FILE HISTORY
`60/013,522
`
`INVENTORS: HAROLD KOHN , HOUSTON, TX (US)
`
`TITLE:
`
`ANTICONVULSANT ENANTIOMERIC AMINO
`ACID DERIVATIVES
`
`APPLICATION
`NO:
`FILED:
`
`60/013,522
`
`15 MAR 1996
`
`COMPILED:
`
`19 FEB 2014
`
`IPR2014-01126- Exhibit 1012, p. 1
`
`

`
`(0
`
`= U-
`U/) W
`00
`
`ROVISIONAL
`PPLICATION
`
`UMBER60 /013'0
`
`SERIAL NUMBER
`
`FILUNG DATE
`LI/ E / 9 6
`
`I;
`
`ICLASS
`
`ISUBCLASS
`
`IGROUP ART UNIT I XMIE
`
`fIIiSID
`
`.1
`
`44:IN I l!M1 10:
`
`r:lI*~~E r Ffl\I/I U: I
`V .. ~.,.AhI'
`
`I.!
`
`F I)NS 4*4 4
`
`t. 4.
`
`F i:iF F C, N F:*I Lr hir?G
`
`I.. l FIT 1
`
`I
`
`F.r
`
`-1
`
`r4.v4±'.iI\IK1 L
`
`IEI'i1 ] f/
`
`44 4 .4. .4:
`
`Foreign priority claimed
`35 USC 119 conditions met
`Verified and Acknowledged
`
`01 no
`0 yes
`0 no
`0 ye
`Exariiner's initials
`
`AS
`FILE
`
`ee'
`
`SAEOR ISHEETS
`T07AL
`CLAIMS
`COUNTRY DRWGS.
`I1111.
`I
`
`IINDEP
`CLAIMS
`
`FILUNG FEE
`RECEIVED
`
`IATTORNEYS
`DOCKET NO.
`
`I
`
`1 I'J1135c'
`
`0N I\ C INVJ
`
`-f Ni N T 1. 1.] ly1 F:; .i: C 0 Ni l
`
`AC7IfD
`
`[:ERPJW.YI:* q
`
`U.S DEPT OF COMM./ PAT& TM-PTO-436L (Row.12-94)
`
`Form PTO-1 625
`(Rev. 5/95
`
`IPR2014-01126- Exhibit 1012, p. 2
`
`

`
`60/013,522
`
`ANTICONVULSANT ENANTIOMERIC AMINO ACID DERIVATIVES
`
`Transaction History
`
`
`Transaction Description
`Date
`Initial Exam Team nn
`03-27-1996
`05-14-1996 Preexamination Location Change
`09-21-2001 Set Application Status
` 
`
`IPR2014-01126- Exhibit 1012, p. 3
`
`

`
`rg~
`
`APPROVED FOR LICENSE
`PATENT APPLICATION
`APR qj
`II I fThI~JJIIIrIjrrIII.ITIALS
`'
`
`i
`
`60013522
`CONTENTS
`
`Reeie
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`o
`1Ied
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`1. Ap fiation _______papers.
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`(FRONT)
`
`IPR2014-01126- Exhibit 1012, p. 4
`
`

`
`POSITION
`CLASSIFIER
`EXAMINER
`TYPIST
`VERIFIER
`CORPS CORR.
`
`SPEC._HAND
`FILE_MAINT
`DRAFTING
`
`ID NO.
`
`DATE
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`(LEFT INSIOE)
`
`IPR2014-01126- Exhibit 1012, p. 5
`
`

`
`-
`
`r
`
`_____________
`
`-
`
`IPR2014-01126- Exhibit 1012, p. 6
`
`

`
`PATENT APPLICATION SERIAL NO.60013522
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
`
`260 YC 19-3886 04/01/96 60013522
`75.OOCH P-10030
`26094 214
`
`PTO-15 56
`(5/87)
`
`IPR2014-01126- Exhibit 1012, p. 7
`
`

`
`BAR CODE LABEL
`
`N~ rn O HU.S. PATENT APPLICATION
`IIIlhYI 111 I!fhII
`
`
`SERIAL NUMBER
`
`FILING GATE
`
`CLASS
`
`GROUP ART UNIT
`
`60/013, 522
`PROVISIONAL
`
`03/15/96
`
`I_________________I________
`
`HAROLD KOHN, HOUSTON, TX.
`
`**CONTINUING DATA*********************
`VERIFIED
`
`**FOREIGN/PCT APPLICATIONS************
`VERIFIED
`
`FOREIGN FILING LICENSE GRANTED 04/22/96
`STATE OR
`COUNTRY
`
`CLAIMS
`
`TX
`
`LEOPOLD PRESSER
`SCULLY SCOTT MURPHY AND PRESSER
`S 400 GARDEN CITY PLAZA
`GARDEN CITY NY 11530
`
`*****
`
`SMALL ENTITY *****
`
`RECEIVED
`
`$75.00
`
`P-10030
`
`ANTICONVULSANT ENANTIOMERIC AMINO ACID DERIVATIVES
`
`P
`
`This is to certify that annexed hereto is a true copy from the records of the United States
`Patent and Trademark Office of the application which is identified above.
`By authority of the
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`Date
`
`Certifying Officer
`
`IPR2014-01126- Exhibit 1012, p. 8
`
`

