2-Substituted-2-acetamido-H-benzylacetamides. Synthesis, Spectroscopic
`and Anticonvulsant Properties
`
`A Thesis
`
`Presented to
`
`the Faculty of the Department of Chemistry
`
`University of Houston-University Park
`
`In Partial Fulfillment
`
`of the Requirements for the Degree
`
`Master of Science
`
`By
`
`Philippe Le Gall
`
`December, 1987
`
`IPR2014-01126-Exhibit 1005, p. 1
`
`
`and Anticonvulsant Properties
`
`A Thesis
`
`Presented to
`
`the Faculty of the Department of Chemistry
`
`University of Houston-University Park
`
`In Partial Fulfillment
`
`of the Requirements for the Degree
`
`Master of Science
`
`By
`
`Philippe Le Gall
`
`December, 1987
`
`IPR2014-01126-Exhibit 1005, p. 1
`
`
`
`2-Substituted-2-acetamido-H-benzylacetamides.
`Synthesis, Spectroscopic and Anticonvulsant Properties
`
`APPROVED:
`
`Dr. Harold L. Kohn I
`
`~2>2 .~
`·~~~
`Dr. Thomas L. Lemke
`.....__;
`
`e of Natural Sciences and Mathematics
`
`i i
`
`IPR2014-01126-Exhibit 1005, p. 2
`
`
`
`ACKNOWLEDGEMENT
`
`I would
`
`like
`
`to
`
`thank Dr. Kohn, whose enthusiasm and
`
`knowledge were always on my side when needed.
`
`I also want
`
`to
`
`thank all the past and present members of this
`
`research group.
`
`I
`
`am
`
`indebted to
`
`their
`
`friendship and assistance.
`
`I would like to acknowledge all
`
`those who have contributed
`
`to the completion of this work.
`
`In particular,
`
`I would
`
`like to thank
`
`Dr. Gary E. Martin and
`
`the N.M.R.
`
`laboratory at
`
`the University of
`
`Houston, Dr. John Chinn at
`
`the University of Texas at Austin, and
`
`Dr. J. David Leander and Dr. David Robertson at
`
`the Eli Lilly
`
`Research Center,
`
`Indianapolis,
`
`Indiana,
`
`for their kind cooperation.
`
`Finally, I would
`
`like to thank Dr. Kurt L Loaning, Director of
`
`Nomenclature, Chemical Abstracts Services, Columbus, Ohio, for his
`
`help in naming
`
`the synthesized compounds.
`
`iii
`
`IPR2014-01126-Exhibit 1005, p. 3
`
`
`
`2-Substituted-2-acetamido-N-benzylacetamides. Synthesis, Spectroscopic
`and Anticonvulsant Properties
`
`An Abstract of a Thesis
`
`Presented to
`
`the Faculty of the Department of Chemistry
`
`University of Houston-University Park
`
`In Partial Fulfillment
`
`of the Requirements for the Degree
`
`Master of Science
`
`By
`
`Philippe Le Gall
`
`December, 1987
`
`iv
`
`IPR2014-01126-Exhibit 1005, p. 4
`
`
`
`ABSTRACT
`
`Select functionalized. amino acid derivatives of the potent anti(cid:173)
`
`convulsant agent a-acetamido-.N.-benzylphenylacetamide
`
`(.2&2,) and
`
`2-acetamido-.N.-benzylpropionamide
`
`(§.aa) have been prepared and
`
`evaluated.
`Attention has been
`focused on
`the replacement of the
`a-phenyl and a-methyl groups in &la and .6812 by five-membered ring
`
`hetereoaromatic moieties, benzo-fused
`
`heteroaromatic groups, and
`
`simple polar substituents.
`
`The synthetic and pharmacological studies revealed several
`
`notable
`
`findings. First,
`
`the use of amidoalkylation procedures using
`
`boron trifluoride etherate provided a straightforward and
`
`reliable
`
`method
`
`to · introduce an electron-rich heteroaromatic substituent
`
`i:lt
`
`the a-carbon
`
`in
`
`the amino acid derivatives.
`
`This
`
`technology
`
`permitted
`
`the
`
`incorporation
`
`of
`
`acid sensitive, unsubstituted
`
`heteroaromatic
`
`compounds
`
`(i.e.,
`
`pyrrole
`
`(.ZA),
`
`indole CZ2.) and
`
`benzofuran ~) within
`
`the molecule. Second, all
`
`the
`
`five-membered
`
`ring heteroaromatic analogues of a-acetamido-N.:benzylphenylaceta(cid:173)
`
`mide proved highly active in the MES seizure test.
`
`In particular,
`
`a-acetamido-N-benzyl-2-furanacetamide (~ and a-aceta(cid:173)
`
`mido-.N.-benzyl-2-pyrroleacetamide
`
`(§.ab) exhibited activities similar to
`
`phenytoin and diazepam. Third,
`
`the a-alkoxy derivatives, 2~aceta
`
`mido-N-benzyl-2-methoxyacetamide ~ and 2-acetamido-N-benzyl-2-
`
`ethoxyacetamide, exhibited significant activity in
`
`the MES seizure test.
`
`v
`
`IPR2014-01126-Exhibit 1005, p. 5
`
`
`
`'"'
`
`Fourth, neither
`
`the benzo-fused heteroaromatic derivatives nor
`
`the
`
`compounds bearing an electron-withdrawing
`
`substituent at
`
`the
`
`a-carbon had significant activity. Fifth, the composite pharmacolog(cid:173)
`
`ical data suggested
`
`that small substituents are
`
`required at
`
`the
`
`a-carbon of
`
`the 2-acetamido-.N-benzylglycine derivative
`
`for maximal
`
`activity in
`
`the MES
`
`test and
`
`that
`
`this activity is enhanced by
`
`the
`
`presence of electron-donating groups at this site.
