HK1216747B - Dihydroxyphenyl neurotransmitter compounds, compositions and methods - Google Patents

Abstract

The present invention relates to new dihydoxyphenyl modulators of neurotransmitter levels, pharmaceutical compositions thereof, and methods of use thereof.

Description

Dihydroxyphenyl neurotransmitter compounds, compositions, and methods

This application claims priority to U.S. provisional application No. 62/010,098 filed on 10.6.2014 and 61/843,549 filed on 8.7.2013, the disclosures of both of which are hereby incorporated by reference as if fully set forth herein.

Disclosed herein are novel dihydroxyphenyl compounds and compositions and their use as medicaments for the treatment of disorders. Also provided are methods of modulating neurotransmitter levels in a subject for treating a disorder such as: hypotension, orthostatic hypotension, neurogenic orthostatic hypotension, symptomatic neurogenic orthostatic hypotension, neurogenic orthostatic hypotension associated with Multiple System Atrophy (MSA), orthostatic hypotension associated with schei-delger (Shy-Drager) syndrome, neurogenic orthostatic hypotension associated with Familial Amyloid Polyneuropathy (FAP), neurogenic orthostatic hypotension associated with simple autonomic failure (PAF), idiopathic orthostatic hypotension, non-sympathetic hypersensitivity (asympathiconic) hypotension, neurogenic orthostatic hypotension associated with parkinson's disease, intradialytic hypotension (IDH), hemodialysis-induced hypotension, hypotension associated with fibromyalgia syndrome (FMS), gait in spinal cord injury, hypotension associated with Chronic Fatigue Syndrome (CFS), freezing in parkinson's disease, freezing, multiple sclerosis, multiple, Akinesia and dysarthria, lewy body dementia, Rapid Eye Movement (REM) behavioral disorders, chronic heart failure, stress-related disorders, movement or speech confusion, chronic pain, stroke, cerebral ischemia, nasal congestion, mood disorders, sleep disorders, narcolepsy, insomnia, Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), hyposmia, Mild Cognitive Impairment (MCI), Down's syndrome, Alzheimer's disease, postural reflex abnormalities caused by Parkinson's disease, autoimmune autonomic failure, familial autonomic abnormalities, diabetic autonomic neuropathy, amyloidosis in the background of multiple myeloma, Parkinson's disease, pre-prandial hypotension, dopamine beta-hydroxylase deficiency, pain, progressive supranuclear palsy, Menkes disease, familial autonomic abnormalities (Riley-Day) syndrome), PD-associated autonomic abnormalities (autonomic dysfunction), juvenile upright intolerance, neuropsychogenic syncope (vasovagal), postural tachycardia syndrome (POTS), fibromyalgia, allodynia, hyperalgesia, fatigue, sleep disorders, depression, chronic upright intolerance, childhood developmental disorders, genetic disorders involving reduced norepinephrine synthesis or action, regulated multiple system disorders, pain, neurodegenerative disorders, cognitive dysfunction, olfactory disorders, neuroendocrine disorders, and autoimmune disorders.

Droxidopa (Droxidopa; northern; DOPS; L-DOPS; L-threo-DOPS; SM 5688; (2S,3R) -3- (3, 4-dihydroxyphenyl) -2-amino-3-hydroxypropionic acid; or L-threo-dihydroxyphenylserine) is a neurotransmitter modulator. Droxidopa is converted in vivo to norepinephrine (synonymous with noradrenaline) by the action of the enzyme L-aromatic amino acid decarboxylase. Droxidopa is therefore a norepinephrine precursor.

Norepinephrine is an important chemical in the brain and periphery. In the brain, norepinephrine is a classical neurotransmitter, and is thought to be involved in many neurobehavioral phenomena, such as attention, memory, arousal, and pain. In the periphery, norepinephrine is the major neurotransmitter of the sympathetic nervous system responsible for circulatory regulation.

When a person rises, the drop in venous return volume relieves the load on the baroreceptors and reflexively increases sympathetic communication. This enhances the release of norepinephrine from sympathetic nerves in the heart and blood vessel walls. The released norepinephrine binds to adrenergic receptors and thereby causes constriction of blood vessels, which helps to maintain blood pressure during the quiescent position (orthostasis). It is predictable that orthostatic hypotension, i.e., a decrease in blood pressure at the person's stand-up, is a major manifestation of sympathetic norepinephrine failure.

Both a wide variety of common and rare medical and psychiatric disorders are known or suspected to involve norepinephrine deficiency due to denervation of norepinephrine, inability to synthesize norepinephrine, or insufficient or inappropriate release or inactivation of norepinephrine. However, oral norepinephrine is ineffective for treating norepinephrine deficiency because norepinephrine is efficiently metabolized in the intestine. Norepinephrine in portal reflux is also extensively metabolized in the liver. Furthermore, because of the blood-brain barrier against catecholamines, very little norepinephrine in the systemic circulation enters the brain unchanged.

In contrast, droxidopa orally enters the bloodstream and, as a neutral amino acid, it can cross the blood brain barrier. Droxidopa can therefore be an effective treatment for disorders associated with norepinephrine deficiency.

Droxidopa is approved for use in symptomatic neurogenic orthostatic hypotension. Birkmayer et al, journal of neurotransmission (j. neural Trans.), 1983, 58(3-4), 305-13; freiman et al, clinical neuropharmacology (clin. neuropharmacol.), 1991, 14(4), 296-304; mosaic (Mathias), et al, clinical autonomic studies: the Official journal of the clinical Society for Autonomic nervous Research (clinical Automic Research: Official J. clinical Automic Research Society), 2001, 11(4), 235-42; goldstein (Goldstein), Cardiovascular Drug review (Cardiovascular Drug Rev.), 2006, 24(3-4), 189-; wakanalatt (Vichayanrat) et al, Future Neurology (Future Neurology), 2013, 8(4), 381-; and houser et al, journal of parkinson's Disease, 2014, 4(1), 57-65. Droxidopa is currently in the study for the treatment of: neurogenic orthostatic hypotension associated with Multiple System Atrophy (MSA), orthostatic hypotension associated with the schei-delger syndrome, neurogenic orthostatic hypotension associated with Familial Amyloid Polyneuropathy (FAP), neurogenic orthostatic hypotension associated with simple autonomic failure (PAF), idiopathic orthostatic hypotension, non-sympathetic anaphylactic hypotension, neurogenic orthostatic hypotension associated with parkinson's disease, intradialytic hypotension (IDH), hemodialysis-induced hypotension, hypotension associated with fibromyalgia syndrome (FMS), hypotension in spinal cord injury, and hypotension associated with Chronic Fatigue Syndrome (CFS). Suzuki et al, Neurology (Neurology)1981, 31(10), 1323-6; eda (Iida), et al, neurology, dialysis, transplantation: european Dialysis and Transplantation Association-European Kidney Association Official publications (physiology, analysis: Official Publication of the European analysis and Transplantation Association-European Renal Association), 1994, 9(8), 1130-5; frieman (Freeman) et al, Neurology, 1996, 47(6), 1414-20; wikstrom et al, Amyloid (Amyloid), 1996, 3(3), 162-; kavallo et al, journal of the autonomic nervous system (j. autonomic nerve system.), 1997, 62(1/2), 63-71; terakaki et al, J.Autonomic Nervous Syst., 1998, 68(1-2), 101-8; frieman (Freeman), et al, Neurology, 1999, 53(9), 2151-7; goldstein et al, Cardiovascular Drug Review (Cardiovascular Drug Review), 2006, 24(3-4), 189-; and eda (Iida) et al, am. j. nephrology, 2002, 22(4), 338-46. Droxidopa has also shown promise in the treatment of: frozen gait, akinesia and dysarthria in parkinson's disease, lewy body dementia, Rapid Eye Movement (REM) behavioral disorders, chronic heart failure, stress-related disorders, movement or speech disorders, chronic pain, stroke, cerebral ischemia, nasal congestion, mood disorders, sleep disorders, narcolepsy, insomnia, Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), hyposmia, Mild Cognitive Impairment (MCI), down's syndrome, alzheimer's disease, and postural reflex abnormalities caused by parkinson's disease, autoimmune autonomic failure, familial autonomic abnormalities, diabetic autonomic neuropathy, amyloidosis in the background of multiple myeloma, parkinson's disease, pre-prandial hypotension, dopamine beta-hydroxylase deficiency, pain, progressive supranuclear palsy, menkes disease, familial autonomic abnormalities (Lyrics-Town syndrome), PD-associated autonomic abnormalities (autonomic dysfunction), juvenile intolerance, neurogenic syncope (vasovagal), postural tachycardia syndrome (POTS), fibromyalgia, allodynia, hyperalgesia, fatigue, sleep disturbances, and depression. Ogawa et al, J.Medicine, 1985, 16(5-6), 525-34; yamamoto et al, clinical neuropharmacology (clin. neuropharmacol.), 1985, 8(4), 334-42; CA 2133514 a 1; tacari et al, europachyharmacol (eur. neuropsychopharmacol.), 1996, 6(1), 43-7; EP 887078 a 1; uterine well (Miyai), et al, Neurorehabilitation and neurorestoration (Neurorehabilitation and neuro Repair), 2000, 14(2), 141-7; WO 2005084330 a 2; WO 2008137923 a 2; WO2010132128 a 1; WO 2012158612a 1; carinin (kalin) et al, neurobiology of Aging (neurobiology Aging), 2012, 33(8), 1651-1663; goldstein et al, Cardiovascular Drug Review (Cardiovascular Drug Review), 2006, 24(3-4), 189-; US 8383681; and US 8008285.

The droxidopa chemical structure contains a number of features that we conclude will produce inactive or toxic metabolites whose formation can be reduced by the pathways described herein. Droxidopa is subject to metabolism by aromatic L-amino acid decarboxylase to give norepinephrine (noradrenaline), which is further methylated by phenylethanolamine-N-methyltransferase to give epinephrine (adrenaline). Norepinephrine and epinephrine are subject to oxidative metabolism by monoamine oxidase (MAO) to give the toxic metabolite 3, 4-Dihydroxyphenylethanolal (DOPEGAL).

Monoamine oxidase not only limits the efficacy of droxidopa as a prodrug of norepinephrine but can also cause toxicity. The immediate products of the action of monoamine oxidase on norepinephrine are catechuic novolac, dihydroxyphenylethanol aldehyde. Dihydroxyphenylethanolaldehyde is potentially toxic by causing cross-linking and thereby inactivating proteins, as well as autoxidation to form harmful quinones. Enzymatic deamination produces hydrogen peroxide, an oxidative stressor.

These transformations, along with other metabolic transformations, occur in part by enzymes that are expressed in a polymorphic manner, thus exacerbating inter-patient variability. In addition, some droxidopa metabolites may have undesirable side effects. Side effects associated with droxidopa administration include headache, dizziness, nausea, hypertension, falls, urinary tract infections, syncope, supine hypertension, hyperpyrexia, confusion, exacerbation of existing ischemic heart disease, arrhythmia, and congestive heart failure. To overcome its short half-life, the drug may have to be taken three times per day, which increases the probability of patient non-compliance and discontinuities. In addition, sudden cessation of droxidopa treatment may lead to withdrawal syndrome or withdrawal syndrome. Drugs with longer half-lives will likely attenuate these deleterious effects.

