(12) United States Patent
`Lane et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,410,131 B2
`Apr. 2, 2013
`
`US008410l31B2
`
`CANCER TREATMENT
`
`Inventors: Heidi Lane, Easel (CH); Terence
`O’Reilly, Bascl (CH); Jeanette
`Marjorie Wood, Bicl-Bcnkcn (CH)
`
`Assignee: Novartis Pharmaceuticals
`Corporation, East Hanover, NJ (US)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1189 days.
`
`Appl. No.2
`
`10/468,520
`
`PCT Filed:
`
`Feb. 18, 2002
`
`PCT No.:
`
`PCT/EP02/01714
`
`§ 371 (CX1).
`(2),
`Dale:
`
`Jan. 27, 2004
`
`PCT Pub. No.: W002/066019
`
`PCT Pub. Date: Aug. 29, 2002
`
`Prior Publication Data
`
`US 2004/0147541 Al
`
`Jul. 29, 2004
`
`(30)
`
`Foreign Application Priority Data
`
`Feb. 19, 2001
`Oct. 17, 2001
`
`(GB) ..
`(GB)
`
`0104072.4
`...................... .. 0124957.2
`
`(51)
`
`Int. Cl.
`(200601 )
`A6lK 3]/436
`(2006.01)
`A61P 35/00
`(52) U.S.Cl.
`..................................................... .. 514/291
`(58) Field of Classification Search ...................... .. None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`(Continued)
`OTHER PI IEI ICATIONS
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`Lien et al. Therapeutic anti-VEGF antibodies. Therapeutic Antibod-
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`Zhu et a1. (“Inhibition of tumor growth and inetasmsis by targeting
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`Shi et al. (“Rapamycin enhances apoptosis and increases sensitivy to
`cisplatin in vilro” Cancer Research, 1995, 55, 1982-l988).*
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`
`(Continued)
`
`Primary Examiner — Kortney L Klinkel
`(74) Attorney, Agent, or Firm — Ann R. Pokalsky, Esq.;
`Dilworth & Earrese, I,I,P
`
`ABSTRACT
`(57)
`Rapainycin derivatives have interesting effects in the treat-
`ment of solid tumors, optionally i11 combination with a che-
`motherapeutic agent.
`
`9 Claims, No Drawings
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 001
`
`

`
`US 8,410,131 B2
`Page 2
`
`\VO
`VVO
`VVO
`VVO
`VVO
`VVO
`
`FOREIGN PATENT DOCUMENTS
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`0213802
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`Res 2001, 61(4): 1527-1532.
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`Mediates the Suppression of Metastases by a I.ewis I,ung Carci-
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`Cancer Research 1999, 59: 5209-5218.
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`
`* cited by cxamincr
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 002
`
`

`
`US 8,410,131 B2
`
`1
`CANCER TREATMENT
`
`The present invention relates to a new use, in particular a
`new use for a compound group comprising rapamycin and
`derivatives thereof.
`Raparnycin is a known macrolide antibiotic produced by
`Strepzomyces hygroscopicus. Suitable derivatives ofraparny—
`cin include e.g. compounds of formula 1
`
`5
`
`wherein
`R, is CH3 or C3_6alkynyl,
`R2 is H or —CH1—CH2OH, and
`X is _O, fl{,H) or (H,OH)
`provided that R2 is other than H when X is _O and R1 is CH3 .
`Compounds offormula I are disclosed e.g. ii1U.S. Pat. Nos.
`5,665,772; 6,440,990; 5,985,890; and 6,200,985, which are
`incorporated herein by reference. They may be prepared as
`disclosed or by analogy to the procedures described in these
`references.
`
`Preferred C011‘1p01111dS are 32-deoxorapamycin, 16-pent-2-
`ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-di-
`hydro-rapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-40-O-
`(2-hydroxyethyl)-rapamycin and, more preferably, 40-O-(2-
`hydroxyethyl)-rapamycin (referred thereafter as Compound
`A), disclosed as Example 8 in US. Pat. Nos. 5,665,772 and
`6,440,990.
