Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-12
2004-07-13
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S257000
Reexamination Certificate
active
06762188
ABSTRACT:
The present invention relates to novel benzoquinazoline thymidylate synthase inhibitors, to processes for preparing them and pharmaceutical formulations containing them. U.S. Pat. No. 4,814,335 discloses inter alia that compounds of the formula (0):
wherein R is hydrogen, fluoro, nitro, optionally substituted amino, carboxy, azido, alkoxy, trimethylsulphonyl, trifluoromethylsulphonyl or alkoxycarbonyl have biological response-modifying activity, i.e. antiviral, antibacterial and anticancer activity. However, no specific examples of compounds of the formula (0) are provided.
Thymidylate synthase is an enzyme catalysing the terminal step in the de novo synthesis of thymidylate required for DNA synthesis. It has been postulated that inhibitors of this enzyme may be expected to have anti-tumour activity and it has been reported (Jones et al, J. Med. Chem. 1986, 29, 468) that the in-vivo antitumour activity of N
10
-propargyl-5,8-dideazafolic acid arises solely from its inhibitory effect on this enzyme.
It has now been found that a group of benzoquinazoline compounds are inhibitors of the enzyme thymidylate synthase and have antitumour activity.
Accordingly, the present invention provides compounds of the formula (I)
or a salt thereof, wherein the dotted line represents a single or double bond,
R
1
is C
1-4
alkyl or amino optionally substituted by a C
1-4
alkyl, C
1-5
alkanoyl or benzyl group;
R
2
, R
3
, R
4
and R
5
are the same or different and each is selected from hydrogen, phenyl, halo, nitro,
a group S(O)
n
R
8
wherein n is the integer 0, 1 or 2 and R
8
is halo or is C
1-4
alkyl or a group NR
9
R
10
wherein R
9
and R
10
are both hydrogen,
a group NR
11
R
12
wherein R
11
and R
12
are the same or different and each is hydrogen or C
1-4
alkyl,
a group OR
13
wherein R
13
is hydrogen or C
1-4
alkyl optionally substituted by halo;
a C
1-4
aliphatic group optionally substituted by a group OR
14
or NR
14
R
15
wherein R
14
and R
15
are the same or different and each is hydrogen or C
1-4
alkyl;
or two of R
2
to R
5
are linked together to form a benzo group,
or one of R
2
to R
5
is a group —X—Y—R
16
wherein X is CH
2
, NR
17
, CO or S(O)
m
and m is 0, 1 or 2 and R
17
is hydrogen or a C
1-4
aliphatic group and Y is CH
2
, NR
17′
, O, or S(O)
m
, wherein m′ is 0, 1 or 2 and R
17′
is hydrogen or a C
1-4
aliphatic group provided that X and Y are only the same when each is CH
2
, or —X—Y— is a group —O—, —NR
17
—, —CH═CH— or —N═N— wherein R
17
is as hereinbefore defined, R
16
is a C
1-4
aliphatic group or a 5- or 6-membered aromatic ring optionally substituted by a group R
18
at a position at least one carbon atom removed from that linked to Y, the 5- or 6-membered ring being optionally further substituted by a halo atom; and R
18
is halo, C
1-4
alkoxy, nitro, nitrile, C
1-4
alkyl optionally substituted by halo, halo or a group COR
19
wherein R
19
is hydroxy, C
1-4
alkoxy or C
1-6
alkyl optionally substituted by one or two carboxyl groups or C
1-12
esters thereof or R
19
is a group NR
20
R
21
wherein R
20
and R
21
are the same or different and each is hydrogen or C
1-4
alkyl optionally substituted by hydroxy or R
19
is an amino acid group or an ester thereof in which the first nitrogen atom of the amino acid group may be linked to the 5- or 6-membered aromatic ring to form a further 5- or 6-membered heterocyclic ring or R
19
is an C
2-3
alkylene group linked to the 5- or 6-membered aromatic ring to form a further 5- or 6-membered ring;
R
6
and R
7
are the same or different and each is C
1-4
alkyl optionally substituted by hydroxy or C
1-4
alkoxy or together form a benzo group;
provided that at least one of R
2
to R
7
is other than hydrogen and that R
4
is not methoxy when R
1
is hydroxy or methyl.
By the term halo is meant fluoro, bromo, chloro and iodo.
By the term C
1-4
aliphatic group is meant a C
1-4
alkyl, alkenyl, or alkynyl group.
By the term amino acid group is meant naturally occurring amino acids.
Preferred amino acid groups include glycine, glutamic acid and polyglutamic and groups.
