Europaisches Patentamt
`
`Q European Patent Office
`Office européen des brevets
`
`® Publication number:
`
`0
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 90109596.8
`
`(9 Da*e°*“"“9=2‘-05-9°
`
`@ lnt.C|.5: C07D 307/54, C07D 333/40,
`C07D 207/40, C07D 213/60,
`co7c 237/52, co7c 323/59,
`A61K 31/16, A61K 31/38,
`A61K 31/34, A61K 37/02
`
`
`
`Q2)
`
`Inventor: Kohn, Harold L.
`3735 Latma Drive
`
`Houston, Texas(US)
`inventor: Watson, Darrell
`2714 Norbert
`
`Flint, Michigan 48504(US)
`
`Representative: Brauns, Hans-Adolf, Dr. rer.
`nat. et al
`
`Hoffmann, Eitle & Partner, Patentanwéilte
`Arabellastrasse 4
`
`@ Priority: 19.05.89 us 354057
`
`Date of publication of application:
`05.12.90 Bulletin 90/49
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IT LI LU NL SE
`
`@ Applicant: Research Corporation
`Technologies, Inc
`6840 East Broadway Boulevard
`
`
`
`Tucson Arizona 85710-2815(US)
`
`D-8000 Miinchen 81(DE)
`
`@ Amino acid derivative anticonvulsant.
`
`@ The present invention ‘relates to compounds exhibiting central nervous system (CNS) activity which are
`useful in the treatment of epilepsy and other CNS disorders. The compounds of this invention have the following
`general formula:
`
`EXHIBIT
`ACTAVIS.AMNEAL.
`AUROBINDO.
`BRECKENRIDGE.
`VENNOOT.
`SANDOZ. SUN
`IPR20l4-01126-1024 p. 1
`
`
`
`3
`
`R [
`
`2
`R-NI-I-':C-CNH‘7 c—R1
`“_ 1
`11
`«
`O P,
`-O
`
`EP0400440A1
`
`and pharmaceutically acceptable salts thereof wherein
`R is aryl, aryl
`lower alkyl, heterocyclic or heterocyclic lower alkyl, wherein R is unsubstituted or
`substituted with at least one electron withdrawing group or an electron donating group;
`R1 is hydrogen or lower alkyl and R1 is unsubstituted or is substituted with at least one electron withdrawing
`substituent or at least one electron donating substituent;
`R2 and R3 are independently each hydrogen, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocycli,
`heterocycli
`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;
`2 is O. S. NR4, PR; or a chemical bond;
`lower alkynyl, or halo, and Y may be
`lower alkenyl,
`Y is hydrogen.
`lower alkyl, aryl, aryl
`lower alkyl,
`unsubstituted or substituted with at least one electron donating group or electron donating group; provided
`that when Y is halo, Z is a chemical bond or
`ZY taken together
`is NR4.NR5Rs, NR4.OR5, ONR4Rs, OPRARS, PRILORS, SNR4.R5, NR4SRs, SPR4.Hs,
`|PR2014-01125- Exhibit 1024 p. 1
`
`is
`
`IPR2014-01126- Exhibit 1024 p. 1
`
`

`
`EP 0 400 440 A1
`
`PR4.SR5, NRAPR5 R5 or PRa,NR5 R5,
`
`lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl,
`R4, R5 and R5 are independently hydrogen,
`and R4, R5 and He may be unsubstituted or substituted with an electron withdrawing group or an electron
`donating group and
`n is 1-4.
