U.S. patent application number 10/399022 was filed with the patent office on 2004-04-01 for pyridinone derivatives for treatment of atherosclerosis.
Invention is credited to Hickey, Deirdre Mary Bernadette, Ife, Robert John, Leach, Colin Andrew, Liddle, John, Pinto, Ivan Leo, Smith, Stephen Allan, Stanway, Steven James.
Application Number | 20040063753 10/399022 |
Document ID | / |
Family ID | 9901006 |
Filed Date | 2004-04-01 |
United States Patent
Application |
20040063753 |
Kind Code |
A1 |
Hickey, Deirdre Mary Bernadette ;
et al. |
April 1, 2004 |
Pyridinone derivatives for treatment of atherosclerosis
Abstract
Compounds of formula (I): are inhibitors of the enzyme
L.sub.p-PLA.sub.2 and are of use in therapy, in particular for
treating atherosclerosis.
Inventors: |
Hickey, Deirdre Mary
Bernadette; (Stevenage, GB) ; Ife, Robert John;
(Stevenage, GB) ; Leach, Colin Andrew; (King of
Prussia, PA) ; Liddle, John; (Stevenage, GB) ;
Pinto, Ivan Leo; (Stevenage, GB) ; Smith, Stephen
Allan; (Stevenage, GB) ; Stanway, Steven James;
(Harlow, GB) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION
CORPORATE INTELLECTUAL PROPERTY-US, UW2220
P. O. BOX 1539
KING OF PRUSSIA
PA
19406-0939
US
|
Family ID: |
9901006 |
Appl. No.: |
10/399022 |
Filed: |
September 9, 2003 |
PCT Filed: |
October 5, 2001 |
PCT NO: |
PCT/EP01/11610 |
Current U.S.
Class: |
514/312 ;
546/153 |
Current CPC
Class: |
A61P 17/06 20180101;
A61P 3/10 20180101; C07D 495/04 20130101; C07D 221/04 20130101;
C07D 401/12 20130101; C04B 35/632 20130101; A61P 9/10 20180101;
C07D 513/04 20130101; C07D 471/04 20130101; A61P 9/00 20180101;
A61P 9/12 20180101; C07D 215/36 20130101; A61P 19/02 20180101; C07D
211/74 20130101; A61P 29/00 20180101 |
Class at
Publication: |
514/312 ;
546/153 |
International
Class: |
A61K 031/4709; C07D
41/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 10, 2000 |
GB |
0024808.8 |
Claims
1. A compound of formula (I): 304in which: R.sup.1 is an aryl
group, optionally substituted by 1, 2, 3 or 4 substituents which
may be the same or different selected from C.sub.(1-6)alkyl,
C.sub.(1-6)alkoxy, C.sub.(1-6)alkylthio, hydroxy, halogen, CN, mono
to perfluoro-C.sub.(1-4)alkyl, mono to
perfluoro-C.sub.(1-4)alkoxyaryl, and arylC.sub.(1-4)alkyl; R.sup.2
is halogen, C.sub.(1-3)alkyl, C.sub.(1-3)alkoxy,
hydroxyC.sub.(1-3)alkyl, C.sub.(1-3)alkylthio,
C.sub.(1-3)alkylsulphinyl, aminoC.sub.(1-3)alkyl, mono- or
di-C.sub.(1-3)alkylaminoC.sub.(1-3)allyl,
C.sub.(1-3)alkylcarbonylaminoC.- sub.(1-3)alkyl,
C.sub.(1-3)alkoxyC.sub.(1-3)alkylcarbonylaminoC.sub.(1-3)a- lkyl,
C.sub.(1-3)alkylsulphonylaminoC.sub.(1-3)alkyl,
C.sub.(1-3)alkylcarboxy, C.sub.(1-3)alkylcarboxyC.sub.(1-3)alkyl,
and R.sup.3 is hydrogen, halogen, C.sub.(1-3)alkyl, or
hydroxyC.sub.(1-3)alkyl; or R.sup.2 and R.sup.3 together with the
pyridone ring carbon atoms to which they are attached form a fused
5-or 6-membered carbocyclic ring; or R.sup.2 and R.sup.3 together
with the pyridone 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.sub.(1-4)alkyl, cyano,
C.sub.(1-3)alkoxyC.sub.(1-3)alkyl, C.sub.(1-4)alkoxy or
C.sub.(1-4)alkylthio, or mono to perfluoro-C.sub.(1-4)alkyl;
R.sup.4 is hydrogen, C.sub.(1-6)alkyl which may be unsubstituted or
substituted by 1, 2 or 3 substituents selected from hydroxy,
halogen, OR.sup.7, COR.sup.7, carboxy, COOR.sup.7,
CONR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.7COR.sup.8, mono- or
di-(hydroxyC.sub.(1-6)allyl)amino and
N-hydroxyC.sub.(1-6)alkyl-N--C.sub.- (1-6)alkylamino; or R.sup.4 is
Het-C.sub.(0-4)alkyl in which Het is a 5- to 7-membered
heterocyclyl ring comprising N and optionally O or S, and in which
N may be substituted by COR.sup.7, COOR.sup.7, CONR.sup.9R.sup.10,
or C.sub.(1-6)alkyl optionally substituted by 1, 2 or 3
substituents selected from hydroxy, halogen, OR.sup.7, COR.sup.7,
carboxy, COOR.sup.7, CONR.sup.9R.sup.10 or NR.sup.9R.sup.10, for
instance, piperidin4-yl, pyrrolidin-3-yl; R.sup.5 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.sub.(1-6)alkyl,
C.sub.(1-6)alkoxy, C.sub.(1-6)alkylthio, arylC.sub.(1-6)alkoxy,
hydroxy, halogen, CN, COR.sup.7, carboxy, COOR.sup.7,
NR.sup.7COR.sup.8, CONR.sup.9R.sup.10, SO.sub.2NR.sup.9R.sup.10,
NR.sup.7SO.sub.2R.sup.8, NR.sup.9R.sup.10, mono to
perfluoro-C.sub.(1-4)alkyl and mono to perfluoro-C.sub.(1-4)alkoxy;
R.sup.6 is an aryl or a heteroaryl ring which is further optionally
substituted by 1, 2, 3 or 4 substituents which may be the same or
different selected from C.sub.(1-6)alkyl, C.sub.(1-6)alkoxy,
C.sub.(1-6)alkylthio, C.sub.(1-6)alkylsulfonyl,
arylC.sub.(1-6)alkoxy, hydroxy, halogen, CN, COR.sup.7, carboxy,
COOR.sup.7, CONR.sup.9R.sup.10, NR.sup.7COR.sup.8,
SO.sub.2NR.sup.9R.sup.10, NR.sup.7SO.sub.2R.sup.8,
NR.sup.9R.sup.10, mono to perfluoro-C.sub.1-4)alkyl and mono to
perfluoro-C.sub.(1-4)alkoxy, or C.sub.(5-10)alkyl; R.sup.7 and
R.sup.8 are independently hydrogen or C.sub.(1-12)alkyl, for
instance C.sub.(1-4)alkyl (e.g. methyl or ethyl); R.sup.9 and
R.sup.10 which may be the same or different is each selected from
hydrogen, or C.sub.(1-12)alkyl, or R.sup.9 and R.sup.10 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.sub.(1-4)alkyl, C.sub.(1-4)alkylcarboxy, aryl, e.g. phenyl, or
aralkyl, e.g benzyl, for instance morpholine or piperazine; and X
is a C.sub.(2-4)alkylene group (optionally substituted by 1, 2 or 3
substituents selected from methyl and ethyl), CH.dbd.CH,
(CH.sub.2).sub.nS or (CH.sub.2).sub.nO where n is 1, 2 or 3.
2. A compound of formula (I) as claimed in claim 1 in which R.sup.1
is phenyl optionally substituted by halogen, C.sub.(1-6)alkyl,
trifluoromethyl, C.sub.(1-6)alkoxy.
3. A compound of formula (I) as claimed in claim 1 or 2 in which
R.sup.2 and R.sup.3 together with the pyridone ring carbon atoms to
which they are attached form a fused thiazolyl ring substituted by
methyl, or a fused 5-membered carbocyclic (cyclopentenyl) ring, or
a fused benzo, pyrido, thieno or pyrazolo ring.
4. A compound of formula (I) as claimed in any of claims 1 to 3 in
which R.sup.4 is selected from the group consisting of
2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl,
1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperdin-4-yl or
1-ethylpyrrolidin-3-yl.
5. A compound of formula (I) as claimed in any of claims 1 to 4 in
which R.sup.5 is phenyl.
6. A compound of formula (I) as claimed in any of claims 1 to 5 in
which R.sup.6 is phenyl substituted by trifluoromethyl or ethyl in
the 4-position.
7. A compound of formula (I) as claimed in any of claims 1 to 6 in
which R.sup.5 and R.sup.6 together form a 4-(phenyl)phenyl or a
2-(phenyl)pyridinyl substituent in which the remote phenyl ring may
be optionally substituted by halogen or trifluoromethyl, preferably
at the 4-position.
8. A compound of formula (I) as claimed in any of claims 1 to 7 in
which X is C.sub.(2-4)alkylene or CH.sub.2S.
9. A compound of formula (I) as claimed in any of claims 1 to 8 in
which R.sup.1 is phenyl substituted by 2,3-difluoro; R.sup.2 and
R.sup.3, together with the pyridone ring carbon atoms to which they
are attached, form a fused 5-membered carbocyclic (cyclopentenyl)
ring, or a fused benzo or pyrido ring; R.sup.4 is
2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl,
1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or
1-ethylpyrrolidin-3-yl; R.sup.5 is phenyl; R.sup.6 is phenyl
substituted by ethyl or trifluoromethyl in the 4-position; and X is
CH.sub.2S.
10. A compound of formula (I) as claimed in any of claims 1 to 9 in
which R.sup.1 is phenyl substituted by 2,3-difluoro; R.sup.2 and
R.sup.3, together with the pyridone ring carbon atoms to which they
are attached, form a fused thiazolyl ring substituted by methyl, or
a benzo or pyrido ring; R.sup.4 is 2-(diethylamino)ethyl,
1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl,
1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl; R.sup.5 is
phenyl; R.sup.6 is phenyl substituted by trifluoromethyl in the
4-position; and X is (CH.sub.2).sub.2.
11. A compound of formula (I) as claimed in any of claims 1 to 10
in which R.sup.1 is phenyl substituted by 2,3-difluoro; R.sup.2 and
R.sup.3, together with the pyridone ring carbon atoms to which they
are attached, form a fused benzo or pyrido ring; R.sup.4 is
1-(2-methoxyethyl)piperidin- -4-yl; R.sup.5 and R.sup.6 together
form a 4-(phenyl)phenyl substituent in which the remote phenyl ring
is substituted by trifluoromethyl, preferably at the 4-position;
and X is CH.sub.2S or (CH2).sub.2.
12. A compound of formula (I) as claimed in claim 1 and as named in
any one of Examples 1 to 115.
13. A compound of formula (I) as defined in claim 1 selected from
the group consisting of
N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluo-
robenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylme-
thyl)acetamide;
N-(1-(2-methoxyethyl)piperidin-yl)-2-[2-(2-(2,3-difluoroph-
enyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-
-4-ylmethyl)acetamide; or a pharmaceutically acceptable salt
thereof, in particular the bitartrate, hydrochloride,
dihydrochloride or paratoluenesulfonate salt.
14. A pharmaceutical composition comprising a compound of formula
(I) as claimed in claim 1 and a pharmaceutically acceptable
carrier.
15. A compound of formula (I) as claimed in claim 1 for use in
therapy.
16. The use of a compound of formula (I) as claimed in claim 1 for
the manufacture of a medicament for treating atherosclerosis.
17. A method of treating a disease state associated with activity
of the enzyme Lp-PLA.sub.2 which method involves treating a patient
in need thereof with a therapeutically effective amount of a
compound of formula (1) as claimed in claim 1.
18. A process for preparing a compound of formula (I) as defined in
claim 1 which process comprises reacting an acid compound of
formula (II): 305in which X, R.sup.1, R.sup.2 and R.sup.3 are as
hereinbefore defined, with an amine compound of formula (III):
R.sup.6--R.sup.5--CH.sub.2NHR.su- p.4 (III) in which R.sup.4,
R.sup.5 and R.sup.6 are as hereinbefore defined; under amide
forming conditions.
Description
[0001] 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.
[0002] WO 95/00649 (SmithKline Beecham plc) describes the
phospholipase A.sub.2 enzyme Lipoprotein Associated Phospholipase
A.sub.2 (Lp-PLA.sub.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.sub.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.sub.2 and suggest that it may have potential as a
therapeutic protein for regulating pathological inflammatory
events.
[0003] It has been shown that Lp-PLA.sub.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.sub.2 action are biologically active with
lysophosphatidylcholine, in particular having several
pro-atherogenic activities ascribed to it including monocyte
chemotaxis and induction of endothelial dysfunction, both of which
facilitate monocyte-derived macrophage accumulation within the
artery wall. Inhibition of the Lp-PLA.sub.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.
[0004] 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.sub.2 is an independent risk factor in coronary
artery disease.
[0005] 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.sub.2 could therefore prove beneficial in the treatment
of this phenomenon. An Lp-PLA.sub.2 inhibitor could also find
utility in other disease states that exhibit endothelial
dysfunction including diabetes, hypertension, angina pectoris and
after ischaemia and reperfusion.
[0006] In addition, Lp-PLA.sub.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.sub.2. Examples of such disorders include psoriasis.
[0007] Furthermore, Lp-PLA.sub.2 inhibitors may also have a general
application in any disorder that involves lipid oxidation in
conjunction with Lp-PLA.sub.2 activity to produce the two injurious
products, lysophosphatidylcholine and oxidatively modified fatty
acids. Such conditions include the aforementioned conditions
atherosclerosis, diabetes, rheumatoid arhritis, stroke, myocardial
infarction, ischaemia, reperfusion injury and acute and chronic
inflammation.
[0008] 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.sub.2. These are irreversible,
acylating inhibitors (Tew et al, Biochemistry, 37, 10087,
1998).
[0009] A further class of compounds has now been identified which
are non-acylating inhibitors of the enzyme Lp-PLA.sub.2. Thus, WO
99/24420, WO 00/10980, WO 00/66566, WO 00/66567 and WO 00/68208
(SmithKline Beecham plc) disclose a class of pyrimidone compounds.
We have now found that the pyrimidone ring may be replaced by a
pyridone ring, to give compounds having good activity as inhibitors
of the enzyme Lp-PLA.sub.2.
[0010] Accordingly, the present invention provides a compound of
formula (I): 1
[0011] in which:
[0012] R.sup.1 is an aryl group, optionally substituted by 1, 2, 3
or 4 substituents which may be the same or different selected from
C.sub.(1-6)alkyl, C.sub.(1-6)alkoxy, C.sub.(1-6)alkylthio, hydroxy,
halogen, CN, mono to perfluoro-C.sub.(1-4)alkyl, mono to
perfluoro-C.sub.(1-4)alkoxyaryl, and arylC.sub.(1-4)alkyl;
[0013] R.sup.2 is halogen, C.sub.(1-3)alkyl, C.sub.(1-3)alkoxy,
hydroxyC.sub.(1-3)alkyl, C.sub.(1-3)alkylthio,
C.sub.(1-3)alkylsulphinyl, aminoC.sub.(1-3)alkyl, mono- or
di-C.sub.(1-3)alkylaminoC.sub.(1-3)alkyl,
C.sub.(1-3)alkylcarbonylaminoC.sub.(1-3)alkyl,
C.sub.(1-3)alkoxyC.sub.(1-- 3)alkylcarbonylaminoC.sub.(1-3)alkyl,
C.sub.(1-3)alkylsulphonylaminoC.sub.- (1-3)alkyl,
C.sub.(1-3)alkylcarboxy, C.sub.(1-3)alkylcarboxyC.sub.(1-3)alk- yl,
and
[0014] R.sup.3 is hydrogen, halogen, C.sub.(1-3)alkyl, or
hydroxyC.sub.(1-3)alkyl; or
[0015] R.sup.2 and R.sup.3 together with the pyridone ring carbon
atoms to which they are attached form a fused 5-or 6-membered
carbocyclic ring; or
[0016] R.sup.2 and R.sup.3 together with the pyridone 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.sub.(1-4)alkyl,
cyano, C.sub.(1-3)alkoxyC.sub.(1-3)alkyl, C.sub.(1-4)alkoxy or
C.sub.(1-4)alkylthio, or mono to perfluoro-C.sub.(1-4)alkyl;
[0017] R.sup.4 is hydrogen, C.sub.(1-6)alkyl which may be
unsubstituted or substituted by 1, 2 or 3 substituents selected
from hydroxy, halogen, OR.sup.7, COR.sup.7, carboxy, COOR.sup.7,
CONR.sup.9R.sup.10, NR.sup.9R.sup.10, NR.sup.7COR.sup.8, mono- or
di-(hydroxyC.sub.(1-6)alkyl- )amino and
N-hydroxyC.sub.(1-6)alkyl-N--C.sub.(1-6)alkylamino; or
[0018] R.sup.4 is Het-C.sub.(0-4)alkyl in which Het is a 5- to
7-membered heterocyclyl ring comprising N and optionally O or S,
and in which N may be substituted by COR.sup.7, COOR.sup.7,
CONR.sup.9R.sup.10, or C.sub.(1-6)alkyl optionally substituted by
1, 2 or 3 substituents selected from hydroxy, halogen, OR.sup.7,
COR.sup.7, carboxy, COOR.sup.7, CONR.sup.9R.sup.10 or
NR.sup.9R.sup.10, for instance, piperidin-4-yl,
pyrrolidin-3-yl;
[0019] R.sup.5 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.sub.(1-6)alkyl, C.sub.(1-6)alkoxy,
C.sub.(1-6)alkylthio, arylC.sub.(1-6)alkoxy, thydroxy, halogen, CN,
COR.sup.7, carboxy, COOR.sup.7, NR.sup.7COR.sup.8,
CONR.sup.9R.sup.10, SO.sub.2NR.sup.9R.sup.10,
NR.sup.7SO.sub.2R.sup.8, NR.sup.9R.sup.10, mono to
perfluoro-C.sub.(1-4)alkyl and mono to
perfluoro-C.sub.(1-4)alkoxy;
[0020] R.sup.6 is an aryl or a heteroaryl ring which is further
optionally substituted by 1, 2, 3 or 4 substituents which may be
the same or different selected from C.sub.(1-6)alkyl,
C.sub.(1-6)alkoxy, C.sub.(1-6)alkylthio, C.sub.(1-6)alkylsulfonyl,
arylC.sub.(1-6)alkoxy, hydroxy, halogen, CN, COR.sup.7, carboxy,
COOR.sup.7, CONR.sup.9R.sup.10, NR.sup.7COR.sup.8,
SO.sub.2NR.sup.9R.sup.10, NR.sup.7SO.sub.2R.sup.8,
NR.sup.9R.sup.10, mono to perfluoro-C.sub.(1-4)alkyl and mono to
perfluoro-C.sub.(1-4)alkoxy, or C.sub.(5-10)alkyl;
[0021] R.sup.7 and R.sup.8 are independently hydrogen or
C.sub.(1-12)alkyl, for instance C.sub.(1-4)alkyl (e.g. methyl or
ethyl);
[0022] R.sup.9 and R.sup.10 which may be the same or different is
each selected from hydrogen, or C.sub.(1-12)alkyl, or R.sup.9 and
R.sup.10 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.sub.(1-4)alkyl, C.sub.(1-4)alkylcarboxy, aryl, e.g.
phenyl, or aralkyl, e.g benzyl, for instance morpholine or
piperazine; and
[0023] X is a C.sub.(2-4)alkylene group (optionally substituted by
1, 2 or 3 substituents selected from methyl and ethyl), CH.dbd.CH,
(CH.sub.2).sub.nS or (CH.sub.2).sub.nO where n is 1, 2 or 3.
[0024] In a further aspect the present invention provides a
compound of formula (I) as defined above in which:
[0025] R.sup.2 and R.sup.3 together with the pyridone 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.sub.(1-4)alkyl,
cyano, C.sub.(1-4)alkoxy or C.sub.(1-4)alkylthio, or mono to
perfluoro-C.sub.(1-4)alkyl.
[0026] Representative examples of R.sup.1 when an aryl group
include phenyl and naphthyl. Preferably, R.sup.1 is phenyl
optionally substituted by halogen, C.sub.(1-6)alkyl,
trifluoromethyl, C.sub.(1-6)alkoxy, preferably, from 1 to 3 fluoro,
more preferably, 2,3-difluoro.
