United States Patent [191
`Kohn et al.
`
`[54] AMINO ACID DERIVATIVE
`ANTICONVULSANT
`
`[75] Inventors: Harold L. Kohn. Houston; Darrell
`Watson. Belton. both of Tex.
`
`[73] Assignee: Research Corporation Technologies,
`Inc., Tucson, Ariz.
`
`[21]
`[22]
`
`Appl. No.: 3,208
`Filed:
`Jan. 12, 1993
`
`Related US. Application Data
`
`[63] Continuation-in-part of Ser. No. 710,610, Jun. 4, 1991, Pat
`No. 5,378,729, which is a continuation-in-part of Ser. No.
`354,057, May 19, 1989, abandoned, and a continuation-in
`part of Ser. No. 392,870, Aug. 11, 1989, abandoned, said Ser.
`No. 354,057, is a continuation-in-part of Ser. No. 80,528,
`Jul. 31, 1987, abandoned, which is a continuation-in-part of
`Ser. No. 916,254, Oct 7, 1986, abandoned, which is a
`continuation-in-part of Ser. No. 702,195, Feb. 15, 1985,
`abandoned, said Ser. No. 392,870, is a continuation of Ser.
`No. 80,528, Jul. 31, 1987, abandoned, which is a continu
`ation-in-part of Ser. No. 916,254, Oct. 7, 1986, abandoned,
`which is a continuation-impart of Ser. No. 702,195, Feb. 15,
`1985, abandoned.
`Foreign Application Priority Data
`
`[30]
`
`Jun. 4, 1992 [W0] WIPO ............................ .. US92/O4687
`
`[51] Int. Cl.6 ...................... .. A61K 31/445; A61K 31/34;
`CO7D 211/72; CO7D 261/04
`[52] US. Cl. ..................... .. 514/231.2; 514/315; 514/397;
`514/406; 514/415; 514/424; 514/461; 514/468;
`514/486; 514/616; 546/292; 548/125; 548/225;
`548/250; 548/347.1; 548/245; 548/371.4;
`564/152; 564/154; 564/292
`[58] Field of Search ................................... .. 564/148, 155,
`564/154. 152; 548/125, 245, 371.4; 514/315,
`357, 461. 406. 548, 424, 415, 549, 618,
`486, 231.2; 546/252, 152, 154
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4/1954 Bruce et a1. .......................... .. 424/319
`2,676,188
`2,721,197 10/1955 Sheehan ..
`564/155
`3,340,147
`9/1967 Martin et al.
`514/616
`3,657,341
`4/1972 Thorne et al.
`260/558 A
`
`3,707,559 12/1972 Mazur et al. . . . . . . . .
`
`. . . . . .. 564/158
`
`564/215
`4,018,826 4/1977 Gless, Jr. et a1.
`564/155
`4,260,684
`4/1981 Schult .................... ..
`564/155
`4,303,673 12/1981 Biedermann et a1.
`4,372,974 2/1983 Fish et al. ............................. .. 260/559
`4,513,009 4/1985 Roques et al. .
`514/616
`4,595,700
`6/1986 Donald et al.
`564/154
`4,618,708 10/1986 Roques et al. ..
`564/215
`4,873,241 10/1989 Napier et a1.
`5,378,729
`1/1995 Kohn et a1. ........................ .. 514/231.2
`
`FOREIGN PATENT DOCUMENTS
`
`0885303 3/1981 Belgium .
`0007441 2/1980 European Pat. 01f. .
`0194464 2/1980 European Pat. 01f. .
`0038758 10/1981 European Pat. Off. .
`0042626 12/1981 European Pat. Off. .
`0046707 3/1982 European Pat. 01f. .
`
`USOO5654301A
`Patent Number:
`[11]
`[45] Date of Patent:
`
`5,654,301
`Aug. 5, 1997
`
`0263506
`0400400
`1927692
`0393355
`1051220
`
`10/1987
`European Pat. Off. .
`5/1990
`European Pat. Oif. .
`12/1969
`Germany .
`10/ 1965 Switzerland .
`12/1966 United Kingdom .
`
`OTHER PUBLICATIONS
`Remington, Pharmaceutical Sciences, Mack Publishing
`Company, (1980) pp. 400-427.
`Chemical Abstracts. vol. 92; No. 7:51712r (Feb. 18. 1990).
`Chemical Abstracts, vol. 96; No. 5:35710r (Feb. 1. 1982).
`Chemical Abstracts, vol. 101; No. 9; 72124v (Aug. 27,
`1984).