Kinetic isotope effect of deuterium

To eliminate foreign substances (e.g., therapeutic agents), the animal body expresses various enzymes (e.g., cytochrome P)₄₅₀Enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases) to react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Such metabolic reactions typically involve the oxidation of carbon-hydrogen (C-H) bonds to carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bonds. These generated metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic and acute and long term toxicity profiles relative to the parent compound. For most drugs, such oxidation is usually rapid and ultimately results in multiple or high dose administrations per day.

The relationship between activation energy and reaction rate can be quantified by the Arrhenius equation, where k is Ae^-Eact/RT. The Arrhenius equation states that the rate of chemical reaction at a given temperature depends exponentially on the activation energy (E)_act)。

The transition state in the reaction is a transient state along the reaction pathway during which the original bond stretches to its limit. By definition, the activation energy E of the reaction_actIs the energy required to reach the transition state of the reaction. Once the transition state is reached, these molecules can revert back to the original reactants, or form new bonds to produce reaction products. The catalyst promotes the reaction process by lowering the activation energy leading to the transition state. Enzymes are examples of biocatalysts.

The strength of a carbon-hydrogen bond is proportional to the absolute value of the ground-state vibrational energy of the bond. The vibrational energy depends on the mass of the atoms forming the bond and increases as the mass of one or both of the atoms making up the bond increases. Since deuterium (D) has twice protium: (¹H) The C-D bond is stronger than the corresponding C-¹And (4) a H bond. If C-¹The H bond is broken during the rate determining step of the chemical reaction (i.e., the step with the highest transition state energy), then the substitution of deuterium for the protium results in a reduction in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The size of DKIE can be expressed for a given reaction (where C-¹H bond rupture) and the rate of the same reaction (in which deuterium is substituted for protium). DKIE can range from about 1 (no isotopic effect) to very large numbers (e.g., 50 or more). Substitution of hydrogen with tritium also produces a stronger bond than deuterium and produces a numerically greater isotopic effect.

Deuterium (1)²H or D) is a stable and nonradioactive isotope of hydrogen having about twice protium (b:)¹H) Is the most common isotope of hydrogen. Deuterium oxide (D)₂O or "heavy water") looks and tastes like H₂O, but have different physical properties.

When pure D is administered to rodents₂O, it is easily absorbed. The amount of deuterium required to cause toxicity is extremely high. When about 0-15% of the body water has been removed by₂When O replaced, animals were healthy but did not gain weight as quickly as the control (untreated) group. When about 15% -20% of the body water has been removed by₂When O is substituted, these animals become excitable. When about 20% -25% of the body water has been removed by D₂When O is replaced, these animals become so excitable that they enter frequent convulsions when stimulated. Skin lesions, ulcers and tail necrosis were present in the paws and snout. These animals also become very aggressive. When about 30% of the body water has been removed by₂When O replaced, these animals refused to eat and became comatose. Their body weight is drastically reduced, and their metabolic rate drops far below normal levels,in the range of about 30% to about 35% by weight of D₂Death occurs when O is replaced. Unless more than thirty percent of the previous body weight is due to D₂O is lost and these effects are reversible. Studies have also shown the use of D₂O can delay the growth of cancer cells and enhance the cytotoxicity of certain antineoplastic agents.

Deuteration of drugs to improve Pharmacokinetic (PK), Pharmacodynamic (PD) and toxicity profiles has been previously demonstrated using several classes of drugs. For example, DKIE was assumed to be used to reduce the hepatotoxicity of halothane by limiting the production of reactive components such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic diversion. Metabolic diversion occurs when xenogen sequestered by the first stage enzyme transiently binds and re-binds in multiple conformations prior to a chemical reaction (e.g., oxidation). Metabolic diversion is achieved by the relatively large size of the binding pocket in many first-stage enzymes and the promiscuous nature of many metabolic reactions. Metabolic diversion can result in different proportions of known metabolites along with all new metabolites. This new metabolic profile may confer more or less toxicity. Such defects are non-obvious and are not predictable a priori for any drug class.

Droxidopa is a neurotransmitter modulator. The carbon-hydrogen bond of droxidopa contains a distribution of naturally occurring hydrogen isotopes, i.e.¹H or protium (about 99.9844%),²h or deuterium (about 0.0156%), and³h or tritium (in each 10 th day)¹⁸Protium atoms in a range between about 0.5 and 67 tritium atoms). Increased deuterium incorporation levels can produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that can affect the pharmacokinetic, pharmacological and/or toxicological profile of such droxidopa compared to compounds having naturally occurring deuterium levels.

Based on findings in our laboratory, and considering the literature, droxidopa may be metabolized in humans to give epinephrine and norepinephrine, which are further metabolized at their N-methylene group. Current methods have the potential to prevent metabolism at this site. Other sites on the molecule may also undergo transformation, thereby producing metabolites with hitherto unknown pharmacology/toxicology. Limiting the production of these metabolites has the potential to reduce the risk of administration of such drugs and may even allow for increased dosages and/or increased efficacy. All of these transformations can occur through enzymes expressed in a polymorphic manner, thus exacerbating inter-patient variability. In addition, it is desirable to treat some disorders when the subject is taking medication around the clock or over a long period of time. For all of the foregoing reasons, drugs with longer half-lives may result in higher efficacy as well as cost savings. Different deuteration patterns can be used to (a) reduce or eliminate undesirable metabolites, (b) increase the half-life of the parent drug, (c) reduce the number of doses required to achieve a desired effect, (d) reduce the number of doses required to achieve a desired effect, (e) increase the formation of active metabolites, if formed, (f) reduce the production of harmful metabolites in specific tissues and/or (g) produce a more efficacious drug and/or a safer drug for multiple administration (whether or not the multiple administration is intended). The deuteration method has the powerful potential to slow droxidopa metabolism and reduce interpatient variability.

Novel compounds and pharmaceutical compositions, some of which have been found to act as prodrugs of neurotransmitters, and methods of synthesizing and using these compounds, including methods for treating neurotransmitter-mediated disorders in a patient by administering these compounds, have been discovered.

In certain embodiments of the invention, the compounds have structural formula I:

or a salt thereof, wherein:

R₁-R₂independently selected from the group consisting of: hydrogen, deuterium, methyl, deuterium-substituted methylAlkyl, ethyl, deuterium-ethyl, propyl, deuterium-propyl, butyl, deuterium-butyl, C₁-C₆-alkyl, and C₅-C₆-cycloalkyl, wherein said C₁-C₆-alkyl and C₅-C₆-cycloalkyl may be optionally substituted with deuterium;

R₃-R₈independently selected from the group consisting of: hydrogen and deuterium;

R₉-R₁₁independently selected from the group consisting of: hydrogen, deuterium, methyl, deuteromethyl, ethyl, deuteroethyl, propyl, deuteropropyl, butyl, deuterobutyl, C₁-C₆-alkyl, and C₅-C₆-cycloalkyl, wherein said C₁-C₆-alkyl and C₅-C₆-cycloalkyl may be optionally substituted with deuterium; and is

R₃-R₆And R₈Is deuterium.

Certain compounds disclosed herein can have useful neurotransmitter-modulating activity and can be used to treat or prevent disorders in which neurotransmitter levels play a positive role. Accordingly, certain embodiments also provide pharmaceutical compositions comprising one or more of the compounds disclosed herein, together with a pharmaceutically acceptable carrier, and methods of making and using the compounds and compositions. Certain embodiments provide methods for modulating neurotransmitter activity. Other embodiments provide methods for treating a neurotransmitter-mediated disorder in a patient in need of such treatment, which methods comprise administering to the patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein for use in: manufacture of a medicament for preventing or treating a disorder ameliorated by modulating neurotransmitter levels.

For other elements, compounds as disclosed herein may also contain less common isotopes, including, but not limited to, for carbon¹³C or¹⁴C for sulfur³³S、³⁴S, or³⁶S, for nitrogen¹⁵N, for oxygen¹⁷O or¹⁸O。

In certain embodiments, the compounds disclosed herein can contact patients with a maximum of about 0.000005% D₂O or about 0.00001% DHO, assuming all C-D bonds as D in the compounds as disclosed herein₂O or DHO is metabolized or released. In certain embodiments, D is shown to cause toxicity in animals₂The level of O is even much greater than the maximum limit of contact caused by administration of deuterium-enriched compounds as disclosed herein. Thus, in certain embodiments, after drug metabolism, deuterium-enriched compounds disclosed herein should not be due to D₂The formation of O or DHO causes any additional toxicity.

In certain embodiments, the compound is not carbon-13 rich.

In certain embodiments, if R₆Is deuterium, then R₃-R₅Or R₈At least one of (A) is deuterium, or R₁-R₂、R₇Or R₉-R₁₀Is selected from the group consisting of: deuterium, methyl, deuterium-depleted methyl, ethyl, deuterium-depleted ethyl, propyl, deuterium-depleted propyl, butyl, deuterium-depleted butyl, C₁-C₆-alkyl, and C₅-C₆-cycloalkyl, wherein said C₁-C₆-alkyl and C₅-C₆-cycloalkyl may be optionally substituted with deuterium.

In certain embodiments, R₁-R₁₁Independently selected from the group consisting of: hydrogen and deuterium; and R is₃-R₆And R₈Is deuterium.

In certain embodiments, R₁-R₂、R₆And R₈-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅Is deuterium; r₇Is hydrogen; and areAnd R is₁₁Selected from the group consisting of: hydrogen, deuterium, C₁-C₆-alkyl, and C₅-C₆-cycloalkyl, wherein said C₁-C₆-alkyl and C₅-C₆-cycloalkyl may be optionally substituted with deuterium.

In certain embodiments, R₁-R₂、R₆And R₉-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅And R₈Is deuterium; r₇Is hydrogen; and R is₁₁Selected from the group consisting of: deuterium, C₁-C₆-alkyl, and C₅-C₆-cycloalkyl, wherein said C₁-C₆-alkyl and C₅-C₆-cycloalkyl may be optionally substituted with deuterium.

In certain embodiments, R₁-R₂、R₆And R₉-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅And R₈Is deuterium; r₇Is hydrogen; and R is₁₁Selected from the group consisting of: hydrogen, deuterium, C₁-C₆-alkyl, and C₅-C₆-cycloalkyl, wherein said C₁-C₆-alkyl and C₅-C₆-cycloalkyl may be optionally substituted with deuterium.

In certain embodiments, R₁-R₂、R₆And R₉-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅And R₈Is deuterium; r₇Is hydrogen; and R is₁₁Selected from the group consisting of: c₁-C₆-alkyl and C₅-C₆-a cycloalkyl group.

