This is a request for filin a PROVISIONAL APPLICATION under 37 CFR 1.53 b 2 .
`
`PROVISIONALAPPLICATIONCOVER SHEET
`
`1
`
` Docket Number
`PC10677
`Type a plus sign (+) inside this box
`
`K.
`
`lNVENTOR(s)IAPPLICANT(s)
`
`
`
`
`
`
`
`
`
`
`'
`
`I
`
`
`Z— —
`
`‘
` TITLE OF THE INVENTION (280 characters max)
`STABLE POLYMORPH OF N-(3-ETHYNYLPHENYLAMINO)-6,7-BlS(2-METHOXYETHOXY)
`
`—4wQUINAZOI_INAMINE HYDROCHLORIDE AND METHOD OR PRODUCTION
`CORRESPONDENCE ADDRESS
`
`Paul H. Ginsburg
`Pfizer Inc
`235 East 42nd Street
`New York, NY 10017-5755
`
`
`
`
`
`
`
`
`METHOD OF PAYMENT (check one)
`
` ENCLOSED APPLICATION PARTS {check all that apphl)
`Eispecification 16 Number of Pages
`C|aim(s)
`Number of Pages 6 pages
`
`
`|:]Drawing(s)
`Number of Sheets
`1 page
`Other (specify) Abstract
`
`
` PROVISIONAL
`FILING FEE
`
`
`
`
`
`AMOUNT($)
`
`
`
`A check or money order is enclosed to cover the Provisional filing fees
`The Commissioner is hereby authorized to charge all required
`filing fees to, and credit any overpayment to Deposit Account Number:
`16-1445. Two copies of this page are enclosed.
`
`
`
`)4
`
`
`
`
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`[XI No.
`D Yes, the name of the US. Government agency and the Government contract number are:
`
`Respectfully submitted,
`
`SIGNATURE
`
`‘j‘\\\\_
`
`DATE: Novemberli 1999
`
`
`
`TYPED or PRINTED NAME Israel Nissenbaum
`
`REGISTRATION NO: 27,582
`
`E]
`
`Additional inventors are being named on separately numbered sheets attached hereto.
`
`(if appropriate)
`
`PROVISIONAL APPLICATION FILING ONLY
`
`USERS\DOCS\I..A2 I952\LPINN\30XAOEI DOC I 141 180 I Prov Cav Sheet - PC1067?/IN [1 1/I 1/99]
`
`APOTEX EX. 1007-001
`
`

`
`CERTIFICATE OF MAILING - EXPRESS MAIL
`
`PFIZER DOCKET NO: PC1067?
`
`TITLE: STABLE POLYMORPH OF N-(3-ETHYNYLPHENYLAMINO)-6,7-BIS(2—
`METHOXYETHOXY)—4-QUINAZOLINAMINE HYDROCHLORIDE AND METHOD OR
`PRODUCTION
`
`APPLICANT: Timothy Norris et al.
`
`"Express Mail" mailing label number EE645346462US
`
`
`Date of Deposit November 11 1999
`
`I hereby certify that this paper or fee is being deposited with the United States
`Postal Service "Express Mail Post Office to Addressee" service under 37 CFR
`1.10 on the date
`indicated above
`and is addressed to Assistant
`Commissioner for Patents, Box Patent Application, Washington, D.C. 20231.
`
`Vilma Pizarro
`
`(Typed or printed name 0
`
`erson mailing paper or fee)
`
`
`
`
`
`iling paper or fee)
`
`(Signature of person
`
`Pfizer, Inc
`
`Patent Department, 20th Floor
`235 East 42nd Street
`
`New York, NY 10017-5755
`
`USERS\D0CS\LAZI952'.\LPINN\30'l'101I DOCI 141013 I Exp Mail Cert 1-"CX934A [11/9/99]
`
`APOTEX EX. 1007-002
`
`.
`
`
`
`
`
`

