Polymer conjugates of drugs having central nervous system (CNS) action and peripheral NMDAR blocking activity and / or immune system modulating action

Abstract

The present invention discloses novel molecules consisting of N-methyl-D-aspartate receptor (NMDAR) antagonist-polymer conjugates having the general structure D-(X-Poly-T) n wherein D is a high affinity, i.e. (+)-, (-)-or (+-)-dezocycline, or a low affinity, i.e. (+)-, (-)-or (+-)-methadone, CNS active NMDAR antagonist, n is an integer from 1 to 6. X is a stable (enzymatic and / or hydrolytic under physiological conditions) linker comprising a covalent bond or atomic chain covalently linking a small molecule NMDAR antagonist drug moiety to the Poly derivative. Poly is a covalently bonded chain of repeating monomer units forming a polymer backbone of synthetic or natural origin. T, if present, is another molecule of D, or an end group of Poly, represented by any suitable chemical group which, according to preference, does not react with or with other chemical moieties, or has targeting properties.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of the filing date of U.S. Patent Application No. 63 / 341,198, filed on May 12, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] Aspects of the present invention generally relate to polymer conjugates of N-methyl-D-aspartate receptor (NMDAR) antagonists and their therapeutic and preventive aspects for the respiratory system and inflammation. Background Art

[0004] This section is intended to introduce the reader to various aspects of the technology that may be related to various aspects of the present invention, which are described below and / or as claimed. It is believed that this discussion is helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present invention. Therefore, it should be understood that these statements should be read in this light, and not as admissions of prior art.

[0005] NMDAR is an ionotropic receptor that requires the binding of glutamate (the major excitatory neurotransmitter in the human brain), glycine, and voltage-dependent Mg 2+ detachment, which then allows for isoform-specific tight regulation of Ca 2+ [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, a neurodegenerative disorder caused by excessive Ca. 2+Influx induces a toxic cellular state that can lead to impaired neuroplasticity and cell death. Many investigated and approved drugs are known to antagonize the activity of NMDARs by binding to receptors within the NMDAR pore with varying affinities, including MK-801, ketamine, dextromethorphan, and dextromethadone (esmethadone). In addition to its role in the CNS, NMDARs are also abundantly expressed in peripheral (outside the 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, drugs that modulate NMDARs may also therapeutically target additional CNS receptors whose downstream effects on dysregulated Ca 2+And / or along with potential therapeutic value. The inventors previously disclosed the potential peripheral (outside 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 previous applications - also have central nervous system effects. Therefore, preferentially targeting peripheral NMDARs by limiting access to the CNS with high- and low-affinity antagonists is a potential new strategy to exert peripheral NMDAR modulatory therapeutic effects while avoiding CNS effects, including psychiatric effects, including dissociative or hallucinogenic effects, and cytotoxic effects, including Olney lesions [Olney, JW, Labruyere, J., and Price, MT (1989). Pathological Changes Induced in Cerebrocortical Neurons by Phencyclidine and Related Drugs. Science 244, 1360-1362. Doi: 10.1126 / science.2660263; Olney, JW, Labruyere, J., Wang, G., Wozniak, DF, Price, MT, and Sesma, MA (1991). NMDA Antagonist Neurotoxicity: Mechanism and Prevention. Science 254,1515-1518.Doi:10.1126 / science.l835799; Fix,AS,Hom,JW,Wightman,KA,Johnson,CA,Long,GG,Starts,RW,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.l993.1153].

[0006] CNS psychoactive drugs cross the BBB and reach receptors in the brain, including NMDARs, and exert specific CNS effects, including therapeutic effects and side effects, including potential toxic CNS effects. The CNS effects of NMDAR antagonists are mainly caused by their binding to NMDARs located in the membranes of brain neurons. NMDARs are heterotetramers formed by subunits of three groups of genes (named GluN1, GluN2, and GluN3). Like the GluN1 subunits, the GluN3 subunits encoded by two different genes (AB) bind to the co-agonists glycine or d-serine, while the GluN2 subunits encoded by four different genes (AD) bind to glutamate or NMDA. NMDARs cannot form functional homotetramers. Obligate heterotetramers can be composed of a variety of subunit combinations and confer functional diversity. Typically this includes either one of two GluN2 subunits of the same or different subtypes and two GluN1 subunits, or two GluN1 subunits and one GluN2 and one GluN3 subunit.

[0007] Furthermore, NMDARs with different subunit compositions show spatiotemporal variation, with expression of GluN2B and GluN2D being highest in early development, shifting later in life to increased but not exclusive expression of GluN2A and GluN2C, whose expression levels vary in different brain regions. Drugs that act as NMDAR antagonists may have significant therapeutic psychiatric effects, including therapeutic effects, such as antidepressant effects. However, NMDAR noncompetitive antagonists with high affinity for NMDARs, such as MK-801 and ketamine, can cause dissociative effects even when administered at potentially therapeutic doses. NMDAR antagonists are approved or in clinical investigation for the treatment of a variety of psychiatric or neurodegenerative diseases and symptoms, including depression (esketamine, arketamine, ketamine, dextromethorphan), Alzheimer's disease (memantine), Parkinson's disease (amantadine), or for anesthesia induction, procedural sedation, and analgesia (ketamine). However, some NMDAR antagonists may have significant CNS effects, including dissociative effects (MK-801, ketamine, and esketamine), and these effects have hindered their development as potential therapeutic agents. There are strong public safety and regulatory concerns about the therapeutic use of substances that may induce dissociative effects. In summary, the development of psychoactive substances for the treatment of diseases, disorders, conditions, and symptoms, including extra-CNS diseases, disorders, conditions, and symptoms, remains problematic due to the potent CNS effects of these drugs, which can currently only be regulated by reducing the dose. Summary of the invention

[0008] Some exemplary aspects of the present invention are described below. It should be understood that these aspects are presented only to provide the reader with a brief overview of some forms that the present invention may take, and these aspects are not intended to limit the scope of the present invention. In fact, the present invention may include various aspects that may not be clearly described below.