In certain embodiments, R₁-R₂、R₆And R₉-R₁₀Independently selected from the group consisting ofConsists of the following components: hydrogen and deuterium; r₃-R₅And R₈Is deuterium; r₇Is hydrogen; and R is₁₁Is methyl.

In certain embodiments, R₁-R₂、R₆And R₉-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅And R₈Is deuterium; r₇Is hydrogen; and R is₁₁Is ethyl.

In certain embodiments, R₁-R₂、R₆And R₉-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅And R₈Is deuterium; r₇Is hydrogen; and R is₁₁Is a fully deuterated methyl group.

In certain embodiments, R₁-R₂、R₆And R₉-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅And R₈Is deuterium; r₇Is hydrogen; and R is₁₁Is an all-deuterium ethyl group.

In certain embodiments, R₁-R₂、R₆And R₈-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅Is deuterium; r₇Is hydrogen; and R is₁₁Is a fully deuterated methyl group.

In certain embodiments, R₁-R₂、R₆And R₈-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₃-R₅Is deuterium; r₇Is hydrogen; and R is₁₁Is an all-deuterium ethyl group.

In certain embodiments, R₁-R₂Is deuterium; r₃-R₆And R₈-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₇Is hydrogen; and R is₁₁Is all deuteriumA methyl group.

In certain embodiments, R₁-R₂Is deuterium; r₃-R₆And R₈-R₁₀Independently selected from the group consisting of: hydrogen and deuterium; r₇Is hydrogen; and R is₁₁Is an all-deuterium ethyl group.

In certain embodiments, R₃-R₆And R₈Independently have deuterium enrichment of no less than about 10%.

In certain embodiments, R₃-R₆And R₈Independently have deuterium enrichment of no less than about 50%.

In certain embodiments, R₃-R₆And R₈Independently have deuterium enrichment of no less than about 90%.

In certain embodiments, R₃-R₆And R₈Independently have deuterium enrichment of no less than about 98%.

In certain embodiments of the invention, the compound has structural formula II:

or a salt thereof, wherein:

R₁-R₁₁independently selected from the group consisting of: hydrogen and deuterium; and is

R₁-R₁₁Is deuterium.

In certain embodiments, the compound has a structural formula selected from the group consisting of:

and

in certain embodiments, the compound has the following structural formula:

in certain embodiments, the compound has the following structural formula:

in certain embodiments, the compound has the following structural formula:

in certain embodiments, the deuterated compounds disclosed herein substantially increase the maximum tolerated dose, reduce toxicity, increase half-life (T) while maintaining the beneficial aspects of the corresponding non-isotopically enriched molecules_1/2) Maximum plasma concentration (C) to reduce Minimum Effective Dose (MED)_max) Reducing the effective dose and thereby reducing non-mechanism related toxicity, and/or reducing the probability of drug-drug interactions.

In certain embodiments, disclosed herein are extended release pharmaceutical formulations comprising, in a solid dosage form for oral delivery between about 100mg and about 1g total weight:

between about 2% and about 18% of a compound as disclosed herein;

between about 70% and about 96% of one or more diluents;

between about 1% and about 10% of a water soluble binder; and

between about 0.5% and about 2% surfactant.

In certain embodiments, the one or more diluents are selected from mannitol, lactose, and microcrystalline cellulose; the binder is polyvinylpyrrolidone; and the surfactant is polysorbate.

In certain embodiments, the extended release pharmaceutical formulation comprises between about 2.5% and about 11% of a compound as disclosed herein.

In certain embodiments, the extended release pharmaceutical formulation comprises:

between about 60% and about 70% mannitol or lactose;

between about 15% and about 25% microcrystalline cellulose

About 5% polyvinylpyrrolidone K29/32; and

between about 1% and about 2% Tween (Tween) 80.

In certain embodiments, the extended release pharmaceutical formulation comprises:

between about 4% and about 9% of a compound as disclosed herein;

between about 60% and about 70% mannitol or lactose;

between about 20% and about 25% microcrystalline cellulose

About 5% polyvinylpyrrolidone K29/32; and

about 1.4% tween 80.

In certain embodiments, disclosed herein are extended release pharmaceutical formulations comprising, in a solid dosage form for oral delivery between about 100mg and about 1g total weight:

between about 70% and about 95% of particles of a compound as disclosed herein, wherein the active ingredient comprises between about 1% and about 15% of the particles;

between about 5% and about 15% of one or more diluents;

between about 5% and about 20% of a sustained release polymer; and

between about 0.5% and about 2% of a lubricant.

In certain embodiments, the extended release pharmaceutical formulation comprises:

between about 5% and about 15% of one or more of spray dried mannitol or spray dried lactose;

between about 5% and about 20% of a sustained release polymer; and

between about 0.5% and about 2% magnesium stearate.

In certain embodiments, the sustained release polymer is selected from the group consisting of a polyvinyl acetate-polyvinyl pyrrolidone mixture and a poly (ethylene oxide) polymer.

In certain embodiments, the sustained release polymer is selected from colewhenSR、N60K, and carbomer

In certain embodiments, the sustained release polymer isSR。

In certain embodiments, the sustained release polymer isN60K。

In certain embodiments, the sustained release polymer is

In certain embodiments, the extended release pharmaceutical formulation comprises from about 5mg to about 100mg of a compound as disclosed herein.

In certain embodiments, the compounds disclosed herein may be formulated as extended release pharmaceutical formulations, as described in U.S. patent application No. 14/030,322 filed on 2013, 9, 18.

All publications and references cited herein are expressly incorporated herein by reference in their entirety. However, for any similar or identical terms found in the incorporated publications or references, as well as those explicitly set forth or defined in this document, the definitions or meanings of those terms explicitly set forth in this document shall control in various respects.

As used herein, the following terms have the indicated meanings.

The singular forms "a" and "an" and "the" may refer to the plural articles unless expressly stated otherwise.

As used herein, the term "about" is intended to define the value that it modifies, meaning that the value is a variable within the bounds of error. When no specific margin of error is set forth (such as the standard deviation of the mean values reported in a chart or data sheet), the term "about" should be understood to mean that the range for the recited value is covered, as well as ranges that are included by rounding to that number, taking into account significant figures.

When a range of values is disclosed, and the notation "from n" is used₁… to n₂"or" n₁-n₂When n is₁And n₂Is a number, the symbol is intended to include such unless otherwise indicatedThe numbers themselves and the ranges between them. This range can be whole or continuous between and including the endpoints.

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

The term "is deuterium" when used to describe a given position in a molecule (e.g., R)₁-R₁₁Or the symbol "D"), when used to refer to a given position in a molecular structure diagram, means that the designated position is enriched in deuterium at a distribution higher than that of naturally occurring deuterium. In one embodiment, the deuterium enrichment at a given position is no less than about 1%, in another embodiment no less than about 5%, in another embodiment no less than about 10%, in another embodiment no less than about 20%, in another embodiment no less than about 50%, in another embodiment no less than about 70%, in another embodiment no less than about 80%, in another embodiment no less than about 90%, or in another embodiment no less than about 98% deuterium.

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

The term "non-isotopically enriched" refers to a molecule in which the percentage of each isotope is substantially the same as the percentage found in nature.

Asymmetric centers are present in the compounds disclosed herein. These centers are designated by the symbol "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. It is to be understood that the present invention encompasses all stereochemically isomeric forms, including diastereoisomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of a compound may be prepared synthetically from commercially available starting materials containing chiral centers or by preparing mixtures of enantiomeric products, followed by separation (e.g., conversion to a mixture of diastereomers), followed by separation or recrystallization, chromatographic techniques, direct separation of the enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds of a particular stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. In addition, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis (cis), trans (trans), homo (syn), trans (anti), hetero (E), and ipsilateral (Z) isomers, as well as suitable mixtures thereof. In addition, the compounds may exist as tautomers; all tautomers are provided by the present invention. In addition, the compounds disclosed herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, these solvated forms are considered equivalent to unsolvated forms.

The term "bond" refers to a covalent linkage between two atoms or two moieties when the atoms joined by the bond are considered part of a larger substructure. The bond may be a single bond, a double bond, or a triple bond, unless otherwise specified. The dashed line between two atoms in the molecular diagram indicates that additional bonds may or may not be present at that position.

The term "disorder" as used herein is intended to be synonymous with and used interchangeably with the terms "disease" and "condition" generally (as in medical conditions), as both reflect abnormal conditions of the human or animal body or parts thereof that impair normal function, typically manifested as distinguishing signs and symptoms.

The terms "treat", "treating" and "treatment" are intended to include alleviation or elimination of the disorder or one or more symptoms associated with the disorder, or alleviation or eradication of one or more causes of the disorder itself. As used herein, reference to "treatment" of a disorder is intended to include prophylaxis. The terms "preventing", "preventing" and "prevention" refer to a method of delaying or arresting the onset of a disorder and/or its attendant symptoms, arresting a subject from suffering from a disease, or reducing the risk of suffering from a disease in a subject.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the disorder being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sought by a researcher, veterinarian, medical doctor or clinician to elicit a biological or medical response in a cell, tissue, system, animal or human.

The term "subject" refers to an animal, including but not limited to a primate (e.g., human, monkey, chimpanzee, gorilla, etc.), rodent (e.g., rat, mouse, gerbil, hamster, ferret, etc.), lagomorpha, pig (e.g., house pig, mini-pig), equine, canine, feline, etc. The terms "subject" and "patient" are used interchangeably herein when, for example, in reference to a mammalian subject (e.g., a human patient).

The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic disorder described in the present disclosure. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, e.g., in a single capsule with a fixed ratio of active ingredients or multiple separate capsules for each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the disorders described herein.

The term "neurotransmitter" refers to an endogenous chemical that transmits a signal from one neuron (brain cell) to another 'target' neuron across synapses. Neurotransmitters are packaged into synaptic vesicles that accumulate under the membrane in the axonal terminal on the presynaptic side of the synapse. Neurotransmitters are released and diffuse across the synaptic cleft where they bind to specific receptors in the membrane on the postsynaptic side of the synapse. Many neurotransmitters are synthesized from large and simple precursors, such as amino acids, which are readily available from the diet and require only a few biosynthetic steps to convert. The levels of specific neurotransmitters, including norepinephrine and epinephrine, are modulated by the compounds disclosed herein.

Norepinephrine is a catecholamine with multiple roles, including those as hormones and neurotransmitters. It is used medically for those with severe hypotension. This is achieved by increasing vascular tone (tension of vascular smooth muscle) through activation of alpha adrenergic receptors. One of the most important functions of norepinephrine is its role in affecting the heart as a neurotransmitter released from sympathetic neurons. Elevation of norepinephrine from the sympathetic nervous system increases cardiac contractility. As a stress hormone, norepinephrine affects various parts of the brain, such as the amygdala, which controls attention and response. Norepinephrine also forms the basis for a battle flight response, along with epinephrine, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscles. It increases oxygen supply to the brain. Norepinephrine is synthesized from polydopamine by dopamine β -hydroxylase in secretory granules of medullary pheochromocytes. It is released as a hormone from the adrenal medulla into the blood and is also a neurotransmitter in the central and sympathetic nervous systems, where it is released from norepinephrine neurons in the locus ceruleus nucleus. These effects of norepinephrine are via binding to adrenergic receptors.

