19 United States
`12 Reissued Patent
`Kohn
`
`ID OD IH IIH
`
`USOORE38551EI
`
`IH
`
`10 Patent Number
`45 Date of Reissued Patent
`
`US RE38551
`Jul
`2004
`
`54 ANTICONVULSANT ENANTLOMERIC
`AMINO ACID DERIVATIVES
`
`75 Inventor
`
`Harold Kohn Chapel Hill NC US
`
`73 Assignee Research Corporation Technologies
`Inc Tucson AZ US
`
`21 Appl No 10/058634
`22 Filed
`Jan 28 2002
`
`Related US Patent Documents
`
`Reissue of
`
`64 Patent No
`Issued
`Appl No
`Filed
`
`5773475
`Jun 30 1998
`08/818688
`Mar 17 1997
`
`U.S Applications
`60 Provisional application No 60 013522 filed on Mar 15
`1996
`51 Int Cl.7
`52 U.S CI
`58 Field of Search
`
`A61K 31/165 CO7C 233 05
`564 155 564/158
`514/616
`514 616 564 155
`564158
`
`56
`
`References Cited
`
`U.S PATENT DOCUMENTS
`
`5378729
`5654301
`
`1995 Kohn et al
`Kohn et al
`8/1997
`
`514 231.2
`
`514 231.2
`
`FOREIGN PATENT DOCUMENTS
`
`OTHER PUBLICATIONS
`
`Am Chem Soc 8919 PP 50125017
`
`Anderson et al
`1967
`Kohn Harold et al Preparation and anticonvulsant
`of
`series of functionalized alph.heteroatom---substituted
`IVIed Chem 34 24442452 1991
`amino acids
`Kohn Harold et al Marked stereospecificity in new class
`109 1988
`Chemical Abatracts
`of anticonvulsants
`Abstract No 183045
`
`activity
`
`Choi Daeock
`et al Synthesis and Anticonvulsant Activi
`ties of NBenzyl2acetamidopropionamide
`Derivatives
`Med Chem 39 19071916 1996
`
`Primary ExaminerShailendra Kumar
`74 Attorney Agent or FirmScully Scott Murphy
`
`Presser
`
`57
`
`The present
`
`configuration about
`formula
`
`ABSTRACT
`
`compound
`invention is directed
`in the
`the asymmetric carbon in the following
`
`to
`
`ArCH2NHCC NCQi
`CH
`
`same and the use
`compositions containing
`pharmaceutical
`in treating CNS disorders in animals
`
`thereof
`
`EP
`
`194 464
`
`1986
`
`13 Claims No Drawings
`
`MYLAN - EXHIBIT 1001
`
`

`
`US RE38551
`
`ANTICONVULSANT ENANTIOMERIC
`AMINO ACID DERIVATIVES
`
`in an acid pH range are useful
`these compounds
`disorders and also
`treatment of convulsion
`
`possess
`
`in the
`anxi
`
`Matter enclosed in heavy brackets
`appears in the
`original patent but forms no part of this reissue specifi-
`cation matter printed in italics indicates the additions
`made by reissue
`
`RELATED APPLICATION
`
`This application claims priority from U.S provisional
`application No 60/013522
`filed on Mar 15 1996
`
`GOVERNMENT SUPPORT
`
`This invention was made with Government support under
`Grant/Contra ct No NIH MS 15604 awarded by the Nati onal
`Institute of Health The Government has certain rights in the
`invention
`
`FIELD OF THE INVENTION
`
`invention relates to novel enantiomeric com-
`The present
`pounds and pharmaceutical
`compositions useful
`ment of epilepsy and other CNS disorders
`
`in the treat-
`
`BACKGROUND OF THE INVENTION
`
`of anticonvulsant
`
`The predominant application
`drugs is
`the control and prevention of seizures associated with epi-
`lepsy or related central nervous
`system disorders Epilepsy
`to many
`refers
`types of
`seizures produced
`by
`recurrent
`paroxysmal excessive neuronal discharges in the brain the
`seizures are petit mal which is asso-
`two main generalized
`ciated with myoclonic jerks akinetic seizures transient
`loss
`of consciousness
`but without convulsion and grand mal
`which manifests
`continuous
`and
`in
`series of seizures
`
`convulsions with loss of consciousness
`
`olytic and sedative properties
`U.S Pat No 5378729 to Kohn et al discloses com
`and
`central
`pounds
`pharmaceutical
`compositions having
`system CNS activity which
`nervous
`are useful
`treatment of epilepsy and other CNS disorders having the
`formula
`
`following general
`
`in the
`
`10
`
`15
`
`20
`
`R2
`
`RNHCCNHJCRl
`
`R3
`
`lower alkynyl
`lower alkenyl
`is hydrogen lower alkyl
`aryl aryl lower alkyl heterocyclic heterocyclic
`lower alkyl
`lower cycloalkyl
`lower alkyl heterocyclic lower cycloalkyl
`or is substituted with at
`lower alkyl and
`is unsubstituted
`least one electron withdrawing group or electron donating
`group
`
`heterocyclic
`
`is
`
`35
`
`lower
`lower alkenyl
`lower alkyl
`R1 is hydrogen
`or
`lower alkyl aryl heterocyclic
`lower alkyl
`alkynyl aryl
`lower cycloalkyl
`25 heterocyclic lower cycloalkyl
`lower alkyl
`each unsubstituted
`or substituted with an electron donating
