(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0149622 A1
`(43) Pub. Date:
`Jun. 28, 2007
`Gant et al.
`
`US 200701 49.622A1
`
`SUBSTITUTED PHENETHYLAMINES WITH
`SEROTONNERGIC AND/OR
`NOREPINEPHRINERGIC ACTIVITY
`
`Inventors: Thomas G. Gant, Carlsbad, CA (US);
`Sepehr Sarshar, Cardiff by the Sea,
`CA (US)
`Correspondence Address:
`KNOBBE MARTENS OLSON & BEAR LLP
`2O4O MAN STREET
`FOURTEENTH FLOOR
`IRVINE, CA 92614 (US)
`Assignee: AUSPEX Pharmaceuticals, Inc., Vista,
`CA (US)
`Appl. No.:
`11/565,451
`
`(54)
`
`(75)
`
`(73)
`
`(21)
`(22)
`
`(60)
`
`ABSTRACT
`(57)
`Chemical syntheses and medical uses of novel inhibitors of
`the uptake of monoamine neurotransmitters and pharmaceu
`tically acceptable salts and prodrugs thereof, for the treat
`ment and/or management of psychotropic disorders, anxiety
`disorder, generalized anxiety disorder, depression, post
`traumatic stress disorder, obsessive-compulsive disorder,
`panic disorder, hot flashes, senile dementia, migraine,
`hepatopulmonary syndrome, chronic pain, nociceptive pain,
`neuropathic pain, painful diabetic retinopathy, bipolar
`depression, obstructive sleep apnea, psychiatric disorders,
`premenstrual dysphoric disorder, social phobia, Social anxi
`ety disorder, urinary incontinence, anorexia, bulimia ner
`Vosa, obesity, ischemia, head injury, calcium overload in
`brain cells, drug dependence, and/or premature ejaculation
`are described.
`
`Formula 1
`
`Filed:
`
`Nov. 30, 2006
`
`
`
`Related U.S. Application Data
`Provisional application No. 60/741,315, filed on Dec.
`1, 2005. Provisional application No. 60/841,366, filed
`on Aug. 30, 2006.
`
`Publication Classification
`
`(51)
`
`(52)
`
`Int. C.
`(2006.01)
`A6 IK 3L/37
`U.S. Cl. ............................................ 514/649; 564/335
`
`Apotex Ex. 1011
`
`Apotex v. Auspex
`IPR2021-01507
`
`

`

`US 2007/O 149622 A1
`
`Jun. 28, 2007
`
`SUBSTITUTED PHENETHYLAMINES WITH
`SEROTONNERGIC AND/OR
`NOREPINEPHRINERGIC ACTIVITY
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`0001. This application claims priority to U.S. Provisional
`Application Nos. 60/741,315, entitled “SUBSTITUTED
`PHENETHYLAMINES WITH SEROTONINERGIC AND/
`OR NOREPINEPHRINERGIC ACTIVITY, filed Dec. 1,
`2005; and 60/841,366, entitled “SUBSTITUTED PHEN
`ETHYLAMINES WITH SEROTONINERGIC AND/OR
`NOREPINEPHRINERGIC ACTIVITY, filed Aug. 30, 2006,
`both of which are incorporated by reference in their entire
`ties.
`
`BACKGROUND OF THE INVENTION
`0002) 1. Field of the Invention
`0003. The present invention is directed to inhibitors of
`the uptake of monoamine neurotransmitters and pharmaceu
`tically acceptable salts and prodrugs thereof, the chemical
`synthesis thereof, and the medical use of Such compounds
`for the treatment and/or management of psychotropic dis
`orders, anxiety disorder, generalized anxiety disorder,
`depression, post-traumatic stress disorder, obsessive-com
`pulsive disorder, panic disorder, hot flashes, senile dementia,
`migraine, hepatopulmonary syndrome, chronic pain, noci
`ceptive pain, neuropathic pain, painful diabetic retinopathy,
`bipolar depression, obstructive sleep apnea, psychiatric dis
`orders, premenstrual dysphoric disorder, social phobia,
`Social anxiety disorder, urinary incontinence, anorexia,
`bulimia nervosa, obesity, ischemia, head injury, calcium
`overload in brain cells, drug dependence, and/or premature
`ejaculation.
