Unlted States Patent
`
`[19]
`
`|||Il|lllllllllllllllllllll||||||||||||||||||l|||||||l|||||||||||I||||l||||
`U8005378729A
`[in Patent Number:
`
`5,378,729
`
`
`Kohn et a1.
`[45] Date of Patent:
`Jan. 3, 1995
`
`[54] ANTICOO§VCIIII)L1S)EII§TIVA
`
`‘
`
`[75]
`
`Inventors: Harold L. Kohn, Houston; Darrell
`Watson, Belton, both of Tex.
`
`[73] Assignee: Research Corporation Technologies,
`Inc., Tucson, Ariz.
`
`[21]
`
`A 1' N _,
`pp
`°
`.
`‘
`[22] Ffled‘
`
`1
`”0’6 0
`
`Jun” 4’ 1991
`
`[63]
`
`Related US. Application Data
`Confinmmmimpm of Sen No. 354,057, May 19,
`1989, abandoned, and Ser. No. 392,870, Aug. 11, 1989,
`abandoned, whichisacontinuation of Ser. No. 80,528,
`Jul. 31, 1987, abandoned, which is a continuation-in-
`Par? 013% N0,- 91‘3’25‘?’ 0°“ 7, 1935; abandoned,
`which 18 a continuanon-m-part of Ser. No. 702,195,
`Feb. 15, 1985, abandoned, said Ser. No. 354,057, is a
`continuation-in-part of Ser. No. 80,528, Feb. 15, 1985.
`
`[51]
`
`Int. Cl.6 ................. A61K 31/535; A61K 31/445;
`C07D 211/72; C07D 261/04
`[52] US. 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
`[58] Field of Search ............... 564/148, 155, 154, 152;
`548/616’ 245’ 371'4; 514/461’ 5512632292,
`
`56
`
`1
`
`1
`
`Cit d
`R f
`e
`e erences
`US. PATENT DOCUMENTS
`564/155
`2,676,188 4/1954 Bruce etal.
`
`564/155
`2,721,197 10/1955 Sheehan
`3,340,147
`9/1967 Martin et a1. ........... 514/616
`
`3,657,341 4/1972 Theme eta1..
`.. 260/558 A
`3,707,55912/1972 Mazur etal. ............. 564/158
`
`4,018,826 4/1977 G1ess,Jr. etal..
`564/215
`
`4,260,684 4/1981 Schult ...................
`564/155
`4,303,673 12/1981 Biedermann et a1.
`564/155
`
`4,513,009 4/1985 Roques et al.
`564/155
`
`4,595,700
`6/1986 Donald et a1.
`514/616
`
`4,618,708 10/1986 Roques et al. ........... 564/154
`4,873,241 10/1989 Napier et a1.
`.................... 514/237.8
`
`FOREIGN PATENT DOCUMENTS
`0885303
`3/1981 Belgium .
`0194464 2/1980 _European Pat. Off.
`00074-41 10/ 1980 European Pat. Off.
`0038758 10/1981 European Pat. Off.
`0042626 12/1981
`131110139211 Pat. Off.
`0046707
`3/1982 European Pat. Off.
`0263506 10/1987 European Pat. Off.
`0400400 5/1990 European Pat. Off.
`1927692 12/1969 Germany .
`0393355 10/1965 Switzerland .
`1051220 12/1966 United Kingdom .
`
`.
`.
`.
`.
`.
`.
`.
`
`OTHER PUBLICATIONS
`Chemical Abstracts, vol. 92; No. 7:51712r (Feb. 18,
`1990)-
`Chemical Abstracts, vol. 96; No. 5:35710r (Feb.
`1982)_
`Chemical Abstracts, vol. 101; No. 9; 72124v (Aug. 27,
`1984)
`.
`'
`.
`Chemical Abstracts, vol. 91; No. 21.175147, (Nov. 19,
`1979).
`
`1,
`
`' "
`
`(List continued on next page)
`.
`.
`.
`.
`.
`PM”? Exammer’Mmme 1‘" 0‘”th
`Assistant Examiner—T. Criares
`.
`A‘wmey’ Agent, 0’ Fl’m—Sc‘fllya 50°“! Murphy &
`Presser
`[57]
`ABSTRACT
`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;
`
`R2
`I
`R—NH'E'C—CISNHi'fi—RI
`"
`R3
`I
`
`and pharmaceutically acceptable salts thereof.
