Unlted States Patent
`
`[19]
`
`[11] Patent Number:
`
`9
`9
`5 747 498
`
`Schnur et al.
`
`[45] Date of Patent:
`
`May 5, 1998
`
`US005747498A
`
`[54] ALKYNYL AND AZIDO-SUBSTITUTED 4-
`ANILINOQUINAZOLINES
`
`[75]
`
`Inventors: Rodney Caughren Schnur. Noank.
`Conn’; Lee Daniel Arnold‘
`Westborough. Mass.
`
`[73] Assignee: Pfizer I_nc,_ New York N.Y_
`
`[21] Appl. N0.: 653,786
`
`[22] Filed:
`
`May 28’ 1996
`
`566226
`602851
`635498
`
`EHFDPBNI Pat 03- A
`10/1993
`6/1994 European Pat. Off.
`.
`1/1995 European Fat 011“.
`A
`
`W092’20642 “/1992 WIPO -
`W095/15758
`6/1995 VVIPO .
`
`Primary Examiner—Matthew V. Grumbling
`Attorney, Agent, or Fifln—PCtBl‘ C. Richardson; Paul H.
`Ginsburg; Bryan C. Zielinski
`
`[57]
`
`ABSTRACT
`
`The invention relates to compounds of the formula
`
`Related U.S. Application Data
`
`1
`
`[63] Continuation-in-part of PC1"/[B95/00436, Jun. 6, 1995.
`[51]
`Int. Cl.“ ...................... A6lK 31/495; A61K 31/505;
`C07D 239/70: C07D 239/94
`[52] U.S. Cl. ........................... 514/259; 544/283; 544/293
`[53] Field of Search ..................................... 544/283. 293;
`514/259
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`,
`10/1993 Pnmeau .................................. 5l4f2S9
`5,256,781
`
`10/1995 Barker ......
`....... 514/259
`5,457,105
`12/1995 Barker ..................................... 514/259
`5.475,oo1
`FOREIGN PATENT DOCUMENTS
`
`W)»
`
`R4
`
`R2
`
`\
`
`\
`
`N
`
`N
`Q
`
`(R!)
`
`"‘
`
`and to pharmaceutically acceptable salts thereof. wherein
`R1. R2. R3. R“. n and m are as defined herein. The com-
`ounds of formula I are useful in the treatment of hyper-
`P lif
`‘
`(ii
`I’!
`Th '
`'
`furth
`pro eratrve
`seases. we as cancer.
`e mvenuon
`er
`-
`r°1:‘°St° gl’°§:'SSf"‘s 9f mkifg the °°":1P".““"111S °f f°“““la§
`3“ ‘° mc,
`0’ P “‘_"‘g 5"“ °°mP°““ 5"‘
`5 ‘”‘‘‘"“°“‘ °
`hyperprolnferatrve dtseases.
`
`520722 12/1992 European Pat. Off. .
`
`32 Claims, No Drawings
`
`APOTEX EX. 1009-001
`
`

`
`1
`ALKYNYL AND AZIDO-SUBSTITUTED 4-
`ANILINOQUINAZOLINES
`
`2
`SUMMARY on THE INVENTION
`
`This invention relates to compounds of the formula
`
`5.747.498
`
`This application is a continuation-in-part of PCT inter-
`national application number PCI‘/IB95/00436. filed Jun. 6.
`1995. which designates the United States.
`
`5
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to 4-(substituted phenylamino)
`quinazoline derivatives which are useful in the treatment of
`hyperproiiferative 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
`rapidly 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
`proliferative disorders. sometimes resulting in a malignant
`phenotype.
`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
`residues 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 athyrnic 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
`properties which result from their tyrosine kinase inhibitory
`properties. Also PCT publication WO 92120642 discloses
`bis-mono and bicyclic aryl and heteroaryl compounds as
`tyrosine kinase inhibitors.
`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
`pharmaceuticals.
`
`(R3):-
`
`(W)...
`
`and to pharmaceutically acceptable salts and prodrugs
`thereof. wherein:
`m is 1. 2. or 3;
`each R‘ is independently selected from the group con-
`sisting of hydrogen. halo. hydroxy. hydroxyamino.
`carboxy. nitro. guanidino. ureido. cyano.
`trifluoromethyl. and -(C1-C4 alky1ee)—W-(phenyl)
`wherein W is a single bond. 0. S or NH;
`or each R‘ is independently selected from R9 and (C 1-C4)
`-alkyl substituted by cyano. wherein R9 is selected
`from the group consisting of R5. —-CR6. —NR6R6.
