Therapeutic metal complexes and ligands and methods of making and using same

Abstract

Therapeutic agents are provided that can reproducibly treat ALS and other neurological and / or copper deficiency-related diseases. The present invention relates to a compound having a structure satisfying Formula I: JPEG2026041735000100.jpg5060

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is an earlier application of U.S. Provisional Patent Application No. 62 / 553,714, filed September 1, 2017. No. 60 / 699,999 filed on Dec. 2, 2003, which claims the benefit of the same; the entire contents of which are incorporated herein by reference.

[0002] Acknowledgments of government support This invention was made with Government support under Contract No. W81XWH-15-1-0289 awarded by the U.S. Department of Defense. The Government has certain rights in this invention.

[0003] field The present disclosure provides embodiments of therapeutic compounds, particularly therapeutic agents capable of treating neurological disorders, and methods of making and using such compound embodiments. . Summary of the Invention [Problem to be solved by the invention]

[0004] Background Amyotrophic lateral sclerosis (ALS) affects 30,000 people at any one time. It is estimated to affect over 400,000 Americans and people worldwide each year. Approximately 5,000 Americans are diagnosed with the disease, which causes the relentless death of motor neurons. It causes a progressive paralysis that kills its victims within one to five years on average. Only two drugs have been approved by the FDA for the treatment of ALS, and both slows disease progression in a subset of patients, and It only extends the lifespan of a dog by a few months. Many common breeds of dogs, including the Purd and Rhodesian Ridgeback, are often For example, they carry a homozygous mutation (also called a homozygous mutation) in the SOD gene. These dogs have been diagnosed with canine degenerative myelopathy, a motor disorder that has many similarities to the human disease. They develop a progressive disease that affects the neurons.

[0005] This technology allows for the reproducible treatment of ALS and other neurological and / or copper deficiency-related diseases. There is a need for therapeutic agents that can Overview [Means for solving the problem]

[0006] Disclosed herein are embodiments of compounds having a structure satisfying Formula I. [ka]

[0007] In yet additional embodiments, the compounds have structures satisfying other formulas described herein. The variables exemplified above in Formula I are now explained.

[0008] Also disclosed herein are pharmaceutical formulations, which contain a compound that satisfies any one or more of the formulas described herein. In some embodiments of the pharmaceutical formulation, compounds and dosage forms having the structure and only a small amount, if any, of the compound crystallizes when combined with a pharmaceutical dosage form. .

[0009] Also described herein are method embodiments that involve administering a therapeutic amount of a compound described herein to a subject. In certain disclosed embodiments, the method includes administering to a motor neuron disease or sample. Disclosed herein are methods for treating rheumatoid arthritis, including administering to a subject a therapeutic amount of a compound described herein. In some embodiments, the motor neuron disease is ALS, Lucy Gehrig's disease, or Rigg's disease, primary lateral sclerosis, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, or any combination thereof.

[0010] Also disclosed herein are certain method embodiments, in which compounds as described herein are used in The metal component of the substance is an isotope of the metal and includes administering it to a subject or sample. In the disclosed embodiment, the isotope is 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+ In some embodiments, the method comprises determining the presence of a motor neuron disease. Imaging an object or sample using positron emission tomography to determine the presence of It may further include:

[0011] The foregoing and other objects, features, and advantages of the present disclosure will become more apparent from the following detailed description. This will become clearer as it proceeds with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0012] [Figure 1] Graph of cytochrome c oxidase activity in mouse brain, where the line labeled with the symbol "○" represents untreated CCS-only mice; the line labeled with "●" represents CuATSM-treated CCS mice; the line labeled with "□" represents untreated CCSxSOD mice; and the line labeled with "black square" represents CuATSM-treated CCSxSOD mice. [Figure 2] Illustrated is a titration curve obtained from a titration in which copper is added to the free ATSM ligand component. [Figure 3] Illustrated are the reduction standard potentials (left) versus oxidation standard potentials (right) for the ligand components. [Figure 4] 1 is a graph showing the results obtained from exposing mice to CuATSM and different compound embodiments described herein, confirming that the disclosed compound embodiments effectively increase mature Cu,Zn SOD formation; the sample size of the number of mice in each group is indicated by the numbers provided above each bar in the graph. [Figure 5] FIG. 10 is a composite mass spectrum showing the mass spectra of SODWT (top spectrum) and SODG93A (middle and bottom spectra) from a ventral spinal cord sample before and after exposing the sample to CuATSM (top and middle spectra vs. bottom spectrum). [Figure 6] A graph showing the results obtained from exposing mice to CuATSM and different compound embodiments described herein, confirming that the disclosed compound embodiments effectively reduce the amount of immature forms of SOD; the sample size in terms of the number of mice in each group is indicated by the numbers above each bar in the graph. [Figure 7] Figures 7A and 7B are graphs showing the results obtained from exposing mice to CuATSM and different compound embodiments described herein, confirming that the disclosed compound embodiments effectively increase COX activity in the brain (Figure 7A) and spinal cord (Figure 7B); the sample size in terms of the number of mice in each group is indicated by the numbers above each bar in the graph. [Figure 8] Illustrated is a titration curve obtained from a titration in which copper is added to the free PhMeTSM ligand component. [Figure 9] Illustrated is a titration curve obtained from a titration in which copper is added to the free NO2PhMeTSM ligand component. [Figure 10]1 is a graph illustrating the survival rate of low-expressing G93A SOD mice crossed with CCS-overexpressing mice after treating the mice with CuPhMeTSM (50 mg / kg / day) at 4 days of age; the graph shows that most mice (specifically, 9 out of 11) still survived after treatment with CuPhMeTSM (line labeled "A"), whereas untreated mice (line labeled "B") showed a significantly lower survival rate (confidence levels are shown as dashed lines, lines "C" and "D" correspond to treated mice, and lines "E" and "F" correspond to untreated mice). [Figure 11] 1 illustrates a space-filling model of an embodiment of the compounds described herein. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description

[0014] I. Terminology Overview

[0015] The following explanations of terms will better explain the present disclosure and be useful in the practice of the present disclosure. It is provided for the guidance of those of ordinary skill in the art. So, "comprising" means "including," and the singular "a" or "an" or "the" includes plural references unless the context clearly indicates otherwise The term "or" refers to any of the alternative elements listed, unless the context clearly indicates otherwise. Reference may be made to a single element or a combination of two or more elements.

[0016] Some steps of the disclosed methods may be presented in a particular sequential order for convenient presentation. I will explain it in the following specific language (also called unique language). Therefore, unless a specific order is required, the description of this manner does not include rearrangement. For example, in some cases, the steps listed in order Further, the description is intended to illustrate the disclosed method. To describe the process, we sometimes use terms such as "produce" and "provide." These terms are high-level abstractions of the actual steps to be performed. The actual steps involved will vary depending on the particular implementation and may be used in conjunction with the techniques of the present invention. readily recognized by a person of ordinary skill in the art.

[0017] Unless otherwise explained, all technical and scientific terms used herein are It has the same meaning as commonly understood by a person of ordinary skill in the art to which the disclosure pertains. Methods and compounds similar or equivalent to those described herein may be used in the practice or testing of the present disclosure. Suitable methods and compounds that can be used are described below. The descriptions and examples are illustrative only and, unless otherwise specified, are not intended to be limiting. Other features of the present disclosure will be apparent from the following detailed description and claims.

[0018] Unless otherwise specified, as used in this specification or claims, the term "component" refers to an ingredient. All numbers expressing amounts, molecular weights, percentages, temperatures, times, and the like are expressly stated as "about." Therefore, unless otherwise indicated, Unless otherwise expressly or implicitly stated, the numerical parameters recited are intended to provide the desired characteristics sought. It is an approximation that may depend on the quality and / or the limit of detection under standard test conditions / methods. When directly and explicitly distinguishing an embodiment from the prior art being discussed, the use of "about" Unless specifically recited, the numerical values ​​of the embodiments are not approximations. Not all substitutes are equivalent.

[0019] Embodiments of the compounds disclosed herein may include one or more (also referred to as one or more) non- Symmetry elements, such as stereocenters, stereoaxies, and the like, e.g. In this way, chemical conjugates can exist in different stereoisomeric forms. These compound embodiments may include, for example, racemic or optically active compounds. In the case of embodiments of compounds having two or more asymmetric elements, In this case, these compound embodiments may additionally be mixtures of diastereomers. For embodiments of compounds having asymmetric centers, all optically isomeric compounds in pure form may be used. isomers and mixtures thereof are included unless the context clearly indicates otherwise or isomers are excluded. Unless a more explicit statement is given, the compounds are encompassed by the corresponding general formula. In this case, a single enantiomer (also called a mirror image, mirror image isomer, or antipodes) The therapeutically active forms can be prepared by methods known to those of ordinary skill in the art, e.g., asymmetric synthesis, photocatalytic synthesis, by synthesis from chemically pure precursors or by resolution of the racemate. Resolution of the racemate can also be achieved by conventional methods, for example by the use of a resolving agent. crystallization in the presence of methyltrimethylsilyl methylsilyl or chromatography using, for example, a chiral HPLC column. Here, we will explain how to achieve them. All isomers are contemplated, regardless of how they are prepared.

[0020] All forms of the active drug (e.g., solvates, optical isomers, enantiomers, polymorphs, isomers) The compounds and salts may be employed alone or in combination.

[0021] The stereochemical definitions and conventions used herein are largely based on those in S.P. Parker, Ed. McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, USA and Eliel, E. and Wilen, S., Stereochemistry Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc. John Wiley & Sons, New York. Many organic compounds are optically active. Optically active compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In the explanation, the chiral center(s) (groups) are shown to indicate that there can be multiple groups. The prefixes (+ / -) D and L or R and L are used to indicate the absolute configuration of the molecule with respect to the The prefixes d and l or (+) and (-) indicate the rotation of plane-polarized light by the compound. is used to designate the sign of the compound, and (-) or l means that the compound is levorotatory. Compounds beginning with (+) or d are dextrorotatory.

[0022] In order to facilitate review of the various embodiments of the present disclosure, the following definitions of specific terms and abbreviations are provided: Provide an explanation of:

[0023] Adjuvant: An excipient that modifies the effect of another drug, typically an active ingredient. Adjuvants are often pharmacological and / or immunological agents. By increasing beneficial neurological responses, such as immune responses, the active ingredient Adjuvants can also act as stabilizers for formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, and the like. Aluminum, killed bacteria, squalene, detergents, surfaces activators, cytokines, paraffin oil, and combination adjuvants, e.g. For example, Freund's complete adjuvant or Freund's incomplete adjuvant. This includes things like:

[0024] Aldehyde: -C(O)H.

[0025] Aliphatic: at least 1 carbon atom to 50 carbon atoms (C 1-50 ), for example, 25 carbon atoms (C 1-25 ), or one to ten carbon atoms (C 1-10 ) and so on and includes alkanes (or alkyls), alkenes ( or alkenyl), alkyne (or alkynyl), and their cyclic versions and further including linear and branched chain configurations, and all stereoisomers and Additionally, positional isomers are included.

[0026] Aliphatic-aryl: coupled to (also called paired with) the compounds disclosed herein; or an aryl group that can be coupled through an aliphatic group To couple or become coupled.

[0027] Aliphatic-heteroaryl: A heteroaryl group that is coupled to or coupled with the compounds disclosed herein. A heteroaryl group that can be bonded through an aliphatic group. and couple or become coupled.

[0028] Alkenyl: an alkyl group having at least 2 carbon atoms and at least 50 carbon atoms (C 2-50 ), for example, 25 to 25 carbon atoms (C 2-25 ), or two to ten carbon atoms (C 2-10 ) and so on. and unsaturated monovalent hydrocarbons having at least one carbon-carbon double bond, So unsaturated monovalent hydrocarbons are formed by removing one hydrogen atom from one carbon atom of the parent alkene. The alkenyl group may be branched, straight-chain, or cyclic (e.g., cyclo alkenyl), cis, or trans (e.g., E or Z).

[0029] Alkoxy: -O-aliphatic (such as, for example, -O-alkyl), in exemplary embodiments is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Examples include butyl, t-butoxy, sec-butoxy, and n-pentoxy.

[0030] Alkyl: at least 1 carbon atom to 50 carbon atoms (C 1-50 ), for example, 25 carbon atoms (C 1-25 ), or one to ten carbon atoms (C 1-10 ) and so on. where the saturated monovalent hydrocarbon is a saturated monovalent hydrocarbon having a It can be derived from the removal of one hydrogen atom from one carbon atom of the alkyl group. Alkyl groups can be branched, straight chain, or cyclic (eg, cycloalkyl).

[0031] Alkylaryl / Alkenylaryl / Alkynylaryl: The compounds disclosed herein may be is an aryl group that is or can be coupled, where the aryl The alkyl group is coupled through an alkyl, alkenyl, or alkynyl group, respectively; Or they become coupled.

[0032] Alkylheteroaryl / alkenylheteroaryl / alkynylheteroaryl: Heteroaryls that are coupled or can be coupled to the compounds disclosed in heteroaryl groups, where the heteroaryl group is an alkyl, alkenyl, or alkynyl group; Through this, they are coupled or become coupled with each other.

[0033] Alkynyl: an alkyl group having at least 2 carbon atoms and at least 50 carbon atoms (C 2-50 ), for example, 25 to 25 carbon atoms (C 2-25 ), or two to ten carbon atoms (C 2-10 ) and so on. and unsaturated monovalent hydrocarbons having at least one carbon-carbon triple bond, Thus, unsaturated monovalent hydrocarbons are formed by removing one hydrogen atom from one carbon atom of the parent alkyne. The alkynyl group may be branched, straight-chain, or cyclic (e.g., cycloalkynyl).

[0034] Amide: -C(O)NR a R b , so each R a and Rb is hydrogen, aliphatic, heteroaliphatic, aryl The aryl group is independently selected from aryl, heteroaryl, or any combination thereof.

[0035] Amine: -NR a R b , so each R a and R b is hydrogen, aliphatic, aryl, heteroaliphatic , heteroaryl, and any combination thereof. In terms of form, R a and R b are bonded together (also called joined), and the nitrogen Together with the atoms, a heterocyclic ring can be formed.

[0036] Aromatic: Unless otherwise specified, a single ring (e.g., phenyl, pyridinyl, or pyridine) naphthyl) or multiple fused rings in which at least one ring is aromatic (e.g., naphthyl a ring of 5 to 15 ring atoms having a ring structure (e.g., hydroxyl, indolyl, or pyrazolopyridinyl); Conjugated groups or moieties; i.e. , at least one ring, and optionally multiple fused rings, with contiguous, delocalized π-electrons. Typically, the number of out-of-plane π electrons corresponds to the Huckel rule (4n+2). The point of attachment to the parent structure is typically through the aromatic portion of a fused ring system. For example: [ka] However, in certain instances, the context or explicit disclosure may dictate that the point of attachment is a non-aromatic ring system. Sometimes we refer to something through its parts. For example, [ka] Aromatic groups or moieties include rings, e.g., aryl groups or moieties. It may contain only carbon atoms, or it may contain one or more ring carbon atoms and one The ring may contain one or more heteroatoms, and lone pairs (e.g., S, O, N, P, or Si) may be present, e.g., For example, heteroaryl groups or moieties are included.

[0037] Aryl: A group having at least five carbon atoms and up to 15 carbon atoms (C5-C 15 ), for example, Ten carbon atoms (C5-C 10 ) and can be monocyclic or multiple fused rings. rings, which may or may not be fused rings aromatic, provided that , wherein the point of attachment to the remainder of the compounds disclosed herein is through an atom of the aromatic carbocyclic group. An aryl group may contain one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, such as alkyl, aryl, heteroaryl, other functional groups, or any combination thereof. It can be replaced by

[0038] Carboxyl: -C(O)OR a , so R a is hydrogen, aliphatic, aromatic, aliphatic-aromatic, hetero aliphatic-aromatic, heteroaliphatic, and any combination thereof.

