liii
`
`11111
`
`III
`
`111111
`
`11111
`
`11111
`
`11111111 II
`
`11111
`
`11111
`
`11111
`
`111111 IIIIIIU 11111111
`
`US005378729A
`Patent Number
`
`Date of Patent
`
`5378729
`Jan
`
`1995
`
`United States Patent
`Kohn et
`
`AMINO ACID DERIVATIVE
`ANTICONVULSANT
`
`Kohn Houston Darrell
`Inventors Harold
`Watson Belton both of Tex
`
`Assignee
`
`Research Corporation Technologies
`Inc Tucson A.riz
`AppI No 710610
`
`Filed
`
`Jun
`
`1991
`
`Related U.S Application Data
`of Ser No 354057 May 19
`Continuation-in-part
`1989 abandoned and Ser No 392870 Aug Ii 1989
`continuation of Ser No 80528
`abandoned which is
`Jul 31 1987 abandoned which is
`continuation-in-
`part of Ser No 916254 Oct
`1986 abandoned
`of Ser No 702195
`which is
`continuation-in-part
`Feb 15 1985 abandoned said Ser No 354057 is
`of Ser No 80528 Feb 15 1985
`continuation-in-part
`
`mt Cl.6
`
`A61K 31/535 A61K 31/445
`CO7D 21 1/72 CO7D 261/04
`U.S Cl
`514/231.2 514/315
`514/397 514/406 514/415 514/424 514/461
`514/468 514/486 546/292 548/371.4
`548/245 564/148 564/152 564/154
`564/148 155 154 152
`Field of Search
`14/461 548 549
`548/616 245 371.4
`546/292
`
`References Cited
`U.S PATENT DOCUMENTS
`
`FOREIGN PATENT DOCUMENTS
`
`0885303
`
`0194464
`
`0007441
`0038758
`0042626
`0046707
`0263506
`
`0400400
`
`1927692
`0393355
`
`3/1981
`
`2/1980
`
`10/1980
`
`10/1981
`
`12/198
`
`3/1982
`
`10/1987
`
`5/1990
`
`12/1969
`
`10/1965
`
`Belgium
`European Pat Off
`European Pat Off
`European Pat Off
`European Pat Off
`European Pat Off
`European Pat Off
`European Pat Off
`Germany
`Switzerland
`
`1051220
`
`12/1966
`
`United Kingdom
`
`OTHER PUBLICATIONS
`Chemical Abstracts vol 92 No 751712r Feb 18
`1990
`Chemical Abstracts
`1982
`Chemical Abstracts vol 101 No
`1984
`Chemical Abstracts vol 91 No 21175147 Nov 19
`1979
`
`vol 96 No 535710r Feb
`
`72124v Aug 27
`
`List continued on next page
`
`Primary ExaminerMariamie
`Assistant .Examiner.-T Criares
`Attorney Agent or FirmScully Scott Murphy
`Presser
`
`Cintins
`
`ABSTRACF
`
`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
`
`564/155
`
`564/155
`
`514/616
`
`260/558
`
`564/158
`
`564/215
`
`564/155
`
`564/155
`
`564/155
`
`514/616
`
`564/154
`
`514/237.8
`
`R_NHf_NH_RI
`
`R3
`
`and pharmaceutically
`
`acceptable
`
`salts thereof
`
`150 Claims No Drawings
`
`4/1954
`
`Bruce et al
`Sheehan
`10/1955
`9/1967 Martin etal
`Thorne et al
`4/1972
`12/1972 Mazur et al
`4/1977
`Gless Jr et al
`Schuit
`Biedermann et al
`
`4/1981
`
`12/1981
`
`2676188
`2721197
`3340147
`3657341
`3707559
`4018826
`4260684
`4303673
`4513009
`4595700
`4618708
`4873241
`
`4/1985
`
`6/1986
`
`10/1986
`
`10/1989
`
`Roques et al
`Donaldetal
`
`Roques at ai
`Napier et ai
`
`Breckenridge Exhibit 1009
`Breckenridge v. Research Corporation Technologies, Inc.
