1/19/1
DIALOG(R)File 452: Drug Data Report
(c) 2007 Prous Science. All rights reserved.


00271217 
Entry Number:   271217 (Actively Investigated) 
Compound Type:   Preferred 
Drug Name:   CGP-79787 (free base)
      CGP-79787D 
      PTK-787 
      PTK/ZK 
      ZK-222584 
Generic Name:   Vatalanib
succinate (recommended INNM; USAN) 
Chemical Name:   N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine
succinate 
Formula:   C24H21CLN4O4 
CAS Registry No.:   212142-18-2
      212141-51-0 (diHCl) 
      212141-52-1 (hydrochloride) 
      212141-54-3 (free base) 
      212141-89-4 (fumarate) 
      212141-90-7 (methanesulfonate) 
      212142-19-3 (oxalate salt) 



Development Phase:   Phase
III 
Originator:   National Cancer
Institute (US)
      Nihon Schering
      Novartis 
      Schering AG 
Class:   16500 (Treatment of Age-Related Macular Degeneration) 
      75016 (Astrocytoma Therapy) 
      75019 (Glioblastoma Multiforme Therapy)
      75020 (Breast Cancer Therapy)
      75025 (Colorectal Cancer Therapy)
      75036 (Kaposi's Sarcoma Therapy)
      75042 (Myeloid Leukemia Therapy)
      75046 (Lung Cancer Therapy)
      75047 (Non-Small Cell Lung Cancer Therapy)
      75056 (Multiple Myeloma Therapy)
      75057 (Myelodysplastic Syndrome Therapy)
      75063 (Pancreatic Cancer Therapy)
      75065 (Prostate Cancer Therapy)
      75070 (Renal Cancer Therapy)
      75080 (Solid Tumors Therapy)
      75751 (Angiogenesis Inhibitors)
      75855 (Inhibitors of Signal Transduction Pathways) 
Related Entry:   271218 (secondary)
      271220 (secondary)
      271221 (secondary) 
      271222 (secondary) 
      271223 (secondary) 
      271224 (secondary) 
      271225 (secondary) 
      271226 (secondary) 
      271228 (secondary) 
      271230 (secondary) 
      271231 (secondary) 
      271233 (secondary) 
      271234 (secondary) 
      271235 (secondary) 
      271236 (secondary) 
      271237 (secondary) 
      271238 (secondary) 
      271241 (secondary) 
      271243 (secondary) 
      364757 (non-specific)
ACTION: Antiangiogenic agent that acts by inhibiting
vascular endothelial growth factor (VEGF) receptor
tyrosine kinase (IC50 = 0.1-0.26 mcM). In vivo, compound
was shown to inhibit tumor growth in nude mice bearing
s.c.-implanted human epidermoid carcinoma A-431 tumors
(T/C x 100 = 21, 16 and 9 at 25, 50 and 100 mg/kg/day
p.o., respectively). Within this series of phthalazine
derivatives, the following are also specifically claimed:271218,
271220, 271221, 271222, 271223, 271224, 271225, 271226,
271228, 271230, 271231, 271233, 271234, 271235, 271236,
271237, 271238, 271241, 271243. (Drug Data Report,
Vol. 21, No. 2, p. 175, 1999) 

ACTION: Orally active antineoplastic agent with inhibitory
activity against vascular endothelial growth factor
(VEGF) receptor tyrosine kinase (IC50 = 0.1-0.26 mcM)
and high selectivity over kinases from other receptor
families including epidermal growth factor (EGF), fibroblast
growth factor (FGF-1, FGF-2), Tek, c-Src, v-Abl and
protein kinase C (PKC). In the submicromolar range,
compound also inhibited KDR and platelet-derived growth
factor (PDGF) receptor autophosphorylation, the proliferation
of human umbilical vein endothelial cells (HUVEC) and
the sprouting of rat aortic pieces cultured in a fibrin
gel. Compound did not have any cytotoxic or antiproliferative
activity against cells not expressing VEGF receptors.
At doses of 12.5-50 mg/kg/day p.o., it dose-dependently
inhibited VEGF- and PDGF- induced angiogenesis in an
in vivo mouse growth factor implant model and inhibited
tumor growth in nude mice bearing s.c.-implanted human
epidermoid carcinoma A-431 tumors or VEGF-dependent
human ovarian carcinoma SKOV3. Preliminary data from
a phase I clinical study in advanced cancer patients
demonstrated that compound is well tolerated, is rapidly
absorbed with a tmax of 1.1- 2.0 h, has a terminal
half-life of 4.5 h and is not associated with accumulation
following once-daily dosing. (Drug Data Report, Vol.
21, No. 2, p. 175, 1999 Drug Data Report, Vol. 22,
No. 2, p. 188, 2000) 
Previously Published in:   Drug Data Report, Vol. 21, No.  2, p. 175, 1999 
      Drug Data Report, Vol.  22, No. 2, p. 188, 2000
      Drugs of the  Future, Vol. 27, No. 1, p. 43, 2002 

