DD
`DD
`US005773475A
`Patent Number
`
`Date of Patent
`
`DD
`
`5773475
`Jun 30 1998
`
`IIII
`
`Kahn Harold et al Marked stereospecificity
`Chemical Abstracts
`
`of anticonvulsants
`Abstract No 183045
`
`in new class
`
`1988
`
`109
`
`Choi Daeock et al Synthesis and Anticonvulsant Activities
`
`of NBenzyl2acetamidopropionamide
`Med Chem 1996 39 19071916
`
`Derivatives
`
`Primary ExaminerShailendra Kumar
`Attorney Agent or FirmScully Scott Murphy
`
`Presser
`
`ABSTRACT
`
`The present
`
`invention is directed
`
`to
`
`United States Patent
`Kohn
`
`ANTICONVULSANT ENANTIOMERIC
`AMINO ACID DERIVATIVES
`
`Inventor
`
`Harold Kohn Houston Tex
`
`Assignee Research Corporation Technologies
`Inc Tucson Ariz
`
`Appl No 818688
`
`Filed
`
`Int Cl.6
`
`Mar 17 1997
`A61K 31/16 A6IK 31 165
`CO7C 233 05
`
`U.S Cl
`
`Field of Search
`
`514/616
`
`564 155 564 158
`514 616 564 155
`564 158
`
`compound
`the asymmetric carbon in the following
`
`in the
`
`References Cited
`
`U.S PATENT DOCUMENTS
`
`configuration about
`
`formula
`
`5378729
`5.654301
`
`11995 Kohn et al
`1997 Kohn et al
`
`514/231.2
`
`514 231.2
`
`FOREIGN PATENT DOCUMENTS
`
`194 464
`
`1986
`
`European Pat Off
`
`OTHER PUBLICATIONS
`
`ArCH2NHCCNCQ1
`
`II
`
`II
`
`CH2
`
`et al J.Am.Chem Soc 8919 pp 50125017
`
`Anderson
`1967
`Kohn Harold et al Preparation and anticonvulsant
`series of functionalized alph.heteroatomsubstituted
`of
`Med Chem 1991 34 24442452
`amino acids
`
`activity
`
`same and the use
`pharmaceutical
`compositions containing
`thereof in treating CNS disorders in animals
`
`13 Claims No Drawings
`
`Breckenridge Exhibit 1005
`Breckenridge v. Research Corporation Technologies, Inc.
`
`-1-
`
`

`
`5773475
`
`ANTICONVULSANT ENANTIOMERIC
`AMINO ACID DERIVATIVES
`
`FIELD OF THE INVENTION
`
`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
`
`The present
`invention relates to novel enantiorneric
`pounds and pharrnaceutical
`cornpositions useful in the treat-
`rnent of epilepsy and other CNS disorders
`BACKGROUND OF THE INVENTION
`
`corn-
`
`The predorninant
`drugs is
`of anticonvulsant
`application
`the control and prevention of seizures associated with epi-
`lepsy or related central nervous systern disorders Epilepsy
`refers
`recurrent
`types of
`seizures produced by
`to
`rnany
`paroxysrnal excessive neuronal discharges
`in the brain the
`two rnain generalized
`seizures are petit rnal which is asso-
`ciated with rnyoclonic jerks akinetic seizures transient
`loss
`but without convulsion and grand rnal
`of consciousness
`which rnanifests
`continuous
`and
`in
`series of seizures
`
`10
`
`convulsions with loss of consciousness
`
`heterocyclic
`
`is
`
`lower
`lower alkenyl
`or lower alkyl
`R1 is hydrogen
`lower alkyl aryl heterocyclic
`lower alkyl
`alkynyl aryl
`heterocyclic lower cycloalkyl
`lower cycloalkyl
`lower alkyl
`each unsubstituted
`or substituted with an electron donating
`group or an electron withdrawing group and
`lower
`hydrogen lower alkyl
`R2 and R3 are independently
`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 rnay be unsubstituted
`least
`one electron withdrawing group or electron donating group
`NR4 PR4 or
`chernical bond
`lower
`is hydrogen lower alkyl aryl aryl lower alkyl
`lower alkynyl halo heterocyclic or heterocyclic
`alkenyl
`lower alkyl and
`or substituted with
`rnay be unsubstituted
`an electron withdrawing
`an electron
`group
`donating
`that when
`chernical bond
`group provided
`or
`
`or
`
`is halo
`
`is
`
`NR4OR5 ONR4R7
`SPR4R5 PR4SR7
`
`20
`
`30
`
`40
`
`for such disorders has been the
`The rnainstay of treatrnent
`long-terrn and consistent adrninistration of anticonvulsant
`drugs Most drugs in use are weak acids that presurnably
`exert their action on neurons glial cells or both of the central
`ZY taken together
`systern The rnajority of
`nervous
`these cornpounds
`is NR4NR5R7
`are