[0009] The present invention discloses NMDAR antagonist polymer conjugates having therapeutic advantages over known NMDAR antagonists. The chemically modified drugs described herein have applications in the fields of drug discovery and pharmacotherapy, 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.

[0010] In the present invention, the purpose of reducing the CNS side effects of NMDAR non-competitive antagonists is achieved by reducing the ability of these drugs to pass through (1) BBB (an anatomical-functional barrier that effectively eliminates or reduces different molecules from entering the brain) and / or (2) intestinal barrier (IB) (an anatomical-functional barrier that effectively eliminates or reduces different molecules from passing through the digestive system). In order to achieve this, the inventors have designed polymer-drug conjugates (PDCs) of NMDAR antagonists to prevent, reduce or regulate them from passing through the BBB. For some compounds, there may also be advantages in regulating the passage through the intestinal barrier (IB). The potential therapeutic peripheral effects of these conjugates may become more favorable in the absence or with the reduction of BBB and IB passing through, resulting in the downregulation of the accompanying CNS effects or even limiting the drug to the gastrointestinal tract. In fact, due to the specific characteristics of the polymer structure, their molecular weight and / or their hydrodynamic volume and their chemical-physical properties, the molecules disclosed in this application cannot pass through the BBB or have a regulated or limited BBB passing ability. Their coupling to specific tailor-made polymers may generate new molecules with improved pharmacokinetic and pharmacodynamic profiles for selected diseases and disorders with a favorable risk-benefit ratio. In summary, the present invention provides PDCs with the purpose and ability to preferentially target NMDARs located outside the CNS for the treatment of diseases, disorders and conditions associated with unbalanced activity and / or excitotoxicity due to peripheral NMDAR dysregulation and / or immune system dysfunction.

[0011] Some aspects of the invention relate to NMDAR antagonist polymer conjugates having the general structure D-(X-Poly-T)n, wherein D is a CNS-active NMDAR antagonist and n is an integer from 1-6.

[0012] X is a stable (enzymatic and / or hydrolyzed under physiological conditions) linker, which includes a covalent bond or an atomic chain, which covalently connects a small molecule NMDA antagonist drug moiety to a 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 there is no chemically reactive functional group, the group can be chemically introduced, and the side group of the group reacts chemically with the linker to form a covalent bond. Examples of linkers include, but are not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbon hydrazone, carbamate, peptide, nucleotide, CC bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, thioether.

[0013] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin. Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethyl 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 of 80 to 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), which has a linear or branched structure, monofunctional, difunctional or heterobifunctional, and an average molecular weight of 120 to 40,000 Da. Some Poly suitable for use in 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, wherein "m" represents a methoxy group.

[0014] If present, T is D or a terminal group of Poly, when T is a terminal group, it is represented by any suitable chemical group, which chemical group, according to preference, does not react with other chemical moieties or reacts with other chemical moieties. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxyl, 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), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, orthopyridyl disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy, formyl. We have begun to synthesize PEG derivatives of dexmethadone by attaching a short PEG chain (oligo(ethylene glycol)) to one of the phenyl functional groups of dexmethadone. We chose the benzene ring for PEG conjugation because our previous studies on dexmethadone analogs showed that modifications at the benzene ring level minimally hindered NMDAR activity.

[0015] In a specific embodiment, the present invention includes compounds according to formula I in free base form and / or in the form of pharmaceutically acceptable salts thereof, which include structural analogs of (R)-methadone ((-)-methadone, levomethadone):

[0016]

[0017] wherein ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0018] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-methadone to the Poly derivative;

[0019] Poly is a covalently bonded chain of repeating monomer units forming the backbone of a polymer of synthetic or natural origin; and

[0020] T, if present, is (-)-methadone or is a terminal group of Poly (and "X", "Poly" and "T" may be as described above).

[0021] In another specific embodiment, the present invention includes compounds according to Formula II in free base form and / or pharmaceutically acceptable salt form thereof, which include structural analogs of (S)-methadone ((+)-methadone, dextromethadone, dextromethadone):

[0022]

[0023] wherein ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0024] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-methadone to the Poly derivative;

[0025] Poly is a covalently bonded chain of repeating monomer units forming the backbone of a polymer of synthetic or natural origin; and

[0026] T, if present, is (-)-methadone or the terminal group of Poly (and "X", "Poly" and "T" may be as described above).

[0027] In another specific embodiment, the present invention includes a compound according to formula III in free base form and / or a pharmaceutically acceptable salt form thereof having a structural analog of (S,R)-methadone ((±)-methadone, racemic methadone, methadone):

[0028]

[0029] wherein ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0030] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-methadone to the Poly derivative;

[0031] Poly is a covalently bonded chain of repeating monomer units forming the backbone of a polymer of synthetic or natural origin; and

[0032] T, if present, is (-)-methadone or the terminal group of Poly (and "X", "Poly" and "T" may be as described above).

[0033] In another specific embodiment, the present invention includes a compound according to formula IV in free base form and / or a pharmaceutically acceptable salt form thereof, which has a structural analog of (-)-dizocilpine ((-)-MK-801):

[0034]

[0035] wherein m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0036] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-methadone to the Poly derivative;

[0037] Poly is a covalently bonded chain of repeating monomer units forming the backbone of a polymer of synthetic or natural origin; and

[0038] T, if present, is (-)-methadone or the terminal group of Poly (and "X", "Poly" and "T" may be as described above).

[0039] In another specific embodiment, the present invention includes a compound according to formula V in free base form and / or a pharmaceutically acceptable salt form thereof, which has a structural analog of (+)-dizocilpine ((+)-MK-801):

[0040]

[0041] wherein m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0042] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-methadone to the Poly derivative;

[0043] Poly is a covalently bonded chain of repeating monomer units forming the backbone of a polymer of synthetic or natural origin; and

[0044] T, if present, is (-)-methadone or the terminal group of Poly (and "X", "Poly" and "T" may be as described above).