[0039] Carrier (also called carrier, carrier, etc.): A substance capable of delivering the compounds described herein. In some embodiments, the carrier is an excipient that functions as the active ingredient. It can be a suspending aid, a solubilizing aid, or an aerosolizing aid. The nature of the formulation will depend on the particular mode of administration employed. For example, parenteral formulations may be Typically, a pharmaceutically and physiologically acceptable fluid, such as water, physiological saline (physiological Salt solution (also called physiological saline), balanced salt solution, aqueous dextrose, glycerol Injectable fluids containing as a vehicle such as acetone or the like In some instances, a pharmaceutically acceptable carrier may be administered to a subject (e.g., parenterally, It can be sterilized to be suitable for intramuscular or subcutaneous injection. In addition to the carrier, the administered pharmaceutical preparation may contain small amounts of non-toxic auxiliary substances, such as wetting agents or Emulsifiers, preservatives, and pH buffers (also referred to as "sodium acetate") and the like, for example, sodium acetate or Sorbitan monolaurate may be included.

[0040] Haloaliphatic: one or more hydrogen atoms, such as one to ten hydrogen atoms. Regardless, halogen atoms such as fluoro, bromo, chloro, or iodo are also included. Aliphatic groups substituted by

[0041] Haloaliphatic-aryl: Coupling or coupling to the compounds disclosed herein an aryl group that can be coupled through a haloaliphatic group; The ring or coupling occurs.

[0042] Haloaliphatic-heteroaryl: A heteroaryl group that is coupled to or coupled with the compounds disclosed herein. a heteroaryl group capable of ring formation, wherein the heteroaryl group is a haloaliphatic group; The coupling is, or will be, via an aromatic group.

[0043] Haloalkyl / haloalkenyl / haloalkynyl: at least one halogen atom or 20 halogen atoms, for example, 1 to 15 halogen atoms, or 1 to 5 halogen atoms Such atoms include, but are not limited to, bromine, chlorine, fluorine, and the like. is an alkyl, alkenyl, or alkynyl group, including those that can be selected from iodine (They can be branched, straight chain, or cyclic).

[0044] Heteroaliphatic: At least one heteroatom to 20 heteroatoms, e.g., one or and 15 heteroatoms, or 1 to 5 heteroatoms, etc., includes, but is not limited to, oxygen, nitrogen, sulfur, selenium, phosphorus, and their oxidized forms within the group Aliphatic groups, including those selected from:

[0045] Heteroaliphatic-aryl: A heteroaliphatic group that is coupled to or coupled with the compounds disclosed herein. an aryl group that can be coupled through a heteroaliphatic group; The two will be paired or coupled.

[0046] Heteroalkyl / heteroalkenyl / heteroalkynyl: Heteroalkyl containing at least one heteroatom. 1 to 20 heteroatoms, for example, 1 to 15 heteroatoms, or 1 to 5 heteroatoms atoms such as, but not limited to, oxygen, nitrogen, sulfur, selenium, , phosphorus, and their oxidized forms in the group, including alkyl , alkenyl, or alkynyl groups (which may be branched, straight-chain, or cyclic) (This is the case.)

[0047] Heteroalkyl-aryl / heteroalkenyl-aryl / heteroalkynyl-aryl: Aryl groups that are coupled or can be coupled to the compounds disclosed herein groups, where the aryl group is a heteroalkyl, heteroalkenyl, or heteroaryl group, respectively. The coupling is, or will be, via the terephthaloalkynyl group.

[0048] Heteroalkyl-heteroaryl / heteroalkenyl-heteroaryl / heteroalkynyl -heteroaryl: A heteroaryl that is coupled or can be coupled to a compound disclosed herein. and heteroaryl groups, where the aryl group can be heteroalkyl, heteroaryl, or heteroaryl groups, respectively. Coupling or coupling through a heteroalkenyl, or heteroalkynyl group You will start to like it.

[0049] Heteroaryl: At least one heteroatom to six heteroatoms, e.g., and four heteroatoms, such as, but not limited to, oxygen, nitrogen, and the like. , sulfur, selenium, phosphorus, and their oxidized forms within the ring. Such heteroaryl groups may have a single ring or multiple condensed rings. wherein the fused rings may or may not be aromatic and / or heteroatomic. may or may not contain atoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. Heteroaryl groups are groups that contain one or more groups other than hydrogen, such as aliphatic groups. , heteroaliphatic, aryl, heteroaryl, other functional groups, or any combination thereof etc. can be replaced by

[0050] Imidoester: -C(NH2+ ) OR a , in the formula R a are aliphatic, aromatic, aliphatic-aromatic, and heteroaliphatic The aromatic group is selected from aromatic, heteroaliphatic, and any combination thereof.

[0051] Ketone: -C(O)R a , in the formula R a are aliphatic, aromatic, aliphatic-aromatic, and heteroaliphatic-aromatic , heteroaliphatic, and any combination thereof.

[0052] Motor neuron disease: In some embodiments, this term refers to a neurodegenerative disorder that affects neurons in the brain and spinal cord. This can affect the nervous system and lead to muscle weakness, often with visible signs of wasting. Used to refer to a group of diseases with visible wasting symptoms. In some embodiments, and in some countries, the term "exercise" is used to designate a particular disease. The term "neuronal disease" can be used, and is synonymous with amyotrophic lateral sclerosis. It can be righteous.

[0053] Pharmaceutically acceptable excipient: A substance other than the active ingredient (e.g., a compound described herein). As used herein, an excipient is a compound that is included in a formulation of an active ingredient. , may be incorporated within the particles of the pharmaceutical formulation, or it may be physically intertwined with the particles of the pharmaceutical formulation. The excipients may also be mixed into solutions, suspensions, emulsions (also called emulsions), or The excipient may be, for example, a diluent for diluting the active agent. and / or can be used to modify the properties of pharmaceutical formulations. Excipients include, but are not limited to, anti-adherents, binders, coatings, enteric coatings, Disintegrants, flavorings, sweeteners, colorings, lubricants, glidants, adsorbents, preservatives, ajuva Excipients may include starches and modified starches. Starch, cellulose and cellulose derivatives, sugars and their derivatives, e.g., Sugars, polysaccharides and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, etc. Exemplary excipients include, but are not limited to, glycerides, sorbitol, PEG-14, PEG-24, PEG-34, PEG-44, PEG-45, PEG-46, PEG-47, PEG-48, PEG-49, PEG-50, PEG-51, PEG-52, PEG-53, PEG-54, PEG-55, PEG-56, PEG-57, Contains magnesium stearate, stearic acid, vegetable stearin, sucrose, and Sugar, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose cereals, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone ( PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 sucrose Cinnamate (also known as Vitamin E TPGS, or TPGS), Carboxymethylcellulose Roasted rice, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin Vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate Thorium, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate , sodium starch glycolate, tartrazine, aspartame, benzalkonium Ingredients: methylparaben, sesame oil, propyl gallate, sodium metabisulfite Contains sodium metabisulfite, sodium disulfite, etc.) or lanolin. can be.

[0054] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts of the compounds described herein are defined in the art. As will be known to those of ordinary skill in the art, various organic and inorganic counterions can be derived from and by way of example only, sodium, potassium, calcium, magnesium, ammonium ammonium, tetraalkylammonium, and the like; and the molecules are basic When it contains a functional group, it may be a salt of an organic or inorganic acid, for example, a hydrochloride, a hydrobromide, a tartrate, or the like. tartrate, mesylate, acetate, maleate, oxalate and the like. "Pharmaceutically acceptable acids" "Addition salts" are a subset of "pharmaceutically acceptable salts" and are intended to be salts that are biologically active compounds of the free base. In particular, embodiments of the disclosed compounds are Examples of suitable acids include, but are not limited to, various pharmaceutically acceptable acids, inorganic acids such as hydrochloric acid, hydrobromic acid, etc. , sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids. , for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, Oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethane Sulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid and It forms salts with other substances of the same type, etc. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" and are salts of inorganic bases, e.g. For example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron , zinc, copper, manganese, aluminum salts and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, sodium salts. primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and and basic ion exchange resins, e.g., isopropylamine, trimethylamine, diethyl Amines, triethylamine, tripropylamine, ethanolamine, 2-dimethylamine Ethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine Histidine, Caffeine, Procaine, Hydrabamine, Choline, Betaine, Ethylene Diamines, glucosamine, methylglucamine, theobromine, purines, piperazine, pipet Such as lysine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases include isopropylamine, diethylamine, ethanol, and the like. dicyclohexylamine, trimethylamine, dicyclohexylamine, choline, and caffeine (See, for example, SM Berge et al., "Pharmaceutical Salts" "Medical Salts," J. Pharm. Sci. (Ences., 1977; 66:1-19, which is incorporated herein by reference.)

[0055] Pharmaceutically / therapeutically effective amount: Amount sufficient to treat a particular disorder or disease or to alleviate one of its symptoms. sufficient to ameliorate or eradicate the above and / or prevent the occurrence of a disease or disorder The amount of a compound that constitutes a "therapeutically effective amount" is determined by the compound, the disease state, and the Varies depending on its severity, age of patient being treated, and the like A therapeutically effective amount can be determined by one of ordinary skill in the art. can.

[0056] Prodrug: A compound that is biologically active, especially the parent compound, most typically is converted in vivo, for example, by hydrolysis or enzymatic conversion in the intestine, Embodiments of the disclosed compounds. Common examples of prodrug moieties include, but are not limited to: Pharmaceutically acceptable esters and derivatives of compounds having active forms that possess a carboxylic acid moiety. Pharmaceutically acceptable esters of embodiments of the compounds of the present disclosure include esters and amide forms. Examples include, but are not limited to, phosphoric acid groups (also called phosphate groups) and carboxylic acid groups. Esters, such as aliphatic esters, especially alkyl esters (e.g., C 1-6 Alkyl Other prodrug moieties include phosphate esters. For example, -CH2-OP(O)(OR d )2 or a salt thereof, and the like, wherein R d H also is aliphatic (e.g., C 1-6 Acceptable esters also include cycloalkyl. esters and arylalkyl esters, such as, but not limited to, benzyl Examples of pharmaceutically acceptable amides of compound embodiments of this disclosure include: , including, but not limited to, primary amides, and secondary and tertiary alkyl amides (e.g., mono- and tertiary alkyl amides). and six carbon atoms). The amides and esters of the preferred embodiments can be prepared according to conventional methods. A thorough discussion of drug-resistant drugs is given by T. Higuchi and V. Stella, "P Pro-drug as Novel Delivery Systems ),” Vol. 14, ACS Symposium Series, and Bio Bioreversible Carriers in Drug Design ), ed. Edward B. Roche, American Pharmaceutical Association Association and Pergamon Press (American Pharmaceutical Association) and Pergamon Press, 1987, both of which are incorporated herein by reference. Incorporate it here.

[0057] Subjects: Mammals and other animals, e.g., humans, companion animals (pets, etc.) (Examples include dog, cat, rabbit, etc.), utility Animals (also called utility animals) and feed animals (also called feed animals) ); therefore, the disclosed methods are applicable to both human therapy and veterinary applications. is.

[0058] Thioketone: -C(S)R a where R a are aliphatic, aromatic, aliphatic-aromatic, and heteroaliphatic The aromatic group is selected from aromatic, heteroaliphatic, and any combination thereof.

[0059] Treating / Treatment: A subject, particularly a human or canine, with a disease or condition of interest. Treatment of a disease or condition of interest in an animal, and including, by way of example only, Includes, without limitation: (i) to prevent a disease or condition from occurring in a subject, or where particularly necessary; when such a subject is susceptible to the condition but has not yet been diagnosed with the condition; , prophylactic administration to improve symptoms associated with the condition; (ii) inhibiting a disease or condition, e.g., halting or slowing its progression; To make; (iii) alleviating a disease or condition, e.g., after a disease or condition or its symptoms causing a retreat; or (iv) stabilizing the disease or condition;

[0060] As used herein, the terms "disease" and "condition" are used interchangeably and Or a particular malady or condition may have no known causative agent (so that The etiology has not yet been determined, and therefore it is not yet a disease, but it is desirable. are recognized only as unrelated conditions or syndromes, where they are more or less specific to the clinician. The set of symptoms identified can vary.

[0061] Those of ordinary skill in the art will recognize substitution patterns ( It is recognized that examples are not intended to include groups such as methyl substituted with five different groups. Such impermissible substitution patterns would be obvious to one of ordinary skill in the art. In the formulas and specific compounds disclosed herein, hydrogen atoms are present. and any formal valence requirements, even if functional groups or other atoms are not exemplified. (However, it is not necessarily an example.) For example, [ka] The phenyl ring depicted as has a carbon atom attached to each carbon atom of the phenyl ring except for the "a" carbon. Hydrogen atoms are included even if such hydrogen atoms are not exemplified.

[0062] Any functional group disclosed herein and / or defined above may be any group unless otherwise specified herein. Unless otherwise specified, they can be substituted or unsubstituted.

[0063] II. Introduction

[0064] CuATSM is a highly expressed superoxide dismutase inhibitor, which is produced by the strict criteria established in this technology. dismutase ("SOD")SOD G93A It has been shown to be protective in mice; however, Due to the high copper affinity of CuATSM, this agent naturally enhances copper transport into the central nervous system ("CNS"). Cu becomes an inefficient delivery vehicle for bypassing the distribution system that limits Continuous treatment with ATSM inhibits the maturation of Cu,Zn SOD by the SOD copper chaperone (referred to as "CCS"). However, CuATSM has many drawbacks associated with its use. There are many adverse side effects, and the present technology is There is a need for improved therapeutic agents that can treat copper deprotection by CuATSM. The recovery rate is slow in vivo (also called in vivo). See Figure 1, which shows that CuATSM is C Figure 1 illustrates the slow copper delivery to the CNS in CS and CCSxSOD mice. It may take several weeks for c oxidase and SOD to replenish copper-deficient enzymes in the CNS. The reducing potential of uATSM is more negative than any common biological reducing agent. The release mechanism is Cu in CuATSM.2+ is Cu 1+ is reduced to The reduced CuATSM also potentially transports molecular oxygen to the copper carrier. Superoxide radicals (O2 .- The fast reoxidation of CuATSM compounds is This further limits copper release in non-hypoxic tissues and generates harmful species. A small proportion of copper ions (e.g., Cu 2+ or Cu 1+ ) is slowly released from the CuATSM complex. Furthermore, CuATSM does not show any significant effect in vivo for more than a few hours, which limits its acute therapeutic efficacy. It is metabolized by the liver within 2 days, and it is metabolized by its terminal methyl group (e.g., Demethylation of CuATSM results in the removal of one of the free amino groups (such as the methyl group). This creates a hydroxyl group that prevents metabolites from entering the CNS and other targets. Furthermore, CuATSMs have been shown to be effective in delivering copper to other non-human animals, e.g. Human serum albumin compared to albumin in mice, rats, dogs, etc. Its affinity for phospholipids is much higher than that of phospholipids, which limits its distribution to the CNS in human subjects. Limited. [ka]

[0065] Another limitation is that the ATSM ligand component of the CuATSM complex is pharmacologically active at the binding metal. and therefore can react in potentially undesirable side reactions. For example, ZnATSM (which contains zinc but not copper) has been shown to inhibit the ALS-SOD pathway in mouse models. However, when ZnATSM was applied to the skin of mice, These animals experience pain and the compound becomes ineffective in protecting the mice. Ligands such as GTSM and PTSM (both exemplified below) are useful in immature mice. This causes a significant delay in the growth of the [ka]

[0066] CuATSM has a compact symmetric structure, which contributes to another limitation associated with this compound. Due to its compact structure, the ATSM ligand moiety rapidly forms highly stable crystals. This allows for the synthesis of several compounds, which poses several challenges in the creation and formulation of this compound. This can cause oxidative stress, hindering its ability to function as a proper drug. The SM ligand components crystallize within seconds during their synthesis in all common refluxing solvents. therefore, the final step of the synthesis requires careful consideration, especially for producing the large quantities required for clinical use. Copper cannot be added later on the industrial scale required for this purpose.