`group or an electron withdrawing group and
`lower
`R2 and R3 are independently
`hydrogen lower alkyl
`lower alkynyl aryl
`lower alkyl aryl heterocyclic
`alkenyl
`lower alkyl
`lower alkyl heterocyclic lower
`lower alkyl or ZY wherein
`lower cycloalkyl
`cycloalkyl
`or substituted with at
`R2 and R3 may be unsubstituted
`least
`one electron withdrawing group or electron donating group
`NR4 PR4 or
`chemical bond
`lower
`is hydrogen lower alkyl aryl aryl lower alkyl
`lower alkynyl halo heterocyclic or heterocyclic
`alkenyl
`lower alkyl and may be unsubstituted or substituted with
`an electron withdrawing
`an electron
`or
`group
`donating
`group provided that when
`chemical bond
`40 or
`
`is halo
`
`is
`
`for such disorders has been the
`The mainstay of treatment
`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
`least one amide unit and
`characterized
`of at
`by the
`presence
`one or more benzene rings that are present as phenyl group
`or part of
`cyclic system
`Much attention has been focused upon the development of
`drugs and today many such drugs are well
`anticonvulsant
`known For example the hydantions such as phenytoin are
`seizures and all forms of
`useful
`in the control of generalized
`partial seizures The oxazolidinediones such as trimethadi-
`one and paramethadione are used in the treatment of non-
`seizures Phenacemide
`convulsive
`phenylacetylurea is
`known
`the most well
`employed
`one of
`anticonvulsants
`today while much attention has recently been dedicated to
`and piperazines For
`the
`investigation of
`the diazepines
`example U.S Pat Nos 4002764 and 4178378
`Allgeier et al disclose esterified diazepine derivatives
`use-
`in the treatment of epilepsy and other nervous disorders
`ful
`U.S Pat No 3887543 to Nakanishi
`et al describes
`compound also having anticon-
`thieno
`vulsant activity and other depressant activity U.S Pat No 60
`4209516 to Heckendorn
`et al relates to triazole derivatives
`which exhibit anticonvulsant
`activity and are useful
`treatment of epilepsy and conditions
`of tension and agita-
`tion U.S Pat No 4372974 to Fish et al discloses
`amino
`pharmaceutical
`formulation containing
`an aliphatic
`in which the carboxylic acid and primary
`acid compound
`amine are separated by three or four units Administration of
`
`45
`
`to 55
`
`ZY taken together
`NR4OR5 ONR4R7
`is NR4NR5R7
`OPR4R5 PR4OR5 SNR4R7
`NR4SR7 SPR4R5 PR4SR7
`NR4PR5R6 PR4NR5R7
`
`NR4CR5
`
`SCR5
`
`NR4C0R5
`
`SCOR5
`
`II
`
`R4 R5 and
`hydrogen lower alkyl
`are independently
`lower alkyl
`lower alkenyl or lower alkynyl
`aryl aryl
`wherein R4 R5 and R6 may be unsubstituted
`or substituted
`with an electron withdrawing group or an electron donating
`group
`R7 is R6 COOR8 or COR8
`lower alkyl and the
`R8 is hydrogen lower alkyl or aryl
`aryl or alkyl group may be unsubstituted or substituted with
`an electron withdrawing group or an electron donating group
`and
`
`in the
`
`is 14 and
`is 13
`Unfortunately despite the many available pharmacothera
`significant percentage of the population with
`peutic agents
`epilepsy or related disorders are poorly managed Moreover
`65 none of the drugs presently available are capable of achiev
`and most have
`seizure control
`disturbing side
`ing total
`effects Toxicities may appear upon repeated dosing that are
`
`

`
`US RE38551
`
`not apparent with acute administration Because many drugs
`which require chronic
`administration ultimately place an
`extra burden
`on the liver
`including for example liver
`enzyme induction or oxidative metabolism that may gener-
`have associated
`ate reactive species many anticonvulsants
`therewith liver
`
`toxicity
`
`Ar_CH2_N_C_C_N_C_Qi
`
`II
`
`CH
`
`II
`
`Research is continuing
`effective
`anticonvulsant
`
`treatment
`
`in this area to find better and more
`
`for
`
`long term
`
`the
`
`ideal
`
`agents
`especially
`chronic administration Obviously
`drug is one that has high pharmacological activity minimal
`side effects and is relatively non-toxic and safe to the animal
`is being treated More specifically the ideal anticon-
`vulsant drug is one that satisfies the following four criteria
`
`that
`
`low
`
`has
`
`index
`
`high anticonvulsant
`has
`activity expressed as
`ED50
`has minimal neurological toxicity as expressed
`by the median toxic dose TD50 relative to its potency