`
`vi
`
`IPR2014-01126-Exhibit 1005, p. 6
`
`
`
`TABLE OF CONTENTS.
`
`iii
`viii
`xiii
`xiv
`1
`2
`5
`
`44
`
`Acknowledgements
`Ust of Tables
`List of Schemes
`List of Figures
`Introduction.
`
`I .
`I I .
`
`Biogenesis of the Epileptic Seizure
`Symptomatology and Classification of
`Epileptic Seizures.
`13
`I I I. Evaluation of Anticonvulsant Agents.
`17
`Antiepileptic Drugs.
`IV.
`v.
`25
`Clinical Applications
`30
`VI . Mechanism of Drug Action.
`32
`vi I. Structure-activity Relationships.
`VI I I • Anticonvulsant Amino Acids and Amino 35
`Acid Derivatives
`Chapter I. Synthesis, Spectroscopic and Anticonvulsant Proper-
`ties of Structural Analogues §B. of 2-Acetamido-N-ben(cid:173)
`zylphenylacetamide {.2m2) and 2-Acetamido-N-benzyl-
`2-alkoxyacetamides (B.Q).
`
`I .
`I I .
`
`Introduction
`Results and Discussion
`1. Synthesis.
`2. Spectral Evaluation.
`a. Infrared Spectra.
`b. Mass Spectral Data.
`c. 1 H NMR Spectral Data.
`d. 13c NMR Spectral Data.
`3. Pharmacological Evaluation.
`I I I . Experimental Section.
`Chapter I I . Synthesis, Spectroscopic and Anticonvulsant Proper-
`ties of Polar Analogues 1QZ of 2-Acetamido-N-ben(cid:173)
`zylpropionamide (6.aa)
`Introduction.
`I .
`Results and Discussion
`I I .
`1. Synthesis.
`2. Spectral Evaluation.
`a. Infrared Spectra.
`
`44
`4 7
`47
`7 4
`7 4
`79
`80
`93
`1 02
`1 09
`132
`
`132
`132
`132
`139
`139
`
`vii
`
`IPR2014-01126-Exhibit 1005, p. 7
`
`
`
`b. Mass Spectral Data.
`c. 1 H NMR Spectral Data.
`d. 13c NMR Spectral Data.
`3. Pharmacological Evaluation.
`III. Experimental Section
`General Conclusions.
`References.
`
`144
`144
`147
`153
`155
`164
`166
`
`viii
`
`IPR2014-01126-Exhibit 1005, p. 8
`
`
`
`LIST OF TABLES. ·
`
`Table.
`
`1.
`
`The International Classification of Epileptic Seizures.
`
`2. .
`
`The Revised Classification of Epilpetic Seizures.
`
`8
`
`9
`
`18
`
`29
`
`45
`
`46
`
`48
`
`50
`
`3.
`
`4.
`
`5a.
`
`5b.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`Sequential Test Phases Utilized for the Anticonvulsant
`the Antiepileptic Drug Develop-
`Screening Project of
`ment Program.
`
`Antiepileptic Drugs Marketed in the United States.
`
`Monocyclic Heteroaromatic Analogues §9. of
`2-Acetamido-N-benzylphenylacetamide (~}.
`
`Benzofused Heteroaromatic Analogues 29. of
`2-Acetamido-N-benzylphenylacetamide (~}.
`
`Examples of Amino Acids with an a-Heterocyclic
`Substituent.
`
`Synthesis of Amino Acid Derivatives by the Amido-
`alkylation Technique.
`
`Amidoalkylation Reactions
`2-Methylfuran <.Z.Q.b).
`
`Involving Furan (ZQ.a} and
`
`53
`
`Amidoalkylation Reactions Involving Pyrrole Cl.4) and
`Substitut~d Pyrroles.
`
`Amidoalkylation Reactions Involving Indole
`
`(12}.
`
`Amidoalkylation Reactions Involving Thiophene (11).
`
`55
`
`56
`
`57
`
`Amidoalkylation Reactions Involving Other Heterocycles. 58
`
`ix
`
`- - - - - - - - - - - - · - - - - - - - - --------~--
`
`IPR2014-01126-Exhibit 1005, p. 9
`
`
`
`Selected Physical and Spectral Data for Alkyl 2-Aceta- 61
`. mido-2-alkoxyacetate UiQ.}.
`
`Selected Physical and Spectral Data for a-Substitu-
`ted Alkyl 2-Acetamidoacetates all).
`
`. 15.
`
`Selected Physical and Spectral Data for a-Substitu-
`ted 2-Acetamidoacetic Acids (a2).
`
`13.
`
`14.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21 ..
`
`22.
`
`23.
`
`24.
`
`62
`
`64
`
`67
`
`Selected Physical and Spectral Data for a-Substitu-
`ted 2-Acetamido-N-benzylacetamides (§9}.
`
`Selected Physical and Spectral Data
`N-benzyl-2-alkoxyacetamides (.86.).
`
`for 2-Ace.tamido- 69
`
`Comparison of Several Amidoalkylation Reactions lnvol- 73
`ving Furan (ZQa), Pyrrole (B), Thiophene (11),
`Indole
`(Z2.), Benzofuran (15) and Benzo[b]thiophene {.m) Be(cid:173)
`.B..2..a and t2 or ..B.QQ.
