Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-21
2003-05-06
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...
C540S601000, C540S544000, C540S553000, C540S575000, C544S003000, C544S054000, C544S058600, C544S063000, C544S096000, C544S120000, C544S123000, C544S296000, C514S211150, C514S211080, C514S217060, C514S227800, C514S226800, C514S235800, C514S255050
Reexamination Certificate
active
06559155
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, Arterioscier 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.
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 peroxidation 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. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242, WO97/217675, WO97/217676, WO 96/41098, and WO97/41099 (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).
WO 99/24420 (SmithKline Beecham) describes a new class of compounds which are inhibitors of Lp-PLA
2
, namely a group of pyrimidone compounds. We have now identified a particular subset of pyrimidone compounds which have a 5-(2-oxopyrimid-5-ylmethyl) substituent and which are potent inhibitors of Lp-PLA
2
Accordingly, the present invention provides a compound of the formula (I):
in which:
R
1
is COOH or a salt thereof, COOR
10
, CONR
11
R
12
, CN or CH
2
OH;
R
2
is a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, or a mono- or bicyclic heteroaromatic ring system including up to 4 heteroatoms selected from N, O and S; optionally substituted by 1, 2, 3 or 4 substituents selected from C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylthio, aryl, aralkyl, hydroxy, oxo, halogen, CN, COOH or a salt thereof, COO—C
1-6
alkyl, CONR
15
R
16
, NR
15
COR
16
, SO
2
NR
15
R
16
, NR
15
SO
2
R
16
, NR
15
R
16
, mono to perfluoro C
1-4
alkyl and mono to perfluoro C
1-4
alkoxy;
R
3
is C
1-20
alkyl, C
3-6
cycloalkyl, C
3-6
cycloalkylC
1-5
alkyl, or C
1-10
alkoxyC
1-10
alkyl, each optionally substituted by 1 or 2 substituents selected from hydroxy, C
1-10
alkoxy, COOH or a salt thereof, COOC
1-15
alkyl, CONR
17
R
18
, NR
17
R
18
, NR
17
COR
18
, NR
19
or an aromatic or heteroaromatic ring system as defined for R
2
, or R
3
is an aromatic or heteroaromatic ring system as hereinbefore defined for R
2
;
R
10
is C
1-4
alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group;
R
11
and R
12
which may be the same or different is each selected from hydrogen, C
1-12
alkyl, CH
2
R
13
, CHR
14
CO
2
H or a salt thereof, or R
11
and R
12
together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C
1-4
alkyl, C
1-4
alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine;
R
13
is COOH or a salt thereof, COOR
10
, CONR
11
R
12
, CN or CH
2
OH;
R
14
is an amino acid side chain such as CH
2
OH from serine;
R
15
and R
16
are independently hydrogen or C
1-4
alkyl e.g. methyl or ethyl;
R
17
and R
18
are independently hydrogen, C
1-15
alkyl, eg methyl or ethyl, C
1-10
alkoxyC
1-10
alkyl or arylC
1-10
alkyl, e.g. benzyl;
R
19
together with the nitrogen atom to which it is attached forms a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C
1-4
alkyl, aryl, e.g. phenyl, or aralkyl, e.g benzyl;
W is SO
2
or a bond;
X is O or S; and
Y is a group of the formula —A
1
—A
2
—A
3
— in which A
1
and A
3
each represent a bond or a straight chain or branched alkylene group, said alkylene group(s) containing a total of 1 to 10 carbon atoms and A
2
represents a bond or O, S, SO, SO
2
, CO, C═CH
2
, CONH, NHCO, CR
15
R
16
, CH═CH or C≡C, providing that when A
2
is O, S, SO, SO
2
or CONH, A
3
contains at least two carbon atoms linking the A
2
group and the CH
2
group in formula (I).
Representative examples of R
1
include carboxy (COOH) and corresponding salts, esters (COOR
10
) and amides (CONR
11
R
12
) thereof, for instance a sodium salt, an ethyl ester or an amide comprising an N-alkyl substituent, for instance, methyl, 2-methoxyethyl, octyl, dodecyl, N-benzyl, N-naphthylmethyl or a disubstitued amide comprising a combination thereof, or an amide in which the N forms part of a heterocyclic ring, for instance a piperidine ring.
Representative examples of the aromatic ring system represented by R
2
include phenyl and naphthyl. Representative examples of the heteroaromatic ring system which may be represented by R
2
include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl. Representative examples of R
2
include the phenyl group optionally substituted by 1, 2 or 3 substituents selected from halogen (e.g. chlorine or fluorine), C
1-4
Leach Colin Andrew
Smith Stephen Allan
Ford John M.
Kanagy James M.
Kinzig Charles M.
SmithKline Beecham p.l.c.
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