UNITED S’I ATES DLPAI(I MLN 1 OF COMMERCE
`
`IJnited States Patent and Trademark Office
`
`January 17, 2013
`
`THIS IS TO CERI IFY THAT ANNEXED HERE I O IS A TRUE COPY FROM
`
`THE RECORDS OF ~IHIS OF!: ICE OF:
`
`U.S, PATENT: 6,248~775
`
`ISSUE DATE: ,hute 19, 2001
`
`By Authority of the
`
`Under Sect,etary of Con~merce for Intellectual Proper~y
`and Director’ of the Umted Statc~ Patent and T~ademark Office
`
`Certit~ing Officer
`
`Lupin Ex. 1003 (Page 1 of 115)
`
`

`
`o2) United States Patent
`Vazquez et al.
`
`(lO) Patent No.: US 6,248,775 B1
`(45) Date of Patent: Jun. 19, 2001
`
`US006248775B1
`
`(54) a- AND [~-AMINO ACID
`HYDROXYETHYLAMINO SULFONAMIDES
`USEFUL AS RETROVIRAL PROTEASE
`INHIBITORS
`
`(75) Inventors:
`
`Michael L. Vazquez, Gurnee; Richard
`A. Mueller, Glencoe, both of IL (US);
`John J. Talley, Brentwood, MO (US);
`Daniel P. Getman, Chestertfield, MO
`(US); Gary A. DeCrescenzo, St. Peters,
`MO (US); John N. Freskos, Clayton,
`MO (US); Deborah E. Bertenshaw,
`Brentwood, MO (US); Robert M.
`Heintz, Ballwin, MO (US)
`
`(73)
`(*)
`
`Assignee: G.D. Searle & Co., Chicago, IL (US)
`
`Notice:
`
`Subject to any di~laimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/288,080
`
`(22) Filed:
`
`Apr. 8, 1999
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 08/294,468, filed on Aug.
`24, 1994, now Pat. No. 5,968,942, which is a continuation-
`in-part of application No. 08/204,827, filed on Mar. 2, 1994,
`now Pat. No. 6,060,476, which is a continuation-in-part of
`application No. PCT/US93/07814, filed on Aug. 24, 1993,
`and a continuation-in-part of application No. 08/110,911,
`filed on Aug. 24, 1993, now Pat. No. 5,843,946, which is a
`continuation-in-part of application No. 07/934,984, filed on
`Aug. 25, 1992, now abandoncd.
`
`(51)
`
`lilt. CI.7 .......................... A61K 31/38; A61K 31/34;
`C07D 333/32; C07D 307/93
`(52) U.S. C! ............................. 514/445; 514/470; 549/65;
`549/465
`(58) Field of Search ..................................... 514/445, 470;
`549/65, 465
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`H725
`4,450,164
`4,477,441
`4,514,391
`4,548,926
`4,599,198
`4,616,088
`4,668,769
`4,668,770
`4,757,050
`4,826,815
`4,880,938
`4,963,530
`
`1/1990 Gordon ................................ 548/533
`5/1984 Bristol et al ......................... 424/256
`10/1984 Boger et al .......................... 424/177
`4/1985 Gordon et al ............................ 514/2
`10/1985 Matsueda et al ...................... 514/19
`7/1986 Hoover .............................. 260/998.2
`10/1986 Ryono et al ......................... 546/336
`5/1987 Hoover ................................. 530/331
`5/1987 Boger et al .......................... 530/331
`7/1988 Natara~an et al ...................... 514/18
`5/1989 Luly et al .............................. 514/19
`11/1989 Freidinger ............................ 548/492
`10/1990 Hemmi et al .......................... 514/19
`
`4,977,277
`5,585,397
`5,723,490
`5,843,946
`5,856,353
`
`12/1990 Rosenberg et al ................... 549/215
`12/1996 Tung et al ........................... 514/473
`3/1998 Tung .................................... 514/476
`12/1998 Vazquez et al ...................... 514/252
`1/1999 Tung et al ........................... 514/473
`
`FOREIGN PATENT DOCUMENTS
`
`79823/87
`104041
`114993
`172347
`223437
`0 264 795
`337714
`0 342 541
`0 346 847
`356223
`389898A2
`393445
`393457
`402646
`468641
`2 184 730
`2 200 115
`2 209 752
`WO84/031N4
`92/08699
`94/04492
`W094/05639
`WO 99/33792
`
`4/1988
`3/1984
`6/1984
`2/1986
`5/1987
`4/1988
`10/1989
`11/1989
`12/1989
`2/1990
`10/1990
`10/1990
`10/1990
`12/1990
`1/1992
`7/1987
`7/1988
`8/1989
`8/1984
`5/1992
`3/1994
`3/1994
`4/1999
`
`(AU).
