1111111111111111111101
`
`IIHI
`
`1111111111100
`
`liii
`
`11111
`
`III
`
`IIIN1I
`
`11111
`
`US005654301A
`
`Patent Number
`
`Date of Patent
`
`5654301
`Aug
`
`1997
`
`0263506
`0400400
`
`10/1987
`
`5/1990
`
`1927692
`
`12/1969
`
`0393355
`
`10/1965
`
`1051220
`
`12/1966
`
`European Pat Off
`European Pat Off.
`Gennany
`Switzerland
`United Kingdom
`
`OTHER PUBLICATIONS
`
`Sciences Mack Publishing
`
`Remington
`Pharmaceutical
`Company 1980 pp 400-427
`Chemical Abstracts vol 92 No 751712r Feb 18 1990
`Chemical Abstracts vol 96 No 535710r Feb
`1982
`Chemical Abstracts vol 101 No
`72124v Aug 27
`1984
`Chemical Abstracts voL 91 No 21175147 Nov 19
`1979
`Kohn et al 1988 Brain Research 457 37 1375 Marked
`Stereospecifldty in New Class of Anticonvulsants
`Chemical Abstracts voL 97145266d 1982
`Chemical Abstracts vol 89 129286q Zafloukal
`1978
`1981 JACS 10342314239 ActiveSiteDi
`White et
`rected Inhibition of alphaChymotrypsin by Deaminatively
`Produced Carbonium Ions An Example of Suicide
`of
`EnzymeActivatedSubstrate
`Inhibition
`Protein Res 32279291 Syn
`1988 mt
`Legall et
`thesis of Functionalized NonNatural Amino Acid Deriva
`tives via Aniidoalkylation Transformations
`1985 Med Chem 28601606 Effect of
`Cortes et
`Structural Modification of the Hydantion Ring on Anticon
`vulsant Activity
`Ikeda et al 1977 Tetrahedron 335489495 photo
`123
`chemical
`of
`Synthesis
`from NChloracetylben
`
`et al
`
`United States Patent
`
`Kobn et al
`
`AMINO ACID DERIVATiVE
`ANTICONVULSANT
`
`Kohn Houston Darrell
`Inventors Harold
`Watson Belton both of Tex
`
`Assignee Research Corporation Technologies
`Inc Tucson Ariz
`
`Appi No 3208
`
`Filed
`
`Jan 12 1993
`
`Related U.S Application Data
`
`Continuation-in-part of Ser No 710610 Jun
`1991 Pat
`No 5378729 which is
`continuation-in-part of Ser No
`354057 May 19 1989 abandoned
`and
`continuation-in-
`part ofSer No 392870 Aug 11 1989 abandoned
`said Ser
`No 354057 is
`continuation-in-part of Ser No 80528
`Jul 31 1987 abandoned which is
`continuation-in-part of
`Ser No 916254 Oct
`1986 abandoned
`which is
`of Ser No 702195 Feb 15 1985
`continuation-in-part
`abandoned said Ser No 392870 is
`continuation of Set
`No 80528 Jul 31 1987 abandoned which is
`continu-
`ation-in-part of Ser No 916254 Oct
`1986 abandoned
`continuation-in-part of Ser No 702195 Feb 15
`which is
`1985 abandoned
`
`Foreign Application Priority Data
`
`Jun
`
`1992
`
`WIPO
`
`US92/04687
`
`mt Cl.6
`
`U.S Cl
`
`A61K 31/445 A61K
`1/34
`CO7D 211/72 CO7D 261/04
`
`514/231.2
`
`514/315
`
`514/397
`
`514/406
`
`514/415
`
`14/424
`
`514/461
`
`14/468
`
`14/486
`
`14/616 5461292 548/125
`
`548/225
`
`548/250
`
`548/347.1
`548/245
`548/371.4
`564/152 564/154
`
`Field of Search
`
`564/292
`155
`564/148
`152 548/125 245 371.4 514/315
`564/154
`357 461 406 548 424 415 549 618
`486 231.2 546/252
`152 154
`
`References Cited
`
`U.S PATENT DOCUMENTS
`
`4/1954
`
`Bruce et al
`
`10/1 955 Sheehan
`
`9/1967 Martin et al
`Thonie et al
`4/1972
`12/1972 Mazur et al
`
`4/1977 Gless Jr et al
`Schult
`4/1981
`12/1981 Biedennann et al
`
`2/1983
`
`4/1985
`
`Fish et al
`Roques et al.
`6/1986 Donald et al
`
`10/1986
`
`Roques et al
`
`2676188
`2721197
`3340147
`3657341
`3707559
`4018826
`4260684
`4303673
`4372974
`4513009
`4595700
`4618708
`
`4873.241
`5378729
`
`10/1989
`Napier et al
`1/1995 Kohn et al
`
`FOREIGN PATENT DOCUMENTS
`
`0885303
`
`0007441
`0194464
`0038758
`0042626
`0046707
`
`3/1981
`
`2/1980
`
`2/1980
`
`10/1981
`
`12/1981
`
`3/1982
`
`Belgium
`European Pat Off.