[0045] In another specific embodiment, the present invention includes a compound according to formula VI in free base form and / or a pharmaceutically acceptable salt form thereof, which has a structural analog of (±)-dizocilpine ((±)-MK-801):

[0046]

[0047] wherein m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0048] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-methadone to the Poly derivative;

[0049] Poly is a covalently bonded chain of repeating monomer units forming the backbone of a polymer of synthetic or natural origin; and

[0050] T, if present, is (-)-methadone or the terminal group of Poly (and "X", "Poly" and "T" may be as described above). BRIEF DESCRIPTION OF THE DRAWINGS

[0051] 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.

[0052] Figure 1A-1B Shown are the effects of the NMDAR antagonists dexmethadone and MK-801 on the mRNA expression of inflammatory cytokines in A-549 cells in two different experimental settings. The effects of the tested NMDAR antagonists on lung cells were mediated by macrophages. *P<0.05, **P<0.01, ***P<0.001.

[0053] Figure 2 : is a graph showing the effect of MK-801 and MK-801-EGME conjugate at an equivalent dose of 0.3 mg / kg MK-801 on the distance traveled by mice in 10 minutes in the open field test (n=7 mice per 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.

[0054] Figure 3 is a schematic diagram showing the synthesis of (+)-MK-801-EGME conjugate using the strategy proposed in this specification.

[0055] Figure 4 is a graph showing (5S,10R)-5-methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-TetraEGME x HCl) 1 Figure 1. H NMR spectrum of the 3D image.

[0056] Figure 5is a graph showing (5S,10R)-5-methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-TetraEGME x HCl) 13 Figure 3 C NMR spectrum.

[0057] Figure 6 is a graph showing (5S,10R)-5-methyl-12-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-HexaEGME x HCl) 1 Figure 1. H NMR spectrum of the 3D image.

[0058] Figure 7 is a graph showing (5S,10R)-5-methyl-12-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-HexaEGME x HCl) 13 Figure 3 C NMR spectrum.

[0059] Figure 8 is a graph showing (5S,10R)-5-methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-OctaEGME xHCl) 1 Figure 1. H NMR spectrum of the 3D image.

[0060] Fig. 9 is a graph showing (5S,10R)-5-methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-OctaEGME xHCl) 13 Figure 3 C NMR spectrum.

[0061] Fig.10is a graph showing (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-decaoxatriacontan-31-yl)-5-methyl-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-DecaEGME x HCl) 1 Figure 1. H NMR spectrum of the 3D image.

[0062] Fig.11 is a graph showing (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-decaoxatriacontan-31-yl)-5-methyl-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-DecaEGME x HCl) 13 Figure 3 C NMR spectrum. DETAILED DESCRIPTION

[0063] One or more specific embodiments of the present invention will be described below. In order to provide a concise description of these embodiments, all features of the actual implementation may not be described in the specification. It should be understood that in the development of any such actual implementation, as in any engineering or design project, many implementation-specific decisions must be made to achieve the developer's specific goals, such as meeting system-related and business-related constraints, which may vary from one embodiment to another. In addition, it should be understood that such development efforts may be complex and time-consuming, but for those of ordinary skill in the art who benefit from this disclosure, it is still a routine task of design, production and manufacture.

[0064] In addition to CNS receptors, NMDAR antagonists also target NMDARs located outside the CNS, and their pharmacodynamic effects have potential therapeutic value. The peripheral effects of these potential treatments may be offset by the CNS effects of these drugs. Therefore, targeting these peripheral NMDARs by limiting their entry into the central nervous system (CNS) is a potential new treatment option that prevents potentially harmful central nervous system effects while maintaining potential therapeutic peripheral glutamate system modulation effects. This goal of preferentially targeting peripheral NMDARs can be achieved with new chemical entities that are designed to bind to NMDARs and have regulated ability to cross the BBB and IB. Physiologically, the BBB protects the brain by limiting the entry of potentially toxic molecules. The BBB allows and regulates the passage of essential nutrients and selected substances, and effectively eliminates or reduces the passage of many other molecules (sometimes called exogenous substances), thereby regulating the rate at which many substances reach brain tissue. The BBB can also completely block certain molecules from entering the brain. Polymer conjugates of NMDAR antagonists can prevent, reduce or regulate active molecules from crossing the BBB barrier. The potential therapeutic effects of NMDAR antagonists are designed to have regulated or no access to the CNS, which may improve the safety window of these drugs while improving their therapeutic effects in the central and preferably peripheral areas. Polymer conjugates of NMDAR antagonists that cannot cross the BBB or IB or have regulated or limited BBB or IB crossing ability may preferentially exert peripheral effects with potential therapeutic effects while reducing or avoiding CNS side effects.

[0065] Although current research on NMDAR antagonists has focused on addressing CNS pathologies, including psychiatric and neurodegenerative diseases, NMDAR receptors may play a role in the pathogenesis and potential treatment of other diseases, including peripheral diseases, as these receptors are present in peripheral organs, including the lungs, heart, GI system, GU system, and accessory organs (blood vessels, liver, pancreas, ovaries, testes, kidneys, and immune cells).

[0066] In summary, NMDAR antagonists also target receptors outside the CNS, thereby exerting potential therapeutic effects, including anti-inflammatory effects in macrophages (see Example 1) and improvements in inflammatory lung diseases (see citations below), and these effects can be preferably achieved by using the new molecular targets of the present application. In addition, by avoiding or limiting entry into the CNS, the dose of these new molecules can be increased to increase peripheral efficacy without causing dissociation effects mediated by binding to CNS receptors.

[0067] To best benefit from extra-CNS effects and / or avoid CNS effects, NMDAR antagonists can be modified by covalent attachment of polymers, such as polyethylene glycol (PEG, PEGylated) and other polymers, thereby modulating or impeding BBB crossing depending on the size and characteristics of the polymer chain.

[0068] The present application aims to obtain new molecules with different degrees of affinity for NMDAR to preferentially target peripheral (ie, outside the CNS) receptors to preferentially treat diseases, disorders and conditions associated with unbalanced activity of peripheral glutamate receptors.