[0027] Representative examples of R.sup.2 include methyl, ethyl,
and trifluoroethyl when R.sup.3 is hydrogen. Representative
examples of R.sup.3 include methyl when R.sup.2 is methyl.
[0028] Further representative examples of R.sup.2 and R.sup.3
include when R.sup.2 and R.sup.3 together with the pyridone ring
carbon atoms to which they are attached form a fused 5-membered
carbocyclic (cyclopentenyl) ring, or a fused benzo, pyrido,
pyrazolo or thieno ring.
[0029] Further representative examples of R.sup.2 and R.sup.3
include when R.sup.2 and R.sup.3, together with the pyridone ring
carbon atoms to which they are attached, form a pyrazolo ring
substituted on the N atom by C.sub.(1-3)alkyl or methoxyethyl; and
when R.sup.2 and R.sup.3, together with the pyridone ring carbon
atoms to which they are attached, form either a thiazolyl, thieno
or pyrido ring substituted by methyl.
[0030] Preferably, R.sup.2 and R.sup.3 together with the pyridone
ring carbon atoms to which they are attached form a fused
5-membered carbocyclic (cyclopentenyl) ring or a fused benzo,
pyrido, thieno or pyrazolo ring.
[0031] Preferably, R.sup.2 and R.sup.3, together with the pyridone
ring carbon atoms to which they are attached, form a fused
thiazolyl ring substituted by methyl.
[0032] Representative examples of R.sup.4 include hydrogen, methyl,
2-(diethylamino)ethyl, 2-(piperidin-1-yl)ethyl,
2-(pyrrolidin-1-yl)ethyl, 3-(morpholin-4-yl)propyl,
1-ethyl-piperidin-4-yl and 1-ethyl-pyrrolidin-2-ylmethyl.
Preferably R.sup.4 is 2-diethylamino)ethyl or
1-ethyl-piperidin-4-yl.
[0033] Further representative examples of R.sup.4 include
piperidin-4-yl substituted at the 1-position by methyl, isopropyl,
1-(2-methoxyethyl), 1-(2-hydroxyethyl), t-butoxycarbonyl or
ethoxycarbonylmethyl; ethyl substituted at the 2-position by
aminoethyl; 1-ethylpiperidinylmethyl; piperidin-4-yl;
3-diethylaminopropyl; 4-pyrrolidin-1-ylbutyl and
1-ethylpyrrolidin-3-yl.
[0034] Preferably R.sup.4 is 1-(2-methoxyethyl)piperidin-4-yl,
1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl.
[0035] Representative examples of R.sup.5 include phenyl and
pyridyl. Preferably, R.sup.5 is phenyl.
[0036] Representative examples of R.sup.6 include phenyl optionally
substituted by halogen, or trifluoromethyl, preferably at the
4-position and hexyl. Preferably, R.sup.6 is phenyl substituted by
trifluoromethyl at the 4-position.
[0037] Further representative examples of R.sup.6 include phenyl
substituted by 1 or more C.sub.(1-3)alkyl. Preferably, R.sup.6 is
phenyl substituted by ethyl in the 4-position.
[0038] Preferably, R.sup.5 and R.sup.6 together form a
4-(phenyl)phenyl or a 2-(phenyl)pyridinyl substituent in which the
remote phenyl ring may be optionally substituted by halogen or
trifluoromethyl, preferably at the 4-position.
[0039] Preferably X is C.sub.(2-4)alkylene, more preferably
C.sub.(2-3)alkylene, most preferably, (CH.sub.2).sub.2, or
CH.sub.2S.
[0040] It will be appreciated that within the compounds of formula
(I) there is a sub-group of compounds (group A) in which:
[0041] R.sup.1 is phenyl substituted by 2,3-difluoro;
[0042] R.sup.2 and R.sup.3, together with the pyridone ring carbon
atoms to which they are attached, form a fused 5-membered
carbocyclic (cyclopentenyl) ring, or a fused benzo or pyrido
ring;
[0043] R.sup.4 is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl,
1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or
1-ethylpyrrolidin-3-yl;
[0044] R.sup.5 is phenyl;
[0045] R.sup.6 is phenyl substituted by ethyl or trifluoromethyl in
the 4-position; and
[0046] X is CH.sub.2S.
[0047] It will be appreciated that within the compounds of formula
(I) there is a further sub-group of compounds (group B) in
which:
[0048] R.sup.1 is phenyl substituted by 2,3-difluoro;
[0049] R.sup.2 and R.sup.3, together with the pyridone ring carbon
atoms to which they are attached, form a fused thiazolyl ring
substituted by methyl, or a benzo or pyrido ring;
[0050] R.sup.4 is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl,
1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or
1-ethylpyrrolidin-3-yl;
[0051] R.sup.5 is phenyl;
[0052] R.sup.6 is phenyl substituted by trifluoromethyl in the
4-position; and
[0053] X is (CH.sub.2).sub.2.
[0054] It will be appreciated that within the compounds of formula
(I) there is a further sub-group of compounds (group C) in
which:
[0055] R.sup.1 is phenyl substituted by 2,3-difluoro;
[0056] R.sup.2 and R.sup.3, together with the pyridone ring carbon
atoms to which they are attached, form a fused benzo or pyrido
ring;
[0057] R.sup.4 is 1-(2-methoxyethyl)piperidin-4-yl;
[0058] R.sup.5 and R.sup.6 together form a 4-(phenyl)phenyl
substituent in which the remote phenyl ring is substituted by
trifluoromethyl, preferably at the 4-position; and
[0059] X is CH.sub.2S or (CH.sub.2).sub.2.
[0060] It will be appreciated that compounds of the present
invention may comprise one or more chiral centres so that
stereoisomers may be formed. The present invention covers all such
stereoisomers, including individual diastereoisomers and
enantiomers, and mixtures thereof.
[0061] It will be appreciated that in some instances, compounds of
the present invention may include a basic function such as an amino
group as a substituent. Such basic functions may be used to form
acid addition salts, in particular pharmaceutically acceptable
salts. Pharmaceutically acceptable salts include those described by
Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such
salts may be formed from inorganic and organic acids.
Representative examples thereof include maleic, fumaric, benzoic,
ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic,
ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,
gluconic, aspartic, stearic, palmitic, itaconic, glycolic,
p-aminobenzoic, glutamic, taurocholic acid, benzenesulfonic,
p-toluenesulfonic, hydrochloric, hydrobromic, sulfuric,
cyclohexylsulfamic, phosphoric and nitric acids.
[0062] It will be appreciated that in some instances, compounds of
the present invention may include a carboxy group as a substituent.
Such carboxy groups may be used to form salts, in particular
pharmaceutically acceptable salts. Pharmaceutically acceptable
salts include those described by Berge, Bighley, and Monkhouse, J.
Pharm. Sci., 1977, 66, 1-19. Preferred salts include alkali metal
salts such as the sodium and potassium salts.
[0063] When used herein, the term "alkyl" and similar terms such as
"alkoxy" includes all straight chain and branched isomers.
Representative examples thereof include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and
n-hexyl.
[0064] When used herein, the term "aryl" refers to, unless
otherwise defined, a mono- or bicyclic aromatic ring system
containing up to 10 carbon atoms in the ring system, for instance
phenyl or naphthyl.
[0065] When used herein, the term "heteroaryl" refers to a mono- or
bicyclic heteroaromatic ring system comprising up to four,
preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen
and sulphur. Each ring may have from 4 to 7, preferably 5 or 6,
ring atoms. A bicyclic heteroaromatic ring system may include a
carbocyclic ring.
[0066] When used herein, the terms "halogen" and "halo" include
fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo
and iodo, respectively.
[0067] Most preferred compounds of formula (1) are:
[0068]
N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)--
4-oxo4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide;
[0069]
N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)et-
hyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylme-
thyl)acetamide;
[0070] or a pharmaceutically acceptable salt thereof, in particular
the bitartrate, hydrochloride, dihydrochloride or
paratoluenesulfonate salt.
[0071] Since the compounds of the present invention, in particular
compounds of formula (I), are intended for use in pharmaceutical
compositions, it will be understood that they are each provided in
substantially pure form, for example at least 50% pure, more
suitably at least 75% pure and preferably at least 95% pure (% are
on a wt/wt basis). Impure preparations of the compounds of formula
(I) may be used for preparing the more pure forms used in the
pharmaceutical compositions. Although the purity of intermediate
compounds of the present invention is less critical, it will be
readily understood that the substantially pure form is preferred as
for the compounds of formula (I). Preferably, whenever possible,
the compounds of the present invention are obtained in crystalline
form.
[0072] When some of the compounds of this invention are allowed to
crystallise or are re-crystallised from organic solvents, solvent
of crystallisation may be present in the crystalline product. This
invention includes within its scope such solvates. Similarly, some
of the compounds of this invention may be crystallised or
re-crystallised from solvents containing water. In such cases water
of hydration may be formed. This invention includes within its
scope stoichiometric hydrates as well as compounds containing
variable amounts of water that may be produced by processes such as
lyophilisation. In addition, different crystallisation conditions
may lead to the formation of different polymorphic forms of
crystalline products. This invention includes within its scope all
polymorphic forms of the compounds of formula (I).
[0073] Compounds of the present invention are inhibitors of the
enzyme lipoprotein associated phospholipase A.sub.2 (Lp-PLA.sub.2)
and as such are expected to be of use in therapy, in particular in
the treatment of atherosclerosis. In a further aspect therefore the
present invention provides a compound of formula (I) for use in
therapy.
[0074] The compounds of formula (I) are inhibitors of
lysophosphatidylcholine production by Lp-PLA.sub.2 and may
therefore also have a general application in any disorder that
involves endothelial dysfunction, for example atherosclerosis,
diabetes, hypertension, angina pectoris and after ischaemia and
reperfusion. In addition, compounds of formula (I) may have a
general application in any disorder that involves lipid oxidation
in conjunction with enzyme activity, for example in addition to
conditions such as atherosclerosis and diabetes, other conditions
such as rheumatoid arthritis, stroke, inflammatory conditions of
the brain such as Alzheimer's Disease, myocardial infarction,
ischaemia, reperfusion injury, sepsis, and acute and chronic
inflammation.
[0075] Further applications include any disorder that involves
activated monocytes, macrophages or lymphocytes, as all of these
cell types express Lp-PLA.sub.2. Examples of such disorders include
psoriasis.
[0076] Accordingly, in a further aspect, the present invention
provides for a method of treating a disease state associated with
activity of the enzyme Lp-PLA.sub.2 which method involves treating
a patient in need thereof with a therapeutically effective amount
of an inhibitor of the enzyme. The disease state may be associated
with the increased involvement of monocytes, macrophages or
lymphocytes; with the formation of lysophosphatidylcholine and
oxidised free fatty acids; with lipid oxidation in conjunction with
Lp-PLA.sub.2 activity; or with endothelial dysfunction.
[0077] Compounds of the present invention may also be of use in
treating the above mentioned disease states in combination with an
anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic,
anti-anginal, anti-inflammatory, or anti-hypertension agent or an
agent for lowering Lp(a). Examples of the above include cholesterol
synthesis inhibitors such as statins, anti-oxidants such as
probucol, insulin sensitisers, calcium channel antagonists, and
anti-inflammatory drugs such as NSAIDs. Examples of agents for
lowering Lp(a) include the aminophosphonates described in WO
97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and
SmithKline Beecham).
[0078] A preferred combination therapy will be the use of a
compound of the present invention and a statin. The statins are a
well known class of cholesterol lowering agents and include
atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin,
lovastatin and rosuvastatin (also referred to as S-4522 or ZD 4522,
Astra Zeneca). The two agents may be administered at substantially
the same time or at different times, according to the discretion of
the physician.
[0079] A further preferred combination therapy will be the use of a
compound of the present invention and an anti-diabetic agent or an
insulin sensitiser, as coronary heart disease is a major cause of
death for diabetics. Within this class, preferred compounds for use
with a compound of the present invention include the PPARgamma
activators, for instance GI262570 (GlaxoSmithlhine) and the
glitazone class of compounds such as rosiglitazone (Avandia,
GlaxoSmithKline), troglitazone and pioglitazone.
[0080] In therapeutic use, the compounds of the present invention
are usually administered in a standard pharmaceutical composition.
The present invention therefore provides, in a further aspect, a
pharmaceutical composition comprising a compound of formula (I) and
a pharmaceutically acceptable carrier.
[0081] Suitable pharmaceutical compositions include those which are
adapted for oral or parenteral administration or as a
suppository.
[0082] Suitable pharmaceutical compositions include those which are
adapted for oral or parenteral administration or as a suppository.
Compounds of formula (I) which are active when given orally can be
formulated as liquids, for example syrups, suspensions or
emulsions, tablets, capsules and lozenges. A liquid formulation
will generally consist of a suspension or solution of the compound
or pharmaceutically acceptable salt in a suitable liquid carrier(s)
for example, ethanol, glycerine, non-aqueous solvent, for example
polyethylene glycol, oils, or water with a suspending agent,
preservative, flavouring or colouring agent. A composition in the
form of a tablet can be prepared using any suitable pharmaceutical
carrier(s) routinely used for preparing solid formulations.
Examples of such carriers include magnesium stearate, starch,
lactose, sucrose and cellulose. A composition in the form of a
capsule can be prepared using routine encapsulation procedures. For
example, pellets containing the active ingredient can be prepared
using standard carriers and then filled into a hard gelatin
capsule; alternatively, a dispersion or suspension can be prepared
using any suitable pharmaceutical carrier(s), for example aqueous
gums, celluloses, silicates or oils and the dispersion or
suspension then filled into a soft gelatin capsule. Typical
parenteral compositions consist of a solution or suspension of the
compound of formula (I) in a sterile aqueous carrier or
parenterally acceptable oil, for example polyethylene glycol,
polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
Alternatively, the solution can be lyophilised and then
reconstituted with a suitable solvent just prior to administration.
A typical suppository formulation comprises a compound of formula
(I) which is active when administered in this way, with a binding
and/or lubricating agent such as polymeric glycols, gelatins or
cocoa butter or other low melting vegetable or synthetic waxes or
fats.
[0083] Preferably the composition is in unit dose form such as a
tablet or capsule. Each dosage unit for oral administration
contains preferably from 1 to 500 mg (and for parenteral
administration contains preferably from 0.1 to 25 mg) of a compound
of the formula (I). The daily dosage regimen for an adult patient
may be, for example, an oral dose of between 1 mg and 1000 mg,
preferably between 1 mg and 500 mg, or an intravenous,
subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,
preferably between 0.1 mg and 25 mg, of the compound of the formula
(I), the compound being administered 1 to 4 times per day. Suitably
the compounds will be administered for a period of continuous
therapy, for example for a week or more.
[0084] A compound of formula (I) may be prepared by reacting an
acid compound of formula (II): 2
[0085] in which X, R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore
defined,
[0086] with an amine compound of formula (III):
R.sup.6--R.sup.5--CH.sub.2NHR.sup.4 (III)
[0087] in which R.sup.4, R.sup.5 and R.sup.6 are as hereinbefore
defined; under amide forming conditions.
[0088] Suitable amide forming conditions are well known in the art
and include treating the acid of formula (II) with the amine of
formula (III) in the presence of a coupling agent such as
1-(3-dimethyl-aminopropyl)-3-- ethylcarbodiimide (DEC) and
1-hydroxybenzotriazole (HOBt), or
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) and di-isopropylethylamine, in an
aprotic solvent such as dichloromethane or dimethylfomiamide.
[0089] A compound of formula (II) may be readily prepared from a
corresponding ester of formula (IV): 3
[0090] in which X, R.sup.1, R.sup.2 and R.sup.3 are as hereinbefore
defined, and R.sup.11 is C.sub.(1-6)alkyl, for example ethyl or
t-butyl,
[0091] by treating with a de-esterifying agent, for instance, when
R.sup.11 is t-butyl trifluoroacetic acid or when R.sup.11 is ethyl,
sodium hydroxide in dioxan.
[0092] The overall synthesis of compounds of formula (I) is
illustrated in the following scheme wherein R.sup.1 to R.sup.11 are
as hereinbefore defined: 45
[0093] Referring to the scheme, the ester (IV) is usually prepared
by N-1 alkylation of (V) using (VI), in which R.sup.11 is as
hereinbefore defined e.g. (VI) is t-butyl bromoacetate or ethyl
bromoacetate, in the presence of a bas e.g. BuLi THF or sodium
hydride in N-methyl pyrrolicinone (NMP) (step c).
[0094] When X is CH.sub.2S, the key intermediate (IV) may be
synthesised by reacting (XX) with dimethyloxosulfonium methylide,
generated via the treatment of trimethylsulfoxonium iodide with
sodium hydride at low temperature, to yield a sulfur ylid (XXII)
(step q). Subsequent treatment of (XXII) with carbon disulfide in
the presence of diisopropylamine, followed by
R.sup.1CH.sub.2--L.sup.4, where L.sup.4 is a leaving group, yields
intermediate (IV) (step r).
[0095] Alternatively, when X is CH.sub.2S, the R.sup.1X substituent
may be introduced by displacement of a leaving group L.sup.2 (e.g.
Cl) (step e) either on a pyridine (VIII) or pyridine N-oxide (XIV),
to give 2-substituted pyridines (VII) and (XV). Transformation of
(VII) or (XV) to the 4-pyridone (V) is accomplished by deprotection
of the 4-oxygen (e.g. using (Ph.sub.3P).sub.3RhCl when in aq.
ethanol when R.sup.12=allyl) (step d), followed, for (XVI), by
removal of the N-oxide substituent, using hydrogen in the presence
of Pd/C in acetic acid (step k). The pyridine (VIII) or pyridine
N-oxide (XIV) may be prepared by steps (i), (h), (g), (f), and (j),
in which:
[0096] (j) treatment of (VIII) with m-chloroperbenzoic acid in
dichloromethane;
[0097] (f) treatment of (IX) with R.sup.12OH (X), in which R.sup.12
is allyl, and sodium hydride in DMF;
[0098] (g) treatment of (XI) with phosphorus oxychloride;
[0099] (h) treatment of (XII) with aq HCl with heating;
[0100] (i) treatment of (XIII) with di-lower alkyl malonate and
sodium alkoxide in alcohol (in which R.sup.13 is C.sub.(1-6)alkyl,
typically R.sup.13=Et); and
[0101] R.sup.1--CH.sub.2SH (XIX) is typically prepared from the
thioacetate, which is formed from the corresponding alkyl bromide
R.sup.1--CH.sub.2Br.
[0102] Alternatively, when X is CH.sub.2S and R.sup.2 and R.sup.3,
together with the pyridone ring carbon atoms to which they are
attached, form a fused benzo ring, intermediate (IV) may be
synthesised from known starting materials by steps (s), (c) and (v)
in which:
[0103] (s) treatment of Meldrum's acid (XXIII) with sodium hydride
at low temperature, followed by reaction with phenylisothiocyanate
and subsequent treatment with R.sup.1CH.sub.2--L.sup.4;
[0104] (c) as hereinbefore discussed;
[0105] (v) treatment of (XXV) with trifluoroacetic acid.
[0106] When X is alkylene, it is preferable to use steps (m) and
(h) (intermediates (XVII), (XVIII)) or steps (n) and (p)
(intermediates (XIX), (XX), (XXI)) in which:
[0107] (h) transformation of a 4-substituted pyridine into a
4-pyridone e.g. by treatment of (XVII) R.sup.14.dbd.Cl with aq HCl
and dioxan, or deprotection of R.sup.14.dbd.OR.sup.12, e.g. using
conditions of step (d).
[0108] (m) chain extension of a 2-alkyl pyridine, e.g. where
X.dbd.YCH.sub.2CH.sub.2 by treatment of a 2-methylpyridine (XVIII)
with R.sup.1--Y--CH.sub.2--L.sup.4 (XVI) in which L.sup.4 is a
leaving group and a strong base, such as BuLi, in THF.
[0109] In the alternative route, the 3-ester group is removed from
intermediate (XIX) R.sup.15.dbd.C.sub.(1-6)alkyl by heating in
diphenyl ether where R.sup.15=tBu (step n); Intermediate (XIX) is
formed from the 2,6-dioxo-1,3-oxazine (XX) and ester (XXI) by
treatment with a base such as NaH in DMF or
1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane.
[0110] Synthesis of (XX) from known starting materials may be
achieved via steps (w) and (c) or steps (y) and (c) in which:
[0111] (w) treatment of (XXVII) with azidotrimethylsilane in
THF;
[0112] (y) treatment of (XXVI) with phosgene;
[0113] (c) as hereinbefore described.
[0114] It will be appreciated by those skilled in the art that all
other starting materials and intermediates are either known
compounds or may be prepared by literature methods, such as those
described in "Comprehensive Organic Transformations: a guide to
functional group preparations" by Richard Larock (VCH, 1989),
incorporated herein by reference.
