U.S. patent application number 11/290322 was filed with the patent office on 2006-04-20 for compounds as pde iv and tnf-inhibitors.
This patent application is currently assigned to AVENTIS PHARMA LIMITED. Invention is credited to Garry Fenton, Tahir Nadeem Majid, Malcolm Norman Palfreyman.
Application Number | 20060084809 11/290322 |
Document ID | / |
Family ID | 26303291 |
Filed Date | 2006-04-20 |
United States Patent
Application |
20060084809 |
Kind Code |
A1 |
Fenton; Garry ; et
al. |
April 20, 2006 |
Compounds as PDE IV and TNF-inhibitors
Abstract
This invention is directed to a [di(ether or
thioether)heteroaryl or fluoro substituted aryl] compound or an
N-oxide thereof or a pharmaceutically acceptable salt thereof,
which is useful for inhibiting the production or physiological
effects of TNF in the treatment of a patient suffering from a
disease state associated with a physiologically detrimental excess
of tumor necrosis factor (TNF). Compounds within the scope of the
present invention also inhibit cyclic AMP phosphodiesterase, and
are useful in treating a disease state associated with pathological
conditions that are modulated by inhibiting cyclic AMP
phosphodiesterase, such disease states including inflammatory and
autoimmune diseases, in particular type IV cyclic AMP
phosphodiesterase. The present invention is therefore directed to
their pharmacological use for inhibiting TNF and/or cyclic AMP
phosphodiesterase, pharmacological compositions comprising the
compounds and methods for their preparation.
Inventors: |
Fenton; Garry; (Kent,
GB) ; Majid; Tahir Nadeem; (Hoboken, NJ) ;
Palfreyman; Malcolm Norman; (Kent, GB) |
Correspondence
Address: |
ROSS J. OEHLER;AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
AVENTIS PHARMA LIMITED
Kent
GB
|
Family ID: |
26303291 |
Appl. No.: |
11/290322 |
Filed: |
November 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10792579 |
Mar 3, 2004 |
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11290322 |
Nov 30, 2005 |
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10207493 |
Jul 29, 2002 |
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|
10792579 |
Mar 3, 2004 |
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08592817 |
Jan 26, 1996 |
6472412 |
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10207493 |
Jul 29, 2002 |
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PCT/GB94/01630 |
Jul 28, 1994 |
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08592817 |
Jan 26, 1996 |
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Current U.S.
Class: |
546/255 ;
546/272.1; 546/285; 546/308; 558/410; 564/152; 564/163; 564/170;
564/74 |
Current CPC
Class: |
C07D 213/89 20130101;
A61P 19/02 20180101; C07C 235/56 20130101; C07D 213/65 20130101;
A61P 11/00 20180101; A61P 27/16 20180101; A61P 31/18 20180101; A61P
13/12 20180101; A61P 31/00 20180101; C07D 213/70 20130101; A61P
17/06 20180101; A61P 25/16 20180101; C07D 213/79 20130101; C07D
401/12 20130101; C07D 413/12 20130101; A61P 11/02 20180101; A61P
37/06 20180101; C07D 213/75 20130101; C07D 213/82 20130101; A61P
17/04 20180101; A61P 7/12 20180101; A61P 35/02 20180101; A61P 43/00
20180101; C07C 2603/66 20170501; A61P 33/00 20180101; C07C 237/30
20130101; A61P 1/04 20180101; A61P 17/00 20180101; A61P 25/00
20180101; A61P 29/00 20180101; C07C 327/48 20130101; A61P 31/04
20180101; A61P 19/00 20180101; C07C 255/60 20130101; A61P 17/02
20180101; A61P 11/06 20180101; C07C 217/58 20130101; A61P 19/08
20180101; A61P 25/28 20180101; C07C 43/247 20130101; C07C 2603/64
20170501; C07D 213/69 20130101; C07D 417/12 20130101; A61P 31/12
20180101; A61P 33/06 20180101; C07C 2601/08 20170501; C07D 213/81
20130101; A61P 3/10 20180101; A61P 37/08 20180101; A61P 11/08
20180101; C07D 409/12 20130101 |
Class at
Publication: |
546/255 ;
546/308; 546/272.1; 558/410; 564/152; 564/163; 564/170; 546/285;
564/074 |
International
Class: |
C07D 401/02 20060101
C07D401/02; C07D 413/02 20060101 C07D413/02; C07D 213/75 20060101
C07D213/75; C07C 255/28 20060101 C07C255/28; C07C 237/10 20060101
C07C237/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 1993 |
GB |
9315581.0 |
Jul 28, 1993 |
GB |
9315632.1 |
Claims
1-38. (canceled)
39. A compound of formula I ##STR51## wherein R.sup.1 is lower
alkyl optionally substituted by one or more of halo, cycloalkyl or
cycloalkenyl; R.sup.2 is alkyl, alkenyl or alkynyl each optionally
substituted by one or more of halo, cycloalkyl or cycloalkenyl; or
cycloalkyl or cycloalkenyl each optionally substituted by one or
more of halo, methylidene or alkyl; or optionally substituted
cyclothioalkyl consisting of a non-aromatic monocyclic or
multicyclic ring system of 3 to about 10 ring atoms wherein at
least one of the ring atoms is sulphur and the other ring atoms are
carbon and the substituted cyclothioalkyl is substituted by one or
more halo, or any ring sulphur atom is optionally oxidized to the
corresponding S-oxide or S,S-dioxide; or optionally substituted
cyclothioalkenyl consisting of a non-aromatic monocyclic or
multicyclic ring system of 3 to about 10 ring atoms wherein at
least one of the ring atoms is sulphur, the other ring atoms are
carbon and the ring system contains a carbon-carbon double bond and
the substituted cyclothioalkenyl is substituted by one or more halo
or any ring sulphur atoms is optionally oxidized to the
corresponding S-oxide or S,S-dioxide; R.sup.3 is optionally
substituted aryl or heteroaryl, wherein the substituted aryl or
substituted heteroaryl group is substituted by one or more
substituents which may be the same or different and are selected
from alkyl, aryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy,
aralkyloxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarboxyl, aryloxycarbonyl, aralkyloxycarbonyl, acylamino,
aroylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,
arylsulfinyl, alkylthio, arylthio, aralkylthio, Y.sup.1Y.sup.2N--,
Y.sup.1Y.sup.2 NCO-- or Y.sup.1Y.sup.2 NSO.sub.2--, where Y.sup.1
and Y.sup.2 are independently hydrogen, alkyl, aryl, and aralkyl;
Q.sup.1, Q.sup.2 and Q.sup.3 are independently nitrogen or CH,
provided that at least one of Q.sup.1, Q.sup.2 and Q.sup.3 is other
than CH; Z, Z.sup.1 and Z.sup.2 are independently oxygen or sulfur;
Z.sup.3 is --CH.dbd.CH--, --CZCH.sub.2--, --CZ-CZ-,
--CH.sub.2--NH--, --CH.sub.2--O--, --CX.sub.2--O--,
--CH.sub.2--S--, --CH.sub.2--SO.sub.2-- or --CZNH--; and X is halo;
or an N-oxide thereof or a pharmaceutically acceptable salt
thereof; with the proviso that R.sup.1Z.sup.1 and R.sup.2Z.sup.2
cannot both represent methoxy.
40. The compound according to claim 39 wherein R.sup.2 is alkyl
optionally substituted by one or more halo, cycloalkyl or
cycloalkenyl; cycloalkyl or cycloalkenyl each optionally
substituted by one or more of halo, methylidene or alkyl; or
optionally substituted cyclothioalkyl consisting of a non-aromatic
monocyclic or multicyclic ring system of 3 to about 10 ring atoms
wherein at least one of the ring atoms is sulphur and the other
ring atoms are carbon and the substituted cyclothioalkyl is
substituted by one or more halo, or any ring sulphur atom is
optionally oxidized to the corresponding S-oxide or S,S-dioxide;
R.sup.3 is phenyl, substituted phenyl or azaheteroaryl; Q.sup.1 and
Q.sup.2 are independently nitrogen or CH, provided that at least
one of Q.sup.1 and Q.sup.2 is other than CH; Q.sup.3 is CH; and
Z.sup.3 is --CZCH.sub.2-- or --CZNH--.
41. The compound according to claim 40 wherein R.sup.1 is methyl or
difluoromethyl; R.sup.2 is isopropyl, cyclopropylmethyl,
cyclopentyl, trinorbornyl, trinorbornenyl,
tricyclo[2.2.1.0.sup.2.6.]heptanyl and tetrahydrothiophenyl;
Z.sup.1 is oxygen or sulphur; Z.sup.2 is oxygen; and Z.sup.3 is
--COCH.sub.2-- or --CONH--.
42. The compound according to claim 39 wherein Q.sup.1 and Q.sup.2
are independently nitrogen or CH, and at least one of Q.sup.1 and
Q.sup.2 is nitrogen, and Q.sup.3 is CH.
43. The compound according to claim 39 wherein Q.sup.1 is N, and
Q.sup.2 and Q.sup.3 are CH; Q.sup.2 is N, and Q.sup.1 and Q.sup.3
are CH; or Q.sup.1 and Q.sup.2 are N, and Q.sup.3 is CH.
44. The compound according to claim 39 wherein independently
Q.sup.1, Q.sup.2 or Q.sup.3 is N-oxide or R.sup.3 is
azaheterocyclyl having an imine moiety thereof as an N-oxide.
45. The compound according to claim 39 wherein Q.sup.1 and Q.sup.3
are CH, and Q.sup.2 is an N-oxide.
46. The compound according to claim 39 wherein R.sup.3 is phenyl
substituted on the 2-position or on both the 2- and
6-positions.
47. The compound according to claim 39 wherein R.sup.3 is
heteroaryl substituted on one or both of the positions adjacent to
the position of R.sup.3 that is attached to Z.sup.3.
48. The compound according to claim 39 wherein R.sup.3 is
azaheteroaryl substituted on one or both of the positions adjacent
to a position of R.sup.3 that is attached to Z.sup.3.
49. The compound according to claim 48 wherein R.sup.3 is a
3,5-dihalo-pyrid-4-yl.
50. The compound according to claim 49 wherein R.sup.3 is
3,5-dihalo-1-oxido-4-pyridinium.
51. The compound according to claim 39 wherein Z.sup.2 is --CZNH--
or --CZCH.sub.2--.
52. The compound according to claim 51 wherein Z is oxygen.
53. The compound according to claim 39 wherein Z.sup.1 and Z.sup.2
are oxygen, or Z.sup.1 is sulfur and Z.sup.2 is oxygen.
54. The compound according to claim 53 wherein Z.sup.1 and Z.sup.2
are oxygen.
55. The compound according to claim 39 wherein Z.sup.1 is
oxygen.
56. The compound according to claim 39 wherein R.sup.1 is lower
alkyl optionally substituted by one or more halo.
57. The compound according to claim 56 wherein the substitution is
on a position of R.sup.1 that is attached to Z.sup.1.
58. The compound according to claim 39 wherein R.sup.2 is lower
alkyl, cycloalkyl or cyclothioalkyl optionally substituted by one
or more halo.
59. The compound according to claim 58 wherein the substitutition
is on a position of R.sup.2 that is attached to Z.sup.1.
60. The compound according to claim 58 wherein R.sup.2 is
cyclothioalkyl substituted on a position of R.sup.2 that is
attached to Z.sup.1 or on a position adjacent to the thio moiety of
the cyclothioalkyl.
61. The compound according to claim 39 wherein R.sup.2 is
isopropyl, cyclopropylmethyl, cyclopentyl, trinorbornyl,
trinorbornenyl, tricyclo[2.2.1.0.sup.2.6.]heptanyl and
tetrahydrothiophenyl.
62. The compound according to claim 39 wherein R.sup.2 is
cyclothioalkyl oxidized to the corresponding S-oxide or
S,S-dioxide.
63. The compound according to claim 39 wherein R.sup.1 is lower
alkyl optionally substituted by halo; and R.sup.2 is isopropyl,
cyclopropylmethyl, cyclopentyl, trinorbornyl, trinorbornenyl,
tricyclo[2.2.1.0.sup.2.6.]heptanyl and tetrahydrothiophenyl.
64. The compound according to claim 39 which is:
5-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide;
N-(2,6-dichlorophenyl)-5-cyclopentyloxy-6-methoxynicotinamide;
5-cyclopentyloxy-N-(3,5-dimethylisoxazol-4-yl)-6-methoxynicotinamide
5-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-6-methoxynicotinamide
6-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-5-methoxypyridine-2-carboxami-
de;
1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)-
ethanone;
5-cyclopentyloxy-N-(3,5-dichloro-4-pyridyl)-6-methylthionicotin-
amide;
N-(3,5-dichloro-4-pyridyl)-5-isopropyloxy-6-methylthionicotinamide-
;
2-(3,5-dichloro-4-pyridyl)-1-(5-isopropyloxy-6-methylthio-3-pyridyl)eth-
anone;
1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloro-1-oxido-4-
-pyridinio)ethanone hemihydrate;
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-
-2-yloxy)nicotinamide;
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)nicotinamide monohydrate;
N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de;
N-(2,6-difluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de;
N-(2-chloro-6-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carb-
oxamide;
N-(2-trifluoromethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-
-carboxamide;
N-(2,4,6-trichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e;
N-(2,6-dibromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide-
;
N-(2-chloro-6-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide;
N-(2,6-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide;
N-(2-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; N-phenyl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(3-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2,6-dimethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-methylthiophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-bromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide;
N-(2-aminosulfonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide;
N-(2-benzoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide;
N-(2-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2,5-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(3-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-dimethylaminophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e;
N-(2-acetylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(2-hydroxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(4-chloropyrid-3-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-pyrid-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-pyrazin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-pyrimidin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(3-methylpyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-pyrid-3-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(3-chloropyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(3-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-pyrid-4-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(3,5-dimethylisoxazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide;
N-(3,5-dibromopyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-car-
boxamide;
N-(3,5-dimethylpyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-
-carboxamide;
N-(2,6-dichloro-4-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide;
N-(2,6-dichloro-4-methoxycarbonylphenyl)-4-cyclopentyloxy-5-metho-
xypyridine-2-carboxamide;
N-(2,3,5-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide;
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxy-
pyridine-2-carboxamide;
N-(2,6-dichloro-4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide;
N-(3,5-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-c-
arboxamide;
N-(3-bromo-5-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide;
N-(2,4,6-trifluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-ca-
rboxamide;
N-(2,6-dichloro-4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-car-
boxamide;
N-(4,6-dichloropyrimid-5-yl)-4-cyclopentyloxy-5-methoxypyridine-
-2-carboxamide;
N-(2,3,5,6-tetrafluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-ca-
rboxamide;
N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridin-
e-2-carboxamide;
N-(5-cyano-3-methylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2--
carboxamide;
N-(2,6-dichloro-4-carbamoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-c-
arboxamide;
N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-
-2-carboxamide;
N-(4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
N-(3-methyl-5-bromoisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2--
carboxamide;
N-(3,5-dimethylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carb-
oxamide;
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxyp-
yridine-2-carboxamide;
1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)et-
hanone;
(.+-.)-N-(3,5-difluoropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorb-
orn-2-yloxy)nicotinamide;
(.+-.)-N-(3,5-dichloropyridin-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-2--
yloxy)nicotinamide;
(.+-.)-N-(3,5-dichloropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)pyridine-2-carboxamide;
(.+-.)-N-(3,5-difluoropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)pyridine-2-carboxamide hydrate;
(.+-.)-N-(3,5-dichloropyridin-4-yl)-5-methoxy-4-(tetrahydrothiophen-3-ylo-
xy)pyridine-2-carboxamide;
N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-car-
boxamide;
N-(3,5)dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-
-carboxamide;
(.+-.)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0-
..sup.2.6.]-hept-2-yloxy)pyridine-2-carboxamide;
(.+-.)-N-(3,5-difluoro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0-
..sup.2.6.]-hept-2-yloxy)pyridine-2-carboxamide;
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxypyridine-2-c-
arboxamide;
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxypyridi-
ne-2-carboxamide hemihydrate;
(.+-.)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tetrahydrothioph-
en-3-yloxy)pyridine-2-carboxamide;
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-oxidopy-
ridinium-2-carboxamide;
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxi-
dopyridinium-2-carboxamide;
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyri-
dinium-2-carboxamide;
1-(5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridin-2-yl)-2-(-
3,5-dichloropyridin-4-yl)ethanone;
(.+-.)-1-(5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridin-2-yl)-2-(3,5-di-
chloropyridin-4-yl)ethanone;
1-(4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)-5-methoxypyridin-2-yl)-2-(-
3,5-dichloro-1-oxido-4-pyridinio)ethanone;
N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridi-
nium-2-carboxamide;
N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-
-carboxamide;
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-
-2-carboxamide hemihydrate;
N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxy-2-aminomethylpyridine;
trans-2-(2,6-dichlorophenyl)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)ethe-
ne;
trans-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(2,6-difluorophenyl)-
ethene;
1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethane-1,2-
-dione;
N-(3,5-dichloropyrid-4-yl)-5-cyclopentyloxy-6-methoxypyridazine-3-
-carboxamide;
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-difluoromethoxypyridine-2-
-carboxamide;
N-(3,5-dichloro-1'-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxyp-
yridine-2-carboxamide;
N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-difluoromethoxy-1-oxidopyri-
dium-2-carboxamide;
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxy-1-
-oxidopyridium-2-carboxamide;
1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloropyrid-
in-4-yl)ethanone;
1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichlo-
ropyridin-4-yl)ethanone;
1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloro-1-ox-
ido-4-pyridinio)ethanone;
1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichlo-
ro-1-oxido-4-pyridinio)ethanone;
N-(3,5-dichloropyrid-4-yl)-5,6-dimethoxypyridazine-3-carboxamide;
and
1-(5,6-dimethoxypyridazine-3-yl)-2-(3,5-dichloropyridin-4-yl)ethanone.