`least one arnide unit and 25 OPR4R5 PR4OR5 SNR4R7 NR4SR7
`by the presence of at
`characterized
`one or rnore benzene rings that are present as phenyl group
`NR4PR5R6 PR4NR5R7
`or part of
`cyclic systern
`Much attention has been focused upon the developrnent of
`drugs and
`today rnany such drugs are well
`anticonvulsant
`known For exarnple the hydantions such as phenytoin are
`useful in the control of generalized seizures and all forrns of
`partial seizures The oxazolidinediones such as trirnethadi-
`are used in the treatrnent of non-
`one and pararnethadione
`seizures Phenacernide
`convulsive
`phenylacetylurea is
`known
`one of
`ernployed
`the
`rnost well
`anticonvulsants
`today while rnuch attention has recently been dedicated to
`and piperazines For
`the
`investigation of
`the diazepines
`exarnple U.S Pat Nos 4002764 and 4178378
`to
`Allgeier et al disclose esterified diazepine derivatives use-
`in the treatrnent of epilepsy and other nervous disorders
`ful
`U.S Pat No 3887543 to Nakanishi
`et al describes
`cornpound also having anticon
`thieno
`vulsant activity and other depressant activity U.S Pat No
`4209516 to Heckendorn
`et al relates to triazole derivatives
`which exhibit anticonvulsant
`activity and are useful
`treatrnent of epilepsy and conditions
`of tension and agita-
`tion U.S Pat No 4372974 to Fish et al discloses
`arnino
`forrnulation containing
`an aliphatic
`pharrnaceutical
`in which the carboxylic acid and prirnary
`acid cornpound
`
`NR4CR5
`
`SCR5 NR4C0R5 SCOR5
`
`R4 R5 and R6 are independently
`hydrogen lower alkyl
`lower alkyl
`lower alkenyl or
`lower alkynyl
`aryl aryl
`wherein R4 R5 and R5 rnay be unsubstituted
`or substituted
`with an electron withdrawing group or an electron donating
`group
`R7 is R6 COOR8 or COR8
`R8 is hydrogen lower alkyl or aryl lower alkyl and the
`aryl or alkyl group rnay be unsubstituted or substituted with
`an electron withdrawing group or an electron donating group
`and
`
`in the
`
`arnine are separated by three or four units Adrninistration of
`in an acid pH range are useful
`these cornpounds
`in the
`treatrnent of convulsion
`and also possess anxi-
`disorders
`olytic and sedative properties
`U.S Pat No 5378729 to Kohn et al discloses
`and
`pounds
`having
`pharrnaceutical
`cornpositions
`systern CNS activity which
`nervous
`in the
`are useful
`treatrnent of epilepsy and other CNS disorders having the
`forrnula
`following general
`
`central
`
`corn-
`
`R2
`
`RNH_CNHCR
`
`R3
`
`lower alkenyl
`is hydrogen lower alkyl
`aryl aryl lower alkyl heterocyclic heterocyclic
`
`lower alkynyl
`lower alkyl
`
`is 14 and
`is 13
`Unfortunately despite the rnany available pharrnacothera
`significant percentage of the population with
`peutic agents
`epilepsy or related disorders are poorly managed Moreover
`none of the drugs presently available are capable of achiev
`and
`rnost have
`ing total seizure control
`disturbing side
`so effects Toxicities rnay appear upon repeated dosing that are
`not apparent with acute adrninistration Because rnany drugs
`which require
`chronic adrninistration ultirnately place an
`extra burden
`on the
`
`liver
`
`including for exarnple liver
`
`ss
`
`enzyrne induction or oxidative rnetabolisrn that rnay gener
`have associated
`rnany anticonvulsants
`ate reactive species
`therewith liver toxicity
`Research is continuing in this area to find better and rnore
`effective
`anticonvulsant
`for
`agents
`long terrn
`especially
`adrninistration Obviously
`treatrnent
`the
`ideal
`chronic
`60 drug is one that has high pharrnacological
`activity rninirnal
`side effects and is relatively non-toxic and safe to the anirnal
`is being treated More specifically the ideal anticon
`that
`vulsant drug is one that satisfies the following four criteria
`low
`has
`high anticonvulsant
`activity expressed as
`65 ED50
`has rninirnal neurological toxicity as expressed
