`Kohn et al.
`
`1111m1n1111111~1 Ill I~~ 11111 ~II Ull llllll Ill lllll IUI
`5,654,301
`Aug. 5, 1997
`
`US005654301A
`Patent Number:
`Date of Patent:
`
`[11]
`
`[45]
`
`[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] Appl. No.: 3,208
`Jan. 12, 1993
`
`[22] Filed:
`
`Related U.S. 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(cid:173)
`partofSer. 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(cid:173)
`ation-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.
`
`[30)
`
`Foreign Application Priority Data
`
`[51]
`
`Jun. 4, 1992 [WO] WIPO ····························- US92/04687
`Int. Cl.6
`
`···-··············-··· A61K 31/445; A61K 31134;
`C07D 21ln2; C07D 261/04
`[52] U.S. 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; 5141315,
`357' 461, 406. 548, 424, 415, 549, 618,
`486, 231.2; 546/252, 152, 154
`
`[56]
`
`References Cited
`
`U.S. P.!ITENT DOCUMENTS
`
`2,676,188
`2,721,197
`3,340,147
`3,657,341
`3,707,559
`4,018,826
`4,260,684
`4,303,673
`4,372,974
`4,513,009
`4,595,700
`4,618,708
`4,873,241
`5;378,729
`
`4/1954 Bruce et al. ······-······--·····-·· 424/319
`10/1955 Sheehan .................................. 564/155
`9/1967 Martin et al. ........................... 514/616
`4/1972 Thome et al. ..•....•...••......... 260/558 A
`1211972 Mazur et al. ........................... 564/158
`4/1977 Gless, Jr. et al .••..•••..•.•........... 5641215
`4/1981 Schult .....................•............... 564/155
`12/1981 Biedermann et al .•.•....•.......... 564/155
`2/1983 Fish et al. ............................... 2601559
`4/1985 Roques et al ..
`6/1986 Donald et al .•..............•..•..•.... 514/616
`10/1986 Roques et al .........................•• 564/154
`10/1989 Napier et al ............................ 5641215
`111995 Kohn et al ........................... 514/2312
`
`FOREIGN PJITENT DOCUMENTS
`
`0885303
`0007441
`0194464
`0038758
`0042626
`0046707
`
`3/1981
`2/1980
`211980
`10/1981
`12/1981
`3/1982
`
`Belgium.
`European Pat. Off ..
`European Pat. Off ..
`European Pat. Off ..
`European Pat Off. .
`European Pat. Off ..
`
`Breckenridge Exhibit 1019
`Breckenridge v. Research Corporation Technologies, Inc.
`
`0263506 1011987 European Pat. Off ..
`5/1990 European Pat. Off ..
`0400400
`1927692 1211969 Germany .
`0393355 10/1965 Switzerland .
`1051220 12/1966 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Remington, Phannaceutical 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
`Stereospecificity in a New Oass of Anticonvulsants.
`Chemical Abstracts, vol. 97;145266d (1982).
`Chemical Abstracts, vol. 89; 129286q; Zafloukal, et al.
`(1978).
`White, et al. (1981) JACS, 103:4231-4239, Active-Site-Di(cid:173)
`rected Inhibition of alpha-Chymotrypsin by Deaminatively
`Produced Carbonium Ions: An Example of Suicide of
`Enzyme-Activated-Substrate Inhibition.
`Legall, et al. (1988) Int. J. Protein Res .. 32:279-291 Syn(cid:173)
`thesis of Functionalized Non-Natural Amino Acid Deriva(cid:173)
`tives via Amidoalkylation Transformations.
`Cortes, et al. (1985) J. Med. Chem., 28:601-606, Effect of
`Structural Modification of the Hydantion Ring on Anticon(cid:173)
`vulsant Activity;
`Ikeda, et al. (1977) Tetrahedron, 33(5):489-495, photo(cid:173)
`chemical
`Synthesis
`of
`1,23,
`4-Tetrahydroisoquinolin-3-ones from N-Chloracetylben(cid:173)
`-zylamines.
`Conley, et al. (1987) J. Med. Chem., 30(3): 567-574 Func(cid:173)
`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 Site-Site Interactions in Functionalized Polysty(cid:173)
`renes.
