r3»&~oO
`,
`.
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`PHARMACEUTICAL USES FOR N—(3-ETHYNYLPHENYLAMINO)~6,7-BlS(2-METHOXYETHOXY)-4-
`QUINAZOLINAMINES
`
`TITLE OF THE INVENTION (280 characlers max)
`
`CORRESPONDENCE ADDRESS
`
`
`
`
`
`
`Paul H. Ginsburg
`Pfizer Inc
`235 East 42nd Street
`
`New York, NY 10017-5755
`
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`
`
`
`Specification Number of Pages
`
`6
`
`ClaiII1(s)
`
`Number of Pages
`
`1 pages
`
`I:[Drawing(s)
`
`Number of Sheets
`
`page
`
`IVIETHOD OF PAYNIENT (check one)
`
`
`1 Other (specify) Abstract
`
`
`
`
`
`
`
` PROVISIONAL
`
`E]
`A check or money order is enclosed to cover the Provisional filing fees
`FILING FEE
`The Commissioner is hereby authorized to charge all required
`R
`
`filing fees to, and credit any overpayment to Deposit Account Number:
`16-1445. Two copies of this page are enclosed.
`
`
`
`
`
`AMOUNT($)
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`)2
`No.
`
`D
`
`Yes, the name of the U.S. Government agency and the Government contract number are:
`
`Respectfully submitted,
`
`‘fix
`.
`SIGNATURE km DATE: March 30, 2000
`
`TYPED or PRINTED NAME
`
`REGISTRATION NO: 27,582
`(If appropriate)
`Additional inventors are being named on separately numbered sheets attached hereto.
`
`Israel Nissenbaum
`
`E]
`
`PROVISIONAL APPLICATION FILING ONLY
`
`APOTEX EX. 1008-001
`
`

`
`
`
`PC10678
`
`PHARMACEUTICAL USES FOR N-(3—ETHYNYLPHENYLAlVl|NO_)-6,7—BlS_{2—
`
`METHOXYETHOXY)-4-QUlNAZOLlNAMlNES
`Field of the invention
`
`The present
`
`invention relates to novel uses for N-(3-ethynylphenyl)-6,7-bis(2-
`
`5
`
`hydrochloride ,.and g
`the mesylate,
`particularly
`and
`metho><yethoxy)~4wquinazolinamine
`anhydrous and hydrate forms. These compounds are currently described as being useful in
`
`the treatment of hyperproliferative disorders, such as cancers, in mammals.
`
`Background of the invention
`
`United States Patent No. 5,747,498 issued May 5, 1998, which is incorporated in its
`
`10
`
`entirety herein by reference thereto, refers to [6,7—bis(2—methoxyethoxy)—quinazolin—4—yl]—(3—
`
`ethynylphenyi)amine hydrochloride as 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 mesyiate compounds in the various polymorph forms, described in co-pending
`
`15
`
`application USSN 09/355534, filed April 8, 1999, are of particular use in most administration
`
`applications, while the hydrochlorides, further described in co-pending provisional application
`
`USSN 60/164907, filed November 11, 1999. are particularly useful
`
`in oral administration
`
`applications. The disclosures of both applications are fully incorporated herein, by reference
`thereto.
`
`20
`
`Summary of the invention
`
`The present invention relates to the use of the various forms of N-(3—ethynylphenyl)-
`
`6,7—bis(2—methoxyethoxy)—4-quinazolinamine including the mesylate and hydrochloride forms
`
`(all polymorph forms) as well as other pharmaceutically acceptable salt forms, and anhydrous
`
`and hydrate forms, for treatment, with a therapeuticallyeffective amount of the aforementioned
`
`25
`
`compounds and a pharmaceuticaily acceptable carrier, of the specific conditions 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) and adrenal and skin cancers as well as auto immune and neoplastic cutaneous
`
`diseases such as mycoses fungoides, in a mammal, as well as for the chemoprevention of basal
`
`30
`
`or squamous cell carcinomas of the skin, especially in areas exposed to the sun or in persons
`
`known to be at high risk for such cancers. in addition, the aforementioned compounds are useful
`
`in treatment of atherosclerosis, with epidermal growth factor having been impiicated in the
`
`hyperproliferation of vascular smooth muscle cells responsible for atherosclerotic plaques (G.E.
`
`Peoples et al., Proc. Nat. Acad. Sci. USA 92:6547-6551, 1995).