`maximum protective
`sometimes known
`as
`selectivity or margin of safety which measures the rela-
`tionship between the doses of
`drug required to produce
`and desired effects and is measured as the ratio
`undesired
`between the median toxic dose and the median effective dose
`
`and
`is relatively safe as measured by the
`TD50/ED50
`lethal dose LD50 relative to its potency
`and
`median
`non-toxic to the animal that is being treated e.g it exhibits
`minimal adverse effects on the remainder of
`the treated
`
`is
`
`animal
`
`its organs blood its bodily functions etc even at
`during long term chronic
`high concentrations
`especially
`administration of the drug Thus for example it exhibits
`
`minimal
`
`i.e little
`
`or no liver
`
`toxicity Although not
`
`as
`
`critical
`
`term or acute administration of an anti-
`in short
`convulsant since the animal may tolerate some low levels of
`toxicity the fourth criteria outlined above is extremely
`for an anti-convulsant which is to be taken over
`
`important
`
`10
`
`15
`
`20
`
`25
`
`30
`
`wherein
`Ar is aryl which is unsubstituted or substituted with halo
`is lower alkoxy and
`Q1 is CH3
`invention contemplates employing the com
`The present
`pound of Formula
`in
`pharmaceutical
`composition
`the administration of an effective amount of the
`Moreover
`
`in their pharmaceutically acceptable
`
`compounds
`present
`forms provides
`regime for the treatment
`an excellent
`of
`epilepsy nervous anxiety psychosis insomnia and other
`related central nervous disorders
`These drugs exhibit high anti-convulsant
`activity mini-
`and minimal
`mal neurological
`toxicity high P.1
`These anti-convulsants
`
`toxicity
`
`regime
`
`are utilized in
`treatment
`and especially chronic
`
`dosing
`
`requiring acute dosing
`thereof
`to the patient
`As shown hereinbelow the
`compounds of
`the present
`invention exhibit minimal effects
`on liver which is
`in
`compounds
`
`contrast
`
`to other anti-convulsant
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`As used herein the term alkoxy refers to an 0-alkyl
`group attached to the main chain through an oxygen bridge
`is as defined hereinabove
`35 wherein alkyl
`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
`phenyl group which is unsubstituted or substituted
`refers to
`with halo
`
`40
`
`The term halo includes fluoro chloro bromo iodo and the
`like The preferred halo is fluoro
`
`It
`
`is
`
`in the compound of formula
`is preferred that
`alkoxy having 13 carbon atoms The most preferred alkoxy
`group is propoxy isopropoxy ethoxy and especially meth
`oxy
`The Ar group as defined herein is phenyl which may be
`as defined herein It
`is most
`unsubstituted
`or substituted
`the aryl group i.e phenyl
`preferred that
`substituted with only one halo group It
`is more preferred
`is in the para or meta
`that
`if substituted the halo substituent
`is even more preferred that
`the phenyl group is
`55 position It
`unsubstituted
`
`is unsubstituted
`
`or
`
`Examples of
`include
`
`the
`
`compounds
`
`of
`
`the present
`
`invention
`
`60
`
`propionamide
`R-N-Benzyl-2-acetamido-3-methoxy
`-3 Flu or benz
`-2- ace tam do -3
`methoxypropionamide
`R-N-4-Fluorobenzyl-2-acetamide-3-
`methoxypropionamide
`
`time chronic
`long period of
`dosage It may be the most
`which anti-convulsant
`to administer to
`
`or in high
`administration
`in determining
`
`factor
`
`important
`
`patient especially
`if chronic dosing is required Thus an anti-convulsant
`agent
`which has
`has minimal
`high anti-convulsant
`activity
`toxicity and maximal P.1 protective index
`neurological
`may unfortunately exhibit such toxicities which
`appear upon
`repeated high levels of administration In such an event
`it would not
`acute dosing of the drug may be considered but
`be used in
`regime which requires
`treatment
`administration of the anti-convulsant
`In fact
`
`chronic
`
`if an anti-
`
`convulsant
`
`treatment
`
`convulsant
`
`long term
`is required for repeated dosing in
`physician may prescribe an anti-
`regime
`that may have weaker activity relative
`second anti-convulsant
`it exhibits relatively low toxicity
`to the animal An anti-convulsant
`agent which meets all four
`
`if
`
`to
`
`criteria is very rare
`
`inventor has found such
`
`However
`
`compounds
