Compositions of expandable thyroid integrin antagonists with improved blood brain barrier permeability and better retention in brain tumors

Abstract

The present application provides compounds / compositions, synthetic methods, methods of use. The compounds / compositions are directed to thyroid integrin antagonists conjugated to polymers. The compounds / compositions further include additional substituents that are also conjugated to the polymers. The compounds / compositions exhibit increased absorption across the blood brain barrier and increased retention therein and within tumors. The compounds / compositions can also include improved synthetic scalability, improved purity, improved water solubility, and solid products or intermediates. The compounds / compositions can exhibit improved anti-angiogenic effects, and improved efficacy against diseases, particularly cancers that require blood brain barrier permeability, such as malignant gliomas (GBM).

Description

Technical Field

[0001] This invention generally relates to improved thyroid hormone receptor antagonist compounds (referred to as "thyroid integrin antagonists"), compositions comprising such compounds, methods of using the compounds and compositions for treating diseases, and synthetic methods. More particularly, this invention relates to α-V-β-3 (αvβ3) integrin-thyroid hormone receptor antagonists bound to a polymer, wherein the polymer is also bound to another substituent or functional group. The disclosed compounds and compositions using such compounds exhibit improved blood-brain barrier permeability and retention, improved synthetic scalability, water solubility, and / or solid products or intermediates. The compounds are also readily scalable for purification, for example by normal-phase chromatography. Due to increased permeability across the blood-brain barrier and increased retention in brain tumors, the disclosed compositions and compounds are particularly effective for treating certain diseases, such as malignant gliomas, gliomas, astrocytomas, central nervous system lymphomas, medulloblastomas, meningiomas, metastatic brain tumors, pituitary adenomas, primitive neuroectodermal tumors (PNETs), and other brain-related diseases. Background Technology

[0002] Integrins are a superfamily of cell surface adhesion receptors that control cell attachment to their fixed extracellular environment, including the extracellular matrix (ECM) and other cells. Adhesion is crucial for cells, providing signals for localization, migration pathways, growth, and differentiation. Integrins are directly involved in many normal bodily and pathological conditions, making them prime targets for therapeutic interventions. Integrins are whole transmembrane proteins, heterodimers whose specific binding depends on which of the 14 α-chains binds to which of the 8 β-chains. Integrins are divided into four overlapping subfamilies: β1, β2, β3, or αv chains. Cells can express several different integrins from each subfamilie. Over the past few decades, integrins have been shown to be major receptors involved in cell adhesion, thus potentially suitable targets for therapeutic interventions. Integrin αvβ3 regulates cell growth and survival because, in certain situations, the binding of these receptors may induce apoptosis in tumor cells. Anti-αvβ3 antibodies, RGD peptides, and other integrin antagonists have been shown to slow tumor growth by disrupting cell adhesion. For example, cilengitide failed in a phase III clinical trial for malignant gliomas due to its limited blood-brain barrier permeability and limited retention within brain tumors.

[0003] The applicant has previously disclosed compounds and compositions comprising a non-cleavable polymer that binds to an αvβ3 integrin thyroid antagonist, and related methods thereof, for example in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616, and U.S. Patent Application No. 16 / 223,176, the contents of which are incorporated herein by reference.

[0004] In addition, the applicant has previously disclosed compounds, compositions, and methods that include αvβ3 integrin thyroid antagonists, norepinephrine transporter targets, or catecholamine transporter targets (e.g., benzylguanidine or its derivatives), as well as related methods, for example in U.S. Patent Application No. 15 / 950,870, now U.S. Patent No. 10,328,043, and U.S. Application No. 16 / 398,342, the contents of which are incorporated herein by reference.

[0005] While the compounds, compositions, and methods described in these prior applications and granted patents represented improvements over the prior art at the time, these compounds and compositions may have one or more drawbacks, including low blood-brain barrier permeability, poor synthetic scalability, lack of water solubility, and lack of solid product or intermediate formation. Purification difficulties may also have arisen. The disclosed compounds and compositions comprising these compounds represent improvements in these areas and have demonstrated unexpected efficacy in treating malignant gliomas, other brain tumors, and similar diseases.

[0006] Blood-brain barrier permeability is important for targeting certain diseases, such as gliomas, meningiomas, pituitary adenomas, vestibular schwannomas, and medulloblastomas. Malignant gliomas (glioblastoma multiforme or GBM) are a specific example of diseases requiring effective treatment with adequate blood-brain barrier permeability. In conventional techniques, drug delivery methods that improve blood-brain barrier permeability are advantageous. See, for example, Bhowmik A, Khan R, Ghosh MK., “Blood-Brain Barrier: The Challenge to Effective Treatment of Brain Tumors,” BioMed Research International, Vol. 2015; and Upadhyay RK., “Drug Delivery Systems,” *CNS Proteins*, and *Blood-Brain Barrier*, BioMed Research International, Vol. 2014. The improved compounds, compositions, and methods described herein exhibit improved blood-brain barrier permeability and provide significantly improved efficacy for these types of diseases. Furthermore, the improved compounds, compositions, and methods described herein exhibit improved retention within the brain, particularly at tumor sites within the brain. This improved retention provides further enhanced efficacy in treating these types of diseases. The improved compounds, compositions, and methods described herein also have improved scalability and solubility, and can produce solid products or intermediates.

[0007] Compounds or compositions comprising αvβ3 integrin-thyroid hormone receptor antagonists (thyroid integrin antagonists) and having the aforementioned improved blood-brain barrier permeability and retention, such as those described herein, will be highly favored in the art, as will therapeutic methods using these compounds and / or compositions. Furthermore, compounds or compositions having this improved blood-brain barrier permeability, and with improved synthetic scalability, water solubility, and / or formation of solid products or intermediates, will also be highly favored in the art. Summary of the Invention

[0008] According to one aspect, the compound includes a thyroid integrin antagonist, a non-biodegradable polymer, a linking group, and a substituent A, wherein the linking group is covalently linked to the thyroid integrin antagonist and the non-biodegradable polymer via an indestructible covalent bond, and the substituent A is bound to the non-biodegradable polymer.

[0009] According to another perspective, compounds include those of the general formula:

[0010]

[0011] Where n1≥0; where n2 is between 5 and 200; where R 1 -R4 R 9 Independently selected from H, Me, Et, iPr (isopropyl), nPr (n-propyl), nBu (n-butyl), iBu (isobutyl), secBu (sec-butyl), tBu (tert-butyl), C5-C 12 n-alkyl (C5-C) 12 The group consisting of n-alkyl, cyclopentyl, cyclohexyl, phenyl, F, Cl, Br, I, CN, CF3, OCF3, CHF3, OCHF2, SO2Me, NO2, -O-alkyl, -O-aryl, -CH2-O-alkyl, -CH2-O-aryl, esters, or amides; wherein R 10 -R 13 Each is independently selected from the group consisting of hydrogen, iodine, and alkane groups; and Y is selected from:

[0012]

[0013] According to another aspect, the compound includes a thyroid integrin antagonist bound to the polymer and a substituted benzyl group bound to the polymer, wherein the compound is absorbed across the blood-brain barrier.

[0014] According to another approach, one treatment method involves providing a compound, and administering a pharmaceutically effective amount of the compound to the desired patient, the compound having a thyroid integrin antagonist linked by a polymer and a substituted benzyl group. Attached Figure Description

[0015] This patent or application document contains at least one color drawing. Upon request and payment of the necessary fees, the Patent Office will provide a copy of this patent or the publication of this invention with color drawings.