`-C(0)R". —NHOR5. ———0C(O)R°. cyano. A and
`—-YR’; R5 is C1-C4 alkyl; R‘ is inde ndently hydro-
`gen or R5; R7 is R5. ——OR° or --NR 6: A is selected
`from piperidino. morpholino. pyrrolidino. 4-R6-
`piperazin-1-yl. imidazol-l-yl. 4-pyridon-1-yl. —(C1-C4
`allrylene)(CO2H). phenoxy. phenyl. phenylsulfanyl.
`C2-C4 alkenyl. and —(c1—(:,, alkylene)C(O)NR5R°; and
`Y is S. S0. or S02; wherein the alkyl moieties in R5.
`--ORG and —NR6R° are optionally substituted by one
`to three substituents independently selected from halo
`and R9. and wherein the alkyl moieties of said optional
`substituents are optionally substituted by halo or R9.
`with the proviso that two heteroatoms 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 R‘ is independently selected from —-NHSO2R5.
`phthalimido-(C1-C4)-alkylsulfonylamino. benzamido.
`benzenesulfonylamino. 3-phenylureido.
`2-oxopyrrolidin-1-yl. 2.5-dioxopyrrolidin-l-yl. and
`R10-(C2-C4)-alkanoylamino wherein R10 is selected
`from halo. —OR°. C2-C4 alkanoyloxy. —-C(O)R". and
`—NR°R°; and wherein the foregoig R1 groups are
`optionally substituted by 1 or 2 substituents indepen-
`dently selected from halo. C1-C4 alkyl. cyano. meth-
`anesulfonyl and C1-C4 alkoxy;
`or two R1 groups are taken together with the carbons to
`which they are attached to form a 5-8 membered ring
`that includes 1 or 2 heteroatoms selected from O. S and
`N;
`R2 is hydrogen or C1-C6 alkyl optionally substituted by 1
`to 3 substituents independently selected from halo.
`C1-C4 alkoxy. —NR°R6. and —SO2R5;
`n is 1 or 2 and each R3 is independently selected from
`hydrogen. halo. hydroxy. C1-C6 alkyl. ——~NR°R‘. and
`C1-C4 alkoxy. wherein the alkyl moieties of said R3
`groups are optionally substituted by l to 3 substituents
`independently selected from halo. C1-C4 alkoxy.
`—NR°R5. and ——SO2R5; and.
`R‘ is azido or -(ethynyl)-R” wherein R“ is hydrogen or
`C1-C5 alkyl optionally substituted by hydroxy. —OR°.
`or -—N'R5R‘5.
`Preferred compounds of formula I include those wherein
`R2 is hydrogen and R‘ is -(ethynyl)-R“.
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`APOTEX EX. 1009-002
`
`

`
`3
`
`5,747,498
`
`4
`
`Other preferred compounds of formula I include those
`wherein m is 1 or 2;
`each R‘ is independently selected from the group con-
`sisting of hydrogen. hydroxy. hydroxyamino. carboxy.
`nitro. earbamoyl. ureido. R5 optionally substituted with
`halo. ——()R". carboxy. ~——C(O)NR5R . A or —NR"R‘5;
`—OR5 optionally substituted with halo. —0R5. —OC
`(0)115. —NR5R‘. or A; —NR°R6. —C(O)R°R5.
`—SR5. phenyl-(C2—C4)—alkoxy. cynno. phenyl:
`—NHR5 optionally substituted with halo or R9 wherein
`said R9 is optionally substituted by R9; —NHOR5.
`—sR5. C1-C4 allrylsulfonylamino. phthalimldo-
`(C1—C4)—alkylsulfonylamino. 3—phenylureido.
`2-oxopyrrolidin-l-yl. 2.5-dioxopyrrolidin-1-yl. halo-
`(C2—C4)-alkanoylamino. hydroxy-(C,—C4)-
`alkanoylamino.
`(C2-C4)-alkanoyloxy-(C2—C4)-
`alkanoylamino.
`(C,—C4)-alkoxy-(C2—C.,)-
`alkanoylamino.
`(C,—C4)-alkoxycarbonyl-(C2—C4)-
`alkanoylamino. carbamoyl-(C2-C4)—alkanoylarnino.
`N-(C1—C4)-alkylearbamoyl—(C2-C4)-alkanoylamino.
`N.N-di-[(C1—C4)-alkyl]carbamoyl—(C2—C,.)-
`alkanoylamino. arnino—(C2-C4)-alkanoylamino.