`
`150 Claims, No Drawings
`
`EXHIBIT
`ACTAVIS, AMNEAL,
`AUROBINDO,
`BRECKENRIDGE,
`VENNOOT, SANDOZ,
`SUN
`
`|PF1201 4-01126-1 008, p. 1
`
` IPR2014-01126- Exhibit 1008, p. 1
`
`
`
`
`

`

`Page 2
`
`5,378,729
`
`OTHER PUBLICATIONS
`
`(1988) Brain Research 457: 371—375,
`a1.
`Kohn, et
`Marked Sterospecificity in a New Class of Anticonvul-
`sants.
`v
`
`Chemical Abstracts, vol. 97; l45266d (1982).
`White,
`et
`a1.
`(1981)
`JACS,
`103:4231—4239, Ac-
`tive—Site—Directed Inhibition of alpha—Chymotrypsin
`by Deaminatively Produced Carbonium Ions: An Ex-
`ample of Suicide of Enzyme—Activated—Substrate Inhi-
`bition.
`
`Legal], et al. (1988) Int. J. Protein Res., 12:279—291
`Synthesis of Functionalized Non—Natural Amino Acid
`Derivatives via Amidoalkylation Transformations.
`Conley, et al. (1987) J. Med. Chem, 30(3):574-—580,
`Functionalized DL—Amino Acid Derivatives, Potent
`New Agents for the Treatment of Epilepsy.
`Garcia, et
`a1.
`(1984) Tetrahedron Letters, 25(42)
`4841—4844, New Synthetic “Tricks” Triphenylphos-
`phine—Mediated Amide Formation from Carboxylic
`Acids and Azides.
`
`Rebek, et a1. (1979), J. Am. Chem. Soc., 101(3):737, 0n
`the Rate of Site—Site Interactions in Functionalized
`
`Polystyrenes.
`Cortes, et al. (1985) J. Med. Chem, 28:601—606, Effect
`of Structural Modification of the Hydantion Ring on
`Anticonvulsant Activity.
`Ikeda, et al. (1977) Tetrahedron, 33(5): 489—495, Photo-
`
`1,2,3,4-—Tetrahy-
`of
`Synthesis
`chemical
`droisoquinolin-3~ones from N—Chloroacetylbenzyla—
`mines.
`f
`Katritzky, et al. (1990) J. Org. Chem. 55: 2206—2214,
`Benzotriazole—Assisted Synthesis of Monoacyl Animals
`and Their Peptide Derivatives.
`105;
`Lipshutz et al.
`(1983)
`J. Am. Chem. Soc.
`7703—7713, Heterocycles as Masked Diamide/Dipep-
`tide Equivalents, Formation and Reactions of Substi-
`tuted 5-(Acy1amino) Oxazoles as
`Intermediates en
`Route to the Cyclopeptide Alkaloids.
`Lipshutz et al. (1983) J. Org. Chem. 48:3745—3750, An
`Approach to the Cyclopeptide Alkaloids (Phenylcy—
`clopeptines)
`via Heterocyclic Diamide/Dipeptide
`Equivalents, Preparation and N-Alkylation Studies of
`2,4(5)—Disubstituted Imidazoles.
`Rogues, (1987) 193rd ACS National Meeting Amer.
`Chem. Society, Apr. 15—10, 1987, Use of Various Metal-
`lopeptidase Inhibitors to Study the Physilogical Rate of
`Endogenous Neuropeptides.
`Kohn, et al. (1990) J. Med Chem. 33:919—926, Prepara-
`tion and Anticonvulsant Activity of a Series of Funcg
`tionalized ,B—Aromatic and a Heteroaromatic Amino
`Acids.
`
`. Imidaz-
`.
`Lipshutz et al. “Heterocycles in Synthesis .
`oles” Journal of the American Chemical Society, vol.
`106, No. 2, pp. 457—459 CA 102(19): 160030n (1985)._
`
`|PR2014-01126— Exhibit 1008, p. 2
`
` IPR2014-01126- Exhibit 1008, p. 2
`
`
`
`
`

`

`1
`
`5,378,729
`
`AMINO ACID DERIVATIVE ANTICONVULSANT
`
`This invention was made with Government support
`under NS15604 awarded by the National Institutes of
`Health. The vaernment has certain rights in the in-
`vention.
