Therapeutic metal complexes and ligands, and methods for their preparation and use.

Abstract

Disclosed herein are compound embodiments useful for treating a variety of diseases, particularly neurological diseases, motor neuron diseases, copper deficiency-related diseases, and / or mitochondrial dysfunction. The compound embodiments described herein can also be used in PET procedures. Also disclosed herein are method embodiments for making and using the compound embodiments, as well as pharmaceutical formulations containing the disclosed compound embodiments.

Description

Cross-references to related applications

[0001] This application claims the benefit of an earlier filing date of U.S. Provisional Patent Application No. 62 / 553,714, filed 1 September 2017; the entirety of which is incorporated herein by reference.

[0002] Acknowledgment of government support This invention was made with government support under contract number W81XWH-15-1-0289, given by the U.S. Department of Defense. The government has certain rights in this invention.

[0003] field This disclosure relates to embodiments of therapeutic compounds, particularly therapeutic substances capable of treating neurological disorders, and embodiments of methods for creating and using such embodiments of compounds. [Overview of the project] [Problems that the invention aims to solve]

[0004] background Amyotrophic lateral sclerosis (ALS) is estimated to affect 30,000 Americans and over 400,000 people worldwide at any given time. Approximately 5,000 Americans are diagnosed with ALS each year. The disease causes the relentless death of motor neurons, resulting in progressive paralysis that kills its victims within an average of one to five years. Only two drugs have been approved by the FDA for the treatment of ALS, and both only slow the progression of the disease and extend life by a few months at best in a subset of patients. Furthermore, many common dog breeds, including Corgis, German Shepherds, and Rhodesian Ridgebacks, often carry homozygous mutations (also called homozygous mutations) in the SOD gene. Between the ages of 6 and 12 years, these dogs develop canine degenerative myelopathy, a progressive disease affecting motor neurons that shares many similarities with human diseases.

[0005] This technology presents a need for therapeutic substances that can reliably treat ALS and other neurological and / or copper deficiency-related diseases. Outline [Means for solving the problem]

[0006] Embodiments of compounds having a structure satisfying formula I are disclosed here. [ka]

[0007] In further embodiments, the compound may have a structure that satisfies other formulas described herein. The variables exemplified above in Formula I are described herein.

[0008] Furthermore, the pharmaceutical preparations disclosed herein include compounds and dosage forms having a structure that satisfies any one or more of the formulas described herein. In some embodiments of the pharmaceutical preparations, if any, only small amounts of the compound crystallize when combined with a pharmaceutical dosage form.

[0009] Furthermore, embodiments of a particular method are described herein, which include administering a therapeutic amount of the compound described herein to a subject or sample. In certain embodiments disclosed herein, a method for treating motor neuron disease is disclosed herein, where the method includes administering a therapeutic amount of the compound described herein to a subject. In some embodiments, the motor neuron disease is selected from ALS, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, or any combination thereof.

[0010] Furthermore, embodiments of a certain method are disclosed herein, which involve applying a compound as described herein, where the metallic component of the compound is a metallic isotope, to a subject or sample. In certain embodiments disclosed herein, the isotope is 60 Cu 2+ , 61 Cu2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ or 65 Cu 2+ and can be. In some embodiments, the method can further include imaging a subject or sample using positron emission tomography to determine the presence of a motor neuron disease.

[0011] The foregoing and other objects, features, and advantages of the present disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying drawings.

Brief Description of the Drawings

[0012] [Figure 1] Graph of cytochrome c oxidase activity in the mouse brain, where the line labeled by the symbol "○" represents mice with untreated CCS only; the line labeled by "●" represents CuATSM-treated CCS mice; the line labeled by "□" represents untreated CCSxSOD mice; the line labeled by "black square" represents CuATSM-treated CCSxSOD mice. [Figure 2] Illustrates a titration curve obtained from titration, where copper is added to the free ATSM ligand component. [Figure 3] Illustrates the reduction standard potential (left side) versus the oxidation standard potential (right side) for the ligand component. [Figure 4] Graph showing the results obtained from exposing mice to embodiments of CuATSM and different compounds described herein, and embodiments of the disclosed compounds are confirmed to 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]This is a composite mass spectrum showing the mass spectra of SODWT (upper spectrum) and SODG93A (mid- and bottom spectra) from ventral spinal cord samples before and after exposure to CuATSM (upper and mid-spectrum vs. bottom spectrum). [Figure 6] This graph shows the results obtained from exposing mice to embodiments of CuATSM and different compounds described herein, confirming an effective reduction in the amount of immature forms of SOD in the embodiments of the disclosed compounds; 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 embodiments of CuATSM and different compounds described herein, confirming that the embodiments of the disclosed compounds effectively increase COX activity in the brain (Figure 7A) and spinal cord (Figure 7B); the sample size for the number of mice in each group is indicated by the numbers above each bar in the graphs. [Figure 8] An example of a titration curve obtained from the titration is shown, where copper is added to the free PhMeTSM ligand component. [Figure 9] An example of a titration curve obtained from the titration is shown, where copper is added to the free NO2PhMeTSM ligand component. [Figure 10] This graph illustrates the survival rate of low-expression G93A SOD mice that were treated with CuPhMeTSM (50 mg / kg / day) at four days of age and then mated with CCS-overexpressing mice; the graph shows that the majority of mice (specifically, nine out of eleven) survived after treatment with CuPhMeTSM (line labeled "A"), while untreated mice (line labeled "B") showed a significantly lower survival rate (confidence levels are indicated by dashed lines, with lines "C" and "D" corresponding to treated mice, and lines "E" and "F" corresponding to untreated mice). [Figure 11] The following illustrates a space-filling model for the embodiments of the compounds described here. [Modes for carrying out the invention]

[0013] Detailed description

[0014] I. Overview of Terminology

[0015] The following definitions of terms are provided to better describe this disclosure and to guide those skilled in the art in the practice of this disclosure. As used herein, “comprising” means “including,” and the singular forms “a,” “an,” or “the” include multiple references unless the context otherwise explicitly indicates. The term “or” refers to a single element or a combination of two or more elements of the alternative elements stated unless the context otherwise explicitly indicates.

[0016] While some steps of the disclosure method are described in a specific, sequential order for the sake of convenient presentation, it should be understood that this description of manners includes rearrangement unless a specific order is required by the specific language (also known as the native language, etc.) described below. For example, in some cases, steps described sequentially may be rearranged or performed simultaneously. Furthermore, the description may sometimes use terms such as “produce” and “provide” to describe the disclosure method. These terms are high-level abstractions of the actual steps to be performed. The actual steps corresponding to these terms will vary depending on the specific performance and will be readily apparent to a person of ordinary skill in this art.

[0017] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as that commonly understood by a person of ordinary skill in the art to which this disclosure belongs. Similar or equivalent methods and compounds may be used in the practice or testing of this disclosure, but appropriate methods and compounds are listed below. Compounds, methods, and examples are for illustrative purposes only and are not intended to limit unless otherwise specified. Other features of this disclosure are evident from the detailed description and claims below.

[0018] Unless otherwise specified, all figures representing quantities, molecular weights, percentages, temperatures, times, and others of components, as used in this specification or claims, should be understood to be modified by the term “approximately.” Therefore, unless otherwise indicated, implicitly or explicitly, the numerical parameters described are approximations that may depend on the desired properties and / or detection limits under standard test conditions / methods. When directly and explicitly distinguishing embodiments from the prior art being discussed, the numerical values ​​of embodiments are not approximations unless the word “approximately” is enumerated. Furthermore, not all substitutes enumerated herein are equivalent.

[0019] Embodiments of the compounds disclosed herein may include one or more (also known as one or more) asymmetric elements, such as stereocenters, stereoaxials, and other of the same kind, for example, an asymmetric carbon atom, so that the chemical conjugate can exist in different stereoisomeric forms. Embodiments of these compounds may be, for example, racemates or optically active forms. In the case of embodiments of compounds having two or more asymmetric elements, embodiments of these compounds may additionally be mixtures of diastereomers. In the case of embodiments of compounds having asymmetric centers, all optical isomers and mixtures thereof in their pure form are encompassed by the corresponding general formula unless the context otherwise clearly indicates or unless a clear description excluding isomers is expressed. In these situations, a single enantiomer (also known as a mirror image, enantiomer, or mirror image), i.e., an optically active form, may be obtained by methods known to those of ordinary skill in the art, such as asymmetric synthesis, synthesis from an optically pure precursor, or by the decomposition of a racemate. The decomposition of racemic mixtures can also be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or by chromatography using a chiral HPLC column, for example. Here, all isomers are assumed, regardless of the method used to obtain them.

[0020] All forms of the active agent (e.g., solvates, optical isomers, enantiomers, polymorphs, free compounds, and salts) may be used individually or in combination.

[0021] The stereochemical definitions and conventions used here generally follow those of SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, USA, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in an optically active form, that is, they have the ability to rotate the plane of polarization. In describing optically active compounds, the prefixes (+ / -) D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral centers(s), where a group can be multiple. The prefixes d and l, or (+) and (-), are used to specify the sign of the rotation of plane-polarized light by the compound, with (-) or l indicating that the compound is levorotatory. Compounds beginning with (+) or d are dextrorotatory.

[0022] To facilitate review of the various embodiments of this disclosure, the following explanations of specific terms and abbreviations are provided:

[0023] Adjuvants are excipients that modify the effects of other drugs, typically the active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modify the effects of the active ingredient by increasing desired neurological responses, such as immune responses. Adjuvants can also act as stabilizers for formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents (also called detergents, surfactants, etc.), cytokines, paraffin oils, and combination adjuvants, such as Freund's complete adjuvant or Freund's incomplete adjuvant.

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

[0025] Aliphatic: At least one carbon atom to 50 carbon atoms (C) 1-50 ), for example, one to 25 carbon atoms (C 1-25 ), or one to ten carbon atoms (C 1-10 These are hydrocarbon groups having such as alkanes (or alkyls), alkenes (or alkenyls), alkynes (or alkynyls), their cyclic versions, and also linear and branched arrangements, and all stereoisomers and positional isomers thereon.

[0026] Aliphatic-aryl: An aryl group that couples (also called pairs) with, or can couple with, the compounds disclosed herein, so that the aryl group couples or becomes coupled through the aliphatic group.

[0027] Aliphatic-heteroaryl: A heteroaryl group that couples to or can couple to the compounds disclosed herein, where the heteroaryl group couples or becomes coupled through the aliphatic group.

[0028] Alkenyl: at least two carbon atoms to 50 carbon atoms (C 2-50 ), for example, two to 25 carbon atoms (C 2-25 ), or two to ten carbon atoms (C 2-10 ) and unsaturated monovalent hydrocarbons having at least one carbon-carbon double bond, where the unsaturated monovalent hydrocarbon can be derived by removing one hydrogen atom from one carbon atom of the parent alkene. The alkenyl group can be branched, linear, cyclic (e.g., cycloalkenyl), cis, or trans (e.g., E or Z).

[0029] Alkoxy: -O-aliphatic (e.g., -O-alkyl, etc.), exemplary embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0030] Alkyl: at least one carbon atom to 50 carbon atoms (C 1-50 ), for example, one to 25 carbon atoms (C 1-25 ), or one to ten carbon atoms (C 1-10 A saturated monovalent hydrocarbon having such as ), where a saturated monovalent hydrocarbon can be derived by removing one hydrogen atom from one carbon atom of a parent compound (e.g., an alkane). The alkyl group can be branched, linear, or cyclic (e.g., a cycloalkyl group).

