United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,585,397
`
`Tung et al.
`
`‘
`
`[45] Date of Patent:
`
`Dec. 17, 1996
`
`llllllllllllllIllllllllllllllillllllll||l||||||llllllllllllllllllllllllllll
`US005585397A
`
`[54] SULFONAMIDE INHIBITORS OF ASPARTYL
`PROTEASE
`I
`Inventors. Roger D_ Tung’ Arlington; Mark A_
`Murcko’ Honiston; Govinda R_
`Bhisetti, Lexington, all of Mass.
`
`[75]
`
`[73] Assigneez Vertex pharmaceuticals’
`Incorporated, Cambridge, Mass.
`
`142,327
`
`[21] APP1- N0-5
`_
`.
`Se“ 7’ 1993
`[22] PCT med‘
`PCTIUS93/08458
`[86] PCT No.:
`S
`7 1993
`371 D .
`’
`91)‘
`ate‘
`§
`§ 102(6) Date; Sep_ 7, 1993
`
`T
`
`[87] PCT Pub. No.: W094/05639
`_
`PCT Pub’ Date'Mar' 17’,1994
`Related U_S_ Application Data
`
`[51]
`
`[63] Continuation-in-part of ser. No. 941,982, sep. 8, 1992,
`abandoned.
`Int. Cl.6 ...................... C07D 407/12; C07D 307/20;
`A61K 31/34
`.......................... 514/473; 514/464; 549/475;
`549/448; 546/169
`[58] Field of Search ........................... .. 546/169; 549/475,
`549/448: 514/473, 464
`
`[52] U.S. Cl.
`
`[56]
`
`References Cited
`U_S_ PATENT DOCUNIENTS
`
`5/1992 Descamps et a1.
`................ .. 424/248.5
`4,330,542
`
`3/1993 Martin Ct al.
`. .. . .. . ..
`. ..... 514/311
`5,196,438
`5,354,866 10/1994 Kempf et al.
`...... 546/265
`
`FOREIGN PATENT DOCUMENTS
`022118A1
`1/1931
`European Pat. oir.
`CO7K 143/822
`181071A2
`3/1986 European Pat. on.
`.......... C07K 5/06
`264795A2
`4/1988
`European Pat. Off.
`........ .. C07K 5/00
`
`OTHER PUBLICATIONS
`G. Fontenot et al., “PCR Amplification of HIV-1 Proteinase
`Sequences Directly from Lab Isolates Allows Deterirunation
`of Five Conserved Domains , Wrology, 190, pp. 1-10
`0992)‘
`,
`_
`,
`A. Goldblum, “Modulation of the Afiinity of ASpaI‘I'.1C Pro-
`teases by the Mutated Residues in Active Site Models”,
`FEES’ 261’ PP- 241444 (1990)-
`J. R. Huff, “HIV Protease: A Novel Chemotherapeutic Target
`for AIDS”, Journal of Medicinal Chemistry, 34(8), pp.
`23052314 (1991).
`K. Y. Hui et al., “A Rational Approach in the Search for
`Potent Inhibitors Against HIV Proteinase”, FASEB, 5, pp.
`2606-2610 (1991).
`I
`X. Linret al., “Enzyiriic Activities of Two—Chain Pepsino-
`gen, Two—Chain Pepsin, and the Amino—Termina1 Lobe of
`Pepsinogen”, J. Biol. Chem., 267(24), pp. 17257-17263
`(1992),
`K. P. Manfredi et al., “Examination of HIV-1 Protease
`Secondary Structure Specificity Using Conformationally
`Constrained Inhibitors”, J. Med. Chem., 34, pp. 3395-3399
`(1991).
`'
`
`1- A- Merlin: “Reeem Adwmeee in the Design Of HIV
`Proteinase Inhibitors”, Antiviral Research, 17, pp. 265-278
`0992)‘M. Miller et al., “Crystal Structure of a Retroviral Protease
`.
`.
`.
`.
`P
`Rlti hitAartiPt
`F
`l”,Nt,
`3§‘;:'°psp_ §7a6_‘;’;s9 ("19§9)_sp
`° "wage my
`“"3
`J. Palca “Shooting at a New HIV Target” Science 247 p.
`410 (1990)_
`N. A. Roberts, “Rational Design of Peptide—Based HIV
`Proteinase Inhibitors", Science, 248, pp. 358-361 (1990).
`S. Scharpe et al., “Proteased and Their Inhibitors: Today and
`Tomorrow”, Blochlmze, 73, pp. 121-126 (1991).
`S. K. Sharma et al., “Could Angiotensin I Be Produced from
`algcnin substrate by the H]V_1 P1-ot6aSe"_}”, Andi Biachemq
`
`'
`’
`Primary Examiner—David B. Springer
`Attorney, Agent, or Firm——Fish & Neave; James F. Haley,
`Jn; Jeffrey D- Hsi
`[57]
`
`ABSTRACT
`
`The present invention relates to a novel class of su1fona-
`rnides which are aspartyl protease inhibitors. In one embodi-
`ment, this invention relates to a novel class of HIV aspartyl
`Protease inhi1_3i‘°T5 Characterized Pl’ Speeifie Slluemrel and
`physicochemical features. This invention also relates to
`pharmaceutical compositions comprising these compounds.