`
`t
`
`7
`
`PC10677
`
`STABLE POLYMORPH or N~(3—ETHYNYLPHENYLAMlNO)-6,7-BlS(2-
`
`METHOXYETHOXY)-4-QU|NA;Qblfl§M|NE HYDROCHLORIDE AND METHOD OF
`PRODUCTION
`
`Backgroundgof the invention
`
`5
`
`The present invention relates to polymorphs and methods for the selective production
`
`of
`
`N—(3-ethynylphenyl)-8,7—bis(2—methoxyethoxy)—4—quinazolinamine
`
`hydrochlorides,
`
`particularly in the stable polymorph form. These compounds are useful in the treatment of
`
`hyperproliferalive disorders, such as cancers,
`
`in mammals. United States Patent No.
`
`5,747,498,
`
`issued May 5, 1998, which is incorporated herein by reference in its entirety,
`
`10
`
`refers,
`
`in Example 20,
`
`to [6,7-bis(2—methoxyethoxy)—quinazo|in—4—yl]—(3—ethynylpheny|)amine
`
`hydrochloride, which, the patent discloses, is an inhibitor of the erbB family of oncogenic and
`
`protoonoogenic 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.
`
`15
`
`The mesylate compound (formula 1):
`
`H3C\O/X/O
`H30 \/\o
`
`/O
`
`HN
`\ N
`N//I
`
`QCH
`
`.CH so H
`
`3
`
`3
`
`
`
`described in co—pending USSN 09/355534, filed April 8, 1999 (the entire disclosure of said
`
`20
`
`application being incorporated herein by reference thereto), and assigned to a common
`
`assignee,
`
`is useful and more preferred for the treatment of proliferative disorders, 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
`
`25
`
`delivered according to parenteral methods of administration. The hydrochloride compound is
`
`however preferred with respect
`administration.
`
`to solid administration such as with tablets and oral
`
`it
`
`is accordingly an object of the present
`
`invention to provide a method for the
`
`30
`
`production of N~(3~ethynylphenyl)—6,7-bis(2—methoxyethoxy)—4-quinazolinamine in HCI form
`
`Summary of the invention
`
`(Formula 2):
`
`APOTEX EX. 1007-003
`
`

`
`
`
`H3C\O/\/O
`H30 \/\o
`
`,0
`
`2 (Polymorph form A and B)
`
`\
`\cH
`
`HN
`
`\ N
`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
`
`5
`
`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 use thereof in the treatment
`
`of patients for the enumerated conditions since variations will affect effective dosage level and
`
`10
`
`administration. It has been discovered that the hydrochloride of N—(3~ethynyiphenyl)-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
`
`15
`
`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 hydrochloride compound disclosed in the aforementioned patent actually
`
`comprised a mixture of the polymorphs A and B, which, because of its partially reduced
`
`20
`
`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 hydrochioride
`
`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—
`
`25
`
`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 diffraction patterns for the hydrochloride
`
`polymorph A (A1 and A2) and B (B1 and B2) forms are as follows (Graphs A1 and B1 are over a
`
`larger range to show the first peaks respectively and A2 and B2 are over a shorter range to
`
`30
`
`show more detail):
`
`APOTEX EX. 1007-004
`
`

`
`X-ray Powder diffraction pattern oipolymorph A, the thermodynamically less stable form:
`
`
`
`1..L+..u.Lu....u.u.L..m...:..4.;._....
`
`
`
` -éi§§§§ji§¢3i§§§E§§§§?.§%§§%§a§§§§§§E¥§?EE§§%§§§
`
`
`
`“\%~"k.,J\u~/~v\.,.*_,,,:.‘.*V*%
`uxsnv1a<onlav:uuunumauzn:z1.\uu2\IIuaI>o:Inn:n:sx)7lD
`2-Theta Scan
`§£]c935s17.m:xso7s\a.m-rs. m74suw-ryp- 2Yn/Ymo.-;ma—sum:ooc*-em -ccn4c'«suuoo4a‘-an-am» 10:-T-nv z1o‘c~1"»nusunpu1ox-2-nnuano
`Opovalntalrrvufl
`
`0
`
`A
`
`A1
`
`-
`
`
`...'..y.Q....um;....».......a;.=.....n,....n,...,...,...
`Z-Thu-SCSI
`.51. Pfldlnw-Typo zfwfmadud-sun.:3ooa' Ev-amino‘ swat)-w’-suonnn III:-Tnmp 27D'C-T-1u5un-dl6sA2Yhctn.500
`
`on-rnuansnr-pm
`
`APOTEX EX. 1007-005
`
`

`
`X—ray Powder diffraction pattern of poiymorph B, the more thermodynamically stable form:
`/
`
`1
`
`V
`
`3:
`
`wanna
`W,
`
`W .
`
`..,:
`
`. i
`
`mgs
`a
`
`$00
`
` 2~Theka—Scale
`
`.:......‘.....~,...au,.z.;.n....=x..,,...n,..
`Fri. L992!aw~Type 2T'!vT'hIod<|d-S1xL3000'»End 40000’-Step D540‘-Sisclsvnn ID:-Tamp 270‘C-Tmoslannd I81-2-‘morn.
`
`
`
`
`
`zrnaxnrnnan
`
`Crpevauonl
`
`Import
`
`lavas:
`35...»....‘}...;.......,»...._.n=,....
`2—Tne:a-Scare
`F1}: L992vau—7ypa 2T'h/Thlodmd S|art.30Q0' End 4D000“»SLop00l0'-Slnswrn ‘G:-Tcmv 27D"C—VrmsSlA‘Bv.t16l-2-Thcix
`
`APOTEX EX. 1007-006
`
`
`
`