[0031] Alkylaryl / Alkenylaryl / Alkynylaryl: Aryl groups that are coupled to or can be coupled to the compounds disclosed herein, where the aryl group is coupled to or becomes coupled through an alkyl, alkenyl, or alkynyl group, respectively.

[0032] Alkyl heteroaryl / alkenyl heteroaryl / alkynyl heteroaryl: heteroaryl groups that couple to or can couple to the compounds disclosed herein, where the heteroaryl group couples or couples through an alkyl, alkenyl, or alkynyl group, respectively.

[0033] Alkynyl: at least two carbon atoms to 50 carbon atoms (C 2-50 ), for example, two to 25 carbon atoms (C 2-25 ), or two to ten carbon atoms (C 2-10 ) and unsaturated monovalent hydrocarbons having at least one carbon-carbon triple bond, where the unsaturated monovalent hydrocarbon can be derived by removing one hydrogen atom from one carbon atom of the parent alkyne. The alkynyl group can be branched, linear, or cyclic (e.g., cycloalkynyl).

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

[0035] Amine:-NR a R b Therefore, each R a and R b R is independently selected from hydrogen, aliphatic, aryl, heteroaliphatic, heteroaryl, and any combination thereof. In some embodiments, R a and R b These atoms can join together (also called bonding), and together with the nitrogen atoms to which they are bonded, they can form a heterocyclic ring.

[0036] Aromatic: Unless otherwise specified, a ring, conjugated group, or moiety of 5 to 15 ring atoms having a monocycle (e.g., phenyl, pyridinyl, or pyrazolyl) or a multiple fused ring (e.g., naphthyl, indolyl, or pyrazolopyridinyl) in which at least one ring is aromatic; that is, having a continuous, delocalized π-electron system of at least one ring and optionally multiple fused rings. Typically, the number of out-of-plane π-electrons corresponds to Huckel's rule (4n+2). Attachment to the parent structure is typically through the aromatic portion of the fused ring system. For example, [ka] However, in certain cases, the context or explicit disclosure may indicate that the attachment site is through the non-aromatic portion of the fused ring system. For example, [ka] Aromatic groups or moieties may contain only carbon atoms in a ring, such as an aryl group or moiety, or they may contain one or more ring carbon atoms and one or more ring heteroatoms, with lone pairs of electrons (e.g., S, O, N, P, or Si) present in a ring, such as a heteroaryl group or moiety.

[0037] Aryl: at least five carbon atoms to 15 carbon atoms (C5-C 15 ), for example, five to ten carbon atoms (C5-C 10 These include such groups, having monocyclic or multiple fused rings, where the fused rings may or may not be aromatic, provided that the attachment sites to the rest of the compounds disclosed herein are through atoms of the aromatic carbocyclic group. The aryl group may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, aryl, heteroaryl, other functional groups, or any combination thereof.

[0038] Carboxyl:-C(O)OR a Therefore, R a These are hydrogen, aliphatic, aromatic, aliphatic-aromatic, heteroaliphatic-aromatic, heteroaliphatic, and any combination thereof.

[0039] A carrier (also called a support or carrier) is an excipient that functions as an ingredient capable of delivering the compounds described herein. In some embodiments, the carrier may be a suspension aid, a solubilizing aid, or an aerosolizing aid. Often, the properties of the carrier will depend on the specific mode of administration employed. For example, parenteral preparations typically contain an injectable fluid that includes a pharmaceutically and physiologically acceptable fluid as a vehicle, such as water, physiological sarin (also called physiological saline solution, physiological saline solution, etc.), equilibrium salt solution, aqueous dextrose, glycerol, or others of the same kind. In some examples, the pharmaceutically acceptable carrier may be sterilized to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to a biologically neutral carrier, the pharmaceutical preparation may contain small amounts of non-toxic adjuncts, such as humectants or emulsifiers, preservatives, and pH buffers and similar substances, such as sodium acetate or sorbitan monolaurate.

[0040] Haloaliphatic: An aliphatic group in which one or more hydrogen atoms, such as one to ten hydrogen atoms, are substituted by halogen atoms, such as fluoro, bromo, chloro, or iodine.

[0041] Haloaliphatic-aryl: An aryl group that is coupled to or can be coupled to the compounds disclosed herein, where the aryl group is coupled or coupled through a haloaliphatic group.

[0042] Haloaliphatic-heteroaryl: A heteroaryl group that is coupled to or can be coupled to the compounds disclosed herein, where the heteroaryl group is coupled or coupled through the haloaliphatic group.

[0043] Haloalkyl / haloalkenyl / haloalkynyl: an alkyl, alkenyl, or alkynyl group (which can be branched, linear, or cyclic) containing at least one to 20 halogen atoms, such as one to 15 halogen atoms, or one to 5 halogen atoms, which are not limited but can be selected from bromine, chlorine, fluorine, or iodine.

[0044] Heteroaliphatic: an aliphatic group comprising at least one heteroatom to 20 heteroatoms, such as one to 15 heteroatoms, or one to 5 heteroatoms, which are not limited to but include oxygen, nitrogen, sulfur, selenium, phosphorus, and their oxidized forms within the group.

[0045] Heteroaliphatic-aryl: an aryl group that is coupled to or can be coupled to the compounds disclosed herein, where the aryl group is coupled or coupled through a heteroaliphatic group.

[0046] Heteroalkyl / heteroalkenyl / heteroalkynyl: alkyl, alkenyl, or alkynyl groups (they can be branched, linear, or cyclic) comprising at least one heteroatom to 20 heteroatoms, such as one to 15 heteroatoms, or one to 5 heteroatoms, and which are not limited but can be selected from oxygen, nitrogen, sulfur, selenium, phosphorus, and their oxidized forms within the group.

[0047] Heteroalkyl-aryl / heteroalkenyl-aryl / heteroalkynyl-aryl: aryl groups that are coupled to or can be coupled to the compounds disclosed herein, where the aryl group is coupled or coupled through a heteroalkyl, heteroalkenyl, or heteroalkynyl group, respectively.

[0048] Heteroalkyl-heteroaryl / heteroalkenyl-heteroaryl / heteroalkynyl-heteroaryl: Heteroaryl groups that couple to or can couple to the compounds disclosed herein, where the aryl group couples or becomes coupled through a heteroalkyl, heteroalkenyl, or heteroalkynyl group, respectively.

[0049] Heteroaryl: an aryl group comprising at least one heteroatom to six heteroatoms, such as one to four heteroatoms, which are not limited but can be selected from oxygen, nitrogen, sulfur, selenium, phosphorus, and their oxidized forms within the ring. Such heteroaryl groups may have a monocyclic or multiple fused ring, where the fused ring may or may not be aromatic and / or may or may not contain heteroatoms, provided that the attachment site passes through an atom of an aromatic heteroaryl group. Heteroaryl groups may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, aryl, heteroaryl, other functional groups, or any combination thereof.

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

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

[0052] Motor neuron disease: In some embodiments, this term is used to refer to a group of diseases that affect the nerves in the brain and spinal cord and may result in muscle weakness, often accompanied by visible wasting symptoms. In some embodiments, and in some countries, the term “motor neuron disease” may be used to specify a particular disease and may be synonymous with amyotrophic lateral sclerosis(s).

[0053] Pharmaceutically acceptable excipients: substances other than the active ingredient (examples are the compounds described herein) that are included in the preparation of the active ingredient. As used herein, excipients may be incorporated into the particles of the pharmaceutical preparation, or they may be physically mixed with the particles of the pharmaceutical preparation. Excipients may also be in the form of solutions, suspensions, emulsions (also called turbidities), or other such forms. Excipients may be used, for example, to dilute the active ingredient and / or to modify the properties of the pharmaceutical preparation. Excipients may include, but are not limited to, antifouling agents, binders, coatings, enteric coatings, disintegrants, flavorings, sweeteners, colorants, lubricants, flow enhancers, adsorbents, preservatives, adjuvants, carriers, or vehicles. Excipients may include starch and modified starch, cellulose and cellulose derivatives, sugars and their derivatives, such as disaccharides, polysaccharides and sugar alcohols, proteins, synthetic polymers, crosslinked polymers, antioxidants, amino acids, or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, taltrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, and sodium metabisulfite. It contains metabisulphite (also known as sodium pyrosulfite or sodium disulfite) or lanolin.

[0054] Pharmacopoeia-acceptable salts: The pharmaceutically acceptable salts of the compounds described herein are derived from a variety of organic and inorganic counterions, as would be known to those of ordinary skill in this art, and to name just a few, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and others of the same kind; and, when the molecule contains a basic functional group, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and others of the same kind. "Pharmacopoeia-acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed by an acid partner while retaining the biological efficacy of the free base. In particular, embodiments of the disclosed compounds are not limited and form salts with a variety of pharmaceutically acceptable acids, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and others of the same kind, as well as organic acids such as 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, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and others of the same kind. "Pharmacologically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts," which are derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and others of the same kind. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts.Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and other similar substances. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (For example, see S.M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. (Journal of Pharmaceutical Sciences), 1977; 66:1-19, which is incorporated here by reference.)

[0055] Pharmaceutical / therapeutic dose: The amount of a compound sufficient to treat a particular disorder or disease, improve or eliminate one or more of its symptoms, and / or prevent the onset of the disease or disorder. The amount of compound constituting a "therapeutic dose" will vary depending on the compound, the disease state and its severity, the age of the patient being treated, and other similar factors. The therapeutic dose can be determined by a person of ordinary skill in this technique.

[0056] Prodrug: Embodiments of the compounds disclosed herein that are converted, most typically in vivo, for example, by hydrolysis or enzymatic conversion in the intestines, to produce a biologically active compound, particularly the parent compound. Common examples of prodrug moieties include, but are not limited to, pharmaceutically acceptable ester and amide forms of compounds having an active form possessing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of embodiments of the compounds disclosed herein include, but are not limited to, esters of phosphate groups (also known as phosphate groups, etc.) and carboxylic acids, e.g., aliphatic esters, in particular alkyl esters (e.g., C 1-6 This includes things like alkyl esters. Other prodrugs include phosphate esters, for example, -CH2-OP(O)(OR d )2 or a salt thereof, etc., in the formula R d is H or aliphatic (e.g., C 1-6The alkyl group is also acceptable esters, including cycloalkyl esters and arylalkyl esters, such as benzyl, for example, but not limited to these. Examples of pharmaceutically acceptable amides of embodiments of the compounds of this disclosure include, but not limited to, primary amides and secondary and tertiary alkylamides (e.g., those with one and six carbon atoms). The exemplary embodiments of amides and esters disclosed in embodiments of the compounds according to this disclosure can be prepared by conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drug as Novel Delivery Systems,” Vol. 14, ACS Symposium Series, and in “Bioreversible Carriers in Drug Design,” ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated here by reference.

[0057] The subjects are mammals and other animals, such as humans, companion animals (also known as pets, etc.) (e.g., dogs, cats, rabbits, etc.), utility animals (also known as working animals, etc.), and feed animals (also known as feed animals, etc.); therefore, the disclosed methods are applicable to both human therapeutic and veterinary uses.

[0058] Thioketone:-C(S)R a And in the formula R a These are selected from aliphatic, aromatic, aliphatic-aromatic, heteroaliphatic-aromatic, heteroaliphatic, and any combination thereof.

