Polymer conjugates of drugs having central nervous system (CNS) effects, peripheral NMDAR blockade activity and / or immune system modulating effects

Abstract

The present invention discloses a novel molecule consisting of an N-methyl-D-aspartic acid receptor (NMDAR) antagonist-polymer conjugate having the general structure D-(X-Poly-T)n, wherein D is a high-affinity, i.e., (+)-, (-)-, or (±)- dizocilpine, or a low-affinity, i.e., (+)-, (-)-, or (±)-methadone, CNS-active NMDAR antagonist, n is an integer included between 1 and 6. X is a stable (enzymatically and / or hydrolytically under physiological conditions) linker that includes a covalent bond or an atomic chain that covalently attaches a small molecule NMDAR antagonist drug moiety to the Poly derivative. Poly is a covalent chain of repeating monomer units that forms a polymer or oligomer backbone of synthetic or natural origin. T, when present, is either another molecule of D or a terminal group of Poly, and is represented by any suitable chemical group that, depending on preference, either does not react or reacts with other chemical moieties, or has targeting properties.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of the filing date of U.S. Patent Application No. 63 / 341,198, filed May 12, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION Aspects of the present invention relate generally to polymer conjugates of N-methyl-D-aspartate receptor (NMDAR) antagonists and their therapeutic and prophylactic aspects for the respiratory system and inflammation. [Background technology]

[0003] This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present invention, which are described and / or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present invention. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.

[0004] NMDARs are tightly regulated Ca in a subtype-specific manner 2+ The influx of glutamate (the major excitatory neurotransmitter in the human brain), glycine binding, and voltage-dependent Mg 2+ NMDARs are ionotropic receptors that require the release of NMDA receptors [Hansen KB, Yi F, Perszyk RE, et al., Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol. 2018;150(8):1081-1105. doi:10.1085 / jgp.201812032]. In the brain, NMDARs play a role in synaptic plasticity, a neural mechanism underlying memory formation. Excessive NMDAR activity is associated with excitotoxicity, which is caused by excessive Ca release. 2+NMDARs are a toxic cellular state caused by influx of NMDARs, potentially leading to impaired neuroplasticity and cell death. Many investigational and approved drugs, including MK-801, ketamine, dextromethorphan, and esmethadone (dextromethorphan), are known to antagonize NMDAR activity by binding to receptors within the NMDAR pore with varying affinities. Apart from their role in the CNS, NMDARs are also abundantly expressed in peripheral (extra-CNS) tissues (Du J, Li XH, Li YJ. Glutamate in peripheral organs: Biology and pharmacology. Eur J Pharmacol. 2016;784:42–48. doi:10.1016 / j.ejphar.2016.05.009). Therefore, NMDAR modulators may therapeutically target extra-CNS receptors as well, potentially addressing dysregulated Ca2+ release. 2+and / or downstream effects with potential therapeutic value against inflammation. The inventors previously disclosed the potential peripheral (outside the CNS) therapeutic effects of NMDAR antagonists in U.S. Patent Application Publication No. 2023 / 0017786. However, NMDAR antagonist drugs that cross the blood-brain barrier (BBB), such as those in the previous application, also act on the central nervous system. Therefore, preferential targeting of peripheral NMDARs with high- and low-affinity antagonists with limited access to the CNS is a potential novel strategy for exerting therapeutic effects that modulate peripheral NMDARs while avoiding CNS effects, including psychoactive effects such as dissociative or hallucinogenic effects, and cytotoxic effects such as Olney lesions.[Olney, J. W., Labruyere, J., & Price, M. T. (1989). Pathological Changes Induced in Cerebrocortical Neurons by Phencyclidine and Related Drugs. Science 244, 1360 - 1362. Doi:10.1126 / science.2660263; Olney, J. W., Labruyere, J., Wang, G., Wozniak, D. F., Price, M. T., & Sesma, M. A. (1991). NMDA Antagonist Neurotoxicity: Mechanism and Prevention. Science 254, 1515 - 1518. Doi:10.1126 / science.1835799; Fix, A. S., Horn, J. W., Wightman, K. A., Johnson, C. A., Long, G. G., Storts, R. W., et al. (1993). Neuronal Vacuolization and Necrosis Induced by the Noncompetitive N-Methyl-D-Aspartate (NMDA) Antagonist MK(+)801 (Dizocilpine Maleate): a Light and Electron Microscopic Evaluation of the Rat Retrosplenial Cortex. Exp. Neurol. 123, 204 - 215. Doi:10.1006 / exnr.1993. 1153].

[0005] CNS psychoactive drugs cross the BBB to reach receptors in the brain, including NMDARs, and exert specific central nervous system (CNS) effects, including therapeutic effects and potentially toxic CNS side effects. The CNS effects of NMDAR antagonists are primarily mediated by binding to NMDARs located in the membranes of neurons in the brain. NMDARs are heterotetramers formed from subunits from three gene families, designated GluN1, GluN2, and GluN3. Similar to the GluN1 subunit, the GluN3 subunit, encoded by two distinct genes (A-B), binds to the coagonist glycine or d-serine, while the GluN2 subunit, encoded by four distinct genes (A-D), binds to glutamate or NMDA. NMDARs cannot form functional homotetramers. The essential heterotetramers are composed of a wide variety of subunit combinations, conferring functional diversity. Typically, this includes two GluN1 subunits and two GluN2 subunits of either the same or different subtypes, or two GluN1 subunits, one GluN2 subunit and one GluN3 subunit.