[0069] In addition, the activity of these novel drugs to NMDAR in CNS may not be completely eliminated by the polymer conjugation of drugs, but may be simply regulated, so the polymer conjugation of these drugs may lead to more favorable pharmacodynamics or pharmacokinetic characteristics of central and peripheral receptors. For example, the platform based on pegylation can also be developed to optimize and enhance the brain delivery (Lu W, Zhang Y, Tan YZ, Hu KL, Jiang XG, FuSK. Cationic albumin-conjugated pegylated nanoparticles as novel drug carrier for brain delivery. J Control Release. 2005; 107: 428-48.) of molecules characterized by poor BBB penetration. Therefore, these molecules can produce the therapeutic effect of diseases outside CNS and CNS, which represents the improvement of the efficacy / safety ratio of the parent molecule.

[0070] To this end, various aspects of the invention relate to NMDAR antagonist polymer conjugates having the general formula D-(X-poly-T)n, wherein D is a CNS-active NMDAR antagonist and n is an integer from 1-6.

[0071] X is a stable (enzymatic and / or hydrolyzed under physiological conditions) joint, which includes a covalent bond or an atomic chain, which covalently connects a small molecule NMDA antagonist drug moiety to a 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 there is no such group, the group can be chemically introduced, and the side group of the group reacts chemically with the joint to form a covalent bond. The example of a joint includes, but is not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbon hydrazone, carbamate, peptide, nucleotide, CC bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, thioether.

[0072] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin. Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethyl 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 of 80 to 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), which has a linear or branched structure, monofunctional, difunctional or heterobifunctional, and an average molecular weight of 120 to 40,000 Da. Some Poly suitable for use in 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, wherein "m" represents a methoxy group.

[0073] T, if present, is a terminal group of D or Poly, and when T is a terminal group, it is represented by any suitable chemical group that, according to preference, does not react with other chemical moieties or reacts with other chemical moieties. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxyl, 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), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy, formyl. We have begun to synthesize PEG derivatives of dextromethadone by attaching a short PEG chain (oligo(ethylene glycol)) to one of the phenyl functional groups of dextromethadone. We chose the benzene ring for PEG conjugation because our previous studies with dexmethadone analogs showed that modifications at the benzene ring level minimally hindered NMDAR activity.

[0074] In a specific embodiment, the present invention includes compounds according to formula I in free base form and / or in the form of pharmaceutically acceptable salts thereof, which include structural analogs of (R)-methadone ((-)-methadone, levomethadone):

[0075]

[0076] wherein ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0077] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently attaches (-)-methadone to the Poly derivative [examples of linkers include, but are not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbamate, peptide, nucleotide, C-C bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, thioether];

[0078] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin [Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethylmethacrylamide 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 of 80 to 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), which has a linear or branched structure, is monofunctional, bifunctional or heterobifunctional, and has an average molecular weight of 120 to 40,000 Da. In certain embodiments, Poly can 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, mPEG-O-559Da, wherein "m" represents a methoxy group; and

[0079] T, if present, is a terminal group of (-)-methadone or Poly, [when T is a terminal group, it is represented by any suitable chemical group, which chemical group, according to preference, does not react with other chemical moieties or reacts with other chemical moieties; examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxyl, 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, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy and formyl].

[0080] In another specific embodiment, the present invention includes compounds according to formula II in free base form and / or pharmaceutically acceptable salt form, which include structural analogs of (S)-methadone ((+)-methadone, dextromethadone, dextromethadone):

[0081]

[0082] wherein ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0083] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-methadone to the Poly derivative [examples of linkers include, but are not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbamate, peptide, nucleotide, C-C bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, thioether];

[0084] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin [Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethylmethacrylamide 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 of 80 to 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), which has a linear or branched structure, is monofunctional, bifunctional or heterobifunctional, and has an average molecular weight of 120 to 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, wherein "m" represents a methoxy group; and

[0085] T, if present, is a terminal group of (+)-methadone or Poly. When T is a terminal group, it is represented by any suitable chemical group, which, according to preference, does not react with other chemical moieties or reacts with other chemical moieties [Examples of terminal groups include but are not limited to the following: hydroxyl, amino, sulfide, carboxyl, cyano, optionally substituted aryloxy, lower alkoxy

[0086] [e.g., methoxy, ethoxy, propoxy or butoxy), aryl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen atom (e.g., fluorine, chlorine, bromine, iodine), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy and formyl].

[0087] In another specific embodiment, the present invention includes a compound according to formula III in free base form and / or a pharmaceutically acceptable salt form thereof having a structural analog of (S,R)-methadone ((±)-methadone, racemic methadone, methadone):

[0088]

[0089] wherein ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0090] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently attaches (±)-methadone to the Poly derivative (examples of linkers include, but are not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbamate, peptide, nucleotide, C-C bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, and thioether);

[0091] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin. Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethyl 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 of 80 to 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), which has a linear or branched structure, monofunctional, difunctional or heterobifunctional, and an average molecular weight of 120 to 40,000 Da. Some Poly suitable for the present invention may 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, wherein "m" represents a methoxy group; and

[0092] T, if present, is a terminal group of (±)-methadone or Poly-, and when T is a terminal group, it is represented by any suitable chemical group, which chemical group, according to preference, does not react with other chemical moieties or reacts with other chemical moieties. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxyl, 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), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy and formyl.

[0093] In another specific embodiment, the present invention includes a compound according to formula IV in free base form and / or a pharmaceutically acceptable salt form thereof, which has a structural analog of (-)-dizocilpine ((-)-MK-801):

[0094]

[0095] wherein m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0096] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (-)-dizocycline to the Poly derivative. Examples of linkers include, but are not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbamate, peptide, nucleotide, C-C bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, and thioether;

[0097] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin. Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethyl 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 of 80 to 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), which has a linear or branched structure, monofunctional, difunctional or heterobifunctional, and an average molecular weight of 120 to 40,000 Da. Some Poly suitable for the present invention may 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, wherein "m" represents a methoxy group; and

[0098] T, if present, is a terminal group of (-)-dizocilpine or Poly-, and when T is a terminal group, it is represented by any suitable chemical group, which chemical group, according to preference, does not react with other chemical moieties or reacts with other chemical moieties. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxyl, 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), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy and formyl.

