(12) Ulllted States Patent
`Norris et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,900,221 B1
`May 31, 2005
`
`US006900221B1
`
`............. .. 514/253
`10/1998 Brown et al.
`5,821,246 A
`9/1999 Fujiwara el al.
`.
`.....’7514/268
`5,948,784 A
`12/[1999 McMahon et al.
`..... .. 514/266.4
`6,004,967 A
`12/1999 Cl6II1€I1C€
`61 al.
`........ ..
`6,0U4,979 A
`10/2000 Morsdorf et al.
`514/253
`6,130,218 A
`1/2001 Cockerill et al
`514/228 2
`6 169 091 B1
`6,476,040 B1 * 11/2002 Norris et al.
`.. 514/266.4
`6,706,721 B1
`3/2004
`‘ill
`t
`l.
`............ .. 514/266.3
`2002/0061304 A1
`5/2002 fvfilelgreetaal.
`‘
`FOREIGN PATENT DOCUMENTS
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`3101093
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`
`
`
`AU
`AU
`AU
`CA
`CZ
`DE
`01’
`EP
`
`1:1’
`EP
`EP
`EP
`EP
`Ep
`EP
`
`EP
`JP
`
`JP
`JP
`
`JP
`JP
`JP
`-113
`JP
`
`0566226
`0579496
`0602851
`0635498
`0635507
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`0737722
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`
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`
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`
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`
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`
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`6/1992
`
`11/1992
`7/[1923
`7/11)“ 3
`9/1993
`12/1993
`
`(C°“““”“‘1)
`OTHER PUBLICATIONS
`‘
`,
`.
`H ‘
`7
`‘
`‘
`Agharkara 5% 0‘ “T: "h0h00C?m"“‘ 01 50100111‘? 01 D013
`Salts by Hydrophilic Coiinterions: Properties of Organic
`
`Salts of an Antimalarial Dru g,” Journal of Pharmaceutical
`Sciences 1976, vol. 65, No. 5, p.p. 747-749 (Exhibit 73).
`Rerge S. et al. “Pharmaceutical Salts ” Journal of Phar-
`Ifl£lC€MliC(llSCi8I1C€S
`V01. 66, NO. 1,
`74).
`
`_
`j
`((A0““0“00)
`.
`,
`_
`.
`.
`P””WV Ex“m‘”e’“Th°m‘F5 C" M"K°“Z“’Q .
`(74) 40070923 Agent 07 FWm—50hH E Whfieé COOP“ &
`Dunham LLP
`
`(57)
`
`ABSTRACT
`-
`-
`_
`,
`_
`,_ ,
`-
`,
`Elheglreffinll1‘f;'eEu°“,fe1?e; 1,3.“ fable t"g551“_111t‘f [Dim if
`'3 .3“? P 3“? )‘ ’>
`‘ ‘S1-‘me
`.°XV° OX3)‘
`‘
`quinazolinamine hydrochloride designated the ‘I3
`polyinorph, its production in essentially pure form, and its
`use. The invention also relates to the pharmaceutical com-
`positions containing the stable polymorph B form of N-(3-
`efhynylphenyl)-6,7-biS(2-me1_hOXyeth0Xy).4-
`quinazolinamine as hydrochloride, as well other forms of the
`compound, and to methods of treating hyperproliferative
`disorders such as cancer b I adiiiinisterin the coin ound
`‘
`*’ *
`‘
`’
`5
`*
`g
`P
`
`"
`
`79 Claims, 4 Drawing Sheets
`
`APOTEX EX. 1001-001
`
`(54) STABLE POLYMORPH ON
`N-(‘3-ET[-]YNYL])HENYL)-6’ 7-BIS
`(ZMETHOXYETHOXY)
`
`NIETHODS OF PRODUCTION’ AND
`PHARMACEUT [CAL U555 THEREOF
`Inventors:
`N0[‘I'1S, Gales Ferry,
`Jelfrey W. Raggon, North Stonington,
`CT (US); Richard D. Connell, East
`Lyme, CT (US); Jaines D. Moyer, East
`Lyme, CT (US), MlChaE1
`lV[OI‘lIl,
`Waterford, CT (US); Shaina M. Kajiji,
`Mystic, (TT (US); Barbara A. Foster,
`Mystic, CT (US); Karen J. Ferrante,
`East Greenwich, RI (US); Sandra L.
`Silberman, Randolph, NJ (US)
`
`(73)
`
`.
