Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-27
2004-05-25
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S312000
Reexamination Certificate
active
06740757
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, prodrugs thereof and pharmaceutically acceptable salts and solvates of said enantiomers and prodrugs. The compounds of the present invention are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. The compounds are also useful as inhibitors of the enzyme farnesyl protein transferase, which is involved in cancerous tumor growth.
In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (−) or d or I are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or I meaning that the compound is levorotatory and with (+) or d meaning that the compound is dextrotatory. For a given chemical structure the optically active isomers having opposite sign of optical rotation are called enantiomers. Said enantiomers are identical except that they are mirror images of each other. A 1:1 mixture of such enantiomer is called a racemic mixture.
It should be noted that optical rotation of chemical substances is dependent upon experimental parameters. The values shown hereinunder are specific rotations and the experimental conditions such as temperature, the wavelength of the plane polarized light used, the solvent as well as the concentration of the sample are indicated in the conventional way. The optical rotation may vary when for instance an acid addition salt is formed.
Stereochemical purity is of importance for biologically active substances that are used in pharmaceutical compositions for human application since the respective enantiomers may have a different potency or may have a different activity. Often, one of the enantiomers presents the desired optimum biological activity. Additionally, the presence of the other enantiomer in a composition or agent may cause or invigorate certain side effects. It is generally desirable to administer the biologically active substance in the form of a substantially pure enantiomer, which specifically exhibits the desired biological activity. Therefore, the resolution of a racemate into its enantiomers is often an important step in the preparation process of pharmacologically active substances.
The present invention provides for the enantiomers (−)- and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, and derivatives thereof. The invention further provides a number of processes to isolate the enantiomers (−)- and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, the derivatives thereof, in high yields and in a high enantiomeric excess (e.e.). More particularly, the invention relates to the process for production of enantiomerically pure and/or optically enriched (−)- and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one from a racemate mixture using continuous chromatography or chiral salt precipitation methods.
SUMMARY OF THE INVENTION
The invention relates to (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one and (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, prodrugs thereof and pharmaceutically acceptable salts and solvates of said compounds and prodrugs.
The present invention further relates to (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, L-(+)-tartaric acid and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl-methyl]-4-[3-(3-methyl-but-1-ynyl)-phenyl-]-1-methyl-1H-quinolin-2-one, (S)-(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of one of the compounds described herein, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and prodrugs, that is effective in treating abnormal cell growth or inhibiting farnesyl protein transferase.
In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal a therapeutically effective amount of one of the compounds described herein, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and prodrugs 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.
The present invention also relates to a method for the treatment of an infection in a mammal, including a human, that is facilitated by farnesyl protein transferase, such as hepatitis delta virus or malaria, which comprises administering to said mammal a therapeutically effective amount of one of the compounds described herein, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and prodrugs.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of one of the compounds described herein, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and prodrugs, that is effective in inhibiting farnesyl protein transferase, and a pharmaceutically acceptable carrier.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of one of the compounds described herein, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and prodrugs, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a
Ewing Marcus Douglas
Guhan Subramanian Sam
Guinn R. Mark
Li Bryan
Meltz Clifford N.
Juarez Z. E.
Pfizer Inc
Richardson P. C.
Seaman D. Margaret
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