Isotopically labeled derivatives of trapidil

Abstract

Isotopically labeled trimetazidine derivatives useful for treating Parkinson's disease and movement disorders associated with Parkinson's disease are provided. The isotopically labeled trimetazidine derivatives include deuterated trimetazidine derivatives. In addition, combination therapies of isotopically labeled trimetazidine derivatives and additional therapeutic agents for treating Parkinson's disease and movement disorders associated with Parkinson's disease are also provided.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180038452.7, filed on March 25, 2021, having a corresponding PCT application with an application date of March 25, 2021, and application number PCT / US2021 / 024226, entitled “Isotopically Labeled Trapidil Derivatives.”

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 000,347, filed March 26, 2020, and U.S. Provisional Application Serial No. 63 / 063,846, filed August 10, 2020, which are hereby incorporated by reference in their entirety.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0005] This application was made with government support under R44 GM121117 awarded by the National Institutes of Health. The government has certain rights in the application. SUMMARY

[0006] In certain embodiments, provided herein is a compound of Formula (I), or a pharmaceutically salt, co-crystal, or solvate thereof:

[0007]

[0008] wherein:

[0009] R 1 is -CH3, -CD3, -CHD2, or -CH2D;

[0010] R 2 is hydrogen or -D;

[0011] R 3 is hydrogen or -D;

[0012] R 4 is hydrogen, -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3; -CH2CH2H; -CH2CHH2; -CHHCH2; -CHHCHH; -CHHCD3; -CDHCH2; -CDHCHH; -CHHCD2H; -CDHCD2H; -CDHCDH2; -CDHCDH2; or -CDHCD2H;

[0013] CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3; -CDHCDH2; -CDHCD2H; -CDHCDH2; or -CDHCD2H;

[0014] CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3; -CDHCDH2; -CDHCD2H; -CDHCDH2; or -CDHCD2H;

[0015] R 5 is hydrogen, -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3; -CH2CH2H; -CH2CHH2; -CHHCH2; -CHHCHH; -CHHCD3; -CDHCH2; -CDHCHH; -CHHCD2H; -CDHCD2H; -CDHCDH2; -CDHCDH2; or -CDHCD2H;

[0016] CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3; -

[0017] CDHCDH2; or -CDHCD2H; and

[0018] wherein at least one of R 1 , R 2 , R 3 , R 4 or R 5 comprises at least one deuterium atom.

[0019] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, namely:

[0020]

[0021] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, namely:

[0022]

[0023] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, namely:

[0024]

[0025] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, namely:

[0026]

[0027] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, namely:

[0028]

[0029] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, namely:

[0030]

[0031] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, namely:

[0032]

[0033] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, i.e.,

[0034]

[0035] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, i.e.,

[0036]

[0037] In certain embodiments, provided herein is a compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, i.e.,

[0038]

[0039]

[0040] In some embodiments, in any one of the compounds disclosed herein, or in a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment at the position denoted as D is at least 98%. In some embodiments, in any one of the compounds disclosed herein, or in a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment at the position denoted as D is at least 90%. In some embodiments, in any one of the compounds disclosed herein, or in a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment at the position denoted as D is at least 50%. In some embodiments, in any one of the compounds disclosed herein, or in a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment at the position denoted as D is at least 10%.

[0041] In certain embodiments, provided herein is a pharmaceutical composition comprising any one of the compounds disclosed herein, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, and a pharmaceutically acceptable carrier.

[0042] In certain embodiments, provided herein is a method of treating Parkinson’s disease or a movement disorder associated with Parkinson’s disease in a subject in need thereof, comprising administering to the subject any one of the compounds disclosed herein or a pharmaceutical composition disclosed herein.

[0043] In certain embodiments, provided herein is a method of treating Parkinson's disease or a movement disorder associated with Parkinson's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective combination of (a) any one of the compounds disclosed herein or a pharmaceutical composition disclosed herein and (b) an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedile, lysuride, or apomorphine, or a combination thereof. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedile, lysuride, or apomorphine, or a combination thereof. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide. In some embodiments, in any of the methods provided herein, the movement disorder to be treated is dyskinesia. In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID), diphasic dyskinesia, or peak dose dyskinesia.

[0044] In some embodiments, in any of the methods provided herein, the movement disorder to be treated is dystonia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, in any of the methods provided herein, the movement disorder to be treated is akathisia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoresponsive akathisia, or withdrawal akathisia. In some embodiments, in any of the methods provided herein, the subject to be treated is diagnosed with Parkinson's disease.

[0045] In some embodiments, provided herein is a pharmaceutical combination for treating or preventing Parkinson’s disease or a movement disorder associated with Parkinson’s disease in a subject in need thereof, comprising: (a) any of the compounds disclosed herein or any of the pharmaceutical compositions disclosed herein; and (b) a therapeutic combination of an additional therapeutic agent for treating Parkinson’s disease. In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide. In some embodiments, the movement disorder is dyskinesia. In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID), biphasic dyskinesia, or peak dose dyskinesia. In some embodiments, the movement disorder is dystonia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the movement disorder is akathisia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoresponsive akathisia, or withdrawal akathisia. In some embodiments, the subject is diagnosed with Parkinson’s disease. BRIEF DESCRIPTION OF DRAWINGS

[0046] FIG. 1 Blood concentration (ng / mL, linear scale) time profiles following oral administration of trimetazidine (diamonds), Example 3-1 (squares), 3-2 (triangles), and 3-3 (circles) in male Sprague Dawley rats are shown.

[0047] FIG. 2 Showing the logarithmic scale with FIG. 1 Same result.

[0048] FIG. 3 The plasma concentration (ng / mL, linear scale) time curves after intravenous administration of tropidil (rhombus), Example 3-1 (square), 3-2 (triangle), and 3-3 (circle) to male Sprague Dawley rats are shown.

[0049] FIG. 4 Showing the logarithmic scale with FIG. 3 Same result. Detailed Implementation

[0050] In some embodiments, this document provides tropidil derivatives for treating Parkinson's disease and Parkinson's disease-related motor disorders in subjects with this need. In some embodiments, the tropidil derivative is isotopically labeled. In some embodiments, the tropidil derivative is deuterated. In some embodiments, the motor disorder is an adverse drug reaction to a therapeutic agent used to treat Parkinson's disease. In some embodiments, the tropidil derivative of this disclosure is administered alone or in combination with an adjunct therapeutic agent to a subject with this need. In some embodiments, the adjunct therapeutic agent is a dopamine precursor, a dopamine agonist, a catechol O-methyltransferase (COMT) inhibitor, a monoamine oxidase B (MAOB) inhibitor, or a dopa decarboxylase inhibitor.

[0051] Parkinson's disease (PD) is the second most common neurodegenerative disorder. PD is associated with severe motor, cognitive, and emotional disturbances. Although the mechanisms of neurodegeneration in PD remain unclear, the loss of dopaminergic terminals in the neostriatum and neuronal cell bodies is the basis for motor symptoms. Pharmacological treatment of PD primarily targets motor symptoms, and PD typically increases the activation of two types of dopamine receptors: dopamine 1 receptors (D1, D5) and dopamine 2 receptors (D2-D4). Dopamine 1 receptors (D1R) are located on the substantia nigra neurons of the striatum and are activated by dopamine. Dopamine 2 receptors (D2R) are located on the globus pallidus neurons of the striatum and are inhibited by dopamine. Pharmacological activation of D1R in PD models increases the expression of several transcripts associated with dyskinesia, including FOS, FOSB, JUNB, ARC, and EGR4.

[0052] Levodopa is the gold standard for treating Parkinson's disease and related motor disorders. Long-term use of levodopa in Parkinson's patients can lead to motor complications, including loss of efficacy and levodopa-induced dyskinesia. Furthermore, current adjuvants to levodopa (such as COMT inhibitors, MAOB inhibitors, and D2 agonists) can exacerbate dyskinesia. Therefore, there is a need for therapeutic agents with fewer side effects that do not cause motor complications in Parkinson's patients.

[0053] In some embodiments, this document discloses a combination therapy of a tropidil derivative and an adjunct therapeutic agent. In some embodiments, the adjunct therapeutic agent is levodopa and / or carbidopa. In some embodiments, the tropidil derivative of this disclosure is an isotopically labeled tropidil derivative. In some embodiments, the isotopically labeled tropidil derivative is a deuterated tropidil compound.

[0054] This document further discloses a method for treating Parkinson's disease and Parkinson's disease-related motor disorders in a subject by administering the disclosed tropidil derivative to the subject in need. In some embodiments, the method includes further administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is levodopa and / or carbidopa. In some embodiments, levodopa and / or carbidopa are administered to the subject before, after, or simultaneously with the isotopically labeled tropidil derivative.