[0059] Treatment / Treatment: Treatment of a disease or condition of interest in a subject, particularly in a human or canine animal, and includes, but is not limited to, the following: (i) Prophylactic treatment to prevent the occurrence of a disease or condition in a subject, or, when particularly necessary, to alleviate symptoms associated with a condition, when such subject is susceptible to that condition but has not yet been diagnosed with it; (ii) To suppress a disease or condition, for example, to stop or slow its progression; (iii) to alleviate a disease or condition, for example, to cause a regression of the disease or condition or its symptoms; or (iv) To stabilize a disease or condition.

[0060] As used herein, the terms “disease” and “condition” may be used interchangeably, or they may differ in that a particular disease or condition does not necessarily have known causative factors (and consequently, its etiology has not yet been determined), and therefore it is not yet recognized as a disease but only as an undesirable condition or syndrome, where a more or less specific set of signs is identified by a clinician.

[0061] A person of ordinary skill in this art will recognize that the provisions provided above are not intended to include unacceptable substitution patterns (e.g., methyl substituted by five different groups). Such unacceptable substitution patterns are easily recognizable by a person of ordinary skill in this art. The formulas and specific compounds disclosed herein satisfy any formal valence requirements even if hydrogen atoms are present and functional groups or other atoms are not illustrated (but are not necessarily illustrated). For example, [ka] The phenyl ring depicted as such includes hydrogen atoms attached to each carbon atom of the phenyl ring other than the carbon atom of "a," even if such hydrogen atoms are not exemplified.

[0062] Any functional group disclosed and / or specified herein may be substituted or unsubstituted unless otherwise specified herein.

[0063] II. Introduction

[0064] CuATSM is a highly expressive superoxide dismutase ("SOD") according to the strict standards established in this technology. G93A It has been shown to be protective in mice; however, due to CuATSM's high copper affinity, this agent is an inefficient delivery vehicle for bypassing the distribution system that naturally limits copper transport to the central nervous system ("CNS"). Continuous treatment with CuATSM may eventually provide enough copper for the SOD copper chaperone (called "CCS") to complete the maturation of Cu,Zn SOD; however, CuATSM has many adverse aspects associated with its use, and in this technology, there is a need for improved therapeutic agents that can treat neurological disorders and / or copper deficiency-related disorders. For example, the rate of copper delivery by CuATSM is slow in vivo. See Figure 1, which illustrates that CuATSM is slow for copper delivery to the CNS in CCS and CCSxSOD mice. It may take several weeks for cytochrome c oxidase and SOD to replenish the copper-deficient enzymes in the CNS. The reducing capacity of CuATSM is negative compared to any ordinary biological reducing agent. The acceptable release mechanism is CuATSM 2+ ga Cu 1+ This is because it is reduced to a more likely form of copper, which then migrates to intracellular copper carriers. Reduced CuATSM also converts molecular oxygen into potentially toxic superoxide radicals (O2). .-) is reduced to ). Rapid reoxidation of CuATSM compounds further restricts copper release in non-hypoxic tissues and generates harmful species. As a result, only a small amount of copper ions (e.g., Cu 2+ or Cu 1+ Only the methyl group is slowly released from the CuATSM complex, which limits its acute therapeutic effect. Furthermore, CuATSM is metabolized by the liver within a few hours in vivo, which results in the removal of one of its terminal methyl groups (e.g., the methyl group at the position exemplified below). Demethylation of CuATSM creates a free amino group, which prevents the metabolite from entering the CNS and facilitates the delivery of copper to other targets (also called targets). In addition, CuATSM has a much higher affinity for human serum albumin compared to albumin in other non-human animals, such as mice, rats, and dogs, which limits its distribution to the CNS in human subjects. [ka]

[0065] Another limitation is that the ATMM ligand component of CuATSM complexes is pharmacologically active in the binding metal and can therefore react in potentially undesirable side reactions. For example, ZnATSM (which contains zinc instead of copper) is slightly protective against denaturation in the ALS-SOD mouse model; however, when ZnATSM is applied to the skin of mice, the animals experience pain, and the compound becomes ineffective in protecting the mice. Also, free ligands, such as GTSM and PTSM (both illustrated below), cause significant delays in the growth of young mice. [ka]

[0066] CuATSM possesses a compact, symmetrical structure, which contributes to another limitation associated with this compound. Its compact structure allows the ATMS ligand component to rapidly form highly stable crystals, which presents several challenges in the synthesis and preparation of this compound, hindering its ability to function as a suitable drug. For example, the metal-free ATMS ligand component crystallizes within seconds during its synthesis in all common refluxing solvents; therefore, adding copper later in the final step of synthesis is difficult, especially on an industrial scale required to produce the large quantities needed for clinical use.

[0067] Furthermore, the semithiocarbazide side arms of the ATMM ligand are quite flexible and readily rotate around the central carbon bond that junctions the imine methyl group. This flexibility makes it difficult to form the final 1:1 complex using stoichiometric copper. Titration of copper to the ATMM ligand to form CuATSM does not show the formation of a stoichiometric complex, but does show the formation of a stoichiometric complex (see Figure 2, which shows that as the addition of copper approaches 1:1, the isosbestic point deviates and undesirable non-stoichiometric behavior is exhibited). Mass spectrometry also showed the formation of a complex with a matching empirical formula with three copper atoms and two ATMM ligands. The formation of such complexes is problematic because these complexes are difficult to remove. Consequently, ATMM must be diluted to minimize the formation of polymeric complexes of several copper atoms associated with two or more ATMM moieties due to the flexible semithiocarbazide groups. However, due to the low solubility of ATMM, achieving a diluted solution is difficult even under reflux conditions.

[0068] Furthermore, CuATSM exhibits high propensity for crystallization and has a very high melting point of 245°C. This crystallization and high melting point create problems in the formation of orally active CuATSM compounds and hinder the use of solid dispersant methods for compounding complexes for oral delivery. As such, the production of formulations with appropriate dosage limits for CuATSM leaves limitations in the therapeutic use of this compound, especially considering CuATSM's tendency to gradually crystallize from the matrix and form insoluble crystals. Large amounts of crystallized CuATSM pass through the intestines and thereby contribute to gastrointestinal discomfort. Another negative potential of CuATSM is that it makes it very difficult for biological reducing agents to reduce cells, which reflects a slow effect in supplementing SOD and COX over several weeks. As a result, most of the administered CuATSM is excreted in the urine, while the copper remains bound.

[0069] The embodiments of the compound described herein address the above-mentioned limitations of CuATSM compounds. The embodiments of the disclosed compound exhibit improved formulation properties. For example, the disclosed embodiments crystallize with significantly less efficiency than CuATSM because crystallization is suppressed in the embodiments of the compound. The disclosed embodiments also typically exhibit even lower negative reduction potentials, contributing to their improved ability to release copper in vivo. The embodiments of the compound disclosed herein also exhibit reduction potentials that allow for easier reduction compared to CuATSM, and therefore the embodiments of the disclosed compounds are more effective in delivering copper to the area of ​​interest, particularly the CNS. The superior features of the embodiments of the disclosed compound are not limited to those listed above, as illustrated by the following disclosures.

[0070] III. Embodiments of Compounds

[0071] Herein, embodiments of compounds having a structure satisfying the following formula I are disclosed. Formula I is exemplified by a metal species ("M") that is complexed with a ligand (also called a ligand, etc.) as shown in the figure, but this disclosure intends for a free ligand, where the metal species has not yet been complexed. When such a free ligand is not complexed with a metal species, the free ligand can exist in tautomeristic forms as shown in the following formulas IA and IB. As such, embodiments of the compounds disclosed herein include metal complexes having a structure satisfying formula I and free ligand components having structures satisfying formulas IA and IB. Embodiments of the compounds disclosed herein (which include either metal-complexed compounds and / or free ligand components throughout this disclosure) can be used as therapeutic compounds, for example, to treat neurological disorders and other copper deficiency-related diseases. [ka]

[0072] Referring to Formula I, M is a divalent metal or its radioactive isotope. Referring to Formulas I, IA, and IB, the following features can be applied: R 1 It can be an aliphatic group or an aromatic group, for example, an aryl or heteroaryl group, and it is C a Adhering directly or indirectly (for example, through a linker group); R 2 The group can be selected from hydrogen, aliphatic, heteroaliphatic, or aromatic (e.g., aryl or heteroaryl), where the aromatic group is C b It can adhere directly or indirectly (for example, through a linker group); or R 1 and R 2They can be bound together to form a fused ring system comprising two to seven fused rings; and Each R 3 and R 4 -NH2, -NHR, -NRR', -OR, -SR, or -C(R) 1-2 R' can be chosen independently, so that each R and R' is chosen independently from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl. In some embodiments, R and R', together with the nitrogen or carbon atom to which they are bonded, can form a heterocyclic or heteroaryl group, or a cyclic aliphatic group; or R 3 and / or R 4 When is -C(R)1R', then one of the R or R' groups forms a double bond with a carbon atom and further bonds with the remaining R or R' group to form an aryl group.

[0073] R 1 and / or R 2 In embodiments in which the linker group indirectly attaches to the respective exemplary imine carbon atoms via a linker group, the linker group can be an aliphatic linker, a heteroaliphatic linker, a heteroatom, an aromatic group, or any combination thereof. Exemplary linker groups include, but are not limited to, alkyl, alkynyl, or alkenyl linker groups; polyalkylene glycol linker groups; oxygen, sulfur, or heteroatoms selected from NR (where R can be selected from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl); carbonyl groups; thioketone groups; amide groups; sulfone groups; sulfoxide groups; phenyl; pyridyl; or other suitable linkers.

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

[0075] In some embodiments, R 1 can be selected from phenyl, pyridyl, naphthyl, anthracenyl, quinolinyl, quinazolinyl, quinoxalinyl, benzoquinolinyl, benzoquinoxalinyl, benzoquinazolinyl, or other such species. Still further in some additional embodiments, R 1 is phenyl-(R 5 ), pyridyl-(R 5 ), naphthyl-(R 5 ), anthracenyl-(R 5 ), quinolinyl-(R 5 ), quinazolinyl-(R 5 ), quinoxalinyl-(R<l 5 ), benzoquinolinyl-(R 5 ), benzoquinoxalinyl-(R 5 ), benzoquinazolinyl-(R 5 ), and can be selected from, where each R 5 ​​​​​​​​​​​​​​​​​​​​R is either an electron-donating group or an electron-withdrawing group (it can be attached to the indicated aromatic group directly or indirectly, for example, through an aliphatic or heteroaliphatic linker), and n is an integer selected from 1 to 10, for example, 1 to 8, or 1 to 6, or 1 to 4. As indicated above, R 1 Any of these groups mentioned can be directly or indirectly bonded to the compound residue through a linker as described herein.

[0076] In a particular disclosed embodiment, each R 5 is aliphatic;aryl;haloaliphatic;heteroaliphatic;aliphatic-aryl;heteroaryl;aliphatic-heteroaryl;heteroaliphatic-aryl;heteroaliphatic-heteroaryl;hydroxyl;-NH2;-P + (R d )3 or -N + (R d )3(Therefore each R d The group can be independently selected from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl); nitro; thiol; halogen; phosphate; phosphoryl; sulfino; sulfo; azide; linker-X group; or any combination of such groups.

