Polycyclic compounds

Details Polycyclic compounds Polycyclic compounds

2002-09-25

2004-01-20

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S070000, C546S065000, C546S058000, C544S233000, C544S246000, C544S343000, C514S280000, C514S257000, C514S250000, C514S248000

Reexamination Certificate

active

06680326

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel polycyclic compounds having anti-tumor activity, pharmaceutical composition containing these compounds, the use of these compounds in the medical therapy as well as a process for the preparation of these compounds.
BACKGROUND OF THE INVENTION
Indeno[2,1-c]quinolin-7-one derivatives having a substituted aminoalkylamino radical as a side chain are known to have anti-tumor activity. For example, 6-(2-dimethylamino-ethylamino)-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one and its derivatives have been disclosed to have anti-tumor activity. See, EP 0713870 (1996). However, anti-tumor activity in this reference may not be sufficient for the treatment of tumor and thus, more potent anti-tumor compounds are desirable.
It is therefore advantageous in the art to provide more potent anti-tumor compounds for treatment of tumor.
SUMMARY OF THE INVENTION
The present invention is directed to novel polycyclic compounds of the formula [I],
wherein;
ring A is a nitrogen-containing 5 or 6 membered heteroaromatic ring which may be substituted by R
1
and R
2
;
R
1
and R
2
are independently hydrogen, halogen, (C1-C5) alkyl, hydroxy, mercapto, (C1-C5) alkoxy, (C4-C7) cycloalkyloxy, (C3-C7)cycloalkyl(C1-C5)alkyloxy, (C1-C5) alkylthio, (C1-C5) alkylsulfinyl, (C1-C5) alkylsulfonyl, amino, mono-(C1-C5)-alkylamino, di-(C1-C5)-alkylamino or —Y′—Z′—N(R
6
′)(R
7
′);
wherein
Y′ is O, S or N(R
9
′), wherein R
9
′ is hydrogen or (C1C5) alkyl; or when Y′ is N(R
9
′), N(R
9
′) forms an aliphatic ring together with N(R
6
′) and Z′;
Z′ is (C2-C5) alkylene; or Z′ forms an aliphatic ring together with N(R
6
′) and (NR
9
′); or Z′ forms an aliphatic ring together with N(R
6
′);
R
6
′ and R
7
′ are independently hydrogen, (C1-C5) alkyl, (C3-C5) alkenyl, (C4-C7) cycloalkyl, (C3-C7)cycloalkyl(C1-C5)alkyloxy or aryl(C1-C5)alkyl optionally substituted with one to three substituents selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino radical(s); or R
6
′ and R
7
′ form an aliphatic ring optionally containing one to three heteroatom(s) selected from oxygen, nitrogen and sulfur together with the adjacent nitrogen; or R
6
′ forms an aliphatic ring together with the adjacent nitrogen and Z′; or R
6
′ forms an aliphatic ring together with the adjacent nitrogen, N(R
9
′) and Z′;
ring B is a benzene ring, naphthalene ring or benzene ring substituted with (C1-C5) alkylenedioxy group which is optionally substituted by R
3
, R
4
and R
5
;
R
3
, R
4
and R
5
are independently hydrogen, halogen, hydroxy, mercapto, (C1-C5) alkyl, (C1-C5) halogeno-alkyl, (C1-C5) alkoxy, (C1-C5) halogeno-alkoxy, (C3-C5) alkenyloxy, (C4-C7) cycloalkyloxy, (C3-C7)cycloalkyl(C1-C5)alkyloxy, aryl(C1-C5)alkyloxy, (C1-C5) alkylthio, (C1-C5) alkylsulfinyl, (C1-C5) alkylsulfonyl, amino, mono-(C1-C5)-alkylamino or di-(C1-C5)-alkylamino;
X is O or N—O—R
8
wherein R
8
is a hydrogen, (C1-C5) alkyl, (C3-C5) alkenyl, (C4-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C5)alkyloxy, aryl, or aryl(C1-C5)alkyl;
Y is O, S or N(R
9
) wherein R
9
is hydrogen or (C1-C5) alkyl; or when Y is N(R
9
), N(R
9
) forms an aliphatic ring together with N(R
6
) and Z;
Z is (C2-C5) alkylene optionally substituted with (C1-C5) alkyl radical(s); or Z forms an aliphatic ring together with N(R
6
) and N(R
9
); or Z forms an aliphatic ring together with N(R
6
);
and
R
6
and R
7
are independently hydrogen, (C1-C5) alkyl, (C3-C5) alkenyl, (C4-C7) cycloalkyl, (C3-C7)cycloalkyl(C1-C5)alkyloxy or aryl(C1-C5)alkyl optionally substituted with hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5)-alkylamino or di-(C1-C5)-alkylamino radical(s); or R
6
and R
7
