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  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
  • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
  • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
  • C07C211/60—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton containing a ring other than a six-membered aromatic ring forming part of at least one of the condensed ring systems
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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  • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
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  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/001—Acyclic or carbocyclic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

• R-PAI R (+) -N-propargyl-l-aminoindan
• Rasagiline mesylate in a 1 mg tablet is commercially available for the treatment of idiopathic Parkinson's disease as AZILECT ® from Teva Pharmaceuticals Industries Ltd. (Petach Tikva, Israel) and H. Lundbeck A/S (Copenhagen, Denmark).
• the subject invention provides a deuterium enriched compound having the structure:
• R 1 -R3 are independently H or D, and wherein at least one of R 1 -R 3 is deuterium enriched.
• the subject invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the deuterium enriched compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the subject invention further provides a mixture of at least two different deuterium enriched compounds, each compound having the structure:
• R 1 -R 3 are independently H or deuterium enriched.
• the subject invention yet further provides a pharmaceutical composition comprising the mixture described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the subject invention yet further provides a method of treating a neurodegenerative disorder in a subject in need thereof, the method comprising periodically administering to the subject in need a therapeutically effective amount of a dosage form comprising as an active ingredient the deuterium enriched compound described herein, or a pharmaceutically acceptable salt thereof, thereby to effectively treat the subj ect .
• the subject invention yet further provides a method of reducing the rate of progression of Parkinson's disease in an early stage Parkinson's disease patient, the method comprising periodically administering to an early stage Parkinson's disease patient an amount of the deuterium enriched compound described herein, or a pharmaceutically acceptable salt thereof, effective to reduce the rate of progression of Parkinson's disease of the early stage Parkinson's disease patient .
• the subject invention yet further provides a process for the preparation of a deuterium enriched compound having the structure :
• R x is D and R2 and R3 are independently H or D,
• the subject invention provides a deuterium enriched compound having the structure:
• R 1 -R 3 are independently H or D, and wherein at least one of R 1 -R 3 is deuterium enriched.
• Ri is deuterium enriched, and each of R 2 and R 3 is H. In another embodiment of the deuterium enriched compound or a pharmaceutically acceptable salt thereof, Ri is H, and each of R 2 and R 3 is deuterium enriched.
• each of Ri, R 2 and R 3 is deuterium enriched.
• the at least one of R 1 -R 3 is deuterium enriched to have an isotopic purity of at least 10%.
• the at least one of R 1 -R 3 is deuterium enriched to have an isotopic purity of at least 50%.
• the at least one of R 1 -R 3 is deuterium enriched to have an isotopic purity of at least 70%.
• the at least one of R 1 -R 3 is deuterium enriched to have an isotopic purity of at least 90%.
• the at least one of R 1 -R 3 is deuterium enriched to have an isotopic purity of at least 95%.
• the compound in the form of free base.
• the compound in the form of a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of citrate, mesylate, maleate, malate, fumarate, tannate, tartrate, esylate, p- toluenesulfonate, benzoate, acetate, phosphate, oxalate and sulfate salts.
• the compound in the form of a mesylate salt or a citrate salt .
• the subject invention also provides a pharmaceutical composition comprising the deuterium enriched compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the subject invention further provides a mixture of at least two different deuterium enriched compounds, each compound having the structure:
• R1-R3 are independently H or deuterium enriched.
• R1-R3 are independently H or deuterium enriched.
• At least one of the at least two deuterium en nds has the structure:
• At least one of the at least two deuterium ounds has the structure:
• the subject invention yet further provides a pharmaceutical composition
• a pharmaceutical composition comprising the mixture described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the subject invention yet further provides a method of treating a neurodegenerative disorder in a subject in need thereof, the method comprising periodically administering to the subject in need a therapeutically effective amount of a dosage form comprising as an active ingredient the deuterium enriched compound described herein, or a pharmaceutically acceptable salt thereof, thereby to effectively treat the subj ect .
• the therapeutically effective amount of the base form of the deuterium enriched compound is 0.2-2.5 mg per day.
• the therapeutically effective amount of the base form of the deuterium enriched compound is 0.5 mg per day.
• the therapeutically effective amount of the base form of the deuterium enriched compound is 1 mg per day. In yet another embodiment of the method, the therapeutically effective amount of the base form of the deuterium enriched compound is 2 mg per day.