[0099] In another specific embodiment, the present invention includes a compound according to formula V in free base form and / or a pharmaceutically acceptable salt form thereof, which has a structural analog of (+)-dizocilpine ((+)-MK-801):

[0100]

[0101] wherein m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0102] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links (+)-dizocycline to the Poly derivative. Examples of linkers include, but are not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbamate, peptide, nucleotide, C—C bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, and thioether;

[0103] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin. Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethyl 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 of 80 to 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), which has a linear or branched structure, monofunctional, difunctional or heterobifunctional, and an average molecular weight of 120 to 40,000 Da. Some Poly suitable for the present invention may 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, wherein "m" represents a methoxy group; and

[0104] T, if present, is a terminal group of (+)-dizocilpine or Poly-, and when T is a terminal group, it is represented by any suitable chemical group, which chemical group, according to preference, does not react with other chemical moieties or reacts with other chemical moieties. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxyl, 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), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy and formyl.

[0105] In another specific embodiment, the present invention includes a compound according to formula VI in free base form and / or a pharmaceutically acceptable salt form thereof, which has a structural analog of (±)-dizocilpine ((±)-MK-801):

[0106]

[0107] wherein m1, m2, m3, m4, m5 and m6 are independently 0 or 1, and m1+m2+m3+m4+m5+m6 is between 1 and 6, such that there is at least one X-Poly-T;

[0108] X is a stable (enzymatically and / or hydrolytically stable under physiological conditions) linker comprising a covalent bond or chain of atoms that covalently links the (±)-dizocycline to the Poly derivative. Examples of linkers include, but are not limited to, the following: carboxylate, phosphate, anhydride, acetal, ketal, acyloxyalkyl ether, imine, hydrazone, carbamate, peptide, nucleotide, C—C bond (e.g., in an aliphatic chain), ether, amide, oxime, enamine, semicarbazone, semicarbazide, and thioether;

[0109] Poly is a covalently bonded chain of repeating monomer units that forms a polymer backbone of synthetic or natural origin. Examples of polymer backbones include, but are not limited to, the following: poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethyl 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 of 80 to 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), which has a linear or branched structure, a single-, bi-functional or hetero-bi-functional, and an average molecular weight of 120 to 40,000 Da. Some Poly suitable for the present invention may 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, wherein "m" represents a methoxy group; and

[0110] T, if present, is a terminal group of (±)-dizocilpine or Poly-, and when T is a terminal group, it is represented by any suitable chemical group, which chemical group, preferably, does not react with other chemical moieties or reacts with other chemical moieties. Examples of terminal groups include, but are not limited to, the following: hydroxyl, amino, sulfide, carboxyl, 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), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy and formyl.

[0111] In some cases, depending on the size / characteristics of the coupled polymer chains, these molecules can reduce / eliminate intestinal absorption and these molecules will preferentially target intestinal receptors for the treatment of digestive tract diseases, including inflammatory diseases of the digestive tract, such as inflammatory bowel disease, including ulcerative colitis and Crohn's disease, and for the treatment of irritable bowel syndrome.

[0112] Based on the desired therapeutic effect, it may be necessary to maintain a certain degree of CNS NMDAR antagonism, or a selective increase in peripheral modulators of NMDARs could be produced, even in the absence of CNS activity. BBB penetration could be altered, and intestinal penetration could be modified to achieve the desired therapeutic use of these novel molecules.

[0113] Diseases and conditions in which inflammation simultaneously triggers or maintains pathological processes are relevant. With regard to respiratory system, COVID-19 and other infections, long COVID-19, inflammatory bowel disease, ARDS and inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis are some examples of these diseases. In Du and colleagues' article (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), other examples of diseases, disorders, conditions and symptoms that can be treated with the molecules disclosed in this application are described. As discussed above, changes in NMDAR signals have been described in inflammatory diseases of the respiratory system. The expression of NMDAR 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 arterial hypertension (Saide 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. I. 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).Therefore, studies have shown that high-affinity NMDAR antagonists, such as MK-801, can reduce oxidative stress in acute lung injury induced by intratracheal lipopolysaccharide (LPS) injection (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). Notably, the non-competitive NMDAR antagonist memantine alleviates acute lung injury (ALI) by acting on macrophages present in the respiratory tract (Ding et al., Memantinealleviates acute lung injury via inhibiting macrophage pyroptosis, Shock 56:1040-1048, 2021), and alleviates septic lung injury (Hu et al., Memantine nitrate MN-08suppresses NLRP3 inflammasome activation to protect against sepsis-induced acute lung injury in mice. Biomed and Pharmacother 156:113804, 2022).

[0114] Furthermore, it has been shown that inhibition of NMDARs by memantine is 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 more than 15 million adults in the United States, and the disease is a leading cause of disability. According to the Centers for Disease Control and Prevention (CDC), COPD, which is closely related to smoking, is the fourth leading cause of death in the United States. Current treatments for COPD are relatively ineffective because existing drugs do not significantly slow disease progression or have a substantial effect on inflammation. Therefore, inhibiting the inflammatory response by acting on macrophages that reside in the airways is considered a fundamental strategy for COPD treatment. Together, these observations suggest that NMDARs could serve as potential pharmacological agents for therapeutic intervention in different diseases that affect the respiratory tract.

[0115] Based on these observations, our results (Example 1) show that NMDAR antagonists, such as dextromethadone and MK-801, reduce macrophage-induced inflammation in lung cells. In mice, MK-801 conjugated with PEG molecules of different lengths did not cause behavioral changes observed for unconjugated MK-801 (Example 2), which indicates regulation of PEG-related and / or other potential mechanisms of BBB-crossing. Based on our experiments and previously described experimental findings, NMDAR antagonists may have a strong therapeutic potential for treating diseases, disorders, conditions and symptoms caused by dysregulated peripheral NMDARs (including NMDARs that may be dysregulated in inflammatory lung diseases). The inventors confirmed that in vitro, dextromethadone and MK-801 can reduce the mRNA expression of inflammatory cytokines in lung cells co-cultured with macrophages. Based on these studies, the inventors draw the following conclusions: targeting inflammatory peripheral diseases (including lung diseases) with NMDAR antagonists with preferential peripheral effects may be a promising strategy. Based on the same principle, these same polymer conjugates have potential therapeutic effects on all diseases, disorders, conditions and symptoms caused by dysregulation of NMDARs on cells outside the CNS, including cellular parts of the respiratory, digestive, cardiovascular, immune, renal and reproductive systems.