`0004 2. Description of the Related Art
`0005. In an attempt to breakdown or to help solubilize
`chemicals and nutrients that have been absorbed into the
`blood, the human body expresses various enzymes (e.g. the
`cytochrome Paso enzymes or CYPs, esterases, proteases,
`reductases, dehydrogenases, and the like) that react with the
`chemicals and nutrients to produce novel intermediates or
`metabolites. Some of the most common metabolic reactions
`of pharmaceutical compounds involve the oxidation of a
`carbon-hydrogen (C-H) bond to either a carbon-oxygen
`(C O) or carbon-carbon (C C) U-bond. The resultant
`metabolites may be stable or unstable under physiological
`conditions, and can have Substantially different pharmaco
`kinetic, pharmacodynamic, acute and long-term toxicity
`profiles relative to the parent compounds. For most drugs,
`Such oxidations are generally rapid and ultimately lead to
`administration of multiple or high daily doses. There is
`therefore an obvious and immediate need for improvements
`of Such drugs.
`0006 Chemical kinetics is the study of reaction rates. The
`activation energy E in chemistry is the energy that must be
`Supplied to a system in order to initiate a particular chemical
`process. In other words, this is the minimum energy required
`for a specific chemical reaction to take place. A reaction will
`occur between two properly oriented molecules if they
`possess a minimum requisite energy. During the approach,
`the outer shell electrons of each molecule will induce
`
`repulsion. Overcoming this repulsion requires an input of
`energy (i.e. the activation energy), which results from the
`heat of the system; i.e. the translational, vibrational, and
`rotational energy of each molecule. If Sufficient energy is
`available, the molecules may attain the proximity and ori
`entation necessary to cause a rearrangement of bonds to
`form new Substances.
`0007. The relationship between the activation energy and
`the rate of reaction may be quantified by the Arrhenius
`equation which states that the fraction of molecules that
`have enough energy to overcome an energy barrier—those
`with energy at least equal to the activation energy, E
`depends exponentially on the ratio of the activation to
`thermal energy k=Ae'". In this equation, RT is the
`average amount of thermal energy that molecules possess at
`a certain temperature T, where R is the molar gas constant,
`k is the rate constant for the reaction and A (the frequency
`factor) is a constant specific to each reaction that depends on
`the probability that the molecules will collide with the
`correct orientation.
`0008. The transition state in a reaction is a short lived
`state (on the order of 10' sec) along the reaction pathway
`during which the original bonds have stretched to their limit.
`By definition, the activation energy E for a reaction is the
`energy required to reach the transition state of that reaction.
`Reactions that involve multiple steps will necessarily have a
`number of transition states, and in these instances, the
`activation energy for the reaction is equal to the energy
`difference between the reactants and the most unstable
`transition state. Once the transition state is reached, the
`molecules can either revert, thus reforming the original
`reactants, or the new bonds form giving rise to the products.
`This dichotomy is possible because both pathways, forward
`and reverse, result in the release of energy. A catalyst
`facilitates a reaction process by lowering the activation
`energy leading to a transition state. Enzymes are examples
`of biological catalysts that reduce the energy necessary to
`achieve a particular transition state.
`0009. A carbon-hydrogen bond is by nature a covalent
`chemical bond. Such a bond forms when two atoms of
`similar electronegativity share some of their valence elec
`trons, thereby creating a force that holds the atoms together.
`This force or bond strength can be quantified and is
`expressed in units of energy, and as such, covalent bonds
`between various atoms can be classified according to how
`much energy must be applied to the bond in order to break
`the bond or separate the two atoms.