• the dosage form is an oral dosage form.
• the dosage form is a transdermal patch.
• the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Restless Legs Syndrome, Multiple System Atrophy, Progressive Supranuclear Palsy, Glaucoma, Macular
• the neurodegenerative disorder is Parkinson's disease.
• the subject invention yet further provides a method of reducing the rate of progression of Parkinson's disease in an early stage Parkinson's disease patient, the method comprising periodically administering to an early stage Parkinson's disease patient an amount of the deuterium enriched compound described herein, or a pharmaceutically acceptable salt thereof, effective to reduce the rate of progression of Parkinson's disease of the early stage Parkinson's disease patient.
• the subject invention yet further provides a process for the preparation of a deuterium enriched compound having the structure :
• R x is D and ]3 ⁇ 4 and R3 are independently H or D,
• step f) separating the racemic N-propargyl aminoindan using a chiral separation method to obtain the compound.
• the solvent is diethyl ether.
• step b) comprises steps of:
• each of the first solvent and second solvent is DCM and the third solvent is DMF.
• the organic is 2-mercaptoacetic acid.
• step b) comprises steps of:
• each of the first and third solvent is THF and the second solvent is MeOH.
• step ii) the catalyst is Pd/C.
• the chiral separation method is SFC or chiral preparative HPLC in combination with SFC.
• the subject invention yet further provides a process for the preparation of a compound having the structure:
• Ri is H and R 2 and R 3 are independently H or D, and wherein at least one of R 2 and R 3 is deuterium enriched,
• step b) the base is solid KOH.
• each of the first and second solvent is ethyl ether and the third solvent is THF.
• Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen atom in a compound naturally occurs as a mixture of the isotopes 1H (hydrogen or protium) , D (2H or deuterium) , and T (3H or tritium) . The natural abundance of deuterium is 0.0156%. Thus, a compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156%, is novel over its non- enriched counterpart.
• a “deuterium-enriched” compound means that the abundance of deuterium at any relevant site of the compound is more than the abundance of deuterium naturally occurring at that site in an amount of the compound.
• a relevant site in a compound as used above is a site which would be designated as "H” in a chemical structure representation of the compound when not deuterium-enriched.
• Naturally occurring as used above refers to the abundance of deuterium which would be present at a relevant site in a compound if the compound was prepared without any affirmative step to enrich the abundance of deuterium.
• a characteristic of a compound refers to any quality that a compound exhibits, e.g., peaks or retention times, as determined by 1H nuclear magnetic spectroscopy, mass spectroscopy, infrared, ultraviolet or fluorescence spectrophotometry, gas chromatography, thin layer chromatography, high performance liquid chromatography, elemental analysis, Ames test, dissolution, stability and any other quality that can be determined by an analytical method.
• the information can be used to, for example, screen or test for the presence of the compound in a sample.
• a “pharmaceutically acceptable” carrier or excipient is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
• a “pharmaceutically acceptable salt” of rasagiline, as well as of the deuterated compounds herein, includes citrate, mesylate, maleate, malate, fumarate, tannate, tartrate, esylate, p-toluenesulfonate, benzoate, acetate, phosphate, oxalate and sulfate salts.
• the free base can be reacted with the desired acids in the presence of a suitable solvent by conventional methods.
• drug substance refers to the active ingredient in a drug product, which provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.
• drug product refers to the finished dosage form containing the drug substance as well as at least one pharmaceutically acceptable carrier.
• an "isolated" compound is a compound separated by an affirmative act from the crude reaction mixture in which the compound was first formed. The separation of the compound is from the other known components of the crude reaction mixture, with some impurities, unknown side products and residual amounts of the other known components of the crude reaction mixture permitted to remain. Purification is an example of an affirmative act of isolation.
• a composition that is "free" of a chemical entity means that the composition contains, if at all, an amount of the chemical entity which cannot be avoided following an affirmative act intended to eliminate the presence of chemical entity in the composition.
• stability testing refers to tests conducted at specific time intervals and various environmental conditions (e.g., temperature and humidity) to see if and to what extent a drug product degrades over its designated shelf life time.
• the specific conditions and time of the tests are such that they accelerate the conditions the drug product is expected to encounter over its shelf life.
• detailed requirements of stability testing for finished pharmaceuticals are codified in 21 C.F.R ⁇ 211.166, the entire content of which is hereby incorporated by reference.