[0006] Furthermore, NMDARs with different subunit compositions exhibit spatiotemporal variation, with GluN2B and GluN2D expression being highest early in development, followed by increased expression of GluN2A and GluN2C, but not exclusively, and their expression levels differ across various brain regions. Drugs that act as NMDAR antagonists can have significant therapeutic psychoactive effects, including antidepressant effects. However, non-competitive NMDAR antagonists with high affinity for NMDARs, such as MK-801 and ketamine, can sometimes cause dissociative effects, even when administered at therapeutic doses. NMDAR antagonists are approved or in clinical trials for a variety of psychiatric or neurodegenerative diseases and conditions, including depression (esketamine, arketamine, ketamine, esmethadone, dextomethorphan), Alzheimer's disease (memantine), and Parkinson's disease (amantadine), or for the induction of anesthesia, procedural analgesia, and sedation (ketamine). However, some NMDAR antagonists can have significant central nervous system effects, including dissociative effects (MK-801, ketamine, and esketamine), which in some cases have hindered their development as therapeutic agents. There are significant public safety and regulatory concerns regarding the therapeutic use of substances that can induce dissociative effects. In summary, the development of psychoactive substances for the treatment of diseases, disorders, conditions, and symptoms, including diseases, disorders, conditions, and symptoms outside the CNS, remains problematic due to the potent central nervous system effects of these drugs, which can currently only be modulated by reducing the dose. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent Application Publication No. 2023 / 0017786 [Non-patent literature]

[0008]

Non-patent document 1

Non-patent document 2

Non-patent document 3

Non-patent document 4

Non-patented document 5

[0009] Certain exemplary aspects of the present invention are described below. It should be understood that these aspects are presented merely to provide the reader with a brief summary of certain forms that the invention may take, and that these aspects are not intended to limit the scope of the invention. Indeed, the present invention may encompass a variety of aspects that may not be explicitly set forth below.

[0010] The present invention discloses NMDAR antagonist polymer conjugates, which have therapeutic advantages over known NMDAR antagonists.The chemically modified drugs described herein are applied in the fields of drug discovery and drug therapy, polymer chemistry, etc. Of particular interest are the therapeutic and preventive effects of these new molecular entities on the immune system, respiratory system, digestive system, urogenital system, and cardiovascular system.

[0011] The present invention aims to reduce the CNS side effects of NMDAR non-competitive antagonists by reducing their ability to (1) cross the BBB, an anatomical and functional barrier that effectively eliminates or reduces the passage of various molecules into the brain, and / or (2) cross the intestinal barrier (IB), an anatomical and functional barrier that effectively eliminates or reduces the passage of various molecules through the digestive system. To achieve this, the inventors have designed polymer-drug conjugates (PDCs) of NMDAR antagonists to prevent, reduce, or regulate BBB passage. For certain compounds, regulating the passage through the intestinal barrier (IB) may also be beneficial. The potentially therapeutic peripheral effects of these conjugates may be more advantageous by eliminating or reducing passage through the BBB and IB, which may simultaneously lead to down-modulation of CNS effects, or by restricting the drug to the gastrointestinal tract. Indeed, the molecules disclosed herein are unable to cross the BBB or have regulated or limited BBB crossing ability due to specific characteristics such as polymer structure, its molecular weight, and / or hydrodynamic volume, and chemical-physical properties. By coupling with specific tailored polymers, novel molecules may be obtained with improved pharmacokinetic and pharmacodynamic profiles for selected diseases and disorders, resulting in favorable risk-benefit ratios. In summary, the present invention provides PDCs with the intent and ability to preferentially target NMDARs located outside the CNS for the treatment of diseases, disorders, and conditions associated with imbalanced activity and / or excitotoxicity due to dysregulation of peripheral NMDARs and / or immune system dysfunction.

[0012] An embodiment of the present invention relates to NMDAR antagonist polymer conjugates having the general structure D-(X-Poly-T)n, where D is a CNS-active NMDAR antagonist and n is an integer between 1 and 6.

[0013] X is a stable (enzymatically and / or hydrolyzably under physiological conditions) linker that contains a covalent bond or a chain of atoms that covalently attaches the small molecule NMDAR antagonist drug moiety to the Poly derivative. The drug moiety has at least one chemically reactive functional group (e.g., primary or secondary amine, hydroxyl, sulfhydryl, carboxyl, aldehyde, or ketone), or if this group is not present, is chemically introduced to form a covalent bond between the pendant and the linker. Examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, CC bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers.

[0014] Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides. In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the present invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. Some Poly suitable for the present invention include mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, mPEG-O-559Da, where "m" means methoxy.

[0015] T, when present, is either D or a terminal group of Poly, and when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl. We began the synthesis of PEG derivatives of esmethadone by attaching a short PEG chain (oligo(ethylene glycol)) to one of the phenyl functional groups of esmethadone. We chose the phenyl ring for PEG attachment because our previous studies of esmethadone analogs suggested that modifications at the phenyl ring level would result in the least inhibition of NMDAR activity.

[0016] In one particular embodiment, the present invention provides a compound of formula I:

[0017] [ka]

[0018] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (−)-methadone to the Poly derivative; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone of synthetic or natural origin; and T, when present, is either (-)-methadone or the terminal group of Poly (where "X," "Poly," and "T" are as defined above).

[0019] In another particular embodiment, the present invention provides a compound of formula II:

[0020] [ka]

[0021] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (+)-methadone to the Poly derivative; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone of synthetic or natural origin; and T, when present, is either (+)-methadone or the terminal group of Poly (where "X," "Poly," and "T" are as defined above).

[0022] In another particular embodiment, the present invention provides a compound of formula III:

[0023] [ka]

[0024] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (±)-methadone to the Poly derivative; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone of synthetic or natural origin; and T, when present, is either (±)-methadone or an end group of Poly (where "X," "Poly," and "T" are as defined above).

[0025] In another particular embodiment, the present invention provides a compound of formula IV:

[0026] [ka]

[0027] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (−)-dizocilpine to the Poly derivative; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone of synthetic or natural origin; and T, if present, is either (-)-dizocilpine or the terminal group of Poly (where "X," "Poly," and "T" are as defined above).

[0028] In another particular embodiment, the present invention provides a compound of formula V:

[0029] [ka]

[0030] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (+)-dizocilpine to the Poly derivative; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone of synthetic or natural origin; and T, if present, is either (+)-dizocilpine or the terminal group of Poly (where "X," "Poly," and "T" are as defined above).

[0031] In another particular embodiment, the present invention provides a compound of formula VI:

[0032] [ka]

[0033] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (±)-dizocilpine to the Poly derivative; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone of synthetic or natural origin; and T, if present, is either (±)-dizocilpine or the terminal group of Poly (where "X," "Poly," and "T" are as defined above).