[0055] Deuterium kinetic isotope effect

[0056] To remove foreign substances, such as therapeutic agents, from their circulatory system, animals express various enzymes that react with these foreign substances and convert them into more polar intermediates or metabolites for excretion by the kidneys, such as cytochrome P. 450 Enzymes or CYPs, esterases, proteases, reductases, dehydrogenases, and monoamine oxidases. Some of the most common metabolic reactions of drug compounds involve the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) π bonds. The resulting metabolites may be stable or unstable under physiological conditions, and their pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles can vary considerably relative to the parent compound. For most drugs, this type of oxidation is typically rapid and ultimately leads to daily administration of multiple or high doses.

[0057] The relationship between activation energy and reaction rate can be expressed by the Arrhenius equation k = Ae -Eact / RT To quantify, where E actis the activation energy, T is the temperature, R is the molar gas constant, k is the rate constant of the reaction, and A (the frequency factor) is a constant unique to each reaction, which depends on the probability of molecules colliding with the correct orientation. The Arrhenius equation states that the proportion of molecules with enough energy to overcome the energy barrier (i.e. molecules with at least the activation energy) depends exponentially on the ratio of the activation energy to the thermal energy (RT) that the molecules possess at a certain temperature.

[0058] The transition state of a reaction is a short-lived activated state (approximately 10 -14 sec) along the reaction pathway during which the original bonds have stretched to their limit. By definition, the activation energy E act of a reaction is the energy required to reach the transition state of that reaction. Reactions involving multiple steps will necessarily have several transition states, in which case the activation energy of the reaction is equal to the energy difference between the reactants and the least stable transition state. Once the transition state is reached, the molecule can either revert back to the original reactants, re-forming the original bonds, or form new bonds, resulting in the product. This dichotomy is possible because both pathways (forward and reverse) result in the release of energy. Catalysts facilitate the reaction process by lowering the activation energy that leads to the transition state. Enzymes are examples of biological catalysts that reduce the energy required to achieve a particular transition state.

[0059] Carbon-hydrogen bonds are covalent chemical bonds in nature. Such bonds are formed when two atoms of similar electronegativity share some of their valence electrons, resulting in a force that holds the atoms together. This force, or bond strength, can be quantified and expressed in units of energy, and thus, covalent bonds between various atoms can be classified according to how much energy must be applied to the bond to break it or separate the two atoms.

[0060] The strength of a bond is directly proportional to the absolute value of the ground state vibrational energy of the bond. This vibrational energy, also known as the zero point vibrational energy, depends on the mass of the atoms that form the bond. The absolute value of the zero point vibrational energy increases with the increase in the mass of one or both of the atoms that form the bond. Since deuterium (D) has twice the mass of hydrogen (H), a C-D bond is stronger than the corresponding C-H bond. Compounds with C-D bonds are often infinitely stable in H2O and are widely used in isotopic studies. If a C-H bond is broken during the rate limiting step of a chemical reaction (i.e., the step with the highest transition state energy), replacing that hydrogen with deuterium will result in a decrease in the rate of the reaction and the process will slow down. This phenomenon is known as the deuterium kinetic isotope effect (DKIE) and can range from about 1 (no isotope effect) to a very large number, such as 50 or more, meaning that the reaction can slow down to 1 / 50 or less when the hydrogen is replaced with deuterium. High DKIE values can be due in part to a phenomenon known as the tunneling effect, which is a consequence of the uncertainty principle. The tunneling effect is attributed to the small size of the hydrogen atom and occurs because the transition state involving a proton can sometimes form in the absence of the required activation energy. Deuterium is larger and, statistically, the probability of this happening is much lower. Replacing hydrogen with tritium results in an even stronger bond and an even larger isotope effect in numbers.

[0061] Deuterium (D), discovered by Urey in 1932, is a stable and non-radioactive isotope of hydrogen. It was the first isotope to be isolated in pure form from its element and has twice the mass of hydrogen, accounting for about 0.02% of the total mass of hydrogen (in this usage, referring to all isotopes of hydrogen) on Earth. When two deuterium atoms combine with one oxygen, deuterium oxide (D2O or "heavy water") is formed. D2O has a similar appearance and taste to H2O but has different physical properties. It boils at 101.41 °C and freezes at 3.79 °C. Its heat capacity, heat of fusion, heat of vaporization, and entropy are all higher than H2O. It is more viscous than H2O and has different solubility properties.

[0062] When pure D2O is administered to rodents, it is readily absorbed and reaches equilibrium levels, typically around 80 percent of the concentration consumed by the animal. The amount of deuterium required to induce toxicity is very high. When 0% to up to 15% of body water is replaced by D2O, the animals are healthy but do not gain weight as quickly as the control (untreated) group. When about 15% to about 20% of body water is replaced by D2O, the animals become excitable. When about 20% to about 25% of body water is replaced by D2O, the animals become so excitable that they convulse frequently when stimulated. Skin lesions, ulcers on the claws and muzzle, and necrosis of the tail appear. The animals also become very aggressive; males become almost unmanageable. When about 30% of body water is replaced by D2O, the animals refuse to eat and become comatose. Their weight drops drastically, and their metabolic rate drops far below normal levels; death occurs when about 30% to about 35% of body water is replaced by D2O. This effect is reversible unless more than 30% of the previous body weight has already been lost due to D2O. Studies have also shown that using D2O can slow the growth of cancer cells and enhance the cytotoxicity of certain anti-tumor drugs.

[0063] Tritium (T) is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Mixing tritium with phosphorescent agents provides a continuous light source, a technique commonly used in watches, compasses, rifle sights, and export markings. It was discovered by Rutherford, Oliphant, and Harteck in 1934 and is naturally produced in the upper atmosphere when cosmic rays react with H2 molecules. Tritium is a hydrogen atom with two neutrons in its nucleus and an atomic weight close to 3. It exists naturally in the environment at very low concentrations, most commonly found as T2O, a colorless and odorless liquid. Tritium decays slowly (half-life = 12.3 years), releasing low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope; however, it must be ingested in large quantities to pose a significant health risk.

[0064] Previously, deuteration of drugs has been shown to improve pharmacokinetic (PK), pharmacodynamic (PD), and toxicity profiles in some classes of drugs. For example, DKIE may have been used to reduce the hepatotoxicity of halothane by limiting the production of reactive species such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For instance, deuteration can lead to metabolic conversion, which may even result in a faster dissociation rate by activated phase I enzymes (such as cytochrome P450). 4503A4) generates oxidative intermediates. The concept of metabolic switching posits that when sequestered by an I-phase enzyme, xenobiotics can temporarily bind and rebind in various conformations prior to a chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large size of the binding pockets of many I-phase enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially lead to different ratios of known metabolites as well as completely new metabolites. This new metabolic profile can be more or less toxic. For any drug class, such approaches have not been sufficient to predict a priori to date.

[0065] Isotopically labeled derivatives of trapidil

[0066] The carbon-hydrogen bonds of trapidil contain the naturally occurring hydrogen isotope distribution, i.e. 1 H or protium (about 99.9844%), 2 H or deuterium (about 0.0156%), and 3 H or tritium (ranging from about 0.5 to 67 tritium atoms per 10 18 protium atoms). An increase in the level of deuterium incorporation results in a detectable kinetic isotope effect (KIE) that can affect pharmacokinetic, pharmacological, and / or toxicological parameters compared to compounds with the naturally occurring level of deuterium.

[0067] Disclosed herein, in certain embodiments, are derivatives of trapidil of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof:

[0068]

[0069] wherein

[0070] R 1 is -CH3, -CD3, -CHD2, or -CH2D;

[0071] R 2 is hydrogen or -D;

[0072] R 3 is hydrogen or -D;

[0073] R 4 is hydrogen; -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3;

[0074] CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3;

[0075] CDHCDH2; or -CDHCD2H;

[0076] R 5It is hydrogen; -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3; -

[0077] CH2CDH2;-CH2CD2H;-CD2CDH2;-CD2CD2H;-CDHCD3;-

[0078] CDHCDH2; -CDHCD2H;

[0079] Where R 1 R 2 R 3 R 4 Or R 5 At least one of them contains at least one deuterium atom.

[0080] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, cocrystal, or solvation, R 1 It is -CH3. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, or solvates, R 1 It is -CD3. In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, cocrystal, or solvation, R 1 Yes -CHD2. In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, cocrystal, or solvation, R 1 It is -CH2D.

[0081] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, cocrystal, or solvation, R 2 It is hydrogen. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, or solvates, R 2 Yes -D.

[0082] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, cocrystal, or solvation, R 3 It is hydrogen. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, or solvates, R 3 Yes -D.

[0083] In some embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, cocrystal, or solvation, R 4 It is hydrogen. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, or solvates, R 4 It is -CH2CH3. In some embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, cocrystals, or solvates, R 4-CD2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CD2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CH2CD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CDHCH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CH2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CH2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CD2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CD2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CDHCD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CDHCDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 -CDHCD2H.

[0084] -CH2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 -CH2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 -CD2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 -CD2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 -CH2CD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 -CDHCH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5is -CH2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CH2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CD2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CD2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CDHCD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CDHCDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CDHCD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 98%.

