(19) United States
`(12) R€iSSll€d
`Patent
`Kohn
`
`US RE38,551 E
`(10) Patent Number:
`(45) Date of Reissued Patent:
`Jul. 6, 2004
`
`USO0RE38551E1
`
`(54) ANTICONVULSANT ENANTIOMERIC
`AMINO ACID DERIVATIVES
`
`OTHER PUBLICATIONS
`
`(75)
`
`Inventor: Harold Kohn, Chapel Hill, NC (US)
`
`(73) Assignee: Research Corporation Technologies,
`Inc., Tucson, AZ (US)
`
`(21) Appl. No‘: 10/053,634
`.
`Flledi
`
`J311- 23, 2002
`
`(22)
`
`Related US_ Patent Documents
`
`Reissue Of:
`(64) Patent No‘:
`Issued:
`Appl. NOJ
`Filedi
`
`5,773,475
`Jun. 30, 1998
`03/313,633
`M312 17, 1997
`
`Anderson, et al. J. Am. Chem. Soc. 89:19 pp. 5012-5017,
`(1967).
`Kohn, Harold, et a1. “Preparation and anticonvulsant activity
`of a series of functionalized. a1ph.-heteroatom-substituted
`amino acids”, J. Med. Chem. 34, 2444-2452 (1991).
`
`Kohn, Ilarold, et all:/Marked stereospecificity in a new class
`of anticonvulsants , Chemzcal Abstracts,
`109 (1988)
`Abstract No. 183045.
`
`Choi, Daeock, et a1. “Synthesis and Anticonvulsant Activi-
`ties of N-Benzyl-2-acetamidopropionamide Derivatives ,
`J. Med. Chem., 39: 1907-1916 (1996).
`
`Primary Examiner—Shai1endra Kumar
`(74) Attorney, Agent, or Firm—Scu11y, Scott, Murphy &
`Presser
`
`U.S. Applications:
`(60)
`Provisional application No. 60/013,522, filed on Mar. 15,
`1996.
`
`(57)
`
`ABSTRACT
`
`7
`.
`
`.
`
`.
`
`...................... A5611:j6i:/
`...................... ..
`;
`;
`(58) Field of Search ........................ .. 514/616; 564/155,
`564/158
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`The present invention is directed to a compound in the R
`(f:onfigpration about the asymmetric carbon in the following
`ormu a:
`
`Ar—CH2NHfi—%|:I—§—fi—Q1,
`0
`(|3H2
`0
`Q
`
`............ .. 514/231.2
`1/1995 Kohn et al.
`5,378,729 A
`............ N 514/231.2
`8/1997 Kohn et al.
`5,654,301 A
`FOREIGN PATENT DOCUMENTS
`
`.
`.
`.
`.
`.
`pharmaceutical compositions containing same and the use
`thereof in treating CNS disorders in animals.
`
`EP
`
`0 194 464
`
`9/1986
`
`13 Claims, No Drawings
`
`EXHIBIT
`ACTAVIS, AMNEAL,
`AUROBINDO,
`BRECKENRIDGE,
`VENNOOT, SANDOZ,
`SUN
`
`IPR2014-01126-1001, p. 1
`
`IPR2014-01126, Exhibit 1001, p. 1
`
`
`
`

`
`US RE38,551 E
`
`1
`ANTICONVULSANT ENANTIOMERIC
`AMINO ACID DERIVATIVES
`
`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 APPLICA TION
`
`This application claims priority from US. provisional
`application No. 60/013,522 filed on Mar I5, 1996.
`
`GOVERNMENT S UPPOR T
`
`This invention was made with Government support under
`Grant/Contract No. NIH MS I5604 awarded by the National
`Institute ofHealth. The Government has certain rights in the
`invention.
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel enantiomeric com-
`pounds and pharmaceutical compositions useful in the treat-
`ment of epilepsy and other CNS disorders.