`Compounds of formula I have, on thc basis of observed
`activity, c.g. binding to macrophilin-12 (also known as '
`FK—506 binding protein or FKBP—12), e.g. as described in
`WO 94/09010, WO 95/16691 or WO 96/41807, been found to
`be useful e.g. as immunosuppressant, e.g. in the treatment of
`acute allograft rejection. It has now been found that Com-
`pounds of formula 1 have potent antiproliferative properties
`which make them useful for cancer chemotherapy, particu-
`larly of solid tumors. especially of advanced solid tumors.
`There is still the need to expand the armarnentarium of cancer
`treatment of solid tumors, especially in cases where treatment
`with anticancer compounds is not associated with disease
`regression or stabilization.
`1n accordance with the particular findings of the present
`invention, there is provided:
`1.1 A method for treating solid tumors in a subject in need
`thereof, comprising administering to said subject a thera-
`peutically effective amount of a compound of formula I.
`
`60
`
`65
`
`2
`1.2 A method for inhibiting growth of solid tumors in a
`subject in need thereof, comprising administering to said
`subject a therapeutically effective amount of a compound
`of formula 1.
`1.3 A method for inducing tumor regression, e.g. tumor mass
`reduction, in a subject in need thereof comprising admin-
`istering to said subject a therapeutically effective amount
`of a compound of formula 1.
`1.4 A method for treating solid tumor invasiveness or symp-
`toms associated with such tumor growth in a subject in
`need thereof, comprising administering to said subject a
`therapeutically effective amount of a compound offormula
`I.
`1.5 A method for preventing metastatic spread of tumours or
`for preventing or inhibiting growth of micronietastasis in a
`subject in need thereof, comprising administering to said
`subject a therapeutically effective amount of a compound
`of formula 1.
`By “solid tumors” are meant tumors andjor metastasis
`(whereever located) other than lymphatic cancer, e.g. brain
`and other central nervous system tumors (eg. tumors of the
`mcningcs, brain, spinal cord, cranial nerves and othcr parts of
`central nervous system, e.g. glioblastomas or medulla blas-
`tomas); head and/or neck cancer; breast tumors: circulatory
`system tumors (e.g. heart, mediastinum and pleura, and other
`intrathoracic organs, vascular tumors and tiimor-associated
`vascular tissue); excretory system tumors (eg. kidney, renal
`pelvis, ureter, bladder, other and unspecified urinary organs);
`gastrointestinal tract tumors (e.g. oesophagus, stomach, small
`intestine, colon, colorectal, rectosigmoid jimction, rectum,
`anus and anal canal), tumors involving the liver and iiitrahe-
`patic bile ducts, gall bladder, other and unspecified parts of
`binary tract, pancreas. other and digestive organs); head and
`neck; oral cavity (lip, tongue, guru, floorofmouth, palate, and
`other parts of mouth, parotid gland, and other parts of the
`salivary glands, tonsil, oropharynx, nasopharynx, pyriforin
`sinus, hypopharynx, and other sites in the lip, oral cavity and
`pharynx); reproductive system tumors (e.g. vulva, vagina,
`Cervix uteri, Corpus uteri, uterus, ovary, and other sites asso-
`ciated with female genital organs, placenta, penis, prostate,
`testis, and other sites associated with male genital organs);
`respiratory tract tumors (e.g. nasal cavity and middle ear,
`accessory sinuses, larynx, trachea, bronchus and lung, e.g.
`small cell lung cancer or non-small cell lung cancer); skeletal
`system tumors (c.g. bonc and articular cartilage of limbs,
`bone articular cartilage and other sites); skin tumors (e.g.
`malignant melanoma of the skin, non-melanoma skin cancer,
`basal cell carcinoma of skin, squamous cell carcinoma of
`skin, mesothelioma, Kaposi’s sarcoma); and tumors involv-
`ing other tissues incluing peripheral nerves and autonomic
`nervous system. connective and soft tissue, retroperitoneuin
`and peritoneum, eye and adnexa, thyroid, adrenal gland and
`other endocrine glands and related structures, secondary and
`unspccificd malignant ncoplasm of lymph nodes, sccondary
`malignant neoplasm ofrespiratory and digestive systems and
`secondary malignant neoplasm of other sites.