• a "neurodegenerative disorder” is a disorder in which progressive loss of neurons occurs either in the peripheral nervous system or in the central nervous system.
• Non-limiting examples of neurodegenerative disorders include Parkinson's disease, Restless Legs Syndrome, Multiple System Atrophy (MSA) , Progressive Supranuclear Palsy (PSP) , Glaucoma, Macular Degeneration, Hearing loss, Retinitis Pigmentosa, and Olfactory Dysfunction.
• a dosage unit may comprise a single compound or mixtures of compounds thereof.
• a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, and granules .
• R(+)PAI or deuterated compounds (deuterated R(+)PAI) disclosed herein may be obtained by optical resolution of racemic mixtures of R and S-enantiomer of N-propargyl-l-aminoindan (PAI) .
• Such a resolution can be accomplished by any conventional resolution method, well known to a person skilled in the art, such as those described in "Enantiomers , Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, N.Y., 1981.
• the resolution may be carried out by preparative chromatography on a chiral column.
• Another example of a suitable resolution method is the formation of diastereomeric salts with a chiral acid such as tartaric, malic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine, followed by recrystallisation to isolate the diastereomeric salt of the desired R enantiomer.
• a chiral acid such as tartaric, malic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine
• the racemic mixture of R and S enantiomers of PAI may be prepared, e.g. as described in WO 95/11016.
• the racemic mixture of PAI can also be prepared by reacting 1-chloroindan or 1-bromoindan with propargylamine .
• this racemate may be prepared by reacting propargylamine with 1- indanone to form the corresponding imine, followed by reduction of the carbon-nitrogen double bond of the imine with a suitable agent, such as sodium borohydride.
• Rasagiline or deuterated compounds disclosed herein may be prepared as pharmaceutical compositions particularly useful for treating: Parkinson's disease, brain ischemia, head trauma injury, spinal trauma injury, neurotrauma, neurodegenerative disease, neurotoxic injury, nerve damage, dementia, Alzheimer's type dementia, senile dementia, depression, memory disorders, hyperactive syndrome, attention deficit disorder, multiple sclerosis, schizophrenia, and/or affective illness, but with a reduced risk of peripheral MAO inhibition that is typically associated with administration of rasagiline with known oral dosage forms.
• Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described, e.g., in U.S. Pat. No. 6,126,968 to Peskin et al . , issued Oct.
• Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, melting agents, stabilizing agents, solubilizing agents, antioxidants, buffering agent, chelating agents, fillers and plasticizers .
• the active drug component can be combined with an oral, non ⁇ toxic, pharmaceutically acceptable, inert carrier such as gelatin, agar, starch, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like.
• Suitable binders include starch, gelatin, natural sugars such as corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
• Antioxidants include ascorbic acid, fumaric acid, citric acid, malic acid, gallic acid and its salts and esters, butylated hydroxyanisole, editic acid.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, stearic acid, sodium stearyl fumarate, talc and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like, suitable plasticizers include triacetin, triethyl citrate, dibutyl sebacate, polyethylene glycol and the like.
• compositions may be prepared as medicaments to be administered orally, parenterally, rectally or transdermally .
• suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, sublingual tablets, syrups and suspensions; for parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion; for rectal administration there are provided suppositories with hydrophilic or hydrophobic vehicles; and for topical application as ointments and transdermal delivery there are provided suitable delivery systems as known in the art .
• Transdermal Formulations are medicated adhesive patches placed on the skin to deliver a time-released dose of medication through the skin and into the bloodstream.
• a wide variety of pharmaceuticals can be delivered through transdermal patches, such as nicotine for smoking cessation, scopolamine for motion sickness, estrogen for menopause, and prevention of osteoporosis, nitroglycerin for angina, lidocaine for pain relief from shingles.
• Some pharmaceuticals must be combined with other substances, such as alcohol, to increase their ability to penetrate the skin. Molecules of insulin, and many other pharmaceuticals, however, are too large to pass through the skin.
• Transdermal patches have several important components, including a liner to protect the patch during storage, the drug, adhesive, a membrane (to control release of the drug from the reservoir) , and a backing to protect the patch from the outer environment.
• the two most common types of transdermal patches are matrix and reservoir types.