[0067] Furthermore, the semithiocarbazide side arms of the ATSM ligands are quite flexible and It rotates easily around the central carbon bond joining the imine methyl group and the methyl group. However, it becomes difficult to form the final 1:1 complex using stoichiometric copper. Titration of copper onto the ATSM ligand to obtain the stoichiometric complex did not reveal the formation of stoichiometric behavior. (See Figure 2, which shows that as the copper addition approaches 1:1, the isosbestic point deviates and the desired (The results show undesirable non-stoichiometric behavior.) Mass spectrometry also revealed that three copper The formation of a complex with an empirical formula consistent with the atoms and two ATSM ligands was demonstrated. The formation of such complexes is problematic because they are difficult to remove. Several multimeric complexes of copper atoms associated with two or more ATSM moieties via mithiocarbazato groups were prepared. To minimize the formation of ATSM, the ATSM must be diluted. Due to the low solubility, dilute solutions are difficult to achieve even under reflux conditions.

[0068] Furthermore, CuATSM exhibits a high propensity for crystallization and It has a very high melting point. This crystallization and high melting point allows for the formation of orally active CuATSM compounds. Problems have been created in the solid dispersion method ( As such, the use of CuATSM is hindered. The production of formulations with limited dosages is particularly problematic due to the tendency of the matrix to gradually crystallize and become insoluble. Considering the tendency of CuATSM to form crystalline solids, this poses a limitation for the therapeutic use of this compound. Large amounts of crystallized CuATSM pass through the intestine and thereby contribute to gastrointestinal distress. In addition, the negative potential of CuATSM makes it very difficult for biological reducing agents to reduce it inside the cell. This reflects the slow effect of replenishing SOD and COX over several weeks. As a result, most of the administered CuATSM is eliminated in the urine, with the copper still remaining bound.

[0069] The compound embodiments described herein address the above limitations of CuATSM compounds. Embodiments of the compounds exhibit improved formulation properties. For example, disclosed embodiments include: In some compound embodiments, crystallization is suppressed, resulting in significantly less efficient crystallization than CuATSM. The disclosed embodiments also typically have a less negative reduction potential and do not crystallize in vivo. This contributes to improving their ability to release copper in the presence of hydroxybenzoates. , exhibit a reduction potential that allows for facile reduction compared to CuATSM, and therefore the disclosed compounds Embodiments of the invention are more effective in delivering copper to areas of interest, particularly the CNS. The advantageous features of embodiments of the disclosed compounds are as exemplified by the following disclosure: The present invention is not limited to the above.

[0070] III. COMPOUND EMBODIMENTS

[0071] Disclosed herein are embodiments of compounds having a structure satisfying Formula I below: The metal species ("M") complexed with the ligand (also called a ligand) is shown. Although shown, the present disclosure contemplates free ligands, where the metal species is not yet complexed. When such free ligands are not complexed with a metal species, the free ligands have the following formulas IA and It can exist in tautomeric forms as shown in IB and IB. As such, embodiments of the compounds disclosed herein include metal complexes having a structure satisfying Formula I. and free ligand moieties having structures satisfying formulas IA and IB. The embodiments of compounds (which include metal complexed compounds and and / or free ligand components) can be used as therapeutic compounds, e.g., It can be used to treat neurological disorders and other copper deficiency-related disorders. Cut. [ka]

[0072] Referring to Formula I, M is a divalent metal or a radioactive isotope thereof. Formulas I, IA, and IB may be used interchangeably. With reference to it, the following features can be applied: R 1 is an aliphatic or aromatic group, e.g., an aryl or heteroaryl group; and it is C a directly or indirectly (e.g., through a linker group) te) adhere; R 2 is hydrogen, aliphatic, heteroaliphatic, or aromatic (e.g., aryl or heteroaryl). where the aromatic group is C b directly or indirectly (e.g., phosphorus can be attached (such as through a carbonyl group); or R 1 and R 2 can be joined together to form a fused ring system containing from two to seven fused rings. can be bound together form a fused ring system comprising two to seven fus ed rings); and Each R 3 and R 4 is -NH2, -NHR, -NRR', -OR, -SR, or -C(R) 1-2 Regardless of R' where each R and R' can be selected from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or are independently selected from heteroaliphatic-heteroaryl. In some embodiments, R and and R', together with the nitrogen or carbon atom to which they are attached, form a heterocycle or heteroaryl. or a cycloaliphatic group; or R 3 and / or R 4 -C(R)1R' When R or R' is a double bond with a carbon atom, then one of the R or R' groups forms a double bond with a carbon atom, and the aryl The aryl group is further joined to the remaining R or R' group to form a aryl group.

[0073] R 1 and / or R 2 are indirectly connected to the imine carbon atom exemplified by each of the formulas via a linker group. In embodiments where the linker group is an aliphatic linker, a heteroaliphatic linker, a heteroaryl linker, Exemplary linker groups include alkyl, alkylene, aryl, aryl groups ... may be, but is not limited to, an alkyl, alkynyl, or alkenyl linker group; a polyalkynyl a olefinic linker group; a heteroatom selected from oxygen, sulfur, or NR (where R is Hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-hetero Heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl. carbonyl group; thioketone group; amide group; sulfone group; sulfoxide group; Phenyl; pyridyl; or other suitable linkers are included.

[0074] In some disclosed embodiments, M is copper (e.g., Cu 2+ ), iron, palladium, cadmium In yet further embodiments, M is Cu, manganese, or a radioactive isotope thereof. 2 + , 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ ,64 Cu 2+ ,or 65 Cu 2+ is.

[0075] In some embodiments, R 1 is phenyl, pyridyl, naphthyl, anthracenyl, quinolinyl, quinazolinyl, quinoxalinyl, benzoquinolinyl, benzoquinoxalinyl, benzoquinazolinyl, or the like. In some additional embodiments, R 1 is phenyl-(R 5 ) n , pyridyl-(R 5 ) n , naphthyl-(R 5 ) n , anthracenyl-(R 5 ) n , quinolinyl-(R 5 ) n , quinazolinyl-(R 5 ) n , quinoxalinyl-(R 5 ) n , benzoquinolinyl-(R 5 ) n , benzoquinoxalinyl-(R 5 ) n , benzoquinazolinyl-(R 5 ) n You can choose from 5 is independently an electron donating or electron withdrawing group (which is , the indicated aromatic group may be directly or indirectly, for example, an aliphatic or heteroaliphatic (e.g., through a linker), and n is 1 to 10, e.g., For example, it is an integer selected from 1 to 8, or 1 to 6, or 1 to 4. As shown, R 1 Any of these groups listed for the aryl group can be linked via a linker as described herein. The compound may be attached directly or indirectly to the remainder of the compound.

[0076] In certain disclosed embodiments, each R 5 are aliphatic; aryl; haloaliphatic; heteroaliphatic; Aliphatic-aryl;Heteroaryl;Aliphatic-heteroaryl;Heteroaliphatic-aryl; Heteroaliphatic-heteroaryl; Hydroxyl; -NH2; -P + (R d )3 or -N + (R d )3(There Each R d can be hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, or heteroaryl, regardless of aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl You can choose from: reels; nitro; thiol; halogen; phosphate (phosphate salt) ; phosphoryl; sulfino; sulfo; azido; linker-X group; or any such group can be chosen independently from the combinations of

[0077] With respect to the "Linker-X" group above, the linker group may be an aliphatic linker, a heteroaliphatic linker, In certain disclosed embodiments, the aryl group may be selected from a carbon, heteroatom, or aromatic group. , the linker may be a carbonyl-containing group; an alkylene oxide; an alkyl, alkenyl, or It can be an alkynyl group; an imidoester; or other linker group described herein; Alternatively, the linker may be derived from a maleimide, haloacetyl, or pyridyl disulfide. Also, with respect to the "Linker-X" group, X can be used to deliver the compound to the target. In certain disclosed embodiments, the moiety comprises a functional group suitable for promoting cleavage. wherein X is a target capable of promoting or facilitating the penetration of a compound through a membrane. In some embodiments, the targeting moiety The ty increases the delivery of compounds to the cytosol, e.g. 10-fold (compared to similar compounds without a targeting moiety) and / or or mitochondria at a 100-fold rate (similar to a compound containing no targeting moiety). It can be a moiety that has the ability to increase the amount of Embodiments of compounds satisfying these formulas may further include a counterion in embodiments. where X includes a charged group, thereby providing electron neutrality. For example, In some embodiments, each X is a phosphonium group, an ammonium group, or a positively charged The moieties may be independently selected from other such groups containing the moieties. In embodiments, a counterion used in combination with a hydrophobic, positively charged moiety can be a negatively charged counterion and is typically pharmaceutically acceptable. Exemplary negatively charged counterions include, but are not limited to, , halogens (e.g., Br - , Cl - , F - , I - ), sulfonate (also called sulfonate salt) ( Examples are mesylates, sulfates, hydrobromides, acetates, citrates, maleates, nitrate, tartrate, phosphate, nitrate, salicylate, fumarate, lactate This includes, for example, a card, or other such items.

[0078] In certain disclosed embodiments, the linker-X group described herein is —C(O)R c X, -C[(R c )2] m X, -[(CH2)2O] m X, -O(CH2) m X, -[O(CH2)2] m X, -NR c (CH2) m X, -(CH2)2NR c ] m X, -[NR c (CH2)2] m X, -C(=NH2 + )NR c X, -CH2C(O)NHR c X, -SR c X, or [ka] You can choose from; In the formula, each R c are independently aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaliphatic aliphatic-heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl each X is independently selected from -P + (R d )3 or -N + (R d ) You can choose from 3 Then, each R d are independently hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl Heteroaryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic aliphatic-heteroaryl; and each m is independently from 1 to 30, e.g., 1 is an integer selected from the range of 1 to 20, or 1 to 10, or 1 to 5, etc. It is possible.

[0079] Particularly disclosed embodiments include a linker-X group, which is a —C(O)(CH 2) 1-30 P + Ph3·Br - , -C(=NH2 + )N(CH2) 1-30 P + Ph3·Br - , -CH2C(O)NH(CH2) 1-30 P + Ph3·Br - , -S(CH2) 1-30 P + Ph3·Br - , -(CH2) 1-30 P + Ph3·Br - , -O(CH2) 1-30 P + Ph3·Br - , -NH(CH2) 1-30 P + Ph3·Br - , -C(O)[O(CH2)2] 1-30 P + Ph3·Br - , -C(=NH2 + )NCH2[O(CH2)2] 1-30 P + Ph3·Br - , -CH2C(O)NH[O(CH2)2] 1-30 P + Ph3 Br - , -[O(CH2)2] 1-30 P + Ph3 Br - , -C(O)(CH2) 1-30 N + Me3 ·Br - , -C(=NH2 + )N(CH2) 1-30 N + Me3·Br - , -CH2C(O)NH(CH2) 1-30 N + Me3·Br - , -S(CH2) 1-30 N + Me3·Br - , -(CH2) 1-30 N + Me3·Br - , -O(CH2) 1-30 N + Me3·Br - , -NH(CH2) 1-30 N + Me3·Br - , -C(O)[O(CH2)2] 1-30 N + Me3·Br - , -C(=NH2 + )NCH2[O(CH2)2] 1-30 N + Me3·Br - , -CHC(O)NH [O(CH2)2] 1-30 N + Me3·Br - , -S[O(CH2)2] 1-30 N + Me3·Br - , [ka] You can choose from.

[0080] In some embodiments, each R 5 is independently alkyl, alkynyl, alkynyl, Amine, carboxylic acid, ester, alkoxy, amide, cyano, ether, haloalkyl , silyl ethers, phosphines, thioethers, disulfides, isothiocyanates, isothiocyanates Socyanate, carbonate, ketone, sulfinyl, sulfonyl, thioketone, isononyl Tolyl, or any combination of such groups. In the embodiment, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0081] In yet another embodiment, R 1 is phenyl; -PhC[(Rc )2] m PPh3;-Ph[(CH2)2O] m PPh3;- Ph[O(CH2)2] m PPh3;-PhOH;-PhOPPh3;-PhNRPPh3;-Ph[(CH2)2NR] m PPh3, or -Ph[NR(C H2)2] m PPh3, where R is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaliphatic, aliphatic-heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl -PhO-aliphatic (e.g., -PhOMe, -PhOEt, -PhOPr, -PhOiPr, -PhOnBu) , -PhOiBu, -PhOtBu, where the OMe, OEt, OPr, or OBu group is used to separate the phenyl ring from the remainder of the compound. ortho, meta, or para to the phenyl ring relative to the position of attachment to Aliphatic (e.g., -PhN(R)Me, -PhN(R)Et, -PhN(R)Pr, -PhN(R)iPr, -PhN(R)nBu, -PhN(R)iB -u, -PhN(R)tBu, where the N(R)Me, N(R)Et, N(R)Pr, or N(R)Bu group is a phenyl ring bonded to a compound. located in the ortho, meta, or para position of the phenyl ring relative to the point of attachment to the remainder of the compound, and and wherein R is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl. aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl or -Ph(Z) 1-5 (Wherein Z is Cl, F, Br, or I, NO2, CF3, C(CF3)3) where halogen atoms and NO2, CF3, and C(CF3)3 groups can be present at all positions on the phenyl ring. or at the orthogonal position of the phenyl ring relative to the position at which the phenyl ring is attached to the remainder of the compound and n is 1.

[0082] In certain disclosed embodiments, R 1 is phenyl, -Ph p OMe, -Ph p [ O(CH2)] 1-10 PPh3, -Ph p [NH(CH2)] 1-10 PPh3, -Ph p Cl, -Ph p NO2, -Ph p CF3, or -Ph p C(CF3)3, -PhF5, and -P h p NMe2, where p is OMe, Cl, NO2, CF3, and / or C(CF3)3 groups are present in the remainder of the compound. This indicates that the phenyl ring is in the para position relative to the position where the phenyl ring is attached to the phenyl ring.

[0083] In some embodiments, R 2 can be selected from alkyl or phenyl. In the disclosed embodiments, R 2 is methyl, ethyl, propyl, butyl, or phenyl In some embodiments, the phenyl ring is R 1 As discussed above, one or more R 5 In still further embodiments, R 2 is the linker-X group as described above It can be.

[0084] In some embodiments, each R 3 and R 4 -NH2, -N(H)(CH2) n CH3, -N(H)(CH2) n C F3, -N[(CH2) n CH3]2, or -N[(CH2)n CF3]2, wherein each n is independently selected from 0 to is an integer chosen from the range 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In yet further embodiments, each R 3 and R 4 is independently -N(H) linker -X, -N[(CH2 ) n CH3] linker-X, or -N[(CH2) n CF3] linker-X, where The -X group is R 5 and R 2 As described above.

[0085] In some embodiments, the disclosed representative compounds have any one or more of the following formulae: In some embodiments, representative compounds may have a structure that satisfies the following: It can be the free ligand component of the complexes exemplified below.

[0086] [ka] [ka]

[0087] Referring to the above formula, each M, R 3 , R 4 , each R 5 , and n independently, are represented by Formulas I, IA, and and IB can be selected from the group listed above; 6 Regardless of R 5 Regarding the above In some embodiments, each R 5 Each R 5 Same as Each R 6 is each other R 6can be the same as or different from and / or R 5 and R 6 can be the same as or different from each other.

[0088] In still further embodiments, embodiments of the compounds described herein have any of the following formulae: In some embodiments, the exemplary compound may have a structure satisfying one or more of the following: The substance can be the free ligand component of the complexes exemplified below.

[0089] [ka] [ka] [ka]

[0090] Referring to the above formula, each R 1 , R 2 , R 3 , R 4 are as described above for Formulas I, IA, and IB. each linker and X group can be independently selected from the group listed; Each Y can be independently O, S, or or NR, where R is hydrogen, aliphatic, aryl, heteroaliphatic, or aliphatic. Aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, hetero (b) aliphatic, heteroaryl, or any combination thereof; each R is independently selected from methyl, trifluoromethyl, C(CF3)3; each m is from 1 to 30, e.g. , an integer selected from 1 to 20, or 1 to 10, or 1 to 5, etc. each q is from 0 to 30, e.g., from 1 to 20, or from 1 to 10, or from 1 to 5, etc. and each n is an integer selected from 1 to 5, inclusive. .

[0091] Representative compounds are provided having a structure satisfying any one or more of the formulas above. In some embodiments, the representative compound is the free ligand component of the complex exemplified below: It is possible.

[0092] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0093] Representative embodiments of compounds containing groups that facilitate transport across membranes are illustrated below: In some embodiments, the representative compound is the free ligand of the complex illustrated below. It can be a component.