`ginning with Either .B.Q.,
`
`Selected Infrared Spectral Data for Alkyl 2-Acetamido-2- · 75
`alkoxyacetates
`(.B.Q.).
`
`Selected Infrared Spectral Data for Alkyl 2-Substituted 76
`-2-acetamidoacetates
`(.6.1).
`
`Selected Infrared Spectral Data for 2-Substituted-2-ace- 77
`tamidoacetic Acids {~.
`
`Selected Infrared Spectral Data for 2-Substituted-2-ace- 78
`tamido-N-benzylacetal'!lides ~ • .e.6.).
`
`1 H NMR Spectral Properties for Alkyl 2-Acetamido-2-
`alkoxyacetates {.B.Q.).
`
`1 H NMR Spectral Properties for Alkyl 2-Substituted-2-
`Acetamidoacetates all).
`
`86
`
`87
`
`X
`
`IPR2014-01126-Exhibit 1005, p. 10
`
`
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`1 H NMR Spectral Properties for 2-Substituted-2-aceta-
`midoacetic Acids (82.).
`1 H NMR Spectral Properties for 2-Substituted-2-aceta-
`mido-N-benzylacetamides (.§.a, .B.2).
`
`13c NMR Spectral Properties for Alkyl 2-Acetamido-
`2-alkoxyacetates (.a.Q).
`
`13c ~MR Spectral Properties for Alkyl 2-Acetamido-
`2-acetamidoacetates UU).
`
`13c NMR Spectral Properties for Alkyl 2-Substituted-
`2-acetamidoacetic Acids (.6.2.).
`
`89
`
`90
`
`94
`
`95
`
`96
`
`13c NMR Spectral Properties for 2-Substituted-2-aceta- 98
`mido-N-benzylacetamides (.6.9. • .B.2).
`
`Pharmacological Evaluation of 2-Substituted-2-acetami-
`do-N-benzylacetamides (.6.9.) Containing a Monocyclic He(cid:173)
`terocyclic Moiety.
`
`104
`
`Pharmacological Evaluation of 2-Substituted-2-acetami-
`do-N-benzylacetamides (.6.9.) Containing a Benzo-fused
`Heterocyclic Moiety.
`
`Pharmacological Evaluation of 2-Aikyl-2-acetamido- H-
`benzylacetamides (aiD.
`
`Pharmacological Activity of Some Proven Anticonvul-
`sants.
`
`2-Acetamido-N-benzylpropionamide Analogues l.QI.
`
`Selected Physical and Spectral Properties for the Po-
`lar Analogues of 2-Acetamido-N-benzylpropionamide
`(2aa).
`
`1 05
`
`1 06
`
`1 07
`
`133
`
`137
`
`xi
`
`IPR2014-01126-Exhibit 1005, p. 11
`
`
`
`37.
`
`38.
`
`39.
`
`40.
`
`41.
`
`42.
`
`43.
`
`44.
`
`Selected Physical and Spectral Data for Oxazole De-
`rivatives ll.1 and ill.
`
`Selected Infrared Spectral Data for the Polar Analo-
`gues 1 OZa-e of 2-Acetamido-N-benzylpropionamide
`WB.a).
`
`Selected Physical and Spectral Data for Oxazole De-
`rivatives ll.1 and ill.
`
`1 H NMR Spectral Properties for the Polar Analogues
`1 OZa-e of 2-Acetamido-.ti-benzylpropionamide (.6.6.a).
`
`1 H NMR Spectral Properties for the Oxazole Deriva-
`tives ll.1 and ill.
`
`13c NMR Spectral Properties for the Polar Analo-
`gues 1 OZa-e of 2-Acetamido-.ti-benzylpropionamide
`(Qaa).
`
`141
`
`142
`
`143
`
`145
`
`148
`
`149
`
`13c NMR Spectral Properties
`tives ll.1 and ill.
`
`for Oxazole Deriva-
`
`151
`
`the Polar Analogues
`Pharmacological Evaluation of
`of 2-Acetamido-N-benzylpropionamide (2.6a).
`
`154
`
`xii
`
`IPR2014-01126-Exhibit 1005, p. 12
`
`
`
`LIST OF SCHEMES
`
`Scheme.
`
`Page
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`1 0.
`
`11.
`
`12.
`
`Synthesis of 2-Substituted-2-acetamido-N-benzyl-
`acetamides (69 a.b.f.h) by Method A.
`
`Preparation of a-Acetamido-2-benzo[b]thiophenacetic
`Acid~).
`
`Synthesis of 2-Substituted-2-acetamido-N-benzylaceta-
`mides (69 a.b.f-h) by Method B.
`
`Acid Catalysed Trimerization of Indole (12).
`
`Selected Mass Spectral Patterns Observed for Alkyl-2-
`substituted-2-acetamidoacetates (.fll).
`
`Selected Mass Spectral Cleavage Patterns Observed
`for 2-Substituted-2-acetamido-N-benzylacetamides
`(Qa, a.Q).
`
`Selected Mass Spectral Cleavage Patterns Observed
`for Alkyl 2-Acetamido-2-alkoxyacetates (.00).
`
`Selected Mass Spectral Patterns Observed for 2-
`Substituted-2-acetamidoacetic Acids W,Z).
`
`Preparation of the Polar Analogues 1 OZa-e of 2-
`Acetamido-N-benzylpropionamide (SB.a).