[0016] Some embodiments will be described in detail with reference to the following figures, wherein the same reference numerals denote the same components, wherein:

[0017] Figure 1 The general formula of exemplary compounds according to embodiments of the present invention is described;

[0018] Figure 2 Further detailed general formulas of exemplary compounds according to embodiments of the present invention are described;

[0019] Figure 3 Further detailed general formulas of exemplary compounds according to embodiments of the present invention are described;

[0020] Figure 4 Exemplary compound 2 is described;

[0021] Figure 5 The exemplary compound 3 is described;

[0022] Figure 6 Exemplary compound 4 is described;

[0023] Figure 7 Exemplary compound 1 is described;

[0024] Figure 8 Exemplary compound 5 is described;

[0025] Figure 9A The invention described in the embodiments of the present invention is from Figure 1 Examples of substituent A;

[0026] Figure 9B The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0027] Figure 9C The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0028] Figure 10A The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0029] Figure 10B The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0030] Figure 10C The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0031] Figure 11 The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0032] Figure 12A The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0033] Figure 12B The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0034] Figure 13A The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0035] Figure 13B The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0036] Figure 13C The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0037] Figure 13D The invention described in the embodiments of the present invention is from Figure 1 Another embodiment of substituent A;

[0038] Figure 14 An exemplary synthetic route for compound 1 according to embodiments of the present invention is described;

[0039] Figure 15 An exemplary synthetic route for compound 2 according to embodiments of the present invention is described;

[0040] Figure 16 An exemplary synthetic route for compound 3 according to embodiments of the present invention is described;

[0041] Figure 17 An exemplary synthetic route for compound 4 according to embodiments of the present invention is described;

[0042] Figure 18 An exemplary synthetic route for compound 5 according to embodiments of the present invention is described;

[0043] Figure 19 The expression level of integrin αvβ3 in malignant glioma cancer cells was described by flow cytometry analysis;

[0044] Figure 20 The results of the parallel artificial membrane permeability assay (PAMPA) for exemplary compounds 1–4 are described;

[0045] Figure 21 The fluorescence intensity of exemplary compound 5 in different organs and the brain with and without malignant gliomas is described.

[0046] Figure 22 The levels of an exemplary compound 2 present in brain tissue over time after subcutaneous administration to mice are described.

[0047] Figure 23 The study described the plasma and brain contents of the exemplary compound 2 over time after brain tissue resection and subcutaneous administration of 15 mg / kg to cynomolgus monkeys for 14 consecutive days, and analyzed the extracted blood samples by LC / MS / MS.

[0048] Figure 24 The anti-angiogenic effect of exemplary compound 2 in the presence of multiple growth factors is described;

[0049] Figure 25 Describes known compounds In the presence of multiple growth factors, it only has an anti-angiogenic effect on VEGF, but lacks an anti-angiogenic effect on other growth factors.

[0050] Figure 26 The bioluminescent signals of GBM tumors in the brain were described;

[0051] Figure 27 The blood-brain barrier uptake of exemplary compound 5 in the brains of mice with and without GBM tumors is described.

[0052] Figure 28A The blood-brain barrier absorption of exemplary compound 5 in the brains of mice with and without GBM tumors is described, wherein exemplary compound 5 is administered together with compounds that are available in humans and may potentially compete for absorption and retention.

[0053] Figure 28B The absorption of exemplary compound 5 of the blood-brain barrier in brain regions with and without GBM tumors is also described, wherein exemplary compound 5 is administered together with compounds that are available in the human body and may potentially compete for absorption and retention.

[0054] Figure 29 The absorption of exemplary compound 5 in the brains of mice with and without tumors, as well as drug accumulation or deficiency in other organs, were described.

[0055] Figure 30 The effects of different doses of the exemplary compound 2 on tumor weight were described in mice with GMB xenografts.

[0056] Figure 31 The effects of different doses of the exemplary compound 2 on the intensity of luminescent signals in tumor cells were described in mice with GMB xenografts.

[0057] Figure 32 The effect of an exemplary Example 2 dose of 6 mg / kg on tumor weight was described in mice with GMB xenografts, compared to a known dose of silengiptide at 75 mg / kg.

[0058] Figure 33 The effect of an exemplary Example 2 dose of 6 mg / kg on the intensity of luminescent signal in tumor cells was described in mice with GMB xenografts, compared to a dose of the known compound silengiptide at 75 mg / kg. Detailed Implementation

[0059] This document provides a detailed description of embodiments of the disclosed compositions and methods described below, by way of example and not limited to the accompanying drawings. Although certain embodiments are shown and described in detail, it should be understood that various changes and modifications can be made without departing from the scope of the appended claims. The scope of the invention is by no means limited to the number of constituent parts, the materials of the parts, the shapes of the parts, the colors of the parts, the relative arrangements of the parts, etc., and is disclosed merely as examples of embodiments of the invention. A more complete understanding of the embodiments of the invention and their advantages can be obtained by referring to the following description, in conjunction with the accompanying drawings, wherein the same reference numerals denote the same features.

[0060] As a preamble to the detailed embodiments, it should be noted that, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” used in this specification and claims include the plural forms.

[0061] Overview

[0062] The embodiments of the present invention describe novel compounds, compositions comprising the novel compounds, methods of their synthesis, and treatment methods using the compounds and compositions.

[0063] The compounds disclosed herein (including, but not limited to, exemplary compounds described in detail below, such as compounds 2, 3, 4, and 5, and compositions prepared from these compounds) exhibit improved blood-brain barrier permeability and retention in brain tumors. Furthermore, these compounds and their corresponding compositions have shown unexpectedly enhanced efficacy against brain tumors and other diseases, such as glioblastoma (GBM).

[0064] The unexpected improvement in efficacy for these diseases may be due to a combination of factors—including active transport across the blood-brain barrier, overexpression of integrin αvβ3 in GBM and similar diseases, and the effects of other substituents of thyroid integrin antagonists on absorption / retention.

[0065] First, the compounds and compositions described herein include thyroid integrin antagonists. Thyroid integrin antagonists, such as those described herein, may be actively transported across the blood-brain barrier via thyroid-binding proteins. The transport of thyroid hormones and their analogues in the brain is discussed in Wirth EK, Schwiezer U, and Kohrle J., Frontiers in Endocrinology, June 2014, Vol. 5, No. 98. Drug delivery methods with improved blood-brain barrier permeability may be difficult to achieve; however, the compounds and compositions disclosed by the applicant are actively transported across the blood-brain barrier and thus reach predetermined targets of therapeutic activity.

[0066] Second, due to the overexpression of integrin αvβ3 in GBM and similar diseases, the compounds and compositions described herein can remain within the blood-brain barrier. For example, Figure 19 As shown, αvβ3 overexpression in GBM can reach levels of 80%-97%. Like other thyroid integrin antagonists, the disclosed compounds can bind to these integrin binding sites. Therefore, in addition to delivery to the brain, the compounds and compositions bind to tumor cells and can remain within the blood-brain barrier and at predetermined target sites. Furthermore, this reduces arbitrary unintended effects on non-tumor tissues.

[0067] Third, as described in more detail below, the compounds and compositions described herein include additional functional groups. These additional functional groups can bind to polymers. For example, in embodiments having linear polymers, the additional functional groups may bind to opposite sides of the polymer, rather than to the side of the thyroid integrin antagonist. Nonlinear polymers may also be used, and the additional functional groups may also improve blood-brain barrier permeability and retention, and may also improve scalability and / or water solubility. For example, the enhancement of absorption is not via passive transport because (as described below) Figure 20 Analysis using the passive transport parallel artificial membrane permeability assay (PAMPA) showed that all derivatives exhibited low permeability in the absence of thyroid-binding protein. Conversely, the additional functional groups increased active transport, for example, by facilitating the entry of thyroid integrin antagonists (transporter targets). PAMPA was performed on PMT36 and related compounds 2-4, where all compounds exhibited low permeability (below 1.5x ET). -6 Similarly, compound 5 and P-bi-TAT (compounds described in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616, and U.S. Patent Application No. 16 / 223,176) also exhibited low permeability, both <1.5E. -6 cm / s. The results indicate that these compounds do not permeate across the blood-brain barrier via passive diffusion, which clearly demonstrates that blood-brain barrier permeability (BBB permeability) is primarily facilitated by an active transport system using thyroid-binding proteins in the blood, such as thyroxine carrier protein (TTR), which deliver the bound complexes across the blood-brain barrier.

[0068] Exemplary compounds will now be discussed in more detail, along with additional background information on potential thyroid integrin antagonists and polymers that may be used in embodiments of the present invention.

