DIHYDROXYPHENYL NEUROTRANSMITTER COMPOUNDS, COMPOSITIONS AND METHODS

Abstract

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

##STR00001##

Claims

1. A compound of structural Formula I: ##STR00040## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1-R.sub.2 are independently selected from the group consisting of hydrogen, deuterium, methyl, perdeuteromethyl, ethyl, perdeuteroethyl, propyl, perdeuteropropyl, butyl, perdeuterobutyl, C.sub.1-C.sub.6-alkyl, and C.sub.5-C.sub.6-cycloalkyl, wherein said C.sub.1-C.sub.6-alkyl and C.sub.5-C.sub.6-cycloalkyl may be optionally substituted with deuterium; R.sub.3-R.sub.8 are independently selected from the group consisting of hydrogen and deuterium; R.sub.9-R.sub.11 are independently selected from the group consisting of hydrogen, deuterium, methyl, perdeuteromethyl, ethyl, perdeuteroethyl, propyl, perdeuteropropyl, butyl, perdeuterobutyl, C.sub.1-C.sub.6-alkyl, and C.sub.5-C.sub.6-cycloalkyl, wherein said C.sub.1-C.sub.6-alkyl and C.sub.5-C.sub.6-cycloalkyl may be optionally substituted with deuterium; and at least one of R.sub.3-R.sub.6 and R.sub.8 is deuterium.

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

3. The compound as recited in claim 1 wherein said compound has a structural formula selected from the group consisting of: ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064##

4. The compound as recited in claim 3 wherein each position represented as D has deuterium enrichment of no less than about 10%.

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

6. The compound as recited in claim 3 wherein each position represented as D has deuterium enrichment of no less than about 90%.

7. The compound as recited in claim 3 wherein each position represented as D has deuterium enrichment of no less than about 98%.

8. The compound as recited in claim 3 wherein said compound has a structural formula selected from the group consisting of: ##STR00065##

9. The compound as recited in claim 8 wherein said compound has the structural formula: ##STR00066##

10. The compound as recited in claim 8 wherein said compound has the structural formula: ##STR00067##

11. The compound as recited in claim 8 wherein said compound has the structural formula: ##STR00068##

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier together with a compound of structural Formula I: ##STR00069## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1-R.sub.2 are independently selected from the group consisting of hydrogen, deuterium, methyl, perdeuteromethyl, ethyl, perdeuteroethyl, propyl, perdeuteropropyl, butyl, perdeuterobutyl, C.sub.1-C.sub.6-alkyl, and C.sub.5-C.sub.6-cycloalkyl, wherein said C.sub.1-C.sub.6-alkyl and C.sub.5-C.sub.6-cycloalkyl may be optionally substituted with deuterium; R.sub.3-R.sub.8 are independently selected from the group consisting of hydrogen and deuterium; R.sub.9-R.sub.11 are independently selected from the group consisting of hydrogen, deuterium, methyl, perdeuteromethyl, ethyl, perdeuteroethyl, propyl, perdeuteropropyl, butyl, perdeuterobutyl, C.sub.1-C.sub.6-alkyl, and C.sub.5-C.sub.6-cycloalkyl, wherein said C.sub.1-C.sub.6-alkyl and C.sub.5-C.sub.6-cycloalkyl may be optionally substituted with deuterium; and at least one of R.sub.3-R.sub.6 and R.sub.8 is deuterium.

13. A method of treatment of a neurotransmitter-mediated disorder comprising the administration of a therapeutically effective amount of a compound of structural Formula I: ##STR00070## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1-R.sub.2 are independently selected from the group consisting of hydrogen, deuterium, methyl, perdeuteromethyl, ethyl, perdeuteroethyl, propyl, perdeuteropropyl, butyl, perdeuterobutyl, C.sub.1-C.sub.6-alkyl, and C.sub.5-C.sub.6-cycloalkyl, wherein said C.sub.1-C.sub.6-alkyl and C.sub.5-C.sub.6-cycloalkyl may be optionally substituted with deuterium; R.sub.3-R.sub.8 are independently selected from the group consisting of hydrogen and deuterium; R.sub.9-R.sub.11 are independently selected from the group consisting of hydrogen, deuterium, methyl, perdeuteromethyl, ethyl, perdeuteroethyl, propyl, perdeuteropropyl, butyl, perdeuterobutyl, C.sub.1-C.sub.6-alkyl, and C.sub.5-C.sub.6-cycloalkyl, wherein said C.sub.1-C.sub.6-alkyl and C.sub.5-C.sub.6-cycloalkyl may be optionally substituted with deuterium; and at least one of R.sub.3-R.sub.6 and R.sub.8 is deuterium.