[0077] With respect to the “linker-X” group described above, the linker group can be selected from an aliphatic linker, a heteroaliphatic linker, a heteroatom, or an aromatic group. In certain disclosed embodiments, the linker may be a carbonyl-containing group; an alkylene oxide; an alkyl, alkenyl, or alkynyl group; an imide ester; or any other linker group described herein; or the linker may be generated from a maleimide, a haloacetyl, or a pyridyl disulfide. Also with respect to the “linker-X” group, X is a moisture containing a functional group suitable for facilitating the delivery of the compound to a target. In certain disclosed embodiments, X may be a targeting moisture capable of promoting or facilitating the penetration of the compound through a membrane. In some embodiments, the targeting moisture may be a moisture capable of increasing the delivery of the compound to the cytosol, for example, increasing the delivery of the compound by a factor of 10 (compared to a similar compound without the targeting moisture) and / or by a factor of 100 (compared to a similar compound without the targeting moisture). Embodiments of compounds satisfying these formulas may further include a counterion in embodiments, where X includes a charged group, thereby providing electronic neutrality. For example, in some embodiments, each X can be independently selected from a phosphonium group, an ammonium group, or other such groups including a positively charged moisture. In certain embodiments disclosed, the counterion used in combination with a hydrophobic, positively charged moisture may 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 - This includes sulfonates (also called sulfonates, etc.) (e.g., mesylate), sulfates, hydrobromide, acetate, citrate, maleate, tartrat, phosphate, nitrate, salicylate, fumarate, lactate, or other of the same kind.

[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 X is independently selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, 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, and then each R d m can be independently selected from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; and each m can be an integer independently selected from 1 to 30, for example, 1 to 20, or 1 to 10, or 1 to 5, etc.

[0079] In particular, the disclosed embodiments include a linker-X group, the linker-X group being -C(O)(CH2) 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 - 、

Chem.

[0080] In some embodiments, each R 5 is independently selected from alkyl, alkenyl, alkynyl, amine, carboxylic acid, ester, alkoxy, amide, cyano, ether, haloalkyl, silyl ether, phosphine, thioether, disulfide, isothiocyanate, isocyanate, carbonate, ketone, sulfinyl, sulfonyl, thioketone, isonitrile, or any combination of such groups. In certain disclosed embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0081] In yet another embodiment, 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] mPPh3, wherein R is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; -PhO-aliphatic (examples are -PhOMe, -PhOEt, -PhOPr, -PhOiPr, -PhOnBu, -PhOiBu, -PhOtBu, wherein the OMe, OEt, OPr, or OBu group is located at the ortho, meta, or para position of the phenyl ring with respect to the position where the phenyl ring is attached to the rest of the compound); -PhN(R)aliphatic (examples are -PhN(R)Me, -PhN(R)Et, -PhN(R)Pr, -PhN(R)iPr, -PhN(R)nBu, -PhN(R)iBu, -PhN(R)tBu, wherein the N(R)Me, N(R)Et, N(R)Pr, or N(R)Bu group is located at the ortho, meta, or para position of the phenyl ring with respect to the position where the phenyl ring is attached to the rest of the compound, 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 the halogen atoms and NO2, CF3, C(CF3)3 groups are located at all positions of the phenyl ring, or may be at the ortho, meta, or para positions of the phenyl ring with respect to the position where the phenyl ring is attached to the rest of the compound) and can be selected from; 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 -Ph pThe compound is NMe2, where p indicates that OMe, Cl, NO2, CF3, and / or C(CF3)3 groups are located in the para position of the phenyl ring relative to the position where the phenyl ring is attached to the remainder of the compound.

[0083] In some embodiments, R 2 R can be selected from alkyl or phenyl. In certain 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 It may include a base. In further embodiments, R 2 As described above, it can be a linker-X group.

[0084] In some 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 Selected from CF3]2, where each n is an integer selected from 0 to 10, independently of the others (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In further embodiments, each R 3 and R 4 Regardless of the -N(H) linker -X, -N[(CH2) n CH3] Linker-X, or -N[(CH2) n [CF3] can be selected from linker-X, where the linker-X group is R 5 and R 2 As stated above.

[0085] In some embodiments, the representative compounds disclosed may have a structure that satisfies any one or more of the following formulas. In some embodiments, the representative compounds may be the free ligand components of the complexes illustrated below.

[0086] [ka] [ka]

[0087] Referring to the above formula, each M, R 3 , R 4 , each R 5 Regardless of n, and R can be selected from the groups listed above for equations I, IA, and IB; each R 6 R is unrelated 5 You can choose from any of the groups listed above. In some embodiments, each R 5 Each R is a different R 5 It can be the same as or different, each R 6 Each of the other R 6 It can be the same as, or different from, and / or R 5 and R 6 They can be the same as or different from each other.

[0088] In further embodiments, the embodiments of the compounds described herein may have a structure that satisfies one or more of the following formulas. In some embodiments, the representative compound may be the free ligand component of the complex illustrated below.

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

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

[0091] Representative compounds having structures that satisfy any one or more of the above formulas are provided. In some embodiments, the representative compounds can be the free ligand components of the complexes exemplified below.

[0092]

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0093] Representative embodiments of compounds containing groups that promote transport across membranes are illustrated below. In some embodiments, the representative compound may be the free ligand component of the complex illustrated below.

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

[0095] Bromide counterions are included for embodiments of the compounds described above. A person of ordinary skill in the art will understand that other counterions may be used to form therapeutically active compounds within the scope of this disclosure. Embodiments of compounds in which the TPP group is instead a quaternary amine are also included in this disclosure in some embodiments. With respect to embodiments of the compounds illustrated above, m may be as described for the above formula, and q may be an integer selected from 0 to 30, for example, 1 to 20, or 1 to 10, or 1 to 5, etc. In some embodiments, q may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0096] In an independent embodiment, the compound is either not or otherwise: [ka]

[0097] In yet another independent embodiment, R 1 is methyl, and R 2 If R is methyl or hydrogen, then R 2 , R 3 , or R 4 At least one of them contains a linker-X group as described herein.

[0098] IV.How to use

[0099] The embodiments of the compounds described herein are therapeutic substances useful for treating neurological diseases (e.g., motor neuron diseases), other copper deficiency-related diseases, and / or mitochondrial deficiencies (also known as mitochondrial deficiencies, etc.) (e.g., cytochrome c oxidase deficiency). Examples of neurological and motor neuron diseases that can be treated using the embodiments and methods of the compounds described herein include, but are not limited to, ALS, Parkinson's disease, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, frontal temporal dementia associated with ALS, spinal muscular atrophy, Menke's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, neuropathies (also known as neuropathy, etc.), prion diseases, and any other neurological diseases associated with copper deficiency. In additional embodiments, embodiments of the compounds disclosed herein can be used to treat copper deficiency-related diseases in canids, such as degenerative myelopathy in canids, ALS-like canid diseases, and others of the same kind. In exemplary embodiments, embodiments of the compounds are used to treat ALS, Parkinson's disease, Menkes disease, Lou Gehrig's disease, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, primary lateral sclerosis, and degenerative myelopathy in canids.

[0100] In some embodiments, the method may include administering one or more effective (or therapeutically effective) amounts of the disclosed compound to a subject or sample (e.g., a biological sample, such as a blood, tissue, or cell sample). In some embodiments, the method may further include monitoring the subject for changes in neurological function (e.g., monitoring the subject for evidence of motor neuron degeneration, muscle atrophy, and other similar conditions). In some embodiments, the compound may be administered using a pharmaceutically appropriate preparation of the compound, which may include the compound and a pharmaceutically appropriate dosage form. Any suitable pharmaceutically appropriate dosage form, such as those described below, may be used. In certain embodiments of the disclosed, the pharmaceutically appropriate dosage form may be a transdermal patch, tablet, capsule, lotion, or injectable solution. In even more specific embodiments, the compound may be administered orally as a solid dispersant, or it may be administered using percutaneous endoscopic gastrostomy to subjects that cannot be orally fed.

[0101] In some embodiments, embodiments of the compounds described herein stabilize the Cu,Zn SOD protein in ALS-affected tissue at rates and levels not achieved by other metal complexes known in this art, such as CuATSM. Embodiments of the compounds described herein deliver the metal (e.g., copper) into the CNS more rapidly than conventional agents and effectively stabilize SOD, thereby preventing the toxicity caused by mutations in this protein that are typically present in subjects prone to developing ALS or other neurological diseases. Each subunit of SOD contains both copper and zinc, which play important catalytic and structural roles in the stabilization of the SOD protein. Copper is used for enzymatic activity, and zinc can determine the folding of SOD. Intracellular copper also binds primarily in cytochrome c oxidase. As a result, SOD often accumulates in zinc-containing, copper-deficient forms, awaiting interaction with its CCS. The intracellular delivery of copper to these two enzymes is facilitated by a complex network of copper transporters and chaperones, and the net distribution is driven by the relative affinity gradient for copper. SOD and CCS have the highest affinity for copper in the CNS. Zinc strongly stabilizes the unfolded SOD protein, so immature SOD accumulates in the spinal cord and awaits copper from CCS to complete Cu,Zn SOD formation. The transport of copper to other organs is much faster than to the spinal cord and brain, and therefore the accumulation of copper-deficient SOD is typically much higher in the CNS. In some embodiments, the method may include applying embodiments of the compound to subjects with one or more mutations in the superoxide dismutase gene. In certain embodiments disclosed, the mutation is not, but rather, a mutation in the G85, H46, or H48 residue of the superoxide dismutase gene. Such mutations affect the copper binding site and thus invalidate the protective effect of SOD.

[0102] Mouse and rat models of ALS produced by overexpression of mutant SOD correlate with human disease with greater fidelity than other more recently discovered rodent models based on ALS-related mutations. Mutant SODs result in toxic gain of function, leading to motor neuron degeneration in various subjects, such as humans, dogs, mice, rats, zebrafish, and Drosophila (fruit flies). Toxic gain-of-function involves a partially unfolded intermediate of SOD lacking two metal cofactors that stabilize SOD. In particular, highly expressed SOD G93A The mouse model has become the most widely used model by experts in evaluating treatment for neurodegenerative diseases. Signs of ALS become apparent in these mice as early as 100 days, as they lose weight and their hind limbs atrophy before reaching final paralysis at 130 days. As such, this model is widely accepted as a model that reasonably correlates with the outcomes of treatment for neurological diseases, such as ALS and other motor neuron diseases, in human subjects.

[0103] This technology has shown that a common characteristic of mutations that cause ALS is the disruption of copper and zinc binding to the SOD protein, but there is an unmet need in the field of ALS treatment for effective therapy in the target population. This technology addresses the issue of high-expression SOD G93AFew treatments in mice can extend lifespan by more than 10-15%, and no pharmaceutical agents (also known as medicinal drugs) have been successfully translated for human treatment. While there is growing evidence that CuATSM is effective in treating ALS in human subjects, this particular compound has other drawbacks related to its structure, as discussed above. However, the embodiments of the compound described herein can move metals (e.g., copper) at rates not achieved by CuATSM, CuGTSM, or CuPTSM, and therefore the embodiments of the compound described herein can exhibit superior activity to CuATSM and CuGTSM and CuPTSM derivatives, and furthermore, do not involve the challenges faced by these complexes (e.g., solubility issues, pharmaceutical compounding issues, and synthesis issues).