`T:
`
`5
`
`The present.application is a continuation-in-part of
`copending U.S. patent application Ser. No. 07/354,057
`filed on May 9, 1989 and a CIP of U.S. patent applica-
`tion Ser. No. 07/392,870 filed on Aug. 11, 1989 both
`now abandoned. U.S. patent application Ser. No.
`07/354,057 filed on May 19, 1989, now abandoned being
`a continuation-impart of U.S. patent application having
`Ser. No. O7/080,528, filed on Jul. 31, 1987 now aban-
`doned, which is a continuation-in-part of U.S. patent
`application Ser. No. 06/916,254, filed Oct. 7, 1986, now
`abandoned which is a continuation-in-part of U.S. pa-
`tent application Ser. No. 06/702,195, filed Feb. 15, 1985
`now abandoned said U.S. patent application Ser. No.
`07/392,870 filed Jul. 11, 1989, abandoned being a con-
`tinuation application of U.S. patent application having
`Ser. No. O7/080,528, filed on Jul. 31, 1987, now aban-
`doned, which is a continuation-in—part of U.S. patent
`application Ser. No. 06/916,254, filed Oct. 7, 1986, now
`abandoned, which is a continuation-in—part of U.S. pa-
`tent application Ser. No. 06/702,195 filed on Feb. 15,
`1985 now abandoned.
`
`invention relates to compounds and
`The present
`pharmaceutical compositions having central nervous
`system (CNS) activity which are useful in the treatment
`of epilepsy and other CNS disorders. More specifically,
`the compounds of this invention can be characterized as
`protected amino acid derivatives having the following
`general formula:
`
`Iliz
`R—NHffi—fNHiglcl—Rl
`0 R3
`0
`
`R is hydrogen, lower alkyl, lower alkenyl, lower
`alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocy—
`clic lower alkyl, lower alkyl heterocyclic, lower cyclo-
`alkyl, lower cycloalkyl lower alkyl, and R is unsubsti-
`tuted or is substituted with at least one electron with-
`
`drawing 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 het-
`erocyclic, lower cycloalkyl,
`lower cycloalkyl lower
`alkyl, or Z—Y wherein R2 and R3 may be unsubstituted
`or substituted with at least one electron withdrawing
`group or electron donating group;
`Z is O, S,S(O)a, NR4, PR4 or a chemical bond;
`Y is hydrogen, lower alkyl, aryl, aryl lower alkyl,
`lower alkenyl, lower alkynyl, halo, heterocyclic, heter-
`ocyclic lower alkyl, lower alkyl and Y may be unsubsti-
`tuted 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
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`2
`is NR4NR5R7, NR40R5,
`together
`ZY taken
`0NR4R7, 0PR4R5, PR40R5, SNR4R7, NR45R7,
`SPR4R5 or PR4$R7, NR4PR5R6 or PR4NR5R7,
`
`NR4C—R5,
`II0
`
`SCRs,
`II
`0
`
`NR4C—OR5,
`ll
`0
`
`50—0125
`ll
`0
`
`R4, R5 and R5 are independently hydrogen, lower
`alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower
`alkynyl, wherein R4, R5 and R5 may be unsubstituted or
`substituted with an electron withdrawing group or an
`electron donating group and
`R7 is R5 or COORg or CORg
`R3 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
`n is 1—4 and
`a is 1—3.
`
`The predominant application of anticonvulsant drugs
`is the control and prevention of seizures associated with
`epilepsy or related central nervous system disorders.
`Epilepsy refers to many types of recurrent seizures
`produced by paroxysmal excessive neuronal discharges
`in the brain; the two main generalized seizures are petit
`mal, which is associated with myoclonic jerks, akinetic
`seizures, transient loss of consciousness, but without
`convulsion; and grand mal which manifests in a continu-
`ous series of seizures and convulsions with loss of con-
`sciousness.