• a drug is combined with a non- volatile, insert liquid, such as mineral oil, whereas drug in matrix type patches a drug is dispersed in a lipophilic or hydrophilic polymer matrix such as acrylic or vinylic polymers.
• Adhesive polymers such as polyisobutylene , are used to hold the patch in place on the skin.
• transdermal drug-delivery The major limitation to transdermal drug-delivery is the intrinsic barrier property of the skin. Penetration enhancers are often added to transdermal drug formulations in order to disrupt the skin surface and cause faster drug delivery. Typical penetration enhancers include high-boiling alcohols, diols, fatty acid esters, oleic acid and glyceride-based solvents, and are commonly added at a concentration of one to 20 percent (w/w) . (Melinda Hopp, "Developing Custom Adhesive Systems for Transdermal Drug Delivery Products," Pharmaceutical Technology, March 2002, pages 30-36). Rasagiline or the deuterated compounds disclosed herein, may be used alone, or alternatively, they may be used as an adjunct to existing treatments.
• a pharmaceutical composition for oral use in the form of tablets or capsules may comprise a disclosed compound, Levodopa, and a decarboxylase inhibitor.
• a composition may comprise 0.01- 20 mg of a disclosed compound in base form, 50-100 mg of Levodopa, and 12.5-50 mg of benserazide.
• the preferred dosages of R(+)PAI or its deuterated forms in any of the disclosed compositions may be within the following ranges: for oral or suppository formulations 0.01-20 mg per dosage unit to be taken daily, preferably 0.5-5 mg per dosage unit to be taken daily and more preferably 1 mg or 2 mg per dosage unit to be taken daily may be used; and for injectable formulations 0.05-10 mg/ml per dosage unit to be taken daily and more preferably 0.5-3 mg/ml per dosage unit to be taken daily and more preferably 1 mg/ml per dosage unit to be taken daily may be used.
• the amounts herein refer to the weight of the base compound, not the salt form thereof.
• any range disclosed herein it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention.
• 0.01 mg to 50 mg means that 0.02, 0.03 ... 0.09; 0.1, 0.2 ... 0.9; and 1, 2 ... 49 mg unit amounts are included as embodiments of this invention.
• a range of 0.01-20 mg means that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention.
• 0.02, 0.03 ... 0.09; 0.1, 0.2 ... 0.9; and 1, 2 ... 19 mg unit amounts are included as embodiments of this invention .
• Metabolites from chemical compounds, whether inherent or pharmaceutical, are formed as part of the natural biochemical process of degrading and eliminating the compounds.
• the rate of degradation of a compound is an important determinant of the duration and intensity of its action.
• Profiling metabolites of pharmaceutical compounds, drug metabolism, is an important part of drug discovery, leading to an understanding of any undesirable side effects.
• Rasagiline is slowly metabolized by CYP1A2 to form several primary metabolites as shown below:
• Drugs deuterated (C-D instead of C-H) at the site of metabolic biotransformation are more resistant to metabolic changes, especially when those changes are mediated by cytochrome P450 systems. This is due to so called Deuterium Kinetic Isotope Effect (DKIE) .
• DKIE Deuterium Kinetic Isotope Effect
• deuterated forms of rasagiline may have different metabolic profile than the protonated forms.
• the increased levels of deuterium incorporation may produce a detectable DKIE that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of rasagiline compared with rasagiline having naturally occurring levels of deuterium .
• Deuteration of the C-H bond to be oxidized may also change the pathway of drug metabolism (metabolic switching) .
• the metabolic scheme below illustrates different ways to slow CYPlA2-mediated metabolism of rasagiline, such as
• Literature illustrates a similar pathway blocking in the phenalzine molecule, which is also potent MAO inhibitor but catabolized by MAO.
• Dyck LE et al . "Effect of chronic deuterated and non-deuterated phenelzine on rat brain monoamines and monoamine oxidase", Naunyn Schmiedebergs Arch Pharmacol., 1988 Mar; 337 (3) : 279-83) .
• the phenalzine molecule studied in Dyck LE et al. was modified by deuteration at alpha and beta carbons of hydrazine moiety as shown below:
• Dyck LE et al. Study results in Dyck LE et al. indicated that the deuterated phenelzine is a more potent MAO inhibitor, but not in-vitro meaning most probably higher stability to oxidation. Another potential mechanism discussed in Dyck LE et al. was an increased neuronal uptake which was also shown for other amines, e.g. D3-NA.