[0034] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the general description of the invention given above and the detailed description of the embodiments given below, serve to explain the principles of the invention. [Brief explanation of the drawings]

[0035] [Figure 1A] Graphs showing the effects of NMDAR antagonists esmethadone and MK-801 on mRNA expression of inflammatory cytokines in A-549 cells in an experimental setup. The effects of the tested NMDAR antagonists on lung cells are mediated by macrophages. *P<0.05, **P<0.01, ***P<0.001. [Figure 1B] Graphs showing the effects of NMDAR antagonists esmethadone and MK-801 on mRNA expression of inflammatory cytokines in A-549 cells in an experimental setup. The effects of the tested NMDAR antagonists on lung cells are mediated by macrophages. *P<0.05, **P<0.01, ***P<0.001. [Figure 2]1 is a graph showing the effect of 0.3 mg / kg MK-801 and a dose of MK-801-EGME conjugate equivalent to 0.3 mg / kg MK-801 on the distance traveled by mice over 10 minutes in the open field test (n=7 mice / group). Data are reported as mean ± SEM. ****P<0.0001 vs. vehicle; ####P<0.0001 vs. MK-801 by one-way ANOVA followed by Bonferroni post hoc multiple comparisons. [Figure 3] FIG. 1 is a schematic diagram showing the synthesis of a (+)-MK-801-EGME conjugate using the strategy proposed herein. [Figure 4] FIG. 1 is a graph showing the H NMR spectrum of (5S,10R)-5-methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-tetraEGME×HCl). [Figure 5] FIG. 1 is a graph showing the C NMR spectrum of (5S,10R)-5-methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-tetraEGME×HCl). [Figure 6] FIG. 1 is a graph showing the H NMR spectrum of (5S,10R)-5-methyl-12-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-hexaEGME×HCl). [Figure 7] FIG. 1 is a graph showing the C NMR spectrum of (5S,10R)-5-methyl-12-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-hexaEGME×HCl). [Figure 8]FIG. 1 is a graph showing the H NMR spectrum of (5S,10R)-5-methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-octaEGME×HCl). [Figure 9] FIG. 1 is a graph showing the C NMR spectrum of (5S,10R)-5-methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-octaEGME×HCl). [Figure 10] FIG. 1 is a graph showing the H NMR spectrum of (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-decaoxahentriacontan-31-yl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-decaEGME×HCl). [Figure 11] FIG. 1 is a graph showing the C NMR spectrum of (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-decaoxahentriacontan-31-yl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-decaEGME×HCl). DETAILED DESCRIPTION OF THE INVENTION

[0036] One or more specific embodiments of the present invention are described below. In an effort to provide a concise description of these embodiments, all features of an actual implementation may not be described herein. It should be understood that, like any engineering or design project, the development of such an actual implementation requires making numerous implementation-specific decisions to achieve the developer's particular goals, including compliance with system-related and business-related constraints, and that these decisions may vary from implementation to implementation. Moreover, it should be understood that such a development effort might be complex and time-consuming, but would nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill in the art having the benefit of this disclosure.

[0037] In addition to CNS receptors, NMDAR antagonists also target NMDARs located outside the CNS, and their pharmacological effects have potential therapeutic value. These potentially therapeutic peripheral effects may be offset by the CNS actions of these drugs. Therefore, targeting these peripheral NMDARs by restricting their access to the CNS represents a potential novel therapeutic option, preserving potentially therapeutic peripheral glutamatergic modulatory effects while preventing potentially harmful central nervous system effects. This goal of preferentially targeting peripheral NMDARs can be pursued by new chemical entities designed to bind to NMDARs and modulate their passage through the BBB and IB. Physiologically, the BBB protects the brain by restricting the access of potentially toxic molecules. The BBB allows and regulates the passage of essential nutrients and selected substances, regulates the rate at which many substances reach brain tissue, and effectively eliminates or reduces the passage of many other molecules, sometimes referred to as xenobiotics. The BBB can also completely block certain molecules from accessing the brain. Polymer conjugates of NMDAR antagonists may prevent, reduce, or regulate the passage of active molecules through the BBB. The potential therapeutic effect of NMDAR antagonists designed to regulate or eliminate access to the CNS may improve the safety window of these drugs, while improving the therapeutic effect in the central and, preferentially, peripheral areas. Polymer conjugates of NMDAR antagonists may be unable to pass through the BBB or IB, or have regulated or limited ability to pass through the BBB or IB, thereby reducing or avoiding side effects in the central nervous system, while preferentially exerting potentially therapeutic peripheral effects.

[0038] Although current research into NMDAR antagonists is primarily focused on solving CNS pathologies, including psychiatric and neurodegenerative diseases, NMDAR receptors may play a role in the development and potential treatment of other diseases, including peripheral diseases, due to the presence of these receptors in peripheral organs, including the lungs, heart, GI system, GU system, and accessory organs (blood vessels, liver, pancreas, ovaries, testes, kidneys, and immune cells).

[0039] In summary, NMDAR antagonists also target extra-CNS receptors and exert potential therapeutic effects, including anti-inflammatory effects in macrophages (see Example 1) and amelioration of inflammatory lung diseases (see references below), which are the objective of this application and can be preferentially achieved through the use of novel molecules. Furthermore, by avoiding or limiting access to the CNS, the dose of these novel molecules can be increased, enhancing peripheral efficacy without causing dissociative effects mediated by binding to CNS receptors.

[0040] To maximize extra-CNS effects and / or avoid CNS actions, NMDAR antagonists can be modified by covalent conjugation with polymers such as polyethylene glycol (PEG, PEGylated) and other polymers, which, depending on the size and properties of the polymer chain, can modulate or impede BBB crossing.

[0041] The present application aims to obtain novel molecules with varying degrees of affinity for NMDARs that depreferentially target peripheral (i.e., outside the CNS) receptors to preferentially treat diseases, disorders, and conditions associated with imbalanced activity of peripheral glutamate receptors. Furthermore, the activity of these novel drugs against NMDARs in the CNS may not be completely abolished but merely modulated by polymer conjugation of the drug; therefore, polymer conjugation of these drugs may result in more favorable pharmacodynamic or pharmacokinetic profiles at both central and peripheral receptors. For example, PEGylation-based platforms can also be utilized to optimize and enhance the brain delivery of molecules characterized by poor BBB permeability (Lu W, Zhang Y, Tan YZ, Hu KL, Jiang XG, Fu SK. Cationic albumin-conjugated pegylated nanoparticles as novel drug carriers for brain delivery. J Control Release. 2005;107:428-48). Thus, these molecules may offer therapeutic benefits for both CNS and extra-CNS conditions, demonstrating improved efficacy / safety ratios compared to the parent molecules.