`( * ) Notice:
`
`ASS1gi]CCZ OSI Pharmaceuticals, Inc., Melville,
`NY (US)
`_
`.
`.
`.
`S11bJ6C1.IO any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. l54(b) by 0 days.
`
`(21) Appl. No.2 09/711,272
`
`(22) Filed:
`
`NOV.
`
`.9, 2000
`
`(60)
`
`Related U.S. Application Data
`Provisional application No. 60/206,420, filed on May 23,
`2000, provisional application No. 60/193,191, filed on Mar.
`30, 2000, and provisional application No. 60/164,907, filed
`on Nov. 11, 1999.
`
`(51)
`
`Int. Ci? .................. .. C07D 239/94, A61K 31/517,
`A611’ 35/00
`................................... .. 514/266.4; 544/293
`(52) U.S. Cl.
`(58) Field of Search ...................... .. 544/293; 514/266.4
`
`(56)
`
`References Cited
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`
`
`
`

`
`US 6,900,221 131
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`NZ
`RU
`VVO
`W0
`VVO
`W0
`VVO
`W0
`Vi/0
`W0
`W0
`W0
`W0
`W0
`W0
`VVO
`W0
`VVO
`W0
`W()
`W0
`VVO
`W0
`
`7118266
`0673025
`7126255
`8151377
`7188244
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`WO9503283
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`Bleicher, L., et al., “Aryl- and Hetero-Alkyne Coupling
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`Inhibitors of
`the Epidermal Growth Factor Receptor:
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`[3,2-d]pyrimidine-6-acrylamides Bearing Additional Solu-
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`lates,”Acta Chemica Scandinavica, vol. B42, p.p. 448-454
`(Exhibit 87).
`
`Pollack, V., et al., “Inhibition of Epidermal Growth Factor
`Receptor-Associated Tyrosine Phosphorylation in Human
`Carcinomas with CP-358,774: Dynamics of Receptor Inhi-
`bition In Situ and Antitumor Elfects in Athymic Mice,”
`Journal of Pharmacology and Experimental Therapeutics,
`1999, vol. 291, No. 2, p.p. 739-748 (Exhibit 83).
`
`Rosenberg, S., et al., “Studies Directed toward the Design of
`Orally Active Renin Inhibitors. 2. Development of the
`Efficacious, Bioavailable Renin Inhibitor (2S)-2-Benzyl-3-
`[[(1-methylpiperazin-4-yl)sulfonyl]propionyl]
`3-thiazol-4-yl-L-alanine
`Amide
`of
`4S)-2-Amino-1-eyclohexyl-3,
`4-dihydorxy-6-methylheptane (A-72517),” J. Med. Chem.
`1993, Vol. 36, p.p. 460-467 (Exhibit 84).
`
`(2S,
`
`3R,
`
`Hussain, M., et al., “Parenteral Formulation of the Kappa
`Agonist Analgesic, DuP 747, via Micellar Solubilization,”
`Pharmaceutical Research 1992, vol. 9, No. 6, pp. 750-752
`(Exhibit 79).
`
`Moyer, J ., et al., “Induction of Apoptosis and Cell Cycle
`Arrest by CP-358,774, an Inhibitor of Epidermal Growth
`Factor Receptor Tyrosine Kinase,” Cancer Research 1997,
`Vol. 57, p.p. 4838-4848 (Exhibit 80).
`
`Norris, T., et al., “Discovery of a New Stable Polymorph of
`4-(3—ethynylphenylamino)-6,
`7-bis(2-methoxy-ethoxy)quinazoliniuni Methanesulfonate
`Using Near-Infrared Spectroscopy to Monitor Form Change
`Kinetics,” J. Chem. Soc., Perkin Trans. 2000, vol. 2, p.p.
`1233-1236 (Exhibit 81).
`
`()nopchenl<o, et al., “Selective Catalytic Hydrogenation of
`Aromatic Nitro Groups in the Presence of Acetylenes.
`Synthesis of (3-Aminophenyl)acetylene via Hydrogenation
`of Dimethylcarbinol Substituted (3-Nitrophenyl) acetylene
`over Heterogeneous Metallic Ruthenium Catallyst,” Journal
`of Organic Chemistry 1979, vol. 44, No. 8, p.p. 1233-1236
`(Exhibit 82).
`
`Melissaris, A.P. et al., “A Simple and Economical Synthetic
`Route to p-Ethynylaniline and Ethynyl-Terminated Sub-
`strates” (1994) J. Org. Chem. 59:58l8-5821 (Exhibit 16).