`European Pat Off.
`European Pat Off
`European Pat Off
`European Pat Off.
`
`424/319
`
`564/155
`
`514/616
`
`2601558
`
`564/158
`
`564/215
`
`564/155
`
`564/155
`
`260/559
`
`514/616
`
`564/154
`
`564/215
`
`514/231.2
`
`4Tetrahydroisoquinolin3---ones
`zybuttifles
`Conley et al 1987 Med Chem 303 567574 Func
`tionalized DLAmino Acid Derivatives Potent New Agents
`for the Treatment of Epilepsy
`1984 Tetrahedron Letters 2542 4841-4844
`Garcia et
`New Synthetic
`Tricks
`TriphenyiphosphineMediated
`Amide Formation from Carboxylic Acids and Azides
`1979 Am Chem Soc 1013737 On the
`Rebek et
`Rate of SiteSite Interactions
`
`in Functionalized Polysty
`
`renes
`Org Chem. 5522062214 Ben
`Kalritzky et al 1990
`of Monacyl Animals and
`zotrialzoleAssisted
`Synthesis
`Their Peptide Derivatives
`Am Chem Soc 10577037713
`1983
`Lipshutz et
`as masked Diamide/Dipeptide
`Equivalents
`Heterocycles
`Formation and Reactions of Substituted 5Acylaminoox-
`azoles as Intermidiates en route to the Cyclopeptide Alka
`bids
`
`List continued on next page
`
`Primary ExaminerTheodore
`Criares
`Attorney Agent or FinnScully Scott Murphy
`
`Presser
`
`ABSTRACT
`
`The present
`
`invention relates to conpounds of the formula
`
`112
`
`RNCCN.C--Rj
`
`II
`
`113
`
`47 Claims No Drawings
`
`MYLAN - EXHIBIT 1019
`
`

`
`5654301
`Page
`
`OTHER PUBLICATIONS
`
`Lipshutz
`
`Org Chem 4837453750 An
`et al 1993
`Approach
`to the Cyclopeptide Alkaloids Phencycopep-
`tines via Heterocydic Dianiide/Dipeptide Equivalents
`and NAlkylation Studies of 2.45Disubsti-
`Preparation
`tuted Imidazoles
`Roques 91987 193rdACS National Meeting Amer Chem
`Soc. Apr 510 1987 Use of Various Metallopeptides
`
`Inhibitors to Study the Physiological Role of Endogenous
`Neuropetides
`Kohn et al 1990 Med Chem. 33 919926 Preparation
`and Anticonvulsant Activity of
`Series of Functionalized
`ctAromatic and cHeteroaromatic Amino Acids
`et al JACS 1062457459 Heterocycles in
`Lipshutz
`Imidazoles 1984
`Synthesis.
`Kohn et al 1988 Chemistry in Britain pp 231233 New
`Antiepileptic Agents
`
`

`
`5654301
`
`AMINO ACID DERiVATIVE
`ANTICONVULSANT
`
`RELATED APPLICATIONS
`
`ZY taken together
`is NR4NR5R7
`OPR4R5 PR4OR5
`SNR4R1 NR4SR7
`NR4PR5R6 PR4NR5R7
`
`NR4OR5 ONR4R7
`SPR4R5 PR4SR7
`
`is
`
`is
`
`continuation
`
`is
`
`NR4CRs SCR5NR4COR5 SCOR5 NR4CNR5R6
`
`II
`
`II
`
`II
`
`II
`
`continuation-in-part
`
`NR4CNR5SO R4 NR4CNR5R NRCMNR5COR6
`
`or NH2
`
`ii
`
`10
`
`25
`
`R4 R5 and R6 are independently
`hydrogen lower alkyl
`aryl aryl lower alkyl
`lower alkenyl or lower alkynyl
`wherein R4 R5 and R6 may be unsubstituted
`or sub-
`stituted with an electron withdrawing group or an
`electron donating group and
`R7 is R6 or COOR8 or COR8
`R8 is hydrogen or lower alkyl or aryl lower alkyl and the
`aryl or alkyl group may be unsubstituted or substituted
`with an electron withdrawing group or an electron
`donating group and
`and
`is an alkylene chain
`are independently
`or
`chemical bond
`carbon atoms or
`up to
`
`continuation-in-part of U.S
`The present application
`patent application Ser No 710610 filed on Jun
`1991
`now U.S Pat No 5378729 which is
`of U.S patent application Ser No 354057 ified on May 19
`1989 now abandoned and U.S patent application Ser No
`392.870 filed on Aug 11 1989 now abandoned U.S patent
`application Ser No 354057 is
`continuation-in-part of
`U.S patent application having Ser No 080528 filed on Jul
`31 1987 now abandoned which is
`continuation-in-part of
`U.S patent application Ser No 916254 ified Oct
`1986
`now abandoned which
`continuation-in-part of U.S 15
`patent application Ser No 702195 filed Feb 15 1985 now
`abandoned U.S patent application Ser No 392870 is
`application of U.S patent application having
`Ser No 080528 filed Jul 31 1987 now abandoned which
`continuation-in-part of U.S patent application Ser No 20
`916254 ified Oct
`1986 now abandoned which is
`application Ser No
`continuation-in-part of U.S patent
`702195 ified on Feb 15 1985 now abandoned
`containing
`is 1-4 and
`This invention was made with Government
`support under
`is 13
`NS15604 awarded by the National Institutes of Health The
`The predominant application
`of anticonvulsant
`Government
`has certain rights to this invention
`drugs is
`the control and prevention
`of seizures associated with epi
`BACKGROUND OF THE INVENTION