`
`ABSTRACT
`
`The present invention is directed to a
`compound in the R configuration about the asymmetric
`
`carbon in the following formula:
`
`HH
`Ar-CH2 NHC-C-N- C-Ql
`
`O CH2 0
`
`pharmaceutical compositions containing same and the
`use thereof in treating CNS disorders in animals.
`
`IPR2014-01126- Exhibit 1012, p. 9
`
`

`
`MAR
`
`~
`
`J b6
`
`1003 0.MJC
`
`bb\F: \WORK\030\1003O\spec\10030.mjc60/013522
`
`FIELD OF THE INVENTION
`
`5
`The present invention relates to novel
`enantiomeric compounds and pharmaceutical compositions
`
`useful in the treatment of epilepsy and other CNS
`
`disorders.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`The predominant application of
`
`anticonvulsant drugs is the control and prevention of
`
`seizures associated with epilepsy or related central
`
`15
`
`nervous system disorders. Epilepsy refers to many
`types of recurrent seizures produced by paroxysmal
`
`excessive neuronal discharges in the brain; the two
`main generalized seizures are petit mal, which is
`
`20
`
`associated with myoclonic jerks, akinetic seizures,
`transient loss of consciousness, but without
`
`convulsion; and grand mal which manifests in a
`continuous series of seizures and convulsions with
`
`25
`
`30
`
`loss of consciousness.
`The mainstay of treatment for such disorders
`has been the long-term and consistent administration
`
`of anticonvulsant drugs. Most drugs in use are weak
`
`acids that, presumably, exert their action on neurons,
`glial cells or both of the central nervous system.
`The majority of these compounds are characterized by
`the presence of at least one amide unit and one or
`
`IPR2014-01126- Exhibit 1012, p. 10
`
`

`
`5
`
`10
`
`1 more benzene rings that are present as a phenyl group
`or part of a cyclic system.
`Much attention has been focused upon the
`development of anticonvulsant drugs and today many
`such drugs are well known. For example, the
`hydantions, such as phenytoin, are useful in the
`control of generalized seizures and all forms of
`partial seizures. The oxazolidinediones, such as
`trimethadione and paramethadione, are used in the
`treatment of nonconvulsive seizures. Phenacemide, a
`phenylacetylurea, is one of the most well known
`anticonvulsants employed today, while much attention
`has recently been dedicated to the investigation of
`15 the diazepines and piperazines. For example, U.S.
`Pat. Nos. 4,002,764 and 4,178,378 to Allgeier, et al.
`disclose esterified diazepine derivatives useful in
`the treatment of epilepsy and other nervous disorders.
`
`20
`
`25
`
`U.S. Pat. No. 3,887,543 to Nakanishi, et al. describes
`a thieno [2,3-el [1,4]diazepine compound also having
`anticonvulsant activity and other depressant activity.
`U.S. Pat. No. 4,209,516 to Eeckendorn, et al. relates
`to triazole derivatives which exhibit anticonvulsant
`activity and are useful in the treatment of epilepsy
`
`and conditions of tension and agitation. U.S. Pat.
`No. 4,372,974 to Fish, et al. discloses a
`pharmaceutical formulation containing an al.iphatic
`30 amino acid compound in which the carboxylic acid and
`primary amine are separated by three or four units.
`Administration of these compounds in an acid pH range
`
`IPR2014-01126- Exhibit 1012, p. 11
`
`

`
`are useful in the treatment of convulsion disorders
`and also possess anxiolytic and sedative properties.
`U.S. Pat. No. 5,378,729 to Kohn, et al.
`5 disclose compounds and pharmaceutical compositions
`having central nervous system (CNS) activity which are
`useful in the treatment of epilepsy and other CNS
`disorders having the following general formula:
`
`10
`
`R2-
`
`II
`
`1.5
`
`R is hydrogen, lower alkyl, lower alkenyl,
`lower alkynyl, aryl, aryl lower alkyl, heterocyclic,
`
`heterocyclic lower alkyl, lower alkyl heterocyclic,
`lower cycloalkyl, lower cycloalkyl lower alkyl, and R
`
`is unsubstituted or is substituted with at least one
`electron withdrawing group, or electron donating
`
`20
`
`group.
`
`R, is hydrogen or lower alkyl, lower
`alkenyl, lower alkynyl, aryl lower alkyl, aryl,
`heterocyclic lower alkyl, heterocyclic, lower
`cycloalkyl, lower cycloalkyl lower alkyl, each
`
`unsubstituted or substituted with an electron donating
`
`group or an electron withdrawing group and
`R2 and R3 are independently hydrogen,
`alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl,
`aryl, heterocyclic, heterocyclic lower alkyl, lower
`
`lower
`
`25
`
`30
`
`IPR2014-01126- Exhibit 1012, p. 12
`
`