`' The compounds and pharmaceutical compositions of this
`invention are particularly well suited for inhibiting I-HV-1
`and HIV-2 protease activity and consequently, may be
`advantageously used as anti-viral agents against the HIV-1
`HIV-*2 viruses. This invention also relates to methods for
`inhibiting the activity of HIV aspartyl protease using the
`compounds of this invention and methods for screening
`_
`,
`_
`compounds for antl-HIV activity.
`
`8 Claims, 3 Drawing Sheets
`
`Janssen Ex. 2032
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
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`
`1/1992 E“’°P°a“ Pa“ 03' """"" C°7K 5/02
`458641A2
`5/1992 European Pat. 011'.
`C07D 213/26
`486948A2
`3/1984
`Japan
`C07C 103/44
`59_0462S2
`""""""
`3/1984
`Japan
`Cmc 103,375
`59_048449
`4/1986
`Japan ............. ..
`BOIF 17/46
`61-071830
`7/1933 United Kingdom _
`_ C07c 103/()0
`2200115
`W091/18866 12/1991 WIPO ..............
`C07C 237/22
`W092/17176 10/1992 WIPO ..
`.. A16K 31/44
`W093/23368 11/1993 WIPO ..
`C07C 275/24
`W093/23379 “/1993 WIPO --
`C0713 217/25
`"
`C071) 303/36
`3/1994 WIPO H
`3/1994 WIPO H
`Cmc 317/44
`c07C 307,06
`5/1994 w11>o ..
`5/1994 WIPO ..
`co7c 317/44
`C07D 401/14
`8/1994 WIPO ..
`9/1994 WIPO .......................... C07D 209/34
`
`
`
`_
`
`W094/04492
`W094/04493
`W094/10134
`W094/10136
`W094/18192
`W094/19322
`
`

`
`U.S. Patent
`
`Dec. 17, 1996
`
`Sheet 1 of 3
`
`5,585,397
`
`FIGURE1
`
`Janssen Ex. 2032
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`|PR2015-01030
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`
`

`
`U.S. Patent _
`
`Dec.17, 1996
`
`Sheet 2 of3
`
`5,585,397
`
`FIGURE2
`
`Janssen Ex. 2032
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
`|PR2015-01030
`
`(Page 3 of 96)
`
`

`
`U.S. Patent
`
`Dec. 17, 1996
`
`Sheet 3 of 3
`
`5,585,397
`
`FIGURE3
`
`Janssen Ex. 2032
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`|PR2015-01030
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`
`

`
`5,585,397
`
`1
`SULFONAMIDE INHIBITORS OF ASPARTYL
`PROTEASE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a 371 PCT/US93/08458, filed Sep. 7,
`1993, and a continuation-in-part of U.S. patent application
`Ser. No. 941,982, filed Sep. 8, 1992, now abandoned.
`
`TECHNICAL FIELD OF THE INVENTION
`
`The present invention relates to a novel class of sulfona-
`rrrides which are aspartyl protease inhibitors. In one embodi-
`ment, this invention relates to a novel class of HIV aspartyl
`protease inhibitors characterized by specific structural and
`physicochemical features. This invention also relates to
`pharmaceutical compositions comprising these compounds.
`The compounds and pharmaceutical compositions of this
`invention are particularly well suited for inhibiting HIV-1
`and HIV-2 protease activity and consequently, may be
`advantageously used as anti-viral agents against the I-lIV-1
`and HIV-2 viruses. This invention also relates to methods for
`inhibiting the activity, of HIV aspartyl protease using the
`compounds of this invention and methods for screening
`compounds for anti-HIV activity.
`
`20
`
`25
`
`BACKGROUND OF THE INVENTION
`
`2
`virions in chronically infected cells. Furthermore, adrr1inis-
`tration of some of these agents in effective amounts has led
`to cell-toxicity and unwanted side effects, such as anemia
`and bone marrow suppression.
`More recently, the focus of anti-viral drug design has been
`to create compounds which inhibit the formation of infec-
`tious virions by interfering with the processing of viral
`polyprotein precursors. Processing of these precursor pro-
`teins requires the action of virus-encoded proteases which
`are essential for replication (Kohl, N. E. et al. “Active HIV
`Protease is Required for Viral Infectivity” Proc, Natl. Acad.