[0115] As will be appreciated by those skilled in the art it may be
necessary or desirable at any stage in the synthesis of compounds
of formula (I) to protect one or more sensitive groups in the
molecule so as to prevent undesirable side reactions. The
protecting groups used in the preparation of compounds of formula
(I) may be used in conventional manner. See for example, those
described in `Protective Groups in Organic Synthesis` by Theodora W
Green and Peter G M Wuts, second edition, (John Wiley and Sons,
1991), incorporated herein by reference, which also describes
methods for the removal of such groups.
[0116] The present invention will now be illustrated by the
following examples.
EXAMPLES
[0117] The structure and purity of the intermediates and examples
was confirmed by 1H-NMR and (in nearly all cases) mass
spectroscopy, even where not explicitly indicated below
[0118] Intermediate A1 4-(4-Trifluoromethylphenyl)benzaldehyde
6
[0119] A 3 L 3-neck flask fitted with top stirrer, condenser and
argon inlet/outlet was charged with 4-trifluoro-methybenzene
boronic acid (90.0 g, 0.474 mol), 4-bromobenzaldehyde (83.29 g,
0.450 mol) and 1,2-dimethoxyethane (1.3 L), followed by 2M aqueous
sodium carbonate (474 ml) and palladium acetate (5.32 g, 0.0237
mol). The stirring mixture was heated to reflux for 4 h under
argon, then allowed to cool to room temperature over 16 h. The
reaction mixture was filtered through hyflo. The filtrate was
diluted with saturated brine and extracted 3.times. with ethyl
acetate. The combined extracts were dried over magnesium sulfate
and filtered through hyflo, giving a clear orange filtrate which
was evaporated to a solid (ca. 120 g, crude). Flash chromatography
(silica, 10-50% dichloromethane in pet. ether, 10% steps) gave a
white solid which dissolved in hexane (500 ml) on boiling.
Crystallisation, finally in ice, gave the title compound as a solid
which was filtered off, washed with ice cold hexane and dried,
(86.33 g, 77%). .sup.1H-NMR (CDCl.sub.3) .delta.7.77-8.03 (8H, m),
10.09 (1H, s).
[0120] Intermediate A2
N,N-diethyl-N'-4'-trifluoromethylbiphenyl-4-ylmethy-
l)ethane-1,2-diamine 7
[0121] 4-(4-Trifluoromethylphenyl)benzaldehyde (85.43 g, 0.3414
mol) (Int. A1) and 4A molecular sieve (400 g, predried at
120.degree. C.) were suspended in dichloromethane (1.4 L), then
N,N-diethyl-ethylenediamine (47.97 ml, 0.3414 mol) was added. The
mixture was left at room temperature for 16 h with occasional
shaking, then the sieves were filtered off and washed with
dichloromethane. The combined filtrates were evaporated to a yellow
solid and dried under high vacuum. This material (1 14.3 g, 0.328
mol) in ethanol (1 L) was cooled in an ice bath, and sodium
borohydride (12.41 g, 0.328 mol) was added under argon with
stirring. Hydrogen evolution was observed. After 30 min the ice
bath was removed, and the cloudy yellow solution was left to stand
at room temperature for 16 h. The solvent was removed in vacuo,
water and brine were added, and the mixture was extracted 3.times.
with dichloromethane. The combined extracts were dried over
potassium carbonate and evaporated to give the title compound as a
yellow solid, (112.1 g, 98%). .sup.1H-NMR (CDCl.sub.3) .delta.7.66
(4H, s), 7.53-7.56 (2H, m), 7.40-7.44 (2H, m), 3.86 (2H, s),
2.47-2.75 (9H, m), 0.96-1.10 (6H, m); MS(APCI+) found (M+1)=-351,
C.sub.20H.sub.25F.sub.3N.sub.2 requires 350.
[0122] Intermediate A3--4-(4-Trifluoromethylphenyl)benzonitrile
8
[0123] Prepared by the method of intermediate A1 using
4-trifluoromethylbenzeneboronic acid and 4-bromobenzonitrile.
.sup.1H-NMR (d6 DMSO) .delta.7.99-7.94 (6H, m), 7.86 (2H, d);
MS(APCI+) found (M+1)=248, C.sub.14H.sub.8NF.sub.3 requires
247.
[0124] Intermediate A4--(4-Trinfluoromethylphenyl)benzylamine, Free
Base and hydrochloride salt 9
[0125] (a) A solution of intermediate A3 (75.5 g, 0.306 mol) in
anhydrous THF (500 ml) was added dropwise to a solution of lithium
aluminum hydride (460 ml, 1.0M solution in TRF) at 0.degree. C.
under argon. The mixture was stirred at room temperature for 16 h,
then water (17 ml), 10% aqueous sodium hydroxide solution (10 ml)
and water (50 ml) were carefully added dropwise over 8 h under
argon. The mixture was stirred for 16 h, then filtered through
celite and the filtrate evaporated. The residue was dissolved in
dichloromethane (500 ml) and washed with brine, dried and
evaporated to give the title compound as a cream solid (66.3 g,
86%). .sup.1H-NMR (CDCl.sub.3) .delta.7.68 (4H, s), 7.57 (2H, d),
7.42 (2H, d), 3.94 (2H, s), 1.50 (2H, s); MS(APCI+) found
(M-NH.sub.2)=235, C.sub.14H.sub.12F.sub.3N requires 251.
[0126] (b) To a solution of intermediate A3 (96.7 g, 0.39 mol) in
absolute ethanol (5L) and concentrated hydrochloric acid (200 ml)
was added 10% palladium on charcoal (30.0 g, 54% H.sub.2O paste).
The mixture was stirred under 50 psi hydrogen for 16 h. Additional
10% palladium on charcoal (25.0 g, 54% H.sub.2O paste) was added
and the mixture was stirred under 50 psi hydrogen for further 16 h.
The mixture was filtered through celite and the solvent evaporated
to give the hydrochloride salt of the title compound as a cream
solid (102.5 g, 91%). .sup.1H-NMR (d6 DMSO) .delta.8.61 (3H, s),
7.93 (2H, d), 7.83 (2H, d), 7.80 (2H, d), 7.65 (2H, d), 4.08 (2H,
s); MS(APCI+) found (M-NH.sub.2)=235, C.sub.14H.sub.12F.sub.3N
requires 251.
[0127] Intermediate
A5--N-(1-Methyl-piperidin-4-yl)-4-(4-trifluoromethylph-
enyl)benzylamine 10
[0128] A mixture of intermediate A4 hydrochloride salt (6.0 g,
20.87 mmol), 1-methyl-piperidin-4-one (2.56 ml, 20.84 mmol), sodium
triacetoxyborohydride (6.20 g, 29.25 mmol) and acetic acid (1.3 ml)
in dichloroethane (50 ml) was stirred at room temperature under
argon for 16 h then poured into 2M sodium hydroxide solution (150
ml). The organic phase was separated and the aqueous layer
extracted with dichloromethane. The combined organic phases were
washed with brine, dried and evaporated. Chromatography (silica,
dichloromethane to 97:3 dichloromethane/methanoli- c ammonia) gave
the product as a cream solid (6.3 g, 87%). .sup.1H-NMR (CDCl.sub.3)
.delta.7.68 (4H, s), 7.57 (2H, d), 7.42 (2H, d), 3.87 (2H, s), 2.82
(2H, m), 2.52 (1H, m), 2.27 (3H, s), 1.90-2.02 (4H, m), 1.45-1.51
(2H, m); MS(APCI+) found (M+1)=349, C.sub.20H.sub.23N.sub.2F.su-
b.3 requires 348.
[0129] The following intermediate was made as described in WO
00/66567
1 No. Structure Name A6 11 4-(4-Chloro- phenyl)- benzylamine
[0130] The following intermediates were made by the method of
Intermediate A1:
2 No. Precursors Name A7 4-bromobenzaldehyde, 4-
4-methylbenzeneboronic acid (4-methylphenyl)benzaldehyde A8
4-bromobenzaldehyde, 4- 4-ethylbenzeneboronic acid
(4-ethylphenyl)benzaldehyde A9 4-isopropyliodobenzene 4-
4-formylbenzeneboronic acid (4-isopropylphenyl)benzaidehyde A10
4-bromo-o-xylene 4- 4-formylbenzeneboronic acid
(3,4-dimethylphenyl)benzaldehyde A11 3,4-difluoroiodobenzene 4-
4-formylbenzeneboronic acid (3,4-difluorophenyl)benzaldehyde
[0131] The following intermediates were made by the method of
Intermediate A2: Amine precursors were either commercially
available, or readily prepared from commercially available
materials by literature methods or minor modifications thereof.
3 No. Precursor Structure Name A20 Int. A1 12
N-(2-(piperidin-1-yl)ethyl)-4-(4- trifluoromethylphenyl)be-
nzylamine A22 Int. A1 13 N-(2-(pyrrolidin-1-yl)ethyl)-4-(4- -
trifluoromethylphenyl)benzylamine A23 Int. A1 14
(.+-.)-N-(1-ethylpyrrolidin-2-ylmethyl)-
4-(4-trifluoromethylphenyl)benzy- lamine A24 Int. A1 15
N-(3-diethylaminopropyl)-4-(4- trifluoromethylphenyl)benzylamine
A25 Int. A1 16 N-(1-ethylpiperidin-4-ylmethyl)-4-(4-
trifluoromethylphenyl)benzylamine A26 Int. A7 17
N-(2-diethylaminoethyl)-4-(4-methyl- phenyl)benzylamine A27 Int. A8
18 N-(2-diethylaminoethyl)- -4-(4-ethyl- phenyl)benzylamine A28
Int. A9 19 N-(2-diethylaminoethyl)-4-(4-
isopropylphenyl)benzylamine A29 Int. A8 20
N-(1-ethylpiperidin-4-yl)-4-(4-ethyl- phenyl)benzylamine A30 Int.
A10 21 N-(2-diethylaminoethyl)-4-(3,4- dimethylphenyl)benzylamine
A31 Int. A11 22 N-(2-diethylaminoethyl)-4-(3,4-
difluorophenyl)benzylamine A32 Int. A1 23
N-(4-(pyrrolidin-1-yl)butyl)-4-(4-
trifluoromethylphenyl)benzylamine A33 Int. A1 24
N-(2-(N'-t-butoxycarbonyl-N'- ethylamino)ethyl)-4-(4-trifluoro-
methylphenyl)benzylamine
[0132] The following intermediates were made by the method of
Intermediate A5: Piperidone precursors were either commercially
available, or readily prepared from commercially available
materials by literature methods or minor modifications thereof.
4 No. Precursor Structure Name A40 Int. A4 25
N-(1-ethylpiperidin-4-yl)-4-(4- trifluoromethylphenyl)benz- ylamine
A41 Int. A4 26 N-(1-isopropylpiperidin-4-yl)-4-
(4-trifluoromethylphenyl)benzylamine A42 Int. A4 27
N-(1-(2-methoxyethyl)piperidin-4- yl)-4-(4-trifluoromethylphenyl)-
benzylamine A43 Int. A4 28 N-(1- ethoxycarbonylmethylpipe- ridin-4-
yl)-4-(4-trifluoromethylphenyl)- benzylamine A44 Int. A6 29
N-(1-ethylpiperidin-4-yl)-4- (chlorophenyl)benzylamine A45 Int. A6
30 N-(1-methylpiperidin-4-yl)-4-(4- chlorophenyl)benzylamine A46
Int. A6 31 N-(1-isopropylpiperidin-4-yl)-4-
(4-chlorophenyl)benzylamine A47 Int. A6 32
N-(1-(2-methoxyethyl)piperidin-4- yl)-4-(4-chlorophenyl)benzylamine
A48 Int. A4 33 N-(1-(t-butoxycarbonyl)piperidin-
4-yl)-4-(4-trifluoromethyl- phenyl)benzylamine
[0133] Intermediate B1--Thioacetic Acid S-(2,3-difluorobenzyl)ester
34
[0134] Potassium thioacetate (13.45 g, 1.2 equiv) was added
portionwise to a solution of 2,3-difluorobenzyl bromide (20 g, 1
equiv) in dimethylformamide (200 ml) and the reaction stirred for 4
h at room temperature. The resultant solid was filtered off and the
filtrate partitioned between diethyl ether and water, the organic
phase was dried and evaporated. Chromatography (silica, 20:1
petrol/ethyl acetate) gave the title compound as a yellow oil
(18.35 g). .sup.1H-NMR (CDCl.sub.3) .delta.2.35 (3H, s), 4.15 (2H,
d), 6.98-7.13 (5H, m).
[0135] Intermediate B2--2,3-Difluorobenzyl mercaptan. 35
[0136] A mixture of thioacetic acid S-(2,3-difluorobenzyl)ester
(Intermediate B1) (18.35 g, 1 equiv) and potassium carbonate (25.11
g, 2 equiv) in methanol (200 ml) and water (400 ml) was stirred
overnight before being poured into dichloromethane (500 ml). The
organic phase was dried and evaporated and distilled (125.degree.
C. @ 5.6 mBar) to give the title compound as a colourless oil
(12.15 g). .sup.1H-NMR (CDCl.sub.3) .delta. 1.89 (1H, t), 3.78 (2H,
d), 7.05 (3H, m).
[0137] Intermediate B3--Ethyl 2,4-dihydroxy-6,7-dihydro-5
H-[1]pyrindine-3-carboxylate. 36
[0138] A mixture of ethyl 2-amino-1-cyclopentene-1-carboxylate
(10.1 g, 1 equiv), diethyl malonate (9.9 ml, 1 equiv), sodium
ethoxide (26.7 ml, 1.1 equiv, 21 wt. % solution in ethanol) in
ethanol was heated in a sealed vessel to 110.degree. C. for 96 h.
After cooling the solvent was removed and the residue suspended in
water. The suspension was acidified with aqueous hydrochloric acid
(pH .about.3) and the precipitate was collected and dried to give
the title compound as a light brown solid (11.52 g). .sup.1H-NMR
(d6-DMSO) .delta.1.27 (3H, t), 2.00 (2H, qn), 2.60 (2H, t), 2.73
(2H, t), 4.30 (2H, q), 11.62 (1H, br s), 13.18 (1H, br s).
[0139] Intermediate B4--2,4-Dihydroxy-6,7-dihydro-5H-[1]pyrindine.
37
[0140] A mixture of ethyl
2,4-dihydroxy-6,7-dihydro-5H-[1]pyrindine-3-carb- oxylate (Int. B3)
(11.52 g) and aqueous hydrochloric acid (2M, 100 ml) was heated
together overnight. After cooling the solvent was removed by freeze
drying and the title compound obtained as a brown solid (8.02 g).
.sup.1H-NMR (d.sub.6-DMSO) 2.09 (2H, qn), 2.72 (2H, t), 2.93 (2H,
t), 6.56 (1H, s); MS (APCI+) found (M+1)=152;
C.sub.8H.sub.9NO.sub.2 requires 151.
[0141] Intermediate B5--2,4-Dichloro-6,7-dihydro-5 H-[1]pyrindine.
38
[0142] A mixture of 2,4-dihydroxy-6,7-dihydro-5H-[1]pyrindine (Int
B4) (8.02 g) and phosphorous oxychloride (40 ml) was heated to
reflux overnight. The excess phosphorous oxychloride was evaporated
off and the residue poured over ice. The resulting brown solid was
filtered off and dried (7.36 g). .sup.1H-NMR (CDCl.sub.3)
.delta.2.17 (2H, m), 2.96 (2H, t), 3.07 (2H, t), 7.12 (1H, s); MS
(APCI+) found (M+1)=188; C.sub.8H.sub.7.sup.35Cl.sub.2N requires
187.
[0143] Intermediate
B6--4-Allyloxy-2-chloro-6,7-dihydro-5H-[1]pyrindine. 39
[0144] Allyl alcohol (4.1 ml, 1.2 equiv) was added dropwise to a
suspension of sodium hydride (2.2 g, 1.1 equiv, 60% dispersion in
mineral oil) in dimethylformamide (80 ml) under argon at 0.degree.
C. The reaction mixture was stirred for 20 min prior to adding
dropwise to a solution of 2,4-dichloro-6,7-dihydro-5H-[1]pyrindine
(Int. B5) (9.42 g, 1 equiv) in dimethylformamide (70 ml) at
0.degree. C., stirring was continued at ambient temperature
overnight. The solvent was evaporated and the residue partitioned
between water and ethyl acetate, the organic phase was dried and
evaporated. Chromatography (silica, 10:1 toluene/ethyl acetate)
gave the title compound as an off white solid (8.99 g). .sup.1H-NMR
(CDCl.sub.3) .delta.2.11 (2H, m), 2.84 (2H, t), 2.97 (2H, t), 4.58
(2H, m), 5.30-5.46 (2H, m), 5.94-6.07 (1H, m), 6.59 (1H, s); MS
(APCI+) found (M+1)=210; C.sub.11H.sub.12.sup.35ClNO requires
209.
[0145] Intermediate
B7--4Allyloxy-2-chloro-6,7-dihydro-5H-[1]pyrindine-1-o- xide 40
[0146] A mixture of 3-chloroperbenzoic acid (19.5 g, 1.5 equiv) and
4-allyloxy-2-chloro-6,7-dihydro-5H[1]-[1]pyrindine (Int B6) (8.99
g, 1 equiv) in dichloromethane (100 ml) was stirred at ambient
temperature under argon for 4 h, washed with aqueous sodium
bicarbonate, dried and evaporated. Chromatography (silica, 5%
methanol in dichloromethane) gave the title compound as a white
solid (6.98 g). .sup.1H-NMR (CDCl.sub.3) .delta.2.19 (2H, qn), 2.97
(2H, t), 3.22 (2H, t), 4.57 (2H, m), 5.30-5.45 (2H, m), 5.93-6.08
(1H, m), 6.80 (1H, s); MS (APCI+) found (M+1)=226;
C.sub.11H.sub.12.sup.35ClNO.sub.2 requires 225.
[0147] Intermediate
B8--4-Allyloxy-2-(4-fluorobenzylthio)-6,7-dihydro-5H-[- 1]pyrindine
1-oxide 41
[0148] 4-Fluorobenzyl mercaptan (1.59 g, 1.2 equiv) was added
dropwise to a suspension of sodium hydride (0.372 g, 1.0 equiv, 60%
dispersion in mineral oil) in dimethylformamide (30 ml) under argon
at 0.degree. C. The reaction was stirred for 20 min, before adding
dropwise to a solution of 4-allyloxy-2-chloro-6,7-dihydro-5
H-[1]pyrindine-1-oxide (Int. B7) (2.1 g, 1 equiv) in
dimethylformamide (20 ml) at 0.degree. C., stirring was continued
at ambient temperature overnight. The solvent was evaporated and
the residue partitioned between water and ethyl acetate, the
organic phase was dried and evaporated. Chromatography (silica, 3%
methanol in dichloromethane) gave the title compound as an off
white solid (2.65 g). .sup.1H-NMR (CDCl.sub.3) .delta.2.16 (2H,
qn), 2.91 (2H, m), 3.18 (2H, t), 4.14 (2H, s), 4.43 (2H, m), 5.28
(2H, m), 5.84-5.97 (1H, m), 6.37 (1H, s), 7.00 (2H, m), 7.39 (2H,
m); MS (APCI+) found (M+1)=332; C.sub.18H.sub.18FNO.sub.2S requires
331.
[0149] Intermediate
B9--2-(4-Fluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1pyri- ndin-4-ol
42
[0150] A mixture of
4-allyloxy-2-(4-fluorobenzylthio)-6,7-dihydro-5H-[1]py- rindine
1-oxide (Int. B8) (2.65 ), triphenylphosphine rhodium (I) chloride
(0.740 g, 10 mol %) and 1,4-diazobicyclo[2,2,2]octane (0.27 g, 30
mol %) in ethanol (90 ml) and water (10 ml) was heated to reflux
overnight. The solvent was removed and the residue chromatographed
(silica, 4% methanol in dichloromethane) to yield the title
compound as a brown solid (1.75 g). .sup.1H-NMR (d.sub.6-DMSO)
.delta.2.07 (2H, m), 2.80 (2H, t), 2.91 (2H, t), 4.14 (2H, s), 6.58
(1H, s), 7.15 (2H, m), 7.47 (2H, m); MS (APCI+) found (M+1)=292;
C.sub.15H.sub.14FNO.sub.2S requires 291.