[0069] As discussed in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616, and U.S. Patent Application No. 16 / 223,176, compounds or compositions comprising αvβ3 integrin-thyroid hormone receptor antagonists, which are incorporated herein by reference, may include an anti-angiogenic thyroid hormone or a derivative thereof bound to a polymer via a non-cleavable linker group, forming a single chemical monomer that can be considered a small molecule or a large molecule (depending on the size of the polymer covalently bound to the thyroid hormone or a derivative thereof). The size of the single chemical monomer and the strength of the non-cleavable covalent bond may help prevent the thyroid hormone or a derivative thereof from entering cells containing cell surface receptors containing integrin αvβ3 variants. Due to the size of the bound polymer and the inability of the cellular environment to cleave the strong and non-cleavable covalent bonds of the thyroid hormone from the polymer, the thyroid hormone portion of the chemical monomer may not be assimilated within the cell nucleus, and the thyroid hormone or a derivative thereof may interact within the cell nucleus. Therefore, thyroid hormones may interact with non-genomic cells and avoid genomic interactions caused by thyroid hormones or their derivatives entering cells and interacting with nuclear receptors in the cell nucleus.

[0070] As discussed in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616, and U.S. Patent Application No. 16 / 223,176, and which are incorporated herein by reference, compounds or compositions comprising an αvβ3 integrin-thyroid hormone receptor antagonist can be synthesized, including but not limited to monomers comprising a non-biodegradable polymer bound to the αvβ3 integrin antagonist via a non-cleavable linker group, such as polyethylene glycol (PEG) (1,000-15,000 Daltons, for example, between 4,000-8,000 Daltons), α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin, chitosan, alginate, or hyaluronic acid, wherein the non-cleavable linker group comprises an amine or triazole bond and is free of short-chain PEG (100-800 M.W.). Examples of thyroid antagonists combined with polymers may include tetraiodothyronine (tetrac), triiodothyronine (triac), and their derivatives and variants. In some embodiments, examples of one or more variants of thyroid hormone antagonists including tetrac and triac may include diaminotetrac (DAT) or diaminotriiodothyronine (DATri) (hereinafter interchangeably referred to as "DAT"), monoaminotetrac (MAT) or monoaminotriiodothyronine (MATri) (hereinafter interchangeably referred to as "MAT"), triazoletetrac (TAT) or triazoletriac (TATri) (hereinafter interchangeably referred to as "TAT"), their derivatives, or other thyroid antagonists known to those skilled in the art.

[0071] As discussed in U.S. Patent Application No. 15 / 616,637 (now U.S. Patent No. 10,201,616) and U.S. Patent Application No. 16 / 223,176, and which are incorporated herein by reference, compounds or compositions comprising αvβ3 integrin-thyroid hormone receptor antagonists have been further synthesized and characterized as DAT, MAT, or TAT bound to polyethylene glycol of varying molecular weights (1,000-15,000 Daltons). Examples of the applicant have been used to proportionally increase the relatively majority soluble PEG-DAT (P-Mono-DAT, P-bi-DAT) and PEG-TAT (P-Mono-TAT, P-bi-TAT) for biocharacterization in various in vivo and in vitro biological systems. Chemical labeling of DAT or TAT, PEG-DAT or PEG-TAT, and C-DAT and C-TAT has been used for imaging and cell kinetics. Data show that, compared to the strong uptake of DAT or TAT by the cell nucleus, the binding of polymers to DAT or TAT results in limited uptake of those polymers by the cell nucleus. This unique cellular distribution, compared to unbound polymers, results in a lack of genomic activity for polymers bound to DAT, MAT, or TAT. Other polymers, such as hyaluronic acid, alginate, and chitosan, are described, with or without short-chain PEG (100-1,000 Daltons) to bind to DAT, MAT, or TAT. Additional polymers binding to DAT, MAT, or TAT are synthesized using bifunctional or tetrafunctional PEGs, which may include, but are not limited to, other branched PEGs of up to eight chains.

[0072] As discussed in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616, and U.S. Patent Application No. 16 / 223,176, and which are incorporated herein by reference, compounds or compositions containing an αvβ3 integrin-thyroid hormone receptor antagonist may have a variety of uses in treating several different diseases regulated by angiogenesis or its inhibition. Given the presence of a thyroid antagonist in the compositions, each composition may have an affinity for the integrin receptor αvβ3, which has been found to be located on many cell types throughout the human body and various animal bodies. For example, the compositions may be used to treat disorders of angiogenesis mediated in the human or mammalian body, such as cancers (solid tumors and fibroblasts). Cancers may include malignant gliomas, pancreatic cancer, ovarian cancer, breast cancer, prostate cancer, bladder cancer, lung cancer, and liver cancer. Fibrous tumors may also include acute myeloid leukemia, multiple myeloma, lymphoma, and chronic lymphocytic leukemia. The composition may further treat eye diseases (diabetic retinopathy and age-related macular degeneration), inflammatory diseases (arthritis, osteoarthritis), atherosclerotic diseases, and skin diseases (acne erythematosus, psoriasis, skin cancer), each of which is maintained through angiogenesis or depends on the generation of new blood cells, and its treatment may depend on antagonizing the formation of new blood vessels to slow down or eliminate the angiogenesis pathway.

[0073] The compounds and compositions disclosed herein improve upon the compounds and compositions previously disclosed by the applicant because they achieve one or more of the following: effective blood-brain barrier permeability and retention, good synthetic scalability, good water solubility, and yield of scalable purified solid products.

[0074] This document may refer to specific thyroid integrin compounds, such as tetrac, triac, etc. These terms include derivatives of such compounds as fully taught in this application, even if such derivatives are not specifically listed herein.

[0075] Referring to the attached diagram, Figure 1 Examples of general formula 100 are described, which includes a thyroid integrin antagonist 110 linked to a substituent 120 (generally referred to as "A") via a linking group 130. Hereinafter, the substituent may be referred to as substituent A, substituent 120, or substituent A 120. Figure 1 The carboxylic acid form of general formula 100 is described, and other figures appearing in this application may also depict the carboxylic acid form of general formula 100. It will be apparent to those skilled in the art that salts of general formula 100 (e.g., sodium salts) may also be used.

[0076] In the described embodiments, the linker group 130 includes a spacer region 132 and a polymer 131. The linker group 130 is resistant to biodegradation, such that the linker group remains non-degradable under physiological conditions. In one embodiment, the spacer region 132 includes a repeating link of a CH2 unit and an adjacent methylene (CH2) unit, which may be defined as a repeating n1, where n1 is an integer and ≥0. In other embodiments, n1 may be ≥1, ≥2, or ≥3. The linker group 130 also includes a “Y” portion. Examples of the “Y” portion may be amino groups in some cases. For example, as known from the applicant’s previous applications, the Y portion of a general formula may be a divalent alkane having one amino group or a divalent alkane having two amino groups. In another embodiment, as... Figure 3 As shown, the Y portion can be a triazole as illustrated in the example of general formula 102. Polymer 131 may comprise a polyether, such as polyethylene glycol (PEG). Other polymers may be used, including chitosan, alginate, hyaluronic acid, and other polymers. In embodiments using PEG as polymer 131, the polymer may have a molecular weight ranging from 200 g / mol to 4,000 g / mol.

[0077] The term thyroid integrin antagonist describes a compound having the ability to inhibit or antagonize one or more thyroid hormone receptors, which are known to those skilled in the art, such as integrin families of thyroid hormone receptors, like the thyroid hormone surface receptor αvβ3. Thyroid integrin antagonist 110 may be an anti-angiogenic thyroid hormone or a thyroid hormone receptor antagonist. For example, thyroid integrin antagonist 110 may be an α-V-β-3 (αvβ3) integrin-thyroid hormone receptor antagonist.

[0078] Specific embodiments of the thyroid integrin antagonist 110 may include tetraiodothyronine (tetrac), triiodothyronine (triac), derivatives thereof, and variants thereof. In some embodiments, examples of one or more variants of the thyroid integrin antagonist comprising tetrac and triac may include diaminotetrac (DAT) or diaminotriiodothyronine (DATri) (hereinafter interchangeably referred to as “DAT”), monoaminotetrac (MAT) or monoaminotriiodothyronine (MATri) (hereinafter interchangeably referred to as “MAT”), triazoletetrac (TAT) or triazoletriac (TATri) (hereinafter interchangeably referred to as “TAT”), derivatives thereof, or other thyroid antagonists known to those skilled in the art. Thyroid integrin antagonists may be of one type described in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616, and U.S. Patent Application No. 16 / 223,176, the entire contents of which are incorporated herein by reference, and / or may be of one type described in U.S. Patent Application No. 15 / 950,870, now U.S. Patent No. 10,328,043, and U.S. Patent Application No. 16 / 398,342, the entire contents of which are incorporated herein by reference. As described in those patent documents, in some embodiments, thyroid integrin antagonist 110 is described as R 10 R 11 R 12 R 13 Variants can be independently substituted with molecules such as H, I, or alkanes. In some embodiments, the alkanes have four or fewer carbons.