`
`Montalbetti, C. et al., “A Convergent Synthesis of Function-
`alized B-seco Taxane Skeletons” (1995) Tetrahedron Let-
`ters 36(33):5891-5894 (Exhibit 17).
`
`Trillo et al., (1993) Tratado de Farmacia Galencia, Prinz-
`eria Edicion, pp. 81, 83, 84 (Exhibit 18); and.
`
`Sun Cunji et al., (1981) YaoxueXuebao 16(8):564-570 C.A.
`96 122727 (Exhibit 19).
`
`Driscoll D. et al., “Ellect of Epidermal Growth Factor
`Receptor Tyrosine Kinase Inhibitor PD183805 on Vascular
`Endothelial Growth Factor Secretion from Several Tumor
`
`Models” (1999) XP-001014746 (Abstract only) (Exhibit 4).
`
`Ishiwara T. et al., “Characterization of Keratinocyte Growth
`Factor and Receptor Expression in Human Pancreatic Can-
`cer” (1998) American Journal ofPathology 153(1):213-222
`(Exhibit 5).
`
`Liu N. et al., “Comparative Phenotypic Studies of Duct
`Epithelial Cell Lines Derived from Normal Human Pancreas
`and Pancreatic Carcinoma” (1998) American Journal of
`Pathology 153(1) 263-269 (Exhibit 6).
`
`APOTEX EX. 1001-002
`
`

`
`US 6,900,221 131
`Page 3
`
`Wataiiabe M. et al., Overexpression of Keratinocyte Growth
`Factor
`in Cancer Cells and Enterochromaflin Cells in
`
`Human Colorectal Cancer: (2000) Pathology International
`502363-372 (Exhibit 7) and.
`Woodburn JR. et al., “ZDl839, An Epidermal Growth
`Factor Tyrosine Kinase Inhibitor Selected for Clinical
`Development”
`(1997) XP—00l009911
`(Abstract only)
`(Exhibit 8).
`Norris T., et al. “Discovery of a new stable polymorph of
`4—(3—ethynylphenylamino)—6,
`7—bis(2—methoxyethoxy)quinazolinium methanesulfonate
`using near—infrared spectroscopy to monitor form change
`kinetics”
`J. Chem. Soc., Perkins Trans.
`2
`(2000)
`122498-2502 (Exhibit 2).
`
`SMR Committee:“Protein Kinases: Therapeutic Opportuni-
`ties” The Newsletter for the Society for Medicines Research
`(1999) 5(2):1—8 (Exhibit 3); and.
`
`Pollack et al., “Therapy of human Carcinomas in athymic
`mice by inhibition of EGF receptor—mediated signal trans-
`duction with CP—358774: Dynamics of receptor inhibition
`and anti—tumor etfects” Proceedings of the Annual Meeting
`of the American Association for Cancer Research (1999)
`29l(2):739—748 (Abstract only) (Exhibit 4).
`
`* cited by examiner
`
`APOTEX EX. 1001-003
`
`

`
`U.S. Patent
`
`-3002913ym
`
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`APOTEX EX. 1001-004
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`

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`U.S. Patent
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`APOTEX EX. 1001-005
`
`
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`APOTEX EX. 1001-006
`
`
`

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`U.S. Patent
`
`May 31, 2005
`
`Sheet4 of4
`
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`US 6,900,221 B1
`
`2
`quinazolinamine hydrochloride, particularly in the stable
`polymorph form.
`The present invention also relates to novel uses of N-(3-
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine,
`in either its hydrochloride or mesylate
`forms, in an anhydrous or hydrous form, as well as in its
`various polymorph forms, in the treatment of hyperpro1if-
`erative disorders, such as cancers, in mammals.
`
`10
`
`DESCRIPTION OF THE FIGURES
`
`1
`STABLE POLYMORPH ON
`N-(3-ETHYNYLPHENYL)-6, 7-BIS
`(ZMETHOXYETHOXY)
`-4-QUINAZOLINAMINE HYDROCHLORIDE,
`METHODS OF PRODUCTION, AND
`PHARMACEUTICAL USES THEREOF
`
`This application claims the benefit of U.S. Provisional
`Application No. 60/206,420, filed May 23, 2000, US.
`Provisional Application No. 60/193,191,
`filed Mar. 30,
`2000, and U.S. Provisional Application No. 60/164,907,
`filed Nov. 11, 1999,
`the contents of which are hereby
`incorporated by reference.