`
`that
`
`group of
`the present
`is generally potent exhibit minimal neuro-
`index and is relatively
`logical toxicity has
`high protective
`non-toxic to the body organs including the liver upon
`multiple dosing
`
`SUMMARY OF THE INVENTION
`
`Accordingly
`
`the present
`
`invention
`
`is directed
`
`to 65
`
`N-benzyl-2-acetamido propionamide derivatives
`configuration having the formula
`
`in the
`
`propionamide
`R-N-Benzyl-2-acetamido-3-ethoxy
`As indicated by the asterisk in formula
`the compounds
`least one asymmetric
`invention contain at
`of the present
`carbon The stereochemistry of the asymmetric carbon at the
`
`

`
`asterisk is in the
`
`the
`
`stereoisomer
`
`at
`
`or
`
`It
`
`It
`
`greater
`
`It
`
`tam
`
`greater
`
`US RE38551
`
`10
`
`It
`
`invention con-
`
`ii
`
`ArCH2NCCNCQi
`CH2OH
`
`II
`
`II
`
`acid in the
`
`configuration The inventor has found that
`the asymmetric carbon at
`the asterisk
`is significantly more efficacious
`than the corresponding
`enantiomer
`racemic mixture thereof
`the compound of the present
`invention
`is preferred that
`be substantially pure i.e substantially free from impurities
`is most preferred that
`the compounds
`of
`the present
`least 75% pure w/w and more preferably
`invention be at
`than about 90% pure w/w and most preferably
`than about 95% pure w/w
`greater
`compounds of
`the
`the present
`is also preferred that
`invention be substantially enantiomerically pure i.e sub
`known
`The enantiopurity of was determined
`by techniques
`isomer
`is more
`stantially free from the corresponding
`rotation and 111
`preferred that
`the compounds of the present
`in the art including melting point optical
`stereoisomer and most preferably 15 NMR upon
`at least 90% w/w
`addition of
`an organic
`R-configuration such as R- mandelic acid Crystalliza
`than about 95% w/w in the
`stereoisomer Thus
`invention contemplates
`compounds
`having at
`the present
`most about 10% isomer w/w and even more preferably
`less than about 5% isomer w/w
`The compounds of the present
`prepared by art
`recognized
`techniques
`
`form are
`invention in the
`from commercially
`
`20
`
`available starting materials
`An exemplary procedure is outlined in Scheme
`below
`
`herein-
`
`was achieved
`
`is converted
`
`to the ether
`
`tion of was repeated until
`the desired enantiopurity thereof
`The product of
`it with OX
`under Williamson
`conditions by reacting
`wherein
`is as defined herein above and
`is good leaving
`groups such as OTs OMs or halide e.g CH3I and the like
`in the presence of base e.g Ag20 to form the product
`having Formula
`
`CH2OH
`
`H2N CH3OH
`
`OH
`
`HC1
`
`Scheme
`
`CH2OH
`
`HCl.H2N
`
`PhCH2NH2
`
`CH2OH
`
`CH2OCH3
`
`CH3_1N
`
`CH3I
`
`CH
`
`AcO
`
`recrystallization
`
`CHOH
`
`serine molecule
`conditions with an alcohol
`
`is
`
`of
`
`is esterified under acylation
`such as acidic methanol
`reacted with
`the
`ester
`corresponding
`provide
`ArCH2NH2 such as benzylamine under acylation
`tions to form the corresponding
`amide
`Acylation of the
`free amino group with an acylating derivative
`
`Another variation is depicted in Scheme
`
`to 50
`
`condi
`
`CH2OH
`
`R-1
`
`CH
`
`Ac20
`AcOH
`
`CHOH
`
`R-6
`
`60
`
`65
`
`ArCH2NH2
`Med Anhydride
`Method
`
`Q1COH
`
`II
`
`such as acetic acid or
`acetic anhydride
`
`provides
`
`lower alkyl ester of acetic acid or
`the hydroxymethyl derivative
`
`i.e
`
`

`
`US RE38551
`
`-continued
`
`H0H
`
`CH3Nf NHCH2Ar
`
`CH3I
`
`Ag20
`
`R-7
`
`-continued
`
`OCH3
`
`CbzNH NH
`
`H2 10% Pdc
`______________
`MeOH
`hr 15 mill
`97%
`
`cH2OcH3
`
`cH3N
`
`R-8
`
`10
`
`15
`
`is
`
`treatment with
`For example beginning with D-serine
`of acetic acid such as acetic anhy
`derivative
`an acylating
`which 20
`amide
`dride in acetic acid gives the corresponding
`then reacted with ArCH2NH2 under mixed anhydride
`reaction conditions as described by Anderson et
`coupling
`al in JACS 1967 89 50125017 the contents of which are
`incoorated herein by reference to give the corresponding
`compound of the formula
`
`25
`
`12
`
`OcH3
`
`Ac20 Pyridine DMAP
`
`2N1
`
`13
`
`H3CLN
`
`NH
`
`CH
`
`OH
`
`30
`
`R-8
`
`35
`
`it
`
`Alkylation of this R-product
`e.g
`presence
`under Williamson conditions
`such as methyl
`Ag20 provides
`product of Formula
`
`in the
`
`of base
`
`iodide in
`