Epinephrine is a hormone and neurotransmitter that acts on almost all body tissues. Its action varies with tissue type and tissue expression of adrenergic receptors. For example, high levels of epinephrine cause smooth muscle in the respiratory tract to relax but smooth muscle lining most of the arterioles to contract. Epinephrine acts by binding to a variety of adrenergic receptors. Epinephrine is a non-selective agonist of all adrenergic receptors, including the major subtypes α 1, α 2, β 1, β 2, and β 3. Binding of epinephrine to these receptors triggers a number of metabolic changes. Binding to the alpha-adrenergic receptor inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis in muscle. Beta-adrenergic receptor binding triggers: glucagon secretion in the pancreas increases pituitary corticotropin (ACTH) secretion and increases lipolysis in adipose tissue. Together, these effects result in increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body. Epinephrine is used to treat a number of conditions, including: cardiac arrest, anaphylaxis, and superficial bleeding.

The term "neurotransmitter-mediated disorder" refers to a disorder characterized by abnormal or suboptimal levels of norepinephrine and/or epinephrine. Neurotransmitter-mediated disorders can be mediated, in whole or in part, by modulating neurotransmitter levels. In particular, neurotransmitter-mediated disorders are disorders in which modulating neurotransmitter levels results in some effect on underlying disorders, e.g., administration of a neurotransmitter modulator results in some improvement in at least some of the patients being treated. In some embodiments, the term "neurotransmitter-mediated disorder" refers to a disorder in which there is reduced synthesis, storage, release, reuptake, metabolism, or action of norepinephrine, such as parkinson's disease and idiopathic orthostatic hypotension. In some embodiments, the term "neurotransmitter-mediated disorder" refers to a disorder that involves hypotension, inadequate vasoconstriction, hypovolemia, or other situations where norepinephrine is approved as a drug. In some embodiments, the term "neurotransmitter-mediated disorder" refers to such a disorder

The term "neurotransmitter level modulator" refers to the ability of a compound disclosed herein to alter the levels of norepinephrine and/or epinephrine. Modulators may increase neurotransmitter levels by acting as biosynthetic precursors for norepinephrine and/or epinephrine. This modulation may be manifested only in specific cell types or may depend on specific biological events. In some embodiments, modulation of neurotransmitter levels can be assessed using methods described in the following documents: weinhag root-camembeck (Verhagen-Kamerbeek), et al, in Vivo Methods international conference monitoring molecular neuroscience progress (unit. mol. neurosci., proc. int. conf. in Vivo Methods), 5 th edition, 1991, 373-6; yue (Yue), et al, J.Pharmacy and Pharmacol, 1992, 44(12), 990-5; and coler Mar (Coll Mar), et al, Hepatology (Hepatology) (baltimol, maryland (Md.)), 2012, 56(5), 1849-60.

The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, immunogenicity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier", or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each component must be "pharmaceutically 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 tissues or organs of humans and animals commensurate with a reasonable benefit/risk ratio, without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications. See, remington: pharmaceutical Science and Practice (Remington: The Science and Practice of pharmacy), 21 st edition; RipKorte Williams and Wilkins publishers (Lippincott Williams & Wilkins): philadelphia, Pa., 2005; handbook of pharmaceutical excipients (Handbook of pharmaceutical excipients), 5 th edition; edited by Row (Rowe) et al, pharmaceutical Press and American pharmaceutical Association: 2005; and the Handbook of Pharmaceutical Additives (Handbook), 3 rd edition; ashi (Ash) and ashi editors, goler Publishing Company (Gower Publishing Company): 2007; pharmaceutical preparations and formulations (pharmaceutical preparation and Formulation), jepson (Gibson) ed, CRC press LLC: poka Raton (Boca Raton), Fla.Frida (FL), 2004).

The terms "active ingredient," "active compound," and "active agent" refer to a compound that is administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, to treat, prevent, or ameliorate one or more symptoms of a disorder.

The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a disorder.

The term "controlled release excipient" refers to an excipient that serves the primary function of modifying the duration or location of release of an active agent from a dosage form as compared to conventional immediate release dosage forms.

The term "non-controlled release excipient" refers to an excipient whose primary function does not include altering the duration or location of release of the active agent from the dosage form as compared to conventional immediate release dosage forms.

The term "group which is readily hydrolyzable or enzymatically cleavable under physiological conditions" refers to the commonly used protecting groups used in synthesis or which are commonly used protecting groups which give rise to so-called prodrugs and are known to those skilled in the art as such protecting groups. These groups may be selected from the group consisting of methyl, deuteromethyl, ethyl, deuteroethyl, propyl, deuteropropyl, butyl, deuterobutyl, C which may be branched or unbranched₁To C₆-alkyl, or C₅To C₆Cycloalkyl, deuterated or partially deuterated C which may be branched or unbranched₁To C₆-alkyl, or deuterated or partially deuterated C₅To C₆-a cycloalkyl group.

The term "prodrug" refers to a functional derivative of a compound as disclosed herein, and is readily convertible in vivo to the parent compound. Prodrugs are often useful because they are easier to administer than the parent compound in some cases. For example, they may be bioavailable by oral administration whereas the parent compound is not. Prodrugs also have enhanced solubility over the parent compound in pharmaceutical compositions. Prodrugs can be converted to the parent drug by different mechanisms, including enzymatic processes and metabolic hydrolysis. See Huppe (Harper), Progress of drug research (Progress in drug research)1962, 4, 221-294; maruzisch et al, "Design of Biopharmaceutical Properties through Prodrugs and Analogs" (Design of Biopharmaceutical Properties through drugs and Analogs), "Roche editors (Roche), APHA pharmaceutical sciences (APHA Acad. Pharm. Sci.) 1977; "Bioreversible Carriers in drugs in Drug Design, Theory and Application", edited by Roche, APHA pharmaceutical sciences (APHA acad. pharm. sci.) 1987; "Design of Prodrugs" (Design of produgs), "bindgaard (Bundgaard), eisavir (Elsevier), 1985; king (Wang) et al, current drug design (curr. pharm. design)1999, 5, 265-287; boreiti (Pauletti), et al, reviews on advanced drug delivery (adv. drug. delivery Rev.)1997, 27, 235-); skullcap (Mizen), et al, pharmacogenomics (pharm. biotech.)1998, 11, 345-365; genio et al, medicinal chemistry practice (pract. med. chem.)1996, 671-696; akkernellnjad (Asghannejad) "Transport Process in Pharmaceutical Systems (Transport Processes in Pharmaceutical Systems)", Amidon (Amidon), et al, Masterk (Markel Dekker), 185-; balant (Balant) et al, journal of european drug metabolism and pharmacokinetics (eur.j.drug meta.pharmacokinet.) 1990, 15, 143-53; baliman (Balimane) and Sinko (Sinko), reviews on advanced drug Delivery (adv. drug Delivery Rev.)1999, 39, 183-; brown (brown), clinical neuropharmacology (clin. neuropharmacol.)1997, 20, 1-12; bundgard, pharmacochemistry (arch. pharm. chem.)1979, 86, 1-39; bond high (Bundgaard), Controlled Drug Delivery (Controlled Drug Delivery)1987, 17, 179-96; bundhad (Bundgaard), reviews on advanced drug Delivery (adv. drug Delivery Rev.)1992, 8, 1-38; freisher et al, advanced drug Delivery reviews (adv. drug Delivery Rev.)1996, 19, 115-130; fleisher et al, Methods in enzymology (Methods Enzymol.)1985, 112, 360-381; farkhar (Farquhar) et al, J.Pharm.Sci., 1983, 72, 324-325; freiman et al, journal of the chemical society of communications and chemistry (j.chem.soc., chem.commun.)1991, 875-; fries (Friis) and bindgard (Bundgaard), european journal of pharmaceutical science (eur.j.pharm.sci.)1996, 4, 49-59; okawal et al, design biopharmaceutical properties through prodrugs and Analogs (des. biopharm. prop. produgs Analogs), 1977, 409-; neisenib (Nathwani) and Wood (Wood), Drugs (Drugs)1993, 45, 866-94; sinhababu (Sinhababu) and tachr (Thakker), advanced drug Delivery reviews (adv. drug Delivery Rev.)1996, 19, 241-; stella (Stella) et al, Drugs (Drugs)1985, 29, 455-73; dan (Tan) et al, advanced drug Delivery review (adv. drug Delivery Rev.)1999, 39, 117-; taylor (Taylor), advanced drug Delivery review (adv. drug Delivery Rev.)1996, 19, 131-; valentino (Valentino) and Bohart (Borchardt), Drug Discovery Today (Drug Discovery Today)1997, 2, 148-155; weibei (Wiebe) and krauss (Knaus), reviews on advanced drug Delivery (adv. drug Delivery Rev.)1999, 39, 63-80; waller (Waller) et al, J.Clin.Pharmac., British J.Clin.C.) 1989, 28, 497-Bush 507.

The compounds disclosed herein may exist as therapeutically acceptable salts. As used herein, the term "therapeutically acceptable salt" means a therapeutically acceptable salt or zwitterionic form of a compound disclosed herein as defined herein. These salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with a suitable acid or base. Therapeutically acceptable salts include acid and base addition salts. For a more complete discussion of salt preparation and selection, reference is made to the "handbook of drug salts, properties and uses", edited by sand (Stah) and wemut (Wermuth), (willy) -VCH and VHCA, Zurich (Zurich), 2002), and belrey (Berge) et al, journal of drug science (j.pharm.sci.)1977, 66, 1-19.

Suitable acids for use in preparing pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+) -camphoric acid, camphorsulfonic acid, (+) - (1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-oxo-glutaric acid, and the like, Glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+) -L-lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) -L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, sugar acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

For the production of physiologically acceptable salts of the compounds disclosed herein, general physiologically acceptable inorganic and organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid, as well as salts with suitable zwitterions (like lysine and aspartic salts) can be used. For example in medicineDevelopment of the study (Fortschritte der Arzneimitelforschung) volume 10, page 224-225 (Bickholeze)Additional acids that may be used are described by the publishers, Basel and Stuttgart, 1966) and the Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences) Vol.66, pages 1-5 (1977).

Acid addition salts are generally obtained in a manner known per se by mixing the free base or a solution thereof with the corresponding acid or a solution thereof in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol, or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the named solvents can also be used for better crystal precipitation. Furthermore, physiologically acceptable aqueous solutions of the acid addition salts of the compounds used according to the invention can be produced therefrom in aqueous acid solutions.

The acid addition salts of the compounds disclosed herein can be converted into the free base in a manner known per se, for example, using a base or an ion exchanger. Additional salts may be obtained from the free base by reaction with an inorganic or organic acid, particularly those suitable for forming salts useful in therapy. Still other salts of these or new compounds, such as, for example, picrates, may also be used to purify the free base by converting the free base into a salt, isolating the salt, and releasing the base from the salt again.