`
`-1-
`
`

`

`5378729
`
`Page
`
`OTHER PUBLICATIONS
`457 371375
`Kohn et al 1988 Brain Research
`in New Class of Anticonvul-
`Marked Sterospecificity
`sants
`
`Chemical Abstracts vol 97 145266d 1982
`et al 1981
`JACS 10342314239
`Ac-
`White
`Inhibition of aiphaChymotrypsin
`tiveSiteDirected
`by Deanilnatively Produced Carbonium Ions An Ex-
`ample of Suicide of Enzyme-Activated-Substrate
`Inhi-
`
`bition
`
`Legall et al 1988 mt
`Protein Res 12279291
`Synthesis of Functionalized NonNatural Amino Acid
`Derivatives
`via Amidoalkylation Transformations
`Med Chem 303574580
`Conley et al 1987
`Functionalized DLAmino Acid Derivatives Potent
`New Agents for the Treatment of Epilepsy
`Garcia et al 1984 Tetrahedron
`Letters 2542
`48414844 New Synthetic Tricks Triphenylphos-
`phine-Mediated Amide Formation from Carboxylic
`Acids and Azides
`Rebek et al 1979 Am Chem Soc lOl3737 On
`
`the Rate of SiteSite Interactions
`
`in Functionalized
`
`Polystyrenes
`Med Chem 28601606 Effect
`Cortes et al 1985
`of Structural Modification of the Hydantion Ring on
`Anticonvulsant Activity
`Ikeda et al 1977 Tetrahedron 335 489495 Photo-
`
`chemical
`
`Synthesis
`
`1234-Tetrahy-
`of
`from NChloroacetylbenzyla
`
`droisoquinolin-3ones
`mines
`Org Chem 55 22062214
`Katritzky et at 1990
`BenzotriazoleAssisted Synthesis of Monoacyl Animals
`and Their Peptide Derivatives
`Am Chem Soc
`et al 1983
`105
`Lipshutz
`as Masked Diamide/Dipep
`770377 13 Heterocycles
`tide Equivalents Formation and Reactions of Substi
`tuted 5Acylamino Oxazoles as
`Intermediates
`en
`Route to the Cyclopeptide Alkaloids
`Lipshutz et al 1983 Org Chem 4837453750 An
`Approach to the Cyclopeptide Alkaloids Phenylcy
`Diamide/Dipeptide
`clopeptines
`Heterocyclic
`via
`Equivalents Preparation and NAlkylation Studies of
`245Disubstituted Iniidazoles
`Rogues 1987 193rd ACS National Meeting Amer
`Chem Society Apr 1510 1987 Use of Various Metal
`lopeptidase Inhibitors to Study the Physiogical Rate of
`Endogenous Neuropeptides
`Med Chem 33919926 Prepara
`Kohn et al 1990
`Series of Func
`tion and Anticonvulsant Activity of
`Heteroaromatic Amino
`tionalized /3Aromatic and
`Acids
`Imidaz
`Lipshutz et al Heterocycles in Synthesis.
`oles Journal of the American Chemical Society vol
`106 No
`pp 457459 CA 10219 160030n 1985
`
`-2-
`
`

`

`AMINO ACID DERIVATIVE ANICONVULSANT
`
`5378729
`
`ZY taken
`NR4OR5
`is NR4NRSR7
`together
`ONR4R7
`OPR4R5
`PR4OR5 SNRiR7 NR4SR7
`SPR4RS or PR4SR7 NR4PR5RS or PR4NR5R7
`
`NR4CR5
`
`SCR5 NR4C0R5 SC0R
`
`is
`
`continuation-in-part
`
`continuation-in-part
`
`continuation-in-part
`
`This invention was made with Government support
`under NS15604
`awarded by the National
`Institutes of
`Health The Gvemment
`has certain rights in the in-
`vention
`The present-application
`of
`R5 and R6 are independently hydrogen lower
`copending U.S patent application Set No 07/354057
`lower alkyl
`lower alkenyl or lower
`10 alkyl aryl aryl
`filed on May
`1989 and CIP of U.S patent applica-
`alkynyl wherein R4 Rand R6may be unsubstituted or
`tion Ser No 07/392870 filed on Aug 11 1989 both
`substituted with an electron withdrawing group or an
`now abandoned U.S patent application Ser No
`electron donating group and
`07/354057 flIed on May 19 1989 now abandoned being
`R7 is R6 or COORs or COR8
`of U.S patent application having
`continuation-in-part
`R8 is hydrogen or lower alkyl or aryl lower alkyl
`Set No 07/080528
`filed on Jul 31 1987 now aban-
`and the aryl or alkyl group may be unsubstituted or
`doned which is
`of U.S patent
`continuation-in-part
`substituted with an electron withdrawing group or an
`application Ser No 06/9 16254 filed Oct
`1986 now
`electron donating group and
`abandoned which is
`of U.S pa-
`is 1-4 and
`tent application Ser No 06/702195 ified Feb 15 1985
`is 13
`said U.S patent application Set No
`now abandoned
`The predominant application of anticonvulsant drugs
`07/392870 filed Jul 11 1989 abandoned
`con-
`being
`is the control and prevention of seizures associated with
`tinuation application of U.S patent application having
`epilepsy or related central nervous system disorders
`Set No 07/080528
`filed on Jul 31 1987 now aban-
`refers to many types of recurrent
`Epilepsy
`seizures
`doned which is
`of U.S patent 25 produced by paroxysmal excessive neuronal discharges
`continuation-in-part
`application Ser No 06/916254
`1986 now
`filed Oct
`in the brain the two main generalized seizures are petit