`
`5
`
`10
`
`15
`
`20
`
`25
`
`1 alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl
`
`lower alkyl, or Z-Y wherein R(2 and R3 may be
`unsubstituted or substituted with at least one
`
`electron withdrawing group or electron donating group;
`Z is 0, S,S(0) a, NRl41 PR4 or a chemical bond;
`Y is hydrogen, lower alkyl, aryl, aryl lower
`alkyl, lower alkenyl, lower alkynyl, halo,
`heterocyclic, or heterocyclic lower alkyl, and Y may
`be unsubstituted or substituted with an electron
`donating group or an electron withdrawing group,
`
`provided that when Y is halo, Z is a chemical bond, or
`ZY taken together is NR4NR5R7, NR4OR5, ONR4R7 1
`OPR 4 R5 , PR4 OR5 , SNR4 R7 , NR4 SR 7 , SPR4 R5 1 PR4 SR 7 , NR4 PR 5R 6 ,
`PR4 NR 5R7 I
`
`NR 4 C-R 5 ,
`11
`0
`
`SCR5 ,
`11
`0
`
`NR 4 C-0R 5 ,
`11
`0
`
`SC-OR 5
`11
`0
`
`R4, R5 and R. are independently hydrogen,
`lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or
`lower alkynyl, wherein R1
`R5 and R, may be
`
`unsubstituted or substituted with an electron
`withdrawing group or an electron donating group,
`is
`R6. COOR6 or COR 8 ,
`R is hydrogen, lower alkyl, or aryl lower
`alkyl, and the aryl or alkyl group may be
`
`R(7
`
`unsubstituted or substituted with an electron
`30 withdrawing group or an electron donating group and
`
`IPR2014-01126- Exhibit 1012, p. 13
`
`

`
`n is 1-4 and
`a is 1-3.
`Unfortunately, despite the many available
`5 pharmacotherapeutic agents, a significant percentage
`of the population with epilepsy or related disorders
`
`are poorly managed. Moreover, none of the drugs
`presently available are capable of achieving total
`seizure control, but unfortunately, most have
`
`10
`
`disturbing side effects. Furthermore, many
`anticonvulsants have associated therewith liver
`
`toxicity.
`
`15
`
`20
`
`25
`
`Research is continuing in this area to find
`better and more effective anticonvulsant agents.
`Obviously, the ideal drug is one that has high
`pharmacological activity, minimal side effects and is
`relatively non-toxic and safe to the animal that is
`being treated. More specifically, the ideal
`
`anticonvulsant drug is one that satisfies the
`following four criteria: (1) has a high
`(expressed as ED50 ) ;
`anticonvulsant activity,
`(2) has
`minimal neurological toxicity, (as expressed by the
`median toxic dose (TD50)), relative to its potency; (3)
`has a maximum protective index (sometimes known as
`
`selectivity or margin of safety), which measures the
`
`relationship between the doses of a drug required to
`
`produce undesired and desired effects, and is measured
`
`as the ratio between the median toxic dose and the
`30 median effective dose (TD5 0/E0 50 ); and (4) is relatively
`safe as measured by the median lethal close (LD50)
`
`IPR2014-01126- Exhibit 1012, p. 14
`
`

`
`relative to its potency and is non-toxic to the animal
`
`that is being treated, e.g., it exhibits minimal
`adverse effects on the remainder of the treated
`5 animal, its organs, blood, its bodily functions, etc.
`even at high concentrations. Thus, for example, it
`exhibits little or no liver toxicity.
`Heretofore, no anti-convulsant drug has been
`
`developed that has the following characteristics:
`maximum potency, minimal neurological toxicity,
`
`10
`
`superior protective index and minimal liver toxicity.
`
`However, the present inventor has found such
`
`a group of compounds that is generally potent, exhibit
`
`15
`
`minimal neurologically toxicity, has a high protective
`index and is relatively non-toxic to the body organs,
`including the liver.
`
`SUMMARY OF THE INVENTION
`
`20
`
`Accordingly, the present invention is
`directed to N-benzyl-2-acetamido propionamide
`
`derivatives in the R configuration having the formula:
`
`H
`H H
`I 1 1
`Ar-CH2-- N-C-C*--N-C-Q1
`0OCH 2
`0
`
`Q
`
`R
`
`25
`
`30
`
`wherein
`
`I
`
`IPR2014-01126- Exhibit 1012, p. 15
`
`