14. The method as recited in claim 13 wherein said disorder is selected from the group consisting of hypotension, orthostatic hypotension, neurogenic orthostatic hypotension, symptomatic neurogenic orthostatic hypotension, neurogenic orthostatic hypotension associated with multiple system atrophy (MSA), orthostatic hypotension associated with Shy-Drager syndrome, neurogenic orthostatic hypotension associated with familial amyloid polyneuropathy (FAP), neurogenic orthostatic hypotension associated with pure autonomic failure (PAF), idiopathic orthostatic hypotension, asympathicotonic 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, Lewy body dementia, rapid eye movement (REM) behavior disorder, chronic heart failure, stress-related disorders, motor or speech disturbances, chronic pain, stroke, cerebral ischemia, nasal congestion, mood disorders, sleep disorders, narcolepsy, insomnia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), anosmia, hyposmia, mild cognitive impairment (MCI), Down syndrome, Alzheimer's disease, postural reflex abnormality caused by Parkinson's disease, autoimmune autonomic failure, familial dysautonomia, diabetic autonomic neuropathy, amyloidosis in the setting of multiple myeloma, Parkinson's disease, proprandial hypotension, dopamine beta-hydroxylase deficiency, pain, progressive supranuclear palsy, Menkes disease, familial dysautonomia (Riley-Day Syndrome), PD-related dysautonomia (autonomic dysfunction), orthostatic intolerance in adolescents, neurocardiogenic syncope (vasovagal), postural orthostatic tachycardia syndrome (POTS), fibromyalgia, allodynia, hyperalgesia, fatigue, sleep disturbance, depression, chronic orthostatic intolerance, pediatric developmental disorders, genetic diseases involving decreased norepinephrine synthesis or effects, multi-system disorders of regulation, pain, neurodegenerative diseases, cognitive dysfunction, olfactory disorders, neuroendocrine disorders, and autoimmune disorders.

15. The method as recited in claim 14 wherein said disorder is selected from the group consisting of orthostatic hypotension, neurogenic orthostatic hypotension associated with multiple system atrophy (MSA), orthostatic hypotension associated with Shy-Drager syndrome, neurogenic orthostatic hypotension associated with familial amyloid polyneuropathy (FAP), neurogenic orthostatic hypotension associated with pure autonomic failure (PAF), idiopathic orthostatic hypotension, asympathicotonic 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).

16. The method as recited in claim 14 wherein said disorder is orthostatic hypotension.

17. The method as recited in claim 13 wherein said disorder is selected from the group consisting of dopamine-beta-hydroxylase deficiency, Menkes disease, lack of vitamin C, Lewy body diseases, Parkinson's disease, Lewy body dementia, pure autonomic failure, familial dysautonomia, status-post bilateral endoscopic thoracic sympathectomy, orthostatic intolerance, and orthostatic hypotension.

18. The method as recited in claim 13 further comprising the administration of an additional therapeutic agent.

19. The method as recited in claim 18 wherein said additional therapeutic agent is selected from the group consisting of sympathomimetic agents, S-alkylisothiouronium derivatives, glucocorticoids, analeptics, psychotropics, positive inotropic agents, antihypotensive agents, L-aromatic-amino acid decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, and 5-HT.sub.2A inverse agonist.

20. The method as recited in claim 13, further resulting in at least one effect selected from the group consisting of: a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound; b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

21. The method as recited in claim 13, wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P.sub.450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound.

22. The method as recited in claim 21, wherein the cytochrome P.sub.450 isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

23. The method as recited claim 13, wherein said compound is characterized by decreased inhibition of at least one cytochrome P.sub.450 or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

24. The method as recited in claim 23, wherein said cytochrome P.sub.450 or monoamine oxidase isoform is 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.sub.A, and MAO.sub.B.

25. The method as recited in claim 13, wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

26. The method as recited in claim 25, 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 ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein.

Description

BIOLOGICAL ACTIVITY ASSAYS

[0205] Change of Mean Arterial Blood Pressure in Anesthetized Rats Following Intravenous Administration of 2 mg/kg L-Threo-2,3-Dideutero DOPS in Comparison to the Same Dose of L-Threo-DOPS

[0206] The administration of L-threo-2,3-dideutero DOPS leads to an enhanced and prolonged increase of the mean arterial blood pressure.