`
`The data contained in the above X—ray diffraction patterns are tabulated in the following
`tables 1-4:
`
`Tab|e:1 Polymorph A
`
`An“ggVeV:V_“Qg:__yVWavele_nMgth_1M:_1Q4056 Wavelength 2:1 .54439 (Rel Intensity: 0.500)
`
`5
`
`Range# 1 —Coupled: 3.000 to 40.000 Stepsizer 0.040 StepTime: 1.00
`
`Smoothing Width: 0.300 Threshold: 1.0
`
`l(re|)
`1.7
`2.1
`
`2.3
`
`l(rel)
`d(A)
`4.54453 1 4.8
`4.19685
`4.7
`l
`
`4.16411
`
`4.4
`
`d(A)
`3.61674
`3.50393
`
`3.40200
`
`|(rel)
`8.2
`9.3
`
`6.0
`
`l(re|)
`i
`d(A)
`15.82794 .
`1 100.0
`14.32371‘
`3.9
`
`15
`11.74376
`1.2
`11034081
`1.4
`10.16026
`8.98039 113.1
`
`d(A)
`6.63179
`5.84901
`
`5.69971
`5.46922
`5.21396
`4.80569
`
`7.85825
`
`7.8
`
`4.70077
`
`12.2 F 3.67845
`
`8.8
`
`3.6 $391344
`3.5
`3.78223
`
`12.4
`24.2
`
`3.29005
`3.05178
`
`.
`
`
`2.97750
`.
`
`l(rel)
`3.5
`3.7
`
`1.8
`
`2.73148
`
`2.49243
`
`2.31297
`
`1.7
`
`7
`
`Table:2 Polymorph A
`
`A999.Si1.914..:flex?!2B910.1:..1.§f§9§§.fie!§!§fl9ib-Z§..1_:§éi§§..tt3§l.J£1£§@yi2
`
`10
`
`Range#1 — Coupled: 3.000 to 40.000 Stepsize: 0.040 StepTime: 1.00
`
`Smoothing Width: 0.300 Threshold: 1.0
`
`
`
`Table:3 Polymorph B
`
`Anode: Cu — Wavelength 1 1.54056 Wavelength 2: 1.54439 {Rel lntensitx:0.500}
`
`15
`
`Range # 1 - Coupied 3.000 to. 40.040 Stepsize: 0.040 StepTime 1.00
`
`Smoothing Width: 0.300 Threshold: 1.0
`
`
`
`
`
`3.23688
`
`2.74020
`
`d(A)
`14.11826
`
`d(A)
`l(re|) I
`1
`d(A)
`1
`l(rel)
`E
`
`
`386656
`2.5
`5.01567
`100.0
`
`3.18755
`
`
`
`
`
`3.2
`3.76849
`11.23947
`4.87215 E 0.7
`2.3
`
`
`3.11673
`3.9
`3.71927
`9.25019
`4.72882 Y 1.5
`3.0
`
`
`2.69265
`
`
`
`2.58169
`
`APOTEX EX. 1007-007
`
`