`
`1
`
`Ar is aryl which is unsubstituted or
`substituted with halo;
`
`5
`
`10
`
`Q is lower alkoxy; and
`Q, is CH3.
`The present invention contemplates employing
`the compound of Formula I in a pharmaceutical
`composition. Moreover, the administration of an
`effective amount of the present compounds in their
`pharmaceutically acceptable forms provides an
`excellent regime for the treatment of epilepsy,
`nervous anxiety, psychosis, insomnia, and other
`related central nervous disorders.
`
`15
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The term "alkoxy" refers to an O-alkyl group
`attached to the main chain through an oxygen bridge,
`wherein alkyl is as defined hereinabove. The alkoxy
`
`groups are lower alkoxy groups containing one to six
`carbon atoms, and more preferably, one to three carbon
`atoms. The most preferred alkoxy groups are propoxy,
`isopropoxy, ethoxy and especially methoxy.
`The term "aryl", when used alone or in
`combination, refers to a phenyl group which is
`unsubstituted or substituted with halo.
`The term halo includes fluoro, chloro,
`bromo, iodo and the like. The preferred halo is
`fluoro.
`
`20
`
`25
`
`30
`
`IPR2014-01126- Exhibit 1012, p. 16
`
`

`
`It is preferred that Q in the compound of
`formula I is alkoxy having 1-3 carbon atoms. The most
`preferred alkoxy group is propoxy, isopropoxy, ethoxy
`
`and especially methoxy.
`
`The Ar group as defined herein, is phenyl,
`which may be unsubstituted or substituted as defined
`herein. It is most preferred that the aryl group,
`
`i.e., phenyl, is unsubstituted or substituted with
`
`10
`
`only one halo group. It is more preferred that if
`
`substituted, the halo substituent is in the para or
`meta position. It is even more preferred that the
`
`phenyl group is unsubstituted.
`
`Examples of the compounds of the present
`invention include:
`
`15
`
`(R) -N-Benzyl-2-acetamido-3-methoxy
`
`propionamide,
`
`(R) -N- (3-Fluorobenzyl) -2-acetamido-3-
`
`20
`
`methoxypropionamide,
`CR1-N- (4-Fluorobenzyl)-2-acetamide-3-
`
`methoxypropionamide,
`
`(R) -N-Benzyl-2-acetamido-3-ethoxy
`
`prop ionamide.
`As indicated by the asterisk in formula I,
`
`25
`
`the 6ompounds of the present invention contain at
`
`least one asymmetric carbon and the stereochemistry at
`the asymmetric carbon is in the R configuration. The
`
`inventor has found that the R stereoisomer is
`30 significantly more efficacious than the corresponding
`S enantiomer or a racemic mixture thereof.
`
`IPR2014-01126- Exhibit 1012, p. 17
`
`

`
`1
`
`It is preferred that the compound of the
`present invention be substantially pure, i.e.,
`substantially free from impurities. It is most
`preferred that the compounds of the present invention
`be at least 75% pure (w/w) and more preferably greater
`
`5
`
`than about 90% pure (w/w) and most preferably greater
`
`than about 95% pure (w/w).
`
`Tt is also preferred that the compounds of
`the present invention be substantially
`
`10
`
`enantiomerically pure, i.e., substantially free from
`the corresponding S isomer. It is more preferred that
`
`the compounds of the present invention contain at
`
`least 90% (w/w) R stereoisomer, and most preferably
`15 greater than about 95% (w/w) in the R stereoisomer.
`Thus, the present invention contemplates compounds
`
`having at most about 10% S isomer (w/w), and even more
`preferably less than about 5% 5 isomer (w/w).
`
`20
`
`The compounds of the present invention in
`the R form are prepared by art recognized techniques
`
`from commercially available starting materials.
`
`An exemplary procedure is outlined in Scheme
`
`'I hereinbelow:
`
`25
`
`Scheme 1
`
`30C2HCH
`O CH30HICH3H2
`HCIH2 NkI~
`H1
`0~
`
`20H-
`
`00
`
`H2N94
`
`1
`
`35
`
`2
`
`CH-20"
`
`PhH 2 H2
`
`H 2
`
`A
`
`0
`
`:3
`
`JAC20
`
`IPR2014-01126- Exhibit 1012, p. 18
`
`

`
`-10-
`
`CH3
`
`CH2OCH 3
`
`Ho0
`
`5
`
`meaymombontf
`
`0OCH2 0H
`CH31
`HCH 2Ph
`N19.
`Ag2Q OH3A
`
`H 0
`
`4
`
`15
`
`A D serine molecule (1) is esterified under
`acylation conditions with an alcohol, such as acidic
`
`methanol, to provide the corresponding ester (2) .
`is reacted with ArCH2NH2 . such as benzylamine, under
`acylation conditions to form the corresponding amide
`
`2
`
`20
`
`25
`
`Acylation of the free amino group, with an
`(3) .
`acylating derivative of Q, C-OH,
`11
`0
`such as acetic acid, or lower alkyl ester of acetic
`acid, or acetic anhydride provides the hydroxymethyl
`derivative, i.e.,
`
`0
`H HNHI1
`Ar CH2 N-C-C-N-C-Q1
`
`(4)
`
`0 CH2-OH
`
`IPR2014-01126- Exhibit 1012, p. 19
`
`

