(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0088075A1
`Apr. 19, 2007
`(43) Pub. Date:
`Chou et al.
`
`US 20070088075A1
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`(54)
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`(75)
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`(21)
`(22)
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`DEUTERATED AMNOCYCLOHEXYL
`ETHER COMPOUNDS AND PROCESSES
`FOR PREPARING SAME
`
`Inventors: Doug Ta Hung Chou, Vancouver (CA);
`Bertrand M. C. Plouvier, Vancouver
`(CA); Peter Pang, Richmond (CA);
`James Gee Ken Yee, Vancouver (CA);
`Jeffery Jerome Wheeler, Surrey (CA);
`Aregahegn S. Yifru, Somerville, MA
`(US); Allen W. Davidoff, Calgary (CA)
`Correspondence Address:
`SEED INTELLECTUAL PROPERTY LAW
`GROUP PLLC
`701 FIFTHAVE
`SUTES4OO
`SEATTLE, WA 98104 (US)
`Assignee: Cardiome Pharma Corp., Vancouver
`(CA)
`Appl. No.:
`111581,225
`
`Filed:
`
`Oct. 13, 2006
`
`Related U.S. Application Data
`Continuation-in-part of application No. PCT/US06/
`23668, filed on Jun. 15, 2006.
`Continuation-in-part of application No. PCT/US05/
`11124, filed on Mar. 31, 2005.
`Provisional application No. 60/748.248, filed on Dec.
`7, 2005. Provisional application No. 60/690,989, filed
`on Jun. 15, 2005. Provisional application No. 60/586,
`922, filed on Jul. 12, 2004. Provisional application
`No. 60/559,405, filed on Apr. 1, 2004.
`
`Publication Classification
`
`Int. C.
`(2006.01)
`A6II 3 L/40 15
`U.S. Cl. ............................................ 514/424: 548/541
`
`ABSTRACT
`
`(63)
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`This invention is directed to deuterated aminocyclohexyl
`ether compounds and processes for preparing same and
`methods of using same.
`
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`US 2007/0O8807S A1
`
`Apr. 19, 2007
`
`DEUTERATED AMNOCYCLOHEXYL ETHER
`COMPOUNDS AND PROCESSES FOR PREPARING
`SAME
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`0001. This application is a continuation-in-part of PCT
`Patent Application No. PCT/US06/23668, filed Jun. 15,
`2006, now pending, which claims priority to U.S. Provi
`sional Patent Application No. 60/690,989, filed Jun. 15,
`2005, and U.S. Provisional Patent Application No. 60/748,
`248, filed Dec. 7, 2005, which applications are incorporated
`herein by reference in their entireties.
`0002 This application is also a continuation-in-part of
`PCT Patent Application No. PCT/US05/11124, filed Mar.
`31, 2005, now pending, which claims priority to U.S.
`Provisional Patent Application No. 60/559,405, filed Apr. 1,
`2004, and U.S. Provisional Patent Application No. 60/586,
`992, filed Jul. 8, 2004, which applications are incorporated
`herein by reference in their entireties.
`0003. This application also claims the benefit under 35
`U.S.C. S 119(e) of U.S. Provisional Patent Application No.
`60/748.248, filed Dec. 7, 2005; of U.S. which application is
`incorporated herein by reference in its entirety.
`
`FIELD OF INVENTION
`0004. The present invention is generally directed towards
`deuterated aminocyclohexyl ether compounds and methods
`for their preparation. In particular, this invention is directed
`to deuterated-trans-(1R,2R)-aminocyclohexyl ether com
`pounds, deuterated-trans-(1S,2S)-aminocyclohexyl ether
`compounds, deuterated cis-(1R,2S)-aminocyclohexyl ether
`compounds, and deuterated cis-(1S,2R)aminocyclohexyl
`ether compounds, as well as various intermediates, Sub
`strates and Stereoisomers and methods for their preparation.
`The deuterated compounds of the invention are useful as
`standards in determining the biological efficacy of the cor
`responding non-deuterated compounds. The deuterated
`compounds of the invention are also useful in treating
`arrhythmia in humans.