`
`Preparation of 5-Ethoxy-2-methyloxazole-4-carboxylic
`Acid N-Benzylamide (ill).
`
`Preparation of 5-Amino-2-n:tethyloxazole-4-carboxylic
`Acid N-Benzylamide.
`
`for the Conversion of Com-
`Proposed Mechanism
`pound .1.QZ to the Oxazole Derivative lli.
`
`Xi i i
`
`59
`
`65
`
`68
`
`72
`
`81
`
`82
`
`83
`
`84
`
`134
`
`138
`
`138
`
`140
`
`IPR2014-01126-Exhibit 1005, p. 13
`
`
`
`LIST OF FIGURES.
`
`Figure.
`
`Page
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Prespeetive Drawing of the Three-dimensional
`conformations of Phenyltoin (Right) and Diaze-
`pam (Left).
`
`Amino Acids and Amino Acid Derivatives
`acting with Excitatory Neurotransmission.
`
`Inter-
`
`Inter-
`Amino Acids and Amino Acid Derivatives
`acting with the GABAergic System: GABA Prodrugs.
`
`Inter-
`Amino Acids and Amino Acid Derivatives
`acting with the GABAergic System: Compounds
`Umiting GABA Uptake.
`
`Inter-
`Amino Acids and Amino Acid Derivatives
`acting with
`the GABAergic System: GABA Re-
`ceptors Agonists.
`
`34
`
`37
`
`38
`
`40
`
`41
`
`x iv
`
`IPR2014-01126-Exhibit 1005, p. 14
`
`
`
`INTRODUCTION
`
`Epilepsy is a major neurological disorder. It affects at least 0.5
`
`percent of
`
`the world population 1 ,2 and its symptoms generally appear
`
`early in life.1 ,3
`
`If
`
`the origin of
`
`the disease is unknown, it is termed
`
`idiopathic. Correspondingly, when the epilepsy is of a known origin, the
`
`disease is referred to as symptomatic.3 In the latter situation, prenatal
`
`and postnatal .trauma, brain tumor, and vascular disorders are the major
`
`etiologies associated with
`
`the disease.1 ,3
`
`The occurrence of seizures
`
`is the manisfestation of epilepsy. Seizures may be of different types
`
`and may have sensory. motor and autonomic components.
`
`Historically, epilepsy has been
`
`referred
`
`to as
`
`the
`
`•dread
`
`disease", the "Sacred Disease", the •tailing sickness" or "St. John's
`
`disease".
`
`It was mentioned
`
`in
`
`the babylonian civil code of
`
`Hammurabi
`
`(2080 B.C.) and early akkadian and hebrew
`
`texts.
`
`Hippocrates (ca. 400 B.C.) wrote the first monograph on the affliction and
`
`first anticipated its brain origin. 3,4
`
`Despite the early recognition of this disease, significant activity
`
`directed towards
`
`the
`
`treatment an~ the understanding of epilepsies
`
`began in earnest in the mid-nineteenth century.1 ,3,5
`
`In 1870, H.J.
`
`Jackson described epilepsy as •an occasional and abnormally intense
`
`disorderly discharge of nervous tissue" of which
`
`the seizures are
`
`the
`
`symptom. 3 This statement is still accepted today. Our knowledge of
`
`the brain malfunction has not permitted a more detailed definition.
`
`It is
`
`generally accepted
`
`that
`
`epilepsy
`
`is
`
`reserved
`
`for
`
`those diseases
`
`1
`
`IPR2014-01126-Exhibit 1005, p. 15
`
`
`
`2
`
`· manisfesting
`
`themselves by a chronic occurrence of seizures.
`
`Accordingly. seizures elicited by punctual factors. such as alcohol and
`
`drug intoxication or withdrawal are not considered to be a form of this
`
`disease.
`
`1.
`
`Biogenesis of the Epileptic Seizures.
`
`Although
`
`the neurophysiology of the central nervous system
`
`· and the biochemical processes associated with neuronal activity are
`
`now
`
`fairly well established6-8.
`
`the key events leading to epileptic
`
`activity have not been determined.
`
`It was early recognized that epilepsy
`
`may affect only a part of the brain at
`
`the onset. Subsequently, the
`
`existence of epileptic foci were revealed. 7
`
`In 1975, Ebersole and
`
`Levine9 demonstrated that Enhanced Physiological Response (EPR) of
`
`neurons submitted to an epileptogenic application of penicillin (1) could
`
`lead to Paroxysmal Depolarization Shifts (PDS). The PDSs are charac(cid:173)
`
`terized by abnormally
`
`large, prolonged and repetitive excitatory post(cid:173)
`
`synaptic potential and are believed
`
`to participate
`
`in the spread of
`
`electrical discharge during the seizure.1 0,11 The origins of EPRs are
`
`considered the key step in the epileptogenesis.1 0
`
`These observations have led to a six stage model for the gen(cid:173)
`
`eration of epileptic seizures: (a) the initiation of the EPR; (b) the gen.;
`
`eration of PDSs; (c) the recruitment of normal neurons; (d)
`
`the inter(cid:173)
`
`vention of control mechanisms that
`
`limit
`
`the spread of
`
`the epileptic
`
`discharges or promote selective routes of spread; (e) the establishment
`
`IPR2014-01126-Exhibit 1005, p. 16
`
`
`
`3
`
`of satellite and independent epileptic foci; · and (f)
`
`the engagement of
`
`the brain stem and of the spinal motor neuron pools.10
`
`1
`
`Both
`
`the generation of
`
`the EPR and the
`
`recruitment of
`
`normal neurons
`
`in
`
`the epileptic
`
`seizure have been extensively
`
`examined.