`(~V).
`(EP).
`(EP).
`(~V).
`(EP)
`(EP)
`(EP)
`(EP)
`(EP)
`(EP)
`(EP)
`(EP)
`(EP)
`(EP)
`(OB).
`(GB).
`(OB).
`(wo).
`(wo).
`6vo).
`(wo).
`(wo).
`
`OTHER PUBLICATIONS
`
`Roberts et al, "Rational Design of Peptide-based Proteinase
`Inhibitors," Science, 248, 358 (1990).
`Erickson et al, "Design Activity and 2.8A Crystal Structure
`of a Cz Symmetric Inhibitor Complexed to HIV-1 Pro-
`tease," Science, 249 527 (1990).
`Pearl et al, "Sequence specificity of retroviral proteases,"
`Nature, 328 (1987).
`Martin, Drugs of the Future, 16(3), 210-212 (1991).
`Meek et al, Letter to Nature, 343, 90-92 0990).
`McQuade et al, "A Synthetic HIV-1 Protease Inhibitor with
`Antiviral Activity Arrests HIV-like Particle Maturation,"
`Science, 247, 454-456 (1990).
`Rich et al, "Peptide lnhibitors of Proteases," Design of
`Protease Inhibitors 511-520 0984).
`Rosenberg et al J. Med. Chem., 30, 1224-1228 (1987).
`
`* cited by examiner
`
`Primary Examiner---Deborah C. Lambkin
`(74) Attorney, Agent, or Firm~anner & Witcoff, Ltd.
`
`(57)
`
`ABSTRACT
`
`a- and [3-amino acid hydroxyethylamino sulfonamide com-
`pounds are effective as retroviral protease inhibitors, and in
`particular as inhibitors of HIV protease.
`
`18 Claims, No Drawings
`
`Copy provided by USPTO from the PIRS Image Database on 01110/2013
`
`Lupin Ex, 1003 (Page 2 of 115)
`
`

`
`US 6,248,775 B1
`
`1
`a- AND D-AMINO ACID
`HYDROXYETHYLAMINO SULFONAMIDES
`USEFUL AS RETROVIRAL PROTEASE
`INHIBITORS
`
`RELATED APPLICATION
`
`This application is a continuation of Ser. No. 08/294,468
`filed Aug. 24, 1994, U.S. Pat. No. 5,968,942, which is a
`continuation in part application of U.S. patent application
`Set. No. 08/204,827 filed Mar. 2, 1994 now U.S. Pat. No.
`6,060,476, which is a continuation in part application of
`PCT/US93/07814, and Set. No. 08/110,911 (now U.S. Pat.
`No. 5,843,946) both, filed Aug. 24, 1993, which is a con-
`tinuation in part application of co-owned U.S. patent appli-
`cation Ser. No. 07/934,984 filed Aug. 25, 1992, now
`abandoned, each of which is incorporated herein by refer-
`ence in its entirety.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The present invention relates to retroviral protease inhibi-
`tors and, more particularly, relates to novel compounds and
`a composition and methed for inhibiting retroviral proteases.
`This invention, in particular, relates to suifonamide-
`containing hydroxyethylamine protease inhibitor
`compounds, a composition and method for inhibiting retro-
`viral proteases such as human immunodeficiency virus
`(HIV) protease and for treating a retroviral infection, e.g., an
`HIV infection. The subject invention also relates to pro-
`cesses for making such compounds as well as to interme-
`diates useful in such processes.