`Chemical Abstracts, vol. 91; No. 21:175147; (Nov. 19,
`1979).
`Kohn, et al. (1988) Brain Research 457: 371-375, Marked
`Stereospeci?city in a New Class of Anticonvulsants.
`Chemical Abstracts, Vol. 97;145266d (1982).
`Chemical Abstracts, vol. 89; 129286q; Za?oukal, et a1.
`(1978).
`White, et a1. (1981) JACS, 1031423 1-4239, Active-Site-Di
`rected Inhibition of alpha-Chymotrypsin by Deaminatively
`Produced Carbonium Ions: An Example of Suicide of
`Enzyme-Activated-Substrate Inhibition.
`Legall. et a1. (1988) Int. J. Protein Res.. 322279-291 Syn
`thesis of Functionalized Non-Natural Amino Acid Deriva
`tives via Amidoalkylation Transformations.
`Cortes, et al. (1985) J. Med. Chem., 28:601-606, Effect of
`Structural Modi?cation of the Hydantion Ring on Anticon
`vulsant Activity.
`Ikeda, et a1. (1977) Tetrahedron, 33(5):489-495, photo
`chemical
`Synthesis
`of
`1,23.
`4-Tetrahydroisoquinolin-3-ones from N-Chloracetylben
`-zylamines.
`Conley, et al. (1987) J. Med. Chem, 30(3): 567-574 Func
`tionalized DL-Amino Acid Derivatives. Potent New Agents
`for the Treatment of Epilepsy.
`Garcia, et al. (1984) Tetrahedron Letters, 25(42) 4841-4844,
`New Synthetic ‘Tricks” Triphenylphosphine-Mediated
`Amide Formation from Carboxylic Acids and Azides.
`Rebek. et al. (1979), J. Am. Chem. Soc., 101(3):737, On the
`Rate of SiteASite Interactions in Functionalized Polysty
`renes.
`Katritzky, et al. (1990) J. Org. Chem. 55:2206-2214, Ben
`zotrialzole-Assisted Synthesis of Monacyl Animals and
`Their Peptide Derivatives.
`Lipshutz, et a1. (1983) J. Am. Chem. Soc., 105:7703-7713,
`Heterocycles as masked Diamide/Dipeptide Equivalents.
`Formation and Reactions of Substituted 5-(Acylamino)ox
`azoles as Interrnidiates en route to the Cyclopeptide Alka
`loids.
`
`(List continued on next page.)
`
`Primary Examiner—Theodore J. Criares
`Attomey, Agent, or Firm—Scully, Scott, Murphy & Presser
`[57]
`ABSTRACT
`
`The present invention relates to compounds of the formula
`
`R2
`| H
`H
`R—N(C—(‘I—N),,C—R1
`II
`II
`Q R3
`A
`
`47 Claims, No Drawings
`
`IPR2014-01126, Exhibit 1003, p. 1
`
`

`
`5,654,301
`Page 2
`
`OTHER PUBLICATIONS
`
`Lipshutz. et a1. (1993) J. Org. Chem, 48:3745-3750, An
`Approach to the Cycle-peptide Alkaloids (Phencycopep
`tines) via Heterocyclic Diamide/Dipeptide Equivalents.
`Preparation and N-Alkylation Studies of 2.4(5)-Disubsti
`tuted Imidazoles.
`Roques, 91987) 193rd ACS National Meeting. Amer. Chem.
`Soc.. Apr. 5-10. 1987 Use of Various Metallopeptides
`
`Inhibitors to Study the Physiological Role of Endogenous
`Neuropetides.
`Kohn, et a1. (1990) J. Med. Chem. 33:919-926. Preparation
`and Anticonvulsant Activity of a Series of Functionalized
`ot-Aromatic and oc-Heteroaromatic Amino Acids.
`Lipshutz, et a1. JACS, 106(2):457—459, “Heterocycles in
`Synthesis . .
`. Irnidazoles” (1984).
`Kohn. et a1. (1988) Chemistry in Britain, pp. 231-233, New
`Antiepileptic Agents.
`
`IPR2014-01126, Exhibit 1003, p. 2
`
`

`
`5,654,301
`
`1
`AMINO ACID DERIVATIVE
`ANTICONVULSANT
`
`RELATED APPLICATIONS
`The present application is a continuation-in-part of U.S.
`patent application Ser. No. 710.610 ?led on Jun. 4. 1991.
`now U.S. Pat. No. 5,378,729 which is a continuation-in-part
`of U.S. patent application Ser. No. 354.057 ?led on May 19,
`1989. now abandoned and U.S. patent application Ser. No.