[0079] In embodiments of the present invention, substituent A120 may be or include aryl groups and / or aromatic hydrocarbon groups. For example, in some embodiments, substituent A120 may include benzyl groups, phenyl groups, etc. In some embodiments, substituent A120 may include substituted benzyl groups. In yet another embodiment, heterobenzyl groups may be used. Further, five-membered ring heteroaryl, fused heteroaryl, quinoline, and indole may also be used. Heteroaryl may include heteroarylmethyl. In yet another embodiment, substituent A120 may include esters and amides.

[0080] Figure 2General formula 101 is described, wherein, according to embodiments, substituent A120 is described as comprising an aromatic ring. The substituent A120 comprising the aromatic ring may be, for example, a substituted benzyl group. In some embodiments, the substituent A120 comprising the aromatic ring may be in R... 1 R 2 R 2 R 4 R 9 One or more positions in it are replaced. In some embodiments including the substituent A120 of the aromatic ring, it is described as R 1 R 2 R 3 R 4 R 9 Variants may be independently substituted with the following molecules: H, I, F, Br, methoxy group, nitro group, amino group, cyano group. For example, as described in Table 2 of U.S. Patent Application No. 15 / 950,870, now U.S. Patent No. 10,328,043, and U.S. Patent Application No. 16 / 398,342, in some embodiments including the aromatic ring substituent A120, it is described as R 1 R 2 R 3 R 4 R 9 Variants may be independently substituted into the following molecules: H, I, F, Br, methoxy group, nitro group, amino group, cyano group. Further, described as R... 1 R 2 R 3 R 4 R 9 Variants may be substituted with alkyl, aryl, halogen, amide, etc.

[0081] like Figure 3 As shown, in some embodiments including the described general formula 102, variant R 1 R 2 R 3 R 4 It may be replaced by an H molecule, while R 9 It may be replaced by different molecules or groups, as described in the embodiments. 9 It is replaced by "Z". Therefore, substituent A120 may include the aromatic ring as described above, and possibly more specifically, include the substituted benzyl group 122, wherein the Z molecule or group is in R 9 Replace H. Or, as... Figure 6 As shown, in some embodiments, variant R 1 and R 2 Other variants may be replaced instead of R 9Replaced.

[0082] Figure 3-8 Each of the exemplary compounds shown in (including exemplary compounds 1-5) includes tetrac as a related thyroid integrin αvβ3 receptor antagonist, polyethylene glycol as a related linking group, and triazole as the included Y moiety.

[0083] Turning to more specific exemplary compounds 2-5, these compounds may be broadly referred to as X-PTAT, where the substituent A120 is specified as a substituted benzyl group (e.g. Figure 3 The substituted benzyl group 122 shown is, as Figure 4 and 5 The fluorobenzyl or dichlorobenzyl groups shown in the text, or as... Figure 6 The different substituted benzyl groups shown are designated as X, P is a polymer or polyethylene glycol, and TAT refers to triazole tetraiodothyronine (tetrac). Furthermore, these compounds may be designated as X-PMTAT, where the substituent A120 is currently designated as the substituted benzyl group and designated as X, P is a polymer or polyethylene glycol, and MTAT refers to monotriazole tetraiodothyronine. Further still, these compounds may be designated as X-PMT, where the substituent A is currently designated as the substituted benzyl group and designated as X, P is a polymer or polyethylene glycol, and MT is also known as monotriazole tetraiodothyronine.

[0084] These namings and Figure 7 The compound described herein, namely compound 1, is contrasted with the compound described in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616, and U.S. Patent Application No. 16 / 223,176. Compound 1 comprises specific embodiments of a thyroid integrin antagonist linked to a polymer. This complex may be referred to as compound 1, or PTAT, PMT, or PMTAT. As noted above, these designations indicate that the compound comprises a polymer linked to a (mono)triazole tetrac, in which case the compound is linked only to a methyl group and not to a functional group, such as the substituent A120 as described above (or, more specifically, to a substituted benzyl group).

[0085] Returning to the embodiments currently disclosed in this invention, for example Figure 4 and Figure 5 The compounds shown, variant R 9 It may be replaced by halogens. For example, such as... Figure 4 As shown, R 9It can be replaced with a fluorine molecule. This structure is called compound 2, and may also be called fluorobenzyl (fb), which is linked to a triazole tetrac via polyethylene glycol, or optionally called fb-PTAT, fb-PMTAT, or fb-PMT. In another embodiment, as Figure 5 As shown, R 9 It can be replaced by a chlorine molecule. This structure is called compound 3, also known as chlorobenzyl (cb), which is linked to a triazole tetrac via polyethylene glycol, or alternatively as cb-PTAT, cb-PMTAT, or cb-PMT.

[0086] In a further embodiment, for example Figure 6 As shown, variant R 1 and R 2 It can be replaced. For example, R 1 and R 2 It can be replaced with tert-butyl. This structure is called compound 4, and can also be called di-tert-butylbenzyl (Dtbb), which is linked to triazole tetrac via polyethylene glycol, or alternatively called Dtbb-PTAT, Dtbb-PMTAT, or Dtbb-PMT.

[0087] Additional embodiments may include, for example, dyes, markings, labels, etc., for imaging purposes. In some embodiments, the dyes, markings, labels, etc., may be on a substituted benzyl group. For example, Figure 8 A polymer (PMT) derivative incorporating a monotetrac label is described, referred to as compound 5. In this example, the substituent A120 includes a dye identifier, such as BODIPY. Compound 5 may also be referred to as BODIPY-PMT.

[0088] As described above, additional embodiments with substituent A120 are also contemplated. For example, such as... Figure 9A , 9B As shown in 9C, an additional ring structure is disclosed as the substituent A120. In these embodiments, R 8 It can be H, Me, Et, etc. R 1 -R 7 It can be independently selected from H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, cyclohexyl, phenyl, F, Cl, Br, I, CN, CF3, OCF3, CHF2, OCHF2, SO2Me, NO2, -O-alkyl, -O-aryl, -CH2-O-alkyl, -CH2-O-aryl, esters, amides, etc. Ester substituents can be selected from the following:

[0089]

[0090] The amide substituents can be selected from the following:

[0091] Where R 9 and R 10 It is independently selected from H, alkyl, aryl, etc.

[0092] Furthermore, as described above, additional embodiments of substituent A120 may include heterobenzyl groups, for example... Figures 10A-10C Those shown. In addition, five-membered ring heteroaryl, fused heteroaryl, quinoline, indole, etc., can also be used. R 1 -R 5 and R 8 It can be replaced as described above.

[0093] Products containing phenoxy groups can also be used, for example Figure 11 The examples shown are as embodiments of substituent A120. Furthermore, R... 1 -R 5 It can be replaced as described above.

[0094] In additional embodiments, substituent A120 may include an amide, for example... Figure 12A and 12B Those described in R. 9 and R 10 It can be replaced.

[0095] In the embodiments, esters can be used as substituents A120. For example, esters such as... Figures 13A-13D The esters described in [the text].

[0096] As described above, different types of polymers and polymers of various molecular weights can be used in the embodiments. In some embodiments, monodisperse polymers may be used instead of polydisperse polymers to increase the ease of analysis and scalability. Furthermore, as illustrated in exemplary compounds 2-4, the embodiments may include relatively large polymers, such as PEG36. Large monodisperse polymers, such as monodisperse PEG36, may facilitate solubility and analysis of the exemplary compounds. In addition, such large monodisperse polymers can increase scalability by producing relatively large solid products suitable for purification. Therefore, embodiments including PEG36 bound to monotriazole tetrac may simplify synthesis and increase scalability when compared with other embodiments. In some embodiments, the polymer may have a molecular weight of about 4,000 Daltons, for example, 4,000 ± 10% Daltons. Furthermore, these large monodisperse polymers may facilitate the active transport of compounds, for example by making it easier for thyroid integrin antagonists (transporter targets) to enter.