`2. Related Art
`During the replication cycle of retroviruses, gag and
`gag-pol gene transcription products are translated as pro-
`teins. These proteins are subsequently processed by a virally
`encoded protease (or proteinase) to yield viral enzymes and
`structural proteins of the virus core. Most commonly, the gag
`precursor proteins are processed into the core proteins and
`the pol precursor proteins are processed into the viral
`enzymes, e.g., reverse transcriptase and retroviral protease.
`It has been shown that correct processing of the precursor
`proteins by the retroviral protease is necessary for assembly
`of infectious virons. For example, it has been shown that
`frameshift mutations in the protease region of the pol gene
`of HIV prevents processing of the gag precursor protein. It
`has also been shown through site-directed mutagenesis of an
`aspartic acid residue in the HIV protease active site that
`processing of the gag precursor protein is prevented. Thus,
`attempts have been made to inhibit viral replication by
`inhibiting the action of retroviral proteases.
`Retroviral proteasc inhibition typically involves a
`transition-state mimetic whereby the retroviral protease is
`exposed to a mimetic compound which binds (typically in a
`reversible manner) to the enzyme in competition with the
`gag and gag-pol proteins to thereby inhibit specific process-
`ing of structural proteins and the release of retroviral pro-
`tease itself. In this manner, retroviral replication proteases
`can be effectively inhibited.
`Several classes of compounds have been proposed, par-
`ticularly for inhibition of proteases, such as for inhibition of
`HIV protcase. Such compounds include hydroxyethylamine
`isosteres and reduced amide isosteres. See, for example, EP
`0 346 847; EP O 342,541; Roberts et al, "Rational Design
`of Peptide-Based Proteinase Inhibitors, "Science, 248, 358
`(1990); and Erickson et al, "Design Activity, and 2.8 A
`
`2
`Crystal Structure of a Cz Symmetric Inhibitor Complexed to
`HIV-1 Protease," Science, 249, 527 (1990).
`Several classes of compounds are known to be useful as
`inhibitors of the proteolytic enzyme renin. See, for example,
`5 U.S. Pat. No. 4,599,198; U.K. 2,184,730; G.B. 2,209,752;
`EP 0 264 795; G.B. 2,200,115 and U.S. SIR H725. Of these,
`G.B. 2,200,115, GB 2,209,752, EP O 264,795, U.S. SIR
`H725 and U.S. Pat. No. 4,599,198 disclose urea-containing
`hydroxyethylamine renin inhibitors. EP 468 641 discloses
`10 renin inhibitors and intermediates for the preparation of the
`inhibitors, which include sulfonamide-containing hydroxy-
`ethylamine compounds, such as 3-(t-butoxycarbonyl)amino-
`cyclohexyl-l-(phenylsulfonyl)amino-2(5)-butanol. G.B.
`2,200,115 also discloses sulfamoyl-containing hydroxyethy-
`~s lamine renin inhibitors, and EP 0264 795 discloses certain
`sulfonamide-containing hydroxyethylamine renin inhibi-
`tors. However, it is l~own that, although renin and HIV
`proteases are both classified as aspartyl proteases, com-
`pounds which are effective renin inhibitors generally cannot
`20 be predicted to be effective HIV protease inhibitors.
