United States Patent
`(12)
`(10) Patent N0.:
`US 6,645,970 B2
`.
`D
`.
`V.
`
`Albert et al
`4‘) Date of Patent
`No
`11, 2003
`
`USOO6645970B2
`
`(54)
`
`INDOLYLMALEIMIDE DERIVATIVES
`
`(75)
`
`Inventors: Rainer Albert, Basel (CH); Nigel
`Graham Cooke, Oberwil (CH);
`Sylvain Cottens, Witterswil (CH);
`Claus Ehrhardt, Lorrach (DE);
`Jean-Pierre Evenou, St. Louis (FR);
`Richard Sedrani, Basel (CH); Peter
`Von Matt, Bicl-Bcnkcn (CH); Jiirgen
`Wagner, Bottmingen (CH); Gerhard
`Zenke’ Rhemfelde“ (DE)
`
`(73) Assignee: Novartis AG, Basel
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U~S-C~ 1540’) by 0 daY5~
`
`(21) Appl. No.: 10/007,368
`7
`~
`,.
`filled'
`(2')
`(65)
`
`NOV' 5’ 2001
`Prior Publication Data
`‘.
`/
`US2003'0069424A1Ap1 10’ 2003
`Related US. Application Data
`Provisional application No. 60/246,400, filed on Nov. 7,
`2000, and provisional application No. 60/283,705, filed on
`APT- 13: 2001-
`Int. Cl.7 .................. .. A61K 31/498; A61K 31/475;
`’
`’
`2
`.
`.
`.
`.................. ..
`'
`(5 ) U S (514/777. 514/1774élgl/iz63?
`514/314; 514/307; 514/309; 514/310; 544/284;
`544/235; 546/135; 546/139; 546/141; 546/143
`(58) Field of Search ............................... .. 544/284, 235;
`514/2662, 256’ 269, 272’ 274, 311’ 312,
`313, 314, 307, 309, 310; 5461/35, 139,
`14, 143
`
`(60)
`
`(51)
`
`2
`
`'
`
`'
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`5,057,614 A
`
`10/1991 Davis et a].
`
`5,399,712 A
`5,721,245 A
`6,040,152 A
`
`3/1995 Hill
`2/1998 Davis et al.
`3/2000 Kupfcr et 211.
`
`FF
`EP
`W0
`W0
`$8
`W0
`
`FOREIGN PATENT DOCUMENTS
`0 540 956 B1
`5/1993
`1 224 932 A1
`7/2002
`W0 91/3070
`9/1991
`W0 91/1307 1
`9/1991
`A
`$8
`W0 02‘ 10158 A
`
`2/2002
`
`OTHER pUBLlCAHONS
`
`Derwent Abstract 2001—234973/24 (WO 01/13916 A, Mar.
`1, 2001).
`. and Gene
`.
`Coghlan M. et al., “Selective Small Molecule .
`Transcription”, Chemistry & Biology, vol. 7, No. 10, pp.
`793—803 (2000).
`3
`_,
`“A New One Step Svnthesis of
`al.
`Faul M.M.
`et
`. Esters with Acetamides”, Tetrahedron
`Maleimides .
`.
`letters, vol. 40, pp. 1109—1112 (1999).
`.
`.
`Hendricks R.T. et a1. “27Arylilndolyl Maleimides .
`.
`’.
`’.
`.
`.
`1
`.
`Protein Kinase C”, Bioorganic & Medicmal Chemistry
`Letter5> VOL 5> N0' 1: PP' 67—72 (1995)
`~
`-
`DaVlS P~ D~ 01 a1” “Inhlbltors 0f PTOtcm Kmasc C ~
`2,3—Bisarylmalcimidcs”,
`J. Med. Chem., vol. 35, pp.
`177—184 (1992).
`.
`_
`MCKane
`Prlmary Examiner—Joseph
`Assistant Examiner—Rebecca Anderson
`(74) Attorney, Agent, or Firm—Norbert Gruenfeld
`(57)
`ABSTRACT
`
`IHdOIYImaICimidc deriVafiVCS comprismg Cithcr a SUbSti'
`tuted phenyl, naphthyl,
`tetrahydronaphthyl, quinazolinyl,
`quinolyl, isoquinolyl or pyrimidinyl residue have interesting
`pharmaceutical properties, eg. in the treatment and/or pre—
`vention of T—cell mediated acute or Chronic inflammatory
`diseases or disorders, autoimmune diseases, graft rejection
`or cancer.
`
`20 Claims, N0 Drawings
`
`Par Pharm., Inc.
`Exhibit 1 1 24
`
`Case lPR2016-01479
`
`Par Pharm., Inc. v. Novartis AG
`
`Ex. 1 124-0001
`
`Ex. 1124-0001
`
`

`

`1
`
`INDOLYLMALEIMIDE DERIVATIVES
`
`US 6,645,970 B2
`
`2
`—continued
`
`(0
`
`NR
`><
`
`is—<
`//_
`
`—\<NR14
`
`R15
`
`wherein
`each of R1, R4, R7, R8, R11 and R14 is OII; SII; a
`heterocyclic residue; NRISR17 wherein each of R16
`and R17, independently, is H or C1_4a1kyl or R16 and
`R17form together with the nitrogen atom to which
`they are bound a heterocyclic residue; or a radical of
`formula on
`
`—X—RC—Y
`
`(0.)