`Where hereinbefore and subsequently a tumor, a tumor
`disease, a carcinoma or a cancer is mentioned, also metastasis
`in the original organ or tissue and/or in any other location are
`implied alternatively or in addition, whatever the location of
`the tumor and/or metastasis is.
`In a series of further specific or alternative embodiments,
`the present invention also provides
`1.6 A method for the treatment of a disease associated with
`deregulated angiogenesis in a subject in need thereof, com-
`prising administering to said subject a therapeutically
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 003
`
`

`
`US 8,410,131 B2
`
`5
`
`10
`
`,
`
`3
`effective amount of rapamycin or a derivative thereof, e.g.
`CCI779, ABT578 or a compound offormula I.
`1 .7 A method for inhibiting or controlling deregulated anglo—
`genesis in a subject in need thereof, comprising adminis-
`tering to said subject a therapeutically effective amount of
`rapamycin or a derivative thereof, e.g. CCI779, ABT578 or
`a compound of formula I.
`1 .8 A method for enhancing the activity of a chemotherapeu-
`tic agent or for overcoming resistance to a chemotherapeu-
`tic agent in a subject in need thereof, comprising adminis-
`tering to said subject a therapeutically effective amount of
`rapamycin or a derivative thereof, e.g. CCI779, ABT578 or
`a compound of formula I, either concomitantly or sequen-
`tially With said chemotherapeutic agent.
`1 .9 A n1etl1od according to 1 .8 wherein the chemotherapeutic
`agent
`is an inhibitor of signal
`transduction pathways
`directed either against l1ost cells or processes involved in
`tumor formation and’or metastases formation or utilised by
`tur11our cells for proliferation, survival, di1'fere11tiation or
`development of drug resistance.
`1.10 A method as indicated above, wherein rapamycin or a
`dcrivativc thcrcof, c.g. CCI779, ABT578 or a compound of
`formula I is administered intermittently.
`CCI779 is a rapamycin derivative, i.e. 40-[3-hydroxy-2-
`(hydroxymethyl)-2-r11etl1ylpropanoate]-raparnycin or a phar-
`maceutically acceptable salt thereof, and is disclosed e.g. in
`U.S. Pat. No. 5,362,718. ABT578 is a 40—substituted raparny—
`cin derivative further comprising a diene reduction.
`Examples of diseases associated with deregulated angio-
`genesis include Without limitation e.g. neoplastic diseases,
`e.g. solid tumors. Angiogenesis is regarded as a prerequisite
`for those tumors which grow beyond a certain diameter, e.g.
`about 1-2 nun.
`In a series of further specific or alternative embodiments,
`the present invention also provides:
`2 .1 A compound offormula I for use in any mcthod as dcfincd
`under 1.1 to 1.5 above.
`2.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula 1 for use in any method as
`de inec under 1.6 to I .10 above or 7 below.
`3.1 A compound of formula I for use in the preparation of a
`phannaceutical composition for use in any method as
`de inec under 1.1 to 1.5 above.
`3 .2 Rapamycin or a derivative thereof, eg. CCI779, ABT578
`or a compound of formula I for use in the prcparation of a
`phannaceutical composition for use in any method as
`de lnec under 1.6 to 1.10 above or 7 below.
`4.1 A pharmaceutical composition for use in any method as
`de inec
`under 1.1 to 1.5 above comprising a compound of T
`formula I together with one or more pharmaceutically
`acceptable diluents or carriers therefor.
`4.2 A pharmaceutical composition for use in any method as
`de inec under 1.6 to 1.10 above or 7 below comprising
`rapamycin or a dcrivativc thcrcof, e.g. CCI779, ABT578 or
`a compound of formula I, e.g. Compound A, together with
`one or more pharmaceutically acceptable diluents or car-
`riers therefor.
`5.1 A pharmaceutical combination comprising a) a first agent
`which is rapamycin or a derivative thereof e.g. CCI779,
`ABT578 or a compound of formula I, e.g. Compound A,
`and b) a co-agent Wl1icl1 is a chemotherapeutic agent, e.g.
`as defined hereinafter.
`5.2 A pharmaceutical combination comprising an amount of
`a) a first agent which is rapamycin or a derivative thereof,
`e.g. CCI779, ABT578 or a compound of formula I, e.g.