`
`BRIEF DESCRIPTION OF THE INVENTION
`
`The present invention is directed to virus inhibiting com-
`~5 pounds and compositions. More particularly, the present
`invention is directed to retroviral protease inhibiting com-
`pounds and compositions, to a method of inhibiting retro-
`viral proteases, to processes for preparing the compounds
`and to intermediates useful in such processes. The subject
`30 compounds are characterized as sulfonamide-containing
`hydroxyethylamine inhibitor compounds.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`35
`
`In accordance with the present invention, there is pro-
`vided a retroviral protease inhibiting compound of the
`formula:
`
`40
`
`45
`
`/\
`
`R~
`
`R’ OH
`
`55
`
`or a pharmaceutically acceptable salt, prodrug or ester
`thereof, wherein:
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`50 alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`he terocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, hetero aryloxycarbonyl,
`heteroaroyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
`aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubsti-
`60 tuted aminocarbonyl and mono- and disubstituted ami-
`noalkanoyl radicals wherein the substituents are selected
`from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl, heterocy-
`cloalkyalkyl radicals, or where said aminocarbonyl and
`aminoalkanoyl radicals are disubstituted, said substituents
`along with the nitrogen atom to which they are attached
`form a heterocycloalkyl or heteroaryl radical;
`
`65
`
`Copy provided by USPTO from the PIRS Imacle Database on 0111012013
`
`Lupin Ex, 1003 (Page 3 of 115)
`
`

`
`US 6,248,775 B1
`
`3
`R’ represents hydrogen, radicals as defined for R3 or
`R"SO~--- wherein R" represents radicals as defined for
`R3;
`or R and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`cals;
`R~ represents hydrogen, --CHzSOzNHz, ~CHzCOzCH3,
`~O~CH3, ~ONH~, -~CH~C(O)NHCH3, --C(CH3)~
`(SH), --C(CH3)z(SCH3), --C(CH3)2(S[O]CH3),
`~(CH3)a(S[O]~CH~), alkyl, haloalkyl, alkenyl, alkynyl
`and cycloalkyl radicals, and amino acid side chains
`selected from asparagine, S-methyl cysteine and the sul-
`foxide (SO) and sulfone (S02) derivatives thereof,
`isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,
`phenylalanine, omithine, histidine, norleucinc, glutamine,
`threonine, allo-threonine, serine, O-alkyl serine, aspartic
`acid, beta-cyano alanine and valine side chains;
`Rr and Rr’ independently represent hydrogen and radicals
`as defined for R1, or one of R1’ and R1", together with R1
`and the carbon atoms to which Ra, Rr and Rr’ are
`attached, represent a cycloalkyl radical;
`R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and
`aralkyl radicals, which radicals are optionally substituted
`with a group selected from alkyl and halogen radials,
`--NO~, --CN, --CF~, ----OR9 and --SR9, whcrein R9
`represents hydrogen and alkyl radicals, and halogen radi-
`cals;
`R3 represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,
`hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl,
`aralkyl, heteroaralkyl, aminoalkyl and mono- and disub-
`stituted aminoalkyl radicals, wherein said substituents are
`selected from alkyl, aryl, aralkyl, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, and heterocycloalkylalkyl radicals, or in
`the case of a disubstituted aminoalkyl radical, said sub-
`sfituents along with the nitrogen atom to which they are
`attached, form a heterocycloalkyl or a heteroaryl radical;
`R’* represents radicals as defined by R-~ except for hydrogen;
`R~ represents hydrogen and alkyl radicals;
`x represents 0, 1 or 2;
`t represents either 0 or 1; and
`Y represents O, S and NRis wherein Ras represents hydro-
`gen and radicals as defined for R~.
`A family of compounds of particular interest within
`Formula I are compounds embraced by Formula II:
`
`R..