`392.870 ?led on Aug. 11. 1989. now abandoned. U.S. patent
`application Ser. No. 354.057 is a continuation-in-part of
`U.S. patent application having Ser. No. 080.528. ?led on Jul.
`31. 1987. now abandoned. which is a continuation-in-part of
`U.S. patent application Ser. No. 916,254, ?led Oct. 7, 1986,
`now abandoned which is a continuation-in-part of U.S.
`patent application Ser. No. 702.195, ?led Feb. 15. 1985, now
`abandoned. U.S. patent application Ser. No. 392,870 is a
`continuation application of U.S. patent application having
`Ser. No. 080.528, ?led Jul. 31. 1987, now abandoned, which
`is a continuation-in-part of U.S. patent application Ser. No.
`916.254 ?led Oct. 7, 1986. now abandoned which is a
`continuation-in-part of U.S. patent application Ser. No.
`702.195 ?led on Feb. 15, 1985. now abandoned.
`This invention was made with Government support under
`NS15604 awarded by the National Institutes of Health. The
`Government has certain rights to this invention.
`
`BACKGROUND OF THE INVENTION
`The present invention relates to compounds and pharma
`ceutical compositions having central nervous system (CNS)
`activity which are useful in the treatment of epilepsy and
`other CNS disorders. More speci?cally. the compounds of
`this invention can be characterized as protected amino acid
`derivatives of the formula:
`
`10
`
`15
`
`20
`
`25
`
`35
`
`R;
`
`I
`
`II
`0
`
`II
`o
`
`II
`o
`
`0
`
`o
`
`ll
`0
`
`s
`
`A
`
`3
`
`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
`A and Q are independently O or S, M is an alkylene chain
`containing up to 6 carbon atoms or a chemical bond;
`11 is 1-4 and
`a is 1-3.
`The predominant application of anticonvulsant drugs is
`the control and prevention of seizures associated with epi
`lepsy or related central nervous system disorders. Epilepsy
`refers to many types of recurrent seizures produced by
`paroxysmal excessive neuronal discharges in the brain; the
`two main generalized seizures are petit mal. which is asso
`ciated with myoclonic jerks, aldnetic seizures, transient loss
`of consciousness, but without convulsion; and grand mal
`which manifests in a continuous series of seizures and
`convulsions with loss of consciousness.
`The mainstay of treatment for such disorders has been the
`long-term and consistent administration of anticonvulsant
`drugs. Most drugs in use are weak acids that, presumably,
`exert their action on neurons, glial cells or both of the central
`nervous system. The majority of these compounds are
`characterized by the presence of at least one amide unit and
`one or more benzene rings that are present as a phenyl group
`or part of a cyclic system.
`Much attention has been focused upon the development of
`anticonvulsant drugs and today many such drugs are well
`known. For example, the hydantions, such as phenytoin, are
`useful in the control of generalized seizures and all forms of
`partial seizures. The oxazolidinediones. such as trimethadi
`one and paramethadione, are used in the treatment of non
`convulsive seizures. Phenacemide, a phenylacetylurea, is
`one of the most well known anticonvulsants employed
`today, while much attention has recently been dedicated to
`the investigation of the diazepines and piperazines. For
`example, U.S. Pat. Nos. 4,002,764 and 4,178,378 to
`Allgeier, et al. disclose esteri?ed diazepine derivatives use
`ful in the treatment of epilepsy and other nervous disorders.
`U.S. Pat. No. 3,887,543 to Nakanishi, et al. describes a
`thieno[2,3-e][l,4]diazepine compound also having anticon
`vulsant activity and other depressant activity. U.S. Pat. No.