`
`|PR2014—01126— Exhibit 1024 p. 2
`
`IPR2014-01126- Exhibit 1024 p. 2
`
`

`
`EP 0 400 440 A1
`
`AMINO ACID DERIVATIVE ANTICONVULSANT
`
`The present invention relates to compounds and pharmaceutical compositions having central nervous
`system (CNS) activity which are useful
`in the treatment of epilepsy and other CNS disorders. More
`specifically,
`the compounds of this invention can be characterized as protected amino acid derivatives
`having the following general formula:
`
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`‘F2
`R"'NH C‘ N ‘
`.-
`‘f “Tut? 31
`-
`‘Ell
`0 R3
`-0
`
`(I)
`
`wherein
`lower alkyl, heterocyclic or heterocyclic lower alkyl and R is unsubstituted or is substituted
`R is aryl, aryl
`with at least one electron withdrawing group, or electron donating group;
`R1 is hydrogen or lower alkyl, unsubstituted or substituted with an electron donating group or an electron
`withdrawing group and
`lower alkyl, aryl,
`lower alkynyl, aryl
`lower alkenyl,
`lower alkyl,
`R2 and R3 are independently hydrogen,
`heterocyclic, heterocylic 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, NR4. PR; or a chemical bond;
`lower alkynyl, or halo and Y may be
`lower alkenyl,
`Y is hydrogen,
`lower alkyl, aryl, aryl
`lower alkyl,
`unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that
`when Y is halo, 2 is a chemical bond, or
`ZY taken together is NRANRSRG, NR4OR5, ONR4R5, OPR4Rs, PR4.0R5, SNR4R5, NR4.SR5, SPR4.R5 0|’
`PRASRS, NR4PR5Re OI’ PR4.NR5Rs,
`R4, R5 and Rs are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl. or lower alkynyl,
`wherein R4, R5 and He may be unsubstituted or substituted with an electron withdrawing group or an
`electron donating group and
`n is 1-4.
`The predominant application of anticonvulsant drugs is the control and prevention of seizures asso-
`ciated with epilepsy 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 associated with myoclonic jerks, akinetic seizures,
`transient
`loss of
`consciousness, but without convulsion; and grand mal which manifests in a continuous series of seizures
`and convulsions with 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 hydantoins, such as phenytoin, are useful
`in the control of
`generalized seizures and all forms of partial seizures. The oxazolidinedoines, such as trimethadione and
`paramethadione, are used in the treatment of nonconvulsive seizures. Phenacemide, a phenylacetylurea, is
`one of
`the most well known anticonvulsants employed today, while much attention has recently been
`dedicated to the investigation of the diazepines and piperazines. For example, U.S. Patent Nos. 4,002,764
`and 4,178,378 to Allgeier, et al. disclose esterified diazepine derivatives useful in the treatment of epilepsy
`and other nervous disorders. U.S. Patent No. 3,887,543 to Nakanishi, et al. describes a thieno [2,3-e][1,4]
`diazepine compound also having anticonvulsant activity and other depressant activity. U.S. Patent 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 agitation. U.S. Patent 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
`these
`compounds in an acid pH range are useful
`in the treatment of convulsion disorders and also possess
`
`3
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`|PR2014—01126— Exhibit 1024 p. 3
`
`IPR2014-01126- Exhibit 1024 p. 3
`
`

`
`EP 0 400 440 A1
`
`anxiolytic and sedative properties.
`Unfortunately, despite the many available pharmacotherapeutic agents, a significant percentage of the
`population with epilepsy or related disorders are poorly managed. Moreover, none of the drugs presently
`available are capable of achieving total seizure control and most have disturbing side-effects. Clearly,
`current therapy has failed to "seize control" of these debilitating‘ diseases.
`It is therefore one object of the present invention to provide novel compounds exhibiting CNS activity.
`particularly anticonvulsant activity.
`-
`Another object of this invention is to provide pharmaceutical compositions useful
`epilepsy and other CNS disorders.
`A further object of this invention is to provide a method of treating epilepsy and related convulsant
`disorders.
`
`in the treatment of
`
`These and other objects are accomplished herein by providing compounds of the following general
`formula:
`
`$7
`R—\'-'I{-CC2?}{'7 C-R
`‘P ill
`“in
`0123
`0
`
`1
`
`-
`
`(I)
`
`wherein R, R1, R2, R3, R4, R5, R,—,, Z. Y are as defined hereinabove.
`in compositions of
`The present
`invention contemplates employing the compounds of Formula I
`pharmaceutically acceptable dosage forms. Where the appropriate substituents are employed. the present
`invention also includes pharmaceutically acceptable addition salts. Moreover,
`the administration of an
`effective amount of the present compounds, in their pharmaceutically acceptable forms or the addition salts
`thereof, can provide an excellent regime for the treament of epilepsy, nervous anxiety, psychosis. insomnia
`and other related central nervous system disorders.