`0010. The bond strength is directly proportional to the
`absolute value of the ground-state vibrational energy of the
`bond. This vibrational energy, which is also known as the
`Zero-point vibrational energy, depends on the mass of the
`atoms that form the bond. The absolute value of the Zero
`point vibrational energy increases as the mass of one or both
`of the atoms making the bond increases. Since deuterium
`(D) is two-fold more massive than hydrogen (H), it follows
`that a C-D bond is stronger than the corresponding C-H
`bond. Compounds with C-D bonds are frequently indefi
`nitely stable in HO, and have been widely used for isotopic
`studies. If a C-H bond is broken during a rate-determining
`step in a chemical reaction (i.e. the step with the highest
`transition state energy), then Substituting a deuterium for
`that hydrogen will cause a decrease in the reaction rate and
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`US 2007/O 149622 A1
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`Jun. 28, 2007
`
`the process will slow down. This phenomenon is known as
`the Deuterium Kinetic Isotope Effect (DKIE) and can range
`from about 1 (no isotope effect) to very large numbers. Such
`as 50 or more, meaning that the reaction can be fifty, or
`more, times slower when deuterium is substituted for hydro
`gen. High DKIE values may be due in part to a phenomenon
`known as tunneling, which is a consequence of the uncer
`tainty principle. Tunneling is ascribed to the Small size of a
`hydrogen atom, and occurs because transition states involv
`ing a proton can sometimes form in the absence of the
`required activation energy. A deuterium is larger and statis
`tically has a much lower probability of undergoing this
`phenomenon. Substitution of tritium for hydrogen results in
`yet a stronger bond than deuterium and gives numerically
`larger isotope effects.
`0011 Discovered in 1932 by Urey, deuterium (D) is a
`stable and non-radioactive isotope of hydrogen. It was the
`first isotope to be separated from its element in pure form
`and is twice as massive as hydrogen, and makes up about
`0.02% of the total mass of hydrogen (in this usage meaning
`all hydrogen isotopes) on earth. When two deuteriums bond
`with one oxygen, deuterium oxide (DO or “heavy water)
`is formed. DO looks and tastes like HO but it has different
`physical properties. It boils at 101.41° C. and freezes at
`3.79°C. Its heat capacity, heat of fusion, heat of vaporiza
`tion, and entropy are all higher than H2O. It is also more
`viscous and is not as powerful a solvent as H.O.
`0012 Tritium (T) is a radioactive isotope of hydrogen,
`used in research, fusion reactors, neutron generators and
`radiopharmaceuticals. Mixing tritium with a phosphor pro
`vides a continuous light source, a technique that is com
`monly used in wristwatches, compasses, rifle sights and exit
`signs. It was discovered by Rutherford, Oliphant and
`Harteck in 1934 and is produced naturally in the upper
`atmosphere when cosmic rays react with H molecules.
`Tritium is a hydrogen atom that has 2 neutrons in the nucleus
`and has an atomic weight close to 3. It occurs naturally in the
`environment in very low concentrations, most commonly
`found as TO, a colorless and odorless liquid. Tritium decays
`slowly (half-life=12.3 years) and emits a low energy beta
`particle that cannot penetrate the outer layer of human skin.
`Internal exposure is the main hazard associated with this
`isotope, yet it must be ingested in large amounts to pose a
`significant health risk.
`0013 When pure DO is given to rodents, it is readily
`absorbed and reaches an equilibrium level that is usually
`about eighty percent of the concentration that is consumed
`by the animals. The quantity of deuterium required to induce
`toxicity is extremely high. When 0 to as much as 15% of the
`body water has been replaced by DO, animals are healthy
`but are unable to gain weight as fast as the control
`(untreated) group. Between 15 to 20% DO, the animals
`become excitable. At 20 to 25%, the animals are so excitable
`that they go into frequent convulsions when stimulated. Skin
`lesions, ulcers on the paws and muzzles, and necrosis of the
`tails appear. The animals also become very aggressive;
`males becoming almost unmanageable. At 30%, the animals
`refuse to eat and become comatose. Their body weight drops
`sharply and their metabolic rates drop far below normal,
`with death occurring at 30 to 35% replacement. The effects
`are reversible unless more than thirty percent of the previous
`body weight has been lost due to D.O. Studies have also
`
`shown that the use of DO can delay the growth of cancer
`cells and enhance the cytotoxicity of certain antineoplastic
`agents.