`
`d(A)
`7.74623
`
`l(rel)
`
`d(A)
`
`3.63632
`
`4.39330 .
`
`4.28038
`
`4.2
`
`
`
`"@828" 2.1
`
`4.20645
`
`14.4
`
`
`
`we»
`94>
`mm
`
`3.53967
`7.08519
`10.0
`2.99596
`2.1
`2.47356
`1.0
`
`
`5.60941
`9.6
`3.47448
`
`
`
`
`3.9
`2.89151
`1.6
`2.41068
`1.1
`
`
`3.43610
`2.8
`2.83992
`2.2
`238755
`1.4
`3.35732
`
`
`
`
`
`5.63253
`
`
`
` T%6€7
`
`4.06007
`
`3.31029
`
`
`5.6
`
`2.81037
`
`2.4
`
`2.35914 " 1.77
`""""“A
`
`Table:4 Polymorph B
`
`Anode: Cu — Wavelength 1 1.54058 Wavelength 2: 1.54439 {Rel lntensity:0.500)
`
`Range# 1
`
`- Coupled: 3.000 to 40.040 Stepsize 0.040 StepTime: 1.00
`
`5
`
`Smothing Width:0.300 Threshold: 1.0
`
`
`
`
`2'“‘e*a
`“'68 We‘)
`6.255
`100017.568
`
`73%“ 3.2
`
`18193
`
`T9557? 3.9
`11.414
`1.5
`
`”"1";2”.4“8T:s"'
`6.4
`l”“1"§'i‘3“85“"""‘ 9.6
`14.781
`2.1
`15.720
`2.9
`16.959
`5.5
`
`18.749
`19.379
`
`20.195
`20734
`21.103
`21.873
`22.452
`
`2.5
`
`0.7
`
`1.5
`1.0
`
`22.982
`
`23.589
`
`23.906
`24.459
`
`4.8
`
`2.3
`
`3.0
`6.8
`
`28.617
`29.000
`
`27.534
`
`0.9
`
`32.652
`
`28.148
`
`1.5
`
`'”""33.245
`
`1.7
`
`1.7
`
`
`
`14.4 “2%“
`42
`25.617
`3.7
`30.267 E 35.809
`14.4
`25.908
`3.9
`30.900
`37.269
`4.7
`26.527
`2.8
`31.475
`37.643
`4.5
`26.911
`5.6
`31.815
`
`0.6
`1.1
`1.4'
`
`As described in the aforementioned patent and patent application, the compounds
`
`made in accordance with the present
`
`invention are useful
`
`for
`
`the treatment of a
`
`10
`
`hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of
`
`the hydrochloride compound in stable polymorph form of N-(3~ethynylphenyl)-6,7-bis(2-
`
`methoxyethoxy)-4-quinazolinamine, and a pharmaceutically acceptable carrier.
`
`in one
`
`embodiment, said pharmaceutical composition is for the treatment of cancer such as brain,
`
`lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal (such as kidney),
`
`15
`
`ovarian, prostate, colorectal, oesophageal, gynecological or
`
`thyroid cancer.
`
`In another
`
`embodiment, said pharmaceutical composition is
`
`for
`
`the treatment of a non-cancerous
`
`hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or prostate
`
`(e.g., benign prostatic hypertropy (BPH), as well as for the treatment of pancreatitis or kidney
`
`disease (including proliferative glomerulonephritis and diabetes—induced renal disease) in a
`
`20
`
`mammal which comprises a therapeutically effective amount of the hydrochloride of N-(3-
`
`APOTEX EX. 1007-008
`
`

`
`
`
`ethynylphenyl)-6,‘/—bis(2—methoxyethoxy)-4-quinazolinamine
`
`and
`
`a
`
`pharmaceutically
`
`acceptable carrier.
`
`in addition, pharmaceutical compositions including the compounds made in accordance
`
`with the present invention provide for the prevention of blastocyte implantation in a mammal,
`
`5
`
`which composition comprises a therapeutically effective amount of hydrochloride N-(3-
`
`ethynylphenyl)—6,7—bis(2-methoxyethoxy)-4-quinazolinamine
`
`and
`
`a
`
`pharmaceutically
`
`acceptable carrier.
`
`The invention also relates to a pharmaceutical composition for treating a disease in a
`
`mammal which comprises a therapeutically effective amount of N—(3-ethynylphenyl)—6,7—bis(2—
`
`10
`
`methoxyethoxy)—4-quinazolinamine hydrochloride and a pharmaceutically acceptable carrier.
`
`in one embodiment, said pharmaceutical composition is for treating a disease selected from the
`
`group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid
`
`arthritis, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes,
`
`diabetic
`
`retinopathy,
`
`retinopathy
`
`of
`
`prematurity,
`
`age—reiated macular
`
`degeneration,
`
`15
`
`hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,
`
`lung, pancreatic,
`
`prostate, colon and epidermoid cancer.
`
`The invention also relates to a method of treating a hyperproliferative disorder in a
`
`mammal which comprises administering to said mammal a therapeutically effective amount of
`
`N—(3-ethynylphenyl)-6,7—bis(2—methoxyethoxy)—4~quinazolinamine
`
`hydrochloride.
`
`In one
`
`20
`
`embodiment, said method relates to the treatment of cancer such as brain, squamous cell,
`
`bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, renal
`
`(such as kidney), ovarian, gynecological or thyroid cancer.
`
`in another embodiment, said
`
`method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign
`
`hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign prostatic hypertropy (BPH)).
`
`25
`
`The invention also reiates to production of compounds used in a method for the
`
`treatment of a hyperproliferative disorder in a mammal which comprises administering to said
`
`mammal a therapeutically effective amount of N-(3-ethynylphenyl)-6,7—bis(2-methoxyethoxy)-4-
`
`quinazolinamine hydrochloride in combination with an anti—tumor agent selected from the group
`
`consisting of mitotic inhibitors, alkylating agents, anti~metabo|ites,
`
`intercalating antibiotics,
`
`30
`
`growth factor inhibitors, ceil cycle inhibitors, enzymes,
`
`topoisomerase inhibitors, biological
`
`response modifiers, anti—hormones, and anti~androgens.
`
`Patients that can be treated with N—(3-ethynylphenyl)-6,7-t>is(2—methoxyethoxy)-4-
`
`quinazoiinamine hydrochloride according to the methods of
`
`this
`
`invention include,
`
`for
`
`example, patients that have been diagnosed as having psoriasis, BPH, lung cancer, bone
`
`35
`
`cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular
`
`melanoma. ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon
`
`cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian
`
`APOTEX EX. 1007-009
`
`