[0042] Thus, embodiments of the present invention relate to NMDAR antagonist polymer conjugates having the general structure D-(X-Poly-T)n, where D is a CNS-active NMDAR antagonist and n is an integer between 1 and 6.

[0043] X is a stable (enzymatically and / or hydrolyzably under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking the small molecule NMDA antagonist drug moiety to the Poly derivative. The drug moiety has at least one chemically reactive functional group (e.g., primary or secondary amine, hydroxyl, sulfhydryl, carboxyl, aldehyde, or ketone), or, if this group is not present, is chemically introduced to which the pendant can be chemically reacted to form a covalent bond with the linker. Examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C-C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers.

[0044] Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides. In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the present invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. Some Poly suitable for the present invention include mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, mPEG-O-559Da, where "m" means methoxy.

[0045] T, when present, is either D or a terminal group of Poly, and when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl. We began the synthesis of PEG derivatives of esmethadone by attaching a short PEG chain (oligo(ethylene glycol)) to one of the phenyl functional groups of esmethadone. We chose the phenyl ring for PEG attachment because our previous studies of esmethadone analogs suggested that modifications at the phenyl ring level would result in the least inhibition of NMDAR activity.

[0046] In one particular embodiment, the present invention provides a compound of formula I:

[0047] [ka]

[0048] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (-)-methadone to the Poly derivative (examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C-C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers); Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. [Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides.] In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. In certain embodiments, Poly may be selected from mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, and mPEG-O-559Da, where "m" means methoxy; and T, when present, is either (-)-methadone or a terminal group of Poly [when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired; examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl].

[0049] In another particular embodiment, the present invention provides a compound of formula II:

[0050] [ka]

[0051] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (+)-methadone to the Poly derivative (examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C—C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers); Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. [Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides.] In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. In certain embodiments, Poly can be mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, or mPEG-O-559Da, where "m" means methoxy; and T, when present, is either (+)-methadone or a terminal group of Poly, and when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired (examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl).

[0052] In another particular embodiment, the present invention provides a compound of formula III:

[0053] [ka]

[0054] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is comprised between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolyzably under physiological conditions) linker comprising a covalent bond or a chain of atoms that covalently attaches (±)-methadone to the Poly derivative (examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C—C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers); Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides. In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the present invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. Some Poly that may be suitable for the present invention include mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, and mPEG-O-559Da, where "m" means methoxy; and T, when present, is either the terminal group of (±)-methadone or Poly-, and when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl.

[0055] In another particular embodiment, the present invention provides a compound of formula IV:

[0056] [ka]

[0057] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is comprised between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (-)-dizocilpine to the Poly derivative. Examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C-C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides. In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the present invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. Some Poly suitable for the present invention include mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, and mPEG-O-559Da, where "m" means methoxy; and T, when present, is either the terminal group of (-)-dizocilpine or Poly-, and when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl.

[0058] In another particular embodiment, the present invention provides a compound of formula V:

[0059] [ka]

[0060] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is comprised between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (+)-dizocilpine to the Poly derivative. Examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C—C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides. In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the present invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. Some Poly suitable for the present invention include mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, and mPEG-O-559Da, where "m" means methoxy; and T, when present, is either the terminal group of (+)-dizocilpine or Poly-, and when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl.

[0061] In another particular embodiment, the present invention provides a compound of formula VI:

[0062] [ka]

[0063] in its free base form and / or pharmaceutically acceptable salt form, wherein m1, m2, m3, m4, m5, and m6 are, independently of one another, 0 or 1, and m1+m2+m3+m4+m5+m6 is comprised between 1 and 6, and therefore, at least one X-Poly-T is present; X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or a chain of atoms covalently linking (±)-dizocilpine to the Poly derivative. Examples of linkers include, but are not limited to, carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C—C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers; Poly is a covalently linked chain of repeating monomer units forming a polymer backbone, either synthetic or naturally occurring. Examples of polymer backbones include, but are not limited to, poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethyl methacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, or polysialic acid, or other polysaccharides. In certain embodiments, the polymer Poly has an average molecular weight between 80 and 40,000 Da. In some embodiments, the average molecular weight is at least 100 Da. In some embodiments, the average molecular weight is at least 200 Da. In some embodiments of the present invention, Poly is a derivative of poly(ethylene glycol) (PEG) that is linear or branched in structure and monofunctional, difunctional, or heterobifunctional, and has an average molecular weight between 120 and 40,000 Da. Some Poly suitable for the present invention include mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, and mPEG-O-559Da, where "m" means methoxy; and T, when present, is either the terminal group of (±)-dizocilpine or Poly-, and when T is a terminal group, it is represented by any suitable chemical group that is unreactive or reactive with other chemical moieties, as desired. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atoms (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl.

[0064] In some cases, these molecules reduce / eliminate intestinal absorption depending on the size / characteristics of the coupled polymer chain, and these molecules preferentially target intestinal receptors and are useful in treating GI tract disorders, including inflammatory disorders of the GI tract, such as inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, and in treating irritable bowel syndrome.

[0065] Depending on the desired therapeutic effect, it may be desirable to maintain some degree of central nervous system NMDAR antagonism, or alternatively, more selective peripheral modulators of NMDARs can be generated in the absence of CNS activity. To achieve the desired therapeutic use of these novel molecules, BBB permeability may be altered, and intestinal permeability may be altered.