`
`BACKGROUND OF THE INVENTION
`
`The predominant application of anticonvulsant drugs is
`the control and prevention of seizures associated with epi-
`lepsy or related central 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 asso-
`ciated 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 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 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 trimethadi-
`one and paramethadione, are used in the treatment of non-
`convulsive 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 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 use-
`ful in the treatment of epilepsy and other nervous disorders.
`U.S. Pat. No. 3,887,543 to Nakanishi, et al. describes a
`thieno [2,3-e][1,4]diazepine compound also having anticon-
`vulsant activity and other depressant activity. U.S. Pat. No.
`4,209,516 to Heckendorn, et al. relates to triazole derivatives
`which exhibit anticonvulsant activity and are useful in the
`treatment of epilepsy and conditions of tension and agita-
`tion. U.S. Pat. No. 4,372,974 to Fish, et al. discloses a
`pharmaceutical formulation containing an aliphatic amino
`acid compound in which the carboxylic acid and primary
`amine are separated by three or four units. Administration of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`these compounds in an acid pH range are useful in the
`treatment of convulsion disorders and also possess anxi-
`olytic and sedative properties.
`U.S. Pat. No. 5,378,729 to Kohn, ct al. discloses com-
`pounds 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:
`
`R2
`I
`R*NH fi:(|:NH C*R1
`0
`R3
`1:
`
`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
`group.
`
`lower
`lower alkenyl,
`R1 is hydrogen or lower alkyl,
`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, lower alkyl, lower
`alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic,
`heterocyclic lower alkyl, lower alkyl heterocyclic, lower
`cycloalkyl, lower cycloalkyl lower alkyl, or Z—Y wherein
`R2 and R3 may be unsubstituted or substituted with at least
`one electron withdrawing group or electron donating group;
`Z is O, S, S (0)6, NR4, 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,
`OPR4R5, PR4OR5, SNR4R7, NR4SR7, SPR4R5, PR4SR7,
`NR4PR5R6, PR4NR5R7,
`
`NR4C—R5,
`II
`o
`
`SCR5,
`II
`o
`
`NR4C— OR5,
`II
`o
`
`SC—OR5
`II
`0
`
`R4, R5 and R6 are independently hydrogen, lower alkyl,
`aryl, aryl
`lower alkyl,
`lower alkenyl, or lower alkynyl,
`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,
`R8 is hydrogen, lower alkyl, or aryl lower alkyl, and the
`aryl or alkyl group may be unsubstituted or substituted with
`an electron withdrawing group or an electron donating group
`and
`n is 1-4 and
`a is 1-3.
`
`Unfortunately, despite the many available pharmacothera-
`peutic 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 achiev-
`ing total seizure control, and most have disturbing side
`effects. Toxicities may appear upon repeated dosing that are
`
`IPR2014-01126, Exhibit 1001, p. 2
`
`IPR2014-01126, Exhibit 1001, p. 2
`
`
`
`

`
`US RE38,551 E
`
`3
`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-
`ate reactive species, many anticonvulsants have associated
`therewith liver toxicity.
`
`Research is continuing in this area to find better and more
`effective anticonvulsant agents, especially for long term
`treatment (chronic administration). 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 anticon-
`vulsant drug is one that satisfies the following four criteria:
`(1) has a high anticonvulsant activity, (expressed as a low
`ED50); (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 rela-
`tionship 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 median effective dose
`
`(TD50/ED5O); and (4) is relatively safe as measured by the
`median lethal dose (LD50) 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
`
`animal, its organs, blood, its bodily functions, etc. even at
`high concentrations, especially during long term chronic
`administration of the drug. Thus, for example, it exhibits
`minimal, i.e.,
`little or no liver toxicity. Although not as
`critical in short term or acute administration of an anti-
`
`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 a
`long period of time (chronic administration) or in high
`dosage. It may be the most important factor in determining
`which anti-convulsant to administer to a patient, especially
`if chronic dosing is required. Thus, an anti-convulsant agent
`which has a high anti-convulsant activity, has minimal
`neurological toxicity and maximal P.I. (protective index)
`may unfortunately exhibit such toxicities 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 a treatment regime which requires chronic
`administration of the anti-convulsant. In fact, if an anti-
`convulsant is required for repeated dosing in a long term
`treatment
`regime,
`a physician may prescribe an anti-
`convulsant
`that may have weaker activity relative to a
`second anti-convulsant, if it exhibits relatively low toxicity
`to the animal. An anti-convulsant agent which meets all four
`criteria is very rare.