`Compound A, a11d b) a co-agent which is a chemothera-
`
`4
`peutic agent selected from the compounds defined under
`paragraph (iv) or (v) below, to produce a synergistic thera-
`peutic effect.
`6. A method as defined above comprising co-administration,
`e.g. concomitantly or in scqucncc, of a therapeutically
`effective amount of rapamycin or a derivative thereof, e.g.
`CCI779, ABT578 or a compound of formula I, e.g. Com-
`pound A, and a second drug substance, said second drug
`substance being a chemotherapeutic agent, eg. as indi-
`cated hereinafter.
`7. A method for treating post—transplant lymphoproliferative
`disorders or a lymphatic cancer, e.g. for treating tumor
`invasiveness or symptoms associated with such tumor
`growth in a subj cct in nccd thcrcof, comprising co-admin-
`istering to said subject, e.g. concomitantly or in sequence,
`ofrapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula I, e.g. Compound A, and a
`second drug substance, said second drug substance being a
`chemotherapeutic agent, e.g. as indicated hereinafter.
`By “lymphatic cancer” are meant e.g. tumors of blood and
`lyr11pl1atic system (e.g. Hodgkin’s disease, Non-Hodgkin’s
`lymphoma, Burkitt’s lymphoma, AIDS-related lymphomas,
`malignant immunoprolifcrativc discascs, multiplc mycloma
`and malignant plasma cell neoplasms, lymphoid leukemia,
`myeloid leukemia, acute or chronic lymphocytic leukemia,
`monocytic leuke111ia, other leukemias of specified cell type,
`leukemia of unspecified cell type, other and unspecified
`malignant neoplasms of lymphoid, haematopoletic and
`related tissues, for example diffuse large cell lymphoma,
`T-cell lyn1pl1on1a or cutaneous T-cell lymphoma).
`By the term “chemotherapeutic agent” is meant especially
`any chemotherapeutic agent other than rapamycin or a deriva-
`tive thereof. It includes but is not limited to,
`i. an aromatase inhibitor,
`ii. a11 antiestrogen, a11 anti-androgen (especially in the case of
`prostate cancer) or a gonadorelin agonjst,
`iii. a topoisomcrasc I inhibitor or a topoisomcrasc II inhibitor,
`iv. a microtubule active agent, an alkylating agent, an antine—
`oplastic antimetabolite or a platin compound,
`v. a compound targeting/decreasing a protein or lipid kinase
`activity or a protein or lipid phosphatase activity, a further
`anti—angiogenic compound or a compound which induces
`cell differentiation processes,
`vi. a bradykinin I receptor or an angiotensin II antagonist,
`vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone
`dcacctylasc inhibitor, a hcparanasc inhibitor (prcvcnts
`heparan sulphate degradation), e.g. PI—88, a biological
`response modifier, preferably a lymphokine or i11terferons,
`e.g. interferon y, an ubiquitination inhibitor, or an inhibitor
`which blocks anti-apoptotic pathways,
`viii. an inhibitor of Ras oncogenic isoforms, e.g. H—Ras,
`K-Ras or N-Ras. or a farnesyl transferase inhibitor, e.g.
`L-744,832 or DKSGSS7,
`ix. a telomerase inhibitor, e.g. telomestatin,
`x. a protease inhibitor, a matrix mctalloprotclnasc inhibitor, a
`methionine aminopeptidase inhibitor, e. g. bengamide or a
`derivative thereof, or a proteosome inhibitor, e.g. PS-341.