`Sci. USA, 85, p. 4686 (1988)). The anti-viral potential of
`HIV protease inhibition has been demonstrated using pep-
`tidal inhibitors. Such peptidal compounds, however, are
`typically large and complex molecules that tend to exhibit
`poor bioavailability and are not generally consistent with
`oral administration. Accordingly, the need still exists for
`compounds that can effectively inhibit the action of viral
`proteases, for use as agents for preventing and treating
`chronic and acute viral infections.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides a novel class of com-
`pounds,
`and
`pharmaceutically
`acceptable
`derivatives
`thereof, that are useful as inhibitors of aspartyl proteases, in
`particular, HIV aspartyl protease. These compounds can be
`used alone or in combination with other therapeutic or
`prophylactic agents, such as anti-virals, antibiotics, immu-
`nomodulators or vaccines, for the treatment or prophylaxis
`of viral infection.
`
`According to a preferred embodiment, the compounds of
`this invention are capable of inhibiting HIV viral replication
`in human CD4+ T-cells. These compounds are useful as
`therapeutic and prophylactic agents to treat or prevent
`infection by HIV-1 and related viruses which may result in
`asymptomatic infection, AIDS—related complex (“ARC"),
`acquired immunodeficiency syndrome (“AIDS”), or similar
`disease of the immune system.
`It is a principal object of this invention to provide a novel
`class of sulfonarnides which are aspartyl protease inhibitors,
`and particularly, HIV aspartyl protease inhibitors. This novel
`class of sulfonarnides is represented by formula I:
`
`1'3
`A-(B),--IFI-Cl-I--CH--CH2-If-S02-E
`H
`OH
`D‘
`
`(1)
`
`wherein:
`A is selected from the group consisting of H; Het;
`—R1——Het; -—R1—C1—C6 alkyl, which may be optionally
`substituted with one or more groups selected from the group
`
`—R1——-C2-C5 alkenyl, which may be optionally substituted
`with one or more groups selected from the group czonsisting
`of hydroxy, C —C alkoxy, Het, —O—Het, —NR ——CO——
`N(R2> <R2>an1c1—4co—N<R2> (R2);
`each R‘ is independently selected from the group con-
`sisting
`of —C(O)—, —S(O)2—, —C(O)—C(O)—,
`—O—C(O)——, —S (0)2, —S(O)2—C(O)— and
`—NR2C(O)— and —NR2—C(O)—C(O)—-;
`each Het is independently selected from the group con-
`sisting of C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C5—C10
`aryl; and 5-7 membered saturated or unsaturated hetero-
`cycle, containing one or more heteroatoms selected from N,
`
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`Lupin Ltd. v. Janssen Sciences Ireland UC
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`
`35
`
`40
`
`The human immunodeficiency virus (“HIV”) is the caus-
`ative agent
`for acquired immunodeficiency syndrome
`(“AIDS”)———a disease characterized by the destruction of the
`immune system, particularly of CD4+ T-cells, with attendant
`susceptibility to opportunistic infections—and its precursor
`AIDS-related complex (“ARC”)——a syndrome characterized
`by symptoms such as persistent generalized lymphadenopa-
`thy, fever arrd weight loss.
`As in the case of several other retroviruses, HIV encodes
`the production of a protease which carries out post-transla-
`tional cleavage of precursor polypeptides in a process nec-
`essary for the formation of infectious virions (S. Crawford
`et al., “A Deletion Mutation in the 5' Part of the pol Gene of
`Moloney Murine Leukemia Virus Blocks Proteolytic Pro-
`cessing of the gag and pol Polyproteins”, J., Virol., 53, p. 899
`(1985)). These gene products include pol, which encodes the
`virion RNA-dependent DNA polymerase (reverse tran-
`scriptase), an endonuclease, HIV-protease, and gag, which
`encodes the core-proteins of the virion (H. Toh et al., “Close
`Structural Resemblance Between Putative Polymerase of a
`Drosophila Transposable Genetic Element 17.6 and pol gene
`product of Moloney Murine Leukemia Virus", EMBO J. 4,
`p. 1267 (1985); L. H. Pearl et al., “A Structural Model for
`the Retroviral Proteases”, Nature, pp. 329-351 (1987); M.
`D. Power et al., “Nucleotide Sequence of SRV—1, a Type D
`Simian Acquired Immune Deficiency Syndrome Retrovi-
`ms”, Science, 231, p. 1567 (1986)).
`A number of synthetic anti-viral agents have been
`designed to target various stages in the replication cycle of
`HIV. These agents include compounds which block viral
`binding to CD4+ T—lymphocytes (for example, soluble CD4),
`and compounds which interfere with viral replication by 60
`inhibiting
`viral
`reverse
`transeriptase
`(for
`example,
`didanosine and zidovudine (AZT)) and inhibit integration of
`viral DNA into cellular DNA (M. S. Hirsh and R. T.