[0151] Intermediate
B10--4Chloro-2-(2-2,3difluorophenyl)ethyl)quinoline 43
[0152] Butyllithium (4.76 ml, 2.5M in hexanes, 1 equiv) was added
dropwise to a solution of 4-chloroquinaldine (2.4 ml, 1 equiv) in
tetrahydrofuran (30 ml) at -78.degree. C. and the reaction mixture
stirred for 15 min. 2,3-Difluorobenzyl bromide (1.82 ml, 1.2 equiv)
was added dropwise and stirring was continued for 1 h. After
warming to room temperature the solution was diluted with water and
ethyl acetate and the organic phase dried and evaporated.
Chromatography (silica, 10:1 petrol/ethyl acetate) gave the title
compound as a white solid (3.16 g). .sup.1H-NMR (CDCl.sub.3)
.delta.3.23 (4H, m), 6.89-6.99 (3H, m), 7.33 (1H, s), 7.59 (1H, m),
7.74 (1H, m), 8.04 (1H, d), 8.15 (1H, d); MS (APCI+) found
(M+1)=304; C.sub.17H.sub.12.sup.35ClF.sub.2N requires 303.
[0153] The following intermediates were prepared by the method of
intermediate B10
5 No. Precursor Structure Name B11 4-Fluorobenzyl bromide 44
4-Chloro-2-(2-(4-fluorophenyl)ethyl)- quinoline B12
3,4-Difluorobenzyl bromide 45 4-Chloro-2-(2-(3,4-difluorophenyl)-
ethyl)quinoline B13 2,4-Difluorobenzyl bromide 46
4-Chloro-2-(2-(2,4-difluorophenyl)- ethyl)quinoline B14
2-Fluorobenzyl bromide 47 4-Chloro-2-(2-(2-fluorophenyl)-
ethyl)quinoline B15 3-Chlorobenzyl bromide 48
4-Chloro-2-(2-(3-chlorophenyl)- ethyl)quinoline B16
2,3,4-Trifluoro- benzyl bromide 49 4-Chloro-2-(2-(2,3,4-trifluoro-
phenyl)ethyl)quinoline B17 3-Fluorobenzyl bromide 50
4-Chloro-2-(2-(3-fluorophenyl)- ethyl)quinoline
[0154] Intermediate B20--2,4-Dichloroquinoline 51
[0155] A mixture of 2,4-dihydroxyquinoline (14 g) and phosphorus
oxychioride (40 ml) was heated to reflux overnight. The excess
phosphorous oxychloride was evaporated off and the residue poured
over ice. The resulting solid was filtered off and dried to give
the title compound as a brown solid (13.86 g). .sup.1H-NMR
(CDCl.sub.3) .delta.7.82 (1H, m), 7.96 (2H, m), 8.03 (1H, d), 8.21
(1H, dd); MS (APCI+) found (M+1)=198;
C.sub.9H.sub.5.sup.35Cl.sub.2N requires 197.
[0156] Intermediate B21 --4-Allyloxy-2-chloroquinoline 52
[0157] Allyl alcohol (7.1 ml, 1.2 equiv) was added dropwise to a
suspension of sodium hydride (3.83 g, 1.1 equiv, 60% dispersion in
mineral oil) in dimethylformamide (120 ml) under argon at 0.degree.
C. The reaction mixture was stirred for 20 min prior to adding
dropwise to a solution of 2,4-dichloroquinoline (Int. B20) (17.26
g, 1 equiv) in dimethylformamide (80 ml) at 0.degree. C., stirring
was continued at ambient temperature overnight The solvent was
evaporated and the residue partitioned between water and ethyl
acetate, the organic phase was dried and evaporated. Chromatography
(silica, toluene) gave the title compound as an off white solid
(13.56 g). .sup.1H-NMR (CDCl.sub.3) .delta.4.77 (2H, m), 5.30-5.57
(2H, m), 6.08-6.20 (1H, m), 6.73 (1H, s), 7.52 (1H, m), 7.71 (1H,
m), 7.92 (1H, d), 8.17 (1H, dd); MS (APCI+) found (M+1)=220;
C.sub.12H.sub.10.sup.35ClNO requires 219.
[0158] Intermediate
B22--4-Allyloxy-2-(2,3-difluorobenzylthio)quinoline 53
[0159] 2,3-Difluorobenzyl mercaptan (Int B2) (2 g, 1.1 equiv) was
added dropwise to a suspension of sodium hydride (0.477 g, 1.05
equiv, 60% dispersion in mineral oil) in dimethylformamide (50 ml)
under argon at 0.degree. C. The reaction mixture was stirred for 20
min, before adding dropwise to a solution of
4-allyloxy-2-chloroquinoline (Int. B21) (2.49 g, 1 equiv) in
dimethylformamide (30 ml) at 0.degree. C. and stirring was
continued at ambient temperature overnight. The solvent was
evaporated and the residue partitioned between water and ethyl
acetate, the organic phase was dried and evaporated. Chromatography
(silica, 2:1 petrol/toluene) gave the title compound as an off
white solid (2.26 g). .sup.1H-NMR (CDCl.sub.3) .delta.4.68 (4H, m),
5.34-5.53 (2H, m), 6.06-6.17 (1H, m), 6.54 (1H, s), 6.96 (2H, m),
7.41 (2H, m), 7.41 (2H, m), 7.65 (1H, dt), 7.90 (1H, dd), 8.11 (1H,
dd); MS (APCI+) found (M+1)=344; C.sub.19H15F.sub.2NOS requires
343.
[0160] The following intermediate was prepared by the method of
intermediate B22:
6 No. Precursors Structure Name B23 Int. B21, 4-Fluorobenzyl
mercaptan 54 4-Allyloxy-2-(4-fluorobenzylthi- o)quinoline
[0161] Intermediate
B24--4-Allyloxy-2-(2,3-difluorobenzylthio)-6,7-dihydro-
-5H-[1]pyrindine-1-oxide 55
[0162] The title compound was prepared from Intermediate B7 and
2,3-difluorobenzylthiol by the method of Intermediate B8.
[0163] Intermediate
B25--2-(2,3-Difluorobenzylthio)-1-oxy-6,7-dihydro-5H-[-
1]pyrindin-4-ol 56
[0164] The title compound was prepared from Intermediate B24 by the
method of Intermediate B9.
[0165] Intermediate B26-3-azaisatoic anhydride 57
[0166] To a stirring solution of 2,3-pyridinedicarboxylic anhydride
(100 g, 1 equiv) in anhydrous tetrahydrofuran (1L) was added
dropwise under argon at 38-46.degree. C. over 1.25 h
azidotrimethylsilane (97.9 ml, 1.1 equiv). The temperature was
maintained at 45-50.degree. C. for a further 2 h then the mixture
refluxed for 30 min, cooled to ambient temperature and ethanol (43
ml, 1.1 equiv) added dropwise. On stirring for 16 h an off-white
solid was obtained which was filtered, washed and dried, to give
the title compound (90.7 g). .sup.1H-NMR (d.sub.6-DMSO)
.delta.7.25-7.35 (1H, m), 8.30-8.35 (1H, dd), 8.65-8.7 (1H, dd),
11.3 (1H, br s)
[0167] Intermediate
B30--6-Methyl-1H-thieno[3,2-d](1,3]oxazine-2,4-dione 58
[0168] Methyl 3-amino-5-methylthiophene-2-carboxylate (2.0 g, 11.7
mmol) and sodium hydroxide (0.89 g, 22.2 mmol) in 1:1 dioxan/water
(40 ml) was heated at reflux for 18 h, then the solvent was removed
in vacuo. The crude solid was dissolved in water (30 ml) and
phosgene (15 ml, 20% solution in toluene, 30 mmol) was added over
10 min with stirring. After a further 30 min the precipitate was
filtered off, washed with water and dried to yield the title
compound (0.44 g). .sup.1H-NMR (CDCl.sub.3) .delta.2.5 (3H, s), 6.7
(1H, s), 12.5 (1H, s); MS (APCI+) found (M+H--CO.sub.2)=140.
[0169] The following intermediates were prepared by the method of
Intermediate B30:
7 No. Structure Name B31 59 1H-thieno[3,2-d][1,3]oxazine-2,4-dione
B32 60 1H-thieno[2,3-d][1,3]oxazine-2,4-dione B33 61
1H-thieno[3,4-d][1,3]oxazine-2,4-dione B34 62
2-methylthiazolo[4,5-d][1,3]oxazine-5,7-dione B35 63
2-methyl-2,7-dihydropyrazolo[3,4-d][1,3]oxazine-4,6-dione B36 64
2-(4-methoxybenzyl)-2,7-dihydropyrazolo[3,4-d][,3]oxazine-
4,6-dione B37 65 4-fluoroisatoic anhydride
[0170] The following intermediates were prepared by the method of
Washburne and Park, Tet Lett. 243 (1976):
8 No. Structure Name B40 66 5-ethyl-3H-[1,3]oxazine-2,6-dione B41
67 4,5-dimethyl-3H-[1,3]oxazine-2,6-dione
[0171] Intermediate
B45--1,5,6,7-tetrahydrocyclopenta[d][1,3]oxazine-2-4-d- ione 68
[0172] Tetrarnethylsilylazide (1.28 ml, 1 equiv) was added dropwise
to a solution of 1-cyclopentene-1,2-dicarboxylic anhydride (1.33 g,
1 equiv) in dichloromethane (20 ml) and the mixture was warmed to
35.degree. C. After ca. 4 h gas evolution had ceased. Ethanol (1
equiv) was added and stirring continued for 10 min, then the
solvent was removed in vacuo and the residue triturated with ether
to obtain the title compound (0.74 g). .sup.1H-NMR (d.sub.6-DMSO)
.delta.2.00 (2H, m), 2.47 (2H, m), 2.68 (2H, m), 11.8 (1H, br s);
MS (APCI-) found (M-1)=152; C.sub.7H.sub.7NO.sub.3 requires
153.
[0173] The following intermediate was prepared by the method of
Int. B45
9 No. Structure Name B46 69 5,6,7,8-tetrahydro-1H-
benzo[d][1,3]oxazine-2-4-dione
[0174] Intermediate B50--Ethyl
(2,4-dioxo4H-pyrido[2,3-d][1,3]oxazin-1-yl)- acetate 70
[0175] A 2:1 mixture of 3- and 6-azaisatoic anhydride (3.55 g, 21.6
mmol) (Synthesis 1982, 11, 972) was added portionwise to a
suspension of sodium hydride (0.95 g, 60% in oil, 23.8 mmol) in DMF
(40 ml). After stirring for 1 h, ethyl bromoacetate (2.64 ml, 23.8
mmol) was added. The reaction mixture was stirred overnight. The
solvent was removed under reduced pressure. Ice/water was added to
the residue and stirred for 1h. The resulting pink solid was
collected by filtration, washed with water and dried under vacuum
at 40.degree. C. The product was a 4:1 mixture of the [2,3-d] and
the [3,2-d]isomers. .sup.1H-NMR data of the title compound.
.sup.1H-NMR (d.sub.6-DMSO) .delta.1.21 (3H, t), 4.18 (2H, q), 4.92
(2H, s), 7.45 (1H, dd), 8.47 (1H, dd), 8.77 (1H, dd); MS (APCI+)
found (M+1)=251; C.sub.11H.sub.10N.sub.2O.sub.5 requires 250.
[0176] The title compound could also be prepared by the following
method:
[0177] To a stirring mixture of 3-azaisatoic anhydride (Int. B26)
(84.36 g, 1 equiv) and N,N-diisopropylethylamine (94 ml, 1.05
equiv) in N-methylpyrrolidone (420 ml) was added dropwise under
argon at 45-50.degree. C., ethyl bromoacetate (57 ml, 1 equiv).
After 16 h at 50.degree. C. the mixture was cooled (ice bath) and
water (560 ml) added with vigorous stirring. The solid which
precipitated was filtered, washed with water and partitioned
between ethyl acetate and saturated aqueous sodium bicarbonate. An
insoluble solid was filtered off and discarded and the ethyl
acetate layer washed again with saturated sodium bicarbonate, dried
(Na.sub.2SO.sub.4) and evaporated. The residue was triturated with
a 1:1 mixture of ether/light petrol, filtered, washed and dried to
give the title compound as an off-white solid, yield (56.0 g).
[0178] The following intermediates were prepared by the method of
Intermediate B50:
10 No. Precursor Structure Name B51 Int. B40 71
ethyl(5-ethyl-2,6-dioxo-6H-[1,3]oxazin-3-yl)acetate B52 Int. B41 72
ethyl(4,5-dimethyl-2,6-dioxo-6H- [1,3]oxazin-3-yl)acetate B53 Int.
B37 73 ethyl 7-fluoro-2,4-dioxo-4H-benzo[d][1,3]-
oxazin-1-yl)acetate B54 Int. B30 74 ethyl(6-methyl-2,4-dioxo-4H-
thieno[3,2-d][1,3]oxazin-1-y- l)acetate B55 Int. B33 75
ethyl(2,4-dioxo-4H- thieno[3,4-d][1,3]oxazin-1-yl)acetate B56 Int.
B31 76 ethyl(2,4-dioxo-4H-thieno[3,2-d]- [1,3]oxazin-1-yl)acetate
B57 Int. B32 77 ethyl(2,4-dioxo-4H-thieno[2,3-d]-
[1,3]oxazin-1-yl)acetate B58 Int. B34 78
ethyl(6-methyl-2,4-dioxo-4H-
thiazolo[4,5-d][1,3]oxazin-1-yl)acetate B59 Int. B35 79
ethyl(2-methyl-4,6-dioxo-2,4-dihydro-
pyrazolo[3,4-d][1,3]oxazin-7-yl)acetate B60 Int. B36 80
ethyl(2-(4-methoxybenzyl)-4,6-dioxo-2,4-
dihydropyrazolo[3,4-d][1,3]oxazi- n-7-yl)acetate B61 Int. B45 81
ethyl(2,4-dioxo-1,5,6,7-tet- rahydro-
cyclopenta[d][1,3]oxazin-3-yl)acetate B62 Int. B46 82
ethyl(2,4-dioxo-5,6,7,8-tetrahydro-1H- benzo[d][1,3]oxazin-3-yl)ac-
etate
[0179] Intermediate B70--5-(2,3-difluorophenyl)-3-oxopentanoic acid
tert-butyl ester 83
[0180] To an ice cooled stirring suspension of sodium hydride (1.96
g, 49.1 mmol, 60% dispersion in oil) in dry tetrahydrofuran (100
ml) was added dropwise under an argon atmosphere
tert-butylacetoacetate (7.4 ml, 44.6 mmol). After a further 15 min,
n-butyllithium (18.7 ml, 46.8 mmol, 2.5M in hexanes) was added
dropwise maintaining the reaction temperature below 10.degree. C.
2,3-Difluorobenzyl bromide (11.08 g, 53.5 mmol) was added dropwise
20 min later, then the mixture allowed to warm to ambient
temperature. After a further 15 min the reaction mixture was poured
onto a mixture of water (150 ml) and glacial acetic acid (10 ml),
extracted 3 times with ethyl acetate and the combined extracts
washed with saturated sodium hydrogen carbonate then brine, dried
(MgSO.sub.4) and evaporated to a yellow oil. Chromatography (fine
silica, ethyl acetate-light petrol) gave the title compound as a
yellow oil, yield 9.05 g (71%). .sup.1H NMR (CDCl.sub.3)
.delta.1.45 (9H, s), 2.84-2.91 (2H, m), 2.95-3.00 (2H, m), 3.35
(2H, s), 6.92-7.04 (3H, m).
[0181] Intermediate
B71--(3-tert-butoxycarbonylmethyl-2-[2-(2,3-difluoroph-
enyl)ethyl]-4-oxo-4H-[1,8]naphthyridin-1-yl)acetic acid ethyl ester
84
[0182] To a stirring suspension of sodium hydride (0.562 g, 14.06
mmol, 60% dispersion in oil) in dry DMF (50 ml) was added dropwise
5-(2,3-difluorophenyl)-3-oxopentanoic acid tert-butyl ester (Int.
B70) (3.63 g, 12.78 mmol). After 10 min,
(2,4-dioxo-4H-pyrido[2,3-d][1,3]oxazi- n-1-yl)acetic acid ethyl
ester (Int. B50 (3.21 g, 12.78 mmol) was added and the mixture
stirred for 16 h. The solvent was evaporated and the residue
treated with saturated aq. ammonium chloride and extracted 3 times
with ethyl acetate. The combined extracts were washed with brine,
dried (MgSO.sub.4) and concentrated. Chromatography (fine silica,
ethyl acetate-light petrol) gave the title compound as a light
brown solid, yield 1.88 g (31%). .sup.1H NMR (d6-DMSO) .delta.1.31
(3H, t), 1.63 (9H, s), 2.95-3.03 (2H, m), 3.08-3.13 (2H, m), 4,27
(2H, q), 5.31 (2H, s), 7.01-7.11(3H, m), 7.35-7.38 (1H, m),
8.67-8.71 (2H, m).
[0183] The title compound was also made by the following
method:
[0184] To an ice-cooled solution of intermediate B50 (55.9 g, 1
equiv) and intermediate B70 (63.5 g, 1 equiv) in dichloromethane
(700 ml) was added dropwise under argon over 45 min
1,8-diazabicyclo[5.4.0]undec-7-ene (40 ml, 1.2 equiv). After 1 h
the ice bath was removed and after a further 2.5 h the mixture was
washed with saturated aqueous ammonium chloride, dried
(Na.sub.2SO.sub.4) and evaporated. The crude product was
chromatographed (fine silica, ethyl acetate-dichloromethane) then
triturated with light petrol to give the title compound (80.27
g).
[0185] The following intermediates were prepared by the method of
Intermediate B71:
11 No. Precursor Structure Name B72 Int. B51 85
2-[2-(2,3-difluorophenyl)ethyl)-3-tert-
butoxycarbonyl-5-ethyl-4-oxo-4H- pyridin-1-yl]acetic acid, ethyl
ester B73 Int. B52 86 2-[2-(2,3-difluorophenyl)ethyl)-3-tert-
butoxycarbonyl-5,6-dimethyl-4-oxo- 4H-pyridin-1-yl]acetic acid,
ethyl ester B74 Int. B54 87 5-[2-(2,3-difluorophenyl)ethyl)-6-t-
ert- butoxycarbonyl-2-methyl-7-oxo-7H-
tieno[3,2-b]pyridin-4-yl]acetic acid, ethyl ester B75 Int. B55 88
2-[2-(2,3-difluoropheny- l)ethyl)-3-tert- butoxycarbonyl-4-oxo-4H-
thieno[3,4-b]pyridin-1-yl]acetic acid, ethyl ester B76 Int. B58 89
2-[5-(2,3-difluoropheny- l)ethyl)-6-tert-
butoxycarbonyl-2-methyl-7-oxo-7H- thiazolo[4,5-b]pyridin--
4-yl]acetic acid, ethyl ester B77 Int. B59 90
2-[6-(2,3-difluorophenyl)ethyl)-5-tert-
butoxycarbonyl-2-methyl-4-oxo-4H-
pyrazolo[3,4-b]pyridin-7-yl]acetic acid, ethyl ester B78 Int. B61
91 2-[2-(2,3-difluorophenyl)ethyl)-3-tert-
butoxycarbonyl-4-oxo-5,6- trimethylenepyridin-1-yl]acetic acid,
ethyl ester B79 Int. B62 92 2-[2-(2,3-difluorophenyl)ethyl)-3-t-
ert- butoxycarbonyl-4-oxo-5,6- tetramethylenepyridin-1-yl]acetic
acid, ethyl ester
[0186] Intermediate B80--5-(2,3-difluorophenyl)-3-oxopentanoic acid
ethyl ester 93
[0187] Prepared from ethyl acetoacetate by the method of Int. B70.
.sup.1H NMR (CDCl.sub.3) .delta.1.27 (3H, t), 2.86-3.02 (4H, m),
3.43 (2H, s), 4.18 (2H, q), 6.92-7.07 (3H, m).
[0188] Intermediate B91--Ethyl
2-[6-(2-(2,3-difluorophenyl)ethyl)-2-(4-met-
hoxybenzyl)-4-oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7-yl]acetate
94
[0189] To sodium hydride (0.315 g) in dry DMF (8 ml) at 0.degree.
C. under argon was added a solution of intermediate B70 (2.23 g) in
dry DMF (8 ml) dropwise. After stirring at 0.degree. C. for 30 min,
a solution of intermediate B60 (2.82 g) in dry DMF was added and
the mixture allowed to warm to room temperature. After 4 h at room
temperature, the mixture was poured into saturated ammonium
chloride solution and extracted with ethyl acetate. The combined
extracts were dried over MgSO.sub.4 and evaporated under reduced
pressure to give an oil that was chromatographed on silica gel.