`(C1—C4)—alkyl-amino-(C2-C4)-alkanoylarnino. and di-
`(C 1-C4)—alkyl—amino-(C2—C4)-alkanoylarnino. and
`wherein said phenyl or phenoxy or anilino substituent
`in the foregoing R’ groups is optionally substituted
`with one or two substituents independently selected
`from halo. C ,—C4 alkyl and C ,~C4 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 R‘ is independently selected from hydrogen.
`hydroxy. hydroxyamino. nitro. carbamoyl. ureido. R5
`optionally substituted with halo. --OR‘. carboxy. or —C(_O)
`NH2; —-OR5 optionally substituted with halo. -0126. ——oc
`(0)116. ——NR5R°. or A; —NR‘R6. ——C(O)NR"R°. 4R5.
`phenyl-(C2-C4)-alkoxy wherein said phenyl moiety is
`optionally substituted with 1 or 2 substituents independently
`selected from halo. R5 or -09.5.
`Other preferred compounds of formula I include those
`wherein R2 is hydrogen and R‘ is azido.
`Other preferred compounds of formula I include those
`wherein R3 is halo and R1 is hydrogen or —OR5.
`Other preferred compounds of formula I include those
`wherein R‘ is methoxy.
`Specific preferred compounds of formula I include the
`following:
`(6.7-dimethoxyquinazolin-4-yl)—(3-ethynylphenyl)-amine;
`(6.7—dirnethoxyquinazolin—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-dirnethoxyquinazolin-4-yl)—(4-ethynylphenyl)-amine;
`(6.7-dimethoxyquinazolin-4-yl)-(3-ethynyl—2—
`rnethyiphenyl)-amine;
`(6-arninoquinazo1in—4—yl)-(3-ethynylphenyl)-amine;
`(3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-
`yl)-amine;
`(3-ethynylphenyl)-(6.7-methylenedioxyquinazolin-4-yl)-
`amine;
`(6.7-dimethoxyquinazolin—4-yl)-(3-ethynyl-6-
`rnethylphenyl)-amine;
`(3-ethynylphenyl)-(7—nitroquinazolin-4-yl)-amine;
`(3-ethynylphenyl}[6—(4'-toluenesulfonylarn.ino)quinazolin-
`4-yl]-amine;
`
`(3~ethynylphenyl)-{ 6- [ 2‘-phthalirnido-eth— l'»-yl-
`sulfonylamino] quinazolin-4-yl }-amine;
`(3-ethynylphenyl)-(6-guanidinoquinazolin—4-yl)-amine:
`(7-arninoquinazolin-4-yl)-(3-ethynylphenyl)-amine;
`(3—ethynylphenyl)—(7-methoxyquinazolin-4-yl)-amine;
`(6—carbomethoxyquinazolin-4-yl)-(3 -ethynylphenyl)-amine;
`(7-carbomethoxyquinazolin—4—y1)-(3—ethynylphenyl)-amine:
`I 6.7-bis(2—methoxyethoxy)quinazolin-4-yl I--(3-
`ethyny1phenyl)—amine;
`(3—az.idophenyl)—(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-methan sulfonyl-quinazolin-4--yl)-
`amine;
`(6—ethansulfanyl—quinazo1in-4-yl)—(3 —ethynylphenyl)-amine
`(6.7-dirnethoxy-quinazolin—4-yl)-(3-ethynyl-4-fl uoro-
`phenyl)-amine;
`(6.7 -d.imethoxy—quinazol.in—4—yl)-i3-(propyn- 1'-yl)-phenyl] -
`amine;
`I 6.7-bis-(2-methoxy—ethoxy)-quinazolin-4-yl l—(5 —ethynyl-2-
`methy1—phenyl)-amine;
`[6.7-bis-(2—methoxy-ethoxy)-quinazolin—4—y1]-(3-ethynyl-4-
`fiuoro-phenyl)-amine;
`[ 6.7-bis-(2-chloro—ethoxy)-quinazolin-4--yl I —(3 -ethynyl-
`phenyl)-amine;
`I6-(2—chloro-ethoxy)-7-(2-methoxy—ethoxy)-quinazolin-4-
`yl]—(3—ethynyl—phenyl)—amine;
`(6.7-bis —(2 —acetoxy- ethoxy)—quinazo1in-4-yl J -(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-
`yll-(3 -ethynyl-phenyl)-amine;
`[7-(2-chloro-ethoxy)-6—(2-methoxy-ethoxy)-quinazolin—4-