[0085] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 90%. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 80%.

[0086] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 70%. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 60%.

[0087] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 50%. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 40%.

[0088] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 30%. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 20%.

[0089] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 10%. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 5%. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 1%.

[0090] In some embodiments, the troponin derivative disclosed herein is

[0091] In some embodiments, the troponin derivative disclosed herein is

[0092] In some embodiments, the troponin derivative disclosed herein is

[0093] In some embodiments, the troponin derivative disclosed herein is

[0094] In some embodiments, the troponin derivative disclosed herein is

[0095] In some embodiments, the troponin derivative disclosed herein is

[0096] In some embodiments, the troponin derivative disclosed herein is

[0097] In some embodiments, the troponin derivative disclosed herein is

[0098] In some embodiments, the troponin derivative disclosed herein is

[0099] In some embodiments, the troponin derivative disclosed herein is

[0100] In some embodiments, the troponin derivative disclosed herein is

[0101] In some embodiments, the troponin derivative disclosed herein is

[0102] In some embodiments, the troponin derivative disclosed herein is

[0103] In some embodiments, the troponin derivative disclosed herein is

[0104] In some embodiments, the troponin derivative disclosed herein is

[0105] In some embodiments, the troponin derivative disclosed herein is

[0106] In some embodiments, the troponin derivative disclosed herein is

[0107] In some embodiments, the troponin derivative disclosed herein is

[0108] In some embodiments, the troponin derivative disclosed herein is

[0109] In some embodiments, the troponin derivative disclosed herein is

[0110] In some embodiments, the troponin derivative disclosed herein is

[0111] In some embodiments, the troponin derivative disclosed herein is

[0112] In some embodiments, the troponin derivative disclosed herein is

[0113] In some embodiments, the troponin derivative disclosed herein is

[0114] In some embodiments, the troponin derivative disclosed herein is

[0115] In some embodiments, the troponin derivative disclosed herein is

[0116] In some embodiments, the troponin derivative disclosed herein is

[0117] In some embodiments, the troponin derivative disclosed herein is

[0118] In some embodiments, the troponin derivative disclosed herein is

[0119] In some embodiments, the trimetazidine derivatives disclosed herein are

[0120] In some embodiments, the trimetazidine derivatives disclosed herein are

[0121] In some embodiments, the deuterated trimetazidine derivatives provided herein retain the beneficial aspects of the corresponding non-isotopically enriched molecules, while increasing the half-life (T 1 / 2 ), reducing the maximum plasma concentration (C max ) of the minimum effective dose (MED), reducing the effective dose, thereby reducing non-mechanism related toxicities, and / or reducing the likelihood of drug-drug interactions. In some embodiments, the deuterated trimetazidine derivatives cause a change in the pharmacological activity of the drug.

[0122] Isotopic hydrogen can be introduced into the compounds of Formula (I) provided herein by synthetic techniques employing deuterated reagents in which the rate of incorporation is predetermined; and / or by exchange techniques in which the rate of incorporation is determined by equilibrium conditions and can vary highly depending on the reaction conditions. Synthetic techniques in which tritium or deuterium is directly and specifically inserted by known isotopically content of the tritiation or deuteration reagents can result in high tritium or deuterium enrichment, but can be limited by the desired chemical reactions. In addition, the labeled molecule can be altered depending on the strength of the synthetic reaction employed. On the other hand, exchange techniques can result in lower tritium or deuterium incorporation, with the isotopes often distributed over many sites in the molecule, but have the advantage that they do not require separate synthetic steps and are less likely to disrupt the structure of the labeled molecule.

[0123] The trimetazidine derivatives provided herein can be prepared by any suitable method.

[0124] Deuterium can be incorporated synthetically in different positions by using appropriate deuterated intermediates. These deuterated intermediates are either commercially available or can be prepared by any suitable method or following procedures analogous to those described in Journal of Organic Chemistry, 48(20), 3458-3464, 1983 or Journal of Chemical and Engineering Data, 55(5), 2048-2054; 2010 and routine modifications thereof.

[0125] Pharmaceutically acceptable salts

[0126] In some embodiments, the trandilapril derivatives described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating Parkinson’s disease and movement disorders associated with Parkinson’s disease, comprising administration of such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating Parkinson’s disease and movement disorders associated with Parkinson’s disease, comprising administration of such pharmaceutically acceptable salts as pharmaceutical compositions. In some embodiments, the movement disorder is dyskinesia. In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID), diphasic dyskinesia, or peak dose dyskinesia. In some embodiments, the movement disorder is dystonia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the movement disorder is akathisia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoresponsive akathisia, or withdrawal akathisia.

[0127] In some embodiments, the trandilapril derivatives described herein have acidic or basic groups and therefore react with any of the inorganic or organic bases and acids inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the trandilapril derivatives disclosed herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0128] Examples of pharmaceutically acceptable salts include those salts prepared from the derivatives of trimetazidine described herein with a mineral or organic acid or an inorganic base, such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, besylate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, mesylate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propyne, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0129] In addition, the trimetazidine derivatives described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the trimetazidine derivative with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to: inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like; and organic acids such as acetic, propionic, hexanoic, cyclopentanepropionic, glycolic, ketopic, lactic, malonic, succinic, malic, maleic, fumaric, p-toluenesulfonic, tartaric, trifluoroacetic, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, cinnamic, mandelic, arylsulfonic, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 2-naphthalenesulfonic, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic, glucoheptonic, 4,4'-methylenebis-(3-hydroxy-2- ene-1-carboxylic), 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, and muconic. See Stahl, P. Heinrich and Camille G. Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use. Verlag Helvetica Chimica Acta, 2008. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in the obtaining of the trimetazidine derivatives disclosed herein or solvates thereof and their pharmaceutically acceptable acid addition salts.

[0130] In some embodiments, those trimetazidine derivatives described herein that contain a free acid group are reacted with a suitable base as a hydroxide, carbonate, bicarbonate, sulfate, with ammonia, or with a pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amine. Representative salts include alkali or alkaline earth inorganic salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, and the like.

[0131] Representative organic amines which can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the trimetazidine derivatives described herein also include quaternized

[0132] solvate

[0133] In some embodiments, the trandolapril derivatives described herein exist in solvate form. For certain embodiments, provided herein are methods of treating Parkinson's disease and movement disorders associated with Parkinson's disease, comprising administering such solvates. For certain embodiments, provided herein are methods of treating Parkinson's disease and movement disorders associated with Parkinson's disease, comprising administering such solvates as a pharmaceutical composition. In some embodiments, the movement disorder is dyskinesia. In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID), biphasic dyskinesia, or peak dose dyskinesia. In some embodiments, the movement disorder is dystonia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the movement disorder is akathisia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal akathisia.

[0134] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during crystallization with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Solvates of the trandolapril derivatives described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the trandolapril derivatives described herein can be conveniently prepared using organic solvents by recrystallization from aqueous / organic solvent mixtures, including but not limited to dioxane, tetrahydrofuran, or methanol. Additionally, the trandolapril derivatives provided herein can exist in non-solvated as well as solvated forms. In general, for the purposes of the trandolapril derivatives and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0135] Pharmaceutical compositions and administration

[0136] Provided herein are pharmaceutical compositions comprising a trandolapril derivative disclosed herein in a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof; and one or more pharmaceutically acceptable excipients or carriers.

[0137] The pharmaceutical compositions provided herein can be provided in unit dosage form or multiple unit dosage form. As used herein, unit dosage form refers to the physically discrete unit suitable for administration to human and animal subjects, and is packaged individually as is known in the art. Each unit dosage contains a predetermined quantity of active ingredient(s) sufficient to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms can be administered in fractions or multiples thereof. Multiple unit dosage form is a plurality of identical unit dosage forms packaged in separate containers for administration in discrete unit dosage forms. Examples of multiple unit dosage forms include vials, bottles of tablets or capsules, or pint or gallon bottles.

[0138] The pharmaceutical compositions provided herein can be administered at one time, or can be administered multiple times at intervals of time. It will be appreciated that the precise dose and duration of treatment will vary with the age, weight and condition of the patient being treated, and can be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It will also be appreciated that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

[0139] In the event that Parkinson's disease or movement disorder associated with Parkinson's disease is not improved, administration of the trimetazidine derivative can be administered chronically, i.e., for an extended period of time, including throughout the life of the patient, according to the judgment of the physician, to improve or otherwise control or limit the symptoms of Parkinson's disease or movement disorder associated with Parkinson's disease.

[0140] In some embodiments, the pharmaceutical compositions described herein are administered for therapeutic applications. In some embodiments, the pharmaceutical compositions are administered once a day, twice a day, three times a day or more. The pharmaceutical compositions are administered daily, every day, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month or more. The pharmaceutical compositions are administered for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years or more.