`D’Aqulia, “Therapy for Human Immunodeficiency Virus
`Infection”, N. Eng. J. Meal, 328, p. 1686 (1393)). However, 65
`such agents, which are directed primarily to early stages of
`viral replication, do not prevent the production of infectious
`
`45
`
`50
`
`55
`
`

`
`IS
`
`20
`
`25
`
`30
`
`N(R2), O, S and S(O),_, wherein said heterocycle may
`optionally be benzofused; and wherein any member of said
`Het may be optionally substituted with one or more sub-
`stituents selected from the group consisting of 0x0, —-OR’,
`-R2, —N(R2), —R2—OH, —CN, —CO2R2, —C(O)—
`N(R2)
`(R2), —S(0)2—N(R2)(R2), —N(R )—C(0)—R2,
`-—C(O)-R2, —S(O),,—R2, —OCF3, —S(O),,—Ar, meth-
`ylenedioxy, —N(R2)—S(O)2(R2), halo, —CF3, —NO2, Ar
`and —O—Ar;
`each R2 is independently selected from the group con-
`sisting of H and C1-C3 alkyl optionally substituted with Ar;
`B, when present, is -N(R2)-C(R )(R3)—C(O)—;
`x is 0 or 1;
`each R3 is independently selected from the group con-
`sisting of H, Het, C1-C5 alkyl, C2-C5 alkenyl, C3-C5
`cycloalkyl and C5-C5 cycloalkenyl, wherein any member of
`said R3, except H, may be optionally substituted with one or
`more substituents selected from the group consisting of
`—-OR2, —C(O)—NH—R2, -—S(O),1— N(R2)
`(R2), Het,
`-CN, -SR2, —CO2R2, NR2—C(O)—R2;
`each ii is independently l or 2;
`D and D‘ are independently selected from the group
`consisting of Ar; C1-C4 alkyl, which may be optionally
`substituted with one or more groups selected from C3-C5
`cycloalkyl, —OR2, —R3, —O—Ar and Ar; C2-C4 alkenyl,
`which may be optionally substituted with one or more
`groups
`selected from the group consisting of C5-C5
`cycloalkyl,
`-CR2, —R3, —O—Ar
`and Ar; C3-C5
`cycloalkyl, which may be optionally substituted with or
`fused with Ar; and C5-C5 cycloalkenyl, which may be
`optionally substituted with or fused with Ar;
`. °.a°h AI is independently Selected from he.gmup Con‘
`sisting of phenyl; 3-6 membered carbocyclic ring and 5-6
`membered heterocyclic ring containing one or more het-
`eroatoms selected from 0, N, s, s(o),, and N(R2), wherein
`said carbocyclic or heterocyclic ring may be saturated or 35
`unsaturated and optionally substituted with one or more
`groups selected from the group consisting of oxo, —OR2,
`_R2, _N(R2) (R2), _N(R2)_ C(0)_R2’ _R2_OH’
`__CN, __C()2R2, _C(0)_N(R2) (R2), halo a11o._.C1:3;
`E is selected from the group consisting of Het; O-Het; 40
`Ho;-He[; _O_R3; _NR2R3; C1_C6 alkyh which may be
`optionally substituted with one or more groups selected from
`the group consisting of R4 and Het; C2-C5 alkenyl, which
`may be optionally substituted with one or more groups
`selected from the group consisting of R4 and Het; C5-C5 45
`saturated carbocycle, which may optionally be substituted
`with one or more groups selected from the group consisting
`of R4 311d Her? and C5-C5 11r15311_1rated Carbocyclea Which
`may optionally be substituted with one or more groups
`selected from the group consisting of R4 and Het; and
`_ e_ach Rf“ Is lrgigpendently selectgd from the grolzlp 6011-
`:1§(3)(_-JEINHR ’ S(0)2_NHR ’ halo’
`.
`.
`.
`.'
`.
`.
`Celiliiilsalaggiflpatiiiiiiflgt($EI:11E)1:i;ii1‘geil;1?I;lifi:(5)II:I‘fiii1if3:)tE)Ei'Ii‘r;:- 55
`mula I and methods for their use as inhibitors of HIV
`aspanyl protease
`It is a further object of this invention to provide a novel
`class of HIV aspartyl protease inhibitor compounds charac-
`terized by the following novel combination of structural and 60
`physicochemica] feamrog;
`(1) a first and a second hydrogoh bond aoooptor moiety, at
`least one of which is more highly polarizable than a carbo-
`nyl, said moieties being the same or different, and being
`capable of hydrogen bonding with the hydrogen atoms of the 65
`flap water molecule of an HIV aspartyl protease when the
`compound is bound thereto;
`
`50
`
`3
`
`5,585,397
`
`4
`(2) substantially hydrophobic moieties which associate
`with the P1 and P1‘ binding pockets of said HIV aspartyl
`protease when the compound is bound thereto;
`(3) a third hydrogen bonding moiety, which may be either
`a hydrogen bond donor or acceptor, capable of simulta-
`neously hydrogen bonding to Asp25 and Asp25‘ of said HIV
`aspartyl protease when the compound is bound thereto;
`(4) an additional occupied volume of space of at least 100
`A3 when the compound is bound to the active site of said
`HIV aspartyl protease, said space overlapping with the
`volume of space that would be filled by a native substrate of
`said HIV aspartyl protease or a nonhyrolyzable isostere
`thereof;
`(5) a deformation energy of binding of the compound to
`said HIV aspartyl protease of not greater than 10 kcal/mole;
`and
`(6) a neutral or favorable enthalpic contribution from the
`sum of all electrostatic interactions between the compound
`and the protease when the compound is bound to said HIV
`aspartyl protease.