`
`BACKGROUND OF THE INVENTION
`0005 Deuterated drugs are widely used in studies of
`metabolism of drugs and toxic Substances in humans and
`other animals. The deuterated forms of drugs often have
`different actions than the protonated forms. Some deuterated
`drugs show different transport processes. Most are more
`resistant to metabolic changes, especially those changes
`mediated by cytochrome P450 systems. Deuteration may
`also change the pathway of drug metabolism (metabolic
`Switching). Changed metabolism may lead to increased
`duration of action and lower toxicity. It may also lead to
`lower activity, if the drug is normally changed to the active
`form in vivo. Deuteration can also lower the genotoxicity of
`the anticancer drug tamoxifen and other compounds. Deu
`teration increases effectiveness of long-chain fatty acids and
`fluoro-D-phenylalanine by preventing their breakdown by
`target microorganisms.
`0006 Deuterium (D) is a nonradioactive isotope which
`contains one additional neutron than the normally abundant
`isotope of hydrogen which does not contain any neutrons.
`
`Deuterium behaves similarly to ordinary hydrogen, but it
`can be distinguished from ordinary hydrogen by its mass
`using mass spectrometry or infrared spectrometry. Conse
`quently, deuterated compounds have been long used in
`pharmaceutical research to investigate the in vivo metabolic
`fate of the compounds by evaluation of the mechanism of
`action and metabolic-pathway of the non deuterated parent
`compound. Such metabolic studies are important in the
`design of safe, effective therapeutic drugs.
`0007 Incorporation of deuterium for a hydrogen atom in
`a drug can give rise to an isotope effect that can alter the
`pharmacokinetics of the drug. This effect is usually insig
`nificant if the label is placed in a molecule at the metaboli
`cally inert position of the molecule. For instance, deutera
`tion, as exemplified by deuterated Rapamycin (see U.S. Pat.
`No. 6,503.921), Cyclosporine (see U.S. Pat. No. 6,613,739)
`or Nifedipine (see U.S. Pat. No. 5,846,514) has been
`reported to alter the pharmacokinetics of a drug. Forster et
`al. (Isotechnica, AB) have shown that deuteration can
`enhance duration of action.
`0008 Deuterium-labeling of a drug can alter its physico
`chemical properties such as pKa and lipid solubility. These
`changes may influence the fate of the drug at different steps
`along its passage through the body. Absorption, distribution,
`metabolism or excretion can be changed. Absorption and
`distribution are processes that depend primarily on the
`molecular size and the lipophilicity of the substance.
`0009 Drug metabolism can give rise to large isotopic
`effect if the breaking of a chemical bond to a deuterium atom
`is the rate limiting step in the process. While some of the
`physical properties of a deuterium-labeled molecule are
`different from those of the unlabeled one, the chemical and
`biological properties are the same, with one important
`exception: because of the increased mass of the heavy
`isotope, any bond involving the heavy isotope and another
`atom will be stronger than the same bond between the light
`isotope and that atom. In any reaction in which the breaking
`of this bond is the rate limiting step, the reaction will
`proceed slower for the molecule with the heavy isotope due
`to kinetic isotope effect. A reaction involving breaking a C-D
`bond can be up to 700 percent slower than a similar reaction
`involving breaking a C-H bond.
`0010 More caution has to be observed when using deu
`terium-labeled drugs. If the C-D bored is not involved in any
`of the steps leading to the metabolite, there may not be any
`effect to alter the behavior of the drug. If deuterium is placed
`at a site involved in the metabolism of a drug, an isotope
`effect will be observed only if breaking of the C-D bond is
`the rate limiting step. There are evidences to suggest that
`whenever cleavage of an aliphatic C-H bond occurs,
`usually by oxidation catalyzed by a mixed-function oxidase,
`replacement of the hydrogen by deuterium will lead to
`observable isotope effect. It is also important to understand
`that the incorporation of deuterium at the site of metabolism
`slows its rate to the point where another metabolite produced
`by attack at a carbon atom not substituted by deuterium
`becomes the major pathway by a process called “metabolic
`Switching.