• Deuterated R-rasagiline free base (Compound 1-4) (1.1 g) was dissolved in 8 g of isopropanol and 0.7 g of methanesulfonic acid was added at stirring and cooling. During the addition crystallization of rasagiline mesylate took place. The resulting suspension was heated to reflux and after complete dissolution of solids was cooled to 10°C. At cooling rasagiline mesylate crystallized, the mixture was stirred at 10 °C for 15 minutes and then filtered. The solid product was washed with ether and was dried under vacuum at 60 °C to obtain Compound 1. Compound 1 elutes at good chromatographic purity (99.2 % area in a HPLC chromatogram) .
• Lithium aluminum deuteride (5.0 g, 0.12 mol) was suspended in 200 mL of ethyl ether in a 500-mL round-bottom flask fitted with an addition funnel. The flask was cooled to -78°C, methyl propiolate (13.5 g, 0.16 mol) in 100 mL of ether was added drop wise over 4 h. After complete addition, the solution was stirred at -40°C overnight. Water (5.0 g) was added drop wise to the flask, which was then allowed to warm to room temperature. Aqueous NaOH (5 g, 15% solution) and 15 g of water were then added. The precipitate was filtered and washed with ether. The combined ethereal fractions were evaporated and distilled at atmospheric pressure. The residue containing prop-2-yn-l-ol (Compound 2-3) was used directly for the next step .
• the product was extracted with DCM (3 x 50 ml) , followed by washing with 10 % aqueous NaOH (2 x 30ml) and water (2 x 3ml) .
• the DCM was removed under reduced pressure at 40 °C to obtain a residue.
• the residue was then purified by preparative HPLC to provide Compound 2-5 as colorless oil.
• Deuterated rasagiline base (Compound 2-5) (1.1 g) was dissolved in 8 g of isopropanol and 0.7 g of methanesulfonic acid was added at stirring and cooling. During the addition crystallization of rasagiline mesylate took place. The resulting suspension was heated to reflux and cooled to 10 °C after complete dissolution of solid. At cooling rasagiline mesylate crystallized, the mixture stirred at 10°C for 15 minutes and filtered. Solid product was washed with ether and dried in vacuum at 60°C to provide Compound 2. Compound 2 elutes at good chromatographic purity (98.5% area in a HPLC chromatogram) .
• Deuterated R-rasagiline free base (Compound 3-4) (1.33 g) was dissolved in 8 g of isopropanol and 0.8 g of methanesulfonic acid was added at stirring and cooling. During the addition crystallization of rasagiline mesylate took place. The resulting suspension was heated at stirring to reflux and then cooled to 10°C after complete dissolution of solid. At cooling rasagiline mesylate was crystallized, the mixture stirred at 10°C for 15 minutes and filtered. Solid product was washed with ether and dried under vacuum at 60°C to provide Compound 3. Compound 3 elutes at good chromatographic purity (99.0 in a HPLC chromatogram) .
• Test formulations containing Compounds 1, 2, 3, or rasagiline at 1 mg dose level are prepared and are administered to mice.
• a "dose level”, such as in “1 mg dose level” refers to the weight of the base form of Compounds 1, 2, 3, or rasagiline, not the weight of the corresponding salt form, which is heavier.
• concentrations of Compound 1, Compound 2, Compound 3, and rasagiline in the plasma samples of the mice are determined using reliable LC/MS/MS assay. Pharmacokinetic parameters are calculated and the mean plasma levels versus time curves are evaluated.
• the following pharmacokinetic parameters are determined from the mean plasma concentration-time data (mean of three animals at each time point) of Compound 1, Compound 2, Compound 3 and rasagiline .
• AUC (0-t) Area under the plasma concentration-time curve from time zero up to time of last detectable concentration (tz)
• AUC (O-oo) Area under the plasma concentration-time curve from time zero up to infinity
• Rasagiline has been shown to be active against various diseases in various models, for example, as described in U.S. Patent No. 5,387, 612.
• Compounds 1, 2, and 3 used are prepared according to the processes described in Examples 1, 2, and 3, respectively.
• Each of Compounds 1, 2 and 3 are individually tested using the models as described in U.S. Patent No. 5, 387, 612 and are each found to have similar activity when compared to the activity of rasagiline which is not deuterium enriched .

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