`lepsy or related central nervous system disorders Epilepsy
`to many types of recurrent seizures produced by
`The present
`invention relates to compounds and pharma-
`refers
`ceutical compositions having central nervous system CNS 30 paroxysmal excessive neuronal discharges in the brain the
`seizures are petit ma which is asso
`two main generalized
`and
`activity which are useful
`in the treatment of epilepsy
`other CNS disorders More specifically the compounds of
`ciated with myoclonic jerks akinetic seizures transient
`but without convulsion and grand ma
`of consciousness
`this invention can be characterized
`as protected amino acid
`which manifests
`series of seizures and
`of the formula
`derivatives
`
`in
`
`continuous
`
`loss
`
`or ZY wherein R2 and R3 may be thieno compound also having anticon
`
`35
`
`convulsions with loss of consciousness
`for such disorders has been the
`The mainstay of treatment
`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
`system The majority of
`40 nervous
`these compounds
`are
`least one amide unit and
`characterized by the presence of at
`one or more benzene rings that are present as phenyl group
`cyclic system
`or part of
`Much attention has been focused upon the development of
`drugs and today many such drugs are well
`anticonvulsant
`known For example the hydantions such as phenytoin are
`useful in the control of generalized seizures and all forms of
`partial seizures The oxazolidinediones such as trimethadi
`one and paramethadione are used in the treatment of non
`seizures Phenacemide
`phenylacetylurea is
`50 convulsive
`the most well known
`one of
`employed
`anticonvulsants
`today while much attention has recently been dedicated to
`and piperazines For
`the investigation of the diazepines
`example U.S Pat Nos 4002764 and 4178378
`to
`disclose esterifted diazepine derivatives use
`55 Allgeier et
`ful in the treatment of epilepsy and other nervous disorders
`U.S Pat No 3887.543 to Nakanishi et al describes
`
`vulsant activity and other depressant activity U.S Pat No
`60 4209516 to Heckendorn
`et
`relates to triazole derivatives
`which exhibit anticonvulsant
`activity and are useful
`in the
`treatment of epilepsy and conditions of tension and agita
`tion U.S Pat No 4322974 to Fish et
`discloses
`an aliphatic amino
`pharmaceutical
`formulation containing
`65 acid compound
`in which the carboxylic acid and primary
`amine are separated by three or four units Administration of
`in an acid pH range are useful
`in the
`these compounds
`
`R2
`
`R_NH_NHt_Rl
`
`R3
`
`or the N-oxides thereof or pharmaceutically acceptable salts
`thereof wherein
`
`alkyl
`
`cycloalkyl
`
`lower alkynyl
`lower alkenyl
`is hydrogen lower alkyl
`lower alkyl heterocydic heterocycic lower
`aryl aryl
`loweralkyl heterocydic lower cycloalkyl
`lower
`lower alkyl and
`is unsubstituted
`or is
`least one electron withdrawing
`substituted with at
`group or electron donating group
`lower
`lower alkenyl
`or lower alkyl
`R1 is hydrogen
`alkynyl aryl lower alkyl aryl heterocydic lower alkyl
`lower
`lower cycloalkyl
`lower cycloalkyl
`heterocydic
`alkyl each unsubstituted or substituted with an electron
`group or an electron withdrawing group and
`donating
`R2 and R3 are independently hydrogen lower alkyl lower
`lower alkynyl aryl
`lower alkyl aryl
`aikenyl
`lower alkyl
`lower alkyl
`heterocycic
`heterocydic
`lower
`lower cycloalkyl
`heterocydic
`lower cycloalkyl
`aikyl S03
`unsubstituted
`
`or substituted with at
`
`least one electron
`
`is
`
`withdrawing group or electron donating group
`S.SO0 NR4 PR4 or
`chemical bond
`lower alkyl
`is hydrogen lower alkyl aryl aryl
`lower alkynyl halo heterocydic
`alkenyl
`heterocydic
`lower alkyl andY may be
`lower alkyl cycloalkyl cycloalkyl
`unsubstituted or substituted with an electron donating group
`chemical
`or an electron withdrawing group provided
`bond only when
`is halo or
`
`lower
`
`is
`
`

`
`5654301
`
`disorders and also possess anxi-
`treatment of convulsion
`olytic and sedative properties
`Unfortunately despite the many available pharmacothera-
`significant percentage of the population with
`peutic agents
`epilepsy or related disorders are poorly managed Moreover
`none of the drugs presently available are capable of achiev-
`ing total seizure control and most have disturbing side-