65. A pharmaceutical composition comprising a pharmaceutically
acceptable amount of the compound of claim 39 and a
pharmaceutically acceptable carrier.
66. A method for treating a disease state capable of being
modulated by inhibiting TNF comprising administering to a patient
suffering from said disease state an effective amount of the
compound of claim 39.
67. The method of claim 66 wherein the disease state is an
inflammatory disease or autoimmune disease.
68. The method of claim 66 wherein the disease state is selected
from the group consisting of joint inflammation, arthritis,
rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis,
sepsis, septic shock, gram negative sepsis, toxic shock syndrome,
acute respiratory distress syndrome, asthma, bone resorption
diseases, reperfusion injury, graft vs host reaction, allograft
rejection, malaria, myalgias, HIV, AIDS, cachexia, Crohn's disease,
ulcerative colitis, pyresis, systemic lupus erythematosus, multiple
sclerosis, type I diabetes mellitus, psoriasis, Bechet's disease,
anaphylactoid purpura nephritis, chronic glomerulonephritis,
inflammatory bowel disease and leukemia.
69. The method of claim 66 wherein the disease state is joint
inflammation.
70. A method for treating a disease state capable of being
modulated by inhibiting production of cyclic AMP phosphodiesterase
comprising administering to a patient suffering from said disease
state an effective amount of the compound of claim 39.
71. The method of claim 70 wherein the disease state is a
pathological condition associated with a function of cyclic AMP
phophodiesterase, eosinophil accumulation or a function of the
eosinophil.
72. The method of claim 71 wherein the pathological condition is
asthma, atopic dermatitis, urticaria, allergic rhinitis, psoriasis,
rheumatic arthritis, ulcerative colitis, Crohn's disease, adult
respiratory distress syndrome, diabetes insipidus, keratosis,
dermatitis, cerebral senility, multi-infarct dementia, senile
dementia, memory impairment associated with Parkinson's disease,
cardiac arrest, stroke and intermittent claudication.
73. The method of claim 71 wherein the pathological condition is
asthma.
74. The compound according to claim 39 which is ##STR52##
75. The compound according to claim 39 wherein Q.sup.2 is N.
Description
[0001] This is a continuation-in-part of PCT Application Serial No.
GB94/01630 filed Jul. 28, 1994, that designates the United States,
now pending.
FIELD OF THE INVENTION
[0002] This invention is directed to [di(ether or
thioether)heteroaryl or fluoro substituted aryl] compounds, their
preparation, pharmaceutical compositions containing these
compounds, and their pharmaceutical use in the treatment of disease
states associated with proteins that mediate cellular activity.
[0003] Disease states associated with abnormally high physiological
levels of cytokines such as TNF are treatable according to the
invention. TNF is an important pro-inflammatory cytokine which
causes hemorrhagic necrosis of tumors and possesses other important
biological activities. TNF is released by activated macrophages,
activated T-lymphocytes, natural killer cells, mast cells and
basophils, fibroblasts, endothelial cells and brain astrocytes
among other cells.
[0004] The principal in vivo actions of TNF can be broadly
classified as inflammatory and catabolic. It has been implicated as
a mediator of endotoxic shock, inflammation of joints and of the
airways, immune deficiency states, allograft rejection, and in the
cachexia associated with malignant disease and some parasitic
infections. In view of the association of high serum levels of TNF
with poor prognosis in sepsis, graft versus host disease and acute
respiratory distress syndrome, and its role in many other
immunological processes, this factor is regarded as an important
mediator of general inflammation.
[0005] TNF primes or activates neutrophils, eosinophils,
fibroblasts and endothelial cells to release tissue damaging
mediators. TNF also activates monocytes, macrophages and
T-lymphocytes to cause the production of colony stimulating factors
and other pro-inflammatory cytokines such IL.sub.1, IL.sub.6,
IL.sub.8 and GM-CSF, which in some case mediate the end effects of
TNF. The ability of TNF to activate T-lymphocytes, monocytes,
macrophages and related cells has been implicated in the
progression of Human Immunodeficiency Virus (HIV) infection. In
order for these cells to become infected with HIV and for HIV
replication to take place the cells must be maintained in an
activated state. Cytokines such as TNF have been shown to activate
HIV replication in monocytes and macrophages. Features of endotoxic
shock such as fever, metabolic acidosis, hypotension and
intravascular coagulation are thought to be mediated through the
actions of TNF on the hypothalamus and in reducing the
anti-coagulant activity of vascular endothelial cells. The cachexia
associated with certain disease states is mediated through indirect
effects on protein catabolism. TNF also promotes bone resorption
and acute phase protein synthesis.
[0006] The discussion herein related to disease states associated
with TNF include those disease states related to the production of
TNF itself, and disease states associated with other cytokines,
such as but not limited to IL-1, or IL-6, that are modulated by
association with TNF. For example, an IL-1 associated disease
state, where IL-1 production or action is exacerbated or secreted
in response to TNF, would therefore be considered a disease state
associated with TNF. TNF-alpha and TNF-beta are also herein
referred to collectively as "TNF" unless specifically delineated
otherwise, since there is a close structural homology between
TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them
has a capacity to induce similar biologic responses and bind to the
same cellular receptor.
[0007] Disease states associated with pathological conditions that
are modulated by inhibiting enzymes, which are associated with
secondary cellular messengers, such as cyclic AMP
phosphodiesterase, are also treatable according to the invention
Cyclic AMP phosphodiesterase is an important enzyme which regulates
cyclic AMP levels and in turn thereby regulates other important
biological reactions. The ability to regulate cyclic AMP
phosphodiesterase, including type IV cyclic AMP phosphodiesterase,
therefore, has been implicated as being capable of treating
assorted biological conditions.
[0008] In particular, inhibitors of type IV cyclic AMP
phosphodiesterase have been implicated as being bronchodilators and
asthma-prophylactic agents and as agents for inhibiting eosinophil
accumulation and of the function of eosinophils, and for treating
other diseases and conditions characterized by, or having an
etiology involving, morbid eosinophil accumulation. Inhibitors of
cyclic AMP phosphodiesterase are also implicated in treating
inflammatory diseases, proliferative skin diseases and conditions
associated with cerebral metabolic inhibition.
REPORTED DEVELOPMENTS
[0009] Chemical Abstracts, 108(15), Apr. 11, 1988, abstract no.
131583p pertains to an abstract of Japanese Patent Application
Publication No. JP-A-62 158,253 which discloses that a substituted
phenyl compound of formula ##STR1## is a cardiotonic, but does not
disclose or suggest that the compound inhibits cyclic AMP
phosphodiesterase or TNF. JP-A-62 158,253 also does not disclose or
suggest that the moiety that is ortho to R.sup.1 may be anything
other than benzyloxy. JP-A-62 158,253 furthermore does not disclose
compounds wherein a methine (.dbd.CH--) moiety of the phenyl moiety
of the benzamido moiety is substituted by a halomethine (.dbd.CX--;
wherein X is a halo atom) moiety or an imine (.dbd.N--) moiety.
[0010] Chemical Abstracts, 99(6), Aug. 8, 1983, abstract no. 43556z
pertains to an abstract of Japanese Patent Application Publication
No. JP-A-5 869,812 which discloses that a phenyl compound of
formula ##STR2## is a hypoglycemic agent, but does not disclose or
suggest that the compound inhibits cyclic AMP phosphodiesterase or
TNF. JP-A-5 869,812 also does not disclose or suggest that the
benzamido moiety may be substituted by anything other than
methoxy.
[0011] Panos Grammaticakis, Bull. Soc. Chim. Fr., 848-857 (1965)
discloses a phenyl compound of the formula ##STR3## Grammaticakis
examines the ultraviolet and visible absorbances of compounds
bearing different substituents. Grammaticakis does not disclose or
suggest that the compound exhibits any pharmacological activity.
JP-A-5 869,812 also does not disclose or suggest that the benzamido
moiety may be substituted by anything other than methoxy.
[0012] Ian W. Mathison, et al., J. Med. Chem., 16(4), 332-336
(1973), discloses that a phenyl compound of formula ##STR4## is a
hypotensive agent, but do not disclose or suggest that the compound
inhibits cyclic AMP phosphodiesterase or TNF. Mathison, et al.,
also do not disclose or suggest that the benzamido moiety may be
substituted by anything other than methoxy.
[0013] European Patent Application Publication No. EP 232199 B1
discloses that phenyl compounds of formula ##STR5## wherein R.sup.2
is alkyl or mono- or polycyclic cycloalkyl, exhibit
anti-inflammatory and/or anti-allergic activity. EP 232199 B1 does
not disclose or suggest compounds wherein the R.sup.2 substituent
is bonded to the phenyl moiety via an oxygen or sulfur atom. EP
232199 B1 furthermore does not disclose compounds wherein a methine
moiety of the phenyl moiety of the benzamido moiety is substituted
by a halomethine moiety or an imine moiety.
[0014] European Patent Application Publication No. EP 470,805 A1
discloses phenyl compounds of the formula ##STR6## wherein R may be
C.sub.3-7 alkyl, C.sub.3-7 cycloalkyl or ##STR7## Z may be a bond;
o is 1-4; a and b are independently 1-3; and c is 0-2. EP 470,805
A1 discloses that these compounds are useful intermediates for
preparing PDE IV inhibitors, but does not disclose or suggest that
the compounds have any pharmacological activity. EP 470,805 A1
furthermore does not disclose compounds wherein a methine moiety of
the phenyl moiety of the phenylacyl moiety is substituted by a
halomethine moiety or an imine moiety.
[0015] Japanese Patent Application Publication No. JP-A-0 4360847
discloses compounds of the formula ##STR8## wherein R.sup.1,
R.sup.2 and R.sup.3 may be the same or different and may be halo or
lower alkoxy or lower alkyl both optionally substituted by halo;
and A may be optionally substituted aryl or 5-6 membered
heterocyclyl group. JP-A-0 4360847 discloses that the compounds are
useful intermediates for preparing antimicrobial agents, but does
not disclose or suggest that the compounds have any pharmacological
activity. JP-A-0 4360847 also does not disclose that the compounds
wherein the phenylacyl moiety is substituted in the 3,4 positions
relative to the acyl moiety by lower alkoxy groups and has a
methine moiety of the phenyl moiety substituted by a halomethine
moiety or an imine moiety.
[0016] WO Patent Application No. 92/12961 discloses that compounds
of the formula ##STR9## inhibit cyclic AMP phosphodiesterase. WO
Patent Application No. 92/12961 does not disclose or suggest that
these compound inhibit TNF. WO Patent Application No. 92/12961 also
does not disclose compounds wherein a methine moiety of the diether
phenyl moiety is substituted by a halomethine moiety or an imine
moiety.
[0017] WO Patent Application No. 93/25517 discloses that compounds
of the following formula inhibit PDE IV. WO Patent Application No.
93/25517 does ##STR10## not disclose or suggest that these compound
inhibit TNF. WO Patent Application No. 93/25517 also does not
disclose compounds wherein a methine moiety of the diether phenyl
moiety is substituted by a halomethine moiety or an imine
moiety.
[0018] WO Patent Application No. 93/10228 discloses that compounds
of the following formula inhibit PDE IV and as such are useful in
treatment of inflammatory diseases. WO Patent Application No.
93/10228 does not disclose or suggest ##STR11## that these
compounds inhibit TNF. WO Patent Application No. 93/10228 also does
not disclose compounds wherein a methine moiety of the diether
phenyl moiety is substituted by a halomethine moiety or an imine
moiety.
[0019] WO Patent Application No. 93/07111 discloses that compounds
of the following formula wherein X may be YR.sub.2; Y is O or
S(O).sub.m; X.sub.3 is halogen or ##STR12## hydrogen; and A is a
group of formula ##STR13## inhibit PDE IV. WO Patent Application
No. 93/07111 does not disclose or suggest compounds wherein the A
substituent is a [(--CXNH-- or --CXCH.sub.2--)aryl or heteroaryl]
moiety wherein X is O or S.
[0020] WO Patent Application No. 91/16303 discloses that compounds
of the following formula wherein R.sub.1, R.sub.2 and R.sub.3 may
be hydrogen, halogen, lower alkyl, ##STR14## lower alkoxy or
cycloalkoxy inhibit PDE IV. WO Patent Application No. 91/16303 does
not disclose or suggest compounds wherein the lactam moiety is
substituted by a [(--CXNH-- or --CXCH.sub.2--)aryl or heteroaryl]
moiety wherein X is O or S.
[0021] WO Patent Application No. 92/19594 discloses that compounds
of the following formula wherein X may be YR.sub.2; Y is O or
S(O).sub.m; and X.sub.3 may be ##STR15## hydrogen or halogen
inhibit PDE IV. WO Patent Application No. 92/19594 does not
disclose or suggest compounds wherein the lactam moiety is
substituted by a [(--CXNH-- or --CXCH.sub.2--)aryl or heteroaryl]
moiety wherein X is O or S.
