Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-09
2004-01-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S267000, C544S247000, C544S250000, C544S251000, C544S343000, C544S345000
Reexamination Certificate
active
06673798
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to PDGF receptor kinase inhibitory compounds and pharmaceutical compositions such as, but not limited to, slow release compositions. More particularly, the present invention relates to enriched or purified geometrical isomers of compounds of the quinoxaline family known to be PDGF receptor kinase inhibitors, compositions including same, methods of their synthesis, purification and formulation and their use for treatment of proliferative malignant and non-malignant diseases or disorders, such as, but not limited to, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis, restenosis, vascular graft restenosis, in-stent stenosis, angiogenesis, ocular diseases, pulmonary fibrosis, obliterative bronchiolitis, glomerular nephritis, rheumatoid arthritis and PDGF receptor associated malignancies, such as, but not limited to, leukemias and lymphomas.
Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal, glial, and capillary endothelial cells (for reviews, see, [1] and [2]). The three isoforms of PDGF, PDGF-AA, PDGF-AB, and PDGF-BB, interact differentially with structurally related receptors designated PDGF &agr;- and &bgr;-receptors. Each of these receptors has an extracellular part featuring five immunoglobulin-like domains, a lipophilic transmembrane domain and an intracellular part with a tyrosine kinase domain containing a characteristic insert amino acid sequence [3-5]. The tyrosine kinase activity of these receptors is essential for transmission of the mitogenic signal into the cell [6].
PDGF and its receptors participate in various physiological processes such as embryonal development and wound healing. An abnormally high activity of PDGF is believed to play a central role in the etiology of certain adverse pathophysiological situations, such as atherosclerosis and restenosis [7, 8], as well as in other non-malignant diseases such as pulmonary fibrosis [9], glomerular nephritis [10], and rheumatoid arthritis [11]. Moreover, the PDGF B-chain was acquired as the sis oncogene by the acutely transforming simian sarcoma virus [12, 13]. The expression of a PDGF-like growth factor in cells infected with simian sarcoma virus or transfected with the sis oncogene leads to their transformation due to the persistent autocrine stimulation of the resident PDGF receptors.
Furthermore, certain human tumors possess PDGF receptors and express the genes for PDGF which suggest that autocrine growth stimulation via PDGF receptors contributes to the malignant phenotype of these tumors [2, 14].
The fact that PDGF is likely to be involved in the development of certain disorders has prompted the search for agents to block the action of PDGF. The approaches for interference with PDGF-induced signalling include peptides competing with PDGF for receptor binding [15], dominant negative mutants of PDGF [16, 17] or of PDGF receptor [18], and low molecular weight blockers of the receptor tyrosine kinase activity known as tyrphostins [19, PCT/US98/16232].
Certain tyrphostins which block PDGF-dependent proliferation of rabbit vascular smooth muscle cells [20] and of human bone marrow fibroblasts [21] have already been reported.
A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 was described by Kovalenko et al. [22]. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells (EC) with 50% inhibitory concentrations below 5 and 1 &mgr;M, respectively. These PDGF receptor blockers have no effect on epidermal growth factor receptor autophosphorylation, weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis.
AG1296 potently inhibits signalling of human PDGF &agr;- and &bgr;-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells [22].
In U.S. Pat. No. 5,932,580, further low molecular weight PDGF receptor kinase inhibitors, of the quinoxaline family, are described. Specifically, substituted analogs of 1,2-dimethyl-imidazolo[5,4-g]quinoxaline were shown to selectively inhibit PDGFR autophosphorylations and proliferation of PDGFR expressing cells, like porcine arterial smooth muscle cells (SMC), porcine endothelial cells and human internal mammary artery SMC, at &mgr;M concentration range.
The present invention describes enriched or purified geometrical isomers of compounds of the quinoxaline family known to be PDGF receptor kinase inhibitors, compositions including same, methods of their synthesis, purification and formulation and their use for treatment of proliferative malignant and non-malignant diseases or disorders, which show differential selectivity towards the PDGF receptor kinase. It is shown herein for the first time that geometrical isomers of compounds belonging to the quinoxaline are producable, isomerically purifyable and have differential affinity towards PDGF receptor kinase.
SUMMARY OF THE INVENTION
It is an object of the present invention to provided PDGF receptor kinase inhibitory compounds of the quinoxaline family, methods for their synthesis and purification and containment in, for example, slow release pharmaceutical compositions, and their use for treatment of a variety of diseases and disorders by local or systemic application.
According to one aspect of the present invention there is provided a preparation of a tyrphostin comprising a compound of a general formula:
wherein,
4, 5, 6, 7, 8 and 9 indicate positions on a terminal 6-member ring;
A, B, D, X and Y are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;
R
1
, R
2
, R
3
, R
5
and R
7
are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hydroxy, alkoxy, halo, C-carboxy, O-carboxy, carbonyl, thiocarbonyl, C-amido, guanly, sulfonyl, trihalomethane-sulfonyl and a pair of electrons, or alternatively, R
1
and R
2
or R
2
and R
3
form a 5-7 member ring structure;
R
6
is selected from the group consisting of alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, is halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and a physiologically acceptable salt or a prodrug thereof;
R
4
and R
8
are each independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, N-sulfonamido, S-sulfonamido, trihalomethylsulfonamido, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, ureido, guanyl, guanidino, amino and —NR
10
R
11
and, a physiologically acceptable salt or a prodrug thereof;
R
10
and R
11
are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or alternatively R
10
and R
11
form a five- or six-member heter
Banai Shmuel
Boehmer Frank D.
Gazit Aviv
Gertz David S.
Golomb Gershon
G. E. Ehrlich (1995) Ltd.
Shah Mukund J.
Truong Tamthom N.
Yissum Research Development Company of the Hebrew University of
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