Tricyclic polyhydroxylic tyrosine kinase inhibitors

Details Tricyclic polyhydroxylic tyrosine kinase inhibitors Tricyclic polyhydroxylic tyrosine kinase inhibitors

1993-11-23

2001-02-27

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S411000, C546S276700, C548S440000, C548S443000, C548S444000, C548S445000

Reexamination Certificate

active

06194439

ABSTRACT:

This invention relates to tricyclic polyhydroxylic compounds which are tyrosine kinase inhibitors useful for the control of cancer, atherosclerosis and angiogenic-based disorders.
BACKGROUND OF THE INVENTION
Tyrosine-specific protein kinases (tyrosine kinases) represent a family of enzymes which catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. The first members of this class to be identified were tyrosine kinases associated with viral genes (termed oncogenes) which were capable of cell transformation (i.e. pp60v-src and pp98v-fps). Later it was shown that there were normal cellular counterparts (i.e. pp60c-src and pp98c-fps) to these viral gene products. A third category of tyrosine kinases to be identified are those termed the growth factor receptors, which includes insulin, epidermal growth factor, and p185HER-2 receptors. All of these tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions.
Though the exact mechanisms of signal transduction have yet to be elucidated, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Therefore, inhibitors of these tyrosine kinases are useful for the prevention and chemotherapy of proliferative diseases dependent on these enzymes.
SUMMARY OF THE INVENTION
This invention is directed to tricyclic polyhydroxylic compounds that are useful as tyrosine kinase inhibitors. The compounds of this invention have the formula
and the pharmaceutically-acceptable cationic salts and prodrugs thereof
wherein
Q is
at least two and no more than four of R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are OH, the remainder being H;
R
9
is H or halo, with the proviso that R
9
is halo only when Q is
Z
1
is H, benzyl, alkyl(C
1
-C
4
), —(CH
2
)
n
—phenyl—R
22
, —(CH
2
)
n
—dichlorophenyl,
 —SO
2
—R
21
, —CH
2
—pyridyl or
 wherein n is 0-3;
R
20
is H, t-butyl, CF
3
, —SO
2
—alkyl(C
1
-C
4
), halo, alkyl(C
1
-C
4
), phenyl or NO
2
;
R
21
is phenyl, alkyl(C
1
-C
4
), benzyl, nitrophenyl, dichlorophenyl or halophenyl;
R
22
is —C≡N, CF
3
, phenylsulfonyl, halo or alkyl(C
1
-C
4
);
Z
2
is H, ═O, benzyl, hydroxylbenzyl, ═N—phenyl—R
10
═CH—phenyl—R
10
, —CH
2
—pyridyl, —CH
2
—quinolyl, —CH
2
—pyridyl, ═CH—quinolyl or
wherein
R
10
is —C≡N, H, CF
3
, OH, NO
2
, alkyl(C
1
-C
4
) or —SO
2
—alkyl(C
1
-C
4
) with the proviso that when Z
2
is bonded with a single bond to the carbon to which it is attached that that carbon is also bonded to a hydrogen;
X is N—Z
3
or O; and
Z
3
is H, alkyl(C
1
-C
4
), —CH
2
phenyl—R
11
or (dichlorophenyl)methyl wherein R
11
is H, —NO
2
,
 hydroxyl or halo.
A first group of preferred compounds of Formula I are compounds wherein R
2
, R
3
and R
4
are H or OH; R
6
and R
7
are OH; R
5
and R
8
are H; R
9
is H or halo;
Q is
Z
1
is H, benzyl, alkyl(C
1
-C
4
), —(CH
2
)
n
—phenyl—R
22
, —(CH
2
)
n
—dichlorophenyl,
 —CH
2
—pyridyl, and
 wherein n is 0-3;
R
20
is H, t-butyl, CF
3
, —SO
2
—alkyl(C
1
-C
4
), halo, alkyl(C
1
-C
4
), phenyl or NO
2
;
R
21
is phenyl, alkyl(C
1
-C
4
), benzyl, nitrophenyl, dichlorophenyl or halophenyl; and
R
22
is —C≡N, CF
3
, phenylsulfonyl, halo or alkyl(C
1
-C
4
).
A first group of especially preferred compounds within this first preferred group of Formula I compounds are compounds wherein R
2
, R
3
, R
6
and R
7
are OH; R
5
and R
8
are H; and R
9
is H or halo. A second group of especially preferred compounds within this first preferred group of Formula I compounds are compounds wherein R
3
, R
4
, R
6
, R
7
are OH; R
2
, R
5
, R
8
and R
9
are H; and Z
1
is H,
 benzyl, —alkyl(C
1
-C
4
), —SO