`
`However, the present inventor has found such a group of
`compounds that is generally potent, exhibit minimal neuro-
`logical toxicity, has a high protective index and is relatively
`non-toxic to the body organs,
`including the liver upon
`multiple dosing.
`
`SUMMARY OF THE INVENTION
`
`invention is directed to
`the present
`Accordingly,
`N-benzyl-2-acetamido propionamide derivatives in the R
`configuration having the formula:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Ar—CH2—N—C
`
`C*—N—C—Q1
`
`0
`
`CH2
`
`0
`
`wherein
`
`Ar is aryl which is unsubstituted or substituted with halo;
`Q is lower alkoxy; and
`Q1 is CH3.
`The present invention contemplates employing the com-
`pound 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.
`
`These drugs exhibit high anti-convulsant activity, mini-
`mal neurological toxicity, high P.I. and minimal toxicity.
`These anti-convulsants are utilized in a treatment regime
`requiring acute dosing, and especially chronic dosing
`thereof to the patient.
`the compounds of the present
`As shown hereinbelow,
`invention exhibit minimal effects on liver, which is in
`contrast to other anti-convulsant compounds.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`As used herein 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.
`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 meth-
`oxy.
`
`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 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
`include:
`
`invention
`
`(R)-N-Benzyl-2-acetamido-3-methoxy propionamide,
`(R)-N-(3-Fluorobenzyl)-2-acetamido-3-
`methoxypropionamide,
`(R)-N-(4-Fluorobenzyl)-2-acetamide-3-
`methoxypropionamide,
`(R)-N-Benzyl-2-acetamido-3-ethoxy propionamide.
`As indicated by the asterisk in formula I, the compounds
`of the present invention contain at least one asymmetric
`carbon. The stereochemistry of the asymmetric carbon at the
`
`IPR2014-01126, Exhibit 1001, p. 3
`
`IPR2014-01126, Exhibit 1001, p. 3
`
`
`
`

`
`US RE38,551 E
`
`5
`asterisk is in the R configuration. The inventor has found that
`the R stereoisomer at the asymmetric carbon at the asterisk
`is significantly more efficacious than the corresponding S
`enantiomer or a racemic mixture thereof.
`
`O
`
`(4)
`
`H
`ArcH2N—c—EI—§—c—Q1
`I
`CH2_OH
`
`0
`
`10
`
`It is preferred that the compound of the present invention 5
`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 than about 90% pure (W/W) and most preferably
`greater than about 95% pure (W/W).
`It is also preferred that the compounds of the present
`invention be substantially enantiomerically pure, i.e., sub-
`The enantiopurity 0f4 Was determined by techniques kI10WI1
`stantially free from the corresponding S isomer. It is more
`in the art, including melting point, optical rotation and 1H
`preferred that the compounds of the present invention con-
`tain at least 90% (W/W) R stereoisomer, and most preferably 15 NMR upon addition of an organic acid in the
`greater thah about 95% (W/W) 1h the R Stefe01S0H1ef-‘Thus,
`R-configuration, such as R(—)- mandelic acid. Crystalliza-
`the present mventton contemplates Compounds havmg at
`tion of 4 was repeated until the desired enantiopurity thereof
`most about 10% S 1S0I.ner(W/W)’ and even more preferably
`was achieved. The product of 4 is converted to the ether
`less than about 5% S isomer (W/W).
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`under Williamson conditions by reacting it With QX,
`The compounds of the present invention in the R form are 20
`d X .