`The alkyl groups when used alone or in combination with other groups, exemplary of the substituents
`are lower alkyl containing from 1
`to 6 carbon atoms and may be straight chain or branched. These groups
`include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl, and the like.
`The aryl
`lower alkyl groups include,
`for example, benzyl, phenethyl, phenpropyl. phenisopropyl.
`phenbutyl, and the like. diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl, and the like.
`The term aryl refers to an aromatic group which contains up to 18 ring carbon atoms and up to a total
`of 25 carbon atoms and includes the polynuclear aromatic substituents. These aryl groups may be
`monocyclic, bicyclic,
`tricyclic or polycyclic and are fused rings. This group includes phenyl, naphthyl.
`anthracenyl, phenanthrenyl, azulenyl and the like. It also includes groups like ferrocenyl.
`Lower alkenyl is a alkenyl group containing from 2 to 6 carbon atoms and at least one double bond.
`These groups may be straight chained or branched and may be in the Z or E form. Such groups include
`vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl. (Z)-2-penten—yl, (E_)-2-pentenyl,
`iZ)~4-methyl-2-
`pentenyl, (E-)-4-methyl-2-pentenyl, pentadienyl, e.g., 1,3 or 2,4-pentadienyl, and the like.
`The term alkynyl
`include alkyne substituents containing 2 to 6 carbon atoms and may be straight
`chained as well as branched. It includes such groups as ethynyl. propynyl, 1-butynyl. 2-butynyl, 1-pentynl,
`2-pentynyl, 3-methyl-1-pentynl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like:
`The term "electron-withdrawing and electron donating" refer to the ability of a substituent to withdraw or
`donate electrons relative to that of hydrogen if the hydrogen atom occupied the same position in the
`molecule. These terms are well understood by one skilled in the art and are discussed in Advanced Organic
`Chemistry, by J. March, John Wiley and Sons, New York NY, pp. 16-18 (1985) and the discussion therein is
`incorporated herein by reference. Electron withdrawing groups include halo, including bromo. fluoro, chloro.
`iodo and the like: nitro, carboxy,
`lower alkenyl,
`lower alkynyl,
`formyl, carboxamido, aryl, quaternary
`ammonium and the like. Electron donating groups include such groups as hydroxy. lower alkoxy, including
`methoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl, and the like; amino, lower alkylamino, di-
`(loweralkyl) amino, aryloxy such as phenoxy, mercapto, alkylthio, disulfide, and the like. One skilled in the
`art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing
`properties under different chemical conditions. Moreover. the present invention contemplates any combina-
`tion of substituents selected from the above-identified groups.
`The term halo includes fluoro, chloro, bromo. iodo and the like.
`As employed herein, the heterocyclic substituent contains at least one sulfur, nitrogen or oxygen, but
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`|PR2014—01126— Exhibit 1024 p. 4
`
`IPR2014-01126- Exhibit 1024 p. 4
`
`

`
`EP 0 400 440 A1
`
`.
`
`also may include one or several of said atoms. The heterocyclic substituents contemplated by the present
`invention include heteroaromatics and saturated and partially saturated heterocyclic compounds. These
`heterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. The may contain up
`to 18 ring atoms and up to a total of 17 ring carbon atoms and a total of up to 25 carbon atoms. The
`heterocyclics are also intended to include the so-called benzoheterocycles. Representative heterocyclics
`include furyl,
`thienyl, pyrazolyl, pyrrolyl,
`imidazolyl,
`indolyl,
`thiazolyl, oxazolyl,
`is othiazolyl,
`isoxazolyl,
`piperidyl, pyrrolinyl, piperazinyl, quinolyl,
`triazolyl,
`tetrazolyl; isoquinolyl, benzofuryl, benzothienyl, mor-
`pholinyl, benzoxazolyl,
`tetrahydrofuryl, pyranyl,
`indazolyl, purinyl,
`indolinyl, pyrazolidinyl.
`imidazolinyl.