Patents: 
PHTHALAZINES WITH ANGIOGENESIS INHIBITING ACTIVITY
AUTHOR(s):     Traxler, P., Frei, J., Wood, J., Bold, G., Altmann, K.-H.,
               Mett, H., Stover, D.R.
APPLICANT(s):  Novartis
FAMILY:        0970070    [EP 0970070]  European Patent Office, January 12, 2000
               5-01508800 [JP 501508800]Japan, July 3, 2001
                          [US 2002091261]United States of America, July 11, 2002
                          [US 2003191129]United States of America, October 9, 2003
               6,258,812  [US 6258812]  United States of America, July 10, 2001
               6,514,974  [US 6514974]  United States of America, February 4, 2003
               6,710,047  [US 6710047]  United States of America, March 23, 2004
               WO98-035958[WO 9835958]  W.I.P.O., August 20, 1998
PRIORITY:      315        [CH 97315]    Switzerland, February 13, 1997



PHTHALAZINE DERIVATIVES FOR TREATING INFLAMMATORY DISEASES
AUTHOR(s):     Manley, P.W., Frei, J., Bold, G., Heng, R., Wood, J.M.,
               Dawson King, J., Wietfeld, B.
APPLICANT(s):  Novartis
FAMILY:        1165085    [EP 1165085]  European Patent Office, January 2, 2002
                          [US 2003013718]United States of America, January 16, 2003
                          [US 2004142934]United States of America, July 22, 2004
                          [US 2005176711]United States of America, August 11, 2005
                          [US 2006217388]United States of America, September 28, 2006
               6,686,347  [US 6686347]  United States of America, February 3, 2004
               6,911,440  [US 6911440]  United States of America, June 28, 2005
               WO00-059509[WO 0059509]  W.I.P.O., October 12, 2000
PRIORITY:      603        [CH 99603]    Switzerland, March 30, 1999
               9916064    [GB 9916064]  Great Britain, July 8, 1999

METHOD FOR TREATING OCULAR NEOVASCULAR DISEASES
AUTHOR(s):     Wood, J.M., Brazzell, R.K., Campochiaro, P.A., Kane, F.E.
APPLICANT(s):  Novartis
FAMILY:        5-02522475 [JP 502522475]Japan, July 23, 2002
               WO00-009098[WO 0009098]  W.I.P.O., February 24, 2000
PRIORITY:      2-133,855  [US 133855]   United States of America, August
               13, 1998

IMPROVED TREATMENT OF NEOVASCULARIZATION
AUTHOR(s):     Brazzell, R.K.
APPLICANT(s):  Novartis
FAMILY:        1570859    [EP 1570859]  European Patent Office, September
               7, 2005
               WO01-074389[WO 0174389]  W.I.P.O., October 11, 2001
PRIORITY:      2-191,807  [US 191807]   United States of America, March 24,
               2000

USE OF 4-PYRIDYLMETHYLPHTHALAZINES FOR CANCER TREATMENT
AUTHOR(s):     Dugan, M.H., Wood, J.M.
APPLICANT(s):  Novartis
FAMILY:        1712234    [EP 1712234]  European Patent Office, October 18,
               2006
               WO03-022282[WO 0322282]  W.I.P.O., March 20, 2003
PRIORITY:      2-318,694  [US 318694]   United States of America, September 12, 2001
               2-331,025  [US 331025]   United States of America, September 12, 2001
               2-322,044  [US 322044]   United States of America, September 14, 2001
               2-388,163  [US 388163]   United States of America, June 12, 2002


USE OF C-KIT INHIBITORS FOR THE TREATMENT OF MYELOMA
AUTHOR(s):     Anderson, K.C.
APPLICANT(s):  Dana-Farber Cancer Institute, Novartis
FAMILY:        WO03-028711[WO 0328711]  W.I.P.O., April 10, 2003
PRIORITY:      2-325,491  [US 325491]   United States of America, September
               27, 2001