`
`wherein X is a direct bond, 0, S or NR18 wherein R18
`is H or C1_4alky1,
`RC is C1_4alkylcnc or C1_4alkylcnc wherein one CH2
`is replaced by CRny wherein one of R, and R, is
`H and the other is CH3, each of Rx and Ry is CH3
`or R, and Ry form together 7CH27CH27, and
`Y is bound to the terminal carbon atom and is
`selected from OH, a heterocyclic residue and
`—NR1L,R20 wherein each of R19 and R20 indepen-
`dently is H, C3_6cycloa1kyl, C3_6cycloalky1-C1_4
`alkyl, aryl-Cl_4a1ky1 or Cl_4a1ky1 optionally sub-
`stituted on the terminal carbon atom by OH, or R19
`and R20 form together with the nitrogen atom to
`which they are bound a heterocyclic residue;
`each of R2, R3, R5, R5, R9, R10, R12, R13, R15 and R'ls,
`independently, is H, halogen, C1_4alky1, CF3, OH, SH,
`NHZ, C1_4alkoxy, C1_4alkylthio, NHC1_4alkyl, N(C1_4
`alkyl)2 or CN;
`either E is —N= and G is —CH= or E is —CH= and
`G is —N=; and
`ring A is optionally substituted.
`Any alkyl or alkyl moiety in e.g. alkoxy may be linear or
`branched. Halogen may be F, Cl, Br or I, preferably F or Cl.
`Any aryl may be phenyl or naphthyl, preferably phenyl.
`By heterocyclic residue as R1, R4, R7, R8, R11, R]L4 or Y
`or formed, respectively, by NRJGR17 or NngRZO, is meant
`a three to eight, preferably five to eight, membered saturated,
`unsaturated or aromatic heterocyclic ring comprising 1 or 2
`heteroatoms, preferably selected from N, O and S, and
`optionally substituted. Suitable examples include e.g.
`pyridyl, e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin-l-yl, 3-
`or 4—piperidyl, homopiperidyl, piperazinyl,
`homopiperazinyl, morpholin—4—y1,
`imidazolyl,
`imidazolidinyl, pyrrolyl or pyrrolidinyl, optionally
`substituted, e.g. mono- or polysubstituted. When the hetero-
`cyclic residue is substituted, this may be on one or more ring
`carbon atoms and/or on a ring nitrogen atom when present.
`Examples of a substituent on a ring carbon atom include e.g.
`C1_4alky1 e.g. CH3;
`C3_6cycloalkyl e.g. cyclopropyl, optionally further substi-
`tuted by C1_4alkyl;
`
`CH2
`< I
`(CH2)},
`
`wherein p is 1,2 or 3, preferably 1; CF3; halogen; OH;
`NH2; —CH2—NH2; —CH2—OH; piperidin-l-yl; pyr-
`
`Ex. 1 124-0002
`
`Ul
`
`10
`
`20
`
`tom
`
`This application claims the benefit of provisional appli-
`cation No. 60/246,400 filed Nov. 7, 2000 and of provisional
`application No. 60/283,705 filed Apr. 13, 2001.
`The present
`invention relates to indolylmaleimide
`derivatives, process for their production and pharmaceutical
`compositions containing them,
`More particularly the present invention provides a com-
`pound of formula I
`
`
`
`wherein
`
`R, is H; C1_4alkyl; or C1_4alkyl substituted by OH, NHZ,
`NHC1_4alkyl or N(C1_4alkyl)2;
`Rb is H; or Cl_4alkyl;
`
`R is a radical of formula (a), (b), (c), (d), (e) or
`
`R3
`R i\ \2 |
`/ R1
`
`
`
`R6
`R i\ \5 |
`/
`
`
`
`R4
`
`R7
`
`(3)
`
`mm
`
`40
`
`('3)
`
`(C)
`
`50
`
`(d)
`
`55
`
`(e)
`
`60
`
`Ex. 1124-0002
`
`

`

`US 6,645,970 B2
`
`3
`rolidinyl, Examples of a substituent on a ring nitrogen
`atom are e.g. C1_6alkyl; acyl, e.g. R'X-CO wherein R'x is
`H, Clalkyl or phenyl optionally substituted by
`C1_4alkyl, C1_4alkoxy or amino, e.g formyl;
`C3,6cycloalkyl; C3,6cycloalkyl—Cl,4alkyl; phenyl;
`phenyl-CMalkyl e.g. benzyl; a heterocyclic residue,
`e.g. as disclosed above, e.g. an aromatic heterocyclic
`residue comprising 1 or 2 nitrogen atoms; or a residue
`of formula [3
`
`—R21—Y'
`
`([5)
`
`wherein R21 is C1_4alkylene or C2_4alkylene interrupted by
`O and Y' is OH, NHZ, NH(C1_4alkyl) or N(C1_4alkyl)2.
`C2_4alkylene interrupted by 0 may be e.g. —CH2—
`CHz—O—CHz—CH2—.
`When the substituent on a cyclic nitrogen is a heterocyclic
`residue, it may be a five or six membered saturated, unsat—
`urated or aromatic heterocyclic ring comprising 1 or 2
`heteroatoms, preferably selected from N, O and S. Examples
`include e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin—l-yl, 3-
`or 4-piperidy1, homopiperidyl, piperazinyl,
`homopiperazinyl, pyrimidinyl, morpholin-4-yl, imidazolyl,
`imidazolidinyl, pyrrolyl or pyrrolidinyl,
`When Ra is substituted C1_4alkyl, the substituent is pref-
`erably on the terminal carbon atom.
`When ring A is substituted,
`it may be mono- or
`polysubstituted, preferably monosubstituted, the substituent
`(s) being selected from the group consisting of e.g. halogen,
`OH, C1_4a1koxy, e.g. OCH3, C1_4alky1, e.g. CH3, N02, CF3,
`NHZ, NHCMalkyl, N(C1,4alkyl)2 and CN. For example,
`ring A may be a residue of formula
`
`f:
`
`wherein
`
`R, is H; C1_4alky1; or halogen; and
`RE is OH; N02; NHZ; NHCl,4alky'l; or N(C1,4alkyl)2.