`An alternative route is depicted in Scheme
`
`OH
`
`H2N1cOOH
`
`R-1
`
`cbzcl MgO
`H20 ET2O 68%
`
`OH
`
`cbzNHcOOH
`
`MecN Ag20 cH3I
`
`24 hrs RT 94%
`
`ocH3
`
`cbzNHcOOcH3
`
`10
`
`ocH3
`
`cbzNHX
`
`cooH
`
`11
`
`80% MeOH/I-120
`
`K2c03 RT
`
`hrs
`
`N-Methylmorpholine
`
`isobutyl chioroformate
`
`benzylamine dry
`THF -78
`78%
`
`is protected with
`Serine
`N-protecting group
`known in the art by standard techniques Thus for example
`chloride CBZ-cl benzyl
`is reacted with carbobenzoxy
`the N-protected CBZ-D-serine
`chloroformate
`generating
`The product
`is converted
`adduct
`serine adduct
`to the
`ether under Williamson conditions by react
`corresponding
`ing it with QX wherein
`and
`are defined hereinabove
`40 e.g CH3I in the presence of base e.g Ag20 to form an
`ether 10 Under
`these conditions the acid is also esterified
`in 10 permits
`Subsequent hydrolysis of
`the ester group
`amide coupling with ArCH2 NH2 using
`amide coupling
`methodology e.g mixed
`anhydride 11
`to give the amide 12 Deprotection
`45 Carbonyldiimidazole
`the free amine 13 which is
`the N-protecting group provide
`then reacted with an acylating agent such as acetic anhydride
`the product R-8
`in base e.g pyridine to provide
`described
`the procedures
`If necessary
`in any of
`the optical purity of
`the product may be
`so hereinabove
`enhanced by further separation of the
`enantiomer
`from the
`enantiomer by standard techniques known in the art such
`as chiral chromatography
`standard chiral support
`known in the art
`
`of
`
`using
`
`55
`
`60
`
`65
`
`Alternatively
`
`the procedures provided
`in any of
`serine may be utilized as the
`racemic
`hereinabove
`starting material Following the procedures
`in any of the
`schemes outlined hereinabove would provide
`the racemic
`be
`mixture which can
`isomer by
`resolved
`into the
`known in the art such as chiral chro
`standard techniques
`
`matography
`The active ingredients
`of the
`compositions
`and the compounds of the present
`invention exhibit excellent
`activity when administered
`in amounts rang
`anticonvulsant
`ing from about mg to about 100 mg per kilogram of body
`weight per day This dosage regimen may be adjusted by the
`response For
`physician to provide the optimum therapeutic
`
`therapeutic
`
`

`
`US RE38551
`
`10
`
`example several divided doses may be administered daily or
`the dose may be proportionally reduced as indicated by the
`decided practical
`situation
`exigencies of the therapeutic
`the active compound may be administered
`advantage is that
`in an convenient manner such as by the oral
`intravenous
`or subcutaneous
`where water soluble intramuscular
`routes
`The active compound may be orally administered
`for
`example with an inert diluent or with an assimilable edible
`it may be enclosed in hard or soft shell gelatin 10
`carrier or
`capsules or it may be compressed into tablets
`or it may be
`the diet For oral
`directly into the food of
`incorporated
`administration the active compound may be
`therapeutic
`incorporated with excipients
`and used in the form of ingest-
`buccal
`troches
`ible tablets
`capsules elixirs 15
`tablets
`syrups wafers and the like Such compositions
`suspensions
`least 1% of active com-
`should contain at
`and preparations
`pound The percentage of the compositions and preparations
`may of course be varied and may conveniently
`be between
`to about 80% of the weight of the unit The amount
`about
`of active compound
`in such therapeutically useful compo-
`sitions is such that
`be obtained
`dosage will
`suitable
`
`ethanol polyol for example glycerol propylene glycol and
`liquid polyethylene glycol and the like suitable mixtures
`and
`can
`be
`vegetable oils The proper
`thereof
`fluidity
`coating such as
`maintained for example by the use of
`lecithin by the maintenance
`of the required particle size in
`and by the use of surfactants The
`the case of dispersions
`prevention of the action of microorganisms can be brought
`and antifungal agents
`about by various antibacterial
`for
`example parabens chlorobutanol
`sorbic acid
`phenol
`thimerosal and the like In many cases
`it will be preferable
`sugars or sodium
`isotonic agents for example
`to include
`composi
`of the injectable
`chloride Prolonged
`absorption
`tions can be brought about by the use in the compositions of