`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 major-
`ity of these compounds are characterized by the pres-
`ence 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 develop-
`ment of anticonvulsant drugs and today many such
`drugs are well known. For example, the hydantions,
`such as phenytoin, are useful in the control of general-
`ized seizures and all forms of partial seizures. The ox-
`azolidinediones, such as trimethadione and parametha-
`dione, are used in the treatment of nonconvulsive sei-
`zures. 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 All-
`geier, et al. disclose esterified diazepine derivatives
`useful 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][1,4]diazepine compound also
`having anticonvulsant activity and other depressant
`activity. U.S. Pat. No. 4,209,516 to Heckendom, et a1.
`relates to triazole derivatives which exhibit anticonvul-
`
`sant activity and are useful in the treatment of epilepsy
`and conditions of tension and agitation. U.S. Pat. No.
`4,372,974 to Fish, et al. discloses a pharmaceutical for-
`mulation 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 treat-
`ment of convulsion disorders and also possess anxiolytic
`and sedative properties.
`
`|PR2014-01126- Exhibit 1008, p. 3
`
` IPR2014-01126- Exhibit 1008, p. 3
`
`
`
`
`

`

`5,378,729
`
`3
`Unfortunately, despite the many available pharmaco-
`therapeutic agents, a significant percentage of the popu-
`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 disgrbing side-effects. Clearly, current ther-
`apy has failedito “seize control” of these debilitating
`diseases.
`_
`
`It is therefore one object of the present invention to
`provide novel compounds exhibiting CNS activity,
`particularly anticonvulsant activity.
`Another object of this invention is to provide phar-
`maceutical compositions useful in the treatment of epi-
`lepsy and other CNS disorders.
`A further object of this invention is to provide a
`method of treating epilepsy and related convulsant dis-
`orders.
`
`These and other objects are accomplished herein by
`providing compounds of the following general formula:
`
`1:2
`R—NHffi—(fmigfi—Rl
`0 R3
`0
`
`wherein R, R1, R2, R3, R4, R5, R5, R7, R3, n, Z, Y are as
`defined hereinabove.
`
`The present invention contemplates employing the
`compounds of Formula I in compositions of pharma-
`ceutically acceptable dosage forms. Where the appro—
`priate substituents are employed, the present invention
`also includes pharmaceutically acceptable addition
`salts. Moreover,
`the administration of an effective
`amount of the present compounds, in their pharmaceuti—
`cally acceptable forms or the addition salts thereof, can
`provide an excellent regime for the treatment of epi-
`lepsy, 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, phenbu—
`tyl, 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 encompass bicyclic,
`tricyclic
`fused aromatic ring system containing from 10—18 ring
`carbon atoms and up to a total of 25 carbon atoms. The
`aryl group includes phenyl, and the polynuclear aro-
`matics 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, pro-
`penyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-
`2-pentenyl,
`(E)-2-pentenyl,
`(Z)—4-methyl-2-pentenyl,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4s
`
`50
`
`55
`
`65
`
`4
`(E-)—4—methyl-2-pentenyl, pentadienyl, e.g., 1,3 or 2,4-
`pentadienyl, and the like.
`The term alkynyl include alkyene substituents con~
`taining 2 to 6 carbon atoms and may be straight chained
`as well as branched. It includes such groups as ethynyl,
`propynyl, l-butynyl, 2-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 combina-
`tion 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, tricy—
`clic, or polycyclic and the rings are fused. The cycloal-
`kyl may be completely saturated or partially saturated.
`Examples include cyclopropyl, cyclobutyl, cyclopen~
`tyl, cyclohexyl, cycloheptyl, cyclooctyl, cycIodecyl,
`cyclohexenyl, cyclopentenyl, cyclooctenyl, cyclohep—
`tenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pine—
`nyl, 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 sys-
`tems.
`
`The term “electron—withdrawing and electron donat-
`ing” 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 mole-
`cule. 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 discussion therein is incorporated
`herein by reference. Electron withdrawing groups in—
`clude halo, including br
`.0, fluoro, chloro, iodo and
`the like; nitro, carboxy,
`JWCI‘ alkenyl, lower alkynyl,
`formyl, carboxyamido,
`iryl, quaternary ammonium,
`trifluoromethyl, aryl lower alkanoyl, carbalkoxy 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 alkylmercapto, disulfide (lower alkyldithio) and
`the like. One skilled in the art will appreciate that the
`aforesaid substituents may have electron donating or
`electron withdrawing properties under different chemi-
`cal conditions. Moreover, the present invention con-
`templates any combination of substituents selected from
`the above-identified groups.