`
`35
`
`In addition to direct treatment of the above ailments with the compounds, the utilization
`
`and treatment in these and general applications may be as palliative or neo-adjuvant/adjuvant
`
`monotherapy. in blocking epidermal growth factor receptors (EGFR) and for use in treatment of
`
`APOTEX EX. 1008-002
`
`

`
`
`
`tumors that express a variant form of EGFR known as EGFRvlll as described in the scientific
`literature (e.g., DK Moscatello et al. Cancer Res. 55:5536—5539, 1995), as well as in a
`combination with chemotherapy and immunotherapy. Treatment is also possible with both anti-
`EGFR and anti—EGF antibody combinations or with combination of inhibitors of MMP (matrix-
`metallo—proteinase), other tyrosine kinases including VEGFR (vascular endothelial growth factor
`receptor), farnesyl transferase, CTLA4 (cytotoxic T-lymphocyte antigen 4) and erbB2. Further
`treatments include MAb to VEGFr, and other cancer~related antibodies including rhuMAb—
`VEGF (Genentech, Phase ill), the erbB2 MAb available as Herceptin (Genentech, Phase III),
`or the avb3 MAb available as Vitaxin (Applied Molecular Evolution/Medlmmune, Phase ll).
`Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172
`(published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent
`Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 993086172
`(filed October 29, 1999), WO 98/07697 (published February 26, 1996), WO 98/03516
`(published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915
`(published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566
`(published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994),
`European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published
`May 331, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published
`October 21, 1999), WO 99/29667 (published June 17, 1999), PCT international Application
`No. PCT/lB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed
`March 25, 1999), Great Britain patent application number 99129611 (filed June 3, 1999),
`United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States
`Patent 5,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January
`19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which
`are incorporated herein in their entireties by reference.
`
`EGFR inhibitors are described in, for example in WO 95/19970 (published July 27,
`1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998),
`and United States Patent 5,747,498 (issued May 5, 1998), and such substances can be used in
`the present invention as described herein. EGFR-inhibiting agents include, but are not limited to
`the monoclonal antibodies C225 and anti—EGFR 22Mab (lmClone Systems incorporated of New
`York, New York, USA),
`the compounds ZD-1839 (Astrazeneca), BlBX-1382 (Boehringer
`lngelheim), MDX-447 (Medarex lnc. of Annandale, New Jersey, USA), and OLX-103 (Merck &
`Co. of Whitehouse Station, New Jersey, USA), VRCTC—31O (Ventech Research) and EGF
`fusion toxin (Seragen inc. of Hopkinton, Massachusettes). These and other EGFR~inhibiting
`agents can be used in the present invention.
`
`VEGF inhibitors and VEGF receptors are described in, for example in WO 99/24440
`(published May 20, 1999), PCT international Application PCT/lB99/00797 (filed May 3, 1999),
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`APOTEX EX. 1008-003
`
`

`
`
`
`in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999),
`
`United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published
`
`November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States
`
`Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11,
`
`5
`
`1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12,
`
`1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998),
`
`WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO
`
`98/02437 (published January 22, 1998), all of which are incorporated herein in their entireties by
`
`reference thereto. Other examples of some specific VEGF inhibitors are lM862 (Cytran Inc. of
`
`10
`
`Kirkland, Washington, USA); anti-VEGF monoclonal antibody of Genentech,
`
`inc. of South
`
`San Francisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder,
`
`Colorado) and Chiron (Emeryville, California).
`
`ErbB2 receptor
`
`inhibitors, such as GW—282974 (Glaxo Wellcome pic), and the
`
`monoclonal antibodies AR—209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA)
`and 2B—1
`(Chiron), can furthermore be combined with a compound used in the present
`
`15
`
`invention, for example those indicated in WO 98/02434 (published January 22, 1998), WO
`
`99/35148 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437
`(published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970
`(published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and
`United States Patent 5,877,305 (issued March 2, 1999), which are all hereby incorporated
`herein in their entireties by reference thereto. ErbB2 receptor inhibitors useful in the present
`invention are also described in United States Provisional Application No. 60/117,341,
`filed
`January 27, 1999, and in United States Provisional Application No. 60/117,346, filed January
`27, 1999, both of which are incorporated in their entireties herein by reference. The erbB2
`receptor inhibitor compounds and substance described in the aforementioned PCT applications,
`U.S. patents, and U.S. provisional applications, as well as other compounds and substances
`
`that inhibit the erbB2 receptor, can be used with a compound used in the present invention.