[0104] The low reduction potential of the ATMS ligand for the cupric ion (in the 2+ ionized state), or in other words, its high copper affinity, prevents copper release in most tissues but allows for selective copper release in hypoxic tissues or cells with damaged mitochondrial electron transport chains; however, even slight modifications to CuATSM compounds (e.g., removing one or both methyl groups from the carbon atoms of the diimine functional group) can result in rapid copper release, which can lead to toxicity in the SOD ALS model. As such, while CuATSM exhibits high copper affinity, it is an inefficient delivery vehicle for bypassing the distribution system that naturally limits copper transport to the CNS. Therefore, continuous treatment is required to provide the CNS with enough copper to complete the maturation of Cu,Zn SOD. However, such continuous treatment can also lead to toxicity due to increased copper uptake. Furthermore, given the potential for negative reduction of CuATSM, it is extremely difficult to reduce, which reflects a delayed efficacy over several weeks in replenishing SOD and COX. As a result, the majority of CuATSM (e.g., >95%) is excreted in the urine with copper still bound. In contrast, the reduction potential of the embodiments of the compounds disclosed herein allows the compounds to be reduced more readily than CuATSM, yet still exhibit superior efficacy in treating SODxCCS mice and also avoids the potential toxic release of copper into cells. See, for example, Figure 3, which illustrates the reduction (left) versus oxidation standard potential (right) for the ligand component (measured in anhydrous DMSO). Furthermore, embodiments of the compounds described herein can exhibit activity exceeding that of CuATSM and other ALS treatments. For example, in some embodiments, embodiments of the compounds disclosed herein were able to keep mice alive for at least 10 months or more, compared to 4 to 5 months achieved using conventional treatments. Embodiments of the compounds disclosed are also able to deliver more than four times the amount of copper that CuATSM can deliver over a two-week period (see, for example, Figure 4).

[0105] Certain embodiments of the compounds described herein can also be used for radioimaging. For example, embodiments of compounds containing radioactive metal isotopes can be used as contrast agents. In some embodiments, such contrast agents may contain a structure that satisfies any one of the formulas described herein, where the complexed metal "M" is selected from radioactive isotopes of copper, iron, palladium, cadmium, or manganese. In some embodiments, embodiments of compounds containing radioactive metals can be used in combination with positron emission tomography (PET) to image a target. In exemplary embodiments, the metal is radioactive copper, and typically, 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ ,or 64 Cu 2+ , or any combination thereof. In some embodiments, the method may include applying a contrast agent to the subject or sample, and in some additional embodiments, the method may further include exposing the subject or sample to a PET scan.

[0106] In certain embodiments disclosed herein, embodiments of the compounds disclosed herein can be applied to subjects such as humans or non-human animals. In some embodiments, embodiments of the compounds can be formulated as pharmaceutical preparations. Pharmaceutical preparations contemplated by this disclosure may include, but are not limited to, at least one embodiment of the compounds disclosed herein, and pharmaceutically acceptable excipients, such as adjuvants, carriers, stabilizers, or combinations thereof. Pharmaceutical preparations may also include additional components, such as diluents, fillers, binders, humectants, preservatives, acids, and other similar substances, as well as any and all combinations thereof. Embodiments of the compounds described herein may be used alone, in combination with one or more additional compounds, or as adjuncts to or in combination with established treatments. In some embodiments, embodiments of the compounds may be used in combination with other therapeutic agents useful for the disorder or condition being treated. Other exemplary therapeutic agents that can be used to treat the diseases / conditions described herein include, but are not limited to, edaravone and riluzole. These compounds can be administered simultaneously and sequentially in any order, either via the same route of administration or via different routes.

[0107] Pharmaceutical preparations including embodiments of the compounds disclosed herein can be administered as pharmaceutically acceptable preparations in solid, liquid, and / or lotion forms. Suitable solid forms of administration include, but are not limited to, tablets, capsules, powders, solid dispersions, and other similar forms. In certain embodiments disclosed herein, embodiments of the compounds described herein are more favorably suited to preparation by solid dispersant methods compared with CuATSM. Embodiments of the compounds disclosed herein have lower melting points than CuATSM (e.g., 50°C to less than 80°C, e.g., 50°C to less than 70°C, or 50°C to less than 60°C). Certain embodiments of the compounds disclosed melt in the range of 140°C to 180°C, e.g., 145°C to 170°C, or 150°C to 160°C. As such, embodiments of the compounds described herein can be formulated as solid dispersants and / or other solid dosage forms and thus administered orally, whereas CuATSM is not suitable for solid dispersant formulations or other solid dosage forms. In certain embodiments disclosed herein, the compounds 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%, crystallizes when combined with the pharmaceutical dosage form. Furthermore, CuATSM is not suitable for pill / tablet / capsule dosage forms because it gradually crystallizes from the matrix to form insoluble crystals. As indicated above, this means that large amounts of CuATSM can pass through the intestines and thus cause gastrointestinal discomfort.

[0108] Embodiments of the compounds disclosed herein may also be provided as liquid or lotion formulations, taking into account their tendency to resist crystallization. Suitable liquid or lotion forms include, but are not limited to, oil-in-water or water-in-oil emulsions, aqueous gel compositions, or liquids or lotions formulated for use in foams, films, sprays, ointments, pessaries, suppositories, creams, liposomes, or other forms in which they are embedded in a matrix for sustained or controlled release of the compound to the skin or surface to which they are applied or in contact. In certain disclosed embodiments, such formulations may be included with dermal patches to facilitate administration of the compound.

[0109] Embodiments of the compound or compositions containing pharmaceutically acceptable components may be formulated to suit a variety of modes of administration, but are not limited to, including, topological, ocular, oral, oral (also called buccal), systemic, nasal, injection (e.g., intravenous, intraperitoneal, subcutaneous, intramuscular, or intrathecal (also called subarachnoid)), percutaneous (e.g., by mixing with a osmotic agent, such as DMSO), rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0110] For oral or bodily administration, pharmaceutical preparations may take the form of lozenges (also known as troches), tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients. Tablets or capsules may be coated, for example, with sugar, film, or enteric coating by methods well known in this art.

[0111] Liquid preparations of the orally administered compounds disclosed herein may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they may be provided as dry products to be combined with water or other suitable vehicle before use. Preparations for orally administered compounds may also be appropriately formulated to provide a controlled release of the compound.

[0112] For topical administration, the compound can be formulated as a solution, lotion, gel, ointment, cream, suspension, etc. For transmucosal administration, a suitable penetration agent can be used in the formulation to address the barrier to penetration.

[0113] Systemic preparations include those designed for administration by infusion, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal infusion, as well as those designed for percutaneous, transmucosal oral, or pulmonary administration. Useful injectable preparations include sterile suspensions, solutions, or emulsions of compounds in aqueous or oily vehicles. Pharmaceutical preparations may also include suspending agents, such as suspenders, stabilizers, and / or dispersants.

[0114] For administration via the rectal and vaginal routes, embodiments of the compound or its composition may be formulated as a solution (for retained enemas) suppository or ointment containing a conventional suppository base, such as cocoa butter or other glycerides.

[0115] For nasal administration or administration by inhalation or inhalation, embodiments and / or compositions of the compound can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer (also known as a nebulizer) using a suitable propellant. In the case of pressurized aerosols, the dosage unit may be determined by providing a valve for delivering the measured amount. Capsules and cartridges (e.g., capsules and cartridges made of gelatin) for use in inhalers or insufflators (also known as blowers) may be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0116] The dosage of embodiments of the compounds disclosed herein depends on a variety of factors, including the age, weight, general health, and severity of the condition of the subject being treated, as understood by a person of ordinary skill in the art relating to the benefits of this disclosure. The dosage may also be adjusted to suit the sex and / or species of the subject. The dosage and frequency of administration of embodiments of the compounds also depend on whether embodiments of the compounds are formulated for the treatment of an acute episode of a condition (also known as an acute onset) or for preventive treatment of a disorder. In some embodiments, a loading dosage can be used as initial treatment for a patient newly diagnosed with or suspected of having a neurological disorder. Loading dosages may be administered once, twice, three times, or more times per day. In some embodiments, a loading dose is administered up to four times a day for a period of time until a sufficient amount of copper is delivered to the central nervous system / brain (e.g., so that an amount of copper ranging from 15 to 20 mg is continuously maintained in the central nervous system). In further embodiments, a maintenance dosage or prophylactic dose may be administered, for example, once a day. The maintenance dosage typically provides enough copper to meet the daily needs of the CNS.

[0117] The effective dosage can be estimated initially from an in vitro assay. For example, the initial dosage to be used in a subject can be determined by the IC of a particular compound measured in an in vitro assay. 50 or EC 50 The drug can be formulated to achieve a circulating blood or serum concentration of the active compound at or above this level. The dosage can be calculated to achieve such a circulating blood or serum concentration, taking into account the bioavailability of the specific compound.

[0118] The dosage, such as a therapeutically effective dose, of the disclosed compound or its pharmaceutically effective preparation is typically in the range of more than 0 mg / kg / day (e.g., 0.0001 mg / kg / day, 0.001 mg / kg / day, or 0.01 mg / kg / day) up to 100 mg / kg / day. In some embodiments, the dosage (or therapeutically effective dose) may range from 0.0025 mg / kg to 30 mg / kg or from 0.0025 mg / kg to 1 mg / kg and be administered at least once a day (e.g., from 0.01 mg / kg to 0.5 mg / kg, or from 0.05 mg / kg to 0.15 mg / kg). The total daily dosage can range from 0.1 mg / kg to 5 mg / kg per day, or up to 20 mg / kg per day (for example, from 0.5 mg / kg to 10 mg / kg per day, or from 0.7 mg / kg to 2.5 mg / kg per day). In some embodiments, the dosage may be a loading dose, which may include the compound (or its pharmaceutical preparation) being administered in amounts ranging from 10 mg / kg / day to 100 mg / kg / day. In further embodiments, the dosage may be a maintenance dose, which may include the compound (or its pharmaceutical preparation) being administered in amounts ranging from 1 mg / kg / day to 50 mg / kg / day. In even further embodiments, the dosage may be a prophylactic dosage, which may include the compound (or its pharmaceutical preparation) being administered in amounts ranging from 0.1 mg / kg / day to 30 mg / kg / day.

[0119] In further embodiments, for example, in such specific embodiments for administering to human and / or canine subjects, the dosage, e.g., a therapeutically effective amount, such as an embodiment of the disclosed compound or its pharmaceutical preparation, would typically range from more than 0 mg / day (e.g., 0.0001 mg / day, 0.001 mg / day, or 0.01 mg / day, etc.) to 100 mg / day. In some embodiments, the dosage (or therapeutically effective amount) may range from 0.0025 mg / day to 30 mg / day, or from 0.0025 mg / day to 1 mg / day, and be administered at least once a day (e.g., from 0.01 mg / day to 0.5 mg / day, or from 0.05 mg / day to 0.15 mg / day). The total daily dosage can range from 0.1 mg to 5 mg, or up to 20 mg per day (for example, from 0.5 mg / day to 10 mg / day, or from 0.7 mg / day to 2.5 mg / day). In some embodiments, the dosage can be a loading dose, which may include the compound (or its pharmaceutical preparation) being administered in amounts ranging from 10 mg / day to 100 mg / day. In further embodiments, the dosage can be a maintenance dose, which may include the compound (or its pharmaceutical preparation) being administered in amounts ranging from 1 mg / day to 50 mg / day. In even further embodiments, the dosage can be a prophylactic dose, which may include the compound (or its pharmaceutical preparation) being administered in amounts ranging from 0.1 mg / day to 30 mg / day.

