Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-03
2003-11-18
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...
C544S253000
Reexamination Certificate
active
06649619
ABSTRACT:
The present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.
WO 95/00649 (SmithKline Beecham plc) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A
2
(Lp-PLA
2
), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it is referred to as LDL-PLA
2
. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, Apr. 6, 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA
2
and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.
It has been shown that Lp-PLA
2
is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA
2
action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA
2
enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
A recently published study (WOSCOPS—Packard et al,
N. Engl. J. Med
. 343 (2000) 1148-1155) has shown that the level of the enzyme Lp-PLA
2
is an independent risk factor in coronary artery disease.
The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA
2
could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA
2
inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
In addition, Lp-PLA
2
inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA
2
. Examples of such disorders include psoriasis.
Furthermore, Lp-PLA
2
inhibitors may also have a general application in any disorder that involves lipid oxidation in conjunction with Lp-PLA
2
activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation.
Patent applications WO 96/12963, WO 96/13484, WO 96/19451, WO 97/02242, WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKline Beecham plc) disclose inter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA
2
. These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).
A further class of compounds has now been identified which are non-acylating inhibitors of the enzyme Lp-PLA
2
. Thus, WO 99/24420 (SmithKline Beecham plc) discloses a class of pyrimidone compounds. International patent applications WO 00/10980, WO 00/66566, WO 00/66567 and WO 00/68208 (SmithKline Beecham plc, published after the priority date of the present application) disclose other classes of pyrimidone compounds. We have now found a further class of pyrimidone compounds which are distinguished by the substitution pattern at the 5 and 6 position of the pyrimidone ring and which have good activity as inhibitors of the enzyme Lp-PLA
2
.
Accordingly, the present invention provides a compound of formula (I):
in which:
R
a
is hydrogen, halogen, C
(1-3
)alkyl C
(1-3)
alkoxy, hydroxyC
(1-3)
alkyl, C
(1-3)
alkylthio, C
(1-3)
alkylsulphinyl, aminoC
(1-3)
alkyl, mono- or di-C
(1-3)
alkylaminoC
(1-3)
alkyl, C
(1-3)
alkylcarbonylaminoC
(1-3)
alkyl, C
(1-3)
alkoxyC
(1-3)
alkylcarbonylaminoC
(1-3)
alkyl, C
(1-3)
alkylsulphonylaminoC
(1-3)
alkyl, C
(1-3)
alkylcarboxy, or C
(1-3)
alkylcarboxyC
(1-3)
alkyl;
R
b
is hydrogen, halogen, C
(1-3)
alkyl, or hydroxy
(1-3)
alkyl, with the proviso that R
a
and R
b
are not simultaneously each hydrogen; or
R
a
and R
b
together are (CH
2
)
n
where n is 3 or 4, to form, with the pyrimidine ring carbon atoms to which they are attached a fused 5-or 6-membered carbocyclic ring; or
R
a
and R
b
together with the pyrimidine ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, C
(1-4)
alkyl, cyano, C
(1-4)
alkoxy or C
(1-4)
alkylthio, or mono to perfluoro-C
(1-4)
alkyl);
R
c
is hydrogen or C
(1-3)
alkyl;
R
2
is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C
(1-18)
alkyl (preferably C
(1-6)
alkyl), C
(1-18)
alkoxy (preferably C
(1-6)
alkoxy), C
(1-18)
alkylthio (preferably C
(1-6)
alkylthio), arylC
(1-18)
alkoxy (preferably arylC
(1-6)
alkoxy), hydroxy, halogen, CN, COR
6
, carboxy, COOR
6
, NR
6
COR
7
, CONR
8
R
9
, SO
2
NR
8
R
9
, NR
6
SO
2
R
7
, NR
8
R
9
, mono to perfluoro-C
(1-4)
alkyl, mono to perfluoro-C
(1-4)
alkoxyaryl, and arylC
(1-4)
alkyl;
R
3
is hydrogen, C
(1-6)
alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR
6
, COR
6
, carboxy, COOR
6
, CONR
8
R
9
, NR
8
R
9
, NR
8
COR
9
, mono- or di-(hydroxyC
(1-6)
alkyl)amino and N-hydroxyC
(1-6)
alkyl-N—C
(1-6)
alkylamino, for instance, 1-piperidinoethyl; or
R
3
is Het-C
(0-4)
alkyl in which Het is a 5- to 7- membered heterocyclyl ring comprising N and optionally O or S, bonded through a carbon ring atom and in which N may be substituted by COR
6
, COOR
6
, CONR
8
R
9
, or C
(1-6)
alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR
6
, COR
6
, carboxy, COOR
6
, CONR
8
R
9
or NR
8
R
9
, for instance, piperidin-4-yl, pyrrolidin-3-yl;
R
4
is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C
(1-18)
alkyl (preferably C
(1-6)
alkyl), C
(1-18)
alkoxy (preferably C
(1-6)
alkoxy), C
(1-18)
alkylthio (preferably C
(1-6)
alkylthio), arylC
(1-18)
alkoxy (preferably arylC
(1-6)
alkoxy), hydroxy, halogen, CN, COR
6
, carboxy, COOR
6
, NR
6
COR
7
, CONR
8
R
9
, SO
2
NR
8
R
9
, NR
6
SO
2
R
7
, NR
8
R
9
, mono to perfluoro-C
(1-4)
alkyl a perfluoro-C
(1-4)
alkoxy;
R
5
is an aryl or heteroaryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C
(1-18)
alkyl (preferably C
(1-6)
alkyl), C
(1-18)
alkoxy (preferably C
(1-6)
alkoxy), C
(1-18)
alkylthio (preferably C
(1-6)
alkylthio), arylC
(1-18)
alkoxy (preferably arylC
(1-6)
alkoxy), hydroxy, halogen, CN, COR
6
, carboxy, OOR
6
, CONR
8
R
9
, NR
6
COR
7
, SO
2
NR
8
R
9
, NR
6
SO
2
R
7
, NR
8
R
9
, mono to perfluoro-C
(1-4)
alkyl and mono to perfluoro-C
(1-4)
alkoxy;
R
6
and R
7
are i
Hickey Deirdre Mary Bernadette
Ife Robert John
Leach Colin Andrew
Pinto Ivan Leo
Smith Stephen Allan
Ford John M.
Kanagy James M
Kinzig Charles M.
SmithKline Beecham p.l.c.
Venetianer Stephen
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