`0014 Deuteration of pharmaceuticals to improve phar
`macokinetics (PK), pharmacodynamics (PD), and toxicity
`profiles, has been demonstrated previously with some
`classes of drugs. For example, DKIE was used to decrease
`the hepatotoxicity of halothane by presumably limiting the
`production of reactive species such as trifluoroacetyl chlo
`ride. However, this method may not be applicable to all drug
`classes. For example, deuterium incorporation can lead to
`metabolic Switching which may even give rise to an oxida
`tive intermediate with a faster off-rate from an activating
`Phase I enzyme (e.g. cytochrome Paso 3A4). The concept of
`metabolic Switching asserts that Xenogens, when seques
`tered by Phase I enzymes, may bind transiently and re-bind
`in a variety of conformations prior to the chemical reaction
`(e.g. oxidation). This claim is Supported by the relatively
`vast size of binding pockets in many Phase I enzymes and
`the promiscuous nature of many metabolic reactions. Meta
`bolic Switching can potentially lead to different proportions
`of known metabolites as well as altogether new metabolites.
`This new metabolic profile may impart more or less toxicity.
`Such pitfalls are non-obvious and have not been heretofore
`Sufficiently predictable a priori for any drug class.
`0015. It has been hypothesized that the efficacy of ven
`lafaxine (Effexor(R) is mainly due to its ability to inhibit
`Serotonin reuptake and, potentially, norepinephrine reuptake
`in neuronal cells. The latter is purported to take effect only
`at high doses. The drug substance is sold as a 50/50 racemic
`mixture of R- and S-enantiomers. The mechanism of action
`of this drug has been extensively studied.
`
`HO
`
`Wenlafaxine
`
`0016. The benefits and shortcomings of this drug have
`been extensively reviewed as well. Some of these shortcom
`ings can be traced to metabolism-related phenomena. Ven
`lafaxine is converted in vivo by oxidative and conjugative
`degradation to multiple metabolites, at least 48 of which are
`documented. The major metabolites include much phase I
`metabolism leading to demethylation at the oxygen and/or
`nitrogen centers, and cyclohexyl ring hydroxylation, as well
`as significant phase II metabolism including glucuronidation
`of the hydroxylated metabolites. Because this drug is
`metabolized by polymorphically-expressed isozymes of
`cytochrome Paso including CYPs 2C19 and 2D6, and
`because it can act as an inhibitor of CYP2D6, its application
`in polypharmacy is necessarily complex and has potential
`for adverse events. These CYPs are involved in the metabo
`lism of many medications that are typically prescribed
`concurrently with Venlafaxine. This phenomenon increases
`inter-patient variability in response to polypharmacy. An
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`
`example of the critical need for improvement is the pub
`lished interpatient variability observed in “poor metaboliz
`ers” having either defective CYP2D6 alleles or total lack of
`CYP2D6 expression. These patients fail to convert venlafax
`ine to its equipotent metabolite, O-desmethylvenlafaxine.
`Venlafaxine also suffers from a short half-life relative to the
`majority of serotonin reuptake inhibitors. The half-life of
`venlafaxine in humans is ~5 hours, while its active metabo
`lite has a T of ~11 hours. As a consequence of its 5-11
`hour pharmacological half-life, those taking Venlafaxine are
`at significant risk of SRI discontinuation symptoms if the
`drug is abruptly discontinued. Furthermore, in order to
`overcome its short half-life, the drug must be taken 2 (BID)
`or 3 (TID) times a day, which increases the probability of
`patient incompliance and discontinuance. Most other sero
`tonin reuptake inhibitors (SRIs) have half-lives 224 hours.
`A 24-72 hour half-life is regarded as ideal for this class of
`compounds by most clinicians. There is therefore an obvious
`and immediate need for improvements in the development
`of monoamine reuptake inhibitors such as paroxetine.