In Vitro Liver Microsomal Stability Assay

[0207] Liver microsomal stability assays are conducted at 1 mg per mL liver microsome protein with an NADPH-generating system in 2% NaHCO.sub.3 (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM MgCl.sub.2). Test compounds are prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay concentration 5 microgram per mL) and incubated at 37° C. Final concentration of acetonitrile in the assay should be <1%. Aliquots (50 μL) are taken out at times 0, 15, 30, 45, and 60 min, and diluted with ice cold acetonitrile (200 μL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 min to precipitate proteins. Supernatants are transferred to microcentrifuge tubes and stored for LC/MS/MS analysis of the degradation half-life of the test compounds.

In Vitro Monoamine Oxidase a Degradation Assay

[0208] Norepinephrine and d.sub.6-norepinephrine were incubated with monoamine oxidase-A (MAO-A).

##STR00039##

The appearance of 3,4-dihydroxyphenylglycolaldehyde and the disappearance of norepinephrine were tracked. Compared to non-deuterated norepinephrine, d.sub.6-norepinephrine was associated with about a 5-fold decrease in digestion by MAO-A and about a 75% decrease in 3,4-dihydroxyphenylglycolaldehyde production.

[0209] The assay method is a batch alumina extraction followed by liquid chromatography with electrochemical detection. The post-column electrodes are arranged in series, with an oxidizing potential at the first electrode and reducing potential at the third. This series arrangement of flow-through electrodes reduces the solvent front substantially and improves the sensitivity and specificity for detecting reversibly oxidized species such as catechols. 3,4-Dihydroxyphenylglycolaldehyde is identified by a broad, short peak within the solvent front.

In Vitro Metabolism Using Human Cytochrome P.SUB.450 .Enzymes

[0210] The cytochrome P.sub.450 enzymes are expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, Calif.). A 0.25 milliliter reaction mixture containing 0.8 milligrams per milliliter protein, 1.3 millimolar NADP.sup.+, 3.3 millimolar glucose-6-phosphate, 0.4 U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound of Formula I, the corresponding non-isotopically enriched compound or standard or control in 100 millimolar potassium phosphate (pH 7.4) is incubated at 37° C. for 20 min. After incubation, the reaction is stopped by the addition of 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 (10,000 g) for 3 min. The supernatant is analyzed by HPLC/MS/MS.

TABLE-US-00001 Cytochrome P.sub.450 Standard CYP1A2 Phenacetin CYP2A6 Coumarin CYP2B6 [.sup.13C]-(S)-mephenytoin CYP2C8 Paclitaxel CYP2C9 Diclofenac CYP2C19 [.sup.13C]-(S)-mephenytoin CYP2D6 (+/−)-Bufuralol CYP2E1 Chlorzoxazone CYP3A4 Testosterone CYP4A [.sup.13C]-Lauric acid

Monoamine Oxidase A Inhibition and Oxidative Turnover

[0211] The procedure is carried out using the methods described by Weyler, Journal of Biological Chemistry 1985, 260, 13199-13207, which is hereby incorporated by reference in its entirety. Monoamine oxidase A activity is measured spectrophotometrically by monitoring the increase in absorbance at 314 nm on oxidation of kynuramine with formation of 4-hydroxyquinoline. The measurements are carried out, at 30° C., in 50 mM NaP.sub.i buffer, pH 7.2, containing 0.2% Triton X-100 (monoamine oxidase assay buffer), plus 1 mM kynuramine, and the desired amount of enzyme in 1 mL total volume.

Monooamine Oxidase B Inhibition and Oxidative Turnover

[0212] The procedure is carried out as described in Uebelhack, Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby incorporated by reference in its entirety.

In Vitro Rat CNS Extracellular Norepinephrine Production

[0213] The procedure is carried out as described in Verhagen-Kamerbeek et al., Monit. Mol. Neurosci., Proc. Int. Conf. In Vivo Methods, 5th, 1991, 373-6, which is hereby incorporated by reference in its entirety.

Endogenous Norepinephrine Release from Presynaptic Receptors in Rat Hypothalamic Slices

[0214] The procedure is carried out as described in Yue et al., J. Pharmacy and Pharmacol., 1992, 44(12), 990-5, which is hereby incorporated by reference in its entirety.

Hemodynamic and Renal Alterations of Portal Hypertensive Rats

[0215] The procedure is carried out as described in Coll Mar et al., Hepatology (Baltimore, Md.), 2012, 56(5), 1849-60, which is hereby incorporated by reference in its entirety.

[0216] 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.