[0141] In the event that Parkinson's disease or movement disorder associated with Parkinson's disease is indeed improved, administration of the composition is continued according to the judgment of the physician; alternatively, the dosage of the composition being administered is temporarily reduced or administration is temporarily discontinued for a certain period of time (i.e., a "drug holiday"). In some embodiments, the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dosage reduction during the drug holiday is 10%-100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0142] Once Parkinson's disease or movement disorder associated with Parkinson's disease is improved, a maintenance dose is administered as necessary. Subsequently, the dose or frequency of administration, or both, can be reduced, as symptoms wax and wane, to a level at which improvement of Parkinson's disease or movement disorder associated with Parkinson's disease is maintained.

[0143] In some embodiments, the amount of a trimetazidine derivative administered for the treatment of Parkinson's disease or movement disorder associated with Parkinson's disease varies depending on factors such as the particular trimetazidine derivative, the severity of the disease, the identity of the subject or host in need of treatment (e.g., body weight), but is routinely determined in an appropriate manner according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, and the subject or host being treated, notwithstanding the above-mentioned guidelines. In some embodiments, the desired dose is conveniently presented in a single dose or as equally divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example, two, three, four or more divided doses per day.

[0144] The foregoing ranges are merely suggestive, as the number of variables in an individual regimen is large, and considerable deviation is common with respect to these suggested values. Changes in such dosages are made under the judgment of the practitioner and are uniquely dependent upon the circumstances of the individual patient, including, for example, the activity of the trimetazidine derivative, the movement disorder associated with Parkinson's disease being treated, the mode of administration, the requirements of the individual subject, the severity of the Parkinson's disease or movement disorder associated with Parkinson's disease being treated, and the judgment of the practitioner.

[0145] In some embodiments, toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. A preferred trapiodil derivative exhibits a high therapeutic index. The data obtained from the cell culture assays and animal studies are used to formulate a range of dosage for use in humans. The dosage of such trapiodil derivatives is preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage varies within this range depending upon the dosage form employed and the route of administration utilized.

[0146] In some embodiments, the trapiodil derivatives disclosed herein are administered in a single dose. In some embodiments, the trapiodil derivatives disclosed herein are administered in several doses, for example, 2, 3, 4, 5, 6 or more doses per day. In some embodiments, the trapiodil derivatives disclosed herein are administered intravenously or subcutaneously. In this case, the intravenous or subcutaneous dose ranges from about 1 mg / kg of body weight to about 10 mg / kg of body weight, from about 2 mg / kg of body weight to about 10 mg / kg of body weight or from about 4 mg / kg of body weight to about 8 mg / kg of body weight.

[0147] In some embodiments, the pharmaceutical compositions are formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the chosen route of administration. Any of the well-known techniques, carriers, and excipients used in the art are used and are applied as the context requires. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0148] As used herein, a pharmaceutical composition refers to a mixture of a troponyl derivative disclosed herein with other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition or combination facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a troponyl derivative disclosed herein is administered in a pharmaceutical composition to a mammal having Parkinson’s disease or a movement disorder associated with Parkinson’s disease. Preferably, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the Parkinson’s disease or movement disorder associated with Parkinson’s disease, the age and relative health of the subject, the potency of troponyl derivative used, and other factors.

[0149] Methods of use

[0150] In certain embodiments, disclosed herein are methods of treating Parkinson’s disease and movement disorders associated with Parkinson’s disease in a subject in need thereof, comprising administering to the subject a troponyl derivative of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof:

[0151]

[0152] wherein

[0153] R 1 is -CH3, -CD3, -CHD2, or -CH2D;

[0154] R 2 is hydrogen or -D;

[0155] R 3 is hydrogen or -D;

[0156] R 4 is hydrogen; -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3; -

[0157] CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3; -

[0158] CDHCDH2; or -CDHCD2H;

[0159] R 5 is hydrogen; -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3; -

[0160] CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3; -

[0161] CDHCDH2; or -CDHCD2H;

[0162] wherein at least one of R 1 , R 2 , R 3 , R 4 , or R 5 comprises at least one deuterium atom.

[0163] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 1 is -CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 1 is -CD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 1 is -CHD2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 1 is -CH2D.

[0164] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 2is hydrogen. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 2 is -D.

[0165] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 3 is hydrogen. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 3 is -D.

[0166] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is hydrogen. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CH2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CD2CD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CD2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CH2CD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CDHCH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CH2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CH2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CD2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CD2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CDHCD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CDHCDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 4 is -CDHCD2H.

[0167] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CH2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CD2CD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CD2CH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CH2CD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CDHCH3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CH2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CH2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CD2CDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CD2CD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CDHCD3. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CDHCDH2. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, R 5 is -CDHCD2H. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, the deuterium enrichment of any position denoted as D is at least 98%.

[0168] In some embodiments, the method further comprises treating the subject with an additional therapeutic agent. In some embodiments, the method comprises administering a troponin derivative disclosed herein and an additional therapeutic agent separately or together.

[0169] In some embodiments, the adjunctive therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the adjunctive therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, ergoestradiol, or apomorphine. In some embodiments, the adjunctive therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, ergoestradiol, or apomorphine. In some embodiments, the adjunctive therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tocapone. In some embodiments, the COMT inhibitor is entacapone, tocapone, or octopcapone. In some embodiments, the adjunctive therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tocapone, or octopcapone. In some embodiments, the adjunctive therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the adjunctive therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the adjunctive therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the adjunctive therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0170] In some implementations, the subject is diagnosed with Parkinson's disease. In some implementations, the movement disorder associated with Parkinson's disease is a movement disorder resulting from treatment of Parkinson's disease. In some implementations, the movement disorder is an adverse drug reaction or negative side effect of medications used to treat Parkinson's disease, such as levodopa.

[0171] In some embodiments, the subject to be treated with the tropidil derivatives described herein is diagnosed with or suspected of having Parkinson's disease. In some embodiments, the subject exhibits motor symptoms of Parkinson's disease. In some embodiments, the subject's motor impairment manifests as an adverse drug reaction to therapeutic agents useful for treating Parkinson's disease, such as levodopa.

[0172] In some embodiments, the subject is diagnosed with Parkinson's disease using the Unified Parkinson's Disease Rating Scale (UPDRS), or the Movement Disorder Society (MDS)-UPDRS. In some embodiments, the subject has a score of at least 2, 3, or 4 on Part III of the UPDRS or MDS-UPDRS (motor examination section). In some embodiments, the subject has a score of at least 2, 3, or 4 on Part IV of the UPDRS or MDS-UPDRS (motor complications score). In some embodiments, the subject is not diagnosed with Parkinson's disease. In some embodiments, the subject is suspected of having Parkinson's disease, but is not diagnosed with Parkinson's disease.

[0173] In some embodiments, the subject is a human. In some embodiments, the subject is a pediatric subject. In some embodiments, a "pediatric subject" is a human less than about 15 years of age. In some embodiments, the subject is 5-10 years of age, 6-11 years of age, 7-12 years of age, 8-13 years of age, 9-14 years of age, 10-15 years of age. In some embodiments, the subject is not a pediatric subject. In some embodiments, the subject is at least or about 40-45 years of age, 45-50 years of age, 50-55 years of age, 55-60 years of age, 60-65 years of age, 65-70 years of age, 70-75 years of age, or 75-80 years of age, or older. In some embodiments, the subject is a female. In some embodiments, the subject is a male.

[0174] Parkinson's disease and movement disorders associated with Parkinson's disease

[0175] In certain embodiments, disclosed herein are methods of treating Parkinson's disease and dyskinesia associated with Parkinson's disease in a subject in need thereof, comprising administering to the subject a trimetazidine derivative according to Formula (I) disclosed herein, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof. In some embodiments, the trimetazidine derivative is an isotopically labeled trimetazidine derivative. In some embodiments, the isotopically labeled trimetazidine derivative is a deuterated trimetazidine compound. In some embodiments, the method further comprises administering to the subject an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0176] In some embodiments, the dyskinesia associated with Parkinson's disease is alien limb syndrome, akinesia, akathisia, chorea, hyperkinesia, abnormal involuntary movements, acute alien limb syndrome, oral dyskinesia, tongue protrusion, facial tics, jerking episodes, restlessness, compulsive motor restlessness, levodopa-induced dyskinesia, dystonia, drug-induced parkinsonism, pseudoparkinsonism, bradykinesia, tremor, or any combination thereof. In some embodiments, treating Parkinson's disease comprises treating a symptom of Parkinson's disease. In some embodiments, the symptom of Parkinson's disease is tremor, bradykinesia, dystonia, rigidity, or any combination thereof.

[0177] Dyskinesia

[0178] In some embodiments, the movement disorder associated with Parkinson’s disease is dyskinesia. In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID), biphasic dyskinesia, or peak dose dyskinesia. In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID). In some embodiments, the dyskinesia is biphasic dyskinesia. In some embodiments, the dyskinesia is peak dose dyskinesia.

