Anti-quinazoline compounds

Details Anti-quinazoline compounds Anti-quinazoline compounds

2001-10-19

2004-03-02

Berch, Mark L (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252170, C514S267000, C514S266200, C514S266210, C514S266220, C514S266230, C544S116000, C544S119000, C544S249000, C544S284000

Reexamination Certificate

active

06699861

ABSTRACT:

This invention relates to dihydroquinazoline derivatives, or pharmaceutically acceptable salts thereof, which possess anti-cancer activity. The invention includes dihydroquinazoline derivatives, processes for their manufacture, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment or prevention of cancer in a warm-blooded animal such as man.
It is known that inhibitors of enzymes which use folic acid derivatives often possess anti-cancer activity. Examples of such compounds include antimetabolites such as aminopterin and methotrexate. A newer compound of this type which showed considerable promise in clinical trials is known as CB3717 and is described in UK-B-2065653. Despite its promising activity against human breast, ovarian and liver cancer, however, CB3717 shows symptoms of toxicity in humans, particularly in relation to the liver and kidney (Cancer Treatment Reports, 1986, 70, 1335). A newer compound which possesses inhibitory activity against thymidylate synthase and which is showing promise in clinical trials is known as raltitrexed or ZD1694 (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid) and is described in EP-A-239362. The compound has been shown to possess promising activity against human breast, ovarian, colorectal and non-small cell lung cancer and against adenocarcinoma (8
th
NCI-EORTC Symposium, Amsterdam, March, 1994; Abstract Nos. 240 and 242 to 245).
Compounds of the ZD1694 and CB3717-type are believed to act as anti-tumour agents by inhibiting the enzyme thymidylate synthase, which catalyses the methylation of deoxyuridine monophosphate to produce thymidine monophosphate which is required for DNA synthesis. The anti-cancer activity of ZD1694 and CB3717 may be assessed in vitro by determining its inhibitory effect on that enzyme, and in cell cultures by its inhibitory effect on cancer cell lines such as the mouse leukaemia cell line L1210, the mouse lymphoma cell line L5178Y TK−/− and the human breast cancer cell line MCF-7.
Other compounds of the ZD1694 and CB3717-type have been described and claimed in EP-A-239362, EP-A-284338, EP-A-339976, EP-A-373891, EP-A-459730, EP-A-509643 and EP-A-562734, and in WO 93/19051, WO 94/07869 and WO 94/11354. These compounds may have their anti-cancer activity assessed by their activity against, for example, thymidylate synthase and the L1210, L5178Y TK−/− and MCF-7 cell lines.
Although inhibitors of thymidylate synthase are useful in many conditions, there is a need for anti-cancer compounds which operate by a different mechanism. Such compounds are required for treating patients with cancers refractory to standard chemotherapeutic agents. Further, it is highly desirable that anti-cancer compounds are water soluble, as increased water solubility generally enables a higher bioavailability.
4-[N-[7-bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (CB 30865) is a known anti-cancer compound which acts via a non-folate dependent locus (Skelton et al, Cytometry 33 56-66 (1998)). However, the compound has very low water-solubility and is not suitable for in vivo administration. The compound is also still a good inhibitor of isolated thymidylate synthase and in some cell lines (resistant to the primary effects of the compound) this becomes a growth rate limiting target for CB 30865 at compound concentrations in the micromolecular range.
The present invention therefore seeks to provide new anti-cancer compounds which do not operate via inhibition of thymidylate synthase and which have an acceptable bioavailability.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein:
either R
1
and R
1
′ together form an oxo group and R
2
is hydrogen, C
1
-C