`4,209,5 16 to Heckendorn, et a1. relates to triazole derivatives
`which exhibit anticonvulsant activity and are useful in the
`treatment of epilepsy and conditions of tension and agita
`tion. U.S. Pat. No. 4.322.974 to Fish, et al. discloses a
`pharmaceutical formulation containing an aliphatic amino
`acid compound in which the carboxylic acid and primary
`amine are separated by three or four units. Administration of
`these compounds in an acid pH range are useful in the
`
`A
`
`or the N-oxides thereof or pharrnaceutically acceptable salts
`thereof wherein
`R is hydrogen. lower alkyl, lower alkenyl, lower alkynyl,
`aryl, aryl lower alkyl, heterocyclic. heterocyclic lower
`alkyl. loweralkyl heterocyclic, lower cycloalkyl. lower
`cycloalkyl lower alkyl, and R is unsubstituted or is
`substituted with at least one electron withdrawing
`group or electron donating group;
`R1 is hydrogen or lower alkyl, lower alkenyl, lower
`alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl,
`heterocyclic, lower cycloalkyl, lower cycloalkyl lower
`alkyl. each unsubstituted or substituted with an electron
`donating group or an electron withdrawing group and
`R2 and R3 are independently hydrogen, lower alkyl, lower
`alkenyl, lower alkynyl, aryl lower alkyl, aryl,
`heterocyclic, heterocyclic lower alkyl, lower alkyl
`heterocyclic, lower cycloalkyl, lower cycloalkyl lower
`alkyl. S0; or Z--Y wherein R2 and R3 may be
`unsubstituted or substituted with at least one electron
`withdrawing group or electron donating group;
`Z is O. S,S(O),,, NR4, PR, or a chemical bond;
`Y is hydrogen, lower alkyl. aryl. aryl lower alkyl, lower
`alkenyl, lower alkynyl, halo. heterocyclic, heterocyclic
`lower alkyl, cycloalkyl, cycloalkyl lower alkyl andY may be
`unsubstituted or substituted with an electron donating group
`or an electron withdrawing group. provided Z is a chemical
`bond only, when Y is halo, or
`
`45
`
`55
`
`65
`
`IPR2014-01126, Exhibit 1003, p. 3
`
`

`
`3
`treatment of convulsion disorders and also possess anxi
`olytic and sedative properties.
`Unfortunately. despite the many available pharmacothera
`peutic agents. a signi?cant percentage of the population with
`epilepsy or related disorders are poorly managed. Moreover,
`none of the drugs presently available are capable of achiev
`ing total seizure control and most have disturbing side
`effects. Clearly. current therapy has failed to “seize control”
`of these debilitating diseases.
`It is therefore one object of the present invention to
`provide novel compounds exhibiting CNS activity. particu
`larly anticonvulsant activity.
`Another object of this invention is to provide pharmaceu
`tical compositions useful in the treatment of epilepsy and
`other CNS disorders.
`A further object of this invention is to provide a method
`of treating epilepsy and related convulsant disorders.
`These and other objects are accomplished herein by
`providing compounds of the following general formula:
`
`Q R3
`
`" ll
`A
`
`wherein R. R1. R2. R3. R4. R5. R6. n. Z. Y, A and Q are as
`de?ned hereinabove.
`The present invention contemplates employing the com
`pounds of Formula I 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 pharrnaceutically acceptable forms or the addition salts
`vthereof. 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
`other groups. are lower alkyl containing from 1 to 6 carbon
`atoms and may be straight chain or branched. These groups
`include methyl. ethyl. propyl. isopropyl. butyl. isobutyl,
`tertiary butyl. amyl. hexyl. and the like.
`The aryl lower alkyl groups include. for example. benzyl.
`phenethyl. phenpropyl. phenisopropyl, phenbutyl. and the
`like. diphenylmethyl. 1.1-diphenylethyl. 1.2-diphenylethyl,
`and the like.
`The term aryl. when used along or in combination. refers
`to an aromatic group which contains from 6 up to 18 ring
`carbon atoms and up to a total of 25 carbon atoms and
`includes the polynuclear aromatics. These aryl groups may
`be monocyclic. bicyclic. tricyclic or polycyclic and are fused
`rings. Polynuclear aromatic compound is meant to encom
`pass bicyclic, tricyclic fused aromatic ring system contain
`ing from 10-48 ring carbon atoms and up to a total of 25
`carbon atoms. The aryl group includes phenyl, and the
`polynuclear aromatics e. g.. naphthyl. anthracenyl.
`phenanthrenyl, azulenyl and the like. The aryl group also
`includes groups like ferrocenyl.
`Lower alkenyl is an alkenyl group containing from 2 to 6
`carbon atoms and at least one double bond. These groups
`may be straight chained or branched and may be in the Z or
`E form. Such groups include vinyl. propenyl. l-butenyl.
`isobutenyl. 2-butenyl. l-pentenyl. (Z)-2-pentenyl. (E)-2
`pentenyl. (Z)-4-methyl-2-pentenyl, (E-)-4-methyl-2
`pentenyl. pentadienyl. e.g.. 1.3 or 2,4-pentadienyl, and the
`like.
`The term alkynyl include alkyene substituents containing
`2 to 6 carbon atoms and may be straight chained as well as
`
`5 .654,301
`
`4
`branched. It includes such groups as ethynyl. propynyl.