`Katritzky, et al. (1990) J. Org. Chem., 55:2206-2214, Ben(cid:173)
`zotrialzole;-Assisted Synthesis of Monacyl Animals and
`Their Peptide Derivatives.
`Llpshutz, et al. (1983) J. Am. Chem. Soc., 105:7703-7713,
`Heterocycles as masked Diamideillipeptide Equivalents.
`Formation and Reactions of Substituted 5-(Acylamino)ox(cid:173)
`azoles as Intennid.iates en route to the Cyclopeptide Alka(cid:173)
`ioids.
`
`(List continued on next page.)
`
`Primary Examiner-Theodore J. Glares
`Attorney, Agent; or Finn-Scully, Scott, Murphy & Presser
`
`[57]
`
`ABSTRACT
`
`The present invention relates to compounds of the formula
`
`Ri
`I H
`H
`R-N(C-C-N).C-R1
`I
`II
`ll
`Q R3
`A
`
`47 Claims, No Drawings
`
`-1-
`
`
`
`5,654,301
`Page 2
`
`OTHER PUBLlCXI'IONS
`
`Llpshutz. et al. (1993) J. Org. Chem., 48:3745-3750, An
`Approach to the Cyclo---peptide Alkaloids (Phencycopep(cid:173)
`tines) via Heterocyclic Diamide/Dipeptide Equivalents.
`Preparation and N-Allcylation Studies of 2.4(5)-Disubsti(cid:173)
`tuted Irnidazoles.
`Roques, 91987) 193rdACS National Meeting.Amer. Chem.
`Soc .. Apr. 5-10. 1987 Use of Various Metallopeptides
`
`Inhibitors to Study the Physiological Role of Endogenous
`Neuropetides.
`Kohn, et al. (1990) J. Med. Chem., 33:919-926. Preparation
`and Anticonvulsant Activity of a Series of Punctionalized
`a-Aromatic and a.-Heteroaromatic Amino Acids.
`Lipshutz, et al. JACS, 106(2):457-459, "Heterocycles in
`Synthesis ... Imidazoles" (1984).
`Kohn. et al. (1988) Chemistry in Britain, pp. 231-233, New
`Antiepileptic Agents.
`
`-2-
`
`
`
`5,654,301
`
`1
`AMINO ACID DERIVATIVE
`ANTICONVULSANT
`
`2
`'ZY taken together is NR4NRsR7 , NR4 0R5 , ONR4R7,
`OPR4Rs, PR40R5, SNR4~, NR4S~, SPR4R 5 , PR4S~,
`NR4PRs~ PR4NRsR7 •
`
`NR..iC-Rs, SCRs, NR,C-ORs, SC-ORs, NJ4CNR5R,;,
`II
`II
`II
`II
`II
`0
`0
`0
`0
`0
`
`NR.CNR5S(O).R,;, NR.CNRsR,;, NR.CMNRsCOR,; or C-NHi,
`II
`II
`II
`II
`II
`Q
`0
`S
`A
`S
`
`RELPJED APPUCATIONS
`The present application is a continuation-in-part of U.S. 5
`patent application Ser. No. 710,610 filed 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 filed 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 IO
`application Ser. No. 354,057 is a continuation-in-part of
`U.S. patent application having Ser. No. 080.528. filed on Jul.
`31. 1987. now abandoned, which is a continuation-in-part of
`U.S. patent application Ser. No. 916,254, filed Oct. 7, 1986,
`now abandoned which is a continuation-in-part of U.S. 15
`patent application Ser. No. 702,195, filed 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,filedJul. 31.1987, now abandoned, which
`is a continuation-in-part of U.S. patent application Ser. No. 20
`916.254 filed Oct. 7, 1986, now abandoned which is a
`continuation-in-part of U.S. patent application Ser. No.
`702,195 filed on Feb. 15, 1985, now abandoned.
`This invention was made with Government support under
`NS15604 awarded by the National Institutes of Health. The 25
`Government has .certain rights to this invention.
`
`R2
`I
`R-NH.Y.,C-CNHf.:-C-R1
`I
`II
`"II
`Q R3
`A
`
`R4, R5 and ~ are independently hydrogen, lower alkyl.
`aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl.
`wherein R4 , R5 and R6 may be unsubstituted or sub(cid:173)
`stituted with an electron withdrawing group or an
`electron donating group and
`R7 is ~ 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 Qare independently 0 or S, Mis an alkylene chain
`containing up to 6 carbon atoms or a chemical bond;
`n 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
`BACKGROUND OF THE INVEN'TION
`refers to many types of recurrent seizures produced by
`The present invention relates to compounds and pharma-
`ceutical compositions having central nervous system (CNS) 30 paroxysmal excessive neuronal discharges in the brain; the
`activity which are useful in the treatment of epilepsy and
`two main generalized seizures are petit mal, which is asso-
`other CNS disorders. More specifically, the compounds of
`ciated with myoclonic jerks, akinetic seizures, transient loss
`this invention can be characterized as protected amino acid
`of consciousness, but without convulsion; and grand mal
`derivatives of the formula:
`which manifests in a continuous series of seizures and
`35 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
`40 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
`45 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(cid:173)
`one and paramethadione, are used in the treatment of non-
`50 convulsive seizures. Phenacemide, a phenylacetylurea, is
`one of the most well known anticonvulsants employed
`today, while much attention bas 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
`55 Allgeier, et al. disclose esteri:fied diazepine derivatives use(cid:173)
`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][L4]diazepine compound also having anticon(cid:173)
`vulsant activity and other depressant activity. U.S. Pat. No.
`60 4,209,516 to Heckendorn, et al. relates to triazole derivatives
`which exhibit anticonvulsant activity and are useful in the
`treatment of epilepsy and conditions of tension and agita(cid:173)
`tion. U.S. Pat. No. 4322,974 to Fish. et al. discloses a
`pharmaceutical formulation containing an aliphatic amino
`65 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
`
`or the N-o:xides thereof or pharmaceutically 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;
`R 1 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, S03 - 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 0, 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, heterocyclic
`lower alkyl, cycloalkyl, cycloalkyl lower alkyl and Y 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
`
`-3-
`
`
`
`5,654,301
`
`10
`
`Rz
`I
`R-NH-t-C-CNHJ:-C-R1
`I
`II
`"II
`Q R3
`A
`
`3
`treatment of convulsion disorders and also possess anxi(cid:173)
`olytic and sedative properties.
`Unfortunately, despite the many available pharmacothera(cid:173)
`peutic agents, a significant percentage of the population with
`epilepsy or related disorders are poorly managed. Moreover, 5
`none of the drugs presently available are capable of achiev(cid:173)
`ing total seizure control and most have disturbing side(cid:173)
`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(cid:173)
`larly anticonvulsant activity.
`Another object of this invention is to provide pharmaceu(cid:173)
`tical compositions useful in the treatment of epilepsy and
`other CNS disorders.
`A further object of this invention is to provide a method 15
`of treating epilepsy and related convulsant disorders.
`These and other objects are accomplished herein by
`providing compounds of the following general formula:
`
`4
`branched. It includes such groups as ethynyl, propynyl,
`1-butynyl, 2-butynyl, 1-pentynl, 2-pentynyl, 3-methyl-1-
`pentynyl. 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and
`the like.
`The tenn 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 cycloal.1.J'l
`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
`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 J. March, John Wiley
`and Sons, New York N.Y., pp. 16-18 (1985) and the dis(cid:173)
`cussion therein is incorporated herein by reference. Electron
`wherein R. R 1 , R 2 , R,, R4 , R 5 • R 6 , n, z, Y, A and Qare as 25 withdrawing groups include halo, including bromo, fluoro,
`defined hereinabove.
