(19) United States
`(12) Reissued Patent
`(10) Patent Number:
`US RE41,065 E
`
`Schnur et a].
`(45) Date of Reissued Patent:
`Dec. 29, 2009
`
`USOORE41065E
`
`(54) ALKYNL AND AZIDO-SUBSTITUTED 4-
`ANILINOQUINAZOLINES
`
`(75)
`
`Inventors: Rodney Caughren Schnur, Noank, CT
`(US); Lee DanielArnold, Mt. Sinai, NY
`(Us)
`
`.
`(73) Ass1gnees: Pfizer, Inc., New York, NY (US); OSI
`Pharmaceuticals, Inc., Me1v111e, NY
`(US)
`
`(21) App1.No.: 12/03s,530
`
`(22)
`
`Filed;
`
`Feb_ 27, 2003
`
`EP
`EP
`EP
`
`SU
`W0
`WO
`W0
`WO
`WO
`WO
`W0
`WO
`
`W0
`W0
`
`W0
`WO
`
`635498
`0 635 498 A1
`0 635 507 A1
`
`466233
`W0 92/20642
`92/20642 A1
`WO 93/04047 A1
`1995/03283
`WO 95/15758
`95/15758 A1
`1996/15118
`1996/28430
`
`199732856
`1998/13354
`
`2004/072049 A1
`1997/30035
`
`1/1995
`1/1995
`1/1995
`
`4/ 1975
`11/1992
`11/1992
`3/1993
`2/1995
`6/1995
`6/1995
`5/1996
`9/1996
`
`9/ 1997
`4/1998
`
`8/2004
`8/2007
`
`.
`Reissue of:
`
`Related US. Patent Documents
`
`OTHER PUBLICATIONS
`
`(64) Patent No.2
`Issued:
`APPL N0~¢
`Filed:
`
`US. Applications:
`
`5,747,498
`May 5’ 1998
`03/653386
`May 28, 1996
`
`(63) Continuation-in-part of application No. PCT/IB95/00436,
`filed on Jun. 6, 1995.
`
`(51)
`
`Int. Cl.
`C07D 239/94
`C07D 239/70
`A61K 31/517
`A6IP 1 7/06
`A6IP 35/00
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`.................... .. 514/266.1; 544/293; 544/283
`(52) US. Cl.
`(58) Field of Classification Search ................ .. 544/293;
`5 1 4/266 .1
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
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`Wolft Manfred E. “Burger’s Medicinal Chemistry, 5ed, Part
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`Cecil Textbook of Medicine, edited by Bennet, J.C., and
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`Dermer et a1., Bio/Technology, 1994, 12:320.*
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`Cohen et a1., Current Opinion in Chemical Biology, 3,
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`Opposition filed by Natco Pharma on Apr. 5, 2007, in respect
`of Indian Patent Application No. 537 DEL/96.
`
`(Continued)
`
`Primary ExamineriVenkataraman Balasubramanian
`(74) Attorney, Agent, or Firm7Woodcock Washburn LLP
`
`(57)
`
`ABSTRACT
`
`The invention relates to compounds of the formula
`
`/ |—(R3)n
`J
`R2
`\N \\R4
`
`\N
`/ I
`(R011.—\ N9
`
`and to pharmaceutically acceptable salts thereof, wherein
`R1, R2, R3, R4, 11 and m are as defined herein. The com-
`pounds of formula I are useful in the treatment of hyperpro-
`liferative diseases, such as cancer. The invention further
`relates to processes of making the compounds of formula I
`and to methods of using such compounds in the treatment of
`hyperproliferative diseases.
`
`18 Claims, No Drawings
`APOTEX EX. 1056—001
`
`APOTEX EX. 1056-001
`
`

`

`US RE41,065 E
`
`Page 2
`
`OTHER PUBLICATIONS
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`ents Act for Revocation of Patent No. 196774 Titled “A
`
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`
`APOTEX EX. 1056—002
`
`APOTEX EX. 1056-002
`
`

`

`US RE41,065 E
`
`Page 3
`
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`, Rejoinder to the Reply
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`HofmaniLa Roche Ltd., & Anr. vs. Cipla Limited.