`
`The EPR has sometimes been related
`
`to local deteriora-
`
`tion of neurons by extraneuronal
`
`factors.
`
`In 1880, Sommer
`
`observed an extensive
`
`loss of neural mass in
`
`the hippocampal area
`
`of one
`
`third of
`
`the epileptic patients examined.
`
`Shortly after,
`
`Alzheimer and Chaslin independently reported an associated abnor(cid:173)
`
`mal proliferation of glial cells
`
`in
`
`the same area.7 Gliosis has
`
`been related to seizures
`
`in three ways. First, this process may be
`
`a biological response
`
`to a decrease in neural matter. 7 Second, ab-
`
`normal proliferation of
`
`glial cells may mechanically
`
`irritate
`
`the
`
`neurons and
`
`initiate
`
`the EPA-mediated processes7.
`
`Third, glial
`
`cells are known
`
`to participate in the regulation of the potassium ion
`
`concentration
`
`in
`
`the brain and
`
`in
`
`the metabolism of y - amino
`
`IPR2014-01126-Exhibit 1005, p. 17
`
`
`
`4
`
`butyric acid
`
`(2}.
`
`These substances may
`
`influence
`
`the seizure
`
`processes.1 0 Finally, De Moor and Westrum noticed dendritic
`
`alterations adjacent
`
`to epileptic
`
`foci
`
`in
`
`human cortices and
`
`experimentally generated epileptic centers,
`
`respectively. 7,12
`
`2
`
`Other factors which may be
`
`responsible
`
`for
`
`the generation of
`
`the EPR are associated with
`
`the blood-brain barrier.
`
`Scheibel?
`
`observed
`
`that neurons
`
`in epileptic
`
`foci were often altered
`
`in
`
`regions nearby damaged capillaries.
`
`He attributed
`
`the generation
`
`of
`
`epileptic neurons . to exogenic
`
`factors
`
`such as viruses
`
`and
`
`toxins.
`
`Despite
`
`these
`
`important initiation processes,
`
`the majority of
`
`researchers consider metabolic disorders existent
`
`in
`
`the epileptic
`
`patient to be the primary cause of the disease. 3,10 Most sub-
`
`stances
`
`involved
`
`in the no.rmal neuronal activity as well as
`
`their
`
`associated metabolic cycles have been claimed
`
`to participate
`
`in
`
`the
`
`EPR
`
`generation.1 0,13
`
`Extensive experimental
`
`evidence
`
`exists
`
`which demonstrate
`
`the
`
`involvement both of potassium ion8,1 0,14-15
`
`and
`
`the neuronal sodium-potassium pump 10 in the
`
`first step of the
`
`IPR2014-01126-Exhibit 1005, p. 18
`
`
`
`5
`
`seizure.
`
`Other ions (i.e., cr. ca++, NH4+) may also be involved
`
`in abnormal membrane depolarization processes.8
`
`Disorders
`
`in
`
`the metabolic cycles of all
`
`the substances regulating
`
`the concen(cid:173)
`
`tration and
`
`·the transport of these
`
`ions across
`
`the membrane of
`
`the neuron, as well as structural disorders
`
`in the neuron mem(cid:173)
`
`brane can ultimately be responsible
`
`for the EPA generation.
`
`Several explanations have been offered
`
`for the mechanism
`
`involved
`
`in
`
`the
`
`recruitment of normal neurons
`
`in
`
`the seizure.
`
`Variations
`
`in
`
`the proteinic constitution of
`
`the synapses have been
`
`invoked
`
`to explain
`
`the propagation of
`
`the epileptic discharge by
`
`selective
`
`neuronal circuits.
`
`The same explanation
`
`has been
`
`suggested
`
`for
`
`the creation of secondary epileptic foci.1 0 Exten-
`
`sive documentation does exist
`
`in support of various other phenom-
`
`ena.
`
`These
`
`include
`
`-the enhancement of the excitatory neuro-
`
`transmissions
`
`induced by
`
`substances such as acetylcholine <a),
`
`aspartic acid {4), glutamic acid
`
`(.5.)
`
`and some neuropeptides as
`
`we.ll as
`
`the decrease
`
`in
`
`inhibitory
`
`regulation
`
`promoted by
`
`substances such as norepinephrine (§), dopamine (1). serotonin (.6.)
`
`and
`
`'Y- aminobutyric acid
`
`(GABA) (2.).8• 17-20
`
`Finally, · transient
`
`modifications of the membrane of
`
`the normal neuron and anomalies
`
`in
`
`the dendritic and axon structures
`
`are
`
`also believed
`
`to
`
`participate
`
`in
`
`the epileptic discharge propagation.1 0,19,21
`
`II. Symptomatology and Classification of Epileptic Seizures.
`
`The part of the brain affected by the epileptic discharges has
`
`- - · - · - · - · - - · - - · · · - - - - - - - - - - - - - - - - -
`
`IPR2014-01126-Exhibit 1005, p. 19
`
`
`
`6
`
`CH3
`~.cl-
`o
`H,c,....l~o~
`CH3 3
`
`0
`HO~OH
`O
`NHz
`
`4
`
`NHz
`
`HO~(OH
`0
`0
`
`5
`
`OH
`7
`
`OH
`6
`
`HO
`
`H
`
`8
`
`IPR2014-01126-Exhibit 1005, p. 20
`
`
`
`7
`
`direct bearing on
`
`the clinical manisfestation of the disease.