`
`Specific CTLA4 antibodies that can be used in the present invention include those
`
`described in United States Provisional Application 60/113,647 (filed December 23, 1998)
`which is incorporated by reference in its entirety, however other CTLA4 antibodies can be
`used in the present invention.
`
`20
`
`25
`
`30
`
`The compounds are also useful as radiation sensitizers for cancer treatment and may be
`
`combined with anti-hormonal
`
`therapies. Parameters of adiuvant radiation therapies are for
`
`example contained in PCT/US99/10741, as published on 25 November 1999,
`
`in international
`
`35
`
`Publication No. WO 99/60023, the disclosure of which is included herein by reference thereto.
`
`A specific embodiment of the present invention comprises the use of the anhydrous
`form of N-(3-ethynylphenyl)-6,7-bis(2—methoxyethoxy)—4—quinazolinamine mesylate alone or in
`
`APOTEX EX. 1008-004
`
`

`
`
`
`the aforementioned combinations or combination treatments.
`
`in particular, the anhydrous
`
`form includes polymorphs A, B, and C, having X—ray powder diffraction patterns as described
`in USSN 09/355534.
`
`Another specific embodiment of the present invention comprises N-(3—ethynylphenyl)—
`
`5
`
`6,7—bis(2—methoxyethoxy)-4—quinazolinamine mesylate monohydrate described
`
`in
`
`said
`
`application.
`
`The hydrochlorides,
`
`in polymorphs A and B as described in USSN 60/164907 filed
`
`November 11, 1999, with described X—ray diffraction patterns, are particularly suitable for oral
`use.
`
`10
`
`Patients who can be treated with N~(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`
`quinazolinamine including mesylate and hydrochloride forms, according to the methods of this
`
`invention include, for example, patients who have been diagnosed as having 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) and
`
`15
`
`adrenal and skin cancers as weli as auto immune and neoplastic cutaneous diseases such as
`
`mycoses fungoides, as well as patients with atherosclerosis and for persons known to be high
`
`risks for cancers such as basal or squamous cell carcinomas of the skin, especially in areas
`
`exposed to the sun, for the chemoprevention thereof.
`
`20
`
`N-(3-ethynylphenyl)—6,7—bis(2—methoxyethoxy)—4—quinazolinamine mesylate has been
`
`found to exist in three distinct anhydrous polymorphic forms A, B and C and also as a
`
`Detailed Description of the invention
`
`monohydrate.
`
`N—(3—ethynylphenyl)—6,7—bis(2-methoxyethoxy)-4-quinazolinamine
`
`hydrochloride,
`
`exists in two polymorph forms. The various forms may be prepared in any of the ways
`
`25
`
`described in said patent and appiications, referred to above.
`
`The in vitro activity of the compounds of the present invention in inhibiting the receptor
`
`tyrosine kinase (and thus subsequent proliferative response, e.g., cancer) may be determined
`
`by procedures described in the above referred to and incorporated patent and patent
`applications.
`
`30
`
`Administration of the compounds of the present
`
`invention (hereinafter the “active
`
`compound(s)”) can be effected by any method that enables delivery of the compounds to the
`
`site of action. These methods include oral routes,
`
`intraduodenal routes, parenteral injection
`
`(including intravenous, subcutaneous,
`
`intramuscular,
`
`intravascular or infusion),
`
`topical, and
`
`rectal administration. Parenteral administration is usually preferred but for the hydrochloride
`
`35
`
`form, oral administration is preferred.
`
`The amount of the active compound administered will be dependent on the subject
`
`being treated,
`
`the severity of the disorder or condition, the rate of administration and the
`
`APOTEX EX. 1008-005
`
`

`
`
`
`judgement of the prescribing physician. However, an effective dosage is in the range of about
`
`O.1mg to about 30 mg per kg body weight per day, preferably about t to about 35 mg/kg/day, in
`
`single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 2.2
`
`g/day, preferably about 0.2 to about 2.5 g/day.
`
`In some instances, dosage levels below the
`
`5
`
`lower limit of the aforesaid range may be more than adequate, while in other cases still larger
`
`doses may be employed without causing any harmful side effect, provided that such larger
`
`doses are first divided into several small doses for administration throughout the day.