`It is also an object of this invention to provide pharma-
`ceutical compositions comprising compounds having the
`above-mentioned features and methods for their use as
`inhibitors of IHV aspartyl protease.
`It is a further object of this invention to provide a method
`for identification, design, or prediction of HIV aspartyl
`protease inhibitors comprising the steps of:
`(a) selecting a candidate compound of defined cherriical
`structure containing a first and a second hydrogen bond
`acceptor moiety, at least one of which is more highly
`pokm-Zable than a carbonyl
`said moieties being the
`same or different; a third hydrogen bonding moiety,
`which may be either a hydrogen bond donor or accep_
`_
`-
`.
`-_
`ggsind at lea“ tw° Substantially h-yd’°ph°b‘° mm
`’
`.
`_
`.
`_
`,
`(b) df3rer111111111g310W-Cnergyconforination for binding of
`sald Compound to the acuve me of an HIV aspartyl
`protease;.
`H
`‘
`(c) evaluating the capability of said first and second
`1'1Ydro8er1 bond acceptor rr1o1e11eS to _forr11 hydrogen
`bonds to the fiap.water molecule of said HIV aspartyl
`Protease “(hen 331d eo111Po1111o 13 bound thereto 111 S3111
`oor1for1T1er1or1i
`(d) evaluating the capability of said substantially hydro-
`phobic moieties to associate with the P1 and P1‘ binding
`pockets of said HIV aspartyl protease when said com-
`pound is bound thereto in said conformation;
`(e) evaluating the capability of said third hydrogen bond-
`111g moiety to fonn hyd1ogo11 bonds to AS1125 and
`AS1225 of Said HIV aspartyl protease when said oom_
`pound is bound thereto in said conformation;
`(1) evaluating the overlap of the occupied volume of said
`compound when said compound is bound to said HIV
`aSPa“y1Pr°‘Wi"said°°“f°m*i°“a“d“1°°°°"Pi°d
`volume of a nauve Subst-rate of HIV aspartyl proteaie
`or a nonhydrolyzable isostere thereof, when said
`polypcptidc ls bound to S_a1d HIV aspal-t_y1 r0teaSci_
`(g) evaluating the _d°f°rmat1°n energy of bmdmg of Said
`Compound t° Sad HIV aspartyl protease;
`(h) evaluating the enthalpic contribution of the sum of all
`electrostatic interactions between said compound and
`53111 HIV a5P3_rtY1 Protease When Said Compound 13
`130111111 thereto 111 Said Coflfofmatlofl; and
`(i) accepting or rejecting said candidate compound as an
`HIV protease inhibitor based upon the determinations
`and evaluations carried out in steps (b) through (h).
`
`Janssen Ex. 2032
`
`Lupin Ltd. v. Janssen Sciences Ireland UC
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`
`

`
`5,585,397
`
`5
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 depicts a stereo drawing of a low-energy confor-
`mation of Compound 140, as predicted by computer-mod-
`elling.
`FIG. 2 depicts a stereo drawing of the actual crystal
`structure of Compound 140, as observed by X-ray crystal-
`lography.
`FIG. 3 depicts a stereo drawing of the correlation between
`the predicted (thin line) and observed (thick line) confor-
`mation of Compound 140.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`In order that the invention herein described may be more
`fully understood, the following detailed description is set
`forth. In the description, the following abbreviations are
`used:
`
`Designation
`
`Reagent or Fragment
`
`Ac
`Me
`Et
`Bzl
`Trityl
`Asn
`Ile
`Phe
`Val
`Boc
`Cbz
`Fmoc
`DCC
`DIC
`EDC
`
`HOBt
`I-IOSu
`TFA
`DIEA
`DBU
`EtOAc
`
`acetyl
`methyl
`ethyl
`benzyl
`triphenylmethyl
`D— or L-asparugine
`D- or L-isoleucine
`D- or L—phenylala.nine
`D— or L-valine
`tert-butoxycarbony]
`benzyloxycarbonyl (carbobenzyloxy)
`9—fluorenylmetl1oxycarbonyl
`dicyclohexylcarbodiirnide
`diisopropylcarbodiimide
`l—(3—dirnethy1aminopropyl)-3-
`ethylcarbodiimide hydrochloride
`1-hydroxybenzotriazole
`l-hydroxysuccinimide
`trifluoroacetic acid
`diisopropylethylamine
`l,8—diazabieyc1o(5.4.0)undec-7—ene
`ethyl acetate
`
`The following terms are employed herein:
`the terms
`Unless expressly stated to the contrary,
`“——SO2—” and “—S(O)2—” as used herein refer to a
`sulfone or sulfone derivative (i.e., both appended groups
`linked to the S), and not a sulfinate ester.
