Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-29
2004-03-16
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S293000
Reexamination Certificate
active
06706721
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrous and hydrate forms. These compounds are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals.
U.S. Pat. No. 5,747,498, issued May 5, 1998, which is incorporated herein by reference in its entirety, refers to [6,7-bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride which, the patent application discloses, is an inhibitor of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and is therefore useful for the treatment of proliferative disorders, such as cancers, in humans. The mesylate compounds of the present invention are similarly useful for the treatment of proliferative disorders, but they also possess certain advantages over the foregoing hydrochloride compound. One advantage is that the mesylate compounds of the present invention are more soluble in aqueous compositions than the above hydrochloride compound, and thus the mesylate compounds of the present invention are easily delivered according to parenteral methods of administration.
SUMMARY OF THE INVENTION
The present invention relates to the anhydrous and hydrate forms of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate.
A specific embodiment of the present invention comprises the anhydrous form of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate. In particular, the anhydrous form includes polymorphs A, B, and C, having X-ray powder diffraction patterns as described below.
Another specific embodiment of the present invention comprises N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate monohydrate.
The invention also relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal (such as kidney), ovarian, prostate, colorectal, oesophageal, gynecological or thyroid cancer. In another embodiment, said pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign prostatic hypertropy (BPH)).
The invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced renal disease) in a mammal which comprises a therapeutically effective amount of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the prevention of blastocyte implantabon in a mammal which comprises a therapeutically effective amount of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema, and scieroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The invention also relates to a method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate. In one embodiment, said method relates to the treatment of cancer such as brain, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, renal (such as kidney), ovarian, gynecological or thyroid cancer. In another embodiment, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign prostatic hypertropy (BPH)).
The invention also relates to a method for the treatment of a hyperproliferaive disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
Patients that can be treated with N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, BPH, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphonas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphona, spinal axis tumors, brain stem gliomas or pituitary adenomas).
DETAILED DESCRIPTION OF THE INVENTION
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate has been found to exist in three distinct anhydrous polymorphic forms A, B and C and also as a monohydrate. The relationship of these forms is illustrated in the Scheme below.
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride may be prepared as described in U.S. Pat. No. 5,747,498, issued May 5, 1998, referred to above. N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate monohydrate may be prepared by mixing N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride in ethyl acetate and water, warming the mixture to a temperature of about 60-70° C., adding sodium hydroxide to adjust the pH to within a range of about 10-11, separating the organic ethyl acetate phase, and then adding methanesulfonic acid to the organic phase to provide the mesylate monohydrate.
The anhydrous mesylate characterized as polymorph A may be prepared by mixing the mesylate monohydrate, prepared as described above, in ethyl acetate or isopropanol, heating the mixture to reflux for about 1 day, and then cooling to ambient temperature to allow crystallization.
The anhydrous mesylate characterized as polymorph B may be prepared by mixing the mesylate monohydrate in isopropanol and heating the mixture to about 45-55° C. for a period of about 5 hours. The anhydrous mesylate characterized as polymorph B may also be prepared by mixing N-(3-ethynylphenyl)-6,7-bis(2-m
Allen Douglas John Meldrum
Norris Timothy
Raggon Jeffrey William
Santafianos Dinos Paul
Shanker Ravi Mysore
Cooper & Dunham LLP
Ford John M.
OSI Pharmaceuticals, Inc.
White John P.
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