`imidazolidinyl, pyrrolidinyl,
`furazanyl, N-methylindolyl, methylfuryl, puridazinyl, pyrimidinyl. pyrazinyl,
`pyridyl. epoxy, aziridino, oxetanyl, azetidinyl, the N-oxides of the nitrogen containing heterocycles. such as
`the ni.tric oxides of pyridyl, pyrazinyl, and pyrimidinyl and the like. The preferred heterocyclic are thienyl,
`furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl. The preferred heterocyclic is a
`5 or 6-membered heterocyclic compound. The especially preferred heterocyclic is furyl.
`The preferred compounds are those wherein n is 1, but di. tri and tetrapeptides are acceptable.
`The preferred values of R is aryl lower alkyl, especially benzyl, and the preferred R1 is H or lower alkyl.
`The most preferred R1 group is methyl.
`The most preferred electron donating substituent and electron donating substituent for R1 e.g., are halo,
`nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamide, cyano, sulfonyl, sulfoxide,
`heterocyclic, guanidine, quaternary ammonium. lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower
`alkoxy, lower alkyl, amino, lower alkylamino, dl(|oweralky)lamino, amino lower alkyl. mercapto and alkylthio.
`The ZY groups representative of R2 and R3 include alkoxy, such as methoxy, ethoxy, aryloxy, such as
`phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy, alkylamino, such as
`methylamino. ethylamino,
`arylamino.
`such as
`anilino,
`lower dialkylamino,
`such as, dimethylamino,
`hydrazino, alkylhydrazino and aryl hydrazino, such as N-methylhydrazino and N-phenylhydrazino, and
`hydroxylamino, such as N-hydroxylamino (-NH-OH) and O-hydroxylamino (-O-NH2).
`It
`is preferred that at least one of R2 and R3 is hydrogen and that the other is heterocyclic. The
`preferred heterocyclics include furyl, thienyl, benzothienyl, benzofuryl, morpholinyl, indolyl, pyrrolyl, methyl-
`pyrrolyl.
`It is also preferred that one of R2 and R3 is methyl, phenyl, isopropyl, 2-thiomethylethyl, ethoxy,
`methoxy, anilino, propenyl, ethylamino and methylamino.
`Preferred compounds of the present invention have the following general formula:
`
`$2
`\ CHZNHE-cflfifi-R1
`0 R3 o
`/
`
`\.-—-—i"‘
`Ain?
`
`wherein R» is H or lower alkyl, R2 and R3 are as defined above and A is hydrogen or an electron donating
`group or electron-withdrawing group and m is 0-5.
`It is preferred that A is hydrogen (i.e., m =0). However.
`values of m, equalling 1, 2, or 3 are also preferred.
`Especially preferred compounds of the Formula I have the formula
`
`l'§2°
`R-\NH%-Q-NH C-R1
`‘__.O
`R3
`n
`
`wherein
`lower alkyl, heterocyclic or heterocyclic alkyl which is unsubstituted or substituted with at
`R is aryl, aryl
`least one electron withdrawing group or at least one electron donating group;
`R1 is hydrogen or lower alkyl which is unsubstituted or substituted with at leat one electron withdrawing
`group or one electron donating group.
`R2 and R3 are independently hydrogen, lower alkenyl, lower alkynyl, Z-Y or a heterocyclic group which may
`be unsubstituted or substituted with at least one electron withdrawing or one electron donating group, with
`
`|PR2014—01126— Exhibit 1024 p. 5
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`IPR2014-01126- Exhibit 1024 p. 5
`
`

`
`EP 0 400 440 A1
`
`the proviso that R2 and R3 cannot both be hydrogen;
`2 is O, S, NR4, PR. or a chemical bond;
`
`lower alkynyl or halo, and Y may be
`lower alkenyl,
`lower alkyl,
`lower alkyl, aryl, aryl
`Y is hydrogen,
`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 NRa,NR5Rs, NR4OR5, ONRARS, OPRLRS, PR4.OR5, SNR4R5, NR4SR5, SPRARS, Ol’
`PR4.SR5, NR4PR5R5 0|’ PR-1.NR5R5
`'
`R4, R5 and Rs are independently hydrogen, lower alkyl, aryl. aryl lower alkyl, lower alkenyl. or lower alkynyl,
`wherein R4, R5 and R5 may be unsubstituted or substituted with an electron withdrawing group or an
`electron donating group; and
`n is 1-4.