`
`In
`
`some cases, careful monitoring of ·the patient can permit
`
`the physi(cid:173)
`
`cian
`
`to follow
`
`the spread of
`
`the abnormal brain electrical activity.
`
`The observed clinical symptoms serve as a basis
`
`for the currently
`
`employed classifications of the various seizure states.
`
`The first widely accepted classification of the epileptic seizures
`
`(Table 1) was
`
`established · by the
`
`International League Against
`
`Epilepsy
`
`in 1969.1,22
`
`This classification attempted
`
`to correlate
`
`the symptoms and
`
`electroencephalographic
`
`(EEG)
`
`data
`
`to the
`
`anatomic substrate, the etiology, and
`
`the age of
`
`the patient.
`
`This
`
`system differentiated
`
`seizures which had
`
`a
`
`focal onset and
`
`evolved
`
`into generalized
`
`seizures,
`
`from
`
`those
`
`which are
`
`generalized
`
`from
`
`the beginning.1
`
`A
`
`revised classification (Table
`
`2) appeared in 1981. This new classification was
`
`fostered by
`
`the
`
`development of
`
`better methods
`
`to analyze the seizures . (i.e.,
`
`telemetered EEG, videotaping) The major changes · incorporated
`
`in
`
`the new system were
`
`the exclusive use of
`
`the clinical
`
`and
`
`electroencephalographic data
`
`to determine
`
`the seizure
`
`type,
`
`and
`
`the
`
`restructuring of
`
`the partial
`
`seizures
`
`into
`
`simple
`
`partial
`
`seizures and complex partial
`
`seizures depending on whether or
`
`not consciousness
`
`is altered at
`
`the onset or
`
`in
`
`the
`
`further
`
`evolution of
`
`the seizure.1
`
`Although,
`
`a clinical discussion
`
`of
`
`the various types of
`
`seizures
`
`is beyond the scope of
`
`this
`
`thesis a brief review of the
`
`major forms of the disease follows.
`
`IPR2014-01126-Exhibit 1005, p. 21
`
`
`
`8
`
`J]lble 1. The
`
`International Classification of Epileptic Seizures.1
`
`I.
`
`locally)
`Partial seizures (seizures beginning
`A. Partial seizures with elementary symptomatology (generally
`without impairment of consciousness)
`1. With motor symptoms (includes Jacksonian. seizures)
`2. With special sensory or somatosensory symptoms
`3. With automatic symptoms
`4.
`Compound forms
`B. Partial seizures with complex -symptomatology (generally
`with impairment of consciousness) (temporal lobe or psycho(cid:173)
`motor seizures)
`1. With impairment of consciousness only
`2. With cognitive symptomatology
`3. With affective symptomatology
`4. With "psychosensory" symptomatology
`5. With "psychomotor" symptomatology (automatisms)
`6.
`Compound forms
`C. Partial seizures secondarily generalized
`
`II. Generalized seizures (bilaterally symmetrical and without local
`onset)
`A. Absence (petit mal)
`B. Bilateral massive epileptic myoclonus
`C. Infantile spasms
`D. Clonic features
`E. Tonic features
`F. Tonic-clonic seizures (grand mal)
`G. Atonic seizures
`H~ Akinetic seizures
`
`III. Unilateral seizures
`
`(or predominately)
`
`IV. Unclassified epileptic seizures (due to incomplete data)
`
`IPR2014-01126-Exhibit 1005, p. 22
`
`
`
`l;abte 2. The Revised Classification of Epileptic Seizures.1
`
`9
`
`1 .
`
`impaired)
`
`Simple partial seizures (consciousness not
`A. With motor signs
`1.
`Focal motor without march
`2.
`Focal motor with march (Jacksonian)
`3.
`Versive
`4.
`Postural
`5.
`Phonatory (vocalization or arrest of speech)
`B. With somatosensory or special·sensory symptoms (simple
`hallucinations, e.g., tingling, light flashes, buzzing)
`1. Somatosensory
`2.
`Visual
`3.
`Auditory
`4. Olfactory
`5. Gustatory
`6.
`Vertiginous
`C. With automatic symptoms or signs
`D. With psychic symptoms (disturbance of higher cortical function)
`1. Dysphasic
`2.
`Dysnesmic (e.g., deja vu)
`3.
`Cognitive (e.g., forced thinking)
`4.
`Affective (e.g., fear, anger)
`5.
`Illusions (e.g., macropsia)
`6.
`Structured hallucinations (e.g., music, scenes)
`II. Complex partial seizures (generally with
`impairment of conscious(cid:173)
`ness; .may sometimes begin with simple symptomatology)
`A. Simple partial onset followed by impairment of consciousness
`1. With simple partial
`features
`(A-D) and
`impaired
`consciousness
`2. With automatisms
`B. With impairment of consciousness at onset
`1. With impairment of consciousness only
`2. With automatisms
`to generalized
`III. Partial seizures evolving
`seizures (GTC with partial or focal onset)
`A. Simple partial seizures (I) evolving to GTC
`B. Complex partial seizures (II) evolving to GTC
`C. Simple partial seizures evolving to complex partial seizures
`evolving to GTC
`·
`
`tonic-clonic
`
`(GTC)
`
`IPR2014-01126-Exhibit 1005, p. 23
`
`
`
`Iable 2 con't.