`l-butynyl. Z-butynyl. l-pentynl. 2-pentynyl. 3-methyl-l
`pentynyl. 3-pentynyl. l-hexynyl. 2-hexynyl, 3-hexynyl and
`the like.
`The term cycloalkyl when used alone or in combination is
`a cycloalkyl group containing from 3 to 18 ring carbon
`atoms and up to a total of 25 carbon atoms. The cycloalkyl
`groups may be monocyclic. bicyclic, tricyclic. or polycyclic
`and the rings are fused. The cycloalkyl may be completely
`saturated or partially saturated. Examples include
`cyclopropyl, cyclobutyl. cyclopentyl. cyclohexyl.
`cycloheptyl. cyclooctyl. cyclodecyl. cyclohexenyl.
`cyclopentenyl. cyclooctenyl, cycloheptenyl. decalinyl.
`hydroindanyl. indanyl, fenchyl. pinenyl. adamantyl. and the
`like. Cycloalkyl includes the cis or trans forms.
`Furthermore. the substituents may either be in endo or exo
`positions in the bridged bicyclic systems.
`The term “electron-withdrawing and electron donating”
`refer to the ability of a substituent to withdraw or donate
`electrons relative to that of hydrogen if the hydrogen atom
`occupied the same position in the molecule. These terms are
`well understood by one skilled in the art and are discussed
`in Advanced Organic Chemistry. by J. March. John Wiley
`and Sons. New York N.Y.. pp. 16-18 (1985) and the dis
`cu ssion therein is incorporated herein by reference. Electron
`withdrawing groups include halo. including bromo. ?uoro.
`chloro. iodo and the like; nitro. carboxy. lower alkenyl,
`lower alkynyl. formyl, carboxyarnido. aryl. quaternary
`ammonium, tri?uoromethyl, aryl lower alkanoyl. car
`balkoxy and the like. Electron donating groups include such
`groups as hydroxy. lower alkoxy. including methoxy. ethoxy
`and the like; lower alkyl, such as methyl. ethyl. and the like;
`amino. lower alkylamino. di(loweralkyl)amino, aryloxy
`such as phenoxy. mercapto, lower alkylthio, lower
`alkyhnercapto, disul?de (lower alkyldithio) and the like.
`One skilled in the art will appreciate that the aforesaid
`substituents may have electron donating or electron with
`drawing properties under di?erent chemical conditions.
`Moreover, the present invention contemplates any combi
`nation of substituents selected ?'om the above-identi?ed
`groups.
`The term halo includes ?uoro. chloro. bromo. iodo and the
`like.
`The term acyl includes lower alkanoyl.
`As employed herein. the heterocyclic substituent contains
`at least one sulfur. nitrogen or oxygen. but also may include
`one or several of said atoms. The heterocyclic substituents
`contemplated by the present invention include heteroaro
`matics and saturated and partially saturated heterocyclic
`compounds. These heterocyclics may be monocyclic.
`bicyclic. tricyclic or polycyclic and are fused rings. They
`may contain up to 18 ring atoms and up to a total of 17 ring
`carbon atoms and a total of up to 25 carbon atoms. The
`heterocyclics are also intended to include the so-called
`benzoheterocycles. Representative heterocyclics include
`furyl, thienyl. pyrazolyl, pyrrolyl, imidazolyl. indolyl.
`thiazolyl, oxazolyl. isothiazolyl, isoxazolyl. piperidyl,
`pyrrolinyl, piperazinyl, quinolyl. triazolyl. tetrazolyl.
`isoquinolyl. benzofuryl, benzothienyl, morpholinyl.
`benzoxazolyl. tetrahydrofuryl, pyranyl. indazolyl. purinyl,
`indolinyl. pyrazolidinyl, imidazolinyl, imidazolidinyl.
`pyrrolidinyl. furazanyl. N-methylindolyl. methylfuryl.
`pyridazinyl, pyrimidinyl. pyrazinyl. pyridyl, epoxy.
`aziridino. oxetanyl, azetidinyl. the N-oxides of the nitrogen
`containing heterocycles, such as the nitric oxides of pyridyl.
`pyrazinyl. and pyrimidinyl and the like. The preferred het
`erocyclic are thienyl. furyl. pyrroly. benzofuryl.
`benzothienyl. indolyl. methylpyrrolyl. merpholinyl, pyridyl,
`
`10
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`IPR2014-01126, Exhibit 1003, p. 4
`
`

`
`5,654,301
`
`5
`pyrazinyl, imidazolyl. pyrirnidinyl. pyrazolyl or pyridazinyl.