SUMMARY OF THE INVENTION
[0022] This invention is directed to a compound of formula I, which
is useful for inhibiting the production or physiological effects of
TNF in the treatment of a patient suffering from a disease state
associated with a physiologically detrimental excess of tumor
necrosis factor (TNF), where formula I is as follows: ##STR16##
wherein
[0023] R.sup.1 is lower alkyl optionally substituted by one or more
of halo, cycloalkyl or cycloalkenyl;
[0024] R.sup.2 is alkyl, alkenyl or alkynyl each optionally
substituted by one or more of halo, cycloalkyl or cycloalkenyl; or
cycloalkyl or cycloalkenyl each optionally substituted by one or
more of halo, methylidene or alkyl; or optionally substituted
cyclothioalkyl consisting of a non-aromatic monocyclic or
multicyclic ring system of 3 to about 10 ring atoms wherein at
least one of the ring atoms is sulphur and the other ring atoms are
carbon and the substituted cyclothioalkyl is substituted by one or
more halo, or any ring sulphur atom is optionally oxidised to the
corresponding S-oxide or S,S-dioxide; or optionally substituted
cyclothioalkenyl consisting of a non-aromatic monocyclic or
multicyclic ring system of 3 to about 10 ring atoms wherein at
least one of the ring atoms is sulphur, the other ring atoms are
carbon and the ring system contains a carbon-carbon double bond and
the substituted cyclothioalkenyl is substituted by one or more halo
or any ring sulphur atoms is optionally oxidised to the
corresponding S-oxide or S,S-dioxide;
[0025] R.sup.3 is optionally substituted aryl or heteroaryl,
wherein the substituted aryl or substituted heteroaryl group is
substituted by one or more substituents which may be the same or
different and are selected from alkyl, aryl, aralkyl, hydroxy,
hydroxyalkyl, alkoxy, aryloxy, aralkyloxy, carboxy, acyl, aroyl,
halo, nitro, cyano, carboxy, alkoxycarboxyl, aryloxycarbonyl,
aralkyloxycarbonyl, acylamino, aroylamino, alkylsulfonyl,
arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio,
aralkylthio, Y.sup.1Y.sup.2N--, Y.sup.1Y.sup.2NCO-- or
Y.sup.1Y.sup.2NSO.sub.2--, where Y.sup.1 and Y.sup.2 are
independently hydrogen, alkyl, aryl, and aralkyl;
[0026] Q.sup.1, Q.sup.2 and Q.sup.3 are independently nitrogen, CX
or CH, provided that at least one of Q.sup.1, Q.sup.2 and Q.sup.3
is other than CH;
[0027] Z, Z.sup.1 and Z.sup.2 are independently oxygen or
sulfur;
[0028] Z.sup.3 is --CH.dbd.CH--, --CZCH.sub.2--, --CZ-CZ-,
--CH.sub.2--NH--, --CH.sub.2--O--, --CX.sub.2--O--,
--CH.sub.2--S--, --CH.sub.2--SO.sub.2-- or --CZNH--; and
[0029] X is halo;
[0030] or N-oxide thereof or a pharmaceutically acceptable salt
thereof; with the proviso that R.sup.1Z.sup.1 and R.sup.2Z.sup.2
cannot both represent methoxy.
[0031] Compounds within the scope of the present invention also
inhibit cyclic AMP phosphodiesterase, and are useful in treating a
disease state associated with pathological conditions that are
modulated by inhibiting cyclic AMP phosphodiesterase, such disease
states including inflammatory and autoimmune diseases, in
particular type IV cyclic AMP phosphodiesterase. The present
invention is therefore directed to their pharmacological use,
pharmacological compositions comprising the compounds and methods
for their preparation.
DETAILED DESCRIPTION OF THE INVENTION
[0032] As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated, shall
be understood to have the following meanings:
Definitions
[0033] "Patient" includes both human and other mammals.
[0034] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched having about 1 to about 15 carbon atoms in the
chain. Preferred alkyl groups have 1 to about 12 carbon atoms in
the chain. Branched means that one or more lower alkyl groups such
as methyl, ethyl or propyl are attached to a linear alkyl chain.
"Lower alkyl" means about 1 to about 4 carbon atoms in the chain
which may be straight or branched. The alkyl group is optionally
substituted by one or more of halo, cycloalkyl or cycloalkenyl
groups. Exemplary alkyl groups include methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, cyclopropylmethyl,
cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl,
n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl;
preferred are methyl, difluoromethyl and i-propyl.
[0035] "Alkenyl" means an aliphatic hydrocarbon group containing a
carbon-carbon double bond and which may be straight or branched
having about 2 to about 15 carbon atoms in the chain. Preferred
alkenyl groups have 2 to about 12 carbon atoms in the chain; and
more preferably about 2 to about 4 carbon atoms in the chain.
Branched means that one or more lower alkyl groups such as methyl,
ethyl or propyl are attached to a linear alkenyl chain. "Lower
alkenyl" means about 2 to about 4 carbon atoms in the chain which
may be straight or branched. The alkenyl group is optionally
substituted by one or more halo, cycloalkyl or cycloalkenyl.
Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl,
i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and
decenyl.
[0036] "Alkynyl" means an aliphatic hydrocarbon group containing a
carbon-carbon triple bond and which may be straight or branched
having about 2 to about 15 carbon atoms in the chain. Preferred
alkynyl groups have 2 to about 12 carbon atoms in the chain; and
more preferably about 2 to about 4 carbon atoms in the chain.
Branched means that one or more lower alkyl groups such as methyl,
ethyl or propyl are attached to a linear alkynyl chain. "Lower
alkynyl" means about 2 to about 4 carbon atoms in the chain which
may be straight or branched. The alkynyl group is optionally
substituted by one or more halo, cycloalkyl or cycloalkenyl.
Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl,
2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and
decynyl.
[0037] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system of about 3 to about 10 carbon atoms. The cycloalkyl group is
optionally substituted by one or more halo, methylidene
(H.sub.2C.dbd.) or alkyl. Exemplary monocyclic cycloalkyl rings
include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl;
more preferred is cyclopentyl. Exemplary multicyclic cycloalkyl
rings include 1-decalin, adamant-(1- or 2-)yl, trinorbornyl and
tricyclo[2.2.1.0.sup.2.6.]heptyl.
[0038] "Cycloalkenyl" means a non-aromatic monocyclic or
multicyclic ring system containing a carbon-carbon double bond and
having about 3 to about 10 carbon atoms. The cycloalkenyl group is
optionally substituted by one or more halo, alkyl and methylidene
(CH.sub.2.dbd.). Preferred monocyclic cycloalkenyl rings include
cyclopentenyl, cyclohexenyl or cycloheptenyl; more preferred is
cyclopentenyl. A preferred multicyclic cycloalkenyl ring is a
norbornylenyl.
[0039] "Cyclothioalkyl" means a non-aromatic monocyclic or
multicyclic ring system of about 3 to about 10 ring atoms wherein
at least one of the ring atoms is sulfur and the other ring atoms
are carbon. Preferred rings include about 5 to about 6 ring atoms.
Also preferred are rings in which one or two of the ring atoms
is/are sulfur. The cyclothioalkyl is optionally substituted by one
or more halo. The thio moiety of the cyclothioalkyl ring may also
be optionally oxidized to the corresponding S-oxide or S,S-dioxide.
Preferred monocyclic cyclothioalkyl rings include
tetrahydrothiophenyl and tetrahydrothiopyranyl; more preferred is
tetrahydrothiophenyl.
[0040] "Cyclothioalkenyl" means a non-aromatic monocyclic or
multicyclic ring system having about 3 to about 10 ring atoms
wherein at least one of the ring atoms is sulfur and the other ring
atoms are carbon and the ring system contains a carbon-carbon
double bond. Preferred rings include about 5 to about 6 ring atoms.
Also preferred are rings in which one or two of the ring atoms
is/are sulfur. The cyclothioalkenyl is optionally substituted by
one or more halo. The thio moiety of the cyclothioalkenyl may also
be optionally oxidized to the corresponding S-oxide or S,S-dioxide.
Preferred monocyclic cyclothioalkyl rings include dihydrothiophenyl
and dihydrothiopyranyl; more preferred is dihydrothiophenyl.
[0041] "Aromatic" means aryl or heteroaryl as defined below.
Preferred aromatic groups include phenyl, halo substituted phenyl
and azaheteroaryl.
[0042] "Aryl" means aromatic carbocyclic radical containing about 6
to about 10 carbon atoms. Exemplary aryl include phenyl or
naphthyl, or phenyl or naphthyl substituted with one or more aryl
group substituents which may be the same or different, where "aryl
group substituent" includes hydrogen, alkyl, aryl, aralkyl,
hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkyloxy, carboxy, acyl,
aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl,
aryloxycarbonyl, aralkyloxycarbonyl, acylamino, aroylamino,
alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl,
alkylthio, arylthio, aralkylthio, Y.sup.1Y.sup.2N--,
Y.sup.1Y.sup.2NCO-- or Y.sup.1Y.sup.2NSO.sub.2--, where Y.sup.1 and
Y.sup.2 are independently hydrogen, alkyl, aryl, and aralkyl.
Preferred aryl group substituents include hydrogen, alkyl, hydroxy,
acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino,
alkylthio, Y.sup.3Y.sup.4N--, Y.sup.3Y.sup.4NCO-- and
Y.sup.3Y.sup.4NSO.sub.2--, where Y.sup.3 and Y.sup.4 are
independently hydrogen and alkyl.
[0043] "Heteroaryl" means about a 5- to about a 10-membered
aromatic monocyclic or multicyclic hydrocarbon ring system in which
one or more of the carbon atoms in the ring system is/are
element(s) other than carbon, for example nitrogen, oxygen or
sulfur. The heteroaryl may also be substituted by one or more aryl
group substituents. "Azaheteroaryl" means a subclass of heteroaryl
wherein one or more of the atoms in the ring system is/are replaced
by nitrogen. Imine nitrogen moieties of an azaheteroaryl group may
also be in an oxidized state such as the corresponding N-oxide.
Exemplary heteroaryl groups include pyrazinyl, furanyl, thienyl,
pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, pyridazinyl,
1,2,4-triazinyl, quinolinyl, and isoquinolinyl. Preferred
heteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl,
isoxazolyl and isothiazolyl. Preferred azaheteroaryl groups include
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or
1,2,4-triazinyl.
[0044] "Aralkyl" means an aryl-alkyl-group in which the aryl and
alkyl are as previously described. Preferred aralkyls contain a
lower alkyl moiety. Exemplary aralkyl groups include benzyl,
2-phenethyl and naphthlenemethyl.
[0045] "Hydroxyalkyl" means a HO-alkyl-group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Exemplary hydroxyalkyl groups include hydroxymethyl and
2-hydroxyethyl.
[0046] "Acyl" means an H--CO-- or alkyl-CO-- group in which the
alkyl group is as previously described. Preferred acyls contain a
lower alkyl. Exemplary acyl groups include formyl, acetyl,
propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
[0047] "Aroyl" means an aryl-CO-- group in which the aryl group is
as previously described. Exemplary groups include benzoyl and 1-
and 2-naphthoyl.
[0048] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Exemplary alkoxy groups include
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
[0049] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Exemplary aryloxy groups include phenoxy
and naphthoxy.
[0050] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl
groups is as previously described. Exemplary aralkyloxy groups
include benzyloxy and 1- or 2-naphthalenemethoxy.
[0051] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Exemplary alkylthio groups
include methylthio, ethylthio, i-propylthio and heptylthio.
[0052] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Exemplary arylthio groups include
phenylthio and naphthylthio.
[0053] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. An exemplary aralkylthio
group is benzylthio.
[0054] "Y.sup.3Y.sup.4N--" means a substituted or unsubstituted
amino group, wherein Y.sup.3 and Y.sup.4 are as previously
described. Exemplary groups include amino (H.sub.2N--),
methylamino, ethylmethylamino, dimethylamino and diethylamino.
[0055] "Alkoxycarbonyl" means an alkyl-O--CO-- group. Exemplary
alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
[0056] "Aryloxycarbonyl" means an aryl-O--CO-- group. Exemplary
aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
[0057] "Aralkyloxycarbonyl" means an aralkyl-O--CO-- group. An
exemplary aralkyloxycarbonyl group is benzyloxycarbonyl.
[0058] "Y.sup.1Y.sup.2NCO--" means a substituted or unsubstituted
carbamoyl group, wherein Y.sup.1 and Y.sup.2 are as previously
described. Exemplary groups are carbamoyl (H.sub.2NCO--) and
dimethylcarbamoyl (Me.sub.2NCO--).
[0059] "Y.sup.1Y.sup.2NSO.sub.2--" means a substituted or
unsubstituted sulfamoyl group, wherein Y.sup.1 and Y.sup.2 are as
previously described. Exemplary groups are sulfamoyl
(H.sub.2NSO.sub.2--) and dimethylsulfamoyl
(Me.sub.2NSO.sub.2--).
[0060] "Acylamino" is an acyl-NH-- group wherein acyl is as defined
herein.
[0061] "Aroylamino" is an aroyl-NH-- group wherein aroyl is as
defined herein.
[0062] "Alkylsulfonyl" means an alkyl-SO.sub.2-- group. Preferred
groups are those in which the alkyl group is lower alkyl.
[0063] "Alkylsulfinyl" means an alkyl-SO-- group. Preferred groups
are those in which the alkyl group is lower alkyl.
[0064] "Arylsulfonyl" means an aryl-SO.sub.2-- group.
[0065] "Arylsulfinyl" means an aryl-SO-- group.
[0066] "Halo" means fluoro, chloro, bromo, or iodo. Preferred are
fluoro, chloro or bromo; more preferred are fluoro or chloro, and
further preferred is fluoro.
[0067] "N-oxide" means a moiety of the following structure
##STR17##
PREFERRED EMBODIMENTS
[0068] A compound of formula I is preferred for use in treating a
disease state associated with a physiologically detrimental excess
of tumor necrosis factor. Disease states associated with
pathological conditions that are modulated by inhibiting tumor
necrosis factor are treatable with a compound of formula I.
[0069] A compound of formula I is also preferred for use in
treating a disease state associated with a physiologically
detrimental excess of cyclic AMP phosphodiesterase. Disease states
associated with pathological conditions that are modulated by
inhibiting cyclic AMP phosphodiesterase are treatable with a
compound of formula I.
[0070] According to a compound aspect of the invention, preferred
compounds are described formula I,
wherein
[0071] R.sup.2 is alkyl, cycloalkyl, cycloalkenyl or
cyclothioalkyl;
[0072] R.sup.3 is phenyl, substituted phenyl or azaheteroaryl;
[0073] Q.sup.1 and Q.sup.2 are independently nitrogen, CX or CH,
and at least one of Q.sup.1 and Q.sup.2 is other than CH;
[0074] Q.sup.3 is CH; and
[0075] Z.sup.3 is --CZCH.sub.2-- or --CZNH--.
[0076] According to a further compound aspect of the invention,
preferred compounds are described formula I,
wherein
[0077] R.sup.1 is methyl or difluoromethyl;
[0078] R.sup.2 is isopropyl, cyclopropylmethyl, cyclopentyl,
trinorbornyl, trinorbornenyl, tricyclo[2.2.1.0.sup.2.6.]heptanyl
and tetrahydrothiophenyl;
[0079] Q.sup.3 is CH;
[0080] Z.sup.1 is oxygen or sulphur;
[0081] Z.sup.2 is oxygen; and
[0082] Z.sup.3 is --COCH.sub.2-- or --CONH--.
[0083] According to another aspect of the invention, more preferred
compounds of formula I are described wherein Q.sup.1 and Q.sup.2
are independently nitrogen, CX or CH, and at least one of Q.sup.1
and Q.sup.2 is nitrogen or CX, and Q.sup.3 is CH. Also preferred
are compounds of the invention wherein Q.sup.1 is CX, and Q.sup.2
and Q.sup.3 are CH; Q.sup.2 is CX, and Q.sup.1 and Q.sup.3 are CH;
Q.sup.1 is N, and Q.sup.2 and Q.sup.3 are CH; Q.sup.2 is N, and
Q.sup.1 and Q.sup.3 are CH; Q.sup.1 and Q.sup.2 are CH, and Q.sup.3
are N; and Q.sup.1 and Q.sup.2 are N, and Q.sup.3 are CH. CX is
preferably CF. Further preferred are compounds wherein Q.sup.2 is
nitrogen or CF.
[0084] According to a further aspect of the invention, preferred
are N-oxide compounds of formula I, that is compounds of formula I
wherein independently Q.sup.1, Q.sup.2 or Q.sup.3 is N-oxide and/or
R.sup.3 is azaheterocyclyl having an imine moiety thereof as an
N-oxide. Futher preferred are compounds of formula I wherein
Q.sup.1 and Q.sup.3 are CH, and Q.sup.2 is an N-oxide. Also futher
preferred are compounds of formula I wherein R.sup.3 is
3,5-dihalo-1-oxido-4-pyridinium.
[0085] Compounds of the invention wherein R.sup.1 is lower alkyl
optionally substituted by one or more halo, preferably fluoro, are
also preferred. Compounds of the invention wherein R.sup.2 is
substituted by one or more halo, preferably fluoro, are also
preferred. It is further preferred that the halo substitution is on
a position of R.sup.1 or R.sup.2 that is attached respectively to
Z.sup.1 and Z.sup.2. Where R.sup.2 is cyclothioalkyl or
cyclothioalkenyl substituted by halo, it is also preferred that the
halo substitution is on a position adjacent to the thio moiety of
the cyclothioalkyl or cyclothioalkenyl.
