Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-05-18
2003-11-11
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S287000, C544S283000, C544S293000, C544S284000
Reexamination Certificate
active
06645969
ABSTRACT:
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation, the control of abnormal cell growth and cell inflammatory response. More specifically, this invention relates to the use of mono- and/or bicyclic aryl or heteroaryl quinazoline compounds which exhibit selective inhibition of differentiation, proliferation or mediator release by effectively inhibiting CSF-1R tyrosine kinase activity.
Normal cell growth is believed to be triggered by the exposure of the cellular substrate to one or more growth factors, examples of which are insulin, epidermal growth factor (EGF) and platelet-derived growth factor (PDGE). Receptors for such growth factor are imbedded in and penetrate through the cellular membrane. The initiation of cellular reproduction is believed to occur when a growth factor binds to the corresponding receptor on the external surface of the cellular membrane. This growth factor-receptor binding alters the chemical characteristics of that portion of the receptor which exists within the cell and which functions as an enzyme to catalyze phosphorylation of either an intracellular substrate or the receptor itself, the latter being referred to as autophosphorylation. Examples of such phosphorylating enzymes include tyrosine kinases, which catalyze phosphorylation of tyrosine amino acid residues of substrate proteins.
Many disease states are characterized by the uncontrolled growth of cells. These disease states involve a variety of cell types and include disorders such as cancer, leukemia, psoriasis, inflammatory diseases, bone diseases, atherosclerosis and restenosis occuring subsequent to angioplastic procedures. The inhibition of tyrosine kinases is believed to have utility in the control of deregulated cellular proliferation, i.e., cellular proliferative disorders.
Initiation of autophosphorylation, i.e., phosphorylation of the growth factor receptor itself, and of the phosphorylation of a host of intracellular substrates are some of the biochemical events which are involved in mediator release and cell proliferation.
REPORTED DEVELOPMENTS
Inhibitors of p56
Ick
tyrosine kinase have been reported in the literature by Bolen, J. B. et al.
FASEB J
. 1992, 3403., Mustelin, T. et al.
TIBS
1993 , 215.; Eichmann, K.
Angew. Chem. Int. Ed. Eng
. 1993, 54.; and Klausner, R. D. Samelson, L. E.
Cell
1991 , 875. These include compounds that are potent but nonselective inhibitors, such as staurosporine, which is competitive with ATP or compounds that are very weak tyrosine kinase inhibitors, but are somewhat selective, such as the flavonoid quercetin.
A series of dihydroxy-isoquinolines have been been reported by Burke, T. R. et al. (
Biorg
. &
Med. Chem. Lett
. 1992, 1771
; J. Med. Chem
. 1993 3010 and
J. Med. Chem
. 1993 , 3015) that have potent p56
Ick
inhibiting activity. Potential therapeutic uses for selective inhibitors of p56
Ick
include the treatment of autoimmune diseases such as rheumatoid arthritis or transplant rejection.
p56
Ick
, which is a non-receptor tyrosine kinase, has been shown to be important in intracellular signaling in T-cells. It is assumed that inhibitors of p56
Ick
kinase activity perturb the activation of T-cells and therefore a selective inhibitor could prove useful in the treatment of T-cell mediated conditions such as organ rejection, rheumatoid arthritis or other auto-immune diseases.
SUMMARY OF THE INVENTION
The present invention describes compounds which are inhibitors of the colony stimulating factor-1 receptor tyrosine kinase, CSF-1R, activity and have activity in a p56
Ick
cell-free assay. These compounds do not appear to have any significant serine/threonine kinase inhibitory activity and in addition, compounds within the scope of this invention do not demonstrate significant PDGF-R activity in a cell-free assay. Compounds of this invention are also weak inhibitors of PDGF-induced mitogenesis which may suggest that these compounds inhibit other sic-like tyrosine kinases involved in the signal transduction pathway.
Compounds within the scope of this invention are inhibitors of the colony stimulating factor-1 receptor tyrosine kinase, CSF-1R, activity. A selective inhibitor of the tyrosine kinase activity of this receptor, which is closely related to the platelet-derived growth factor receptor (PDGF-R), has never been reported. Compounds of this invention are selective inhibitors of CSF-1R tyrosine kinase activity and are useful for elucidating the importance of CSF-1 and CSF-1 receptor signaling in bone remodeling and hematopoeisis. In addition compounds inhibiting growth factor-induced CSF and/or Ick signalling are described herein.
In accordance with the present invention, there is provided pharmaceutical compositions for inhibiting abnormal cell proliferation and/or differentiation or mediator release in a patient suffering from a disorder characterized by such proliferation activity, comprising the administration to a patient a tyrosine kinase composition which effectively inhibits CSF-1R tyrosine kinase activity in a CSF-1R inhibiting effective amount of a mono- aryl or heteroaryl quinazoline compound exhibiting inhibition of differentiation, proliferation or mediator release activity wherein each aryl group is a ring system containing 0-4 hetero atoms, said compound being optionally substituted or polysubstituted.
Another aspect of the present invention relates to a method of inhibiting abnormal cell proliferation and/or differentiation or mediator release comprising, in admixture with a pharmaceutically acceptable carrier, a pharmaceutically effective amount of a compound of the aforementioned type. Another aspect of this invention comprises compounds useful in the practice of the present method.
With respect to the aspects of this invention, the compounds described by Formula I below constitute a class of the aforementioned mono- and bicicyclic aryl or heteroaryl quinazoline compounds for use in the practice of the present invention:
wherein
Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of about 5 to about 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R.;
X is a bond, O, S, SO, SO
2
, OCH
2
, C═C, C≡C, C═S, SCH
2
, NH, NHCH
2
, NR
4
or NR
4
CH
2
;
R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, alkylthio, alkylsulfinyl, sulfonyl, mono- and di-alkyl sulfonyl, sulfamoyl, mono- and di-alkyl sulfamoyl, halophenyl or benzoyl; and R and R together may also form a ketone group.
R
4
is alkyl, —CH
2
—CH
2
— or —CH
2
—CH
2
—CH
2
—; and
R
5
, R
6
and R
7
are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or
a pharmaceutically acceptable salt thereof.
Preferred Ar monocyclic aryl or heteroaryl rings include substituted or unsubstituted benzene, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, pyridine, 2(1H)-pyridone, 4(1H)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole and tetrazole.
Preferred Ar bicyclic aryl or heteroaryl rings include substituted and unsubstituted naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[
Hsu Chin-Yi Jenny
Johnson Susan E.
Maguire Martin P.
Myers Michael R.
Persons Paul E.
Aventis Pharmaceuticals Inc.
Butch Peter J.
Parker III Raymond S.
Pryor Alton
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