[0094] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0095] Bromide counterions are included for the above compound embodiments. Those of skill in the art will appreciate that other counterions may be used to form therapeutically active compounds within the scope of this disclosure. It will be appreciated that in some embodiments, the TPP group may instead be a quaternary alkyl group. Also included in the present disclosure are embodiments of compounds in which the compound is a methylamine. For the embodiment, m can be as described for the formula above, and q can be 0 to 3. 0, for example, 1 to 20, or 1 to 10, or 1 to 5, etc. In some embodiments, q can be 0, 1, 2, 3, 4, 5, 6, or any integer. , 7, 8, 9, or 10.

[0096] In an independent embodiment, the compound is not or is other than: [ka]

[0097] In yet another independent embodiment, R 1 is methyl, and R 2 is methyl or water If R is prime, then 2 , R 3 , or R 4 At least one of the following must be linked as described here: Contains an anchor-X group.

[0098] IV.How to use

[0099] Embodiments of the compounds described herein are useful in treating neurological diseases (e.g., Neuronal diseases, other copper deficiency-related diseases, and / or mitochondrial dysfunction Mitochondrial deficiencies (e.g., cytochrome c oxidase) The compounds described herein are useful therapeutic agents for treating inflammatory bowel disease (inflammatory bowel disease). Examples of neurological and motor neuron diseases that can be treated using the methods include: Including but not limited to: ALS, Parkinson's disease, Lou Gehrig's disease, primary lateral sclerosis, Kennedy's disease ALS-related frontal temporal dementia, spinal myopathy, and cerebrospinal fluid dysplasia. Spinal muscular atrophy, Menke's disease, Alzheimer's Disease, Huntington's disease, multiple sclerosis, and neuropathies ), prion disease, and any other neurological disease associated with copper deficiency In additional embodiments, embodiments of the compounds disclosed herein can be used to treat canines. Copper deficiency-related diseases in animals, such as canine degenerative myelopathy, ALS-like canine disease, and and the like. In an exemplary embodiment, In some embodiments, the compounds are used to treat ALS, Parkinson's disease, Menkes disease, Leukemia, and other conditions. Gehrig's disease, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, It is used to treat primary lateral sclerosis and degenerative myelopathy in canines.

[0100] In some embodiments, the method comprises administering to a subject a therapeutically effective amount of one or more of the disclosed compound embodiments. A therapeutically effective amount of the antibody or antibody fragment is administered to a subject or sample (e.g., a biological sample, e.g., blood, This may involve administering to tissue or cell samples, etc. In embodiments, the method includes monitoring a subject for changes in neurological function (e.g., Monitor subjects for evidence of neuromuscular degeneration, muscle atrophy, and the like. In some embodiments, the compound may further comprise: The administration can be carried out using a pharmaceutical formulation, which can include the compound and a pharmaceutical dosage form. Any suitable pharmaceutical dosage form can be used, such as those described below. In certain disclosed embodiments, the pharmaceutical dosage form is a transdermal patch. h, also known as transdermal patches, tablets, capsules, lotions, or solution injections (Also called a table solution, injection, injection liquid, etc.) Further specific embodiments In this form, the compound can be taken orally as a solid dispersion, or it can be taken orally as a food. For subjects who cannot undergo percutaneous endoscopic gastrostomy, This can be done using a strostomy.

[0101] In some embodiments, the compound embodiments described herein may be substituted with other metals known in the art. AL at rates and levels not achieved by complexes such as CuATSM. Cu,Zn stabilizes SOD protein in ALS-affected tissue. Embodiments of the compounds described deliver metals (e.g., copper) into the CNS more rapidly than conventional drugs. and effectively stabilize SOD, thereby reducing the tendency to develop ALS or other neurological diseases. This prevents toxicity due to mutations in this protein that are typically present in subjects with SO. Each subunit of D contains both copper and zinc, which stabilize the SOD protein. Copper plays an important catalytic and structural role in enzyme activity, and Zinc can determine the folding of SOD. SOD also binds primarily to cytochrome c oxidase. They often accumulate as zinc-containing, copper-deficient forms awaiting interaction with CCS. Intracellular delivery of copper to these two enzymes is mediated by copper transporters and chaperones. It is provided by a complex network, and the net distribution is SOD and CCS are driven by a relative affinity gradient for copper in the CNS. Zinc has the highest affinity for unfolded SOD proteins. Therefore, immature SOD accumulates in the spinal cord and waits for copper from CCS to complete Cu,Zn SOD formation. Copper transport to other organs is much faster and therefore more efficient than that to the spinal cord and brain. As a result, copper-deficient SOD accumulation is typically higher in the CNS. The method involves administering a compound to a subject with one or more mutations in the superoxide dismutase gene. In certain disclosed embodiments, the mutations are not at or other than G85, H46, or H48 residues of the peroxide dismutase gene Such mutations affect the copper binding site and therefore the protection of SOD. Disable the effect.

[0102] Mouse and rat models of ALS produced by overexpression of mutant SOD are more promising than others. A more faithful model of the human disease than rodent models based on recently discovered ALS-associated mutations Mutant SODs have been shown to be associated with various diseases, including human, dog, mouse, rat, and zebrafish. Motor neurons in fish and other organisms such as Drosophila Produces a toxic gain of function that leads to degeneration of the ATP. Toxic gain-of-function occurs when SOD lacks the two metal cofactors that stabilize it. Partially unfolded intermediates are involved. In particular, highly expressed SOD G93A The mouse model in evaluating treatments for neurodegenerative diseases It has become the most widely used model by experts. Mice lose weight and 13 Signs of ALS appear in these mice as their hind limbs atrophy before reaching terminal paralysis at day 0. As such, this model is applicable to human subjects. in the treatment of neurological diseases such as ALS and other motor neuron diseases It is widely accepted as a model that correlates reasonably well with results on

[0103] A common feature of ALS-causing mutations is the binding of copper and zinc to the SOD protein. Although it is known in the art that the destruction of There is an unmet need in the field of ALS treatment. G93A Few treatments are able to extend lifespan by more than 10-15% in mice. and pharmaceutical agents that have been successfully converted into human treatments. There is no evidence that CuATSM is effective in treating ALS in human subjects. Although there is a growing number of compounds with similar structures, this particular compound has other similar structures, as discussed above. However, embodiments of the compounds described herein are not limited to CuATSM, CuGTSM, or transports metals (e.g., copper) at rates not achieved by CuPTSM, and therefore Embodiments of the compounds exhibit superior activity to CuATSM, CuGTSM, and CuPTSM derivatives. Furthermore, it is possible to overcome the challenges faced by these complexes (e.g., solubility issues). , pharmaceutical formulation issues, and synthesis issues) are not included.

[0104] The low reduction potential of the ATSM ligand towards cupric ion (in the 2+ ionized state), In other words, high copper affinity prevents copper release in most tissues, but not in damaged myocytes. In hypoxic tissues or cells with mitochondrial electron transport chains, copper selection however, only minor modifications of the CuATSM compound (e.g., diimine moieties) (removal of one or both methyl groups from the carbon atom of the functional group) also results in rapid copper oxidation. Such a compound is released rapidly, which can lead to toxicity in the SOD ALS model. As a substance, CuATSM exhibits high copper affinity, which naturally limits copper transport into the CNS. Therefore, it is an inefficient delivery vehicle to bypass the distribution system. Continued treatment is necessary to provide sufficient copper for CCS to complete the maturation of Cu,Zn SOD. However, such continuous treatment may also cause toxicity due to increased copper intake. Furthermore, considering the possibility of negative reduction of CuATSM, it is very difficult to reduce it. This is due to the slow onset of efficacy over several weeks in replenishing SOD and COX. As a result, the majority (e.g., >95%) of CuATSM is excreted in the urine with the copper remaining bound. In contrast, the reduction potential of embodiments of the compounds disclosed herein is such that the compounds are less reactive than CuATSM. This allows the ATP to be easily reduced, but remains superior in treating SODxCCS mice. This shows efficacy and also avoids potential toxic release of copper within the cell. , which illustrates the reduction (left) versus oxidation standard potentials (right) for the ligand components (see (Measured in water DMSO). Also, embodiments of the compounds described herein may be used in combination with CuATSM and It is possible that some embodiments may exhibit activity exceeding that of other ALS treatments. In some embodiments, the compounds disclosed herein can be administered in a manner that is not achieved using conventional procedures. However, it was possible to keep mice alive for at least 10 months compared to 5 months. Embodiments of the disclosed compounds also demonstrate that CuATSM delivers over a two-week period. It is possible to deliver more than four times the amount of copper that can be delivered with a conventional copper ion exchanger (see Figure 4 for an example).

[0105] Certain compound embodiments described herein may also be used for radioimaging. For example, embodiments of compounds containing radioactive metal isotopes can be used as imaging agents. In some embodiments, such imaging agents can be of any of the formulas described herein. It can contain a structure that satisfies either one of the above, and where complex metals (complex metals) "M" is copper, iron, palladium, cadmium, or manganese. In some embodiments, the compound includes a radioisotope. The state uses positron emission tomography (POSTOM) to image the subject. It can be used in combination with PET (positron emission tomography). In an exemplary embodiment, the metal is radioactive copper, typically 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , or 64 Cu 2+ or any combination thereof. The method can include administering an imaging agent to a subject or sample, and In additional embodiments, the method further comprises exposing the subject or sample to a PET scan. It can be done.

[0106] In certain disclosed embodiments, the presently disclosed compound embodiments are directed to a subject, e.g., a human In some embodiments, the method may be administered to a subject, such as a human or non-human animal. Embodiments of the compound can be formulated as pharmaceutical formulations. Pharmaceutical formulations that include, but are not limited to, at least one compound embodiment disclosed herein. and a pharmaceutically acceptable excipient, such as an adjuvant, carrier, stabilizer, or The present invention may include pharmaceutical preparations containing a combination thereof. It may also contain additional ingredients such as diluents, fillers, binders, humectants, preservatives, acids, and the like. and the like, and any and all combinations thereof. The compound embodiments described herein may be used alone or in combination with one or more additional compounds. in combination with other drugs, or as an adjunct to established treatments In some embodiments, the compound embodiments may be used in the treatment of the disorder being treated. May be used in combination with other therapeutic agents useful for the injury or condition. Exemplary other therapeutic agents that can be used to treat the diseases / conditions described herein include: These compounds include, but are not limited to, edaravone and riluzole. They may be administered sequentially in any order, by the same route of administration, or by different routes. do.

[0107] Pharmaceutical formulations containing embodiments of the compounds disclosed herein may be solid, liquid, and / or It can be administered as a pharmaceutically acceptable formulation in the form of a lotion. Suitable solid forms include, but are not limited to, tablets, capsules, powders, solid dispersions, and other In certain disclosed embodiments, the compounds described herein are The embodiment is advantageous in that it can be formulated by a solid dispersant method compared to CuATSM. Embodiments of the compounds disclosed herein have lower melting points (e.g., lower melting points) than CuATSM. is 50°C to less than 80°C, for example, 50°C to less than 70°C, or 50°C to less than 60°C, etc. Certain disclosed compound embodiments have a melting point of 140° C. to 180° C., e.g. For example, it melts in the range of 145°C to 170°C, or 150°C to 160°C, etc. As such, embodiments of the compounds described herein may be used in solid dispersions and / or or other solid dosage form and can therefore be administered orally. However, CuATSM is not suitable for solid dispersion formulations or other solid dosage forms. In embodiments, the compounds described herein can be formulated in oral dosage forms, where less than 25% of the total amount of the compound, e.g., less than 20%, or less than 15%, or less than 10%, or Less than 5% of CuATSM crystallizes when combined with pharmaceutical dosage forms. (also called pills) / tablets / capsules, which is not suitable for This is because it gradually crystallizes out of the matrix to form insoluble crystals. As indicated by Figure 1, this allows for the passage of large amounts of CuATSM into the intestine, and and therefore may cause gastrointestinal distress.

[0108] Embodiments of the compounds disclosed herein also have the advantage that they tend to resist crystallization. It may also be provided as a liquid or lotion formulation. The form of the emulsion may include, but is not limited to, an oil-in-water or water-in-oil emulsion, an aqueous gel composition, substance, or foam, film, spray, ointment, pessary form, suppository form, cream , as liposomes, or by administration to the skin or surface to which it is applied or which it comes into contact with. It can also be used in other forms embedded in a matrix for the slow or controlled release of compounds. In certain disclosed embodiments, the present invention includes liquids or lotions formulated for use in Such formulations may be combined with dermal patches to facilitate administration of the compounds. Both can be included.

[0109] The compound embodiments or compositions containing pharmaceutically acceptable components may be administered in a variety of modes. It may be formulated as appropriate, including but not limited to, topical, ophthalmic, oral, buccal (also called oral), Systemic, intranasal, injection (e.g., intravenous, intraperitoneal, subcutaneous, intramuscular), or intrathecal (subarachnoid and (also called intradermal, etc.), transdermal (e.g., penetrating agents, e.g., DMSO, etc.) By mixing with ), rectum, vagina, etc., or by inhalation or insufflation These include forms suitable for administration by insufflation (also known as insufflation).

[0110] For oral or buccal administration, pharmaceutical preparations are prepared in conventional formulations with pharmaceutically acceptable excipients. In the form of lozenges (also called troches), tablets or capsules prepared by such means The tablets or capsules may be coated with, for example, sugar, film, or enteric coatings. It can then be coated by methods well known in the art.

[0111] Liquid preparations of embodiments of the compounds disclosed herein for oral administration may be prepared, for example, as elixirs. They may take the form of solutions, syrups or suspensions, or they may be rehydrated with water or other liquids before use. For oral administration, the composition may be presented as a dry product for constitution with a suitable vehicle. The preparations may also be suitably formulated to give controlled release of the compound.

[0112] For topical application, embodiments of the compounds may be in the form of solutions, lotions, gels, ointments, creams, For transmucosal administration, the agent may be formulated as a solution appropriate to the barrier to be penetrated. Any suitable penetrant can be used in the formulation.

[0113] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, Intramuscular, intrathecal, or intraperitoneal injection, as well as transdermal, transmucosal oral, or Useful injectable preparations include those designed for intravenous or pulmonary administration. These include sterile suspensions, solutions or emulsions of the compound in a suitable vehicle. The formulation may also contain suspending agents, such as suspending agents, stabilizers and / or Dispersants and the like may also be included.

[0114] For rectal and vaginal administration, embodiments of the compound or compositions thereof may be administered in a conventional suppository form. A solution containing a base such as cocoa butter or other glycerides (suspended It can be prepared as a suppository (for retention enemas) or ointment.

[0115] In the case of nasal administration or administration by inhalation or insufflation, the compound embodiment and / or its The composition may be dispensed into pressurized packs or nebulizers using a suitable propellant. It can be conveniently delivered in the form of an aerosol spray from a pressurized aerosol. In this case, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules for use with inhalers or insufflators (also called insufflators) Cells and cartridges (e.g., capsules and cartridges composed of gelatin) ) is a mixture of the compound and a suitable powder base, such as lactose or starch. It may be formulated to contain a powder mix of

[0116] Dosages for embodiments of the compounds as disclosed herein will depend on a variety of factors and may vary with the benefits of the present disclosure. As will be appreciated by those of ordinary skill in the art, the age of the subject being treated will be These would include weight, general health, and severity of condition. The dosage may also be adjusted to suit the sex and / or species of the subject. The frequency of administration of embodiments may also be varied depending on whether the compound embodiments are administered during acute episodes of a condition (e.g., acute onset). whether they are dispensed for the treatment of a condition (also known as a steroid) or for the prophylactic treatment of a disorder In some embodiments, the loading dosage is administered to a patient with a neurological disorder. Initial treatment for newly diagnosed or suspected patients The loading dose can be administered once, twice, three times, or In some embodiments, a sufficient amount of Until copper is delivered to the central nervous system / brain (e.g., amounts of copper ranging from 15 to 20 mg) so that the loading dose is continuously maintained in the central nervous system for a period of time In yet further embodiments, a maintenance dose is administered up to four times per day. administration of a maintenance or prophylactic dosage, e.g., once per day Maintenance doses typically provide enough copper to meet daily CNS needs. provide.