This gave a yellow oil (2.3 g). A portion of this material (0.50 g)
in TFA (5 ml) was stirred at room temperature for 4 h, then
evaporated to dryness. A portion of the residue was added to
diphenyl ether (5 ml), heated to reflux for 40 min, then cooled and
poured into hexane. The precipitate was filtered off and washed
with hexane to obtain the title compound. .sup.1H-NMR (CDCl.sub.3)
.delta.1.27 (3H, t), 2.81 (2H, m), 3.01 (2H, m), 3.81 (3H, s), 4.25
(2H, s), 5.27 (2H, s), 5.96 (1H, s), 6.88-7.10 (5H, m), 7.23 (2H,
d), 7.88 (1H, s).
[0190] Intermediate B92--Ethyl
2-[6-(2-(2,3-difluorophenyl)ethyI)4-oxo-2,4-
-dihydropyrazolo[3,4-b]-pyridin-7-yl]acetate 95
[0191] A mixture of Int. B91 (0.48 g) and TFA (50 ml) was heated at
reflux for 17 h, then the TFA was removed in vacuo. The residue was
extracted with dichloromethane, and the combined extracts were
chromatographed (silica, 10% methanol in dichloromethane) to obtain
the title compound as a dark solid (0.23 g, 64%). .sup.1H-NMR
(CDCl.sub.3) .delta.1.27 (3H, t), 2.85 (2H, m), 3.02 (2H, m), 4.97
(2H, s), 6.01 (1H, s), 6.95-7.09 (3H, m), 8.24 (1H, s).
[0192] Intermediate
B93--5-(2-(2,3-Difluorophenyl)ethyl)-3-(pyrazol-4-ylam-
ino)pent-2-enoic acid ethyl ester 96
[0193] 4-Nitropyrazole (3.55 g, 1 equiv) in ethanol (150 ml) was
hydrogenated over 10% palladium on charcoal, then the catalyst was
filtered off, Int. B80 (8.0 g, 1 equiv) was added and the solvent
was removed in vacuo. Concentrated hydrochloric acid (0.5 ml) was
added, and the mixture was heated to 100.degree. C. under argon for
2 h. Ethyl acetate was added and the solution was washed with aq.
sodium bicarbonate, dried and evaporated. Chromatography (silica,
dichloromethane/ethyl acetate) yielded the title compound as a pale
solid (5.7 g, 56%). .sup.1H-NMR (CDCl.sub.3) .delta.1.29 (3H, t),
2.48 (2H, t), 2.80 (2H, t), 4.15 (2H, q), 4.74 (1H, s), 6.78 (1H,
m), 6.95 (2H, m), 7.46 (2H, s), 9.75 (1H, s), 11.1 (1H, br s).
[0194] Intermediate
B94--5-(2-(2,3-Difluorophenyl)ethyl)-2,4-dihydropyrazo-
lo[4,3-b]pyridin-7-one 97
[0195] Intermediate B93 (6.7 g) was added portionwise to refluxing
Dowtherm (100 ml) and heating was continued for 1 h. After cooling,
the mixture was poured into hexane and the precipitate was filtered
off, washed with hexane and dried; yield 4.5 g (78%). .sup.1H-NMR
(d.sub.6-DMSO) .delta.2.89 (2H, m), 3.06 (2H, m), 5.81 (1H, s),
7.07-7.36 (3H, m), 7.76 (1H, s), 11.7 (1H, br s), 13.6 (1H, br
s).
[0196] Intermediate
B95--7Chloro-5-(2-(2,3-difluorophenyl)ethyl)-2,4-dihyd-
ropyrazolo[4,3-b]pyridin 98
[0197] A mixture of Intermediate B94 (4.5 g) and phosphorus
oxychloride (90 ml) was heated at reflux for 2 h, then excess
phosphorus oxychloride was removed in vacuo and the residue was
poured into water and basified with sodium bicarbonate. The product
was extracted into ethyl acetate and the extracts dried and
evaporated to obtain the title compound (4.6 g, 96%). .sup.1H-NMR
(CDCl.sub.3) .delta.3.22 (4H, m), 6.89-7.06 (3H, m), 7.21 (1H, s),
8.34 (1H, s), 11.0 (1H, br s).
[0198] Intermediates B96 and
B97--5-(2-(2,3-difluorophenyl)ethyl)-l-methyl-
-2,4-dihydropyrazolo[4,3-b]-pyridin-7-one and
5(2-(2,3-difluorophenyl)ethy-
l)-2-methyl-2,4-dihydropyrazolo[4,3-b]pyridin-7-one 99
[0199] A mixture of Intermediate B95 (4.3 g, 1 equiv), sodium
hydroxide (l.5 g, 2.5 equiv) and 90% aq. ethanol (15 ml) was heated
to reflux and a solution of iodomethane (1.82 ml, 2 equiv) in
diethyl ether (15 ml) was added dropwise (CARE). After 3 h at
reflux a flirter 2 equivalents of iodomethane was added, and
heating was continued for 2 h. The solvent was removed in vacuo,
the residue was dissolved in ethyl acetate, and the solution washed
with water, dried and evaporated to obtain a crude mixture of
products in a ratio of ca. 3:2. These were separated by
chromatography (silica, dichloromethane-ethyl acetate). Early
fractions gave the 1-methyl isomer (Int. B96, 2.1 g); .sup.1H-NMR
(CDCl.sub.3) .delta.3.17 (4H, m), 4.36 (3H, s), 6.90-7.04 (3H, m),
7.12 (1H, s), 8.15 (1H, s). Later fractions gave the 2-methyl
isomer (Int. B97, 1.2 g); .sup.1H-NMR (CDCl.sub.3) .delta.3.16 (4H,
m), 4.29 (3H, s), 6.90-7.04 (3H, m), 7.15 (1H, s), 8.14 (1H, s).
The identity of the two isomers was confirmed by NOE
experiments.
[0200] Intermediate
B98-5-(2-(2,3-Difluorophenyl)ethyl)-1-methyl-2,4-dihyd-
ropyrazolo[4,3-b]pyridin-7-one 100
[0201] A mixture of Int. B96 (2.1 g), 2M hydrochloric acid (10 ml)
and dioxan (3 ml) was heated at reflux for 4 days, then extracted
with dichloromethane/methanol. Drying and evaporation of the
extracts gave the title compound (1.7 g). .sup.1H-NMR
(d.sub.6-DMSO) .delta.2.98-3.14 (4H, m), 4.22 (3H, s), 6.22 (1H,
s), 7.12-7.33 (3H, m), 7.89 (1H, s), 13 (1H, v br s); MS (APCI+)
found (M+1)=290; C.sub.15H.sub.13F.sub.3N.sub.2O requires 289.
[0202] Intermediate
B99--5-(2-(2,3-Difluorophenyl)ethyl)-2-methyl-2,4-dihy-
dropyrazolo[4,3-b]pyridin-7-one 101
[0203] Hydrolysis of Int. B97 was carried out by the method of Int.
B98. .sup.1H-NMR (d.sub.6-DMSO) .delta.2.82 (2H, m), 3.03 (2H, m),
4.02 (3H, s), 5.66 (1H, s), 7.10 (2H, m), 7.25 (1H, m), 8.00 (1H,
s), 11.5 (1H, b br s); MS (APCI+) found (M+1)=290;
C.sub.15H.sub.13F.sub.3N.sub.2O requires 289.
[0204] Intermediate
B100--Dimethyloxosulphonium-2-(ethoxycarbonylmethylami-
no)benzoylmethylide 102
[0205] To a solution of trimethylsulphoxonium iodide (99 g, 0.45
mol) in DMSO (1L) at 5.degree. C. was added sodium hydride (19.4 g,
0.485 mol, 60% in oil) over 0.5 h and the solution stirred for a
flither 0.5 h until the reaction subsided. Ethyl
2-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-yl)ace- tate (100 g, 0.44
mol) was then added to the solution over 0.33 h and stirred for a
further 3 h after which time the reaction mixture was heated at
50.degree. C. for 1.5 h. After cooling to ambient the solution was
poured onto ice and the precipitate filtered off and washed with
water then pentane. The solids were dried in vacuo at 40.degree. C.
to provide the product (124.4 g, 94%). .sup.1H-NMR (d.sub.6-DMSO)
.delta.1.2 (3H, t), 3.5 (6H, s), 3.98 (2H, q), 5.46 (1H, s), 6.44
(1H, d), 6.52 (1H, t), 7.17 (1H, t), 7.47 (1H, d), 8.93 (1H, br
t).
[0206] The following intermediates were prepared by the method of
intermediate B100
12 No. Precursor Structure Name B101 Int. B53 103
Dimethyloxosulphonium-2-(ethoxycarbonyl-
methylamino)-4-fluorobenzoylmethylide B102 Int. B56 104
Dimethyloxosulphonium-3-(ethoxycarbonyl-
methylamino)thien-2-ylcarbonylme- thylide B103 Int. B57 105
Dimethyloxosulphonium-2-(ethoxyc- arbonyl-
methylamino)thien-3-ylcarbonylmethylide B104 Int. B59 106
Dimethyloxosulphonium-3-(ethoxycarbonyl- methylamino)-1-methylpyr-
azin-4- ylcarbonylmethylide B105 Int. B50 107
Dimethyloxosulphonium-2-(ethoxycarbonyl-
methylamino)pyridin-3-ylcarbonyl- methylide
[0207] Intermediate
B110--5-(1-(2,3-Difluorobenzylthio)-1-phenylaminomethy-
lene)-2,2-dimethyl-[1,3]dioxane-4,6-dione 108
[0208] To hexane washed sodium hydride (7.45 g, 60% in oil) under
argon, was added N-methylpyrrolidone (NMP) (270 ml) and the mixture
cooled in an ice-salt bath. 2,2-Dimethyl-1,3-dioxane-4,6-dione
(26.8 g) was added portionwise over 20 min keeping the temperature
between 5-10.degree. C. Effervescence was noted during the
addition. The mixture was stirred at room temperature for 1 h and
phenylisothiocyanate (25.2 g) added over 15 min. The mixture was
stirred at room temperature for 2.5 h and cooled to 15.degree. C.
in a cold water bath. 2,3-Difluorobenzyl bromide (38.6 g) was added
over 10 min and stirred at room temperature overnight. The solvent
was removed under reduced pressure and the residue partitioned
between ethyl acetate (1.2L) and water. The organic layer was
washed with further water and then brine and dried over MgSO.sub.4.
The solvent was removed under reduced pressure and the residue
triturated with 40-60.degree. C. petrol and the solid collected by
filtration. Crystallisation from methyl t.butyl ether gave the
title compound as a pale yellow solid (51.4 g). .sup.1H-NMR
(d.sub.6-DMSO) .delta.1.64 (6H, s), 4.16 (2H, d), 7.1-7.25 (2H, m),
7.25-7.5 (6H, m), 12.12 (1H, br s); MS (APCI-) found (M-1)=404;
C.sub.20H.sub.17F.sub.2NO.sub.4S requires 405.
[0209] Intermediate B111--Ethyl
2-(1-(2,3-difluorobenzylthio)-1-(2,2-dimet-
hyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-methyl)phenylamino)acetate
109
[0210] To hexane washed sodium hydride (1.0 g, 60% in oil) under
argon, was added NMP (30 ml). A solution of
5-(1-(2,3-Difluorobenzylthio)-1-phen-
ylaminomethylene)-2,2dimethyl-[1,3]dioxane-4,6-dione (10.0 g)
(intermediate B110) in NMP (20 ml) was added by syringe over 15 min
at room temperature and stirred for 30 min. Ethyl bromoacetate (4.5
g) was added and the mixture heated at 60.degree. C. for 6 h. The
mixture was partitioned between ethyl acetate and water and the
aqueous layer extracted with further ethyl acetate. The combined
organic layers were washed with further water and brine, dried over
MgSO.sub.4, and the solvent removed under reduced pressure. The
orange oil so obtained was triturated with diethyl
ether/40-60.degree. C. petrol to give a solid that was collected by
filtration. This solid was recrystallised from methyl t-butyl ether
to give the title compound (7.37 g). .sup.1H-NMR (d.sub.6-DMSO)
.delta.1.24 (3H, t), 1.55 (6H, br s), 4.19 (2H, q), 4.37 (2H, d),
4.81 (2H, br s), 6.85-7.5 (8H, 2.times.m).
[0211] Intermediate
B112--2-(2-(2,3-Difluorophenyl)ethyl)-6-methylpyrido[1-
,2-a]pyrimid-4-one 110
[0212] A mixture of 2-amino-6-methylpyridine (0.55 g, 1 equiv),
Int. B80 (1.5 g, 1.15 equiv) and polyphosphoric acid (3 ml) was
heated to 110.degree. C. for 6 h, then ice/water was added and the
solution adjusted to pH 7 with aq. sodium hydroxide. The
precipitate was filtered off, washed with water and dried to obtain
the title compound (1.3 g). .sup.1H-NMR (d.sub.6-DMSO) .delta.2.89
(2H, m), 3.04 (3H, s), 3.12 (2H, m), 6.11 (1H, s), 6.62 (1H, d),
6.95-7.04 (3H, m), 7.35-7.44 (2H, m); MS (APCI+) found (M+1)=301;
C.sub.17H.sub.14F.sub.2N.sub.2O requires 300.
[0213] Intermediate
B113--2-(2-(2,3-Difluorophenyl)ethyl)-7-methyl-1H-[1,8-
]naphthyridin-4-one 111
[0214] A mixture of Int. B112 (1.0 g) and diphenyl ether (10 ml)
was heated to reflux for 4 h, then cooled to 0.degree. C. The
resulting solid was filtered off, washed thoroughly with hexane and
dried to obtain the title compound (0.67 g). .sup.1H-NMR
(d.sub.6-DMSO) .delta.2.58 (3H, s), 2.91 (2H, m), 3.09 (2H, m),
5.90 (1H, s), 6.62 (1H, d), 7.10-7.30 (4H, m), 8.26 (1H, d); MS
(APCI+) found (M+1)=301; C.sub.17H.sub.14F.sub.2N.su- b.2O requires
300.
[0215] Intermediate
C1--2-(2,3-Difluorobenzylthio)-1H-quinolin-4-one 112
[0216] A mixture of 4-allyloxy-2-(2,3-difluorobenzylthio)quinoline
(Int. B22) (2.24 g), triphenylphosphine rhodium (I) chloride (0.302
g, 5 mol %) and 1,4-diazobicyclo[2,2,2]octane (0.147 g, 20 mol %)
in ethanol (30 ml) and water (1.5 ml) was heated to reflux for 4 h.
The solvent was removed and the residue partitioned between water
and dichloromethane, the organic phase dried and evaporated.
Chromatography (silica, 4% methanol in dichloromethane) yielded the
title compound as an off white solid (1.25 g). .sup.1H-NMR
(d.sub.6-DMSO) .delta.4.55 (2H, s), 6.37 (1H, br s), 7.15 (1H, m),
7.31 (3H, m), 7.65 (2H, m), 8.02 (1H, d), 11.75 (1H, br s); MS
(APCI+) found (M+1)=304; C.sub.16H.sub.11F.sub.2NOS requires
303.
[0217] The following intermediate was prepared by the method of
intermediate C1:
13 No. Precursor Structure Name C2 Int. B23 113
2-(4-Fluorobenzylthio)-1H-quinolin-4-one
[0218] Intermediate
C3--2-(2-(2,3-Difluorophenyl)ethyl)-1H-quinolin-4-one 114
[0219] 4-Chloro-2-(2,3-difluorophenylethyl)quinoline (Int B10)
(2.83 g) was heated to reflux in aqueous hydrochloric acid (2M, 15
ml) and dioxane (6 ml) for 72 h. The reaction mixture was extracted
with dichloromethane (90 ml) and methanol (10 ml), and the organic
phase dried and evaporated to give the title compound as a white
solid (2.61 g). .sup.1H-NMR (d.sub.6-DMSO) .delta.3.15 (4H, s),
6.46 (1H, s), 7.15 (2H, m), 7.27 (1H, m), 7.51 (1H, m), 7.82 (2H,
m), 8.15 (1H, d); MS (APCI+) found (M+1)=286;
C.sub.17H.sub.13F.sub.2NO requires 285.
[0220] The following intermediates were prepared by the method of
intermediate C3:
14 No. Precursor Structure Name C4 Int. B11 115
2-(2-(4-Fluorophenyl)ethyl)-1H-quinolin-4-one C5 Int. B12 116
2-(2-(3,4-Difluorophenyl)ethyl)-1H-quinolin-- 4- one C6 Int. B13
117 2-(2-(2,4-Difluorophenyl)ethyl)-1H-- quinolin-4- one C7 Int.
B14 118 2-(2-(2-Fluorophenyl)ethyl- )-1H-quinolin-4-one C8 Int. B15
119 2-(2-(3-Chlorophenyl)ethyl)-1H-quinolin-4-one C9 Int. B16 120
2-(2-(2,3,4-Trifluorophenyl)ethyl)-1H-quinolin-4- one C10 Int. B17
121 2-(2-(3-Fluorophenyl)ethyl)-1H-quinolin-4-one
[0221] Intermediate
C11--2-(4-Fluorobenzylthio)-1,5,6,7-tetrahydro-[1]pyri- ndin-4-one
122
[0222] A mixture of
2-(4-fluorobenzylthio)-1-oxy-6,7-dihydro-5H-[1]pyrindi- n-4-ol
(Int. B9) (1.54 g) and palladium/carbon (0.3 g, 20 wt %) in acetic
acid (80 ml) was heated to 50.degree. C. in an atmosphere of
H.sub.2 at 50 psi overnight. The catalyst was filtered off and
solvent evaporated to give the title compound as a brown foam (1.21
g). .sup.1H-NMR (CDCl.sub.3) .delta.2.03 (2H, m), 2.81 (4H, m),
4.14 (2H, s), 6.46 (1H, s), 6.89 (2H, m), 7.21 (2H, m); MS (APCI+)
found (M+1)=276; C.sub.15H.sub.14FNOS requires 275.
[0223] The following intermediate was prepared by the method of
Int. C11
15 No. Precursor Structure Name C12 Int. B25 123
2-(2,3-Difluorobenzylthio)-1,5,6,7-tetrahydro-
[1]pyrindin-4-one
[0224] Intermediate
D1--[2-(2,3-Difluorobenzylthio)-4-oxo-4H-quinolin-1-yl- ]acetic
acid tert butyl ester. 124
[0225] Butyllithium (2.5 M in hexanes, 1.52 ml, 1.05 equiv) was
added dropwise to a solution of
2-(2,3-difluorobenzylthio)-1H-quinolin-4-one (Int. C1) (1.1 g, 1
equiv) in tetrahydrofuran (20 ml) at 0.degree. C. under argon. The
reaction mixture was stirred for 10 min prior to the addition of
t-butyl bromoacetate (1.76 ml), 3 equiv) and stirring continued for
60 h at 45.degree. C. The solution was diluted with dichloromethane
(40 ml) and washed with aqueous ammonium chloride and aqueous
sodium bicarbonate, dried and evaporated. Chromatography (silica,
5% [2M ammonia in methanol] in dichloromethane) yielded the title
compound as a yellow foam (0.193 g). .sup.1H-NMR (CDCl.sub.3)
.delta.1.44 (9H, s), 4.29 (2H, s), 5.30 (2H, br s), 6.45 (1H, s),
7.06-7.24 (4H, m), 7.39 (1H, t), 7.63 (1H, dt), 8.41 (1H, dd); MS
(APCI+) found (M+1)=418; C.sub.22H.sub.21F.sub.2NO.sub.3S requires
417.
[0226] The following intermediates were prepared by the method of
Intermediate D1:
16 No. Precursor Structure Name D2 Int. C3 125
[2-(2-(2,3-Difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic
acid tert butyl ester. D3 Int. C2 126
[2-(4-Fluorobenzylthio)-4-oxo-4H- quinolin-1-yl]acetic acid tert
butyl ester. D4 Int. C4 127 [2-(2-(4-Fluorophenyl)ethyl)--
4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester. D5 Int. C5
128 [2-(2-(3,4-Difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic
acid tert butyl ester. D6 Int. C6 129
[2-(2-(2,4-Difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic
acid tert butyl ester. D7 Int. C7 130 [2-(2-(2-Fluorophenyl)et-
hyl)-4-oxo-4H- quinolin-1-yl]acetic acid tert butyl ester. D8 Int.