`therapy has failed to seize control
`effects Clearly current
`of these debilitating diseases
`one
`the present
`is therefore
`object of
`invention to
`It
`provide novel compounds exhibiting CNS activity particu-
`larly anticonvulsant
`activity
`Another object of this invention is to provide pharmaceu-
`in the treatment of epilepsy and
`compositions
`useful
`tical
`other CNS disorders
`further object of this invention is to provide method
`of treating epilepsy and related convulsant disorders
`These and other objects
`herein by
`are accomplished
`providing compounds of the following general formula
`
`R2
`
`RNH-E-CCNThI-CR
`
`ii
`
`R3
`
`wherein
`
`and
`
`are as
`
`R1 R2 R3 R4 R5 R6
`defined hereinabove
`The present
`invention contemplates employing the com-
`pounds of Formula
`in compositions of pharmaceutically
`acceptable dosage forms Where the appropriate substituents
`are employed the present
`invention also includes pharma-
`ceutically acceptable addition salts Moreover the adminis-
`tration 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 treatment of
`epilepsy nervous anxiety psychosis insomnia and other
`related central nervous disorders
`The alkyl groups when used alone or in combination with
`from to
`carbon
`other groups are lower ailcyl containing
`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 11-diphenylethyl
`12-diphenylethyl
`and the like
`The term aryl when used along or in combination refers
`to an aromatic group which contains from up to 18 ring
`total of 25 carbon atoms and
`carbon atoms and up to
`the polynuclear aromatics These aryl groups may
`includes
`be monocycle bicycle tricycle or polycydic and are fused
`compound
`is meant
`to encom-
`rings Polynuclear aromatic
`pass bicycle tricycle fused aromatic ring system contain-
`ing from 1018 ring carbon atoms and up to
`total of 25
`carbon atoms The aryl group
`and the
`includes phenyl
`polynuclear aromatics e.g naphthyl anthracenyl
`phenanthrenyl azulenyl and the like The aryl group also
`groups like ferrocenyl
`includes
`Lower alkenyl is an alkenyl group containing from to
`carbon atoms and at least one double bond These groups
`may be straight chained or branched and may be in the
`or
`form Such groups include vinyl propenyl 1-butenyl
`1-pentenyl Z-2-pentenyl E-2-
`isobutenyl
`2-butenyl
`pentenyl Z-4-methyl-2-pentenyl E--4-methyl-2-
`pentenyl pentadienyl e.g 13 or 24-pentadienyl
`and the
`like
`The term alkynyl include alkyene substituents
`containing
`carbon atoms and may be straight chained as well as
`to
`
`li
`
`It
`
`such groups
`branched
`as ethynyl propynyl
`includes
`1-pentyni 2-pentynyl 3-methyl-i-
`1-butynyl 2-butynyl
`pentynyl 3-pentynyl 1-hexynyl 2-hexynyl 3-hexynyl and
`the like
`The term cycloallcyl when used alone or in combination is
`from to 18 ring carbon
`group
`cycloallcyl
`containing
`total of 25 carbon atoms The cycloalkyl
`atoms and up to
`groups may be monocycic bicycle tricydic or polycyclic
`and the rings are fused The cycloalkyl may be completely
`saturated Examples
`include
`saturated or partially
`cyclohexyl
`cyclobutyl cyclopentyl
`cyclooctyl
`cyclodecyl
`cyclohexenyl
`
`cyclopropyl
`cycloheptyl
`
`10
`
`if
`
`decalinyl
`cycloheptenyl
`cyclooctenyl
`cyclopentenyl
`indanyl fenchyl pinenyl adaniantyl and the
`hydroindanyl
`trans forms
`includes
`the cis or
`like Cycloalkyl
`15 Furthermore the substituents may either be in endo or exo
`positions in the bridged bicycic systems
`The term electron-withdrawing
`and electron donating
`to withdraw or donate
`substituent
`refer to the ability of
`atom
`electrons relative to that of hydrogen
`the hydrogen
`20 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 March John Wiley
`and Sons New York N.Y. pp 1618 1985 and the dis
`cussion therein is incorporated herein by reference Electron
`25 withdrawing groups include halo including bromo fluoro
`chioro iodo and the like nitro carboxy lower alkenyl
`lower ailcynyl
`formyl carboxyamido aryl quaternary
`animonium trifluoromethyl aryl
`lower alkanoyl
`car-
`balkoxy and the like Electron donating groups include such
`30 groups as hydroxy lower alkoxy including methoxy ethoxy
`and the like lower alkyl such as methyl ethyl and the like
`amino lower alkylaniino diloweralkylamino
`aryloxy
`such
`lower alkylthio lower
`as phenoxy mercapto