[0117] An effective dosage can be estimated initially from in vitro assays. The initial dosage for use in the method is determined by the specific compound as determined in an in vitro assay. IC of the product 50 or EC 50 at or above circulating blood or serum concentrations of the active compound. The dosage can be formulated to achieve this. The dosage should take into account the bioavailability of the particular compound. and the amount of the active ingredient can be calculated to achieve such a circulating blood or serum concentration.

[0118] The embodiments of the disclosed compounds, such as dosages, e.g., therapeutically effective amounts, etc. The pharmaceutical formulations typically contain a dose greater than 0 mg / kg / day (e.g., 0.0001 mg / kg / day, 0.0 0.01 mg / kg / day, or 0.01 mg / kg / day, etc.) to 100 mg / kg / day In some embodiments, the dosage (or therapeutically effective amount) is from 0.0025 mg / kg to 30 mg / kg. kg or 0.0025 mg / kg to 1 mg / kg, administered at least once daily ( For example, 0.01mg / kg to 0.5mg / kg or 0.05mg / kg to 0.15mg / kg The total daily dosage is 0.1 mg / kg to 5 mg / kg per day, or 20 mg / kg per day. g per day (e.g., 0.5 mg / kg to 10 mg / kg per day, or In some embodiments, the dose may be from 0.7 mg / kg to 2.5 mg / kg / day. The dosage can be a loading dose, which can range from 10 mg / kg / day to 100 mg / kg / day. The compound (or pharmaceutical formulation thereof) is administered in an amount ranging from In yet further embodiments, the dosage may be a maintenance dosage. , which includes administering the compound (or its pharmaceutical equivalents) in amounts ranging from 1 mg / kg / day to 50 mg / kg / day. In yet a further embodiment, the dosage may include administering a predetermined formulation. The prophylactic dosage may range from 0.1 mg / kg / day to 30 mg The compound (or pharmaceutical formulation thereof) may be administered in amounts ranging from 100 mg / kg / day to 100 mg / kg / day. It can include.

[0119] In still further embodiments, for example, human and / or canine subjects are administered In certain such embodiments, dosages, e.g., therapeutically effective amounts, of the disclosed Such embodiments of the compound or pharmaceutical formulations thereof typically have a dose of less than 0 mg / day. Higher doses (e.g., 0.0001 mg / day, 0.001 mg / day, or 0.01 mg / day) In some embodiments, the dosage (or therapeutic effect) may range from 0.1 mg / day to 100 mg / day. The effective dose may range from 0.0025 mg / day to 30 mg / day, or from 0.0025 mg / day to 1 mg / day. and administered at least once daily (e.g., from 0.01 mg / day to 0.5 mg / day, or 0.05 mg / day). g / day to 0.15 mg / day). The total daily dosage ranges from 0.1 mg to 5 mg per day, or 2 0 mg (e.g., 0.5 mg / day to 10 mg / day, or 0.7 mg / day to 2. In some embodiments, the dosage is a loading dose. can be administered by administering the compound (or compounds) in amounts ranging from 10 mg / day to 100 mg / day. In yet additional embodiments, the method may further comprise administering a pharmaceutical formulation thereof to the subject. The dosage can be a maintenance dosage, which can include amounts ranging from 1 mg / day to 50 mg / day. and administering the compound (or a pharmaceutical formulation thereof) to the subject. In additional embodiments, the dosage can be a prophylactic dosage, which can include from 0.1 mg / day The compound (or pharmaceutical formulation thereof) is administered in amounts ranging up to 30 mg / day. may include:

[0120] Compositions containing one or more compound embodiments disclosed herein typically contain a total weight percentage of Depending on the sample, the compound may range from greater than 0 up to 99%. Compositions containing one or more compound embodiments disclosed herein may contain from 1 to 20 total weight percent compound, and 80 to 99 weight percent of at least one pharmaceutically acceptable salt thereof Contains tolerable ingredients.

[0121] In some embodiments, the CCSxSOD mouse data may reflect the responses of human ALS patients. This is because the balance of CCS with SOD is closer to that of humans than other SOD mouse models of ALS. In an exemplary embodiment, a dosage of approximately 10 mg / kg / day is used to treat mice. In this embodiment, the dosage is divided into two treatments per day. To adapt to humans, two factors are taken into account: the allometric growth from mouse to human; Scaling (also known as allometric scaling) is recommended by the FDA. The second is the mutation of the SOD gene. The fact that the number of ALS patients in the United States is approximately 30 copies compared to human ALS patents is a significant factor. So the average dose is 5 / 360 = 0.014 mg / kg (or The copper content is calculated as approximately 1 / 6 of the weight of the compound described here. Thus, two doses of 1 mg per day would provide approximately 0.3 mg of copper per day. do.

[0122] V. How to Create Compounds

[0123] Disclosed herein are method embodiments for making the compound embodiments described herein. In certain disclosed embodiments, the method comprises the steps of any of the method embodiments described below. The method may include using any one or more of the following ligands: forming a complex between the ligand and the metal provided by the metal precursor; The method can include exposing the ligand component to a metal precursor composition to form Those of ordinary skill in the art having the benefit of this disclosure will readily appreciate that the methods described herein are The following schemes can be adapted to prepare embodiments of the contemplated compounds: It will be recognized that the compounds described herein may not be expressly included in the present application. The embodiment remains dissolved in the refluxing solvent, which is a complexing metal. In certain disclosed embodiments, the present invention facilitates one-pot synthesis involving the addition of a hydroxybenzoate (e.g., hydroxybenzoate) to a hydroxybenzoate (e.g., hydroxybenzoate). The yield of the described method can be as high as 99%.

[0124] In some embodiments, the ligand moiety of the compound embodiments described herein is represented by Scheme It can be prepared using the method illustrated in Scheme 1. , ligand precursor compound 100 (or a combination of ligand precursor compounds 100 and 100′, e.g. , so R 3 and R 4 (such as a different group) to form the diimine product 104 The diketone reactant 102 can be exposed to the diketone reactant 102 for the reaction. Suitable solvents include those typically used in organic synthesis. and at temperatures above ambient (also known as ambient) temperatures ( For example, temperatures such as reflux temperature can be used. [ka]

[0125] Diimides can be obtained by preparing the diketone analogs of formula 204 (also called diketone analogs). To generate other analogs of product 104, the method illustrated in Scheme 2 can be used. The method of Scheme 1 can be modified by, for example, adding any suitable An appropriate solvent can be used, and the catalyst can be a metal-containing catalyst, e.g., a cobalt-containing catalyst. (Example: CoCl2) to create diketone compound 204. For this purpose, benzaldehyde compound 200 can be used; benzaldehyde analogs are commercially available (e.g., 4-(trifluoromethyl)benzaldehyde is available from Sigma Aldrich). and / or the benefit of this disclosure. These compounds can be readily synthesized using methods known to those of ordinary skill in the art. As illustrated in Scheme 3, the diketone analog compound having formula 204 can be prepared by pre-liganding. The ligand precursor compound 100 is reacted with the ligand precursor compound 100 (or a combination of the ligand precursor compounds 100 and 100'). can. [ka]

[0126] An exemplary method for preparing a particular species of ligand moiety is illustrated in Scheme 4. To utilize analog compounds obtained using the methods of Schemes 2 and 3, Other analogs can be made by modifying the method of 4. [ka]

[0127] To provide embodiments of the compounds disclosed herein, compounds of formula (I) prepared using the methods described above are 300 (and / or diimine compound 104) in combination with a metal In some embodiments, the diimine compound can be exposed to a metal precursor composition. The metal component of the metal precursor can be selected to provide compound 500, as illustrated in Scheme 5. To provide this, the ligand component will form a complex. [ka]

[0128] In additional embodiments, embodiments of the methods for making compounds containing linker-X groups can be used. A suitable method for preparing such compounds is shown in Scheme 6 below. and 7. Those of ordinary skill in the art having the benefit of this disclosure will be able to 3 Mori The method can be modified so that the anchor-X group is are substitution reactions and reactions that will be recognized by those of ordinary skill in the art with the benefit of this disclosure. It will be appreciated that this can be accomplished using functional group modifications. The precursor compound 600 used to form the ligand component containing the X group is shown in Scheme 8. The method can be prepared using the methods exemplified below. [ka] [ka]

[0129] Representative embodiments for creating the Linker-X group are illustrated below in Scheme 9: Schemes 10 and 11 show representative methods for coupling the linker-X group to the precursor. Illustrated are methods for forming ligand moieties containing linker-X groups. [ka] [ka]

[0130] In some embodiments, the methods described herein can be used to identify metals and corresponding ligands. A 1:1 complex can be formed between the components. As such, the methods described herein This embodiment is particularly well suited for large-scale synthesis. As such, the methods described herein To produce gram-scale and even kilogram-scale quantities of embodiments of the compounds of The method can be used to prepare even higher order complexes (e.g., complexes containing one or more ligands). avoiding the formation of compounds containing two or three metal atoms complexed to a metal moiety; and Thus, complex separation techniques required to separate the reaction products are avoided. [Example]

[0131] VI. Examples

[0132] General methods for mass spectrometry assays

[0133] Tissue preparation for SOD and cytochrome c oxidase assays - Whole brain and spinal cord The transgenic mice were euthanized and rapidly dissected, then placed in liquid nitrogen. The samples were immediately frozen and then stored at -80°C until use. To prepare brain tissue for the ROM c oxidase assay, slice it with a razor blade. The temperature at which the fragile frozen tissue can be warmed to the temperature at which it will be possible to freeze it (approximately -10°C) was the maximum temperature at which it could be frozen. First, the frozen brain was placed on a plate on top of a slab of dry ice. The brain and surrounding tissue were cut into sections approximately 1 mm thick with a razor blade. Three punches of approximately 250 μg each were isolated from each mouse tissue, Technical replicates were provided for the analysis and for the cytochrome c oxidase example. The Cahn 25 Automatic Electrobalance (Cerritos) The samples were weighed using a 1000-kJ / kg ion exchange membrane (California, USA) with a sensitivity of ±0.1 μg. VWR Handheld cordless motorized homogenizer Homogenize the tissue punch for 12 seconds using a homogenizer to obtain a homogenized solution of 5 μg tissue / μl. The concentration of the homogenization buffer (also called buffer solution) The homogenization buffer (prepared fresh daily) consisted of 10 mM ammonium acetate, pH 7.0. For SOD measurement, 300 nM bovine SOD (Sigma) was used as an internal standard. The ratio of human SOD to bovine SOD internal standard was used to detect SOD in mouse tissues. The concentration of human SOD was calculated. After homogenization, the sample was transferred to an Eppendorf tube. Centrifuge in a Dorf 5415 R centrifuge for 2 minutes at 16,000 x g at 4°C to pellet cell debris. The supernatant was then transferred to a clean tube for mass spectrometry or cytochrome c oxidase assay. The reproducibility of downstream assays was evaluated by measuring the amount of lysate in a 1.7 ml plastic centrifuge tube. This was achieved by homogenizing in a volume between 100 μl for each tissue punch.

[0134] Mass spectrometry - pipette tips, e.g., C4 ZipTips (R)(商標) (C4 Zip Tip) (Mi Millipore, Billerica, MA, USA, etc. Human SOD from mouse brain supernatant was bound and desalted using a method such as ZipTip (R) The preparation of the solution was first wetted with three volumes of 10 μl of acetonitrile, then 10 μl of The samples were then rinsed three times with 10 ml of water. (R) 10 μl of sample supernatant across the matrix Wet ZipTip by aspirating ten times, then rinsing eight times with 10 μl of water (R) bound to the matrix.

[0135] Finni configured for electrospray ionization (ESI) in positive ion mode LTQ-FT Ul with Finnigan Ion Max API source tra hybrid linear ion trap-Fourier transform ion cyclotron resonance mass spectr meter (LTQ-FT Ultra Hybrid Linear Ion Trap-Fourier Transform Ion Cyclometer All quality control data were obtained from a 1000kJ / s 1000kcal ion resonance mass spectrometer (Thermo, San Jose, CA). All SOD quantification was performed using a linear inversion technique in the scan range of 800 to 2000 m / z. This was performed using on-trap, which allowed for the detection of multiple charge states of SOD +9 to +13. The solvent used for mass spectrometry was 30:70 acetonitrile:100 μM formic acid. The solvent was water. (R) It passes through a 0.22 micron filter and and flowed directly into the electrospray needle.

[0136] To assay for the presence of the C57-146 disulfide bridge normally found in mature SOD, S-methyl methanethiosulfonate (MMTS) was added to the homogenate before mass spectrometry analysis. MMTS reacts with free sulfhydryls to add a mass SOD-WT (wild type) forms one methyl disulfide that can be detected by the assay. There is a cysteine ​​residue, Cys6, which faces the interior of the beta barrel of SOD and is normally solvent accessible. C57 and C146 form an intramonomer disulfide bridge in mature SOD, and does not react when crosslinks are formed; and C111 is usually available for reaction. Therefore, the extra mass of one SCH3 group is due to the presence of the C57-146 disulfide bridge. The three SCH3 masses indicate that the disulfide bridges have been reduced. did.

[0137] Data were quantified in a custom Matlab program. Peak intensities of Human SOD apo, 1 mtl, and 2 mtl across all charge states The mature SOD was calculated as follows: Superoxide disulfide containing both copper and zinc and with oxidized intramolecular disulfide bonds Immature SOD is defined as a mutase protein. It is a mutase protein that is dependent on either copper or zinc. Superoxide dismutase protein lacking or with reduced intramolecular disulfide bonds It is defined as protein.

[0138] Cytochrome c oxidase assay - Assay buffer contains 20 μM EDTA and 24 μM ammonium peroxidase. 30 μM reduced cytochrome P450 in 50 mM potassium phosphate buffer pH 7.0 containing 10 μg / ml catalase The final dilution of the reduced cytochrome c stock contained should yield an absorbance of 0.7 at 550 nm. To start the assay, add 2 μl of CNS Tissue homogenate was added to 1 ml of assay buffer at 25°C, and following reduction of cytochrome c, The decrease continued over time at 550 nm. The absorbance at 550 nm was then subtracted from the absorbance at 580 nm. The change in absorbance was monitored over a 1-minute period. Then, 2 μl of 100 mM sodium cyanide was added and the change in absorbance was measured for another 20 seconds. Cyanide inhibits the activity of cytochrome c oxidase and The enzyme activity was calculated per mg wet tissue weight according to the following rule: It is expressed in units of 1.0 μmol of ferrocytochrome c per minute. will oxidize (a) at 25°C and pH 7.0. The values ​​reported here are consistent with those in the literature.

[0139] Example 1

[0140] Using the high-resolution mass spectrometry method described above, we were able to identify SOD proteins in the ventral spinal cord of ALS-affected tissues. These assays allow direct quantification of copper and zinc binding to proteins. In the spinal cord of heterozygous SOD mice, almost half of the SOD protein was Cu,Zn SOD, whereas S The other half of the OD protein contains primarily zinc rather than copper, and effective copper delivery requires We also demonstrate that co-expression of CCS may be required (see Figure 5). Although we do not wish to be influenced by these results, currently, these results are G93A Copper's effect on SOD in the mouse CNS The rate-limiting process occurs when the load is too slow to keep pace with SOD synthesis, and the human SOD suggest that this may be due to the limited amount of endogenous mouse CCS compared to protein. In certain disclosed embodiments, the assay is Embodiments of the compounds are effective therapeutics in the treatment of neurological disorders. This can be used to support the idea that a substance can be useful as a therapeutic agent.

[0141] In some embodiments, CCSxSOD wt Mice were tested for the ability of embodiments of the compounds described herein to penetrate the CNS. To determine how well cytochrome c oxidase and SOD can be recruited in In some embodiments, the mouse pups are 4- or 6-month-old. Treatment was initiated on day 1 and followed for 6-21 days before sacrifice, and the two enzymes were administered to CNS tissue. Assay in SO by mass spectrometry using the mass spectrometry assay discussed above. Copper uptake in D is followed.

[0142] Example 2 This example shows that CSSxSOD is better than CuATSM. WT Maturation of copper-deficient SOD in transgenic mice. To make the process even more efficient, embodiments of the compounds disclosed herein may deliver copper. In this example, CuATSM inhibits the growth of intact SOD. W T The specific compound described here increased mature SOD by 13 μM compared to mice. The embodiment of the present invention can show even higher increase, and CuPhMeTSM increases SOD by 60uM. The amount of immature SOD was also most significantly reduced by CuPhMeTSM. Without any evidence, it is currently believed that immature SOD is a toxic factor that causes motor neuron death in vivo. It is most likely that it is involved in the production of SOD.