`The term “aromatase inhibitor” as used herein relates to a
`compound which inhibits the estrogen production, i.e. the
`conversion of the substrates androstenedione and testoster-
`one to estrone and estradiol. respectively. The tenn includes,
`but is not limited to steroids, especially atar11estar1e, exemes-
`tane and formestane and, in particular, non-steroids, espe-
`cially aminoglutcthimidc, roglcthimidc, pyridoglutcthimidc,
`trilostane, testolactone, ketokonazole, vorozole, fadrozole,
`anastrozole a11d letrozole. Exemestane can be administered,
`e.g., hi the fonn as it is marketed, e.g. under the trademark
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 004
`
`

`
`US 8,410,131 B2
`
`5
`AROMASINTM. Fomiestane can be administered, e.g., in the
`form as it
`is marketed, e.g. under the trademark LEN-
`TARONTM. Fadrozole can be administered, e.g., in the forr11
`as it is marketed, e.g. under the trademark A1~'l:'MA'“"1. Anas-
`trozole canbe administered, e.g., in the form as it is marketed,
`e.g. under the trademark ARIMIDEXTM. Letrozole can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark FEMARAT“ or F3 ARTM An1i11oglutetl1in1ide
`can be administered, e.g., in {'16 form as it is marketed, e.g.
`under the trademark ORIMETENTM. A combination of the
`invention comprising a chemotherapeutic agent which is an
`aromatase inhibitor is particularly useful for the treatment of
`hormone receptor positive tumors, e.g. breast tumors.
`The term “antiestrogen” as used herein relates to a com-
`pound which antagonizes the effect of estrogens at the estro-
`gen receptor level. The term includes, but is not limited to
`tamoxifen, fulvestrant, raloxifene and ra oxifene hydrochlo-
`ride. Tamoxifen can be administered, e.g., in the form as it is
`marketed, e.g. under the trademark NOLVADEXTM. Ralox—
`ifene hydrochloride can be administered, e.g., in the form as
`it is marketed, e.g. under the trademark ,:VlS AT“. Fulves-
`trant can be formulated as disclosed in U.S. Pat. No. 4,659,
`516 or it can be administered, e.g., in the form as it is mar-
`keted, e.g. under the trademark FASLODETM. A combination
`of the invention comprising a chemotherapeutic agent which I
`is an antiestrogen is particularly useful for the treatment of
`estrogen receptor positive tumors, e.g. breast tumors.
`The term “anti—androgen” as used herein relates to any
`sub stance which is capable of inhibiting the biological effects
`of androgenic hormones and includes, but is not limited to,
`bicalutamide (CAS()l_)l:'X'““), which can be formulated, eg.
`as disclosed in U.S. Pat. No. 4,636,505.
`The term “gonadorelin agonist” as used herein includes,
`but is not limited to abarelix, goserelin and goserelin acetate.
`Goserelin is disclosed in U.S. Pat. No. 4,100,274 and can be
`administered, eg., in the form as it is marketed, e.g. under the
`trademark ZOLADEXT“. Abarelix can be formulated, e.g. as
`disclosed in U.S. Pat. No. 5,843,901.
`The term “topoisomerase 1
`inhibitor” as used herein
`includes, but is not limited to topotecan, irinotecan, 9-nitro-
`camptothecin and the macromolecular camptothecin conju-
`gate PNU—166148 (compound A1 in W099/17804). 1rinote—
`can can be administered, e.g. in the form as it is marketed, e.g.
`under the trademark CAMPTOSARTM. Topotecan can be
`administered, eg., in the form as it is marketed, e.g. under the
`trademark HYCAMTINTM.
`inhibitor” as used herein
`The term “topoisomerase 11
`includes, but is not limited to the anthracyclines such as
`doxorubicin (including liposomal fonnulation, e.g. CAE-
`LYXTM), daunorubicin, epirubicin, idarubicin and nemorubi-
`cin, the anthraquinones mitoxantrone and losoxantrone, and
`the podophillotoxines etoposide and teniposide. Etoposide
`can be administered, eg. in the form as it is marketed, e.g.
`under the trademark ETOPOPHOSTM. Teniposide can be
`administered, e.g. in the form as it is marketed, e.g. l1I1dCI' the
`trademark VM 26—BRISTOLTM Doxorubicin can be admin-
`istered, e.g. in the fonn as it is marketed, e.g. under the
`trademark ADRIBLASTINTM. Epirubicin ca11 be adminis-
`tered, eg. in the form as it is marketed, e.g. under the trade-
`mark FARMORUBICINTM. ldarubicin can be administered,
`e.g. in the form as it is marketed, e.g. under the trademark
`ZAVEDOST“. Mitoxantrone car1 be administered, e.g. ir1 the
`form as
`it
`is marketed,
`e.g. under
`the
`trademark
`NOVANTRONTM.