`Throughout this application various publications are ref-
`erenced. The disclosures of these publications in their entire-
`ties are hereby incorporated by reference into this applica-
`tion in order to more fully describe the state of the art to
`which this invention pertains.
`
`BACKGROUND OF THE INVENTION
`
`20
`
`N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine, in either its hydrochloride or mesylate
`forms, or in an anhydrous and hydrous form, is useful in the
`treatment of hyperproliferative disorders, such as cancers, in
`mammals.
`
`U.S. Pat. No. 5,747,498, issued May 5, 1998, which is
`incorporated herein by reference in its entirety, refers, in
`Example 20,
`to [6,7—bis(2-methoxyethoxy)-quinazolin-4-
`yl]-(3—ethynylphenyl)amine hydrochloride, which,
`the
`patent discloses,
`is an inhibitor of the erbB family of
`oncogenic and protooncogenic protein tyrosine kinases,
`such as epidermal growth factor receptor (EGFR), and is
`therefore useful for the treatment of proliferative disorders,
`such as cancers, in humans.
`The mesylate form, described in PCT International Pub-
`lication No. WO 99/55683 (PCT/IB99/00612, filed Apr. 8,
`1999), the entire disclosure of which is incorporated herein
`by reference, and assigned to a commo11 assignee, and
`shown in formula 1 below:
`
`30
`
`35
`
`40
`
`H3°\O/‘\/O
`0
`H3C/ \/\o
`
`HN
`
`\ N
`9
`N
`
`\\
`
`-CH3SO3H
`
`is useful for the treatment of proliferative disorders, and
`more preferred with parenteral methods of administration, as
`compared to the hydrochloride compound, i.e. with greater
`effectiveness in solution.
`The mesylate compounds are more soluble in aqueous
`compositions than the hydrochloride compound, and thus
`the mesylate compounds are easily delivered according to
`parenteral methods of administration. The hydrochloride
`compound is however preferred with respect to solid admin-
`istration such as with tablets and oral administration.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to polymorphs, and methods
`for
`the selective production of polymorphs of N-(3-
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)—4-
`
`55
`
`60
`
`65
`
`FIG. 1 The X-ray powder diffraction patterns for the
`hydrochloride polymorph A,
`the thermodynamically less
`stable form, over a larger range to show the first peaks.
`FIG. 2 The X-ray powder diffraction patterns for the
`hydrochloride polymorph A,
`the thermodynamically less
`stable form, are over a shorter range to show more detail.
`FIG. 3 The X-ray powder diffraction patterns for the
`hydrochloride polymorph B, the thermodynamically more
`stable form, over a larger range to show the first peaks.
`FIG. 4 The X-ray powder diffraction patterns for the
`hydrochloride polymorph B, the thermodynamically more
`stable form, over a shorter range to show more detail.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Disclosed is a substantially homogeneous crystalline
`polymorph of the hydrochloride salt of N-(3-
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine designated the B polymorph that exhibits
`an X-ray powder dilfraction pattern having characteristic
`peaks expressed in degrees 2-theta at approximately 6.26,
`12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and,
`26.91. The polymorph is also characterized by the X-ray
`powder diffraction pattern shown in FIG. 3.
`Disclosed is a crystalline polymorph of the hydrochloride
`salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine designated the B polymorph that exhibits
`an X-ray powder diffraction pattern having characteristic
`peaks expressed in degrees 2-theta at approximately 6.26,
`12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and,
`26.91, which is substantially free of the polymorph desig-
`nated the Apolymorph. The polymorph is also characterized
`by the X-ray powder diffraction pattern shown in FIG. 3.
`The polymorph designated the B polymorph may be in
`substantially pure form, relative to the A polymorph.
`Also disclosed is a composition comprising a substan-
`tially homogeneous crystalline polymorph of the hydrochlo-
`ride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-
`4-quinazolinamine that exhibits an X-ray powder diffraction
`pattern having characteristic peaks expressed in degrees
`2-theta at approximately 6.26, 12.48, 13.39, 16.96, 20.20,
`21.10, 22.98, 24.46, 25.14 and, 26.91. The hydrochloride
`salt of N-(3—ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine also exhibits an X-ray powder diffraction
`pattern having characteristic peaks expressed in degrees
`2-theta at approximately the values show in Table 3 or in
`Table 4 below.