`alkylmercapto disulfide lower alkyldithio and the like
`35 One skilled in the art will
`that
`the aforesaid
`appreciate
`substituents may have electron
`donating or electron with-
`under different
`chemical
`conditions
`drawing properties
`any combi
`Moreover
`invention contemplates
`selected from the above-identified
`
`the present
`nation of substituents
`
`40 groups
`The term halo includes fluoro chloro bromo iodo and the
`like
`
`includes
`
`lower alkanoyl
`The term acyl
`As employed herein the heterocydic substituent contains
`45 at least one sulfur nitrogen or oxygen but also may include
`one or several of said atoms The heterocydic substituents
`invention include heteroaro
`contemplated
`by the present
`matics and saturated
`and partially saturated heterocydic
`These heterocydics may be monocycle
`compounds
`and are fused rings They
`50 bicycle tricycle or polycycic
`may contain up to 18 ring atoms and up to
`total of 17 ring
`carbon atoms and
`total of up to 25 carbon atoms The
`are also intended
`to include
`the so-called
`
`heterocycics
`benzoheterocycles Representative
`
`heterocydics
`
`include
`
`55
`
`furyl
`
`thienyl pyrazolyl pyrrolyl
`
`imidazolyl
`
`indolyl
`
`thiazolyl oxazolyl
`
`isothiazolyl
`
`isoxazolyl piperidyl
`
`pyrrolinyl piperazinyl quinolyl
`
`triazolyl
`
`tetrazolyl
`
`isoquinolyl
`
`benzofuryl benzothienyl morpholinyl
`
`benzoxazolyl
`
`tetrahydrofuryl pyranyl
`
`indazolyl purinyl
`
`60
`
`imidazolidinyl
`imidazolinyl
`indolinyl pyrazolidinyl
`furazanyl N-methylindolyl methylfuryl
`pyrrolidinyl
`pyridazinyl pyrimidinyl pyrazinyl pyridyl epoxy
`the N-oxides of the nitrogen
`aziridino oxetanyl azetidinyl
`containing heterocycles such as the nitric oxides of pyridyl
`65 pyrazinyl and pyriinidinyl and the like The preferred het
`erocyclic are
`thienyl
`furyl pyrroly benzofuryl
`
`benzothienyl
`
`indolyl methylpyrrolyl merpholinyl pyridyl
`
`

`
`and 15
`
`are independently CH or
`and
`and
`selected from the group consisting of
`is CH or
`heteroatom selected from the group con-
`and
`sisting of
`is CH or heterocydic selected from
`but when
`the group consisting of NH
`and with the proviso
`that at most two of
`and
`are heteroatoms
`the ring depicted hereinabove contains
`If
`nitrogen ring
`atom then the N-oxide forms are also contemplated
`to be
`within the scope of the invention
`When R2 or R3 is
`of the above formula it
`heterocyclic
`ring carbon atom
`may be bonded to the main chain by
`20 When
`R2 or R3 may additionally be bonded to the
`nitrogen ring atom
`main chain by
`also be S03 or S02
`R2 or R3 may independently
`Furthermore ZY may also be
`
`is
`
`is
`
`5654301
`
`pyrazinyl iniidazolyl pyrimidinyl pyrazolyl or pyridazinyl
`or 6-membered heterocy-
`The preferred heterocycic is
`dc compound The especially
`furyl pyridyl pyrazinyl
`irnidazolyl pyrazolyl
`
`preferred heterocycic
`
`is
`
`triazolyl
`
`tetrazolyl oxadiazolyl epoxy pyrimidinyl or pyridazinyl
`The most preferred heterocydics are furyl pyrazolyl PY
`rolyl and pyridyl
`The preferred compounds are those wherein
`to be within the
`In and tetrapeptides
`are also contemplated
`scope of the claims
`
`but di
`
`is
`
`10
`
`XE
`
`or those corresponding
`thereof wherein
`is
`
`or
`
`partially or fully saturated
`
`form
`
`heteroatom
`
`The preferred values of
`lower alkyl especially
`is aryl
`or lower a1k1 The most
`benzyl and the preferred R1 is
`preferred R1 group is methyl
`The most preferred electron
`
`substituent
`
`donating
`are halo nilno alkanoyl
`electron withdrawing substituent
`formyl arylalkanoyl aryloyl carboxyl
`carbalkoxy
`carboxamide
`cyano sulfonyl sulfoxide heterocydic
`ammonium lower alkenyl
`lower
`guanidine quaternary
`alkynyl sulfonium salts hydroxy lower alkoxy lower alkyl
`amino lower alkylamino diloweralkylamino amine lower
`alkyl mercapto mercaptoalkyl alkylthio and alkyldithio
`The term sulfide encompasses mercapto mercapto alkyl
`and alkylthio while the term disuffide
`encompasses alky
`ldithio These preferred substituents may be substituted
`on
`anyone ofR1R2R3R4R5 orR5R7 orR8 as defined
`herein
`The ZY groups
`of R2 and R3 include
`representative
`hydroxy alkoxy such as methoxy ethoxy aryloxy such as
`phenoxy thioalkoxy such as thiomethoxy thioethoxy thio
`aryloxy such as thiophenoxy amino alkylamino
`such as