[0179] Dyskinesia refers to a class of movement disorders characterized by involuntary muscle movements, including movements that resemble tics, dystonia, chorea, and abnormal involuntary movements. Dyskinesia includes, for example, from slight tremors of the hands to uncontrollable movements of the upper body or lower extremities. In some embodiments, the dyskinesia is drug-induced dyskinesia. In some embodiments, the dyskinesia is a side effect of levodopa therapy. Dyskinesia can be a symptom of other conditions besides Parkinson’s disease.

[0180] In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID). Levodopa-induced dyskinesia refers to a form of dyskinesia associated with the use of levodopa in the treatment of motor symptoms of Parkinson’s disease. LID typically involves hyperkinesia, including chorea, dystonia, and athetosis.

[0181] In some embodiments, the dyskinesia is biphasic dyskinesia. Biphasic dyskinesia refers to a type of levodopa-induced dyskinesia that occurs at elevations or declines in plasma levodopa levels, but is independent of peak levels. Biphasic dyskinesia occurs primarily in the lower extremities and is usually dystonic or clonic in nature. This form of dyskinesia does not respond to reductions in levodopa dose.

[0182] In some embodiments, the dyskinesia is peak dose dyskinesia. Peak dose dyskinesia refers to a form of levodopa-induced dyskinesia that is associated with the peak plasma levels of levodopa. Peak dose dyskinesia involves the head, trunk, and extremities, and sometimes the respiratory muscles. Peak dose dyskinesia responds to reductions in levodopa dose, but at the cost of worsening of Parkinsonism.

[0183] In some embodiments, disclosed herein are methods of treating or preventing dyskinesia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a trimetazidine derivative according to Formula I disclosed herein, or a pharmaceutical salt, co-crystal, or solvate thereof. In some embodiments, the method further comprises administering a therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the method further comprises administering a sub-therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0184] In some embodiments, the dyskinesia is levodopa-induced dyskinesia (LID), diphasic dyskinesia, or peak dose dyskinesia.

[0185] In certain embodiments, disclosed herein are methods of treating or preventing levodopa-induced dyskinesia (LID) in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a trimetazidine derivative according to Formula I disclosed herein, or a pharmaceutical salt, co-crystal, or solvate thereof. In some embodiments, the method further comprises administering a therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the method further comprises administering a sub-therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0186] In certain embodiments, disclosed herein are methods of treating or preventing dystonia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a treprostinil derivative according to Formula I disclosed herein, or a pharmaceutical salt, co-crystal, or solvate thereof. In some embodiments, the method further comprises administering a therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the method further comprises administering a sub-therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0187] In certain embodiments, disclosed herein are methods of treating or preventing peak dose dyskinesia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a trimetazidine derivative according to Formula I disclosed herein, or a pharmaceutical salt, co-crystal, or solvate thereof. In some embodiments, the method further comprises administering a therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the method further comprises administering a sub-therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0188] dystonia

[0189] In some embodiments, the movement disorder associated with Parkinson’s disease, or the symptom of Parkinson’s disease, is dystonia. In some embodiments, the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia. In some embodiments, the dystonia is generalized dystonia. In some embodiments, the dystonia is focal dystonia. In some embodiments, the dystonia is segmental dystonia. In some embodiments, the dystonia is acute dystonia.

[0190] Dystonia refers to a movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. In some embodiments, the movements resemble tremors. Dystonia is often triggered or worsened by voluntary movements and the symptoms "spill over" into adjacent muscles. In some embodiments, the dystonia is drug-induced dystonia. Dystonia reactions are characterized by intermittent, spastic contractions or sustained, involuntary contractions of the muscles of the face, neck, trunk, pelvis, extremities, and larynx.

[0191] In some embodiments, the dystonia is a generalized dystonia. Generalized dystonia is a form of dystonia that affects most or all of the body.

[0192] In some embodiments, the dystonia is a focal dystonia. Focal dystonia refers to a form of dystonia that is localized to a specific part of the body. In some embodiments, the focal dystonia is a multifocal dystonia, which involves two or more unrelated body parts.

[0193] In some embodiments, the dystonia is a segmental dystonia. Segmental dystonia refers to a form of dystonia that affects two or more adjacent parts of the body.

[0194] In some embodiments, the dystonia is an acute dystonia. Acute dystonia refers to a form of dystonia that consists of sustained, often painful muscle spasms, producing twisted, abnormal postures.

[0195] In certain embodiments, disclosed herein are methods of treating or preventing dystonia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a trimetazidine derivative according to Formula I disclosed herein, or a pharmaceutically salt, co-crystal, or solvate thereof. In some embodiments, the method further comprises administering a therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the method further comprises administering a sub-therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide. In some embodiments, the dystonia is a generalized dystonia, a focal dystonia, a segmental dystonia, or an acute dystonia. In some embodiments, disclosed herein are methods of treating or preventing generalized dystonia with administration of a therapeutically effective dose of a trimetazidine derivative or a pharmaceutically acceptable salt thereof and / or an additional therapeutic agent (e.g., levodopa). In some embodiments, disclosed herein are methods of treating or preventing focal dystonia with administration of a therapeutically effective dose of a trimetazidine derivative or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein are methods of treating or preventing segmental dystonia with administration of a therapeutically effective dose of a trimetazidine derivative or a pharmaceutically acceptable salt thereof and / or an additional therapeutic agent (e.g., levodopa). In some embodiments, disclosed herein are methods of treating or preventing acute dystonia with administration of a therapeutically effective dose of a trimetazidine derivative disclosed herein.

[0196] akathisia

[0197] In some embodiments, the movement disorder associated with Parkinson's disease is akathisia. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal or "rebound" akathisia. In some embodiments, the akathisia is acute akathisia. In some embodiments, the akathisia is chronic akathisia. In some embodiments, the akathisia is pseudoakathisia. In some embodiments, the akathisia is withdrawal or "rebound" akathisia.

[0198] In some embodiments, the movement disorder is akathisia. In some embodiments, akathisia is a movement disorder characterized by a feeling of inner unrest and an urgent need to keep moving, as well as movements such as rocking while standing or sitting, lifting the feet as if to take steps in place, and crossing and uncrossing the legs while sitting. In some embodiments, akathisia is drug-induced.

[0199] In some embodiments, the akathisia is acute akathisia. Acute akathisia refers to a form of akathisia that occurs shortly after 1) the initiation of a medication or an increase in dose, 2) a switch to a high-potency drug, or 3) withdrawal of a drug. In some embodiments, acute akathisia lasts less than six months and includes intense dysphoria, awareness of unrest, and complex and purposeless motor agitation.

[0200] In some embodiments, the akathisia is chronic akathisia. Chronic akathisia refers to a form of akathisia that persists for more than six months after the last dose increase of a drug. In some embodiments, chronic akathisia includes mild dysphoria, awareness of unrest, motor agitation with stereotypic movements, and limb and orofacial dyskinesias.

[0201] In some embodiments, the akathisia is pseudoakathisia. In some embodiments, pseudoakathisia is a late stage of chronic akathisia. Exemplary symptoms include motor manifestations with subjective components, motor agitation with stereotypic movements, and limb and orofacial dyskinesias.

[0202] In some embodiments, the akathisia is withdrawal or "rebound" akathisia. In some embodiments, withdrawal or "rebound" akathisia refers to akathisia associated with a medication change that typically begins within six weeks of drug withdrawal or dose reduction.

[0203] In certain embodiments, disclosed herein are methods of treating akathisia in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a treprostinil derivative according to Formula I disclosed herein, or a pharmaceutical salt, co-crystal, or solvate thereof. In some embodiments, the methods further comprise administering a therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the methods further comprise administering a sub-therapeutically effective amount of an additional therapeutic agent (e.g., levodopa). In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide. In some embodiments, the akathisia is acute akathisia, chronic akathisia, pseudokathisia, or withdrawal or “rebound” akathisia.

[0204] In some embodiments, disclosed herein are methods of treating or preventing acute akathisia with administration of a therapeutically effective dose of a treprostinil derivative disclosed herein and / or an additional therapeutic agent (e.g., levodopa).

[0205] In some embodiments, disclosed herein are methods of treating or preventing chronic akathisia with administration of a therapeutically effective dose of a treprostinil derivative disclosed herein and / or an additional therapeutic agent (e.g., levodopa).

[0206] In some embodiments, disclosed herein are methods of treating or preventing akathisia with administration of a therapeutically effective dose of a troponin derivative disclosed herein and / or an additional therapeutic agent (e.g., levodopa).

[0207] In some embodiments, disclosed herein are methods of treating or preventing withdrawal or “rebound” akathisia with administration of a therapeutically effective dose of a troponin derivative disclosed herein and / or an additional therapeutic agent (e.g., levodopa).

[0208] Combination therapy treatment with troponin derivative

[0209] In certain embodiments, disclosed herein are methods of treating Parkinson’s disease and movement disorders associated with Parkinson’s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a troponin derivative according to Formula I disclosed herein, or a pharmaceutical salt, co-crystal, or solvate thereof. In some embodiments, are methods of treating or preventing movement disorders associated with levodopa utilization. In certain embodiments, disclosed herein are methods of treating Parkinson’s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a troponin derivative according to Formula I disclosed herein, or a pharmaceutical salt, co-crystal, or solvate thereof, and an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an agent for treating Parkinson’s disease.