[0097] The synthesis of the specific exemplary compounds (compounds 1-5) described herein will be described below. The synthetic descriptions are for illustrative purposes only and are not intended to limit the scope of the invention. This example uses propynylated tetraiodothyronine (PGT). The preparation of PGT or derivatives thereof from tetraiodothyronine (tetrac) is described in U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616.

[0098] Example 1: Synthesis of Compound 1 (PMT)

[0099]

[0100] In U.S. Patent Application No. 15 / 616,637, now U.S. Patent No. 10,201,616 (see, for example) Figure 7 c and Figure 8 (Compound 730) describes Compound 1 and similar compounds or compositions, the preparation of which is as follows. However, the applicant also provides the following sample methods;

[0101] Figure 14 An overview of the synthetic route for compound 1 has been described. The individual steps of the synthetic scheme for compound 1 will be described in more detail below.

[0102] Step 1: Add 1g (0.625mmol) of monodisperse MeOPEG 36 OH (PurePEG, San Diego, CA) and 0.285 mL (4 equivalents) of TEA were dissolved in 10 mL of DCM. 238 mg (2 equivalents) of toluenesulfonyl chloride (ToSCl) was added in portions over 10 min with stirring, and the mixture was stirred overnight. 10 mL of DCM was added, and the mixture was washed with 2 x 5 mL saturated ammonium chloride, 2 x 5 mL saturated sodium bicarbonate, and 1 x 5 mL saturated brine to remove the solvent under vacuum. The solid was dissolved in 10 mL of hot THF, and an equal volume of hot hexane was added. The liquid was poured off from a small amount of insoluble material, allowing the product to precipitate overnight at -20°C. The product was filtered, washed with hexane, and dried under vacuum to a yield of 995 mg (90%).

[0103] Step 2: 990mg of MeOPEG 36OTs (0.565 mM) were dissolved in 5 mL of CH3CN. 110 mg (3 equivalents) of sodium azide was added, and the mixture was stirred overnight at 70 °C. The reaction was then cooled, and most of the acetonitrile was removed under reduced pressure. The residues were separated using 10 mL each of DCM and water. The aqueous phase was extracted three times with 5 mL of DCM, and the bound organic layer was washed with 5 mL of water and saturated brine, respectively. The material was precipitated from THF / hexane by dropwise addition of solvent under reduced pressure, using a process similar to step 1, with a yield of 832 mg (89%).

[0104] Step 3: Add 830 mg (505 mmol) of MeO-PEG 36 474 mg of (4-{3,5-diiodo-4-[(2-prop-2-yn-1-yl)oxy]-phenoxy]-3,5-diiodophenyl)acetic acid (1.2 equivalents) and 13.7 mg of TBTA (5%) were dissolved in 20 mL of THF. 12.6 mg (0.1 equivalents) of copper sulfate hydrate and 60 mg (0.6 equivalents) of sodium ascorbate were dissolved in 5 mL of water and added to the THF solution. The mixture was stirred under N2 for 16 hours, and the liquid was then slowly poured off the blue solid at the bottom of the flask. THF was removed from the solution under reduced pressure, 10 mL of water was added, and the solution was acidified to pH 3 with dilute hydrochloric acid. Extraction was performed three times with 40 mL of DCM. The bound organic layer was washed three times with 5 mL of saturated EDTA solution, followed by washing with 5 mL of saturated brine. DCM was removed under reduced pressure, and the remainder was dissolved in 20 mL of warm THF. Add 20 mL of hot hexane and heat until almost all substances dissolve. Cool to room temperature, then slowly pour the liquid from the small amount of solid and oil at the bottom of the test tube. Allow the mixture to precipitate at -20°C, filter the solid, and wash with cold hexane. Dry the remaining white solid under reduced pressure to give 685 mg. Dissolve the white solid in 6.5 mL of water with 2.5 mL of 1 M NaOH and 1 mL of saturated NaCl. Wash twice with 25 mL of 3:2 hexane:DCM. Add another 1 mL of saturated NaCl and wash twice more with 25 mL of 3:2 hexane:DCM. Acidify the aqueous phase to pH 2.0 with dilute hydrochloric acid and extract three times with 25 mL of DCM. Wash the bound organic layer with saturated NaCl and remove the solvent under reduced pressure. The residue precipitates in 20 mL of THF and 20 mL of hexane, yielding 491 mg of product. 1H NMR(600MHz,DMSO D6,)d(PPM):8.258(s,1H),7.850(s,2H),7.195(s,2H),5.015(s,2H),4.581(br.s,2H),3.851(br.s,2H),3.6-3.3(m,144H),3.239(S,3H). MS m / z 2452.2(M+Na),1215.4(M+2H),810.2(M+3H),608.2(M+4H).

[0105] Example 2: Synthesis of Compound 2 (fb-PMT)

[0106]

[0107] Figure 15 An overview of the synthetic route for compound 2 has been described. Each step of the synthetic scheme for compound 2 will be described in detail below.

[0108] Step 1: Add 250mg HO-PEG 36 - An azide compound (0.155 mmol, PurePEG, San Diego, California) was added to 19 mg of 60% NaH (3 equivalents) dissolved in 5 mL of THF. The mixture was stirred for 30 minutes, and then 58 μL of 4-(fluorobenzyl)bromo (Aldrich) dissolved in 2 mL of THF (3 equivalents) was added dropwise. The mixture was stirred for 18 hours, and then 2 mL of saturated sodium bicarbonate was added. Under vacuum, THF was removed, and 10 mL of saturated brine was added. The mixture was extracted three times with 15 mL of DCM. The bound organic layer was washed with 5 mL of saturated brine, and the solvent was removed under vacuum. The material was then analyzed by HPLC on a 24 g silica gel column with 0–10% MeOH dissolved in DCM. The product yield was 170 mg, and the purity was >99%.

[0109] Step 2: Dissolve 170 mg (0.147 mmol) of 4-fluorobenzyl PEG azide, 138 mg (0.176 mmol) of (4-{3,5-diiodo-4-[(2-prop-2-yn-1-yl)oxy]-phenoxy]-3,5-diiodophenyl)acetic acid, and 3 mg of tert-butyltrichloroacetylimine ester (TBTA) in 8 mL of tetrahydrofuran (THF). Add 3 mg of CuSO4 hydrate dissolved in 2 mL of water and 23 mg of sodium ascorbate, and stir under N2 for 4 hours. Remove THF under vacuum, then add 5 mL of saturated brine and 0.5 mL of 1M HCl. Extract three times with 10 mL of dichloromethane (DCM), wash three times with 5 mL of saturated ethylenediaminetetraacetic acid (EDTA), wash once with 5 mL of saturated brine, and remove the solvent under vacuum. Dissolve the residue in 10 mL of warm THF, then add hexane until it begins to turn cloudy. Incubate overnight at -20°C to allow the product to precipitate. Filter the solid to give 180 mg of product. 1 ¹H NMR (600MHz, DMSO D₆₆)d (PPM): 8.246 (s, 1H), 7.879 (s, 2H), 7.361 (dd, 2H), 7.167 (m, 4H), 5.013 (s, 2H), 4.575 (m, 2H), 4.466 (s, 2H), 3.847 (m, 2H), 3.640 (s, 2H), 3.55–3.4 (m, 144H). MS m / z 1262.8 (M+2H), 842.5 (M+3H), 632.2 (M+4H). The product was further purified by chromatography on normal-phase silica gel.

[0110] Example 3: Synthesis of Compound 3 (cb-PMT)

[0111]

[0112] Figure 16 An overview of the synthetic route for compound 3 has been described. The steps of the synthetic scheme for compound 3 will be described in detail below.

[0113] Step 1: 250 g of PEG azide compound (0.155 mmol) was added to 19 mg of 60% NaH (3 equivalents) dissolved in 5 mL of THF. The mixture was stirred for 30 minutes, then 95.5 mg of 4-(chlorobenzyl)bromo (Aldrich) dissolved in THF was added dropwise. The mixture was stirred for 18 hours, then a saturated sodium bicarbonate solution was added, and THF was removed under vacuum. 10 mL of saturated brine was added, and the mixture was extracted three times with 15 mL of DCM. The bound organic layer was washed with saturated brine, and the solvent was removed under vacuum. Chromatography was performed on a silica gel column using 0-10% MeOH dissolved in DCM; the yield was 190 mg.