`d 1
`h
`.
`.
`d fi
`d h
`.
`b
`.
`prepared by art recognized techniques from commercially
`W erem Q L5 ago; HEM ereutll algve an Cfislgood Zajlig
`available starting materials.
`groupsisuc as
`S>
`S>0r
`a 1 e(e'g'>
`3 ) an t e 1 6
`An exemplary procedure is outlined in Scheme 1 herein-
`1h the Presehee Or base (e~g~> Agzo) to rerrh the Predhet (5)
`below;
`having Formula I.
`
`Sch_en1e_l
`
`HZN
`
`CHZOH
`*
`
`O
`
`i
`
`CII3OII
`OH 4»
`Her
`
`HC1.H2N
`
`CHZOH
`*
`
`O
`
`2
`
`PhCH2NH2
`OCH3 T»
`
`CHZOH
`*
`
`NHCH2Ph
`
`HZN
`
`O
`3
`
`O
`CHZOCH3
`i *
`CH3
`N
`H
`
`NHCH2Ph «j
`AEZO
`
`O
`
`5
`
`l Ac2O
`I recrystallization
`O
`CHZOH
`i *
`CH3
`N
`H
`
`NHCH2Ph
`
`O
`
`4
`
`A D serine molecule (1) is esterified under acylation
`conditions with an alcohol, such as acidic methanol,
`to
`provide the corresponding ester (2). 2 is reacted with
`ArCH2NH2, such as benzylamine, under acylation condi-
`tions to form the corresponding amide
`Acylation of the
`free amino group, with an acylating derivative of
`
`QiC—OH,
`
`such as acetic acid, or lower alkyl ester of acetic acid, or
`acetic anhydride provides the hydroxymethyl derivative,
`i.e.,
`
`50
`
`55
`
`60
`
`65
`
`Another variation is depicted in Scheme 2.
`
` 2
`
`AC2O
`OH 4»
`AcOH
`
`HZN
`
`CH;OH
`*
`
`O
`
`(R)-1
`
`O
`CHZOH
`A *
`CH3
`N
`H
`
`0
`
`OH
`
`(R)-5
`
`A CH NH
`
`Mixed Anhydride
`Method
`
`IPR2014-01126, Exhibit 1001, p. 4
`
`IPR2014-01126, Exhibit 1001, p. 4
`
`
`
`

`
`US RE38,551 E
`
`0
`
`CH3
`
`N
`H
`
`-continued
`CHZOH
`*
`
`CH3I
`NHCH2Ar —»
`Ag20
`
`O
`
`(R)-7
`
`O
`CHZOCH3
`A *
`NHCH2Ar
`CH3
`NH
`
`O
`
`(R)-8
`
`For example, beginning with D-serine (1), treatment with
`an acylating derivative of acetic acid such as acetic anhy-
`dride 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 JACS, 1967, 89, 5012-5017, the contents of which are
`incorporated herein by reference, to give the corresponding
`compound of the formula:
`
`H
`
`H
`
`H
`
`Ar—cH2— N—fi—(|:— N—fi—Q1
`o
`(|ZH2
`0
`OH
`R
`
`e.g., 7. Alkylation of this R-product in the presence of base
`under Williamson conditions, such as methyl
`iodide in
`Ag2O, provides a product of Formula I
`
`An alternative route is depicted in Scheme 3.