`abandoned which is
`of U.S pa-
`mal which is associated with myoclonic jerks akinetic
`tent application Ser No 06/702195 filed on Feb 15
`loss of consciousness but without
`seizures transient
`1985 now abandoned
`convulsion and grand mal which manifests in continu
`The present
`relates to compounds
`invention
`and 30 ous series of seizures and convulsions with loss of con-
`sciousness
`compositions having central nervous
`pharmaceutical
`system CNS activity which are useful in the treatment
`The mainstay of treatment
`for such disorders has
`of epilepsy and other CNS disorders More specifically
`been the long-term and consistent administration of
`anticonvulsant drugs Most drugs in use are weak acids
`the compounds of this invention can be characterized as
`protected amino acid derivatives having the following 35 that presumably
`their action on neurons glial
`exert
`cells or both of the central nervous system The major
`general formula
`ity of these compounds are characterized by the pres
`ence of at least one amide unit and one or more benzene
`phenyl group or part of
`rings that are present as
`cyclic system
`Much attention has been focused upon the develop-
`ment of anticonvulsant
`drugs and today many such
`drugs are well known For example the hydantions
`lower alkenyl
`is hydrogen lower alkyl
`such as phenytoin are useful
`in the control of general
`alkynyl aryl aryl lower alkyl heterocycic heterocy-
`forms of partial seizures The ox
`ized seizures and all
`clic lower alkyl lower alkyl heterocyclic
`lower cyclo-
`such as trimethadione and parametha
`azolidinediones
`alkyl lower cycloalkyl
`lower alkyl and
`is unsubsti-
`dione are used in the treatment of nonconvulsive sei
`tuted or is substituted with at
`least one electron with-
`zures Phenacemide
`is one of the
`phenylacetylurea
`drawing group or electron donating group
`most well known anticonvulsants
`employed
`today
`Ri is hydrogen or lower alkyl
`lower
`lower alkenyl
`50 while much attention has recently been dedicated to the
`alkynyl aryl lower alkyl aryl heterocycic
`lower alkyl
`the diazepines and piperazines For
`investigation of
`lower cycloalkyl
`lower cycloalkyl
`lower
`heterocyclic
`example U.S Pat Nos 4002764 and 4178378 to All
`alkyl each unsubstituted or substituted with an electron
`geier et al disclose esterified diazepine derivatives
`donating group or an electron withdrawing group and
`in the treatment of epilepsy and other nervous
`useful
`disorders U.S Pat No 3887543 to Nakanishi
`R2 and R3 are independently hydrogen lower alkyl
`et al
`lower alkyl Y1
`lower alkenyl
`lower alkynyl aryl
`compound also
`thieno
`describes
`heterocycic heterocycic lower alkyl
`lower alkyl het-
`having anticonvulsant activity and other depressant
`activity U.S Pat No 4209516 to Heckendom et al
`erocyclic lower cycloalkyl
`lower cycloalkyl
`lower
`alkyl or Z-Y wherein R2 and R3 may be unsubstituted
`relates to triazole derivatives which exhibit anticonvul
`or substituted with at
`least one electron withdrawing 60 sant activity and are useful
`in the treatment of epilepsy
`and conditions of tension and agitation U.S Pat No
`group or electron donating group
`SSOa NR.j PRor
`chemical bond
`4372974 to Fish et al discloses
`for
`pharmaceutical
`is hydrogen lower alkyl aryl aryl
`lower alkyl
`mulation containing an aliphatic amino acid compound
`in which the carboxylic
`lower aikenyl
`lower alkynyl halo heterocycic heter-
`acid and primary amine are
`ocyclic lower alkyl
`lower alkyl and may be unsubsti-
`separated by three or four units Administration of these
`compounds in an acid pH range are useful
`tuted or substituted with an electron donating group or
`in the treat-
`ment of convulsion disorders and also possess anxiolytic
`an electron withdrawing group provided that when
`chemical bond or
`and sedative properties
`is halo
`
`R_NHrNHrR1
`OR3
`
`15
`
`20
`
`65
`
`lower
`
`is
`
`is
`
`-3-
`
`

`

`5378729
`
`pentadienyl e.g 13 or 24-
`
`Unfortunately despite the many available pharmaco-
`significant percentage of the popu-
`therapeutic agents
`lation with epilepsy or
`related disorders are poorly
`managed Moreover none of the drugs presently avail-
`able are capable- of achieving total seizure control and
`most have disturbing side-effects Clearly current
`ther-
`apy has failectto seize control of these debilitating
`diseases
`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 phar-