`chloro, iodo and the like; nitro, carboxy, lower alkenyl,
`The present invention contemplates employing the com-
`lower alkynyl, fonnyl, carboxyarnido, aryl, quaternary
`pounds of Fonriula I in compositions of pharmaceutically
`ammonium, trifluoromethyl, aryl lower alkanoyL car-
`acceptable dosage forms. Where the appropriate substituents
`balkoxy and the like. Electron donating groups include such
`are employed. the present invention also includes pharma- 30 groups as hydroxy, lower alkoxy, including methoxy. ethoxy
`and the like; lower alkyl, such as methyl. ethyl, and the like;
`ceutically acceptable addition salts. Moreover, the adminis-
`tration of an effective amount of the present compounds, in
`amino. lower al.1.]'larnino, di(loweralkyl)amino, aryloxy
`their pharmaceutically acceptable forms or the addition salts
`such as phenoxy, mercapto, lower alkylthio, lower
`·thereof, can provide an excellent regime for the treatment of
`alkylmercapto, disulfide (lower al.1.]'lclithio) and the like.
`epilepsy, nervous anxiety, psychosis. insomnia and other 35 One skilled in the art will appreciate that the aforesaid
`related central nervous disorders.
`substituents may have electron donating or electron with-
`The al.1.J'l groups when used alone or in combination with
`drawing properties under different chemical conditions.
`other groups. are lower alkyl containing from 1 to 6 carbon Moreover, the present invention contemplates any combi-
`nation of substituents selected from the above-identified
`atoms and may be straight chain or branched. These groups
`include methyl, ethyl. propyl, isopropyL butyl, isobutyl, 40 groups.
`tertiary butyl, amyl, hexyl, and the like.
`The term halo includes fluoro, chloro, bromo, iodo and the
`The aryl lower all..'Yl groups include. for example, benzyl,
`like.
`phenethyl. phenpropyl, phenisopropyl, phenbutyl, and the
`The term acyl includes lower alkanoyl.
`like, diphenylmethyl. 1.1-diphenylethyl, 1,2-diphenylethyl,
`As employed herein, the heterocyclic substituent contains
`and the like.
`45 at least one sulfur, nitrogen or oxygen, but also may include
`The term aryl. when used along or in combination, refers
`one or several of said atoms. The heterocyclic substituents
`to an aromatic group which contains from 6 up to 18 ring
`contemplated by the present invention include heteroaro-
`carbon atoms and up to a total of 25 carbon atoms and
`matics and saturated and partially saturated heterocyclic
`includes the polynuclear aromatics. These aryl groups may
`compounds. These heterocyclics may be monocyclic,
`be monocyclic. bicyclic, tricyclic or polycyclic and are fused 50 bicyclic, tricyclic or polycyclic and are fused rings. They
`rings. Polynuclear aromatic compound is meant to encom-
`may contain up to 18 ring atoms and up to a total of 17 ring
`pass bicyclic, tricyclic fused aromatic ring system contain-
`carbon atoms and a total of up to 25 carbon atoms. The
`ing from 10-18 ring carbon atoms and up to a total of 25
`heterocyclics are also intended to include the so-called
`carbon atoms. The aryl group includes phenyl, and the
`benzoheterocycles. Representative heterocyclics include
`polynuclear aromatics e.g., naphthyl. anthracenyl, 55 furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl,
`phenanthrenyl, azulenyl and the like. The aryl group also
`thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl,
`includes groups like ferrocenyl.
`pyrrolinyl, piperazinyl, quinolyl. triazolyl, tetrazolyl,
`Lower alkenyl is an alkenyl group containing from 2 to 6
`isoquinolyl, benzofuryl, benzothienyl, morpholinyl,
`carbon atoms and at least one double bond. These groups
`benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl,
`may be straight chained or branched and may be in the Z or 60 indolinyl, pyrazolidinyl, irnidazolinyl, imidazolidinyl,
`:B form. Such groups include vinyl. propenyl. 1-butenyl,
`pyrrolidinyl, furazanyl, N-methylindolyl. methylfuryl,
`isobutenyl. 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-
`pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy,
`pentenyl. (Z)-4-methyl-2-pentenyl, (E-)-4-methyl-2-
`aziridino, oxetanyl, azetidinyl. the N-oxides of the nitrogen
`pentenyl, pentadienyl. e.g., 1,3 or 2,4-pentadienyl, and the
`containing heterocycles, such as the nitric oxides of pyridyl.
`like.
