specified, independent and explicit lists of both the unsubstituted and substituted groups (e.g., substituted in one embodiment and unsubstituted in another). Unless otherwise specified, substituted groups are defined as the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR a -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O)t Ure a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2) is arbitrarily replaced by one or more of these, R a Each of these is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0231] In the compounds disclosed herein, any reference to an atom includes a reference to its isotope. For example, a reference to H means 1 H, 2 H, 3 Includes references to any isotope of H, such as H or mixtures thereof.

[0232] In general, the listing of “Anecoltab” in this specification refers to “Anecoltab” in the deacetate form shown in Figure 1D. However, where applicable, the listing of “Anecoltab” includes disclosures of the “deacetate” and “acetate” forms, respectively.

[0233] The terms “opioid” and “opiate” are used interchangeably herein and generally refer to ligands that bind to, for example, delta (δ)-opioid receptors (DOR), kappa (κ)-opioid receptors (KOR), mu (μ)-opioid receptors (MOR), nociceptin opioid receptors (NOR), zeta (ζ)-opioid receptors (ZOR), or any combination thereof. In some embodiments, the opioid is an opioid agonist, an opioid antagonist, or an opioid agonist / antagonist mixture of an opioid receptor. In some embodiments, the opioid agonist is a partial opioid agonist or an inverse opioid agonist. In some embodiments, the opioid is an opioid radical. In some embodiments, an opioid radical binds to a therapeutically active drug radical via a linker described herein to form an opioid dimer. In some embodiments, the opioid dimer is the heterodimer described above. In some embodiments, an opioid radical binds to a second radical via a linker described herein to form an opioid heterodimer, the second radical being not an opioid radical, such as a therapeutically active drug radical (e.g., a steroid). In some embodiments, a first opioid radical, such as a partial opioid agonist, binds to a second opioid radical, which is a different opioid radical from the first opioid radical, such as an opioid antagonist, to form a heterodimer.

[0234] The term "pellet," as used herein, refers to the shape of the pharmaceutical composition of this disclosure, which is round, spherical, cylindrical, or a combination thereof. In some embodiments, the average diameter of the pellets is about 0.2 to 5 mm, for example, about 0.2 to 1 mm, about 0.2 to 2 mm, about 0.3 to 3 mm, about 1.5 to 5 mm, about 2 to 5 mm, about 2.5 to 5 mm, about 3 to 5 mm, about 3.5 to 5 mm, about 4 to 5 mm, or about 4.5 to 5 mm.

[0235] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts. Any pharmaceutically acceptable salt of any one of the agents described herein is intended to encompass any and all pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0236] "Pharmacologically acceptable acid addition salts" refer to salts that retain the bioeffects and properties of a free base, and these salts are not biologically or otherwise unwanted, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. Similarly, salts formed from organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids are also included, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Furthermore, salts of amino acids such as alginates, glucons, and galacturonic acids have also been considered (see, for example, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0237] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the bioeffects and properties of a free acid and is not biologically or otherwise unwanted. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines such as alkali metals, alkaline earth metals, or organic amines. Examples of salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and base ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al. above.

[0238] As used herein, the terms “treat,” “treating,” or “treatment” include reducing, weakening, alleviating, improving, mitigating, or decreasing symptoms associated with a disease, condition, or indication (e.g., glaucoma) in either a long-term or short-term treatment scenario. In one embodiment, treatment includes reducing intraocular pressure. Furthermore, the treatment of a disease or condition as described herein includes the disclosure of the use of the aforementioned compounds or compositions for the treatment of such disease, condition, or indication.

[0239] In many cases, the ultimate obstacle to drug development—producing the final pharmaceutical product from active pharmaceutical ingredients (APIs), which are solid or liquid at room temperature—is the large-scale and costly process. Pharmaceutical formulations of APIs that are liquid at room temperature often require excipients (e.g., stabilizers, additives, adjuvants, etc.) or conjugation to another molecule (e.g., polymer) to stabilize and / or produce a processable and / or storable product. Instead, APIs that are solid at room temperature are often used in pharmaceutical formulations to avoid the additional processing and formulation required to produce a pharmaceutical product from liquid APIs. Nevertheless, the formulation into the final pharmaceutical product still incurs considerable costs. Therefore, in addition to the cost of formulating solid or liquid APIs, the limitations of the processability of liquid APIs also limit the efficacy and / or adoption of potentially beneficial therapeutics.

[0240] Furthermore, patient compliance is often an unresolved issue in clinical settings. In some cases, controlled-release formulations can improve patient compliance. For example, sustained-release (ER) formulations, such as extended-release (SR) or controlled-release (CR) formulations, may promote adherence to treatment regimens in some cases. SR and CR formulations are generally designed to release the API at a certain rate, such as maintaining a specific drug concentration over a period of time. For example, SR maintains drug release over a period of time rather than at a constant rate, while CR maintains drug release at a more consistent (e.g., nearly constant) rate (e.g., zero-order) over a period of time. Despite their ability to extend the administration of the active ingredient, such formulations can be difficult to develop. Moreover, such formulations often contain controlled-release excipients (e.g., polymers) and / or controlled-release extracellular matrices to facilitate controlled release. For liquid or other low-melting-point active ingredients, controlled-release formulations may be even more difficult to develop. Furthermore, even under ideal conditions, patient compliance remains a problem with many controlled-release formulations because the duration of dynamic release (e.g., a 24-hour release window) is limited.

[0241] In some embodiments herein, treatable compounds are provided that address not only the burden of formulation of pharmaceutical products but also patient compliance. In some embodiments, the compounds described herein are solid at body temperature (e.g., below about 37°C). In some embodiments, the compounds provided herein include a first group or radical (e.g., a structure provided for any one of formulas (I), (IA), (IB), (IB'), (IC), (II), (IIA), (IIB), (III), (IV), or (V)) which is conjugated (e.g., by covalent bonding) to a second group. In some embodiments, the first group is a radical of formula (I), (IA), (IB), (IB'), or (IC). In some embodiments, the second group is a group that is not treatable in itself in its free form (e.g., has a melting temperature higher than its decomposition temperature, is insoluble overall in aqueous media, or is otherwise unsuitable for treatment). In some embodiments, the second group is a group that is not processable in dimer form (e.g., directly on itself or when conjugated via a linker such as those described herein). In some embodiments, the second group is a group having a melting point and / or glass transition temperature such as below 50°C, below 40°C, or below 37°C. Generally, such compounds may not be suitable for use as implants because they may melt or deform in a physiological environment, even if they are solid at room temperature. In some embodiments, the compound is formed into an implantable article (e.g., a pellet) by using a method described herein (e.g., as described in the examples). In some embodiments, the implantable article has a controlled release rate (e.g., zero-order) over a long period (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 12 weeks, 52 weeks, or longer) in an aqueous medium (e.g., buffer, serum, biological environment (e.g., in the eye), in vivo, etc.).In some embodiments, the compounds provided herein (or implants containing such compounds) are administered to individuals suffering from acute or chronic diseases or illnesses (for example, as therapeutic agents for acute or chronic diseases or illnesses) in any suitable form (e.g., route of administration such as implantation, and / or frequency of administration) such as single doses or sequential doses (e.g., once or twice at intervals of 1, 2, 3, 4, 6, 12, 52 weeks or more).

[0242] In some examples, the compounds provided herein (e.g., conjugates) are used to improve treatment options and / or patient compliance for acute diseases and / or disorders. In some examples, the treatable compounds described herein are used to improve treatment options and / or patient compliance for chronic diseases and / or disorders. In some embodiments, the treatable compounds described herein are used to improve treatment options and / or patient compliance in ophthalmology, neurology, postoperative medicine, orthopedics, and pain management.

[0243] This specification provides processable compounds (e.g., conjugates) (e.g., into articles). Processable compounds are compounds that can be processed by heat or a solvent to form a solid with little (e.g., less than 20% by weight, less than 10% by weight, or less than 5% by weight) or no further excipients added. In some examples, the solids prepared by the following processes are amorphous solids or solids having a highly amorphous form (e.g., discussed in detail herein). In some examples, the processable compounds provided herein are solid at room temperature (e.g., 20°C) and / or physiological temperature (e.g., 37°C). In some examples, compounds having a dissolution temperature or glass transition temperature such as at least 37°C, at least 40°C, at least 50°C, at least 60°C, at least 70°C, or at least 100°C are heat-processable. In some embodiments, it is beneficial that the compound is solid at room temperature but processable at temperatures that are not extremely high. In some embodiments, the compounds provided herein have dissolution temperatures and / or glass transition temperatures such as less than 200°C, less than 150°C, less than 140°C, less than 130°C, less than 125°C, and less than 120°C.

[0244] In some embodiments, the compound exhibits any form suitable for promoting treatment and / or pharmacodynamic effects (e.g., release profile). In some embodiments, the compound (or an implant or pharmaceutical composition containing the compound) is amorphous (or contains highly amorphous contents). In some embodiments, the compounds (e.g., forms) provided herein have a melting point (T) at a physiological temperature (e.g., at least 37°C). m ) and / or glass transition temperature (T gThe compound is solid, having a glass transition temperature (T g The melting point (T) is greater than or equal to ( m ) has. In some embodiments, the compound has a melting point of at least 37°C. In some embodiments, the compound (e.g., form) has a melting point of at least 100°C. In some embodiments, one or both of the compound (e.g., drug conjugate) and the first radical and / or second radical (or its (e.g., active) fragment or metabolite) of the (e.g., active) drug are released (e.g., in free form), and this release is controlled release and / or sustained release. In some embodiments, one or both of the compound and the first radical and / or second radical of the drug are released (e.g., in free form) for at least 15 days (e.g., in solution, buffer, serum, biological environment, in vivo, etc.).

[0245] In some embodiments of this specification, a treatable agent (e.g., a compound) is described that is formed from treatable groups (e.g., radicals that make treatable radicals treatable when linked or bonded) and treatable moieties (e.g., radicals that, when in free form, are not treatable by thermal techniques, etc., due to a melting point below physiological temperature). In some embodiments, the treatable agents described herein are treatable to solids (e.g., at temperatures of at least 20°C, 25°C, 20°C, 37°C or higher). In some embodiments, compounds useful as therapeutic agents for treating acute, chronic, or both diseases or disorders are provided herein. In some examples, the conjugates provided herein represent a significant advance in the art as treatable compounds suitable for being formed into or formulated into controlled-release and / or sustained-release articles, coatings, or other pharmaceutical compositions that are beneficial for treating acute and / or chronic diseases or disorders, for example, when administered infrequently (e.g., once, weekly, monthly, or less frequently).

[0246] In one embodiment, this specification provides for a compound comprising a first radical and a second radical, or a pharmaceutically acceptable salt or solvate thereof, wherein the first radical is of formula (I):

[0247] [ka] It includes the structure, During the ceremony,

[0248] [ka] It is either a single bond or a double bond. R a , R b , and R cEach is independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, and alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted. Or R a , R b , or R c One of the following is R a , R b , or R c By combining with another of these, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl group. X 1 , X 2 , X 3 , and X 4 These are independently combined and Q y Selected from the group consisting of -O-, -NR-, and -S(R) x -, and -C(R) z - Selected from the group consisting of, m, n, and o are each independently between 0 and 6. x is independently between 0 and 5. y is independently 1 to 3, z is independently either 1 or 2, Each R is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, and thiol (e.g., alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are optionally substituted), or one R combines with another R to form an oxo. The second radical is a therapeutically active drug (or substance), and unlike the second radical (e.g., prostaglandins), Here, the first radical, the second radical, or both the first and second radicals are not steroids. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0249] In some embodiments herein, a compound comprising a first radical and a second radical, or a pharmaceutically acceptable salt or solvate thereof, wherein the first radical is of formula (IA):

[0250] [ka] It includes the structure, During the ceremony,

[0251] [ka] It is either a single bond or a double bond. R a , R b , and R c Each is independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, and alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted. Or R a , R b , or R c One of the following is R a , R b , or R c By combining with another of these, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl group. m, n, and o are each independently between 0 and 6. The second radical is a therapeutically active drug (or substance), and unlike the second radical (e.g., prostaglandins), Here, the first radical, the second radical, or both the first and second radicals are not steroids. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0252] In some embodiments herein, a compound comprising a first radical and a second radical, or a pharmaceutically acceptable salt or solvate thereof, wherein the first radical or the second radical is of formula (IB'):

[0253] [ka] It includes the structure, During the ceremony,

[0254] [ka] It is either a single bond or a double bond. G a Each is independently selected from the group consisting of oxo, halogen, -CN, -NO2, azide, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, ester, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, hydrazone, oxime, or thiol, and alkyl, heteroalkyl, cycloalkyl, alkoxy, aryloxy, hydrazone, or heterocycloalkyl are optionally substituted. Or the first G a This is another G a By integrating with it, it forms optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl molecules. G 1 Each of these is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl, and the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted. G 2is hydrogen, hydroxy, alkyl, heteroalkyl, alkoxy, cycloalkyl, or heterocycloalkyl, where alkyl, heteroalkyl, cycloalkyl, alkoxy, or heterocycloalkyl is optionally substituted. s is 0 to 8, and q is either 1 or 2. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0255] In some embodiments of this specification, a compound comprising a first radical and a second radical, or a pharmaceutically acceptable salt or solvate thereof, wherein the first radical is of formula (IB):

[0256] [ka] It includes the structure, During the ceremony,

[0257] [ka] It is either a single bond or a double bond. R a , R b , R c , and R d Each is independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, and alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted. Or R a , R b , R c , and R d One of the following is R a , R b , R c , and R d By combining with another of these, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl group. m, n, o, and p are each independently between 0 and 6. The second radical is a therapeutically active drug (or substance), and unlike the second radical (e.g., prostaglandins), Here, the first radical, the second radical, or both the first and second radicals are not steroids. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0258] In some embodiments, rings A, B, C, or D of formula (I), formula (IA), or formula (IB) each optionally and independently contain one or more heteroatoms (e.g., O, S, or N) within the ring.