`maceuticai compositions useful in the treatment of epi-
`lepsy and other CNS disorders
`further object of this invention
`is to provide
`method of treating epilepsy and related convulsant dis-
`orders
`These and other objects are accomplished herein by
`providing compounds of the following general formula
`
`E--4-methyl-2-pentenyl
`and the like
`pentadienyl
`The term alkynyl
`include alkyene substituents con-
`carbon atoms and may be straight chained
`to
`taming
`as well as branched It
`includes such groups as ethynyl
`propynyl 1-butynyl 2-butynyl 1-pentynl 2-pentynyl
`3-methyl-l-pentynyl 3-pentynyl 1-hexynyl 2-hexynyl
`3-hexynyl and the like
`The term cycloalkyl when used alone or in combina
`cycloalkyl group containing from to 18 ring
`tion is
`total of 25 carbon atoms The
`carbon atoms and up to
`cycloalkyl groups may be monocyclic bicyclic tricy
`clic or polycycic and the rings are fused The cycloal
`kyl may be completely saturated or partially saturated
`15 Examples include cyclopropyl cyclobutyl
`cyclopen
`tyl cyclohexyl cycloheptyl cyclooctyl cyclodecyl
`cyclooctenyl cyclohep
`cyclohexenyl cyclopentenyl
`indanyl
`fenchyl pine-
`tenyl decalinyl hydroindanyl
`nyl adamantyl
`and the like Cycloalkyl
`includes the cis
`20 or trans forms Furthermore the substituents may either
`be in endo or exo positions in the bridged bicyclic sys
`tems
`The term electron-withdrawing and electron donat
`ing refer to the ability of
`to withdraw or
`substituent
`25 donate electrons relative to that of hydrogen if
`the
`hydrogen atom occupied the same position in the mole
`cule These terms are well understood by one skilled in
`R1 R2 R3 R4 R5 R6 R7 Rg
`the art and are discussed in Advanced Organic Chemisty
`defmed hereinabove
`by March John Wiley and Sons New York N.Y pp
`The present
`invention contemplates employing the
`30 1618 1985 and the discussion therein is incorporated
`compounds of Formula
`in compositions of pharma-
`herein by reference Electron withdrawing groups in
`dosage forms Where the appro-
`acceptable
`dude halo including br
`ceutically
`.o fluoro chloro iodo and
`priate substituents are employed the present invention
`iwer alkenyl
`lower alkynyl
`the like nitro carboxy
`includes pharmaceutically
`acceptable
`also
`addition
`ammonium
`formyl carboxyamido
`quatemary
`tryl
`salts Moreover
`the administration
`of an effective
`lower alkanoyl carbalkoxy
`and
`trifluoromethyl
`aryl
`amount of the present compounds in their pharmaceuti-
`the like Electron donating groups include such groups
`forms or the addition salts thereof can
`cally acceptable
`as hydroxy lower alkoxy including methoxy ethoxy
`regime for the treatment of epi-
`provide an excellent
`and the like lower alkyl such as methyl ethyl and the
`lepsy nervous anxiety psychosis insomnia and other
`like amino lower alkylamino diloweralkyl amino
`related central nervous disorders
`40 aryloxy such as phenoxy mercapto lower alkylthio
`The alkyl groups when used alone or in combination
`lower alkylmercapto disulfide lower alkyldithio and
`with other groups are lower alkyl containing from to
`the like One skilled in the art will appreciate that
`the
`carbon atoms and may be straight chain or branched
`aforesaid substituents may have electron donating or
`These groups include methyl ethyl propyl
`electron withdrawing properties under different chemi
`isopropyl
`butyl isobutyl tertiary butyl amyl hexyl and the like
`cal conditions Moreover
`invention con-
`the present
`The aryl
`lower alkyl groups include for example
`templates any combination of substituents selected from
`benzyl phenethyl phenpropyl phenisopropyl phenbu-
`the above-identified groups
`and the like diphenylmethyl 11-diphenylethyl
`The term halo includes fluoro chloro bromo iodo
`tyl
`12-diphenylethyl and the like
`and the like
`The term aryl when used along or in combination
`The term acyl
`includes lower alkanoyl
`refers to an aromatic group which contains from up to
`As employed herein the heterocyclic
`substituent
`total of 25 carbon
`18 ring carbon atoms and up to
`contains at least one sulfur nitrogen or oxygen but also
`atoms and includes the polynuclear
`may include one or several of said atoms The heterocy
`aryl groups may be monocyclic
`bicyclic tricyclic or
`clic substituents contemplated by the present invention
`polycycic and are fused rings Polynuclear
`aromatic
`55 include heteroaromatics
`and
`saturated and partially
`compound is meant