[0114] Step 2: Dissolve 190 mg (0.111 mmol) of benzyl chloroPEG azide, 131 mg of (4-{3,5-diiodo-4-[(2-prop-2-yn-1-yl)oxy]-phenoxy]-3,5-diiodophenyl)acetic acid (1.5 equivalents), and 3 mg of TBTA in 8 mL of THF. Add 3 mg of CuSO4 hydrate dissolved in 2 mL of water and 23 mg of sodium ascorbate, and stir for 4 hours. Remove THF under vacuum, then add 5 mL of saturated brine and 0.5 mL of 1 M HCl. Extract three times with DCM, wash three times with saturated EDTA, wash once with saturated brine, and remove solvent under vacuum. Dissolve the residue in 10 mL of warm THF, then add hexane until it begins to turn cloudy. Freeze at -20°C to allow the product to precipitate, yielding 180 mg of product. 1 ¹H NMR (800MHz, D₂O) d(PPM): 8.369 (s, 0.3H), 8.147 (s, 0.7H), 7.758 (s, 2H), 7.261 (m, 6H), 4.993 (s, 2H), 4.541 (m, 2H), 4.451 (s, 2H), 3.849 (m, 2H), 3.640 (s, 2H), 3.65–3.54 (m, 142H), 3.346 (s, 2H). MS m / z 1281.2 (M+2H), 854.9 (M+3H), 641.4 (M+4H). The product can be further purified by normal-phase silica gel chromatography.

[0115] Example 4: Synthesis of Compound 4 (Dtbb-PMT)

[0116]

[0117] Figure 17 An overview of the synthetic route for compound 4 has been described. The steps of the synthetic scheme for compound 4 will be described in detail below.

[0118] Step 1: Add 250g of HO-PEG 36 The azide compound (0.155 mmol) was added to 19 mg of 60% NaH (3 equivalents) dissolved in 5 mL of THF. The mixture was stirred for 30 minutes, followed by dropwise addition of 131 mg of bromide (Aldrich) dissolved in THF (3 equivalents). The mixture was stirred for 18 hours, then saturated sodium bicarbonate solution was added, and THF was removed under vacuum. 10 mL of saturated brine was added, and the mixture was extracted three times with 15 mL of DCM. The bound organic layer was washed with saturated brine, and the solvent was removed under vacuum. Chromatography was performed on a silica gel column using 0–20% MeOH dissolved in DCM, yielding 270 mg.

[0119] Step 2: 270 mg (0.147 mmol) of di-tert-butylbenzyl PEG azide, 171 mg of (4-{3,5-diiodo-4-[(2-prop-2-yn-1-yl)oxy]-phenoxy]-3,5-diiodophenyl)acetic acid, and 4 mg of TBTA were dissolved in 8 mL of THF. 4 mg of CuSO4 hydrate dissolved in 2 mL of water and 34 mg of sodium ascorbate were added, and the mixture was stirred for 4 hours. THF was removed under vacuum, and then 5 mL of saturated brine and 0.5 mL of 1 M HCl were added. The mixture was extracted three times with DCM, washed three times with saturated EDTA, and washed once with saturated brine. The solvent was removed under vacuum. Chromatographic analysis was performed on a silica gel column using 0-10% MeOH dissolved in DCM, yielding 310 mg. 1 H NMR(600MHz,DMSO D6,d(PPM):8.248(s,1H),7.842(s,2H),7.300(s,1H),7.188(s,2H),7.130(s,2H),5.00 7(s,2H),4.564(m,2H),4.455(s,2H),3.843(m,2H),3.6-3.3(m,144H),1.274(s,18H). m / z 1309.3(M+2H), 873.4(M+3H), 655.8(M+4H).

[0120] Example 5: Synthesis of Compound 5 (BODIPY-PMT)

[0121]

[0122] Figure 18 An overview of the synthetic route for compound 5 has been described. The steps of the synthetic scheme for compound 5 will be described in detail below.

[0123] Step 1: Treat 250 mg of NH2-PEG in 5 mL of DCM with 1.5 equivalents of BOC anhydride and 3 equivalents of triethylamine. 36 -N3. Stir at room temperature for 18 hours, dilute the mixture with 20 mL of DCM, and wash with 0.1 M HCl, followed by washing with saturated sodium bicarbonate and saturated brine. Remove the solvent under reduced pressure, dissolve the residue in 5 mL of warm THF, and add hexane until the mixture begins to become turbid. Let the mixture stand overnight before filtering and washing with hexane. Recover 240 mg of product.

[0124] Step 2: Dissolve 235 mg of the product from Step 1, 171 mg of (4-{3,5-diiodo-4-[(2-prop-2-yn-1-yl)oxidized]-phenoxy]-3,5-diiodophenyl)acetic acid, and 4 mg of TBTA in 8 mL of THF. Add 4 mg of CuSO4 hydrate dissolved in 2 mL of water and 34 mg of sodium ascorbate, and stir for 18 hours. Remove THF under vacuum, then add 5 mL of saturated brine and 0.5 mL of 1 M HCl. Extract three times with DCM, wash three times with saturated EDTA, wash once with saturated brine, and remove the solvent under vacuum. Dissolve the residue in 5 mL of warm THF, and add hexane until the mixture begins to become turbid. Allow the mixture to stand overnight before filtration and washing with hexane, recovering 220 mg of product.

[0125] Step 3: Dissolve 215 mg of the product from Step 2 in 2 mL of DCM, and add 2 mL of 5 M HCl dissolved in dioxane. Stir the mixture for 18 hours, remove the solvent under reduced pressure, and use the product for the next step.

[0126] Step 4: Dissolve 18 mg of the product (0.0076 mmol) obtained in the previous step and 10 μL of triethylamine in 1 mL of DCM. Add 5 mg of BODIPY 630 / 650NHS ester (Thermo Fisher Scientific) dissolved in 100 μL of DCM. Shake the mixture for 18 hours, remove the solvent under reduced pressure, and perform residue chromatography on a silica gel column using 0-20% methanol dissolved in DCM. 4.5 mg was recovered. 1H NMR(800MHz, CDCl3)d(PPM): 8.221(s,1H),8.058(s,1H),7.850(s,2H),7.642(m,3H),7.51 3(d,1H),7,237(m,3H)7.075(m,1H),7.021(m,1H),6.993(m,3H),6.828(m,1H),6.729(m,1 The 2H and 3H phases were: 5.218 (s, 2H), 4.619 (m, 2H), 4.570 (s, 2H), 3.836 (m, 2H), 3.75-3.6 (m, 140H), 3.545 (m, 2H), 3.416 (m, 2H), 3.310 (m, 2H), 2.223 (m, 2H), 1.688 (m, 2H), 1.603 (m, 2H), 1.359 (m, 2H). The product had a retention time of 34.05 min in the HPLC system: Pursuit XRs3C18 column, mobile phase A (water containing 0.1% formic acid and 5% acetonitrile), mobile phase B (methanol). The flow rate was 1.0 mL / min, with a linear gradient from 0 min, 50% B solution to 40-45 min, 95% B solution, and a column temperature of 25 °C.

[0127] In addition to the synthetic routes described above, other synthetic routes can be used to prepare the exemplary compounds. Furthermore, the techniques described above can be used to produce additional compounds, which can be tailored to the specific substituents required.

[0128] Application methods / treatment methods

[0129] As described above, the compounds and compositions described herein increase absorption across the blood-brain barrier into the brain. Table 1 below illustrates this increased absorption by showing the average brain concentration of each exemplary compound 1-4.

[0130] The concentration readings were obtained 3 hours after administration, as shown below.

[0131] Table 1: Brain permeability data

[0132]

[0133] The data in Table 1 were generated using the following study: Compositions 1-4 were administered subcutaneously to C57BL / 6 mice at 10 mg / kg. Each group contained 4 mice. Mice were sacrificed 3 hours after administration, and brain tissue was excised for bioanalytical measurements of compounds 1-4 within the brain. The average concentrations are shown above, and each of compounds 2-4 showed increased absorption compared to compound 1.