`
`* cited by examiner
`
`APOTEX EX. 1056—003
`
`APOTEX EX. 1056-003
`
`

`

`US RE41,065 E
`
`1
`ALKYNL AND AZIDO-SUBSTITUTED 4-
`ANILINOQUINAZOLINES
`
`Matter enclosed in heavy brackets [ ] appears in the
`original patent but forms no part of this reissue specifica-
`tion; matter printed in italics indicates the additions
`made by reissue.
`This application is a continuation-in—part of PCT interna-
`tional application number PCT/IB95/00436, filed Jun. 6,
`1995, which designates the United States.
`BACKGROUND OF THE INVENTION
`
`This invention relates to 4-(substituted phenylamino)
`quinazoline derivatives which are useful in the treatment of
`hyperproliferative diseases, such as cancers, in mammals.
`Many of the current treatment regimes for cancer utilize
`compounds which inhibit DNA synthesis. Such compounds
`are toxic to cells generally but their toxic effect on the rap-
`idly dividing tumor cells can be beneficial. Alternative
`approaches to anti-cancer agents which act by mechanisms
`other than the inhibition of DNA synthesis have been
`explored in order to enhance the selectivity of action against
`cancer cells.
`
`It is known that a cell may become cancerous by virtue of
`the transformation of a portion of its DNA into an oncogene
`(i.e. a gene which, on activation, leads to the formation of
`malignant tumor cells). Many oncogenes encode proteins
`which are aberrant tyrosine kinases capable of causing cell
`transformation. Alternatively, the overexpression of a nor-
`mal proto-oncogenic tyrosine kinase may also result in pro-
`liferative disorders, sometimes resulting in a malignant phe-
`notype.
`Receptor tyrosine kinases are large enzymes which span
`the cell membrane and possess an extracellular binding
`domain for growth factors such as epidermal growth factor, a
`transmembrane domain, and an intracellular portion which
`functions as a kinase to phosphorylate specific tyrosine resi-
`dues in proteins and hence to influence cell proliferation. It
`is known that such kinases are frequently aberrantly
`expressed in common human cancers such as breast cancer,
`gastrointestinal cancer such as colon, rectal or stomach
`cancer, leukemia, and ovarian, bronchial or pancreatic can-
`cer. It has also been shown that epidermal growth factor
`receptor (EGFR) which possesses tyrosine kinase activity is
`mutated and/or overexpressed in many human cancers such
`as brain, lung, squamous cell, bladder, gastric, breast, head
`and neck, oesophageal, gynecological and thyroid tumors.
`Accordingly, it has been recognized that inhibitors of
`receptor tyrosine kinases are useful as a selective inhibitors
`of the growth of mammalian cancer cells. For example,
`erbstatin, a tyrosine kinase inhibitor selectively attenuates
`the growth in athymic nude mice of a transplanted human
`mammary carcinoma which expresses epidermal growth
`factor receptor tyrosine kinase (EGFR) but is without effect
`on the growth of another carcinoma which does not express
`the EGF receptor.
`Various other compounds, such as styrene derivatives,
`have also been shown to possess tyrosine kinase inhibitory
`properties. More recently five European patent publications,
`namely EP 0 566 226 A1, EP 0 602 851 A1, EP 0 635 507
`A1, EP 0 635 498 A1 and EP 0 520 722 A1 have disclosed
`that certain quinazoline derivatives possess anti-cancer prop-
`erties which result from their tyrosine kinase inhibitory
`properties. Also PCT publication WO 92/20642 discloses
`bis-mono and bicyclic aryl and heteroaryl compounds as
`tyrosine kinase inhibitors.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`Although the anti-cancer compounds described above
`make a significant contribution to the art there is a continu-
`ing search in this field of art for improved anti-cancer phar-
`maceuticals.