`
`OH
`
`Scl1e1ne_3_
`
`Cbz:Cl, MgOT»
`H20, ETZO, 68%
`
`HZN
`
`*
`
`COOH
`
`(R)-1
`
`OH
`
`CbzNH
`
`*
`
`9
`
`COOH
`
`OCH3
`
`CbzNH
`
`CbzNH
`
`*
`10
`
`*
`11
`
`COOCH3
`
`OCH3
`
`COOH
`
`MeCN, Ag2O, CH3IT,
`24 hrs, RT, 94%
`
`80% MeOH/H20T,
`KZCO3, RT, 8 hrs 95%
`
`N-MethylmorpholineT,
`isobutyl chloroformate,
`benzylamine dry
`THF, —78° C., 78%
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`OCH3
`
`NH
`
`O
`
`CbzNH
`
`*
`
`HZN
`
`*
`
`12
`OCH3
`
`NH
`
`O
`
`13
`
`8
`-continued
`
`H2, 10% Pd—CT,
`MeOH, 1 hr 15 min
`97%
`
`Ac2O, Pyridine, DMAP >
`
`0
`
`JL
`
`OCH3
`
`NH
`
`H3C
`
`T
`H
`
`*
`
`O
`
`(R)-8
`
`is protected with a N-protecting group
`D Serine (1)
`known in the art, by standard techniques. Thus, for example,
`it is reacted witl1 carbobe11zoxy chloride (CBZ-cl, be11zyl
`chloroformate) generating the N-protected CBZ-D-serine
`adduct 9. The product serine adduct is converted to the
`corresponding ether under Williamson conditions by react-
`ing it with QX wherein Q and X 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.
`Subsequent hydrolysis of the ester group in 10 permits
`amide coupling with ArCH2 NH2 using amide coupling
`methodology (e.g., mixed anhydride
`1,1‘
`Carbonyldiimidazole) to give the amide 12. Deprotection of
`the N-protecting group provide the free amine 13 which is
`then reacted with an acylating agent such as acetic anhydride
`in base, (e.g., pyridine) to provide the product (R)-8.
`If necessary,
`in any of the procedures described
`hereinabove,
`the optical purity of the product may be
`enhanced by further separation of the S enantiomer from the
`R enantiomer, by standard techniques known in the art, such
`as chiral chromatography using a standard chiral support
`known in the art.
`
`in any of the procedures provided
`Alternatively,
`hereinabove, a racemic D serine may be utilized as the
`starting material. Following the procedures in any of the
`schemes outlined hereinabove would provide the racemic
`mixture, which can be resolved into the R isomer by
`standard techniques known in the art such as chiral chro-
`matography.
`The active ingredients of the therapeutic compositions
`and the compounds of the present invention exhibit excellent
`anticonvulsant activity when administered in amounts rang-
`ing from about 1 mg 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
`
`IPR2014-01126, Exhibit 1001, p. 5
`
`IPR2014-01126, Exhibit 1001, p. 5
`
`
`
`

`
`US RE38,551 E
`
`9
`example, several divided doses may be administered daily or
`the dose may be proportionally reduced as indicated by the
`exigencies of the therapeutic situation. A decided practical
`advantage is that the 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 ingest-
`ible tablets, buccal
`tablets,
`troches, capsules, elixirs,
`suspensions, syrups, wafers, and the like. Such compositions
`and preparations should contain at least 1% of active com-
`pound. The percentage of the compositions and preparations
`may, 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 compo-
`sitions is such that a suitable dosage will be obtained.
`Preferred compositions or preparations according to the
`present invention are prepared so that an oral dosage unit
`form contains between about 5 and 100 mg of active
`compound.
`The tablets, troches, pills, capsules and the like may also
`contain the following: A binder such as gum tragacanth,
`acacia, corn starch or gelatin; excipients such as dicalcium
`phosphate; a disintegrating agent such as corn starch, potato
`starch, alginic acid and the like; a lubricant such as magne-
`sium stearate; and a sweetening agent such as 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
`of 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 the resin.
`The active compound may also be administered parenter-
`ally or intraperitoneally. Dispersions can also be prepared in
`glycerol, liquid polyethylene 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 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 microorgan-
`isms such as bacteria and fungi. The carrier can be a solvent
`or dispersion medium containing, for example, water,
`
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`ethanol, polyol (for example, glycerol, propylene glycol, and
`liquid 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 microorganisms can be brought
`about by various antibacterial and antifungal agents, for
`example, parabens, chlorobutanol, phenol, sorbic acid,
`thimerosal, and the like. In many cases, it will be preferable
`to include isotonic agents, for example, sugars or sodium
`chloride. Prolonged absorption of the injectable composi-
`tions can be brought about by the use in the compositions of
`agents delaying absorption,
`for example, aluminum
`monostearate and gelatin.