`0011. It is also observed that one of the most important
`metabolic pathways of compounds containing aromatic sys
`tems is hydroxylation leading to a phenolic group in the 3 or
`4 position to carbon Substituents. Although this pathway
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`
`involves cleavage of the C–H bond, it is often not accom
`panied by an isotope effect, because the cleavage of this
`bond is mostly not involved in the rate-limiting step. The
`substitution of hydrogen by deuterium at the stereo center
`will induce a greater effect on the activity of the drug.
`0012 Clinically relevant questions with respect to deu
`terium-labeled drugs include the toxicity of the drug and its
`metabolite derivatives, the changes in distribution or elimi
`nation (enzyme induction), lipophilicity which will have an
`effect on absorption of the drug. Replacement of hydrogen
`by deuterium at the site involving the metabolic reaction will
`lead to increased toxicity of the drug. Replacement of
`hydrogen by deuterium at the aliphatic carbons will have an
`isotopic effect to a larger extent. Deuterium placed at an
`aromatic carbon atom, which will be the site of hydroxyla
`tion, may lead to an observable isotope effect, although this
`is less often the case than with aliphatic carbons. In few
`cases, such as in penicillin, the Substitution on the aromatic
`ring will induce the restriction of rotation of the ring around
`the C C bond leading to a favorable stereo-specific situa
`tion to enhance the activity of the drug.
`0013 Side-effects with acute deuterium dosing have been
`shown to be transitory with no demonstrated evidence of
`permanent deleterious action. The threshold of deuterium
`toxicity has been defined in animals and is far in excess of
`concentrations conceivably used in human studies. The
`possibility that deuterium may have additional beneficial
`pharmacological applications can therefore not be excluded.
`0014 PCT Published Patent Application, WO 2004/
`099.137 discloses a class of aminocyclohexyl ether com
`pounds as being useful in the treatment of arrhythmias. One
`class of compounds disclosed therein are particularly effec
`tive in the treatment and/or prevention of arrhythmia, par
`ticularly atrial fibrillation.
`0.015 There exists, therefore, a need to prepare deuter
`ated compounds which can be used, inter alia, as standards
`or tracer molecules in biological or bioanalytical assays in
`order to determine the biological effectiveness and meta
`bolic pathway for a class of compounds disclosed in PCT
`Published Patent Application WO99/50225.
`
`SUMMARY OF THE INVENTION
`In one aspect, this invention is directed to com
`0016.
`pounds of formula (I):
`
`
`
`(I)
`
`wherein:
`0017 R", R°, R, R, R5, R, R7, R, Ril, R12, R13, R14,
`R" and R'' are each independently hydrogen or deute
`rium;
`0018) Rand R'' are each independently hydroxy, meth
`oxy or —OCD; and
`at least one deuterium is present;
`0019)
`0020 as an isolated stereoisomer or as a mixture of
`Stereoisomers;
`0021 or a pharmaceutically acceptable salt thereof.
`0022. In another aspect, this invention is directed to
`compounds of formula (I), as described above, wherein:
`0023) R' and Rare both hydrogen or are both deuterium;
`0024 RandR are both hydrogen or are both deuterium;
`0.025 RandR are both hydrogen or are both deuterium;
`0026 RandR are both hydrogen or are both deuterium;
`0027 R and R'' are each independently hydroxy, meth
`oxy or —OCD:
`0028) R' is hydrogen or deuterium;
`0029) R' and R' are both hydrogen or are both deute
`rium; and
`0030) R'', R'' and R'' are each hydrogen;
`0031 wherein at least one of the following applies:
`0032) a) R' and Rare both deuterium:
`0033 b) R and R are both deuterium;
`0034 c) R and Rare both deuterium:
`d) R7 and R are both deuterium;
`0035)
`e) R is OCD,
`0036)
`f) R' is OCD,
`0037)
`g) R' is deuterium; or
`0038
`h) R'' and R' are both deuterium:
`0039)
`0040 as an isolated stereoisomer or as a mixture of
`Stereoisomers;
`0041 or a pharmaceutically acceptable salt thereof.