`methylamino ethylamino arylamino such as anilino lower
`onium
`such as dimethylamino tnialkyl
`dialkylaniino
`salt hydrazino alkylhydrazino and arylhydrazino such as
`N-methylhydrazino N-ph enylhydrazino carbalkoxy
`hydrazino aralkoxycarbonyl
`hydrazino aryloxycarbonyl
`hydrazino hydroxylamino such
`as N-hydroxylamino
`wherein R18
`
`ic5it NR4CNR5SOaR6 NR4CNRR6 CN12oror
`
`R4CMM15COR6
`
`II
`
`II
`
`25
`
`30
`
`When R2 is alkenyl the alkenyl group is
`lower alkenyl
`group having 16 carbon atoms The alkenyl group may be
`substituted with an electron donating group and more pref
`erably with an electron withdrawing group such as COOH
`and Amay be
`As indicated hereinabove
`in other
`
`or
`
`the compounds of the present
`
`words the main chain may contain only CO onlyCS
`thereof All such permutations are contem
`or combinations
`plated herein It
`of the
`is preferred that
`the compounds
`invention contain no more than CS moieties it
`40 present
`is even more preferred that
`invention contain no more than CS moiety The most
`preferred embodiment are when
`and
`are both oxygen
`An embodiment of the present application is one in which
`are of Formula
`wherein
`is lower
`45 the compounds
`lower alkyl andRis unsub
`cycloalkyl or lower cycloalkyl
`stituted or is substituted with at least one electron withdraw-
`ing group or electron donating group and R1 R2 R3
`or ZY taken together R4 R5 R6 R7 R8
`and
`are as
`50 defined herein
`Another embodiment of the present
`invention include
`compounds of Formula wherein R1 is lower cycloalkyl or
`lower cycloalkyl
`lower alkyl and R1 may be unsubstituted or
`substituted with an electron
`group or electron
`donating
`or ZY taken
`55 withdrawing group and R1 R2 R3
`together R4 R5 R6 R7 R8
`and
`are as defined herein
`above
`Another embodiment of the present
`invention includes
`compounds of Formula wherein R2 is lower cycloalkyl or
`lower alkyl and R2 may be unsubstituted or
`lower cycloalkyl
`substituted with an electron
`group or electron
`donating
`R1 R3 R4 R5 R6 R7 R8 and
`withdrawing group and
`are as defined hereinabove
`Still another embodiment of the present
`invention include
`compounds of Formula wherein R3 is lower cycloalkyl or
`lower cycloalkyl
`lower alkyl and R3 may be unsubstituted or
`substituted with an electron donating or electron withdraw
`
`NHOH lower alkoxy amino
`
`independently
`
`is lower alkyl N-lower alkyihydroxyl amino
`wherein R18 is lower alkyl N-lower alkyl-O-lower alkyl
`wherein R18 and R19 are
`hydroxyarnino i.e
`lower alkyl and o-hydroxylaniino
`NH2 alkylamido such as acetaniido trilluoroacetamido
`lower alkoxyamino e.g NHOCH3 and
`such as pyrazoylamino
`heterocydicamino
`Furthermore in still another embodiment may
`NR4 or PR4 andY may be hydrogen lower alkyl or aryl and
`R1 R2 R3 R4 R5 R5 R7 R8
`and
`are as defined
`hereinabove
`
`In
`
`still
`
`further embodiment ZY may be
`
`NR4CR5 or SCR5 or NR4C0R5 or SCOR5
`
`ii
`
`ii
`
`ii
`
`and
`
`and
`
`are as defined
`
`R1 R2 R3 R4 R5 R6 R7 R8
`hereinabove
`When R2 or R3 is heterocycic the preferred heterocydics
`tetrahydrofuryl pyridyl pyrazinyl
`imidazolyl
`are furyl
`tetrazolyl oxadiazolyl or epoxy The
`pyrazolyl triazolyl
`most preferred heterocydic is furyl pyridyl pyrazoyl and
`pyrrolyl
`The preferred heterocydic groups representative
`and R3 have the formula
`
`of R2
`
`60
`
`65
`
`

`
`5654301
`
`and
`
`are as
`
`is SO and
`
`R1 R2 R4 R5 R6 R7 R8
`lag group and
`defined hereinabove
`further embodiment of the present
`invention include
`R1 R2
`compounds of Formula wherein
`R3
`R4 R5 R6 R7 R8
`are as defined herein
`and
`is preferred that one of R2 and R3 is hydrogen
`preferred embodiment one of R2 and R3 is hydrogen
`In
`and that
`is preferred that one of
`the other is heterocyclic It
`heterocydic having Formula XI The pre-
`and R3 is
`ferred heterocydics include
`thienyl benzothienyl
`furyl
`
`It
`
`10
`
`indolyl
`isoxazolyl
`thiazolyl
`benzofuryl oxazolyl
`pyrazolyl
`isoxazolidinyl
`benzothienyl benzofuryl
`morpholinyl indolyl pyrrolyl furfuryl and methylpyrrolyl
`pyridyl pyrazinyl
`imidazolyl pyrimidinyl or pyridazinyl
`pyrazolyl or epoxy In another preferred embodiment one
`of R2 and R3 is alkyl e.g methylisopropyl aryl e.g 15
`lower alkoxy e.g ethoxy
`phenyl 2-thiomethylethyl
`methoxy anilino propenyl ailcylamino e.g ethylaniino or