`
`Of this preferred group, it is especially preferred that n is 1.
`The compounds of the present invention may contain one (1) or more asymmetric carbons and may
`exists in racemic and optically active forms. The configuration around each asymmetric carbon can be in
`either the D or L, form. (It is well known in the art that the configuration around a chiral carbon atoms can
`also be described as R or S in the Cahn-Prelog-Ingold nomenclature system). All of
`the various
`configurations around each asymmetric carbon,
`including the various enantiomers and diastereomers as
`well as racemic mixtures and mixtures of enantiomers, diastereomers or both are contemplated by the
`present invention.
`In the principal chain, there exists asymmetry at the carbon atoms to which the groups R2 and R3 are
`attached as substituted. When n is 1, the compounds of the present invention is of the formula
`
`$2’?
`-
`R-.NI-I-‘Ci-(‘Z-N-E-R1
`0
`R3
`0
`
`the term
`wherein R, R«, R2, R3, R4, R5, R5, Z and Y are as defined previously. As used herein,
`configuration shall refer to the configuration around the carbon atom to which R2 and R3 are attached. even
`though other chiral centers may be present in the molecule. Therefore, when referring to a particular
`configuration, such as D or L,
`it
`is to be understood to mean the stereoisomer,
`including all possible
`enantiomers and diaste—r'eome—rs. The compounds of
`the present
`invention are directed to the optical
`isomers, i.e., the compounds of the present invention are either the L-stereoisomer or the D-stereoisomer,
`These stereoisomers may be found in mixtures of the L and D stereoisomer, e.g., racemic mi—xtures.
`Depending upon the substituents, the present cornpound_s may form addition salts as well. All of these
`forms are contemplated to be within the scope of this invention including mixtures of the stereoisomeric
`forms.
`
`The following three schemes of preparation are generally exemplary of the process which can be
`employed for the preparation of the present complex:
`
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`|PR2014—01126— Exhibit 1024 p. 6
`
`IPR2014-01126- Exhibit 1024 p. 6
`
`

`
`EP 0 400 440 A1
`
`Scheme I
`
`R
`I 2
`.
`HOOC-‘C*NH2
`I
`
`3
`
`SOCIZ
`Meoa
`
`E
`
`excess
`_ RNH2
`
`5
`
`‘$2
`‘u’
`‘R-NH-C-§—NH2
`R3
`
`‘F2
`?’
`RHN-C-C—NH-C-R
`I
`u
`R3
`0'
`
`1
`
`Scheme 11
`
`$2
`HOOC-C-NH
`3
`R3
`
`2
`
`0'0
`_
`u
`u
`—RnCOCR1
`
`0
`.3 ~
`u
`:2
`Hooc—e-Nn—cn1
`R3
`
`5?
`ClCO R7
`yexgiary amine
`
`1
`
`RN32
`
`‘
`
`.0 o R
`o
`n
`n
`42
`n
`R7°coc-e~NH-cal
`R3
`
`o
`0 R
`u
`n
`x2e
`hnfi-c-c-Nnca
`
`I R
`
`3
`
`+
`
`co + Rpfl
`2
`
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`30
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`
`wherein
`
`R7 = lower alkyl, aryl. ary! lower alkyl,
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`7
`
`|PR2014—01126— Exhibit 1024 p. 7
`
`IPR2014-01126- Exhibit 1024 p. 7
`
`

`
`EP 0 400 440 A1
`
`scheme Ii:
`
`8
`R CNH -
`1
`2
`
`00
`P Hg
`.2c on
`
`ouo
`o
`l
`u
`u
`R1CNHrC—COH
`
`2
`
`v
`
`R708/H+
`
`0
`
`on o
`
`‘é 7"
`R Elm:
`1 “ ,’"CNHR
`at
`
`‘M’
`5’
`RICNH-C-COR7
`I
`R2
`
`RNH2
`é-————
`w1th'or
`without catalyst
`(Q-e.} M+cN')
`33g
`Lewis acid: such as BF3 o(Et)2
`
`0
`R O
`u
`i3u
`R1cNH—c—cNHR
`R2
`
`wherein R3 = aryl, heteroaromatic and R7 is as defined hereinabove.