`0042. In another aspect, this invention is directed to
`pharmaceutical compositions comprising a pharmaceuti
`cally acceptable excipient and a compound of formula (I), as
`described above, as an isolated Stereoisomer or as a mixture
`of stereoisomers, or a pharmaceutically acceptable salt
`thereof.
`0043. In another aspect, this invention is directed to
`methods of treating arrhythmia in a human, wherein the
`methods comprise administering to the human in need
`thereof a therapeutically effective amount of a compound of
`formula (I), as described above, as an isolated Stereoisomer
`or as a mixture of stereoisomers, or a pharmaceutically
`acceptable salt thereof.
`0044) In another aspect, this invention is directed to
`methods of preparing compounds of formula (I), as
`described above, where R'', R'' and R'' are each hydrogen,
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`as an isolated Stereoisomer or as a mixture of stereoisomers,
`or a pharmaceutically acceptable salt thereof.
`0045. In another aspect, this invention is directed to
`methods of determining the concentration of a compound in
`a biological matrix, wherein the method comprises contact
`ing a compound of formula (I), as described above, where
`R'', R' and R'' are each hydrogen, as an isolated stereoi
`Somer or as a mixture of stereoisomers, or a pharmaceuti
`cally acceptable salt thereof, with a biological matrix con
`taining a compound of formula (1):
`
`(1)
`
`'', N
`
`R10a
`
`OH
`
`wherein each R* and R'' are independently hydroxy or
`methoxy; as an isolated Stereoisomer or as a mixture of
`Stereoisomers, or a pharmaceutically acceptable salt thereof;
`and determining the concentration of the compound of
`formula (1) in the biological matrix.
`0046.
`In another aspect, this invention is directed to
`compounds of formula (II):
`
`(II)
`
`R9
`
`R10:
`
`O
`
`R5 R6
`
`R1 R2
`
`N
`
`3 R4 R12 R13
`
`R11
`
`OH
`
`wherein:
`0047 R', R. R. R. R. R. R7, R, R', R'' and Rare
`each independently hydrogen or deuterium;
`0048 R and R'' are each independently hydroxy, meth
`oxy or —OCD; and
`at least one deuterium is present;
`0049)
`0050 as an isolated stereoisomer or as a mixture of
`stereoisomers;
`0051 or a pharmaceutically acceptable salt thereof.
`0.052
`In another aspect, this invention is directed to
`compounds of formula (II) described above, wherein:
`0053) R' and Rare both hydrogen or are both deuterium:
`0054 RandR are both hydrogen or are both deuterium;
`0055 Rand Rare both hydrogen or are both deuterium:
`
`0056 R7 and Rare both hydrogen or are both deuterium;
`0057 R and R'' are each independently hydroxy, meth
`oxy or —OCD:
`0.058) R' is hydrogen or deuterium; and
`0059) R' and R' are both hydrogen or are both deute
`rium;
`0060 wherein at least one of the following applies:
`a) R' and Rare both deuterium;
`0061
`b) R and R are both deuterium:
`0062)
`c) R and Rare both deuterium;
`0063
`d) R7 and Rare both deuterium:
`0.064
`e) R is OCD:
`0065
`f) R' is OCD,
`0066)
`g) R' is deuterium; or
`0067)
`h) R'' and R' are both deuterium:
`0068
`0069 as an isolated stereoisomer or as a mixture of
`Stereoisomers;
`0070 or a pharmaceutically acceptable salt thereof.
`0071. In another aspect, this invention is directed to
`pharmaceutical compositions comprising a pharmaceuti
`cally acceptable excipient and a compound of formula (II),
`as described above, as an isolated Stereoisomer or as a
`mixture of stereoisomers, or a pharmaceutically acceptable
`salt thereof.
`0072. In another aspect, this invention is directed to
`methods of treating arrhythmia in a human, wherein the
`methods comprise administering to the human in need
`thereof a therapeutically effective amount of a compound of
`formula (II), as described above, as an isolated Stereoisomer
`or as a mixture of stereoisomers, or a pharmaceutically
`acceptable salt thereof.