`yl]-(3-ethynyl-phenyl)-amine;
`17—(2—acetoxy-ethoxy)-6—(2-methoxy-ethoxy)—quinazo1in-4-
`yl] -(3 —ethynyl~phenyl)-amine;
`2-[4-(3-ethynyl-phenylamino)-6-(2—hydroxy—ethoxy)-
`quinazolin-7-yloxy}—ethanol;
`2- [4-(3-ethyny1—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 —rnethoxy—ethoxy)-quinazolin—4—
`yl] -(3 —ethynyl—phenyl)-amine;
`(3-ethynyl—phenyl)-{ 6—(2-methoxy-ethoxy)-7-[ 2-(4methyl—
`piperazin- 1-yl)-ethoxy]-quinazolin—4-yl }-amine;
`(3-ethynyl—phenyl)- [7 —(2-methoxy—ethoxy)-6-(2
`-rnorpholin-4-y1)-ethoxy)-quinazolin—4-yl}-amine;
`(6.7—diethoxyquinazolin~ l—yl)-(3 -ethynylphenyl)-amine;
`(6.7 -dibutoxyquinazolim 1-yl)-(3-ethynylphenyl)—a_mine;
`(6 .7 ~diisopropoxy quinazolin- l—y l)-( 3-ethynylphenyl)—
`amine;
`(6.7—diethoxyquinazolin-1-yl)-(3-ethynyl—2-methyl-phenyl)
`-amine;
`[6.7-his-(2-methoxy-ethoxy)-quinazolin- 1—y1]-(3—ethynyl—2-
`methyl-phenyl)-amine;
`(3-ethyny1pheny1)-[6-(2-hydroxy—ethoxy)-7-(2-methoxy—
`ethoxy)—quinazolin- 1 -yl I-amine;
`[6.7-bis—(2—hydroxy-ethoxy)—quinazolin- l—yl]-(3-
`ethynylpheny1)—amine; and
`2 — [ 4-(3-ethynyl-pheny1amino)-6- (2-methoxy -ethoxy )-
`quinazolin-7-yloxy 3-ethanol.
`Other specific preferred comp-ounds of formula I include
`the following:
`(6.7-dipropoxyaquinazolin-4-yl)-(3-ethynyl-phenyl)-amine;
`
`10
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`S5
`
`65
`
`APOTEX EX. 1009-003
`
`

`
`5,747,498
`
`5
`
`(6.7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-phenyl)
`-amine;
`
`(6.7-diethoxy-quinazolin—4—y1)-(3—ethynyl-4-fluoro-phenyl)
`-amine;
`(6.7-diethoxy»quinazolin-4-yl)-(5-ethynyl—2-rnethyl-
`phenyl)-amine;
`(6.7—diethoxy-quinazolin-4-yl)-(3-ethynyl-4—methyl-
`phenyl)—amine;
`(6-aminomethyl-7-rnethoxy-quinazolin-4-yl)-(3-ethynyl-
`phenyl)—amine;
`(6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-amine;
`(6—arninocarbonylmethyl-7-rnethoxy-quinazolin—4-yl)-(3-
`ethynylphenyl}-amine;
`(6-aminocarbonylethyl-7-methoxy-quinazolin—4-yl)—(3-
`ethynylphenyl)-amine;
`(6—aminocarbonylrnethyl-7-ethoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-arnine;
`(6-arninocarbonylethyl-7-ethoxy-quinazolin-4-yl)—(3~
`ethynylphenyl)-amine;
`(6—aminocarbonylmethyl-7-isopropoxy-quinazolin—4—yl)-(3—
`ethynylphenyl)-amine;
`(6-an1inocarbony1methyl—7-propoxy-quinazolin-4—yl)-(3-
`ethynylphenyl)—am.ine:
`(6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)—(3-
`ethynylphenyl)-amine;
`(6—aminocarbonylethyl-7-isopropoxy-quinazolin—4-yl)—(3~
`ethynylphenyl)-amine; and
`(6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-(3-
`ethynylphenyl)-amine.
`Other specific preferred compounds of formula I include
`the following:
`(6.7-diethoxyquinazolim 1-yl)-(3-ethynylphenyl)-amine;
`(3—ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2—methoxy-
`ethoxy)-quinazolln-1-yl]-amine;
`[6.7-bis-(2-hydroxy-ethoxy)-quinazolin- l-yl]-(3-
`ethynylphenyl)-amine;
`[6.7—bis-(2-methoxy-ethoxy)-quinazolin- l-yll-(3-
`ethynylphenyl)-amine;
`1
`(6.7-dimethoxyquinazolim 1-yl)-(3-ethynylphenyl)-amine;
`(3-ethynylphenyl)-(6-methanesulfonylamino-quinazolim1-
`yl)-amine; and.