`by the rnedian toxic dose TD50 relative to its potency
`index sornetirnes known
`rnaxirnurn protective
`
`has
`
`as
`
`-2-
`
`

`
`5773475
`
`is
`
`chronic
`
`to
`
`critical
`
`convulsant
`
`treatment
`
`if
`
`selectivity or margin of safety which measures the rela-
`tionship between the doses of
`drug required to produce
`undesired and desired effects and is measured as the ratio
`between the median toxic dose and the median effective dose
`and
`is relatively safe as measured by the
`Th50/ED50
`lethal close LD50 relative
`median
`and
`to its potency
`non-toxic to the animal that
`is being treated e.g it exhibits
`minimal adverse effects on the remainder of
`the treated
`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
`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
`important for an anti-convulsant which is to be taken over
`long period of
`or in high
`time chronic
`administration
`dosage It may be the most
`factor
`in determining
`important
`which anti-convulsant
`to administer to
`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 toxicites which appear upon
`repeated high levels of administration In such an event
`acute dosing of the drug may be considered but
`it would not
`be used in
`regime which requires
`treatment
`administration of
`the anti-convulsant
`In fact
`if an anti-
`long term
`is required for repeated dosing in
`physician may prescribe an anti-
`regime
`that may have weaker activity relative
`convulsant
`second anti-convulsant
`it exhibits relatively low toxicity
`to the animal An anti-convulsant
`agent which meets all four
`criteria is very rare
`However
`inventor has found such
`group of
`the present
`is generally potent exhibit minimal neuro-
`compounds
`that
`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
`invention
`
`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
`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
`
`10
`
`preferred alkoxy groups
`and especially methoxy
`
`are propoxy isopropoxy ethoxy
`
`The term aryl when used alone or in combination
`phenyl group which is unsubstituted or substituted
`refers to
`
`with halo
`
`The term halo includes fluoro chloro bromo iodo and the
`like The preferred halo is fluoro
`
`20
`
`It
`
`of formula
`in the compound
`is preferred that
`alkoxy having 13 carbon atoms The most preferred alkoxy
`group is propoxy isopropoxy ethoxy and especially meth
`oxy
`
`is
`
`The Ar group as defined herein is phenyl which may be
`as defined herein It
`is most
`unsubstituted
`or substituted
`
`25 preferred that the aryl group i.e phenyl
`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
`
`is unsubstituted
`
`or
`
`position It
`
`unsubstituted
`
`30
`
`Examples of
`include
`
`the
`
`compounds
`
`of
`
`the present
`
`invention
`
`R-N-Benzyl-2-acetamido-3-methoxy
`
`propionamide
`
`methoxypropionamide
`R-N-4-Fluorobenzyl-2-acetamide-3-
`methoxypropionamide
`
`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
`configuration The inventor has found that
`asterisk is in the
`the asymmetric carbon at
`the asterisk
`is significantly more efficacious
`than the corresponding
`enantiomer
`racemic mixture thereof
`
`the
`
`stereoisomer
`
`at
`
`or
`
`the present
`Accordingly
`N-benzyl-2-acetamido propionamide derivatives
`configuration having the formula
`
`is directed to
`
`I-I
`
`I-I
`
`I-I
`
`Ar_CH2_N_C_C_N_C_Qi
`
`ii
`
`II
`
`CH2
`
`in the
`
`40
`
`45
`
`wherein
`Ar is aryl which is unsubstituted or substituted with halo 50
`is lower alkoxy and
`Q1 is CH3
`The present
`invention contemplates employing the com-
`pound of Formula
`pharmaceutical
`composition
`in
`amount of the
`Moreover
`the administration of an effective
`in their pharmaceutically acceptable
`compounds
`present
`forms provides
`the treatment of
`an excellent
`regime for
`epilepsy nervous anxiety psychosis insomnia and other