[0143] Example 3 This example demonstrates that embodiments of the compounds disclosed herein also have anti-inflammatory properties in the brain (Figure 7A) and spinal cord (Figure 7B). It also shows superior activity to CuATSM in increasing COX activity in the In this example, for the CuPhMeTSM compound, there was an increase in COX activity to almost twice the extent of CuATSM (Figure 1). The compound was administered together with DMSO at a dose of 50 mg / kg / day once daily for 4 days. The nitroanalogue was administered starting from day 1 and measured on day 21. Although not as effective as the CuPhMeTSM embodiment, other analogs showed increases, e.g. , halogenated analogs, etc. Figures 7A and 7B illustrate the results from this example. and evaluating the efficacy of embodiments of the compounds disclosed herein in increasing COX activity. The sample size for the number of mice in each group is indicated by the numbers. indicates the level of COX activity in untreated mice. COX activity in untreated SODxCCS mice was The IL-10 level was consistently 0.04 units / mg at all ages, and two mice survived to 21 days. (Figure 6A) and 6B, CuPhMe = copper phenylmethyl TSM; CuNO2PhMe = copper 4-nitrophenylmethyl TSM; CuCl-PhMe = copper 4-chlorophenylmethyl; TSM; CuBenzil (Cu benzyl) = copper diphenyl SM; Cu-MeO Benzil = copper di-4-methoxyphenyl TSM.

[0144] Example 4 In this example, G93A SODxCCS mice were treated with 50 mg / kg / day of CuPhMeTSM starting at 4 days of age. The compound was able to maintain survival of six G93A SODxCCS mice for 300 days. It was possible (n=6). The results are illustrated in Figure 10. Currently, there is no obvious toxicity from the treatment. There was none.

[0145] Example 5 In this example, titration curves obtained from the addition of copper to embodiments of the ligands described herein are compared. Figure 2 shows a titration where copper is added to the ligand ATSM, except that the copper addition is 1:1. As they approach, the isosbestic points move farther apart, indicating the formation of undesirable non-stoichiometric behavior. The ligand produced a clean isosbestic point and formed a 1:1 complex with NO2PhMeTSM. Ligands also exhibit similar reactivity. For example, Figure 2 (which shows the copper titration curve for the ATSM ligand) 8 and 9 (which show the copper titration curves for the PhMeTSM and NO2PhMeTSM ligands) As can be seen in Figure 2, successive additions of copper (each addition increases the ATSM ligand) The absorbance increased with a clear apparent isosbestic point at 354 nm. However, as the copper concentration approaches 1:1, some copper atoms and at least two ATSMs The isosbestic behavior was lost due to the formation of a third type of complex involving the ligand. With successive additions of copper (each addition was 25% of the ligand concentration), the absorbance Clear peaks at 311 and 362 nm for SM and 302 and 363 nm for NO2-PhMeATSM The copper concentration increased with the isosbestic point (Figures 8 and 9). At a ratio of 1:1, the isosbestic behavior was preserved, unlike ATSM. These data are consistent with the Cu PhMeTSM and other analogs described herein exhibit chemical stability suitable for large-scale synthesis, and Therefore, we confirm its usefulness and applicability in the industrial and pharmaceutical fields.

[0146] CuPhMeTSM and other compound embodiments described herein have physiologically beneficial effects, as illustrated in FIG. Reduction potentials that release copper through reduction are more easily achieved with commercially reasonable reducing agents. The specific compounds described herein have the following intermediates: The steric strain created by the phenyl group in the embodiment (see Figure 11) is 1+ Stabilize The oxidation potential of CuATSM is higher than that of CuPhMeTSM. This indicates that it is more susceptible to oxidation by approximately 40 mV.

[0147] Example 6

[0148] Synthesis of CuPhMeTSM - In a 50 ml round bottom flask, 20 ml of absolute ethanol was heated in an oil bath. The mixture was heated to 75°C and stirred continuously. 15 mmol (millimoles) of solid 4-methylsemi- The ocarbazide was thoroughly dissolved, and then 7.5 mmol of 1,2-phenylpropanedione (1 ml) was added. Five drops of concentrated sulfuric acid were added to initiate the reaction and allowed to stir for an additional 30 minutes. The mixture was cooled to room temperature and then refrigerated overnight. The filtrate was cooled and washed with cold water. and dried under high vacuum. The PhMeTSM ligand was isolated in >70% yield.

[0149] The ligand was redissolved in hot methanol and 1:1 dissolved in methanol. CuPhMeTSM formed a solid red precipitate, which was dissolved in cold water. It was further washed to remove excess copper and then dried under vacuum.

[0150] Example 7

[0151] 6-Bromohexylammonium bromide [ka] A small amount of 6-aminohexanol (0.5090 g, 4.27 mmol) was added to a solution of 48% HBr (5.10 mL) at 0°C. Once the 6-aminohexanol was dissolved, the reaction was warmed to room temperature and then refluxed. The mixture was cooled to 80° C. and heated to 80° C. TLC (1:1 Et The consumption of the starting alcohol was monitored with HCl (OAc:MeOH). The reaction was complete after 20 hours and The reaction was complete after 20 hours and the solution was concentrated in vacuo to give a yellow A tan solid was produced, which was recrystallized from toluene / ethanol (50:1). This gave a white solid.

[0152] Data:R f 0.33 (1:1 EtOAc:MeOH) 1 HNMR (400 MHz, D2O) δ 3.46-3.41 (2H, t, J = 7), 2.96 -2. 89 (2H, t, J = 8), 1.84 -1. 75 (2H, m), 1.64 -1.55 (2H, m),1.43-1. 30 (4H, m).

[0153] 6-(Boc-amino)hexyl bromide [ka] 6-Bromohexylammonium bromide (0.100 g, 0.383 mmol) in 5.00 mL of anhydrous DCM Triethylamine (0.11 mL, 0.804 mmol) was added dropwise to the stirred solution, followed by The reaction was stirred at room temperature and ninhydride (0.092 g, 1.10 mmol) was added. The reaction was monitored by TLC using phosphorus stain. After 20 hours, all of the starting amine had been consumed. The reaction was concentrated in vacuo to give a white solid, which was dissolved in H2O and The organic layer was dried over Na2SO4 and extracted 3x with 10.00 mL of EtOAc. Filtration and concentration in vacuo provided a brown oil as the desired product.

[0154] Data:R f = 0.57 (1:1 EtOAc:MeOH) ninhydrin stain. 1 HNMR (400 MHz, DMSO) δ 7 .94-7.86 (3H, m) 7.86-7.65 (12H, m), 6.80-6.70 (1H, t ), 3.64-3.50 (2H, m), 2.91 -2.80 (2H, q ), 1.59-1.40 (4H, m), 1.38-1.30 (9H, s), 1.30-1.19 (4H, m).

[0155] 6-(Boc-amino)hexyltriphenylphosphonium bromide [ka] 6-Bromo-boc-hexylamine (1.240 g, 4.42 mmol) was dissolved in 3.00 mL of CH3CN. Triphenylphosphine (1.43 g, 5.45 mmol) was added to the stirring solution. A stirrer was attached and the stirring reaction was brought to a gentle reflux. The reaction was monitored by TLC using a dye and after 16 hours all the starting amine was consumed. The solution was concentrated under reduced pressure to give a crude oil. Gradient: EtOAc to EtOAc / MeOH (4:1) followed by elution of unreacted triphenylphosphine The second fraction provided the desired product.

[0156] Data:R f = 0.10 (1:1 EtOAc:Hex). 1 HNMR (400 MHz, DMSO) δ 7.90-7.75 (m, 15H) , 6.74 (t, 1H, J = 5.3), 3.35 (m, 2H), 2.85 (m, 2H), 1.57-1.42 (m, 4H), 1.39-1.3 3 (s, 9H), 1.33-1.20 (m, 4H).

[0157] 6-(triphenylphosphonium)-hexylammonium-di-trifluoroacetate [ka] Hartwig, S. et al., Polym. Chem., 2010 , 1, 69-71 The Boc-amine was dissolved in 5.00 mL of anhydrous dichloromethane and placed in a 25 mL round-bottom flask at 0 °C. An equal volume of trifluoroacetic acid (5.00 mL) was added. The reaction was allowed to warm to room temperature and The reaction was concentrated and the ammonium trifluoroacetate salt was obtained. Supplied.

[0158] Data:R f =0.42 (2:1 EtOAc:MeOH 1% AcOH) 1 HNMR (400 MHz, DMSO) δ 10.132 (brs, 3H), 8.062-7.691 (m, 15H), 3.578 (m, 2H), 2.749 (m, 2H), 1.598-1.437 (m, 6H), 1 .332 (m, 2H).

[0159] 6-(triphenylphosphonium)-isothiocyanate hydroxide [ka] The ammonium trifluoroacetate salt was dissolved in 5.00 mL of DI H2O and then hydrated with K2CO3 at pH = 11. Carbon disulfide was added dropwise and the reaction was stirred at room temperature and analyzed by TLC. After 3 hours, no starting material was observed and the reaction was cooled to 0°C. Trichlorotriazine in 0.00 mL is added dropwise and conversion is observed by TLC. The solution was vigorously stirred for 30 minutes until the pH reached 1.0. The solution was then treated with 6M NaOH to pH 12. The reaction mixture was transferred to a separatory funnel and extracted 3x with DCM. The organic layer was dried over Na2SO4 and filtered. and concentrated under reduced pressure to give a viscous yellow oil.

[0160] Data:R f = 0.75 (2:1 EtOAc:MeOH) 1 HNMR (400 MHz, DMSO) 7.85-7.69 (3H, m), 7. 85-7.69 (12H, m), 3.66-3.49 (4H, m), δ 1.70-1.30 (8H, m).

[0161] 6-[(hydrazinylthioxomethyl)amino]-hexyltriphenylphosphonium hydrochloride oxide [ka] Hydrazine hydrate (1.0 equivalent (eq.)) was added to 10.00 mL of MeOH in a 100 mL round-bottom flask. and heated to 75°C. The isothiocyanate (0.265g, 0.628mmol, 1.0 equiv) was added to 10.0 The reaction mixture was dissolved in 0 mL of MeOH and added dropwise over 1 h. The reaction was stirred for an additional 30 min. and then concentrated under reduced pressure. This was purified by column chromatography (100% ethyl acetate - Further purification by HCl (>20% MeOH / EtOAc) provided a white solid (0.251 g, 97% yield) .

[0162] Data:R f = 0.30 (1:1 EtOAC:MeOH) 1 HNMR (400 MHz, DMSO) δ 8.59 (1H, s), 7.9 9-7.65 (15H, m), 4.49 (2H, brs), 3.66-3.55 (2H, m), 3.44-3.45 (2H, m), 3.16 (1H, s), 1.60-1.36 (6H, m), 1.32-1.26 (2H, m).

[0163] Monosubstituted ATSM-diacetyl [ka] Diacetyl (1.00 mL, 11.38 mmol) was added to 20.00 mL of DI H2O and acidified with 5 drops of concentrated HCl. The solution was cooled to 0°C and then 4-methylthiosemicarbazide (1.08 g, 10.27 mmol) was added in portions over 1.5 hours. The mixture was then stirred for an additional 30 minutes. The white precipitate was filtered, washed with cold DI H2O, and further dried under reduced pressure to give a white solid (1.22 g, 68% yield).

[0164] data: 1 HNMR (400 MHz, DMSO) δ 10.59 (1H, s), 8.65 (1H, m), 3.06 (3H, d, J = 4.6), 2.42 (3H, s), 1.97 (3H, s).

[0165] Asymmetric TPP-diacetyl [ka] Add diacetyl (0.32 mL, 3.60 mmol) to 20.00 mL of DI HO and acidify with 5 drops of concentrated HCl. The solution was cooled to 0°C and then TPP-hexylthiosemicarbazide (1.49 g, 3. 27 mmol) was added portionwise over 1.5 hours. The mixture was then stirred for an additional 30 minutes. The resulting white precipitate was filtered and washed with cold DI H2O and further dried under vacuum. .

[0166] data: 1 HNMR (400 MHz, DMSO) δ 10.58 (1H, s), 8.63 - 8.59 (1H, t, J = 6.0), 7.95 - 7.68 (15H, m), 3.68 - 3.51 (4H, m), 2.39 (3H, s), 1.96 (3H, s), 1.57 - 1. 47 (6H, m), 1.38 - 1.31 (2H, m).

[0167] Asymmetric TPP / ATSM [ka] The monosubstituted diacetyl compound (0.7225 g, 4.17 mmol) was added to 50.00 mL of anhydrous DCM, followed by TPP -hexylthiosemicarbazide (0.172 g, 3.79 mmol) was added. Five drops of glacial acetic acid were added to the mixture. The reaction was stirred at room temperature for 4 hours until a yellow precipitate formed, which was filtered. and purified by flash column chromatography. 100% EtOAc to 30% MeOH / EtO A gradient to Ac provided the desired product in a 30% MeOH eluent. The material was obtained in 10% MeOH. The fractions were concentrated under reduced pressure to give a yellow solid (2. 13 g, 85% yield).

[0168] data: 1 HNMR (400 MHz, DMSO) δ 10.17 (1H, s), 10.13 (1H, s), 8.43 - 8.35 (2H , m), 7.94 - 7.24 (15H, m), 3.63 - 3.49 (4H, m), 3.04 (3H, d, J = 4.6), 2.21 (3H , s), 2.18 (3H, s), 1.60 - 1.47 (6H, m), 1.37 - 1.27 (2H, m).

[0169] TPP-containing copper-ligand complexes [ka]

[0170] Asymmetric TPP-ATSM In an oven-dried 250 mL round-bottom flask, add 4-methyl-3-thiosemicarbazide (1.0 eq.) Add 50.00 mL of absolute EtOH and mix with stirring until completely dissolved. The mixture was heated to 65° C. The appropriate TPP-compound (1.0 equiv.) was added dropwise to the stirred solution, followed by Five drops of concentrated H2SO4 were added. Within 5 minutes a precipitate formed. This was stirred overnight. Then The mixture is filtered and washed with deionized water, MeOH, and EtOH. [ka]

[0171] VII. Overview of Some Embodiments

[0172] Disclosed herein are embodiments of compounds having a structure satisfying Formula I as described herein. In this state, the following variable notations apply: M is a divalent metal or a radioactive isotope thereof; R 1 is an aliphatic or aromatic group, which is connected to C through a linker group a directly or indirectly The linker group may be an aliphatic linker, a heteroaliphatic linker, a heteroaryl linker, or a heteroaryl linker. an alkyl group, an aromatic group, or any combination thereof; R 2 is selected from hydrogen, an aliphatic, heteroaliphatic, or aromatic group, which is Through C b wherein the linker group is an aliphatic linker, a heterocyclic linker, or selected from an aliphatic linker, a heteroatom, an aromatic group, or any combination thereof; and teeth R 1 and R 2 are joined together to form a fused ring system containing two to seven fused rings und together form a fused ring system comprising two to seven fused rings); Each R 3 and R 4 is -NH2, -NHR, -NRR', -OR, -SR, or -C(R) 1-2 Regardless of R' where R and R' are selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaliphatic, aliphatic-heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl or wherein R and R' are independently selected from the group consisting of the nitrogen to which they are attached and the heteroaryl. or together with carbon atoms form a heterocyclic or heteroaryl group, or a cycloaliphatic group, respectively. or there R 3 and / or R 4 is -C(R)1R', then one of the R or R' groups forms a double bond with the carbon atom, and the remaining R or R' groups form an aryl group. and further joined with; and However, the following: (i)R 1 is methyl, and R 2is methyl or hydrogen, then R 2 , R 3 , or R 4 At least one of the groups includes a linker-X group, where the linker is a carbonyl- or the linker is selected from a group consisting of a substituted or unsubstituted alkylene oxide, an aliphatic group, an imide ester; , maleimide, haloacetyl, or pyridyl disulfides; and X is a functional group suitable for facilitating delivery of the compound to a target. and wherein the linker-X group is (CH2)2 is not or is other than N(CH3)3; and (ii) The compound is: [ka] provided that it is not or other than those.