`65 pyrazinyl, and pyrirniclinyl and the likt:. Thi: prefem:<l ht:L-
`The term alkynyl include alkyene substituents containing
`erocyclic are thienyL furyL pyrroly. benzofuryL
`2 to 6 carbon atoms and may be straight chained as well as
`benzothienyl. indolyl, methylpyrrolyl, merpholinyl, pyridyl,
`
`-4-
`
`
`
`5
`pyrazinyl, imidazolyl, pyrimidinyl. pyrazolyl orpyridazinyl.
`The preferred heterocyclic is a 5 or 6-membered heterocy(cid:173)
`clic compound. The especially preferred heterocyclic is
`furyl, pyridyl, pyrazinyl. imidazolyl, pyrazolyl, triazolyl,
`tetrazolyl. oxadiazolyl. epoxy, pyrimidinyl, or pyridazinyl. 5
`The most preferred heterocyclics are furyl. pyrazolyl, pyr(cid:173)
`rolyl and pyridyl.
`The preferred compounds are those wherein n is 1, but di,
`tri and tetrapeptides are also contemplated to be within the 10
`scope of the claims.
`The preferred values of R is aryl lower alkyl. especially
`benzyl. and the preferred R 1 is H or lower alkyl. The most
`preferred R 1 group is methyl.
`The most preferred electron donating substituent and 15
`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. di(loweralkyl)amino, amine lower
`alkyl mercapto, mercaptoalkyl, alkylthio; and alkyldithio.
`The term "sulfide" encompasses mercapto, mercapto alkyl
`and alkylthio. while the term disulfide encompasses alky- 25
`ldithio. These preferred substituents may be substituted on
`any one of R 1 , R 2 • R3 , R4 • Rs or R 6 , R, or Rs as defined
`herein.
`The 'LY groups representative of R 2 and R 3 include
`hydroxy. alkoxy. such as methoxy, ethoxy, aryloxy, such as 30
`phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thio(cid:173)
`aryloxy such as thiophenoxy; amino; alkylamino, such as
`methylamino. ethylamino; arylarnino, such as anilino; lower
`dialkylarnino, such as. dimethylamino; trialkyl ammonium
`salt, hydrazino, alkylhydrazino and arylhydrazino, such as 35
`N-methylhydrazino, N-phenylhydrazino, carbalkoxy
`hydrazino. aralkoxycarbonyl hydrazino, aryloxycarbonyl
`hydrazino, hydroxylamino, such as N-hydroxylamino
`(-NH-OH), lower alkoxy amino [(NHOR18) wherein R 18
`is lower alkyl], N-lower alkylhydroxyl amino [(NCR18)0H
`wherein R 18 is lower alkyl], N-lower alkyl-0-lower alkyl
`hydroxyamino, i.e., [N(R18)0R19 wherein R 18 and R 19 are
`independently lower alkyl] and o-hydroxylarnino (--O-(cid:173)
`NH0; alkylarnido such as acetamido, lrifluoroacetamido, 45
`lower alkoxyamino, (e.g. NH(OCH 3 ); and
`heterocyclicarnino, 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. R 1• R 2 • R3 • R4 , R 5 • R 6 , R,, Rg, n and a are as defined 50
`hereinabove.
`In a still further embodiment, 'ZX may be
`
`NJtiCRs, or SCRs or NJtiC-ORs, orSC-ORs
`II
`II
`II
`II
`0
`0
`0
`0
`
`and R. R 1 , R 2 • R 3 • R 4 • R5 • R 6 , ~, Rg, n and a are as defined
`hereinabove.
`When R 2 or R 3 is heterocyclic. the preferred heterocyclics
`are furyl. tetrahydrofuryl, pyridyl, pyrazinyl, imidazolyl,
`pyrazolyl. triazolyl, tetrazolyl, oxadiazolyl or epoxy. The
`most preferred heterocyclic is furyl, pyridyl. pyrazoyl and
`pyrrolyl.
`The preferred heterocyclic groups representative of R 2
`and R3 have the formula
`
`5,654,301
`
`6
`
`XI
`
`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, 0, S, and
`G is CH, or a heteroatom selected from the group con(cid:173)
`sisting of N, 0 and S,
`but when n is 0, G is CH, or a heterocyclic selected from
`the group consisting of NH, 0 and S with the proviso
`that at most two of A, E. L, J 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 R 3 is a heterocyclic of the above formula, it
`may be bonded to the main chain by a ring carbon atom.