[0259] In some embodiments herein, a compound comprising a first radical and a second radical, or a pharmaceutically acceptable salt or solvate thereof, wherein the first radical is of formula (IC):

[0260] [ka] It includes the structure, During the ceremony,

[0261] [ka] It is either a single bond or a double bond. R a is hydrogen, -OH, or oxo, R a’ Each of these is independently selected from hydrogen, -OH, halogen, C1-C3 alkyl, and alkoxy. R a” It is either absent, hydrogen, or a C1-C3 alkyl group. R b It is either absent, or is hydrogen, halogen, or C1-C3 alkyl. R b’These are hydrogen, halogen, -OH, oxo, or C1-C3 alkyl, R b” is hydrogen or -OH, R c Each of these is independently hydrogen, -OH, oxo, or C1-C3 alkyl. R c’ Each is independently either hydrogen or a C1-C3 alkyl group. R c” is hydrogen, -OH, C1-C3 alkyl, or -C(=O)H, R d These are independently hydrogen, -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or R d Each of these combines to form an oxo, and alkyl or heteroalkyl groups are optionally substituted. R d’ is hydrogen, -OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. Or one R d R d’ By becoming integrated with, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl, The second radical is a therapeutically active drug (or substance), and unlike the second radical (e.g., prostaglandins), Here, the first radical, the second radical, or both the first and second radicals are not steroids. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0262] In some embodiments, R d The alkyl or heteroalkyl group is substituted with one or more of the group consisting of -SH, -OH, -COOH, oxo, halogen, amino, alkyl (e.g., alkenyl, alkynyl), heteroalkyl, ester, amide, sulfonic acid, and sulfone. In some embodiments, one R d Rd’ By integrating with it, it forms a substituted heterocycloalkyl group.

[0263] In some embodiments, the first radical and the second radical are linked by a linker (e.g., a bond). In some embodiments, the first radical is linked to the R of the first radical. a , R b , R c , or R d The first radical is bonded to the second radical via one of the following. In some embodiments, the first radical is R a , R b , R c , or R d R is bonded to the second radical via one of the following, and the first radical is bonded to the second radical. a , R b , R c , or R d These include hydroxyl radicals (e.g., when combined with a linker or a second radical (where the linker is a bond), they form ethers), thiol radicals (e.g., when combined with a linker or a second radical (where the linker is a bond), they form thioethers), or carboxylate radicals (e.g., when combined with a linker or a second radical (where the linker is a bond), they form esters or carbonates).

[0264] In some embodiments, R is used to bond the first radical to the second radical. a , R b , R c , or R d This includes a hydroxyl radical that forms an ether by combining with a linker or a second radical. In some embodiments, R is used to bond the first radical to the second radical. a , R b , R c , or R d This includes a thiol radical that forms a thioether by combining with a linker or a second radical. In some embodiments, R is used to bond the first radical to the second radical.a , R b , R c , or R d This includes a carboxylate radical that combines with a linker or a second radical to form an ester or carbonate.

[0265] In some embodiments, both the first radical and the second radical have one of the structures of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC). In some embodiments, both the first radical and the second radical have one of the structures of formula (I), formula (IA), or formula (IB'). In some embodiments, both the first radical and the second radical have the structure of formula (I) or formula (IA). In some embodiments, both the first radical and the second radical have the structure of formula (I). In some embodiments, both the first radical and the second radical have the structure of formula (IA). In some embodiments, the first radical and the second radical (e.g., having one of the structures of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC)) are linked by a linker (e.g., a hydrolyzable linker). In some embodiments, the linker (e.g., a hydrolyzable linker) is the linkage.

[0266] In some embodiments, the first radical has one of the structures of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC). In some embodiments, the second radical has one of the structures of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC). In some embodiments, the second radical (for example, being unprocessable in its free form, unprocessable in its dimeric form, and / or liquid or adaptable at physiological temperatures) does not have one of the structures of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC).

[0267] In some embodiments, the radical of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC) is a steroid, opioid agonist, opioid antagonist, adrenergic receptor antagonist (e.g., β-blockers, α-1 blockers), or serotonergic antagonist (e.g., serotonin 5-HT3 receptor antagonist). In some embodiments, the first radical and / or the second radical is an anti-inflammatory agent, an antipsychotic (e.g., a typical antipsychotic, an atypical antipsychotic, a schizophrenic, etc.).

[0268] In some embodiments, the first radical and / or the second radical is a beta-blocker that can be used to treat intraocular pressure. In some embodiments, the beta-blocker is timolol. In other embodiments, the beta-blocker is levubonolol, metipranolol, or carteolol. In some embodiments, the β-blocker is selected from the group consisting of dichloroisoprenaline, propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebiborol, esmolol, butoxamine, ICI-118,551, SR 59230A, nebiborol, acebutolol, pindolol, labetalol, mepindolol, oxprenolol, celiprolol, and penbutolol. In some embodiments, the β-blocker is selected from the group consisting of betaxolol, carteolol, levobunolol, timolol, and metipranolol.

[0269] In some embodiments, the first radical is a solid in its free form (e.g., having a melting point of at least 30°C). In some embodiments, the second radical is a liquid in its free form (e.g., having a melting point of less than 30°C).

[0270] In some embodiments, the first or second radical is a steroid (e.g., dexamethasone, Anecoltab (e.g., Anecoltab deacetate)). In some embodiments, the first radical is Anecoltab (e.g., Anecoltab acetate or Anecoltab deacetate) or obtained from Anecoltab. In some embodiments, the first radical is a steroid (e.g., dexamethasone, Anecoltab (e.g., Anecoltab deacetate)). In some embodiments, the steroid is a corticosteroid (e.g., glucocorticoid or mineralocorticoid), a sex steroid, a neurosteroid, an aminosteroid, or a secosteroid. In some embodiments, the second radical is not a steroid. In some embodiments, the second radical is a radical that does not have the structure of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC).

[0271] In some embodiments, the steroid is a glucocorticoid. In some embodiments, the glucocorticoid is medrizone, alclomethasone, alclomethasone dipropionate, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasol, crocortol, loprednol, cortisol, cortisone, cortivazole, deflazaco Dexamethasone, desoximetasone, dexoxycorton, dexamethasone, diflorasone, diflorasone acetate, diflucortone, diflucortone valerate, difluorocortone, difluprednate, flurolon, flurolon acetonide, fludrocortide, flumetasone, flumetasone, flumetasone pivalate, flunisolide, flunisolide, flusinone Fluocinolone acetonide, fluocinonide, fluocortin, fluocortin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolon, flupredniden, flupredniden acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halomethasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone butyrate, hydrocortisone The following are selected from the group consisting of thison, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, parametasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, and urobetasol.

[0272] In some embodiments, the steroid is a mineralocorticoid. In some embodiments, the mineralocorticoid is selected from the group consisting of aldosterone, fludrocortisone, deoxycorticosterone, and corticosterone. In some embodiments, the mineralocorticoid is canrenone (e.g., potassium canrenoate), drospirenone, eplerenone, spirolactone, or their metabolites (e.g., 7α-thiomethylspironolactone, canrenone, 6β-hydroxy-7α-thiomethylspironolactone, and 7α-thiospironolactone).

[0273] In some embodiments, the steroid is an anabolic steroid. In some embodiments, the anabolic steroid is selected from the group consisting of androisoxazole, androstenediol, boranediol, borasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methanedriol, metenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenborone, and trenborone.

[0274] In some embodiments, the steroid is an androgenic steroid. In some embodiments, the androgenic steroid is selected from the group consisting of boldenone, fluoxymesterone, mestanolone, mesterone, metaandrostenolone, 17-methyltestosterone, 17-α-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normetandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal, testosterone propionate, testosterone enanthate, thiomesterone, dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androsterone, dihydrotestosterone (DHT), and androstanolone.

[0275] In some embodiments, the steroid is a progestin steroid. In some embodiments, the progestin steroid is progesterone, norethisterone, norethisterone acetate, gestodene, levonorgestrel, allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethinodiol, ethinodiol diacetate, etonogestrel, gestodene, ethinylestradiol, haloprogesterone, 17-hydroxy-16-methyleneprogesterone, 17-α-hydroxy The following are selected from the group consisting of progesterone, linestrenol, medroxyprogesterone, melengestrol, norethindrone, norethinodrel, norgesterone, gestorone, norgestimate, norgestrel, levonorgestrel, norgestrienone, norbinisterone, pentagestrol, MENT (7-methyl-19-testosterone), norergestromine, and trimigestone, drospirenone, tiborone, and megestrol.

[0276] In some embodiments, the steroid is an estrogen steroid. In some embodiments, the estrogen steroid is selected from the group consisting of estradiol, estrone, eguilenin, ecchiline, benzoestradiol, estriol, ethinylestradiol, mestranol, moxestrol, mitatrienediol, kinestradiol, and kinestrol.

[0277] In some embodiments, the steroid is selected from the group consisting of abiraterone, cyproterone acetate, dutasteride, enzalutamide, finasteride, galeterone, fusidic acid, cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocorticosterone, 5α-dihydropregesterone, flugestone, prevediolone, chromazinone acetate, medroguestone, and segesterone acetate.

[0278] In some embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid. In some embodiments, the anti-angiogenic steroid or IOP lowering steroid is selected from the group consisting of anecoltab acetate, anecoltab (e.g., anecoltab deacetate), 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, and tetrahydrocortisol. In some embodiments, the anti-angiogenic steroid or IOP lowering steroid is anecoltab deacetate.

[0279] In some embodiments, the steroid is a cholic acid-related bile acid steroid. In some embodiments, the cholic acid-related bile acid steroid is selected from the group consisting of deoxycholic acid, apocholic acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid, α-mulicolic acid, β-mulicolic acid, γ-mulicolic acid, ω-mulicolic acid, taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurolisocholic acid, and tauroursodeoxycholic acid.

[0280] In some embodiments, the steroid is a neurosteroid. In some embodiments, the neurosteroid is selected from the group consisting of alfaxalone, alfadron, hydroxydione, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolonone, ganoxolone, 3α-androstanediol, epipregnanolonone, isopregnanolone, and 24(S)-hydroxycholesterol.

[0281] In some embodiments, the steroid is a steroid pheromone. In some embodiments, the steroid pheromone is selected from the group consisting of androstadienol, androstadienone, androstenol, androstenone, estrateraenol, 5-dehydroprogesterone, 6-dehydro-retroprogesterone, allopregnanolone, and hydroxyprogesterone caproate.

[0282] In some embodiments, the steroid is a steroid metabolite. In some embodiments, the steroid metabolite is selected from the group consisting of tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydropregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone.

[0283] In some embodiments, the steroid is a progestin. In some embodiments, progestin is allopregnon-3α,20α-diol, allopregnon-3β,20β-diol, allopregnan-3β,21-diol-11,20-dione, allopregnan-3β,17α-diol-20-one, 3,20-alopregnandione, 3β,11β,17α,20β,21-pentol, allopregnan-3β,17α,20β,21-tetrol, allopregnan-3α,11β,17α,21-tetrol-20-one, allopregnan-3β,11β,17α,21-tetrol-20-one, allopregnan-3β,17α,20β-triol, allopregnan-3β,17α,21 The following are selected from the group consisting of -triol-11,20-dione, allopregnan-3β,11β,21-triol-20-one, allopregnan-3β,17α,21-triol-20-one, allopregnan-3α-ol-20-one, allopregnan-3β-ol-20-one, pregnanediol, 3,20-pregnanedione, 4-pregnen-20,21-diol-3,11-dione, 4-pregnen-11β,17α,20β,21-tetrol-3-one, 4-pregnen-17α,20β,21-triol-3,11-dione, 4-pregnen-17α,20β,21-triol-3-one, and pregnenolone.

[0284] In some embodiments, the first radical and the second radical are linked by a linker (e.g., a hydrolyzable linker). In some embodiments, the first radical and the second radical are linked by a bond.

[0285] In some embodiments, the linker is a bond, alkyl, heteroalkyl, or alkoxy, and the alkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, heteroalkyl, or alkoxy is each independently substituted with one or more groups, each independently selected from the group consisting of bond, -O-, -S-, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g., polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker is a bond. In some embodiments, the linker is alkyl(alkylene), and the alkyl(alkylene) is substituted with one or more groups selected from -OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker is alkyl(alkylene), and the alkyl(alkylene) is an unsubstituted alkylene. In some embodiments, the linker is a heteroalkyl (heteroalkylene), and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl. In some embodiments, the linker is a heteroalkyl (heteroalkylene), and the heteroalkyl (heteroalkylene) is an unsubstituted heteroalkylene. In some embodiments, the linker is a bond, -O-, -S-, unsubstituted alkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n It comprises one or more linker groups selected from, where n is 1 to 20. In some embodiments, the linker is a bond, an unsubstituted alkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O)n , and C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n C=O(CH2CH2) n C=O(CH(CH3)C(=O)O) n Here, n is 1 to 20. In some embodiments, the linker is a bond.

[0286] In some embodiments, the linker is hydrolyzed in a buffer. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or esterase).

[0287] In some embodiments, the first radical is

[0288] [ka]

[0289] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0290] In some embodiments, the first radical is

[0291] [ka]

[0292] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0293] In some embodiments, the disclosure provides compounds having the structures provided in Table 1, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds provided in Table 1, or pharmaceutically acceptable salts thereof, are solid at a temperature of at least 20°C (e.g., at least 30°C, at least 40°C, at least 50°C, at least 70°C, at least 100°C, etc.). In some embodiments, the compounds provided in Table 1, or pharmaceutically acceptable salts thereof, are processable at at least 20°C (e.g., at temperatures as described in the examples). In some embodiments, the compounds provided in Table 1, or pharmaceutically acceptable salts thereof, are processable into articles at a temperature of at least 20°C (e.g., by machining, molding, emulsion treatment, electrospinning, electrospraying, blow molding, or extrusion to form fibers, fiber meshes, woven fabrics, nonwoven fabrics, films, surface coatings, pellets, cylindrical bodies, rods, fine particles, nanoparticles, or other molded articles). In some embodiments, the compounds provided in Table 1, or pharmaceutically acceptable salts thereof, contain both a first radical and a second radical. In some embodiments, the compounds in Table 1 are treatable when a first radical and a second radical are linked by a linker. In some embodiments, the linker is a bond.