COMBINATIONS COMPRISING A SELECTIVE CYCLOOXYGENASE-2 INHIBITOR
AUTHOR(s):     Wood, A.W., Lassota, P., Chen, Y.-N.P.
APPLICANT(s):  Novartis
FAMILY:        WO03-035047[WO 0335047]  W.I.P.O., May 1, 2003
PRIORITY:      2-344,734  [US 344734]   United States of America, October
               25, 2001
               2-344,735  [US 344735]   United States of America, October
               25, 2001
               2-336,033  [US 336033]   United States of America, November
               15, 2001



USE OF 4-PYRIDYLMETHYL-PHTHALAZINE DERIVATIVES FOR THE MANUFACTURE OF A
MEDICAMENT FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROMES
AUTHOR(s):     Dugan, M.H., List, A.
APPLICANT(s):  Novartis, University of Arizona
FAMILY:        5-06502195 [JP 506502195]Japan, January 19, 2006
               WO04-028542[WO 0428542]  W.I.P.O., April 8, 2004
PRIORITY:      2-413,176  [US 413176]   United States of America, September
               24, 2002


TREATMENT OF AMM
AUTHOR(s):     Giles, F.
APPLICANT(s):  Novartis
FAMILY:        5-06503874 [JP 506503874]Japan, February 2, 2006
               WO04-033042[WO 0433042]  W.I.P.O., April 22, 2004
PRIORITY:      2-417,622  [US 417622]   United States of America, October
               10, 2002


TREATMENT OF VON HIPPEL LINDAU DISEASE
AUTHOR(s):     Kaelin, W.
APPLICANT(s):  Dana-Farber Cancer Institute
FAMILY:        1581228    [EP 1581228]  European Patent Office, October 5,
               2005
               5-06512360 [JP 506512360]Japan, April 13, 2006
                          [US 2006252763]United States of America, November
               9, 2006
               WO04-056367[WO 0456367]  W.I.P.O., July 8, 2004
PRIORITY:      2-435,049  [US 435049]   United States of America, December
               20, 2002
               2-538,990  [US 538990]   United States of America, June 21,
               2006


INHIBITORS OF THE MUTANT FORM OF KIT
AUTHOR(s):     Fabbro, D., Buchdunger, E.
APPLICANT(s):  Novartis
FAMILY:        1686997    [EP 1686997]  European Patent Office, August 9,
               2006
               WO05-049032[WO 0549032]  W.I.P.O., June 2, 2005
PRIORITY:      2-520,714  [US 520714]   United States of America, November
               18, 2003


COMPOSITIONS AND USE FOR TYROSINE KINASE INHIBITORS TO TREAT PATHOGENIC
INFECTION
AUTHOR(s):     Bornmann, W.G., Kalman, D., Sherman, M.A., Reeves, P.M.,
               Swimm, A.I.
APPLICANT(s):  Emory University
FAMILY:        1725295    [EP 1725295]  European Patent Office, November
               29, 2006
               WO05-072826[WO 0572826]  W.I.P.O., August 11, 2005
PRIORITY:      2-537,960  [US 537960]   United States of America, January
               21, 2004
               2-553,681  [US 553681]   United States of America, March 16,
               2004
               2-614,203  [US 614203]   United States of America, September
               29, 2004



COMBINATIONS OF A VEGF RECEPTOR INHIBITOR WITH OTHER THERAPEUTIC AGENTS
AUTHOR(s):     Manley, P.W., Bold, G., Wood, J.M., Kinder, F.R., Lane, H.,
               Latour, E.J., Brueggen, J.B., Huang, J.M.-J.
APPLICANT(s):  Novartis
FAMILY:        1667721    [EP 1667721]  European Patent Office, June 14, 2006
               WO05-027973[WO 0527973]  W.I.P.O., March 31, 2005
PRIORITY:      2-505,255  [US 505255]   United States of America, September
               23, 2003



COMBINATION OF A VEGF RECEPTOR INHIBITOR WITH A CHEMOTHERAPEUTIC AGENT
AUTHOR(s):     Manley, P.W., Bold, G., Wood, J.M., Kinder, F.R. Jr., Lane,
               H., Latour, E.J., Brueggen, J.B., Huang, J.M.-J.
APPLICANT(s):  Novartis
FAMILY:        1682181    [EP 1682181]  European Patent Office, July 26, 2006
               WO05-027972[WO 0527972]  W.I.P.O., March 31, 2005
PRIORITY:      2-505,250  [US 505250]   United States of America, September
               23, 2003