`
`SUMMARY OF THE INVENTION
`0017 Disclosed herein are compounds of Formula 1:
`
`
`
`Formula 1
`
`0018 or a single enantiomer, a mixture of the (+)-enan
`tiomer and the (-)-enantiomer, a mixture of about 90% or
`more by weight of the (-)-enantiomer and about 10% or less
`by weight of the (+)-enantiomer, a mixture of about 90% or
`more by weight of the (+)-enantiomer and about 10% or less
`by weight of the (-)-enantiomer, an individual diastereomer,
`a mixture of diastereomers, or a pharmaceutically acceptable
`salt, Solvate, or prodrug thereof, wherein:
`0019) R. R2, Rs. R4, Rs. R. R7. Rs. R9. Rio. R11, R12.
`R. R. R. R. R7, and Rs are independently selected
`from the group consisting of hydrogen, and deuterium;
`0020 R. R. and R are independently selected from
`the group consisting of —CH, —CHD, —CHD, and
`—CD:
`0021 provided that compounds of Formula 1 contain at
`least one deuterium atom; and provided that deuterium
`enrichment in compounds of Formula 1 is at least about 1%.
`0022. Also disclosed herein are pharmaceutical compo
`sitions comprising a compound of Formula 1, a single
`enantiomer of a compound of Formula 1, a mixture of the
`
`(+)-enantiomer and the (-)-enantiomer, a mixture of about
`90% or more by weight of the (-)-enantiomer and about
`10% or less by weight of the (+)-enantiomer, a mixture of
`about 90% or more by weight of the (+)-enantiomer and
`about 10% or less by weight of the (-)-enantiomer, an
`individual diastereomer of a compound of Formula 1 a
`mixture of diastereomers, or a pharmaceutically acceptable
`salt, Solvate, or prodrug thereof, with a pharmaceutically
`acceptable carrier.
`0023. Further, disclosed herein are methods of eliciting,
`modulating and/or regulating the reuptake of monoamine
`neurotransmitters including serotonin and/or norepineph
`rine.
`0024. In addition, disclosed herein are methods of treat
`ing a mammalian Subject having, Suspected of having, or
`being prone to a disease or condition, such as a disease or
`condition selected from the group consisting of anxiety
`disorder, generalized anxiety disorder, depression, post
`traumatic stress disorder, obsessive-compulsive disorder,
`panic disorder, a hot flash, senile dementia, migraine,
`hepatopulmonary syndrome, chronic pain, nociceptive pain,
`neuropathic pain, painful diabetic retinopathy, bipolar
`depression, obstructive sleep apnea, psychiatric disorders,
`premenstrual dysphoric disorder, social phobia, Social anxi
`ety disorder, urinary incontinence, anorexia, bulimia ner
`Vosa, obesity, ischemia, head injury, calcium overload in
`brain cells, drug dependence, and/or premature ejaculation.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`0025 Certain monoamine reuptake inhibitors are known
`in the art and are shown herein. Venlafaxine (EffexorR) is
`one such compound. The carbon-hydrogen bonds of Ven
`lafaxine contain a naturally occurring distribution of hydro
`gen isotopes, namely H or protium (about 99.984.4%), H
`or deuterium (about 0.0156%), and H or tritium (in the
`range between about 0.5 and 67 tritium atoms per 10'
`protium atoms). Increased levels of deuterium incorporation
`produce a detectable Kinetic Isotope Effect (KIE) that could
`affect the pharmacokinetic, pharmacologic and/or toxico
`logic parameters of Such monoamine reuptake inhibitors
`relative to compounds having naturally occurring levels of
`deuterium. Aspects of the present invention disclosed herein
`describe a novel approach to designing and synthesizing
`new analogs of these monoamine reuptake inhibitors
`through chemical modifications and derivations of the car
`bon-hydrogen bonds of the modulators and/or of the chemi
`cal precursors used to synthesize said modulators. Suitable
`modifications of certain carbon-hydrogen bonds into car
`bon-deuterium bonds may generate novel monoamine
`reuptake inhibitors with unexpected and non-obvious
`improvements of pharmacological, pharmacokinetic and
`toxicological properties in comparison to the non-isotopi
`cally enriched monoamine reuptake inhibitors. This inven
`tion relies on the judicious and Successful application of
`chemical kinetics to drug design. Deuterium incorporation
`levels in the compounds of the invention are significantly
`higher than the naturally-occurring levels and are Sufficient
`to induce at least one substantial improvement as described
`herein.