`
`1 The enantiopurity of 4 was determined by techniques
`
`known in the art, including melting point, optical
`rotation and 1H NM4R upon addition of an organic acid
`5 in the R-configuration, such as El(-)- mandelic acid.
`Crystallization of 4 was repeated until the desired
`enantiopurity thereof was achieved. The product of 4
`is converted to the ether under Williamson conditions
`by reacting it with OX, wherein Q is as defined herein
`above and X is good leaving groups, such as OTs, CMs,
`or halide (e.g., CH3I) and the like in the presence of
`base (e.g., Ag 2O) to form the product
`(5) having
`Formula I.
`
`Another variation is depicted in Scheme 2.
`
`10
`
`15
`
`ScIlelic 2
`
`AC20
`ACOH
`
`H2N
`
`C
`
`ICU(
`
`(M)- 1
`
`0
`cH20H
`( OH
`cH3At4 )
`H
`0
`
`M6
`
`ArCH 2NH2
`Mixed Anhydd&
`Metliod
`
`o C 1i20H-
`CHL A NS NHCH2At
`Ho0
`(R)-7
`
`CH31
`Ag2O
`
`o CH20CH3
`IIHA
`N o
`,,t
`0i) ~
`
`IPR2014-01126- Exhibit 1012, p. 20
`
`

`
`1-
`
`10
`
`151
`
`For example, beginning with D-serine (1),
`treatment with an acylating derivative of acetic acid.
`
`5 such as acetic anhydride in acetic acid, gives the
`corresponding amide 6 which is then reacted with
`ArCH2NH2 under mixed anhydride coupling reaction
`conditions, as described by Anderson, et al., in JAS
`1967, L, 5012-5017, the contents of which are
`incorporated herein by reference, to give the
`
`corresponding compound of the formula:
`H HEH
`Ar-CH12-N--C-C-N-C-Q,
`
`0 CH2 0
`
`OH
`
`R
`
`e.g., 7. Alkylation of this R-product in the presence
`
`20
`
`of base under Williamson conditions, such as methyl
`iodide in Ag2 0, provides a product of Formula I (.a).
`The active ingredients of the therapeutic
`
`compositions and the compounds of the present
`invention exhibit excellent anticonvulsant activity
`when administered in amounts ranging from about 1 mg
`25 to about 100 mg per kilogram of body weight per day.
`This dosage regimen may be adjusted by the physician
`
`to provide the optimum therapeutic response. For
`
`example, several divided doses may be administered
`
`30) daily or the dose may be proportionally reduced as
`indicated by the exigencies of the therapeutic
`
`IPR2014-01126- Exhibit 1012, p. 21
`
`

`
`-13-
`
`I situation. A decided practical advantage is that the
`
`5
`
`10
`
`15
`
`active compound may be administered in an convenient
`manner such as by the oral, intravenous (where water
`
`soluble), intramuscular or subcutaneous routes.
`The active compound may be orally
`administered, for example, with an inert diluent or
`with an assimilable edible carrier, or it may be
`enclosed in hard or soft shell gelatin capsules, or it
`may be compressed into tablets, or it may be
`incorporated directly into the food of the diet. For
`oral therapeutic administration, the active compound
`may be incorporated with excipients and used in the
`form of ingestible tablets, buccal tablets, troches,
`capsules, elixirs, suspensions, syrups, wafers, and
`the like. Such compositions and preparations should
`contain at least 1% of active compound. The
`percentage of the compositions and preparations may,
`
`20
`
`of course, be varied and may conveniently be between
`about 5 to about 80% of the weight of the unit. The
`
`amount of active compound in such therapeutically
`
`useful compositions is such that a suitable dosage
`
`will be obtained. Preferred compositions or
`preparations according to the present invention are
`
`25
`
`prepared so that an oral dosage unit form contains
`between about 5 and 1000 mg of active compound.
`
`The tablets, troches, pills, capsules and
`30 the like may also contain the following: A binder
`such as gum tragacanth, acacia, corn starch or
`
`gelatin; excipients such as dicalcium phosphate; a
`
`IPR2014-01126- Exhibit 1012, p. 22
`
`