`When Ra has a CH2 replaced by CRny, it is preferably
`the CH2 bearing Y.
`Examples of heterocyclic residue as R1, R4, R7, R8, R11,
`R14 or Y or formed, respectively, by NRlsR17 or NngRzo,
`include e.g. a residue of formula (y)
`
`10
`
`20
`
`tom
`
`mm
`
`40
`
`(Y)
`
`50
`
`55
`
`60
`
`wherein
`
`the ring D is a 5, 6 or 7 membered saturated, unsaturated
`or aromatic ring;
`
`Xb is —N—, —C= or —CH—;
`XC is N—, NR,
`,
`CR;
`or
`CHRIS wherein
`Rf is a substituent as indicated above for a ring nitrogen
`atom, and Rf' is a substituent as indicated above for a
`ring carbon atom;
`the bond between C, and C2 is either saturated or unsat-
`urated;
`
`4
`each of C]L and C2, independently, is a carbon atom which
`is optionally substituted by one or two substituents
`selected among those indicated above for a ring carbon
`atom; and
`the line between C3 and Xb and between Cl and X17,
`respectively, represents the number of carbon atoms as
`required to obtain a 5, 6 or 7 membered ring D.
`A preferred residue of formula
`is one wherein the ring
`D forms a 1,4-piperazinyl
`ring optionally C- and/or
`N—substituted as indicated.
`Representative examples of a residue of formula (7) are
`e.g. 3- or 4- pyridyl; piperidin—l-yl; 1-N-(C174alkyl)- or
`7(u)—hydroxinL4all<yl)—3—piperidyl; morpholin—4—yl;
`imidazolyl; pyrrolidinyl; 1—piperazinyl; 2—C1_4alkyl— or —C3_6
`cycloalkyl—l—piperazinyl; 3—C1_4a1kyl— or —C3_5cycloa1kyl—
`l-piperazinyl; 2,2- or 3,5- or 2,5- or 2,6-di(C1_4a1kyl)-l-
`piperazinyl; 3,4,5-tri-(C1_4a1kyl)-1-piperazinyl; 4-N-(C,_4
`alkyl)- or —(u)-hydroxy-Cl_4a1kyl)- or —(u)-
`dimethylamino-Cl_4a1kyl)-1-piperazinyl; 4-N-pyridin-4-yl-
`1-piperazinyl; 4-N-phenyl- or —C3_6cycloalky1-1-
`piperazinyl; 4-N-(C1_4alkyl)- or —((n-hydroxy-C1_4alkyl)-
`3-C1_4alkyl- or —3,3-di(C1_4alkyl)-l -piperazinyl; 4-N—(1-
`C1_4a1kyl-C3_6cycloalky1)-l-piperazinyl; 4-N-formyl-1-
`piperazinyl; 4-N-pyrimidin-2-yl—1-piperazinyl; or 4-N—C1_4
`alkyl-l-h0mopiperazinyl.
`The compounds of formula 1 may exist in free form or in
`salt form, e.g. addition salts with e.g. organic or inorganic
`acids, for example, hydrochloric acid, acetic acid, when R1,
`R4: R7> R85 R11 0r R14 and/01' R2> R35 R5: R5> R9> Rina R12:
`R13 or R1s comprises an optionally substituted amino group
`or a heterocyclic residue which can form acid addition salts.
`It will be appreciated that the compounds of formula I
`may exist
`in the form of optical
`isomers, racemates or
`diastereoisomers. For example, a ring carbon atom bearing
`a substituent in the heterocyclic residue as R1, R4, R7, R8,
`R11, R14 or Y or formed, respectively, by NRMR17 or
`NR19R20, is asymmetric and may have the D- or L- con-
`figuration. It is to be understood that the present invention
`embraces all enantiomers and their mixtures. Similar con-
`siderations apply in relation to starting materials exhibiting
`asymetric carbon atoms as mentioned.
`In the compounds of formula I, the following significan—
`ces are preferred individually or in any sub—combination:
`1. Rd is 11 or C113;
`2. Rb is H;
`3. Ring A is unsubstituted; or is substituted by methyl in
`position 7;
`4. Preferred heterocyclic residue as formed by NR16R17 is
`e.g. piperazin-l-yl optionally N—substituted, e.g. by
`Cl,4aakyl, 03-hy'droxy-C1,4alkyl,
`(n-dimethylamino-
`CL4 alkyl, C5_6cycloalkyl, C1_4alkyl-C5_6cycloalkyl, an
`aromatic heterocyclic residue comprising 1 or 2 nitro—
`gen atoms, e. g. pyridyl or pyrimidin—2—yl, or aresidue of
`formula [3 as defined above and/or optionally
`C-substituted, e.g. by CH3 e.g. in positions 2, and/or 3
`and/or 5 and/or 6 and/or 2,2 or 3,3 or by
`
`in position 2 or 3; piperidin—l—yl optionally
`e.g.
`C—substituted, e.g. in position 4, by NH2, —CH2—NH2
`or piperidin—l—yl, or in position 3, e.g. by OH or NH2;
`or pyrrolidinyl optionally C-substituted in position 3 by
`OH or NHZ;
`
`Ex. 1 124-0003
`
`Ex. 1124-0003
`
`

`

`US 6,645,970 B2
`
`6
`b) reacting a compound of formula IV
`
`O
`
`N112
`
`(1")
`
`\ Rb
`
`N |R
`
`a
`
`wherein Ra, Rb and ring A are as defined above, with a
`compound of formula V
`
`R—CO—CO—OCH3
`
`(V)
`
`wherein R is as defined above; or
`c) converting in a compound of formula I a substituent R1,
`R4, R7, R8, R11 or Rl4 into another substituent R1, R4,
`R7, R8, R11 0r R14
`and, where required, converting the resulting compound of
`formula I obtained in free form to a salt form or vice versa,
`as appropriate.