`related central nervous disorders
`These drugs exhibit high anti-convulsant
`activity mini- 60
`mal neurological
`toxicity high P.1 and minimal toxicity
`These anti-convulsants
`are utilized in
`treatment
`requiring acute dosing and especially chronic
`thereof to the patient
`As shown hereinbelow the compounds of
`the present
`invention exhibit minimal effects
`on liver which is
`in
`compounds
`
`It
`
`It
`
`greater
`
`It
`
`the compound of the present
`invention
`is preferred that
`be substantially pure i.e substantially free from impurities
`is most preferred that
`of
`the present
`the compounds
`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
`is also preferred that
`the compounds of
`the present
`invention be substantially enantiomerically pure i.e sub-
`isomer It
`stantially free from the corresponding
`is more
`invention con
`preferred that
`the compounds of the present
`tam at least 90% w/w
`stereoisomer and most preferably
`than about 95% w/w in the
`stereoisomer Thus
`greater
`the present
`invention contemplates
`compounds
`having
`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
`
`at
`
`form are
`invention in the
`from commercially
`
`techniques
`
`55
`
`regime
`dosing
`
`contrast
`
`to other anti-convulsant
`
`65 available starting materials
`An exemplary procedure is outlined in Scheme
`below
`
`herein
`
`-3-
`
`

`
`5773475
`
`Scheme
`
`in the presence of base e.g Ag20 to form the product
`having Formula
`
`Another variation is depicted in Scheme
`
`cI-12o1-i
`
`H2 HC1
`
`CH3OH
`
`CH2OH
`
`OCH3
`
`PhCH2NH2
`
`CF12OH
`
`H2N___LJ1__
`
`NHCI-12Ph
`
`AC2O
`
`Scheme
`
`Ac20
`
`011 ACOH
`
`CH2OH
`
`H2
`
`R-1
`
`CH2OH
`
`CH3__L
`
`R-6
`
`CH3
`
`CH2OH
`
`II
`
`R-7
`
`ArCF12NF12
`Mixed Anhydride
`Method
`
`CH3I
`
`NHCH2Ar Ag20
`
`10
`
`15
`
`20
`
`25
`
`CH3I
`
`Ag20
`
`CH3
`
`recrysta11ation
`
`CH2OH
`
`NHCH2Ph
`
`II
`
`30
`
`CH2OCH3
`
`NHCH2Ar
`
`CH3
`
`R-8
`
`CHL j1H3
`
`NHCH2Ph
`
`is esterified under
`serine molecule
`acylation
`such as acidic methanol
`conditions with an alcohol
`to
`reacted with
`corresponding
`ester
`the
`provide
`ArCH2NH2 such as benzylamine under acylation
`condi-
`amide
`tions to form the corresponding
`Acylation of the
`free amino group with an acylating
`derivative
`of
`
`is
`
`Q1COH
`
`such as acetic acid or
`acetic anhydride
`i.e
`
`provides
`
`lower alkyl ester of acetic acid or
`the hydroxymethyl derivative
`
`treatment with
`
`For example beginning with D-serine
`of acetic acid such as acetic anhy
`derivative
`an acylating
`amide
`which
`35 dride in acetic acid gives the corresponding
`is then reacted with ArCH2NH2 under mixed anhydride
`reaction conditions as described by Anderson et
`coupling
`al inJACS 1967 89 50125017 the contents of which are
`herein by reference to give the corresponding
`incorporated
`compound of the formula
`HH
`ArCH2NCCNCQi
`
`40
`
`45
`
`50
`
`ii
`
`II
`
`CH2
`
`OH
`
`e.g
`Alkylation of this R-product
`in the presence of base
`under Williamson conditions
`such as methyl
`iodide in
`Ag20 provides
`product of Formula
`An alternative
`route is depicted in Scheme
`
`HHII
`ArCH2NCCNCQ
`CH2OH
`
`by techniques known
`The enantiopurity of was determined
`rotation and 1H 60
`in the art including melting point optical
`NMR upon addition of
`acid
`an organic
`R-configuration such as R- mandelic acid Crystalliza
`
`tion of was repeated until
`the desired enantiopurity thereof
`is converted
`was achieved
`The product of
`to the ether
`it with QX 65
`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
`
`Scheme
`
`OH
`
`CbzC1 MgO
`2COOH H20Et2068%
`
`R-1
`
`OH
`
`MeCN Ag20 CH3I
`24 hrs RT 94%
`
`CbzN
`
`COOH
`
`-4-
`
`

`
`-continued
`
`Scheme
`
`OCH3
`
`80% MeOH/H20
`K2C03 RT
`hrs
`
`CbzN
`
`COOCH3
`
`10
`
`OCH3
`
`N-Methylmorpholine
`isobutyl chioroformate benzylamine
`dry THF -78
`78%
`
`CbzNH
`
`cooi
`
`11
`
`OCH3
`
`NH
`