Suitable bases for use in preparing pharmaceutically acceptable salts include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary and quaternary amines, aliphatic and aromatic amines, including L-arginine, benzphetamine, benzathine, choline, dandol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amine, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, and tromethamine.

While the compounds of the present invention may be administered as the original chemical, it is also possible to provide them as pharmaceutical compositions. Accordingly, provided herein are pharmaceutical compositions comprising one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. Suitable formulations depend on the chosen route of administration. Any of these well known techniques, carriers, and excipients may be suitably and as understood in the art used; for example in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting methods. The pharmaceutical compositions may also be formulated as modified release dosage forms, including delayed release, extended release, prolonged release, sustained release, pulsatile release, controlled release, accelerated and fast release, targeted release, programmed release, and gastric retention. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in The art (see, Remington: The Science and practice of Pharmacy (Remington: The Science and practice of Pharmacy), supra; Modified Release Drug delivery technology (Modified-Release Drug delivery technology), Rathbone, et al, Drugs and pharmaceuticals (Drugs and The pharmaceutical Science), Markel Dekker, N.Y., New York, N.Y. (NY), 2002; volume 126; Hager's Handbook [ Handbook of Handbook ] (Handbook)]) (5 th edition) 2, 622-; list et al, pharmaceutical form description (Arzneifommenlehre [ I ]nstructions for Drug Forms]) Stuttgart (Stuttgart): visa girs (wiss.verlagsges.) 1985; zukker (Sucker), et al, Pharmaceutical Technology (Pharmaceutical Technology]) Stuttgart (Stuttgart): calyx et fructus mume (Thieme) 1991; encyclopedia (Ullmann's)[Encyclopedia]) (5 th edition) A19, 241-271; forgat (Voigt), pharmaceutical technology (Pharmazeutische technology [ pharmaceutical technology ]]) Berlin (Berlin): ullstein (Ullstein) Mos ratio (Mosby) 1995).

These compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. These compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts. Typically, these methods include the steps of: a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or solvate thereof ("active ingredient") is combined with a carrier that constitutes one or more accessory ingredients. Typically, these compositions are prepared by the following steps: uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product to give the desired formulation.

These compositions include those suitable for oral administration. These compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts. Typically, these methods include the steps of: a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or solvate thereof ("active ingredient") is combined with a carrier that constitutes one or more accessory ingredients. Typically, these compositions are prepared by the following steps: uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product to give the desired formulation.

Formulations of the compounds disclosed herein suitable for oral administration can be presented in discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; in the form of powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Pharmaceutical preparations for oral use include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Plug-in capsules may contain the active ingredients in admixture with fillers (e.g. lactose), binders (e.g. starches), and/or lubricants (e.g. talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, for example fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or colorants can be added to the tablets or dragee coatings for the purpose of identifying or characterizing different combinations of active compound doses.

The solutions or suspensions containing the active substances used according to the invention may additionally contain taste-improving agents, such as saccharin, cyclamate or sugar, together with, for example, taste enhancers (such as vanilla or orange extract). They may also contain suspension adjuvants (e.g. sodium carboxymethylcellulose) or preservatives (e.g. p-hydroxybenzoic acid). Capsules containing the active substance can be produced, for example, by mixing the active substance with an inert carrier, for example lactose or sorbitol, and encapsulating this mixture in gelatin capsules. Suitable suppositories may be created, for example, by mixing with a carrier (e.g. neutral fat or polyethylene glycol or derivatives thereof) thus provided.

In certain embodiments, the diluent is selected from the group consisting of: mannitol powder, spray-dried mannitol, microcrystalline cellulose, lactose, dicalcium phosphate, tricalcium phosphate, starch, pregelatinized starch, compressible sugar, silicified microcrystalline cellulose, and calcium carbonate.

In certain embodiments, the surfactant is selected from the group consisting of: tween 80, sodium lauryl sulfate, and docusate sodium.

In certain embodiments, the binder is selected from the group consisting of: povidone (PVP) K29/32, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), Ethyl Cellulose (EC), corn starch, pregelatinized starch, gelatin, and sugar.

In certain embodiments, the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, mineral oil, polyethylene glycol 4000-6000, talc, and glyceryl behenate.

In certain embodiments, the sustained release polymer is selected from the group consisting of:(poly (ethylene oxide)),N60K grade,SR, HPMC (high viscosity), HPC (high viscosity), and

in certain embodiments, the extended/controlled release coating is selected from ethylcellulose polymers such as ETHOCEL^TMAnd Stichi silkA group of aqueous ethylcellulose dispersions.

In certain embodiments, the antioxidant is selected from the group consisting of: butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), sodium ascorbate, and alpha-tocopherol.

In certain embodiments, the tablet coating is selected from the group of: opadry200、II、fx、amb, obaglos2、tm、NS, OcimumOuba butylOlpaspori (r) de bokNitlar fizzie

Preferred unit dose formulations are those containing an effective dose of the active ingredient as described below, or an appropriate fraction thereof.

The compounds may be administered orally at a dose of from 0.1 to 500 mg/kg/day. For adults, the dose will usually range from 5mg to 2 g/day. The tablets or other presentation forms provided in discrete units may conveniently contain an amount of one or more compounds effective at this dose or as a multiple of an equivalent dose, for example units containing from 5mg to 500mg, typically around 10mg to 200 mg.

These compounds may be formulated for parenteral administration by injection (e.g., by single bolus intravenous injection or continuous infusion). Formulations for injection may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers) with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. These formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds may also be formulated as depot formulations. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, these compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, such as a sparingly soluble salt.

For buccal or sublingual administration, these compositions may take the form of tablets, lozenges, pastilles, or gels in a conventional manner. Such compositions may include the active ingredient in a flavoring base such as sucrose and acacia or tragacanth.

These compounds may also be formulated in rectal compositions (e.g., suppositories or retention enemas), e.g., containing conventional suppository bases (e.g., cocoa butter, polyethylene glycols, or other glycerides).

Certain compounds disclosed herein can be administered locally, i.e., by non-systemic administration. This includes applying the compounds disclosed herein to the exterior of the epidermis or the oral cavity and dripping such a compound into the ear, eye and nose so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for transdermal delivery to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

For administration by inhalation, the compounds may be delivered by an insufflator, nebulizer press pack, or other means of conveniently delivering an aerosol. The pressurized pack may include a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example, a powder mix of the compound with a suitable powder base such as lactose or starch. The powder compositions may be presented in unit dosage form in, for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered by means of an inhaler or insufflator.

Preferred unit dose formulations are those containing an effective dose of the active ingredient as described below, or an appropriate fraction thereof.

The compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg/day. For adults, the dose will usually range from 5mg to 2 g/day. The tablets or other presentation forms provided in discrete units may conveniently contain an amount of one or more compounds effective at this dose or as a multiple of an equivalent dose, for example units containing from 5mg to 500mg, typically around 10mg to 200 mg.

The dosage of the active ingredient may vary between 100 and 1500 mg/day in divided doses in order to obtain the desired effect.

Each single dose may contain from 50 to 1000mg of the active ingredient in combination with a pharmaceutical carrier. This single dose may be administered from 1 to 4 times per day.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

These compounds can be administered in a variety of ways, for example, orally, topically, or by injection. The precise amount of compound administered to a patient is the responsibility of the physician. The specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated and the severity of the disorder being treated. In addition, the route of administration may vary depending on the disorder and its severity.

In cases where the patient's condition does not improve, as determined by the physician, the compound may be administered chronically, i.e., over an extended period of time, including throughout the life of the patient, in order to ameliorate or otherwise control or limit the symptoms of the patient's disorder.

In cases where the patient's condition does not improve, as determined by the physician, the compound may be administered continuously or temporarily suspended for a period of time (e.g., a "drug withdrawal period").

Once the patient's condition has improved, maintenance doses are administered as necessary. Subsequently, the dose or frequency of administration, or both, may be reduced as a function of the symptoms to a level at which the improved disorder is maintained. However, patients may require long-term intermittent treatment based on the recurrence of any symptoms.

Disclosed herein are methods of treating tyrosine kinase mediated disorders comprising administering to a subject having or suspected of having such a disorder a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Neurotransmitter-mediated disorders include, but are not limited to: hypotension, orthostatic hypotension, neurogenic orthostatic hypotension, symptomatic neurogenic orthostatic hypotension, neurogenic orthostatic hypotension associated with Multiple System Atrophy (MSA), orthostatic hypotension associated with Chari-Delger syndrome, neurogenic orthostatic hypotension associated with Familial Amyloid Polyneuropathy (FAP), neurogenic orthostatic hypotension associated with simple autonomic failure (PAF), idiopathic orthostatic hypotension, non-sympathetic anaphylactic hypotension, neurogenic orthostatic hypotension associated with Parkinson's disease, intradialytic hypotension (IDH), hemodialysis-induced hypotension, hypotension associated with fibromyalgia syndrome (FMS), hypotension in spinal cord injury, hypotension associated with Chronic Fatigue Syndrome (CFS), frozen gait, akinesia and dysarthria in Parkinson's disease, dementia with lewy bodies, Rapid Eye Movement (REM) behavioral disorders, chronic heart failure, stress-related disorders, movement or speech disorders, chronic pain, stroke, cerebral ischemia, nasal congestion, mood disorders, sleep disorders, narcolepsy, insomnia, Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), hyposmia, Mild Cognitive Impairment (MCI), Down's syndrome, Alzheimer's disease, postural reflex abnormalities caused by Parkinson's disease, autoimmune autonomic failure, familial autonomic abnormalities, diabetic autonomic neuropathy, amyloidosis in the background of multiple myeloma, Parkinson's disease, pre-prandial hypotension, dopamine β -hydroxylase deficiency, pain, progressive supranuclear palsy, Menkes disease, familial autonomic abnormalities (Lei-wear syndrome), PD-associated autonomic abnormalities (autonomic dysfunction), juvenile upright intolerance, neuropsychogenic syncope (vasovagal), postural tachycardia syndrome (POTS), fibromyalgia, allodynia, hyperalgesia, fatigue, sleep disorders, depression, chronic upright intolerance, childhood developmental disorders, genetic disorders involving reduced norepinephrine synthesis or action, regulated multiple system disorders, pain, neurodegenerative disorders, cognitive dysfunction, olfactory disorders, neuroendocrine disorders, and autoimmune disorders.

In certain embodiments, the neurotransmitter-mediated disorder is selected from the group consisting of: dopamine-beta-hydroxylase deficiency, Menkes 'disease, vitamin C deficiency, Lewy body disease, Parkinson's disease, Lewy body dementia, simple autonomic failure, familial autonomic abnormalities, bilateral endoscopic post-thoracic sympathotomy status, intolerance to orthostatic, and orthostatic hypotension.