`
`And, the N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-
`4-quinazolinamine hydrochloride in the polymorph B forn1
`may characterized by the X-ray powder diffraction pattern
`shown in FIG. 3.
`
`Also disclosed is a composition comprising a crystalline
`polymorph of the hydrochloride salt of N-(3-
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine designated the B polymorph that exhibits
`
`APOTEX EX. 1001-008
`
`

`
`US 6,900,221 B1
`
`4
`The compound of formula 4 is prepared by chlorinating a
`compound of formula 3
`
`OH
`
`N
`Q
`
`N\
`
`H3C
`
`0
`
`\o/\\/
`0
`H3C/ \/\o
`
`Also disclosed is a pharmaceutical composition for the
`treatment of a hyperproliferative disorder in a mammal
`which substantially comprises a therapeutically effective
`amount of the polymorph B and a pharmaceutically accept-
`able carrier.
`
`The pharmaceutical composition may be adapted for oral
`administration. It may be in the form of a tablet.
`Also disclosed is a method of treating a hyperproliferative
`disorder in a mammal which comprises administering to said
`mammal a therapeutically effective amount of the poly-
`morph B.
`The method may be for the treatment of a cancer selected
`from brain, squamous cell, bladder, gastric, pancreatic,
`breast, head, neck, oesophageal, prostate, colorectal, lung,
`renal, kidney, ovarian, gynecological and thyroid cancer.
`The method may also be for the treatment of a cancer
`selected from non-small cell lung cancer (NSCLC), refrac-
`tory ovarian cancer, head and neck cancer, colorectal cancer
`and renal cancer.
`
`In the method, the therapeutically effective amount may
`be from about 0.001 to about 100 mg/kg/day, or from about
`1 to about 35 mg/kg/day.
`In the method, the therapeutically effective amount may
`also be from about 1 to about 7000 mg/day; from about 5 to
`about 2500 mg/day; from about 5 to about 200 mg/day; or
`from about 25 to about 200 mg/day.
`Further disclosed is a tnethod for the treattnent of a
`
`3
`an X-ray powder diffraction pattern having characteristic
`peaks expressed in degrees 2-theta at approximately 6.26,
`12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and,
`26.91 in a Weight % of the B polymorph relative to the A
`polymorph which is at least 70%. This composition may
`comprise at least 75% polymorph B, by Weight; at least 80%
`polymorph B, by weight; at least 85% polymorph B, by
`weight; at least 90% polymorph B, by Weight; at least 95%
`polymorph B, by Weight; at least 97% polymorph B, by
`weight; at least 98% polymorph B, by Weight; or at least
`99% polymorph B, by Weight relative to the A polymorph.
`Further disclosed is a process for producing the poly-
`morph B of the hydrochloride salt of N-(3-ethynylphenyl)-
`6,7-bis(2-methoxyethoxy)-4-quinazolinamine by recrystal-
`lization of N-(3-ethynylphenyl)-6,7-bis(2—methoxyethoxy)—
`4-quinazolinamine hydrochloride in a solvent comprising
`alcohol and water.
`
`the recrystallization may comprise the
`
`In the process,
`steps of:
`a) heating to reflux alcohol, Water and the hydrochloride
`salt of N-(3-ethynylphenyl)-6,7-bis(2-
`methoxyethoxy)-4-quinazolinamine so as to form a
`solution;
`b) cooling the solution to between about 65 and 70° C.;
`c) clarifying the solution; and
`d) precipitating polymorph B by further cooling the
`clarified solution.
`
`5
`
`10
`
`15
`
`20
`
`the N-(3-ethynylphenyl)-6,7-bis(2-
`In the process,
`methoxyethoxy)-4—quinazolinamine hydrochloride is pre-
`pared by the steps of:
`coupling a compound of formula 6
`
`30
`
`%
`
`NH2
`
`6
`
`35
`
`40
`
`with a compound of formula 4
`
`0
`
`HC
`9 \~O/‘\./
`O
`H3C/ \/\o
`
`4
`
`Cl
`
`\. N
`2 -
`N
`
`The compound of formula 6 is prepared by reacting a
`compound of formula formula 5
`
`CII3
`
`(:21,
`OH
`
`%
`
`NH2
`
`in a suspension of metal alkali and solvent and with heating.