`Process steps a) and (b) may conveniently be elfected in
`the presence of a strong base, e.g.
`t-BuOK. When corri-
`pounds of formula III or V comprising an OH group which
`should not participate to the reaction are used, such OH
`group is in protected form. The OH-protecting group may be
`removed according to methods known in the art at the end
`of condensation step a) or b). Process step c) may be carried
`out according to known methods: for example when R1, R4,
`R7, R8, R11, or R14 comprises a final OH group, this OH
`group may be replaced by the desired —NR15R17 or
`—NR19R20’
`Compounds of formula II may be prepared by reacting the
`corresponding indol compound with an oxalyl halogenide,
`e.g. chloride, or with a monoalkyl oxalyl chloride under
`basic conditions, e.g. as disclosed in Example 28.
`Compounds of formula III or V, used as starting materials,
`may be prepared in accordance with known methods, e.g. by
`introducing the desired substituent R1, R4, R7, R8, R11 or
`R14, respectively, in a compound of formula III‘ or V‘
`
`R'—CH2—CO—NH2
`
`R"—CO—CO—OCH3
`
`(III')
`
`(v')
`
`wherein each of R' or R" is respectively a radical of formula
`(a), (b), (c), (d), (e) or (f), each of which comprising a
`leaving group, e.g. halogen, in place of R1, R4, R7, R8, R1,,
`or R14.
`Alternatively, compounds of formula III wherein R is a
`radical of formula (a), (b) or (c), R1, R/| or R7 being a radical
`of formula (0.), may be prepared in accordance with known
`methods by reacting a compound of formula 111' wherein R'
`is respectively a radical of formula (a), (b) or (c), each of
`which comprising OH in place of R1, R4or R7, with a
`compound of formula Xa—X—RC—Y wherein Xa is a
`leaving group, e.g. Cl, and X, RC or Y are as defined above.
`Compounds of formula I wherein R is a radical of formula
`(e) wherein E is —N=, G is —CH= and R11 is
`—O—RC—Y or —S—RC—Y may also be prepared by
`reacting together a compound of formula II as defined above
`with a compound of formula 111' wherein R’ is a radical of
`formula (e')
`
`Ex. 1 124-0004
`
`Ul
`
`10
`
`20
`
`tom
`
`mm
`
`40
`
`50
`
`55
`
`60
`
`5
`
`5. R18 is H or CH3;
`6. RC is C1_4a1kylene or C1_4alkylene wherein the terminal
`CH2 is replaced by CRxRy wherein Rx and Ry form
`together —CH2—CH2—;
`7. X is O;
`30
`. The radical of formula (a) is —O—CH2—CH2—Y;
`9. Each of R19 and R20 is H, C,_4alkyl, e.g. methyl,
`C1_4alkyl substituted on the terminal carbon atom by
`OH, e.g. —CH2—CH2—OH, or cyclopropyl;
`10. Preferred heterocyclic residue as formed by NRlQR20
`is e.g. piperazin—l—yl optionally N—substituted by
`C1_4alkyl or a residue of formula [3; piperidin-l-yl;
`l-(C,_4alkyl)-piperidin-3-yl; 3- or 4-pyridyl;
`imida-
`zolyl; pyrrolidinyl; or morpholin-4-yl;
`11. Each of R1, R4, R7, R8, R11 or RM, independently, is
`1—N—methyl—piperidin—4—yl; 4—methyl—piperazin—1—yl;
`4—methyl—1—homopiperazinyl; 4—(2—hydroxyethyl)—
`piperazin—l—yl; or —X'—C1;2 or 3—alkylene—NR10R20
`wherein X' is a direct bond, 0 or NH;
`12. In the residue of formula (a) either each of R2 and R3
`is H or one of R2 and R3 is H and the other is F, Cl, CH3,
`OH, OCH3 or CF3;
`13. In the residue of formula (a) R2 is OH;
`14. In the residue of formula (b) either each of RS and R6
`is H or one of R5 and R6 is H and the other is F, Cl, CH3,
`OCH3 or CF3;
`15. In the residue of formula (b) R4 is a radical of formula
`(0) or NR15R17;
`16. In the residue of formula ((1) either each of R9 and R10
`is H or one of R9 and R10 is H and the other is F, Cl,
`CH3, OCH3 or CF3; preferably R10 is H and R9 is in
`position 5, 6, 7 or 8, preferably in position 6;
`17. In the residue of formula (e) each of R12 and R13 is H;
`18. In the residue of formula (e) one of R12 and R3 is H
`and the other is F, Cl, CH3, OCH3 or CF3;
`when E is —N= and G is —CH=, preferably R13 is
`H and R12 is in position 6 or 7;
`when E is —CH= and G is —N=, preferably R13 is
`H and R12 is in position 7;
`19. In the residue of formula R15 is H, CH3 or Cl, e.g.
`in position 5 or 6;
`20. In the residue of formula (f) R15 is H or CH3, e.g. in
`position 5, preferably H;
`21. R is a radical of formula (d), (e) or (f).
`The present invention also includes a process for the
`preparation of a compound of formula I which process
`comprises
`a) reacting a compound of formula II
`
`O
`
`O
`
`0/
`
`(11)
`
`\ Rb
`
`N |R
`
`a
`
`wherein Ra, Rb and ring A are as defined above, with a
`compound of formula III
`
`R—CHz—CO—NHZ
`
`wherein R is as defined above,
`
`(III)
`
`Ex. 1124-0004
`
`

`

`7
`
`US 6,645,970 B2
`
`8
`EXAMPLE 1
`
`Rlfi/ ’
`R13—r
`\
`
`l
`
`\
`
`N/
`
`Xa
`
`3-(1.II.-lndol-3-yl)—4-[3-(2-dimethylamino-ethoxy)-
`5-hydroxy-phenyl]-pyrrole-2,5-dione
`
`2m
`
`(6’)
`
`Ul
`
`10
`
`wherein R12 and R13 are as defined above and Xa is a leaving
`group, e.g. halogen, and with a compound of formula VI
`
`R‘llH
`
`(VI)
`
`wherein R11 is iOiRciY or isiRciY. This reaction
`may be carried out in accordance with know methods, e.g.