[0294] [Table 1-1]

[0295] [Table 1-2]

[0296] [Table 1-3]

[0297] [Table 1-4]

[0298] [Table 1-5]

[0299] [Table 1-6]

[0300] [Table 1-7]

[0301] [Table 1-8]

[0302] In some embodiments, the disclosure provides compounds (e.g., conjugates such as heterodimer conjugates) or pharmaceutically acceptable salts thereof, as provided in Table 2. In other embodiments, parent conjugate compounds that do not form a processable solid are shown in Table 2. In some embodiments, the compounds provided in Table 2 or pharmaceutically acceptable salts thereof are not solid at a temperature of at least 20°C. In some embodiments, the compounds provided in Table 2 or pharmaceutically acceptable salts thereof are not processable at a temperature of at least 20°C. In some embodiments, the compounds provided in Table 2 or pharmaceutically acceptable salts thereof are not processable into articles described herein at a temperature of at least 20°C.

[0303] In some embodiments, the compounds provided in Table 2, or their pharmaceutically acceptable salts, contain both a first radical and a second radical. In some embodiments, the heterodimer conjugates in Table 2 are not pharmacopoeias when the first and second radicals are linked by a linker. In some embodiments, the linker is not linked. In some embodiments, the linker is alkyl, heteroalkyl, or alkoxy, and the alkyl, heteroalkyl, or alkoxy is optionally independently substituted with one or more groups, each independently selected from the group consisting of bonded, -O-, -S-, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g., polyTHF), and optionally substituted cycloalkyl.

[0304] [Table 2-1]

[0305] [Table 2-2]

[0306] Eye disease or disorder Intraocular diseases are a group of diseases including, but not limited to, glaucoma, ocular inflammation, diabetic macular edema, posterior segment inflammation, anterior segment inflammation, macular degeneration (e.g., exudative macular degeneration (AMD) and atrophic AMD), post-cataract surgery, and retinal vein occlusion. Notable aspects of intraocular diseases include elevated intraocular pressure and inflammation. In some embodiments, the intraocular disease is macular degeneration. In some embodiments, the intraocular disease is exudative AMD. In some embodiments, the intraocular disease is atrophic AMD.

[0307] Glaucoma In some embodiments, glaucoma is a group of eye diseases that result in damage to the optic nerve and loss of vision. Glaucoma is one of the leading causes of blindness worldwide, and currently there is no cure for it. Glaucoma management is limited to preventing glaucoma damage and nerve damage, as well as maintaining visual field and overall quality of life. This management system relies on diagnostic techniques and follow-up examinations, as well as thoughtful selection of treatments for individual patients.

[0308] Treatment strategies for glaucoma are limited to medications (e.g., intraocular pressure (IOP) lowering agents, e.g., prostaglandins), surgery (e.g., implantation), laser treatment, or any combination thereof. The rate of non-adherence to topical glaucoma medications varies widely, from 16% to 67%, and it is estimated that less than one-third of patients remained on their initial treatment after 12 months (Robin et al., "Exp. Rev. Ophth. (2019)"; 14:4-5, 199-210). Poor compliance with medication and follow-up visits is the main reason for vision loss in glaucoma patients.

[0309] Ocular hypertension (elevated intraocular pressure (IOP)) is one of the main risk factors for glaucoma, and lowering IOP is the primary goal of glaucoma treatment. IOP is regulated by aqueous humor production by the ciliary process of the eye, as well as its drainage through the trabecular meshwork. In glaucoma, the drainage mechanism is disrupted and / or blocked, leading to elevated IOP. Furthermore, inflammation blocks the outflow of aqueous humor through the trabecular meshwork, resulting in secondary glaucoma. This inflammation is often difficult to treat because anti-inflammatory steroids (e.g., corticosteroids) restrict blood flow to the eye, further increasing IOP. This specification describes compounds that achieve a balance between IOP reduction (e.g., by IOP-lowering agents such as prostaglandins or IOP-lowering steroids) and inflammation reduction (e.g., by corticosteroids). In some embodiments, this specification describes compounds that significantly increase patient compliance by reducing the frequency of API administration (e.g., once a month).

[0310] This specification describes treatable agents for glaucoma, which are formed from treatable and untreatable portions. In some embodiments, the treatable agents for glaucoma described herein are treatable to a solid (e.g., at temperatures of at least 20°C, 25°C, 20°C, and 37°C or higher). The treatable agents for glaucoma described herein have a controlled-release profile (e.g., zero-order) and / or a sustained-release profile (e.g., at least 1, 2, 3, 4, 5, 6, 7, 15, 30 days or more) in solution (e.g., buffer, serum, biological environment, in vivo, etc.). The compounds for glaucoma described herein are useful for treating both acute and chronic diseases or disorders. In some embodiments, the compounds for glaucoma are tested using assays and methods described herein (e.g., those described in the examples). The compounds for glaucoma described herein represent a significant advance in the art, as the treatable agents produce controlled-release and sustained-release profiles that are beneficial for treating acute and / or chronic forms of glaucoma with a single dose.

[0311] This specification provides heteromer conjugates comprising a first radical and a second radical. In some embodiments, both the first and second radicals have one of the structures of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC). In some embodiments, the first radical is an anti-inflammatory agent. In some embodiments, the second radical is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), intraocular pressure (IOP) lowering agents, beta-blockers, Rho kinase inhibitors, carbonic anhydrase inhibitors, alpha-adrenergic agonists, tyrosine kinase inhibitors, neuroprotective agents, antioxidants, antimicrobial agents, antiviral agents, and the like. In some embodiments, the second radical is an IOP lowering agent. In some embodiments, the first radical is an anti-inflammatory agent and the second radical is an IOP lowering agent. In some embodiments, the first radical is an IOP-lowering steroid (e.g., Anecoltab (e.g., Anecoltab deacetate)) or a benign steroid (e.g., cholesterol), and the second radical is an IOP-lowering agent. In some embodiments, the IOP-lowering agent is a prostaglandin. In some embodiments, the first radical is a steroid, and the second radical is a prostaglandin.

[0312] In one embodiment, the first radical has one of the structures of formula (I), formula (IA), formula (IB'), formula (IB), or formula (IC).

[0313] In some embodiments, the second radical is given by formula (II):

[0314] [ka] Having the structure of, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 1 , R 2 , R 3 , R 4 , and R 5Each is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. Or R 1 , R 2 , R 3 , R 4 , or R 5 One of these, when combined, forms an optionally substituted cycloalkyl or heterocycloalkyl group. X is -O-, -NR-, -S(R) a -, and -C(R) b - Selected from the group consisting of, a is independently 0 to 2, and b is independently either 1 or 2.

[0315] In some embodiments, R 4 X is an alkyl group substituted with one or more of -COOH, -CONH2, and alkyl groups (e.g., alkylene or alkenyl). In some embodiments, X is S, -C(R)1-, or -C(R)2-. In some embodiments, X is -CH- or -CH2-.

[0316] In some embodiments, the second radical is given by formula (IIA):

[0317] [ka] Having the structure of, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 1 , R 2 , R 3 , R 4 , and R 5Each is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted, and R 6 and R 6’ These are, independently, hydrogen, halogen, alkyl, or R 6 and R 6’ These combine to form an oxo.

[0318] In some embodiments, R 6 and R 6’ Each is independently fluoro. In some embodiments, R 6 is H or methyl, R 6 is -OH. In some embodiments, R 6 and R 6’ These combine to form an oxo. In some embodiments, R 1 and R 3 Each is independently -OH or oxo. In some embodiments, R 3 and R 4 These combine to form a heterocycloalkyl group substituted with an alkyl group (e.g., an alkenyl group) substituted with a -COOH group.

[0319] In some embodiments, the second radical is given by formula (IIB):

[0320] [ka] Having the structure of, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 1 , R 2 , and R 5Each is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. R 6” is oxo or -OH, Y 1 and Y 2 Each is independently bonded or alkylene, G is either O or CH2. g is 1 or 2, and R 10 It is alkyl or hydrogen.

[0321] In some embodiments, R 1 is oxo or -OH. In some embodiments, R 2 It is not hydrogen. In some embodiments, R 5 R is selected from one or more of the group consisting of -O-, -OH, halogen, alkyl (e.g., alkynyl), and aryl, and alkyl (e.g., alkynyl) and aryl are optionally substituted with one or more of alkyl (e.g., fluoroalkyl), halogen, and -OH. In some embodiments, R 5 is an aryl that has been optionally substituted, or an -O-aryl that has been optionally substituted.

[0322] In some embodiments, the first radical and the second radical are linked by a linker (e.g., a hydrolyzable linker). In some embodiments, the first radical and the second radical are linked by a bond.

[0323] In some embodiments, this specification includes: a) Steroids and, b) Prostaglandins and, c) Linkers adjacent to steroids and prostaglandins (e.g., by covalent bonds) (e.g., hydrolyzable linkers) Compounds containing, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0324] In some embodiments, this specification includes formula (III):

[0325] [ka] A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0326] [ka] It is either a single bond or a double bond. R a , R b , R c , and R d Each is independently selected from the group consisting of oxo, halogen, -CN, -NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, or thiol, and alkyl, alkynyl, heteroalkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted. Or R a , R b , R c , and R d One of the following is R a , R b , R c , and R d By combining with another of these, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl group. m, n, o, and p are each independently between 0 and 6. Each R is independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, and thiol, or combines with other R to form an oxo. R 1 , R 2 , R 3 , R 4 , and R 5 Each is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted, and L is a linker. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0327] In some embodiments, this specification includes formula (IV):

[0328] [ka] A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0329] [ka] It is either a single bond or a double bond. R a is hydrogen, -OH, or oxo, R a’ Each of these is independently selected from hydrogen, -OH, halogen, C1-C3 alkyl, and alkoxy. R a” It is either absent, hydrogen, or a C1-C3 alkyl group. R bIt is either absent, or is hydrogen, halogen, or C1-C3 alkyl. R b’ These are hydrogen, halogen, -OH, oxo, or C1-C3 alkyl, R b” is hydrogen or -OH, R c Each of these is independently hydrogen, -OH, oxo, or C1-C3 alkyl. R c’ Each is independently either hydrogen or a C1-C3 alkyl group. R c” is hydrogen, -OH, C1-C3 alkyl, or -C(=O)H, R d These are independently hydrogen, -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or R d Each of these combines to form an oxo, and alkyl or heteroalkyl groups are optionally substituted. R d’ is hydrogen, -OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. Or one R d R d’ By becoming integrated with, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl, R 1 , R 2 , R 3 , R 4 , and R 5 Each is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted, and R 6 and R 6’ These are, independently, hydrogen, halogen, alkyl, or R 6 and R6’ They form an oxo by becoming one. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0330] In one embodiment, this specification includes formula (V):

[0331] [ka] A compound having the structure, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0332] [ka] It is either a single bond or a double bond. R a is hydrogen, -OH, or oxo, R a’ Each of these is independently selected from hydrogen, -OH, halogen, C1-C3 alkyl, and alkoxy. R a” It is either absent, hydrogen, or a C1-C3 alkyl group. R b It is either absent, or is hydrogen, halogen, or C1-C3 alkyl. R b’ These are hydrogen, halogen, -OH, oxo, or C1-C3 alkyl, R b” is hydrogen or -OH, R c Each of these is independently hydrogen, -OH, oxo, or C1-C3 alkyl. R c’ Each is independently either hydrogen or a C1-C3 alkyl group. R c” is hydrogen, -OH, C1-C3 alkyl, or -C(=O)H, R dThese are independently hydrogen, -OH, -COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, or R d Each of these combines to form an oxo, and alkyl or heteroalkyl groups are optionally substituted. R d’ is hydrogen, -OH, C1-C3 alkyl (e.g., alkylene or alkenyl), or heteroalkyl. Or one R d R d’ By becoming integrated with, it forms a substituted or unsubstituted cycloalkyl or heterocycloalkyl, R 1 , R 2 , and R 5 Each is independently selected from one or more of the group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, and alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are optionally substituted. R 6” is oxo or -OH, Y 1 and Y 2 Each is independently bonded or alkylene, G is either O or CH2. g is either 1 or 2. R 10 is alkyl or H, and L is a linker. Compounds, or pharmaceutically acceptable salts or solvates thereof, are provided.

[0333] In some embodiments, R a , R a’ , R b , R b’ , R b” , R c , R c” , R d , or R d’One of these is an ester radical, a hydroxyl radical, or a carboxylate radical, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 One of these is a thiol radical, a hydroxyl radical, or a carboxylate radical. In some embodiments, R a , R a’ , R b , R b’ , R b” , R c , R c” , R d , or R d’ One of these is linked by the linker R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 It is adjacent to any one of the following. In some embodiments, R a , R a’ , R b , R b’ , R b” , R c , R c” , R d , or R d’ One of these is linked by the linker R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10 It is adjacent to any one of the following. In some embodiments, R d or R d’ One of the following is linked by the linker R 4 , R 5 , R 6 , R 6’ , R 6” , or R 10It is adjacent to any one of the following. In some embodiments, the linker is a bond.

[0334] In some embodiments, the linker is a bond, alkyl, heteroalkyl, or alkoxy, and the alkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, heteroalkyl, or alkoxy is each independently substituted with one or more groups, each independently selected from the group consisting of bond, -O-, -S-, silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g., polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker is a bond. In some embodiments, the linker is alkyl(alkylene), and the alkyl(alkylene) is substituted with one or more groups selected from -OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, the linker is alkyl(alkylene), and the alkyl(alkylene) is an unsubstituted alkylene. In some embodiments, the linker is a heteroalkyl (heteroalkylene), and the heteroalkyl (heteroalkylene) is substituted with one or more groups selected from halo or alkyl. In some embodiments, the linker is a heteroalkyl (heteroalkylene), and the heteroalkyl (heteroalkylene) is an unsubstituted heteroalkylene. In some embodiments, the linker is a bond, -O-, -S-, unsubstituted alkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n It comprises one or more linker groups selected from, where n is 1 to 20. In some embodiments, the linker is a bond, an unsubstituted alkylene, C=O(CH2CH2) nC=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n C=O(CH2CH2) n C=O(CH(CH3)C(=O)O) n And n is between 1 and 20.