`
`The active compound may be applied as a sole therapy or may involve one or more
`
`other materials and treatment agents such as both anti—EGFR and anti-EGF antibody
`
`10
`
`combinations or with combination of inhibitors of MMP (matrix- metallo-proteinase), other tyrosine
`
`kinases including VEGFR (vascular endothelial growth factor receptor), farnesyl transferase,
`
`CTLA4 .(cytot0xiC T—lymphocyte antigen 4) and erbB2, as well as MAD to VEGFr, and other
`
`cancer—related antibodies including rhuMAb-VEGF, the erbB2 MAb, or avb3.
`
`The compounds are also used as radiation sensitizers for cancer treatment and may be
`
`15
`
`combined with anti-hormonal therapies. With such mode of treatment for example, for inhibiting
`
`tumor growth, a radiation dosage of 1-100 Gy is utilized preferably in conjunction with at least
`
`50 mg of the pharmaceutical compound, in a preferred dosage regimen of at least five days a
`week for about two to ten weeks.
`
`The aforementioned conjoint treatments may be achieved by way of the simultaneous,
`
`»
`
`20
`
`sequential or separate dosing of the individual components of the treatment.
`
`The pharmaceutical composition may, for example, be in a form suitable for oral
`
`administration as a tablet, capsule, pill, powder, sustained release formulations, solution,
`
`suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical
`
`administration as an ointment or cream or for rectal administration as a suppository. The
`
`25
`
`pharmaceutical composition may be in unit dosage forms suitable for single administration of
`
`precise dosages. The pharmaceutical composition will include a conventional pharmaceutical
`
`carrier or excipient and a compound according to the invention as an active ingredient.
`
`in
`
`addition, it may include other medicinal or pharmaceuticat agents, carriers, adjuvants, etc.
`
`Exemplary parenteral administration forms include solutions or suspensions of active
`
`30
`
`compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose
`
`solutions. Such dosage forms can be suitably buffered, if desired.
`
`Suitable pharmaceutical carriers include inert diluents or fillers, water and various
`
`organic solvents.
`
`The pharmaceutical compositions may,
`
`if desired, contain additional
`
`ingredients such as flavorings, binders, excipéents and the like. Thus for oral administration,
`
`35
`
`tablets containing various excipients, such as citric acid may be employed together with various
`
`disintegrants such as starch. alginic acid and certain complex silicates and with binding agents
`
`such as sucrose, gelatin and acacia. Additionally,
`
`lubricating agents such as magnesium
`
`APOTEX EX. 1008-006
`
`

`
`stearate, sodium lauryl sulfate and talc are often useful
`
`for
`
`tableting purposes.
`
`Solid
`
`compositions of a similar type may also be empioyed in soft and hard filled gelatin capsules.
`
`Preferred materials,
`
`therefor,
`
`include lactose or milk sugar and high molecular weight
`
`polyethylene glycois. When aqueous suspensions or elixirs are desired for oral administration
`
`5
`
`the active compound therein may be combined with various sweetening or flavoring agents,
`
`coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with
`
`diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
`
`Methods of preparing various pharmaceutical compositions with a specific amount of
`
`active compound are known, or will be apparent, to those skilled in this art. For examples. see
`
`10
`
`Remington's Pharmaceutical Sciences,
`
`l\/lack Publishing Company, Easter, Pa., 15th Edition
`
`(1975).
`
`
`
`APOTEX EX. 1008-007
`
`

`
`
`
`CLAIMS
`
`1.
`
`A method for the treatment of NSCLC (non small cell lung cancer), pediatric
`
`malignancies, cervical and other tumors caused or promoted by human papilioma virus
`
`(HPV), melanoma, Barrett’s esophagus (pre-malignant syndrome), adrenal and skin cancers
`
`01
`
`and
`
`auto immune, neoplastic cutaneous diseases and atherosclerosis in a mammal
`
`comprising administering to said mammal
`
`a therapeutically effective amount of a
`
`pharmaceutical composition comprised of at
`
`least one of N—(3—ethynylpheny|)—6,7—bis(2-
`
`metho><yethoxy)—4—quinazolinamine,
`
`and pharmaceutically acceptable salts
`
`thereof
`
`in
`
`anhydrous and hydrate forms.
`
`10
`
`2.