`as disclosed in Example 28 below.
`
`20
`
`Compounds of formula I wherein R is a radical of formula
`(d) or
`wherein R8 or R14 is —O—RC—Y or —S—RC—Y
`may also be prepared by reacting together a compound of
`formula II as defined above with a compound of formula 111'
`wherein R" is a radical of formula (d') or (f)
`
`
`
`01'
`
`R'is
`R15\//_\ \
`
`(‘1')
`
`(f')
`
`mm
`
`wherein R9, R10, R15 and R‘15 are as defined above and X“
`is a leaving group, e.g. halogen, and with a compound of
`formula VI'
`
`(VI)
`
`50
`
`wherein A is —O—RU—Y or —S—RC—Y. This reaction
`may be carried out in accordance with know methods.
`Insofar as the production of the starting materials is not
`particularly described, the compounds are known or may be
`prepared analogously to methods known in the art or as
`described hereafter.
`
`The following Examples are illustrative of the invention.
`RT=room temperature
`THF=tetrahydrofuran
`FCC=flash column chromatography
`TBAF=tetrabutyl ammonium fluoride
`BlNAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
`
`55
`
`60
`
`Asolution of 400 mg (0.58 mmol) of 3—(1.H.—indol—3—yl)—
`4—[3—(2—methanesulfonyloxy—ethoxy)—5—triphenylmethoxy—
`phenyl]-pyrrole-2,5-dione in 5 mL of 33% dimethylamine in
`ethanol is stirred overnight at RT. The reaction mixture is
`diluted with ethyl acetate. The resulting mixture is washed
`with saturated aqueous sodium bicarbonate. The layers are
`separated and the aqueous layer is extracted with three
`portions of ethyl acetate. The combined organic solution is
`washed with saturated brine, dried over anhydrous sodium
`sulfate, filtered and concentrated under reduced pressure.
`The residue is filtered through a plug of silica gel (70:30
`cthyl acetate/methanol) to afford 3-(1.H.-lndol-3-yl)—4-[3-
`(2-dimethylamino-ethoxy)-5-triphenylmethoxy-phenyl]—
`pyrrole—2,5—dione, which is immediately used in the next
`step without further purification.
`To a solution of 370 mg (0.58 mmol) of 3-(1.H.-lndol-3-
`yl)-4-[3-(2-dimethylamino-ethoxy)-5-triphenylmethoxy-
`phcnyl]-pyrrolc-2,5-di0nc in 5 mL of methanol is added 251
`mg (1.46 mmol) of para-tolucncsulfonic acid. After stirring
`for 2 h at room temperature, the mixture is diluted with ethyl
`acetate and washed with saturated aqueous sodium bicar—
`bonate. The aqueous layer is extracted with three portions of
`ethyl acetate. The combined organic layers are washed with
`saturated brine, dried over anhydrous sodium sulfate, filtered
`and concentrated under reduced pressure. The residue is
`purified by column chromatography on silica gel (7:3 ethyl
`acetate/methanol) to afford the title compound as an orange
`foam.
`
`1H NMR (DMSO-ds, 400 MHz) 6 11.89 (s, 1H), 11.00 (s,
`1H), 9.45 (s, 1H), 7.98 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.08
`(t, J=7.4 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.50 (m, 2H), 6.34
`(s, 1H), 6.30 (s, 1H), 3.69 (t, J=5.9 Hz, 2H), 2.35 (t, J=5.9
`Hz, 2H), 2.06 (s, 6H); MS (EI, negative ionization) m/z 390
`[M—H]‘, (El, positive ionization) m/z 392 [M+H]+
`3-(1.H.-Indol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-
`5-hydroxy-phenyl]-pyrrole-2,5-dione, used as starting
`material, may be prepared as follows:
`a)
`[3-(2-Triisopropylsilyloxy-ethoxy)-5-hydroxy-phenyl]—
`acetic Acid Methyl Ester
`A mixture of 9.39 g (51.5 mmol) of (3,5-dihydroxy-
`phenyl)—acetic acid methyl ester (prepared according to U.
`Edcr, G. Saucr, G. Haffcr, G. Nccf, R. Wicchcrt, US. Pat.
`No. 4,066,674), 11.38 g (61.8 mmol) of 1-bromo-2-
`triisopropylsilyloxy—ethane and 14.50 g (51.5 mmol) of
`cesium carbonate is stirred at RT for 1 hour and at 60° C. for
`another hour. The reaction mixture is then treated with
`saturated aqueous sodium carbonate and extracted with ethyl
`acetate. The layers are separated and the organic layer is
`
`Ex. 1 124-0005
`
`Ex. 1124-0005
`
`

`

`US 6,645,970 B2
`
`9
`washed three times with saturated aqueous sodium carbon-
`ate. The aqueous layers are combined and extracted three
`times with ethyl acetate. The combined organic solutions are
`then washed with saturated brine, dried, filtered and con-
`centrated under reduced pressure. The residue is purified by
`column chromatography 011 silica gel (85:15 hexane/ethyl
`acetate then 70:30 hexane/ethyl acetate and finally pure
`ethyl acetate) to afford above title compound as a yellow oil.