[0335] In some embodiments, the linker comprises one or more linker groups, each independently selected from the group consisting of bonded, alkyl, cycloalkyl, heteroalkyl, or alkoxy, and the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally substituted. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, or alkoxy is each independently substituted with one or more substituents, each independently selected from the group consisting of -O- (e.g., -OH), -S- (e.g., -SH), silicone, amino, optionally substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkyl (e.g., polyTHF), and optionally substituted cycloalkyl. In some embodiments, the linker comprises one or more linker groups, each independently selected from the group consisting of alkyl(alkylene) and cycloalkyl(cycloalkylene), and the alkyl(alkylene) or cycloalkyl(cycloalkylene) is either unsubstituted or substituted (for example, each independently selected from the group consisting of -OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl). In some embodiments, the linker comprises unsubstituted or substituted alkylene-cycloalkylene-alkylene. In some embodiments, the linker comprises one or more linker groups, each independently selected from bond, -O-, -O(C=O)-, -O(C=O)-O-, -S-, unsubstituted alkylene, unsubstituted cycloalkylene, C=O(CH2CH2) n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , and (CH(CH3)C(=O)O) n Selected from the group consisting of, where n is 1 to 20. In some embodiments, the linker is bonded, unsubstituted alkylene, unsubstituted alkylene-cycloalkylene-alkylene, C=O(CH2CH2)n C=O, C=O(CHCH) n C=O, C=O(OCH2CH2O) n C=O, O(CH2CH2O) n , and C=O(CH2CH2O) n , (CH(CH3)C(=O)O) n C=O(CH2CH2) n C=O(CH(CH3)C(=O)O) n And n is 1 to 20. In some embodiments, n is 1 to 10. In some embodiments, n is 6. In some embodiments, n is 5. In some embodiments, n is 4. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0336] In some embodiments, the linker is hydrolyzed in a buffer. In some embodiments, the linker is hydrolyzed by an enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a protease or esterase).

[0337] In some embodiments, the first radical is

[0338] [ka]

[0339] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0340] In some embodiments, the second radical is

[0341] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0342] In some embodiments, the second radical is

[0343] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0344] In some embodiments, the second radical is a drug radical. In some embodiments, the drug is a prostaglandin. In some embodiments, the prostaglandin is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost acid, or any of the aforementioned fragments or radicals.

[0345] In some embodiments, the second radical is

[0346] [ka] It is a (e.g., hydroxyl or carboxyl) radical of a compound selected from the group consisting of the following.

[0347] In some embodiments, the Disclosure provides compounds for glaucoma, or pharmaceutically acceptable salts thereof, having the structures provided in Table 3. In some embodiments, parent conjugate compounds that form articles (e.g., pellets) using the methods described in the Examples herein are shown in Table 3. In some embodiments, the compounds for glaucoma, or pharmaceutically acceptable salts thereof, provided in Table 3, are solid at a temperature of at least 20°C. In some embodiments, the compounds for glaucoma, or pharmaceutically acceptable salts thereof, provided in Table 3, are processable at a temperature of at least 20°C. In some embodiments, the compounds for glaucoma, or pharmaceutically acceptable salts thereof, provided in Table 3, are processable into articles described herein at a temperature of at least 20°C. In some embodiments, the compounds for glaucoma, or pharmaceutically acceptable salts thereof, provided in Table 3, comprise a first radical that is processable in its free form and a second radical that is not processable in its free form. In some embodiments, the compounds for glaucoma listed in Table 3 are treatable when a first radical, treatable in its free form, and a second radical, not treatable in its free form, are linked by a linker. In some embodiments, the linker is a bond. In some embodiments, the linker comprises one or more linker groups, each independently selected from the group consisting of bond, alkyl, or cycloalkyl, and the alkyl or cycloalkyl may be optionally substituted. In some embodiments, the linker combines with the first radical and / or the second radical to form an ether. In some embodiments, the linker combines with the first radical and / or the second radical to form an ester. In some embodiments, the linker combines with the first radical and / or the second radical to form a carbonate.

[0348] [Table 3-1]

[0349] [Table 3-2]

[0350] [Table 3-3]

[0351] [Table 3-4]

[0352] Preparation of compounds The compounds used in the reactions described herein are prepared starting from commercially available chemicals and / or compounds described in the chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical It is obtained from standard commercial sources, including Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0353] Suitable reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein, or provide references to papers describing such preparations, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; "Organic Functional Group Preparations" by SRSandler et al., 2nd Ed., Academic Press, New York, 1983; "Modern Synthetic Reactions" by HO House, 2nd Ed., WABenjamin, Inc., Menlo Park, Calif., 1972; "Heterocyclic Chemistry" by TLGilchrist, 2nd Ed., John Wiley & Sons, New York, 1992; and "Advanced Organic Chemistry: Reactions, Mechanisms and Structure" by J. March, 4th Ed., Wiley-Interscience, New York, 1992. Other suitable reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein, or provide references to papers describing such preparations, include, for example, "Organic Synthesis: Concepts, Methods, Starting Materials," Second, Revised and Enlarged Edition (1994) by Fuhrhop, J. and Penzlin G., John Wiley & Sons, ISBN: 3 527-29074-5; "Organic Chemistry, An Intermediate Text" (1996) by Hoffman, RV, Oxford University Press, ISBN 0-19-509618-5; "Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 2nd Edition (1999) by Larock, RC, Wiley-VCH, ISBN: 0-471-19031-4; and March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; "Modern Carbonyl Chemistry" (2000) by Otera, J. (editor) Wiley-VCH, ISBN: 3-527-29871-1; "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) by Patai, S. Interscience, ISBN: 0-471-93022-9; "Organic Chemistry" 7th Edition (2000) by Solomons, TWG John Wiley & Sons, ISBN: 0-471-19095-0; "Intermediate Organic Chemistry" 2nd Edition by Stowell, JC Examples include *Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2*, *Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia* (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes, *Organic Reactions* (1942-2000) John Wiley & Sons, in over 55 volumes, and *Chemistry of Functional Groups* John Wiley & Sons, in 73 volumes.

[0354] Specific and similar reactants are identified, at the discretion of selection, by indicators of known chemical products prepared by the American Chemical Society's Chemical Abstract Service, which is available through most public and university libraries as well as online databases (for details, please contact the American Chemical Society in Washington, D.C.). Chemicals that are known but not commercially available in catalogs are prepared, at the discretion of selection, by specialized chemical synthesis facilities, where many standard chemical supply facilities (e.g., those listed above) offer specialized chemical synthesis services. The reference for the preparation and selection of pharmaceutical salts of dual-acting drugs for meibomian gland dysfunction described herein is "Handbook of Pharmaceutical Salts" by PHStahl & C.G. Wermuth, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0355] Pharmaceutical composition In some embodiments, the compounds described herein have a structure provided for any one of formulas (I), (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), or (V). In some embodiments, the compounds described herein are administered as pure chemical substances. In other embodiments, the compounds described herein are combined with a selected route of administration and a pharmaceutically appropriate or acceptable carrier (hereinafter also referred to herein as a pharmaceutically appropriate (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) selected based on standard pharmacovigilance, such as Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0356] One embodiment provides a pharmaceutical composition comprising any of the compounds provided herein, such as a compound having any one of formulas (I), (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Another embodiment provides a pharmaceutical composition suitable for ocular administration. Another embodiment provides a pharmaceutical composition suitable for intraocular administration. In some embodiments, intraocular administration is performed intraocularly, subretinally, in the eyebrow, forniceal, Schlemm's canal, within a vesicle, intravitreously, suprachoroidally, punctally, posteriorly, or subconjunctivally.

[0357] In some embodiments, the compounds provided herein include those described by any one of the following: formula (I), formula (IA), formula (IB'), formula (IB), formula (IC), formula (II), formula (IIA), formula (IIB), formula (III), formula (IV), formula (V), formula (VI), formula (VI-A), formula (VI-B), formula (VI-C), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), formula (IX), or formula (X). Any composition contains an optimal additional component in which other molecules such as impurities, synthetic materials (e.g., unreacted starting materials (e.g., steroids provided herein in free form), hydrolyzable materials (e.g., steroids provided herein in free form), unreacted intermediates, etc.), or by-products (e.g., by-products of synthesis or by-products of processing produced by heat treatment, solvent treatment, and / or sterilization, etc.) are present in amounts of less than 5%, less than 1%, or less than 0.1%.

[0358] In some embodiments, the compounds (or pharmaceutically acceptable salts thereof) described by any one of formulas (I), (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X) provided herein are included. The article or implant is substantially pure in that it contains less than about 5%, less than about 1%, or less than 0.1% of other small organic molecules, such as impurities, synthetic materials (e.g., unreacted starting materials (e.g., steroids provided herein in free form), hydrolyzable materials (e.g., steroids provided herein in free form), unreacted intermediates, etc.), or by-products (e.g., by-products of synthesis or by-products of processing, produced by heat treatment, solvent treatment, and / or sterilization, etc.).

[0359] In some embodiments, any of the compounds provided herein, such as the compounds described by any one of formulas (I), (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X) (or their pharmaceutically acceptable salts thereof), are substantially pure in that they contain less than about 5%, less than about 1%, or less than 0.1% of other small organic molecules, such as impurities, unreacted intermediates, or by-products (e.g., synthetic by-products or processing by-products produced by heat treatment, solvent treatment, and / or sterilization).

[0360] In some embodiments, any of the compounds provided herein, such as the compounds described by any one of formulas (I), (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X), (X) (or their pharmaceutically acceptable salts thereof), are pharmaceutical implants or articles. In some embodiments, the implant or article comprises at least 50% by weight (at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 98% by weight, etc.) of the compound and / or its pharmaceutically acceptable salt. In some embodiments, the implant or article releases the compound, a first radical, and / or a second radical (and / or other (e.g., active) fragments or metabolites) of the compound (e.g., by surface erosion). In some embodiments, the release occurs in zero or near zero order (e.g., in an aqueous medium such as buffer, serum, biological environment, or in vivo, at physiological temperature (e.g., 37°C)). In some embodiments, the first radical and the second radical are released. 10 ga t 50 They are released from the medical implant or article at a rate of more than 1 / 10 of the rate at 37°C in 100% bovine serum or 37°C in phosphate-buffered saline (PBS). In some embodiments, the first radical and the second radical are released at t 10 ga t 50 It is released from the medical implant or article at a rate of 1 / 10 or more of the above rate in a mixture of fetal bovine serum (FBS) and phosphate-buffered saline (PBS) (e.g., 1% FBS in PBS) at 37°C.

[0361] In some embodiments, certain forms of the pharmaceutical compositions described herein (e.g., fibers, fiber meshes, woven fabrics, nonwoven fabrics, pellets, cylindrical bodies, rods, hollow tubes, fine particles (e.g., microbeads), nanoparticles (e.g., nanobeads), or other molded articles) provide a controllable surface area. In some embodiments, the controllable surface area is injected and does not require removal after completion of drug release, allowing for adjustment of the drug release rate for a given indication. In some embodiments, the methods provided herein do not require (or include) removal of the article or implant, or its remaining material or components (e.g., the implant is completely or nearly completely (e.g., biologically or physiologically) degradable or degradable (e.g., at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, at least 98% by weight, at least 99% by weight, etc.)).

[0362] In some embodiments, the implants, articles, or compositions described herein are amorphous. In some embodiments, the implants, articles, or compositions described herein are formed by heat and solvent treatment methods. Non-limiting examples of heat treatment methods include thermoforming, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion, and / or blow molding. Non-limiting examples of solvent treatments include coating, microprinting, dot printing, micropatterning, fiber spinning, solvent blow molding, emulsion, electrospray, and electrospinning. In some embodiments, in addition to treatment methods for forming any of the heat and solvent methods described above for intermediate glassy states, there are also heat and solvent methods for producing glassy materials without a defined shape (e.g., spray drying, freeze-drying, powder melting, etc.).

[0363] The term “glassy state,” as used herein, generally refers to an amorphous solid containing more than 70%, 80%, 90%, 95%, 98%, or 99% (w / w) of the composition, article, or implant described herein. In some embodiments, the composition, article, or implant described herein exhibits a glass transition temperature above 38°C. In the glassy state, the level of crystallinity, as measured by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), or polarized light microscopy (PLM), is, for example, 0–15% (e.g., less than 1%, 0–1%, 0–3%, 0–5%, 0–7%, 0–9%, 0–10%, or 0–13%). In some embodiments, the glass formulation is formed using a heat treatment or solvent treatment method described herein (e.g., Examples).

[0364] In some embodiments, the pharmaceutical compositions described herein are prepared by electrospinning. In some embodiments, the pharmaceutical compositions of the disclosed herein are dissolved in a solvent (e.g., acetone) at a concentration ranging, for example, 10 to 30% w / v, and subjected to electrospray to form microparticles and nanoparticles. In some embodiments, the solution is filled into a syringe and injected at a constant rate (e.g., 0.5 mL / h) onto a stationary collection plate. In some embodiments, a potential difference (e.g., 18 kV) is maintained between the needle and the collection surface. For example, in one embodiment, a concentration of 10% w / v is used to obtain nanoparticles. In other embodiments, a concentration of 30% w / v is used to obtain fine particles.

[0365] The pharmaceutical compositions of this disclosure are dissolved in a solvent (e.g., THF, or DCM / THF in a 1:1 ratio). In some embodiments, the solution is filled into a syringe and injected at a constant rate (e.g., 0.5 mL / h) onto a cylindrical mandrel rotating at a specific rotation speed, e.g., 1150 rpm, to obtain aligned fibers, or onto a stationary sampling surface to obtain unaligned fibers. In some embodiments, a potential difference (e.g., 18 kV or 17 kV) is maintained between the needle and the sampling surface to obtain aligned and random fibers.