`For the compounds of formula I, and intermediates
`thereof,
`the
`stereochemistry of
`the
`explicitly shown
`hydroxyl is defined relative to D on the adjacent carbon
`atom, when the molecule is drawn in an extended zig-zag
`representation (such as that drawn for compounds of for-
`mula XI, XV, XXII, XXIII and XX)G). If both OH and D
`reside on the same side of the plane defined by the extended
`backbone of the compound,
`the stereochemistry of the
`hydroxyl will be referred to as “syn”. If OH and D reside on
`opposite sides of that plane,
`the stereochemistry of the
`hydroxyl will be referred to as “anti”.
`The term “heterocyclic” refers to a stable 5-7 membered
`monocycle or 8-11 membered bicyclic heterocycle which is
`either saturated or unsaturated, and which may be optionally
`benzofused if monocyclic. Each heterocycle consists of
`carbon atoms and from one to four heteroatoms selected
`from the group consisting of nitrogen, oxygen and sulfur. As
`used herein, the terms “nitrogen and sulfur heteroatoms”
`include any oxidized form of nitrogen and sulfur, and the
`quaternized form of any basic nitrogen. The heterocyclic
`
`6
`ring may be attached by any heteroatom of the cycle which
`results in the creation of a stable structure. Preferred het-
`erocycles defined above include, for example, benzirnida-
`zolyl, imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl,
`isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl,
`pyrazinyl, quinoxolyl, piperidinyl, morpholinyl,
`thiarnor-
`pholinyl, furyl,
`thienyl,
`triazolyl,
`thiazolyl, B-carbolinyl,
`tetrazolyl, thiazolidinyl, benzofuanoyl, thiarnorpholinyl sul-
`fone,
`benzoxazolyl,
`oxopiperidinyl,
`oxopyrroldinyl,
`oxoazepinyl, azepinyl,
`isoxazolyl,
`tetrahydropyranyl,
`tet-
`rahydrofuranyl, thiadiazoyl, benzodioxolyl, thiophenyl, tet-
`rahydrothiophenyl and sulfolanyl.
`The terms “HIV protease” and “HIV aspartyl protease”
`are used interchangeably and refer to the aspartyl protease
`encoded by the human immunodeficiency virus type I or 2.
`In a preferred embodiment of this invention, these terms
`refer to the human immunodeficiency virus type 1 aspartyl
`protease.
`The term “hydrophobic” refers to a moiety which tends
`not to dissolve readily in water and is often fat-soluble.
`Hydrophobic moieties include, but are not limited to, hydro-
`carbons, such as alkanes, alkenes, alkynes, cycloalkarres,
`cycloalkenes, cycloalkynes and aromatic hydrocarbons,
`such as aryls, certain saturated and unsaturated heterocycles
`and moieties that are substantially similar to the side chains
`of hydrophobic natural and unnatural oc-amino acids, includ-
`ing valine, leucine, isoleucine, methionine, phenylalanine,
`or-amino isobutyric acid, alloisoleucine, tyrosine, and tryp-
`tophan.
`The term “substantially hydrophobic” refers to a hydro-
`phobic moiety which may optionally contain polar atoms or
`groups in the region of the moiety which are solvent exposed
`when the compound is bound in the active site of an aspartyl
`protease.
`The term “linker moiety” refers to a group within a
`compound, said group consisting of a backbone of 1-6
`atoms selected from the group consisting of C, N, O, S and
`P, said backbone being substituted with, fused to or other-
`wise associated with a substantially hydrophobic group
`capable of associating with the P1 or F1‘ binding pocket of
`an HIV aspartyl protease when said compound is bound
`thereto. In alternative embodiments of this invention, such
`linker moieties may optionally be substituted with a group or
`groups which occupy a volume of space overlapping with
`the volume of space that would be filled by a native substrate
`of HIV aspartyl protease or a nonhydrolyzable isostere
`thereof.
`
`The term “more highly polarizable than a carbonyl” refers
`to a moiety having a polarizability (Ct) greater than that of a
`carbonyl group of a corresponding aldehyde, ketone, ester or
`amide moiety.
`The term “pharmaceutically effective amount” refers to an
`amount eifective in treating HIV infection in a patient. The
`term “prophylactically efl’ective amount” refers
`to an
`amount eifective in preventing PHV infection in a patient. As
`used herein, the term “patient” refers to a mammal, includ-
`ing a human.
`The term “pharmaceutically acceptable carrier or adju-
`vant” refers to a non-toxic carrier or adjuvant that may be
`administered to a patient, together with a compound of this
`invention, and which does not destroy the pharmacological
`activity thereof.