`The term halo includes fluoro, 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 heterocy-
`clic substituents contemplated by the present invention
`include heteroaromatics and saturated and partially
`saturated heterocyclic compounds. These heterocyclics
`may be monocyclic, bicyclic, tricyclic or polycyclic
`and are fused rings. 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 benzoheterocy-
`cles. Representative heterocyclics include furyl,
`thi-
`enyl, 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, imidazolinylnriaaéflszlid'aademrqléna p. 4
`
` IPR2014-01126- Exhibit 1008, p. 4
`
`
`
`
`

`

`5,378,729
`
`6
`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, J and G are hetero-
`atoms.
`
`5
`nyl, furazanyl, N-methylindolyl, methylfuryl, pyridazi-
`nyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino,
`oxetanyl, azetidinyl, the N-oxides of the nitrogen con-
`taining heterocycles, such as the nitric oxides of pyri-
`dyl, pyrazinyl, and pyrimidinyl and the like. The pre-
`ferred heterocghc are thienyl, furyl, pyrrolyl, benzofu-
`ryl, benzothieiiyl,
`indolyl, methylpyrrolyl, morpholi—
`nyl, pyridyl, _pyrazinyl,
`imidazolyl, pyrimidinyl, or
`pyridazinyl. The preferred heterocyclic is a 5 or 6-mem-
`bered heterocyclic compound. The especially preferred
`heterocyclic is fury], pyridyl, pyrazinyl,
`imidazolyl,
`pyrimidinyl, or pyridazinyl. The most preferred hetero-
`cyclic is furyl 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, espe-
`cially 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, alkan-
`oyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalk-
`oxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocy—
`clic, guanidine, quaternary ammonium, lower alkenyl,
`lower alkynyl, sulfonium salts, hydroxy, lower alkoxy,
`lower alkyl, amino, lower alkylamino, difloweralkyl-
`)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 R1,
`R2, R3, R4, R5 or R5, R7 or R3 as defined 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-
`amino;
`trialkyl ammonium salt, hydrazino, alkylhy—
`drazino and arylhydrazino, such as N-methylhydrazino,
`N—phenylhydrazino, carbalkoxy hydrazino, aralkox-
`ycarbonyl hydrazino, aryloxycarbonyl hydrazino, hy-
`droxylamino, such as N—hydroxylamino (—NH—OH),
`lower alkoxy amino [(NHOng) wherein R13 is lower
`alkyl], N—lower alkylhydroxyl
`amino
`[(NR18)OH
`wherein R13 is lower alkyl], N-lower alkyl-O-lower
`alkyl hydroxyamino, i.e., [N(R18)OR19 wherein R13 and
`R19 are independently lower alkyl] and o-hydrox-
`ylamino (—O——NH2); alkylamido such as acetamido,
`trifluoroacetamido,
`lower
`alkoxyamino,
`(e.g.
`NH(OCH3);
`and
`heterocyclicamino,
`such
`as
`pyrazoylamino.
`The hetereocyclic groups representative of R2 and
`R3 have the formula
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4s
`
`50
`
`55
`
`If the ring depicted hereinabove contains a 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 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.
`It is preferred that one of R2 and R3 is hydrogen
`In a preferred embodiment, one of R2 and R3 is hy-
`drogen and that the other is heterocyclic. It is preferred
`that one of R2 and R3 is a heterocyclic having Formula
`XI. The preferred heterocyclics include furyl, thienyl,
`benzothienyl, benzofuryl, oxazolyl, thiazolyl, isoxazo-
`lyl,
`indolyl, pyrazolyl,
`isoxazolidinyl, benzothienyl,
`benzofuryl, morpholinyl,
`indolyl, pyrrolyl, furfuryl,
`and methylpyrrolyl, pyridyl, pyrazinyl,
`imidazolyl,
`pyrimidinyl or pyridazinyl. In another preferred em-
`bodiment, one of R2 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 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 alkylhydrox—
`yamino,
`lower alkoxyamino, N-lower alkyl-O-lower
`alkylhydroxyamino or aralkoxycarbonylhydrazino,
`Preferred compounds of the present invention have
`the following general formula:
`
`A
`
`’"
`
`Iliz
`CH2NHC— CNHC—R1
`III"
`0R30
`
`wherein R1 is H or lower alkyl, R2 and R3 are as defined
`above and A is hydrogen or an electron donating group
`or electron-withdrawing group and m is 0—5. It is pre-
`ferred that A is hydrogen (i.e., m=0). However, values
`of m equalling 1, 2 or 3 are also preferred.