[0134] Furthermore, each of compounds 2-4 also showed increased absorption compared to BG-P-TAT. BG-P-TAT refers to benzylguanidine bound to tetraiodothyronine via the polymer PEG, and is described in U.S. Patent Application No. 15 / 950,870 (now U.S. Patent No. 10,328,043) and U.S. Patent Application No. 16 / 398,342, as well as other compounds and compositions including αvβ3 integrin thyroid antagonists, and norepinephrine transporter targets or catecholamine transporter targets. An example of BG-P-TAT testing was performed using PEG36. As shown, BG-P-TAT did not cross the blood-brain barrier, and its concentration in the brain was undetectable 3 hours after administration. This contrasts sharply with the high concentrations shown in the brain by currently disclosed compounds, such as exemplary compounds 2-4.

[0135] The increased absorption of currently disclosed compounds is determined by active transport, not passive osmosis. For example, such as... Figure 20 As shown, analysis using the passive transport parallel artificial membrane permeability assay (PAMPA) revealed that each of compounds 1-4 exhibits low permeability. Therefore, blood-brain barrier permeability is extremely low in the absence of thyroid-binding proteins. Because passive permeability is unaffected and each of compounds 1-4 shares the same transporter recognition component (thyroid integrin antagonist, triazoletetraiodothyronine), it can be predicted that each of these compounds is a substrate of a thyroid hormone transporter and will also exhibit similar or identical uptake to enter the brain.

[0136] However, as shown in Table 1 above, the brain concentration levels of exemplary compounds 2-4 showed a significant and unexpected increase compared to compound 1 and BG-P-TAT. Furthermore, as discussed in more detail below, this unexpected increase in brain uptake and concentration led to a similarly unexpected increase in therapeutic efficacy for diseases requiring blood-brain barrier permeability, including, for example, malignant gliomas.

[0137] In addition, such as Figure 21 As shown, absorption increases dramatically when a tumor is present in the brain. This is, at least in part, due to the binding of the compound / composition to αvβ3, which is highly expressed in GBM tumors, as mentioned above. Furthermore, as indicated, absorption is primarily concentrated in the brain, rather than other organs. Figure 21 The data shown were obtained by measuring the absorbance using compound 5 (BODIPY-PMT).

[0138] Figure 22Initial absorption into the brain was also described. As shown, exemplary compound 2 (fb-PMT) demonstrated absorption and retention exceeding 24 hours. Again, mice were treated with a single subcutaneous injection at a dose of 10 mg / kg. The brain tissue in the examples did not contain tumor cells.

[0139] Figure 23 Plasma concentrations and brain contents of the exemplary compound 2 (fb-PMT) in cynomolgus monkeys are described. Peak plasma concentrations were observed over 1–4 hours. Brain contents are also included, as measured using efficient LC / MS / MS methods. Compound 2 was found 24 hours after a 14-day treatment regimen (15 mg / kg, subcutaneous injection once daily (SC QD), 72.3 ng / g and 80.5 ng / g, respectively, in male and female cynomolgus monkeys.

[0140] In addition to good initial absorption, the disclosed compounds also exhibit good anti-angiogenic effects. For example, such as... Figure 24 As shown, exemplary compound 2 (fb-PMT) exhibits broad-spectrum anti-angiogenic effects against various growth factors. Specifically, when compound 2 is administered in the presence of the following growth factors, it effectively reduces the percentage of angiogenesis in the CAM model: bFGF, VEGF, VEGF+bFGF, and bFGF+VEGF+HGF. In the CAM model, each growth factor can increase angiogenesis by 250% or more; however, administration of compound 2 (fb-PMT) at 1.0 μg significantly reduces this increase to only slightly above baseline.

[0141] This broad-spectrum anti-angiogenic effect is comparable to existing therapeutic compounds / combinations, such as (Bevacizumab) forms a contrast. For example... Figure 25 As shown, It is primarily effective against VEGF alone, but cannot significantly reduce the angiogenesis percentage of bFGF or HGF. Furthermore, when bFGF or bFGF and HGF are present alongside VEGF, It did not show good results. (Reference) Figure 24 The exemplary compound 2 (fb-PMT), whether alone or in combination, showed angiogenesis inhibition against all three growth factors.

[0142] refer to Figure 21 When a tumor (GBM) is present in the brain, the exemplary compound 5 (BODIPY-PMT) showed a significant increase in uptake. Furthermore, as shown, the uptake was primarily concentrated in the brain, excluding other organs. The research protocol will now be described further.

[0143] Female mice with or without thymus were used. Mice with GBM received orthotopic transplantation of U87-luc cells (1 million cells) into the brain. Compound 5 (BODIPY-PMT) (a far-infrared fluorescent dye) was administered subcutaneously at 3 mg / kg. Fluorescence signals (excitation wavelength Ex / emission wavelength Em, 630 nm / 650 nm) were detected. The complete treatment groups are shown in the table below:

[0144] Table 2: Fluorescence Scheme

[0145]

[0146] L-T4* (a thyroid hormone used for hypothyroidism) and phenytoin (an anti-throwing agent) both bind to thyroid-binding protein.

[0147] The fluorescence signal of compound 5 was imaged after 1 hour, 2 hours, 6 hours, and 24 hours. After these steps, in vitro fluorescence imaging was performed in the brain and organs. Following imaging, a luciferase substrate was added to detect tumor fluorescence signals in the brain.

[0148] Figure 26 This shows the bioluminescent signals of GBM (U870-luc) tumors in the brain in different treatment groups.

[0149] Figure 27 Compound 5 was observed in the brain at 1-hour, 2-hour, 6-hour, and 24-hour intervals. As shown, compound 5 was absorbed across the blood-brain barrier and remained in all intervals. Furthermore, as shown, compound 5 was generally present in higher concentrations in animals with GBM tumors, further demonstrating that compound 5 is absorbed across the blood-brain barrier and remains in the tumor site.

[0150] Figure 28A The study showed the blood-brain barrier absorption and retention of the exemplary compound 5 24 hours after administration at a dose of 3 mg / kg. Again, the generally higher levels of compound 5 in animals with GBM further demonstrate that compound 5 crosses the blood-brain barrier for absorption and retention at the tumor site. Compound 5 was present and retained when administered alone and when co-administered with other drugs that cross the blood-brain barrier, such as the thyroid hormone L-T4 and phenytoin. Therefore, the disclosed compound / composition exhibits good absorption and retention in the brain even in the presence of drugs that might compete for absorption / binding.

[0151] Figure 28BThe fluorescence signal intensity of compound 5 in brain regions with and without GBM tumors was also shown. Again, compound 5 was administered alone, L-T4 and compound 5 were administered, and phenytoin and compound 5 were administered. It can be seen that absorption generally increases in the presence of a tumor. Furthermore, the presence of L-T4 or phenytoin did not diminish the increase in absorption. Therefore, the disclosed compounds exhibit good absorption, high affinity binding, and high retention at tumor sites in the brain.

[0152] Figure 29 This study demonstrates the brain absorption of a single dose (3 mg / kg, subcutaneously) of exemplary compound 5 (fb-PMT) in mice with and without tumors. A significantly increased amount of the compound was observed in animals with transplanted tumors. Furthermore, Figure 29 The study also revealed accumulation levels in other organs, including the heart and lungs, liver, and kidneys. Drug accumulation was observed in the livers of both test groups; however, no accumulation was observed in the kidneys of animals with tumors, while accumulation was observed in the kidneys of animals without tumors. This provides further evidence of retention at tumor sites. Figure 29 It was also shown that GBM emitted a luminescent signal in animals with tumors, while no signal was emitted in animals without tumors.

[0153] The above Figure 21-29 Increased absorption and retention of the exemplary compounds across the blood-brain barrier are demonstrated. Therefore, the disclosed compounds and compositions comprising these compounds can be delivered across the blood-brain barrier, specifically to tumor sites within the brain. Furthermore, the compounds can be used to target such tumors while minimizing their impact on healthy tissue.