[0366] In other embodiments, the fibers are prepared from a glassy intermediate by melting at high temperatures, or from a solution by dissolving the pharmaceutical composition as described herein in a solvent (e.g., DCM, THF, or chloroform). As used herein, “melt spinning” describes heat treatment from a molten state, “thermal spinning” describes heat treatment from a glassy state, and “wet,” “dry,” and “gel” spinning describe solution treatment.

[0367] In some embodiments, a viscous melt, intermediate, or solution is supplied through a spinneret, and the fibers are formed after cooling (melt or thermal spinning), or after solvent evaporation by warm air so that the compound exits the spinneret (dry spinning). In some embodiments, moisture spinning and gel spinning are used to produce the fibers disclosed herein. "Thermal spinning," as used herein, is similar to melt spinning but is carried out using a glassy intermediate and has a glass transition temperature (T g This describes a process in which heating is performed above a certain point to obtain a viscous fluid that is extruded / spinned instead of a molten material. Alternatively, forceps may be dipped into the molten material or concentrated solution and slowly pulled back to pull the fibers. The speed and distance of the tensile may be varied to obtain fibers and columnar structures of different thicknesses.

[0368] In some embodiments, microparticles or nanoparticles produced from a pharmaceutical composition are formed using an emulsion process. In some embodiments, the pharmaceutical composition is dissolved in an organic solvent (e.g., DCM, THF, etc.). In some embodiments, a surfactant (e.g., SDS, PVA, etc.) is added to the solution / mixture (e.g., 1%). In some embodiments, the resulting mixture is stirred at room temperature for a suitable amount of time to form an emulsion. In some embodiments, the emulsion is then added to Milli-Q water while stirring for a suitable amount of time (e.g., 1 hour) to remove any residual solvent. The resulting microparticles or nanoparticles may be collected by centrifugation and dried.

[0369] In some embodiments, injectable cylindrical or rod-shaped bodies produced from the pharmaceutical compositions described herein are formed by hot extrusion. In some embodiments, the pharmaceutical composition is filled into a hot-melt extruder and heated to a temperature higher than the melting point (e.g., for crystalline compositions) or the glass transition temperature (e.g., for pre-melted or amorphous compositions), and (i) extruded using a compressive force to push the material through a nozzle and a tensile force (or gravity) to push the material out of the extruder. The extruded material may be cut to lengths desired for appropriate drug administration for a medical indication.

[0370] In some embodiments, a milling process is used to reduce the size of an article described as forming beads, for example, particles sized in the micrometer (microbeads) to nanometer (nanobads) size range. The milling process may be carried out using a grinder or other suitable apparatus. In some embodiments, dry and wet milling processes such as jet milling, freeze milling, ball milling, media milling, sonic milling, and homogenization are used in the methods described herein. In some embodiments, to achieve a spherical shape, the milled particles are T gIt is heated further upwards. In some embodiments, non-spherical particles are used during milling.

[0371] In some embodiments, the compositions described herein have a limited window of thermal stability (e.g., a short time frame of seconds to minutes), thereby the purity of the dimer is affected (e.g., minimally) at high temperatures. In some embodiments, an intermediate glassy state form (e.g., a film, surface coating, pellet, microparticle, or other molded article) is produced to avoid decomposition. In some embodiments, heat or solvent treatment is used to remove or reduce the crystallinity of the material to form a glassy composition. In some embodiments, the glassy composition is heat-treated at a lower temperature (e.g., glass transition temperature (T)). g ) directly above, and the melting temperature (T m (Processed at less than ). In some embodiments, further lowering the temperature allows for a longer time frame for heat-treating the glassy material into the final molded article, while simultaneously reducing the influence of the processing conditions on the purity of the prodrug dimer in the article.

[0372] Exemplary processing details are provided in the Examples.

[0373] In some embodiments, the treatable compounds described by any one of formulas (I), (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X) are formulated for administration by injection. In some examples, the injectable formulation is a solid dosage form. In some examples, the injectable formulation is a non-aqueous formulation.

[0374] In some embodiments, the pharmaceutical compositions described herein provide an article (e.g., one described herein) with a gradual reduction in size (e.g., by surface erosion). In some embodiments, surface erosion allows the article to maintain its physical form while simultaneously reducing its size gradually (e.g., at a constant rate) rather than bulk erosion, which is characteristic of some polymer-based drug-release vehicles (e.g., polylactic acid / glycolic acid). In some embodiments, surface erosion inhibits sudden release and / or reduces the formation of inflammatory particles (e.g., no or few crystalline particles are formed or released from the article when the drug is released as described herein). In some embodiments, the compositions described herein are delivered over a period of time. For example, if the rate of delivery is slower and more constant (e.g., less than 10% of the release of the first and second radicals in free form in 100% bovine serum over 5 days at 37°C) (as the total percentage of the drug present in the article, i.e., the first or second radical in free form), the frequency of administration to the target of the pharmaceutical composition decreases, and / or the drug's safety profile improves. In some embodiments, drug release is adjusted to provide a constant release over a relatively short period of time, avoiding the side effect of slower and longer drug release by manipulating the article. In some embodiments, drug release is adjusted to a dose and duration or method of administration appropriate for the indication.

[0375] In some embodiments, the release rate is related to, for example, the drug composition of the dimer. In some embodiments, the drug release rate from the articles described herein is regulated by the cleavage of the dimer-linker bond via hydrolysis or enzymatic degradation. In some embodiments, the linking portion (e.g., the linker) affects the drug release rate. In some embodiments, the drug release rate is controlled by functional groups, e.g., primary vs. secondary hydroxyl groups, on the compositions described herein for conjugation via the linker. In some embodiments, the release rate from the dimer is related to the proportion of filled dimers compared to the final drug dimer formulation (e.g., by the use of pharmaceutical excipients (e.g., fillers / excipients)). In some embodiments, the release rate is controlled by the size of the microbeads. In some embodiments, drug release is regulated based on the solubility of the drug dimer (e.g., through the selection of an appropriate drug and / or linker), which affects the rate of surface erosion (e.g., dissolution / degradation) from the article. In other embodiments, drug release is affected by changes in the surface area of ​​the formulation, e.g., changes in the microbead diameter. By adjusting the factors mentioned above, dissolution, decomposition, diffusion, and controlled release can vary over a wide range. For example, release may be designed to begin within minutes to hours and may be extended over periods of days, weeks, months, or even years.

[0376] In some examples, this specification provides heat-treated pellets (e.g., Figures 2B, 3B, 5B, 7B, 8B, 9B, 15B, and 19B) or rods (e.g., Figures 10A, 11A, 12A, and 13A) of heterodimers illustrated herein (e.g., steroid-prostaglandin heterodimers) (e.g., Figures 2A, 3A, 5A, 6A, 7A, 8A, 9A, 15A, and 19A). In some examples, this specification provides drug release profiles of pellets (e.g., Figures 2C, 2D, 3C, 3D, 5C, 5D, 6B, 6C, 7C, 7D, 8C, 8D, 9C, 9D, and 15C) or rods (Figures 10B, 10C, 11B, 12B, 12C, 13B, and 13C) provided herein over a period of time (e.g., a long period of time) (e.g., 15 days, 30 days, 60 days, 90 days, 120 days, 365 days or more) in fetal bovine serum (FBS), phosphate-buffered saline (PBS), or a combination thereof. In some examples, the release profile of compositions provided herein (e.g., pellets obtained from steroid-prostaglandin heterodimers) is measured as a change (e.g., increase) in the concentration of one or more drugs (e.g., steroids and / or prostaglandins) in the solution over a period of time. In some examples, the release profile of the compositions provided herein (e.g., pellets obtained from steroid-prostaglandin heterodimers) is measured as an increase in steroid concentration over a period of time. Figure 8C illustrates the release of both steroids and prostaglandins in FBS. As illustrated, both steroids and prostaglandins have similar release profiles. Since steroids and prostaglandins are directly coupled, it is expected that their release profiles must be identical. However, steroids and prostaglandins are thought to have slightly different release profiles at many points in time, for example, depending on whether one chromophore (e.g., steroid or prostaglandin) is much more difficult to detect than the other chromophore (e.g., prostaglandin or steroid). Other figures demonstrating drug release illustrate the release of prostaglandins, which may be overestimated or underestimated as a result of the detection method.However, other figures demonstrate that various compounds provided herein and illustrated in the figures demonstrate the release of prostaglandins (implicitly steroids). Thus, this data demonstrates a platform for providing compounds and implants (e.g., those with high drug content, low excipient content (e.g., those requiring removal), and other benefits such as those described herein) that provide long-term release of prostaglandins (and steroids) under desired conditions. In some examples, the release profile of a composition provided herein (e.g., a steroid-prostaglandin heterodimer pellet) is measured as an increase in prostaglandin concentration over a period of time. In some examples, the release profile of a composition provided herein (e.g., a steroid-prostaglandin heterodimer pellet) is measured as an increase in steroid and prostaglandin concentrations over a period of time (e.g., Figure 8B). In some examples, an increase in the concentration of one drug (e.g., a steroid) over a period of time corresponds to an increase in the concentration of another drug (e.g., a prostaglandin) over a period of time. In some cases, drug release (e.g., prostaglandins) is difficult to analyze using HPLC and UV techniques (e.g., those with poor chromophores), and these techniques may overestimate or underestimate release rates (e.g., particularly in sustained-release applications where low levels of prostaglandin analogs are present). In some cases, increasing the concentration of steroids in solution over a period of time is used to quantify the drug (e.g., prostaglandin) release profile.

[0377] In some embodiments, pharmaceutical compositions containing the dimers described herein are administered to a subject by oral, sublingual, nasal, intradermal, subcutaneous, intramuscular, rectal, vaginal, intravenous, intraarterial, intracisional, intraperitoneal, intravitreous, periocular, topical (as a powder, cream, ointment, or infusion), buccal, and inhalation administration, in non-limiting examples. In some examples, the articles described herein are administered parenterally by injection (intravenous, intramuscular, or subcutaneous) or topically by injection (intraocular or articular). In some embodiments, the formulations described herein are mixed under sterile conditions with a pharmaceutically acceptable carrier, preservative, and / or buffer.

[0378] In some embodiments, the implants, articles, or compositions described herein are suitable for ocular, subcutaneous, or intrathecal administration. In some embodiments, ocular administration may be intraocular, subretinal, in the eyebrow, fornix, Schlemm's canal, inside a vesicle, intracavitary, intravitreal, suprachoroidal, lacrimal punctum, posterior ocular, or subconjunctival.

[0379] In some examples, the implants, articles, or compositions described herein are coatings on devices. In some examples, these devices include contact lenses, microshunt devices, minimally invasive glaucoma surgery (MIGS) devices, and intraocular lenses.

[0380] The dose of a composition containing at least one of the compounds described herein may vary depending on the patient's (e.g., human) condition, i.e., relative health status, age, and other factors.

[0381] Pharmaceutical compositions are administered in a manner appropriate to the disease being treated (or prevented). The appropriate dose, as well as the appropriate duration and frequency of administration, will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form and / or potency of the active ingredient, and the method of administration. Generally, the appropriate dose and treatment regimen provides the composition in an amount sufficient to produce therapeutic and / or preventive benefits (e.g., improved clinical outcomes such as more frequent complete or partial remission, longer disease-free survival and / or overall survival, or reduced symptom severity). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body type, weight, or blood volume.

[0382] In other embodiments, the compositions described herein are combined with pharmaceutically appropriate or acceptable carriers (e.g., pharmaceutically appropriate (or acceptable) excipients, physiologically appropriate (or acceptable) excipients, or physiologically appropriate (or acceptable) carriers). Exemplary excipients are, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21 st This is described in Ed. Mack Pub. Co., Easton, PA (2005).

[0383] In some embodiments, the Specified provides a method for treating an ocular, neurological, orthopedic, acute or chronic pain, or postoperative disease or illness in a patient requiring treatment, comprising the step of administering to the patient any of the compounds provided herein, such as a compound having the structure of any one of formulas (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X), or a pharmaceutically acceptable salt thereof, or a composition (e.g., a pharmaceutical) containing such a compound or a pharmaceutically acceptable salt thereof. In one embodiment, the Specified provides a method for treating an eye disease or illness in a patient requiring treatment, comprising the step of administering to the patient any of the compounds provided herein, such as a compound having the structure of any one of formulas (IA), (IB'), (IB), (IC), (II), (IIA), (IIB), (III), (IV), (V), (VI), (VI-A), (VI-B), (VI-C), (VII), (VII-A), (VII-B), (VIII), (VIII-A), (VIII-B), (IX), or (X), or a pharmaceutically acceptable salt thereof, or a composition (e.g., a pharmaceutical) containing such a compound or a pharmaceutically acceptable salt thereof. Another embodiment provides a method in which the pharmaceutical composition is in a solid form suitable for intraocular administration (e.g., injection). In some embodiments, intraocular administration is performed intraocularly, subretinally, in the eyebrow, forniceal, Schlemm's canal, within a vesicle, intravitreously, suprachoroidally, punctally, posteriorly, or subconjunctivally.

[0384] Methods involving the treatment of a subject may include preventing a disease, disorder, or illness from occurring in a subject who is prone to but has not yet been diagnosed with the disease, disorder, or illness; inhibiting a disease, disorder, or illness, e.g., preventing its progression; and alleviating a disease, disorder, or illness, e.g., causing regression of the disease, disorder, or illness. Treatment of a disease or illness may include alleviating at least one symptom of a particular disease or illness, even if the underlying pathophysiology is not affected (e.g., alleviating pain in a subject by administering a drug, even if the drug does not address the cause of the pain).