`
`10
`
`IV. Generalized seizures (bilaterally symmetrical and without local
`· onset)
`A. Absence (petit mal)
`B. Bilateral massive epileptic myoclonus
`C. Infantile spasms
`D. Clonic features
`E. Tonic features
`F. Tonic--clonic seizures (grand mal)
`G. Atonic seizures
`Unilateral seizur.es (or predominately)
`Unclassified epileptic seizures (due to incomplete data)
`
`v.
`VI •
`
`IPR2014-01126-Exhibit 1005, p. 24
`
`
`
`11
`
`Simple partial seizures affect any part of the body depend(cid:173)
`
`ing on the origin of the discharge
`
`in
`
`the motor strip. The clini(cid:173)
`
`cal observations are characterized by tonic contraction of the activa-
`
`ted muscles
`
`followed by a clonus.
`
`Generally. one muscle or a
`
`group of muscles are
`
`involved in
`
`the seizure,
`
`resulting
`
`in
`
`invol(cid:173)
`
`untary movements,
`
`involuntary actions (i.e., vocalization) or posture
`
`change.
`
`The step by step spread of
`
`the electrical disorder
`
`from
`
`strictly
`
`focal
`
`to adjacent areas produce sequential
`
`involvement of
`
`body
`
`parts and
`
`is
`
`referred to as
`
`the epileptic march or
`
`Jacksonian seizure.1 ,5
`
`These muscular disorders find
`
`their origin
`
`in the part of
`
`the cortex responsible
`
`for motor activity.
`
`Likewise,
`
`epileptic discharges originating or spreading
`
`in
`
`the part of
`
`the
`
`cortex
`
`responsible
`
`for automatic
`
`functions
`
`result
`
`in manisfestations
`
`such as vomiting,
`
`incontinence·, pupil
`
`dilatation
`
`and
`
`pallor.1
`
`Involvement of
`
`the cortex area
`
`subversing
`
`somatosensory and
`
`psychic
`
`functions
`
`lead
`
`to additional
`
`seizure manifestations within
`
`this general class of seizures. (Table 2).
`
`In all
`
`instances, partial
`
`seizures are not associated with consciousness
`
`impairment.
`
`Complex partial seizures
`
`are characterized
`
`by partial
`
`seizure symptoms with accompanying
`
`impairment of consciousness.
`
`This often
`
`results
`
`in automatisms
`
`(i.e., verbal, ambulatory, gestural,
`
`masticatory),
`
`and sometimes
`
`results
`
`in confusion.1 ,23
`
`This
`
`state
`disease
`. 5
`amnesia ..
`
`is
`
`always
`
`associated with various degrees of
`
`Generalized seizures which are non-convulsive are
`
`referred
`
`IPR2014-01126-Exhibit 1005, p. 25
`
`
`
`12
`
`'to as absence. (petit mal)
`
`· seizures.
`
`Absence
`
`seizures affect
`
`'children
`
`before puberty and are characterized by
`
`frequent (5 ~ 100
`
`· · 'per day)
`
`attacks of
`
`impaired
`
`consciousness
`
`lasting usually less
`
`than 20 seconds.
`
`Interruption of ongoing activities, staring, occa(cid:173)
`
`sional
`
`eyes movements,
`
`arm
`
`jerks
`
`and modification
`
`of
`
`the
`
`5)0stural
`
`tone are manisfestations of
`
`this type of seizure. The
`
`associated EEG
`
`is characterized by a regular
`
`three per second
`
`spike and wave pattern.
`
`The classification
`
`of generalized seizures,
`
`involving
`
`con-
`
`vulsions has been subdivided
`
`according
`
`to
`
`the characteristics of
`
`the convulsive episodes.
`
`Bilateral massive epileptic myoclonus
`
`and
`
`infantile spasms (West's syndrome) are manisfested by sudden
`
`contractions of major muscle groups. The
`
`latter seizure type occur
`
`before
`
`the age of
`
`four
`
`and
`
`involves
`
`legs, arms and
`
`trunk
`
`muscles.
`
`It
`
`is often
`
`related
`
`to phenylketonuria,
`
`lipidosis and
`
`the
`
`metabolism of piridoxine.
`
`The EEG
`
`shows high voltage sl?w
`
`waves and spikes.
`
`Both of
`
`these seizure types
`
`involve the right
`
`and
`
`left brains.1 ,5 Clonic seizures occur especially
`
`in childhood
`
`and are manisfested by a succession of shock-like spasms affect(cid:173)
`
`ing one or both sides of
`
`the body and are associated with con-
`
`sciousness
`
`impairment.
`
`Tonic seizures are characterized by tonic
`
`contractions of
`
`long duration
`
`(up
`
`to one minute) of
`
`the
`
`trunkal
`
`and
`
`limbs musculatures, and are associated with autonomic activ(cid:173)
`
`ity.
`
`The EEG shows high voltage activity.
`
`Tonic~lonic seizures
`
`(grand mal) are a succession
`
`of
`
`tonic and clonic episodes with
`
`IPR2014-01126-Exhibit 1005, p. 26
`
`
`
`13
`
`loss of consciousness and autonomic hyperactivity.
`
`This
`
`form of
`
`epilepsy can occur
`
`in both children and adults. Grand mal
`
`is
`
`the most common
`
`type of epilepsy and
`
`the most disrupting
`
`in
`
`the
`
`life of
`
`the patient.
`
`The chronicity of . the seizures varies
`
`from one or more a day to
`
`intervals of months between the
`
`seizure episodes.1,5
`
`:r:r:r. Evaluation of Anticonvulsant Agents.