`CbzN
`
`H2 10% Pdc
`MeOH
`
`hr 15 mill
`
`12
`
`OCH3
`
`H2
`
`NH
`
`Ac20 Pyridine DMAP
`
`13
`
`H3C
`
`OCH3
`
`NH
`
`R-8
`
`it
`
`is protected with
`Serine
`N-protecting group
`known in the art by standard techniques Thus for example
`is reacted with carbobenzoxy
`chloride CBZ-cl benzyl
`the N-protected CBZ-D-serine
`chloroformate
`generating
`The protected
`serine adduct
`is converted
`adduct
`to the
`ether under Williamson conditions by react-
`corresponding
`ing it with QX wherein
`and
`are defined hereinabove
`e.g CH3I in the presence of base e.g Ag20 to form an
`ether 10 Under
`these conditions the acid is also esterified
`the ester group in 10 permits
`Subsequent hydrolysis of
`amide
`amide coupling
`coupling with ArCH2 NH2 using
`methodology e.g mixed
`anhydride 11
`to give the amide 12 Deprotection
`Carbonyldiimidazole
`of
`the free amine 13 which is
`the N-protecting group provide
`then reacted with an acylating agent such as acctic anhydide
`the product R-8
`in base e.g pyridine to provide
`described
`the procedures
`in any of
`necessary
`the product may be
`hereinabove
`the optical purity of
`enhanced by further separation of the
`emantiomer from the
`known in the art such
`emantiomer by standard techniques
`
`If
`
`5773475
`
`as chiral chromatography
`known in the art
`
`using
`
`standard chiral support
`
`Alternatively
`the procedures provided
`in any of
`hereinabove
`racemic
`serine may be utilized as the
`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
`
`10
`
`matography
`The active ingredients of
`compositions
`the therapeutic
`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
`15 example several divided doses may be administered daily or
`the dose may be proportionally reduced as indicated by the
`decided practical
`exigencies of the therapeutic situation
`the active compound may be administered
`advantage is that
`in an convenient manner
`such as by the oral
`intravenous
`20 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
`food of the diet For oral
`directly into the
`incorporated
`the active compound may be
`administration
`therapeutic
`and used in the form of ingest-
`incorporated with excipients
`buccal
`troches
`capsules elixirs
`ible tablets
`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
`35 of active compound
`in such therapeutically useful compo
`sitions is such that
`be obtained
`dosage will
`suitable
`
`25
`
`30
`
`50
`
`compositions or preparations
`Preferred
`to the
`according
`invention are prepared so that an oral dosage unit
`present
`and 1000 mg of active
`form contains
`between
`about
`40 compound
`The tablets troches pills capsules and the like may also
`binder such as gum tragacanth
`contain the following
`such as dicalcium
`acacia corn starch or gelatin excipients
`disintegrating agent such as corn starch potato
`phosphate
`45 starch alginic acid and the like
`lubricant such as magne
`and
`sium stearate
`agent such as sucrose
`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
`capsule it may contain in addition
`to materials of the above type
`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
`syrup or elixir may contain the active compound sucrose
`agent methyl and propylparabens as
`sweetening
`dye and flavoring such as cherry or orange
`preservatives
`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
`For example sustained
`preparations and formulations
`release dosage forms are contemplated wherein the active
`resin which
`is bound
`ion exchange
`to an
`ingredient
`optionally can be coated with
`diffusion barrier coating to
`65 modify the release properties of the resin
`The active compound may also be administered parenter
`ally or intraperitoneally Dispersions can also be prepared in
`
`55
`
`as
`
`60
`
`-5-
`
`

`
`5773475
`
`10
`
`liquid polyethylene glycols and mixtures thereof
`glycerol
`and