4
alkyl, —(C
1
-C
4
alkyl)—B, —(C
1
-C
4
alkyl)—COB, —(C
1
-C
4
alkyl)—CO—(C
1
-C
4
alkyl)—B, —(C
1
-C
4
alkyl)—CO
2
—(C
1
-C
4
alkyl)—B, —(C
1
-C
4
alkyl)—CO
2
—(C
2
-C
4
alkenyl)—B or —(C
1
-C
4
alkyl)—CONH—(C
1
-C
4
alkyl)—B wherein B is —CO
2
H, hydroxy, C
1
-C
4
alkoxy, amino, (C
1
-C
4
alkyl)amino, di(C
1
-C
4
alkyl)amino or a 5- or 6-membered heterocyclic group, or R
1
′ and R
2
together form a bond and R
1
is —S—(C
1
-C
4
alkyl), —NHR′ or —NHCOR′ wherein R′ is aryl or C
1
-C
4
alkyl;
R
3
is —(CH
2
)
p
—A wherein p is from 1 to 4 and A is a 5- or 6-membered N-containing heterocyclic ring attached via the N atom or A is —NA′A″ wherein A′ and A″ are the same or different and are each a C
1
-C
4
alkyl group;
either R
4
is hydrogen, oxo or C
1
-C
4
alkyl and R
5
is hydrogen, C
1
-C
4
alkyl or halogen, or R
4
and R
5
, together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic ring;
X
1
is —O—, —S— or —NR″— wherein R″ is hydrogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl or C
2
-C
4
alkynyl;
Y is a divalent aryl or heteroaryl group;
R
6
is hydrogen, oxo or C
1
-C
4
alkyl;
X
2
is —O—, —S— or —NR″— wherein R″ is as defined above;
m is from 1 to 4; and
R
7
is pyridyl, pyrimidyl, imidazolyl, triazolyl, —(C
1
-C
4
alkyl)-imidazolyl, or —(C
1
-C
4
alkyl)-triazolyl.
As used herein, a C
1
-C
4
alkyl group or moiety can be linear or branched but is preferably linear. Suitable such alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Methyl and ethyl are preferred and methyl is particularly preferred. A C
1
-C
4
alkyl group or moiety can be substituted or unsubstituted at any position. Typically, it carries up to 3 substituents, e.g. one or two substituents. Suitable substituents include hydroxy, halogen, amino, (C
1
-C
4
alkyl)amino and di-(C
1
-C
4
alkyl)amino. Preferred substituents are dimethylamino, diethylamino and halogen.
In groups which contain more than one C
1
-C
4
alkyl moiety, the alkyl moieties may be the same or different. Thus, the C
1
-C
4
alkyl moieties present in a di-(C
1
-C
4
alkyl)amino group may be the same or different.
A C
2
-C
4
alkenyl group is typically an allyl group.
An aryl group or moiety is typically a C
6
-C
10
aryl group or moiety. Suitable such aryl groups and moieties include phenyl and naphthyl. Phenyl is preferred. An aryl group or moiety may be substituted or unsubstituted at any position. Preferably, it is unsubstituted. However, it can carry, for example, 1, 2, 3 or 4 substituents. Suitable substituents include halogen, hydroxyl, said C
1
-C
4
alkyl such as methyl or ethyl, C
1
-C
4
alkoxy such as methoxy or ethoxy, amino, (C
1
-C
4
alkyl)amino and di-(C
1
-C
4
alkyl)amino. A divalent aryl moiety is preferably a 1,4-phenylene group.
p is typically 1 or 2.
A halogen is typically chlorine, fluorine, bromine or iodine. Chlorine and bromine are preferred.
A said 5- or 6-membered carbocyclic ring may be a substituted or unsubstituted, aromatic or non-aromatic 5- or 6-membered ring made up of carbon atoms. Preferably, it is a 5-membered ring. Preferably, it is saturated except for the double bond it shares with the dihydroquinazoline moiety. Preferably, it is unsubstituted. However, it may carry, for example, 1 or 2 substituents. Suitable substituents include halogen, hydroxyl, said C
1
-C
4
alkyl such as methyl or ethyl, C
1
-C
4
alkoxy such as methoxy or ethoxy, amino, (C
1
-C
4
alkyl)amino, di-(C
1
-C
4
alkyl)amino and —(C
1
-C
4
alkyl)—OH.
A C
2
-C
4
alkenyl group or moiety can be linear or branched but is preferably linear. Suitable such alkenyl groups and moieties include ethenyl, n-propenyl, i-propenyl and n-butenyl. Ethenyl and prop-2-enyl are preferred and prop-2-enyl is particularly preferred. A C
2
-C
4
alkenyl group or moiety can be substituted or unsubstituted at any position. Typically, it carries up to three substituents, e.g. one or two substituents. Suitable substituents include hydroxy, halogen, amino, (C
1
-C
4
alkyl)amino and di-(C
1
-C
4
alkyl)ami

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