`(6-amino-quinazolin1-yl)-(3-ethynylphenyl)—amine.
`The invention further relates to a pharmaceutical compo-
`sition for the treatment of a hyperproliferative disorder in a
`mammal which comprises a therapeutically-etfective
`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 hyper-
`proliferative 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.
`In another preferred embodiment. the method of treating
`hyperproliferative disordas includes those wherein said
`hyperproliferative disorder is noncanoerous.
`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.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`6
`The invention further relates to a process for preparing a
`compound of the formula
`
`(R3).
`
`(R‘)».
`
`or a pharmaceutically acceptable salt or prodmg thereof.
`wherein:
`
`mis 1. 2. or 3;
`
`each R‘ is independently selected from the group con-
`sisting of hydrogen. halo. hydroxy. hydroxyamino.
`carboxy. nitro. guanidino. ureido. cyano.
`trifiuoromethyl. and -(C1-C4 alkylene)-W-(phenyl)
`wherein W is a single bond. 0. S or NH;
`or each R‘ is independently selected from R9 and (C1-C4)
`-alkyl substituted by cyano. wherein R9 is selected
`from the group consisting of R5. —0R°. -NR°R6.
`—C(O)R7. —NHOR5. -—OC(O)R5. cyano. A and
`—YI-15; R5 is C1-C4 alkyl; R“ is inde
`ndently hydro-
`gen or R5; R7 is Rs. —0R° or -NR 5; A is selected
`from piperidino. morpholino. pyrrolidino. 4-R5-
`piperazin—l—yl. imidazol-1-yl. 4-pyridon-1-yl. -(C1-C4
`alkylene)(CO2H). phenoxy. phenyl. phenylsulfanyl.
`C,-C4 alkenyl. and -(C1-C4 alkylene)C(O)NR°R°; and
`Y is S. S0. or SO ; wherein the alkyl moieties in R5.
`——OR5 and —NR 6 are optionally substituted by one
`to three substituents independently selected from halo
`and R9. and wherein the alkyl moieties of said optional
`substituents are optionally substituted by halo or R9.
`with the proviso that two heteroatorns 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 R‘ is independently selected from -NHSO2R5.
`phthalimido-(C1-C,1)—alkylsulfonylamino. benzamido.
`benzenesulfonylarnino. 3-phenylureido.
`2-oxopyi-rolidin—1-yl. 2.5-dioxopyrrolidin—l—yl. and
`R1°—(C2—C1)-alkanoylamino wherein R‘° is selected
`from halo. -0R6. C2-C4 alkanoyloxy. —C(O)R7. and
`—NR°R°; and wherein the foregoing R‘ groups are
`optionally substituted by 1 or 2 substituents indepen-
`dently selected from halo. C1-C4 alkyl. cyano. meth-
`anesulfonyl and C1-C4 alkoxy;
`or two R‘ groups are taken together with the carbons to
`which they are attached to form a 5-8 membered ring
`that i.ncludes l or 2 heteroatoms selected from 0. S and
`N;
`
`R2 is hydrogen or C1-C6 alkyl optionally substituted by l
`to 3 substituents independently selected from halo.
`C1-C4 alkoxy. —NR5R°. and -S0-2R5;
`n is 1 or 2 and each R3 is independently selected from
`hydrogen. halo. hydroxy. C1-C6 alkyl. -NR"’R6. and
`C1-C4 alkoxy. wherein the alkyl moieties of said R3
`groups are optionally substituted by 1 to 3 substituents
`independently selected from halo. C1-C1 alkoxy.
`--NRGR6. and —SO2R5; and.
`R‘ is afido or -(ethynyl)-R” wherein R” is hydrogen or
`C1-C6 alkyl optionally substituted by hydroxy. -012‘.
`or -NRGR5; which comprises
`
`APOTEX EX. 1009-004
`
`

`
`a) treating a compound of the formula
`
`7
`
`5 ,747.498
`
`8
`
`SCHEME
`
`(R’),,,
`
`OH
`\ N
`¢i
`
`N
`
`or
`
`(R‘).,.
`
`W
`
`N
`
`NH 5
`2
`
`X
`N /
`1
`HC
`
`‘\\N
`
`wherein R‘ and m are as defined above. with CCL, and
`(C5—Cmaryl)_,P. optionally supported on an inert
`polymer. wherein the aryl moieties of said (C5-Cmaryl)
`3P are optionally substituted by C1-C6 alkyl; and
`b) treating the product of step a) with a compound of
`the formula
`
`10
`
`2
`
`if
`HN
`
`(10%
`
`wherein R2. R3 and n are as defined above. and I is Y or
`R‘. wherein R‘ is as defined above and wherein Y is
`NH2. 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 (C5—Cmaryl)3P
`is phenyl.