[0116] Example

[0117] Example 1: NMDAR antagonists reduce inflammation in vitro

[0118] In vitro studies

[0119] The present inventors used the A-549 lung cell line to establish an in vitro experimental model of inflammatory lung disease by co-culturing these cells with macrophages obtained by differentiating monocytes THP-1 for 24 hours ( Figure 1A ). Figure 1B showed that dextromethadone and MK-80 could reduce the mRNA expression of two inflammatory cytokines, CCL-2 and IL-1, only when A-549 cells were incubated with macrophages, demonstrating the key role of immune cells in the mechanism of action of NMDAR antagonists. Therefore, the anti-inflammatory effects of the NMDAR antagonists MK-801 and dextromethadone (1 μM) are due to their direct interaction with macrophage-like cells [e.g. Figure 1A and Figure 1B The data shown in Figure 1A In the study, mRNA expression of inflammatory cytokines CCL2, IL-Ib, and IL-6 in lung A549 cells was activated by conditioned medium obtained from macrophages (CM); Figure 1B Inflammatory cytokines CCL2, IL-1b, and IL-6 are expressed in the presence of activators mRNA expression in lung A549 cells co-cultured with macrophages derived from THP-1 cells.

[0120] In vivo studies

[0121] The inventors used 7 C57BL6 / J male (3-4 months old) mice per treatment group, which were kept in a temperature-controlled room (22°C) with a 12:12 hour light-dark cycle (lights on at 7:00 am) and fed with a standard pellet diet and tap water ad libitum. The experimental mice were accustomed to the testing room by transferring them to the behavioral room 30 minutes before the start of the test. The open field test was performed between 9:00 am and 4:00 pm. MK-801 and derivatives were dissolved in a vehicle consisting of a 0.9% NaCl physiological solution. Ten minutes after intraperitoneal injection (injection volume 0.1 mL) of vehicle 0.3 mg / kg MK-801 or an equivalent dose of 0.3 mg / kg MK-801 of PEG 4MK-801, PEG 6MK-801, PEG 8MK-801, or PEG 10MK-801 derivatives, each mouse was individually placed in a corner of an open field arena (40×40×30 cm) painted grey. Using an automated behavioural tracking system (VideoTrack, View Point LifeScience), we determined total motor activity measured as the distance the animal moved during the 10-min test period.

[0122] The inventors demonstrated that intraperitoneal injection of 0.3 mg / kg of MK-801 significantly increased the distance traveled by mice not only compared to the vehicle, but also compared to the MK-801 PEG derivative (p<0.0001; one-way ANOVA: F(5,36)=16,40; P<0.0001). Interestingly, all tested PEG derivatives of MK-801 did not change the distance traveled by mice compared to the vehicle, indicating that the PEG derivatives did not cross the BBB.

[0123] The inventors disclose conjugates of NMDAR antagonists, which have regulatory effects and / or other effects that preferentially act on receptors outside the CNS. The inventors of the present application also disclose the polymers used, which can regulate / reduce / eliminate the ability of the parent drug to cross the BBB and / or the intestinal barrier. The inventors of the present application are developing molecules that can be administered, preferably but not limited to, to reach their site of action via oral or pulmonary administration. Oral administration is one of the preferred routes of administration and is also the most common route of administration for small molecule drugs. The length and characteristics of the polymer chain can be adjusted to maintain the intestinal absorption required for the target disease disorder or condition. The desired therapeutic activity may be limited to the gastrointestinal tract, so passing through the digestive tract (GI) is limited or completely blocked.

[0124] Example 3: (5S,10R)-5-methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro- 5H-5,10-Epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-TetraEGMExHCl)

[0125] This Example 3 describes a method for preparing (5S,10R)-5-methyl-12-(2,5,8,11-tetraoxatridecan-13-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-TetraEGMEx HCl), such as Figure 3 shown.

[0126] To a stirred solution of (+)-MK-801 (0.100 g, 0.45 mmol, 1 eq) in anhydrous DMF (1.356 mL) was added CsCO (0.162 g, 0.50 mmol, 1.1 eq) and KI (8 mg, 0.05 mmol, 0.1 eq) followed by a solution of methyl 2,5,8,11-tetraoxatridecan-13-yl 4-benzenesulfonate (TetraEGME, 0.246 g, 0.68 mmol, 1.5 eq) 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 eq). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting at 5% ACN and reaching 50% from 5% ACN in 17 minutes, retention time 16.09 minutes). After freeze drying, the obtained TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After freeze drying, (+) -MK-801-TetraEGME XHCl was obtained as a colorless oil (0.1850 g, 0.353 mmol, 78%). UPLC purity: > 99%.

[0127] HRMS(ESI)m / z:[M+H] + Theoretical value [C 25 H 34 NO4] + 412.2482; measured value: 412.2543.

[0128] Specific rotation [α] D 25 :+88.7°(0.02g / mL,CHCl3).

[0129] 1 H NMR (400MHz, CDCl3) δ13.42(s,1H),7.42(d,J=6.9Hz,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=10.3Hz ,1H),3.84(s,2H),3.80-3.60(m,11H),3.59-3.51(m,2H),3.39-3.33(m,3 H),3.31(s,1H),3.06(d,J=12.4Hz,1H),2.94-2.84(m,1H),2.36(s,3H)–see Figure 4 .

[0130] 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 .

[0131] Example 4: (5S, 10R)-5-methyl-12-(2,5,8,11,14,17-hexaoxa nonadecan-19-yl)-10,11- Dihydro-5H-5,10-epi-iminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-HexaEGMExHCl)

[0132] This Example 4 describes a method for preparing (5S,10R)-5-methyl-12-(2,5,8,11,14,17-hexaoxanodec-19-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-HexaEGME x HCl), such as Figure 3 shown.