`0026 Information has come to light that enables the
`judicious use of deuterium in solving the PD and Absorp
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`tion, Distribution, Metabolism, Excretion, and Toxicological
`(ADMET) shortcomings for Venlafaxine. For example, both
`N-methyl groups, the single O-methyl, and several sites on
`the cyclohexyl ring of Venlafaxine are now known to be sites
`of cytochrome Paso metabolism. The toxicities of all result
`ant metabolites are not known. Furthermore, because poly
`morphically expressed CYPs such as 2C19 and 2D6 oxidize
`Venlafaxine, and because Venlafaxine inhibits the polymor
`phically expressed CYP2D6, the prevention of such inter
`actions decreases interpatient variability, decreases drug
`drug interactions, increases T, decreases the necessary
`C., and improves several other ADMET parameters. For
`example, the half-life of the parent drug of Venlafaxine
`ranges from 3-7 hours. The equipotent metabolite, O-dem
`ethylated Venlafaxine, has a half-life averaging 11 hours.
`Various deuteration patterns can be used to a) alter the ratio
`of active metabolites, b) reduce or eliminate unwanted
`metabolites, c) increase the half-life of the parent drug, and
`for d) increase the half-life of active metabolites and create
`a more effective drug and a safer drug for polypharmacy,
`whether the polypharmacy be intentional or not. High doses
`of Venlafaxine are often prescribed in order to reach levels
`capable of inhibiting norepinephrine reuptake. Unfortu
`nately, high doses are also associated with hypertension.
`Since these phenomenon are linked by the pharmaceutical
`agent rather than the pharmacological target, the two phe
`nomena are theoretically separable by increasing the half
`life thus allowing dosing in a range that lowers the C and
`thus may avoid triggering the mechanism leading to hyper
`tension. Further illustrating this point, Venlafaxine is known
`to display linear kinetics at the low end of the dose range, 75
`mg/day, but displays non-linear kinetics at the high end of
`the dose range, ~400 mg/day, as a result of the Saturation of
`clearance mechanisms. This non-linearity produces an
`ascending, rather than a flat, dose-response curve for ven
`lafaxine. The deuteration approach has strong potential to
`slow metabolism through the previously saturated mecha
`nism allowing linear, more predictable ADMET responses
`throughout the dose range (which would also be lower via
`this invention). This leads to lesser interpatient variability of
`the type that can lead to the hypertensive effects.
`0027. The deuterated analogs of this invention have the
`potential to uniquely maintain the beneficial aspects of the
`non-isotopically enriched drugs while Substantially increas
`ing the half-life (T), lowering the maximum plasma
`concentration (C) of the minimum efficacious dose
`(MED), lowering the efficacious dose and thus decreasing
`the non-mechanism-related toxicity, and/or lowering the
`probability of drug-drug interactions. These drugs also have
`strong potential to reduce the cost-of-goods (COG) owing to
`the ready availability of inexpensive sources of deuterated
`reagents combined with previously mentioned potential for
`lowering the therapeutic dose. The present inventors have
`discovered that deuteration at the methylenedioxy moiety
`alone, and/or deuteration at the methylenedioxy moiety plus
`deuteration of additional sites found to be labile as a result
`of metabolic switching are effective in achieving some of the
`objectives disclosed herein.
`
`0028. Thus, in one aspect, there are provided herein
`compounds having the structural Formula 1:
`
`
`
`Formula 1
`
`0029 or a single enantiomer, a mixture of the (+)-enan
`tiomer and the (-)-enantiomer, a mixture of about 90% or
`more by weight of the (-)-enantiomer and about 10% or less
`by weight of the (+)-enantiomer, a mixture of about 90% or
`more by weight of the (+)-enantiomer and about 10% or less
`by weight of the (-)-enantiomer, an individual diastereomer,
`a mixture of diastereomers, or a pharmaceutically acceptable
`salt, Solvate, or prodrug thereof, wherein:
`0030) R. R2, Rs. R4, Rs. R6. R7. Rs. R9. Rio. R11, R12.