`As used herein, the compounds of this invention, includ-
`ing the compounds of formula I, are defined to include
`pharmaceutically acceptable derivatives thereof. A “phar-
`maceutically acceptable derivative” means any pharmaceu-
`
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`15
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`20
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`30
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`5,585,397
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`8
`The novel sulfonamides of this invention are those of
`formula I:
`
`113
`A-(B),—i;1—ci-i—fi:rr—ci-i2—iI1—so2-is
`H
`on
`D’
`
`(1)
`
`10
`
`7
`tically acceptable salt, ester, or salt of such ester, of a
`compound of this invention or any other compound which,
`upon administration to a recipient, is capable of providing
`(directly or indirectly) a compound of this invention or an
`anti-virally active metabolite or residue thereof.
`Pharmaceutically acceptable salts of the compounds of
`this invention include those derived from pharmaceutically
`acceptable inorganic and organic acids and bases. Examples
`of suitable acids include hydrochloric, hydrobrornic, sulfu-
`,
`,
`_
`,
`,
`,
`_
`_
`ric nitric perchloric fumaric maleic phosphoric glycollic
`lactic salicylic succinic toluene p sfilfonic tartaiic acetic’
`v
`s
`t
`' '
`v
`7
`=
`i2lLllC,2H1E1tfllaIlCSUlfi0k1:lC, forrnic1:%benzoi_t(:1, rrglfinic, nétphthall
`5116-
`-5
`01110 311
`C11ZC11CSl1
`0111C 3C1 3-
`C1 301 S, 3110
`as 0X31iC, While I101 in th6I11S61V6S pharmaceutically aCCePt-
`able, may be employed in the preparation of salts useful as
`interrnediates in obtaining the compounds of the invention
`and their pharmaceutically acceptable acid addition salts.
`Salts derived from appropriate bases include alkali metal
`(e.g., sodium), alkaline earth metal
`(e.g., magnesium),
`ammonium and N——(C,4 alkyl)4+ salts.
`The term “thiocarbamates” refers to compounds contain-
`ing the functional group N—SO2—O.
`The compounds of this invention contain one or more
`asymmetric carbon atoms and thus occur as racemates and
`racemic mixtures, single eriantiomers, diastereomeric mix-
`tures and individual diastereomers. All such isomeric forms
`
`of these compounds are expressly included in the present
`invention. Each stereogenic carbon may be of the R or S
`configuration. The explicitly shown hydroxyl is also pre-
`ferred to be syn to D, in the extended zig—zag conformation
`between the nitrogens shown in compounds of formula I.
`
`30
`
`wherein:
`A is selected from the group consisting of H; Het;
`-——R1——Het; —R‘—C -C alkyl, which may be optionally
`-
`-
`1
`5
`Substituted with one or mcée géougifielecteflfiom flgilflup
`consisting of hydroxy,
`—
`oxy,
`et, —
`ct,
`_NF2_CO_N(R2)(R2)
`lam; __C0_N(R2)(R2);
`and
`——R ———C —C alkenyl, which may be optionally substituted
`15 with one :1‘ rrlore groups selected from the group consisting
`of hydroxy, C —C alkoxy, Het, ——O——Het, ——NR2—-CO-—
`N(R2) (R2) anld —4CO—N(R2) (R2);
`each R1 is independently selected from the group con-
`sisting
`of
`”'C(O)”“:
`“S(0)2‘2"
`_C(O)-C(O),L,_’
`20 ——O—C(0)—, —O—S(O)2, —NR —S(O)2—, —NR —
`C(O)— and —NR2—C(O)—C(O)—;
`each Het is independently selected from the group con-
`sisting of C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6—C,o
`aryl; and 5-7 membered saturated or unsaturated hetero-
`cycle, containing one or more heteroatoms selected from N,
`N(R2), O, S and S(O),,, wherein said heterocycle may
`optionally be benzofused; and wherein any member of said
`Het may be optionally substituted with one or more sub-
`stituents selected from the group consisting of oxo, —-OR2,
`—R2, —N(R2)
`(R2), —R2—OH, —CN, —CO2R2,
`—C(0)-—N(R2)
`(R2), —S(0)2--N(R2) (R2). —N(R2)-
`C(O)—R2, —C(O)—R2, —S(O),,—R2, —OCF3,
`—S(O),,—Ar, methylenedioxy, ——-N(R2)——S(O)2(R2), halo,
`—CF3, —NO2, Ar and —O—Ar;
`each R2 is independently selected from the group con-
`.C(.)mbm'fm°ns of subsmuems and ‘’'‘‘‘‘‘'‘.‘‘’1“ envision.“ by 35
`sisting 0fH and C _C alkyl Optionally Substituted with Ar;
`this invention are only those that result in the formation of
`B when prawn:
`is3__N(R2)___C(R3) (R3)__C(O)_.