`Preferred embodiments include compounds of For-
`mula I
`
`1'12
`R—NH-f‘ICII‘CIINHigfi—Rl
`0 R3
`0
`
`(I)
`
`wherein R and R1, independently, are hydrogen, lower
`alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl,
`aryl, heterocyclic, lower alkyl heterocyclic, each un-
`substituted 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 hav—
`ing Formula I
`|PR2014-01126— Exhibit 1008, p. 5
`
`XI
`
`A
`
`E/ \J
`'6 GT
`\ /
`(CH)n
`
`or those corresponding partially or fully saturated form
`thereof wherein n is 0 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
`consisting of N, O and S,
`
`65
`
` IPR2014-01126- Exhibit 1008, p. 5
`
`
`
`
`

`

`7
`
`1'12
`_
`R—NHi-fi—(IZNHigfi-Rl
`0 R3
`0
`
`5,378,729
`
`(I)
`
`8
`Another preferred embodiment is a compound of
`Formula I
`
`wherein R is aryl, aryl lower alkyl, heterocyclic, lower
`alkyl 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;
`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 un-
`substituted 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 inven-
`tion is a compound of Formula I
`
`Ifz
`R‘-NHfT?—?Nflfl;fi"R1
`0 R3
`0
`
`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, car-
`boxyl, carboalkoxy, carboxamide, cyano, sulfonyl, sulf-
`oxide (sulfmyl), heterocyclic, guanidine, quaternary
`ammonium hydroxy, alkoxy, alkyl, amino, phenoxy,
`mercapto, sulfide or disulfide;
`R1 is H or lower alkyl which may be unsubstituted or
`substituted with at least one halo, nitro, acyl, carboxam-
`ide, cyano, sulfonyl, sulfoxide (sulfinyl), heterocyclic,
`guanidine, quaternary ammonium, hydroxy, lower alk-
`oxy, amino, phenoxy, sulfide, or disulfide;
`R2 is hydrogen, lower alkyl, lower alkenyl, lower
`alkynyl, aryl, heterocyclic, lower alkyl heterocyclic,
`polynuclear aromatic,
`lower alkyl polynuclear aro-
`matic, each unsubstituted or substituted with at least
`one electron withdrawing substituent or at least one
`electron 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,
`polynuclear aromatic,
`lower alkyl polynuclear aro—
`matic, each unsubstituted or substituted with at least
`one electron withdrawing substituent or at least one
`electron 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;
`and n is 1 to 4;
`
`11(2
`R—NH-EIClI—(llNHigfi—m
`0 R3
`0
`
`(1)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`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 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, heterocyclic lower alkyl, or Z—Y wherein
`R2 and R3 may be unsubstituted or substituted with at
`least one electron withdrawing group or electron do-
`nating group;
`Z is O, S,S(O)a, NR4, PR4 or a chemical bond;
`Y is hydrogen, lower alkyl, aryl, aryl lower alkyl,
`lower alkenyl, lower alkynyl, heterocyclic, heterocy-
`clic lower alkyl, or halo and Y may be unsubstituted or
`substituted with an electron donating group or an elec-
`tron withdrawing group, provided that when Y is halo,
`Z is a chemical bond, or
`is NR4NR5R7,
`ZY taken
`together
`ONR4R7, OPR4R5, PR40R5, SNR4R7,
`SPR4R5 or PR4$R7, NR4PR5R5 or PR4R5R7,
`
`NR40R5,
`NR4$R7,
`
`NR4CR5,
`||
`O
`
`SCRs,II
`
`O
`
`NR4C0R5,
`II0
`
`SC—ORs
`ll0
`
`lower
`R4, R5 and Rare independently hydrogen,
`alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower
`alkynyl, wherein R4, R5 and R6 may be unsubstituted or
`substituted with an electron withdrawing group or an
`electron donating group-and
`R7 is R6 or COORg or CORs, R3 is hydrogen or lower
`alkyl, or aryl lower alkyl, wherein the aryl or lower
`alkyl groups may be unsubstituted or substituted with
`an electron withdrawing or electron donating group,
`n is 1—4 and
`a is 1—3.