C8 131 [2-(2-(3-Chlorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic
acid tert butyl ester. D9 Int. C9 132
[2-(2-(2,3,4-Trifluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]acetic
acid tert butyl ester. D10 Int. C10 133
[2-(2-(3-Fluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]acetic acid
tert butyl ester. D11 Int. B99 134 t-Butyl
[5-(2-(2,3-difluorophenyl)ethyl)-2-
methyl-7-oxo-2,7-dihydropyrazolo[4,3-- b]- pyridin-4-yl]acetate D12
Int. B98 135 t-Butyl [5-(2-(2,3-difluorophenyl)ethyl)1-
methyl-7-oxo-1,7-dihydropyrazolo[4,3-b- ]- pyridin-4-yl]acetate D13
Int. C12 136 t-Butyl [2-(2,3-difluorobenzylthio)-4-oxo-
5,6-trimethylenepyridin-1-yl]acetate D14 Int. C3 137 Methyl
2-(2-(2-(2,3-difluorophenyl)ethyl)- 4-oxo-4H-quinolin-1-yl)acetate
D15 Int. B113 138 Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-7-
methyl-4-oxo-4H-[1,8]naphthyridin-1-y- l]- acetate
[0227] Intermediate
D20--[2-(4Fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydro-[-
1]pyrindin-1-yl]acetic acid tert butyl ester. 139
[0228] A mixture of
2-(4-fluorobenzylthio)-1,5,6,7-tetrahydro-[1]pyrindin-- 4-one (Int.
C11) (1.21 g, 1 equiv), t-butyl iodoacetate (3.18 g, 3 equiv) and
diisopropylethylamine (3.05 ml, 4 equiv) in dichloromethane (40 ml)
was stirred at ambient temperature under argon for 48 h, then the
solution was washed with aqueous ammonium chloride and aqueous
sodium bicarbonate, dried and evaporated. Chromatography (silica,
5% methanol in dichloromethane) yielded the title compound as a off
white foam (0.982 g). .sup.1H-NMR (CDCl.sub.3) .delta.1.47 (9H, s),
2.09 (2H, m), 2.84 (4H, m), 4.07 (2H, s), 4.56 (2H, s), 6.45 (1H,
s), 6.99 (2H, m), 7.25 (2H, m); MS (APCI+) found (M+1)=390;
C.sub.21H.sub.24FNO.sub.3S requires 389.
[0229] Intermediate D25--Ethyl
(2-(2,3-difluorobenzylthio)-4-oxo-4H-quinol- in-1-yl)acetate
140
[0230] (a) A mixture of
dimethyloxosulphonium-2-(ethoxycarbonylmethylamino-
)benzoylmethylide (0.30 g, 1.01 mmol) (intermediate B100), carbon
disulphide (0.13 ml, 2.05 mmol) and diisopropylethylamine (0.35 ml,
2.02 mmol) in DMF (4 ml) was shaken under argon for 18 h then
2,3-difluorobenzyl bromide (0.42 g, 2.02 mmol) added and the
reaction shaken for a further 7 h. The solution was concentrated
and the residues separated between ethyl acetate and water. The
organics were isolated, dried (MgSO.sub.4) and concentrated.
Purification by chromatography over silica eluting using a gradient
from dichloromethane to dichloromethane/ether 3:1 yielded the title
compound (0.14 g, 36%). .sup.1H-NMR (d.sub.6-DMSO) .delta.1.2 (3H,
t, J=7Hz), 4.18 (2H, q, J=7Hz), 4.5 (2H, s), 5.3 (2H, s), 6.3 (1H,
s), 7.18 (1H, m), 7.3 (1H, m), 7.4 (2H, m), 7.6 (1H, d, J=8.5Hz),
7.7 (1H, t, J=7Hz), 8.1 (1H, d, J=8 Hz). MS (APCI+) found
(M+1)=390; C.sub.20H.sub.17F.sub.2NO.sub.3S requires 389.
[0231] (b) Ethyl
(1-(2,3-difluorobenzylthio)-1-(2,2-dimethyl-4,6-dioxo-[1,-
3]dioxan-5-ylidene)-methyl)-phenylamino)acetate (intermediate B111)
(0.85 g) under argon was stirred with trifluoroacetic acid (10 ml)
at room temperature overnight. The mixture was evaporated under
reduced pressure, dissolved in dichloromethane, washed with sodium
bicarbonate solution and dried over Na.sub.2SO.sub.4. The solvent
was removed under reduced pressure and the residue triturated with
diethyl ether to give the title compound (0.43 g). .sup.1H-NMR
(CDCl.sub.3) .delta.1.27 (3H, t), 4.26 (2H, q), 4.29 (2H, s), 5.1
(2H, br s), 6.45 (1H, s), 6.95-7.25 (4H, m), 7.39 (1H, t), 7.64
(1H, dt), 8.42 (1H, dd). Mass spectrum as above.
[0232] Intermediate
D26--(2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]na-
phthyridin-1-yl)acetic acid ethyl ester 141
[0233]
(3-tert-Butoxycarbonylmethyl-2-[2-(2,3-difluorophenyl)ethyl]-4-oxo--
4H-[1,8]naphthyridin-1-yl)acetic acid ethyl ester (Int. B71) (1.35
g, 2.86 mmol) was added portionwise to boiling diphenyl ether (10
ml) with stirring. After 20 min, the dark solution was allowed to
cool to ambient temperature. Petroleum ether (b.p. 60-80.degree.
C.) was added to the point of cloudiness to give the product as a
crystalline solid (0.724 g). .sup.1H NMR (d.sub.6-DMSO) .delta.1.19
(3H, t), 3.02-3.09 (4H, m), 4.16 (2H, q), 5.31 (2, s), 6.10 (1H,
s), 7.13-7.21 (2H, m), 7.26-7.33 (1H, m), 7.46-7.49 (1H, m), 8.49
(1H, m), 8.76 (1H, m). MS (APCI+), found (M+1)=373,
C.sub.20H.sub.18F.sub.2N.sub.2O.sub.3 requires 372.
[0234] The following intermediates were prepared by the method of
Intermediate D26:
17 No. Precursor Structure Name D27 Int. B72 142 Ethyl
[2-(2-(2,3-difluorophenyl)ethyl)-
5-ethyl-4-oxo-4H-pyridin-1-yl]acetate D28 Int. B73 143 Ethyl
[2-(2-(2,3-difluorophenyl)ethyl)-
5,6-dimethyl-4-oxo-4H-pyridin-1-y- l]- acetate D29 Int. B74 144
Ethyl 5-[2-(2-(2,3- difluorophenyl)ethyl)-2-methyl-7-oxo-
7H-thieno[3,2-b]pyridin-4-yl]acetat- e D30 Int. B75 145 Ethyl
[2-(2-(2,3-difluorophenyl)ethyl)-
4-oxo-4H-thieno[3,4-b]pyridin-1-yl]- acetate D31 Int. B76 146 Ethyl
[5-(2-(2,3-difluorophenyl)ethyl)- 2-methyl-7-oxo-7H-thiazolo[4,-
5-b]- pyridin-4-yl]acetate D32 Int. B77 147 Ethyl
[6-(2-(2,3-difluorophenyl)ethyl)-
2-methyl-4-oxo-4H-pyrazolo[3,4-b]- pyridin-7-yl]acetate D33 Int.
B78 148 Ethyl [2-(2-(2,3-difluorophenyl)ethyl)-
4-oxo-5,6-trimethylenepyridin-1-yl]- acetate D34 Int. B79 149 Ethyl
[2-(2-(2,3-difluorophenyl)- ethyl)-
4-oxo-5,6-tetramethylenepyridin-1-yl]- acetate
[0235] The following intermediates were prepared by the method of
Intermediate D25, method A:
18 No. Precursor Structure Name D40 Int. B101 150 Ethyl
[2-(2,3-difluorobenzylthio)-7-
fluoro-4-oxo-4H-quinolin-1-yl]acetate D41 Int. B102 151 Ethyl
[5-(2,3-difluorobenzylthio)-7- oxo-7H-thieno[3,2-b]pyridin-4-yl]-
acetate D42 Int. B103 152 Ethyl [5-(2,3-difluorobenzylthi- o)-7-
oxo-7H-thieno[2,3-b]pyridin-4-yl]- acetate D43 Int. B104 153 Ethyl
[6-(2,3-difluorobenzylthio)-2- methyl-4-oxo-2,4-dihydro-
pyrazolo[3,4-b]pyridin-7-yl]acetate D44 Int. B105 154 Ethyl
[2-(2,3-difluorobenzylthio)-4-
oxo-4H-[1,8]naphthyridin-1-yl]acetat- e
[0236] Intermediate D50--Ethyl
[6-(2-(2,3-difluorophenyl)ethyl)-2-ethyl-4--
oxo-2,4-dihydropyrazolo[3,4-b]pyridin-7-yl]acetate 155
[0237] A mixture of Intermediate B92 (0.120 g, 1 equiv), potassium
carbonate (0.070 g, 1.5 equiv) and iodoethane (1 equiv) in dry DMF
(1.5 ml) was stirred at room temperature for 4 days. Ethyl acetate
was added, the solution was washed with aq. sodium bicarbonate,
then dried and evaporated Chromatography (silica, 0-10% methanol in
dichloromethane) gave the title compound as abrown solid (0.1 g,
77%). .sup.1H-NMR (CDCl.sub.3) .delta.1.28 (3H, t), 1.54 (3H, t),
2.82 (2H, m), 3.02 (2H, m), 4.21-4.28 (4H, 2.times.q), 4.93 (2H,
s), 5.96 (1H, s), 6.93-7.08 (3H, m), 8.01 (1H, s); MS (APCI+) found
(M+1)=390; C.sub.20H.sub.21F.sub.2O.su- b.3 requires 389.
[0238] The following intermediate was prepared by the method of
Intermediate 50:
19 No. Precursor Structure Name D51 Int. B92, 2-iodo- propane 156
Ethyl [6-(2-(2,3-difluorophenyl)ethyl)-
2-isopropyl-4-oxo-2,4-dihydropyrazolo- [3,4-b]pyridin-7-yl]acetate
D52 Int. B92, 1-bromo-2- methoxy- ethane 157 Ethyl
[6-(2-(2,3-difluorophenyl)ethyl)-
2-(2-methoxyethyl)-4-oxo-2,4-dihydro-
pyrazolo[3,4-b]pyridin-7-yl]acetate
[0239] Intermediate
E1--[2-(2,3-Difluorobenzylthio)-4-oxo-4H-quinolin-1-yl- ]acetic
acid 158
[0240] (a) Trifluoroacetic acid (0.5 ml) was added to a solution of
Int. D1 (0.193 g) in dichloromethane (5 ml) under argon, and
stirred overnight at room temperature. Evaporation of the solvent
and trituration with ether gave the title compound as a white solid
(0.153 g).
[0241] (b) To a solution of Int. D25 (21.56 g, 0.055 mol) in dioxan
(200 ml) was added sodium hydroxide (6.0 g, 0.15 mol) in water (200
ml) and the solution stirred for 2.5 h then concentrated. The
residues were dissolved in water and acidified to pH 2 with 2M
hydrochloric acid and the precipitate collected and washed
sequentially with water, ether and then hexane. The solids were
dried in vacuo at 40.degree. C. to provide the title compound (20.0
g, 100%). .sup.1H-NMR (d.sub.6-DMSO) .delta.4.5 (2H, s), 5.2 (2H,
br s), 6.3 (1H, s), 7.18 (1H, m), 7.3 (1H, m), 7.4 (2H, m), 7.6
(1H, d, J=8.5 Hz), 7.7 (1H, t, J=8 Hz), 8.1 (1H, d, J=8 Hz). MS
(APCI+) found (M+1)=362; C.sub.18H.sub.13F.sub.2NO.sub.3S requires
361.
[0242] The following intermediates were prepared by the method of
Intermediate E1(a):
20 No. Precursor Structure Name E2 Int. D2 159
[2-(2-(2,3-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic
acid E3 Int. D3 160 [2-(4-Fluorobenzylthio)-4-oxo-4H-
quinolin-1-yl]-acetic acid E4 Int. D20 161
[2-(4-Fluorobenzylthio)-4-oxo-4,5,6,7-
tetrahydro-[1]pyridin-1-yl]-acetic acid E5 Int. D4 162
[2-(2-(4-Fluorophenyl)ethyl-4-oxo- 4H-quinolin-1-yl]-acetic acid E6
Int. D5 163 [2-(2-(3,4-Difluorophenyl)ethyl)-4-
oxo-4H-quinolin-1-yl]-acetic acid E7 Int. D6 164
[2-(2-(2,4-Difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-acetic
acid E8 Int. D7 165 [2-(2-(2-Fluorophenyl)ethyl)-4-oxo-
4H-quinolin-1-yl]-acetic acid E9 Int. D8 166
[2-(2-(3-Chlorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid
E10 Int. D9 167 [2-(2-(2,3,4-Trifluorophenyl)ethyl)-4-
oxo-4H-quinolin-1-yl]-acetic acid E11 Int. D10 168
[2-(2-(3-Fluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-acetic acid
E12 Int. D13 169 [2-(2,3-difluorobenzylthio)-4-oxo-5,6-
trimethylenepyridin-1-yl]acetic acid E13 Int. D11 170
[5-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-2,7-
dihydropyrazolo[4,3-b]pyridin-4-yl]- acetic acid E14 Int. D12 171
[5-(2-(2,3-difluorophenyl)ethyl)-1- methyl-7-oxo-1,7-
dihydropyrazolo[4,3-b]pyridin-4-yl]- acetic acid
[0243] The following intermediates were prepared by the method of
Intermediate E1(b):
21 No. Precursor Structure Name E2 Int. D14 172
(2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl)acetic
acid E21 Int. D26 173 (2-[2-(2,3-difluorophenyl)ethyl]-4-
oxo-4H-[1,8]naphthyridin-1-yl)acetic acid E22 Int. D40 174
[2-(2,3-difluorobenzylthio)-7-fluor- o-4-
oxo-4H-quinolin-1-yl]acetic acid E23 Int. D27 175
[2-(2-(2,3-difluorophenyl)ethyl)-5-
ethyl-4-oxo-4H-pyridin-1-yl]acetic acid E24 Int. D28 176
[2-(2-(2,3-difluorophenyl)ethyl)-5,- 6-
dimethyl-4-oxo-4H-pyridin-1-yl]acetic acid E25 Int. D41 177
[5-(2,3-difluorobenzylthio)-7-oxo-7H-
thieno[3,2-b]pyridin-4-yl]aceti- c acid E26 Int. D29 178
5-[2-(2-(2,3-difluorophenyl)ethyl)- -2- methyl-7-oxo-7H-thieno[3,2-
b]pyridin-4-yl]acetic acid E27 Int. D30 179
[2-(2-(2,3-difluorophenyl)ethyl)-4-
oxo-4H-thieno[3,4-b]pyridin-1-yl]-acetic acid E28 Int. D31 180
[5-(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thiazolo[4,5--
b]- pyridin-4-yl]acetic acid E29 Int. D43 181
[6-(2,3-difluorobenzylthio)-2-methyl-
4-oxo-2,4-dihydropyrazolo[3,4-b]- pyridin-7-yl]acetic acid E30 Int.
D32 182 [6-(2-(2,3-difluorophenyl)ethyl)-2-
methyl-4-oxo-4H-pyrazolo[3,4-b]- pyridin-7-yl]acetic acid E31 Int.
D50 183 [6-(2-(2,3-difluorophenyl)ethyl)-2- ethyl-4-oxo-2,4-
dihdropyrazolo[3,4-b]pyridin-7-yl]- acetic acid E32 Int. D51 184
[6-(2-(2,3-difluorophenyl)ethyl)-2- isopropyl-4-oxo-2,4-dihydropy-
razolo- [3,4-b]pyridin-7-yl]acetic acid E33 Int. D15 185
[2-(2-(2,3-difluorophenyl)ethyl)-7-
methyl-4-oxo-4H-[1,8]naphthyridin-1- yl]acetic acid E34 Int. D44
186 [2-(2,3-difluorobenzylthi- o)-4-oxo-4H-
[1,8]naphthyridin-1-yl]acetic acid E35 Int. D42 187
[5-(2,3-difluorobenzylthio)-7-oxo-7H- thieno[2,3-b]pyridin-4-yl]a-
cetic acid E36 Int. D33 188 [2-(2-(2,3-difluorophenyl)ethy- l)-4-
oxo-5,6-trimethylenepyridin-1-yl]- acetic acid E37 Int. D34 189
[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-5,6-tetramethylenepy-
ridin-1-yl]- acetic acid E38 Int. D52 190
[6-(2-(2,3-difluorophenyl)ethyl)- 2-(2-methoxyethyl)-4-oxo-2,4-
dihydropyrazolo[3,4-b]pyridin-7-yl]acetic acid
Example 1
[0244]
N-(2-Diethylaminoethyl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quin-
olin-1-yl]-N-(4'-trifluoromethylbiphenyl-4ylmethyl)acetamide
bitartrate 191
[0245] A mixture of
2-(2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl)a- cetic acid
(Int. E1) (0.15 g, 1 equiv), N,N-diethyl-N'-(4'-trifluoromethyl-
biphenyl-4-ylmethyl)ethane-1,2-diamine (Int. A2) (0.145 g, 1
equiv), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) (0.154 g, 1.2 equiv) and
diisopropylamine (0.174 ml, 2.4 equiv) in dichloromethane (10 ml)
was stirred at room temperature overnight, then washed with aqueous
ammonium chloride and aqueous sodium bicarbonate. The organic layer
was dried and evaporated, and the product purified by column
chromatography (silica, 4% [2M ammonia in methanol] in
dichloromethane). Product fractions were evaporated to an off-white
foam (0.201 g). This free base (0.201 g) was dissolved in methanol
(10 ml), tartaric acid (0.044 g) was added, the mixture stirred for
5 min then evaporated. Trituration with ether gave the bitartrate
salt as an off-white solid (0.209 g). .sup.1H-NMR (d.sub.6-DMSO, ca
2:1 rotamer mixture) .delta.1.03 (6H, m), 2.59 (6H, m), 3.41-3.62
(2H, m), 4.26 (2H, 2.times. s), 4.65-4.83 (2H, m), 5.12-5.56 (2H,
m), 6.44 (1H, 2.times. s), 6.93-7.12 (3H, m), 7.30-7.75 (11H, m),
8.41 (1H, 2.times. d); MS (APCI+) found (M+1)=694;
C.sub.38H.sub.36F.sub.5N.sub.3O.sub.2S requires 693.
Example 2
[0246]
N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-
-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
192
[0247] A mixture of
2-[2-(2-(2,3-difluorophenyl)ethyl)4oxo-4H-quinolin-1-y- l]-acetic
acid (Int. E2) (0.26 g, 1 equiv), N,N-diethyl-N'-(4'-trifluorome-
thylbiphenyl-4-ylmethyl)ethane-1,2-diamine (Int A2) (0.265 g, 1
equiv), HATU (0.28 g, 1.2 equiv) and diisopropylamine (0.32 ml, 2.4
equiv) in dichloromethane (15 ml) was stirred at room temperature
overnight, then washed with aqueous ammonium chloride and aqueous
sodium bicarbonate. The organic layer was dried and evaporated, and
the product purified by column chromatography (silica, 2% [2M
ammonia in methanol] in dichloromethane). Product fractions were
evaporated to an off-white foam (0.201 g). Trituration with ether
gave the title compound as a white solid (0.476 g). .sup.1H-NMR
(d.sub.6-DMSO, ca 2:1 rotamer mixture) .delta.0.93 (6H, 2.times.
t), 2.38-2.80 (4H, m), 2.90-3.05 (4H, m), 3.45 (2H, m), 4.30-4.95
(4H, m), 5.23-5.58 (2H, m), 6.06 (1H, 2.times. s), 7.14-7.38 (7H,
m), 7.50-7.95 (7H, m), 8.16 (1H, m); MS (APCI+) found (M+1)=676;
C.sub.39H.sub.38F.sub.5N.sub.3O.sub.2 requires 675.
Example 3
[0248]
N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-
-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
bitartrate
[0249] Treatment of
N-(2-Diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)et-
hyl)-4-oxo-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acet-
amide (Ex 2) with d-tartaric acid as for Example 1 gave the title
compound as the bitartrate salt.
Example 4
[0250]
N-(2-Diethylaminoethyl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-5,6-tri-
methylenepyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
bitartrate 193
[0251] The free base was prepared from Int. E12 and Int. A2 by the
method of Example 1. The bitartrate was formed as in example 1.
.sup.1H NMR (d.sub.6-DMSO) .delta.0.93, 0.99 (6H, 2.times. t), 1.95
(2H, m), 2.57-2.88 (8H, m), 3.21-3.60 (4H, m), 4.21 (2H, s), 4.23,
4.29 (2H, 2.times. s), 4.64, 4.75 (2H, 2.times. s) 6.15 6.17 (1H,
2.times. s), 7.12-7.21 (2H, m), 7.34-7.45 (3H, m), 7.67 (1H, d),
7.71 (1H, d), 7.85 (4H, m); MS (APCI) found (M+1)=684;
C.sub.37H.sub.38F.sub.5N.sub.3O.sub.2- S requires 683.