`in oils Under ordinary conditions of storage and use
`contain
`the
`these preparations
`to prevent
`growth of microorganisms
`forms suitable
`The pharmaceutical
`for
`injectable
`use
`sterile aqueous solutions where water soluble or
`include
`and
`sterile powders
`the extemporaneous
`for
`dispersions
`
`preservative
`
`The principal active ingredient
`is compounded
`and effective
`venient
`administration in effective
`
`in
`
`for con-
`amounts
`with suitable pharmaceutically acceptable carrier in dosage
`unit form as hereinbefore described Aunit dosage form can
`active compound
`for example contain
`in
`the principal
`to about 1000 mg Expressed
`amounts ranging from about
`in proportions the active compound
`is generally present
`from about
`to about 750 mg/ml of carrier
`In the case of
`supplementary active ingredients
`compositions containing
`the dosages are determined by reference to the usual dose
`and manner of administration of the said ingredients
`Unless
`are by
`indicated
`the contrary
`
`to
`
`percentages
`
`extent
`
`the
`
`thereof
`
`prevention
`
`ated above
`
`for
`
`10
`
`35
`
`solutions or dispersions In
`preparation of sterile injectable
`the form must be sterile and must be fluid to the
`all cases
`that easy syringability exists It must be stable under
`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
`ethanol polyol for example glycerol propylene glycol and is
`liquid polyethylene glycol and the like suitable mixtures
`and
`can
`be
`vegetable oils The proper
`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 20
`the case of dispersions
`of the action of microorganisms can be brought
`Thomas Hoover
`Melting points were determined with
`and antifungal agents
`about by various antibacterial
`melting point apparatus and are uncorrected Infrared spec
`example parabens chiorobutanol
`phenol
`sorbic acid
`tra IR were run on Perkin-Elmer 1330 283 and
`Mattson
`thimerosal and the like In many cases it will be preferable
`Genesis spectrometer
`and were calibrated against
`isotonic agents for example sugars or sodium 25 cm1 bond of polystyrene Absorption values are expressed
`to include
`bers cm1 Proton 1H NMR and carbon 13C
`composi-
`chloride Prolonged
`of the injectable
`absorption
`in wave-num
`tions can be brought about by the use in the compositions of
`NMR nuclear magnetic
`resonance spectra were taken on
`for example aluminum
`agents
`delaying
`absorption
`Nicolet NT-300 and General Electric QE-300 NMR instru
`and gelatin
`monostearate
`are in parts per million ppm
`ments Chemical shifts
`Sterile injectable
`solutions are prepared by incorporating 30
`relative to Me4Si and coupling constants
`values are in
`in the required amount
`the active compound
`in the appro-
`chemical
`ionization mass spectral
`hertz
`investigations
`priate solvent with various of the other
`ingredients enumer-
`on Finnegan MAT TSQ-70
`were conducted
`instrument
`as required followed by filtered sterilization
`Microanalyses were provided by Atlantic Microlab Inc
`Generally dispersions
`are prepared
`by incorporating the
`Norcross Ga Thin layer chromatography
`was performed
`various sterilized active ingredient
`into
`sterile vehicle
`on precoated silica gel GHLF microscope slides 2.5x10 cm
`the basic dispersion medium and the
`which contains
`Analtech No 21521
`ingredients from those enumerated above In
`required other
`the case of sterile powders
`for
`of sterile
`the preparation
`solutions the preferred methods of preparation
`injectable
`are vacuum drying and the freeze-drying technique which 40
`powder of the active ingredient plus any additional
`yield
`from previously sterile-filtered solution
`desired ingredient
`
`weight
`As used herein the term lower alkyl
`refers to an alkyl
`group containing 16 carbon atoms which may be straight
`chained or branched
`
`For
`better understanding