`Other preferred processes for preparing the compound of
`formula I include those wherein said (C5—C,oa1yl)3P is
`supported on an inert polymer.
`Other preferred processes for preparing the compound of
`formula I include those wherein said inert polymer is a
`divinylbenzene-cross—linked polymer of styrene.
`The term “halo”. as used herein. unless otherwise
`indicated. means chloro. bromo. iodo. or fluoro.
`
`The term “alky1". as used herein, unless otherwise
`indicated. means straight chained. cyclic or branched. satu-
`rated or unsaturated hydrocarbon moiety with the proviso
`that said alkyl must comprise three or more carbon atoms if
`it is branched or cyclic.
`As used herein. the expression “reaction-inert solvent”
`refers to a solvent which does not interact with starting
`
`materials. reagents. intermediates or products in a manner
`which adversely affects the yield of the desired product.
`Other features and advantages will be apparent from the
`specification and claims which describe the invention.
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`R1 m
`)
`
`(
`
`3 H
`(R)
`
`+
`
`R“
`
`N/
`H
`
`Y
`
`4
`
`(R3),
`
`Y
`
`l
`
`N/R2
`
`N I
`I
`
`l-IC .\\ N
`
`3
`
`CW)»:
`
`(R3). N/R2
`
`R
`
`N Z
`
`HC ‘\ N
`
`1
`
`X
`
`N /
`+ Hé
`
`%N
`
`R2
`
`N/
`H
`
`<R*>..
`
`3
`(R).
`
`R
`
`5
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The Formula I compounds. pharmaceutically acceptable
`salts and prodrugs thereof (hereafter the active compounds)
`may be prepared by any process known to be applicable to
`the preparation of chemically-related compounds.
`In general the active compounds may be made from the
`appropriately substituted quinazoline using the appropri-
`ately substituted amine.
`As shown in the Scheme the appropriate 4-substituted
`quinazoline 2 wherein X is a suitable displaeeable leaving
`
`APOTEX EX. 1009-005
`
`

`
`5 .747.498
`
`9
`group such as halo. aryloxy. alkylsulfinyl. alkylsulfonyl such
`as trifluoromethanesulfonyloxy. arylsulfinyl. arylsulfonyl.
`siloxy. cyano. pyrazolo. triazolo or tetrazolo. preferably a
`4-chloroquinazoline. is reacted with the appropriate amine
`or amine hydrochloride 4 or 5. wherein R4 is as described
`above and Y is Br. I. or trifluoromethane-sulfonyloxy in a
`solvent such as a (C 1—C5)alcohol. dimethylformamide
`(DMF). N-methylpyrrolidin-2-one. chloroform. acetonitrile.
`tetrahydrofuran (THF). 1-4 dioxane. pyridine or other apro-
`tic solvent. The reaction may be effected in the presence of
`a base. preferably an alkali or alkaline earth metal carbonate
`or hydroxide or a tertiary amine base. such as pyridine.
`2.6-lutidine. collidine. N-methyl-morpholine. triethylamine.
`4-dimethylamino-pyridine or N.N-dirnethylaniline. These
`bases are hereinafter refered to as suitable bases. The
`reaction mixture is maintained at a temperature from about
`ambient to about the reflux temperature of the solvent.
`preferably from about 35° C. to about reflux. until substan-
`tially no remaining 4-haloquinazoline can be detected. typi-
`cally about 2 to about 24 hours. Preferably. the reaction is
`performed under an inert atmosphere such as dry nitrogen.
`Generally the reactants are combined stoichiometricaily.
`When an amine base is used for those compounds where a
`salt (typically the HCl salt) of an amine 4 or 5 is used. it is
`preferable to use excess amine base. generally an extra
`equivalent of amine base. (Alternatively. if an amine base is
`not used an excess of the amine 4 or 5 may be used).
`For those compounds where a sterically hindered amine 4
`(such as a 2-alkyl-3-ethynylaniline) or very reactive
`4-haloquinazoline is used it is preferable to use t-butyl
`alcohol or a polar aprotic solvent such as DMF or
`N-methylpyrrolidin-2-one as the solvent.
`Alternatively. a 4-substituted quinazoline 2 wherein X is
`hydroxyl or oxo (and the 2-nitrogen is hydrogenated) is
`reacted with carbon tetrachloride and an optionally substi-
`tuted triarylphosphine which is optionally supported on an
`inert polymer (e. g. triphenylphosphine. polymer supported.