`compounds These heterocyclics
`bicyclic tricyclic
`to encompass
`saturated heterocyclic
`fused aromatic ring system containing from 1018 ring
`may be monocyclic bicyclic tricyclic or polycyclic
`total of 25 carbon atoms The
`carbon atoms and up to
`and are fused rings They may contain up to 18 ring
`aryl group includes phenyl and the polynuclear
`atoms and up to
`total of 17 ring carbon atoms and
`aro-
`60 total of up to 25 carbon atoms The heterocycics
`matics e.g naphthyl
`anthracenyl
`phenanthrenyl
`are
`azulenyl and the like The aryl group also includes
`also intended to include the so-called benzoheterocy
`des Representative heterocyclics
`thi
`include furyl
`groups like ferrocenyl
`Lower alkenyl
`is an alkenyl group containing from
`enyl pyrazolyl pyrrolyl
`imidazolyl indolyl thiazolyl
`carbon atoms and at least one double bond These
`oxazolyl
`isoxazolyl piperidyl pyrrolinyl
`to
`isothiazolyl
`groups may be straight chained or branched and may be 65 piperazinyl quinolyl
`form Such groups include vinyl pro-
`in the
`or
`benzofuryl benzothienyl morpholinyl
`isobutenyl 2-butenyl 1-pentenyl Z-
`penyl 1-butenyl
`E-2-pentenyl
`Z-4-methyl-2-pentenyl
`
`It
`
`12
`
`RNHI-C cMc R1
`0R3
`
`II
`
`wherein
`
`are as
`
`10
`
`45
`
`50
`
`aromatics These
`
`2-pentenyl
`
`triazolyl
`
`tetrazolyl
`
`isoquinolyl
`
`benzoxazolyl
`
`tetrahydrofuryl pyranyl
`
`indazolyl purinyl
`
`indolinyl
`
`pyrazolidinyl
`
`imidazolinyl
`
`imadazolidinyl pyrrolidi
`
`-4-
`
`

`

`5378729
`
`is
`
`is
`
`is
`
`nyl furazanyl N-methylindolyl methylfuryl pyridazi-
`nyl pyrimidinyl pyrazinyl pyridyl epoxy aziridino
`the N-oxides of the nitrogen con-
`oxetanyl azetidinyl
`such as the nitric oxides of pyri-
`taming heterocycles
`dyl pyrazinyl and pyrimidinyl and the like The pre-
`ferred heterocycic are thienyl furyl pyrrolyl bejizofu-
`ryl benzothienyl
`indolyl methylpyrrolyl morpholi-
`nyl pyridyl pyrazinyl
`imidazolyl pyrimidinyl or
`pyridazinyl The preferred heterocycic
`or 6-mem-
`compound The especially preferred
`bered heterocycic
`heterocycic
`furyl pyridyl pyrazinyl
`imidazolyl
`pyrimidinyl or pyridazinyl The most preferred hetero-
`cyclic is furyl and pyridyl
`The preferred compounds are those wherein
`but di tn and tetrapeptides are also contemplated to be 15
`within the scope of the claims
`The preferred values of
`is aryl lower alkyl espe-
`cially benzyl and the preferred Ri is
`or lower alkyl
`The most preferred P.1 group is methyl
`The most preferred electron donating substituent and 20
`electron withdrawing substituent are halo nitro alkan-
`oyl formyl arylalkanoyl aryloyl carboxyl carbalk-
`oxy carboxamide cyano sulfonyl sulfoxide heterocy-
`clic guanidine quaternary ammoniuni lower alkenyl
`lower aikynyl sulfoniurn salts hydroxy lower alkoxy 25
`lower alkyl amino lower alkylaniino dioweralkyl-
`amino amino lower alkyl mercapto mercaptoalkyl
`alkylthio and alkyldithio The term sulfide encom-
`passes mercapto mercapto alkyl and alkylthio while
`the term disulfide encompasses alkyldithio These pre-
`ferred substituents may be substituted on any one of Ri
`R2 R3 R4 R5 or R6 R7 or R8 as defmed herein
`The ZY groups representative of R2 and R3 include
`hydroxy alkoxy such as methoxy ethoxy aryloxy
`such as phenoxy thioalkoxy such as thiomethoxy thio-
`ethoxy thioaryloxy such as thiophenoxy amino alkyl-
`amino such as methylamino ethylamino arylamino
`such as anilino lower dialkylamino such as dimethyl
`aromonium salt hydrazino alkyihy
`amino trialkyl
`drazino and arylhydrazino such as N-methylhydrazino
`N-phenylhydrazino carbalkoxy
`hydrazino aralkox-
`
`heterocyclic selected
`and
`with the
`are hetero
`
`and
`
`is
`
`is
`
`It
`
`It
`
`is CH or
`but when
`from the group consisting of NH
`proviso that at most two of
`atoms
`the ring depicted hereinabove contains
`If
`nitrogen
`ring atom then the N-oxide forms are also contem
`plated to be within the scope of the invention
`When R2 or R3 is
`heterocyclic of the above formula
`it may be bonded to the main chain by
`ring carbon
`10 atom When
`R2 or R3 may additionally
`be
`bonded to the main chain by
`nitrogen ring atom
`is preferred that one of R2 and R3 is hydrogen
`preferred embodiment one of P.2 and P.3 is hy
`In
`drogen and that the other is heterocyclic
`is preferred
`having Formula
`that one of P.2 and P.3 is
`heterocycic
`XI The preferred heterocydics
`include furyl
`thienyl
`isoxazo
`benzothienyl
`benzofuryl oxazolyl
