Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-29
2002-01-01
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S250000, C544S251000
Reexamination Certificate
active
06335344
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to phenylamino-substituted tricyclic derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. It is known that such kinases are often aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Thus, it is believed that inhibitors of receptor tyrosine kinases, such as the compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells.
It has also been shown that EGFR inhibitors may be useful in the treatment of pancreatitis and kidney disease, and may reduce successful blastocyte implantation and therefore be useful as a contraceptive. See PCT international application publication number WO 95/19970 (published Jul. 27, 1995).
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts thereof, wherein:
n is 0 to 2;
R
1
is hydrogen or C
1
-C
6
alkyl optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, C
1
-C
4
alkoxy, —NR
6
R
7
, and —SO
2
R
5
;
each R
2
is independently selected from the group consisting of halo, hydroxy, C
1
-C
6
alkyl, —NR
6
R
7
, and C
1
-C
4
alkoxy, wherein said alkyl group and the alkyl moieties of said R
2
groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, C
1
-C
4
alkoxy, —NR
6
R
7
, and —SO
2
R
5
;
R
3
is azido or -(ethynyl)-R
8
wherein R
8
is hydrogen or C
1
-C
6
alkyl optionally substituted by hydroxy, —OR
6
, or —NR
6
R
7
;
R
4
is H, C
1
-C
4
alkyl, (C
1
-C
4
alkoxy)C
1
-C
4
alkyl, C
1
-C
4
alkanoyl, C
1
-C
4
alkoxy or —S(O)
x
(C
1
-C
4
alkyl) wherein x is 0 to 2, and wherein said alkyl group and the alkyl moieties of said R
4
groups are optionally substituted by 1 to 3 halogens;
each R
5
is C
1
-C
4
alkyl optionally substituted by 1 to 3 halogens;
R
6
and R
7
are independently selected from hydrogen and R
5
; and,
Z is a 5 to 8 membered fused ring that includes 0 to 3 heteroatoms selected from O, S and N.
The term “halo”, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties.
The term “alkoxy”, as used herein, unless otherwise indicated, includes O-alkyl groups wherein “alkyl” is defined above.
The term “alkanoyl”, as used herein, unless otherwise indicated, includes —C(O)-alkyl groups wherein “alkyl” is defined above.
In the present invention, the Z moiety of formula I represents a 5 to 8 membered used ring that includes 0 to 3 heteroatoms selected from O, S and N. The Z moiety includes saturated and unsaturated fused rings, and aromatic and non-aromatic fused rings.
Preferred compounds of formula I include those wherein R
3
is -(ethynyl)-R
8
.
Other preferred compounds of formula I include those wherein Z is selected from
Other preferred compounds of formula I include those wherein Z is selected from the group of four moieties referred to above and R
4
is H or C
1
-C
4
alkyl, R
1
is H, and n is 0.
Other preferred compounds of formula I include those wherein R
3
is -(ethynyl)-R
8
and R
8
is H.
Other preferred compounds of formula I include compounds of the formula
wherein R
1
, R
2
, R
3
, R
6
and n are as defined above.
Preferred compounds of formula II include those wherein n is 0, R
1
is H, R
3
is -(ethynyl)-R
8
, and R
6
is H or methyl. Particularly preferred compounds of formula II include those wherein R
8
is H.
Specific preferred compounds of formula I include the following
4-(3-ethynylanilino)-imidazo[4,5-g]quinazoline;
(3-ethynyl-phenyl)-(3-methyl-3H-imidazo[4,5-g]quinazolin-8-yl)-amine;
(3-ethynyl-phenyl)-(1-methyl-1H-imidazo[4,5-g]quinazolin-8-yl)-amine;
benzo[g]quinazolin-4-yl-(3-ethynyl-phenyl)-amine;
[1,3]dioxolo[4,5-g]quinazolin-8-yl-(3-ethynyl-phenyl)-amine; and,
pharmaceutically acceptable salts of the foregoing compounds.
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 a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a preferred embodiment, the pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, prostate, colorectal, oesophageal, gynecological or thyroid cancer.
In another preferred embodiment, the pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as psoriasis or benign hyperplasia of the skin or prostate.
The invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease in a mammal which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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 the compound of formula I or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the method relates to the treatment of cancer such as brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, gynecological or thyroid cancer.
In another preferred embodiment the method relates to the treatment of a non-cancerous hyperproliferative disorder such as psoriasis or benign hyperplasia of the skin or prostate.
The invention also relates to a method of treating pancreatitis or kidney disease in a mammal which comprises administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of blastocyte formation in a mammal which comprises administering to said mammal a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
The phrase “pharmaceutically acceptable salt
Schnur Rodney C.
Schnur Wendy W.
Ginsburg Paul H.
Liu Hong
Myers Jeffrey N.
Pfizer Inc.
Richardson Peter C.
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