`
`SUMMARY OF THE INVENTION
`
`This invention relates to compounds of the formula
`
`/ I—(R3)n
`
`R2\N
`
`R4
`
`\N
`/ I
`(RIM—\ N»
`
`and to pharmaceutically acceptable salts and prodrugs
`thereof, wherein:
`m is 1, 2, or 3;
`each R1 is independently selected from the group consist-
`ing of hydrogen, halo, hydroxy, hydroxyamino,
`carboxy, nitro, guanidino, ureido, cyano,
`trifluoromethyl, and -(C1-C4 alkylene)-W-(phenyl)
`wherein W is a single bond, O, S or NH;
`or each R1 is independently selected from R9 and
`(C17C4)-alkyl substituted by cyano, wherein R9 is
`selected from the group consisting of R5, iOR6,
`7NR6R6, 7C(O)R7, iNHORS, A)C(O)R6, cyano,
`A and iYRS; R5 is CFC4 alkyl; R6 is independently
`hydrogen or R5; R7 is Rs, 40R6 or 7NR6R6; A is
`selected from piperidino, morpholino, pyrrolidino,
`4-R6-piperazin-1-yl,
`imidazol-1-yl, 4-pyridon-1-yl,
`-
`(CliC4 alkylene)(COZH), phenoxy, phenyl,
`phenylsulfanyl, CfC4 alkenyl, and -(C17C4 alkylene)
`C(O)NR6R6; andY is S, SO, or SOz; wherein the alkyl
`moieties in R5, 40R6 and 7NR6R6 are optionally
`substituted by one to three substituents independently
`selected from halo and R9, and wherein the alkyl moi-
`eties of said optional substituents are optionally substi-
`tuted by halo or R9, with the proviso that two heteroat-
`oms are not attached to the same carbon atom, and with
`the further proviso that no more than three R9 groups
`may comprise a single R1 group;
`or each R1 is independently selected from iNHSOZRS,
`phthalimido-(C1£4)-alkylsulfonylamino, benzamido,
`benzenesulfonylamino,
`3-phenylureido,
`2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and
`R1O-(C27C4)-alkanoylamino wherein R10 is selected
`from halo, iOR6, C2£4 alkanoyloxy, 7C(O)R7, and
`7NR6R6; and wherein the foregoing Rl groups are
`optionally substituted by 1 or 2 substituents indepen-
`dently selected from halo, C1£4 alkyl, cyano, meth-
`anesulfonyl and CFC4 alkoxy;
`or two Rl groups are taken together with the carbons to
`which they are attached to form a 578 membered ring
`that includes 1 or 2 heteroatoms selected from O, S and
`N;
`R2 is hydrogen or CliC6 alkyl optionally substituted by 1
`to 3 substituents independently selected from halo,
`CliC4 alkoxy, 7NR6R6, and iSOzRS;
`n is 1 or 2 and each R3 is independently selected from
`hydrogen, halo, hydroxy, C1£6 alkyl, 7NR6R6, and
`CliC4 alkoxy, wherein the alkyl moieties of said R3
`APOTEX EX. 1056—004
`
`APOTEX EX. 1056-004
`
`

`

`US RE41,065 E
`
`3
`groups are optionally substituted by l to 3 substituents
`independently selected from halo, C 17C4 alkoxy,
`7NR6R6, and istRs ; and,
`R4 is azido or -(ethynyl)-Rll wherein R11 is hydrogen or
`C 17C6 alkyl optionally substituted by hydroxy, gOR6,
`or 7NR6R6.
`Preferred compounds of formula I include those wherein
`R2 is hydrogen and R4 is -(ethynyl)-R11.
`Other preferred compounds of formula I include those
`wherein m is l or 2;
`each R1 is independently selected from the group consist-
`ing of hydrogen, hydroxy, hydroxyamino, carboxy,
`nitro, carbamoyl, ureido, R5 optionally substituted with
`halo, iOR6, carboxy, 4C(O)NR6R6, A or 7NR6R6;
`gORs optionally substituted with halo, iOR6, 40C
`(O)R6, 7NR6R6, or A; 7NR6R6, 7C(O)R6 R5,
`isRS, phenyl-(C27C4)-alkoxy, cyano, phenyl;
`iNHRS optionally substituted with halo or R9 wherein
`said R9 is optionally substituted by R9; iNHORS,
`isRS, CliC4 alkylsulfonylamino, phthalimido-
`(C17C4)-alkylsulfonylamino, 3 -phenylureido,
`2-oxopyrrolidin-l -yl, 2,5-dioxopyrrolidin- l -yl, halo-
`(C27C4)-alkanoylamino, hydroxy-(C27C4)-
`alkanoylamino, (C27C4)-alkanoyloxy-(C27C4)-
`alkanoylamino,
`(C 17C4) -alkoxy-(C27C4)-
`alkanoylamino, (C17C4)-alkoxycarbonyl-(C27C4)-
`alkanoylamino, carbamoyl-(C27C4)-alkanoylamino,
`N-(C17C4)-alkylcarbamoyl-(C27C4)-alkanoylamino,
`N,N-di-[(C17C4)-alkyl]carbamoyl-(C27C4)-
`alkanoylamino, amino-(C27C4)-alkanoylamino,
`(C17C4)-alkyl-amino-(C2£4)-alkanoylamino, and di-
`(C17C4)-alkyl-amino-(C27C4)-alkanoylamino, and
`wherein said phenyl or phenoxy or anilino substituent
`in the foregoing Rl groups is optionally substituted
`with one or two substituents independently selected
`from halo, C1£4 alkyl and C1£4 alkoxy;
`each R3 is independently selected from hydrogen, methyl,
`ethyl, amino, halo and hydroxy; and,
`R4 is ethynyl.