`
`-14-
`
`- disintegrating agent such as corn starch, potato
`starch, alginic acid and the like; a lubricant such as
`magnesium stearate; and a sweetening agent such as
`5 sucrose, lactose or saccharin may be added or a
`flavoring agent such as peppermint, oil of
`wintergreen, or cherry flavoring. When the dosage
`unit form is a capsule, it may contain, in addition to
`materials of the above type, a liquid carrier.
`Various other materials may be present as coatings or
`to otherwise modify the physical form of the dosage
`unit. For instance, tablets, pills, or capsules may
`be coated with shellac, sugar or both. A syrup or
`elixir may contain the active compound, sucrose as a
`sweetening agent, methyl and propylparabens as
`preservatives, a dye and flavoring such as cherry or
`orange flavor. Of course, any material used in
`preparing any dosage unit form should be
`
`pharmaceutically pure and substantially non-toxic in
`the amounts employed. In addition, the active
`compound may be incorporated into sustained-release
`preparations and formulations. For example, sustained
`release dosage forms are contemplated wherein the
`active ingredient is bound to an ion exchange resin
`
`which, optionally, can be coated with a diffusion
`barrier coating to modify the release properties of
`
`10
`
`15
`
`20
`
`25
`
`the resin.
`
`The active compound may also be administered
`30 parenterally or intraperitoneally. Dispersions can
`also be prepared in glycerol, liquid polyethylene
`
`IPR2014-01126- Exhibit 1012, p. 23
`
`

`
`glycols, and mixtures thereof and in oils. Under
`
`ordinary conditions of storage and use, these
`preparations contain a preservative to prevent the
`growth of microorganisms.
`The pharmaceutical forms suitable for
`injectable use include sterile aqueous solutions
`(where water soluble) or dispersions and sterile
`powders for the extemporaneous preparation of sterile
`
`10
`
`15
`
`injectable solutions or dispersions. In all cases the
`form must be sterile and must be fluid to the extent
`that easy syringability exists. It must be stable
`under the conditions of manufacture and storage and
`must be preserved against the contaminating action of
`microorganisms such as bacteria and fungi. The
`carrier can be a solvent or dispersion medium
`
`containing, for example, water, ethanol, polyol (for
`example, glycerol, propylene glycol, and liquid
`
`20
`
`polyethylene glycol, and the like), suitable mixtures
`thereof, and vegetable oils. The proper fluidity can
`
`be maintained, for example, by the use of a coating
`such as lecithin, by the maintenance of the required
`
`particle size in the case of dispersions and by the
`use of surfactants. The prevention of the action of
`
`25
`
`micrborganisms can be brought about by various
`
`antibacterial and antifungal agents, for example,
`
`parabens, chlorobutanol, phenol, scrbic acid,
`thimerosal, and the like. In many cases, it will be
`30 preferable to include isotonic agents, for example,
`sugars or sodium chloride. Prolonged absorption of
`
`IPR2014-01126- Exhibit 1012, p. 24
`
`

`
`-16-
`
`the injectable compositions can be brought about by
`the use in the compositions of agents delaying
`absorption, for example, aluminum monostearate and
`5 gelatin.
`
`Sterile injectable solutions are prepared by
`incorporating the active compound in the required
`
`amount in the appropriate solvent with various of the
`other ingredients enumerated above, as required,
`followed by filtered sterilization. Generally,
`
`10
`
`15
`
`dispersions are prepared by incorporating the various
`sterilized active ingredient into a sterile vehicle
`
`which contains the basic dispersion medium and the
`required other ingredients from those enumerated
`above. In the case of sterile powders for the
`preparation of sterile injectable solutions, the
`preferred methods of preparation are vacuum drying and
`the freeze-drying technique which yield a powder of
`
`20
`
`the active ingredient plus any additional desired
`ingredient from previously sterile-filtered solution
`
`thereof.
`
`As used herein, "pharmaceutically acceptable
`
`carrier" includes any and all solvents, dispersion
`media, coatings, antibacterial and antifungal agents,
`
`25
`
`isotonic and absorption delaying agents, and the like.
`The use of such media and agents for pharmaceutical
`
`active substances is well known in the art. Except
`insofar as any conventional media or agent is
`30 incompatible with the active ingredient, its use in
`the therapeutic compositions is contemplated.
`
`IPR2014-01126- Exhibit 1012, p. 25
`
`

`
`Supplementary active ingredients can also be
`
`incorporated into the compositions.
`
`5
`
`It is especially advantageous to formulate
`parenteral compositions in dosage unit form for ease
`of administration and uniformity of dosage. Dosage
`
`unit form as used herein refers to physically discrete
`units suited as unitary dosages for the mammalian
`
`subjects to be treated; each unit containing a
`
`10
`
`predetermined quantity of active material calculated
`
`to produce the desired therapeutic effect in
`
`association with the required pharmaceutical carrier.
`
`The specifics for the novel dosage unit forms of the
`
`15
`
`invention are dictated by and directly, dependent on
`(a) the unique characteristics of the active material
`and the particular therapeutic effect to be achieved,
`
`and (b) the limitations inherent in the art of
`
`compounding such an active material for the treatment
`
`20
`
`of disease in living subjects having a diseased
`condition in which bodily health is impaired as herein
`
`disclosed in detail.
`
`The principal active ingredient is
`
`compounded for convenient and effective administration
`in effective amounts with a suitable pharmaceutically
`
`25
`
`acceptable carrier in dosage unit form as hereinbefore
`described. A unit dosage form can, for example,
`contain the principal active compound in amounts
`ranging from about 5 to about 1000 mg. Expressed in
`proportions, the active compound is generally present
`in from about 1 to about 750 mg/ml of carrier. In the
`
`30
`
`IPR2014-01126- Exhibit 1012, p. 26
`
`