[0133] To a stirred solution of (+)-MK-801 (0.100 g, 0.45 mmol, 1 eq.) in anhydrous DMF (1.356 mL) was added CsCO (0.162 g, 0.50 mmol, 1.1 eq.) and KI (8 mg, 0.05 mmol, 0.1 eq.) followed by a solution of 2,5,8,11,14,17-hexaoxa nonadecan-19-yl 4-benzenesulfonic acid methyl ester (HexaEGME, 0.305 g, 0.68 mmol, 1.5 eq.) in anhydrous DMF (0.452 mL). The mixture was heated to 70 ° C and stirred under nitrogen for 24 hours. The DMF was then diluted with water (1.356 mL) and the residual carbonate was quenched with acetic acid (0.028 mL, 1.1 eq.). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting at 5% ACN and reaching 50% from 5% ACN in 17 minutes, retention time 16.65 minutes). After freeze drying, the obtained TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After freeze drying, (+) -MK-801-HexaEGME X HCl (0.239 g, 0.39 mmol, 87% yield) was obtained as a colorless oil. UPLC purity: > 95%.

[0134] HRMS (ESI) m / z: [M+H] + Theoretical value [C 29 H 42 NO6] + :500.3007; measured value:500.3035.

[0135] Specific rotation [α] D 25 :+81.93°(0.02g / mL, CHCl3).

[0136] 1 H NMR (400MHz, CDCl3) δ13.43 (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=10.5Hz,1H),3.8 5(d,J=11.6Hz,2H),3.77-3.58(m,18H),3.56-3.49(m,2H),3.37(s,3H),3.3 3(d,J=15.6Hz,1H),3.07(t,J=11.1Hz,1H),2.93-2.83(m,1H),2.36(s,3H)–see Figure 6 .

[0137] 13 C NMR (101 MHz, CDC13) 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 .

[0138] Example 5: (5S, 10R)-5-methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosane-25- (+)-MK-801-OctaEGMEx HCl)

[0139] This Example 5 describes a method for preparing (5S,10R)-5-methyl-12-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-OctaEGME xHCl), such as Figure 3 shown.

[0140] To a stirred solution of (+)-MK-801 (0.100 g, 0.45 mmol, 1 eq.) in anhydrous DMF (1.35 mL) was added CsCO (0.162 g, 0.50 mmol, 1.1 eq.) and KI (8 mg, 0.05 mmol, 0.1 eq.), followed by a solution of 2,5,8,11,14,17,20,23-octaoxapentacosane-25-yl 4-benzenesulfonic acid methyl ester (OctaEGME, 0.365 g, 0.68 mmol, 1.5 eq.) 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 eq.). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting at 5% ACN and reaching 56% from 5% ACN in 19 minutes, retention time 17.55 minutes). After freeze drying, the obtained TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After freeze drying, (+) -MK-801-OctaEGME XHCl was obtained as a colorless oil (0.2571 g, 0.37 mmol, 82% yield). UPLC purity: > 99%.

[0141] HRMS(ESI)m / z:[M+H] + Theoretical value [C 33 H50NO8]+:588.3531; measured value:588.3586.

[0142] Specific rotation [α] D 25 :+61.96°(0.019g / mL,CHCl3).

[0143] 1 H NMR (400MHz, CDCl3) δ13.19 (s, 1H), 7.47-6.93 (m, 8H), 5.39 (s, 1H), 4.68 (t, J = 10.4Hz, 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=13.2Hz,1H),3.10-2.98(m,1H),2.91-2.84(m,1H),2.32(s,3H)–see Figure 8 .

[0144] 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 Fig. 9 .

[0145] Example 6: (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-decaoxahetriacontane-31- 5-Methyl-10,11-dihydro-5H-5,10-epi-iminodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801- DecaEGMExHCl)

[0146] This Example 6 describes a method for preparing (5S,10R)-12-(2,5,8,11,14,17,20,23,26,29-decaoxatriacontan-31-yl)-5-methyl-10,11-dihydro-5H-5,10-epiimidodibenzo[a,d][7]annulene hydrochloride ((+)-MK-801-DecaEGME x HCl), such as Figure 3 shown.

[0147] To a stirred solution of (+)-MK-801 (0.016 g, 0.07 mmol, 1 eq) in anhydrous DMF (0.217 mL) was added CsCO (0.026 g, 0.08 mmol, 1.1 eq) and KI (1 mg, 0.01 mmol, 0.1 eq) followed by a solution of 2,5,8,11,14,17,20,23,26,29-decaoxatriacontan-31-yl 4-benzenesulfonic acid methyl ester (DecaEGME, 0.068 g, 0.11 mmol, 1.5 eq) 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 eq). The mixture was purified by preparative RP-HPLC C-18 (eluent water + 0.1% TFA / ACN, starting at 5% ACN and reaching 57% from 5% ACN in 20 minutes, retention time 19.42 minutes). After freeze drying, the obtained TFA salt was redissolved in 30% ACN in water and the trifluoroacetate counterion was exchanged using Amberlite IRA400. After freeze drying, (+) -MK-801-DecaEGME X HCl was obtained as a colorless oil (0.039 g, 0.050 mmol, 72% yield). UPLC purity: > 99%.

[0148] HRMS(ESI)m / z:[M+H] + Theoretical value [C 37 H 58 NO 10 ] + :676.4055; measured value:676.4047.

[0149] Specific rotation [α] D 25 :+63.27°(0.009g / mL,CHCl3).

[0150] 1 H NMR (400MHz, CDCl3) δ7.44-6.99(m,8H),5.38(s,1H),4.72-4.63(m,1H),3.84(d,J=14.2Hz,2H),3.78-3.57(m ,34H),3.57-3.50(m,2H),3.36(s,3H),3.31(d,J=15.3Hz,1H),3.05(s,1H),2.95-2.81(m,1H),2.32(s,3H)-See Fig.10 .

[0151] 13 C 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 Fig.11 .

[0152] Although the present invention has been disclosed with reference to details of various embodiments of the invention, it should be understood that the disclosure is illustrative and not restrictive since modifications may be made by those skilled in the art within the spirit of the invention and the scope of the amended claims.