[0210] In some embodiments, the additional therapeutic agent is a dopamine precursor. In some embodiments, the dopamine precursor is levodopa. In some embodiments, the additional therapeutic agent is a dopamine agonist. In some embodiments, the dopamine agonist is pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lisuride, or apomorphine. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor. In some embodiments, the COMT inhibitor is entacapone or tolcapone. In some embodiments, the COMT inhibitor is entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor. In some embodiments, the MAOB inhibitor is selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor. In some embodiments, the dopa decarboxylase inhibitor is carbidopa or benserazide. In some embodiments, the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0211] In some embodiments, the additional therapeutic agent is administered orally. In some embodiments, the additional therapeutic agent is administered intravenously or subcutaneously.

[0212] In some embodiments, the trapidil derivative according to Formula I, or a pharmaceutically salt, co-crystal, or solvate thereof, and the additional therapeutic agent disclosed herein are administered simultaneously. In some embodiments, the trapidil derivative according to Formula I, or a pharmaceutically salt, co-crystal, or solvate thereof, and the additional therapeutic agent disclosed herein are administered sequentially. In some embodiments, the trapidil derivative according to Formula I, or a pharmaceutically salt, co-crystal, or solvate thereof, is administered prior to the additional therapeutic agent. In some embodiments, the trapidil derivative according to Formula I, or a pharmaceutically salt, co-crystal, or solvate thereof, is administered after the additional therapeutic agent. In some embodiments, the trapidil derivative according to Formula I, or a pharmaceutically salt, co-crystal, or solvate thereof, and the additional therapeutic agent disclosed herein are administered in a unified dosage form. In some embodiments, the trapidil derivative according to Formula I, or a pharmaceutically salt, co-crystal, or solvate thereof, and the additional therapeutic agent disclosed herein are administered in separate dosage forms.

[0213] Kit / article of manufacture

[0214] Also described herein are kits and articles of manufacture for use in the therapeutic applications described herein. Such kits can comprise a carrier, package, or container, positioned to contain one or more containers, such as vials, tubes, etc., each of which contains a separate element to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers can be formed from a variety of materials, such as glass or plastic.

[0215] For example, a container can contain a trimetazidine derivative disclosed herein, optionally in a composition or in combination with another agent disclosed herein (e.g., levodopa and / or carbidopa). The container optionally has a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound having a label or packaging insert describing use of the compound in the methods described herein.

[0216] Kits will typically comprise one or more additional containers, each with one or more of the various materials (such as reagents and / or devices) needed for use of the trimetazidine derivatives disclosed herein, optionally in concentrated form, from a commercial and user standpoint. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; container labels listing contents and / or instructions for use; and package inserts with instructions for use. A set of instructions will typically also be included.

[0217] Labels can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or embossed into the container itself. Labels can be associated with a container when letters, numbers or other characters forming the label are present on a label container or carrier that is also present in or on the container. A label can be used to indicate that the contents are to be used for a particular therapeutic application. A label can also indicate directions for use of the contents, such as use in the methods described herein. These other therapeutic agents can be used, for example, in amounts indicated in the Physicians’ Desk Reference (PDR) or otherwise determined by one of ordinary skill in the art.

[0218] Definitions

[0219] To facilitate the understanding of the disclosure described herein, a number of terms are defined below.

[0220] As used herein, the singular forms “a,” “an,” and “the” refer to both the singular as well as the plural, unless the context clearly indicates otherwise. Generally, the nomenclature used herein, and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are those well- known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. If a term is defined differently herein, the definition provided herein will control.

[0221] The term “subject” refers to any animal, preferably a mammal, including a human or non-human. The terms “subject” and “patient” are used interchangeably herein, for example, in reference to a mammalian subject such as a human subject. Neither of the terms is to be construed as requiring that a medical professional (e.g., a physician, a nurse, a physician’s assistant, a caregiver, a hospice worker) be present.

[0222] The terms “treat,” “treating,” and “treatment” refer to methods comprising alleviating or abrogating a movement disorder, a disease or a condition; or one or more symptoms associated with a movement disorder, a disease or a condition; or alleviating or eradicating the cause of the disorder, disease or condition itself.

[0223] The terms “prevent,” “preventing,” and “prevention” refer to methods of delaying or precluding the onset of Parkinson’s disease or a movement disorder associated with Parkinson’s disease; and / or its attendant symptoms, barring a subject from acquiring a disease or reducing the risk of a subject acquiring Parkinson’s disease or a movement disorder associated with Parkinson’s disease.

[0224] The term “therapeutically effective amount” refers to an amount of a trimetazidine derivative disclosed herein, which when used is sufficient to prevent development of, or to alleviate to some extent, one or more symptoms of Parkinson’s disease or a movement disorder associated with Parkinson’s disease. The term “therapeutically effective amount” also refers to an amount of a trimetazidine derivative disclosed herein, which is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0225] The term “sub-therapeutically effective amount” refers to an amount of a therapeutic agent that is less than the amount of the agent that is considered therapeutically effective for the treatment of the intended indication. In some embodiments, the therapeutic agent is levodopa.

[0226] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" mean a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each component must be "physiologically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21stEd.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5thEd.; Rowe et al. Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rdEd.; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004).

[0227] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.

[0228] The term "deuterium enrichment" refers to the percentage incorporation of deuterium in place of hydrogen at a given position in a molecule. For example, a deuterium enrichment of about 1% at a given position means that about 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. Deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0229] The term "isotope enrichment" refers to the percentage incorporation of a less prevalent element isotope in place of a more prevalent element isotope at a given position in a molecule.

[0230] The term “non-isotopically enriched” refers to a molecule in which the percentage of each isotope is substantially the same as the naturally occurring percentage.

[0231] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, “about” can mean one or more standard deviations.

[0232] The term “active ingredient” refers to a compound administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, to treat, prevent or ameliorate one or more symptoms of a disorder or disease.

[0233] The present invention provides, including but not limited to, the following embodiments:

[0234] 1. A compound of Formula (I) or a pharmaceutically salt, co-crystal, or solvate thereof:

[0235]

[0236] wherein:

[0237] R 1 is -CH3, -CD3, -CHD2, or -CH2D;

[0238] R 2 is hydrogen or -D;

[0239] R 3 is hydrogen or -D;

[0240] R 4 is hydrogen, -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3; -CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3; -CDHCDH2; or -CDHCD2H;

[0241] R 5 is hydrogen, -CH2CH3; -CD2CD3; -CD2CH3; -CH2CD3; -CDHCH3; -CH2CDH2; -CH2CD2H; -CD2CDH2; -CD2CD2H; -CDHCD3; -CDHCDH2; or -CDHCD2H; and

[0242] wherein at least one of R 1 , R 2 , R 3 , R 4 , or R 5 comprises at least one deuterium atom.

[0243] 2. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0244]

[0245] 3. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0246]

[0247] 4. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0248]

[0249] 5. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0250]

[0251] 6. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0252]

[0253] 7. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0254]

[0255] 8. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0256]

[0257] 9. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0258]

[0259] 10. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0260]

[0261] 11. A compound, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, that is:

[0262]

[0263]

[0264] 12. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, wherein the deuterium enrichment at the position denoted D is at least 98%.

[0265] 13. The compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, wherein the deuterium enrichment at the position denoted D is at least 90%.

[0266] 14. A pharmaceutical composition comprising: a compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt, co-crystal, or solvate thereof, and a pharmaceutically acceptable carrier.

[0267] 15. A method of treating Parkinson’s disease or a movement disorder associated with Parkinson’s disease in a subject in need thereof, comprising: administering to the subject a compound of any one of embodiments 1-13 or a pharmaceutical composition of embodiment 14.

[0268] 16. A method of treating Parkinson’s disease or a movement disorder associated with Parkinson’s disease in a subject in need thereof, comprising: administering to the subject (a) a compound of any one of embodiments 1-13 or a pharmaceutical composition of embodiment 14, and (b) a therapeutically effective combination of an additional therapeutic agent.

[0269] 17. The method of embodiment 16, wherein the additional therapeutic agent is a dopamine precursor.

[0270] 18. The method of embodiment 17, wherein the dopamine precursor is levodopa.

[0271] 19. The method of embodiment 16, wherein the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lysuride, or apomorphine, or a combination thereof.

[0272] 20. The method of embodiment 16, wherein the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone.

[0273] 21. The method of embodiment 16, wherein the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline.

[0274] 22. The method of embodiment 16, wherein the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0275] 23. The method of either embodiment 15 or 16, wherein the movement disorder is dyskinesia.

[0276] 24. The method of embodiment 23, wherein the dyskinesia is levodopa-induced dyskinesia (LID), biphasic dyskinesia, or peak dose dyskinesia.