`The preferred heterocyclic is a 5 or 6-membered heterocy
`clic compound. The especially preferred heterocyclic is
`furyl. pyridyl, pyrazinyl. imidazolyl, pyrazolyl, triazolyl,
`tetrazolyl, oxadiazolyl. epoxy, pyrimidinyl, or pyridazinyl.
`The most preferred heterocyclics are furyl. pyrazolyl, pyr
`rolyl and pyridyl.
`The preferred compounds are those wherein n is 1, but di,
`tri and tetrapeptides are also contemplated to be within the
`scope of the claims.
`The preferred values of R is aryl lower alkyl. especially
`benzyl. and the preferred R1 is H or lower alkyl. The most
`preferred R1 group is methyl.
`The most preferred electron donating substituent and
`electron withdrawing substituent are halo, nitro, alkanoyl,
`formyl. arylalkanoyl. aryloyl. carboxyl, carbalkoxy,
`carboxamide. cyano. sulfonyl, sulfoxide. heterocyclic.
`guanidine. quaternary ammonium, lower alkenyl, lower
`alkynyl. sulfonium salts. hydroxy. lower alkoxy. lower alkyl,
`amino. lower alkylamino, d.i(loweralkyl)amino. amine lower
`alkyl mercapto, mercaptoalkyl, alkylthio; and alkyldithio.
`The term “sul?de” encompasses mercapto. mercapto alkyl
`and alkylthio. while the term disul?de encompasses alky
`ldithio. These preferred substituents may be substituted on
`any one of R1. R2. R3. R4, R5 or R6, R7 or R8 as de?ned
`
`10
`
`20
`
`25
`
`herein.
`
`-
`
`E
`
`| (3%
`VCR?
`or those corresponding partially or fully saturated form
`thereof wherein n is O or 1
`A, Z. L and J are independently CH, or a heteroatom
`selected from the group consisting of N, O, S, and
`G is CH, or a heteroatom selected from the group con
`sisting of N, O and S,
`but when n is O, G is CH. or a heterocyclic selected from
`the group consisting of NH, O and S with the proviso
`that at most two of A, E, L, I and G are heteroatoms.
`If the ring depicted hereinabove contains a nitrogen ring
`atom, then the N-oxide forms are also contemplated to be
`within the scope of the invention.
`When R2 or R3 is a heterocyclic of the above formula, it
`may be bonded to the main chain by a ring carbon atom.
`When n is 0. R2 or R3 may additionally be bonded to the
`main chain by a nitrogen ring atom.
`R2 or R3 may independently also be 803-, or SO21
`Furthermore, ZY may also be
`
`I]
`0
`
`o
`
`ll
`o
`
`o
`
`Q
`
`A
`
`When R2 is alkenyl the alkenyl group is a lower alkenyl
`group having 1-6 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.
`As indicated hereinabove, Q and Amay be 0 or S; in other
`words, the main chain may contain only C=O, only ——C=S
`or combinations thereof. All such permutations are contem
`plated herein. It is preferred that the compounds of the
`present invention contain no more than 2 C=S moieties, it
`is even more preferred that the compounds of the present
`invention contain no more than 1 C=S moiety. The most
`preferred embodiment are when A and Q are both oxygen.
`An embodiment of the present application is one in which
`the compounds are of Formula I wherein R is lower
`cycloalkyl or lower cycloalkyl lower alkyl, and R is unsub
`stituted or is substituted with at least one electron withdraw
`ing group or electron donating group and R1, R2, R3, Z, Y
`or ZY taken together, R4, R5, R6, R7, R8, 11 and a are as
`de?ned herein.
`Another embodiment of the present invention include
`compounds of Formula I wherein R1 is lower cycloalkyl or
`lower cycloalkyl lower alkyl and R1 may be unsubstituted or
`substituted with an electron donating group or electron
`withdrawing group and R1, R2, R3, Z, Y, or ZY taken
`together, R4, R5, R6, R7, R8 11 and a are as de?ned herein
`above.
`Another embodiment of the present invention includes
`compounds of Formula I wherein R2 is lower cycloalkyl or
`lower cycloalkyl lower alkyl and R2 may be unsubstituted or
`substituted with an electron donating group or electron
`withdrawing group, and R, R1, R3, R4, R5, R6, R7, R8 and a
`are as de?ned hereinabove.