`More specifically,
`these compounds can be prepared by art-recognized procedures from known
`compounds or readily preparable intermediates. For instance, compounds of Formula I can be prepared by
`reacting amines of Formula ll with an acylating derivative of a carboxylic acid of Formula Ill under amide
`forming conditions:
`
`+
`
`3
`R —c~oa —-——a:
`1
`
`H
`
`A
`
`" 1:
`
`1::
`
`0 R2
`n
`l
`RNH C“~C — as
`
`l R
`
`3
`11
`
`wherein R, R1, R2, R3 and are as defined hereinabove and n = 1.
`
`The amide forming conditions referred to herein involve the use of known derivatives of the described
`acids. such as the acylhalides, (e.g., R:- C")-X,0
`wherein X is Cl, Br, and the like), anhydrides (e.g.,
`O
`0
`ll
`II
`R1- C-O- C-R«), mixed anhydrides, lower alkyl esters, carbodiimides, carbonyldiimidazoles, and the like.
`is preferred that the acylating derivative used is the anhydride.
`0
`0
`ll
`ll
`R1‘ C-O- C‘R‘.. When alkyl esters are employed, amide bond formation can be catalyzed by metal
`cyanides such as sodium or potassium cyanides.
`Another exemplary procedure for preparing compounds wherein at least one of R2 and R3 is aromatic
`or heteroaromatic is as depicted in Scheme IV.
`
`It
`
`|PR2014—01126— Exhibit 1024 p. 8
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`IPR2014-01126- Exhibit 1024 p. 8
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`

`
`EP 0 400 440 A1
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`The ester (IV) is reacted with halogen and ultraviolet light in the presence of a catalyst. e.g., AIBN, to
`form the halo derivative (V). (V) is reacted in the presence of a Lewis acid, such as zinc chloride, with an
`aromatic or heteroaromatic compound to form the compound (VI).
`(VI)
`in turn is hydrolyzed and then
`reacted with alkylhaloformate, such as alkylchloroformate in the presence of a tertiary amine to generate the
`5 mixed N-acyl amino acid carbonic ester anhydride (Vlll). This intermediate is reacted with an amine under
`amide forming conditions to give the compound of Formula I. Alternatively, (VI) can be reacted directly with
`an amine (RNHZ) optionally in the presence of a metal catalyst, such as metal cyanides. e.g., potassium or
`sodium cyanide, under amide forming conditions to form a compound of Formula I. Alternatively, compound
`Vll can be prepared by an independent method and converted to VI which is then reacted with an amine.
`10 with or without catalyst to form the compound of Formula I.
`
`Scheme IV
`0
`0
`
`R ENHCHQOR
`I;
`I
`R3
`
`7
`
`-**£2———-——>
`hmh AIBN
`
`o
`
`'x o
`
`Ext};
`'1 ‘
`
`(‘j
`1
`R3
`
`flog
`
`V
`
`Lewis Acid
`R21-I
`'
`
`_
`
`_
`
`+
`1' M OH
`+
`2‘ H39
`
`a
`
`R20
`0
`I
`"
`H
`RICNH-C-COR7
`'
`'
`R3 VI
`F
`
`O
`
`R O2
`R gNH-c-gen
`1
`VII
`é
`03‘
`ll
`ClCOR7
`tertiary amine
`
`.
`
`75
`
`20
`
`”
`
`30
`
`“
`
`40
`
`‘*5
`
`50
`
`55
`
`IR EN“-c—g—o-£3
`1
`" I
`‘R
`
`O
`
`R 0
`2
`
`3
`
`0
`
`7
`
`'
`
`am;
`
`F Witfi °r
`w3:.thout gatalyst
`(loeo, M
`)
`
`HZNR
`
`R 0
`2
`I
`ll
`RlCNH-(l3-C-NHR
`:
`R3
`. e———————
`
`X = halogen (i.e., Cl, Br)
`R7 = loweralkyl, aryl, arylloweralkyl
`M‘ = metal cation (i.e., Na‘, K’)
`Another useful method for preparing a compound of Formula I involves simple substitution reactions.