[0277] 25. The method of either embodiment 15 or 16, wherein the movement disorder is dystonia.

[0278] 26. The method of embodiment 25, wherein the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia.

[0279] 27. The method of either embodiment 15 or 16, wherein the movement disorder is akathisia.

[0280] 28. The method of embodiment 27, wherein the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal akathisia.

[0281] 29. The method of either embodiment 15 or 16, wherein the subject is diagnosed with Parkinson’s disease.

[0282] 30. A pharmaceutical combination for use in the treatment or prevention of Parkinson’s disease or a movement disorder associated with Parkinson’s disease in a subject in need thereof, comprising a therapeutic combination of:

[0283] (a) a compound according to any one of embodiments 1-13 or a pharmaceutical composition according to embodiment 14; and

[0284] (b) an additional therapeutic agent for the treatment of Parkinson’s disease.

[0285] 31. The pharmaceutical combination of embodiment 30, wherein the additional therapeutic agent is a dopamine precursor.

[0286] 32. The pharmaceutical combination of embodiment 31, wherein the dopamine precursor is levodopa.

[0287] 33. The pharmaceutical combination of embodiment 30, wherein the additional therapeutic agent is a dopamine agonist comprising pramipexole, ropinirole, rotigotine, pergolide, bromocriptine, piribedil, lysuride, or apomorphine.

[0288] 34. The pharmaceutical combination of embodiment 30, wherein the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor comprising entacapone, tolcapone, or opicapone.

[0289] 35. The pharmaceutical combination of embodiment 30, wherein the additional therapeutic agent is a monoamine oxidase B (MAOB) inhibitor comprising selegiline or rasagiline.

[0290] 36. The pharmaceutical combination of embodiment 30, wherein the additional therapeutic agent is a dopa decarboxylase inhibitor comprising carbidopa or benserazide.

[0291] 37. The pharmaceutical combination of embodiment 30, wherein the movement disorder is dyskinesia.

[0292] 38. The pharmaceutical combination of embodiment 37, wherein the dyskinesia is levodopa-induced dyskinesia (LID), biphasic dyskinesia, or peak dose dyskinesia.

[0293] 39. The pharmaceutical combination of embodiment 30, wherein the movement disorder is dystonia.

[0294] 40. The pharmaceutical combination of embodiment 39, wherein the dystonia is generalized dystonia, focal dystonia, segmental dystonia, or acute dystonia.

[0295] 41. The pharmaceutical combination of embodiment 30, wherein the movement disorder is akathisia.

[0296] 42. The pharmaceutical combination of embodiment 41, wherein the akathisia is acute akathisia, chronic akathisia, pseudoakathisia, or withdrawal akathisia.

[0297] 43. The pharmaceutical combination of embodiment 30, wherein the subject is diagnosed with Parkinson’s disease.

[0298] EMBODIMENT

[0299] Example 1: Synthesis of a trimetazidine derivative according to Formula I

[0300] In some embodiments, the compounds disclosed herein are synthesized as shown in Scheme 1. In some embodiments, Y is hydrogen or deuterium.

[0301]

[0302] Example 2: Treatment of movement disorders associated with Parkinson’s disease

[0303] A subject diagnosed with a movement disorder associated with Parkinson’s disease is administered a therapeutically effective amount of a trimetazidine derivative according to Formula I, or a pharmaceutical salt, co-crystal, or solvate thereof, and levodopa, thereby treating or preventing the movement disorder in the subject.

[0304] Example 3: Synthesis of a derivative of trimetazidine from deuterium substituted diethylamine

[0305] Synthesis of Intermediate 3a in Preparation 1

[0306]

[0307] Aminoguanidine hydrochloride (30 g) was added to D2O (25 g) and the solution was stirred at 55 °C for one hour and then refluxed. Toluene (225 mL) was added and water was removed by distillation of the azeotrope. This procedure was repeated 3 times and the product was lyophilized to give 31.9 g (97%) of aminoguanidine-d6 deuterochloride.

[0308] A 2 L 3 -necked round bottom flask, equipped with a temperature probe, magnetic stirrer and N2atmosphere, was charged with aminoguanidine-d6 deuterochloride (26 g, 221 mmol) and formic acid-d2(16 g, 332 mmol). Toluene (1 L) was added and the reaction was heated to 45 °C for 1 h, then heated to 85 °C over 30 min and stirred at 85 °C for 1 h. The flask was equipped with a Dean-Stark trap and heated at reflux overnight. After 16 h, the precipitate was collected, washed with toluene and dried to give 26 g (94%) of 1H-1,2,4-triazole-1,3-d2-5-amine-d2 deuterochloride.

[0309] A 2 L 3 -necked round bottom flask, equipped with a temperature probe, magnetic stirrer and N2atmosphere, was charged with acetonitrile (2000 mL) and 1H-1,2,4-triazole-1,3-d2-5-amine-d2 deuterochloride. (26 g, 206 mmol) and heated to 55 °C. To the suspension was added Cs2CO3(102 g, 315 mmol) and the suspension was stirred for 4 h. The reaction mixture was hot filtered and the filtrate was evaporated to give 1H-1,2,4-triazole-1,3-d2-5-amine-d2 as a light yellow solid (18.3 g, 40%).

[0310] A 250 mL 3-necked round bottom flask, equipped with a temperature probe, magnetic stirrer and N2 atmosphere, was charged with 1H-1,2,4-triazole-1,3-d2-5-amine-d2 (7.3 g, 83 mmol), ethyl acetoacetate (11.9 g, 91 mmol) and acetic acid (58 mL) and the reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled to 15 °C and to the stirred solution was added diethyl ether (100 mL). The suspension was stirred for 15 min and the precipitate was collected and washed with diethyl ether. After standing for 1 h, a second batch of precipitate formed in the filtrate and this was collected. The batches were combined and lyophilized to give 8.5 g (56 mmol, 68%) of 5-(methyl-d3)-[1,2,4]triazolo[1,5-a]pyrimidine-2,6-d2-7-ol as a light pink solid.

[0311] Synthesis of intermediate 3b in Preparation 2

[0312]

[0313] A sample of 1H-1,2,4-triazole-5-amine (25 g) was treated with 50 g of methanol-d4 at 45 °C for 24 h and evaporated. This procedure was repeated 4 times and the product was lyophilized to give 25 g (97%) of 1H-1,2,4-triazole-1-d-5-amine-d2.

[0314] A mixture of ethyl acetoacetate-d5 (CDN Isotopes, 9.16 g, 68 mmol) and 1H-1,2,4-triazole-1-d-5-amine-d2 (5 g, 68 mmol) was refluxed for 5.5 h, cooled to room temperature and stirred overnight. The precipitate was collected and washed with cold ethyl acetate (1 x 50 mL) to give 5-(methyl-d3)-[1,2,4]triazolo[1,5-a]pyrimidine-2,6-d2-7-ol (7.3 g, 70%) as a white solid.

[0315] The following troxputil derivatives, wherein Y represents a hydrogen atom or a deuterium atom, were synthesized according to the following Scheme 2 using the appropriate deuterated diethylamine.

[0316]

[0317] A sample of 7 g of non-deuterated 5-(methyl)-[l,2,4]triazolo[l,5-a]-pyrimidin-7-ol or intermediate 3a or intermediate 3b was suspended in 56 mL of phosphorus oxychloride (600 mmol, 13 equivalents) and heated at reflux for 2-3 h. The mixture was evaporated and the residue diluted with water (1 L) and neutralized to a final pH of 7.5 with 30% ammonium hydroxide. The aqueous solution was extracted with chloroform (1 x 1000 mL, 2 x 500 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over sodium sulfate and evaporated. The residue was treated with 1 : 1 chloroform: ethyl acetate, loaded onto 100 g of silica gel and the product eluted with ethyl acetate. The combined eluates were evaporated to give 4-5 g (50-70%) of the appropriate chloride intermediate as a light white solid.

[0318] To a stirred solution of deuterated diethylamine (0.719 g, 1.1 equivalents) in ethanol (50 mL) at room temperature was added triethylamine (2.088 g, 2.5 equivalents) followed by the chloride-intermediate (1.4 g, 1.0 equivalents) and the reaction mixture was heated at reflux for 2 h. The reaction was evaporated and the residue treated with water (25 mL) and extracted with toluene (4 x 75 mL). The combined toluene layers were washed with brine (1 x 25 mL), dried over sodium sulfate and evaporated. The crude product was purified on silica gel with a 0-20% ethyl acetate gradient in dichloromethane. Typical yield: 1 g, 60%.

[0319] Examples 3-1, 3-2 and 3-3 were prepared by 1 H and 13 C NMR and GCMS characterization, the results of which are shown in Table A below. Example 3-1 ("3-1") has 4 deuterium atoms on the diethylamino chain, Example 3-2 ("3-2") has 6 deuterium atoms, and Example 3-3 ("3-3") has a total of 10 deuterium atoms (combining the 4 deuterium atoms of 3-1 and the 6 deuterium atoms of 3-2).