`thiazolyl
`
`lyl
`
`indolyl pyrazolyl
`
`isoxazolidinyl ben.zothienyl
`
`furfuryl
`
`indolyl pyrrolyl
`benzofuryl morpholinyl
`and methylpyrrolyl pyridyl pyrazinyl
`imidazolyl
`In another preferred em
`pynimidinyl or pynidazinyl
`bodiment one of P.2 and R3 is alkyl e.g methylisopro
`pyl aryl e.g phenyl 2-thiomethylethyl
`lower alk
`oxy e.g ethoxy methoxy anilino propenyl alkyl
`amino e.g ethylamino or methylaxnino In another
`preferred embodiment one of R2 and R3 is hydrogen
`and the other is heterocyclic lower alkyl
`lower alkenyl
`amino lower alkoxy
`amino N-lower alkylhydrox
`yaniino lower alkoxyamino N-lower alkyl-0-lower
`alkylhydroxyamino or aralkoxycarbonyihydrazino
`Preferred compounds of the present invention have
`the following general formula
`
`Am
`
`CH2NHC CNHCRj
`
`II
`
`R3
`
`30
`
`ycarbonyl hydrazino aryloxycarbonyl hydrazino hy-
`
`droxylamino such as N-hydroxylamino NHOH ferred that
`
`or lower alkyl R2 and P.3 are as defmed
`wherein R1 is
`is hydrogen or an electron donating group
`above and
`is 0-5 It
`or electron-withdrawing
`group and
`is pre
`
`is hydrogen i.e m0 However values
`
`of
`
`or
`are also preferred
`equalling
`Preferred embodiments include compounds of For-
`mula
`
`50
`
`R_NH_NH_Rl
`
`k3
`
`ylamino 0NH2 alkylamido
`tnifluoroacetamido
`NHOCH3
`and
`pyrazoylamino
`The hetereocyclic groups representative of R2 and
`R3 have the formula
`
`wherein R18 is lower
`lower alkoxy amino
`alkyl N-lower alkylhydroxyl
`amino
`wherein R1 is
`lower alkyl N-lower alkyl-0-lower
`wherein P.13 and
`alkyl hydroxyaniino i.e
`lower alkyl and o-hydrox
`such as acetamido
`e.g
`alkoxyamino
`heterocycicamino
`as
`
`P.19 are independently
`
`lower
`
`such
`
`and R1 independently
`are hydrogen lower
`wherein
`lower alkenyl
`lower alkynyl aryl
`lower alkyl
`lower alkyl heterocycic each un
`aryl heterocyclic
`substituted or substituted with at least one substituent
`P.2 and R3 independently
`are hydrogen lower alkyl
`lower alkenyl
`lower alkynyl aryl
`lower alkyl aryl
`60 heterocycic lower alkyl heterocydic each unsubsti
`tuted or substituted with at least one substituent halo
`gen or
`heteroatom containing oxygen nitrogen sulfur
`or phosphorous substituted with hydrogen lower alkyl
`or those corresponding partially or fully saturated form
`or aryl said lower alkyl or aryl groups being substituted
`thereof wherein
`or
`Land
`are independently CII or heteroatom 65 or unsubstituted and
`selected from the group consisting of
`and
`to
`is CH or
`Another preferred embodiment
`heteroatom selected
`from the group
`ing Formula
`consisting of
`
`alkyl
`
`is
`
`is
`
`compound hay-
`
`EJ
`
`CH
`
`is
`
`and
`
`-5-
`
`

`

`5378729
`
`Another preferred embodiment
`Formula
`
`is
`
`compound of
`
`RNTht-CCNT1CRj
`
`is
`
`is ai3r1 aryl lower alkyl heterocyclic lower
`wherein
`aikyl heterocyclic polynuclear aromatic or lower alkyl
`polynuclear aromatic each unsubstituted or substituted
`with at least one electron withdrawing substituent or at
`least one electron donating substituent
`or lower alkyl unsubstituted or substituted
`Ri
`with at least one electron withdrawing substituent or at
`least one electron donating substituent
`R2 and R3 independently
`are hydrogen lower alkyl
`lower alkenyl
`lower alkynyl aryl aryl
`lower alkyl
`lower alkyl heterocydic
`heterocycic
`polynuclear
`aromatic lower alkyl polynuclear aromatic each un-
`substituted or substituted with at
`one electron
`least
`heteroatom contain-
`donating substituent halogen or
`ing oxygen nitrogen sulfur or phosphorous substituted
`with hydrogen lower alkyl or aryl said lower alkyl or
`aryl groups being substituted or unsubstituted and
`to
`Another preferred embodiment of the present inven-
`compound of Formula
`tion is
`
`is
`
`as
`
`RNH-t-CCNHt-CR
`
`II
`
`RNBtCCNHCRi
`
`R3
`
`wherein
`
`10
`
`or
`
`lower alkyl heterocyclic
`is aryl aryl
`is unsubstituted or is
`lower aikyl and
`heterocyclic
`substituted with at
`one electron withdrawing
`least
`group or electron donating group
`Ri is hydrogen or lower alkyl unsubstituted or substi
`tuted 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 lower alkyl or Z-Y wherein
`heterocyclic
`20 R2 and R3 may be unsubstituted or substituted with at
`least one electron withdrawing group or electron do
`nating group
`SSOa NR4 PR4 or
`chemical bond
`is
`is hydrogen lower alkyl aryl aryl
`lower alkyl
`25 lower alkenyl
`lower alkynyl heterocyclic
`heterocy