`An exemplary procedure is as follows:
`
`|PR2014—01126— Exhibit 1024 p. 9
`
`IPR2014-01126- Exhibit 1024 p. 9
`
`

`
`EP 0 400 440 A1
`
`.
`
`R
`
`1
`
`a ‘ft?
`‘ii
`— C-[N-C-0-}NHa + R
`,
`9
`32
`
`IX
`
`3
`x
`
`- :.———---> I
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`wherein R, R1, R2 and R4 and n have the aforesaid meanings and R3 is defined heretofore except it is not
`aryl, heteroaromatic or polynuclear aromatic and L and L’ are independently a good leaving group. such as
`halide, tosylates, mesoylates, brosylates, benzyloxy and the like. In this procedure the amine of Formula IX
`is reacted with a compound of Formula X under substitution conditions. The reaction may take place in the
`presence of an acid. such as inorganic acid, e.g., hydrochloric acid, sulfuric acid or Lewis acid. such as
`boron trifluoride and the like or in the presence of a base, such as triethylamine.
`in the procedure
`However, when R3 is heteroaromatic, aryl or polynuclear aromatic, L is hydrogen.
`under these circumstances, the reaction should take place in the presence of an acid catalyst. such as an
`inorganic acid, e.g., hydrochloric acid or a Lewis acid, such as borontrifluoride.
`As in any organic reaction, solvents can be employed such as methanol, ethanol, propanol. acetone,
`tetrahydrofuran. dioxane, dimethylformamide, dichloromethane, chloroform, and the like. The reaction is
`normally effected at or near
`room temperature, although temperatures from 0° C up to the reflux
`temperature of the reaction mixture can be employed.
`As a further convenience, the amide forming reaction can be effected in the presence of a base. such
`as tertiary organic amine, e g., triethylamine, pyridine, 4-methylmorpholine, picolines and the like, particu-
`larly where hydrogen halide is formed by the amide forming reaction, e.g., acyl halide and the amine of
`Formula II. Of course,
`in those reactions where hydrogen halide is produced, any of the commonly used
`hydrogen halide acceptors can also be used.
`The exact mineral acid or Lewis acid employed in the reaction will vary depending on the given
`transformation, the temperature required for the conversion and the sensitivity of the reagent toward the
`acid in the reaction employed.
`As an example of the process described hereinabove, D-(-)-or-acetamido-N-benzyl-2-furanacetamide can
`be prepared by reacting under amide forming conditions or-acetamide-2-furanacetic acid or an acylating
`derivative thereof, i.e., esters, e.g. alkyl esters containing 1-6 carbon atoms, or acid anhydrides and the like.
`The diastereomers formed from the reactions can then be separated by techniques known to one skilled in
`the art.
`
`The a-acetamido-2-furanacetic acid can be prepared by reacting under substitution conditions, furan
`with an acylating derivative of 2-acetamido-2-haloacetic acid wherein the halo group is bromo or chloro. By
`an acylating derivative of 2-acetamido-2-haloacetic acid, it is meant to include lower alkyl esters thereof or
`the known carboxy protecting groups.
`The various substituents on the present new compounds, e.g., as defined in R. R«, R; and R3 can be
`present in the starting compounds, added to any one of the intermediates or added after formation of the
`final products by the known methods of substitution or conversion reactions. For example. the nitro groups
`can be added to the aromatic ring by nitration and the nitro group converted to other groups. such as amino
`by reduction, and halo by diazotization of the amino group and replacement of the diazo group. Alkanoyl
`groups can be substituted onto the aryl groups by Friedel—Crafts acylation. The acyl groups can be then
`transformed to the corresponding alkyl groups by various methods,
`including the Wolff-Kishner reduction
`and Clemmenson reduction. Amino groups can be alkylated to form mono, dialkylamino and trialkylamino
`groups; and mercapto and hydroxy groups can be alkylated to form corresponding thioethers or ethers,
`respectively. Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids
`or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or alteration
`reactions can be employed to provide a variety of substituents throughout the molecule of the starting
`material, intermediates, or the final product.