`
`-18-
`
`case of compositions containing supplementary active
`ingredients, the dosages are determined by reference
`to the usual dose and manner of administration of the
`
`5 said ingredients.
`Unless indicated to the contrary,
`percentages are by weight.
`As used herein, the term lower alkyl refers
`to an alkyl group containing 1-6 carbon atoms which
`10 may be straight chained or branched.
`For a better understanding of the present
`invention reference is made to the following
`
`description and examples.
`
`15
`
`20
`
`25
`
`30
`
`IPR2014-01126- Exhibit 1012, p. 27
`
`

`
`1
`
`GENERAL METHODS
`
`Melting points were determined with a Thomas
`
`5 Hoover melting point apparatus and are uncorrected.
`Infrared spectra (IR) were run on Perkin-Elmer 1330,
`283 and a Mattson Genesis spectrometer and were
`calibrated against the 1601 cm-f' bond of polystyrene.
`Absorption values are expressed in wave-numbers (cm-').
`("C NMR) nuclear magnetic
`10 Proton ('H NMR)
`and carbon
`resonance spectra were taken on Nicolet NT-300 and
`General Electric QE-300 NMR instruments. Chemical
`shifts (8) are in parts per million (ppm) relative to
`15 Me4Si and coupling constants (J values) are in hertz.
`All chemical ionization mass spectral investigations
`
`were conducted on Finnegan MAT TSQ-70 instrument.
`Ethyl c-acetamido cyanoacetate was obtained from
`
`Aldrich Chemical Co. Microanalyses were provided by
`
`Thin layer
`20 Atlantic Microlab Inc. (Norcross, Ga) .
`chromatography was performed on precoated silica gel
`
`GHLF microscope slides (2.5 x 10 cm; Analtech No.
`
`21521).
`
`25
`
`30
`
`IPR2014-01126- Exhibit 1012, p. 28
`
`

`
`-20-
`
`EXAMPLE 1
`
`5
`
`(R) -N-Benzyl-2-Acetamido-3-
`
`methoxypropionamide
`
`Hydrochloric acid (8.0Og, 219.4 mmol) was
`passed into MeGH (250 mL) and then D-Serine (20.00g,
`
`190.3 mmol) was added. The reaction solution was
`10 heated at reflux (18 hours), benzylamine (81.6 mL, 761
`
`mmol) was added and then the reaction was heated for
`
`an additional eighteen hours. The solvent was removed
`under reduced pressure, the insoluble salts filtered,
`15 and the excess benzylamine was removed under high
`vacuum (Kugelrohr). The residue was dissolved in
`
`water (100 mL), and the product was extracted with
`CHCl3 (8 x 200 mL) .
`The organic layers were combined,
`dried. (Na 2 SO4),
`and the solvent was removed under
`20 reduced pressure. The residue was triturated with
`mL) and filtered to give 10.0 g (27%) of the
`Et 2O (11;
`product R-enriched N-benzyl 2-aminohydracrylamide, as
`a white solid: mp 74-78 0C.; [a]D0
`2 1 (c=l, MeOH) = -. 6',
`(DMSO-dQ)
`61.87 (br s,
`Rf 0.30
`(10% MeOH-CHC1 3 );
`'H NM4R
`25 NH2 ) , 3. 23
`J=5. 4 Hz, CH) , 3. 39-3. 55
`(t,
`(in, CH20H) ,
`4. 28 (d, J=5. 7 Hz, NHCH2) 4. 76 (t, J=5. 4 Hz, CH20H) ,
`'7.18-7.32 (in, 5PhH), 8.34 (t J=5.7 Hz, NH), 13 C NMR
`126.6
`(CH20H),
`(CH),
`(NHCH 2 ), 56.9
`64.3
`6) 41.8
`(DMSO-d
`
`30
`
`139.5
`1 ),
`(2C 2 ' or 2C3
`128.1
`(2C 2 ' or 2C3 '),
`(C 4.), 127.0
`C11), 173.3 (C(0)NH) ppm, MS (+Cl) (rel intensity),
`
`IPR2014-01126- Exhibit 1012, p. 29
`
`