[0086] Among the compounds of the invention wherein R.sup.3 is
substituted phenyl, the phenyl group is preferably substituted on
the 2-position or on both the 2- and 6-positions; more preferably
on both the 2- and 6-positions. It is also preferred that the
phenyl substituent is halo; preferably chloro or fluoro.
[0087] Similarly, among compounds of the invention where R.sup.3 is
substituted heteroaryl, the heteroaryl group is preferably
substituted on one or both, more preferably on both, of the
positions adjacent to a position of R.sup.3 that is attached to
Z.sup.3.
[0088] Special embodiments of the compounds of the invention
include those of formula I wherein R.sup.3 is azaheteroaryl
substituted on one or both, more preferably on both, of the
positions adjacent to a position of R.sup.3 that is attached to
Z.sup.3, or an N-oxide thereof. Further preferred are compounds
wherein R.sup.3 is a 3,5-dihalopyrid-4-yl moiety, preferably
wherein halo is chloro or fluoro, or an N-oxide thereof.
[0089] Special embodiments of the compounds of the invention also
include those of formula I wherein Z.sup.3 is --CZNH-- or
--CZCH.sub.2--, more preferably wherein Z is oxygen.
[0090] Special embodiments of the compounds of the present
invention include those wherein R.sup.2 is isopropyl,
cyclopropylmethyl, cyclopentyl, trinorbornyl, trinorbornenyl,
tricyclo[2.2.1.0.sup.2.6.]heptanyl and tetrahydrothiophenyl.
[0091] Another special embodiment of the compounds of the invention
include those of formula I wherein R.sup.1 is lower alkyl
optionally substituted by halo, preferably fluoro; and R.sup.2 is
isopropyl, cyclopropylmethyl, cyclopentyl, trinorbornyl,
trinorbornenyl, tricyclo[2.2.1.0.sup.2.6.]heptanyl and
tetrahydrothiophenyl.
[0092] According to a further aspect of the invention, preferred
compounds of formula I are described wherein Z.sup.1 and Z.sup.2
are oxygen, and Z.sup.1 is sulfur and Z.sup.2 is oxygen are
preferred. More preferred are where Z.sup.1 and Z.sup.2 are
oxygen.
[0093] Preferred compounds for use according to the invention are
selected from the following: [0094] A
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0095] B
N-(2,6-difluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenza-
mide; [0096] C
N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0097] D
N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0098] E
N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0099] F
N-(2,6-dibromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzam-
ide; [0100] G
N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0101] H
N-(2,6-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0102] I
N-(2-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide- ;
[0103] J N-phenyl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide; K
N-(2-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0104] L
N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0105] M
N-(3-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide- ;
[0106] N
N-(4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0107] O
N-(2,6-dimethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0108] P
N-(2-methylthiophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenza-
mide; [0109] Q
N-(2-bromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0110] R
N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamid-
e; [0111] S
N-(2-aminosulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0112] T
N-(2-benzoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamid- e;
[0113] U
N-(2-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0114] V
N-(2,5-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0115] W
N-(3-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide- ;
[0116] X
N-(2-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0117] Y
N-(2-dimethylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0118] Z
N-(2-acetylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0119] AA
N-(2-hydroxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0120] AB
N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0121] AC
N-pyrid-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide; [0122]
AD N-pyrazin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0123] AE
N-pyrimidin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0124] AF
N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0125] AG
N-pyrid-3-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide; [0126]
AH
N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0127] AI
N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0128] AJ
N-pyrid-4-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide; [0129]
AK
N-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamid-
e; [0130] AL
N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0131] AM
N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0132] AN
N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0133] AO
N-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-meth-
oxybenzamide; [0134] AP
N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamid-
e; [0135] AQ
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-metho-
xybenzamide; [0136] AR
N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0137] AS
N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0138] AT
N-(3-bromo-5-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0139] AU
N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0140] AV
N-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenza-
mide; [0141] AW
N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide-
; [0142] AX
N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenz-
amide; [0143] AY
N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-metho-
xybenzamide; [0144] AZ
N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybe-
nzamide; [0145] BA
N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxyben-
zamide; [0146] BB
N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methox-
ybenzamide; [0147] BC
N-(4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0148] BD
N-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methox-
ybenzamide; [0149] BE
N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzam-
ide; [0150] BF
N-(2,6-difluorophenyl)-3-cyclohexyloxy-6-fluoro-4-methoxybenzamide;
[0151] BG
N-(2,6-difluorophenyl)-3-butoxy-6-fluoro-4-methoxybenzamide; [0152]
BH N-(2,6-difluorophenyl)-3-propoxy-6-fluoro-4-methoxybenzamide;
[0153] BJ
N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzam-
ide; [0154] BL
N-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzam-
ide; [0155] BN
N-(2-methylsulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0156] BP
N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide);
[0157] BR
N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzami-
de); [0158] BT
N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzami-
de); [0159] BV
N-(2,6-dichloro-4-acetylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxyb-
enzamide; [0160] BX
N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methox-
ybenzamide; [0161] BZ
N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzam-
ide; [0162] CB sodium salt of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0163] CC
(.+-.)N-(3,5-dichloropyrid-4-yl)-3-exonorbornyloxy-6-fluoro-4-methoxybenz-
amide; [0164] CD
N-(3,5-dichloropyrid-4-yl)-2-fluoro-5-isopropyloxy-4-methoxybenzamide;
[0165] CE
(.+-.)N-(3,5-dichloropyrid-4-yl)-2-fluoro-4-methoxy-5-(tricyclo[2.2.1.0]h-
ept-2-yloxy)benzamide hemihydrate; [0166] CF
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoromethoxy-6-fluoroben-
zamide [0167] CG
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenza-
mide; [0168] CH
2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)e-
thanone; [0169] CI
N-(3,5-dichloro-1-oxido-4-pyridinio)-2-fluoro-5-isopropyloxy-4-methoxyben-
zamide; [0170] CJ (.+-.)
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-exo-(8,9,10-trinorbornyloxy)-6-flu-
oro-4-methoxybenzamide; [0171] CK
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-6-fluoro-4-methoxyb-
enzamide; [0172] CL
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-4-difluoromethoxy-6-
-fluorobenzamide; [0173] CM
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxy-2-fluoro-5-isoprop-
yloxybenzamide; [0174] CN
2-(3,5-Dichloro-1-oxido-4-pyridinio)-1-(3-cyclopentyloxy-6-fluoro-4-metho-
xyphenyl)ethanone; [0175] CO
5-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide;
[0176] CP
N-(2,6-dichlorophenyl)-5-cyclopentyloxy-6-methoxynicotinamide;
[0177] CQ
5-cyclopentyloxy-N-(3,5-dimethylisoxazol-4-yl)-6-methoxynicotinamide
[0178] CR
5-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-6-methoxynicotinamide
[0179] CS
6-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-5-methoxypyridine-2-carbo-
xamide; [0180] CT
1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)etha-
none; [0181] CU
5-cyclopentyloxy-N-(3,5-dichloro-4-pyridyl)-6-methylthionicotinamide;
[0182] CV
N-(3,5-dichloro-4-pyridyl)-5-isopropyloxy-6-methylthionicotinamide;
[0183] CW
2-(3,5-dichloro-4-pyridyl)-1-(5-isopropyloxy-6-methylthio-3-pyridyl)ethan-
one; [0184] CX
1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloro-1-oxido-4-pyridi-
nio)ethanone hemihydrate; [0185] CY
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-
-2-yloxy)nicotinamide; [0186] CZ
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)nicotinamide monohydrate; [0187] DA
N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0188] DB
N-(2,6-difluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0189] DC
N-(2-chloro-6-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0190] DD
N-(2-trifluoromethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0191] DE
N-(2,4,6-trichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0192] DF
N-(2,6-dibromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0193] DG
N-(2-chloro-6-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0194] DH
N-(2,6-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0195] DI
N-(2-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0196] DJ
N-phenyl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide; [0197]
DK
N-(2-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0198] DL
N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0199] DM
N-(3-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0200] DN
N-(4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0201] DO
N-(2,6-dimethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0202] DP
N-(2-methylthiophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0203] DQ
N-(2-bromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0204] DR
N-(2-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0205] DS
N-(2-aminosulfonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0206] DT
N-(2-benzoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0207] DU
N-(2-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0208] DV
N-(2,5-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0209] DW
N-(3-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0210] DX
N-(2-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0211] DY
N-(2-dimethylaminophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0212] DZ
N-(2-acetylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0213] EA
N-(2-hydroxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0214] EB
N-(4-chloropyrid-3-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0215] EC
N-pyrid-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0216] ED
N-pyrazin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0217] EE
N-pyrimidin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0218] EF
N-(3-methylpyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0219] EG
N-pyrid-3-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0220] EH
N-(3-chloropyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0221] EI
N-(3-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0222] EJ
N-pyrid-4-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0223] EK
N-(3,5-dimethylisoxazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide; [0224] EL
N-(3,5-dibromopyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0225] EM
N-(3,5-dimethylpyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0226] EN
N-(2,6-dichloro-4-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0227] EO
N-(2,6-dichloro-4-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridi-
ne-2-carboxamide; [0228] EP
N-(2,3,5-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide; [0229] EQ
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridin-
e-2-carboxamide; [0230] ER
N-(2,6-dichloro-4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0231] ES
N-(3,5-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0232] ET
N-(3-bromo-5-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0233] EU
N-(2,4,6-trifluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0234] EV
N-(2,6-dichloro-4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-car-
boxamide; [0235] EW
N-(4,6-dichloropyrimid-5-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxa-
mide; [0236] EX
N-(2,3,5,6-tetrafluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-ca-
rboxamide; [0237] EY
N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridin-
e-2-carboxamide; [0238] EZ
N-(5-cyano-3-methylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2--
carboxamide; [0239] FA
N-(2,6-dichloro-4-carbamoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-c-
arboxamide; [0240] FB
N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-
-2-carboxamide; [0241] FC
N-(4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0242] FD
N-(3-methyl-5-bromoisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2--
carboxamide; [0243] FE
N-(3,5-dimethylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carb-
oxamide; [0244] FF
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxypyridine-2-
-carboxamide; [0245] FG
1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)et-
hanone; [0246] FH
(.+-.)-N-(3,5-difluoropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-2-yl-
oxy)nicotinamide; [0247] FI
(.+-.)-N-(3,5-dichloropyridin-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-2--
yloxy)nicotinamide; [0248] FJ
(.+-.)-N-(3,5-dichloropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)pyridine-2-carboxamide; [0249] FK
(.+-.)-N-(3,5-difluoropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)pyridine-2-carboxamide hydrate; [0250] FL
(.+-.)-N-(3,5-dichloropyridin-4-yl)-5-methoxy-4-(tetrahydrothiophen-3-ylo-
xy)pyridine-2-carboxamide; [0251] FM
N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-car-
boxamide; [0252] FN
N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-carboxami-
de; [0253] FO
(.+-.)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0-
..sup.2.6.]-hept-2-yloxy)pyridine-2-carboxamide; [0254] FP
(.+-.)-N-(3,5-difluoro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0-
..sup.2.6.]-hept-2-yloxy)pyridine-2-carboxamide; [0255] FQ
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxypyridine-2-c-
arboxamide; [0256] FR
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxypyridi-
ne-2-carboxamide hemihydrate; [0257] FS
(.+-.)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tetrahydrothioph-
en-3-yloxy)pyridine-2-carboxamide; [0258] FT
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-oxidopy-
ridinium-2-carboxamide; [0259] FU
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxi-
dopyridinium-2-carboxamide; [0260] FV
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyri-
dinium-2-carboxamide;
[0261] FW
1-(5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridin-2-yl)-2-(-
3,5-dichloropyridin-4-yl)ethanone; [0262] FX
(.+-.)-1-(5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridin-2-yl)-2-(3,5-di-
chloropyridin-4-yl)ethanone; [0263] FY
1-(4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)-5-methoxypyridin-2-yl)-2-(-
3,5-dichloro-1-oxido-4-pyridinio)ethanone; [0264] FZ
N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridi-
nium-2-carboxamide; [0265] GA
N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-
-carboxamide; [0266] GB
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-
-2-carboxamide hemihydrate; [0267] GD
N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzylamine;
[0268] GE
N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxy-2-aminomethylpyridine;
[0269] GG
trans-2-(2,6-dichlorophenyl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl-
)ethene; [0270] GH
trans-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)-2-(2,6-difluorophenyl-
)ethene; [0271] GI
trans-2-(2,6-dichlorophenyl)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)ethe-
ne; [0272] GJ
trans-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(2,6-difluorophenyl)ethe-
ne; [0273] GL
1-[(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl]-2-(pyrid-4-yl)ethane-1,2--
dione; [0274] GM
1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethane-1,2-dione;
[0275] GN
N-(3,5-dichloropyrid-4-yl)-5-cyclopentyloxy-6-methoxypyridazine-3-carboxa-
mide; [0276] GO
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-difluoromethoxypyridine-2-
-carboxamide; [0277] GP
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxypy-
ridine-2-carboxamide; [0278] GQ
N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-difluoromethoxy-1-oxidopyri-
dium-2-carboxamide; [0279] GR
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxy-1-
-oxidopyridium-2-carboxamide; [0280] GS
1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloropyrid-
in-4-yl)ethanone; [0281] GT
1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichlo-
ropyridin-4-yl)ethanone; [0282] GU
1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloro-1-ox-
ido-4-pyridinio)ethanone; [0283] GV
1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichlo-
ro-1-oxido-4-pyridinio)ethanone; [0284] GW
N-(3,5-dichloropyrid-4-yl)-5,6-dimethoxypyridazine-3-carboxamide;
and [0285] GX
1-(5,6-dimethoxypyridazine-3-pyridium)-2-(3,5-dichloropyridin-4-yl)ethano-
ne.
[0286] Preferred compounds include A, CC, CD, CE, CF, CG, CH, CI,
CJ, CK, CL, CM, CN, CO, CP, CQ, CR, CS, CT, CU, CV, CW, CX, CY, CZ,
DA, DB, FF, FG, FH, FI, FJ, FK, FL, FM, FN, FO, FP, FQ, FR, FS, FT,
FU, FV, FW, FX, FY, FZ, GA, GB, GN, GO, GP.
[0287] The letters A-GX are allocated to compounds for easy
reference in this specification.
[0288] Compounds of formula I may be prepared by the application or
adaptation of known methods, by which is meant methods used
heretofore or described in the literature.
[0289] Thus, compounds of formula I wherein R.sup.1, R.sup.2,
R.sup.3, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and ##STR18## Z.sup.2
are as hereinbefore defined, Z.sup.3 represents a --CZNH-- linkage,
and Z is oxygen, may be prepared by the reaction of compounds of
formula II ##STR19## wherein R.sup.1, R.sup.2, Z.sup.1, Z.sup.2,
Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined and X
represents halo, such as bromo or, preferably, chloro, with a
compound of the formula III wherein R.sup.3 is as hereinbefore
defined, preferably in the presence of R.sup.3NH.sub.2 III a base
such as an alkali metal hydride, such as sodium hydride, or an
amine, preferably a tertiary amine, such as triethylamine or
pyridine, optionally in an inert solvent, for example
dichloromethane, dimethylformamide, or an ether, such as diethyl
ether or tetrahydrofuran, preferably at a temperature from about
0.degree. C. to the reflux temperature or at the melting point of
the reaction mixture.
[0290] Alternatively, compounds of formula I wherein R.sup.1,
R.sup.2, R.sup.3, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2
are as hereinbefore defined, Z.sup.3 represents a --CZNH-- linkage,
and Z represents oxygen, may be prepared by the reaction of
compounds of formula II as hereinbefore described, with a compound
of the formula IV wherein R.sup.3 R.sup.4CONHR.sup.3 IV is as
hereinbefore defined, and R.sup.4 represents an alkyl or cycloalkyl
group containing up to 5 carbon atoms, preferably a methyl group,
preferably in the presence of a base, for example an alkali metal
hydride, such as sodium hydride, or an amine, preferably a tertiary
amine, such as triethylamine, in an inert solvent, for example
toluene, dimethylformamide, or an ether, such as tetrahydrofuran or
diethyl ether, at a temperature from about 0.degree. C. to reflux,
then a second base, for example an amine, such as piperidine.