`R. R. Rs. R. R.17, and R1s are independently selected
`from the group consisting of hydrogen, and deuterium;
`0031 R, Rao, and R are independently selected from
`the group consisting of —CH, —CHD, —CHD, and
`—CDs.;
`0032 provided that compounds of Formula 1 contain at
`least one deuterium atom; and provided that deuterium
`enrichment in compounds of Formula 1 is at least about 1%.
`0033 Compounds of this invention have the potential to
`uniquely maintain the beneficial aspects of non-isotopically
`enriched monoamine reuptake inhibitors while substantially
`altering the half-life (T), lowering the maximum plasma
`concentration (C) of the minimum efficacious dose
`(MED), lowering the efficacious dose and thus decreasing
`non-mechanism-related toxicities and/or lowering the prob
`ability of drug-drug interactions. These drugs also have
`potential to reduce the cost-of-goods (COG) due to a poten
`tial for lowering the therapeutic dose when compared to the
`non-isotopically enriched monoamine reuptake inhibitors.
`In sum, many aspects of ADMET of the non-isotopically
`enriched monoamine reuptake inhibitors are substantially
`improved by this invention.
`0034. In some embodiments, agents in the present inven
`tion will expose patients to a maximum of about 0.000005%
`DO (can also be expressed as about 0.00001% DHO). This
`quantity is a small fraction of the naturally occurring back
`ground levels of DO (or DHO) in circulation. This maxi
`mum exposure limit is obtained if all of the C-D bonds of the
`deuterium-enriched drug are metabolized. However,
`because of the DKIE, most if not all, of the C-D bonds of the
`deuterium-enriched drug will not be metabolized prior to
`excretion of said deuterium-enriched drug from the Subject.
`Therefore, the actual exposure of the patient to DO will be
`far less than the aforementioned maximum limit. As dis
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`cussed above, the levels of DO shown to cause toxicity in
`animals is much greater than even the maximum limit of
`exposure because of the deuterium enriched drug. The
`deuterium-enriched compounds of the present invention,
`therefore, do not cause any additional toxicity because of the
`use of deuterium.
`0035 “Deuterium enrichment” refers to the percentage of
`incorporation of deuterium at a given site on the molecule
`instead of a hydrogen atom. For example, deuterium enrich
`ment of 1% means that in 1% of molecules in a given sample
`a particular site is occupied by deuterium. Because the
`naturally occurring distribution of deuterium is about
`0.0156%, deuterium enrichment in compounds synthesized
`using non-enriched starting materials is about 0.0156%. In
`Some embodiments, the deuterium enrichment in the com
`pounds of the present invention is greater than 10%. In other
`embodiments, the deuterium enrichment in the compounds
`of the present invention is greater than 20%. In further
`embodiments, the deuterium enrichment in the compounds
`of the present invention is greater than 50%. In some
`embodiments, the deuterium enrichment in the compounds
`of the present invention is greater than 70%. In some
`embodiments, the deuterium enrichment in the compounds
`of the present invention is greater than 90%.
`0036) “Isotopic enrichment” refers to the percentage of
`incorporation of a less prevalent isotope of an element at a
`given site on the molecule instead of the more prevalent
`isotope of the element. “Non-isotopically enriched refers to
`a molecule in which the percentage of the various isotopes
`is Substantially the same as the naturally occurring percent
`ageS.