[0066] Diseases and disorders in which inflammation is simultaneously involved in inducing or maintaining pathological processes are relevant. With regard to the respiratory system, some examples of such diseases include COVID-19 and other infectious diseases, long-term COVID-19, inflammatory bowel disease, ARDS, and inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. Other examples of diseases, disorders, conditions, and symptoms that may be treated with the molecules disclosed herein are described in a paper by Du and colleagues (Du J, Li XH, Li YJ. Glutamate in peripheral organs: Biology and pharmacology. Eur J Pharmacol. 2016;784:42-48. doi:10.1016 / j.ejphar.2016.05.009). Also, as discussed above, alterations in NMDAR signaling have been described in inflammatory conditions of the respiratory system. NMDAR expression has been found in lung tissue. Glutamate-induced NMDAR activation can cause acute lung injury with acute pulmonary edema and promote pulmonary vascular remodeling in pulmonary hypertension.(Said et al., Excitoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly (ADP-ribose) polymerase, Proc. Natl. Acad. Sci. USA 93: 4688-4692, 1996; Dickman et al., Ionotropic glutamate receptors in lungs and airways: molecular basis for glutamate toxicity, Am. J. Respir. Cell Mol. Biol. 30: 139-144, 2004; Dumas et al., NMDA-type glutamate receptor activation promotes vascular remodeling and pulmonary arterial hypertension, Circulation 137: 2371-2389, 2018). Accordingly, studies have shown that high-affinity NMDAR antagonists such as MK-801 can attenuate oxidative stress in acute lung injury induced by intratracheal lipopolysaccharide (LPS) instillation (da Cunha et al., Treatment with N-methyl-D-aspartate receptor antagonist MK-801 protects against oxidative stress in lipopolysaccharide-induced acute lung injury in the rat, Int. Immunopharmacol. 11: 706-711, 2011).In particular, the noncompetitive NMDAR antagonist memantine acts on respiratory macrophages to alleviate acute lung injury (ALI) (Ding et al., Memantine alleviates acute lung injury via inhibiting macrophage pyroptosis, Shock 56: 1040-1048, 2021) and septic lung injury (Hu et al., Memantine nitrate MN-08 suppresses NLRP3 inflammasome activation to protect against sepsis-induced acute lung injury in mice. Biomed and Pharmacother 156: 113804, 2022).

[0067] Furthermore, NMDAR inhibition by memantine has also been shown to be effective against chronic obstructive pulmonary disease (COPD) (Cheng et al., Memantine ameliorates pulmonary inflammation in a mice model of COPD induced by cigarette smoke combined with LPS. Biomed and Pharmacother 109: 2005–2013, 2019). This is relevant because COPD affects over 15 million adults in the United States, making it a leading cause of disability. COPD is strongly associated with cigarette smoking and, according to the Centers for Disease Control and Prevention (CDC), is the fourth leading cause of death in the United States. Current treatments for COPD are relatively ineffective, as available drugs neither significantly slow disease progression nor have a substantial effect on inflammation. Therefore, suppressing the inflammatory response by acting on airway macrophages may be an important strategy for COPD treatment. Collectively, these observations suggest that NMDARs represent potential pharmacological agents for therapeutic intervention in a variety of diseases affecting the respiratory tract.

[0068] Based on these observations, our results (Example 1) suggest that NMDAR antagonists, such as esmethadone and MK-801, reduce macrophage-induced inflammation in lung cells. In mice, MK-801 conjugated with PEG molecules of different lengths did not induce the behavioral changes observed with unconjugated MK-801 (Example 2), suggesting PEG-related modulation of BBB crossing and / or other potential mechanisms. Based on our and the above-mentioned experimental results, NMDAR antagonists may have potential therapeutic potential for treating diseases, disorders, conditions, and symptoms caused by dysregulated peripheral NMDARs, including NMDARs that may be dysregulated in inflammatory lung diseases. We have demonstrated in vitro that esmethadone and MK-801 reduce the mRNA expression of inflammatory cytokines in lung cells co-cultured with macrophages. Based on these studies, the inventors concluded that targeting peripheral inflammatory diseases, including pulmonary diseases, with peripherally acting NMDAR antagonists may be a promising strategy. By the same rationale, these same polymer conjugates are potentially therapeutic for all diseases, disorders, conditions, and symptoms caused by dysregulation of NMDAR on cells outside the CNS, including cells belonging to the respiratory, digestive, cardiovascular, immune, renal, and reproductive systems. [Example]

[0069] Example 1 NMDAR antagonists reduce inflammation in vitro In vitro studies We established an experimental in vitro model of inflammatory lung disease by co-culturing the A-549 lung cell line with macrophages derived from differentiated THP-1 monocytic cells for 24 hours (Figure 1A). Figure 1B shows that esmethadone and MK-801 reduced the mRNA expression of two inflammatory cytokines, CCL-2 and IL-1β, only when A-549 cells were co-incubated with macrophages, demonstrating the crucial role of immune cells in the mechanism of NMDAR antagonist action. Thus, the anti-inflammatory effects of the NMDAR antagonists MK-801 and esmethadone (1 μM) are due to their direct interaction with macrophage-like cells (Figures 1A and 1B, respectively). (Figure 1A shows mRNA expression of the inflammatory cytokines CCL2, IL-1β, and IL-6 in lung A549 cells activated with conditioned medium (CM) obtained from macrophages; and Figure 1B shows mRNA expression of the inflammatory cytokines CCL2, IL-1β, and IL-6 in lung A549 cells cocultured with macrophages (MΦ) obtained by treating THP-1 cells with the activator PMA).

[0070] In vivo studies We used seven C57BL6 / J male mice (3-4 months old) per treatment group. They were housed in a temperature-controlled room (22°C) under a 12:12-h light / dark cycle (lights on at 7:00 AM) and provided with free access to standard pellet chow and tap water. Experimental mice were transferred to the behavioral room 30 min before the start of the test to allow them to acclimate to the testing room. The open field test was performed between 9:00 AM and 4:00 PM. MK-801 and its derivatives were dissolved in a vehicle composed of 0.9% NaCl saline. Each mouse was placed individually in a corner of a gray-painted open-field arena (40 × 40 × 30 cm) 10 minutes after intraperitoneal injection (0.1 mL injection volume) of either vehicle, 0.3 mg / kg MK-801, or a dose equivalent to 0.3 mg / kg MK-801 of the PEG4, PEG6, PEG8, or PEG10 MK-801 derivative. Total locomotor activity, measured as the distance traveled by the animal during a 10-minute test period, was determined using an automated behavioral tracking system (Videotrack, ViewPoint Life Sciences).