`
`hyperproliferative disorder in a mammal Which comprises
`administering to said mammal a therapeutically effective
`amount of the polymorph B in combination with an anti-
`tumor agent selected from the group consisting of mitotic
`inhibitors, alkylating agents, anti-metabolites, intercalating
`antibiotics, growth factor inhibitors, cell cycle inhibitors,
`_. enzymes,
`topoisomerase inhibitors, biological
`response
`modifiers, anti-hormones, and anti-androgens.
`Yet further disclosed is a method of making a composition
`which composition comprises substantially homogeneous
`crystalline polymorph of the hydrochloride salt of N-(3-
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine designated the B polymorph that exhibits
`an X-ray powder diffraction pattern having characteristic
`peaks expressed in degrees 2-theta at approximately 6.26,
`12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and,
`26.91, comprising admixing the crystalline polymorph desi-
`ganted the B polymorph with a carrier.
`The carrier may be a pharmaceutically acceptable carrier.
`Also disclosed is a method of preparing polymorph B of
`N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine hydrochloride which comprises the step of
`recrystallizing N-(3-ethynylphenyl)-6,7-bis(2-
`methoxyethoxy)-4-quinazolinamine hydrochloride in a sol-
`vent comprising alcohol.
`In the method the solvent may further comprises water.
`In the method,
`the N-(3-ethynylphenyl)-6,7-bis(2-
`methoxyethoxy)-4—quinazolinamine hydrochloride is pre-
`pared by coupling a compound of formula 6
`
`55
`
`60
`
`65
`
`APOTEX EX. 1001-009
`
`

`
`US 6,900,221 B1
`
`C1
`
`N
`A
`
`N\
`
`H3C
`
`o
`
`\\O/\\/
`o
`H3c/ \/\o
`
`by reaction thereof in a solvent mixture of thionyl
`chloride, methylene chloride and dimethylformamide,
`b) preparation of a compound of formula 6
`
`%
`
`NH»
`
`in situ from starting material of compound of formula 5
`
`‘J1
`
`CH3
`
`CH3
`
`OH
`
`%
`
`NH2
`
`IO
`
`20
`
`30
`
`35
`
`NH2
`
`with a compound of formula 4
`
`H3C\O/\\/0
`O
`3
`H c/ \/\o
`
`2 I
`
`N
`
`In the method, the compound of formula 6 is prepared by
`reacting a compound of formula 5
`
`CH3
`
`(:21,
`OII
`
`%
`
`NH2
`
`in a suspension of metal alkali and solvent and with heating.
`
`In the method, the compound of formula 4 is prepared by
`chlorinating a compound of formula 3
`
`40
`
`0
`
`HC
`3 \O/\\/
`0
`1—I3c/ \/\‘o
`
`on
`
`\N
`Q
`
`N
`
`Further disclosed is a method for the production of the
`polymorph B of claim 1 comprising the steps of:
`
`a) substitution chlorination of starting quinazolinamine
`compound of formula 3
`
`55
`
`H3(:\O/\/0
`0
`IrI3C/ \\/\O
`
`OH
`
`\ N
`)
`N
`
`3
`
`60
`
`65
`
`having an hydroxyl group, to provide a compound of for-
`mula 4
`
`by reaction of the latter in a suspension of metal alkali and
`solvent and with heating;
`c) reaction of the compound of formula 6 in situ with the
`compound of formula 4 wherein the compound of
`formula 6 replaces the chlorine in the compound of
`formula 4 to give the N—(3-ethynylphenyl)-6,7—bis(2—
`methoxyethoxy)-4—quinazolinamine hydrochloride;
`(1) recrystallizing the N—(3-ethynylphenyl)—6,7—bis(2-
`methoxyethoxy)—4—quinazolinamine hydrochloride,
`in
`alcohol, into the polymorph B form.
`In this method,
`the substitution chlorination may be
`quenched in the presence of aqueous sodium hydroxide;
`aqueous sodium bicarbonate; aqueous potassium hydroxide;
`aqueous potassium bicarbonate; aqueous potassium carbon-
`ate; aqueous sodium carbonate, or a mixture thereof.
`Yet further disclosed is a method for the production of
`polymorph B of the hydrochloride salt of N-(3-
`ethynylphenyl)-6,7—bis(2—methoxyethoxy)-4-
`quinazolinamine by recrystallization comprising the steps
`of:
`
`a) heating to reflux alcohol, Water and the hydrochloride
`salt of N-(3-ethyi1ylphenyl)-6,7-bis(2-
`methoxyethoxy)-4-quinazolinamine so as to form a
`solution;
`b) cooling the solution to between about 65 and 70° C.;
`c) clarifying the solution; and
`d) precipitating polymorph B by further cooling the
`clarified solution.