`The term “mierotubule active agent” relates to mierotubule
`stabilizing and mierotubule destabilizing agents including,
`but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca
`
`,
`
`,
`
`6
`alkaloids, e.g., vinblastine, especially vinblastine sulfate, vin-
`eristine especially vineristine sulfate. and vinorelbine, disco-
`dermolides and epothilones and derivatives thereof, eg.
`epothilone B or a derivative thereof. Paclitaxel may be admin-
`istered e.g. in the form as it is marketed, e.g. TAXOLTM.
`Docetaxel can be administered, e.g., in the form as it is mar-
`keted, e.g. under the trademark TAXOTERETM. Vmblastine
`sulfate can be administered, e. g., in the form as it is marketed,
`e.g. under the trademark VTNBLASTIN R. TTM. Vincristine
`sulfate can be administered, e. g., in the fomi as it is marketed,
`e.g. under the trademark FARMISTINTM. Discoderrnolide
`can be obtained, e.g., as disclosed ir1 U.S. Pat. No. 5,010,099.
`The term “alkylating agent” as used herein includes, but is
`not limited to eyclophosphamide, ifosfamidc, melphalan or
`nitro sourea (BCNU or GliadelTM). Cyclophosphamide can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark CYCLOSTINTM. Ifo sfamide ca11 be administered,
`e.g., in the form as it is marketed, e.g. under the trademark
`HOLOXANTM.
`The term “antineoplastic antimetabolite” includes, but is
`not
`limited to 5-fluorouracil, capecitabine, gemcitabine,
`methotrexate and edatrexate. Capecitabine can be adminis-
`tered, e.g., in the form as it is marketed, e.g. under the trade-
`mark XELODATM. Gemeitabine can be administered, e.g., in
`the form as
`it
`is marketed, e.g. under the trademark
`GEMZARTM.
`The term “platin compound” as used herein includes, but is
`not limited to carboplatin, cis—platin and oxaliplatin. Carbo-
`platin can be administered, e.g., in the form as it is marketed,
`e.g. under the trademark CARBOPLATTM. Oxaliplatin car1 be
`administered, e.g., in the form as it is marketed, e. g. under the
`trademark El DXATINTM.
`The term “compounds targeting/decreasing a protein or
`lipid kinase activity or further anti-angiogenic compounds"
`as used herein includes, but is not lnnited to protein tyrosine
`kinase and/or serine and/or threonjne kina se inhibitors or
`lipid kinase inhibitors, e.g. compounds targeting, decreasing
`or inhibiting the activity of the epidermal growth factor fam-
`ily ofreceptor tyrosine kinases (* GFR, * rbB2, ErbB3, ErbB4
`as homo- or heterodimers), the vascular endothelial growth
`factor family of receptor tyrosine kinases (VEGFR), the
`platelet—derived growth factor-receptors (PDGFR), the fibro-
`blast growth factor-receptors (FGFR), tie insulin-like growth
`factor receptor 1 (IGF-1R), the Trk receptor tyrosine kinase
`family, the Axl receptor tyrosine kina se family, the Ret recep-
`tor tyrosine kinase, the Kit/SCFR receptor tyrosine kinase,
`members of the c—Abl family and their gene—fusion products
`(e.g. BCR-Abl), members of the protein kinase C (PKC) and
`Raffamily of serine/threonine kinases, members ofthe MEK,
`SRC, JAK, FAK, PDK or Pl(3) kinase family, or ofthe Pl(3)-
`kinase—related kinase family, and/or members of the cyclin-
`dependent kinase family (CDK) and anti-anglogenic com-
`pounds having another mechanism for their activity, eg.
`unrelated to protein or lipid dnase inhibition.