`
`The method of claim 1 wherein the treatment further comprises a palliative or
`
`neo-adjuvant/adjuvant monotherapy,.
`
`3.
`
`The method of claim 1 wherein the treatment further comprises blocking
`
`epidermal growth factor receptors (EGFR).
`
`15
`
`4.
`
`5.
`
`The method of claim 1 for use in treatment of tumors that express EGFRvl|l.
`
`The method of claim 1 wherein the treatment
`
`further comprises a
`
`combination with any of chemotherapy and immunotherapy
`
`The method of claim 1 wherein the treatment further comprises, treatment
`6.
`with either or both anti-EGFR and anti~EGF antibodies.
`
`7.
`
`The method of claim 1 wherein the treatment further comprises a further
`
`20
`
`administration to said mammal of a member of the group consisting of inhibitors of MMP
`
`farnesyl
`(matrix-metallo—proteinase), VEGFR (vascular endothelial growth factor receptor),
`transferase, CTLA4 .(cytotoxic T—lymphocyte antigen 4) and erbB2, MAb to VEGFr, rhuMAb-
`VEGF, erbB2 MAb and avb3 MAb,
`
`8.
`
`The method of claim 1 wherein the pharmaceutical compounds are used as
`
`25
`
`radiation sensitizers for cancer treatment or in combination with anti-hormonal therapies.
`
`9.
`
`The method of claim 1 wherein the pharmaceutical compounds are used for
`
`the inhibition of tumor growth in humans in a regimen with radiation treatment.
`
`10.
`
`A method for the chemoprevention of basal or squamos cell carcinoma of the
`
`skin in areas exposed to the sun or in persons of high risk to said carcinoma, said method
`
`30
`
`comprising administering to said persons
`
`a
`
`therapeutically effective
`
`amount of
`
`a
`
`pharmaceutical composition comprised of at
`
`least one of N—(3—ethynylphenyl)-6,7-bis(2-
`
`metnoxyethoxy)-4-quinazolinamine,
`anhydrous and hydrate forms
`
`and pharmaceutically acceptable
`
`salts
`
`thereof
`
`in
`
`APOTEX EX. 1008-008
`
`

`
`PHARMACEUTECAL USES FOR N—l3—ETHYNYLPHENYLAl\/llNOl—6,7—BlSl2—
`
`METHOXYETHOXYl-4-QUINAZOLINAMINES
`ABSTRACT
`
`A method for treatment of the specific conditions of NSCLC (non small cell
`
`lung
`
`5
`
`cancer), pediatric malignancies,
`
`tumors that express EGFRvlll, cervical and other tumors
`
`caused or promoted by human papilloma virus (HPV), melanoma, atherosclerosis, Barrett’s
`
`esophagus (pre-malignant syndrome) and adrenal and skin cancers as well as auto immune
`
`and neoplastic cutaneous diseases such as mycoses fungoides, in a mammal with the use of
`
`of N-(3—ethynylphenyl)—6,7—bis(2-methoxyetho><y)—4—quinazolinamine
`forms
`various
`the
`including the mesylate and hydrochloride forms (all polymorph forms, pharmaceutically
`
`10
`
`acceptable salt forms, and anhydrous and hydrate forms),
`
`in a therapeutically-effective
`
`amount of the aforementioned compounds and a pharmaceutically acceptable carrier.
`
`in
`
`addition to direct treatment of the above ailments with the compounds, the utilization and
`
`treatment in these and general applications may be as palliative or neo—adjuvant/adjuvant
`
`15 monotherapy,
`
`in blocking epidermai growth factor receptors (EGFR) as well as in a
`
`combination with chemotherapy and immunotherapy. Treatment is also possible with both
`
`anti—EGFR and anti—EGF antibody combinations or with combination of inhibitors of MMP
`
`(matrix—metallo—proteinase), other tyrosine kinases including VEGFR (vascular endothelial
`
`growth factor receptor), farnesyl transferase, CTLA4 ,(cytotoxic T—|ymphocyte antigen 4) and
`
`‘
`
`20
`
`erbB2. The compounds are also useful as radiation sensitizers for cancer treatment and may
`
`be combined with anti—hormonal therapies. The compounds are further useful in preventing
`
`basal and squamos cell carcinoma in persons susceptible thereto
`
`
`
`
`
`
`APOTEX EX. 1008-009