`
`Further disclosed is a composition consisting essentially
`of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine hydrochloride in the form of polymorph A,
`
`APOTEX EX. 1001-010
`
`

`
`US 6,900,221 B1
`
`7
`which is characterized by the following peaks in its X—ray
`powder diffraction pattern shown in FIG. 1.
`Also disclosed is a composition consisting e$entially of
`N—(3-ethynylphenyl)-6,7—bis(2-methoxyethoxy)-4-
`quinazolinamine hydrochloride in the form of polymorph A,
`which is characterized by the peaks shown is Table 1 or
`Table 2 below.
`
`A prodrug of any of the compound herein is also dis-
`closed.
`
`IO
`
`Further disclosed is a method of inducing differentiation
`of tumor cells in a tumor comprising contacting the cells
`with an effective amount of any of the compounds or
`compositions disclosed herein.
`Also discosed is a method for the treatment of NSCLC
`
`(non small cell lung cancer), pediatric malignancies, cervical
`and other tumors caused or promoted by human papilloma
`virus (HPV), melanoma, Barrett’s esophagus (pre—malignant
`syndrome), adrenal and skin cancers and auto immune,
`neoplastic cutaneous diseases and atherosclerosis in a mam-
`mal comprising administering to said mammal a therapeu-
`tically effective amount of a pharmaceutical composition
`comprised of at least one of N—(3-ethynylphenyl)—6,7—bis(2—
`methoxyethoxy)-4-quinazolinamine, and pharmaceutically '
`acceptable salts thereof in anhydrous and hydrate forms.
`The treatment may further comprise a palliative or neo-
`adjuvant/adjuvant monotherapy; or comprises blocking epi-
`dermal growth factor receptors (EGFR).
`The method of may also be used in the treatment of
`tumors that express EGFRVIII.
`The method may further comprise a combination with any
`of chemotherapy and immunotherapy; or treatment with
`either or both anti-EGFR and anti—EGF antibodies; or
`administration to said mammal of a member of the group
`consisting of inhibitors of MMP (matrix—metallo—
`proteinase), VEGFR (vascular endothelial growth factor
`receptor),
`farnesyl
`transferase, CTLA4.
`(cytotoxic
`T-lymphocyte antigen 4) and erbB2, MAb to VEGFr,
`rhuMAb-VEGF, erbB2 MAb and avb3 Mab.
`The pharmaceutical compounds used may be radiation
`sensitizers for cancer treatment or in combination with
`
`20
`
`30
`
`35
`
`40
`
`2 (Polymorph form A and B)
`
`H3C\O/\,‘/O
`
`0
`H3C/ \/\0
`
`HN
`
`\ N
`J
`/
`
`N
`
`\\
`
`°HCl
`
`making it more suitable for tablet and oral administration
`and consisting essentially of the stable polymorphic form
`(polymorph form B) as well as the compound in such
`polymorph B form and the intermediate polymorph A in
`essentially pure form.
`
`It is a further object of the present invention to provide
`such stable polymorph form B in a pharmaceutical orally
`administered composition.
`
`Stability of the hydrochloride compound is of concern for
`its use in the treatment of patients since variations will affect
`effective dosage level and administration. It has been dis-
`covered that the hydrochloride of N—(3—ethynylpl1enyl)—6,7—
`bis(2-methoxyethoxy)-4-quinazolinamine exists in two
`polymorph states, polymorph A and B. This contrasts with
`the mesylate compounds which exist in three polymorph
`states (mesylate polymorphs A, B and C). Polymorph B of
`the hydrochloride was found to be the thermodynamically
`most stable and desirable form and the present invention
`comprises the polymorph B compound in the substantially
`pure polymorphic B form and pharmaceutical compositions
`of the substantially pure form of polymorph B, particularly
`in tablet form and a method of the selective production of the
`compound.
`
`the inhibition of tumor
`therapies, or for
`anti-hormonal
`growth in humans in a regimen with radiation treatment.
`Further disclosed is a method for the chemoprevention of
`basal or squamous cell carcinoma of the skin in areas
`exposed to the sun or in persons of high risk to said
`carcinoma, said method comprising administering to said
`persons a therapeutically effective amount of a pharmaceu-
`tical composition comprised of at
`least one of N-(3-
`ethynylphenyl)-6,7—bis(2—methoxyethoxy)—4—
`quinazolinamine, and pharmaceutically acceptable salts
`thereof in anhydrous and hydrate forms.