`Still another embodiment of the present invention include
`compounds of Formula I wherein R3 is lower cycloalkyl or
`lower cycloalkyl lower alkyl and R3 may be unsubstituted or
`substituted with an electron donating or electron withdraw
`
`30
`
`40
`
`The ZY groups representative of R2 and R3 include
`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. ethylarnino; arylamino. such as anilino; lower
`dialkylamino. such as. dimethylamino; trialkyl ammonium
`35
`salt. hydrazino, alkylhydraziuo and arylhydrazino, such as
`N-methylhydrazino, N-phenylhydrazino, carbalkoxy
`hydrazino. aralkoxycarbonyl hydrazino, aryloxycarbonyl
`hydrazino, hydroxylamiuo, such as N-hydroxylamino
`(—NH—OH). lower alkoxy amino [(NHOR 18) wherein R18
`is lower alkyl], N-lower alkylhydroxyl amino [(NCR18)OH
`wherein R18 is lower alkyl], N-lower alkyl-O-lower alkyl
`hydroxyamino. i.e., [N(R18)OR19 wherein R18 and R19 are
`independently lower alkyl] and o-hydroxylamino (—O—
`NH2); alkylamido such as acetamido, tn'?uoroacetamido,
`45
`lower alkoxyamino, (e.g. NH(OCH3); and
`heterocyclicamino. such as pyrazoylamino.
`Furthermore, in still another embodiment Z may be 0. S,
`NR4 or PR4 and Y may be hydrogen. lower alkyl or aryl and
`R. R1, R2. R3. R4, R5. R6, R7, R8, 11 and a are as de?ned
`hereinabove.
`In a still further embodiment. ZY may be
`
`50
`
`O
`
`O
`
`O
`
`O
`
`55
`
`and R. R1. R2. R3. R4. R5. R6, R7. R8. n and a are as de?ned
`hereinabove.
`When R2 or R3 is heterocyclic, the preferred heterocyclics
`are furyl. tetrahydrofuryl, pyn'dyl, pyrazinyl, imidazolyl,
`pyrazolyl. tn'azolyl, tetrazolyl, oxadiazolyl or epoxy. The
`most preferred heterocyclic is furyl. pyridyl. pyrazoyl and
`pyrrolyl.
`The preferred heterocyclic groups representative of R2
`and R3 have the formula
`
`65
`
`IPR2014-01126, Exhibit 1003, p. 5
`
`

`
`5,654,301
`
`7
`ing group and R. R1. R2. R4. R5. R6, R7. R8, n and a are as
`de?ned hereinabove.
`A further embodiment of the present invention include
`compounds of Formula I wherein Z is 5(0),, and R, R1. R2,
`R3. Y. R4. R5. R6. R7. R8. 11 and a are as de?ned herein.
`It is preferred that one of R2 and R3 is hydrogen.
`In a preferred embodiment. one of R2 and R3 is hydrogen
`and that the other is heterocyclic. It is preferred that one of
`R2 and R3 is a heterocyclic having Formula XI. The pre
`ferred heterocyclics include furyl, thienyl. benzothienyl,
`benzofuryl, oxazolyl. thiazolyl. isoxazolyl, indolyl,
`pyrazolyl, isoxazolidinyl, benzothienyl, benzofuryl,
`morpholinyl. indolyl, pyrrolyl, furfuryl. and methylpyrrolyl,
`pyridyl. pyrazinyl. irnidazolyl. pyrimidinyl or pyridazinyl,
`pyrazolyl. or epoxy. In another preferred embodiment, one
`of R2 and R3 is alkyl (e.g. methylisopropyl), aryl (e.g.,
`phenyl), 2-thiomethylethyl. lower alkoxy (e.g., ethoxy,
`methoxy). anilino. propenyl, alkylamino (e.g., ethylamino or
`methylamino). 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
`alkylhydroxyamino. lower alkoxyamino. N-lower alkyl-O
`lower alkylhydroxyamino or aralkoxycarbonylhydrazino.
`Preferred compounds of the present invention have the
`following general formula:
`
`15
`
`25
`
`8
`nuclear aromatic, each unsubstituted or substituted with
`at least one electron withdrawing substituent or at least
`one electron donating substituent;
`R1 is H or lower alkyl, unsubstituted or substituted 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,
`heterocyclic, lower alkyl heterocyclic. polynuclear
`aromatic, lower alkyl polynuclear aromatic, each
`unsubstituted or substituted with at least one electron
`donating substituent, halogen or a heteroatom contain
`ing oxygen, nitrogen. sulfur or phosphorous substituted
`with hydrogen, lower alkyl or aryl, said lower alkyl or
`aryl groups being substituted or unsubstituted; and
`n is l to 4.