`Sterile injectable solutions are prepared by incorporating
`the active compound in the required amount in the appro-
`priate solvent with various of the other ingredients enumer-
`ated above, as required, followed by filtered sterilization.
`Generally, 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 the active ingredient plus any additional
`desired ingredient from previously sterile-filtered solution
`thereof.
`As used herein, “pharmace11tically acceptable carrier”
`includes any and all solvents, dispersion media, coatings,
`antibacterial and antifungal agents, 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
`incompatible with the active ingredient, its use in the thera-
`peutic compositions is contemplated. Supplementary active
`ingredients can also be incorporated into the compositions.
`It 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 a
`predetermined quantity of active material calculated to pro-
`duce the desired therapeutic effect in association with the
`required pharmaceutical carrier. The specifics for the novel
`dosage unit forms of the 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 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 con-
`venient and effective administration in effective amounts
`with a suitable pharmaceutically acceptable carrier in dosage
`unit form as hereinbefore described. Aunit 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 case of
`compositions containing supplementary active ingredients,
`the dosages are determined by reference to the usual dose
`and manner of administration of the 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 may be straight
`chained or branched.
`
`IPR2014-01126, Exhibit 1001, p. 6
`
`IPR2014-01126, Exhibit 1001, p. 6
`
`
`
`

`
`US RE38,551 E
`
`11
`For a better understanding of the present invention refer-
`ence is made to the following description and examples.
`
`GENERAI. METHODS
`
`Melting points were determined with a Thomas Hoover
`melting point apparatus and are uncorrected. Infrared spec-
`tra (IR) were run on Perkin-Elmer 1330, 283 and a Mattson
`Genesis spectrometer and were calibrated against the 1601
`cm‘1 bond of polystyrene. Absorption values are expressed
`in wave-numbers (cm‘1). Proton (1H NMR) and carbon (“C
`NMR) nuclear magnetic resonance spectra were taken on
`Nicolet NT-300 and General Electric QE-300 NMR instru-
`ments. Chemical shifts (5) are in parts per million (ppm)
`relative to Me4Si and coupling constants (J values) are in
`hertz. All chemical ionization mass spectral investigations
`were conducted on Finnegan MAT TSQ-70 instrument.
`Microanalyses were provided by Atlantic Microlab Inc.
`(Norcross, Ga). Thin layer chromatography was performed
`on precoated silica gel GHLF microscope slides (2.5><10 cm;
`Analtech No. 21521).
`
`EXAMPLE 1
`
`(R)-N-Benzyl-2-Acetamide-3-methoxypropionamide
`
`Hydrochloric acid (8.00 g, 219.4 mmol) was passed into
`MeOH (250 mL) and then D-Serine (20.00 g, 190.3 mmol)
`was added. The reaction solution was 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, and the excess benzylamine was
`removed under high vacuum (Kugelrohr). The residue was
`dissolved in water (100 mL), and the product was extracted
`with CHCI3 (8><200 mL). The organic layers were combined,
`dried (Na2SO4), and the solvent was removed under reduced
`pressure. The residue was triturated with Et2O (150 mL) and
`filtered to give 10.0 g (27%) of the product R-enriched
`N-benzyl 2-aminohydracrylamide, as a white solid: mp
`74°—78° C.;
`[ot]D23 (c=1, MeOH)=1.6°, Rf 0.30 (10%
`MeOH—CHCl3); 1H NMR (DMSO-d6) 51.87 (br s, NH2),
`3.23 (t, J=5.4 Hz, CH), 3.39-3.55 (m, CHZOH), 4.28 (d,
`J=5.7 Hz, NHCH2) 4.76 (t, J=5.4 Hz, CHZOH), 7.18-7.32
`(m, 5PhH), 8.34 (t, J=5.7 Hz, NH), 13C NMR (DMSO-d6)
`41.8 (NHCH2), 56.9 (CH), 64.3 (CHZOH), 126.6 (C4‘),
`127.0 (2C2‘ or 2C3‘), 128.1 (2C2‘ or 2C3‘), 139.5 C1‘), 173.3
`(C(O)NH) ppm, MS (+Cl) (rel intensity), 195 (M++1, 53),
`117 (100), Mr(+Cl) 195.113 56 (M++1)
`(calcd.