`MS (EI, negative ionization) m/z 381 [M—H]‘, (EI, positive
`ionization) m/z 405 [M+Na]+
`b) 2-[3-(2-Triisopropylsilyloxy-ethoxy)-5-hydroxy-phenyl]—
`acetamide
`Amixture of 3.9 g (10.2 mmol) of the compound of step
`a) and 40 mL of concentrated aqueous ammonia is stirred at
`RT for 2 days and the solvents are removed under reduced
`pressure. The residue is dissolved in ethyl acetate and
`filtered through a plug of silica gel. The filtrate is reduced
`under reduced pressure. The residue is dissolved in a mini-
`mum of ethyl acetate and n-hexane is added upon which the
`desired product crystallized, affording above title compound
`after filtration and drying.
`MS (EI, negative ionization) m/z 366 [M—H]‘, (EI, posi—
`tive ionization) m/z 390 [M+Na]+
`c) 2-[3-(2-Triisopropylsilyloxy-ethoxy)-5-
`triphenylmethoxy-phenyl]-acetamide
`A solution of 1.6 g (4.38 mmol) of compound b), 3.7 g
`(13.27 mmol) of triphenyl chloromethane, 3.7 mL (26.69
`mmol) of triethylamine and 535 mg (4.38 mmol) of dim-
`ethylaminopyridine in 50 mL of dichloromethane is stirred
`at room temperature for 2 hours. Saturated aqueous sodium
`bicarbonate is added and the mixture is extracted with three
`portions of ethyl acetate. The combined organic layers are
`washed twice with saturated aqueous sodium bicarbonate
`and once with saturated brine, dried over anhydrous sodium
`sulfate, filtered and concentrated under reduced pressure.
`The residue is purified by column chromatography on silica
`gel (1:2 n—hexane/ethyl acetate followed by 100% ethyl
`acetate) to afford the title compound c) as a white foam. 1H
`NMR (DMSO-dfi, 400 MHz) 6 7.46—7.20 (m, 16H), 6.81 (s,
`1H), 6.38 (s, 1H), 6.28 (s, 1H), 5.92 (s, 1H), 3.81 (dd, J=4.5,
`4.7 Hz, 2H), 3.68 (dd, J=4.5, 4.7 Hz, 2H), 3.13 (s, 2H),
`1.11—0.91 (m, 21H); MS (EI, negative ionization) m/z 608
`[M—H]‘, (EI, positive ionization) m/z 632 [M+Na:|+
`d) 3-(1.H.-Indol-3-yl)-4-[3-(2-triisopropylsilyloxy-ethoxy)-
`5-triphenylmethoxy-phenyl]—pyrrole-2,5-dione
`To a stirred solution of 2.5 g (4.12 mmol) of compound c)
`and 1.3 g (6.40 mmol) of (1.II.-indol-3-yl)-oxo-acetic acid
`methyl ester in 18 mL of THF is added 20.6 mL (20.6 mmol)
`of a 1M solution of t-BuOK in THF at room temperature.
`The reaction mixture is heated to 60° C. for 45 minutes and
`then allowed to cool
`to RT. Saturated aqueous sodium
`bicarbonate is added and the resulting mixture is diluted
`with ethyl acetate. The layers are separated. The aqueous
`layer is extracted three times with ethyl acetate. The com-
`bined organic solutions are washed twice with saturated
`aqueous sodium bicarbonate and once with saturated brine,
`dried over anhydrous sodium sulfate, filtered and concen-
`trated under reduced pressure. The residue is purified by
`column chromatography on silica gel (2:1 n-hexane/ethyl
`acetate followed by 100% ethyl acetate) to afford the title
`compound d) as an orange foam. lII NMR (DMSO-dfi, 400
`MHz) 6 11.90 (s, 1H), 10.95 (s, 1 H), 7.93 (s, 1H), 7.43 (d,
`J=8.0 Hz, 1H), 7.37—7.20 (m, 15H), 7.11 (dd, J=7.4, 7.6 Hz,
`1H), 6.74 (t, J=7.6 Hz, 1H), 6.56 (s, 1H), 6.33 (s, 1H), 6.16
`(d, J=8.0 Hz, 1H), 6.07 (t, J=2.1 Hz, 1H), 3.65 (dd, J=4.1, 5.1
`Hz, 2H), 3.39 (m, 2H), 1.04—0.87 (m, 21H); MS (EI,
`negative ionization) m/z 761 [M—H]’, 518 [M—Ph3C]’, (EI,
`positive ionization) m/z 785 [M+Na]+
`
`Ul
`
`10
`
`20
`
`tom
`
`mm
`
`40
`
`50
`
`55
`
`60
`
`10
`e) 3-(1.H.-Indol-3-yl)-4-[3-(2-hydroxy-ethoxy)-5-
`triphenylmethoxy-phenyl]-pyrrole-2,5-dione
`
`To a stirred, cooled (0° C.) solution of 1.8 compound d)
`in 15 mL of THF is added 7.1 mL (7.1 mmol) of a 1M
`solution of TBAF in THF. After 45 minutes, saturated
`aqueous sodium bicarbonate is added, and the resulting
`mixture is diluted with ethyl acetate. The layers are sepa-
`rated. The aqueous layer is extracted with three portions of
`ethyl acetate. The combined organic layers are washed twice
`with saturated aqueous sodium bicarbonate and once with
`saturated brine, dried over anhydrous sodium sulfate, filtered
`and concentrated under reduced pressure. The residue is
`purified by column chromatography on silica gel
`(1:1
`n-hexane/ethyl acetate) to afford the title compound e) as an
`orange foam.