[0320]

[0321] Table A: C NMR and GCMS characterization of Examples 3-1 to 3-3 1 H and 13 C NMR and GCMS characterization

[0322]

[0323] Examples 3-4 to 3-6 were prepared from intermediate 3a by 1 H and 13 C NMR and GCMS characterization, the results of which are shown in Table B below.

[0324]

[0325] Table B: Characterization of Examples 3-4 to 3-6 by H and 1 H and 13 C NMR and GCMS characterization

[0326] Examples 3-7 to 3-9 made from intermediate 3b were characterized by 1 H and 13 C NMR and GCMS characterization, results of which are provided in Table C below.

[0327]

[0328] Table C: Characterization of Examples 3-7 to 3-9 by H and 1 H and 13 C NMR and GCMS characterization

[0329] Example 4: Pharmacokinetic properties of Examples 3-1 to 3-3 compared to trimetazidine

[0330] Substitution of deuterium for hydrogen in a drug molecule can result in significant changes in metabolism and provide beneficial changes in the biological effects of the drug, such as its pharmacokinetic (PK) profile. Such substitutions can also have a toxicity-reducing effect by reducing the formation of toxic metabolites. In general, it is expected that drug molecules with more deuterium atoms will have reduced metabolism compared to the same drug molecule with fewer deuterium atoms.

[0331] As shown herein, deuterated trimetazidine derivatives exhibit superior PK profiles compared to unmodified trimetazidine. Unexpectedly, the inventors of the present disclosure found that certain deuterated trimetazidine derivatives with fewer deuteriums exhibit superior PK profiles compared to comparable deuterated trimetazidine derivatives with more deuteriums.

[0332] Male Sprague Dawley rats (n=5 per group) were orally administered 17.5 milligrams per kilogram (mg / kg) of trimetazidine, 3-1, 3-2, or 3-3. 17.5 mg / kg was chosen because it corresponds to a physiologically relevant dose of trimetazidine (the Cmax of this rodent dose is equivalent to half of the human Cmax of a 200 mg capsule). Plasma samples were collected at time points of 0.25, 0.50, 0.75, 1, 2, 4, 8, 12, and 24 hours. Tables 1A-1C provide the PK profiles for each of the compounds tested upon oral administration.

[0333] FIG. 1The results of this experiment are shown on a linear scale. All of the dideuterium derivatives of trimetazidine show increased blood concentration Cmaxcompared to trimetazidine. As expected, the higher Cmaxalso corresponds to a higher AUC. However, only 3-1 shows a significant change in half-life compared to trimetazidine. This change is also significant compared to 3-2 and 3-3. This change correspondingly significantly alters the Cmax / AUC ratio compared to trimetazidine, while 3-2 and 3-3 do not significantly alter the Cmax / AUC ratio compared to trimetazidine. This is an unexpected result, as it was expected that trimetazidine derivatives with more deuterium would have a longer half-life than derivatives with fewer deuterium atoms. In particular, it was expected that the largest metabolic change would be observed in 3-3, which contains all of the deuterium atoms of 3-1 plus the deuterium atoms of 3-2. However, what was observed was not an additive effect of 3-1 and 3-2, but rather an antagonistic effect.

[0334] FIG. 2 The same results are shown on a log scale. 3-1 shows a decrease in slope (relative to the other three compounds), indicating that 3-1 is metabolized more slowly in rats when administered orally than 3-2, 3-3, and trimetazidine. The rank order of metabolic rates is unexpected.

[0335] Table 1A. PK characteristics of orally administered test trimetazidine and trimetazidine derivatives. “NS” means “not significant”; “*” means “p < 0.05 compared to 3-2”; “@” means “p < 0.05 compared to 3-3”.

[0336]

[0337] Table IB. Half-life deuterium kinetic isotope effects of orally administered trimetazidine derivatives

[0338] 3-1 3-2 3-3 Half-life KDIE 2.241 1.420 1.109 95% CI [1.65,2.91] [0.997,1.90] [0.93,1.33]

[0339] Table 1C. Coefficients of variation of orally administered trimetazidine derivatives

[0340]

[0341] In addition, it can be seen from Table 1C that the coefficients of variation of Cmaxand AUC are decreased for all of the deuterated derivatives. This decrease in variation indicates that the blood concentration profiles across animals and / or humans exhibit less variability in individual subjects.

[0342] A similar experiment was performed in a new cohort of male Sprague Dawley rats, except that the compounds were administered intravenously (1 mg / kg). Tables 2A-2B provide the PK parameters for each of the compounds tested intravenously.

[0343] FIG. 3 The results of this experiment are shown on a linear scale, and FIG. 4 The same results are shown on a log scale. As shown in Table 2B, all of the trimetazidine derivatives exhibited longer half-lives compared to trimetazidine, with 3-1 exhibiting the longest half-life, similar to the results for oral administration. In addition, 3-1 and 3-2 had increased Cmax, but 3-3 did not. This was an unexpected result.

[0344] Table 2A. PK characteristics of test trimetazidine and trimetazidine derivatives administered intravenously. “NS” means “not significant”; “*” means “p < 0.05 compared to 3-2”; “@” means “p < 0.05 compared to 3-3”.

[0345]

[0346] Table 2B. Half-life deuterium kinetic isotope effect for trimetazidine derivatives administered intravenously

[0347] 3-1 3-2 3-3 Half-life KDIE 1.46 1.33 1.236 95% CI [1.125,1.831] [1.055,1.637] [1.0549,1.443]

[0348] Bioavailability was calculated for trimetazidine and trimetazidine derivatives 3-1, 3-2, and 3-3. Bioavailability refers to the ratio of how much drug reaches the systemic circulation after oral administration. It is calculated by comparing the AUC for oral administration (PO) and the AUC for direct administration into the blood (IV).

[0349]

[0350] Since the doses differ between PO and IV administration, the AUCs were adjusted accordingly by dose. Table 3 provides the calculated bioavailability for trimetazidine, 3-1, 3-2, and 3-3.

[0351] Table 3. Bioavailability (F) of trimetazidine and derivatives

[0352]

[0353] Table 3 shows that 3-1 and 3-3 exhibited significantly more favorable bioavailability, and 3-2 tended to more favorable bioavailability (p = 0.0658). While there was considerable variability, trimetazidine exhibited <100% bioavailability within the 95% confidence interval, while the deuterium-based derivatives all exhibited complete bioavailability within the 95% confidence interval.

[0354] Example 5: Metabolic stability of trimetazidine derivatives (3-1 to 3-9) compared to trimetazidine

[0355] The metabolic stability of trimetazidine and deuterated derivatives was determined using rat and human liver microsomes (0.5 mg / mL protein concentration). Trimetazidine and compounds 3-1 to 3-9 were assayed at 1 uM by the addition of 1 mM NADPH. LC / MS / MS was used to relative quantify the percent compound disappearance at t=0, 15, 30 and 60 min in rat microsomes (n=3 per experiment) and at t=0, 30, 60, 90 and 120 min in human microsomes (n=4 per experiment).

[0356] Based on the percent disappearance of several compounds, in vitro half-lives can be calculated and clearance can be estimated. Tables 4 and 5 show the half-lives of compounds 3-1 to 3-9 relative to trimetazidine in rat and human liver microsomes, respectively. The results in rat microsomes are similar to those in rodents in vivo (Example 4), with a significant increase in half-life for compound 3-1. The increase in half-life in human liver microsomes (Table 5) provides evidence for the translation of pharmacokinetic results in humans.

[0357] Table 4. Relative change in half-life of trimetazidine derivatives (rat liver microsomes)

[0358] Compound Half-life (normalized to trimetazidine) p-value 3-1 1.65 7.31E-04 3-2 1.14 0.253 3-3 1.41 9.81E-03 3-4 3.30 6.00E-03 3-5 2.32 0.0242 3-6 3.57 4.59E-03 3-7 2.89 9.87E-03 3-8 1.10 0.714 3-9 2.40 0.0211

[0359] Table 5. Relative change in half-life of trimetazidine derivatives (human liver microsomes)

[0360] Compound Half-life (normalized to trimetazidine) p-value 3-1 2.03 0.0195 3-2 0.896 0.588 3-3 1.40 0.188 3-4 3.75 0.253 3-5 1.01 0.657 3-6 1.39 0.884 3-7 0.767 0.253 3-8 0.710 0.169 3-9 1.81 0.608

[0361] While preferred embodiments of the application have been shown and described herein, it will be apparent to those skilled in the art that many changes, modifications, and substitutions can be made in the embodiments of the application without departing from the application. It is understood that in the implementation of the application each of the various alternatives so described can be employed independently or in combination. The following claims are intended to define the scope of the application and are also intended to cover methods and structures that fall within the scope of the claims and their equivalents.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: or 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the deuterium enrichment of the position represented as D is at least 98%.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the deuterium enrichment of the position represented as D is at least 90%.

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