In certain embodiments, the neurotransmitter-mediated disorder is selected from the group consisting of: orthostatic hypotension, neurogenic orthostatic hypotension associated with Multiple System Atrophy (MSA), orthostatic hypotension associated with the summer-delger syndrome, neurogenic orthostatic hypotension associated with Familial Amyloid Polyneuropathy (FAP), neurogenic orthostatic hypotension associated with simple autonomic failure (PAF), idiopathic orthostatic hypotension, non-sympathetic anaphylactic hypotension, neurogenic orthostatic hypotension associated with parkinson's disease, intradialytic hypotension (IDH), hemodialysis-induced hypotension, hypotension associated with fibromyalgia syndrome (FMS), hypotension in spinal cord injury, and hypotension associated with Chronic Fatigue Syndrome (CFS).

In certain embodiments, the neurotransmitter-mediated disorder is orthostatic hypotension.

In certain embodiments, a method of treating a neurotransmitter-mediated disorder includes administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to act as: (1) inter-individual differences in plasma levels of the compound or a metabolite thereof, as compared to the corresponding non-isotopically enriched compoundDifferent; (2) increasing the mean plasma level of the compound per dosage unit or decreasing the mean plasma level of at least one metabolite of the compound per dosage unit; (3) reducing at least one cytochrome P in the subject₄₅₀Or inhibition and/or metabolism of monoamine oxidase subtypes; (4) reducing cytochrome P expression via at least one polymorphism in the subject₄₅₀Metabolism of the subtype; (5) statistically significantly improving at least one of the obstacle control and/or obstacle eradication endpoints; (6) improving clinical outcome during treatment of the disorder, (7) preventing relapse, or delaying decline or appearance of abnormal digestive or hepatic parameters, as a primary clinical benefit, or (8) reducing or eliminating deleterious changes in any diagnostic hepatobiliary function endpoint.

In certain embodiments, inter-individual variation in plasma levels of a compound or metabolite thereof as disclosed herein is reduced; the mean plasma levels of the compounds as disclosed herein are increased; the mean plasma levels of metabolites of the compounds as disclosed herein are reduced; cytochrome P pairs Compounds as disclosed herein₄₅₀Or inhibition of monoamine oxidase subtype is reduced; or a compound as disclosed herein, from at least one polymorphically expressed cytochrome P₄₅₀The metabolism of the subtype is reduced; the degree of reduction (increase) is greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or greater than about 50% compared to the corresponding non-isotopically enriched compound.

Plasma levels of a compound or metabolite thereof as disclosed herein can be measured using methods described in the following references: li (Li) et al, Mass Spectrometry in Mass Spectrometry 2005, 19, 1943-1950; huth (Hughes) et al, Xenobiotica 1992, 22(7), 859-69; walar horse (Varma) et al, Journal of drug and Biomedical Analysis (Journal of Pharmaceutical and Biomedical Analysis)2004, 36(3), 669-; massoded (Massoud) et al, journal of chromatography, B: biomedical Sciences and Applications (Journal of Chromatography, B: Biomedical Sciences and Applications)1999, 734(1), 163-167; kim et al, Journal of pharmaceutical and Biomedical Analysis 2003, 31(2), 341-349; and Lindeke et al, Proc. Natl.Sci (Acta pharmaceutical Suecica)1981, 18(1), 25-34.

Cytochrome P in a mammalian subject₄₅₀Examples of the subtypes include, but are not limited to, CYP1a1, CYP1a2, CYP1B 2, CYP2a 2, CYP2B 2, CYP2C 2, CYP2D 2, CYP2E 2, CYP2G 2, CYP2J2, CYP2R 2, CYP2S 2, CYP3A5P2, CYP3a 2, CYP4B 2, CYP4F2, CYP4X 2, CYP4Z 2, CYP5a 2, CYP7B 2, CYP8a 2, CYP8B 2, CYP1B 2, CYP11, CYP3a 2, CYP2B 2, CYP2B 2, CYP2B 2, CYP.

Examples of monoamine oxidase subtypes in mammalian subjects include, but are not limited to, MAO_AAnd MAO_B。

Cytochrome P₄₅₀The inhibition of subtypes was measured by the method of Korea (Ko) et al (British journal of Clinical Pharmacology, 2000, 49, 343- & 351). MAO_AInhibition of subtypes is measured by the method of Wehler et al (J.biol Chem., 1985, 260, 13199-13207). MAO_BInhibition of subtypes is measured by the method described in Belkhak (Uebelhack) et al (pharmacosystemy, 1998, 31, 187-192).

Cytochrome P expressed in a polymorphic manner in a mammalian subject₄₅₀Examples of subtypes include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D 6.

Liver microsome and cytochrome P₄₅₀The metabolic activity of the isoforms, as well as of the monoamine oxidase isoform, is measured by the methods described herein.

Examples of improved disorder control and/or disorder eradication endpoints, or improved clinical effects include, but are not limited to, blood pressure, mean blood pressure, systolic pressure, mean systolic pressure, supine blood pressure, mean supine blood pressure, decline in orthostatic systolic pressure, Orthostatic Hypotension Questionnaire (OHQ) score, dizziness/dizziness score, number of falls, fall-related injuries, hern (Hoehn) rating scale score, yal (Yahr) rating scale score, Visual Analog Scale (VAS) score, heart rate, forearm vascular resistance, and plasma norepinephrine concentration.

Examples of diagnostic hepatobiliary endpoints include, but are not limited to, alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST" or "SGOT"), ALT/AST ratio, serum aldolase, alkaline phosphatase ("ALP"), ammonia level, bilirubin, gamma-glutamyl transpeptidase ("GGTP", "gamma-GTP", or "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5' -nucleotidase, and blood protein. The hepatobiliary endpoints were compared to the normal levels as given in "Diagnostic and Laboratory Test Reference", 4 th edition, morsby, 1999. These assays were performed by approved laboratories according to standard protocols.

In addition to being useful for human therapy, certain compounds and formulations disclosed herein may also be useful for veterinary therapy of pets, exotic animals (exotic animals), and livestock, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

Combination therapy

The compounds disclosed herein may also be used in combination or combination with other agents useful for treating tyrosine kinase mediated disorders. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., which adjuvant alone may have minimal therapeutic benefit, but which, when combined with another therapeutic agent, brings about an enhanced overall therapeutic benefit to the patient).

Such other agents, adjuvants or drugs may be administered by the route and in amounts commonly used therefor, either simultaneously or sequentially with a compound as disclosed herein. When a compound as disclosed herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound disclosed herein may be used, but is not required.

In certain embodiments, the compounds disclosed herein may be combined with one or more compounds of structural formula I as disclosed in U.S. patent No. 7,745,665, which is hereby incorporated by reference in its entirety:

in certain embodiments, the compounds disclosed herein may be combined with a compound having a structural formula selected from the group consisting of:

and mixtures thereof. These compounds are disclosed in U.S. patent No. 8,168,820 and U.S. patent No. 8,247,603, which are hereby incorporated by reference in their entirety.

In certain embodiments, the compounds disclosed herein may be combined with a mixture of compounds having a structural formula selected from the group consisting of:

and

in certain embodiments, the compounds disclosed herein can be combined with about 90% of a compound having the structural formula:a compound of (a) and

about 10% of a compound having the formula:

a mixture of compounds of (a).

In certain embodiments, the compounds disclosed herein may be combined with one or more sympathomimetic agents selected from the group consisting of: epinephrine, norepinephrine, phenylephrine, dobutamine, dopamine, ephedrine, midodrine, and amezium (amezinium).

In certain embodiments, the compounds disclosed herein may be combined with one or more S-alkylisothiouronium (S-alkylisothiouronium) derivatives selected from the group consisting of: donut (difetur) and escitalopram (izotoron).

In certain embodiments, the compounds disclosed herein may be combined with one or more glucocorticoids selected from the group consisting of: hydrocortisone, prednisone, prednisolone, dexamethasone, and betamethasone.

In certain embodiments, the compounds disclosed herein may be combined with one or more wake-up drugs (analeptic) selected from the group consisting of: bemeterd, caffeine, camphor, and codiamine (cordiamine).

In certain embodiments, the compounds disclosed herein may be combined with one or more psychotropic drugs selected from the group consisting of: amphetamine, atomoxetine, bupropion, duloxetine, methamphetamine, methylphenidate, reboxetine, and venlafaxine.

In certain embodiments, the compounds disclosed herein may be combined with one or more inotropic agents selected from the group consisting of: cardiac glycosides, Convolvulus glycoside K, Convallaria total glycosides, digoxin, Anrinone, and Milrinone.

In certain embodiments, the compounds disclosed herein may be combined with one or more anti-hypotensive drugs selected from the group consisting of: angiotensin amine, indomethacin, olofovir, potassium chloride, and yohimbine.

In certain embodiments, the compounds disclosed herein may be combined with one or more L-aromatic amino acid decarboxylase inhibitors selected from the group consisting of: benserazide, carbidopa, methyldopa, and α -difluoromethyl-DOPA.

In certain embodiments, the compounds disclosed herein may be combined with one or more catechol-O-methyltransferase inhibitors selected from the group consisting of: entacapone, tolcapone, and nitecapone.

In certain embodiments, the compounds disclosed herein may be combined with one or more monoamine oxidase inhibitors selected from the group consisting of: isocarboxazid, isoniazid, niazid, phenelzine, tranylcypromine, moclobemide, pirlindole, toloxanone, rasagiline, and selegiline.

In certain embodiments, the compounds disclosed herein may be combined with one or more 5-HT selected from the group consisting of_2AAn inverse agonist phase, the group consisting of pimavanserin (pivalagrin).

The compounds disclosed herein may also be administered in combination with other classes of compounds including, but not limited to, Norepinephrine Reuptake Inhibitors (NRIs), such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepam; norepinephrine-dopamine reuptake inhibitors (NDRI), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRI), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin-converting enzyme (ECE) inhibitors, such as phosphoryl dipeptide; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; a potassium channel opener; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet Activating Factor (PAF) antagonists; antiplatelet agents such as GPIIb/IIIa blockers (e.g., abemumab (abdximab), eptifibatide, and tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; factor VIIa inhibitors and factor Xa inhibitors; a renin inhibitor; neutral Endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as opatra and gemotrilat; HMG CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nivastatin, or nivastatin (nisstatin)), and ZD-4522 (also known as rosuvastatin, or atorvastatin (atavastatin) or visastatin)); a squalene synthetase inhibitor; a fibrate; bile acid sequestrants, such as noble suol; nicotinic acid; anti-atherosclerotic agents, such as ACAT inhibitors; an MTP inhibitor; calcium channel blockers such as amlodipine besylate; a potassium channel activator; alpha-muscarinic agents; beta-muscarinic agents such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide, bendrothiazide, ethacrynic acid, tennic acid (tricrynafen), chlorthalidone, furosemide, musorimine (muscolimine), bumetanide, triamcinolone, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and Anisylated Plasminogen Streptokinase Activator Complex (APSAC); antidiabetic agents such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinide (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR- γ agonists; mineralocorticoid receptor antagonists such as spironolactone and eplerenone; a growth hormone secretagogue; an aP2 inhibitor; phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory agents; anti-malignant cell proliferation agents, such as methotrexate, FK506 (tacrolimus, pramipexole (Prograf)), mycophenolate mofetil; a chemotherapeutic agent; an immunosuppressant; anti-cancer and cytotoxic agents (e.g., alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethyleneimines, and triazenes); antimetabolites such as folic acid antagonists, purine analogs, and pyridine analogs; antibiotics such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule disrupting agents, such as ecteinascidins; microtubule stabilizing agents such as paclitaxel, docetaxel, and epothilones a-F; plant-derived products such as vinca alkaloids, epipodophyllotoxins, and taxanes; and a topoisomerase inhibitor; prenyl-protein transferase inhibitors; and cyclosporin; steroids, such as prednisone and dexamethasone; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-a inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptors such as etanercept, rapamycin, and leflunomide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and various agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes such as cisplatin, satraplatin, and carboplatin.