`20 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 S03-, or so2-.
`Furthermore, 'ZY may also be
`
`NR,CNRsRo, NR,CNRsS(0)'1R6, NR.C-NRsR,;, C-NH2 or or
`II
`II
`II
`II
`0
`0
`0
`0
`
`R.CMNRsCOR,;.
`II
`II
`Q
`A
`
`When R 2 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(cid:173)
`erably with an electron withdrawing group, such as COOH.
`As indicated hereinabove, Q and A may be 0 or S; in other
`words, the main chain may contain only C-0, only-C S
`or combinations thereof. All such permutations are contem(cid:173)
`plated herein. It is preferred that the compounds of the
`40 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(cid:173)
`stituted or is substituted with at least one electron withdraw(cid:173)
`ing group or electron donating group and R 1, ~, R 3 , Z, Y
`or 'ZY taken together, R4 , R5, ~. R,, Rg, n and a are as
`defined herein.
`Another embodiment of the present invention include
`compounds of Formula I wherein R 1 is lower cycloalkyl or
`lower cycloalkyl lower alkyl and R1 may be unsubstituted or
`substituted with an electron donating group or electron
`55 withdrawing group and R 1, R 2, R3 , Z, Y. or 'ZX taken
`together, R4 , R 5, R6 , ~. Rg n and a are as defined herein(cid:173)
`above.
`Another embodiment of the present invention includes
`compounds of Formula I wherein R2 is lower cycloalkyl or
`60 lower cycloalkyl lower alkyl and R2 may be unsubstituted or
`substituted with an electron donating group or electron
`withdrawing group, and R, R 1, R 3, R4 , R5 , ~.~.Rs and a
`are as defined hereinabove.
`Still another embodiment of the present invention include
`65 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-
`
`-5-
`
`
`
`5,654,301
`
`5
`
`10
`
`7
`ing group and R. R 1• R2 • R4 • R 5 • R6 , R7 • Rg, n and a are as
`defined hereinabove.
`A further embodiment of the present invention include
`compounds of Formula I wherein Z is S(O)a and R, R 1• R2 •
`R3 • Y. R4 • R5 • ~- R7 • R8 • n and a are as defined herein.
`It is preferred that one of R 2 and R 3 is hydrogen.
`In a preferred embodiment, one of R2 and R 3 is hydrogen
`and that the other is heterocyclic. It is preferred that one of
`R2 and R3 is a heterocyclic having Formula XL The pre(cid:173)
`ferred heterocyclics include fury!, thienyl, benzothienyl,
`benzofuryl, oxazolyl. thiazolyl. isoxazolyl, indolyl,
`pyrazolyL isoxazolidinyl, benzothienyl, benzofuryl,
`morpholinyl. indolyl, pyrrolyl, furfuryl, and methylpyrrolyl,
`pyridyl. pyrazinyl. irnidazolyl, pyrirnidinyl or pyridazinyl,
`pyrazolyl. or epoxy. In another preferred embodiment, one
`of R 2 and R3 is alkyl (e.g. methylisopropyl), aryl (e.g., 15
`phenyl). 2-thiomethylethyl. lower alkoxy (e.g., ethoxy,
`methoxy). anilino. propenyl, alkylarnino (e.g., ethylamino or
`methylamino). In another preferred embodiment. one of R 2
`and R3 is hydrogen and the other is heterocyclic lower alh.'Yl,
`lower alkenyl. amino. lower alkoxy amino, N-lower
`alkylhydroxyarnino. lower alkoxyamino. N-lower al1.')'l-O(cid:173)
`lower alkylhydroxyamino or aralkoxycarbonylhydrazino.
`Preferred compounds of the present invention have the
`following general formula:
`
`20
`
`-O CHzNHC-CNHC-R1
`
`f2
`II
`I
`II
`0 R, 0
`
`Aml
`
`25
`
`30
`
`wherein R1 is I-I or lower alkyl, R2 and R3 are as defined
`above and A is hydrogen or an electron donating group or
`electron-withdrawing group and mis 0-5. It is preferred that
`A is hydrogen (i.e .• m=O). However. values of m equalling 35
`1. 2 or 3 are also preferred.