`
`50
`
`Another class of preferred compounds of the For—
`mula I have the formula
`
`55
`
`65
`
`1112
`R—NHi-fi—(IDNH-jgfi—m
`0 R3
`0
`
`wherein R is aryl, aryl lower alkyl, heterocyclic or
`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 alken
`nyl, lower alkynyl, aryl, aryl lower alkyl, Z-Y or a
`heterocyclic group which may be unsubstituted or sub-
`stituted with at least one elfisggén hymvgpfgbgqegg p. 6
`
` IPR2014-01126- Exhibit 1008, p. 6
`
`
`
`
`

`

`5,378,729
`
`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 n is 1, the compounds of the
`present invention is of the formula
`
`I!“ l ‘u’
`R—NH_fi—(I:—N—C—Rl
`0 R3
`
`wherein R, R1, R2, R3, R4, R5, R5, Z and Y are as de-
`fined previously. As used herein, the term configuration
`shall refer to the configuration around the carbon atom
`to which R2 and R3 are attached, even though other
`chiral centers may be present in the molecule. There-
`fore, when referring to a particular configuration, such
`as D or L, it is to be understood to mean the stereoiso-
`
`mer, including all possible enantiomers and diastereo-
`mers. The compounds of the present invention are di-
`rected to all of the optical isomers, i.e., the compounds
`of the present invention are either the L—stereoisomer or
`the D-stereoisomer. These stereoisomers may be found
`in mixtures of the L and D stereoisomer, e.g., racemic
`mixtures. The D 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 including mixtures of the stereoisomeric
`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.
`
`Schemel
`
`lilz
`excess
`SOCIZ
`HOOC“$—NH2 W m9
`R3
`
`0
`0
`0 R2
`ll
`ll
`H
`I
`R1C—O—C-R1
`R—NH—C-(IZ—NH2 —————%
`R3
`
`0 R2
`II
`I
`RHN—C—(IE—NH-fi-Rl
`R3
`0
`
`Scheme II
`o 0
`0
`R2
`II
`II
`R2
`I!
`|
`R1COCR1
`l
`HOOC—(IZ—NH2 ———9 HOOC—(IE-NH—CRl
`R3
`R3
`
`0 l
`
`l
`ClCOR17
`tertiary amine
`
`|PR201 -01126— Exhibit 1008. p. 7
`
`10
`
`15
`
`2O
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`9
`electron donating group, with the proviso that R2 and
`R3 cannot both be hydrogen;
`Z is O, S, NR4, PR4 or a chemical bond;
`Y is hydrogen, lower alkyl, aryl, aryl lower alkyl,
`lower alkenyl, lower alkynyl or halo, and Y may be
`unsubstituted gr substituted with an electron donating
`group or an electron withdrawing group, provided that
`when Y is halo, Z is a chemical bond; or
`ZY taken
`together
`is NR4NR5R5, NR40R5,
`0NR4R5, OPR4R5, PR40R5, SNR4R5, NR45R5,
`SPR4R5, or PR4$R5, NR4PR5R5 or PR4NR5R5,
`R4, R5 and R5 are independently hydrogen, lower
`alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower
`alkynyl, wherein R4, R5 and R5 may be unsubstituted or
`substituted with an electron withdrawing group or an
`electron donating group;
`n is 1—4.
`
`Of this preferred group, it is especially preferred that n
`is 1.
`
`The preferred compounds are those in which R is
`aryl, aryl lower alkyl, heterocyclic, or heterocyclic
`lower alkyl, R1 is hydrogen or lower alkyl, R2 and R3
`are independently hydrogen, heterocyclic, lower alkyl,
`aryl,
`lower alkoxy,
`lower alkenyl, amino, hydrox-
`ylamino, lower alkoxy amino, N—lower alkyl hydroxy—
`amino, N—lower alkyl-O-lower alkyl hydroxyamino,
`aralkoxy carbonyl hydrazino or alkylmercapto and n is
`1.
`
`In another preferred emb