`
`tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or
`
`carcinoma of the vulva), Hodgkin’s disease, cancer of the esophagus, cancer of the small
`
`intestine, cancer of the endocrine system (gg_., cancer of the thyroid, parathyroid or adrenal
`
`glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer,
`
`5
`
`chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphonas, cancer of the
`
`bladder, cancer of the kidney or ureter (e_.g,, renal cell carcinoma, carcinoma of the renal
`
`pelvis), or neoplasms of the central nervous system (gig, primary CNS lymphona, spinal axis
`
`tumors, brain stem gliomas or pituitary adenomas).
`Method of Production
`
`10
`
`The polymorph B in
`
`substantially pure form of N-(3-ethynylphenyl)-6,7-bis(2-
`
`methoxyethoxy)-4-quinazolinamine hydrochloride (compound of formula 1) is prepared,
`accordance with the method of the present invention, by the steps of;
`
`in
`
`1)
`
`substitution chlorination of starting quinazolinamine compound (formula 3):
`
`
`
`15
`
`20
`
`OH
`
`//1
`N
`
`/O\/\
`
`H3C
`
`o
`
`3
`
`having an hydroxyi group, such as by reaction thereof in a soivent mixture of thionyl chloride,
`
`methylene chloride, dimethylformamide and heptane. The compound of formula 4:
`
`H3C\O /\/O
`/O\\/\
`
`H30
`
`0
`
`Cl
`
`\ N
`2
`N
`
`is produced in high yield with replacement of the hydroxyl group with chlorine;
`
`2) preparation of compound of formula 6:
`
`4
`
`APOTEX EX. 1007-010
`
`

`
`CH
`//
`
`NH2
`
`6
`
`H3C
`
`CH3
`
`é OH
`
`from starting material of formula 5:
`
`
`
`5
`
`NH2
`
`5
`
`by reaction of the latter in a solution of NaOH in toluene and acetonitrile with heating;
`
`3) reaction of the compound of formula 6 with the compound of formula 4 of step 1
`
`10
`
`wherein the compound of formula 6 replaces the chlorine to give the N—(3—ethynylphenyl)—6,7-
`
`bis(2-methoxyethoxy)-4—quinazolinamine hydrochloride (compound of formula 1)
`
`in the
`
`polymorph A form with a 97% yield.
`
`4) recrystallizing polymorph A (or substantially polymorph A,
`
`i.e., predominately
`
`polymorph A and minimally polymorph B) into substantially the more stable polymorph B in
`
`15
`
`alcohol (e.g. 2B-ethanol and water) with an 85% yield.
`
`Detailed Description of the Invention
`
`N—(3-ethynylphenyl)-6,7-bls(2-methoxyethoxy)-4-quinazolinamine hydrochloride has
`
`been found to exist in two distinct anhydrous polymorphic forms A and B. The production
`
`method for the various polymorphs is with components separately reacted in accordance with
`
`20
`
`the following scheme:
`
`APOTEX EX. 1007-011
`
`