[0291] Alternatively, compounds of formula I, wherein R.sup.1,
R.sup.2, R.sup.3, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore
defined, Z, Z.sup.1 and Z.sup.2 are oxygen, and Z.sup.3 represents
a --CZNH-- linkage, may be prepared by the reaction of compounds of
formula V hereinafter depicted, wherein R.sup.1 and R.sup.2 are as
hereinbefore defined, Q.sup.1, Q.sup.2 ##STR20## and Q.sup.3 are
independently CH or N and at least one of Q.sup.1, Q.sup.2 and
Q.sup.3 is N, with compounds of formula VI wherein R.sup.3 and X
are as hereinbefore defined, R.sup.3X VI preferably X is chloro,
and preferably the preparation takes place in the presence of a
base, for example an alkali metal hydride, such as sodium hydride,
an alkali metal alkoxide, such as potassium t-butoxide, an alkali
metal hydroxide, such as sodium hydroxide or carbonate, or an
amine, preferably a tertiary amine, such as triethylamine or
pyridine, optionally in an inert solvent, for example
dichloromethane, dimethylformamide, or an ether, such as diethyl
ether or tetrahydrofuran, preferably at a temperature from about
0.degree. C. to reflux.
[0292] Alternatively, compounds of formula I, wherein R.sup.1,
R.sup.2, R.sup.3, Z, Z.sup.1, Q.sup.1, Q.sup.2 and Q.sup.3 are as
hereinbefore defined, Z.sup.3 represents a --CZNH-- linkage, and Z
and Z.sup.2 are oxygen, may be prepared by the reaction of
compounds of formula VII wherein R.sup.1, R.sup.3, Z, Z.sup.1,
Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined and
##STR21## Z.sup.3 represents a --CZNH-- linkage, and Z is oxygen,
with compounds of the formula VIII wherein R.sup.2 is as
hereinbefore defined, preferably, X is as R.sup.2X VIII
hereinbefore defined or p-toluenesulfonate, preferably X is bromo,
and preferably the preparation takes place in the presence of a
base, for example an alkali metal hydride, such as sodium hydride,
an alkali metal hydroxide or carbonate, such as sodium hydroxide or
carbonate, or an amine, preferably a tertiary amine, such as.
triethylamine or pyridine, optionally in an inert solvent, for
example dichloromethane, dimethylformamide, or an ether, such as
diethyl ether or tetrahydrofuran, preferably at a temperature from
about 0.degree. C. to reflux, or by the reaction of the compound of
formula VII above with compounds of the formula XXI, as hereinbelow
defined in the presence of, for example,
diisopropylazodicarboxylate and triphenylphosphine.
[0293] Alternatively, compounds of formula I, wherein R.sup.1,
R.sup.2, R.sup.3, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3
are as hereinbefore defined, Z.sup.3 represents a --CZCH.sub.2--
linkage, and Z represents oxygen, are prepared from compounds of
formula IX wherein R.sup.1, ##STR22## R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined,
by oxidation by the application or adaptation of known methods. The
oxidation is carried out, for example, by reaction with oxalyl
chloride and dimethyl sulfoxide, in the presence of a base,
preferably a tertiary amine, preferably triethylamine, in an inert
solvent such as dichloromethane, at temperatures from about
-60.degree. C. to about room temperature, preferably at a reduced
temperature, or by adaptation of known methods for the preparation
of ketone from a secondary alcohol, for example the application of
pyridinium dichromate. Alternatively, the oxidation is carried out
by reaction with chromium trioxide in the presence of
3,5-dimethylpyrazole.
[0294] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z,
Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore
defined, Z.sup.3 represents a --CZCH.sub.2-- linkage, and
preferably those wherein Z represents oxygen, are prepared from
compounds of formula X wherein R.sup.1, ##STR23## R.sup.2, Z,
Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore
defined and R.sup.5 and R.sup.6 represent lower alkyl, such as
methyl, groups, by coupling with compounds of the formula XI
wherein R.sup.3 is as hereinbefore defined, in the presence of a
R.sup.3CH.sub.3 XI strong base such as lithium diisopropylamide
(usually prepared in situ from n-butyl lithium and
diisopropylamine), preferably at a low temperature.
[0295] Alternatively, compounds of formula I, wherein R.sup.1,
R.sup.2, R.sup.3, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3
are as hereinbefore defined, Z.sup.3 represents a --CZCH.sub.2--
linkage, and Z represents oxygen, are prepared from compounds of
formula XII wherein R.sup.1, ##STR24## R.sup.2, Z.sup.1, Z.sup.2,
Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined, and
R.sup.7 is alkyl, cycloalkyl or aralkyl containing up to 8 carbon
atoms, by coupling with compounds of the formula XI above, wherein
R.sup.3 is as hereinbefore defined, in the presence of a strong
base, such as an alkali metal amide or alkyl, for example n-butyl
lithium or lithium diisopropylamide (usually prepared in situ from
butyl lithium and diisopropylamine), in an inert solvent, for
example cyclohexane or an ether, such as tetrahydrofuran or diethyl
ether, at a temperature from about -78.degree. C. to about room
temperature.
[0296] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a --CH2--NH-- linkage are prepared by the
reaction of compounds of formula XIII wherein R.sup.1, R.sup.2,
Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as ##STR25##
hereinbefore defined, with compounds of formula III above, wherein
R.sup.3 is as hereinbefore defined, followed by reduction with a
compound such as sodium cyanoborohydride. This process is
especially suitable for compounds wherein R.sup.3 represents an
optionally substituted phenyl or naphthyl group.
[0297] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a --CH2--NH-- linkage are prepared by the
reaction of compounds of formula XIV wherein X, R.sup.1, R.sup.2,
Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as ##STR26##
hereinbefore defined, and X is preferably bromo, with compounds of
formula III above, wherein R.sup.3 is as hereinbefore defined,
preferably in the presence of a base such as sodium hydride. This
process is especially suitable for compounds wherein R.sup.3
represents an optionally substituted heteroaryl group.
[0298] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a trans --CH.dbd.CH-- linkage are prepared
by the reaction of compounds of formula XIII above, wherein
R.sup.1, R.sup.2, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3
are as hereinbefore defined, with the reaction product of a
compound of the formula XV wherein R.sup.3 is as hereinbefore
defined, R.sup.8 represents
(R.sup.8PCH.sub.2R.sup.3).sup.+(X).sup.- XV an aryl, such as phenyl
group, and X represents halo, preferably bromo, with a base such as
an alkali metal alkoxide, for example potassium t-butoxide. The
reaction is preferably carried out in a solvent such as
tetrahydrofuran.
[0299] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a --CF.sub.2--O-- linkage are prepared by
the reaction of compounds of formula XVI, wherein R.sup.1, R.sup.2,
Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are wherein
##STR27## [0300] R.sup.1, R.sup.2, Z.sup.1, Z.sup.2, Q.sup.1,
Q.sup.2 and Q.sup.3 are as hereinbefore defined, with compounds of
the formula XVII wherein R.sup.3 is as hereinbefore defined,
preferably with the aid R.sup.3OH XVII of a base such as sodium
hydride, preferably in a solvent such as tetrahydrofuran.
[0301] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a --CH.sub.2--O-- linkage are prepared by
the reaction of compounds of formula XVIII wherein R.sup.1,
R.sup.2, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as
##STR28## hereinbefore defined, with compounds of the formula VI
hereinbefore, wherein R.sup.3 and X are as hereinbefore defined,
preferably with the aid of a base such as an alkali metal alkoxide,
such as potassium t-butoxide. The reaction is preferably carried
out in a solvent such as tetrahydrofuran.
[0302] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a --CH.sub.2--O-- linkage are prepared by
the reaction of compounds of formula XIV above, wherein R.sup.1,
R.sup.2, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2, Q.sup.3 and X are as
hereinbefore defined, with compounds of formula XVII above, wherein
R.sup.3 is as hereinbefore defined, preferably with the aid of a
base such as an alkali metal alkoxide, such as potassium
t-butoxide.
[0303] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a --CO--CO-- linkage are prepared by the
oxidation of compounds of formula IX above, wherein R.sup.1,
R.sup.2, R.sup.3, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3
are as hereinbefore defined, for example by reaction with
pyridinium dichromate, preferably in a solvent such as
dichloromethane. This reaction is particularly suitable for
compounds wherein R.sup.3 represents a heteroaryl, preferably an
optionally substituted pyridyl, group.
[0304] According to a further feature of the present invention,
compounds of formula I, wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1,
Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
and Z.sup.3 represents a --CH.sub.2--S-- linkage are prepared by
the reaction of compounds of formula XIV above, wherein X, R.sup.1,
R.sup.2, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as
hereinbefore defined, with compounds of the formula XX wherein
R.sup.3 is R.sup.3--SH XX as hereinbefore defined, preferably with
the aid of a base such as an alkali metal carbonate, such as
potassium carbonate. Compounds of formula I wherein Z.sup.3 is
--CH.sub.2--S--, preferably wherein Z, Z.sup.1 and Z.sup.2 each
represent oxygen, and R.sup.2 is alkyl or cycloalkyl, may then be
oxidized to the corresponding sulphinyl or sulphonyl group. For
example, the oxidation to --CH.sub.2--SO-- can be carried out by
means of potassium hydrogen peroxomonosulfate in a medium such as
aqueous methanol. For example, the oxidation to
--CH.sub.2--SO.sub.2-- can be carried out by means of sodium iodate
in a medium such as aqueous methanol.
[0305] According to another feature of the invention, compounds of
formula I wherein R.sup.1, R.sup.2, R.sup.3, Z.sup.1, Z.sup.3,
Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined, and
R.sup.2 represents cyclosulphonylalkyl, cyclosulphinylalkyl,
cyclosulphonylalkenyl or cyclosulphinylalkenyl, are prepared by
oxidizing the corresponding compounds of formula I wherein R.sup.2
represents cyclosulphonylalkyl or cyclosulphinylalkyl. For example,
the oxidation to sulphinyl can be carried out by means of potassium
hydrogen peroxomonosulfate in a medium such as aqueous methanol.
For example, the oxidation to sulphonyl can be carried out by means
of sodium iodate in a medium such as aqueous methanol.
[0306] As another example, compounds of formula I wherein R.sup.1,
R.sup.2, R.sup.3, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3
are as hereinbefore defined, and Z.sup.3 represents a cis
--C.dbd.C-- isomer linkage are prepared by the action of
ultraviolet radiation upon the trans-isomer.
[0307] As another example, compounds of formula I wherein R.sup.1,
R.sup.2, R.sup.3, Z.sup.1, Z.sup.1, Q.sup.1, Q.sup.2 and Q.sup.3
are as hereinbefore defined, and Z.sup.3 contains a --CS-- moiety,
are prepared from compounds of formula I wherein R.sup.1, R.sup.2,
R.sup.3, Z.sup.1, Z.sup.2, Q.sup.1, Q.sup.2 and Q.sup.3 are as
hereinbefore defined, and Z.sup.3 contains a --CO-- moiety, by
reaction with phosphorus pentasulfide or
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,
preferably in a solvent such as pyridine or toluene, and preferably
at a temperature from about 0.degree. C. to reflux.
[0308] As another example, compounds of formula I wherein R.sup.3
is as hereinbefore defined and contains an alkylsulfonyl,
arylsulfonyl, alkylsulfinyl or arylsulfinyl group, R.sup.1,
R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2 and Z.sup.3
are as hereinbefore defined, are prepared by oxidising the
corresponding compounds of formula I wherein R.sup.3 is as
hereinbefore defined and contains an alkylthio or arylthio group,
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2
and Z.sup.3 are as hereinbefore defined, preferably wherein Z,
Z.sup.1 and Z.sup.2 each represent oxygen, and R.sup.2 is alkyl or
cycloalkyl, preferably with a peroxyacid, such as
3-chloroperbenzoic acid, preferably in an inert solvent, such as
dichloromethane, preferably at about room temperature.
Alternatively, the oxidation is carried out by reaction with a
peroxomonosulfate, such as potassium peroxomonosulfate,
conveniently in a solvent such as methanol, buffered to about pH 5,
at temperatures from about 0.degree. C. to about room temperature.
This latter method is preferred for compounds containing an
acid-labile group, such as those wherein the moiety R.sup.2 is
unsaturated, such as a cyclopent-2-enyloxy group.
[0309] As another example, compounds of formula I wherein R.sup.3
is as hereinbefore defined and contains a hydroxymethyl group, and
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2
and Z.sup.3 are as hereinbefore defined, are prepared by the
reduction of the corresponding compounds of formula I wherein
R.sup.3 is as hereinbefore defined and contains an aryloxycarbonyl
or, preferably, alkoxycarbonyl group, R.sup.1, R.sup.2, Q.sup.1,
Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2 and Z.sup.3 are as
hereinbefore defined, and Z is preferably oxygen, preferably by
means of reacting an alkali metal borohydride, preferably in an
inert solvent, such as tetrahydrofuran, preferably at about room
temperature.
[0310] As another example, compounds of formula I wherein R.sup.3
is as hereinbefore defined and contains a formyl group, and
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2
and Z.sup.3 are as hereinbefore defined, are prepared by the
oxidising the corresponding compounds of formula I wherein R.sup.3
is as hereinbefore defined and contains a hydroxymethyl group,
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2
and Z.sup.3 are as hereinbefore defined, and Z preferably being an
oxygen atom, for example with oxalyl chloride and dimethyl
sulfoxide, in a solvent such as dichloromethane, and preferably at
a temperature lower than about -65.degree. C., or, preferably, by
reaction with a complex of sulfur trioxide with an amine such as
pyridine, preferably in the presence of an amine such as
triethylamine, preferably at about room temperature.
[0311] As another example, compounds of formula I wherein R.sup.3
is as hereinbefore defined and contains an amino group, and
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2
and Z.sup.3 are as hereinbefore defined, are prepared by the
reducing the corresponding compounds of formula I wherein R.sup.3
is as hereinbefore defined and contains a nitro group, R.sup.1,
R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2 and Z.sup.3
are as hereinbefore defined, and Z is preferably oxygen, preferably
with iron in acidic conditions, such as in acetic acid, preferably
at or above room temperature, more especially at the reflux
temperature. Alternatively the reduction are carried out by
reaction with hydrazine hydrate in the presence of ferric chloride
and activated carbon, conveniently in a solvent such as methanol,
at temperatures from about 25.degree. C. to about 80.degree. C.
This latter method is preferred for compounds containing an
acid-labile group, such as those wherein the moiety R.sup.2 is
unsaturated, such as a cyclopent-2-enyloxy group.
[0312] As another example, compounds of formula I wherein R.sup.3
is as hereinbefore defined and contains an alkanoylamino or
aroylamino group, and R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3,
Z, Z.sup.1, Z.sup.2 and Z.sup.3 are as hereinbefore defined, are
prepared from compounds of formula I wherein R.sup.3 is as
hereinbefore defined and contains an amino group, R.sup.1, R.sup.2,
Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2 and Z.sup.3 are as
hereinbefore defined, and Z is preferably oxygen, preferably by
means of reaction with the appropriate acid halide or acid
anhydride in the presence of a tertiary base, such as
triethylamine, optionally in an inert solvent, and preferably at a
temperature from about 0.degree. C. to reflux.
[0313] Compounds of formula I wherein R.sup.3 is as hereinbefore
described, including an azaheteroaryl group containing one or more
nitrogen ring atoms, preferably imine (.dbd.N--), and R.sup.1,
R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2 and Z.sup.3
are as hereinbefore defined, may be converted to the corresponding
compounds wherein a nitrogen atom of the azaheteroaryl moiety is
oxidised to an N-oxide, R.sup.1, R.sup.2, Q.sup.1, Q.sup.2,
Q.sup.3, Z, Z.sup.1, Z.sup.2 and Z.sup.3 are hereinbefore defined,
and preferably Z, Z.sup.1 and Z.sup.2 each represent oxygen, and
R.sup.2 is alkyl or cycloalkyl, preferably by reacting a peracid,
for example peracetic acid in acetic acid or m-chloroperoxybenzoic
acid in an inert solvent such as dichloromethane, at a temperature
from about room temperature to reflux, preferably at elevated
temperature. Preferably wherein Z, Z.sup.1 and Z.sup.2 each
represent oxygen, and R.sup.2 is an oxidised cyclothioalkyl, such
as cyclosulphinyl or sulphonyl, the reaction is carried out at a
temperature from about room temperature to reflux, preferably at a
reduced temperature. Alternatively, the oxidation is carried out by
reaction with hydrogen peroxide in the presence of sodium tungstate
at temperatures from about room temperature to about 60.degree. C.