`stable compounds. The term “stable”, as used herein, refers
`’
`X33 0 or 1.
`’
`to compounds which possess stability sufficient to allow
`each R3 is’ independently selected from the group con-
`manufacture and administration to a mammal by methods
`sisting of H, Het, C1_C6 alkyl, C2_C6 alkenyl, C3_C6
`known in the art. Typically, such compounds are stable ata 40
`temperature of 40° C. or less, in the absence of moisture or
`cycloalkyl and C5-C6 cycloalkenyl, wherein any member of
`other cherriically reactive conditions, for at least a week.
`said R3, except H, may be optionally substituted with one or
`The compounds of the present invention may be used in
`more substituents selected from the group consisting of
`the form of salts derived from inorganic or organic acids.
`—OR2, —C(O)—NH—R2, —S(O),,—N(R2)
`(R2), Het,
`Included among such acid salts, for example, are the fol-
`—CN, —SR2, —CO2R2, NR2—C(O)——R2;
`lowing: acetate, adipate, alginate, aspartate, benzoate, ben-
`each ii is independently 1 or 2;
`zenesulfonate, bisulfate, butyratc, citrate, carnphorate, cam-
`D and D‘ are independently selected from the group
`phorsulfonate,
`cyclopentanepropionate,
`digluconate,
`consisting of Ar; C1-C4 alkyl, which may be optionally
`dodeeylsulfate, ethanesulfonate, fumarate, glucoheptanoate,
`substituted with one or more groups selected from C3-C5
`glycerophosphate,
`hemisulfate,
`heptanoate,
`hexanoate,
`50 cycloalkyl, —OR2, ——R3, —-—0—Ar and Ar; C2-C4 alkenyl,
`which may be optionally substituted with one or more
`hydrochloride:
`hYdT0bT0mid€:
`hYd10i0did€a
`2‘hYdT0XY-
`groups
`gelgctgd
`from the
`group
`consisting
`of
`ethanesulfonate, lactate, maleate, methanesulfonate, 2-naph-
`C3_c5cyc1oa1ky1, _QR2’ _R3, _()_Ar and Ar; C3_C6
`thalenesulfonate, nicotinate, oxalate, pamoate, pectinate,
`cycloalkyl, which may be optionally substituted with or
`persgllfatei3-phenylpropionateapicrateipivalateipropionatea
`fused with Ar; and C5—CG cycloalkenyl, which may be
`succmate, tamrate, thioeyanate, rosylate and undecanoate.
`optionally substituted with or fused with Ar;
`This invention also envisions the quatemization of any
`each Ar is independently selected from the group con-
`basic nitrogen-containing groups of the compounds dis-
`sisting of phenyl; 3-6 membered carbocyelic ring and 5-6
`closed herein. The basic nitrogen can be quaternized with
`membered heterocyelic ring containing one or more het-
`any agents known to those of ordinary skill
`in the art
`including, for example, lower alkyl halides, such as methyl, 60 eroatoms selected from O, N, S, S (0),, and N(R2), wherein
`ethyl, propyl and butyl chloride, bromides and iodides;
`said carbocyelic or heterocyclic ring may be saturated or
`dialkyl sulfates including dimethyl, diethyl, dibutyl and
`unsaturated and optionally substituted with one or more
`diamyl sulfates; long chain halides such as decyl, lauryl,
`groups selected from the group consisting of oxo, —0R2,
`myr-istyl and stearyl chlorides, bromides and iodides; and
`—R2, —N(R2),
`(R2), —N(R2)—-C(O)——R2, —R2—OH,
`aralkyl halides including benzyl and phenethyl bromides. 65 —CN, —CO2R2, ——C(O)——N(R2) (R2), halo and —CF3;
`Water or oil-soluble or dispersible products may be obtained
`E is selected from the group consisting of Het; 0—Het;
`by such quaternization.
`Het-—-Het; -—O—-R3; —NR2R3; C1—C6all<yl, which may be
`
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`Lupin Ltd. v. Janssen Sciences Ireland UC
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`9
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`5,585,397
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`optionally substituted with one or more groups selected from
`the group consisting of R4 and I-let; C2-C6 alkenyl, which
`may be optionally substituted with one or more groups
`selected from the group consisting of R4 and Het; C3-C6
`saturated carbocycle, which may optionally be substituted
`with one or more groups selected from the group consisting
`of R4 and Het; and C3-C6 unsaturated carbocycle, which
`may optionally be substituted with one or more groups
`selected from the group consisting of R4 and Het; and
`each R4 is independently selected from the grou con-
`sisting of —OR3, —C(O)—NHR3, -S(O)2—NHR , halo,
`—NR3C(O)—R3 and —CN.
`Except where expressly provided to the contrary, as used
`herein, the definitions of variables A, R‘—R4, Het, B, x, n, D,
`D‘, Ar and E are to be taken as they are defined above for the
`compounds of formula 1.
`According to one embodiment of this invention, a