[0071] We demonstrated that intraperitoneal injection of 0.3 mg / kg MK-801 significantly increased the distance traveled by mice compared to vehicle as well as to the MK-801 PEG derivative (p<0.0001; one-way ANOVA: F(5,36)=16,40; p<0.0001). Interestingly, none of the MK-801 PEG derivatives tested altered the distance traveled by mice compared to vehicle, suggesting that the PEG derivatives did not cross the BBB.

[0072] The present inventors disclose conjugates of NMDAR antagonists that exert their regulatory and / or other effects preferentially on other extra-CNS receptors. The present inventors also disclose polymers that can modulate / reduce / eliminate the parent drug's ability to cross the BBB and / or intestinal barrier. The present inventors have developed molecules that can be administered, preferably via oral or pulmonary routes, to reach the site of action. Oral administration is one of the preferred routes of administration and is the most common route for small molecule drugs. The length and characteristics of the polymer chain can be adjusted to maintain the desired intestinal absorption for the target disease, disorder, or condition. The desired therapeutic activity may be limited to the gastrointestinal tract, resulting in limited or completely blocked gastrointestinal (GI) passage.

[0073] Example 3 (5S,10R)-5-Methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-tetraEGME×HCl)

[0074] This Example 3 describes the method used to prepare (5S,10R)-5-methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-tetraEGME×HCl), as shown in FIG. 3.

[0075] To a stirred solution of (+)-MK-801 (0.100 g, 0.45 mmol, 1 equiv.) in anhydrous DMF (1.356 mL) was added CsCO (0.162 g, 0.50 mmol, 1.1 equiv.) and KI (8 mg, 0.05 mmol, 0.1 equiv.), followed by a solution of 2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate (tetra-EGME, 0.246 g, 0.68 mmol, 1.5 equiv.) in anhydrous DMF (0.452 mL). The mixture was heated to 70 °C and stirred under nitrogen for 24 h. The mixture was then diluted with water (1.356 mL), and the residual carbonate was quenched with acetic acid (0.028 mL, 1.1 equiv.). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting with 5% ACN, reaching 50% in 17 min, retention time 16.09 min). After lyophilization, the resulting TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After lyophilization, (+)-MK-801-tetraEGME×HCl was obtained as a colorless oil (0.1850 g, 0.353 mmol, 78%). UPLC purity: >99%. HRMS (ESI) m / z: [M+H] + Theoretical value [C 25 H 34 NO4] + 412.2482; Measured value: 412.2543. Specific rotation [α] D 25 :+88.7°(0.02g / mL, CHCl3). 1H NMR (400 MHz, CDCl3) δ 13.42 (s, 1H), 7.42 (d, J = 6.9 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.25 - 7.19 (m, 2H), 7.13 - 7.02 (m, 2H), 5.40 (s, 1H), 4.75 (t, J = 10.3 Hz, 1H), 3.84 (s, 2H), 3.80 - 3.60 (m, 11H), 3.59 - 3.51 (m, 2H), 3.39 - 3.33 (m, 3H), 3.31 (s, 1H), 3.06 (d, J = 12.4 Hz, 1H), 2.94 - 2.84 (m, 1H), 2.36 (s, 3H) - see Figure 4. 13 C NMR (101 MHz, CDCl3) δ 144.29, 136.50, 135.49, 130.16, 130.03, 129.45, 129.26, 129.19, 127.68, 123.23, 122.67, 119.42, 72.13, 72.00, 70.72, 70.58, 70.54, 70.51, 70.29, 66.25, 62.22, 59.11, 44.79, 29.03, 15.46 - see Figure 5.

[0076] Example 4 (5S,10R)-5-Methyl-12-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-HexaEGME×HCl)

[0077] This Example 4 describes the method used to prepare (5S,10R)-5-methyl-12-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-HexaEGME×HCl), as shown in FIG.

[0078] To a stirred solution of (+)-MK-801 (0.100 g, 0.45 mmol, 1 equiv.) in anhydrous DMF (1.356 mL) was added CsCO (0.162 g, 0.50 mmol, 1.1 equiv.) and KI (8 mg, 0.05 mmol, 0.1 equiv.), followed by a solution of 2,5,8,11,14,17-hexaoxanonadecan-19-yl 4-methylbenzenesulfonate (hexa-EGME, 0.305 g, 0.68 mmol, 1.5 equiv.) in anhydrous DMF (0.452 mL). The mixture was heated to 70 °C and stirred under nitrogen for 24 h. The DMF was then diluted with water (1.356 mL), and the residual carbonate was quenched with acetic acid (0.028 mL, 1.1 equiv.). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting with 5% ACN, reaching 50% in 17 min, retention time 16.65 min). After lyophilization, the resulting TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After lyophilization, (+)-MK-801-hexaEGME×HCl was obtained as a colorless oil (0.239 g, 0.39 mmol, 87% yield). UPLC purity: >95%. HRMS (ESI) m / z: [M+H] + Theoretical value [C 29 H 42 NO6] + :500.3007; Actual value:500.3035. Specific rotation [α] D 25 :+81.93°(0.02g / mL, CHCl3). 1H NMR (400 MHz, CDCl3) δ 13.43 (s, 1H), 7.45 - 7.38 (m, 1H), 7.34 - 7.24 (m, 3H), 7.27 - 7.17 (m, 2H), 7.13 - 7.02 (m, 2H), 5.40 (s, 1H), 4.75 (t, J = 10.5 Hz, 1H), 3.85 (d, J = 11.6 Hz, 2H), 3.77 - 3.58 (m, 18H), 3.56 - 3.49 (m, 2H), 3.37 (s, 3H), 3.33 (d, J = 15.6 Hz, 1H), 3.07 (t, J = 11.1 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.36 (s, 3H) - see Figure 6. 13 C NMR (101 MHz, CDCl3) δ 144.41, 136.65, 135.64, 130.13, 130.10, 129.35, 129.17, 129.10, 127.60, 123.19, 122.62, 119.39, 71.99, 70.72, 70.65, 70.63, 70.57, 70.51, 70.27, 66.34, 62.11, 59.11, 44.71, 29.02, 15.45 - see Figure 7.