`Other preferred compounds of formula I include those
`wherein each R1 is independently selected from hydrogen,
`hydroxy, hydroxyamino, nitro, carbamoyl, ureido, R5
`optionally substituted with halo, iOR6, carboxy, or 4C(O)
`NH2; iORS optionally substituted with halo, iOR6, 40C
`(O)R6, 7NR6R6, or A; 7NR6R6, %(O)NR6R6, isRS ,
`phenyl-(C27C4)-alkoxy wherein said phenyl moiety is
`optionally substituted with l or 2 substituents independently
`selected from halo, R5 or gORs .
`Other preferred compounds of formula I include those
`wherein R2 is hydrogen and R4 is azido.
`Other preferred compounds of formula I include those
`wherein R3 is halo and R1 is hydrogen or gORs .
`Other preferred compounds of formula I include those
`wherein R1 is methoxy.
`Specific preferred compounds of formula I include the
`following:
`(6,7-dimethoxyquinazolin-4-yl)-(3 -ethynylphenyl)-amine;
`(6,7-dimethoxyquinazolin—4-yl) -[3-(3'-hydroxypropyn-l -yl)
`phenyl]—amine;
`[3 -(2'- (aminomethyl)-ethynyl)phenyl]-(6,7-
`dimethoxyquinazolin-4-yl)-amine;
`(3-ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine;
`(6,7-dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine;
`(6,7-dimethoxyquinazolin-4-yl) -(3 -ethynyl-2-
`methylphenyl)-amine;
`(6-aminoquinazolin—4-yl)-(3-ethynylphenyl)-amine;
`(3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-
`yl)-amine;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`
`(3 -ethynylphenyl)- (6 ,7 -methylenedioxyquinazolin-4 -yl)-
`amine;
`(6,7-dimethoxyquinazolin-4-yl)- (3 -ethynyl -6-
`methylphenyl) -amine;
`(3 -ethynylphenyl)-(7-nitroquinazolin-4 -yl) -amine;
`(3 -ethynylphenyl)-[6-(4'-toluenesulfonylamino)quinazolin-
`4-yl]—amine;
`(3 -ethynylphenyl) - { 6 -[2'-phthalimido -eth- l '-yl -
`sulfonylamino ]quinazolin—4-yl} -amine;
`(3 -ethynylphenyl)-(6-guanidinoquinazolin-4 -yl) -amine;
`(7-aminoquinazolin-4-yl)-(3 -ethynylphenyl) -amine;
`(3 -ethynylphenyl)-(7-methoxyquinazolin-4 -yl)-amine;
`(6-carbomethoxyquinazolin-4 -yl)-(3-ethynylphenyl)-amine;
`(7-carbomethoxyquinazolin-4 -yl)-(3-ethynylphenyl)-amine;
`[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3 -
`ethynylphenyl) -amine;
`(3 -azidophenyl)-(6,7-dimethoxyquinazolin-4 -yl) -amine;
`(3 -azido -5 -chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-
`amine;
`(4-azidophenyl)-(6,7-dimethoxyquinazolin-4 -yl) -amine;