`clic lower alkyl or halo and may be unsubstituted or
`substituted with an electron donating group or an elec
`tron withdrawing group provided that when
`is halo
`chemical bond or
`is NR4NRR7 NR40R
`ZY taken
`together
`PR4OR5
`SNR4R7 NR4SR7
`ONR4R7
`OPR4R5
`SPR4RS or PR4SR7 NR4PRSR6 or PR4R5R7
`
`is
`
`30
`
`is aryl lower alkyl heterocyclic lower alkyl
`wherein
`heterocycic polynuclear aromatic or lower alkyl poly- 35
`nuclear aromatic each of which may be unsubstituted
`least one halo nitro acyl car
`or substituted with at
`carboxamide cyano sulfonyl sulf-
`boxyl carboalkoxy
`oxide sulfmyl heterocyclic
`guanidine
`quaternary
`ammonium hydroxy alkoxy alkyl amino phenoxy
`mercapto sulfide or disulfide
`or lower alkyl which may be unsubstituted or
`R1 is
`substituted with at least one halo nitro acyl carboxam-
`ide cyano sulfonyl sulfoxide sulfmyl heterocyclic
`guanidine quaternary ansnaonium hydroxy lower alk-
`oxy amino phenoxy sulfide or disulfide
`R2 is hydrogen lower alkyl
`lower
`lower alkenyl
`alkynyl aryl heterocyclic lower alkyl heterocyclic
`aromatic lower
`aJ.kyl polynuclear
`polynuclear
`inatic each unsubstituted or substituted with at
`one electron withdrawing substituent or at
`least one
`heteroatom
`electron donating substituent halogen or
`consisting of oxygen nitrogen sulfur or phosphorous
`said heteroatom being substituted with hydrogen lower
`alkyl or aryl said lower alkyl or aryl groups being
`substituted or unsubstituted
`R3 is hydrogen lower alkyl
`lower
`lower alkenyl
`alkynyl aryl heterocyclic lower alkyl heterocydic
`aromatic lower alkyl polynuclear
`polynuclear
`aro-
`matic each unsubstituted or substituted with at
`least
`one electron withdrawing substituent or at least one
`heteroatom
`electron donating substituent halogen or
`consisting of oxygen nitrogen sulfur or phosphorous
`said heteroatom being substituted with hydrogen lower 65
`alkyl or aryl said lower alkyl or aryl groups being
`substituted or unsubstituted
`and
`
`is
`
`to
`
`NR4CR5
`
`SCR5
`
`NR4COR5
`
`SCOR5
`
`R4 R5 and R6are
`independently hydrogen lower
`lower alkenyl or lower
`lower alkyl
`alkyl aryl aryl
`40 alkynyl wherein R.4 R5 and R6 may be unsubstituted or
`substituted with an electron withdrawing group or an
`electron donating group-and
`R7 is R6 or COORs or COR8 R8 is hydrogen or lower
`lower alkyl wherein the aryl or lower
`alkyl or aryl
`alkyl groups may be unsubstituted or substituted with
`an electron withdrawing or electron donating group
`is 1-4 and
`is 13
`Another class of preferred compounds of the For
`mula
`have the formula
`
`50
`
`aro-
`
`least
`
`a2
`
`RNH--CCNH CR
`
`R3
`
`or
`lower alkyl heterocyclic
`wherein
`is aryl aryl
`heterocyclic alkyl which is unsubstituted or substituted
`with at 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 least one electron withdrawing
`group or one electron donating group
`R2 and R3 are independently hydrogen lower alke
`lower alkyl Z-Y or
`nyl
`lower alkynyl aryl aryl
`heterocyclic group which may be unsubstituted or sub-
`stituted with at
`least one electron withdrawing or one
`
`-6-
`
`

`

`5378729
`
`10
`
`In the principal chain there exists asymmetry at
`the
`carbon atoms to which the groups R2 and R3 are at
`tached as substituted When
`the compounds of the
`present invention is of the formula
`
`is
`
`is
`
`is
`
`is
`
`is especially preferred that
`
`The preferred comrounds are those
`in which
`lower alkyl heterocydic or heterocycic
`aryl aryl
`lower alkyl Ri
`is hydrogen or lower alkyl R2 and R3
`are independently hydrogen heterocycic lower alkyl
`lower alkoxy lower alkenyl amino hydrox-
`aryl
`ylamino lower alkoxy amino N-lower alkyl hydroxy-
`amino N-lower alkyl-O-lower alkyl hydroxyamino
`aralkoxy carbonyl hydrazino or alkylmercapto and
`
`is
`
`is
`
`R2
`
`RNHCCNCR1
`
`II
`
`R3
`
`it
`
`20
`
`25
`
`in mixtures of the
`
`electron donating group with the proviso that R2 and
`R3 cannot both be hydrogen
`NR4 PR4 or
`chemical bond
`is hydrogen lower alkyl aryl aryl
`lower alkyl
`lower alkenyl
`lower alkynyl or halo and
`may be
`unsubstituted
`substituted with an electron donating
`group or an elctron withdrawing group provided that
`when
`chemical bond or
`is hato
`ZY taken
`NR4ORS
`is NR4NRSR6
`together
`NR4SR5 10
`ONR4R5
`OPR4R5
`PR4OR5
`SNR4R5
`SPR4RS or PRsSR5 NR4PR5R6 or PRiNRSR6
`R.4 R5 and R6 are independently hydrogen lower
`are as de
`R1 R2 R3 R4 R5 R6
`wherein
`and
`lower alkyl