Thus, in another aspect, certain embodiments provide methods for treating a tyrosine kinase-mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject an amount of a compound disclosed herein effective to alleviate or prevent the disorder in the subject in combination with at least one additional agent known in the art for treating the disorder. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for treating tyrosine kinase-mediated disorders.

General synthetic method for preparing compounds

Isotopically hydrogen can be obtained by synthetic techniques using deuteration agents (whereby the incorporation rate is predetermined); and/or by exchange techniques (in which the rate of incorporation is determined by the equilibrium state) and can be highly variable depending on the reaction conditions. Synthetic techniques, in which tritium or deuterium is directly and specifically inserted by tritiation or deuteration reagents with known isotopic content, can result in high tritium or deuterium abundance, but can be limited by the chemistry required. On the other hand, exchange techniques can result in lower tritium or deuterium incorporation, with isotopes generally distributed over many sites in the molecule.

The compounds as disclosed herein can be prepared by methods known to those skilled in the art and their conventional modifications, and/or following procedures similar to those described in the examples section herein and their conventional modifications, and/or procedures found in EP 84928B1, EP 128684 a1, DE 19619510 a1, JP 1997249626A, WO 2011001976 a1, and WO 2013142093 a1 (which are hereby incorporated in their entirety), and references cited therein and their conventional modifications. Compounds as disclosed herein can also be prepared as shown in any of the following schemes and their conventional modifications.

The following protocol may be used to practice the present invention. Any position shown as hydrogen may optionally be replaced by deuterium.

Scheme I

Compound 1 is reacted with an appropriate protecting agent (e.g., benzyl chloride) to give compound 2. Compound 2 is treated sequentially with an appropriate chlorinating agent (e.g., thionyl chloride), an appropriate reducing agent (e.g., barium palladium sulfate in combination with hydrogen) to afford compound 3. Compound 4 was reacted with triethyl phosphate to give compound 5. Compound 3 is reacted with compound 5 in the presence of a suitable base, such as sodium hydride, to give compound 6. Compound 6 is reacted with compound 7 in the presence of a suitable base, such as potassium hydroxide, to give compound 8. Compound 8 is reacted with a suitable oxidizing agent (e.g., sodium periodate) and a suitable bromide salt (e.g., lithium bromide) to give compound 9. Compound 9 is reacted with sodium azide to give compound 10. Compound 10 is reacted with an appropriate oxazolidinone deprotecting agent (e.g., a mixture of lithium hydroxide and hydrogen peroxide) to give compound 11. Compound 11 is reacted with a suitable reducing agent, such as a combination of palladium on carbon and hydrogen, to give a compound of formula I. The hydrochloride salt of the compound of formula I may be prepared by reacting the compound of formula I with hydrochloric acid in a suitable solvent, such as a mixture of water and isopropanol.

According to the synthetic procedure as shown in scheme I, deuterium can be incorporated into different positions in the synthesis by using the appropriate deuterated intermediate. For example, to be at R₃-R₅May be used with compound 1 having the corresponding deuterium substitution. To be at R₆Deuterium may be introduced, and deuterium gas may be used. To be at R₈Where deuterium is introduced, compounds 4 with the corresponding deuterium substitution can be used.

Deuterium can pass through the protonThe equilibrium exchange of the sub-deuterium groups is carried out to incorporate into different positions having exchangeable protons (e.g., phenyl hydroxyl O-H, benzyl alcohol hydroxyl O-H, amine N-H, and carboxyl O-H). For example, to be at R₁-R₂、R₇、R₉-R₁₀And R₁₁Where deuterium is introduced, these protons may be selectively or non-selectively replaced by deuterium by proton-deuterium exchange methods known in the art.

Scheme II

Compound 12 is reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to afford compound 13. Compound 13 is treated with a suitable oxidizing agent, such as Dess-Martin oxidizer (Dess-Martin periodinane), in a suitable solvent, such as dichloromethane, to afford compound 14. Compound 14 is reacted with compound 15 in the presence of a suitable base, such as potassium hydroxide, in a suitable solvent, such as a mixture of toluene and methanol, to give compound 16. Compound 16 is reacted with an appropriate amine protecting reagent, such as N-methoxycarbonylphthalimide, in an appropriate solvent, such as water, in the presence of an appropriate base, such as sodium carbonate, followed by reaction with an appropriate acid, such as sulfuric acid, to afford compound 17. Compound 17 is reacted with a suitable chiral resolving agent, such as L-norephedrine, in a suitable solvent, such as methanol, to give the L-norephedrine salt of compound 18, which is further treated with a suitable acid, such as sulfuric acid, in a suitable solvent, such as water, to give compound 18 as the free acid. Compound 18 is reacted with an appropriate methylenedioxy deprotecting agent (e.g., a mixture of aluminum chloride and octanethiol) in an appropriate solvent (e.g., dichloromethane) to afford compound 19. Compound 19 is reacted with a suitable phthalimide deprotecting agent (e.g., a mixture of hydroxylamine hydrochloride and sodium bicarbonate) in a suitable solvent (e.g., methanol) at elevated temperature to give the compound of formula I. The hydrochloride salt of the compound of formula I may be prepared by reacting the compound of formula I with hydrochloric acid in a suitable solvent, such as a mixture of water and isopropanol.

According to the synthetic procedure as shown in scheme I, deuterium can be incorporated into different positions in the synthesis by using the appropriate deuterated intermediate. For example, to be at R₃-R₅May be used with compound 12 having the corresponding deuterium substitution. To be at R₆Where deuterium is introduced, lithium aluminum deuteride may be used. To be at R₈Where deuterium is introduced, compounds 15 with corresponding deuterium substitution may be used.

Deuterium can be incorporated into different positions with exchangeable protons (e.g., phenyl hydroxyl O-H, benzyl alcohol hydroxyl O-H, amine N-H, and carboxyl O-H) via proton-deuterium equilibrium exchange. For example, to be at R₁-R₂、R₇、R₉-R₁₀And R₁₁Where deuterium is introduced, these protons may be selectively or non-selectively replaced by deuterium by proton-deuterium exchange methods known in the art.

The following compounds can generally be prepared using the methods described above. It is expected that these compounds, when made, will have activities similar to those described in the examples above.

The following assays can be used to show changes in the metabolic properties of the compounds disclosed herein, as compared to their non-isotopically enriched analogs. The compounds listed above that have not been prepared and/or tested are also predicted to have altered metabolic properties as shown by one or more of these assays.

Biological activity assay

After intravenous administration of 2mg/kg L-threo-2, 3-dideuterio-DOPS, compared to the same dose of L-threo-DOPS, changes in mean arterial pressure in anesthetized rats

Administration of L-threo-2, 3-dideuterodops resulted in an enhanced and prolonged increase in mean arterial pressure.

In vitro liver microsome stability assay

Liver microsome stability assay at 1mg/mL liver microsome protein along with NADPH production System at 2% NaHCO₃(2.2mM NADPH, 25.6mM glucose-6-phosphate, 6 units glucose 6-phosphate dehydrogenase per mL and 3.3mM MgCl₂) Is carried out in (1). Test compounds were prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay concentration 5 micrograms/mL) and incubated at 37 ℃. The final concentration of acetonitrile in the assay should be<1 percent. Aliquots (50 μ L) were removed at times 0, 15, 30, 45 and 60min and diluted with ice-cold acetonitrile (200 μ L) to terminate the reaction. The sample was centrifuged at 12,000RPM for 10min to precipitate the protein. The supernatant was transferred to a microcentrifuge tube and stored for LC/MS analysis of the degradation half-life of the test compound.

In vitro monoamine oxidase A degradation assay

Noradrenaline and d₆Norepinephrine with monoamine oxidase-A (MAO-A).

The appearance of 3, 4-dihydroxyphenylethanolaldehyde and the disappearance of norepinephrine are followed. Compared to non-deuterated norepinephrine, d₆Norepinephrine is associated with about A5-fold reduction in degradation by MAO-A and about A75% reduction in 3, 4-dihydroxyphenylethanolaldehyde production.

The assay was a batch alumina extraction followed by liquid chromatography using electrochemical detection. The post-column (post-column) electrodes are arranged in series with the oxidation potential at the first electrode and the reduction potential at the third electrode. This series arrangement of flow-through electrodes greatly reduces the solvent front and improves the sensitivity and specificity of detecting reversibly oxidized species such as catechol. 3, 4-dihydroxyphenylethanolaldehyde is identified by a broad short peak within the solvent front.

₄₅₀In vitro metabolism using human cytochrome P enzymes

Cytochrome P₄₅₀The enzymes were expressed from the corresponding human cdnas using a baculovirus expression system (BD Biosciences, San Jose, CA). 0.25 ml of a reaction mixture comprising: 0.8 mg/ml protein, 1.3 mmol NADP⁺3.3 mmoles of glucose-6-phosphate, 0.4U/mL of glucose-6-phosphate dehydrogenase, 3.3 mmoles of magnesium chloride and 0.2 mmoles of the compound of formula I, the corresponding non-isotopically enriched compound or standard or control, in 100 mmoles of potassium phosphate (pH 7.4). After incubation, the reaction is stopped by adding an appropriate solvent (e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000g) for 3 min. The supernatant was analyzed by HPLC/MS/MS.

Monoamine oxidase A inhibition and oxidative Turnover (Turnover)

The procedure was carried out using the method described by Weyler (Weyler), Journal of Biochemistry (Journal of Biologic chemistry)1985, 260, 13199-. Monoamine oxidase a activity was measured spectrophotometrically by monitoring the increase in absorbance at 314nm of the oxidation of kynuramine to form 4-hydroxyquinoline. These measurements were carried out at 30 ℃ in 50mM NaP_iBuffer (pH 7.2) containing 0.2% Triton X-100 (monoamine oxidase assay buffer) was supplemented with 1mM kynuramine, and the required amount of enzyme in a total volume of 1 mL.