`
`,O,
`R,z
`II /
`
`O O
`\\//
`
`R
`
`OH R
`
`wherein:
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cyeloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxyearbonyl, aryloxyearbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, he terocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubsti-
`tuted aminocarbonyl and mono- and disubstituted ami-
`
`5
`
`10
`
`!5
`
`2o
`
`4
`noalkanoyl radicals wherein the substituents are selected
`from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl, heterocy-
`cloalkyalkyl radicals, or where said aminoalkanoyl radi-
`col is disubstituted, said substituents along with the nitro-
`gen atom to which they are attached form a
`heterocycloalkyl or heteroaryl radical;
`R’ represents hydrogen and radicals as defined for R~ or R
`and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`cal;
`Ra represents hydrogen, ---CII:SO~NII~, ---CHzCOzCHa,
`--COzCH3,--CONHz, --CH2C(O) NHCH3,--C(CHa)
`~(SH), --C(CHa)~(SCH~), --C(CH~)a(S[O]CH~),
`--C(CH3)~(S[O]~CH3), alkyl, haloalkyl, alkenyl, alkynyl
`and cycloalkyl radicals, and amino acid side chains
`selected from asparagine, S-methyl cysteine and the sul-
`foxide (SO) and sulfone (SO~) derivatives thereof,
`isolencine, allo-isoleucine, alanine, leucine, tert-leucine,
`phenylalanine, ornithine, histidine, norleucine, glutamine,
`threonine, allo-threonine, serine, O-methyl serine, aspar-
`tic acid, beta-cyano alanine and vallnc side chains;
`R~ represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and
`aralkyl radicals, which radicals are optionally substituted
`25 with a group selected from alkyl and halogen radials,
`--NO~, ~N, CF3, ---OR~, --SR~, wherein R~ rep-
`resents hydrogen and alkyl radicals;
`R~ represents alkyl, haloalkyl, alkenyl, alkynyl,
`hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`3o heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl,
`aralkyl, heteroaraLkyl, aminoalkyl and mono- and disub-
`sfituted aminoalkyl radicals, wherein said substituents are
`selected from alkyl, aryl, aralkyl, cyeloalkyl,
`cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, and heterocyeloalkylalkyl radicals, or in
`the case of a disubsfituted aminoalkyl radical, said sub-
`sfituents along with the nitrogen atom to which they are
`attached, form a heterooycloalkyl or a heteroaryl radical;
`and
`40 R4 represents radicals as defined by R~.
`A more preferred family of compounds within Formula II
`consists of compounds wherein:
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, hot erocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`hete roaralkoxycarbonyl, hetero aryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, araLkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubsti-
`tuted aminoearbonyl and mono- and disubsfituted ami-
`55 noalkanoyl radicals wherein the substituents are selected
`from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heteroeycloalkyl, heterocy-
`cloalkyalkyl radicals, or where said aminoa]kanoyl radi-
`cal is disubsfitnted, said substituents along with the nitro-
`gen atom to which they are attached form a
`heterocycloalkyl or heteroaryl radical;
`R’ represents hydrogen and radicals as defined for R~ or R
`and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`65 cal;
`R~ represents CH~C(O)NHCH3, C(CH~)2(SCH~), C(CH~)2
`(S[O]CH~), C(CH~)z(S[O]~CH~), alkyl, alkenyl and alky-
`
`45
`
`so
`
`60
`
`Copy provided by USPTO from the PIRS Ima(~e Database on 01/10/2013
`
`Lupin Ex, 1003 (Page 4 of 115)
`
`

`
`US 6,248,775 B1
`
`i0
`
`6
`hete re aralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubsti-
`5 tuted aminocarbonyl and mono- and disubstituted ami-
`noalkanoyl radicals wherein the substituents are selected
`from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl, heterocy-
`cloalkyalkyl radicals, or where said aminoalkanoyl radi-
`cal is d/substituted, said substituents along with the nitro-
`gen atom to which they are attached form a
`heterocycloalkyl or heteroaryl radical;
`R’ represents hydrogen and radicals as defined for R3 or R
`and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`i5 cal;
`Ra represents hydrogen, -~CHzSOzNH2, ----CHzCO~CH3,
`--CO~CHa, ~ONHa, --CH~C(O)NHCH~, ~C(CHa)z
`(SH), --C(CHa)a(SCHa), --C(CHa)~(S[O]CHa),
`--C(CH~)~(S[O]~CH~), alkyl, haloalkyl, alkenyl, alkynyl
`2o and cycloalkyl radicals, and amino acid side chains
`selected from asparagine, S-methyl cysteine and the sul-
`foxide (SO) and sulfone (SO~) derivatives thereof,
`isoleucine, allo-isolencine, alanine, lencine, tert-leucine,
`phenylalanine, ornithine, histidine, norleucine, glutamine,
`threonine, allo-threonine, serine, aspartic acid, beta-cyano
`alanine and valine side chains;
`R~ represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and
`aralkyl radicals, which radicals are optionally substituted
`with a group selected from alkyl and halogen radicals,
`--NOz, ~N, CF3, ---OR9, --SR9, wherein R9 rep-
`resents hydrogen and alkyl;
`R~ represents alkyl, haloalkyl, alkenyl, alkynyl,
`hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl,
`aralkyl, heteroaralkyl, aminoalkyl and mono- and dlsub-
`35 stituted aminoalkyl radica|s, wherein said substituents are
`selected from alkyl, aryl, aralkyl, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, and heterocycloalkylalkyl radicals, or in
`the case of a disubstituted aminoalkyl radical, said sub-
`stituents along with the nitrogen atom to which they are
`attached, form a heterocycloalkyl or a heteroaryl radical;
`and
`R4 represents radicals as defined by R3.