This latter method is preferred for compounds containing an
acid-labile group, such as those wherein the moiety R.sup.2
contains a carbon-carbon double bond between its beta- and
gamma-carbon atoms, such as a cyclopent-2-enyloxy group.
[0314] Compounds of formula I wherein R.sup.3 represents an
azaheteroaryl group containing a nitrogen ring atom as an N-oxide,
and R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z, Z.sup.1,
Z.sup.2 and Z.sup.3 are as hereinbefore defined, may be converted
to the corresponding compounds wherein Q.sup.1, Q.sup.2 or Q.sup.3
as a nitrogen atom is oxidised to an N-oxide moiety, R.sup.1,
R.sup.2, Z, Z.sup.1, Z.sup.2 and Z.sup.3 are hereinbefore defined,
and preferably wherein Z, Z.sup.1 and Z.sup.2 each represent
oxygen, and R.sup.2 is alkyl or cycloalkyl, by reacting a peracid,
for example m-chloroperoxy-benzoic acid in an inert solvent such as
dichloromethane, at a temperature from about room temperature to
reflux, preferably at elevated temperature.
[0315] Compounds of formula I wherein R.sup.3 represents a
azaheteroaryl group containing one or more nitrogen ring atoms,
preferably imine (.dbd.N--), and R.sup.1, R.sup.2, Q.sup.1,
Q.sup.2, Q.sup.3, Z, Z.sup.1, Z.sup.2 and Z.sup.3 are as
hereinbefore defined, may be converted to the corresponding
compounds wherein a nitrogen atom of the azaheteroaryl moiety is
oxidised to an N-oxide, wherein Q.sup.1, Q.sup.2 or Q.sup.3 as a
nitrogen atom is oxidised to an N-oxide moiety, R.sup.1, R.sup.2,
Z, Z.sup.1, Z.sup.2 and Z.sup.3 are hereinbefore defined, and
preferably wherein Z, Z.sup.1 and Z.sup.2 each represent oxygen,
and R.sup.2 is alkyl or cycloalkyl, preferably by reacting a
peracid, for example m-chloroperoxybenzoic acid in an inert solvent
such as dichloromethane, at a temperature from about room
temperature to reflux, preferably at elevated temperature.
[0316] Compounds of formula I wherein R.sup.3 represents an
azaheteroaryl group containing a nitrogen ring atom as an N-oxide,
Q.sup.1, Q.sup.2 or Q.sup.3 as a nitrogen atom is oxidised to an
N-oxide moiety, and R.sup.1, R.sup.2, Z, Z.sup.1, Z.sup.2 and
Z.sup.3 are as hereinbefore defined, may be converted to the
corresponding compounds wherein R.sup.3 represents an azaheteroaryl
group containing one or more nitrogen ring atoms, preferably imine
(.dbd.N--), Q.sup.1, Q.sup.2 or Q.sup.3 as a nitrogen atom is
oxidised to an N-oxide moiety, R.sup.1, R.sup.2, Z, Z.sup.1,
Z.sup.2 and Z.sup.3 are hereinbefore defined, preferably by
reacting in a deoxygenating system, for example diphosphorus
tetraiodide in an inert solvent, such as dichloromethane,
preferably at room temperature, or with a chlorotrialkylsilane,
preferably chlorotrimethylsilane, in the presence of an alkali
metal iodide, e.g potassium iodide, and zinc, in an inert solvent,
for example acetonitrile, at temperatures from about 0.degree. C.
to about room temperature, preferably at reduced temperature.
[0317] For example, compounds of formula I wherein R.sup.1 is as
hereinbefore defined and is substituted by fluorine on a carbon
atom thereof alpha to the attachment of R.sup.1 to Z.sup.1 as
sulfur, or wherein R.sup.2 is as hereinbefore defined and is
substituted by fluorine on a carbon atom thereof alpha to the
attachment of R.sup.2 to Z.sup.2 as sulfur, and Q.sup.1, Q.sup.2,
Q.sup.3, R.sup.3 and Z.sup.3 as hereinbefore defined, are prepared
by reacting xenon difluoride with corresponding compounds of
formula I wherein said alpha-carbon atoms carry hydrogen atoms
instead of said fluorine atoms. The reaction is conveniently
carried out in a solvent, such as dichloromethane, in the presence
of a molecular sieve, and in an inert atmosphere, at a low
temperature, such as at about 0.degree. C. Alternatively, compounds
of formula I wherein R.sup.1 is a difluoromethyl group may be
prepared by reacting a compound of formula I or precursor wherein
Z.sup.1 is hydroxy or thiol with HCBrF.sub.2 in the presence of a
strong base in an inert solvent.
[0318] As another example, compounds of formula I wherein R.sup.3
represents a heteroaryl group containing one or more nitrogen ring
atoms but carrying no halogen substituents, and R.sup.1, R.sup.2,
R.sup.3, Z.sup.1, Z.sup.2, Z.sup.3, Q.sup.1, Q.sup.2 and Q.sup.3
are as hereinbefore defined, are prepared by the reduction of the
corresponding compounds of formula I wherein R.sup.3 does carry one
or more halo, such as chloro, substituents, for example by means of
ammonium formate in the presence of a palladium catalyst.
[0319] The compounds of the present invention are useful in the
form of the free base or acid or in the form of a pharmaceutically
acceptable salt thereof. All forms are within the scope of the
invention.
[0320] Where the compound of the present invention is substituted
with a basic moiety, acid addition salts are formed and are simply
a more convenient form for use; and in practice, use of the salt
form inherently amounts to use of the free base form. The acids
which can be used to prepare the acid addition salts include
preferably those which produce, when combined with the free base,
pharmaceutically acceptable salts, that is, salts whose anions are
non-toxic to the patient in pharmaceutical doses of the salts, so
that the beneficial inhibitory effects on TNF and PDE inherent in
the free base are not vitiated by side effects ascribable to the
anions. Although pharmaceutically acceptable salts of said basic
compounds are preferred, all acid addition salts are useful as
sources of the free base form even if the particular salt, per se,
is desired only as an intermediate product as, for example, when
the salt is formed only for purposes of purification, and
identification, or when it is used as intermediate in preparing a
pharmaceutically acceptable salt by ion exchange procedures.
Pharmaceutically acceptable salts within the scope of the invention
are those derived from the following acids: mineral acids such as
hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic
acid; and organic acids such as acetic acid, citric acid, lactic
acid, tartaric acid, malonic acid, methanesufonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
cyclohexylsulfamic acid, quinic acid, and the like. The
corresponding acid addition salts comprise the following:
hydrohalides, such as hydrochloride and hydrobromide, sulfate,
phosphate, nitrate, sulfamate, acetate, citrate, lactate,
tartarate, malonate, oxalate, salicylate, propionate, succinate,
fumarate, maleate, methylene-bis-beta-hydroxynaphthoates,
gentisates, mesylates, isethionates and
di-p-toluoyltartratesmethanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and
quinate, respectively.
[0321] According to a further feature of the invention, acid
addition salts of the compounds of this invention are prepared by
reaction of the free base with the appropriate acid, by the
application or adaptation of known methods. For example, the acid
addition salts of the compounds of this invention are prepared
either by dissolving the free base in aqueous or aqueous-alcohol
solution or other suitable solvents containing the appropriate acid
and isolating the salt by evaporating the solution, or by reacting
the free base and acid in an organic solvent, in which case the
salt separates directly or can be obtained by concentration of the
solution.
[0322] The acid addition salts of the compounds of this invention
can be regenerated from the salts by the application or adaptation
of known methods. For example, parent compounds of the invention
can be regenerated from their acid addition salts by treatment with
an alkali, such as aqueous sodium bicarbonate solution or aqueous
ammonia solution.
[0323] Where the compound of the invention is substituted with an
acidic moiety, base addition salts may be formed and are simply a
more convenient form for use; and in practice, use of the salt form
inherently amounts to use of the free acid form. The bases which
can be used to prepare the base addition salts include preferably
those which produce, when combined with the free acid,
pharmaceutically acceptable salts, that is, salts whose cations are
non-toxic to the animal organism in pharmaceutical doses of the
salts, so that the beneficial inhibitory effects on TNF and PDE
inherent in the free acid are not vitiated by side effects
ascribable to the cations. Pharmaceutically acceptable salts,
including for example alkali and alkaline earth metal salts, within
the scope of the invention are those derived from the following
bases: sodium hydride, sodium hydroxide, potassium hydroxide,
calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium
hydroxide, zinc hydroxide, ammonia, ethylenediamine,
N-methyl-glucamine, lysine, arginine, ornithine, choline,
N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine,
procaine, N-benzylphenethylamine, diethylamine, piperazine,
tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide,
and the like.
[0324] Metal salts of compounds of the present invention may be
obtained by contacting a hydride, hydroxide, carbonate or similar
reactive compound of the chosen metal in an aqueous or organic
solvent with the free acid form of the compound. The aqueous
solvent employed may be water or it may be a mixture of water with
an organic solvent, preferably an alcohol such as methanol or
ethanol, a ketone such as acetone, an aliphatic ether such as
tetrahydrofuran, or an ester such as ethyl acetate. Such reactions
are normally conducted at ambient temperature but they may, if
desired, be conducted with heating.
[0325] Amine salts of compounds of the present invention may be
obtained by contacting an amine in an aqueous or organic solvent
with the free acid form of the compound. Suitable aqueous solvents
include water and mixtures of water with alcohols such as methanol
or ethanol, ethers such as tetrahydrofuran, nitriles such as
acetonitrile, or ketones such as acetone. Amino acid salts may be
similarly prepared.
[0326] The base addition salts of the compounds of this invention
can be regenerated from the salts by the application or adaptation
of known methods. For example, parent compounds of the invention
can be regenerated from their base addition salts by treatment with
an acid, such as hydrochloric acid.
[0327] As will be self-evident to those skilled in the art, some of
the compounds of this invention do not form stable salts. However,
acid addition salts are most likely to be formed by compounds of
this invention wherein R.sup.3 represents a nitrogen-containing
heteroaryl group and/or wherein R.sup.3 contains an amino group as
a substituent. Preferable acid addition salts of the compounds of
the invention are those wherein R.sup.2 is other than an acid
labile group.
[0328] As well as being useful in themselves as active compounds,
salts of compounds of the invention are useful for the purposes of
purification of the compounds, for example by exploitation of the
solubility differences between the salts and the parent compounds,
side products and/or starting materials by techniques well known to
those skilled in the art.
[0329] It will be apparent to those skilled in the art that certain
compounds of formula I can exhibit isomerism, for example
geometrical isomerism and optical isomerism. Optical isomers
include compounds of the invention having asymmetric centers that
may independently be in either the R or S configuration.
Geometrical isomers include the cis and trans forms of compounds of
the invention having alkenyl moieties. Individual geometrical
isomers, stereoisomers and mixtures thereof are within the scope of
the present invention.
[0330] Such isomers can be separated from their mixtures, by the
application or adaptation of known methods, for example
chromatographic techniques and recrystallization techniques, or
they are separately prepared from the appropriate isomers of their
intermediates, for example by the application or adaptation of
methods described herein.
[0331] The starting materials and intermediates are prepared by the
application or adaptation of known methods, for example methods as
described in the Reference Examples or their obvious chemical
equivalents.
[0332] For example, compounds of formula II, wherein R.sup.1,
R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2 are as
hereinbefore defined, are prepared from compounds of formula XIX
wherein R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and
Z.sup.2 are as hereinbefore defined, by the ##STR29## application
or adaptation of known methods for the preparation of acid halides
from carboxylic acids. For example, when the moiety X in a compound
of formula II represents a chloro, the reaction may be carried out
by means of thionyl chloride or, preferably, oxalyl chloride in the
presence of triethylamine, or as prepared by adaptation of the
procedures described by K. R. Reistad et al., Acta. Chemica.
Scandanavica B, 28, 667-72 (1974), incorporated herein by
reference.
[0333] Compounds of formula XIX, wherein R.sup.1, R.sup.2, Q.sup.1,
Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2 are as hereinbefore defined,
are prepared by the oxidation of compounds of formula XIII above,
wherein R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and
Z.sup.2 are as hereinbefore defined, for example by means of
reaction with potassium permanganate, or with a mixture of sulfamic
acid and sodium chlorite in acetic acid, or with sodium chlorite in
the presence of sodium dihydrogen phosphate.
[0334] According to a further feature of the invention, compounds
of formula XIX, wherein R.sup.1, R.sup.2, Q.sup.1, Q.sup.2,
Q.sup.3, Z.sup.1 and Z.sup.2 are as hereinbefore defined, are
prepared by the oxidation of compounds of formula XVIII, ##STR30##
by adaptation of known methods for the preparation of carboxylic
acids from primary alcohols, for example potassium permanganate in
water or a mixture of water and inert organic solvent, e.g
dichloromethane, in the presence of a phase transfer catalyst, such
as aliquat 336, at about room temperature to reflux. Alternatively,
the compound of formula XVIII is oxidized as described by H. C.
Beyerman, Receueil, 77, 249-57, (1958), incorporated herein by
reference.
[0335] Compounds of formula XIII, wherein R.sup.1, R.sup.2,
Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2 are as hereinbefore
defined, are prepared from compounds of formula XX ##STR31##
wherein R.sup.1, Q.sup.1, Q.sup.2, Q.sup.3 and Z.sup.1 are as
hereinbefore defined, by reaction with compounds of formula VIII
wherein R.sup.2 and X are as hereinbefore defined, and X is
preferably bromo, preferably in the presence of a base, for example
an alkali metal hydride, such as sodium hydride, an alkali metal
hydroxide or carbonate, such as sodium hydroxide or carbonate, or
an amine, preferably a tertiary amine, such as triethylamine or
pyridine, optionally in an inert solvent, for example
dichloromethane, dimethylformamide, or an ether, such as diethyl
ether or tetrahydrofuran, preferably at a temperature from about
0.degree. C. to reflux, or alternatively by reaction with compounds
of the formula XXI, wherein R.sup.2 is R.sup.2OH XXI as
hereinbefore defined, preferably in the presence of a compound such
as diisopropyl azodicarboxylate and triphenylphosphine.
[0336] Alternatively compounds of formula XIX above, wherein
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2
are as hereinbefore defined, are prepared by the hydrolysis of
compounds of formula XII above, wherein R.sup.1, R.sup.2, R.sup.7,
Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2 are as hereinbefore
defined, for example by reaction with a base, such as an aqueous
alkali metal hydroxide, alkali metal carbonate or bicarbonate, such
as potassium hydroxide or potassium carbonate, in an inert
co-solvent such as methanol at a temperature from about room
temperature to reflux, and then with an aqueous acid such as
hydrochloric acid or acetic acid.
[0337] Compounds of formula XIII above, wherein R.sup.1, R.sup.2,
R.sup.7, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2 are as
hereinbefore defined, are prepared from compounds of formula XXII
##STR32## by reaction with compounds of the formula XXI above,
wherein R.sup.2 is as wherein R.sup.1, R.sup.7, Q.sup.1, Q.sup.2,
Q.sup.3, Z.sup.1 and Z.sup.2 are as hereinbefore defined,
preferably in the presence of diisopropyl azodicarboxylate and
triphenylphosphine.
[0338] Alternatively, compounds of formula XII above, as
hereinbefore defined, can be prepared from compounds of formula
XXII above, as hereinbefore defined, by reaction with compounds of
the formula VIII above, as hereinbefore defined, in the presence of
base, for example an alkali metal hydride, such as sodium hydride,
a tertiary amine, such as triethylamine, or preferably an alkali
metal carbonate or hydroxide, such as sodium carbonate or
hydroxide, or in the presence of a transition metal carbonate, such
as silver carbonate, optionally in an inert solvent, such as
dimethylformamide or tetrahydrofuran, preferably at a temperature
from about 0.degree. C. to about 80.degree. C.