`lower alkenyl or lower
`alkyl aryl aryl
`fined previously As used herein the term configuration
`alkynyl wherein R4 R5 and R6 may be unsubstituted or
`substituted with an electron withdrawing group or an 15 shall refer to the configuration around the carbon atom
`to which R2 and R3 are attached even though other
`electron donating group
`is 14
`chiral centers may be present in the molecule There
`Of this preferred group it
`fore when referring to
`particular configuration such
`is to be understood to mean the stereoiso
`or
`as
`mer including all possible enantiomers and diastereo
`mers The compounds of the present invention are di-
`isomers i.e the compounds
`rected to all of the optical
`of the present invention are either the L-stereoisomer or
`the D-stereoisomer
`These stereoisomers may be found
`and
`stereoisomer e.g racemic
`mixtures The
`stereoisomer is preferred
`Depending upon the substituents the present com
`pounds may form addition salts as well All of these
`forms are contemplated to be within the scope of this
`invention
`stereoisomeric
`including mixtures of
`
`is
`
`30
`
`In another preferred embodiment
`and R1 are
`as defined hereinabove and one of R2 and R3 is hydro-
`lower
`gen and the other
`is heterocycic heterocyclic
`alkyl aryl N-hydroxylamino lower alkoxyamino N-
`lower alkylhydroxylaniino N-lower alkyl-O-lower al-
`kylhydroxyamino
`Another preferred embodiment
`is wherein
`and Rj are as defined hereinabove one of R2 and R3 is
`as defined hereinabove or the other
`is heterocyclic
`lower alkyl
`lower alkyl heterocydic aryl
`heterocycic
`N-hydroxylamino lower alkoxy amino N-lower alkYl
`hydroxylamino N-lower alkyl-O-lower alkyl hydrox
`lower amino lower
`ylamino lower alkoxy dialkyl
`lower alkylcarbonyl
`alkylamino aryl
`hydrazino or
`lower alkylmercapto
`The various combination and permutations of the
`Markush groups of R1 R2 R3
`and
`described herein
`are contemplated to be within the scope of the present
`invention Moreover the present invention also encom-
`passes compounds and compositions which contain one
`or more elements of each of the Markush groupings in 5o
`R1 R2 R3 ii and
`and the various
`combinations
`thereof Thus for example the present invention con-
`templates that R1 may be one or more of the substituents
`listed hereinabove in combination with any and all of
`the substituents of B.2 R3 and
`to each
`with respect
`value of
`The compounds of the present invention may contain
`or more asymmetric carbons and may exist rn
`one
`racemic and optically active forms The configuration
`around each asymmetric carbon can be in either the
`form It is well known in the art that
`or
`the configu-
`ration around
`chiral carbon atoms can also be de-
`in the Calin-Prelog-Ingold nomencla-
`or
`scribed as
`ture system All of the various configurations
`around
`each asymmetric carbon including the various enantio- 65
`mers and diastereomers as well as racemic mixtures and
`mixtures of enantiomers diastereomers or both are con-
`templated by the present invention
`
`35
`
`is
`
`60
`
`the
`
`forms
`The following three schemes of preparation are gen
`erally exemplary of the process which can be employed
`for the preparation of the present complex
`
`Scheme
`
`HO0CNH2 MeOH RNH2
`
`excess
`
`R3
`
`RNH
`
`r-2
`
`NH2
`
`R3
`
`R1CO
`
`II
`
`Ri
`
`II
`
`R2
`
`R3
`
`II
`
`Scheme II
`
`R2
`
`HOOCCNH2
`
`R1C0CR
`
`R2
`
`HOOCCNH CR1
`
`II
`
`R3
`
`R3
`
`tertiary amine
`
`-7-
`
`

`

`11
`
`-continued
`Scheme
`
`5378729
`
`12
`mixed anhydrides or lower alkyl esters and the like It
`the acylating derivative used is the
`is preferred that
`
`R2
`
`II
`
`II
`
`RNHCC--NHCR1
`
`R112
`
`R3
`
`--
`
`co2
`
`RI7OH
`
`R2
`
`anhydride
`
`II
`
`II
`
`II
`
`R17OCOCCNHCR1
`
`R3
`
`II
`
`R1C---0CRj
`
`II
`
`When alkyl esters are employed amide bond formation
`can be catalyzed by metal cyanides such as sodium or
`
`Scheme III
`
`00
`
`liii
`
`R2CCOH
`
`II
`
`R1CNH2
`
`OHO
`R1CNHCCOH
`
`II
`
`II
`
`R2
`
`R17OHIH
`
`0R170
`R1CNHCCNHR
`
`R2
`
`RNH
`
`withor
`without catalyst
`
`i.e MCN
`
`OR17
`R1CNHCC0R17
`
`R2
`
`R3H
`
`jewis
`
`acid such as BF3OEtz
`
`R30
`R1CNHCCNHR
`
`II
`
`II
`
`R2
`
`wherein R3aryl heteroa.romatic 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 corn-
`pounds of Formula
`can be prepared by reacting
`arnines of Formula II with an acylating derivative of
`acid of Formula III under amide forming
`carboxylic
`conditions
`
`r0 R2
`
`RNH_j_C_j_NH4_H
`