`(3 -ethynylphenyl) -(6 -methansulfonyl -quinazolin-4 -yl) -
`amine;
`(6-ethansulfanyl-quinazolin-4 -yl)-(3 -ethynylphenyl)-amine
`(6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-
`phenyl)-amine;
`(6,7-dimethoxy-quinazolin-4 -yl) -[3 -(propyn- l '-yl) -phenyl]—
`amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4 -yl]—(5 -ethynyl-2-
`methyl-phenyl)-amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4 -yl]-(3 -ethynyl-4-
`fluoro -phenyl)-amine;
`[6 ,7 -bi s- (2 -chloro -ethoxy) -quinazolin-4 -yl ] -(3 -ethynyl-
`phenyl)-amine;
`[6-(2-chloro-ethoxy)-7 -(2 -methoxy-ethoxy)-quinazolin-4 -
`yl]—(3 -ethynyl-phenyl) -amine;
`[6 ,7 -bis- (2-acetoxy-ethoxy) -quinazolin-4 -yl]—(3 -ethynyl-
`phenyl)-amine;
`2 -[ 4 - (3 -ethynyl -phenylamino ) - 7 - (2 -hydroxy -ethoxy) -
`quinazolin—6-yloxy]-ethanol;
`[6-(2 -acetoxy-ethoxy) -7-(2 -methoxy-ethoxy) -quinazolin-4-
`yl]—(3 -ethynyl-phenyl) -amine;
`[7-(2-chloro-ethoxy)-6 -(2 -methoxy-ethoxy)-quinazolin-4 -
`yl]—(3 -ethynyl-phenyl) -amine;
`[7-(2 -acetoxy-ethoxy)-6-(2 -methoxy-ethoxy) -quinazolin-4-
`yl]—(3 -ethynyl-phenyl) -amine;
`2 -[ 4 - (3 -ethynyl -phenylamino ) - 6 - (2 -hydroxy -ethoxy) -
`quinazolin—7-yloxy]-ethanol;
`2 -[4 - (3 -ethynyl -phenylamino) -7 - (2 -methoxy -ethoxy) -
`quinazolin—6-yloxy]-ethanol;
`2 -[4 - (3 -ethynyl -phenylamino) - 6 - (2 -methoxy -ethoxy) -
`quinazolin—7-yloxy]-ethanol;
`[6-(2 -acetoxy-ethoxy)-7-(2 -methoxy-ethoxy)-quinazolin-4-
`yl]—(3 -ethynyl-phenyl) -amine;
`(3 -ethynyl-phenyl)-{ 6-(2 -methoxy-ethoxy)-7-[2-(4methyl-
`piperazin-l -yl) -ethoxy]-quinazolin-4 -yl } -amine;
`(3 -ethynyl-phenyl)-[7-(2 -methoxy-ethoxy)-6-(2 -morpholin-
`4-yl)-ethoxy) -quinazolin—4-yl]—amine;
`(6,7-diethoxyquinazolin-l -yl)-(3-ethynylphenyl)-amine;
`(6,7-dibutoxyquinazolin-l -yl)-(3 -ethynylphenyl)-amine;
`(6,7-diisopropoxyquinazolin- l -yl)-(3 -ethynylphenyl)-
`amine;
`(6,7-diethoxyquinazolin- l -yl)-(3 -ethynyl-2-methyl-
`phenyl)-amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin-l -yl]-(3 -ethynyl-2-
`methyl-phenyl)-amine;
`(3 -ethynylphenyl)-[6 -(2 -hydroxy-ethoxy)-7- (2 -methoxy-
`ethoxy) -quinazolin- l -yl]—amine;
`
`APOTEX EX. 1056—005
`
`APOTEX EX. 1056-005
`
`

`

`US RE41,065 E
`
`5
`[6,7-bis-(2-hydroxy-ethoxy)-quinazolin- l -yl]-(3 -
`ethynylphenyl)-amine; and
`2 -[4 - (3 -ethynyl -phenyl amino) - 6 - (2 -methoxy -ethoxy) -
`quinazolin—7-yloxy] -ethanol.