[0339] Compounds of formula IX above, wherein R.sup.1, R.sup.2,
R.sup.3, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1, Z.sup.2 and Z.sup.3
are as hereinbefore defined, are prepared by the reaction of
compounds of formula XIII above, wherein R.sup.1, R.sup.2, Q.sup.1,
Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.1 are as hereinbefore defined,
with compounds of the formula XI above, wherein R.sup.3 is as
hereinbefore defined, in the presence of a base such as an alkali
metal amide or alkyl, for example n-butyllithium or lithium
diisopropylamide, in an inert solvent, for example cyclohexane or
an ether, such as tetrahydrofuran or diethyl ether, at a
temperature from about -78.degree. C. to about room temperature,
preferably at a reduced temperature.
[0340] Compounds of formula XVI above, wherein R.sup.1, R.sup.2,
Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2 are as hereinbefore
defined, are prepared by the reaction of bromine in carbon
tetrachloride and ultraviolet radiation on the corresponding
compounds wherein the bromodifluormethyl moiety is --CHF.sub.2,
which themselves are prepared by the action of sulfur tetrafluoride
and hydrofluoric acid on compounds of formula XIII above, wherein
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2
are as hereinbefore defined, in the presence of pyridine.
[0341] Compounds of formula XIII above, wherein R.sup.1, R.sup.2,
Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2 are as hereinbefore
defined, are prepared from compounds of formula XVIII above,
R.sup.1, R.sup.2, Q.sup.1, Q.sup.2, Q.sup.3, Z.sup.1 and Z.sup.2
are as hereinbefore defined, by a Swern oxidation using a mixture
of dimethyl sulphoxide and oxalyl chloride in the presence of a
base, preferably a tertiary amine, preferably triethylamine, in an
inert solvent e.g dichloromethane, at temperatures from about
-60.degree. C. to about room temperature, or preferably using
activated manganese dioxide in an inert solvent, for example
dichloromethane or diethyl ether, preferably at about room
temperature.
[0342] Compounds of formula XXII above, wherein R.sup.1, R.sup.7,
Q.sup.1, Q.sup.2, Q.sup.3 and Z.sup.1 are as hereinbefore defined,
and Z.sup.2 represents an oxygen atom are prepared from compounds
of formula XXIII, wherein R.sup.1, R.sup.7, Q.sup.1, Q.sup.2,
Q.sup.3 and Z.sup.1 ##STR33## as hereinbefore described, by
diazotisation of the amino group with an alkali metal nitrite, such
as sodium nitrite, under aqueous acid conditions, such as aqueous
hydrochloric acid, at room temperature or below, preferably at
about 0.degree. C. The diazo species is isolated by the addition of
an alkali metal salt which stabilises the diazonium salt, such as
sodium tetrafluoroborate, at room temperature or below, preferably
at about 0.degree. C. The resulting stabilised diazonium salt is
then decomposed under acid conditions, such as trifluoroacetic
acid, at elevated temperature, such as boiling point of the
acid.
[0343] Alternatively, compounds of formula XXII above, wherein
R.sup.1, R.sup.7, Q.sup.1, Q.sup.2, Q.sup.3 and Z.sup.1 are as
hereinbefore defined, and Z.sup.2 represents a sulphur atom are
prepared from compounds of formula XXIII above, wherein R.sup.1,
R.sup.7, Q.sup.1, Q.sup.2, Q.sup.3 and Z.sup.1 are as hereinbefore
defined, by diazotisation of the amino group with an alkali metal
nitrite, such as sodium nitrite, under aqueous acid conditions,
such as aqueous hydrochloric acid, at room temperature or below,
preferably at about 0.degree. C. The diazo species is isolated by
the addition of an alkali metal salt which stabilises the diazonium
salt, such as sodium tetrafluoroborate, at room temperature or
below, preferably at about 0.degree. C. The resulting stabilised
diazonium salt is then reacted with a sulphydryl anion, such as
sodium hydrogen sulphide.
[0344] Compounds of formula XXIII above, wherein R.sup.1, R.sup.7,
Q.sup.1, Q.sup.2, Q.sup.3 and Z.sup.1 are as hereinbefore defined,
are prepared from compounds of formula XXIV ##STR34## wherein
R.sup.1, R.sup.7, Q.sup.1, Q.sup.2, Q.sup.3 and Z.sup.1 are as
hereinbefore defined, by reduction of the nitro group with hydrogen
and a metal catalyst, such as 5% palladium supported on carbon, in
an inert solvent, such as ethyl acetate, or using a dissolving
metal reduction, for example tin or zinc, preferably iron, in
aqueous acid, for example hydrochloric acid, or preferably acetic
acid, optionally with an inert co-solvent, for example ethanol, at
a temperature from about room temperature to reflux, preferably at
elevated temperature.
[0345] Compounds of formula XXIV above, wherein R.sup.1, R.sup.7,
Q.sup.1, Q.sup.2, Q.sup.3 and Z.sup.1 are as hereinbefore defined,
are prepared from compounds of formula XXV ##STR35## wherein
R.sup.7, Q.sup.1, Q.sup.2 and Q.sup.3 are as hereinbefore defined
(prepared by the method of Berrie et al. J. Chem. Soc. 2590-4
(1951), Ger. Offen. 2,130,311 and U.S. Pat. No. 3,903,146,
incorporated herein by reference), by reaction with compounds of
formula XXVI, wherein Z.sup.1 and R.sup.1 are as hereinbefore
defined, R.sup.1Z.sup.1M XXVI and M represents an alkaline metal,
such as sodium, in an alcohol, such as methanol where Z.sup.1 is
oxygen, or inert solvent, for example where Z.sup.1 is sulphur, at
room temperature or up to 80.degree. C., preferably at room
temperature.
[0346] Alternatively, compounds of formula XII above, wherein
Z.sup.1, R.sup.1, and R.sup.7 are as hereinbefore defined, and
Q.sup.1 and Q.sup.2 are CH, and Q.sup.3 is nitrogen are prepared by
reaction of compounds of formula XXVII, wherein X, Z.sup.1, R.sup.1
and R.sup.7 ##STR36## are as hereinbefore defined, with compounds
of formula XXVI above, wherein Z.sup.2, R.sup.2 and M are as
hereinbefore defined, preferably in the presence of a base, for
example alkali metal or alkali metal hydride, such as sodium or
sodium hydride, without co-solvent or in the presence of an inert
solvent, such as tetrahydrofuran, from about room temperature to
reflux, preferably at about room temperature.
[0347] Compounds of formula XXVII above, wherein Z.sup.1, R.sup.1
and R.sup.7 are as defined hereinbefore, are prepared by the
reaction of compounds of formula XXVIII, wherein X, Z.sup.1 and
R.sup.1 are as hereinbefore defined, with compounds ##STR37## of
formula XXIX, wherein R.sup.7 is as hereinbefore defined,
preferably using the R.sup.7OH XXIX compound of XXIX as the
solvent, from about room temperature to reflux.
[0348] Compounds of formula XXVIII above, wherein X, R.sup.1 and
Z.sup.1 are as hereinbefore defined, are prepared from compounds of
formula XXX, wherein ##STR38## X, R.sup.1 and Z.sup.1 are as
hereinbefore defined, a by adaptation of procedures described by K.
R. Reistad et al., Acta. Chemica. Scandanavica B, 28, 667-72
(1974), incorporated herein by reference.
[0349] Compounds of formula XXX above, wherein X, R.sup.1 and
Z.sup.1 are as hereinbefore defined, are prepared by the reaction
of compounds of formula XXXI, wherein X and Z.sup.1 is as
hereinbefore defined, with compounds of ##STR39## formula XXXII,
wherein R.sup.1 is as hereinbefore defined, by adaptation of
(R.sup.1).sub.2SO.sub.4 XXXII procedures described by K. R. Reistad
et al., Acta. Chemica. Scandanavica B, 28, 667-72 (1974),
incorporated herein by reference.
[0350] Alternatively, compounds of formula XVIII above, wherein
Z.sup.1 represents oxygen, Z.sup.2 represent oxygen or sulphur
atoms, Q.sup.1 and Q.sup.3 represent CH, and Q.sup.2 represents a
nitrogen atom, and R.sup.1 and R.sup.2 are as hereinbefore defined
are prepared from compounds of formula XXXIII, wherein R.sup.1,
R.sup.2 and Z.sup.2 are as ##STR40## hereinbefore defined, and P
represents a protecting group, such as a silyl group, for example
t-butyldimethylsilyl, or a trityl group, by reaction with an excess
or a catalytic quantity of aqueous acid, for example formic acid,
trifluoroacetic acid or acetic acid, neat or in the presence of a
co-solvent, for example ethyl acetate, at a temperature from about
room temperature to about 100.degree. C.
[0351] Compounds of formula XXXIII above, R.sup.1, R.sup.2, Z.sup.2
and P are as hereinbefore defined, are prepared by the reaction of
compounds of formula XXXIV, wherein Y represents P.sup.1 or
R.sup.1, P.sup.1 represents a protecting group, such ##STR41## as
benzyl, and R.sup.1, Z.sup.2 and P are as hereinbefore defined, (1)
where Y and Z.sup.2 of XXXIV represent respectively R.sup.1 and an
oxygen atom, with compounds of formula XXI, wherein R.sup.2 is as
hereinbefore defined, in the presence of a dialkyl
diazodiarboxylate, for example diisopropyldiazodicarboxylate, and a
phosphine, preferably triarylphosphine, such as triphenylphosphine,
in an inert solvent, for example toluene or an ether, such as
tetrahydrofuran or diethyl ether, at a temperature from about
-20.degree. C. to reflux, or (2) where Y and Z.sup.2 of XXXIV
represent respectively R.sup.1 and a sulphur atom, with compounds
of formula VIII above, wherein R.sup.2 and X are as hereinbefore
defined, and X is preferably bromo, preferably in the presence of a
base, for example an alkali metal hydride, such as sodium hydride,
an alkali metal hydroxide or carbonate, such as sodium hydroxide or
carbonate, or an amine, preferably a tertiary amine, such as
triethylamine or pyridine, optionally in an inert solvent, for
example dichloromethane, dimethylformamide, or an ether, such as
diethyl ether or tetrahydrofuran, preferably at a temperature from
about 0.degree. C. to reflux, or (3) where Y of XXXIV represents
P.sup.1, a protecting group as hereinbefore defined, and Z.sup.2 of
XXXIV represents an oxygen or sulphur atom, then XXXIV is treated
as in procedure (1) or (2) herein to prepare compounds of formula
XXXV, wherein Y is P.sup.1, and P, P.sup.1, Z.sup.2 and R.sup.2 are
as herein beforefore defined, ##STR42## that are then selectively
deprotected to remove P.sup.1 as a benzyl group, for example by
hydrogenolysis in the presence of a supported metal catalyst, such
as 5% palladium on charcoal, in an inert solvent, for example ethyl
acetate, or preferably ethanol to yield compounds of formula XXXVI,
wherein P, Z.sup.2 and R.sup.2 ##STR43## are as hereinbefore
defined, that are then alkylated with compounds of formula XXXVII,
wherein R.sup.1 and X are hereinbefore defined, in the presence of
a base, R.sup.1X XXXVII for example an amine, such as
1,8-diazabicyclo[5.4.0]undec-7-ene, or preferably an alkali metal
carbonate, such as potassium carbonate, in an inert solvent, for
example dimethylformamide, at a temperature from about 0.degree. C.
to about 120.degree. C.
[0352] Compounds of formula XXXIV above, wherein Y, Z.sup.2 and P
are as hereinbefore defined, are prepared by the reaction of
compounds of formula XXXVIII, wherein Y is as hereinbefore defined,
and Z.sup.2 represents an oxygen ##STR44## atom, with compounds of
formula XXXIX, wherein P and X are as PX XXXIX hereinbefore
defined, preferably in the presence of base, for example an amine,
preferably a tertiary amine, for example triethylamine or
preferably 4-dimethylaminopyridine, in an inert solvent, for
example dimethylformamide or tetrahydrofuran, at from about room
temperature to about 120.degree. C., preferably from about
60.degree. C. to about 100.degree. C., and the protected product is
optionally converted to the corresponding protected product wherein
Z.sup.2 is sulphur, with phosphorus pentasulfide or
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,
preferably in a solvent such as pyridine or toluene, and preferably
at a temperature from about 0.degree. C. to reflux.
[0353] Compounds of formula XXXVIII above, wherein Z.sup.2
represents an oxygen atom, and Y is as hereinbefore defined, are
prepared from compounds of formula XXXX, wherein Y is as
hereinbefore defined, by adaptation of the ##STR45## procedures
described by H. C. Beyerman, Receueil, 77, 249-57, (1958) and
European Patent 204207 (20 May 1986), incorporated herein by
reference.
[0354] Compounds of formula XXXX wherein Y is as hereinbefore
defined, are prepared by the reaction of compounds of formula
XXXXI, with compounds ##STR46## of formula XXXII above, wherein
R.sup.1 is as hereinbefore defined, by adaptation of the alkylation
procedure described by H. C. Beyerman, Receueil, 77, 249-57, (1958)
and European Patent 204207 (20 May 1986), incorporated herein by
reference.
[0355] Compounds of formula XII above, wherein Z.sup.1 and Z.sup.2
represent an oxygen atoms, Q.sup.1 and Q.sup.3 represent CH,
Q.sup.2 represents N, and R.sup.1, R.sup.2 and R.sup.7 are as
hereinbefore defined are prepared by the reaction of compounds of
formula XXXXII, wherein Z.sup.2 represents an oxygen atom, and
R.sup.1 and R.sup.7 are as ##STR47## hereinbefore defined, with
compounds of formula XXI above, wherein R.sup.2 is as hereinbefore
defined, in the presence of a dialkyl diazodiarboxylate, for
example diisopropyldiazodicarboxylate, and a phosphine, preferably
triarylphosphine, such as triphenylphosphine, in an inert solvent,
for example toluene or an ether, such as tetrahydrofuran or diethyl
ether, at a temperature from about -20.degree. C. to reflux.
[0356] Compounds of formula XXXXII above, wherein Z.sup.2
represents an oxygen atom, and R.sup.1 and R.sup.7 are as
hereinbefore defined, are prepared by the reaction of compounds of
formula XXXXIII, wherein R.sup.1 and Z.sup.2 are as ##STR48##
hereinbefore defined, with compounds of formula XXIX, wherein
R.sup.7 is as hereinbefore defined, in the presence of an acid,
preferably a mineral acid, for example sulphuric acid, or
preferably hydrogen chloride, at a temperature from about 0.degree.
C. to reflux, preferably at an elevated temperature.
[0357] Compounds of formula XXXXIII above, wherein R.sup.1 and
Z.sup.2 are as hereinbefore defined, are prepared from compounds of
formula XXXVIII above, wherein Y is R.sup.1, Z.sup.2 represents an
oxygen atom, and R.sup.1 is as hereinbefore defined, by adaptation
of the procedure described by H. C. Beyerman, Receueil, 77, 249-57,
(1958), incorporated herein by reference.
[0358] Alternatively, compounds of formula XVIII above, wherein
Q.sup.1 and Q.sup.2 are N, Q.sup.3 is CH, R.sup.1, R.sup.2 are as
hereinbefore defined, and Z.sup.1 and Z.sup.2 represent oxygen
atoms, are prepared from compounds of formula XXXXIV, wherein
R.sup.1, ##STR49## R.sup.2, and R.sup.4 are as hereinbefore
defined, by reaction with aqueous alkali metal hydroxide or
carbonate, such as potassium hydroxide or preferably potassium
carbonate, in an inert co-solvent, such as methanol, at a
temperature from about room temperature to reflux.