[0385] Another embodiment provides a method in which the eye disease or disorder is selected from glaucoma, ocular inflammation, diabetic macular edema, posterior segment inflammation, anterior segment inflammation, macular degeneration (e.g., wet macular degeneration (AMD) or atrophic AMD), post-cataract surgery, and retinal vein occlusion. In some embodiments, the eye disease or disorder is glaucoma. [Examples]

[0386] Example 1: Analysis Method

[0387] Analysis Example 1: High-Performance Liquid Chromatography (HPLC):

[0388] A 2 mg / mL solution was prepared by dissolving the sample (20.0 mg) in acetonitrile (10.0 mL). In this system, solvent A was water + 0.05% trifluoroacetic acid (TFA), solvent B was acetonitrile + 0.05% TFA, the flow rate was 1.0 mL / min, and the detection method was UV@242 nm and UV spectroscopy at 190-400 nm. The sample was packed onto an Agilent 1100 series HPLC equipped with either (i) a Phenomenex Gemini-NX C18 column (5 μm, 110 Å, 250 × 4.6 mm, 00G-4454-E0) or (ii) a Phenomenex SecurityGuard Analytical Guard column (KJO-4282) equipped with a Gemini C18 4 × 3.0 mm Guard Cartridge. The solvent gradient profiles are shown in Table 4.

[0389] [Table 4]

[0390] Analysis example 2: Nuclear magnetic resonance (NMR):

[0391] The compound (10 mg) was dissolved in either 666 μL of CDCl3 or DMSO-d6 and packed into an 8-inch long, 5 mm diameter NMR tube. The instrument used was a Varian Mercury 400 nuclear magnetic resonance spectrometer. Sixteen scans were performed using the default method to obtain proton NMR spectra. FIDs were processed with MestRe-C software.

[0392] Analysis example 3: Mass spectrometry (MS):

[0393] The compound was dissolved in acetonitrile at a concentration of 1 mg / ml and used directly for analysis on an Agilent 6538 QTOF using ESI MS+ as the ion source.

[0394] Analysis Example 4: Melting Point: The compound powder was prepared neatly in a glass capillary tube, and the melting temperature was manually measured using a standard glass capillary tube melting point analyzer.

[0395] Analysis Example 5: Differential Scanning Calorimetry (DSC):

[0396] 5–10 mg of the compound was weighed in an aluminum pan. Using a Hitachi differential scanning calorimeter DSC7020, the sample was heated from room temperature to 110–150°C at 10°C / min, cooled to -30°C at 10°C / min, and then heated again to 110–150°C at 10°C / min.

[0397] Example 2: Chemical Synthesis Solvents, reagents, and starting materials were purchased from commercial suppliers and used as is unless otherwise specified. Unless otherwise specified, all reactions were carried out at room temperature. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using procedures found in the literature.

[0398] Chemical synthesis example 1: (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)buta-1-en-1-yl)cyclopentyl)hepta-5-enoic acid (travoprost acid)

[0399] [ka]

[0400] A 16 mL solution of travoprost (1 g, 2.00 mmol) stirred in MeOH (16 mL) is mixed with 1 M NaOH. (aq) (16 mL, 16 mmol) was added and the mixture was stirred for 16 hours. The mixture was then dissolved in 0.5 M HCl. (aq)The sample was added to (32 mL, 16 mmol) and quenched, and the aqueous solution was extracted with DCM (twice in 100 mL). The DCM layers were combined and dried (MgSO4), and concentrated to obtain travoprostic acid (916 mg, 100%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ7.39(1H,t,J=8Hz),7.22(1H,d,J=8Hz),7.15(1H,s),7.08(1H,d,J=8Hz),5 .70(2H,m),5.40(2H,m),4.98(1H,heptet,J=6.5Hz),4.52(1H,m),3.97(3H,m),3.25(2H,br s),2.60(1H,br s),2.38(1H,m),2.30-1.96(7H,m),1.76(1H,dd,J=16,4Hz),1.65(2H,quintet,J=7),1.55(1H,m).

[0401] Chemical synthesis example 2: (8S,10S,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one (anecoltabes acetate)

[0402] [ka]

[0403] To a stirred suspension of annecoltab acetate (3.0 g, 7.76 mmol) in methanol (80 mL), potassium hydroxide solution (0.2 M solution, 77.5 mL, 15.52 mmol) was added, and the mixture was stirred overnight. The reaction mixture was quenched in ice water (400 mL), stirred, and filtered to collect the precipitate. This precipitate was dissolved in DCM (300 mL), washed with water (300 mL), and dried over sodium sulfate to obtain annecoltab deacetate (1.0 g, 37%). 1¹H NMR (400MHz, DMSO-d6): δ 5.66 (s, 1H); 5.52 (d, 1H, J=5Hz), 5.28 (s, 1H, OH), 4.60 (t, J=5Hz, 1H, OH), 4.31 (AB, 2H, J=19Hz, Δν=82.5Hz, further divided by OH (J=5Hz)), 2.60 (m, 3H), 2.50 (m, 1H), 2.25 (m, 3H), 2.05 (m, 3H), 1.80 (m, 2H), 1.55 (m, 2H), 1.22 (m, 1H), 1.20 (s, 3H), 1.02 (q, 1H, J=12Hz), 0.49 (s, 3H).

[0404] Chemical synthesis example 3: 2-((8S,10S,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl(Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)buta-1-en-1-yl)cyclopentyl)hepta-5-enoate (compound 1)

[0405] [ka]

[0406] To a stirred solution of travoprostic acid (180 mg, 0.393 mmol) in dried pyridine (20 mL) under nitrogen, anecoltab desacetate (406 mg, 1.18 mmol), 4-(dimethylamino)pyridine (96 mg, 0.786 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated, and the residue was dissolved in DCM (100 mL). The solution was washed with 0.5 M hydrochloric acid (100 mL) and water (100 mL), dried (MgSO4), and concentrated on 5 g reversed-phase silica. Purification was performed by reversed-phase biotage autochromatography (aqueous solution-MeCN gradient). The fractions containing the product were combined, extracted with DCM, dried (MgSO4), and concentrated to obtain the product as an off-white solid (102 mg, 33%). Melting point: 78~80℃. HPLC retention time: 31.7 minutes, ESI MS+Found,C 44 H 55 F3NaO9 + Exact Mass: 807.3684. 1 H NMR(400MHz,DMSO-d6)δ7.45(1H,t,J=8Hz),7.20(3H,m),5.62(1H,s),5.55-5.40(6H,m),5.20(1H,s,OH),5.11(1H,br s),4.95(1H,d,J=12Hz),4.80(1H,d,J=12Hz),4.48(1H,br s),4.31(2H,m),3.85(3H,m),3.64(1H,m),2.60(2H,m),2.38(1H,m),2.25(3H,m),2.20(3H,m),2.05(3H,m),1. 95(3H,m),1.80(6H,m),1.55(3H,m),1.41(1H,m),1.22(1H,m),1.20(3H,s),1.02(1H,q,J=12Hz),0.49(3H,s).

[0407] Chemical synthesis example 4: 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl(Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)buta-1-en-1-yl)cyclopentyl)hepta-5-enoate (compound 2)

[0408] [ka]

[0409] To a 50 mL stirred solution of travoprostic acid (180 mg, 0.393 mmol) and dexamethasone (1.54 g, 3.93 mmol) under nitrogen, 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated onto 10 g of reversed-phase silica. The mixture was purified by Biotage automated reversed-phase chromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined, extracted with DCM, dried (MgSO4), and concentrated to obtain a solid, which was further purified by normal-phase Biotage automated chromatography (hexane-ethyl acetate gradient). The fractions containing the product were combined and concentrated to obtain the product as an off-white solid (120 mg, 37%). Melting point: 80°C. HPLC retention time: 30.5 minutes, ESI MS+Found,C 45 H 56 F4NaO 10 + Exact Mass: 855.3707. 1H NMR(400MHz,DMSO-d6)δ7.45(1H,t,J=8Hz),7.20(4H,m),6.20(1H,d),5.99(1H,s),5.60-5.35(4H,m),5.20(1H, m),5.11(1H,d),4.95(1H,d,J=12Hz),4.76(1H,d,J=12Hz),4.50(1H,d),4.31(2H,m),4.05(1H,m),3.89(3H,m), 3.64(1H,m),3.59(1H,m),2.83(1H,m),2.60(1H,m),2.38(1H,m),2.25(3H,m),2.20(3H,m),2.05(3H,m),1.95(3 H,m),1.78(2H,m),1.60-1.40(4H,m),1.30(1H,m),1.21(3H,s),1.02(1H,q,J=12Hz),0.82(3H,s),0.78(3H,d).

[0410] Chemical synthesis example 5: (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hepta-5-enoic acid (latanoprost acid)

[0411] [ka]

[0412] Latanoprost (1g, 2.31 mmol) in a stirred solution of MeOH (16mL) is mixed with 1M NaOH. (aq) (18.5 mL, 18.5 mmol) was added and the mixture was stirred for 16 hours. The mixture was then dissolved in 0.5 M HCl. (aq) The solution was quenched in (37 mL, 18.5 mmol) and extracted with DCM (twice in 100 mL). The DCM layers were combined and dried (MgSO4), and concentrated to obtain latanoprost acid (902 mg, 100%) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ11.98(1H,br s),7.23(2H,m),7.12(3H,m),5.42(1H,m),5.23(1H,m),4.39(2H,m),4.20(1H,m),3.82(1H,m),3.60(1H ,m),3.36(1H,m),2.60(1H,m),2.52(1H,m),2.15(3H,m),1.98(4H,m),1.60-1.25(10H,m),1.20(1H,m).

[0413] Chemical synthesis example 6: 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hepta-5-enoate (compound 3)

[0414] [ka]

[0415] To a 50 mL stirred solution of latanoprost acid (153 mg, 0.393 mmol) and dexamethasone (1.54 g, 3.93 mmol) under nitrogen, 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated onto 10 g of reversed-phase silica. The mixture was purified by Biotage automated reversed-phase chromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined, extracted with DCM, dried (MgSO4), and concentrated to obtain a solid, which was further purified by normal-phase Biotage automated chromatography (hexane-ethyl acetate gradient). The fractions containing the product were combined and concentrated to obtain the product as an off-white solid (102 mg, 34%). Melting point: 78°C. HPLC retention time: 30.8 minutes, ESI MS+Found,C 45 H 62 FO9+ Exact Mass: 765.4378 1 H NMR(400MHz,DMSO-d6)δ7.35-7.05(6H,m),6.20(1H,d),5.99(1H,s),5.50-5. 25(3H,m),5.10(1H,s),5.00(1H,d),4.80(1H,d),4.40(2H,d),4.21(2H,m),3. 85(1H,m),3.61(1H,m),2.83(2H,m),2.60(4H,m),2.38(4H,m),2.11(6H,m),1. 75(1H,m),1.60-1.20(18H,m),1.02(1H,q,J=12Hz),0.82(3H,s),0.78(3H,d).

[0416] Chemical synthesis example 7: (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hepta-5-enoate (compound 4)

[0417] [ka]

[0418] To a 50 mL stirred solution of latanoprost acid (153 mg, 0.393 mmol) and estrone (318 mg, 1.179 mmol) under nitrogen, 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated onto 10 g of reversed-phase silica. The mixture was purified by Biotage automated reversed-phase chromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined, extracted by DCM, dried (MgSO4), and concentrated to obtain a solid, which was further purified by normal-phase Biotage automated chromatography (hexane-ethyl acetate gradient). The fractions containing the product were combined and concentrated to obtain the product as an off-white solid (28 mg, 11%). Melting point: 65°C. HPLC retention time: 35.9 minutes, ESI MS+Found,C41H54NaO6+Exact Mass:665.3818 1 H NMR(400MHz,DMSO-d6)δ7.23(2H,m),7.12(3H,m),7.04(1H,d),6.51(1H,m),6.45(1H,m), 5.42(1H,m),5.23(1H,m),4.39(2H,m),4.20(1H,m),3.82(1H,m),3.60(1H,m),3.36(1H,m ),2.75(2H,m),2.60(1H,m),2.52(1H,m),2.42(1H,m),2.30(1H,m),2.15(4H,m),2.05(1H ,m),1.98(4H,m),1.92(2H,m),1.74(1H,m),1.60-1.25(16H,m),1.20(1H,m),0.81(3H,s).

[0419] Chemical synthesis example 8:

[0420] [ka]

[0421] Dexamethasone (314 mg, 0.80 mmol, 1.0 equivalent) was dissolved in THF (20 mL) under nitrogen, and phosgene solution (1.4 M solution in 2.86 mL of toluene, 4.0 mmol, 5 equivalents) was added dropwise while stirring. The mixture was stirred overnight at room temperature. The mixture was concentrated to obtain dexamethasone chloroformate as a concentrated oil, which was dissolved in DCM (50 mL). Triethylene glycol (1.07 mL, 1.20 g, 8 mmol, 10 equivalents) and pyridine (130 μL, 126 mg, 1.60 mmol, 2.0 equivalents) were added, and the mixture was stirred for 2 hours. The reaction solution was washed with water (twice with 50 mL), and the DCM layer was concentrated onto positive-phase silica (2 g) and purified by automated positive-phase chromatography (ethyl acetate-hexane). The fractions containing the product were combined and concentrated under vacuum to obtain the dexamethasone-triethylene glycol ester intermediate as an off-white glassy solid (296 mg, 0.52 mmol, 65%). This was dissolved in DCM (50 mL), and latanoprost acid (202 mg, 0.52 mmol), 4-(dimethylamino)pyridine (127 mg, 1.04 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (198 mg, 1.04 mmol) were added, and the mixture was stirred overnight. The reaction solution was washed with water (twice with 50 mL), and the DCM layer was concentrated onto reverse-phase silica (2 g) and purified by automated reverse-phase chromatography (acetonitrile-water). The fraction containing the product was concentrated under vacuum to obtain dexamethasone-triethylene glycol-latanoprost as a colorless oil (49 mg, 0.052 mmol, 10%). HPLC retention time: 33.9 minutes, ESI MS+Found,C52H74FO14+Exact Mass:941.5063 1H NMR(400MHz,DMSO-d6)δ7.35-7.05(6H,m),6.20(1H,d),5.99(1H,s),5.50-5.25(3H, m),5.10(1H,s),5.00(1H,d),4.80(1H,d),4.40(2H,d),4.21(6H,m),3.85(1H,m),3. 65(4H,m),3.61(1H,m),3.57(4H,s),2.83(2H,m),2.60(4H,m),2.38(4H,m),2.11(6H ,m),1.75(1H,m),1.60-1.20(18H,m),1.02(1H,q,J=12Hz),0.82(3H,s),0.78(3H,d).