`
`-10-
`
`Scheme
`
`cH/ \/\O
`
`OH
`
`N/J
`
`T
`
`CH / ‘/\o
`
`Cl
`
`N;
`
`
`
`3
`
`//
`
`CH3
`OH
`
`—"*
`
`CH
`3
`//
`CH3.o/\/0
`cH/°\/‘o
`
`ct
`‘N
`4
`
`“H2
`
`NH
`
`2
`
`QCH3
`
`HN
`
`\N
`/J
`
`N
`
`.HCl
`
`The compounds of the present invention are potent inhibitors of the erbB family of
`
`oncogenic and protooncogenic protein tyrosine kinases such as epidermal growth factor
`
`5
`
`receptor (EGFR), erbB2, HER3, or HER4 and thus are all adapted to therapeutic use as
`
`antiproliferative agents
`
`(_e_.<_i, anticancer)
`
`in mammals, particularly in humans.
`
`The
`
`compounds
`
`of
`
`the present
`
`invention
`
`are
`
`also inhibitors
`
`of
`
`angiogenesis
`
`and/or
`
`vasculogenesis.
`
`in particular, the compounds of the present invention are useful
`
`in the
`
`prevention and treatment of a variety of human hyperproliferative disorders such as malignant
`
`10
`
`and benign tumors of the liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate,
`
`pancreatic,
`
`lung, vulval,
`
`thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and
`
`neck, and other hyperplastic conditions such as benign hyperplasia of the skin (e._g_.,
`
`psoriasis) and benign hyperplasia of the prostate (E, BPH).
`
`it is expected that a compound
`
`of the present invention may possess activity against a range of
`
`leukemias and lymphoid
`
`15 malignancies.
`
`The compounds of the present invention may also be useful
`
`in the treatment of
`
`additional disorders in which aberrant expression ligand/receptor interactions or activation or
`
`signalling events related to various protein tyrosine kinases are involved. Such disorders may
`
`include those of neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial,
`
`20
`
`stromai, or blastocoelic nature in which aberrant function, expression, activation or signalling of
`
`the erbB tyrosine kinases are involved.
`
`in addition, the compounds of the present invention
`
`may have therapeutic utility in inflammatory, angiogenic and immunologic disorders involving
`
`both identified and as yet unidentified tyrosine kinases that are inhibited by the compounds of
`
`the present invention.
`
`\
`
`25
`
`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 the following procedure.
`
`APOTEX EX. 1007-012
`
`

`
`-11-
`
`The activity of the compounds of the present invention,
`
`in vitro, can be determined by
`
`the amount of inhibition of the phosphorylation of an exogenous substrate (Egg Lysg — Gastrin
`
`or polyGluTyr (4:1) random copolymer (I. Posner _e_t Q, J. Biol. Chem. ggz (29), 20638-47
`
`(1992)) on tyrosine by epidermal growth factor receptor kinase by a test compound relative to a
`
`5
`
`control. Affinity purified, soluble human EGF receptor (96 ng) is obtained according to the
`
`procedure in G. N. Gill, W. Weber, Methods in Enzymology 146, 82-88 (1987) from A431 cells
`
`(American Type Culture Coilection, Rockville, MD) and preincubated in a microfuge tube with
`
`EGF (2pg/ml) in phosphorylation buffer + vanadate (PBV: 50 mM HEPES, pH 7.4; 125 mM
`
`NaC|; 24 mM MgCl2; 100 pM sodium orthovanadate),
`
`in a total volume of 10 pl, for 20-30
`
`10
`
`minutes at room temperature. The test compound, dissolved in dimethylsulfoxide (DMSO),
`
`is
`
`diluted in PBV, and 10 pl
`
`is mixed with the EGF receptor /EGF mix, and incubated for 10-30
`
`minutes at 30°C. The phosphorylation reaction is initiated by addition of 20 pl 33P~ATP/
`
`substrate mix (120 pM Lysg-Gastrin (sequence in single letter code for amino acids,
`
`KKKGPWLEEEEEAYGWLDF), 50 mM Hepes pH 7.4, 40 pM ATP, 2 pCi y—[33P]—ATP) to the
`
`15
`
`EGFr/EGF mix and incubated for 20 minutes at room temperature. The reaction is stopped by
`
`addition of 10 pl stop solution (0.5 M EDTA, pH 8; 2mM ATP) and 6 pl 2N HCl. The tubes are
`
`centrifuged at 14,000 RPM, 4°C, for 10 minutes. 35 pl of supernatant from each tube is pipetted
`
`onto a 2.5 cm circle of Whatman P81 paper, bulk washed four times in 5% acetic acid, 1
`
`liter
`
`per wash, and then air dried. This results in the binding of substrate to the paper with loss of
`
`20
`
`free ATP on washing. The [3319]
`
`incorporated is measured by liquid scintillation counting.
`
`incorporation in the absence of substrate (e._g_., lysygastrin) is subtracted from all values as a
`
`background and percent inhibition is calculated relative to controls without test compound
`
`present.
`
`Such assays, carried out with a range of doses of test compounds, allow the
`
`determination of an approximate lC5O value for the in vitro inhibition of EGFR kinase activity.
`
`25
`
`Other methods for determining the activity of the compounds of the present invention
`
`are described in United States patent application number 08/653,786, the disclosure of which is
`
`incorporated herein.
`
`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
`
`30
`
`site of action. These methods preferably include oral routes such as in the form of tablets,
`
`intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular,
`
`intravascular or infusion), topical, and rectal administration. Oral administration is preferred for
`
`the hydrochloride 8 poiymorph.
`
`The amount of the active compound administered will be dependent on the subject
`
`35
`
`being treated,
`
`the severity of the disorder or condition,
`
`the rate of administration and the
`
`judgement of the prescribing physician. However, an effective dosage is in the range of about
`
`0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in
`
`
`
`APOTEX EX. 1007-013
`
`