`aluminum
`delaying
`absorption
`for example
`agents
`and gelatin
`monostearate
`solutions are prepared by incorporating
`Sterile injectable
`the active compound
`in the required amount
`in the appro
`ingredients enumer
`priate solvent with various of the other
`as required followed by filtered sterilization
`ated above
`Generally dispersions
`are prepared by incorporating the
`20 various sterilized active ingredient
`into
`sterile vehicle
`the basic dispersion medium and the
`which contains
`from those enumerated above In
`required other
`ingredients
`the case of sterile powders
`the preparation
`solutions the preferred methods of preparation
`injectable
`are vacuum drying and the freeze-drying technique which
`powder of the active ingredient plus any additional
`yield
`from previously sterile-filtered solution
`desired ingredient
`thereof
`As used herein
`acceptable carrier
`pharmaceutically
`dispersion media
`any and all solvents
`includes
`coatings
`and antifungal agents isotonic and absorption
`antibacterial
`the like The use of such media and
`delaying agents and
`active substances is well known in
`agents for pharmaceutical
`insofar as any conventional media or agent is
`the art Except
`its use in the thera
`incompatible with the active ingredient
`active
`
`for
`
`of sterile
`
`Preferred
`
`as
`
`extent
`
`the
`
`compositions or preparations
`to the
`according
`invention are prepared so that an oral dosage unit
`present
`100 mg of active 25
`form contains
`between
`and
`about
`compound
`The tablets troches pills capsules and the like may also
`binder such as gum tragacanth
`the following
`contain
`such as dicalcium
`acacia corn starch or gelatin excipients
`disintegrating agent such as corn starch potato
`phosphate
`starch alginic acid and the like
`lubricant such as magne-
`and
`agent such as sucrose
`sium stearate
`sweetening
`lactose or saccharin may be added or
`flavoring agent such
`as peppermint oil of wintergreen or cherry flavoring When
`the dosage unit form is
`it may contain in addition 35
`capsule
`peutic compositions is contemplated Supplementary
`of materials of the above type
`liquid carrier Various other
`ingredients can also be incorporated
`into the compositions
`advantageous to formulate parenteral com
`materials may be present as coatings or to otherwise modify
`is especially
`positions in dosage unit form for ease of administration and
`the physical form of the dosage unit For instance tablets
`uniformity of dosage Dosage unit form as used herein refers
`pills or capsules may be coated with shellac sugar or both
`syrup or elixir may contain the active compound sucrose 40
`to physically discrete units suited as unitary dosages for the
`mammalian subjects
`to be treated each unit containing
`agent methyl and propylparabens as
`sweetening
`dye and flavoring such as cherry or orange
`predetermined quantity of active material calculated to pro-
`preservatives
`duce
`in association with the
`flavor Of course any material used in preparing any dosage
`effect
`the desired therapeutic
`carrier The specifics for the novel
`unit form should be pharmaceutically pure and substantially
`required pharmaceutical
`the invention are dictated by and
`forms of
`non-toxic in the amounts employed In addition the active 45 dosage unit
`compound may be
`directly dependent on
`of the
`the unique characteristics
`incorporated into sustained-release
`preparations and formulations
`For example sustained
`active material and the particular
`effect
`release dosage forms are contemplated wherein the active
`and
`achieved
`the
`limitations inherent
`resin which
`is bound
`such an active material
`compounding
`ion exchange
`to an
`ingredient
`optionally can be coated with
`diseased condition in
`diffusion barrier coating to So disease in living subjects having
`which bodily health is impaired as herein disclosed in detail
`modify the release properties of the resin
`The active compound may also be administered parenter-
`The principal active ingredient is compounded
`for con-
`ally or intraperitoneally Dispersions can also be prepared in
`and effective
`amounts
`venient
`administration in effective
`liquid polyethylene glycols and mixtures thereof
`with suitable pharmaceutically acceptable carrier in dosage