2
—phenyl, —SO
2
—alkyl(C
1
-C
4
) and —CH
2
—3-pyridyl. A third group of especially preferred compounds within this first preferred group of Formula I compounds are compounds wherein R
2
, R
3
, R
4
, R
5
, R
8
and R
9
are H; R
6
and R
7
are OH; and
Z
1
is H or
A second group of preferred compounds of Formula I are compounds wherein
Q is
Z
2
is H, ═O, benzyl, hydroxybenzyl, ═N—phenyl—R
10
, ═CH—phenyl—R
10
, —CH
2
—pyridyl, —CH
2
—quinolyl, ═CH
2
—pyridyl, —CH—quinolyl or
 and
R
10
is —C≡N, H, CF
3
, OH, NO
2
, alkyl(C
1
-C
4
) and —SO
2
—alkyl(C
1
-C
4
).
A first group of especially preferred compounds within this second preferred group of Formula I compounds are compounds wherein R
3
, R
4
, R
6
and R
7
are OH and R
2
, R
5
, R
8
are H.
A second group of especially preferred compounds within this second group of preferred Formula I compounds are compounds wherein R
3
, R
4
, R
7
and R
8
are OH and R
2
, R
5
and R
6
are H.
A third group of especially preferred compounds within this second preferred group of Formula I compounds are compounds wherein Z
2
is H or ═O; R
6
and R
7
are OH; and R
2
, R
3
, R
4
, R
5
and R
8
are H.
A fourth group of especially preferred compounds within this second preferred group of Formula I compounds are compounds wherein Z
2
is ═O, benzyl, H, —CH
2
—4-pyridyl, —CH
2
—4-quinolyl, ═CH—4-pyridyl, ═CH—4-quinolyl or ═CH—phenyl; R
7
and R
8
are OH; and R
2
, R
3
, R
4
, R
5
and R
6
are H.
A third group of preferred compounds are compounds of formula I wherein Q is
Z
3
is H, alkyl(C
1
-C
4
), —CH
2
—phenyl—R
11
or (dichlorophenyl)methyl; and
R
11
is H, —NO
2
,
 hydroxyl or halo. A first group of especially preferred compounds within this third preferred group are compounds wherein X is —O—; and R
5
is H. A second group of especially preferred compounds within this third preferred group are compounds wherein X is N—Z
3
; R
3
, R
4
, R
6
and R
7
are OH; and R
2
, R
5
and R
8
are H. A third group of especially preferred compounds within this third preferred group are compounds wherein X is N—Z
3
; R
3
, R
4
, R
7
and R
8
are OH; and R
2
, R
5
and R
6
are H. A fourth group of especially preferred compounds within this third preferred group are compounds wherein X is N—Z
3
; Z
3
and R
5
are H; and any two R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are OH.
The present invention is also directed to pharmaceutical compositions for the control of tyrosine kinase dependent diseases in mammals which comprise a compound of the formula I in a pharmaceutically-acceptable carrier; and to a method of controlling tyrosine kinase dependent diseases which comprises administering to a mammal suffering from tyrosine kinase dependent diseases a tyrosine kinase dependent disease controlling amount of a compound of the formula I or ellagic acid.
The expression “pharmaceutically-acceptable cationic salt” refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methylglucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
The expression “prodrug” refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. Exemplary prodrugs are alkyl ethers and acyl esters of the phenolic compounds such as methylether, esters of alkanoic (C
1
-C
10
)acids, and acids of the formula
wherein n is 1 to 6 and X is an amino or carboxyl (acid, ester) group, and the formula
Other features and advantages will be apparent from the specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
Ellagic acid is a natural product and is available from Aldrich Co. Its preparation is disclosed in Annual Drug Data Report 1986, 978 and Drugs of the Future 1986, 11, 1029.
According to Reaction Scheme I the desired Formula I compounds wherein Q and R
2
-R
9
are as defined above may be prepared by deprotecting the appropriate formula III, XII and VIII compounds wherein
and R
9
are as defined above and

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