`0073. In another aspect, this invention is directed to
`methods of preparing compounds of formula (II), as
`described above, as an isolated Stereoisomer or as a mixture
`of stereoisomers, or a pharmaceutically acceptable salt
`thereof.
`0074. In another aspect, this invention is directed to
`methods of determining the concentration of a compound in
`a biological matrix, wherein the method comprises contact
`ing a compound of formula (II), as described above, as an
`isolated Stereoisomer or as a mixture of stereoisomers, or a
`pharmaceutically acceptable salt thereof, with a biological
`matrix containing a compound of formula (2):
`
`(2)
`
`N
`
`R10a
`
`OH
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`wherein each R* and R" are independently hydroxy or
`methoxy; as an isolated Stereoisomer or as a mixture of
`Stereoisomers, or a pharmaceutically acceptable salt thereof;
`and determining the concentration of the compound of
`formula (2) in the biological matrix.
`0075) These and other aspects of the invention will be
`apparent upon reference to the following detailed descrip
`tion. To this end, various references are set forth herein
`which describe in more detail certain background informa
`tion, procedures, compounds and/or compositions, and are
`each hereby incorporated by reference in their entirety.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`0.076 An understanding of the present invention may be
`aided by reference to the following explanation of conven
`tions used herein and definitions:
`0077. The compounds of formula (I) and the compounds
`of formula (II) have an ether oxygen atom at position 1 of
`a cyclohexane ring, and an amine nitrogen atom at position
`2 of the cyclohexane ring, with other positions numbered in
`corresponding order as shown below in Structure (Aa) and
`Structure (Ab), respectively, below:
`
`(Aa)
`
`(Ab)
`
`bond, as illustrated above in Structure (Aa) and a dashed full
`bond, as illustrated above in Structure (Aa), means that the
`Substituents, in this case the amine and ether substituents,
`are in a trans-configuration with respect to the plane of the
`r1ng.
`
`0080. Following the standard chemical literature descrip
`tion practice and as used in this specification, a Solid full
`bond, as illustrated above in Structure (Ab) and a solid full
`bond, as illustrated above in Structure (Ab), means that the
`Substituents, in this case the amine and ether substituents,
`are in a cis-configuration with respect to the plane of the
`r1ng.
`Following the standard chemical literature descrip
`0081
`tion practice and as used in this specification, a full wedge
`bond, as exemplified below in Structure (Ac), means that the
`substituent bonded to the ring by this bond, in this case the
`ether substituent, is above the ring plane as illustrated on the
`page in a two dimensional representation, and a dashed
`wedge bond, as exemplified below in Structure (Ac), means
`that the substituent bonded to the ring by this bond, in this
`case the amine Substituent, is below the ring plane as shown
`on the page in a two dimensional representation. In contrast,
`two full wedge bonds, as exemplified below in Structure
`(Ad), means that both substituents bonded to the ring by
`these bonds, in this case both the ether and the amino
`Substituent, are above the ring plane as illustrated on the
`page in a two dimensional representation:
`
`
`
`(Ac)
`
`(Ad)
`
`0078. The bonds from the cyclohexane ring to the 1-oxy
`gen and 2-mitrogen atoms in the Structure (Aa) above are
`disposed in the trans relationship. Therefore, the stere
`ochemistry of the amine and ether substituents of the cyclo
`hexane ring in Structure (Aa) is (1R,2R)-trans or (1S,2S)-
`trans. The bonds from the cyclohexane ring to the 1-oxygen
`and 2-mitrogen atoms in the Structure (Ab) above are dis
`posed in the cis relationship. Therefore, the stereochemistry
`of the amine and ether Substituents of the cyclohexane ring
`in Structure (Ab) is (1R,2S)-cis or (1R,2S)-cis.
`0079. Following the standard chemical literature descrip
`tion practice and as used in this specification, a solid full
`
`In a similar manner, as exemplified below in Struc
`0082
`ture (Ae), the ether substituent is below the ring plane and
`the amino Substituent is above the ring plane, as shown on
`the page in a two dimensional representation. In contrast, as
`exemplified below in Structure (Af), both the ether and the
`amino Substituent are below the ring plane as illustrated on
`the page in a two dimensional representation:
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`
`
`(Ae)
`
`(Af)
`
`0083. Following the standard chemical literature descrip
`tion practice and as used in this specification, a wavy bond,
`as illustrated below in the compound of formula (B), indi
`cates that the substituent, in this case the —OR substituent,
`is either below the plane of the ring or above the plane of the
`r1ng:
`
`(B)
`
`OR.