`Other specific preferred compounds of formula I include
`the following:
`(6,7-dipropoxy-quinazolin-4-yl)-(3 -ethynyl-phenyl)-amine;
`(6,7 -diethoxy-quinazolin-4 -yl)-(3 -ethynyl-5 -fluoro -
`phenyl)-amine;
`(6,7 -diethoxy-quinazolin-4 -yl)-(3 -ethynyl-4-fluoro -
`phenyl)-amine;
`(6,7-diethoxy-quinazolin-4-yl)-(5 -ethynyl-2-methyl-
`phenyl)-amine;
`(6,7-diethoxy-quinazolin-4-yl)-(3 -ethynyl-4-methyl-
`phenyl)-amine;
`(6 -aminomethyl -7 -methoxy-quinazolin-4-yl)-(3 -ethynyl -
`phenyl)-amine;
`(6 -aminomethyl-7-methoxy-quinazolin-4 -yl) -(3 -
`ethynylphenyl) -amine;
`(6 -aminocarbonylmethyl -7-methoxy-quinazolin-4 -yl)-(3 -
`ethynylphenyl) -amine;
`(6 -aminocarbonylethyl -7 -methoxy-quinazolin-4 -yl) - (3 -
`ethynylphenyl) -amine;
`(6 -aminocarbonylmethyl-7 -ethoxy-quinazolin-4 -yl) - (3 -
`ethynylphenyl) -amine;
`(6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3 -
`ethynylphenyl) -amine;
`(6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4 -yl)-(3 -
`ethynylphenyl) -amine;
`(6 -aminocarbonylmethyl-7-propoxy-quinazolin-4 -yl)- (3 -
`ethynylphenyl) -amine;
`(6 -aminocarbonylmethyl -7-methoxy-quinazolin-4 -yl)-(3 -
`ethynylphenyl) -amine;
`(6-aminocarbonylethyl-7-isopropoxy-quinazolin-4 -yl)-(3 -
`ethynylphenyl)-amine; and
`(6 -aminocarb onylethyl -7 -propoxy-quinazo lin-4 -yl) - (3 -
`ethynylphenyl) -amine.
`Other specific preferred compounds of formula I include
`the following:
`(6,7—diethoxyquinazolin-l -yl)-(3 -ethynylphenyl)-amine;
`(3 -ethynylphenyl)-[6 -(2-hydroxy-ethoxy)-7- (2 -methoxy-
`ethoxy) -quinazolin— l -yl]—amine;
`[6,7-bis-(2-hydroxy-ethoxy)-quinazolin- l -yl]-(3 -
`ethynylphenyl) -amine;
`[6,7-bis-(2-methoxy-ethoxy)-quinazolin- l -yl]-(3 -
`ethynylphenyl) -amine;
`(6, 7-dimethoxyquinazolin-l -yl)-(3 -ethynylphenyl)-amine;
`(3 -ethynylphenyl)-(6-methanesulfonylamino-quinazolin- l -
`yl)-amine; and,
`(6-amino-quinazolin-l -yl)-(3 -ethynylphenyl)-amine.
`The invention further relates to a pharmaceutical compo-
`sition for the treatment of a hyperproliferative disorder in a
`mammal which compri s es a therapeutically-effective
`amount of the compound of claim 1 and a pharmaceutically
`acceptable carrier.
`The invention further relates to a method of treating a
`hyperproliferative disorder in a mammal which comprises
`administering to said mammal a therapeutically-effective
`amount of the compound of claim 1.
`In a preferred embodiment, the method of treating hyper-
`proliferative disorders includes those wherein said hyperpro-
`liferative disorder is cancer.
`
`In another preferred embodiment, the method of treating
`hyperproliferative disorders includes those wherein said
`hyperproliferative disorder is said cancer is brain,
`lung,
`squamous cell, bladder, gastric, pancreatic, breast, head,
`neck, oesophageal, gynecological or thyroid cancer.
`
`10
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`20
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`30
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`40
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`60
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`65
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`6
`In another preferred embodiment, the method of treating
`hyperproliferative disorders includes those wherein said
`hyperproliferative disorder is noncancerous.
`In another preferred embodiment, the method of treating
`hyperproliferative disorders includes those wherein said
`hyperproliferative disorder is a benign hyperplasia of the
`skin or prostate.