`
`Many procedures have been designed and evaluated for the
`
`screening of potential anticonvulsant drugs.24 Current protocols can
`
`be divided
`
`into four general categories:
`
`(a)
`
`the employment of a
`
`chemical convulsant
`
`to induce the artifical
`
`seizures in animals;
`
`(b)
`
`the use of electrically induced seizures
`
`in animals; (c)
`
`the em(cid:173)
`
`ployment of genetically predisposed animal strains;
`in 1n YitrQ experiments.17
`
`of nervous tissues
`
`(d)
`
`the use
`
`Many chemical convulsants have been utilized
`
`to generate
`
`artificial seizures.17,24,25
`
`The most widely used chemical convul-
`
`sants are: strychnine (9),
`
`picrotoxin (1Q), bicuculline (11) and pen-
`
`tylenetetrazol (Metrazol)
`
`(12.).
`
`All
`
`these subtances are subcutan-
`
`eously
`
`injected
`
`in
`
`the
`
`test animals after the administration of
`
`the
`
`compound
`
`to be evaluated
`
`for anticonvulsant properties.26
`
`The
`
`augmentation of
`
`the seizure
`
`threshold
`
`reveals
`
`the anticonvul-
`
`sant activity of
`
`the drug.
`
`The pentylenetetrazol (scMet) seizure
`
`threshold test27-29
`
`is of particular
`
`interest
`
`in
`
`the evaluation of
`
`new compounds.
`
`It
`
`is widely
`
`recognized that substances active
`
`IPR2014-01126-Exhibit 1005, p. 27
`
`
`
`14
`I4
`
`
`
`o
`
`0
`
`N__
`
`‘
`
`cu,
`o
`
`0
`
`o
`
`31
`
`M
`9,‘
`’
`N—~—N
`
`E
`
`~
`
`o
`HN/U\u—R3
`RV
`R2
`
`0
`
`13
`
`R3=H
`2
`5; R‘=Ph, R2=Ph,R3=H
`1_ Ph R :Ph,
`3
`R-
`•
`R =Me
`a:
`2
`g: R‘=Ph, R2=Et.R3=l'e‘|e
`1
`h R : Et,
`b· R = p
`3- Et
`'
`-· 1
`R2= H, R -
`§_: R1: PH, R23 H. R3 ‘ Et
`~ R :Ph,
`
`IPRZO14-01126—EXhibit 1005, p. 28
`
`
`
`IPR2014-01126-Exhibit 1005, p. 28
`
`
`
`15
`
`in
`
`this
`
`test are
`
`likely to be effective
`
`in
`
`the treatment of petit
`
`mal seizures provided threshold doses of pentylenetetrazol are em(cid:173)
`
`ployed to produce clonic seizures.
`
`The use of electrically
`
`induced seizures was introduced
`
`in
`
`the mid-1800s after
`
`the pioneering studies of Fritsch, Hitzig and
`
`Albertoni.26
`
`The systematic use of electrically
`
`induced seizures
`
`in
`
`cats
`
`eventually
`
`led Putnam
`
`and Merritt30
`
`to discover
`
`the
`
`anticonvulsant
`
`properties
`
`of
`
`5,5-diphenylhydantoin
`
`(phenytoin,
`
`Dilantin) (13a). This medicinal agent
`
`is
`
`the most extensively used
`
`drug
`
`today for the
`
`treatment of grand mal epilepsy.
`
`Subsequently,
`
`Goodman and his colleagues standardized
`
`the
`
`technique . which
`
`is
`
`now named
`
`the Maximal Electroshock Seizure (MES) test.27-29,31
`
`This
`
`test
`
`is believed
`
`to
`
`identify substances
`
`that will be useful
`
`in
`
`the
`
`treatment of partial and generalized tonic-clonic seizures.3
`
`In
`
`this
`
`technique a 60-cycle alternating
`
`current
`
`is applied for 0.1
`
`or 0.3 seconds to mice and
`
`rats by means of corneal electrodes.
`
`Many other useful electrically
`
`induced
`
`seizure
`
`tests have also
`
`been described.24,27-29,31 ,32
`
`More
`
`recently, kindling procedures
`
`have been
`
`introduced
`
`in
`
`the hopes of
`
`identifying new drugs
`
`specific
`
`for partial seizures.17
`
`The kindling process
`
`refers
`
`to
`
`an experimental protocol where subthreshold
`
`stimuli are
`
`repeat-
`
`edly applied
`
`to
`
`the animal until they become convulsant stimuli.
`
`This method
`
`requires the
`
`implantation of electrodes
`
`in the brain
`
`area where
`
`the epileptic discharge is ·to be generated ..
`
`Genetically predisposed animal strains have been employed
`
`IPR2014-01126-Exhibit 1005, p. 29
`
`
`
`16
`
`in
`
`the anticonvulsant
`
`testing of new substances.
`
`Among
`
`these,
`
`three species have
`
`found extensive use.
`
`They are
`
`the DBA/2
`
`(Dilute Brown Agouti)
`
`strain of house mouse,
`
`in which seizures
`
`are elicited by audiogenic
`
`stimuli such as
`
`a door bell,33
`
`the
`
`Wistar
`
`strain of
`
`rat, in which
`
`seizures appear to be similar to
`
`petit mal;34 and
`
`the baboon Papio papio,
`
`in which responses to
`
`anticonvulsant drugs are similar
`
`to that observed
`
`in
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