`Preferred embodiments include compounds of Formula I
`
`Ri
`I
`R-NHf-C-CNHt:-C-R1
`I
`II
`"II
`Q R3
`A
`
`(I)
`
`40
`
`wherein
`Rand R 1• independently, are hydrogen, lower alkyl. lower
`alkenyl. lower alkynyl, aryl lower alkyl, aryl. 45
`heterocyclic. lower alkyl heterocyclic, each unsubsti(cid:173)
`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- 50
`tuted or substituted with at least one substituent; halo(cid:173)
`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 1 to 4.
`Another preferred embodiment is a compound having
`Formula I
`
`55
`
`8
`nuclear aromatic, each unsubstituted or substituted with
`at least one electron withdrawing substituent or at least
`one electron donating substituent;
`R 1 is I-I 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 all..')'l.
`lower alkenyl, lower alkynyl. aryl, aryl lower al1.')'l,
`heterocyclic. lower all.')'l heterocyclic. polynuclear
`aromatic, lower all..71 polynuclear aromatic, each
`unsubstituted or substituted with at least one electron
`donating substituent, halogen or a heteroatom contain(cid:173)
`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 1to4.
`Another preferred embodiment of the present invention is
`a compound of Formula I
`
`Rz
`I
`R-NH(C-CNHt:-C-R1
`I
`II
`"II
`Q R3
`0
`
`wherein
`
`R is aryl lower alkyl, heterocyclic. lower alkyl
`heterocyclic. polynuclear aromatic or lower all')'l poly(cid:173)
`nuclear aromatic, each of which may be unsubstituted
`or substituted with at least one halo. nitro, acyl,
`carboxyl, carboalkoxy, carboxamide. cyano. sulfonyl,
`sulfoxide (sulfinyl), heterocyclic. guanidine. quater-
`nary ammonium hydroxy, alkoxy, alkyl, amino,
`phenoxy, mercapto, sulfide or disulfide;
`R 1 is H or lower alkyl which may be unsubstituted or
`substituted with at least one halo, nitro. acyl,
`carboxamide, cyano. sulfonyl, sulfoxide (sulfinyl),
`heterocyclic, guanidine, quaternary ammonium,
`hydroxy, lower alkoxy, amino, phenoxy, sulfide. or
`disulfide;
`R2 is hydrogen, lower alkyl, lower alkenyL lower alkynyl,
`aryl, heterocyclic, lower alkyl heterocyclic, poly(cid:173)
`nuclear aromatic, lower alkyl polynuclear aromatic,
`each unsubstituted or substituted with at least one
`electron withdrawing substituent or at least one elec(cid:173)
`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 al1.'Yl or aryl groups being
`substituted or unsubstituted;
`R3 is hydrogen, lower alkyl, lower alkenyl. lower alkynyl.
`aryL heterocyclic, lower alkyl heterocyclic. poly(cid:173)
`nuclear aromatic, lower alkyl polynuclear aromatic,
`each unsubstituted or substituted with at least one
`electron withdrawing substituent or at least one elec(cid:173)
`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
`
`Ri
`I
`R-NHf-C-CNHt:-C-R1
`I
`II
`"II
`Q R,
`0
`
`(1) 60
`
`wherein
`R is aryl. aryl lower all..')'1. heterocyclic, lower al1.')'l
`heterocyclic. polynuclear aromatic or lower alkyl poly-
`
`65
`
`I
`
`-6-
`
`
`
`5,654,301
`
`9
`f2
`R-NH+C-CNHi:-C-R1
`II
`I
`"II
`Q R1
`0
`
`(I)
`
`5
`
`NR.,CRs, SCR5, NR.,CORs, SC-OR5
`II
`II
`II
`II
`0
`0
`0
`0
`
`R4 • R5 and R6 are independently hydrogen, lower alkyl.
`aryl. aryl lower alkyl, lower alkenyl, or lower alkynyl,
`wherein R4 , R5 and ~ may be unsubstituted or sub(cid:173)
`stituted with an electron withdrawing group o