`methylamino In another preferred embodiment one of R2
`and R3 is hydrogen and the other is heterocydic lower
`lower alkenyl amino lower alkoxy amino N-lower
`lower alkoxyamino N-lower alkyl-O-
`alkyhydroxyamino
`lower alkylliydroxyaniino or aralkoxycarbonyihydrazino
`invention have the
`Preferred compounds of the present
`following general formula
`
`20
`
`R2
`
`CH2NHC
`
`II
`
`II
`
`R3
`
`or lower ailcyl R2 and R3 are as defined
`wherein R1 is
`above and
`is hydrogen or an electron donating
`group or
`electron-withdrawing group and mis 05 It
`is preferred that
`i.e m0 However values of
`is hydrogen
`are also preferred
`or
`Preferred embodiments
`include compounds of Formula
`
`equalling
`
`R2
`
`RN1H-f-CCNHCR1
`
`R3
`
`wherein
`Rand R1 independently are hydrogen lower alkyl
`lower
`lower alkynyl
`lower alkyl aryl
`alkenyl
`aryl
`each unsubsti-
`lower alkyl heterocycic
`heterocydic
`tuted or substituted with at
`least one substituent
`R2 and R3 independently are hydrogen lower
`lower alkenyl
`lower alkynyl aryl
`lower alkyl aiy
`lower alkyl heterocycic
`each unsubsti-
`heterocydic
`tuted or substituted with at least one substituent halo
`heteroatom containing oxygen nitrogen sulfur
`gen or
`substituted with hydrogen lower alkyl
`or phosphorous
`or aryl said lower alkyl or aryl groups being substituted
`or unsubstituted and
`
`is
`
`to
`
`Another preferred embodiment
`Formula
`
`is
`
`compound
`
`having
`
`wherein
`
`R3
`
`lower alkyl
`lower alkyl heterocyclic
`is aryl aryl
`heterocydic polynuclear aromatic or lower alkyl poly-
`
`25
`
`30
`
`40
`
`50
`
`60
`
`65
`
`nuclear aromatic each unsubstituted
`
`or substituted with
`
`at
`
`least one electron withdrawing substituent or at least
`one electron donating
`
`substituent
`
`is
`
`or lower allcyl unsubstituted or substituted with
`at least one electron withdrawing substituent or at least
`one electron donating substituent
`R2 and R3 independently are hydrogen lower ailcyL
`lower alkenyl
`lower alkynyl aryl aryl
`lower alkyl
`lower alkyl heterocydic
`polynuclear
`heterocydic
`each
`aromatic
`lower alkyl polynuclear aromatic
`least one electron
`unsubstituted
`or substituted with at
`
`heteroatom contain
`donating substituent halogen or
`ing oxygen nitrogen sulfur or phosphorous
`substituted
`with hydrogen lower alkyl or aryl said lower ailcyl or
`aryl groups being substituted or unsubstituted and
`
`is
`
`to
`Another preferred embodiment of the present
`compound of Formula
`
`invention is
`
`R2
`
`RNMNH.CRl
`
`R3
`
`wherein
`
`lower alkyl heterocyclic lower alkyl
`is aryl
`heterocydic polynuclear aromatic or lower alkyl poly
`nuclear aromatic each of which may be unsubstituted
`or substituted with at
`least one halo nitro acyl
`carboxyl carboalkoxy carboxamide cyano sulfonyl
`sulfoxide sulfinyl heterocydic
`guanidine quater
`nary aimnonium hydroxy alkoxy alkyl amino
`phenoxy mercapto suffide or disuffide
`or lower alkyl which may be unsubstituted
`R1 is
`substituted with at
`least one halo nitro acyl
`cyano sulfonyl sulfoxide suffinyl
`carboxamide
`heterocyclic guanidine quaternary ammonium
`hydroxy lower alkoxy amino phenoxy suffide or
`disuffide
`
`or
`
`lower alkynyl
`lower alkenyl
`R2 is hydrogen lower alkyl
`lower alkyl heterocydic poly
`aryi heterocydic
`nuclear aromatic lower alkyl polynuclear aromatic
`each
`least one
`unsubstituted
`or substituted with at
`least one elec
`heteroatom
`
`electron withdrawing substituent or at
`tron 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
`
`lower alkynyl
`lower alkenyl
`R3 is hydrogen lower alkyl
`lower alkyl heterocydic poly
`aryl heterocydic
`nuclear aromatic lower alkyl polynuclear aromatic
`each
`or substituted with at
`one
`unsubstituted
`least
`
`least one elec
`
`electron withdrawing substituent or at
`tron donating
`substituent halogen or
`consisting of oxygen nitrogen sulfur or phosphorous
`said heteroatom being substituted with hydrogen lower
`alkyl or aryl said lower alkyl of aryl groups being
`substituted or unsubstituted
`
`heteroatom
`
`is
`
`and
`to
`Another preferred embodiment is
`
`compound of Formula
`
`

`
`It2
`
`R3
`
`5654301
`
`is
`
`is
`
`wherein
`
`at
`
`is
`
`10
`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
`lower alkynyl or halo and may be unsub
`alkenyl