`
`-21-
`
`195 (M+ +1,
`53) , 117
`(100) , Mr (+Cl) 195. 113 56 (M+ +1)
`for C1. H15 N2 02/ 195.11335).
`(calcd.
`To a stirred methylene chloride suspension
`
`5 (100 ml) of R enriched N-benzyl 2-aminohydracrylamide
`(10.00 g, 51.5 mmol) was added acetic anhydride (5.8
`mL, 61.8 mnmol), and the reaction suspension was
`stirred at room temperature (1 hour) .
`The solvent was
`removed under reduced pressure to give a white solid.
`10 The product was triturated with Et 2O (250 mL)
`to give
`7.60g (62%) of enriched R-N-benzyl-2-
`acetamidohydracrylamide as a white solid. The
`reaction product was recrystallized (2x) using EtOHl to
`give 3.50 g (29%) of the R-N-benzyl-2-
`15 acetamidohydracrylamide mp 148-1490 C; [aID 23
`Cc=l,
`MeOH) =+22. 40 ; Rf 0. 40
`(10% MeQiH -CHC1 3 ) ;
`(KBr) 3295,
`IR
`3090, 2964, 1642, 1533, 1376, 1281, 1051, 705 cm; 'H
`(DMS0
`-d 6) 61.86 (s,C(0)CH3), 3.57
`NMR
`(dd, J=5.7, 5.7
`
`(d, J=5.7 Hz,
`20 Hz, CH2 OH), 4.25-4.31(m,CH),
`4.27
`NHCH2 ), 4.92 Ct, J=5.7 Hz, CH20H), 7.18-7.32
`Cm, 5 Phil)
`7.94 (d, J=7.8Hz, NH), 8.38 Ct, J=5.7 H, NH), addition
`of excess fl-C-) mandelic acid to a CDC1 3 solution of
`R-N-benzyl 2-acetamidohydracrylamide prepared
`25 hereinabove gave only one signal for the acetyl methyl
`
`(CH2NH),
`(C(0)CH3 ), 42.0
`6) 22.7
`(DMSO-d
`protons; 13 C NMR
`126.7
`55.6
`(CH),
`61.8(CH20H),
`127.0
`(2C2' or
`(C 4'),
`1), 128.2
`2C3
`(2C 2 ' or 2C3 '), 139.4 (C,'), 169.5
`(C(0)CH3
`(+ Cl)
`30 or C(0)NH),
`(C(0)CH3 or C(O)NH) ppm; MS
`170.3
`rel intensity) 237(M+1l,
`100), 219(8); Mr(+Cl)
`
`IPR2014-01126- Exhibit 1012, p. 30
`
`

`
`-22-
`
`10
`
`15 RfO.47
`
`1237. 12388
`(calcd for C12 H17 N2 03 237. 12392);
`[m+-'l1]
`Anal (C,2HI6N20 3), C,EH,N.
`To a stirred acetonitrile solution (300mL)
`5 of (R)-N-benzyl (a-Acetamidohydroacrylamide (2.36g,
`50 mmol)
`10mmol) was successively added Ag 2O (11.59g,
`and methyl iodide (6.2 mL, 100 mmol) at room
`temperature. The reaction mixture was stirred at room
`temperature for 4 days. The insoluble salts were
`filtered, and the solvents were removed in vacuo to
`give a white solid. The residue was filtered with
`Et2O (100 mL) to give 2.20g (88%) of the above-
`identified product.
`mp 143-1440 C; [a1D 2 1 (c=l, MeOH)=+16.40 ;
`(10% MeOH-CHCl3);
`(KBr) 3289,3086, 2923,
`IR
`2876, 2819, 1636, 1547, 1138, 695 cmf'; 'H NMR (CDCl3)
`(dd, J=7.8,
`(s, OCH3 ), 3.43
`(s, C(O)CH3), 3.38
`62.04
`9.0 Hz, CHH'OCH3), 3.82 (dd, J=4.2, 9.0 Hz, CHH'OCH3),
`(br
`6.44
`(m,CH),
`4.48(d, J=6.0 Hz, NH-CH2 ), 4.51-4.57
`d, J=5.4 Hz, NH), 6.75 (br s, NH), 7.25-7.37 (m, 5
`PhH), addition of excess (R)-(-)-mandelic acid to a
`CDCl 3 solution of (R)-18 gave only one signal for the
`acetyl methyl and ether methyl protons; '3C NMR (CDCl3)
`23.2 (C (0) CH3), 4 3. 5
`(CH2NH) , 5 2. 4 (CE) , 5 9. 1
`(OCH 3),1
`(2C2' or 2C3 '),1 12 8.-7
`(C 4'),1 127. 5
`71 .7 (CH20CH3),
`127 .4
`(C (0)CH3 or C (O)NH) ,
`169.9
`(C,),
`(2C2' or 2C3 ' ) 137.9
`170.3 (C(O)CH3 or C(O)NH) ppm; MS (+Cl) (rel
`(+Cl) 251.139 76
`100) , 219 (6) ; Mr
`(M+1l,
`30 intensity) 251
`(calcd for C, 3 , 9 N20 3 251.139 57) ; Anal.
`[M+l1]
`(C1 3H18 N2 0 3 ) C, H, N.
`
`20
`
`25
`
`IPR2014-01126- Exhibit 1012, p.