[0079] Example 5 (5S,10R)-5-Methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-octaEGME×HCl) This Example 5 describes the method used to prepare (5S,10R)-5-methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-octaEGME×HCl), as shown in FIG. 3.

[0080] To a stirred solution of (+)-MK-801 (0.100 g, 0.45 mmol, 1 equiv.) in anhydrous DMF (1.35 mL) was added CsCO (0.162 g, 0.50 mmol, 1.1 equiv.) and KI (8 mg, 0.05 mmol, 0.1 equiv.), followed by a solution of 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl 4-methylbenzenesulfonate (octaEGME, 0.365 g, 0.68 mmol, 1.5 equiv.) in anhydrous DMF (0.45 mL). The mixture was heated to 80 °C and stirred under nitrogen for 24 h. The DMF was then diluted with water (2 mL), and the residual carbonate was quenched with acetic acid (0.028 mL, 1.1 equiv.). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting with 5% ACN, reaching 56% in 19 min, retention time 17.55 min). After lyophilization, the resulting TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After lyophilization, (+)-MK-801-octaEGME×HCl was obtained as a colorless oil (0.2571 g, 0.37 mmol, 82% yield). UPLC purity: >99%. HRMS (ESI) m / z: [M+H] + Theoretical value [C 33 H 50 No. 8] + :588.3531; Actual value:588.3586. Specific rotation [α] D 25 :+61.96°(0.019 g / mL, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 13.19 (s, 1H), 7.47 - 6.93 (m, 8H), 5.39 (s, 1H), 4.68 (t, J = 10.4 Hz, 1H), 3.88 - 3.78 (m, 2H), 3.78 - 3.55 (m, 26H), 3.54 - 3.48 (m, 2H), 3.34 (s, 3H), 3.31 (d, J = 13.2 Hz, 1H), 3.10 - 2.98 (m, 1H), 2.91 - 2.84 (m, 1H), 2.32 (s, 3H) -See Figure 8. 13C NMR (101 MHz, CDCl3) δ 144.04, 136.20, 135.49, 130.11, 129.96, 129.38, 129.28, 127.62, 123.80, 123.09, 122.54, 119.53, 72.36, 71.95, 70.69, 70.60, 70.57, 70.52, 70.46, 70.41, 70.10, 66.00, 62.12, 59.06, 44.82, 29.11, 15.29 - see Figure 9.

[0081] Example 6 (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-Decaoxahentriacontan-31-yl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-DecaEGME×HCl) This Example 6 describes the method used to prepare (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-decaoxahentriacontan-31-yl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-decaEGME×HCl), as shown in FIG. 3.

[0082] To a stirred solution of (+)-MK-801 (0.016 g, 0.07 mmol, 1 equiv.) in anhydrous DMF (0.217 mL), CsCO (0.026 g, 0.08 mmol, 1.1 equiv.) and KI (1 mg, 0.01 mmol, 0.1 equiv.) were added, followed by a solution of 2,5,8,11,14,17,20,23,26,29-decaoxahentriacontan-31-yl 4-methylbenzenesulfonate (decaEGME, 0.068 g, 0.11 mmol, 1.5 equiv.) in anhydrous DMF (0.072 mL). The mixture was heated to 80 °C and stirred under nitrogen for 24 h. The DMF was then diluted with water (3 mL), and the residual carbonate was quenched with acetic acid (0.028 mL, 1.1 equiv.). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting with 5% ACN and reaching 57% in 20 min, retention time 19.42 min). After lyophilization, the resulting TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After lyophilization, (+)-MK-801-decaEGME×HCl was obtained as a colorless oil (0.039 g, 0.050 mmol, 72% yield). UPLC purity: >99%. HRMS (ESI) m / z: [M+H] + Theoretical value [C 37 H 58 NO 10 ] + :676.4055; Actual value:676.4047. Specific rotation [α] D 25 :+63.27°(0.009g / mL, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 7.44 - 6.99 (m, 8H), 5.38 (s, 1H), 4.72 - 4.63 (m, 1H), 3.84 (d, J = 14.2 Hz, 2H), 3.78 - 3.57 (m, 34H), 3.57 - 3.50 (m, 2H), 3.36 (s, 3H), 3.31 (d, J = 15.3 Hz, 1H), 3.05 (s, 1H), 2.95 - 2.81 (m, 1H), 2.32 (s, 3H) - see Figure 10. 13C NMR (101 MHz, CDCl3) δ 144.21, 136.38, 135.67, 130.17, 130.09, 129.39, 129.31, 127.64, 123.14, 122.60, 119.59, 72.30, 72.02, 70.77, 70.68, 70.65, 70.60, 70.54, 70.49, 70.18, 66.97, 66.21, 62.17, 59.13, 44.87, 29.18, 15.40 - see Figure 11.

[0083] While the present invention has been disclosed with reference to details of various embodiments thereof, it is to be understood that the disclosure is intended in an illustrative and not a limiting sense, since modifications within the spirit of the invention and the scope of the amended claims will be apparent to those skilled in the art.

Claims

1. Compound of formula I: 【Chemical 1】 A structural analog of (R)-methadone ((-)-methadone, levomethadone) in its free base form and pharmaceutically acceptable salt forms. (In the formula, m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1 + m2 + m3 + m4 + m5 + m6 is between 1 and 6; X is a stable linker containing a covalent bond or an atomic chain that covalently attaches (-)-methadone to Poly; Poly is a covalent chain of repeating monomer units that forms a polymer backbone; T is optional and is either (-)-methadone or a terminal group of Poly)

2. Compound of formula II: [Chemical 2] A structural analog of (S)-methadone ((+)-methadone, dextromethadone, esmethadone) in its free base form and / or pharmaceutically acceptable salt forms. (In the formula, m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1 + m2 + m3 + m4 + m5 + m6 is between 1 and 6; X is a stable linker containing a covalent bond or an atomic chain that covalently attaches (+)-methadone to Poly; Poly is a covalent chain of repeating monomer units that forms a polymer backbone; T is optional and is either (+)-methadone or a terminal group of Poly)