`Also is a method of inducing differentiation of tumor cells
`in a tumor comprising contacting the cells with an effective
`amount of the compound of at
`least one of N—(3—
`ethynylphenyl)—6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine, and pharmaceutically acceptable salts
`thereof in anhydrous and hydrate forms.
`It is accordingly an object of the present invention to
`provide a method for the production of the hydrochloride
`salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine in HCl form (Formula 2):
`
`The hydrochloride compound disclosed in the U.S. Pat.
`No. 5,747,498 actually comprised a mixture of the polymor-
`, phs A and B, which, because of its partially reduced stability
`(i.e., from the polymorph A component) was not more
`preferred for tablet form than the mesylate salt forms.
`
`Specifically, the present invention relates to methods of
`producing the hydrochloride compound forms of N—(3-
`ethynylphenyl)-6,7—bis(2—methoxyethoxy)—4—
`quinazolinamine and for producing the stable form B in high
`yield. The mesylate salt of N-(3-ethynylphenyl)-6,7-bis(2-
`methoxyethoxy)—4—quinazolinamine has been discovered to
`exist in at least three polymorphic forms which have been
`designated A, B, and C, of increasing stability with different
`X—ray powder diffraction patterns. The X—ray powder dif-
`fraction patterns for the hydrochloride polymorph A(A1 and
`A2) and B (BI and B2) forms are shown in FIGS. 1-4 as
`follows: graphs of FIGS. 1 and 3 are over a larger range to
`fully show the Iirst peaks for A and B, respectively, and
`graphs of FIGS. 2 and 4 are over a shorter range to show
`more overall detail for A and B, respectively.
`
`The data contained in the above X—ray diffraction patterns
`of FIGS. 1-4 are tabulated in the following Tables 1-4:
`
`55
`
`60
`
`65
`
`APOTEX EX. 1001-011
`
`

`
`US 6,900,221 B1
`
`10
`
`9
`
`TABLE 1
`
`Polymorpli A
`Anode: Cu - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Rel Intensit}5 0.500)
`Range #1 — Coupled: 3.000 to 40.000 StepSize: 0.040 StepTime: 1.00
`Smoothing Width: 0.300 Threshold: 1.0
`
`d(A)
`15.82794
`14.32371
`11.74376
`11.03408
`10.16026
`8.98039
`7.85825
`
`I(rcl)
`100.0
`3.9
`1.5
`1.2
`1.4
`13.1
`7.8
`
`d(A)
`6.63179
`5.84901
`5.69971
`5.46922
`5.21396
`4.80569
`4.70077
`
`I(1'cl)
`1.7
`2.1
`2 3
`2.4
`3.6
`3.5
`12.2
`
`d(A)
`4.54453
`4.19685
`4.16411
`3.97273
`3.91344
`3.78223
`3.67845
`
`I(1'el)
`4.8
`4.7
`4.4
`4.7
`12.4
`24.2
`8.8
`
`d(A)
`3.61674
`3.50393
`3.40200
`3.35174
`3.29005
`3.05178
`2.97750
`
`I(rcl)
`8.2
`9.3
`6.0
`5.3
`4.2
`7.1
`3.0
`
`d(A)
`
`2.91238
`2.73148
`2.60193
`2.48243
`2.40227
`
`2.31297
`
`I(rcl)
`3.5
`3.7
`1.8
`1.3
`2.2
`1.7
`
`TABLE 2
`
`«Q
`
`Polymoiph A
`Anode: Cu - Wavelength 1: 1.54056 Wavelength 2: 1.54439 (Rel Intensity: 0.500)
`Range #1 - Coupled: 3.000 to 40.000 Stepsize: 0.040 StepTime: 1.00
`Smoothing Width: 0.300 Threshold: 1.0
`
`2-Theta
`5.579
`6.165
`7.522
`8.006
`8.696
`9.841
`11.251
`
`I(rel)
`100.0
`3.9
`1.5
`1.2
`1.4
`13.1
`7.8
`
`2-Theta
`13.340
`15.135
`15.534
`16.193
`16.991
`18.447
`18.862
`
`I(rel)
`1.7
`2.1
`2.3
`2.4
`3.6
`3.5
`12.2
`
`2-Theta
`19.517
`21.152
`21.320
`22.360
`22.703
`23.502
`24.175
`
`I(rel)
`4.8
`4.7
`4