Monoamine oxidase B inhibition and oxidative turnover

The procedure was carried out as described in Belkhak (Uebelhack), pharmacoscopical (Pharmacopesychiatry) 1998, 31(5), 187-.

In vitro rat CNS extracellular norepinephrine production

The procedure was carried out as described in weinhag root-camembeck (Verhagen-Kamerbeek), et al, in Vivo Methods international conference monitoring molecular neuroscience progress (unit. mol. neurosci., proc. int. conf. in Vivo Methods), 5 th edition, 1991, 373-6, which is hereby incorporated by reference in its entirety.

Endogenous norepinephrine release from presynaptic receptors in rat hypothalamic sheets

The procedure was carried out as described in Yue (Yue), et al, J.Pharmacy and Pharmacol, (J.Pharmacy and Pharmacol.), 1992, 44(12), 990-5, which is hereby incorporated by reference in its entirety.

Hemodynamics and renal alterations in portal hypertension rats

The procedure was performed as described in korman (Coll Mar) et al, Hepatology (Hepatology) (baltimol, maryland), 2012, 56(5), 1849-60, which is hereby incorporated by reference in its entirety.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (40)

1. A compound, which is:

or a pharmaceutically acceptable salt thereof, wherein each position represented by D has deuterium enrichment of no less than 10%.

2. The compound as recited in claim 1, wherein said compound is not carbon-13 rich.

3. The compound as recited in claim 1 wherein each position represented by D has deuterium enrichment of no less than 50%.

4. The compound as recited in claim 1 wherein each position represented by D has deuterium enrichment of no less than 90%.

5. The compound as recited in claim 1 wherein each position represented by D has deuterium enrichment of no less than 98%.

6. The compound as recited in claim 1 wherein said compound has the following structural formula:

7. the compound as recited in claim 1 wherein said compound has the following structural formula:

8. the compound as recited in claim 1 wherein said compound has the following structural formula:

9. a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a compound of claim 1.

10. Use of a compound according to any preceding claim in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by the modulation of neurotransmitter levels.

11. The use as claimed in claim 10, wherein said disorder is selected from the group consisting of: hypotension, Rapid Eye Movement (REM) behavioral disorders, chronic heart failure, stress-related disorders, movement or speech disturbances, stroke, cerebral ischemia, nasal congestion, mood disorders, Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), familial autonomic abnormalities, diabetic autonomic neuropathy, amyloidosis in the context of multiple myeloma, dopamine beta-hydroxylase deficiency, pain, progressive supranuclear palsy, autonomic nervous dysfunction, juvenile upright intolerance, neuropsychotic syncope, postural tachycardia syndrome (POTS), fatigue, sleep disorders, depression, childhood developmental disorders, genetic diseases involving decreased norepinephrine synthesis or action, regulated multiple system disorders, neurodegenerative diseases, cognitive dysfunction, olfactory disorders, neuroendocrine disorders, and autoimmune disorders.

12. The use as claimed in claim 11, wherein said disorder is selected from the group consisting of: neurogenic orthostatic hypotension associated with Multiple System Atrophy (MSA), orthostatic hypotension associated with the schei-delger syndrome, neurogenic orthostatic hypotension associated with Familial Amyloid Polyneuropathy (FAP), neurogenic orthostatic hypotension associated with simple autonomic failure (PAF), idiopathic orthostatic hypotension, non-sympathetic anaphylactic hypotension, neurogenic orthostatic hypotension associated with parkinson's disease, intradialytic hypotension (IDH), hypotension associated with fibromyalgia syndrome (FMS), hypotension in spinal cord injury, and hypotension associated with Chronic Fatigue Syndrome (CFS).

13. The use as claimed in claim 11, wherein the intradialytic hypotension (IDH) is hemodialysis-induced hypotension.

14. The use as claimed in claim 11, wherein the disorder is orthostatic hypotension.

15. The use as claimed in claim 10, wherein said disorder is selected from the group consisting of: dopamine-beta-hydroxylase deficiency, Menkes 'disease, vitamin C deficiency, Lewy body disease, Parkinson's disease, Lewy body dementia, simple autonomic failure, familial autonomic abnormalities, bilateral endoscopic post-thoracic sympathotomy status, intolerance to orthostatic, and orthostatic hypotension.

16. The use as claimed in claim 11, wherein said disorder is selected from the group consisting of: neurogenic orthostatic hypotension, chronic pain, sleep disorders, narcolepsy, insomnia, hyposmia, Mild Cognitive Impairment (MCI), down syndrome, alzheimer's disease, autoimmune autonomic failure, preprandial hypotension, lisi-on syndrome, parkinson's disease associated autonomic abnormalities, vasovagal, and chronic orthostatic intolerance.

17. The use as claimed in claim 11, wherein said disorder is selected from the group consisting of: symptomatic neurogenic orthostatic hypotension, abnormal postural reflexes due to parkinson's disease, fibromyalgia, allodynia, and hyperalgesia.

18. The use as claimed in claim 10, further comprising an additional therapeutic agent.

19. As set forth in claim 18Wherein the additional therapeutic agent is selected from the group consisting of: sympathomimetic agents, S-alkylisothiouronium derivatives, glucocorticoids, revitalizing agents, psychotropic agents, inotropic agents, hypotensive agents, L-aromatic amino acid decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, and 5-HT_2AAn inverse agonist.

20. The use as claimed in claim 19, wherein said sympathomimetic agent is selected from the group consisting of: epinephrine, norepinephrine, phenylephrine, dobutamine, dopamine, ephedrine, midodrine, and ameziam.

21. The use as claimed in claim 19, wherein the S-alkylisothiouronium derivative is selected from the group consisting of: donut tuer and escitalopram.

22. The use as claimed in claim 19, wherein the glucocorticoid is selected from the group consisting of: hydrocortisone, prednisone, prednisolone, dexamethasone, and betamethasone.

23. The use as claimed in claim 19, wherein said wake-up drug is selected from the group consisting of: bemetger, caffeine, camphor, and codiamine.

24. The use as claimed in claim 19, wherein said psychotropic drug is selected from the group consisting of: amphetamine, atomoxetine, bupropion, duloxetine, methamphetamine, methylphenidate, reboxetine, and venlafaxine.

25. The use as claimed in claim 19, wherein said inotropic drug is selected from the group consisting of: cardiac glycosides, Convolvulus glycoside K, Convallaria total glycosides, digoxin, Anrinone, and Milrinone.

26. The use as claimed in claim 19, wherein said L-aromatic amino acid decarboxylase inhibitor is selected from the group consisting of: benserazide, carbidopa, methyldopa, and α -difluoromethyl-DOPA.

27. The use as claimed in claim 19, wherein the catechol-O-methyltransferase inhibitor is selected from the group consisting of: entacapone, tolcapone, and nitecapone.

28. The use as claimed in claim 19, wherein said monoamine oxidase inhibitor is selected from the group consisting of: isocarboxazid, isoniazid, niazid, phenelzine, tranylcypromine, moclobemide, pirlindole, toloxanone, rasagiline, and selegiline.

29. The use as claimed in claim 19, wherein the 5-HT_2AThe inverse agonist is pimavanserin.

30. The use as claimed in claim 19, wherein the additional therapeutic agent is a compound having a structural formula selected from the group consisting of:

and mixtures thereof.

31. The use as claimed in claim 19, wherein the additional therapeutic agent is a mixture of compounds having a structural formula selected from the group consisting of:

32. the use as in claim 19, wherein the additional therapeutic agent is 90% of a compound having the structural formula:

of and

10% of a compound having the formula:

a mixture of compounds of (a).

33. The use as claimed in claim 10, further resulting in at least one effect selected from the group consisting of:

a. (ii) inter-individual variation in plasma levels of the compound or a metabolite thereof, as compared to the non-isotopically enriched compound;

b. increasing the mean plasma level of the compound per dosage unit as compared to the non-isotopically enriched compound;

c. reducing the mean plasma level of at least one metabolite of said compound per dosage unit as compared to the non-isotopically enriched compound;

d. increasing the mean plasma level of at least one metabolite of said compound per dosage unit as compared to the non-isotopically enriched compound; and

e. improving the clinical effect of each dosage unit of the compound during treatment of the subject compared to the non-isotopically enriched compound.

34. The use as claimed in claim 10, further resulting in at least two effects selected from the group consisting of:

a. (ii) inter-individual variation in plasma levels of the compound or a metabolite thereof, as compared to the non-isotopically enriched compound;

b. increasing the mean plasma level of the compound per dosage unit as compared to the non-isotopically enriched compound;

c. reducing the mean plasma level of at least one metabolite of said compound per dosage unit as compared to the non-isotopically enriched compound;

d. increasing the mean plasma level of at least one metabolite of said compound per dosage unit as compared to the non-isotopically enriched compound; and

e. improving the clinical effect of each dosage unit of the compound during treatment of the subject compared to the non-isotopically enriched compound.

35. The use as claimed in claim 10, wherein the compound is characterized by a reduction of the cytochrome P of the compound expressed in a polymorphic manner by at least one of the subjects per dosage unit as compared to the corresponding non-isotopically enriched compound₄₅₀Metabolism of the subtype.

36. The use as claimed in claim 35, wherein the cytochrome P₄₅₀The subtype is selected from the group consisting of: CYP2C8, CYP2C9, CYP2C19, and CYP2D 6.

37. The use of claim 10, wherein the compound is characterized by a reduction in at least one cytochrome P in the subject per dosage unit of the compound as compared to the non-isotopically enriched compound₄₅₀Inhibition of subtype or monoamine oxidase subtype.

38. The use as claimed in claim 37, wherein the cytochrome P is₄₅₀Or a monoamine oxidase subtype selected from the group consisting of: CYP1A1, CYP1A2, CYP1B1、CYP2A6、CYP2A13、CYP2B6、CYP2C8、CYP2C9、CYP2C18、CYP2C19、CYP2D6、CYP2E1、CYP2G1、CYP2J2、CYP2R1、CYP2S1、CYP3A4、CYP3A5、CYP3A5P1、CYP3A5P2、CYP3A7、CYP4A11、CYP4B1、CYP4F2、CYP4F3、CYP4F8、CYP4F11、CYP4F12、CYP4X1、CYP4Z1、CYP5A1、CYP7A1、CYP7B1、CYP8A1、CYP8B1、CYP11A1、CYP11B1、CYP11B2、CYP17、CYP19、CYP21、CYP24、CYP26A1、CYP26B1、CYP27A1、CYP27B1、CYP39、CYP46、CYP51、MAO_AAnd MAO_B。

39. The use as claimed in claim 10, wherein the compound is characterized by a reduction in diagnostic adverse changes in hepatobiliary function endpoints compared to the corresponding non-isotopically enriched compound.

40. The use as recited in claim 39, wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of: alanine aminotransferase ("ALT"), serum glutamic pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST", "SGOT"), ALT/AST ratio, serum aldolase, alkaline phosphatase ("ALP"), ammonia level, bilirubin, gamma-glutamyl transpeptidase ("GGTP", "gamma-GTP", "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5' -nucleotidase, and blood protein.