`A more preferred family of compounds within Formula III
`consists of compounds wherein
`45 R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`
`25
`
`30
`
`4o
`
`5
`nyl radicals, and amino acid side chains selected from the
`group consisting of asparagine, valine, threonine, allo-
`threonine, isoleucine, tert-leucine, S-methyl cysteine and
`the sulfone and sulfoxide derivatives thereof, alanine, and
`allo-isoleucine;
`Rz represents alkyl, cycloalkylalkyl and aralkyl radicals,
`which radicals are optionally substituted with halogen
`radicals and radicals represented by the formula --OR9
`and ---SR9 wherein R9 represents alkyl radicals; and
`R3 and R4 independently represent alkyl, alkenyl,
`alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl and
`heteroaralkyl radicals.
`Of highest interest are compounds within Formula II
`wherein
`R represents alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, aminocarbonyl, aminoalkanoyl, and mono-
`and disubstituted aminocarbonyl and mono- and disub-
`stituted aminoalkanoyl radicals wherein the substituents
`are selected from alkyl, aryl, aralkyl, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, heterocycloalkyalkyl radicals, or where
`said aminoalkanoyl radical is disubstituted, said substitu-
`ents along with the nitrogen atom to which they are
`attached form a heterocycloalkyl or heteroaryl radical;
`R’ represents hydrogen and radicals as defined for R3 or R
`and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`cal;
`R1 represents CHzC(O)NHCH3, C(CH3)2(SCH3), C(CH3)2
`(S[0]CH3), C(CH~)z(S[O]2CH3), methyl, propargyl,
`t-butyl, isopropyl and sec-butyl radicals, and amino acid
`side chains selected from the group consisting of
`asparagine, vafine, S-methyl cysteine, afio-iso-leucine,
`iso-leucine, and beta-cyano alanine side chains;
`Rz represents CH3SCHzCHa--, iso-butyl, n-butyl, benzyl,
`4-fluorobenzyl, 2-naphthylmethyl and cyclohexyh~ethyl
`radicals;
`R-~ represents i~amyl, n-butyl, isobutyl and cyclohexyl
`radicals; and
`R4 represents phenyl, substituted phenyl and methyl radi-
`cals.
`Another family of compounds of particular interest within
`Formula I are compounds embraced by Formula III:
`
`(IID
`
`alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cyeloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`50 heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`he terocyclylalkoxycarbonyl, heteroaralkanoyl,
`here re ar alkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and dlsubsti-
`tuted aminocarbonyl and mono- and disubstituted ami-
`noalkanoyl radicals wherein the substituents are selected
`from alkyl, aryl, aratkyl, cycloalkyl, cycloalkylalkyl,
`hetcroaryl, heteroaralkyl, heterocycloalkyl, heterocy-
`cloalkyalkyl radicals, or where said aminoalkanoyl radi-
`cal is disubstituted, said substituents along with the nitro-
`gen atom to which they are attached form a
`hetcrocycloalkyl or heteroaryl radical;
`R’ represents hydrogen and radicals as defined for R3 or R
`and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`cal;
`
`ss
`
`wherein:
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, hetero cyclylcarbonyl, 65
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyl,
`
`60
`
`Col~v [0rovided bv USP’I’O from the PIRS Imaoe Database an 01/10/~013
`
`Lupin Ex, 1003 (Page 5 of 115)
`
`

`
`7
`R1 re.presents hydrogen, alkyl and alkenyl radicals, and
`amino acid side chains selected from the group consisting
`of asparagine, valine, threonine, allo-threonine,
`isoleucine, tert-leucine, S-methyl cysteine and the sulfone
`and sulfoxide derivatives thereof, alanine, and allo-
`isoleucine;
`R2 represents alkyl, cycloalkylalkyl and aralkyl radicals,
`which radicals are optionally substituted with halogen
`radicals and radicals represented by the formula --OR9
`and ---SR° wherein R~ represents hydrogen and alkyl and
`halogen radicals; and
`R3 and R4 independently represent alkyl, alkenyl,
`alkoxyalkyl, eycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,
`heteroaryl and heteroaralkyl radicals.