Example 5
[0252]
N-1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-
-oxo-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
194
[0253] The free base was prepared from Int. E1 and Int. A42 by the
method of Example 1, except using DMF as solvent in place of
dichloromethane. 1.97 g of this material was crystallised from
n.butyl acetate (10 ml) to give the title compound (1.35 g).
.sup.1H-NMR (CD.sub.3OD) .delta.1.7-2.05 (4H, m), 2.05-2.3 (2H,
2.times. t), 2.5-2.65 (2H, m), 2.95-3.1 (2H, m), 3.3 (3H, s),
3.45-3.55 (2H, m), 3.9-4.05+4.4-4.5 (1H, 2.times. m), 4.37+4.48
(2H, 2.times.s), 4.71+4.87 (2H, 2.times. br s), 5.31+5.68 (2H,
2.times. s), 6.44+6.52 (1H, 2.times.s), 6.95-7.3 (3H, m), 7.35-7.85
(11H, m), 8.2-8.35 (1H, m); MS (APCI+) found (M+1) 736;
C.sub.40H.sub.38F.sub.5N.sub.3O.sub.3S requires 735.
Example 6
[0254]
N-(1-Methylpiperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-q-
uinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
bitartrate 195
[0255] The free base was prepared from Int. E1 and Int. A5 by the
method of Example 1, except using DMF as solvent in place of
dichloromethane. Chromatography (acetone to acetone/MeOH 4:1)
yielded the free base (.about.7:3 rotomer mixture); .sup.1H-NMR
(CDCl.sub.3) .delta.1.7-1.8 (3.7H, m), 1.9-2.15 (2.3H, m), 2.26
(2.1H, s), 2.3 (0.9H, s), 2.9 (1.4H, d, J=11.5 Hz), 2.98 (0.6H, d,
J=10 Hz), 3.7 (0.3H, m), 4.2 (1.4H,s), 4.27 (0.6H, s), 4.62 (0.7H,
m), 4.69 (0.6H, s), 4.73 (1.4H, s), 5.01 (1.4H, br s), 5.35 (0.6H,
(0.6H, br s), 6.41 (0.7H, s), 6.49 (0.3H, s), 6.9-7.2 (4H, m),
7.29-7.75 (1OH, m), 8.38 (0.7H, d, J=8 Hz), 8.4 (0.3H, d, J=8 Hz);
MS (APCI+) found (M+1)=692; C.sub.38H.sub.34F.sub.5N.sub.3O.sub.2S
requires 691
[0256] Conversion to bitartrate salt was carried out as in Example
1.
Example 7
[0257]
N-(1-Methylpiperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-
-4H-[1,8]naphthyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)aceta-
mide bitartrate 196
[0258] To a stirring mixture of intermediate A5 (12.53 g, 1 equiv)
and diisopropylethylamine (18.82 ml, 3 equiv) in dry THF (125 ml)
under an argon atmosphere was added in one portion
O-(7-azabenzotriazol-1-yl)N,N,N- ',N'-tetramethyluronium
hexafluorophosphate (HATU) (16.65 g, 1.5 equiv). A solution of Int.
E21 (12.4 g, 1 equiv), in dry N-methylpyrrolidone (25 ml) and dry
THF (100 ml) was then added dropwise over 1.5 h. After 72 h the
solvents were evaporated under reduced pressure and the residue
treated with aqueous sodium bicarbonate and extracted 3 times with
ethyl acetate. The combined extracts were washed with aqueous
sodium bicarbonate, aqueous ammonium chloride then aqueous sodium
bicarbonate, dried (Na.sub.2SO.sub.4) and evaporated. The residue
was chromatographed (fine silica, 2M ammonia in
methanol/dichloromethane) and the product obtained dissolved in
dichloromethane and washed twice with 0.5M aqueous sodium hydroxide
then brine, dried (Na.sub.2SO.sub.4) and the solvent evaporated.
Crystallisation then recrystallisation from acetonitrile gave the
free base, 10.75 g. This material (10.69 g, 1 equiv) together with
L-tartaric acid (2.39 g, 1 equiv) was dissolved in methanol (50 ml)
and evaporated to a thick syrup which was triturated with ether to
give the bitartrate salt as an off-white solid (12.4 g). .sup.1H
NMR (d.sub.6-DMSO), 81.58-1.66 and 1.80-2.05 (4H, m), 2.40-2.65
(5H, m), 2.93-3.19 (6H, m), 4.15 (2H, s), 4.16-4.38 (1H, m), 4.62,
4.88, 5.42, 5.68 (4H, 4.times. s), 6.00, 6.03 (1H, 2.times. s),
7.10-7.97 (13H, m), 8.48 (1H, m), 8.82-8.90 (1H, m); MS (APCI+)
found (M+1)=675; C.sub.38H.sub.35F.sub.5N.sub.4O.sub.2 requires
674.
Example 8
[0259]
N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)et-
hyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylme-
thyl)acetamide 197
[0260] To a stirring mixture of Int. A42 (14.12 g, 1 equiv) and
diisopropylethylamine (18.82 ml, 3 equiv) in dry THF (125 ml) under
an argon atmosphere was added in one portion
O-(7-azabenzotriazol-1-yl)-N,N,- N',N'-tetramethyluronium
hexafluorophosphate (HATU) (16.65 g, 1.5 equiv). A solution of Int.
E21 (12.4 g, 1 equiv), in dry N-methylpyrrolidone (25 ml) and dry
THF (100 ml) was then added dropwise over 1.5 h. After 16 h the
solvents were evaporated under reduced pressure and the residue
treated with 1M hydrochloric acid (200 ml) and extracted 3 times
with ethyl acetate. The combined extracts were washed with 1M
hydrochloric acid (200 ml), brine, 2M sodium hydroxide .times.2,
dried (Na.sub.2SO.sub.4) and evaporated. The residue was
chromatographed (fine silica, 2M ammonia in
methanol/dichloromethane) and the oil obtained dissolved in ether
and allowed to crystallise then recrystallised from
dichloromethane/ether, yield 11.98 g (free base). 13.64 g of title
compound formed in the same manner as above was recrystallised from
hot n.butyl acetate (70 ml) to give crystalline title compound
(11.5 g). .sup.1H NMR (CD.sub.3OD), .delta.1.6-2.35 (6H, m),
2.45-2.65 (2H, 2.times. m), 2.9-3.12 (4H, m), 3.12-3.55 (2H,
2.times.t), 4.17+4.40 (1H, 2.times. m), 4.71+4.93 (2H, s), 5.3-6.0
(2H, br), 6.26+6.31 (1H, 2.times.s), 7.0-7/35 (3H, m), 7.3-7.4 (1H,
d), 7.45-7.6 (2H, m), 7.6-7.9 (6H, m), 8.61 (1H, br t), 8.87 (1H,
m); MS (APCI+) found (M+1)=719,
C.sub.40H.sub.39F.sub.5N.sub.4O.sub.3 requires 718.
Example 9
[0261]
N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3difluorobenzylthio)-4-
-oxo-4H-[1,8]naphthyridin-1-yl]-N-4'-trifluoromethylbiphenyl-4-ylmethyl)ac-
etamide bitartrate 198
[0262] The free base was prepared from Int. E34 and Int. A42 by the
method of Example 7. Chromatography (EtOAc/acetone/MeOH 9:1)
yielded the free base. .sup.1H-NMR (d.sub.6-DMSO) (.about.1:1
rotomer mixture): a .delta.1.55 (1H, br d, 11 Hz), 1.75-1.9 (4H,
m), 2.15 (0.5H, t, J=8 Hz), 2.3 (1H, br t, J=11 Hz), 2.66 (2H, m),
3.06 (2H, br t, 12 Hz), 3.2 (1.5H, s), 3.25 (1.5H, s), 3.3 (0.5H,
t, J=7 Hz), 3.45 (2H, m), 4.1 (0.5H, m), 4.2 (2H, s), 4.25 (0.5H,
m), 4.5 (1H, s), 4.59 (2H, br s), 4.8 (1H, br), 5.75 (1H, br), 6.35
(0.5H, s), 6.38 (0.5H, s), 7.16 (1H, m), 7.2-7.4 (4H, m), 7.6 (2H,
d, J=8 Hz), 7.7 (5H, m), 8.5 (1H, m), 8.7 (2H, br), 8.82 (1H, m);
MS (APCI+) found (M+1)=737; C.sub.39H.sub.37F.sub.5N.sub.4O.sub.-
3S requires 736.
Example 10
[0263]
N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-qu-
inolin-1-yl]-N-(4'-ethylbiphenyl-4-ylmethyl)acetamide bitartrate
199
[0264] The free base was prepared from Int. E1 and Int A29 by the
method of Example 1, except using DMF as solvent in place of
dichloromethane. The bitartrate salt was formed as in example 1.
.sup.1H NMR (d.sub.6-DMSO) .delta.1.07 (3H, t), 1.22 (3H, t),
1.70-1.91 (4H, m), 2.37 (2H, m), 2.66 (4H, m), 3.20 (2H,m), 4.12
(2H, s), 4.44 (3H, m), 4.70 (2H, m), 5.34 (2H, m), 6.27, 6.33 (1H,
2.times. s), 7.11-7.76 (14H,m), 8.14 (1H, m); MS (APCI) found
(M+1)=666; C.sub.40H.sub.41F.sub.2N.sub.3O.sub.2- S requires
665.
Example 11
[0265]
N-(1-Ethylpiperidin-4-yl)-2-[5-(2-(2,3-difluorophenyl)ethyl)-2-meth-
yl-7-oxo-7H-thiazolo[4,5-b]pyridin-4-yl]-N-(4'-trifluoromethylbiphenyl-4-y-
lmethyl)acetamide bitartrate 200
[0266] Prepared from intermediate E28 (0.15 g) and intermediate A40
(0.149 g) using HATU (0.188 g) and diisopropylamine (0.172 ml)
followed by bitartrate salt formation as in example 1. .sup.1H-NMR
(d.sub.6-DMSO) .delta.0.95-1.15 (3H, m), 1.6-2.1 (4H, m), 2.84 (3H,
2.times.s), 2.3-3.25 (10H, m) 4.14 (2H, s), 4.05-4.4 (1H,
2.times.m), 4.62+4.83 (2H, 2.times. br s), 5.37+5.62 (2H,
2.times.br s), 6.02+6.05 (1H 2.times. s), 7.05-7.4 (4H, m), 7.5-7.7
(2H, m), 7.7-8.0 (5H, m); MS (APCI+) found (M+1)=709;
C.sub.38H.sub.37F.sub.5N.sub.4O.sub.2S requires 708.
Example 12
[0267]
(.+-.)N-(1-Ethylpyrrolidin-3-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-
-4-oxo-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamid-
e bitartrate 201
[0268] Prepared from intermediate E2 (0.295 g) and A23 (0.30 g)
using HATU (0.395 g) and diisopropylamine (0.3 ml) followed by
bitartrate salt formation as in example 1. Spectral details of the
free base are quoted below. .sup.1H-NMR (CDCl.sub.3) .delta.1.0-1.2
(3H, m), 1.8-2.15 (1H, m), 2.15-3.15 (11H, m), 4.6-5.2 (5H, m),
6.14+6.24 (1H, 2.times. s), 6.8-7.8 (14H, m), 8.25-8.45 (1H, m); MS
(APCI+) found (M+1)=674; C.sub.39H.sub.36F.sub.5N.sub.3O.sub.2
requires 673.
Example 13
[0269]
(.+-.)N-(1-Ethylpyrrolidin-3-yl)-2-[2-(2,3-difluorobenzylthio)-4-ox-
o-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
bitartrate 202
[0270] Prepared from intermediate E1 (0.312 g) and A23 (0.30 g)
using HATU (0.395 g) and diisopropylamine (0.3 ml) followed by
bitartrate salt formation as in example 1. Spectral details of the
free base are quoted below. .sup.1H-NMR (CDCl.sub.3)
.delta.0.95-1.35 (3H, m), 1.8-2.8 (6H, m), 2.8-3.1 (2H, m),
4.19+4.25 (2H, 2.times.s), 4.5-5.5 (5H, m), 6.36+6.43 (1H, 2.times.
s), 6.85-7.2 (4H, m), 7.2-7.85 (10H, m), 8.25-8.5 (1H, m).
Example 14
[0271]
N-(4-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)--
4-oxo-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
bitartrate 203
[0272] Example 5 was converted to the bitartrate by the method of
example 1.
Example 15
[0273]
N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)--
4-oxo-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
dihydrochloride 204
[0274] Example 5 (1.0 g) was dissolved in isopropanol (10 ml) and 1
M HCl in diethyl ether (4 ml) added. A thick precipitate formed.
The mixture was evaporated under reduced pressure and the residue
dissolved in isopropanol (10 ml) with heating. On cooling a thick
precipitate formed that was filtered and dried. 0.2 g of this
material was recrystallised from further isopropanol (10 ml) to
give the title compound (0.132 g). .sup.1H-NMR (CD.sub.3OD)
.delta.1.9-2.6 (4H, m), 3.0-3.5 (4H, m), 3.36+3.41 (3H, 2.times.s),
3.5-3.8 (4H, m), 7.0-7.5 (4H, m), 7.5-7.65 (3H, m), 7.65-7.85 (5H,
m), 7.9-8.2 (2H, m), 8.4-8.55 (1H, m).
Example 16
[0275]
N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-2,3-difluorobenzylthio)-4-
-oxo-4H-quinolin-1yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide
mono paratoluenesulphonate 205
[0276] To a solution of example 5 (1.0 g) in tetrahydrofuran (THF)
(10 ml) was added a solution of paratoluenesulphonic acid
monohydrate (1 equiv) in THF (5 ml) and the mixture stirred at
0.degree. C. After 18 h, further THF was added and the mixture
filtered and dried to give a solid (0.87 g). 0.7 g of this material
was dissolved in THF (9 ml) and left at 0.degree. C. for 18 h. The
solid formed was filtered and washed with further THF (2 ml) and
dried to give the title compound as a crystalline salt (0.67 g).
.sup.1H-NMR (CD.sub.3OD) .delta.1.9-2.4 (4H, m), 2.31 (3H, s),
3.0-3.45 (7H, m's), 3.5-3.75 (4H, m), 4.3-4.55 (3H, m), 4.6-5.0
(2H, m), 5.40+5.73 (2H, 2.times. s), 6.47 (1H, s), 6.95-7.3 (5H,
m), 7.3-7.85 (13H, m),
Example 17
[0277]
N-(1-(2-Methoxyethyl)piperidin-4yl)-2-[2-(2-(2,3-difluorophenyl)eth-
yl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmet-
hyl)acetamide bitartrate 206
[0278] Example 8 (8 g, 1 equiv) together with L-tartaric acid (1.67
g, 1 equiv) was dissolved in methanol (50 ml) and evaporated to a
thick syrup which was triturated with ether to give the bitartrate
salt as an off-white solid (9.54 g). .sup.1H NMR (CD.sub.3OD),
.delta.1.53-1.64 and 1.70-1.87 (4H, m), 2.15-2.43 and 2.55-2.69
(4H, m), 2.93-3.50 (11 H, m), 4.05-4.32 (1H, m), 4.19 (2H, s),
4.61, 4.87, 5.42, 5.67 (4H, 4.times. s), 6.08, 6.11 (1H, 2.times.
s), 7.09-7.94 (12H, m), 8.49 (1H, m), 8.82-8.90 (1H, m); MS (APCI+)
found (M+1)=719, C.sub.40H.sub.39F.sub.5N.sub.4O.sub.- 3 requires
718.
Example 18
[0279]
N-(1-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)et-
hyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylme-
thyl)acetamide monohydrochloride 207
[0280] Example 8 (0.5 g) in methylethylketone (4 ml) was mixed with
4M HCl in dioxane (0.174 ml). After 18 h at 0.degree. C., a small
amount of solid was filtered off. The mother liquors were
evaporated under reduced pressure and the residue crystallised from
acetone (4 ml). The solid so formed was recrystallised from acetone
to give the title compound (0.336 g). .sup.1H NMR (CD.sub.3OD),
.delta.1.85-2.5 (4H, m), 2.95-3.15 (4H, br), 3.15-3.5 (7H, ss+m),
3.8 (4H, m), 4.38+4.61 (1H, br m), 4.74+4.97 (2H, 2.times.s),
5.4-6.0 (2H, br), 6.29 (1H, s), 7.0-7.25 (3H, m), 7.3-7.65 (2H, m),
7.65-7.9 (7H, m), 8.6-8.7 (1H, m), 8.8-8.9 (1H, m).
Example 19
[0281]
N-(9-(2-Methoxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)et-
hyl)-4-oxo-4H
-[1,8]naphthyridin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylm-
ethyl)acetamide dihydrochloride 208
[0282] Example 8 (0.321 g) in ethanol (3 ml) was stirred overnight
with 4M HCl in dioxan (0.25 ml). The solid was collected by
filtration, washed with ethanol and dried to give the title
compound (0.31 g). .sup.1H NMR (CD.sub.3OD), .delta.1.8-2.55 (4H,
m), 3.0-3.8 (15H, m), 4.15-5.1 (3H, m), 5.6-6.6 (2H, br), 6.94+6.97
(1H, 2.times.s), 7.0-7.25 (3H, m), 7.3-7.95 (9H, m), 8.8-8.95 (1H,
m), 9.15-9.25 (1H, m).
[0283] The following Examples were made by the general method of
Example 1, using an appropriate solvent such as dimethylformamide
or dichloromethane:
22 Ex. No. Precursors Structure Name 20 Int. E3 Int. A2 209
N-(2-Diethylaminoethyl)-2-[2-- (4-
fluorobenzylthio)-4-oxo-4H-quinolin-1-
yl]-N-(4'-trifluoromethylbiphen- yl-4- ylmethyl)-acetamide
bitartrate 21 Int. E4 Int. A2 210 N-(2-Diethylaminoethyl)-2-[2-(4-
fluorobenzylthio)-4-oxo-5,6-trimethy- lene- pyridin-1-yl]-N-(4'-
trifluoromethyl-biphenyl-4- ylmethyl)acetamide bitartrate 22 Int.
E12 Int. A2 211 N-(2-Diethylaminoethyl)-2-[2-(2,3-
difluorobenzylthio)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4'-
trifluoromethyl-biphenyl-4- ylmethyl)acetamide bitartrate 23 Int.
E5 Int. A2 212 N-(2-Diethylaminoethyl)-2-[2-(4-
fluorophenyl)ethyl)4-oxo-4H- methylbiphenyl-4-ylmethyl)-acetamide
24 Int. E6 Int. A2 213 N-(2-Diethylaminoethyl)-2-[2-(2-
(3,4-difluorophenyl)ethyl)-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 25 Int. E8 Int. A2 214
N-(2-Diethylaminoethyl)- -2-[2-(2- (2-fluorophenyl)ethyl)-4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 26 Int. E9 Int. A2 215
N-(2-Diethylaminoethyl)-2-[2-(2- (3-chlorophenyl)ethyl)-4-- oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 27 Int. E21 Int A2 216
N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-
4H-[1,8]naphthyridin-1-yl)]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 28 Int. E21 Int A40 217
N-(1-Ethylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
4H-[1,8]naphthyridin-1-yl)]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide 29 Int. E2 Int. A40 218
N-(1-Ethylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 30 Int. E2 Int. A22 219
N-(2-Pyrrolidin-1-ylethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)-acetamide bitartrate 31 Int. E2 Int. A41
220 N-(1-Isopropylpiperidin-4-yl)-2-[2-
(2-(2,3-difluorophenyl)ethyl)-4-oxo-4- H- quinolin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 32 Int. E2
Int. A20 221 N-(2-piperidin-1-ylethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 33 Int. E22 Int. A2 222
N-(2-Diethylaminoethyl)-2-[2-(2,3-
difluorobenzylthio)7-fluoro-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 34 Int. E26 Int. A2 223
N-(2-Diethylaminoethyl)-5-[2-(2-
(2,3-difluorophenyl)ethyl)-2-methyl-7-
oxo-7H-thieno[3,2-b]pyridin-4-yl]-N-(4'-
trifluoromethylbiphenyl-4-ylmeth- yl)- acetamide bitartrate 35 Int.