Claims

1. A compound according to formula I, which has a structural analog of (R)-methadone ((-)-methadone, levomethadone), in the form of a free base, and in the form of a pharmaceutically acceptable salt thereof: in ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6; X is a stable linker comprising a covalent bond or a chain of atoms that covalently links (-)-methadone to Poly; Poly is a covalently bonded chain of repeating monomer units that forms the polymer backbone; T is optional and is (-)-methadone or a terminal group of Poly.

2. A compound according to formula II, which has a structural analog of (S)-methadone ((+)-methadone, dextromethadone, right-methadone) in the form of a free base, and / or in the form of a pharmaceutically acceptable salt thereof: in ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6; X is a stable linker comprising a covalent bond or a chain of atoms that covalently links (-)-methadone to Poly; Poly is a covalently bonded chain of repeating monomer units that forms the polymer backbone; and T is optional and is (-)-methadone or a terminal group of Poly.

3. A compound according to formula III having a structural analog of (S,R)-methadone ((±)-methadone, racemic methadone, methadone) in the form of a free base, and / or in the form of a pharmaceutically acceptable salt thereof: in ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6; X is a stable linker comprising a covalent bond or a chain of atoms that covalently links (-)-methadone to Poly; Poly is a covalently bonded chain of repeating monomer units that forms the polymer backbone; and T is optional and is (-)-methadone or a terminal group of Poly.

4. A compound according to formula IV, which has a structural analog of (-)-dizocilpine ((-)-MK-801), in the form of a free base, and in the form of a pharmaceutically acceptable salt thereof: in ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6; X is a stable linker comprising a covalent bond or a chain of atoms that covalently links (-)-methadone to Poly; Poly is a covalently bonded chain of repeating monomer units that forms the polymer backbone; and T is optional and is (-)-methadone or a terminal group of Poly.

5. A compound according to formula V, which has a structural analogue of (+)-dizocilpine ((+)-MK-801), in the form of a free base, and in the form of a pharmaceutically acceptable salt thereof: in ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6; X is a stable linker comprising a covalent bond or a chain of atoms that covalently links (-)-methadone to Poly; Poly is a covalently bonded chain of repeating monomer units that forms the polymer backbone; and T is optional and is (-)-methadone or a terminal group of Poly.

6. A compound according to formula VI, which has a structural analog of (±)-dizocilpine ((±)-MK-801), in the form of a free base, and in the form of a pharmaceutically acceptable salt thereof: in ml, m2, m3, m4, m5 and m6 are independently 0 or 1, and ml+m2+m3+m4+m5+m6 is between 1 and 6; X is a stable linker comprising a covalent bond or a chain of atoms that covalently links (-)-methadone to Poly; Poly is a covalently bonded chain of repeating monomer units that forms the polymer backbone; and T is optional and is (-)-methadone or a terminal group of Poly.

7. A compound according to any one of the preceding claims, wherein X is selected from carboxylates, phosphates, anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, hydrazones, carbamates, peptides, nucleotides, C-C bonds (e.g., in aliphatic chains), ethers, amides, oximes, enamines, semicarbazones, semicarbazides and thioethers.

8. A compound according to any of the above claims, wherein the polymer backbone formed by Poly is selected from poly(ethylene glycol) (PEG), poly(N-vinyl pyrrolidone), N-hydroxy-ethylmethacrylamide 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 the preceding claims, wherein Poly is a derivative of poly(ethylene glycol) (PEG), said derivative having a linear or branched structure, monofunctional, bifunctional or heterobifunctional, and an average molecular weight of 120 to 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, and mPEG-O-559Da.

11. The compound according to any one of the preceding claims, wherein the average molecular weight of Poly is 80 to 40000 Da.

12. A compound according to any one of the preceding claims, wherein Poly has an average molecular weight of at least 100 Da.

13. A compound according to any one of the preceding claims, wherein Poly has an average molecular weight of at least 200 Da.

14. A compound according to any one of the preceding claims, wherein Poly has a molecular weight greater than 500 Da and less than 2000 Da.

15. A compound according to any one of the preceding claims, wherein T is a terminal group and is selected from hydroxy, amino, sulfide, carboxyl, 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), toluenesulfonate, mesylate, isocyanate, hydrazine, azide, maleimide, o-disulfide, N-succinimidyloxy, sulfo-N-succinimidyloxy, 1-benzotriazole, 1-imidazolyloxy, p-nitrophenoxy and formyl.

16. A compound according to the preceding claim, which has a modulated ability to cross the blood-brain barrier.

17. A compound according to the preceding claim for use in the treatment of diseases affecting peripheral cells, which are cells located outside the blood-brain barrier.

18. Use of the compound according to any one of the preceding claims for treating diseases caused by dysfunction of immune system cells, digestive system cells, respiratory system cells, cardiovascular system cells, renal system cells, reproductive system cells.

19. Use of the compound according to any one of the preceding claims for preventing diseases caused by dysfunction of immune system cells, digestive system cells, respiratory system cells, cardiovascular system cells, renal system cells, reproductive system cells.

20. A compound according to any one of the preceding claims for use in the treatment or prevention of respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, infections.

21. A compound according to any one of the preceding claims for use in the treatment or prevention of cardiovascular diseases, including congestive heart failure, ischemic heart disease and cardiac arrhythmias.

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

23. Compounds according to any of the preceding claims for use in the treatment or prevention of diseases of the renal system, including chronic and acute renal failure, nephrotoxicity caused by various substances.

24. A compound according to any one of the preceding claims for use in the treatment or prevention of reproductive system disorders, including infertility.

25. A pharmaceutical or diagnostic composition comprising a compound as defined in any one of the preceding claims, optionally together with one or more pharmaceutically acceptable excipients.

26. A composition according to the preceding claim for oral, sublingual, transmucosal, intranasal, transdermal, parenteral, rectal, topical, vaginal, ophthalmic or inhalation use.

27. A composition according to the preceding claim, which is administered in a dose of 0.001 mg to 1 g.

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