Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-12
2001-04-10
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S361000
Reexamination Certificate
active
06214828
ABSTRACT:
BACKGROUND
The biological significance of the Ras oncogene, and the role of both Ras and the enzyme known as farnesyl protein transferase in the conversion of normal cells to cancer cells, are described in PCT International Publication Nos. WO95/00497 and WO95/10516. Each of those publications also describes a distinct class of compounds which inhibit the activity of the enzyme farnesyl protein transferase, and thereby the farnesylation of the Ras protein.
PCT International Publication No. WO95/10516 relates to tricyclic amide and urea compounds of the general formula (1.0)
and their use in a method for inhibiting Ras function and the abnormal growth of cells. A number of sub-generic classes of compounds of formula (1.0) are described, which include compounds of the formulae (5.0c), (5.1c) and (5.2a)
as well as the 11-R-isomer and 11-S-isomers of compounds (5.0c) and (5.1c). A number of specific compounds within each such sub-genus are also described therein, as is the biological activity of those compounds.
SUMMARY OF THE INVENTION
The present invention provides novel tricyclic amide compounds selected from the group consisting of:
or pharmaceutically acceptable salts thereof.
Optical rotation of the compounds ((+)- or (−)-) are measured in methanol or ethanol at 25° C.
This invention includes the above compounds in the amorphous state or in the cyrstalline state.
Thus, compounds of this invention include compounds selected from the group consisting of: Compounds 1.0, 2.0, 3.0, 50.0, 6.0, 7.0, 7.0A, 8.0, 8.0A, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, and 17.0, or pharmaceutically acceptable salts thereof, wherein said compounds are as defined above.
Compounds of this invention also include compounds selected from the group consisting of: Compounds 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, and 41.0, or pharmaceutically acceptable salts thereof, and wherein said compounds are as defined above.
Compounds of this invention also include compounds selected from the group consisting of: (+)-enantiomer Compounds 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 76.0, 77.0, 78.0, 79.0 and 80.0, or pharmaceutically acceptable salts thereof, and wherein said compounds are as defined above.
Also, compounds of this invention include compounds selected from the group consisting of: Compounds 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0 and 69.0, or pharmaceutically acceptable salts thereof, wherein said compounds are as defined above.
Preferred compounds include the 3,7,8-trihalo compounds having a (−)-optical rotation. For example, Compounds 22.0, 23.0, 25.0 and 27.0.
Preferred compounds also include the 3,8,10-trihalo compounds having a (+)-optical rotation. For example, Compounds 29.0, 31.0, 32.0, 34.0, 36.0, 37.0, 39.0 and 41.0.
Preferred compounds also include the 3,10-dihalo compounds having a (+)-optical rotation, for example, Compound 20.0.
Preferred compounds also include the 3,7-dibromo-8-chloro compounds having S stereochemistry at the C-11 position. For example, Compounds 50.0, 53.0, 55.0 and 57.0.
Preferred compounds also include the 3,10-dibromo-8-chlorocompounds having R stereochemistry at the C-11 position. For example, Compounds 62.0, 64.0, 66.0 and 68.0.
Preferred compounds also include Compounds 16.0, 17.0, 39.0, 40.0, 41.0, 68.0 and 69.0.
More preferred compounds are Compounds 16.0, 39.0, 40.0, 68.0 and 69.0. Most preferred compounds are Compounds 16.0, 39.0 and 68.0. Even more preferred is Compound 39.0 or 68.0.
Those skilled in the art will appreciate that the tricyclic ring system is numbered:
Those skilled in the art will also appreciate that the S and R stereochemistry at the C-11 bond are:
Inhibition of farnesyl protein transferase by the tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras. The compounds of this invention have been demonstrated to have anti-tumor activity in animal models.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancers and prostate cancers.
It is believed that this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes—i.e., the Ras gene itself is not activated by mutation to an oncogenic form—with said inhibition being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited by the tricyclic compounds described herein.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. This invention further provides a method of inhibiting ras farnesyl protein transferase, in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above.
The tricyclic compounds useful in the methods of this invention inhibit the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cel
Doll Ronald J.
Kelly Joseph M.
Mallams Alan K.
Njoroge F. George
Remiszewski Stacy W.
Albanese Margaret M.
Huang Evelyn Mei
Jeanette Henry C.
Schering Corporation
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