`glycerol
`and in oils Under ordinary conditions of storage and use 55 unit form as hereinbefore described Aunit dosage form can
`active compound
`contain
`the
`in
`these preparations
`to prevent
`the principal
`for example contain
`to about 1000 mg Expressed
`amounts ranging from about
`growth of microorganisms
`forms suitable
`The pharmaceutical
`in proportions the active compound
`for
`in
`use
`is generally present
`injectable
`sterile aqueous solutions where water soluble or
`from about
`to about 750 mg/ml of carrier
`include
`In the case of
`and
`sterile powders
`the extemporaneous
`60 compositions containing
`supplementary active ingredients
`for
`dispersions
`the dosages are determined by reference to the usual dose
`preparation of sterile injectable
`solutions or dispersions In
`the form must be sterile and must be fluid to the
`and manner of administration of the said ingredients
`all cases
`Unless
`that easy syringability exists It must be stable under
`are by
`indicated
`the
`contrary percentages
`of manufacture
`be
`and storage and must
`conditions
`the contaminating action of microorgan-
`preserved
`against
`isms such as bacteria and fungi The carrier can be
`solvent
`or dispersion medium containing
`for example water
`
`30
`
`It
`
`therapeutic
`
`to be
`
`in the art of
`
`for the treatment of
`
`preservative
`
`to
`
`65
`
`weight
`As used herein the term lower alkyl
`refers to an alkyl
`group containing 16 carbon atoms which may be straight
`chained or branched
`
`

`
`US RE38551
`
`11
`
`12
`
`For
`better understanding of the present
`is made to the following description
`
`ence
`
`invention refer-
`and examples
`
`GENERAL METHODS
`
`Thomas Hoover
`
`against
`
`To
`
`stirred acetonitrile
`
`10
`
`successively
`
`calcd for
`
`constants
`
`EXAMPLE
`
`R-N-Benzyl-2-Acetamide-3-methoxypropionamide
`
`above-identified
`
`15
`
`20
`
`25
`
`calcd for C13H19N203 251.139
`
`Another Synthesis of R-N-Benzyl 2-Acetamide-3-
`methoxy propionamide
`
`hereinabove
`2-acetamidohydracrylamide
`prepared
`gave
`for the acetyl methyl protons 13C NMR
`only one signal
`DMSO-d6 22.7 COCH3 42.0 CH2NH 55.6 CH
`61.8CH2OH 126.7 C4 127.0 2C2 or 2C3 128.2 2C2
`or 2C3 139.4 C1 169.5 COCH3 or CONH 170.3
`COCH3 or CONH ppm MS Cl rd intensity 237
`Melting points were determined with
`Infrared spec- M1 100 2198 MrCl 237.12388
`melting point apparatus and are uncorrected
`C12H17N203 237.12392 Anal C12H16N203 CHN
`tra IR were run on Perkin-Elmer 1330 283 and Mattson
`solution 300 mL of R-N
`and were calibrated
`the 1601
`Genesis spectrometer
`cm bond of polystyrene Absorption values are expressed
`in wave-numbers cm Proton 1H NMR and carbon 13C
`10 mmol was
`benzyl-2-acetamidohydroacrylamide 2.36
`50 mmol and methyl
`added Ag20 11.59
`NMR nuclear magnetic
`iodide 6.2 mL 100 mmol at
`resonance spectra were taken on
`room temperature The
`Nicolet NT-300 and General Electric QE-300 NMR instru-
`reaction mixture was stirred at room temperature for
`days
`are in parts per million ppm
`filtered and
`The insoluble salts were
`ments Chemical shifts
`solvents were
`the
`removed in vacuo to give
`white solid The residue was
`relative to Me4Si and coupling
`values are in
`filtered with Et20 100 mL to give 2.20
`88% of the
`hertz All chemical
`ionization mass spectral
`investigations
`on Finnegan MAT TSQ-70
`product
`instrument
`conducted
`were
`c1 MeOH16.4 RfO.47
`mp 143144
`Microanalyses were provided by Atlantic Microlab Inc
`10% MeOHCHC13 JR KBr 3289 3086 2923 2876
`Norcross Ga Thin layer chromatography
`was performed
`2819 1636 1547 1138 695 cm 1H NMR CDC13 ö2.04
`on precoated silica gel GHLF microscope slides 2.5x10 cm
`COCH3 3.38
`OCH3 3.43 dd J7.8 9.0 Hz
`Analtech No 21521
`CHHOCH3 3.82 dd J4.2 9.0 Hz CHHOCH3 4.48d
`J6.0 Hz NHCH2 4.514.57 mCH 6.44 br
`J5.4 Hz
`NH 6.75 br NH 7.257.37
`PhH addition of
`excess R--mandelic acid to
`CDC13 solution of R-18
`gave only one signal for the acetyl methyl and ether methyl
`protons 13C NMR CDC13 23.2 COCH3 43.5
`219.4 mmol was passed into
`Hydrochloric acid 8.00
`CH2NH 52.4 CH 59.1 OCH3 71.7 CH2OCH3 127.4
`MeOH 250 mL and then D-Serine 20.00
`190.3 mmol
`was added The reaction solution was heated at reflux 18 C4 127.5 2C2 or 2C3 128.7 2C2 or 2C3 137.9 C1
`169.9 COCH3 or CONH 170.3 COCH3 or CONH