`
`0084 As indicated above, the compounds of the present
`invention contain at least two asymmetric carbon atoms and
`thus exist as enantiomers and diastereoisomers. For the
`present invention, the words diastereomer and diastereoiso
`mer and related terms are equivalent and interchangeable.
`Unless otherwise indicated, the present invention includes
`all enantiomeric and diastereoisomeric forms of the ami
`nocyclohexyl ether compounds of formula (I) and formula
`(II). Pure stereoisomers, mixtures of enantiomers and/or
`diastereoisomers, and mixtures of different compounds of
`the invention are included within the present invention.
`Thus, compounds of formula (I) and compounds of formula
`(II) may occur as racemates, diastereomeric mixtures and as
`individual diastereoisomers, or enantiomers, unless a spe
`cific stereoisomer enantiomer or diastereoisomer is identi
`fied, with all isomeric forms being included in the present
`invention. For the present invention, a racemate or diaste
`reomeric mixture does not imply a 50:50 mixture of stere
`oisomers only. Other enantiomerically or diastereomerically
`enriched mixtures of varying ratios of stereoisomers are also
`contemplated. Unless otherwise noted, the phrase “stereoi
`somerically substantially pure' generally refers to those
`asymmetric carbon atoms that are described or illustrated in
`the structural formulae for that compound.
`
`0085. The definition of stereoisomeric purity (or optical
`purity or chiral purity) and related terminology and their
`methods of determination (e.g., Optical rotation, circular
`dichroism etc.) are well known in the art (see e.g., E. L. Eliel
`and S. H. Wilen, in Stereochemistry of Organic Compounds:
`John Wiley & Sons: New York, 1994; and references cited
`therein). The phrase “stereoisomerically substantially pure'
`generally refers to the enrichment of one of the stereoiso
`mers (e.g., enantiomers or diastereoisomers) over the other
`Stereoisomers in a sample, leading to chiral enrichment and
`increase in optical rotation activity of the sample. Enanti
`omer is one of a pair of molecular species that are mirror
`images of each other and not Superimposable. They are
`“mirror-image' stereoisomers. Diastereoisomers generally
`refer to Stereoisomers not related as mirror-images. Enan
`tiomeric excess (ee) and diastereoisomeric excess (de) are
`terms generally used to refer the Stereoisomeric purity (or
`optical purity or chiral purity) of a sample of the compound
`of interest. Their definition and methods of determination
`are well known in the art and can be found e.g., in E. L. Eliel
`and S. H. Wilen, in Stereochemistry of Organic Compounds;
`John Wiley & Sons: New York, 1994; and references cited
`therein. “Stereoselectively making” refers to preparing the
`compound having enantiomeric excess (ee) or diastereoiso
`meric excess (de).
`0.086 For the present invention, enantiomeric excess (ee)
`or diastereoisomeric excess (de) in the range of about 50%
`to about 100% is contemplated. A preferred range of enan
`tiomeric excess (ee) or diastereoisomeric excess (de) is
`about 60% to about 100%. Another preferred range of
`enantiomeric excess (ee) or diastereoisomeric excess (de) is
`about 70% to about 100%. A more preferred range of
`enantiomeric excess (ee) or diastereoisomeric excess (de) is
`about 80% to about 100%. Another more preferred range of
`enantiomeric excess (ee) or diastereoisomeric excess (de) is
`about 85% to about 100%. An even more preferred range of
`enantiomeric excess (ee) or diastereoisomeric excess (de) is
`about 90% to about 100%. Another even more preferred
`range of enantiomeric excess (ee) or diastereoisomeric
`excess (de) is about 95% to about 100%. It is understood that
`the phrase “about 50% to about 100% includes but is not
`limited to all the possible percentage numbers and fractions
`of a number from 50% to 100%. Similarly, the phrase “about
`60% to about 100% includes but is not limited to all the
`possible percentage numbers and fractions of a number from
`60% to 100%; the phrase “about 70% to about 100%”
`includes but is not limited to all the possible percentage
`numbers and fractions of a number from 70% to 100%; the
`phrase “about 80% to about 100% includes but is not
`limited to all the possible percentage numbers and fractions
`of a number from 80% to 100%; the phrase “about 85% to
`about 100% includes all but is not limited to the possible
`percentage numbers and fractions of a number from 85% to
`100%; the phrase “about 90% to about 100% includes but
`is not limited to all the possible percentage numbers and
`fractions of a number from 90% to 100%; the phrase “about
`95% to about 100% includes all but is not limited to the
`possible percentage numbers and fractions of a number from
`95% to 100%.
