Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-04-09
2004-01-27
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S158000, C544S238000, C544S333000, C544S405000, C514S253030, C514S256000, C514S314000
Reexamination Certificate
active
06683092
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to [3-(C
5-14
alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-phenyl and [3-(C
5-14
alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-heteroaryl derivatives having anti-tumor activity. The present invention also relates to pharmaceutical compositions used for treating tumor bearing mammals in need of such treatment with the compounds of the invention, and particularly for treating mammals, including humans, suffering from breast and/or prostate cancer with the compounds of the invention.
2. Brief Description of Background Art
U.S. Pat. Nos. 6,495,552; 6,291,677; 6,344,463; 6,048,873; 6,124,455; 6,147,224; 5,672,710; 5,677,323; 5,739,338; 5,556,996; 5,602,130; 5,616,712; 5,278,318; 5,399,561; 5,498,755; 4,810,804; 5,739,338, 5,780,647, 6,127,382 and 6,469,028 disclose compounds which include a tetrahydroquinoline or dihydroquinoline nucleus. The compounds of these patents are generally considered to act as retinoids which are generally known and accepted in the art to be useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. Generally speaking, among the conditions treatable with retinoids or like compounds are premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and Kaposi's sarcoma. Nevertheless, depending on the receptor sites through which they act and on other known and unknown factors, retinoid or like compounds can have different modes of action, particularly as anti-tumor activity is concerned.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319-349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324-356.
The present invention is directed to certain N—C
5-11
alkyl and like “long chain” substituted tetrahydroquinolin-2-one derivatives, which surprisingly have significantly better anti-tumor activity than their analogs where the N is substituted with a shorter chain alkyl (or like) groups.
SUMMARY OF THE INVENTION
The present invention relates to compounds of Formula 1
where X is O or S;
m is an integer having the values of 0 to 2;
n is an integer having the values of 0 to 3;
R
1
is independently H, or alkyl of 1 to 6 carbons;
R
2
is independently H, alkyl of 1 to 6 carbons, F, Cl, Br or I;
R
3
is alkyl of 5 to 11 carbons, alkenyl of 5 to 11 carbons and having one or two double bonds, alkynyl of 5 to 11 carbons and having one to two triple bonds, alkenyl-alkynyl having 5 to 11 carbons and one double and one triple bond, or
R
3
is (CH
2
)
r
-phenyl-(CH
2
)
s
—(CH
3
)
t
where r is an integer having the values of 0 to 7, s is an integer having the values of 0 to 6, and t is an integer having the values of 0 to 1, with the provisos that the sum of r, s and t is in the range of 1 to 7, the phenyl group is 1,3 (meta) or 1,4 (para) substituted with the (CH
2
)
r
and (CH
2
)
s
—(CH
3
)
t
groups, the phenyl group optionally being further substituted with one or two R
4
groups;
R
4
is independently H, alkyl of 1 to 6 carbons, F, Cl, Br or I, alkoxy of 1 to 3 carbons, thioalkoxy of 1 to 3 carbons; NO
2
, amino, alkylamino or dialkylamino where the alkyl group has 1 to 3 carbons;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R
4
groups;
A is (CH
2
)
q
where q is 0-5, branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
B is COOH, COOR
8
, CONR
9
R
10
, —CH
2
OH, CH
2
OR
11
, CH
2
OCOR
11
, CHO, CH(OR
1
2)
2
, CHOR
13
O, —COR
7
, CR
7
(OR
12
)
2
, CR
7
OR
13
O, or tri-C
1-6
alkylsilyl, where R
7
is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R
8
is an alkyl group of 1 to 10 carbons, OCH
2
O
C-1-3
alkyl or OCH
2
OCO
C-1-3
alkyl, or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R
8
is phenyl or C
1-6
alkylphenyl, R
9
and R
10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C
1-6
alkylphenyl, R
11
is C
1-6
alkyl, phenyl or C
1-6
alkylphenyl, R
12
is C
1-6
alkyl, and R
13
is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.
The present invention also relates to pharmaceutical compositions incorporating the compounds of Formula 1 and to methods of treatment of tumor bearing mammals with pharmaceutical compositions containing one or more compounds of Formula 1, and particularly to methods of treating breast cancer and prostrate cancer with compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY
Definitions
The term alkyl refers to and covers any and all groups which are known as normal alkyl and branched-chain alkyl.
A pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
The compounds of the present invention include at least one olephinic double bonds about which trans and cis (E and Z) stereoisomerism can exist. Unless specifically indicated by formula or chemical name the compounds of the present invention, including the preferred embodiments can have both the trans and cis (E and Z) orientations of substituents relative to the double bond or bonds. Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover the trans and cis (E and Z) isomers as specifically shown and/or named, as well as pure enantiomers (optical isomers), diastereomers, mixtures of diastereomers and racemic mixtures of enantiomers.
Reaction Scheme 1 discloses a presently preferred synthetic route to compounds of the invention. In accordance with Reaction Scheme 1 a 4-bromo-aniline derivative of Formula 2 is reacted with an acryloyl chloride derivative of Formula 3 in an aprotic neutral solvent in the presence of an acid acceptor, such as triethyl amine (TEA), to provide the phenyl amide derivative of Formula 4. The aniline derivative of Formula 2 is already substituted with the R
4
groups, (the variables R
4
and n are defined as in connection with Formula 1) although the 4-bromo aniline used for the preparation of the presently preferred compounds of the invention is unsubstituted (n=0). The substitituted anilines of Formula 2 are either available commercially, or can be prepared in accordance with the chemical scientific and patent literature, or by such modifications of known synt
Bhat Smita
Chandraratna Roshantha A.
Liu Xiaoxia
Sinha Santosh
Tsang Kwok Yin
Allergan Inc.
Aulakh Charanjit S.
Baran Robert J.
Szekeres Gabor L.
Voet Martin A.
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