[0422] Chemical synthesis example 9:

[0423] [ka]

[0424] To a 50 mL stirred solution of travoprost acid (180 mg, 0.393 mmol) and acetaminophen (297 mg, 1.97 mmol) under nitrogen, 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated onto 5 g of reversed-phase silica. Purification was performed by reversed-phase biotage automated chromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined, extracted by DCM, dried (MgSO4), and concentrated to obtain travoprost-acetaminophen ester (139 mg, 60%) as a colorless oil. HPLC retention time: 22.6 min, ESI MS+Found, C 31 H 37 F3NO7 + Exact Mass: 592.2522. 1H NMR(400MHz,DMSO-d6)δ9.97(1H,s,NH),7.57(2H,d,J=8Hz),7.45(1H,t,J=8Hz),7.22(2H,m),7.15(1H,s ),6.98(2H,d),5.70(2H,m),5.40(2H,m),4.98(1H,Septet,J=6.5Hz),4.52(1H,m),3.97(3H,m),3.25(2H,br s),2.60(1H,br s),2.38(1H,m),2.30-1.96(10H,m),1.76(1H,dd,J=16,4Hz),1.65(2H,quintet,J=7),1.55(1H,m).

[0425] Chemical synthesis example 10:

[0426] [ka]

[0427] To a 50 mL stirred solution of travoprost acid (180 mg, 0.393 mmol) and 1-adamantane methanol (327 mg, 1.97 mmol) under nitrogen, 4-(dimethylamino)pyridine (96 mg, 0.786 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (150 mg, 0.786 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated onto 5 g of reversed-phase silica. Purification was performed by reversed-phase biotage automated chromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined, extracted by DCM, dried (MgSO4), and concentrated to obtain travoprost-acetaminophen ester (71 mg, 30%) as a colorless oil. HPLC retention time: 40.3 min, ESI MS+Found, C 34 H 46 F3O6 + Exact Mass: 607.3246. 1H NMR(400MHz,DMSO-d6)δ7.60(1H,t,J=8Hz),7.22(2H,m),7.15(1H,s),5.60-5.40(3H,m),5.20(1H,m),5.10(1H,d J=8.0Hz),4.52(1H,m),4.30(2H,m),3.88(3H,m),3.63(1H,m),3.56(2H ,s),2.93(1H,m),2.20-1.80(10H,m),1.70-1.40(15H,m),1.25(1H,m).

[0428] Chemical synthesis example 11:

[0429] [ka]

[0430] To a 50 mL DCM solution of latanoprost acid (202 mg, 0.52 mmol) and triethylene glycol (42 μL, 39 mg, 0.26 mmol), 4-(dimethylamino)pyridine (127 mg, 1.04 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (198 mg, 1.04 mmol) were added, and the mixture was stirred overnight. The reaction solution was washed with water (twice with 50 mL), and the DCM layer was concentrated onto reverse-phase silica (2 g) and purified by automated reverse-phase chromatography (acetonitrile-water). The fraction containing the product was concentrated under vacuum to obtain latanoprost-triethylene glycol-latanoprost as a colorless oil (37 mg, 0.042 mmol, 8%). HPLC retention time: 30.2 minutes, ESI MS+Found,C52H79O12+Exact Mass:895.5972 1H NMR(400MHz,DMSO-d6)δ7.23(4H,m),7.12(6H,m),5.42(2H,m),5.23(2H,m),4.39(4H,m),4.25-4.20(6H,m),3.82(2H,m),3.65 (4H,m),3.60-3.55(6H,m),3.36(2H,m),2.60(2H,m),2.52(2H,m),2.15(6H,m),1.98(8H,m),1.60-1.25(20H,m),1.20(2H,m).

[0431] Chemical synthesis example 12:

[0432] [ka]

[0433] To a stirred solution of latanoprost (222.0 mg, 0.51 mmol) in dry DCM (20 mL), n-butylboronic acid (60.1 mg, 0.59 mmol) was added, and the mixture was stirred under reflux under a nitrogen atmosphere for 1 hour. The mixture was concentrated, the residue was dissolved again in dry DCM, and the mixture was heated under reflux for 3 hours to concentrate it, thereby obtaining latanoprost 9,11-boronate (254 mg, 100%) as a colorless, transparent oil, which was used directly without further purification. 1H NMR(400MHz,CDCl3)δ(ppm):7.28-7.17(m,2H),7.17-7.03(m,3H),5.49-5.27(m,2H),4.93( ddd,J=15.2,7.6,4.9Hz,1H),4.28-4.13(m,1H),4.07-3.90(m,1H),3.65-3.46(m,1H),2.78- 2.67(m,1H),2.67-2.41(m,1H),2.28-2.11(m,4H),2.09-1.98(m,2H),1.91-1.79(m,1H),1.7 9-1.53(m,7H),1.53-1.38(m,3H),1.38-1.07(m,12H),0.89-0.75(m,3H),0.64-0.52(m,2H). To a 25 mL solution of 9,11-boronate latanoprost (254 mg, 0.51 mmol) in dry DCM, pyridine (164 μL, 162 mg, 2.04 mmol) and triethylene glycol bis(chloroformate) (52 μL, 70 mg, 0.255 mmol, 0.5 equivalents) were added, and the mixture was stirred for 4 hours. Methanol (5 mL) was added, and the mixture was stirred overnight. The mixture was concentrated onto 1 g of reversed-phase silica. Purification was performed by reversed-phase biotage autochromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined, extracted with DCM, dried (MgSO4), and concentrated to obtain latanoprost-TEG-latanoprost carbonate dimer (68 mg, 25%) as a colorless oil. HPLC retention time: 48.2 minutes, ESI MS+Found,C60H91O16+Exact Mass:1067.6307 1 H NMR(400MHz,DMSO-d6)δ7.23(4H,m),7.12(6H,m),5.42(2H,m),5.23(2H,m),4.39(4H,m),4.25-4.20(6H,m),3.82(2H,m),3.65(4H,m) ,3.60-3.55(6H,m),3.36(2H,m),2.60(2H,m),2.52(2H,m),2.15(6H,m),1.98(8H,m),1.60-1.25(20H,m),1.20(2H,m),1.00(12H,d).

[0434] Chemical synthesis example 13:

[0435] [ka]

[0436] To a 25 mL solution of latanoprost 9,11-boronate (254 mg, 0.51 mmol) in dry DCM, pyridine (82 μL, 81 mg, 1.02 mmol) and ethyl chloroformate (48 μL, 55 mg, 0.51 mmol) were added. The mixture was stirred for 4 hours, then methanol (5 mL) was added, and the mixture was stirred overnight. The mixture was concentrated onto 1 g of reversed-phase silica. Purification was performed by reversed-phase biotage automated chromatography (aqueous solution-MeCN gradient). The fractions containing the product were combined, extracted with DCM, dried (MgSO4), and concentrated to obtain latanoprost-15-ethyl carbonate (154 mg, 60%) as a colorless oil. HPLC retention time: 34.8 min, ESI MS+Found, C29H45O7+Exact Mass: 505.3165 1 H NMR(400MHz,DMSO-d6)δ7.23(2H,m),7.12(3H,m),5.42(1H,m),5.23(1H,m),4.80(1H,m),4.60(1H,m),4.39(2H,m),4.20(1H,m),4.03 (2H,m),3.82(1H,m),3.60(1H,m),2.60(1H,m),2.52(1H,m),2.15(2H,m),1.98(4H,m),1.80-1.25(10H,m),1.20(4H,m),1.16(6H,d).

[0437] Chemical synthesis example 14: (Bimatoprost-anecoltab ester, compound 5)

[0438] [ka]

[0439] To a stirred solution of bimatoprost acid (1.0 g, 2.57 mmol) in dried pyridine (120 mL) under nitrogen, anecoltab desacetate (1.77 g, 5.14 mmol), 4-(dimethylamino)pyridine (0.62 g, 5.14 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.99 g, 5.14 mmol) were added, and the mixture was stirred at 37 °C for 4 days (4d). The mixture was concentrated, the residue was dissolved in DCM (150 mL), the solution was washed with 0.5 M hydrochloric acid (150 mL) and water (100 mL), dried (MgSO4), and concentrated on 5 g reversed-phase silica. Purification was performed by reversed-phase biotage autochromatography (aqueous solution-MeCN gradient), followed by normal-phase biotage autochromatography (hexane-ethyl acetate). The fractions containing the product were combined, concentrated, redissolved in MeCN (50 mL), and concentrated again to obtain the product as an off-white solid (445 mg, 24%). Melting point: 110-115°C. HPLC retention time: 29.7 mins. ESI MS + Calculated for C 44 H 58 NaO8 + ;737.4024, Found:737.4020. 1 H NMR(400MHz,DMSO-d6)δ7.25(t,J=7.5Hz,2H),7.20-7.10(m,3H),5.66(d,J=1.5Hz,1H),5.58-5.17(m,6H),4.97(d,J =17.6Hz,1H),4.84(d,J=17.6Hz,1H),4.65(d,J=4.6Hz,1H),4.49(d,J=5.8Hz,1H),4.34(d,J=5.0Hz,1H),3.92(td,J= 6.4,3.5Hz,2H),3.67(ddd,J=13.6,6.9,4.0Hz,1H),2.72-2.42(m,4H),2.37-1.92(m,16H),1.88-1.75(m,3H),1.75-1 .62(m,2H),1.62-1.49(m,3H),1.44(ddd,J=14.1,5.7,2.4Hz,1H),1.40-1.21(m,5H),1.07-0.93(m,1H),0.48(s,3H).

[0440] Chemical synthesis example 15: (Latanoprost-anecoltab ester, compound 6)

[0441] [ka]

[0442] To a stirred solution of latanoprost acid (1.0 g, 2.56 mmol) in dried pyridine (60 mL) under nitrogen, anecoltab desacetate (1.76 g, 5.12 mmol), 4-(dimethylamino)pyridine (0.62 g, 5.12 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.99 g, 5.14 mmol) were added, and the mixture was stirred at 37°C for 4 days. The mixture was concentrated, the residue was dissolved in DCM (150 mL), the solution was washed with 0.5 M hydrochloric acid (150 mL) and water (100 mL), dried (MgSO4), and concentrated on 4 g reversed-phase silica. Purification was performed by reversed-phase biotage autochromatography (aqueous solution-MeCN gradient), followed by normal-phase biotage autochromatography (hexane-ethyl acetate). The fractions containing the product were combined, concentrated, redissolved in MeCN (50 mL), and concentrated again to obtain the product as an off-white solid (415 mg, 23%). Melting point: 122-124°C. HPLC retention time: 31.4 min, ESI MS + Calculated for C 44 H 60 NaO8 + ;739.4180, Found:737.4183. 1H NMR(400MHz,DMSO-d6)δ7.25(t,J=7.5Hz,2H),7.21-7.10(m,3H),5.65(d,J=1.6Hz,1H),5.55-5.42(m,3H),5.36-5 .25(m,1H),4.99(d,J=17.6Hz,1H),4.85(d,J=17.6Hz,1H),4.45-4.34(m,2H),4.20(d,J=5.4Hz,1H),3.94-3.84(m ,1H),3.68-3.57(m,1H),3.38(d,J=9.8Hz,1H),2.75-2.51(m,5H),2.50-2.42(m,4H),2.41-1.91(m,10H),1.83(dt ,J=11.7,7.5Hz,3H),1.69-1.31(m,12H),1.30(s,3H),1.23(tt,J=9.3,5.5Hz,1H),1.07-0.93(m,1H),0.48(s,3H).

[0443] Chemical synthesis example 16: (Tafluprost-anecoltab ester, compound 7)

[0444] [ka]

[0445] To a solution of tafluprost acid (800 mg, 1.95 mmol) and anecoltab desacetate (1.34 g, 3.90 mmol) in dried pyridine (50 mL), DMAP (476 mg, 3.90 mmol) and EDCI (747 mg, 3.90 mmol) were added at 0°C, and the mixture was stirred at 20°C for 10 hours. The reaction mixture was poured into DCM (50 mL), washed with 1 M aqueous HCl (3 times with 100 mL), the organic layer was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was separated by preparative HPLC (column: Phenomenex luna C18 (250)). * The product (600 mg, 42%) was obtained as an off-white solid by purification using a 70 mm, 15 μm (mobile phase: water (0.225% FA)-ACN) with a B% of 35%-80% concentration (23 mins). Melting point: 107-110°C. HPLC retention time: 33.8 mins. ESI MS + Calculated for C43 H 54 F2NaO8 + ;759.3684, Found:759.3690. 1 H NMR(400MHz,DMSO-d6)δ7.30(t,J=7.8Hz,2H)6.92-7.05(m,3H)6.09(br dd,J=15.7,8.9Hz,1H)5.77(dt,J=15.7,11.2Hz,1H)5.65(s,1H)5.49-5.55(m,2H)5.39-5.48(m,1H)5. 22-5.31(m,1H)4.93-5.02(m,1H)4.79-4.89(m,1H)4.73(d,J=5.9Hz,1H)4.47(d,J=4.8Hz,1H)4.33(br t,J=12.9Hz,2H)3.92(br d,J=3.8Hz,1H)3.75(quin,J=6.9Hz,1H)2.53-2.69(m,3H)1.90-2.37(m,15H)1.74-1.87(m,3 H)1.55(quin,J=7.2Hz,3H)1.39-1.49(m,2H)1.25-1.37(m,4H)0.92-1.07(m,1H)0.48(s,3H)

[0446] Chemical synthesis example 18: (Travoprost-cyclohexanedimethanol-anecoltab, compound 8)

[0447] [ka]

[0448] Anecoltab desacetate (640 mg, 1.86 mmol) was dissolved in dry THF (40 mL) under nitrogen, and phosgene solution (1.4 M solution in 6.64 mL of toluene, 9.29 mmol) was added dropwise while stirring. The mixture was stirred overnight at room temperature. By concentrating the mixture, anecoltab chloroformate was obtained as a pale yellow solid (740 mg, 98%), which was used without further purification or analysis.