`Another preferred embodiment of the present invention is
`a compound of Formula I
`
`wherein R1 is H or lower alkyl, R2 and R3 are as de?ned
`above and A is hydrogen or an electron donating group or
`electron-withdrawing group and m is 0-5. It is preferred that
`A is hydrogen (i.e.. m=0). However. values of m equalling
`l. 2 or 3 are also preferred.
`Preferred embodiments include compounds of Formula I
`
`35
`
`R;
`
`(I)
`
`QR; A
`
`wherein
`R and R1. independently, are hydrogen. lower alkyl, lower
`alkenyl. lower alkynyl. aryl lower alkyl, aryl,
`heterocyclic, lower alkyl heterocyclic, each unsubsti
`tuted or substituted with at least one substituent;
`R2 and R3. independently, are hydrogen, lower alkyl,
`lower alkenyl, lower alkynyl, aryl lower alkyl, aryl,
`heterocyclic. lower alkyl heterocyclic, each unsubsti
`tuted or substituted with at least one substituent; halo
`gen or a heteroatom containing oxygen. nitrogen, sulfur
`or phosphorous substituted with hydrogen, lower alkyl
`or aryl. said lower alkyl or aryl groups being substituted
`or unsubstituted; and
`n is l to 4.
`Another preferred embodiment is a compound having
`Formula I
`
`45
`
`55
`
`60
`
`R is aryl. aryl lower alkyl, heterocyclic, lower alkyl
`heterocyclic. polynuclear aromatic or lower alkyl poly
`
`wherein
`R is aryl lower alkyl, heterocyclic. lower alkyl
`heterocyclic, 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 (sul?nyl), heterocyclic. guanidine. quater
`nary ammonium hydroxy, alkoxy, alkyl, amino,
`phenoxy, mercapto, sul?de or disul?de;
`R1 is H or lower alkyl which may be unsubstituted or
`substituted with at least one halo, nitro, acyl,
`carboxamide, cyano. sulfonyl, sulfoxide (sul?nyl),
`heterocyclic, guanidine, quaternary ammonium,
`hydroxy, lower alkoxy, amino, phenoxy, sulfide. or
`disul?de;
`R2 is hydrogen, lower alkyl. lower alkenyl. lower alkynyl,
`aryl, heterocyclic, lower alkyl heterocyclic, poly
`nuclear aromatic, lower alkyl polynuclear aromatic.
`each unsubstituted or substituted with at least one
`electron withdrawing substituent or at least one elec
`tron donating substituent; halogen or a heteroatom
`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 alkenyl, lower alkynyl,
`aryl, heterocyclic, lower alkyl heterocyclic. poly
`nuclear aromatic, lower alkyl polynuclear aromatic.
`each unsubstituted or substituted with at least one
`electron withdrawing substituent or at least one elec
`tron donating substituent; halogen or a heteroatom
`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;
`and n is 1 to 4;
`Another preferred embodiment is a compound of Formula
`
`I
`
`IPR2014-01126, Exhibit 1003, p. 6
`
`

`
`9
`
`Q R3
`
`0
`
`5,654,301
`
`10
`electron donating group, with the proviso that R2 and
`R3 cannot both be hydrogen;
`Z is O, S, NR4, PR4 or a chemical bond;
`Y is hydrogen, lower alkyl. aryl, aryl lower alkyl, lower
`alkenyl, lower alkynyl or halo. and Y may be unsub
`stituted or substituted with an electron donating group
`or an electron withdrawing group, provided that when
`Y is halo, Z is a chemical bond; or
`
`wherein
`R is aryl. aryl lower alkyl. heterocyclic or heterocyclic
`lower alkyl and R is unsubstituted or is substituted with
`at least one electron withdrawing group. or electron
`donating group;
`R1 is hydrogen or lower alkyl, unsubstituted or substituted
`with an electron donating group or an electron with
`drawing group and
`R2 and R3 are independently hydrogen, lower alkyl, lower
`alkenyl. lower alkynyl, aryl lower alkyl, aryl,
`heterocyclic, heterocyclic lower alkyl. or Z—Y
`wherein R2 and R3 may be unsubstituted or substituted
`with at least one electron withdrawing group or elec
`tron donating group;
`Z is O. S,S(O),,, NR4, PR4 or a chemical bond;
`Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower
`alkenyl. lower alkynyl, heterocyclic, heterocyclic
`lower alkyl, or halo and Y may be unsubstituted or
`substituted with an electron donating group or an
`electron withdrawing group, provided that when Y is
`halo. Z is a chemical bond. or
`
`10
`
`20
`
`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;
`n is 1-4.
`Of this preferred group, it is especially preferred t