`for
`C10H15N2O2, 195.11335).
`To a stirred methylene chloride suspension (100 ml) of R
`enriched N-benzyl-2-aminohydracrylamide (10.00 g, 51.5
`mmol) was added acetic anhydride (5.8 mL, 61.8 mmol),
`and the reaction suspension was stirred at room temperature
`(1 hour). The solvent was removed under reduced pressure
`to give a white solid. The product was triturated with Et2O
`(250 mL) to give 7.60 g (62%) of enriched R-N-benzyl-2-
`acetamidohydracrylamide as a white solid. The reaction
`product was recrystallized (2><) using EtOH to give 3.50 g
`(29%) of the R-N-benzyl-2-acetamidohydracylamide mp
`148°—149° C.; [(X1D23 (c=1, MeOH)=+22.4°; Rf 0.40 (10%
`MeOH—CHC13); IR (KBr) 3295, 3090, 2964, 1642, 1533,
`1376, 1281, 1051, 705 cm; 1H NMR (DMSO-d5) 51.86 (s,
`C(O)CH3), 3.57 (dd, J=5.7, 5.7 Hz, CHZOH), 4.25—4.31(m,
`CH), 4.27 (d, J=5.7 Hz, NHCH2), 4.92 (t, J=5.7 Hz,
`CHZOH), 7.18-7.32 (m, 5 PhH) 7.94 (d, J=7.8Hz, NH), 8.38
`(t, J=5 .7 H, NH), addition of excess R-(—) mandelic acid to
`a
`CDCI3
`solution
`of
`R-N-benzyl
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`12
`2-acetamidohydracrylamide prepared hereinabove gave
`only one signal for the acetyl methyl protons; 13C NMR
`(DMSO-d6) 22.7 (C(O)CH3), 42.0 (CHZNH), 55.6 (CH),
`61.8(CH2OH), 126.7 (C4‘), 127.0 (2C2‘ or 2C3‘), 128.2 (2C2‘
`or 2C3‘), 139.4 (C1‘), 169.5 (C(O)CH3 or C(O)NH), 170.3
`(C(O)CH3 or C(O)NH) ppm; MS (+Cl) rel intensity) 237
`(M"+1, 100), 219(8); Mr(+Cl) 237.12388 [M++1] (calcd for
`C12H1./N203 237.12392); Anal (C12H16N2O3), C,H,N.
`To a stirred acetonitrile solution (300 mL) of (R)-N-
`benzyl-2-acetamidohydroacrylamide (2.36 g, 10 mmol) was
`successively added Ag2O (11.59 g, 50 mmol) 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 2.20 g (88%) of the
`above-identified product.
`mp 143°—144° C.; [oc]D23 (c=1, MeOH)=+16.4°; Rf0.47
`(10% MeOH—CHCl3); IR (KBr) 3289, 3086, 2923, 2876,
`2819, 1636, 1547, 1138, 695 cm'1; 1H NMR (CDCI3) 62.04
`(s, C(O)CH3), 3.38 (s, OCH3), 3.43 (dd, J=7.8, 9.0 Hz,
`CHH‘OCH3), 3.82 (dd, J=4.2, 9.0 Hz, CHH'OCH3), 4.48(d,
`J=6.0 Hz, NHCH2), 4.51-4.57 (m,CH), 6.44 (br 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 CDCI3 solution o