`
`1NMR (DMSO-do, 400 MHz) 6 11.89 (s, 1H), 10.95 (s,
`1H), 7.91 (d, J=2.1 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),
`7.40—7.20 (m, 15H), 7.13 (dd, J=7.4, 7.6 Hz, 1H), 6.77 (dd,
`J=7.2, 7.8 Hz, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 6.20 (d, J=8.0
`Hz, 1H), 6.08 (t, J=2.1 Hz, 1H), 4.66 (s, 1H), 3.37 (s, 4H);
`MS (EI, negative ionization) m/z 605 [M—H]', 362
`[M—Ph3C]', (131, positive ionization) m/z 629 [M+Na]+, 645
`|:M+K]+
`
`f) 3—(1.H.—Indol—3—yl)—4—[3—(2—methanesulfonyloxy—ethoxy)—
`5 —triphenylmethoxy—phenyl]—pyrrole —2,5 —dione
`
`A mixture of compound e), 1.0 g (5.74 mmol) of meth-
`anesulfonic anhydride and 0.76 mL (9.42 mmol) of pyridine
`in 20 mL of THF is stirred at room temperature for 1 hour.
`Saturated aqueous sodium bicarbonate is added, and the
`resulting mixture is diluted with ethyl acetate. The layers are
`separated. The aqueous layer is extracted with three portions
`of ethyl acetate. The combined organic layers are washed
`twice with saturated aqueous sodium bicarbonate and once
`with saturated brine, dried over anhydrous sodium sulfate,
`filtered and concentrated under reduced pressure. The resi-
`due is purified by column chromatography on silica gel (1:2
`n-hexane/ethyl acetate followed by 100% ethyl acetate) to
`afford the title conmpound f) as an orange oil.
`
`The compounds of formula X1
`
`wherein R1 and R2 are as defined in Table 1, may be
`prepared by following the procedure of Example 1 but using
`the appropriate starting materials. Starting materials which
`do not comprise a OH substituent will be prepared without
`the protecting steps as indicated in Example 1.
`
`Ex. 1 124-0006
`
`Ex. 1124-0006
`
`

`

`11
`
`12
`
`US 6,645,970 B2
`
`TABLE 1
`
`Example
`2
`3
`4
`5
`6
`7
`8
`9
`1 0
`
`11
`12
`13
`
`14
`
`15
`1 6
`17
`1 8
`1 9
`20
`21
`22
`23
`24
`25
`26
`27
`
`R1
`OH
`—O—(CII,)3—N(CI13)2
`—O—CH2-4-pyridyl
`—O—CHZ-3-pyridyl
`—O—CIIz—CHQ—OII
`—0—CH2—CH2—piperidin- 1 -yl
`—O—CHZ—CH2—(4-methyl-piperazin-l-yl)
`—O—CH2—CH2—(11101pl1oli11-4-yl)
`—O—CH2—(‘.H2—[4-(2—hydroxyethyl)-
`piperazineleylj
`—O—CH2—CH3—(imidazol-1-yl)
`—o—CH,—CH2—N(CH3)2
`—O—CHZ—CH2—I|\T(CH3)
`HO— CH2— CH;
`
`—o—C112— CIIZ—N(benzyl)
`
`HO — CH2— CH2
`
`R2
`H
`II
`H
`H
`II
`H
`H
`H
`H
`
`H
`H
`H
`
`H
`
`E“
`
`IEEIEEIEE
`
`mam
`
`m
`
`—o—CH2—cn,—N(CH,—cuz—on‘),
`—O—CH2—CH2—(pyrrolidin-1-yl)
`—O—CH2—(1-methyl-piperidin-3-yl)
`—CH,—N(CH,)2
`—0—Cn,—Cn,—N(C113)2
`—o—CH,—CH2—N(CH3)2
`—(4-methyl-piperazi_n-1-yl)
`—(4-r11ethyl-piperaziu-1-yl)
`—(4-methyl-piperazi_n-1-yl)
`7(4emethylepiperazineleyl)
`—(4-1nethyl-piperazin—1-yl)
`—(4-methyl-piperazi_n-1-yl)
`7(4emethylepiperazineleyl)
`
`1—1
`H
`H
`H
`—O—CIIl—CI13
`—o—CH3
`H
`H
`H
`H
`H
`H
`H
`
`.:
`
`SENSE:
`QQEEEEM.
`
`m
`
`,0
`
`MS. Data
`
`J-tH-tfl-tJ-th—thJ-tJ-tt—tfl-
`
`4.4.1.4..
`
`.1.
`
`,3 m
`
` 0:
`
`mamammaaHaamgw
`
`0
`
`0
`
`304
`M+
`390
`MII+
`396
`MH+
`MH+ 396
`M+ 348
`MH+ - 16
`MH+
`31
`MH+
`18
`MH+
`61
`
`ll!
`MH+ 399
`MH' 376
`MH+ >06
`
`MH+ 82
`
`346
`M+ -19
`MH+ -06
`
`387
`
`01
`15
`21
`35
`
`III!
`
`
`
`EXAMPLE 28
`
`3-(1.H.-lndol—3-yl)4-[3-(2-dimethylamino-ethoxy)-
`naphthalen—l —yl]—pyrrole—2,5 —dione
`
`
`
`A suspension of 2.10 g (4.41 mmol) of 3-(1.H.-indol-3-
`yl)-4-[3-(2-meth anesulfonyloxyethoxy)-naphthalen-1 -yl]—
`pyrrole-2,5-dione in 20 ml. of a 33% solution of dimethy-
`lamine in ethanol is stirred at room temperature overnight.
`The solvents are removed under reduced pressure. The
`product is crystallized from 1:1 acetonitrile/water, filtered
`and washed with 1:1 acetonitrile/water, diethlylether and
`n—hexane. This procedure affords the title compound as a
`red—orange crystalline solid.