`Of highest interest are compounds within Formula III
`wherein
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl,
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkanoyI,
`heteroaralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, aminocarbonyl, aminoalkanoyi, and mono-
`and disubstituted aminocarbonyl and mono- and disub-
`stituted aminoalkanoyl radicals wherein the substituents.
`are selected from alkyl, aryl, aralkyl, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, heterocycloalkyalkyl radicals, or where
`said aminoalkanoyl radical is disubstituted, said substitu-
`ents along with the nitrogen atom to which they are
`attached form a heterocycloalkyl or heteroaryl radical;
`R’ represents hydrogen and radicals as defined for R3 or R
`and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`cal;
`R 1 represents hydrogen, methyl, propargyl, t-butyl, isopro-
`pyl and see-butyl radicals, and amino acid side chains
`selected from the group consisting of asparagine, valine,
`S-methyl cysteine, allo-iso-leucine, iso-leucine,
`threonine, serine, aspartic acid, beta-cyano alanine, and
`allo-threonine side chains;
`R2 represents CH3SCHzCH2--, iso-butyl, n-butyl, benzyl,
`4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl
`radicals; and
`R3 represents alkyl, cyclohexyl, isobutyl, isoamyl, and
`n-butyl radicals; and
`R4 represents mothy1, phenyl and substituted phenyl radicals
`wherein the substituents are selected from halo, alkoxy,
`hydroxy, nitro and amino substituents.
`Another family of compounds of particular interest within
`Formula I are compounds embraced by Formula IV:
`
`OH
`
`5
`
`8
`aryloxyalkanoyl, heterocyclylcarbonyl,
`heterocyclyloxycarbonyl, heterocyclylalkanoyl,
`heterocyclylalkoxycarbonyl, heteroaralkano yl,
`hete ro aralkoxycarbonyl, heteroaryloxy-carbonyl,
`heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
`aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,
`aminocarbonyl, aminoalkanoyl, and mono- and disubsti-
`tuted aminocarbonyl and mono- and disubstituted ami-
`noalkanoyl radicals wherein the substituents are selected
`~0 from alkyi, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroaralkyl, heterocycloalkyl, heterocy-
`cloalkyalkyl radicals, or where said aminoalkanoyl radi-
`cal is disubstituted, said substituents along with the nitro-
`gen atom to which they are attached form a
`a5 heterocycloalkyl or heteroaryl radical;
`R’ represents hydrogen and radicals as defined for R3 or R
`and R’ together with the nitrogen to which they are
`attached represent heterocycloalkyl and heteroaryl radi-
`cal;
`~0 R1 represents hydrogen, --CH~SO2NH2, --CH2CO2CH3,
`--COzCH~, ---CONH~,--CH~C(O)NHCH3, --C(CHa):
`(SH), --C(CHa)~(SCHa), --C(CH~)2(S[0]CHa),
`--C(CH3)2(S[O]~CH~), alkyl, haloalkyl, alkenyl, alkynyl
`and cycloalkyl radicals, and amino acid side chains
`~5 selected from asparagine, S-methyl cysteine and the sul-
`foxide (SO) and sulfonc (S02) derivatives thereof,
`isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,
`phenylalanine, ornithinc, histidine, norleucine, glutamine,
`threonine, allo-threonine, serine, aspartic acid, beta-cyano
`30 alanine and valine side chains;
`Rr and Rr~ independently represent hydrogen and radicals
`as defined l’or R~, or one of Rr and R1’’, together with R~
`and the carbon atoms to which R~, Rr and Rr’ are
`attached, represent a cydoaIkyl radical;
`35 R~ represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and
`aralkyl radicals, which radicals are optionally substituted
`with a group selected from alkyl and halogen radials,
`--NO2, ~N, CF3, ---OR~ and --SR9, wherein R9
`represents hydrogen and alkyl radicals;
`40 Ra represents alkyl, haloalkyl, alkenyl, alkynyl,
`hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl,
`aralkyl, heteroaralkyl, aminoalkyl and mono- and disub-
`stituted aminoalkyl radicals, wherein said substituents are
`45 selected from alkyl, aryl, aralkyl, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroaralkyl,
`heterocycloalkyl, and heterocycloalkylalkyl radicals, or in
`the case of a disubstituted aminoalkyl radical, said sub-
`stituents along with the nitrogen atom to which they are
`attached, form a heterocycloalkyl or a heteroaryl radical;
`and
`R4 represents radicals as defined by Ra.