[0173] In some embodiments, the compounds satisfy one or more of Formulas IIA-IIR, as described herein. and there, for the appropriate formula, 5 and R 6 is aliphatic; aryl; heteroaliphatic Aliphatic;Aliphatic-Aryl;Heteroaryl;Aliphatic-Heteroaryl;Heteroaliphatic-Aryl Heteroaliphatic-Heteroaryl; Hydroxyl; -NH2; Nitro; Thiol; Halogen ;phosphate;phosphoryl;sulfino;sulfo;azide; or -C(O)R c X, C[(R c )2] m X, -[(CH2)2O] m X, -O(CH2) m X, -[O(CH2)2] m X, -NR c (CH2) m X, -SR cX, -CH2C(O)NHR c X, -[ (CH2)2NR c ] m X, -NR c (CH2)2] m X, -C(=NH2 + )NR c X, or [ka] are independently selected from the formula c is aliphatic, aryl, heteroaliphatic, aliphatic-aryl Heteroaryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic each X is independently selected from the group consisting of -P + (R d )3 or -N + (R d )3 to irrelevant where each R d is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, hetero Heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic- heteroaryl, and each m is independently selected from 1 to 30. and n is an integer selected from 1 to 5.

[0174] In any or all of the above embodiments, the compound may have one or more of formula IIIA-IIIY'. and wherein, for the appropriate formula, each Y is independently selected from O, S, or NR. where R is selected from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, hetero Heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, heteroaliphatic-hetero aryl, or any combination thereof; each X is independently selected from a targeting moiety Yeti; each m is an integer selected from 1 to 30; each q is an integer selected from 0 to 30. is an integer; and n is an integer selected from 1 to 5.

[0175] In any or all of the above embodiments, M is Cu, Co, Ni, or any of their Radioactive isotopes, e.g., Cu 2+ , 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+ And so on.

[0176] In any or all of the above embodiments, M is Cu. 2+ , 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2 + , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+ is.

[0177] In any or all of the above embodiments, R 1 are phenyl, pyridyl, naphthyl anthracenyl, quinolinyl, quinazolinyl, quinoxalinyl, benzoquinolinyl, Benzoquinoxalinyl, benzoquinazolinyl, phenyl-(R 5 ) n , pyridyl-(R 5 ) n , Nakhchi Ru-(R 5 ) n , anthracenyl-(R5 ) n , quinolinyl-(R 5 ) n , quinazolinyl-(R 5 ) n , Kinokisari Nil-(R 5 ) n , benzoquinolinyl-(R 5 ) n , benzoquinoxalinyl-(R 5 ) n , or benzoquina Zolinyl-(R 5 ) n where each R 5 Aliphatic; Aryl; Haloaliphatic; Heteroaliphatic Aliphatic;Aliphatic-Aryl;Heteroaryl;Aliphatic-Heteroaryl;Heteroaliphatic-Aryl Heteroaliphatic-heteroaryl; Hydroxyl; -NH2; -P + (R d )3 or -N + (R d )3(so Here each R d is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl nitro; thiol; halogen; phosphate; phosphatase hydroxybenzoyl; sulfino; sulfo; azido; linker-X group; or any combination of such groups and n is an integer selected from 1 to 10.

[0178] In any or all of the above embodiments, n is 1 and R 5 is -C(O)R c X , -C[(R c )2] m X, -[(CH2)2O] m X, -O(CH2) m X, -[O(CH2)2] mX, -NR c (CH2) m X, -[(CH2)2NR c ] m X, -[NR c (CH2)2] m X, -C(=NH2 + )NR c X, -CH2C(O)NHR c X, -SR c X, or [ka] wherein each R c are aliphatic, aryl, heteroaliphatic, aliphatic-aryl, and heteroaliphatic. aliphatic-heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl each X is independently selected from -P + (R d )3 or -N + (R d )3 were chosen independently , where each R d is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaliphatic aryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl aryl; and each m is an integer independently selected from 1 to 30.

[0179] In any or all of the above embodiments, each R 5 is alkyl, alkynyl, Alkynyl, amine, carboxylic acid, ester, alkoxy, amide, cyano, ether, Silyl ethers, phosphines, thioethers, disulfides, isothiocyanates, iso Cyanate, carbonate, ketone, sulfinyl, sulfonyl, carbonothioyl, iodo and n is 1. .

[0180] In any or all of the above embodiments, R 1 is phenyl; -PhC[(R c )2] m PPh3 ;-Ph[(CH2)2O] m PPh3;-Ph[O(CH2)2] m PPh3;-PhOH;-PhOPPh3;-PhNRPPh3;-Ph[(CH2)2NR ] m PPh3, or -Ph[NR(CH2)2] m PPh3, where R is hydrogen, aliphatic, aryl, or heteroaliphatic Aliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl -PhO-aliphatic; -PhN(R)aliphatic, where R is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic Heteroaliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl. or -Ph(Z) 1-5 , where Z is Cl, F, Br, or I, NO2, CF3, C(CF3)3. and m is an integer selected from 1 to 30.

[0181] In any or all of the above embodiments, R 1 is phenyl, -PhOH, -PhOMe, - -PhCl, -PhNO2, -PhCF3, -PhC(CF3)3, -PhF5, or -PhNMe2, optionally where R 2 is selected from alkyl or phenyl.

[0182] In any or all of the above embodiments, R 2 is selected from alkyl and phenyl Be found out.

[0183] In any or all of the above embodiments, each R 2 , R 3 , and R 4 There is phosphorus Car-X groups are optionally included, where the linker is a carbonyl-containing group, alkyleneoxy or the linker is selected from maleimide, haloacetyl, aliphatic group, imide ester; and wherein X is a target of the compound. The moiety includes a functional group suitable for facilitating delivery to the subject.

[0184] In any or all of the above embodiments, the linker-X group is —C(O)R c X, -C[(R c )2] m X, -[(CH2)2O] m X, -O(CH2) m X, -[O(CH2)2] m X, -NR c (CH2) m X, -[(CH2)2NR c ] m X, -[NR c (CH2)2] m X, -C(=NH2 + )NR c X, -CH2C(O)NHR c X, -SR c X, or [ka] wherein each R c are aliphatic, aryl, heteroaliphatic, aliphatic-aryl, and heteroaliphatic. aliphatic-heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl each X is independently selected from -P + (R d )3 or -N + (Rd )3 were chosen independently , where each R d is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaliphatic aryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl aryl; and each m is an integer independently selected from 1 to 30.

[0185] In any or all of the above embodiments, the linker-X group is —C(O)(CH) 1-30 P + Ph3 Br - , -C(=NH2 + )N(CH2) 1-30 P + Ph3 Br - , -CH2C(O)NH(CH2) 1-30 P + Ph3 Br - , -S(CH2) 1-30 P + Ph3 Br - , -(CH2) 1-30 P + Ph3 Br - , -O(CH2) 1-30 P + Ph3 Br - , -NH(CH2) 1-30 P + Ph3 Br - , -C(O)[O(CH2)2] 1-30 P + Ph3 Br - , -C(=NH2 + )NCH2[O(CH2)2] 1-30 P + Ph3 Br - , -CH2C(O )NH[O(CH2)2] 1-30 P + Ph3 Br - , -[O(CH2)2] 1-30 P + Ph3 Br -, -C(O)(CH2) 1-30 N + Me3·Br - , -C(=NH2 + )N(CH2) 1-30 N + Me3·Br - , -CH2C(O)NH(CH2) 1-30 N + Me3·Br - , -S(CH2) 1-30 N + Me3· Br - , -(CH2) 1-30 N + Me3·Br - , -O(CH2) 1-30 N + Me3·Br - , -NH(CH2) 1-30 N + Me3·Br - , -C(O)[ O(CH2)2] 1-30 N + Me3·Br - , -C(=NH2 + )NCH2[O(CH2)2] 1-30 N + Me3·Br - , -CH2C(O)NH[O(CH2)2 ] 1-30 N + Me3·Br - , -S[O(CH2)2] 1-30 N + Me3·Br - , [ka] Selected from.

[0186] In any or all of the above embodiments, each R 3 and R 4 is the -N(H) linker -X, -N[(CH2) n CH3] linker-X, or -N[(CH2) nCF3] linker-X, chosen independently from Thus, the linker may be a carbonyl-containing group, an alkylene oxide, an aliphatic group, an imide ester, or a hydroxyl group. or the linker is selected from maleimide, haloacetyl, or pyridyl disulfide and wherein X is a targeting moiety.

[0187] In any or all of the above embodiments, each R 3 and R 4 -NH2, -N(H)( CH2) n CH3, -N(H)(CH2) n CF3, -N[(CH2) n CH3]2, or -N[(CH2) n CF3]2 was chosen independently , where each n is an independently chosen integer between 0 and 10.

[0188] In any or all of the above embodiments, each R 3 and R 4 is -N(H)(CH2)2CF3 and optionally R 3 and R 4 is -N[(CH2)2CH3]2, and / or each R 1 Oh BiR 2 is phenyl.

[0189] In any or all of the above embodiments, each R 3 and R 4 is -N[(CH2)2CH3]2 is.

[0190] In any or all of the above embodiments, each R 1 and R 2 is phenyl .

[0191] In any or all of the above embodiments, the compound may be any of the species disclosed herein. or, for example, selected from any one of the compounds in Table 3 and / or Table 4.

[0192] Also disclosed herein are pharmaceutical formulations or dosage forms, and delivery components, optionally in the form of patches (also known as transdermal patches), tablets, or the like. Choose from tablets, capsules, lotions, or liquid injections (also called injections or injection solutions). and where, when combined with a delivery component, it is less than 15% of the total amount of compound It just doesn't crystallize.

[0193] In some embodiments, the delivery component is a patch, tablet, capsule, lotion, Or it is a solution injection.

[0194] In any or all of the above embodiments, the pharmaceutical preparation or dosage form may contain azidopropyl phosphate. The composition may further comprise a medicament, a therapeutic agent, a pharmaceutically acceptable excipient, or any combination thereof. It can be enjoyed.

[0195] Disclosed herein are method embodiments, which comprise administering to a subject the compounds and / or antibodies disclosed herein. A therapeutic amount of a compound for use in a method of treating an animal is administered to a subject or sample. wherein the compound is a compound according to any or all of the above embodiments. It is a thing.

[0196] In some embodiments, the at least one additional therapeutic agent is administered sequentially or simultaneously with the compound. It is sometimes applied.

[0197] In any or all of the above embodiments, the at least one additional therapeutic agent is edta. Lavon or riluzole.

[0198] In any or all of the above embodiments, the subject is a human or a canine. .

[0199] In any or all of the above embodiments, the compound is administered prophylactically.

[0200] In any or all of the above embodiments, the therapeutic amount ranges from greater than 0 mg / day to up to 100 mg / day.

[0201] In any or all of the above embodiments, the subject is a patient with superoxide dismutase. In some embodiments, the mutations are Mutations at or near the G85, H46, or H48 residues of the oxidodismutase gene Other than et al.

[0202] In any or all of the above embodiments, the subject is a canine, and Canines are susceptible to canine degenerative myelopathy. Belongs to a species.

[0203] In any or all of the above embodiments, the subject is a patient with ALS, Parkinson's disease, Metformin-resistant Staphylococcus aureus (MSA), or Metformin-resistant Staphylococcus aureus (MSA). Associated with Kenneth's disease, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, and ALS Frontal temporal dementia, spinal muscular atrophy trophy), and degenerative myelopathy in canines; diseases due to copper deficiency or mitochondrial dysfunction; or There is a risk of developing it.

[0204] Also disclosed herein is a method for treating a motor neuron disease, comprising: a compound selected from the above compounds; or a method for treating motor neuron disease 1. A compound for use in treating a disease, wherein the compound is selected from one or more of the following compounds:

[0013] In some embodiments, the method includes administering to a subject a therapeutic amount of: [ka]

[0205] In some embodiments, the therapeutic amount ranges from greater than 0 mg / day to 100 mg / day. or the compound is administered in an amount ranging from .

[0206] In any or all of the above embodiments, the therapeutic amount is between 10 mg / day and 100 mg / day. / day, or the compound is administered in an amount ranging from It is carried out in.

[0207] In any or all of the above embodiments, the method comprises administering from 1 mg / day to 50 mg / day, or The compound may further comprise administering a maintenance dose of the compound ranging from It is administered in amounts ranging from .

[0208] In any or all of the above embodiments, the motor neuron disease is ALS, Leukemia, Frontotemporal cognition associated with Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, and ALS The disease is selected from the group consisting of spinal muscular atrophy, rheumatoid arthritis, and spinal muscular atrophy.

[0209] Also disclosed herein are methods for treating neurological disorders, diseases based on copper deficiency, or mitochondrial dysfunction. an embodiment of a compound for use in a method for the treatment of It has a structure satisfying Formula I, and wherein the variables of Formula I are as described herein.

[0210] In some embodiments, the neurological disease is a motor neuron disease.

[0211] In any or all of the above embodiments, the neurological disease is ALS, Parkinson's disease Related to Menkes disease, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, and ALS selected from certain frontotemporal dementias, spinal muscular atrophies, and canine degenerative myelopathy .

[0212] In any or all of the above embodiments, the method comprises administering to a subject suffering from a motor neuron disease. The method includes administering to a subject suffering from or susceptible to the disease a therapeutic amount of a compound. In the present invention, the subject carries one or more mutations to the superoxide dismutase gene.

[0213] In any or all of the above embodiments, the therapeutic amount is between 0.1 mg / day and 30 mg / day. Prophylactic dosages range from 100mg / day to 100mg / day.

[0214] In any or all of the above embodiments, the prophylactic dose may comprise superoxide In some embodiments, the method is administered to subjects who carry one or more mutations in the dismutase gene. In this case, the mutation occurs at residues G85, H46, or H48 of the superoxide dismutase gene. Not mutations or anything else.

[0215] In any or all of the above embodiments, the prophylactic dose is administered to canine degenerative It is administered to canines belonging to breeds susceptible to myelopathy.

[0216] Also disclosed herein are methods and compounds as disclosed herein, wherein M is 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+ The object or sample is and / or have or are at risk of developing motor neuron disease any of the embodiments of the compound described above for use in a method of diagnosing a subject; or A composition comprising all of: 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 6 5 Cu 2+ It is an embodiment of the present invention that includes:

[0217] In some embodiments, the method includes using positron emission tomography to determine the presence of motor neuron disease. Further included is imaging an object or sample using emission tomography.

[0218] In any or all of the above embodiments, the method includes treating Parkinson's disease, multifocal Subjects using positron emission tomography to determine the presence of sclerosis and Alzheimer's disease Or imaging the sample.

[0219] In any or all of the above embodiments, the method includes the step of determining whether the subject has a motor neuron disease. positron emission tomography (PET) to determine whether a patient has or is at risk of developing a disease It involves using layer imaging to image an object or a sample taken from an object. .

[0220] While considering many possible embodiments to which the principles of the present disclosure may be applied, the illustrated embodiment is preferred. These are merely illustrative examples and should not be construed as limiting the scope of the present disclosure. Rather, the scope is defined by the following claims. Therefore, we claim as our invention everything that comes within the scope and spirit of these claims. and assert.

Claims

1. A compound having a structure satisfying Formula I, 【Chemistry 1】 During the ceremony M is a divalent metal or a radioactive isotope thereof; R 1 is an aliphatic or aromatic group, which is connected to C through a linker group a directly or indirectly The linker group may be an aliphatic linker, a heteroaliphatic linker, a heteroaryl linker, or a heteroaryl linker. an alkyl group, an aromatic group, or any combination thereof; R 2 is selected from hydrogen, an aliphatic, heteroaliphatic, or aromatic group, which is Through C b wherein the linker group is an aliphatic linker, a heterocyclic linker, or selected from an aliphatic linker, a heteroatom, an aromatic group, or any combination thereof; and teeth R 1 and R 2 are joined together to form a fused ring system containing from two to seven fused rings; Each R 3 and R 4 is -NH 2 , -NHR, -NRR', -OR, -SR, or -C(R) 1-2 Regardless of R' where R and R' are selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaliphatic, aliphatic-heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl or wherein R and R' are independently selected from the group consisting of the nitrogen to which they are attached and the heteroaryl. or together with carbon atoms form a heterocyclic or heteroaryl group, or a cycloaliphatic group, respectively. or there R 3 and / or R 4 Ha-C(R) 1 When R', then one of the R or R' groups forms a double bond with the carbon atom, and the remaining R or R' groups form an aryl group. and However, the following: (i) R 1 is methyl, and R 2 is methyl or hydrogen, then R 2 , R 3 , or R 4 At least one of the groups includes a linker-X group, where the linker is a carbonyl- or the linker is selected from a group containing a hydroxyl group, an alkylene oxide, an aliphatic group, an imide ester; , maleimide, haloacetyl, or pyridyl disulfides; and X is a moiety containing a functional group suitable for facilitating delivery of the compound to a target. and where the linker-X group is (CH 2 ) 2 N(CH 3 ) 3 Not or otherwise Yes; and (ii) The compound is: 【Chemistry 2】 A compound provided that it is not or is other than those.