`
`-12-
`
`single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day,
`
`preferably about 0.2 to about 2.5 g/day.
`
`In some instances, dosage levels below the 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
`
`5
`
`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 anti-tumour substances, for example those selected from, for example, mitotic inhibitors,
`
`for
`
`example
`
`vinblastine;
`
`alkylating
`
`agents,
`
`for
`
`example
`
`cis—platin,
`
`carboplatin
`
`and
`
`cyclophosphamide; anti-metabolites,
`
`for example 5-fluorouracil, cytosine arabinoside and
`
`10
`
`hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European
`
`Patent Application No. 239362 such as fl—(5—[§—(3,4—dihydro—2-methyl-4-oxoquinazolin-6-
`
`ylmethyl)-E-methylamino]-2-thenoyl)—L—glutamic
`
`acid;
`
`growth
`
`factor
`
`inhibitors;
`
`cell
`
`cycle
`
`inhibitors;
`
`intercalating antibiotics,
`
`for example adriamycin and bleomycin; enzymes,
`
`for
`
`example interferon; and anti-hormones,
`
`for example anti-estrogens such as NolvadeX®
`
`15
`
`(tamoxifen)
`
`or,
`
`for
`
`example
`
`anti—androgens
`
`such
`
`as
`
`Casodex®(4'-cyano-3—(4-
`
`fluorophenylsulphonyl)—2—hydroxy-2—methy|—3'~(trifluoromethyl)propionanilide).
`
`Such conjoint
`
`treatment may be achieved by way of the simultaneous, sequential or separate dosing of the
`
`individual components of the treatment.
`
`The pharmaceuticat composition may, for example and most preferably, be in a form
`
`20
`
`suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations,
`
`solution, and suspension. Less preferred (with the mesylate form being the preferred form), 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 pharmaceutical
`
`composition may be in unit dosage forms suitable for single administration of precise dosages.
`
`25
`
`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 pharmaceutical agents, carriers, adjuvants, etc.
`
`Exemplary parenteral administration forms include solutions or suspensions of active
`
`compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose
`
`30
`
`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 tlavorings, binders, excipients and the like. Thus for oral administration,
`
`tablets containing various excipients, such as citric acid may be employed together with various
`
`35
`
`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
`
`stearate, sodium lauryl sulfate and talc are often useful
`
`for
`
`tableting purposes.
`
`Solid
`
`
`
`
`
`
`APOTEX EX. 1007-014
`
`

`
`-13-
`
`compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
`
`Preferred materials,
`
`therefor,
`
`inciude lactose or milk sugar and high molecular weight
`
`polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration
`
`the active compound therein may be combined with various sweetening or flavoring agents,
`
`5
`
`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
`
`Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition
`
`10
`
`(1975).
`
`The examples and preparations provided below further illustrate and exemplify the
`
`compounds of the present invention and methods of preparing such compounds.
`
`it is to be
`
`understood that the scope of the present invention is not limited in any way by the scope of the
`
`following examples and preparations.
`
`15
`
`Preparation of compound of formula 4
`Reaction:
`
`OH
`l-l3C\O/\/O \ \N
`O
`
`H3C/ ‘/\O
`3
`
`MW=294.31
`
`SOCIZ
`
`N ~—e) H33
`DMF, CHZCI2
`
`H3C\0/\fO
`/ x./‘so
`
`O
`
`Cl
`\N
`NJ
`
`/
`
`4
`
`MW=312.75
`
`
`
`The following materials are used in the synthesis of the compound of formula 4:
`
`Quantity
`
`Units
`
`Equiva|entsNolumes
`
`Materials
`
`Compound of formula 3
`
`Thionyl chloride
`
`Dimethylformamide
`
`methylene chloride
`
`88.0
`
`89.0
`
`11
`
`880.0
`
`kg
`
`kg
`
`kg
`
`L
`
`L
`
`L
`
`1 equivalent
`
`2.5 equivalents
`
`0.5 equivaient
`
`10 L/kg
`
`1 equivalent
`
`10 L/kg
`
`50% sodium hydroxide solution
`
`as required
`
`Heptane
`
`880.0
`
`20
`
`The following procedure is exemplary of the procedure to follow in the synthesis of
`
`the formula 4 compound:
`
`88.0 kg of the compound of formula 3, 880.0 L methylene chloride, and 1.0 kg of
`
`dimethylformamide are charged to a clean,
`
`dry, glass-lined vessel under nitrogen
`
`atmosphere.
`
`89 Kg of thionyl chloride are added to the mix while it
`
`is maintained at a
`
`25
`
`temperature of a less than 30 °C during the charge. The contents of the reaction vessel are
`
`APOTEX EX. 1007-015
`
`

