Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-26
2004-11-23
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S160000, C546S153000, C546S152000, C514S314000, C514S312000, C514S311000
Reexamination Certificate
active
06821988
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain substituted 3-cyanoquinoline compounds as well as the pharmaceutically acceptable salts thereof. The compounds of the present invention inhibit the action of certain growth factor receptor protein tyrosine kinases (PTK) and other protein kinases thereby inhibiting the abnormal growth of certain cell types. The compounds of this invention are therefore useful for the treatment of certain diseases that are the result of deregulation of these PTKs. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals. This invention also relates to the manufacture of said 3-cyanoquinolines, their use for the treatment of cancer and polycystic kidney disease, and the pharmaceutical preparations containing them.
BACKGROUND OF THE INVENTION
Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate. Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or overexpression, these receptors can become deregulated. The result of this is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Wilks A. F.,
Adv. Cancer Res
., 60, 43 (1993) and Parsons, J. T.; Parsons, S. J.,
Important Advances in Oncology
, DeVita V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the Her2 (also referred to as the neu or erbB-2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since overexpressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, overexpression of the receptor kinase product of the Her2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J., et. al.,
Science
, 244, 707 (1989) and
Science
, 235, 1146 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et. al.,
Cancer Res
., 51, 6254 (1991)], breast tumors [Macias, A., et. al.,
Anticancer Res
., 7, 459 (1987)], and tumors involving other major organs [Gullick, W. J.,
Brit. Med. Bull
., 47, 87 (1991)]. Because of the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Burke, T. R.,
Drugs Future
, 17, 119 (1992) and Chang, C. J.; Geahlen, R. L.,
J. Nat. Prod
., 55, 1529 (1992)]. The compounds of this invention inhibit the kinase activity of EGF-R and Her2 and are therefore useful for treating certain disease states, such as cancer, that result, at least in part, from deregulation of these receptors. The compounds of this invention are also useful for the treatment and prevention of certain pre-cancerous conditions, such as the growth of colon polyps, that result, at least in part, from deregulation of these receptors.
It is also known that deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease [Du J., Wilson P. D.,
Amer. J. Physiol
., 269(2 Pt 1), 487 (1995); Nauta, J., et al.,
Pediatric Research
, 37(6), 755 (1995); Gattone, V. H., et al.,
Developmental. Biology
, 169(2), 504 (1995); Wilson, P. D., et al.,
Eur. J. Cell Biol
., 61(1), 131,(1993)]. The compounds of this invention, which inhibit the catalytic function of the EGF receptors, are consequently useful for the treatment of this disease.
Some 3-cyanoquinoline derivatives are inhibitors of tyrosine kinases and are described in the application WO9843960 (U.S. Pat. No. 6,002,008). These 3-cyanoquinolines may be substituted at carbon-5 through carbon-8 with an unsubstituted phenyl, alkene or alkyne group. Applications WO0018761 and WO0018740 also describe 3-cyanoquinoline inhibitors. A 3-cyanoquinoline with a 4-(2-methylanilino) substituent having gastric (H
+
/K
+
)-ATPase inhibitory activity at high concentrations has been described [Ife, R.,
J. Med. Chem
., 35(18), 3413 (1992)].
The compounds of the present invention are 3-cyanoquinolines which inhibit the activity of protein kinases that are required for cell growth and differentiation and are therefore useful for the treatment of certain diseases that result from activity of these protein kinases. In particular, the compounds of this invention inhibit the kinase activity of EGF-R and Her2 kinases. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. Further, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided compounds represented by Formula (I):
wherein:
Z is —NH—, —O—, —S—, or —NR—;
R is alkyl of 1 to 6 carbon atoms, or carboalkyl of 2 to 7 carbon atoms;
X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or
X is pyridinyl, pyrimidinyl, or aryl and may optionally be mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC
1
-C
6
)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, benzoyl, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1 to 6 carbon atoms, alkenoylamino of 3 to 8 carbon atoms, alkynoylamino of 3 to 8 carbon atoms, carboxyalkyl of 2 to 7 carbon atoms, carboalkoxyalkyl of 3 to 8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2 to 9 carbon atoms, N,N-dialkylaminoalkyl of 3 to 10 carbon atoms, N-alkylaminoalkoxy of 2 to 9 carbon atoms, N,N-dialkylaminoalkoxy of 3 to 10 carbon atoms, mercapto, and benzoylamino; or
X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms independently selected from N, O, and S; wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, azido, hydroxyalkyl of 1 to 6 carbon atoms, halomethyl, alkoxymethyl of 2 to 7 carbon atoms, alkanoyloxymethyl of 2 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms (alkylC
1
-C
6
)S—, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2 to 7 carbon atoms, carboalkyl of 2 to 7 carbon atoms, phenoxy, phenyl, thiophenoxy (C
6
H
5
S—), benzoyl, benzyl, amino, alkylamino of 1 to 6,carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylami
Floyd, Jr. Middleton Brawner
Johnson Bernard D.
Overbeek-Klumpers Elsebe Geraldine
Tsou Hwei-Ru
Wissner Allan
Aulakh Charanjit S.
Goudie Joy S.
Wyeth Holdings Corporation
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