`of the present
`ence is made to the following description
`
`invention refer-
`and examples
`
`GENERAL METHODS
`
`the 1601
`
`EXAMPLE
`
`R-N-Benzyl-2-Acetamide-3-methoxypropionamide
`
`It
`
`is
`
`active
`
`thereof
`As used herein pharmaceutically
`acceptable carrier
`any and all solvents dispersion media coatings
`includes
`and antifungal agents isotonic and absorption
`antibacterial
`and the like The use of such media and
`delaying agents
`active substances is well known in
`agents for pharmaceutical
`insofar as any conventional media or agent
`the art Except
`incompatible with the active ingredient
`its use in the thera-
`peutic compositions is contemplated Supplementary
`ingredients can also be incorporated
`into the compositions
`is especially advantageous to formulate parenteral com-
`positions 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
`predetermined quantity of active material calculated to pro-
`duce
`in association with the
`effect
`the desired therapeutic
`for the novel
`carrier The specifics
`required pharmaceutical
`the invention are dictated by and
`forms of
`dosage unit
`directly dependent on
`of the
`the unique characteristics
`active material and the particular
`effect
`therapeutic
`and
`
`achieved
`
`the limitations
`
`inherent
`
`in the art of
`
`such an active material for the treatment of
`compounding
`diseased condition in
`disease in living subjects having
`which bodily health is impaired as herein disclosed in detail
`
`to be
`
`then the
`
`60
`
`for
`
`219.4 mmol was passed into
`Hydrochloric acid 8.00
`MeOH 250 mL and then D-Serine 20.00
`190.3 mmol
`was added The reaction solution was heated at reflux 18
`45 hours benzylamine 81.6 mL 761 mmol was added and
`reaction was heated for an additional eighteen
`hours The solvent was removed under
`reduced pressure the
`insoluble salts filtered and
`the excess benzylamine was
`removed under high vacuum Kugelrohr The residue was
`so dissolved in water 100 mL and the product was extracted
`with CHC13 8x200 mL The organic layers were combined
`dried Na2SO4 and the solvent was removed under
`reduced
`pressure The residue was triturated with Et20 150 mL and
`27% of
`the product R-enriched
`filtered to give 10.0
`white solid mp
`55 N-benzyl 2-aminohydracrylamide
`as
`c1 MeOH1.6 Rf 0.30 10%
`7478
`MeOHCHC13 1H NMR DMSO-d6 ö1.87 br NH2
`J5.4 Hz CH 3.393.55
`CH2OH 4.28
`3.23
`J5.7 Hz NHCH2 4.76
`J5.4 Hz CH2OH 7.187.32
`J5.7 Hz NH 13C NMR DMSO-d6
`5PhH 8.34
`41.8 NHCH2 56.9 CH 64.3 CH2OH 126.6 C4
`127.0 2C2 or 2C3 128.1 2C2 or 2C3 139.5 C1 173.3
`CONH ppm MS Cl rd intensity 195 M1 53
`56 M1 calcd
`117 100 MrCl 195.113
`65 C10H15N202
`195.11335
`stirred methylene chloride suspension 100 ml of
`To
`51.5
`enriched N-benzyl-2-aminohydracrylamide 10.00
`
`-6-
`
`

`
`5773475
`
`to give
`
`7.207.31
`
`R-N-Benzyl-2-Acetamide-3-
`
`methoxypropionamide
`mmol
`To the compound prepared in
`in
`1.42
`stirred solution 300 ml of CH3CN was successively added
`iodide 3.7 mL 60
`30 mmol and methyl
`Ag20 6.95
`20 mmol and stirred at
`days The
`room temperature
`insoluble salts were filtered and the solvent was removed in
`white solid The white solid was triturated
`vacuo to give
`with Et20 100 mL to given 1.30
`87% of the above
`c1
`identified compound mp 143144
`COCH3
`MeOH16.0 1H NMR CDC13 ö2.04
`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
`J5.7 Hz NH
`CH 6.46 br
`NHCH2 4.524.58
`6.78 br NH 7.257.37
`Ph
`addition of excess
`R--mandelic acid to
`the above-
`CDC13 solution of
`identified compound gave only one signal for the acetyl and
`ether methyl protons
`
`for
`
`4.48
`
`solution
`
`of
`
`intensity 237
`
`calcd for
`
`To
`
`stirred acetonitrile
`
`at
`
`above-identified
`
`c1 MeOH16.4 RfO.47
`mp 143144
`10% MeOHCHC13 JR KBr 3289 3086 2923 2876
`2819 1636 1547 1138 695 cm 1H NMR CDC13 ö2.04
`COCH3 3.38
`OCH3 3.43 dd J7.8 9.0 Hz