[0120] A composition comprising one or more embodiments of the compound disclosed herein typically contains the compound in a total weight percentage ranging from more than 0 to a maximum of 99%. More typically, a composition comprising one or more embodiments of the compound disclosed herein contains a total weight percentage of the compound ranging from 1 to 20, and at least one pharmaceutically acceptable component ranging from 80 to 99%.

[0121] In some embodiments, CCSxSOD mouse data can reflect the response of human ALS patients because the balance of CCS to SOD is closer to that of humans than other SOD mouse models of ALS. In a model embodiment, a dosage of approximately 10 mg / kg / day is used to treat mice. In this embodiment, the dosage is divided into two doses per day. Two factors are considered to adapt this dosage to humans. The first is the 12 factors (also called factors or coefficients) recommended by the FDA for allometric scaling (also called relative growth rate) from mouse to human. The second is that the mutant SOD gene has approximately 30 copies compared to human ALS patents. Therefore, the average dose is calculated as 5 / 360 = 0.014 mg / kg (or approximately 1 mg) per dose of the compound for a 70 kg adult human. Copper is approximately 1 / 6 of the weight of the compound described here. Thus, two doses of 1 mg per day can provide approximately 0.3 mg of copper per day.

[0122] V. Method of preparing compounds

[0123] Disclosed herein are embodiments of a method for preparing embodiments of the compounds described herein. In certain disclosed embodiments, the method may include using any one or more embodiments of the method described below. The method may include preparing a ligand component and exposing the ligand component to a metal precursor composition to form a complex between the ligand and the metal provided by the metal precursor. A person of ordinary skill in the art who benefits from this disclosure will recognize that the method described herein may be adapted to prepare embodiments of the compounds contemplated herein, and that it may not be expressly included in the scheme below. The embodiments of the compounds described herein remain dissolved in refluxing solvents, which facilitates one-pot synthesis, including the addition of a complexing metal. In certain disclosed embodiments, the yield of the method described herein can be as high as 99%.

[0124] In some embodiments, the ligand components of the embodiments of the compounds described herein can be prepared using methods as illustrated in Scheme 1. Referring to Scheme 1, the ligand precursor compound 100 (or a combination of ligand precursor compound 100 and 100', for example, R 3 and R 4 Groups (such as different groups) can be exposed to the diketone reactant 102 to form the diimine product 104. Suitable solvents include any organic solvents typically used in organic synthesis, and temperatures above the ambient temperature (e.g., reflux temperature) can be used. [ka]

[0125] The method in Scheme 1 can be modified, for example, by using the method illustrated in Scheme 2, to prepare other analogs of diimine product 104 by preparing diketone analogs (also called diketone analogs) of formula 204. Any suitable solvent can be used, and the catalyst can be selected from metal-containing catalysts, such as cobalt-containing catalysts (e.g., CoCl2). To prepare diketone compound 204, benzaldehyde compound 200 can be used; benzaldehyde analogs are commercially available (e.g., 4-(trifluoromethyl)benzaldehyde is available from Sigma Aldrich) and / or can be synthesized without difficulty using methods known to a person of ordinary skill in the art who is interested in this disclosure. As illustrated in Scheme 3, diketone analog compounds having formula 204 can be reacted with ligand precursor compound 100 (or a combination of ligand precursor compounds 100 and 100'). [ka]

[0126] Scheme 4 illustrates an exemplary method for creating specific species of ligand components. Other analogs can be created by modifying the method in Scheme 4 to utilize the analog compounds obtained using the methods in Schemes 2 and 3. [ka]

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

[0128] In additional embodiments, embodiments of methods for creating compounds containing a linker-X group can be used. Suitable methods for creating such compounds are illustrated in Schemes 6 and 7 below. A person of ordinary skill in the art who is interested in this disclosure may use R 3 The method can be modified so that it can also be a linker-X group, and such modification can be carried out using substitution reactions and / or functional group modifications recognized by a person of ordinary skill in the art with the help of the present disclosure. The precursor compound 600 used to form the ligand component containing the linker-X group can be prepared using the method illustrated in Scheme 8. [ka] [ka]

[0129] Typical embodiments for creating the linker-X group are illustrated below in Scheme 9. Schemes 10 and 11 illustrate typical methods for coupling the linker-X group with a precursor and methods for forming ligand components containing the linker-X group. [ka] [ka]

[0130] In some embodiments, the method described herein can be used to form a 1:1 complex between a metal and the corresponding ligand component. As such, embodiments of the method described herein are particularly well suited for large-scale synthesis. As such, the method can be used to produce gram-scale, and even kilogram-scale quantities of the embodiments of the compounds described herein. The method avoids the formation of higher-order complexes (e.g., compounds containing two or three metal atoms complexed with one or more ligand components), and thus avoids the complex separation techniques required to separate the reaction products. [Examples]

[0131] VI. Example

[0132] General methods for mass spectrometry assays

[0133] Tissue preparation for SOD and cytochrome c oxidase assays—whole brains and spinal cords were rapidly dissected from euthanized transgenic mice, immediately frozen in liquid nitrogen, and then stored at -80°C until use. To prepare brain tissue for mass spectrometry or cytochrome c oxidase assays, the initially frozen brains were placed on a plate on top of a slab of dry ice to allow the fragile frozen tissue to be warmed to a temperature (approximately -10°C) at which sections could be prepared with a razor blade. The motor cortex and surrounding cerebrum were then cut into approximately 1 mm thick sections with a razor blade. Using a 500 μm biopsy needle, three punches of ~(approximately) 250 μg each were isolated from each mouse tissue, thereby providing technical replication for mass spectrometry and cytochrome c oxidase assays. Tissue punches were weighed using a Cahn 25 Automatic Electrobalance (Cerritos, CA, USA) with a sensitivity of ±0.1 μg. The tissue punches were homogenized for 12 seconds using a VWR Handheld cordless motorized homogenizer to a homogenization buffer concentration of 5 μg tissue / μl. The homogenization buffer (freshly prepared daily) was 10 mM ammonium acetate, pH 5.0–5.1. For SOD measurement, 300 nM bovine SOD (Sigma) was added as an internal standard. The concentration of human SOD detected in mouse tissue was calculated using the ratio of human SOD to the bovine SOD internal standard. After homogenization, the samples were centrifuged in an Eppendorf 5415 R centrifuge at 16000 × g for 2 minutes at 4°C to pelletize cell debris. The supernatant was transferred to a clean tube for mass spectrometry or cytochrome c oxidase assay. Reproducibility in downstream assays was achieved by homogenizing each tissue punch in 1.7 ml plastic centrifuge tubes at volumes between 100 μl.

[0134] Mass spectrometry - pipette tips, e.g., C4 ZipTip (R)(商標) Human SOD was bound and desalted from mouse brain supernatant using a ZipTip (C4 ZipTip) (Millipore, Billerica, MA, USA). (R) The preparation involved first moistening with three volumes of 10 μl of acetonitrile, then rinsing three times with 10 μl of water. The sample was then placed in a ZipTip. (R) The entire matrix is ​​aspirated 10 μl of sample supernatant ten times, followed by eight rinses with 10 μl of water, then wet ZipTip (R) It was bound to the matrix.

[0135] All mass spectrometry experiments used an LTQ-FT Ultra hybrid linear ion trap-Fourier transform ion cyclotron resonance mass spectrometer (Thermo, San Jose, CA) equipped with a Finnigan Ion Max API source configured for electrospray ionization (ESI) in positive ion mode. All SOD quantifications were performed using a linear ion trap with a scan range of 800 to 2000 m / z, which enabled the detection of multiple charge states of SOD from +9 to +13. The solvent used for mass spectrometry was water with acetonitrile:100 μM formic acid in a 30:70 ratio. The solvent was prepared using ZipTip. (R) It passed through a 0.22-micron filter and then flowed directly into the electrospray needle.

[0136] To assay the presence of the C57-146 disulfide bridge, which is typically found in mature SOD, S-methylmethanethiosulfonate (MMTS) was added to the homogenate before mass spectrometry. MMTS reacts with free sulfhydryls to form one methyl disulfide on each accessible sulfhydryl, which is detectable by mass spectrometry. SOD-WT (wild type) has four cysteine ​​residues: Cys6, which face inward in the beta barrel of SOD and are usually inaccessible to the solvent; C57 and C146 form intramonomer disulfide bridges in mature SOD and do not react even if a bridge is formed; and C111 is usually available for reaction. Therefore, an extra mass of one SCH3 group indicates the presence of the C57-146 disulfide bridge, while three SCH3 masses indicate the reduction of the disulfide bridge.

[0137] Data were quantified using a custom Matlab program. Peak intensities of Human SOD apo, 1 mtl, and 2 mtl were summed across all charge states and converted to concentrations using bovine SOD as an internal standard. Mature SOD is defined as a superoxide dismutase protein containing both copper and zinc, with oxidized intramolecular disulfide bonds. Immature SOD is defined as a superoxide dismutase protein lacking either or both copper and zinc, or with reduced intramolecular disulfide bonds.

[0138] Cytochrome c oxidase assay - The assay buffer contained 30 μM reduced cytochrome c in 50 mM potassium phosphate buffer pH 7.0 containing 20 μM EDTA and 24 units / ml catalase. The final dilution of the reduced cytochrome c stock should yield an absorbance of 0.7 at 550 nm. To initiate the assay, 2 μl of CNS tissue homogenate was added to 1 ml of assay buffer at 25C, and the reduction of cytochrome c was followed by a decrease over time at 550 nm. To minimize interference from turbidity, the absorbance at 550 nm was monitored by subtracting the absorbance at 580 nm. The change in absorbance was measured for 1 minute. Then, 2 μl of 100 mM sodium cyanide was added and the change in absorbance was monitored for another 20 seconds. Cyanide inhibits the activity of cytochrome c oxidase and completely inhibits the reduction of cytochrome c. Enzyme activity is expressed in units per mg of wet tissue weight according to the following rule: one unit will oxidize 1.0 μmol of ferrocytochrome c per minute (a) 25C, 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, the binding of copper and zinc to SOD protein in the ventral spinal cord of ALS-affected tissue can be directly quantified. These assays reveal that in the spinal cord of mutant SOD mice, nearly half of the SOD protein was Cu,Zn SOD, while the other half of the SOD protein mainly contained zinc rather than copper, and that effective copper delivery may also require co-expression of CCS (see Figure 5). While we do not wish to be bound by any particular theory, these results currently suggest that SOD G93AThis suggests that copper loading to SOD in the mouse CNS reaches a rate-limited process, which is too slow to keep pace with SOD synthesis, possibly due to a limited amount of endogenous mouse CCS compared to human SOD protein. In certain disclosed embodiments, this assay can be used to confirm that embodiments of the compound disclosed herein can serve as effective therapeutic agents in the treatment of neurological disorders.

[0141] In some embodiments, CCSxSOD wt Mice can provide a rapid assay to determine how well the embodiments of the compounds described herein can supplement cytochrome c oxidase and SOD in the CNS. In some embodiments, mouse offspring are treated at 4 days and followed for 6–21 days before sacrificing, and both enzymes are assayed in CNS tissue. Copper uptake in SOD is tracked by mass spectrometry using the mass spectrometry assay discussed above.

[0142] Example 2 This example uses CSSxSOD rather than CuATSM. WT To further improve the efficiency of copper-deficient SOD maturation in transgenic mice, we establish that embodiments of the compounds disclosed herein enable copper delivery (Figures 4 and 6). In this example, CuATSM is used to deliver copper to untreated SOD. WT Compared to mice, mature SOD increased by only 13 μM, while specific embodiments of the compounds described here can show even greater increases; CuPhMeTSM increased SOD by 60 μM. The amount of immature SOD was also most significantly reduced by CuPhMeTSM. Without being bound by any particular theory, it is currently considered most likely that immature SOD is involved in the production of toxic SOD that causes motor neuron death in vivo.