[0154] Now refer to Figures 30-33 The efficacy of these compounds / combinations against GBM tumors was described. The study protocol was as follows: nude mice with U87-luc xenografts were treated for 3 weeks with different doses of compound 2 (fb-PMT). Efficacy was determined by comparing tumor weight and luminescence signal intensity with a control group. Furthermore, the therapeutic efficacy was evaluated by comparison with the known potential treatment silengiptide. Efficacy was determined again after another 3 weeks without additional treatment.

[0155] Figure 30 The effect of exemplary compound 2 (fb-PMT) on tumor weight was shown after 3 weeks of treatment and then again after 3 weeks of treatment followed by 3 weeks of treatment cessation. Results were shown at doses of 1 mg / kg, 3 mg / kg, 6 mg / kg, and 10 mg / kg relative to the control group. After 3 weeks, the tumor weight in the control group was approximately 600 mg. Tumor weight showed a dose-dependent reduction in all treatment groups, decreasing to below 100 mg.

[0156] Tumor weight was also compared 6 weeks later, i.e., 3 weeks after treatment followed by 3 weeks without additional treatment. The control group showed an increase in tumor weight of approximately 750 mg. All treatment groups showed a further, additional reduction in tumor weight after 3 weeks without treatment.

[0157] Figure 31 The effect of compound 2 (fb-PMT) on luminescence signal intensity was shown after 3 weeks of treatment and then again after 3 weeks of treatment followed by 3 weeks of treatment cessation. Results were shown at doses of 1 mg / kg, 3 mg / kg, 6 mg / kg, and 10 mg / kg relative to the control group. After 3 weeks, the luminescence signal intensity in the control group was approximately 600,000 p / s. A dose-dependent decrease in luminescence signal intensity was observed in all treatment groups, decreasing to below 100,000 p / s.

[0158] Signal intensity was also compared 6 weeks after treatment (3 weeks of treatment followed by 3 weeks without additional treatment). The control group showed an increase in signal intensity, exceeding 800,000 p / s. All treatment groups showed a further, additional decrease in luminescent signal intensity after 3 weeks without treatment.

[0159] Figure 32 The effect of compound 2 (fb-PMT) on tumor weight was shown after 3 weeks of treatment and then again after 3 weeks of treatment followed by 3 weeks of treatment cessation. Results at a dose of 6 mg / kg were shown and compared with a control group and a group treated with silengiptide at a dose of 75 mg / kg. Again, after 3 weeks, the tumor weight in the control group was approximately 600 mg. After 3 weeks of treatment, tumor weight decreased in both treatment groups. However, when compared with the group treated with silengiptide, the group treated with compound 2 showed a substantially more significant reduction. For example, it can be seen that the tumor weight in the group treated with silengiptide decreased to approximately 300 mg, while the group treated with compound 2 showed a reduction to less than 50 mg.

[0160] Tumor weight was also compared after 6 weeks of treatment, specifically after 3 weeks of treatment followed by 3 weeks without additional treatment. Again, the control group showed an increase in tumor weight of approximately 750 mg after 3 weeks without treatment. Furthermore, after 3 weeks without treatment, the silengiptide group showed an increase in tumor weight compared to the 3-week treatment period, with the final tumor weight exceeding 400 mg. Therefore, even after 3 weeks of treatment at 75 mg / kg, the tumors in the silengiptide group remained active and were still growing. Conversely, even after 3 weeks without treatment, the compound 2 group showed a further reduction in tumor weight.

[0161] Figure 33The effect of compound 2 on the luminescence signal intensity was shown after 3 weeks of treatment and then again after 3 weeks of treatment followed by 3 weeks of treatment cessation. Results for compound 2 (fb-PMT) at a dose of 6 mg / kg are shown and compared to a control group and a group treated with 75 mg / kg silengiptide. Again, after 3 weeks, the luminescence signal intensity in the control group was approximately 600,000 p / s. Both treatment groups showed a reduction in signal intensity after 3 weeks of treatment. However, when compared to the group treated with silengiptide, the group treated with compound 2 showed a substantially more significant reduction. For example, it can be seen that the group treated with silengiptide showed a signal intensity reduction of approximately 300,000 p / s, while the group treated with compound 2 showed a signal intensity reduction to a negligible level.

[0162] Signal intensity was compared 6 weeks after treatment (3 weeks of treatment followed by 3 weeks without additional treatment). Again, the control group showed increased signal intensity, exceeding 800,000 p / s. Furthermore, after 3 weeks without treatment, the silengiptide group showed increased signal intensity compared to the 3-week treatment period, ultimately exceeding 500,000 p / s. Therefore, even after 3 weeks of treatment at 75 mg / kg, the tumors in the silengiptide group remained active and growing. Conversely, even after the additional 3 weeks without treatment, the compound 2 group showed a further reduction in luminescent activity.

[0163] As illustrated in this study and as shown in these figures, the compound exhibits increased therapeutic efficacy against malignant glioma (GBM) compared to control groups and known therapeutic compounds / compositions with limited blood-brain barrier permeability. As discussed above, the increased therapeutic effect can be attributed to a combination of factors, including active transport across the blood-brain barrier due to the thyroid integrin antagonist moiety of the compound, retention within the brain, particularly at the tumor site, due to the binding of the thyroid integrin antagonist moiety to integrin αvβ3 (which is present and overexpressed in brain tumors such as GBM), and the effect of substituent A on absorption across the blood-brain barrier, for example, by increasing the accessibility of the transporter target in some embodiments. These features contribute to increased initial absorption and increased retention within the brain and at the desired treatment site, leading to increased therapeutic efficacy.

[0164] Furthermore, the disclosed compounds may possess increased scalability, solubility, and yield of solid products or intermediates. Synthetic scalability enables the efficient and cost-effective production of compounds and compositions for patient use. Additionally, for therapeutic purposes, compounds and compositions must be synthesized with sufficient purity. The presence of compounds or compositions as solid products offers improved purification options. This contrasts with other compounds mentioned above, such as P-Bi-TAT, which produces an oily product. The solid exemplary compounds described herein can also be readily purified by normal-phase chromatography on a silica gel column, which is not feasible for many other PEGylated molecules, including P-Bi-TAT. For example, P-Bi-TAT requires reversed-phase chromatography, which is not easily scalable. Similarly, water solubility facilitates certain routes of administration, such as injection methods like subcutaneous injection. Therefore, these characteristics are generally important for the production of compounds / compositions and for achieving effective treatment using said compounds / compositions. The disclosed compounds may be particularly useful as potential therapeutic options for malignant gliomas and other diseases, and can be produced in sufficient quantities to meet therapeutic doses.

[0165] The compounds can also be prepared into compositions comprising the disclosed compounds. Furthermore, the compounds and / or compositions can treat diseases such as GBM by administering a therapeutically effective amount of the compounds / composition to patients in need, such as those suffering from the aforementioned diseases.

[0166] This composition can also be used for cancer cell / tumor imaging. For example, the composition described herein can be used for imaging tumors in the brain, such as malignant gliomas. Imaging may be required for diagnosis and / or treatment monitoring. Furthermore, this composition can be used for simultaneous treatment and imaging. For example, the composition can show increased retention in targeted cancer cells / tumors, thereby increasing treatment efficacy.

[0167] The various embodiments of the present invention have been described for illustrative purposes and are not intended to be exhaustive or limiting to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein has been chosen to best explain the principles of the embodiments, their practical application or improvement relative to commercially available technology, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A compound of the general formula: ###0001### wherein n is 5-200, and wherein A is selected from the group consisting of ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ### ​ consisting of a group consisting of an amide; wherein R 1 -R 7 are independently selected from the group consisting of H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C 12 n-alkyl, F, Cl, Br, I; and ​ 2. The compound of claim 1, wherein said alkyl is selected from the group consisting of Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C 12 n-alkyl.

3. The compound of claim 1, wherein ​ the group consisting of wherein R 9 and R 10 are independently selected from the group consisting of H, alkyl, aryl. ​ ​ ​ ​ ​ ​ ​ wherein R 1 -R 4 , R 9 are independently selected from the group consisting of H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C 12 n-alkyl, F, Cl, Br, I; R 10 -R 13 each independently I; and Y is 6. The compound of claim 5, wherein ​ ​ ​ ​ ​ 8. Use according to claim 7, characterized in that, ​ ​ ​ ​ 9. Use according to claim 8, characterized in that, ​

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