`Aldrich Cat. No. 36.645-5. which is a 2% divinylbenzene
`cross-linked polystyrene containing 3 mmol phosphorous
`per gram resin) in a solvent such as carbon tetrachloride.
`chloroform. dichloroethane. tetrahydrofuran. acetonitrile or
`other aprotic solvent or mixtures thereof. The reaction
`mixture is maintained at a temperature from about ambient
`to reflux. preferably from about 35° C. to reflux. for 2 to 24
`hours. This mixture is reacted with the appropriate amine or
`amine hydrochloride 4 or 5 either directly or after removal
`of solvent. for example by vacuum evaporation. and addition
`of a suitable alternative solvent such as a (C1-C6) alcohol.
`DMF. N-methylpyrrolidin-2-one. pyridine or 1-4 dioxane.
`Then. the reaction mixture is maintained at a temperature
`from about ambient to the reflux temperature of the solvent
`preferably from about 35° C. to about reflux. until substan-
`tially complete formation of product is acheived. typically
`from about 2 to about 24 hours. Preferably the reaction is
`performed under an inert atmosphere such as dry nitrogen.
`When compound 4. wherein Y is Br.
`I. or
`trifluoromethanesulfonyloxy. is used as starting material in
`the reaction with quinazoline 2. a compound of formula 3 is
`formed wherein R‘. R2. R3. and Y are as described above.
`Compound 3 is converted to compounds of formula 1
`wherein R‘ is R“ethynyl. and R“ is as defined above. by
`reaction with a suitable palladium reagent such as tetralris
`(triphenylphosphine)palladium or bis(t:riphenylphosphine)
`palladium dichloride in the presence of a suitable Lewis acid
`such as cuprous chloride and a suitable alkyne such as
`trimethylsilylacetylene. propargyl alcohol or 3-(N.N-
`dimethylamino)-propyne in a solvent such as diethylarnine
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`10
`or triethylamine. Compounds 3. wherein Y is NI-I2. may be
`converted to compounds 1 wherein R4 is azide by treatment
`of compound 3 with a diazotizing agent. such as an acid and
`a nitrite (e.g.. acetic acid and NaNO2) followed by treatment
`of the resulting product with an azide. such as NaN3.
`For the production of those compounds of Formula I
`wherein an R’ is an amino or hydroxyamino group the
`reduction of the corresponding Formula I compound
`wherein R‘ is nitro is employed.
`The reduction may conveniently be carried out by any of
`the many procedures known for such transformations. The
`reduction may be carried out. for example. by hydrogenation
`of the nitro compound in a reaction-inert solvent in the
`presence of a suitable metal catalyst such as palladium.
`platinum or nickel. A further suitable reducing agent is. for
`example. an activated metal such as activated iron (produced
`by washing iron powder with a dilute solution of an acid
`such as hydrochloric acid). Thus. for example. the reduction
`may be carried out by heating a mixture of the nitro
`compound and the activated metal with concentrated hydro-
`chloric acid in a solvent such as a mixture of water and an
`alcohol. for example. methanol or ethanol. to a temperature
`in the range. for example. 50° to 150° C.. conveniently at or
`near 70° C. Another suitable class of reducing agents are the
`alkali metal dithionites. such as sodium dithionite. which
`may be used in (C,_—C4)alkanoic acids. (C1—C,-,)alkanols.
`water or mixtures thereof.
`
`For the production of those compounds of Formula I
`wherein R2 or R3 incorporates a primary or secondary amino
`moiety (other than the amino group intended to react with
`the quinazoline). such free amino group is preferably pro-
`tected prior to the above described reaction followed by
`deprotection. subsequent to the above described reaction
`with 4-(substituted)quinazoline 2.
`Several well known nitrogen protecting groups can be
`used. Such groups include (C , —C5)alkoxycarbonyl. option-
`ally substituted benzyloxycarbonyl. aryloxycarbonyl. trityl.
`vinyloxycarbonyl. O-nitrophenylsulfonyl.
`diphenylphosphinyl. p-toluenesulfonyl. and benzyl. The
`addition of the nitrogen protecting group may be carried out
`in a chlorinated hydrocarbon solvent such as methylene
`chloride or 1.2-dichloroethane. or an ethereal solvent such as
`glyme. diglyme or THF. in the presence or absence of a
`tertiary amine base such as triethylamine. diisopropylethy-
`lamine or pyridine. preferably triethylamine. at a tempera-
`ture from about 0° C.