E24 Int. A2 224 N-(2-Diethylaminoethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-5,6- dimethyl-4-oxo-4H-pyridin-1-yl]-
N-(4'-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 36
Int. E23 Int. A2 225 N-(2-Diethylaminoethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-5-ethyl- 4-oxo-4H-pyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 37 Int. E2
Int. A42 226 N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-
(2-(2,3-difluorophenyl)ethyl)-- 4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 38 Int. E2 Int. A5 227
N-(1-methylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 39 Int. E27 Int. A2 228
N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-
4H-thieno[3,4-b]pyridin-1-yl]-N- (4'-trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 40 Int. E1 Int. A40 229
N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 41 Int. E1 Int. A22 230
N-(2-pyrrolidin-1-ylethyl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 42 Int. E30 Int. A40 231
N-(1-Ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-
methyl-4-oxo-4H-pyrazolo[3,4- b]pyridin-7-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide bitartrate 43 Int. E1 Int.
A41 232 N-(1-isopropylpiperidin-4-yl)-2-[2-
(2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide bitartrate 44 Int. E2 Int.
A25 233 N-(1-ethylpiperidin-4-ylmethyl)-2-
[2-(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 45 Int. E1
Int. A24 234 N-(3-Diethylaminopropyl)-2-[2-
(2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide bitartrate 46 Int. E2 Int.
A32 235 N-(4-pyrrolidin-1-ylbutyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)4-oxo- 4H-quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide bitartrate 47 Int. E2 Int.
A24 236 N-(3-Diethylaminopropyl)-2-[2-(2- (2,3-difluorophenyl)eth-
yl)-4-oxo- 4H-quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide bitaxtrate 48 Int. E1 Int.
A32 237 N-(4-pyrrolidin-1-ylbutyl)-2-[2-
(2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide bitartrate 49 Int. E25 Int.
A40 238 N-(1-Ethylpiperidin-4-yl)-2-[5-(2,3-
difluorobenzylthio)-7-oxo-7H- thieno[3,2-b]pyridin-4-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 50 Int.
E28 Int. A2 239 N-(2-Diethylaminoethyl)-2-[5-(2-
(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thiazolo[4,5-
b]pyridin-4-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 51 Int. E1 Int. A27 240
N-(2-Diethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-
quinolin-1-yl]-N-(4'-ethylbiphenyl- 4-ylmethyl)acetamide bitartrate
52 Int. E2 Int. A27 241 N-(2-Diethylaminoethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4'-
ethylbiphenyl-4-ylmethyl)- acetamide bitartrate 53 Int. E1 Int. A28
242 N-(2-Diethylaminoethyl)-2-[2-(2,3- -
difluorobenzyltbio)-4-oxo-4H- quinolin-1-yl]-N-(4'-
isopropylbiphenyl4-ylmethyl)- acetamide bitartrate 54 Int. E2 Int.
A28 243 N-(2-Diethylaminoethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4'-
isopropylbiphenyl-4-ylmethyl)- acetamide bitartrate 55 Int. E34
Int. A2 244 N-(2-Diethylaminoethyl)-2-[2-(2,3-
difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 56 Int.
E34 Int. A40 245 N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3-
difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 57 Int. E2
Int. A26 246 N-(2-Diethylaminoethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4'-
methylbiphenyl-4-ylmethyl)- acetamide bitartrate 58 Int. E1 Int.
A26 247 N-(2-Diethylaminoethyl)-2-[2-(2,3-
difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4'-
methylbiphenyl-4-ylmethyl)- acetamide bitartrate 59 Int. E2 Int.
A43 248 N-(1-Ethoxycarbonylmethylpiperidin-4-yl)-2-
[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- - methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 60 Int. E21 Int. A41 249
N-(1-isopropylpiperidin-4-yl)-2-[2-
(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-[1,8]naphthyridin-1-yl]-N-
(4'-trifluoromethyibiphenyl-4- ylmethyl)acetamide bitartrate 61
Int. E1 Int. A30 250 N-(2-Diethylaminoethyl)-2-[2-(2,3-
difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(3',4'-
dimethylbiphenyl-4-ylmethyl)- acetamide bitartrate 62 Int. E21 Int.
A48 251 N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2-(2,3-
difluorophenyl)ethyl)-4-oxo-4H- [1,8]naphthyridin-1-yl]- -N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 63 Int. E1
Int. A31 252 N-(2-Diethylaminoethyl)-2-[2-(2,3-
difluoroberizylthio)-4-oxo-4H- quinolin-1-yl]-N-(3',4'-
difluorobiphenyl-4-ylmethyl)- acetamide bitartrate 64 Int. E35 Int.
A2 253 N-(2-Diethylaminoethyl)-2-[6-(2,3-
difluorobenzylthio)-4-oxo-4H- thieno[2,3-b]pyridin-7-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 65 Int.
E34 Int. A5 254 N-(1-methylpiperidin-4-yl)-2-[2-
(2,3-difluorobenzylthio)-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 66 Int. E2
Int. A40 255 N-(1-Ethylpiperidin-4-yl)-2-[2-(2-
(2,3,4-trifluorophenylethyl)-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 67 Int. E29 Int. A2 256
N-(2-diethylaminoethyl)-2-[6-(2,3- difluorobenzylthio)-2-methyl-4-
oxo-2,4-dihydro- pyrazolo[3,4-b]pyridin-7- -yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 68 Int.
E31 Int. A40 257 N-(1-Ethylpiperidin-4-yl)-2-[6-(2-
(2,3-difluorophenyl)ethyl)-2-ethyl- 4-oxo-2,4-
dihydropyrazolo[3,4-b]pyri- din-7-
yl]-N-(4'-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate
69 Int. E32 Int. A40 258 N-(1-Ethylpiperidin-4-yl)-2-[6-(- 2-
(2,3-difluorophenyl)ethyl)-2-isopropyl-4-
oxo-2,4-dihydropyrazolo[3,4-b- ]pyridin-7-
yl]-N-(4'-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate
70 Int. E2 Int. A29 259 N-(1-Ethylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4'-ethyl-
biphenyl-4-ylmethyl)acetamide bitartrate 71 Int. E28 Int. A41 260
N-(1-isopropylpiperidin-4-yl)-2-[5- -
(2-(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-7H-thiazolo[4,5-
b]pyridin-4-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 72 Int. E28 Int. A42 261
N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[5-(2-(2,3-
difluorophenyl)ethyl)-2-methyl-7- oxo-7H-thiazolo[4,5-b]pyridin-4-
yl]-N-(4'-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate
73 Int. E36 Int. A40 262 N-(1-Ethylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
5,6-trimethylenepyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 74 Int. E36 Int. A5 263
N-(1-methylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
5,6-trimethylenepyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 75 Int. E36 Int. A42 264
N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2,3-
difluorophenyl)ethyl)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 76 Int.
E36 Int. A41 265 N-(1-isopropylpiperidin-4-yl)-2-[2-
(2-(2,3-difluorophenyl)ethyl)-4- oxo-5,6-trimethylenepyridin-1-yl]-
N-(4'-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 77
Int. E13 Int. A40 266 N-(1-Ethylpiperidin-4-yl)-2-[5-(2-
(2,3-difluorophenyl)ethyl)-2- methyl-7-oxo-2,7-
dihydropyrazolo[4,3-b]pyr- idin-4-
yl]-N-(4'-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate
78 Int. E14 Int. A40 267 N-(1-Ethylpiperidin-4-yl)-2-[5-(- 2-
(2,3-difluorophenyl)ethyl)-1- methyl-7-oxo-1,7-
dihydropyrazolo[4,3-b]p- yridin-4-
yl]-N-(4'-trifluoromethylbiphenyl- 4-ylmethyl)acetamide bitartrate
79 Int. E36 Int. A2 268 N-(1-Ethylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
5,6-trimethylenepyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 80 Int. E33 Int. A40 269
N-(1-Ethylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7-
methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- - ylmethyl)acetamide bitartrate 81 Int.
E33 Int. A2 270 N-(2-Diethylaminoethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H-
[1,8]naphthyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4- -
ylmethyl)acetamide bitartrate 82 Int. E33 Int. A5 271
N-(1-methylpiperidin-4-yl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-7-
methyl-4-oxo-4H- [1,8]naphthyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- - ylmethyl)acetamide bitartrate 83 Int.
E33 Int. A41 272 N-(1-isopropylpiperidin-4-yl)-2-[2-
(2-(2,3-difluorophenyl)ethyl)-7- methyl-4-oxo-4H-
[1,8]naphthyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4- -
ylmethyl)acetamide bitartrate 84 Int. E33 Int. A42 273
N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2-(2,3-
difluorophenyl)ethyl)-7-methyl-4- oxo-4H-[1,8]naphthyridin-1-yl]-N-
(4'-trifluoromethylbiphenyl-4- ylmethyl)acetamide bitartrate 85
Int. E12 Int. A5 274 N-(1-methylpiperidin-4-yl)-2-[2-
(2,3-difluorobenzylthio)-4-oxo-5,6-
trimethylenepyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 86 Int. E12 Int. A40 275
N-(1-Ethylpiperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-5,6-
trimethylenepyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 87 Int. E12 Int. A41 276
N-(1-isopropylpiperidin-4-yl)-2-[2-
(2,3-difluorobenzylthio)-4-oxo-5,6-
trimethylenepyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 88 Int. E12 Int. A42 277
N-(1-(2-methoxyethyl)piperidin-4-
yl)-2-[2-(2,3-difluorobenzylthio)-4-
oxo-5,6-trimethylenepyridin-1-yl]- N-(4'-trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 89 Int. E37 Int. A2 278
N-(2-Diethylaminoethyl)-2-[2-(2- (2,3-difluorophenyl)ethyl)-4-oxo-
5,6-tetramethylenepyridin-1-yl]-N- (4'-trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 90 Int. E1 Int. A45 279
N-(1-methylpiperidin-4-yl)-2-[2- (2,3-difluorobenzylthio)-4-oxo-4H-
quinolin-1-yl]-N-(4'- chlorobiphenyl-4-ylmethyl)- acetamide
bitartrate 91 Int. E2 Int. A45 280
N-(1-methylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4'-
chlorobiphenyl-4-ylmethyl)- acetamide bitartrate 92 Int. E2 Int.
A44 281 N-(1-Ethylpiperidin-4-yl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo- 4H-quinolin-1-yl]-N-(4'-
chlorobiphenyl-4-ylmethyl)- acetamide bitartrate 93 Int. E2 Int.
A47 282 N-(1-(2-methoxyethyl)piperidin-4- yl)-2-[2-(2-(2,3-
difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4'-
chlorobiphenyl-4-ylmethyl)- acetamide bitartrate 94 Int. E2 Int.
A46 283 N-(1-isopropylpiperidin-4-yl)-2-[2-
(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-N-(4'-
chlorobiphenyl-4-ylmethyl)- acetamide bitartrate 95 Int. E30 Int.
A2 284 N-(2-diethylaminoethyl)-2-[6-(2- (2,3-difluorophenyl)ethy-
l)-2- methyl-4-oxo-4H-pyrazolo[3,4-
b]pyridin-7-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 96 Int. E34 Int. A48 285
N-(1-(t-butoxycarbonyl)piperidin-4-
yl)-2-[2-(2,3-difluorobenzylthio)-4-
oxo-4H-[1,8]naphthyridin-1-yl]-N- (4'-trifluoromethylbiphenyl-4-
ylmethyl)acetamide 97 Int. E38 Int. A40 286
N-(1-ethylpiperidin-4-yl)-2-[6-(2- (2,3-difluorophenyl)ethyl)-2-(2-
methoxyethyl)-4-oxo-4H-pyrazolo-
[3,4-b]pyridin-7-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate
[0284] The following intermediates were prepared by the method of
Example 1, but were not included in biological testing:
23 No. Precursors Structure Name F1 Int. E1 Int. A48 287
N-(1-(t-butoxycarbonyl)piperidin-4-
yl)-2-[2-(2,3-difluorobenzylthio)-4- oxo-4H-quinolin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide F2 Int. E2 Int. A48
288 N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2-(2,3-
difluorophenyl)ethyl)-4-oxo-4H- quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide F3 Int. E36 Int. A48 289
N-(1-(t-butoxycarbonyl)piperidin-4- yl)-2-[2-(2-(2,3-
difluorophenyl)ethyl)-4-oxo-5,6- trimethylenepyridin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide F4 Int. E1 Int. A33
290 N-(2-(N'-ethyl-N'-(t- butoxycarbonyl)aminoethyl)-2-[2-
(2,3-difluorobenzylthio)-4-oxo-4H- quinolin-1-yl]-N-(4'-trifluoro-
methylbiphenyl-4-ylmethyl)- acetamide F5 Int. E2 Int. A33 291
N-(2-(N'-ethyl-N'-(t- butoxycarbonyl)aminoethyl)-2-[2-
(2-(2,3-difluorophenyl)ethyl)-4- oxo-4H-quinolin-1-yl]-N-(4'-
trifluoromethylbiphenyl-4- ylmethyl)acetamide
Example 99
[0285]
N-(2-Diethylaminoethyl)-2-[4-oxo-2-(2-(2,3,4-trifluorophenyl)ethyl)-
-4H-quinolin-1-yl]-N-(4'-trifluoromethyl-biphenyl-4-ylmethyl)acetamide
bitartrate 292
[0286] A solution of
N,N-diethyl-N'-(4'-trifluoromethyl-biphenyl-4-ylmethy-
l)ethane-1,2-diamine (0.242 g, 0.69 mmol) (Int. A2),
1-(3-dimethylaminopropyl)3-ethylcarbodiimide (0.265 g, 1.39 mmol),
1-hydroxybenzotriazole hydrate (0.02 g),
2-(4-oxo-2-[2-(2,3,4-trifluoroph-
enyl)ethyl]-4H-quinolin-1-yl)-acetic acid (Int E10) (0.25, 0.69
mmol) and N,N-diisopropylethylamine (0.15 ml, 0.86 mmmol) in
dichloromethane (5 ml) was stirred at ambient temperature overnight
then washed with aqueous sodium bicarbonate and evaporated. The
residue was purified by chromatography (10 g silica cartridge,
dichloromethane-50% acetone/dichloromethane) and triturated with
hexane to give the title compound as a white solid (0.23 g, 47%).
.sup.1H-NMR (d6 DMSO, rotamer mixture) .delta.0.89-0.98 (6H, m),
2.33-2.67 (6H, m), 2.84-3.00 (4H, m), 3.45-3.61 (2H, m), 4.67/4.92
(2H, 2.times. s), 5.24/5.50 (2H, 2.times. s), 6.02/6.05 (1H,
2.times. s), 7.19-7.20 (4H, m), 7.51-7.88 (9H, m), 8.16 (1H, t); MS
(APCI+) found (M+1)=694; C.sub.39H.sub.37F.sub.6N.sub.3O- .sub.2
requires 693.
[0287] d-Tartaric acid (0.028 g, 0.19mmol) was added to a solution
of the free base (0.13 g, 0.19 mmol) in methanol (5 ml) with
stirring. The resulting solution was evaporated to yield the salt
(0.158 g). .sup.1H-NMR (d6 DMSO, rotamer mixture) .delta.1.00 (6H,
br s), 2.51-2.97 (10H, m), 3.64 (2H, br s), 4.23 (2H, br s),
4.67/4.93 (2H, 2.times. s), 5.28/5.50 (2H, 2.times. s), 6.05 (1H,
br s) 7.23-7.83 (13H, m), 8.17 (1H, s); MS (APCI+) found (M+1)=694;
C.sub.39H.sub.37F.sub.6N.sub.3O.sub.2 requires 693.
[0288] The following compounds were prepared by the method of
Example 99
24 Ex. No. Precursors Structure Name 100 Int. E7 Int. A2 293
N-(2-Diethylaminoethyl)-2-[2-(2- (2,4-difluorophenyl)ethyl)-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 101 Int. E11 Int. A2 294
N-(2-Diethylaminoethyl)-2-[2-(2- (3-fluorophenyl)ethyl)-4- -oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate
Example 105
[0289]
N-(piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin--
1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acetamide bitartrate
295
[0290] To intermediate F1 (0.55 g) in dichloromethane (6 ml) was
added trifluoroacetic acid (2.5 ml) at room temperature. The
mixture was stirred for 2 h, the solvent removed under reduced
pressure and diethyl ether added. The solid so formed was filtered
and washed with diethyl ether to give a solid that was partitioned
between dilute sodium bicarbonate and dichloromethane. The aqueous
layer was extracted with further dichloromethane and the combined
organic layers dried over K.sub.2CO.sub.3, filtered and evaporated
under reduced pressure to a solid (0.42 g). This free base (0.42 g)
was dissolved in methanol (10 ml), tartaric acid (0.044 g) was
added, the mixture stirred for 5 min then evaporated under reduced
pressure. Trituration with ether gave the bitartrate salt as an
off-white solid (0.46 g). .sup.1H-NMR (d6 DMSO, rotamer mixture)
.delta.1.6-2.05 (4H, m), 2.7-3.05 (2H, m), 3.1-3.4 (2H, m), 3.88
(2H, s), 4.1-5.8 (7H, br ms) 6.27+6.32 (1H, 2.times.s), 7.05+7.55
(6H, m), 7.55-7.95 (8H, m), 8.14 (1H, dt); MS (APCI+) found
(M+1)=678; C.sub.37H.sub.32F.sub.5N.sub.3O.sub.2S requires 677.
[0291] The following examples were prepared by the method of
Example 105:
25 Ex. No. Precursors Structure Name 106 Int. F2 296
N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide bitartrate 107 Int. F3 297
N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-5,6-
trimethylenepyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-
ylmethyl)acetamide bitartrate 108 Example 62 298
N-(piperidin-4-yl)-2-[2-(2-(2,3- difluorophenyl)ethyl)-4-oxo-4H-
[1,8]naphthyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-yl-
methyl)acetamide bitartrate 109 Example 96 299
N-(piperidin-4-yl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-
[1,8]naphthyridin-1-yl]-N-(4'- trifluoromethylbiphenyl-4-yl-
methyl)acetamide trifluoroacetate 110 Int. F4 300
N-(2-ethylaminoethyl)-2-[2-(2,3- difluorobenzylthio)-4-oxo-4H-
quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide 111 Int. F5 301 N-(2-ethylaminoethyl)-2-[2-(2-
(2,3-difluorophenyl)ethyl)-4-oxo-
4H-quinolin-1-yl]-N-(4'-trifluoro- methylbiphenyl-4-ylmethyl)-
acetamide
Example 115
[0292]
N-(1-(2-hydroxyethyl)piperidin-4-yl)-2-[2-(2-(2,3-difluorophenyl)et-
hyl)-4-oxo-4H-quinolin-1-yl]-N-(4'-trifluoromethylbiphenyl-4-ylmethyl)acet-
amide bitartrate 302
[0293] A mixture of Example 59 (0.18 g, 1 equiv), lithium
borohydride (0.12 ml, 2M in THF, 1 equiv) and dry THF (2 ml) was
heated at reflux under argon overnight, then a further 0.06 ml
portion of lithium borohydride solution was added and heating
continued for 4 h. Evaporation, aqueous workup and chromatography
(silica, 0-10% methanol in dichloromethane) gave the title compound
(0.06 g). The bitartrate was prepared as in example 1. .sup.1H-NMR
(DMSO, rotamer mixture) .delta.1.5-2.1 (4H, m), 2.5-3.65 (12H, m),
4.15 (2H, s), 3.85-5.8 (SH, br m), 6.01+6.06 (1H, 2.times. s),
7.0-7.95 (14H, m), 8.05-8.2 (1H, m); MS (APCI+) found (M+1)=704;
C.sub.40H.sub.38F.sub.5N.sub.3O.sub.3 requires 703.
[0294] Biological Data
[0295] 1. Screen for Lp-PLA.sub.2 inhibition.
[0296] Enzyme activity was determined by measuring the rate of
turnover of the artificial substrate (A) at 37 C in 50 mM HEPES
(N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid) buffer
containing 150 mM NaCl, pH 7.4. 303
[0297] Assays were performed in 96 well titre plates.
[0298] Recombinant LpPLA2 was purified to homogeneity from
baculovirus infected Sf9 cells, using a zinc chelating column, blue
sepharose affinity chromatography and an anion exchange column.
Following purification and ultrafiltration, the enzyme was stored
at 6 mg/ml at 4.degree. C. Assay plates of compound or vehicle plus
buffer were set up using automated robotics to a volume of 170
.mu.l. The reaction was initiated by the addition of 20 .mu.l of
10.times. substrate (A) to give a final substrate concentration of
20.mu.M and 10 .mu.l of diluted enzyme to a final 0.2 nM
LpPLA2.
[0299] The reaction was followed at 405 nm and 37.degree. C. for 20
minutes using a plate reader with automatic mixing. The rate of
reaction was measured as the rate of change of absorbance.
[0300] Results
[0301] The compounds described in the Examples were tested as
described above and had IC.sub.50 values in the range <0.1 to
100 nM.
* * * * *