`1H NMR (DMSO-ds, 400 MHZ) 0 11.84 (s, 1H), 11.13 (s,
`1H), 7.97 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.4 Hz,
`1H), 7.47 (s, 1H), 7.39 (t, J=7.4 Hz, 1H), 7.31 (d, J=8.2 Hz,
`1H), 7.16 (t, J=7.4 Hz, 1H), 7.12 (s, 1H), 6.92 (dd, J=7.4, 7.6
`Hz, 1H), 6.46 (dd, J=7.4, 7.6 Hz, 1H), 6.25 (d, J=8.2 Hz,
`1H), 4.16 (m, 2H), 2.63 (dd, J=5.5, 5.7 Hz, 2H), 2.20 (s, 6H);
`
`mm
`
`40
`
`50
`
`55
`
`60
`
`13C NMR (DMSO-dfi, 100 MHz) 5 173.3, 173.2, 156.3,
`137.1, 136.6, 135.3, 132.2, 131.6, 128.6, 128.1, 127.7,
`127.3, 126.4, 125.6, 124.7, 122.8, 121.9, 121.3, 120.7,
`112.9, 109.2, 105.9, 66.8, 58.4, 46.4; IR (KBr) 3244, 1698,
`1629, 1597,1220, 1039.
`3-(1.H.-Ind01-3-y1)-4-[3-(2-methanesulfonyloxy-ethoxy)-
`naphthalen-1-y1]—pyrrole-2,5-dione, used as starting materi-
`als may be prepared as follows:
`a) 1-Bromo-3-(2-triisopropylsilyloxy-ethoxy)-naphtalene
`A stirred mixture of 4.38 g (19.6 mmol) of 1—br0mo—
`naphtalen-3-ol (prepared according to the procedure of M. S.
`Newman, V. Sankaran, D. R. Olson, J. Am. Chem. Soc.
`1976, 98, 3237—3242), 5.52 g (19.6 mmol) of 1-bromo-2-
`triisopropylsilyloxy-ethane, 13.56 g (98.1 mmol) of potas-
`sium carbonate and 1.45 g (3.9 mmol) of tetrabutylammo-
`nium iodide in 50 mL of dimethylformamide is heated to 60°
`C. for 4 hours. Then an additional 0.55 g (2.0 mmol) of
`1—bromo—2—triisopropylsilyloxy—ethane are added and stir—
`ring is continued for another hour at 60° C., after which TLC
`analysis indicated complete consumption of 1-br0mo-
`naphtalen-3-ol.
`The mixture is allowed to cool to room temperature and
`brine is added. The resulting solution is extracted with ethyl
`acetate. The organic solution is washed twice with brine and
`the combined aqueous layers are back extracted with ethyl
`acetate. The organic layers are combined, dried, filtered and
`concentrated under reduced pressure. The oily brown resi-
`due is purified by column chromatography on silica gel
`(97.5225 n-hexane/diethylether) to afford above title com-
`pound as a brown solid.
`b) OX0—[3—(2—triisopropylsilyloxy—ethoxy)—naphthalen—1—
`y1]—acetic acid methyl ester
`To a stirred, cooled (—78° C.) solution of 1.59 g the
`compound of step a) in 15 mL of THF is added 2.6 mL (4.13
`
`Ex. 1 124-0007
`
`Ex. 1124-0007
`
`

`

`US 6,645,970 B2
`
`13
`in n-hexane. The
`mmol) of a 1.6 M solution of n-BuLi
`resulting mixture is stirred for 1 h and a solution of 886 mg
`(7.50 mmmol) of dimethyloxalate in 5 mL of THF is added
`dropwise. After stirring the reaction mixture for 30 minutes
`at —78° C., it is warmed to 0° C., and stirring is continued
`at that temperature for 3 hours. Thereafter an additional 132
`mg (1.12 mmol) of dimcthyloxalatc in 1 mL of THF is
`added. Stirring is continued for 1 h at 0° C., and the reaction
`is quenched by the addition of saturated aqueous ammonium
`chloride. Ethyl acetate is added and the layers are separated.
`The organic layer is washed twice with saturated brine. The
`aqueous layers are combined and extracted one more time
`with ethyl acetate. The combined organic solutions are dried,
`filtered and concentrated under reduced pressure. The resi-
`due is purified by column chromatography on silica gel
`(95:5 n—hcxanC/dicthylcthcr) to afford abovc title compound
`as a yellow oil.
`c) 3-(1.H.-Indol-3-yl)-4-[3-(2-triisopropylsilanyloxy-
`ethoxy)-naphthalen-1-yl]—pyrrole-2,5-dione
`To a solution of 1.070 g the compound of step b) and
`0.436 g (2.50 mmol) of 2-(1.H.-lndol—3-yl)—acetamide in 10
`mL of THF is added at RT 12.5 mL (12.5 mmol) of a 1M
`solution of t—BuOK in THF. After the addition is complete
`the mixture is heated to 60° C. for 4 hours and then allowed
`to cool
`to room temperature. Saturated aqueous sodium
`bicarbonate is added and the resulting mixture is extracted
`with ethyl acetate. The organic layer is washed twice with
`saturated brine. The aqueous layers are combined and
`extracted with ethyl acetate. The combined organic extracts
`are dried, filtered and concentrated under reduced pressure.
`The residue is purified by column chromatography on silica
`gel (60:40 n-hexane/ethyl acetate) to afford above title
`compound as a red-orange solid.
`1H NMR (DMSO-ds, 400 MHz) 6 11.85 (s, 1H), 11.15 (s,
`1H), 7.98 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.4 Hz,
`1H), 7.47 (s, 1H), 7.39 (dd, J=7.4, 7.6 Hz, 1H), 7.31 (d, J=8.0
`Hz, 1H), 7.15 (m, 2H), 6.92 (dd, J=7.4, 7.6 Hz, 1H), 6.44
`(dd, J=7.4, 7.8 Hz, 1H), 6.26 (d, J=8.0 Hz, 1H),