PHARMACEUTICAL COMBINATION COMPRISING A CDK INHIBITOR AND A VEGF
               RECEPTOR
INHIBITOR
AUTHOR(s):     Siemeister, G.
APPLICANT(s):  Schering AG
FAMILY:        1568368    [EP 1568368]  European Patent Office, August 31, 2005
PRIORITY:      0490071    [EP 0490071]  European Patent Office, February 26, 2004



COMBINATION OF ONCOLYTIC VIRUSES WITH ANGIOGENESIS INHIBITORS
AUTHOR(s):     Iggo, R., McLaughlin, F., Fuerer, C., Homicsko, K.G.,
               Lukashev, A.N.
APPLICANT(s):  BTG
FAMILY:        WO06-075165[WO 0675165]  W.I.P.O., July 20, 2006
PRIORITY:      05658      [GB 05658]    Great Britain, January 13, 2005
               05659      [GB 05659]    Great Britain, January 13, 2005



COMBINATION COMPRISING AN AGENT DECREASING VEGF ACTIVITY AND AN AGENT
DECREASING EGF ACTIVITY
AUTHOR(s):     Traxler, P., Bold, G., Wood, J.M., Brandt, R.
APPLICANT(s):  Novartis
FAMILY:        2427184    [CA 2427184]  Canada, May 30, 2002
               1339458    [EP 1339458]  European Patent Office, September 3, 2003
               5-04513964 [JP 504513964]Japan, May 13, 2004
                          [US 2004034026]United States of America, February 19, 2004
                          [US 2006270665]United States of America, November 30, 2006
               WO02-041882[WO 0241882]  W.I.P.O., May 30, 2002
PRIORITY:      0028467    [GB 0028467]  Great Britain, November 22, 2000
               0121813    [GB 0121813]  Great Britain, September 10, 2001



USE OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR INHIBITORS FOR THE
TREATMENT OF GASTROINTESTINAL, GENITOURINARY, LYMPHOID AND PULMONARY
CANCERS
AUTHOR(s):     Lebwohl, D., Berg, W., Kay, A.
APPLICANT(s):  Novartis
FAMILY:        WO06-113172[WO 06113172] W.I.P.O., October 26, 2006
PRIORITY:      2-670,870  [US 670870]   United States of America, April 13, 2005
               2-680,396  [US 680396]   United States of America, May 12, 2005


References: 
Wood, J. et al., "Pharmacological profile of a potent and orally active
inhibitor of VEGF receptor tyrosine kinases", Proc Am Assoc Cancer Res
(AACR) 1998,39 Abst 655

Drevs, J. et al., "Phase I dose escalation, pharmacokinetic (pk) study
of a novel vascular endothelial growth factor (VEGF) receptor inhibitor,
PTK787/ZK 222584 (PTK/ZK)", Eur J Cancer 1999,35(Suppl. 4) Abst 1137

Manley, P.W. et al., "Rationalization of the selective inhibition of
VEGF-tyrosine kinase by the angiogenesis inhibitor, PTK787/ZK222584 (1) on
the basis of shape complementarity to hydrophobic domains within teh
ATP-binding site", AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther (Nov
16-19, Washington DC) 1999, Abst 256

Xu, L. et al., "Therapy of VEGF-dependent human ovarian carcinoma by
oral administration of CGP 79787/ZK222584, an inhibitor of the VEGF
receptor tyrosine kinase", Proc Am Assoc Cancer Res (AACR) 1999,40 Abst
3020

Ozaki, H. et al., "Blockade of vascular endothelial cell growth factor
receptor signaling is sufficient to completely prevent retinal
neovascularization", Am J Pathol 2000,156(2): 697

Wood, J.M. et al., "Vascular endothelial growth factor receptor
tyrosine kinase inhibition, an effective therapy against human prostatic
carcinomas in nude mice", Proc Am Assoc Cancer Res (AACR) 2000,41 Abst 299

Wood, J.M. et al., "Magnetic resonance imaging of tumor permeability: A
non-invasive marker for the efficacy of a VEGF-receptor tyrosine kinase
inhibitor", Proc Am Assoc Cancer Res (AACR) 2000,41 Abst 2460

Soorzano, C.C. et al., "Blockade of VEGF-R signaling inhibits growth
and metastasis of human pancreatic cancer", Proc Am Assoc Cancer Res (AACR)
2000,41 Abst 3620