`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
`CH2NH 52.4 CH 59.1 OCH3 71.7 CH2OCH3 127.4
`C4 127.5 2C2 or 2C3 128.7 2C2 or 2C3 137.9 C1
`169.9 COCH3 or CONH 170.3 COCH3 or CONH
`ppm MS Cl rd intensity 251 M1 100 2196 Mr
`
`Cl251.139 76
`57 Anal C13H18N203
`
`calcd for C13H19N203 251.139
`
`11
`12
`mmol was added acetic anhydride 5.8 mL 61.8 mmol
`tional minutes and then benzylamine 10.4 mL 100 mmol
`was added at 78 The reaction mixture was allowed to
`and the reaction suspension was stirred at room temperature
`room temperature 30 minutes and
`hour The solvent was removed under
`reduced pressure
`stir
`at
`the
`4-methylmorpholine hydrochloride salt was filtered The
`white solid The product was triturated with Et2
`250 mL to give 7.60
`62% of enriched R-N-benzyl-2
`in vacuo The product was
`layer was concentrated
`organic
`on Si02 gel 10%
`purified by flash column chromatography
`white solid The reaction
`-acetamidohydracrylamide as
`33% as white solid mp
`MeOHCHC13 to give 3.89
`product was recrystallized 2x using EtOH to give 3.50
`C1 MeOH21.70
`147148
`1H NMR
`29% of
`CO CH3 3.57 dd J5.1 5.1 Hz
`the R-N-benzyl-2-acetamidohydracrylamide mp
`c1 MeOH22.4 Rf 0.40 10%
`DMSO-d6 ö1.86
`148149
`J5.1 Hz OH
`CH2NH CH 4.90
`MeOHCHC13 JR KBr 3295 3090 2964 1642 1533 10 CH2O 4.274.31
`J8.1 Hz NH 8.37
`PhH 7.93
`J6.0
`1376 1281 1051 705 cm 1H NMR DMSO-d6 ö1.86
`Hz NH addition of excess R--mandelic acid to
`COCH3 3.57 dd J5.7 5.7 Hz CH2OH 4.254.31m
`CDC13 solution of the product of
`gave only one signal for
`CH 4.27
`J5.7 Hz NHCH2 4.92
`J5.7 Hz
`the acetyl methyl protons
`J7.8Hz NH 8.38
`CH2OH 7.187.32
`PhH 7.94
`NH addition of excess R- mandelic acid to 15
`J5.7
`CDC13
`R-N-benzyl
`hereinabove
`2-acetamidohydracrylamide
`prepared
`gave
`only one signal for the acetyl methyl protons 13C NMR
`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
`M1 100 2198 MrC1 237.12388
`C12H17N203 237.12392 Anal C12H16N203 CHN
`solution 300 mL of R-N- 25
`10 mmol was
`benzyl-2-acetamidohydroacrylamide 2.36
`50 mmol and methyl
`added Ag20 11.59
`successively
`iodide 6.2 mL 100 mmol
`room temperature The
`reaction mixture was stirred at room temperature
`for
`days
`filtered and
`The insoluble salts were
`the solvents were
`removed in vacuo to give
`white solid The residue was
`filtered with Et20 100 mL to give 2.20
`88% of
`the
`product
`
`30
`
`EXAMPLE
`
`R-N-3-Fluorobenzyl2-Acetamide-3-
`
`Methoxypropionamide
`
`R-N-3-Fluorobenzyl-2-Acetamide-
`
`40
`
`for
`
`as
`
`hydracrylamide
`Utilizing the procedure of Example 2a with the follow-
`50 mmol Ac20 5.7 mL
`ing amounts of D-serine 5.26
`11.0 mL 100 mmol
`60 mmol 4-methylmorpholine
`isobutyl chloroformate 13.0 mL 100 mmol and substitut
`11.8 mL 100 mmol
`ing 3-fluorobenzylamine
`benzylamine gave 4.20 33% of the above compound
`white solid after purification mp 137138
`c1 MeOH20.8 RfO.32 10% MeOHCHC13 JR
`KEr 3282 3101 2944 1636 1542 1252 1050 779 690
`cm 1H NMR DMSO-d6 1.87 sCOCH3 3.563.63
`CH2OH 4.29
`J6.0 Hz CH2NH 4.254.30
`50 CH 4.95
`J5.4 Hz CH2OH 7.007.09
`ArH
`J8.1 Hz NH 8.44
`ArH 7.97
`J6.0
`Hz NH addition of excess R--mandelic acid to
`CDC13 solution of this product gave only one signal for the
`acetyl methyl portions 13C NMR DMSO-d6 22.7 CO
`CH3 41.6 CH2N 53.4 CH 61.7 CH2 OH 113.3
`Jmproved Synthesis of R-N-Benzyl 2-
`jcF200 Hz C2 or C4 113.6
`JCF20.7 Hz C2 or C4
`122.9 C6 130.1
`Acetamidohydracrylamide
`JcF8.2 Hz C5 142.6
`JCF7.0 Hz
`stirred AcOH 20 mL suspension of D-serine 5.26
`CF2414 Hz C3 169.6 COCH3 or
`To
`Cl1 162.3
`CONH 170.5 COCH3 or CONH ppm MS Cl
`50 mmol was added Ac20 4.7 mL 50 mmol and then
`the reaction suspension was stirred at room temperature 24 60 rd intensity 255 M1 100 MrCl 255.113 54
`hours The ACOH was removed in vacuo to give an oily
`255.114 50 Anal
`residue and then THF 150 mL was added to the residue
`The THF suspen