`hours benzylamine 81.6 mL 761 mmol was added and
`ppm MS Cl rd intensity 251 M1 100 2196 Mr
`then the reaction was heated for an additional eighteen
`Cl251.139 76
`hours The solvent was removed under reduced pressure the
`57 Anal C13H18N203
`insoluble salts filtered and
`the excess benzylamine was
`EXAMPLE
`removed under high vacuum Kugelrohr The residue was
`in water 100 mL and the product was extracted
`dissolved
`with CHC13 8x200 mL The organic layers were combined
`dried Na2504 and the solvent was removed under reduced
`pressure The residue was triturated with Et20 150 mL and
`Improved Synthesis of R-N-Benzyl 2-
`27% of
`the product R-enriched
`filtered to give 10.0
`Acetamidohydracrylamide
`white solid mp
`stirred AcOH 20 mL suspension of D-serine 5.26
`N-benzyl 2-aminohydracrylamide
`as
`To
`c1 MeOH1.6 Rf 0.30 10% 40
`7478
`50 mmol was added Ac20 4.7 mL 50 mmol and then
`MeOHCHC13 1H NMR DMSO-d6 1.87 br NH2
`the reaction suspension was stirred at room temperature 24
`J5.4 Hz CH 3.393.55
`CH2OH 4.28
`hours The ACOH was removed in vacuo to give an oily
`J5.7 Hz NHCH2 4.76
`J5.4 Hz CH2OH 7.187.32
`residue and then THF 150 mL was added to the residue
`J5.7 Hz NH 13C NMR DMSO-d6
`The THF suspension was cooled to 78 under N2 and
`SPhH 8.34
`41.8 NHCH2 56.9 CH 64.3 CH2OH 126.6 C4
`4-methylmorpholine 11.0 mL 100 mmol was added After
`127.0 2C2 or 2C3 128.1 2C2 or 2C3 139.5 C1 173.3
`CONH ppm MS Cl rd intensity 195 M1 53
`stirring for two minutes isobutyl chloroformate 13.0 mL
`56 M1 calcd
`100 mmol was added leading to the precipitation of white
`117 100 MrCl 195.113
`solid The reaction was allowed
`to proceed for two addi
`tional minutes and then benzylamine 10.4 mL 100 mmol
`C1QH15N202 195.11335
`50 was added at 78 The reaction mixture was allowed to
`stirred methylene chloride suspension 100 ml of
`To
`room temperature 30 minutes and
`51.5
`enriched N-benzyl-2-aminohydracrylamide
`10.00
`stir
`at
`the
`mmol was added acetic anhydride 5.8 mL 61.8 mmol
`4-methylmorpholine hydrochloride salt was filtered The
`and the reaction suspension was stirred at room temperature
`in vacuo The product was
`layer was concentrated
`organic
`hour The solvent was removed under
`reduced pressure
`on 5i02 gel 10%
`purified by flash column chromatography
`33% as white solid mp
`MeOHCHC13 to give 3.89
`white solid The product was triturated with Et20
`C1 MeOH21.70
`250 mL to give 7.60
`62% of enriched R-N-benzyl-2-
`147148
`1H NMR
`CO CH3 3.57 dd J5.1 5.1 Hz
`white solid The reaction
`DMSO-d6 ö1.86
`acetamidohydracrylamide as
`J5.1 Hz OH
`product was recrystallized 2x using EtOH to give 3.50
`CH2NH CH 4.90
`CH2O 4.274.31
`29% of
`J8.1 Hz NH 8.37
`PhH 7.93
`the R-N-benzyl-2-acetamidohydracylamide mp
`J6.0
`7.207.31
`c1 MeOH22.4 Rf 0.40 10% 60 Hz NH addition of excess R--mandelic acid to
`148149
`MeOHCHC13 JR KBr 3295 3090 2964 1642 1533
`1376 1281 1051 705 cm 1H NMR DMSO-d6 ö1.86
`COCH3 3.57 dd J5.7 5.7 Hz CH2OH 4.254.31m
`CH 4.27
`J5.7 Hz NHCH2 4.92
`J5.7 Hz
`J7.8Hz NH 8.38 65
`CH2OH 7.187.32
`PhH 7.94
`NH addition of excess R- mandelic acid to
`J5.7
`solution
`CDC13
`R-N-benzyl
`
`3.23
`
`to give
`
`for
`
`CDC13 solution of the product of
`the acetyl methyl protons
`
`gave only one signal for
`
`R-N-Benzyl-2-Acetamide-3-
`
`methoxypropionamide
`
`of
`
`mmol
`To the compound
`in
`prepared in
`1.42
`stirred solution 300 ml of CH3CN was successively added
`
`

`
`US RE38551
`
`for
`
`14
`
`for the
`
`identified
`
`4.48
`
`31
`
`269.130 15 Anal
`
`13
`iodide 3.7 mL 60
`30 mmol and methyl
`Ag20 6.95
`above identified compound
`gave only one signal
`acetyl methyl protons and ether methyl protons 13C NMR
`mmol and stirred at room temperature
`days The
`DMSO-d6 22.8 COCH3 42.7 CH2N 52.6 CH 58.9
`insoluble salts were filtered and the solvent was removed in
`0dH3 72.0 dH20dH3 114.0
`C4 122.7 C6 129.9 cF Hz C5 140.6
`CF-215 Hz C2 and
`white solid The white solid was triturated
`vacuo to give
`with Et20 100 mL to given 1.30
`87% of the above-
`c1
`compound mp 143144
`JCF244.4 Hz C3 170.2
`JcF6.8 Hz C1 162.9
`COCH3 or CONH 170.5 COCH3 or CONH ppm
`COCH3
`MeOH16.0 1H NMR CDC13 2.04
`MS Cl rd intensity 269 M1 100 Mr Cl 269.129
`3.38s OCH3 3.44 dd J7.5 9.0 Hz CH H1 OCH3 3.81
`dd J4.2 9.0 Hz CHHOCH3
`J5.7 Hz
`calcd for C13H18FN203