[0143] Example 3 This example illustrates that embodiments of the compound disclosed herein also exhibit superior activity compared to CuATSM with respect to the increase in COX activity in the brain (Figure 7A) and spinal cord (Figure 7B). In this example, the CuPhMeTSM compound showed an increase in COX activity to almost twice the degree of CuATSM (Figures 7A and 7B). The compound was administered once daily at a dose of 50 mg / kg / day with DMSO, starting at 4 days of age, and measured on day 21. Nitro analogs were not as effective as the CuPhMeTSM embodiment in this particular example, but other analogs showed increases, such as halogenated analogs. Figures 7A and 7B illustrate the results from this example, which evaluated the effectiveness of the embodiments of the compound disclosed herein in terms of the increase in COX activity. The sample size in terms of the number of mice in each group is indicated by number. The dashed line indicates the level of COX activity in untreated mice. COX activity in untreated SODxCCS mice was consistently 0.04 units / mg at all ages, and two mice survived until day 21. See Figures 6A and 6B, where CuPhMe = copper phenylmethyl TSM; CuNO2PhMe = copper 4-nitrophenylmethyl TSM; CuCl-PhMe = copper 4-chlorophenylmethyl TSM; CuBenzil(Cu benzyl) = copper diphenyl TSM; Cu-MeO Benzil(Cu-MeO benzyl) = copper di-4-methoxyphenyl TSM.

[0144] Example 4 In this example, G93A SODxCCS mice were treated percutaneously with 50 mg / kg / day of CuPhMeTSM at 4 days of age. This compound was able to keep 6 G93A SODxCCS mice alive for 300 days (n=6). The results are illustrated in Figure 10. To date, no apparent toxicity from the treatment has been observed.

[0145] Example 5 This example compares the titration curves obtained from the addition of copper to embodiments of the ligand described herein. Figure 2 shows the titration when copper is added to the ligand ATMM. However, as the addition of copper approaches 1:1, the isosbestic point moves away, indicating the formation of undesirable non-stoichiometric behavior. The PhMeTSM ligand produces a clean isosbestic point and forms a 1:1 complex, and the NO2PhMeTSM ligand exhibits similar reactivity. For example, compare Figure 2 (which shows the copper titration curve of the ATMM ligand) with Figures 8 and 9 (which show the copper titration curves of the PhMeTSM and NO2PhMeTSM ligands). As can be seen in Figure 2, with successive additions of copper (each addition being 25% of the ATMM ligand concentration), the absorbance increased with a clear isosbestic point at an apparent 354 nm; however, as the copper concentration approached 1:1, the isosbestic behavior was lost as a third type of complex was formed, containing several copper atoms and at least two ATMM ligands. In contrast, sequential addition of copper (each addition being 25% of the ligand concentration) increased the absorbance with distinct isosbestic points at 311 and 362 nm for PhMeATSM and at 302 and 363 nm for NO2-PhMeATSM (Figures 8 and 9). Unlike ATMS, the isosbestic behavior was preserved for both PhMeATSM and NO2-PhMeATSM at a copper concentration of 1:1. These data confirm that CuPhMeTSM and the other analogs described herein exhibit chemical stability suitable for large-scale synthesis, and therefore contribute to their usefulness and applicability in industrial and pharmaceutical fields.

[0146] The embodiments of CuPhMeTSM and other compounds described herein have reduction potential intermediates that release copper via reduction, which is more readily achieved with physiologically appropriate reducing agents, as illustrated in Figure 3. The steric strain created by the phenyl group in the embodiments of the particular compounds described herein (see Figure 11) is Cu 1+By stabilizing it, the reduction potential can be made even more positive. The oxidation wave of CuATSM shows that it is approximately 40mV more easily oxidized than CuPhMeTSM.

[0147] Example 6

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

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

[0150] Example 7

[0151] 6-Bromohexylammonium bromide [ka] 6-aminohexanol (0.5090 g, 4.27 mmol) was slowly added little by little to a solution of 48% HBr (5.10 mL) at 0°C. Once the 6-aminohexanol was dissolved, the reaction mixture was warmed to room temperature, a reflux condenser was attached, and the mixture was heated to 80°C. The consumption of the starting alcohol was monitored by TLC (1:1 siRNA:MeOH) using ninhydrin staining. The reaction was completed after 20 hours, and the solution was concentrated under vacuum to produce a yellowish-brown solid (tan solid). This was recrystallized from toluene / ethanol (50:1) to supply a white solid.

[0152] Data: R f 0.33 (1:1 HCl: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) was dissolved in 5.00 mL of anhydrous DCM. Triethylamine (0.11 mL, 0.804 mmol) was added dropwise to the stirred solution, followed by anhydrous Boc (0.092 g, 1.10 mmol). The reaction was stirred at room temperature and monitored by TLC using ninhydrin staining. After 20 hours, it was determined that all of the starting amine had been consumed. The reaction was concentrated under vacuum to feed a white solid. This was dissolved in H2O and extracted 3× with 10.00 mL of EtOAC. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to feed a brown oil as the desired product.

[0154] Data: R f = 0.57 (1:1 siRNA:MeOH) ninhydrin staining. 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 stirred solution. A condenser was attached, and the stirred reactants were gently refluxed. The reaction was monitored by TLC using ninhydrin staining, and it was found that all the starting amines had been consumed after 16 hours. The solution was concentrated under reduced pressure to provide the crude oil. Column chromatography gradient, siRNA to siRNA / MeOH (4:1), yielded the desired product in a second fraction after elution of unreacted triphenylphosphine.

[0156] Data: R f = 0.10 (1:1 SiO: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), 1.39-1.33 (s, 9H), 1.33-1.20 (m, 4H).

[0157] 6-(triphenylphosphonium)-hexylammonium-di-trifluoroacetate [ka] Hartwig, S.; et al.; Polymer Chem., 2010, 1, 69-71. Boc-amine was dissolved in 5.00 mL of anhydrous dichloromethane and cooled to 0°C in a 25 mL round-bottom flask. Equivolutes of trifluoroacetic acid (5.00 mL) were added. The reaction was warmed to room temperature and monitored by TLC until complete. The reaction was concentrated and supplied with ammonium trifluoroacetate.

[0158] Data: R f =0.42 (2:1 HCl: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] Ammonium trifluoroacetate was dissolved in 5.00 mL of DI H2O, and then continued with K2CO3 at pH=11. Carbon disulfide was added dropwise, and the reaction was stirred at room temperature and monitored by TLC. After 3 hours, no starting material was observed, and the reaction was cooled to 0°C. Trichlorotriazine in 3.00 mL of DCM was added dropwise, and the solution was vigorously stirred for 30 minutes until a transformation was observed by TLC. The solution was then treated with 6 M NaOH to pH=12. The reaction was transferred to a separation funnel and extracted 3× with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a viscous yellow oil.

[0160] Data: R f = 0.75 (2:1 siRNA: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-[(Hydradinylthioxomethyl)amino]-Hexyltriphenylphosphonium Hydroxide [ka] Hydrazine hydrate (1.0 equivalent) was added to 10.00 mL of MeOH in a 100 mL round-bottom flask and heated to 75°C. Isothiocyanate (0.265 g, 0.628 mmol, 1.0 equivalent) was dissolved in 10.00 mL of MeOH and added dropwise over 1 hour. The reaction mixture was stirred for a further 30 minutes and then concentrated under reduced pressure. This was further purified by column chromatography (100% ethyl acetate -> 20% MeOH / siRNA) to supply 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), 7.99-7.65 (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 gradually over 1.5 hours. The mixture was then stirred for a further 30 minutes. The resulting white precipitate was filtered, washed with cold DI H2O, and further dried under reduced pressure to yield 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] Diacetyl (0.32 mL, 3.60 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 TPP-hexylthiosemicarbazide (1.49 g, 3.27 mmol) was added gradually over 1.5 hours. The mixture was then stirred for a further 30 minutes. The resulting white precipitate was filtered, washed with cold DI H2O, and dried under reduced pressure.

[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] A 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). Five drops of glacial acetic acid were added to the mixture, and the reaction was stirred at room temperature for 4 hours until a yellow precipitate formed. This was filtered and purified by flash column chromatography. A gradient from 100% siRNA to 30% MeOH / siRNA was used to feed the desired product in the 30% MeOH eluent. Unreacted starting material was obtained in 10% MeOH. The fraction was concentrated under reduced pressure to feed 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 complex [ka]

[0170] Asymmetric TPP-ATSM 4-methyl-3-thiosemicarbazide (1.0 equivalent) was added to a 250 mL round-bottom flask dried in an oven. 50.00 mL of anhydrous EtOH was added, and the mixture was heated to 65°C while stirring until completely dissolved. A suitable TPP compound (1.0 equivalent) was added dropwise to the stirred solution, followed by 5 drops of concentrated H2SO4. A precipitate formed within 5 minutes. This was stirred overnight. The mixture was then 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, to which the following variable descriptions apply: M is a divalent metal or its radioactive isotope; R 1 It is an aliphatic or aromatic group, and it is connected to the linker group C a The linker group is directly or indirectly attached to the linker, where it is selected from an aliphatic linker, a heteroaliphatic linker, a heteroatom, an aromatic group, or any combination thereof; R 2 It is selected from hydrogen, aliphatic, heteroaliphatic, or aromatic groups, and it is connected to the linker group C b Attached directly or indirectly to the linker group, thereof selected from aliphatic linkers, heteroaliphatic linkers, heteroatoms, aromatic groups, or any combination thereof; or R 1 and R 2 They are bound together to form a fused ring system comprising two to seven fused rings. Each R 3 and R 4 -NH2, -NHR, -NRR', -OR, -SR, or -C(R) 1-2 R' is independently selected from R and R', where R and R' are independently selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl, or where R and R', together with the nitrogen or carbon atom to which they are bonded, form a heterocyclic or heteroaryl group or a cyclic aliphatic group, respectively; or where R 3and / or R 4 When is -C(R)1R', then one of the R or R' groups forms a double bond with a carbon atom and further bonds with the remaining R or R' group to form an aryl group; and However, the following: (i)R 1 is methyl, and R 2 If R is methyl or hydrogen, then R 2 , R 3 , or R 4 At least one of the groups contains a linker-X group, where the linker is selected from a carbonyl-containing group, alkylene oxide, aliphatic group, or imide ester; or the linker is produced from maleimide, haloacetyl, or pyridyl disulfide; and where X is a moiety (also called a part) containing a functional group suitable for facilitating the delivery of the compound to the target (also called a target); and where the linker-X group is not (CH2)2N(CH3)3 or something else; and (ii) The compounds are the following: [ka] It is subject to the condition that it is not one of those, or something other than those.

[0173] In some embodiments, the compound satisfies one or more formulas IIA-IIR as described herein, and therein, with respect to the appropriate formula, each R 5 and R 6 is aliphatic; aryl; heteroaliphatic; 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 c X, -CH2C(O)NHR c X, -[(CH2)2NR c ] m X, -NR c (CH2)2] m X, -C(=NH2) + )NR c X, or [ka] Selected independently from, in the formula, each R c X is independently selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; each X is -P + (R d )3 or -N + (R d )3 are selected independently, and each R d m can be independently chosen from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl, and each m is an independently chosen integer from 1 to 30; and n is an independently chosen integer from 1 to 5.