`A more preferred family of compounds within Formula
`IV consists of compounds wherein
`55 R represents an arylalkanoyl, heteroaroyl, aryloxyalkanoyl,
`aryloxycarbonyl, alkanoyl, aminocarbonyl, mono-
`substituted aminoalkanoyl, or disubstituted
`aminoalkanoyl, or mono- or dialkylaminocarbonyl radi-
`cal;
`60 R’ represents hydrogen and radicals as defined for R3 or R
`and R’ together with the nitrogen to which they are
`attached represent a heterocycloalkyl or heteroaryl radi-
`cal;
`Ra, Rr and R~" independently represent hydrogen and alkyl
`radicals having from 1 to about 4 carbon atoms, alkenyl,
`alkynyl, aralkyl radicals, and radicals represented by the
`formula --CH~C(O)R" or ---C(O)R" wherein R" repro-
`
`US 6,248,775 B1
`
`wherein:
`R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,
`alkylcarbonyl, cycloalkylcarbonyl, 65
`cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl,
`aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,
`
`Copy provided by USPTO from the PIRS Image Database on 01110/2013
`
`Lupin Ex, 1003 (Page 6 of 115)
`
`

`
`US 6,248,775 B1
`
`9
`sents RaS, --NR38R39 and OR38 wherein R38 and Rz°
`independently represent hydrogen and aLkyl radicals hav-
`ing from 1 to about 4 carbon atoms;
`R2 represents alkyl, cycloalkylalkyl and aralkyl radicals,
`which radicals are optionally substituted with halogen
`radicals and radicals represented by the formula --OR9
`and ----SR9 wherein R9 represents hydrogen and alkyl
`radicals; and
`R3 and R4 independently represent alkyl, alkenyl,
`alkoxyalkyl, cycloalkyl, cycloalkylalkyl,
`heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,
`heteroaryl and heteroaralkyl radicals.
`Of highest interest are compounds of Formula IV
`wherein:
`R represents an arylalkanoyl, aryloxycarbonyl,
`aryloxyalkanoyl, alkanoyl, aminocarbonyl, mono-
`substituted aminoalkanoyl, or disubstituted
`aminoalkanoyl, or mono -or dialkylaminocarbonyl radi-
`cal;
`R’ represents hydrogen and radicals as defined for R~ or R
`and R’ together with the nitrogen to which they are
`attached represent a heterocycloaikyl or heteroaryl radi-
`cal;
`R1, R1’ and Ra’’ independently represent hydrogen, methyl,
`ethyl, benzyl, phenylpropyl and propargyl radicals;
`R2 represents CH3SCH:CH:--, iso-butyl, n-butyl, benzyl,
`4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl
`radicals;
`R3 represents alkyl, cyclohexyl, isobutyl, isoamyl and
`n-butyl radicals; and
`R4 represents methyl, phenyl and substituted phenyl radicals
`wherein the substituents are selected from halo, alko