`to about 50° C.. preferably about
`ambient temperature. Alternatively. the protecting groups
`are . conveniently attached using Schottcn-Baumann condi-
`tions.
`
`Subsequent to the above described coupling reaction. of
`compounds 2 and 5. the protecting group may be removed
`by deprotecting methods known to those skilled in the art
`such as treatment with trifluoroacetic acid in methylene
`chloride for the tert-butoxycarbonyl protected products.
`For a description of protecting groups and their use. see
`T. W. Greene and P. G. M. Wuts. “Protective Groups in
`Organic Synthesis” Second Ed.. John Wiley & Sons. New
`York. 1991.
`For the production of compounds of Formula I wherein
`R‘ or R2 is hydroxy. cleavage of a Formula 1 compound
`wherein R‘ or R2 is (C1—C4)alkoxy is preferred.
`The cleavage reaction may conveniently be carried out by
`any of the many procedures known for such a transforma-
`tion. Treatment of the protected formula I derivative with
`molten pyridine hydrochloride (20-30 eq.) at 150° to 175°
`C. may be employed for O-dealkylations. Alternatively. the
`
`APOTEX EX. 1009-006
`
`

`
`11
`
`12
`
`5.747.498
`
`cleavage reaction may be carried out. for example. by
`treatment of the protected quinazoline derivative with an
`alkali metal
`(C1-C4)alkylsulphide.
`such as sodium
`ethanethiolate or by treatment with an alkali metal dia-
`rylphosphide such as lithium diphenylphosphide. The cleav-
`age reaction may also. conveniently. be carried out by
`treatment of the protected quinazoline derivative with a
`boron or aluminum trihalide such as boron uibromide. Such
`reactions are preferably carried out in the presence of a
`reaction-inert solvent at a suitable temperature.
`Compounds of formula L wherein R‘ or R2 is a (C1-C4)
`alkylsulphinyl or (C 1-C4)alkylsulphonyl group are prefer-
`ably prepared by oxidation of a formula I compound
`wherein R‘ or R2 is a (C1—C4)allcylsulfanyl group. Suitable
`oxidizing agents are known in the art for the oxidation of
`sulfanyl
`to sulphinyl and/or sulphonyl. e.g.. hydrogen
`peroxide. 3 peracid (such as 3-chloroperoxybenzoic or per-
`oxyacetic acid). an alkali metal peroxysulphate (such as
`potassium peroxymonosulphate). chromium trioxide or gas-
`eous oxygen in the presence of platinum. The oxidation is
`generally carried out under as mild conditions as possible
`using the stoichiometric amount of oxidizing agent in order
`to reduce the risk of over oxidation and damage to other
`functional groups. In general. the reaction is carried out in a
`suitable solvent such as methylene chloride. chloroform.
`acetone. tetrahydrofuran or tert—butyl methyl ether and at a
`temperature from about —25° to 50° C.. preferably at or near
`ambient temperature. i.e.. in the range of 15° to 35° C. When
`a compound carrying a sulphinyl group is desired a milder
`oxidizing agents should be used such as sodium or potas-
`situn metaperiodate. conveniently in a polar solvent such as
`acetic acid or ethanol. The compounds of formula I con-
`taining 21 (C,—C4)alkylsulphonyl group may be obtained by
`oxidation of the corresponding (C£—C4)alkylsulphinyl com-
`pound as well as of the corresponding (C 1C4)allrylsulfanyl
`compound.
`Compounds of formula I wherein R’ is optionally sub-
`stituted (C2—C4)all~:anoylamino. ureido. 3-phenylureido.
`benzamido or sulfonamido can be prepared by acylation or
`sulfonylation of a corresponding compound wherein R‘ is
`amino. Suitable acylating agents are any agents known in the
`art for the acylation of amino to acylarnino. for example.
`acyl halides. e.g.. a (C2—C4)alkanoyl chloride or bromide or
`a benzoyl chloride or bromide. alkanoic acid anhydrides or
`mixed anhydrides (e.g.. acetic anhydride or the mixed anhy-
`dride formed by the reaction of an alkanoic acid and a
`(C,-Cgalkoxycarbonyl halide. for example (C1-C4)
`allroxycarbonyl chloride. in the presence of a suitable base.
`For the production of those compounds of Formula I
`wherein R‘ is ureido or 3—phenylureido. a suitable acylating
`agent is. for example. a cyanate. e.g.. an alkali metal cyanate
`such as sodium cyanate. or an isocyanate such as phenyl
`isocyanate. N-s