Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-28
2002-07-09
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S296000, C544S309000, C544S310000, C544S311000, C544S313000, C544S314000
Reexamination Certificate
active
06417192
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.
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, WO 96119451, 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). GB 1 582 527 describes, as compounds of formula (7), a group of pyrimidone compounds of the formula (A):
in which Alk is lower alkyl, Het is selected from 2- or 4-imidazolyl, 2-pyridyl, 2-thiazolyl, 3-isothiazolyl, 1,2,5-thiadiazolyl and n is from 1 to 4. These compounds are said to be useful as intermediates in the preparation of further compounds which are H2 antagonists.
A new class of pyrimidone compounds has now been identified which are inhibitors of the enzyme Lp-PLA
2
.
Accordingly, the present invention provides compounds of formula (I):
in which:
Z is a bond and R
1
is halogen; or
Z is CR
3
R
4
, where R
3
and R
4
are each hydrogen or C
(1-4)
alkyl, or R
3
and R
4
together with the intervening carbon atom form a C
(3-6)
cycloalkyl ring; and
R
1
is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents selected from C
(1-18)
alkyl, C
(1-18)
alkoxy, C
(1-18)
alkylthio, arylC
(1-18)
alkoxy, oxo, hydroxy, halogen, CN, COR
5
, COOR
5
, CONR
5
R
6
, NR
5
COR
6
, SO
2
NR
5
R
6
, NR
5
SO
2
R
6
, NR
5
R
6
, mono to perfluoro-C
(1-4)
alkyl and mono to perfluoro-C
(1-4)
alkoxy;
X is O or S;
Y is a group of formula —A
1
—A
2
−A
3
— in which A
1
and A
3
each represent a bond or a straight chain or branched C
(1-10)
alkylene group and A
2
represents a bond or O, S, SO, SO
2
, CO, C═CH
2
, CH═CH , C≡C, CONH, NHCO, or CR
5
R
6
, 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);
R
2
is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents selected from the substituents hereinbefore defined for R
1
, as well as aryl and arylC
(1-4)
alkyl,
W is a bond and R
7
is hydrogen; or
W is SO
2
or a bond; and
R
7
is R
1
or a hydrocarbyl group which hydrocarbyl group may be optionally interupted within the carbon chain by a group selected from O, COO, OCO, CO, CONR
8
, NR
8
CO, NR
8
CONR
9
, NR
8
COO, OCONR
8
, and NR
8
, and which hydrocarbyl group may also be optionally substituted by 1 or 2 substituents selected from mono to perfluoro-C
(1-4)
alkyl, OR
8
, COOR
8
, CONR
8
R
9
, NR
8
COR
9
, NR
8
CONR
9
R
10
, NR
8
COOR
9
, OCONR
8
R
9
, NR
11
R
12
and R
1
;
R
5
and R
6
are independently hydrogen or C
(1-20)
alkyl, for instance C
(1-4)
alkyl (e.g. methyl or ethyl);
R
8
, R
9
and R
10
are independently selected from hydrogen, C
(1-20)
alkyl (for instance C
(1-15)
alkyl), (which may optionally be fluorinated, including up to perfluorinated on the terminal 1 to 3 carbon atoms), C
(1-20)
alkenyl (preferably C
(12-18)
alkenyl), aryl, arylC
(1-10)
alkyl, C
(1-10)
alkoxyC
(1-10)
alkyl, or aryloxyC
(1-10)
alkyl and in which an aryl group may have one or two substituents selected from halogen, C
(1-20)
alkyl, C
(1-20)
alkoxy, aryloxy and COOC
(1-20)
alkyl; and
R
11
and R
12
are independently selected from one of the values hereinbefore defined for R
8
and R
9
or R
11
and R
12
together with the nitrogen atom to which they are attached form a 5- to 7 membered ring optionally containing one or two further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C
(1-4)
alkyl, phenyl, or benzyl.
Preferably, Z is CH
2
.
Representative examples of R
1
when an aryl group include phenyl and naphthyl. Representative examples of R
1
when a heteroaryl group include pyridyl, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.
Preferably R
1
is a 5- or 6-membered, monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatoms, preferably pyridyl, pyrimidyl or pyrazolyl, more preferably, pyrid-4-yl or pyrimid-5-yl and optionally substituted by 1 or 2 substituents preferably selected from arylC
(1-4)
alkyl (e.g. benzyl), C
(1-8)
alkyl (e.g. methyl or ethyl), halogen (e.g. chlorine), oxo, hydroxy, C
(1-4)
alkoxy (e.g. methoxy) and arylC
(1-4)
alkoxy (e.g. benzyloxy). More preferably, R
1
is pyrimid-5-yl or a 2-oxo-pyrimid-5-yl group, optionally substituted at N-1 by C
(1-8)
alkyl (e.g. undecyl, methyl or ethyl), or a 2-C
(1-4)
a
Hickey Deirdre Mary Bernadette
Ife Robert John
Leach Colin Andrew
Pinto Ivan Leo
Porter Roderick Alan
Kanagy James M.
Kinzig Charles M.
McKenzie Thomas C
Raymond Richard L.
SmithKline Beecham p.l.c.
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