`
`-14..
`
`then heated for a minimum of five hours at reflux temperature before sampling for reaction
`
`completion and the pH is adjusted to be maintained between 7.0 to 8.0, by using 50 % NaOH,
`
`as required and the temperature of the reaction mixture is maintained at less than 25 °C. The
`
`biphasic mixture is stirred for fifteen to twenty minutes and aliowed to settle for a minimum of
`
`5
`
`thirty minutes. The layers are separated and the organic layer is concentrated to 1/3 of its
`
`volume by removing methylene chloride. 880 L heptane is added with continued distillation of
`
`the remaining methylene chloride until the distillate reaches a temperature between 65 and 68
`
`“C. The mixture is then cooled to between 10 to 15 °C over 5 hours and granulated for a
`
`minimum of 1 hour with the solids being isolated by filtration and washed with 220 L heptane.
`
`10
`
`The solids (formula 4 compound) are dried in a vacuum drier at 45 to 50 °C.
`
`Step 2: Preparation of compound of formulas 6 and 2 (polymorph A):
`Reaction:
`
`CH/3<CH3
`é O"l\iaoH(Mw=40),
`toluene
`-~——~~-——>
`A
`
`H3C\O/\\/O
`l-539,0./—o
`MW=m'75
`
`Cl
`\N
`NA
`H c
`)3 \O/\/O
`.
`.
`toluene, acetonitrile
`/O\/\O
`
`//CH3
`
`@\
`“N
`QC“
`~.N
`J
`N/
`
`' HCl
`
`NH2
`
`NH2
`
`“ac
`
`MW=175.23
`
`MW=116.2
`
`MW=429.9
`Pmymo;-ph A
`
`15
`
`The following materials are used in the synthesis of the compound of formula 6, as
`
`intermediate, and the compound of formula 2 (polymorph A):
`
`Materials
`
`Quantity
`
`Units
`
`Equivalents/Volumes
`
`Compound of formula 5
`
`Toluene
`
`Sodium hydroxide pellets
`
`Filteraid
`
`Compound of formula 4
`
`Acetonitrile
`
`61.1
`
`489
`
`4.5
`
`0.5
`
`90.8
`
`732
`
`kg
`
`L
`
`kg
`
`kg
`
`kg
`
`L
`
`1.2 equivalents
`
`8 L/kg (WRT to formula 5 c’mpd)
`
`0.16 equivalents
`
`0.01? kg/kg (WRT to c’mpd 5)
`
`1.0 equivalent
`
`12 L/kg (WRT to c’mpd 5)
`
`Preparation of compound of formula 2 (polymorph A form)
`
`The foltowing procedure is exemplary of the procedure to follow in the synthesis of
`
`20
`
`the formula 2 compound (polymorph A) and intermediate compound of formula 6:
`
`61.1 kg of formula 5 compound, 4.5 kg sodium hydroxide pellets and 489 L toluene
`
`are charged to a clean, dry, reaction vessel under nitrogen atmosphere and the reaction
`
`temperature is adjusted to between 105 to 108 °C. Acetone is removed over four hours by
`
`atmospheric distillation while toluene is added to maintain a minimum volume of 6 L of solvent
`
`
`
`APOTEX EX. 1007-016
`
`

`
`-15-
`
`per kg of formula 5 compound. The reaction mixture is then heated at reflux temperature,
`
`returning distillates to pot, until
`
`the reaction is complete. The mixture is then cooled to
`
`between 20 to 25 °C, at which time a slurry of 40.0 L toluene and 1.0 kg filteraid is charged to
`
`the reaction mixture and the mixture is agitated for ten to fifteen minutes. The
`
`resultant
`
`5
`
`material is filtered to remove filteraid, and the cake is washed with 30 L toluene (compound of
`
`formula 6).
`
`The filtrate (compound of formula 6) is placed in a clean, dry reaction vessel under
`
`nitrogen atmosphere, and 90.8 kg of the compound of formula 4 is charged into the reaction
`
`vessel together with 732 L acetonitrile. The reaction vessel is heated to reflux temperature
`
`10
`
`and well agitated. Agitator speed is lowered when heavy solids appear. When the reaction is
`
`complete, the contents of reaction vessel are cooled to between 19 to 25 °C over three to four
`
`hours and the contents are agitated for at least one hour at a temperature between 20 and 25
`
`°C, The solids (compound of formula 2, polymorph A form, or mixture of polymorph A and B)
`
`are then isoiated by filtration and the filter cake is washed with two portions of 50 L
`
`15
`
`acetonitrile and dried under vacuum at a temperature between 40 and 45 °C,
`
`Step 3: Recrystallization of comp