`In the above reactions, if the substituents themselves are reactive, then the substituents can themselves
`
`be protected according to the techniques known in the art. A variety of protecting groups known in the art
`may be employed. Examples of many of these possible groups may be found in "Protective Groups in
`Organic Synthesis," by T.W. Greene,John Wiley & Sons, 1981.
`Resulting mixtures of isomers can be separated into the pure isomers by methods known to one skilled
`in the art, e.g., by fractional distillation, crystallization and/or chromotagraphy.
`The present compounds obviously exist in stereoisomeric forms and the products obtained thus can be
`mixtures of the isomers, which can be resolved. Optically pure functionalized amino acid derivatives can be
`
`10
`
`|PR2014—01126— Exhibit 1024 p. 10
`
`IPR2014-01126- Exhibit 1024 p. 10
`
`

`
`EP 0 400 440 A1
`
`intermediate. Racemic products can likewise be
`prepared directly from the corresponding pure chiral
`resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g., by
`fractional crystallization, by selective enzymatic hydrolysis, e.g., papain digestion, or by use of a chiral
`stationary phase in chromotagraphy (HPLC). For a discussion of chiral stationary phases for HPLC, See,
`DeCamp, Chirality, 1, 2-6 (1989), which is incorporated herein by reference with the same force and efict
`as if fully set forth herein.
`For example, a racemic mixture of any of the intermediate" in any of the schemes, e.g.,
`
`fi
`32
`.°.
`RIC-NH-‘C-COR7:
`R3
`
`wherein R7 is H (which can be prepared according to the procedures of Schemes 1, 2, 3, or 4) is reacted
`with an optically active amine, RNH2, e.g., (R) (+)-a-methylbenzylamine to form a pair of diastereomeric
`salts. The diastereomers can then be separated by recognized techniques known in the art, such as
`chromotagraphy (HPLC), fractional recrystallization and the like.
`In another method, a racemic mixture of final products or intermediates can be resolved by using
`enzymatic methods. Since enzymes are chiral molecules,
`it can be used to separate the racemic
`modification, since it will preferentially act on one of the compounds, without affecting the enantiomer. For
`example, acylase, such as acylase I, can be used to separate the racemic modification of an intermediate
`D,L(:)a-acetamido-2-furanacetic acid.
`it acts on the L (:)a-acetamido-2-furanacetic acid, but will not act on
`the D enantiomer. in this way, the D(-)a-acetamido-2'-_furanacetic acid can be isolated. the intermediate can
`then—react with the amine (RNH2) under amide forming conditions as described hereinabove to form the
`compound of Formula I.
`The active ingredients of the therapeutic compositions and the compounds of the present invention
`exhibit excellent anticonvulsant activity when administered in amounts ranging from about 10 mg to about
`100 mg per kilogram of body weight per day. A preferred dosage regimen for optimum results would be
`from about 20 mg to about 50 mg per kilogram of body weight per day, and such dosage units are
`employed that a total of from about 1.0 gram to about 3.0 grams of the active compound for a subject of
`about 70 kg of body weight are administered in a 24-hour period. This dosage regimen may be adjusted to
`provide the optimum therapeutic response and is preferably administered one to three times a day in
`dosages of about 600 mg per administration. For 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, intraveneous (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 capsule, or it may be
`compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic
`administration. the active compound may be incorporated with excipients and used in the form of ingestible
`tablets, buccal tablets, troches, capsules. elixirs, suspensions, syrups, wafers, and the like. Such composi-
`tions and preparations should contain at least 1% of active compound. 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 compositions 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 1000 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 magnesium 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 to materials of the above type, a liquid carrier. Various other materials may be present as
`coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules
`may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a
`sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or
`orange flavor. Of course, any material used in preparing any dosage unit form shou