`0037. In certain embodiments, the compound of Formula
`1 contains about 60% or more by weight of the (-)-
`enantiomer of the compound and about 40% or less by
`weight of (+)-enantiomer of the compound. In some embodi
`ments, the compound of Formula 1 contains about 70% or
`more by weight of the (-)-enantiomer of the compound and
`about 30% or less by weight of (+)-enantiomer of the
`compound. In some embodiments, the compound of For
`mula 1 contains about 80% or more by weight of the
`(-)-enantiomer of the compound and about 20% or less by
`weight of (+)-enantiomer of the compound. In some embodi
`ments, the compound of Formula 1 contains about 90% or
`more by weight of the (-)-enantiomer of the compound and
`about 10% or less by weight of the (+)-enantiomer of the
`compound. In some embodiments, the compound of For
`mula 1 contains about 95% or more by weight of the
`(-)-enantiomer of the compound and about 5% or less by
`weight of (+)-enantiomer of the compound. In some embodi
`ments, the compound of Formula 1 contains about 99% or
`more by weight of the (-)-enantiomer of the compound and
`about 1% or less by weight of (+)-enantiomer of the com
`pound.
`0038. In certain other embodiments, the compound of
`Formula 1 contains about 60% or more by weight of the
`(+)-enantiomer of the compound and about 40% or less by
`weight of (-)-enantiomer of the compound. In some embodi
`ments, the compound of Formula 1 contains about 70% or
`more by weight of the (+)-enantiomer of the compound and
`about 30% or less by weight of (-)-enantiomer of the
`compound. In some embodiments, the compound of For
`mula 1 contains about 80% or more by weight of the
`
`(+)-enantiomer of the compound and about 20% or less by
`weight of (-)-enantiomer of the compound. In some embodi
`ments, the compound of Formula 1 contains about 90% or
`more by weight of the (+)-enantiomer of the compound and
`about 10% or less by weight of the (-)-enantiomer of the
`compound. In some embodiments, the compound of For
`mula 1 contains about 95% or more by weight of the
`(+)-enantiomer of the compound and about 5% or less by
`weight of (-)-enantiomer of the compound. In some embodi
`ments, the compound of Formula 1 contains about 99% or
`more by weight of the (+)-enantiomer of the compound and
`about 1% or less by weight of (-)-enantiomer of the com
`pound.
`0039. In certain embodiments, R is hydrogen. In other
`embodiments, R is hydrogen. In some embodiments, R is
`hydrogen. In other embodiments, R is hydrogen. In yet
`other embodiments, Rs is hydrogen. In still other embodi
`ments, R is hydrogen. In yet other embodiments, R, is
`hydrogen. In yet other embodiments. Rs is hydrogen. In still
`other embodiments, R is hydrogen. In still other embodi
`ments, Ro is hydrogen. In other embodiments, R is hydro
`gen. In some embodiments, R is hydrogen. In other
`embodiments, R is hydrogen. In still other embodiments,
`Ra is hydrogen. In yet other embodiments, Ris is hydrogen.
`In yet other embodiments, R is hydrogen. In still other
`embodiments, R, is hydrogen. In yet other embodiments,
`R is hydrogen.
`0040. In certain embodiments, R is deuterium. In other
`embodiments, R is deuterium. In some embodiments, R is
`deuterium. In other embodiments, R is deuterium. In yet
`other embodiments, Rs is deuterium. In still other embodi
`ments, R is deuterium. In yet other embodiments, R, is
`deuterium. In yet other embodiments, Rs is deuterium. In
`still other embodiments, R is deuterium. In still other
`embodiments, Ro is deuterium. In other embodiments, R.
`is deuterium. In some embodiments, R is deuterium. In
`other embodiments, R is deuterium. In still other embodi
`ments, R is deuterium. In yet other embodiments, Ris is
`deuterium. In yet other embodiments, R is deuterium. In
`still other embodiments, R, is deuterium. In yet other
`embodiments, Ris is deuterium.
`0041. In certain embodiments, R is not hydrogen. In
`other embodiments, R is not hydrogen. In some embodi
`ments, R is not hydrogen. In other embodiments, R is not
`hydrogen. In yet other embodiments, Rs is not hydrogen. In
`still other embodiments, R is not hydrogen. In yet other
`embodiments, R, is not hydrogen. In yet other embodiments,
`Rs is not hydrogen. In still other embodiments, Ro is not
`hydrogen. In still other embodiments