[0174] In any or all of the above embodiments, the compound has a structure that satisfies one or more formulas IIIA-IIIY', where, with respect to a suitable formula, each Y is independently selected from O, S, or NR, where R is selected from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, heteroaliphatic-heteroaryl, or any combination thereof; each X is independently a targeting moiety; each m is a selected integer from 1 to 30; each q is a selected integer from 0 to 30; and n is a selected integer from 1 to 5.

[0175] In any or all of the above embodiments, M is Cu, Co, Ni, or their radioactive isotopes, for example, Cu 2+ , 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+ These are examples of such things.

[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+ That is the case.

[0177] In any or all of the above embodiments, R 1 Phenyl, pyridyl, naphthyl, anthracenyl, quinolinyl, quinazolinyl, quinoxalinyl, benzoquinolinyl, benzoquinoxalinyl, benzoquinazolinyl, phenyl-(R 5 ) n Pyridyl-(R 5 ) n Naphthyl-(R 5 ) n Anthracenyl-(R) 5 ) n , quinolinyl-(R 5 ) n , quinazolinyl-(R 5 ) n , Kinoxalinyl-(R 5 ) n , benzoquinolinyl-(R 5 ) n , benzoquinoxalinyl-(R 5 ) n, or benzoquinazolinyl-(R 5 ) n Selected from, and there each R 5 is aliphatic;aryl;haloaliphatic;heteroaliphatic;aliphatic-aryl;heteroaryl;aliphatic-heteroaryl;heteroaliphatic-aryl;heteroaliphatic-heteroaryl;hydroxyl;-NH2;-P + (R d )3 or -N + (R d )3(Therefore each R d n can be independently selected from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl); nitro; thiol; halogen; phosphate; phosphoryl; sulfino; sulfo; azide; 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] 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] Selected from; in the formula, each R cX is independently selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; each X is -P + (R d )3 or -N + (R d )3 are selected independently, and each R d m is independently chosen from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; and each m is an independently chosen integer from 1 to 30.

[0179] In any or all of the above embodiments, each R 5 n is independently selected from alkyl, alkylenyl, alkynyl, amine, carboxylic acid, ester, alkoxy, amide, cyano, ether, silyl ether, phosphine, thioether, disulfide, isothiocyanate, isocyanate, carbonate, ketone, sulfinyl, sulfonyl, carbonoyl, isonitrile, or any combination of such groups; 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] mPPh3, where R is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl;-PhO-aliphatic;-PhN(R)aliphatic, where R is hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl); or-Ph(Z) 1-5 Therefore, Z is chosen from Cl, F, Br, or I, NO2, CF3, C(CF3)3; and m is a selectable integer from 1 to 30.

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

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

[0183] In any or all of the above embodiments, each R 2 , R 3 , and R 4 The compound contains an independent linker-X group, where the linker is selected from carbonyl-containing groups, alkylene oxides, aliphatic groups, and imide esters; or the linker is generated from maleimide, haloacetyl, or pyridyl disulfide; and therein X is a moiety containing a functional group suitable for facilitating the delivery of the compound to its target.

[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] mX, -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] Selected from; in the formula, each R c X is independently selected from aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; each X is -P + (R d )3 or -N + (R d )3 are selected independently, and each R d m is independently chosen from hydrogen, aliphatic, aryl, heteroaliphatic, aliphatic-aryl, heteroaryl, aliphatic-heteroaryl, heteroaliphatic-aryl, or heteroaliphatic-heteroaryl; and each m is an independently chosen integer from 1 to 30.

[0185] In any or all of the above embodiments, the linker-X group is -C(O)(CH2) 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] They are selected from among them.

[0186] In any or all of the above embodiments, each R 3 and R 4 -N(H) linker-X, -N[(CH2) n CH3] Linker-X, or -N[(CH2) n [CF3] Linker-X is independently selected, where the linker is selected from a carbonyl-containing group, alkylene oxide, aliphatic group, or imide ester; or the linker is produced from maleimide, haloacetyl, or pyridyl disulfide; and where X is the 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 The values ​​are randomly selected from CF3]2, where each n is a randomly selected 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 R can be optionally used there. 3 and R 4 is -N[(CH2)2CH3]2 and / or each R 1 and R 2 It is phenyl.

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

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

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

[0192] Also disclosed herein are embodiments of pharmaceutical preparations or dosage forms, including compounds such as those disclosed herein; and delivery components, optionally selected from transdermal patches, tablets, capsules, lotions, or injectable solutions, wherein, when combined with the delivery components, less than 15% of the total amount of the compounds crystallizes.

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

[0194] In any or all of the above embodiments, the pharmaceutical preparation or dosage form further includes an adjuvant, a therapeutic agent, a pharmaceutically acceptable excipient, or any combination thereof.

[0195] Disclosed herein are embodiments of a method which involves applying a therapeutic amount of the compound for use in a method of treating the compound disclosed herein and / or a subject to a subject or sample, wherein the compound is a compound according to any or all of the embodiments described above.

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

[0197] In any or all of the above embodiments, at least one additional therapeutic agent is edaravone 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 applied prophylactically.

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

[0201] In any or all of the embodiments described above, the subject has one or more mutations in the superoxide dismutase gene. In some embodiments, the mutation is not, or is not, a mutation in the G85, H46, or H48 residue of the superoxide dismutase gene.

[0202] In any or all of the above embodiments, the subject is a canid, and the canid belongs to a breed susceptible to canine degenerative myelopathy.

[0203] In any or all of the above embodiments, subjects have or are at risk of developing a neurological disorder selected from ALS, Parkinson's disease, Menkes disease, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, frontal temporal dementia associated with ALS, spinal muscular atrophy, and degenerative myelopathy in canids; copper deficiency-based disease; or mitochondrial dysfunction.

[0204] Also disclosed herein are embodiments of a method for treating motor neuron disease, wherein a compound selected from the following one or more compounds; or a compound for use in a method for treating motor neuron disease, wherein the compound is administered in a therapeutic amount selected from the following one or more compounds: [ka]

[0205] In some embodiments, the therapeutic dose ranges from 0 mg / day to 100 mg / day, or the compound is administered in amounts ranging from there.

[0206] In any or all of the above embodiments, the therapeutic dose is a loading dose ranging from 10 mg / day to 100 mg / day, or the compound is administered in an amount ranging from there.

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

[0208] In any or all of the above embodiments, the motor neuron disease is selected from ALS, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, or any combination thereof.

[0209] Also disclosed herein are embodiments of a compound for use in methods for treating neurological disorders, copper deficiency-based diseases, or mitochondrial dysfunction, wherein the compound has a structure satisfying formula I, and therein the variables of formula I are as described herein.

[0210] In some embodiments, neurological disorders are motor neuron disorders.

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

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

[0213] In any or all of the above embodiments, the therapeutic dose is a prophylactic dose ranging from 0.1 mg / day to 30 mg / day.

[0214] In any or all of the embodiments described above, the prophylactic dose is administered to subjects harboring one or more mutations in the superoxide dismutase gene. In some embodiments, the mutation is not, or is not, a mutation in the G85, H46, or H48 residues of the superoxide dismutase gene.

[0215] In any or all of the above embodiments, the prophylactic dose is administered to a canid belonging to a breed susceptible to degenerative myelopathy in canids.

[0216] Also disclosed herein is a method, and a compound disclosed herein, where M is 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+A composition comprising any or all embodiments of the above compound for use in a method of applying the above compound to a subject or sample and / or diagnosing a subject having or at risk of developing motor neuron disease, wherein M is 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+ This is an embodiment of something that includes [something].

[0217] In some embodiments, the method further includes imaging a subject or sample using positron emission tomography to determine the presence of motor neuron disease.

[0218] In any or all of the embodiments described above, the method includes imaging a subject or sample using positron emission tomography to determine the presence of Parkinson's disease, multiple sclerosis, and Alzheimer's disease.

[0219] In any or all of the embodiments described above, the method includes imaging a subject or a sample obtained from a subject using positron emission tomography to determine whether the subject has or is at risk of developing a motor neuron disease.

[0220] Given the many possible embodiments to which the principles of this disclosure may apply, it should be recognized that the exemplary embodiments are merely preferred examples and should not be construed as limiting the scope of this disclosure. Rather, the scope is defined by the following claims. Accordingly, we claim as our invention everything that falls within the scope and spirit of these claims.

Claims

1. The compound has a structure represented by the following formula, 【Chemistry 1】 During the ceremony M is copper or its radioactive isotope; R 1 teeth, 【Chemistry 2】 Selected from; R 1 but 【Transformation 3】 When R 2 CH 3 And R 1 but 【Chemistry 4】 When R 2 teeth, 【Transformation 5】 Each R 3 and R 4 is -N(H)(CH 2 ) n’ CH3, where n’ is an integer selected from 0 to 9; a compound selected independently therefrom.

2. M is Cu, Cu 2+ , 60 Cu 2+ , 61 Cu 2+ , 62 Cu 2+ , 63 Cu 2+ , 64 Cu 2+ ,or 65 Cu 2+ The compound according to claim 1.

3. R 1 teeth, 【Transformation 6】 And; R 2 CH 3 The compound according to claim 1 or claim 2.

4. The aforementioned compound is as follows: 【Transformation 7】 A compound selected from any one of claims 1 to 3.

5. A pharmaceutical composition for treating neurological disorders, comprising the compound described in any one of claims 1 to 4.

6. The pharmaceutical composition according to claim 5, which is a patch, tablet, capsule, lotion, or solution injection.

7. A pharmaceutical composition according to claim 5, comprising an adjuvant, a therapeutic agent, a pharmaceutically acceptable excipient, or any combination thereof.

8. Next, 【Transformation 8】 A compound selected from A pharmaceutical composition for treating neurological disorders selected from ALS, Parkinson's disease, Menkes disease, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, and degenerative myelopathy in canids; diseases based on copper deficiency; or mitochondrial dysfunction.

9. Further comprising edaravone or riluzole, wherein the edaravone or riluzole is applied sequentially or simultaneously with the compound, optionally (i) The subject to which the pharmaceutical composition is applied has one or more mutations in the superoxide dismutase gene, and the mutation is not a mutation in the G85, H46, or H48 residue of the superoxide dismutase gene, or is a mutation other than a mutation in the G85, H46, or H48 residue of the superoxide dismutase gene, and / or (ii) The pharmaceutical composition according to claim 8, wherein the target to which the pharmaceutical composition is applied is a canid, and the canid belongs to a breed susceptible to degenerative myelopathy of canids.

10. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for treating motor neuron disease, and the compound is selected from the compounds described in claim 4.

11. The pharmaceutical composition is applied to a subject such that the compound is provided in an amount ranging from more than 0 mg / day to 100 mg / day, and optionally, (i) The compound is provided in an amount ranging from 10 mg / day to 100 mg / day, or (ii) The pharmaceutical composition according to claim 10, wherein the compound is provided in an amount ranging from 1 mg / day to 50 mg / day.

12. The pharmaceutical composition according to claim 10 or 11, wherein the motor neuron disease is selected from ALS, Lou Gehrig's disease, primary lateral sclerosis, Kennedy syndrome, frontotemporal dementia associated with ALS, spinal muscular atrophy, or any combination thereof.

13. Next, 【Chemistry 9】 A compound selected from A pharmaceutical composition for increasing the level of mature superoxide dismutase in a target.

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