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`0087 As an example, and in no way limiting the gener
`ality of the above, a compound of formula (I):
`
`
`
`(I)
`
`as described above in the Summary of the Invention,
`includes at least three chiral centers (the cyclohexyl carbon
`bonded to the oxygen at the 1 position, the cyclohexyl
`carbon bonded to the nitrogen at the 2 position, and the
`pyrrolidinyl carbon bonded to the hydroxyl at the 3 position
`of the pyrrolidinyl) and therefore has at least four separate
`stereoisomers, which are (1R,2R)-2-(3R)-hydroxypyrro
`lidinyl-1-(substituted phenethoxy)cyclohexane: (1R,2R)-2-
`(3S)-hydroxypyrrolidinyl-1-(substituted phenethoxy)cy
`clohexane;
`(1S,2S)-2-(3R)-hydroxypyrrolidinyl)-1-
`(substituted phenethoxy)cyclohexane; and (1S,2S)-2-(3S)-
`hydroxypyrrolidinyl-1-(substituted
`phenethoxy)cyclohexane; and, unless the context make plain
`otherwise as used in this specification, for example, a
`compound of formula (I) refers to a composition that
`includes a component that is either one of the possible pure
`enantiomeric or diastereoisomeric forms of the indicated
`compound or is a mixture of any two or more of the pure
`enantiomeric or diastereoisomeric forms, where the mixture
`can include any number of the enantiomeric or diastereoi
`Someric forms in any ratio.
`0088 Similarly, a compound of formula (II):
`
`(II)
`
`R9
`
`R10
`
`R7 R8
`
`O
`
`R5 R6
`
`R1 R2
`
`N
`
`3 R4 R12 R13
`
`R11
`
`OH
`
`as described above in the Summary of the Invention, also
`includes at least three chiral centers and therefore has at least
`four separate stereoisomers, which are (1S,2R)-2-(3R)-
`hydroxypyrrolidinyl)-1-(substituted phenethoxy)cyclohex
`ane;
`(1S,2R)-2-(3S)-hydroxypyrrolidinyl-1-(substituted
`phenethoxy)cyclohexane: (1S,2R)-2-(3R)-hydroxypyrro
`lidinyl-1-(substituted phenethoxy)cyclohexane; and (1S,
`2R)-2-(3S)-hydroxypyrrolidinyl-1-(substituted pheneth
`oxy)cyclohexane; and, unless the context make plain
`otherwise as used in this specification, for example, a
`compound of formula (II) refers to a composition that
`includes a component that is either one of the possible pure
`enantiomeric or diastereoisomeric forms of the indicated
`compound or is a mixture of any two or more of the pure
`enantiomeric or diastereoisomeric forms, where the mixture
`can include any number of the enantiomeric or diastereoi
`Someric forms in any ratio.
`0089 Certain chemical groups named herein are pre
`ceded by the shorthand notation “C-C," where x and y
`indicate the lower and upper, respectively, number of carbon
`atoms to be found in the indicated chemical group. For
`example: C-Cacyl describes an acyl group, as defined
`below, having a total of 1 to 8 carbon atoms. Occasionally,
`certain chemical groups named herein are preceded by the
`shorthand notation “C” where Z indicates the total number
`of carbons to be found in the indicated chemical group. The
`total number of carbons in the shorthand notation does not
`include carbons that may exist in Substituents of the group
`described.