3. Compound of formula III: 【Chemical Formula 3】 A structural analog of (S,R)-methadone ((±)-methadone, rac-methadone, methadone) in its free base form and / or pharmaceutically acceptable salt forms. (In the formula, m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1 + m2 + m3 + m4 + m5 + m6 is between 1 and 6; X is a stable linker containing a covalent bond or an atomic chain that covalently attaches (±)-methadone to Poly; Poly is a covalent chain of repeating monomer units that forms a polymer backbone; T is optional and is either (±)-methadone or a terminal group of Poly)

4. Compound of formula IV: 【Chemical Formula 4】 A structural analog of (-)-dizocilpine ((-)-MK-801) in its free base form and pharmaceutically acceptable salt forms. (In the formula, m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1 + m2 + m3 + m4 + m5 + m6 is between 1 and 6; X is a stable linker containing a covalent bond or an atomic chain that covalently attaches (-)-dizocilpine to Poly; Poly is a covalent chain of repeating monomer units that form a polymer backbone; T is optional and is either (-)-dizocilpine or a terminal group of Poly) **Claim 5** Formula V: 【Chemical Formula 5】 A compound having a structural analog of (+)-dizocilpine ((+)-MK-801) in its free base form and pharmaceutically acceptable salt forms. (In the formula, m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1 + m2 + m3 + m4 + m5 + m6 is between 1 and 6; X is a stable linker containing a covalent bond or an atomic chain that covalently attaches (+)-dizocilpine to Poly; Poly is a covalent chain of repeating monomer units that form a polymer backbone; T is optional and is either (+)-dizocilpine or a terminal group of Poly) **Claim 6** Formula VI: [Chemical Formula 6] A compound having a structural analog of (±)-dizocilpine ((±)-MK-801) in its free base form and pharmaceutically acceptable salt forms. (In the formula, m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1 + m2 + m3 + m4 + m5 + m6 is between 1 and 6; X is a stable linker containing a covalent bond or an atomic chain that covalently attaches (±)-dizocilpine to Poly; Poly is a covalent chain of repeating monomer units that form a polymer backbone; T is optional and is either (±)-dizocilpine or a terminal group of Poly) **Claim 7** The compound according to any one of claims 1 to 6, wherein X is selected from carboxylic acid esters, phosphate esters, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbohydrazones, carbamates, peptides, nucleotides, C-C bonds (e.g., in an aliphatic chain), ethers, amides, oximes, enamines, semicarbazones, semicarbazides, and thioethers. **Claim 8** The compound according to any one of claims 1 to 7, wherein the polymer backbone formed by Poly is selected from poly(ethylene glycol) (PEG), poly(N-vinylpyrrolidone), N-hydroxyethylmethacrylamide copolymer, poly(2-ethyl-2-oxazoline), poly(N-acryloylmorpholine), poly(propylene glycol), poly(vinyl alcohol), polyglutamic acid, hyaluronic acid, polysialic acid, and other polysaccharides.

9. The compound according to any one of claims 1 to 8, wherein Poly is a derivative of poly(ethylene glycol) (PEG) having a linear or branched structure, monofunctional, bifunctional, or heterobifunctional, and the average molecular weight is between 120 and 40,000 Da.

10. The compound according to claim 9, wherein Poly is selected from mPEG-O-163Da, mPEG-COO-207Da, mPEG-O-251Da, mPEG-O-295Da, mPEG-O-339Da, mPEG-O-383Da, mPEG-O-427Da, mPEG-O-471Da, mPEG-O-515Da, mPEG-O-559Da.

11. The compound according to any one of claims 1 to 10, wherein the average molecular weight of Poly is between 80 and 40,000 Da.

12. The compound according to any one of claims 1 to 11, wherein the average molecular weight of Poly is at least 100 Da.

13. The compound according to any one of claims 1 to 12, wherein the average molecular weight of Poly is at least 200 Da.

14. The compound according to any one of claims 1 to 13, wherein the molecular weight of Poly is greater than 500 Da and less than 2000 Da.

15. T is a terminal group and is selected from hydroxyl, amino, sulfide, carboxy, cyano, optionally substituted aryloxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atom (e.g., fluorine, chlorine, bromine, iodine), tosylate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyldisulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenyloxy, and formyl, the compound according to any one of claims 1 to 14.

16. The compound according to any one of claims 1 to 15, which has the ability to regulate passage through the blood-brain barrier.

17. The compound according to any one of claims 1 to 16, for use in the treatment of diseases affecting peripheral cells, wherein the peripheral cells are cells existing outside the blood-brain barrier.

18. The compound according to any one of claims 1 to 17, for use in the treatment of diseases caused by dysfunction of immune system cells, digestive system cells, respiratory system cells, cardiovascular system cells, renal system cells, and reproductive system cells.

19. The compound according to any one of claims 1 to 18, for use in the prevention of diseases caused by dysfunction of immune system cells, digestive system cells, respiratory system cells, cardiovascular system cells, renal system cells, and reproductive system cells.

20. The compound according to any one of claims 1 to 19, for the treatment or prevention of respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, and infectious diseases.

21. The compound according to any one of claims 1 to 20, for the treatment or prevention of cardiovascular diseases including congestive heart failure, ischemic heart disease, and arrhythmia.

22. The compound according to any one of claims 1 to 21, for the treatment or prevention of digestive system diseases including Crohn's disease, ulcerative colitis, irritable bowel syndrome, impaired glucose tolerance and diabetes, and liver dysfunction.

23. The compound according to any one of claims 1 to 22, for the treatment or prevention of renal system diseases including chronic and acute renal failure and nephrotoxicity caused by various substances.

24. A compound according to any one of claims 1 to 23 for the treatment or prevention of genital diseases, including infertility.

25. A pharmaceutical or diagnostic composition comprising a compound as defined in any one of claims 1 to 24 and optionally also one or more pharmaceutically acceptable excipients.

26. A composition according to claim 25 for oral, sublingual, transmucosal, nasal, transdermal, parenteral, rectal, topical, vaginal, ocular, or inhalation use.

27. A composition according to claim 26, administered in a dosage range of 0.001 mg to 1 gram.

Images