form an aliphatic ring optionally containing one to three heteroatom(s) selected from oxygen, nitrogen and sulfur together with the adjacent nitrogen; or R
6
forms an aliphatic ring together with the adjacent nitrogen and Z; or R
6
forms an aliphatic ring together with the adjacent nitrogen, N(R
9
) and Z,
as well as pharmaceutically acceptable salts thereof.
This invention is also directed to a pharmaceutical composition containing the above-described compounds, and a method for treating a cell proliferative disorder, especially in treatment of tumor, comprising administering to a patient in need thereof a therapeutically effective amount of the above-described compounds.
This invention is also directed to providing a process for the preparation of those compounds.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention herein.
In this specification, the term “nitrogen-containing 5 or 6 membered heteroaromatic ring” is used to mean a radical of a 5 to 6 membered aromatic ring which contains at least one nitrogen atom and may further contain one or more heteroatom(s) selected from N, S and O. Preferably, “nitrogen-containing 5 or 6 membered heteroaromatic ring” means pyridine, pyrazine, pyridazine, pyrimidine, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrrole, triazole and the like, and more preferably, pyridine.
The term “alkyl” as used herein, alone or in combination, means a straight-chain or branched-chain hydrocarbon group containing a maximum of 12, preferably a maximum of 5, carbon atoms, e.g., methyl, ethyl, n-propyl, 2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl), n-butyl, and 1,1-dimethylethyl (t-butyl), and more preferably a maximum of 4 carbon atoms. The alkyl group may be unsubstituted or may be substituted with one or more substituents, preferably with one to three substituents, and most preferably with one substituent. The substituents are selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, acetoxy, alkylcarbonyloxy, alkoxycarbonyl, carbamoyl and halogen.
The term “alkenyl” as used therein, alone or in combination, refers to a hydrocarbon chain as defined for alkyl having at least one olefinic double bond (including for example, allyl and butenyl) and having the general formula C
m
H
2m−1
wherein m is an integer greater than 2, preferably m is an integer of 3 to 7, and more preferably 3 to 5.
The term “alkylene” refers to a biradical branched or unbranched hydrocarbon chain containing 1 to 5 carbon atoms, such as methylene (—CH
2
—), ethylene, propylene, trimethylene and tetramethylene. The alkylene group may be unsubstituted or may be substituted with one or more substituents, preferably with one to three substituents, and most preferably with one substituent. The substituents are selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, acetoxy, alkylcarbonyloxy, alkoxycarbonyl, carbamoyl and halogen.
The term “aryl” refers to an aromatic carbocyclic radical, i.e., a 6 or 10 membered aromatic or partially aromatic ring, e.g., phenyl (“Ph”), naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, and most preferably phenyl. The aryl moiety is optionally substituted with one or more subsituents, preferably with one to three, most preferably one, selected from the group consisting of halogen, preferably fluorine, chlorine, alkoxycarbonyl (e.g., methoxycarbonyl), alkylcarbonyloxy (e.g., acetoxy), cyano, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkylcarbonylamino, heterocyclyl, sulfamoyl (i.e., H
2
NSO
2
—), amino, 1,3-dioxolyl and 1,4-dioxolyl. Especially preferred substituents are alkyl, alkoxy, hydroxy, halogen, amino, alkylamino, dialkylamino, alkylthio, sulfamoyl, benzyl or heterocyclyl.
The term “aryl(C1-C5)alkyl” refers to an alkyl group as defined above substituted with an aryl as defined above. The aryl group of the aryl(C1-C5)alkyl maybe substituted with one or more substituents, preferably one to three, most preferably with

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