`0090. In accordance with the present invention and as
`used herein, the following terms are defined to have follow
`ing meanings, unless explicitly stated otherwise:
`0091 “Acid addition salts' generally refer to but are not
`limited to those salts which retain the biological effective
`ness and properties of the free bases and which are not
`biologically or otherwise undesirable, formed with inorganic
`acids such as but not limited to hydrochloric acid, hydro
`bromic acid, Sulfuric acid, nitric acid, phosphoric acid and
`the like, or acceptable Lewis acids, or organic acids such as
`but not limited to acetic acid, propionic acid, glycolic acid,
`pyruvic acid, oxalic acid, maleic acid, malonic acid, Succinic
`acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
`cinnamic acid, mandelic acid, methanesulfonic acid, ethane
`Sulfonic acid, p-toluenesulfonic acid, Salicylic acid and the
`like, and include but not limited to those described in for
`example: “Handbook of Pharmaceutical Salts, Properties,
`Selection, and Use'. P. Heinrich Stahl and Camille G.
`Wermuth (Eds.), Published by VHCA (Switzerland) and
`Wiley-VCH (FRG), 2002.
`0092 “Acyl refers to branched or unbranched hydrocar
`bon fragments terminated by a carbonyl —(C=O)—group
`containing the specified number of carbon atoms. Examples
`include acetyl (Ac). CHC(=O)—, a Cacyl and propionyl
`CHCHC(=O)—, a Cacyl).
`0093 “Biological matrix” refers to an environment that
`may or may not be isolated from a warm-blooded animal.
`Non-limiting examples of biological matrices are: urine,
`feces, blood, serum, plasma, saliva, perspiration, tissue fluid,
`cellular cytoplasm, hepatocytes, microsomes, S9 fractions,
`tissues, such as muscle tissue, hepatic tissue, cardiac tissue,
`renal tissue and other bodily environments and/or matrices
`of a warm-blooded animal, preferably a human. A biological
`
`Apotex Ex. 1014
`
`

`

`US 2007/0O8807S A1
`
`Apr. 19, 2007
`
`matrix may be present in Solution or in Solid form or a
`mixture thereof and may be present in or as part of a living
`organism or may be isolated from a living organism Such
`that it forms a sample therefrom.
`0094) “Pharmaceutically acceptable excipients’ for
`therapeutic use are well known in the pharmaceutical art,
`and are described, for example, in Remingtons Pharmaceu
`tical Sciences, Mack Publishing Co. (A. R. Gennaro edit.
`1985). For example, sterile saline and phosphate-buffered
`saline at physiological pH may be used. Preservatives,
`stabilizers, dyes and even flavoring agents may be provided
`in the pharmaceutical composition. For example, sodium
`benzoate, Sorbic acid and esters of p-hydroxybenzoic acid
`may be added as preservatives. In addition, antioxidants and
`Suspending agents may be used.
`0.095 “Pharmaceutically acceptable salt” refers to salts of
`the compounds of the present invention derived from the
`combination of Such compounds and a pharmaceutically
`acceptable organic or inorganic acid (acid addition salts) or
`a pharmaceutically acceptable organic or inorganic base
`(base addition salts) which retain the biological effectiveness
`and properties of the compounds of the present invention
`and which are not biologically or otherwise undesirable.
`Examples of pharmaceutically acceptable salts include, but
`are not limited to, those described in, for example, “Hand
`book of Pharmaceutical Salts, Properties, Selection, and
`Use', P, Heinrich Stahl and Camille G. Wermuth (Eds.),
`Published by VHCA (Switzerland) and Wiley-VCH (FRG),
`2002. The compounds of the present invention may be used
`in either the free base or salt forms, with both forms being
`considered as being within the scope of the present inven
`tion.
`0096) The “therapeutically effective amount” of a com
`pound of the present invention will depend on the route of
`administration, the type of warm-blooded animal being
`treated, and the physical characteristics of the specific warm
`blooded animal under consideration. These factors and their
`relationship to determining this amount are well known to
`skilled practitioners in the m