2. The compound may have one or more of formulas IIA-IIR: 【Chemistry 3-1】 【Chemistry 3-2】 Fulfilling In the formula, each R 5 and R 6 is aliphatic; aryl; heteroaliphatic; aliphatic-aryl; hetero Aryl; Aliphatic-Heteroaryl; Heteroaliphatic-Aryl; Heteroaliphatic-Heteroary hydroxyl; -NH 2 ; nitro; thiol; halogen; phosphate; phosphoryl; sulfino; sulfo; azido; or -C(O)R c X、C[(R c ) 2 ] m X、-[(CH 2 ) 2 O] m X、-O(CH 2 ) m X、-[O(CH 2 ) 2 ] m X、-NR c (CH 2 ) m X、-SR c X, -CH 2 C(O)NHR c X, -[(CH 2 ) 2 NR c ] m X, -NR c (CH 2 ) 2 ] m X, -C(=NH 2 + )NR c X, or 【Chemistry 4】 chosen independently from In the formula, each R c is aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl , aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl are chosen independently from the set of + (R d ) 3 or -N + (R d ) 3 are chosen independently from d is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic from heteroaliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl can be independently selected, and each m is an independently selected integer from 1 to 30; and Call n is an integer selected from 1 to 5, 2. The compound of claim 1 having the structure:

3. One or more of formula IIIA-IIIY': 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 and wherein each Y is independently selected from O, S, or NR, where R is hydrogen, aliphatic, aryl, or Heteroaliphatic, Aliphatic-Aryl, Heteroaryl, Aliphatic-Heteroaryl, Hetero aliphatic-aryl, heteroaliphatic-heteroaryl, or any combination thereof; each X is independently a targeting moiety; each m is an integer selected from 1 to 30; each q is an integer selected from 0 to 30; and n is an integer selected from 1 to 5.

3. The compound of claim 1 or claim 2, wherein

4. Mは、Cu、Co、Ni、またはCu 2+ 、 60 The 2+ 、 61 The 2+ 、 62 The 2+ 、 63 The 2+ 、 64 The 2+ 、または 65 C u 2+ 4. The compound of any one of claims 1 to 3, wherein:

5. R 1 is phenyl, pyridyl, naphthyl, anthracenyl, quinolinyl, quinazolinyl, Quinoxalinyl, benzoquinolinyl, benzoquinoxalinyl, benzoquinazolinyl, phenoxalinyl, Nil-(R 5 ) n , pyridyl-(R 5 ) n , naphthyl-(R 5 ) n , anthracenyl-(R 5 ) n , quinolinyl-(R 5 ) n , quinazolinyl-(R 5 ) n , quinoxalinyl-(R 5 ) n , benzoquinolinyl-(R 5 ) n , benzoquino Xalinyl-(R 5 ) n , or benzoquinazolinyl-(R 5 ) n where each R 5 is an aliphatic ;Aryl;Haloaliphatic;Heteroaliphatic;Aliphatic-Aryl;Heteroaryl;Aliphatic-Hetero Heteroaryl; Heteroaliphatic-aryl; Heteroaliphatic-heteroaryl; Hydroxyl; -NH 2 ;-P + (R d ) 3 or -N + (R d ) 3 (So ​​each R d is hydrogen, aliphatic, aryl, heteroaliphatic , aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl or heteroaliphatic-heteroaryl); nitro; thio Halogen; Phosphate; Phosphoryl; Sulfino; Sulfo; Azide; Linker-X Group or independently selected from any combination of such groups; and n is selected from 1 to 10.

5. The compound of any one of claims 1 to 4, wherein R is an integer.

6. n is 1, and R 5 is -C(O)R c X, -C[(R c ) 2 ] m X, -[(CH 2 ) 2 O] m X, -O(CH 2 ) m X, -[O(CH 2 ) 2 ] m X-NR c (CH 2 ) m X - [(CH 2 ) 2 ARN c ] m X-[NR c (CH 2 ) 2 ] m X, -C(=NH 2 + )NR c X-CH 2 C(O)NHR c X, -SR c X, or 【Transformation 6】 Selected from; In the formula, each R c is aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl , aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl are chosen independently from the set of + (R d ) 3 or -N + (R d ) 3 are chosen independently from d is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic from heteroaliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl and each m is an independently selected integer from 1 to 30. Compound.

7. Each R 5 is an alkyl, alkyenyl, alkynyl, amine, carboxylic acid, ester, alkynyl oxy, amide, cyano, ether, silyl ether, phosphine, thioether, disulfide Sulfides, isothiocyanates, isocyanates, carbonates, ketones, sulfinyls , sulfonyl, carbonothioyl, isonitrile, or any combination of such groups. and n is 1.

8. R 1 is phenyl; -PhC[(R c ) 2 ] m PPh 3 ;-Ph[(CH 2 ) 2 O] m PPh 3 ;-Ph[O(CH 2 ) 2 ] m PPh 3 ;-PhOH ;-PhOPPh 3 ;-PhNRPPh 3 ;-Ph[(CH 2 ) 2 NR] m PPh 3 , or -Ph[NR(CH 2 ) 2 ] m PPh 3 , where R is Hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-hetero Heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; -P hO-aliphatic; -PhN(R)aliphatic, where R is hydrogen, aliphatic, aryl, heteroaliphatic, fatty aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or is heteroaliphatic-heteroaryl; or -Ph(Z) 1-5 , where Z is Cl, F, Br, or or I, NO 2 , C.F. 3 , C(CF 3 ) 3 and m is an integer selected from 1 to 30.

8. The compound of any one of claims 1 to 7, wherein:

9. R 1 Phenyl, -PhOH, -PhOMe, -PhCl, -PhNO 2 , -PhCF 3 , -PhC(CF 3 ) 3 , -PhF 5 ,Also Ha-PhNMe 2 and / or R 2 is selected from alkyl and phenyl, A compound of any one of claims 1 to 8.

10. Each R 2 , R 3 , and R 4 independently includes a linker-X group, where the linker is selected from a carbonyl-containing group, an alkylene oxide, an aliphatic group, an imidoester; or The linker is generated from a maleimide, haloacetyl, or pyridyl disulfide; and and wherein X comprises a functional group suitable for facilitating delivery of the compound to a target.

10. The compound of any one of claims 1 to 9, wherein the moiety is

11. The linker-X group is —C(O)R c X, -C[(R c ) 2 ] m X, -[(CH 2 ) 2 O] m X, -O(CH 2 ) m X, -[O(CH 2 ) 2 ] m X, -NR c (CH 2 ) m X - [(CH 2 ) 2 ARN c ] m X-[NR c (CH 2 ) 2 ] m X, -C(=NH 2 + )NR c X-CH 2 C(O)NHR c X-SR c X ,or 【Transformation 7】 Selected from; In the formula, each R c is aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl , aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl are chosen independently from the set of + (R d ) 3 or -N + (R d ) 3 are chosen independently from d is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic from heteroaliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl and each m is an integer selected independently from 1 to 30. Compound.

12. The linker-X group is —C(O)(CH 2 ) 1-30 P + Ph 3 ・Br - , -C(=NH 2 + )N(CH 2 ) 1-30 P + Ph 3 ・Br - , -CH 2 C(O)NH(CH 2 ) 1-30 P + Ph 3 ・Br - 、-S(CH 2 ) 1-30 P + Ph 3 ・Br - 、-(CH 2 ) 1-30 P + Ph 3 ・Br - 、-O(CH 2 ) 1 -30 P + Ph 3 ・Br - 、-NH(CH 2 ) 1-30 P + Ph 3 ・Br - 、-C(O)[O(CH 2 ) 2 ] 1-30 P + Ph 3 ・Br - 、-C(=NH 2 + )NC H 2 [O(CH 2 ) 2 ] 1-30 P + Ph 3 ・Br - 、-CH 2 C(O)NH[O(CH 2 ) 2 ] 1-30 P + Ph 3 ・Br - 、-[O(CH 2 ) 2 ] 1-30 P + Ph 3 ・Br - 、-C(O)(CH 2 ) 1-30 N + Me 3 ・Br - 、-C(=NH 2 + )N(CH 2 ) 1-30 N + Me 3 ・Br - 、-CH 2 C(O)NH(CH 2 ) 1-30 N + Me 3 ・Br - 、-S(CH 2 ) 1-30 N + Me 3 ・Br - 、-(CH 2 ) 1-30 N + Me 3 ・Br - 、-O(CH 2 ) 1-30 N + Me 3 ・B r - 、-NH(CH 2 ) 1-30 N + Me 3 ・Br - 、-C(O)[O(CH 2 ) 2 ] 1- + Me 3 ・Br - 、-C(=NH 2 + )NCH 2 [O(CH 2 ) 2 ] 1-3 0 N + Me 3 ・Br - 、-CH 2 C(O)NH[O(CH 2 ) 2 ] 1-30 N + Me 3 ・Br - 、-S[O(CH 2 ) 2 ] 1-30 N + Me 3 ・Br - 、 【Transformation 8】 12. The compound of claim 10 or 11, selected from:

13. Each R 3 and R 4 -N(H) linker -X, -N[(CH 2 ) n CH 3 ] linker -X, or -N[(CH 2 ) n C F 3 ] linker-X, where the linker is independently selected from a carbonyl-containing group, alkylene or the linker is selected from a maleimide, haloamine, an aliphatic group, an imide ester, or a hydroxyl group; cetyl, or pyridyl disulfide; and where X is a targeting moiety.

13. The compound of any one of claims 1 to 12, which is Yeti.

14. Each R 3 and R 4 is -NH 2 , -N(H)(CH 2 ) n CH 3 , -N(H)(CH 2 ) n CF 3 , -N[(CH 2 ) n CH 3 ] 2 ,Also is -N[(CH 2 ) n CF 3 ] 2 where each n is an integer between 0 and 10 14. The compound of any one of claims 1 to 13, wherein:

15. Each R 3 and R 4 is -N(H)(CH 2 ) 2 CF 3 or -N[(CH 2 ) 2 CH 3 ] 2 and / or each R 1 and R 2 15. The compound of any one of claims 1 to 14, wherein is phenyl.

16. The compound is: 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 【Chemistry 9-5】 【Chemistry 9-6】 【Chemistry 9-7】 【Chemistry 9-8】 【Chemistry 9-9】 [Chemistry 9-10] 【Chemistry 9-11】 【Chemistry 9-12】 【Chemistry 9-13】 [Chemistry 9-14] 【Chemistry 9-15】 【Chemistry 9-16】 【Chemistry 9-17】 【Chemistry 9-18】 【Chemistry 9-19】 【Chemistry 9-20】 【Chemistry 9-21】 2. The compound of claim 1 selected from:

17. A compound according to any one of claims 1 to 16 or the following: 【Chemistry 10】 a compound selected from: It includes patches, tablets, capsules, lotions, or solution injections, where patches, tablets When combined with capsules, lotions, or solution injections, the total amount of compound is 15 times A dosage form that crystallizes less than 50% by volume.

18. The composition may further comprise an adjuvant, a therapeutic agent, a pharmaceutically acceptable excipient, or any combination thereof. The dosage form of claim 17, which is included in the above.

19. A method according to any one of claims 1 to 16 for use in a method of treatment and / or diagnosis. A compound according to, or a dosage form according to claim 17 or 18.

20. Methods of treatment and / or diagnosis include treatment of ALS, Parkinson's disease, Menkes disease, Lou Gehry disease, leukemia, primary lateral sclerosis, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal cord muscular atrophy, and canine degenerative myelopathy; diseases based on copper deficiency; or mitochondrial The subject is a person who has or is at risk of developing a neurological disorder selected from the group consisting of:

20. The compound or dosage form for use according to claim 19, comprising administering the compound or dosage form to a subject.

21. Edaravone or riluzole may be administered sequentially or simultaneously with the compound or its pharmaceutical composition.

21. A compound or dosage form for use according to claim 19 or claim 20, administered at the same time.

22. the subject carries one or more mutations in the superoxide dismutase gene, and The mutations were at residues G85, H46, or H48 of the superoxide dismutase gene.

22. A compound or compound for use according to claim 20 or claim 21 which is free of or other than is the dosage form.

23. The subject is a canine, and the canine is a member of a family of animals susceptible to canine degenerative myelopathy.

23. A composition for use according to any of claims 20-22, belonging to the species.

24. Compounds for use in methods of treating and / or diagnosing motor neuron diseases Yes, the following: 【Chemistry 11】 A compound selected from

25. The compound is administered in an amount ranging from greater than 0 mg / day to 100 mg / day. A compound for use according to paragraph 24.

26. The compound is administered at a loading dose ranging from 10 mg / day to 100 mg / day. A compound for use according to claim 24 or claim 25.

27. The compound is administered at a maintenance dose ranging from 1 mg / day to 50 mg / day. A compound for use according to paragraph 24 or 25.

28. Motor neuron diseases include ALS, Lou Gehrig's disease, primary lateral sclerosis, and Kennedy syndrome. group, ALS-related frontotemporal dementia, spinal muscular atrophy, or any combination thereof 28. A compound for use according to any one of claims 24-27, selected from:

29. Treatment and / or diagnosis of neurological disorders, copper deficiency-based disorders, or mitochondrial dysfunction 1. A compound for use in the method of claim 1, comprising the compound of formula I: 【Chemistry 12】 and During the ceremony M is a divalent metal; R 1 is an aliphatic or aromatic group, which is connected to C through a linker group a directly or indirectly The linker group may be an aliphatic linker, a heteroaliphatic linker, a heteroaryl linker, or a heteroaryl linker. an alkyl group, an aromatic group, or any combination thereof; R 2 is selected from hydrogen, an aliphatic, heteroaliphatic, or aromatic group, which is Through C b wherein the linker group is an aliphatic linker, a heterocyclic linker, or selected from an aliphatic linker, a heteroatom, an aromatic group, or any combination thereof; and teeth R 1 and R 2 are joined together to form a fused ring system containing from two to seven fused rings; Each R 3 and R 4 is -NH 2 , -NHR, -NRR', -OR, -SR, or -C(R) 1-2 Regardless of R' where R and R' are selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaliphatic, aliphatic-heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl or wherein R and R' are independently selected from the group consisting of the nitrogen to which they are attached and the heteroaryl. or together with carbon atoms form a heterocyclic or heteroaryl group, or a cycloaliphatic group, respectively. or there R 3 and / or R 4 Ha-C(R) 1 When R', then one of the R or R' groups forms a double bond with the carbon atom, and the remaining R or R' groups form an aryl group. A compound that bonds with

30. 30. The compound for use according to claim 29, wherein the neurological disease is a motor neuron disease.

31. Neurological diseases include ALS, Parkinson's disease, Menkes disease, Lou Gehrig's disease, and primary lateral sclerosis. dementia, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, and idiopathic encephalopathy. A compound for use according to claim 29 or claim 30 selected from degenerative myelopathy in mammals. thing.

32. Methods for diagnosing a subject having or at risk of developing a motor neuron disease a compound according to any one of claims 1-16 or the following for use in a method 【Chemistry 13】 where M is a compound selected from 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,Also teeth 65 Cu 2+ A compound.

33. The method includes administering to a subject a therapeutically effective amount of ... obtained from a subject or subjects using positron emission tomography to determine whether 33. The composition for use according to claim 32, comprising imaging the sample.

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