`stituted or substituted with an electron donating group
`or an electron withdrawing group provided that when
`lower alkyl heterocydic or heterocydic
`is aryl aryl
`chemical bond or
`is halo
`is unsubstituted or is substituted with
`lower alkyl and
`ZY taken together
`NR4OR5 ONR4R5
`is NR4NR5R6
`least one electron withdrawing group or electron
`OPR4R5
`PR4OR5
`SNR4R5
`NR4SR5
`SPR4R5
`donating group
`or
`PR4SR5 NR4PR5R6 or PR4NR5R6
`R1 is hydrogen or lower alkyl unsubstituted or substituted
`R4 R5 and R6 are independently
`group or an electron with-
`with an electron donating
`hydrogen lower alkyl
`drawing group and
`lower alkenyl or lower alkynyl
`aryl aryl lower alkyl
`or sub
`wherein R4 R5 and R6 may be unsubstituted
`R2 and R3 are independently hydrogen lower alkyl
`lower
`stituted with an electron withdrawing group or an
`lower alkynyl
`lower alkyl aryl
`alkenyl
`electron donating group
`heterocydic heterocydic
`is 14
`wherein R2 and R3 may be unsubstituted or substituted
`Of this preferred group it
`with at least one electron withdrawing group or elec-
`is especially preferred that
`tron donating group
`are those in which
`The preferred compounds
`is aryl
`SSO0 NR4 PR4 or
`lower alkyl heterocyclic or heterocydic lower alkyl
`aryl
`R1 is hydrogen or lower alkyl R2 and R3 are independently
`is hydrogen lower alkyl aryl aryl lower alkyl
`lower alkoxy
`lower alkyl aryl
`lower alkynyl heterocydic
`hydrogen heterocycic
`alkenyl
`heterocycic
`lower alkenyl amino hydroxylamino lower alkoxy amino
`lower alkyl or halo and
`may be unsubstituted
`group or an 25 N-lower alkyl hydroxyamino N-lower alkyl-o-lower alkyl
`substituted with an electron
`donating
`electron withdrawing group provided that when
`hydroxyaniino
`aralkoxy carbonyl hydrazino or alkylmer
`capto and
`chemical bond or
`halo
`In another preferred embodiment
`and R1 are as
`ZY taken together
`NR4OR5 ONR4R7
`is NR4NR5R7
`defined hereinabove
`and one of R2 and R3 is hydrogen
`and
`NR4SR7
`PR4OR5
`SNR4R7
`SPR4R5 or
`OPR4R5
`heterocycic lower alkyl aryl
`is heterocydic
`the other
`PR4SR7 NR4PR5R6 or PR4NRSR7
`N-hydroxylamino lower alkoxyamino N-lower
`alkyihydroxylamino N-lower alkyl-O-lower alkyihy
`droxyaniino
`and R1
`Another preferred embodiment is wherein
`35 are as defined hereinabove one of R2 and R3 is as defined
`hereinabove or the other is heterocycic heterocyclic
`lower
`lower alkyl heterocycic
`aryl N-hydroxylamino
`alkyl
`lower alkoxy amino N-lower alkyl hydroxylamino N-lower
`lower alkoxy dialkyl
`alkyl-o-lower alkyl hydroxylamino
`40 lower amino lower alkylamino aryl
`lower alkyloxy
`hydrazino or lower alkylmercapto
`The various
`and permutations of
`combination
`Markush groups of R1 R2 R3
`and
`described herein are
`invention
`to be within the scope of the present
`contemplated
`invention also encompasses com
`45 Moreover
`the present
`pounds and compositions which contain one or more ele
`ments of each of the Markush groupings in R1 R2 R3
`and
`and the various combinations thereof Thus for example
`that R1 may be one or
`the present
`invention contemplates
`50 more of the substituents
`listed hereinabove in combination
`with any and all of the substituents of R2 R3 and
`to each value of
`respect
`invention may contain one
`The compounds of the present
`or more asymmetric carbons and may exist in racemic
`55 and optically active forms The configuration around each
`form It is
`asymmetric carbon can be in either the
`or
`well known in the art that
`around
`chiral
`the configuration
`carbon atoms
`can also be described
`as
`or
`Cahn-Prelog-Ingold nomenclature
`system All of the van-
`around each asymmetric carbon includ
`60 ous configurations
`ing the various enantiomers
`and diastereomers
`as well as
`raceniic mixtures and mixtures of enantiomers diastere
`invention
`omers or both are contemplated
`by the present
`In the principal chain there exists asymmetry at
`the
`65 carbon atoms to which the groups R2 and R3 are attached as
`substituted When
`the compounds of
`the present
`invention is of the formula
`
`R4 R5 and R6 are independently
`hydrogen lower alkyl
`lower alkenyl or lower alkynyl
`aryl aryl lower alkyl
`wherein R4 R5 and R5 may be unsubstituted
`or sub-
`stituted with an electron withdrawing group or an
`electron donating group and
`R7 is R6 or COOR8 or COR8 R8