[0449] To a stirred suspension of 1,4-cyclohexanedimethanol (2.48 g, 1.72 mmol) in dry CH2Cl2 (30 mL), Anecoltab chloroformate (700 mg, 1.72 mmol) and dry pyridine (1.08 mL, 13.4 mmol) were added. The solution was stirred at room temperature for 16 hours, concentrated, and the yellow residue was redissolved in CH2Cl2 (50 mL). The solution was washed with 0.5 M hydrochloric acid (twice with 50 mL) and water (50 mL), dried (MgSO4), and evaporated to obtain Anecoltab-CDM as a pale yellow solid (701 mg, 79%). HPLC retention time: 27.4 min. ESI MS + calculated for C 30 H 42 NaO7 + ;537.2823, Found:537.2830. 1 H NMR(400MHz,DMSO-d6)δ5.66(1H,s),5.54-5.51(2H,m),5.04(1H,d,J=17.8,Hz),4.83(1H,d, J=17.8Hz),4.37-4.29(1H,m),4.02(1H,d,J=7.2Hz),3.92(1H,d,J=6.4Hz),3.30-3.25(1H,m ),3.22-3.17(1H,m),2.68-2.43(3H,m),2.36-2.18(3H,m),2.12-1.94(4H,m),1.87-1.69(5H ,m),1.61-1.48(2H,m),1.45-1.28(5H,m),1.30(3H,s),1.06-0.79(3H,m),0.52-0.46(3H,m).

[0450] A 10 mL solution of travoprostic acid (200 mg, 0.436 mmol) in dry MeCN was stirred under nitrogen at -15°C (ice / salt bath). N-methylmorpholine (96.8 μL, 0.872 mmol) and isobutyl chloroformate (57.8 μL, 0.436 mmol) were added, and the solution was stirred for 10 minutes. The solution was then added dropwise to a 20 mL suspension of Anecoltab-CDM (453 mg, 0.872 mmol) in dry MeCN under nitrogen at -15°C (ice / salt bath). After stirring for 10 minutes, the mixture was warmed to room temperature and stirred for 3 hours. The mixture was concentrated onto reverse-phase silica (3 g) and purified by automated reverse-phase chromatography (aqueous solution-MeCN). The fraction containing the product was concentrated under vacuum to obtain the product as a colorless solid (53 mg, 13%). In thermal property measurements, a colorless solid was obtained by dissolving the solid in DCM and concentrating it in a vacuum. Melting point: Not observed (T g = approx. 43℃). HPLC retention time: 37.8 minutes. ESI MS+calculated for C 53 H 69 F3NaO 12 + ;977.4633, Found:977.4640. 1 H NMR(400MHz,DMSO-d6)δ7.49(1H,t,J=8.0Hz),7.26-7.19(2H,m),7.18(1H,s),5.65(1H,s),5.58-5.38(5H,m),5.26-5.18(1H,m ),5.10(1H,d,J=4.8Hz),5.02(1H,dd,J=17.8,1.79Hz),4.82(1H,d,J=17.8Hz),4.52(1H,d,J=5.8Hz),4.35-4.26(2H,m),4.01(1 H,d,J=7.2Hz),3.96-3.86(5H,m),3.78(1H,d,J=6.5Hz),3.71-3.63(1H,m),2.66-2.42(3H,m),2.35-2.25(2H,m),2.25-2.10(6 H,m),2.10-2.03(2H,m),2.00-1.92(5H,m),1.83-1.65(5H,m),1.60-1.26(12H,m),1.29(3H,s),1.05-0.81(3H,m),0.47(3H,s).

[0451] Chemical synthesis example 19: (Travoprost-naltrexone, compound 9)

[0452] [ka]

[0453] To a stirred solution of travoprost acid (122 mg, 0.27 mmol) and naltrexone HCl (100 mg, 0.27 mmol) in dry DCM (20 mL) under nitrogen, 4-(dimethylamino)pyridine (132 mg, 1.08 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated onto 2 g of reversed-phase silica. Purification was performed by Biotage automated reversed-phase chromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined and concentrated. The residue was dissolved in MTBE (20 mL) and concentrated to obtain travoprost-naltrexone ester (84 mg, 40%) as a glassy white solid. Melting point: 56°C. HPLC retention time: 17.6 min, ESI MS + calculated for C 43 H 51 F3NO9 + 782.3516, Found:782.3512. 1H NMR(400MHz,DMSO-d6)δ7.50(t,J=7.9Hz,1H),7.32-7.15(m,3H),6.80(d,J=8.2Hz,1H),6.70(d,J=8.3Hz,1H),5.64-5.39(m,3H),5.34-5.23(m, 1H),5.11(d,J=4.8Hz,2H),4.90(s,1H),4.53(d,J=5.8Hz,1H),4.36(d,J =4.9Hz,1H),4.31(p,J=5.3Hz,1H),3.93(dq,J=8.9,4.8Hz,2H),3.69(p, J=7.4Hz,1H),3.16(d,J=5.6Hz,1H),3.09-3.06(m,1H),2.97-2.84(m,2 H),2.70-2.53(m,2H),2.43-2.30(m,4H),2.26-1.89(m,8H),1.77(td,J= 9.7,5.8Hz,1H),1.62(p,J=7.3Hz,2H),1.49-1.20(m,4H),1.10(s,1H),0 .87(dtd,J=14.1,6.9,4.0Hz,1H),0.58-0.42(m,2H),0.19-0.09(m,2H).

[0454] Chemical synthesis example 20: (チモロール-デオキシコール acid, compound 10)

[0455]

change

[0456] To a stirred solution of timolol free base (316 mg, 1.0 mmol) and deoxycholic acid (393 mg, 1.0 mmol) in dry DCM (20 mL) under nitrogen, 4-(dimethylamino)pyridine (244 mg, 2.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (384 mg, 2.0 mmol) were added, and the mixture was stirred for 2 days. The mixture was concentrated onto 1 g of reversed-phase silica. Purification was performed by Biotage automated reversed-phase chromatography (aqueous solution-MeCN gradient), and the fractions containing the product were combined and concentrated. The residue was dissolved in MTBE (20 mL) and concentrated to obtain timolol-deoxycholic ester (242 mg, 35%) as a glassy white solid. Melting point: 73°C. HPLC retention time: 36.2 min, ESI MS + calculated for C 37 H 63 N4O6 + ;691.4463, Found:691.4464 1 H NMR(400MHz,DMSO-d6)δ5.11(qd,J=6.3,2.8Hz,1H),4.61(dd,J=11.4,2.8Hz,1H),4.51-4.41(m,2H ),4.19(d,J=4.1Hz,1H),3.77(d,J=3.8Hz,1H),3.68(t,J=4.8Hz,4H),3.48-3.34(m,5H),2.70(d,J= 6.3Hz,2H),2.33(ddd,J=14.4,9.0,4.9Hz,1H),2.16(dq,J=15.5,8.1Hz,1H),1.86-1.41(m,11H),1. 38-1.11(m,11H),1.11(s,1H),1.08-0.93(m,11H),0.90(d,J=6.2Hz,3H),0.84(s,3H),0.55(s,3H).

[0457] Chemical synthesis example 21: (bimatoprost (C 15 )-Anecoltab carbonate, compound 11)

[0458] [ka]

[0459] Anecoltab chloroformate (196 mg, 0.482 mmol) was added to a stirred solution of bimatoprostamide (100 mg, 0.241 mmol) in dried pyridine (3 mL) under nitrogen. The yellow solution was stirred for 4 days, concentrated, and redissolved in CH2Cl2 (5 mL). The mixture was concentrated onto reversed-phase silica (2 g) and purified by automated reversed-phase chromatography (aqueous solution-MeCN). The fraction containing the product was concentrated to obtain a solid, which was further purified by Biotage automated positive-phase chromatography (hexane-ethyl acetate gradient). The fraction containing the product was concentrated under vacuum to obtain the product as a colorless solid (23 mg, 12%). Melting point: Not observed (T g = approx. 60℃). HPLC retention time: 30.5 minutes. ESI MS+calculated for C 47 H 63 NNaO9 + ;808.4395, Found:808.4397. 1 H NMR(400MHz,DMSO-d6)7.68(1H,t,J=5.7Hz,NH),7.30-7.22(2H,m),7.19-7.12(3H,m),5.65(1H,s) ,5.55-5.38(5H,m),5.33-5.26(1H,m),5.03(1H,d,J=17.8Hz),4.82-4.76(2H,m),4.70-4.64(2H,m) ,3.98-3.89(2H,m),3.07-2.99(2H,qd,J=7.2,5.7Hz),2.67-2.43(6H,m),2.38-2.15(5H,m),2.15-1 .89(10H,m),1.86-1.63(3H,m),1.59-1.21(8H,m),1.29(3H,s),0.98(3H,t,J=7.2Hz),0.47(3H,s).

[0460] Example 3: Formation and evaluation of a processable conjugate Process Example 1: Heat-treated pellets The compounds of this disclosure were formed into glass-like pellets by thermoforming. The crystalline powder of the conjugate compound was melted between 85°C and 110°C and pressed into a cylindrical mold approximately 1 mm high and 1 mm in diameter.

[0461] Process Example 2: Solvent Treatment of Compound 4 Compound 4 was formed as a thin film coating on the polymer surface by solution casting. Compound 4 was dissolved in acetone at a concentration of 50 mg / ml. 20 μl was cast onto a Dacron coupon and air-dried at room temperature overnight, followed by 2 hours under vacuum at 50°C.

[0462] Process Example 3: Heat-treated rod-shaped body The compounds of this disclosure were formed into glassy rods by hot extrusion. The conjugate compounds were first melted at a maximum temperature of 140°C. The resulting material was then loaded into a hot extruder equipped with a 30G die head and heated between 70°C and 125°C, and pressure was applied to the piston to form an extruder. The extruders were cut to different lengths.

[0463] Example 4: Evaluation of drug release from pellets or extruded rods The drug release from thermoformed pellets or extruded rods of the compounds disclosed herein was evaluated in fetal bovine serum (FBS), phosphate-buffered saline (PBS), or 1% FBS in PBS (v / v). The thermoformed pellets or extruded rods were placed in 20 mL glass vials, to which 2 mL of release buffer was added. The samples were cultured at 37 °C with constant stirring at 115 rpm. The release buffer was evaluated for the released drug at intervals of up to 14 days, and then completely replaced with 2 mL of fresh buffer. To achieve FBS release conditions, acetonitrile was added to precipitate proteins, and the drug release product was extracted. The drug products were quantified by high-performance liquid chromatography (HPLC) analysis of the samples.

[0464] Example 5: Sterilization of heat-treated rod-shaped bodies of compound 5 Compound 5 was formed into a rod-shaped body by melt extrusion and cut to a certain length. The resulting implant was packed into the lumen of a needle, and the end was sterilized with ethylene oxide, gamma irradiation, and E-beam. After sterilization, the sample was dissolved in a suitable solvent, and the change in purity due to sterilization was evaluated by HPLC.

[0465] For example, Figure 18 shows the purity of compound 5 in ethylene oxide, or before or after sterilization by gamma rays or E-beam.

[0466] Example 6: In vivo evaluation Biological Experiment Example 1: Implantation of extruded rods of compound 5 into the eyes of rabbits Compound 5 was formed into a rod shape by melt extrusion and cut into lengths of 1, 1.5, or 2 mm. The resulting implants were filled into the lumen of a needle, the ends were sterilized, and injected into the anterior chamber of a rabbit. The implants were positioned in the lower iris-corneal angle and visualized by optical coherence tomography of the anterior chamber.

[0467] Example of biological experiment 2: Implantation of extruded rods of compound 6 into the eyes of rabbits Compound 6 was formed into a rod-shaped body by melt extrusion and cut into 1.5 mm lengths. The resulting implant was filled into the lumen of a needle, the end was sterilized, and injected into the anterior chamber of a rabbit. The implant was positioned in the lower iris-corneal angle and visualized by optical coherence tomography of the anterior chamber.

[0468] For example, Figure 14 shows an extruded rod-shaped material in the eye of a rabbit of a steroid-prostaglandin heterodimer (bimatoprost-anecoltab, compound 5) as illustrated herein.

Claims

1. Formula (I): 【Chemistry 1】 A compound, or a pharmaceutically acceptable salt thereof, represented by the structure of [the compound].

2. Formula (I): 【Chemistry 2】 A compound represented by its structure.

3. Formula (I): 【Transformation 3】 A pharmaceutical implant comprising a compound represented by the structure of formula (I), or a pharmaceutically acceptable salt thereof, comprising at least 50% by weight of the compound of formula (I).

4. Formula (I): 【Chemistry 4】 A pharmaceutical implant comprising a compound represented by the structure of formula (I), and containing at least 50% by weight of the compound of formula (I).

5. The pharmaceutical implant according to claim 3 or 4, comprising at least about 70% by weight of the compound of formula (I).

6. The pharmaceutical implant according to claim 3 or 4, comprising at least about 80% by weight of the compound of formula (I).

7. The pharmaceutical implant according to claim 3 or 4, comprising at least about 90% by weight of the compound of formula (I).

8. The pharmaceutical implant according to claim 3 or 4, comprising at least about 95% by weight of the compound of formula (I).

9. The pharmaceutical implant according to claim 3 or 4, comprising at least about 98% by weight of the compound of formula (I).

10. The pharmaceutical implant according to claim 3 or 4, wherein the pharmaceutical implant is an implant inside the eyeball.

11. The pharmaceutical implant according to claim 10, wherein the pharmaceutical implant is an implant located inside the eye cavity.

12. The pharmaceutical implant according to claim 10, wherein the pharmaceutical implant is an implant in the vitreous humor.

13. The pharmaceutical implant according to claim 3 or 4, wherein the pharmaceutical implant is an intraocular implant.

14. The pharmaceutical implant according to claim 3 or 4, wherein the pharmaceutical implant is an implant in the vitreous humor.

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