When the amino acid group is linked to the 5- or 6-membered aromatic ring, this is via a carbon atom of the aromatic ring adjacent to carbon to which COR
19
is attached.
Preferably the dotted line is a double bond.
Suitable substituents for the aromatic ring R
16
include halo, C
1-4
alkyl and C
1-4
alkoxy each optionally substituted by one to five halo atoms. Most suitably there are one or two substituents selected from fluoro, chloro, methyl, trifluoromethyl and methoxy, and preferably fluoro, or no substituents on the aromatic ring. In one preferred embodiment, —X—Y—R
16
is a group
wherein R
18
is as hereinbefore defined and preferably a group COR
19
as hereinbefore defined and R
22
is hydrogen or fluoro.
In a further preferred embodiment X—Y—R
16
is a group
wherein H
2
NR
19a
is a glutamic or polyglutamic acid group and Z is CH
2
, S or O.
Suitably, R
1
is an amino group optionally substituted by one or two methyl or ethyl groups or R
1
is a methyl or ethyl group. Preferably R
1
is an amino or methyl group.
Suitably, at most only three, and preferably at most only two, of R
2
to R
5
are other than hydrogen and each is independently selected from hydrogen, halo, hydroxy, nitro, C
1-3
alkyl optionally substituted by hydroxy or C
1-2
alkoxy, C
1-3
alkoxy, amino optionally substituted by one or two methyl or ethyl groups, or a group S(O)nR
23
wherein n is 0, 1 or 2 and R
23
is a C
1-4
alkyl group or an amino group optionally substituted by one or two methyl or ethyl groups, or one of R
2
to R
5
is a group —X—Y—R
24
where R
24
is a group
wherein R
18
, R
19a
, R
22
and Z are as hereinbefore defined. In one preferred embodiment R
18
is nitro or a group
wherein R
25
, R
26
and R
27
are the same or different and each is hydrogen or a C
1-4
alkyl group and t is an integer from 0 to 6. Preferably R
25
, R
26
and R
27
are hydrogen and t is 0. Preferably Z is CH
2
or S.
Preferably one of R
2
to R
5
is a group —X—Y—R
24
as hereinbefore defined. Preferably R
3
is a group —X—Y—R
24
.
Suitably R
6
and R
7
are the same or different and each is hydrogen, methyl, ethyl or methyl substituted by bromo, hydroxy or methoxy. Preferably R
7
is hydrogen and R
6
is methyl.
Preferably —X—Y— is a group —SO
2
NR
17
— or CH
2
NR
17
wherein R
17
is as hereinbefore defined.
Suitably R
17
is hydrogen or a C
1-4
alkyl or alkenyl group and preferably R
17
is hydrogen or methyl.
One group of compounds of the present invention is that of the formula (Ia)
or a salt thereof, wherein the dotted line represents a single or double bond, R
1a
is C
1-4
alkyl or amino optionally substituted by a C
1-4
alkyl, C
1-5
alkanoyl or benzyl group; R
2a
, R
3a
, R
4a
and R
5a
are the same or different and each is selected from hydrogen, halo, nitro, a group S(O)
n
R
8a
wherein n is the integer 0, 1 or 2 and R
8a
is halo or is a C
1-4
alkyl or amino group; a group NR
11a
R
12a
wherein R
1a
and R
12a
are the same or different and each is hydrogen or C
1-4
alkyl, a group OR
13a
wherein R
13a
is hydrogen or C
1-4
alkyl optionally substituted by halo, a C
1-4
aliphatic group optionally substituted by a group OR
14a
or NR
14a
R
15a
wherein R
14a
and R
15a
are the same or different and each is hydrogen or C
1-4
alkyl, or one of R
2a
to R
5a
is a group —X—Y—R wherein X is CH
2
, NR
17a
, CO or S(O)
m
and m is 0, 1 or 2 and R
17a
is hydrogen or a C
1-4
aliphatic group and Y is CH
2
, NR
17′a
, O, or S(O)
m′
wherein m′ is 0, 1 or 2 and R
17′a
is hydrogen or a C
1-4
aliphatic group provided that X and Y are only the same when each is CH
2
, or —X—Y— is a group —NR
17a
, —CH═CH— or —N═N— wherein R
17a
is as hereinbefore defined, R
16a
is a C
1-4
aliphatic group or an optionally substituted 5- or 6-membered aromatic ring substituted by a group R
18a
at a position at least one carbon atom removed from that linked to Y and R
18a
is nitro, nitrile, C
1-4
a
Dickerson Scott Howard
Ferone Robert
Johnson Julius Vass
Pendergast William
Ford John M.
Lemanowicz John L.
SmithKline Beecham Corporation
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