`Compounds which target, decrease or inhibit the activity of
`VEGFR are especially compounds, proteins or antibodies
`which inhibit the VEGF receptor tyrosine kinase, inhibit a
`VEGF receptor or bind to VEGF, a11d are i11 particular those
`compounds, proteins or monoclonal antibodies generically
`and specifically disclosed in VVO 98/35958, e.g. 1—(4—chlo—
`roanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuti-
`cally acceptable salt thereo , e.g. the succinate, or in “/0
`00/09495, VVC) O0/27820, WC) 00/59509, WC) 98/11223, W'O
`00/2781 9 and EP 0 769 947; those as described by M. Prewett
`et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et
`al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770,
`December 1996, by Z. Zhu et al i11 Cancer Res. 58, 1998,
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 005
`
`

`
`US 8,410,131 B2
`
`,
`
`7
`3209-3214, and by J. Mordenti et al in Toxicologic Pathology,
`V01. 27, no. 1, pp 14-21, 1999; in WO 00/37502 and WO
`94/10202; Ar1giostatinTM, described by M. S. O’Reilly et al,
`Cell 79, 1994, 315-328; l:'ndostatin'1’—“, described by M. S.
`O’Reilly et al, Cell 88, 1997, 277-285; anthranilic acid 5
`amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF
`antibodies or anti-VEGF receptor antibodies, e.g. RhuMab.
`By antibody is meant intact monoclonal antibodies, poly-
`clonal antibodies, multispecific antibodies formed from at
`least 2 intact antibodies, and antibodies fragments so long as
`they exhibit the desired biological activity.
`Compounds w11icl1 target, decrease or inhibit the activity of
`the epidennal growth factor receptor family are especially
`compounds, proteins or antibodies which inhibit members of
`the EGF receptor tyrosine kinase family, e.g. EGF receptor,
`ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related
`ligands, and are ir1 oarticular those compounds, proteins or
`monoclonal antibodies generically and specifica ly disclosed
`in WO 97/02266, e.g. the compound ofex. 39, or in EP 0 564
`409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722,
`EP 0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO
`97/30034, WO 97/49688, WO 97/38983 and, especially, WO
`96/30347 (e. g. compound known as CP 358774), WO
`96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.
`compound ZM105180): e. g. trastuzumab (HerpetinR). cetux-
`irnab, lressa, OS1-774, CI-1033, EKB-569, GW-2016, E1.1,
`132.4, 132.5, 136.2, 136.4, 132.11, E6} or 37.6.3.
`Compounds which target, decrease or inhibit the activity of
`PDGFR are especially compounds which inhibit the PDGF
`receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g.
`imatinib.
`Compounds which target, decrease or inhibit the activity of
`c-Abl family members and their gene fusion products, e.g. a
`N-phenyl-2-pyrimidine-amine derivative,
`e.g.
`imatinib;
`PD180970; AG957; or NSC 680410.
`Compounds which target, decrease or inhibit the activity of
`protein kinase C, Raf, MEK, SRC, JAK, FAK and PDK
`family members, or PI(3) kinase or P1 (3) kinase-related fam-
`ily members, and/or members of the cyclin-dependent kinase
`family (CDK) are especially those staurosporine derivatives
`disclosed in BF 0 296 110, e.g. midostaurin; examples of
`further compounds include e.g. UCN-01, safingol, BAY
`43-9006, Bryostatin 1. Perifosine: llmofosinez RO 318220
`and R0 320432; GO 6976;
`Isis 3521; or LY333531/’
`LY3 79196.
`Further anti-angiogcnic compounds are e.g. thalidomide
`(THALOMID) and TNP-470.
`Compounds which target, decrease or inhibit the activity of
`a protein or lipid phosphatase are e.g. inhibitors of phos-
`phatase 1, phosphatase 2A, PTFN or CDC25, e.g. okadaic ,
`acid or a derivative thereof.
`Compounds which induce cell differentiation processes
`are e.g. retinoic acid, 0.-, y- or 6-tocopherol or (x-, y- or
`6-tocotrienol.
`The term cyclooxygenase inhibitor as usedherein includes,
`but is not limited to, e.g. celecoxib (Celebrexk), rofecoxib
`'ioxxR), etoricoxib, valdecoxib or a 5-alkyl-2-arylarni-
`r1opl1e11ylacetic acid, e.g. 5-metl1yl-2-(2'-chloro-6'-fluoroa-
`nilino)phenyl acetic acid.
`The temi “histone deacetylase inhibitor” as used herein
`includes, but is not limited to MS-27-275, SAHA, pyroxam-
`ide, FR-901228 or v