`The invention further relates to a process for preparing a
`compound of the formula
`
`/ I—(R3)n
`
`R2\N
`
`R4
`
`\N
`/ I
`(RIM—\ N»
`
`or a pharmaceutically acceptable salt or prodrug thereof,
`wherein:
`
`m is l, 2, or 3;
`each R1 is independently selected from the group consist-
`ing of hydrogen, halo, hydroxy, hydroxyamino,
`carboxy, nitro, guanidino, ureido, cyano,
`trifluoromethyl, and -(C17C4 alkylene)-W-(phenyl)
`wherein W is a single bond, 0, S or NH;
`or each R1 is independently selected from R9 and
`(C17C4)-alkyl substituted by cyano, wherein R9 is
`selected from the group consisting of R5, 70R6,
`7NR6R6, 7C(O)R7, iNHORS, A)C(O)R6, cyano,
`A and iYRS; R5 is CliC4 alkyl; R6 is independently
`hydrogen or R5; R7 is Rs, 40R6 or 7NR6R6; A is
`selected from piperidino, morpholino, pyrrolidino,
`4-R6-piperazin-l-yl, imidazol-l-yl, 4-pyridon-l-yl,
`-
`(CliC4 alkylene)(COZH), phenoxy, phenyl,
`phenylsulfanyl, CfC4 alkenyl, and -(C17C4 alkylene)
`C(O)NR6R6; andY is S, SO, or 802; wherein the alkyl
`moieties in R5, 40R6 and 7NR6R6 are optionally
`substituted by one to three substituents independently
`selected from halo and R9, and wherein the alkyl moi-
`eties of said optional substituents are optionally substi-
`tuted by halo or R9, with the proviso that two heteroat-
`oms are not attached to the same carbon atom, and with
`the further proviso that no more than three R9 groups
`may comprise a single R1 group;
`or each R1 is independently selected from iNHSOZRS,
`phthalimido-(C1£4)-alkylsulfonylamino, benzamido,
`benzenesulfonylamino,
`3-phenylureido,
`2-oxopyrrolidin- l -yl, 2,5-dioxopyrrolidin- l -yl, and
`R1O-(C27C4)-alkanoylamino wherein R10 is selected
`from halo, iOR6, C2£4 alkanoyloxy, 7C(O)R7, and
`7NR6R6; and wherein the foregoing Rl groups are
`optionally substituted by l or 2 substituents indepen-
`dently selected from halo, C1£4 alkyl, cyano, meth-
`anesulfonyl and CliC4 alkoxy;
`or two Rl groups are taken together with the carbons to
`which they are attached to form a 578 membered ring
`that includes 1 or 2 heteroatoms selected from O, S and
`N;
`R2 is hydrogen or CliC6 alkyl optionally substituted by l
`to 3 substituents independently selected from halo,
`CFC4 alkoxy, 7NR6R6, and isost;
`n is l or 2 and each R3 is independently selected from
`hydrogen, halo, hydroxy, C1£6 alkyl, 7NR6R6, and
`APOTEX EX. 1056—006
`
`APOTEX EX. 1056-006
`
`

`

`7
`
`US RE41,065 E
`
`CliC4 alkoxy, wherein the alkyl moieties of said R3
`groups are optionally substituted by l to 3 substituents
`independently selected from halo, CliC4 alkoxy,
`7NR6R6, and istRs ; and,
`R4 is azido or -(ethynyl)-Rll wherein R11 is hydrogen or
`CliC6 alkyl optionally substituted by hydroxy, 40R6,
`or 7NR6R6; which comprises
`a) treating a compound of the formula
`
`X
`
`5 N/ /
`I
`HC%N \
`2
`
`10
`
`l—(Rl)m
`
`8
`
`
`SCHEME
`
`\
`
`
`(R3)n i
`/ / N/R
`Y
`H
`
`2
`
`4
`
`+
`
`l
`
`\
`
`OH
`(RIMAO j 0r
`N/
`
`(RIMAO
`
`O
`
`\
`
`jH
`N/
`
`15
`
`wherein R1 and m are as defined above, with CCl4 and
`(C67C10aryl)3P, optionally supported on an inert
`polymer, wherein the aryl moieties of said 20
`(C67C10aryl)3 P are optionally substituted by CliC6
`alkyl; and
`b) treating the product of step a) with a compound of
`the formula
`2
`1"
`HN
`
`<R>3n
`
`25
`
`J
`
`wherein R2, R3 and n are as defined above, and J is Y or
`R4, wherein R4 is as defined above and wherein Y is
`NHZ, Br,
`I or trifluoromethanesulfonyloxy, with the
`proviso that when J is Y then the product of step b) must
`further be treated with an alkyne where Y is Br, I or
`trifluoromethanesulfonyloxy, or an azide where Y is
`NH2.
`Preferred processes for preparing the compound of for-
`mula I include those wherein each aryl group is selected
`from phenyl, naphth-l-yl and naphth-2-yl.
`Other preferred processes for preparing the compound of
`formula I include those wherein each Ar in (C6£loaryl)3P
`is phenyl.
`