[0359] Compounds of formula XXXXIV above, wherein R.sup.1, R.sup.2,
and R.sup.4 are as hereinbefore defined, are prepared from
compounds of formula XXXXV, ##STR50## wherein R.sup.1 and R.sup.2
are as hereinbefore defined (prepared by adaptation of the method
of M. Ogata and H. Kano, J. Heterocyclic Chem., 11, 29-35, (1963),
incorporated herein by reference), by reaction with compounds of
the formula XXXXVI, wherein R.sup.4 is as hereinbefore defined,
preferably a (R.sup.4CO).sub.2O XXXXVI methyl group, using compound
XXXXVI as solvent at about room temperature to reflux, preferably
at elevated temperature.
[0360] The present invention is further exemplified but not limited
by the following illustrative examples which illustrate the
preparation of the compounds according to the invention. The
Reference Examples illustrate the preparation of the
intermediates.
[0361] In the nuclear magnetic resonance spectra (NMR) the chemical
shifts are expressed in ppm relative to tetramethylsilane.
Abbreviations have the following significance: s=singlet;
d=doublet; t=triplet; m=multiplet; dd=doublet of doublets;
ddd=doublet of doublets of doublets; dt=doublet of triplets,
b=broad.
EXAMPLE 1
Compounds A-BH
[0362] A suspension of 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic
acid (0.88 g) in dry toluene (10 mL) is treated with thionyl
chloride (2 mL) and the mixture is refluxed for 90 minutes. The
mixture is cooled and concentrated in vacuo, to give "yellow oil
A".
[0363] A suspension of sodium hydride (0.4 g of a 60% dispersion in
mineral oil) in dimethylformamide (5 mL) is treated with a solution
of 4-amino-3,5-dichloropyridine (0.82 g) in dimethylformamide (5
mL) and the reaction mixture is stirred at room temperature for 30
minutes. It is then treated with a solution of the "yellow oil A"
in dimethylformamide (5 mL) and stirred at 45.degree. C. for 16
hours. It is then cooled, poured into water (50 mL) and extracted
with chloroform (3.times.500 mL). The combined extracts are dried
over magnesium sulphate and concentrated. The residual yellow oil
is subjected to flash chromatography [a 3:1 mixture of petroleum
ether (b.p. 60-80.degree. C.) and ethyl acetate is used as eluent
in a silica gel column] to give
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide
(0.77 g), in the form of a white solid, m.p. 143-144.degree. C.
[Elemental analysis:--C,53.75; H,4.28;N,7.29%;
calculated:--C,54.15;H,4.29;N,7.02%. NMR (CDCl.sub.3): 8.56(s,1H),
8.37(d,1H,J=18 Hz),7.62(d,1H,J=8 Hz), 6.71 (d,1H,J=14 Hz),
4.87-4.82(m,1H),3.93(s,3H),2.03-1.57(m,8H)].
[0364] By proceeding in a similar manner, but replacing
4-amino-3,5-dichloropyridine by the appropriate quantities of the
corresponding aniline or aminopyridine derivatives and acid
chlorides there are prepared: [0365]
N-(2,6-difluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0366]
N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybe-
nzamide; [0367]
N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0368]
N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxyben-
zamide; [0369]
N-(2,6-dibromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0370]
N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybe-
nzamide; [0371]
N-(2,6-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0372]
N-(2-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0373] N-phenyl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0374]
N-(2-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0375]
N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0376]
N-(3-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0377]
N-(4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0378]
N-(2,6-dimethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0379]
N-(2-methylthiophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0380]
N-(2-bromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0381]
N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybe-
nzamide; [0382]
N-(2-aminosulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0383]
N-(2-benzoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0384]
N-(2-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0385]
N-(2,5-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0386]
N-(3-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0387]
N-(2-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0388]
N-(2-dimethylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0389]
N-(2-acetylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0390]
N-(2-hydroxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0391]
N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzam-
ide; [0392]
N-pyrid-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide; [0393]
N-pyrazin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide; [0394]
N-pyrimidin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0395]
N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0396]
N-pyrid-3-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide; [0397]
N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0398]
N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0399] N-pyrid-4-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0400]
N-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxy-
benzamide; [0401]
N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0402]
N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxyben-
zamide; [0403]
N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0404]
N-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-meth-
oxybenzamide; [0405]
N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamid-
e; [0406]
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-metho-
xybenzamide; [0407]
N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de; [0408]
N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0409]
N-(3-bromo-5-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methox-
ybenzamide; [0410]
N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0411]
N-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-meth-
oxybenzamide; [0412]
N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide-
; [0413]
N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-m-
ethoxybenzamide; [0414]
N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-metho-
xybenzamide; [0415]
N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybe-
nzamide; [0416]
N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxyben-
zamide; [0417]
N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methox-
ybenzamide; [0418]
N-(4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
[0419]
N-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybe-
nzamide; [0420]
N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzam-
ide; [0421]
N-(2,6-difluorophenyl)-3-cyclohexyloxy-6-fluoro-4-methoxybenzamide;
[0422] N-(2,6-difluorophenyl)-3-butoxy-6-fluoro-4-methoxybenzamide;
and [0423]
N-(2,6-difluorophenyl)-3-propoxy-6-fluoro-4-methoxybenzamide.
EXAMPLE 2
Compounds BI-BJ
[0424] A solution of 4-amino-3,5-dichloropyridine (3.73 g) in dry
tetrahydrofuran (50 mL) under nitrogen at 5-10.degree. C. is
treated portionwise with sodium hydride (60% dispersion in oil;
1.87 g). After 30 minutes it is treated dropwise with a solution of
3-cyclopent-2-enyloxy-4-methoxybenzoyl chloride in dry
tetrahydrofuran (50 mL; that is prepared, as described in Reference
Example 6, from 5.89 g 3-cyclopent-2-enyloxy-4-methoxybenzoic
acid). The resulting mixture is allowed to warm to room temperature
and left to stand overnight. Most of the solvent is then removed
under reduced pressure and the residue is partitioned between water
(250 mL) and dichloromethane (250 mL) and the aqueous layer is
further extracted with dichloromethane (2.times.250 mL). The
combined organic layers are dried over sodium sulfate, the solvent
is removed under reduced pressure, and the resulting residue is
subjected to flash chromatography on silica gel, eluting with
mixtures of ethyl acetate and pentane (3:7 to 1:1 v/v), to give a
cream solid (1.25 g), which is recrystallized from a mixture of
ethyl acetate and pentane, to give
(.+-.)-N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-4-methoxyben-
zamide (0.80 g), as a white solid, m.p. 177-178.degree. C.
[Elemental analysis: C,56.9; H,4.2; N,7.4; Cl,18.6%; calculated:
C,57.0; H,4.3; N,7.4; Cl,18.7%].
[0425] By proceeding in a similar manner, but using
3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoyl chloride (that is
prepared, as described in Reference Example 6) there is prepared
N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzam-
ide.
EXAMPLE 3
Compounds BK-BL
[0426] A solution of 4-amino-3,5-dichloropyridine (0.93 g) in dry
tetrahydrofuran (56 mL) under nitrogen at 5-10.degree. C. is
treated portionwise with sodium hydride (60% dispersion in oil,
0.57 g). After 1 hour it is treated dropwise with a solution of
3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride in dry
tetrahydrofuran (30 mL) that is prepared as described in Reference
Example 7 from 1.33 g 3-cyclopent-3-enyloxy-4-methoxybenzoic acid.
The resulting mixture is allowed to warm to room temperature,
stirred for a further 3 hours and then poured into 5% aqueous
potassium carbonate (430 mL). The resulting emulsion is extracted
with ethyl acetate (3.times.150 mL), the combined organic extracts
washed with water (2.times.20 mL), followed by ice-cold 1 M aqueous
hydrochloric acid (2.times.20 mL) and dried over sodium sulfate.
The solvent is removed under reduced pressure and the resulting
residue subject to flash chromatography on silica gel, eluting with
mixtures of t-butyl methyl ether and cyclohexane (2:3 to 7:3 v/v),
to give a cream solid, which is recrystallized from acetonitrile to
give
N-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-4-methoxybenzamide
(0.54 g), as a white solid, m.p. 193-195.degree. C. [Elemental
analysis: C,56.7; H,4.2; N,7.3%; calculated: C,57.0; H,4.3;
N,7.4%].
[0427] By proceeding in a similar manner, but using
3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoyl chloride (that is
prepared, as described in Reference Example 7) there is prepared
N-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzam-
ide.
EXAMPLE 4
Compounds BM-BN
[0428] A stirred solution of
N-(2-methylthiophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.80 g;
that is prepared as described hereinbefore in Example 5) is treated
with a solution of 3-chloroperbenzoic acid (3.60 g; 85% pure) in
dichloromethane (72 mL), dropwise, and then it is stirred at room
temperature for 5 hours. The reaction mixture is washed with
saturated aqueous sodium bicarbonate solution and then with water,
and then it is dried over magnesium sulfate. The mixture is
concentrated to give
N-(2-methylsulfonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide,
(1.12 g), in the form of a white solid, m.p. 119-121.degree. C.
[NMR(CDCl.sub.3): 1.52-2.16 (m,8H), 3.1
(s,3H),3.94(s,3H),4.9(m,1H), 6.96 (d,1H),7.46 (m,
1H),7.6(m,2H),7.7(t,1H), 7.95(d,1H),8.68(d,1H); Elemental analysis:
C,61.6; H,6.0; N,3.5;S,8.5%; Calculated: C,61.7; H,5.95;
N,3.6;S,8.5%].
[0429] By proceeding in a similar manner, but replacing
N-(2-methylthiophenyl)-3-cyclopentyloxy-4-methoxybenzamide by
N-(2-methylthiophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide,
that is prepared as described above in Example 1), there is
prepared
N-(2-methylsulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.
EXAMPLE 5
Compounds BO-BP
[0430] 3-Cyclopentyloxy-4-methoxybenzoyl chloride (13.3 g) and
2-chloroaniline (6.6 g) are dissolved in pyridine (50 mL) and the
solution is allowed to stand at room temperature for 1 hour.
Phosphorus pentasulfide (13 g) is added and the stirred mixture is
heated at 110.degree. C. for 1.5 hours. After cooling to room
temperature the mixture is poured into an ice-cold solution of
concentrated hydrochloric acid (100 mL) in water (400 mL). The
mixture is stirred for 1 hour and the yellow solid is collected,
washed with water and subjected to flash chromatography on silica
gel, eluting with a mixture of cyclohexane and ethyl acetate (3:1
v/v), to give
N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxy(thiobenzamide) (5.4
g), m.p. 129-131.degree. C. [Elemental analysis: C,62.6; H,5.5;
N,3.9; S,8.9%; Calculated: C,63.1; H,5.6; N,3.9;S,8.9%].
[0431] By proceeding in a manner similar, but using
3-cyclopentyloxy-6-fluoro-4-methoxybenzoyl chloride, instead of
3-cyclopentyloxy-4-methoxybenzoyl chloride, there is prepared
N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide).
EXAMPLE 6
Compounds BQ-BR
[0432] A stirred solution of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0
g) in toluene (50 mL) is treated with
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
(3.0 g), and the mixture is heated at 100.degree. C. for 2 hours.
After cooling to room temperature and filtration, the filtrate is
concentrated in vacuo, to give a yellow oil. This oil is subjected
to flash chromatography on silica gel, using a mixture of pentane
and ethyl acetate (8:2 v/v) as eluent, to give
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy(thiobenzamide)
(0.64 g) m.p. 118-119.degree. C. [Elemental analysis: C,54.1;
H,4.6; Cl,17.4; N,6.8%; calculated: C,54.4; H,4.6; Cl,17.85;
N,7.05%].
[0433] By proceeding in a manner similar, but replacing the
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide by
the appropriate quantity of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide,
which is prepared as described hereinafter in Example 1, there is
prepared
N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(th-
iobenzamide).
EXAMPLE 75
Compounds BS-BT
[0434] A solution of
N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide
(1.5 g) in glacial acetic acid (22 mL) is treated with iron pin
dust (1.3 g) and the mixture is heated with stirring at 90.degree.
C. for 1 hour. The reaction mixture is cooled, basified to pH 8 by
treatment with saturated aqueous sodium carbonate solution, and
extracted with ethyl acetate (2.times.150 mL). The combined organic
extract is dried over magnesium sulfate and concentrated in vacuo,
to give a white solid. This solid is subjected to flash
chromatography, eluting with a mixture of ethyl acetate and pentane
(1:1 v/v), to give
N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide
(0.8 g), m.p. 170-172.degree. C. [Elemental analysis: C,54.8;
H,5.04; N,6.5; Cl,17.4%; calculated: C,57.7; H,5.1; N,7.1;
Cl,17.9%].
[0435] By proceeding in a manner similar, but replacing the
N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide
by the appropriate quantity of
N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de, which is prepared as described hereinafter in Example 1, there
is prepared
N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-6-fluoro-4-metho-
xybenzamide.
EXAMPLE 8
Compounds BU-BV
[0436] Acetic anhydride (10 mL) is treated with
N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide
(0.8 g), and the reaction mixture is stirred for 2 hours and left
to stand overnight. It is then poured into water (100 mL), and
extracted with ethyl acetate (100 mL) and then with dichloromethane
(100 mL). The organic extracts are combined, dried over magnesium
sulfate, and evaporated, to give
N-(4-acetylamino-2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide
(0.4 g), m.p. 250-252.degree. C. [Elemental analysis: C,57.6;
H,5.05; N,6.3; Cl,16.1%; calculated: C,57.5; H,5.1; N,6.4;
Cl,16.2%].
[0437] By proceeding in a manner similar, but replacing the
N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide
by the appropriate quantity of
N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzami-
de, which is prepared as described hereinafter in Example 1, there
is prepared
N-(2,6-dichloro-4-acetylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-
-methoxybenzamide.
EXAMPLE 9
Compounds BW-BX
[0438] A stirred solution of
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzami-
de (6.1 g) in dry tetrahydrofuran (80 mL) at room temperature under
argon is treated dropwise with a solution of lithium borohydride in
tetrahydrofuran (115 mL; 2 M). The mixture is stirred overnight and
then it is treated portionwise with saturated brine (200 mL) and
stirred for 30 minutes. The organic layer is then washed with
water, dried over magnesium sulfate and evaporated. The resulting
residue is subjected to flash chromatography on silica gel, to give
N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamid-
e (4.4 g), m.p. 174-176.degree. C. [Elemental analysis: C,57.1;
H,5.4; N,2.9%; calculated
C.sub.20H.sub.21O.sub.4NCl.sub.2:0.5H.sub.2O: C,57.3; H,5.3;
N,3.3%]
[0439] By proceeding in a similar manner, but using the appropriate
quantity of
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-metho-
xybenzamide (that is prepared as described in Example 1) instead of
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzami-
de, there is prepared
N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methox-
ybenzamide.
EXAMPLE 10
Compounds BY-BZ
[0440] A solution of
N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamid-
e (4.4 g; that is prepared as described in Example 9) in
dichloromethane (30 mL) is treated with activated manganese dioxide
(6.2 g), and the mixture is stirred at reflux for 24 hours. The
mixture is filtered, the filtrate is evaporated, and the resulting
residue is subjected to flash chromatography on silica gel, eluting
with ethyl acetate, to give
N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-4-methoxy-benzamide
(2.4 g), m.p. 96-98.degree. C. [Elemental analysis: C,59.0; H,5.1;
N,3.1%; calculated: C,58.8; H,4.7; N,3.4%].
[0441] By proceeding in a similar manner, but using the appropriate
quantity of
N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methox-
ybenzamide (that is prepared as described in Example 9) instead of
N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamid-
e, there is prepared
N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzam-
ide.
EXAMPLE 11
Compounds CA-CB
[0442] A solution of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.8
g) in dry tetrahydrofuran (25 mL) is treated with a suspension of
sodium hydride (60% dispersion in oil; 0.40 g), and the mixture is
stirred until effervescence has ceased and a solution has formed.
This solution is evaporated in vacuo and the resulting residue is
triturated with t-butyl methyl ether (20 mL). The resulting
off-white solid is filtered off, quickly washed with t-butyl methyl
ether (2.times.20 mL) and dried, to give the sodium salt of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.5
g), m.p. 265-270.degree. C. (with decomposition)
[NMR(DMSO-D.sub.6): 1.52-1.93(m,8H), 4.77(s,3H),4.75-4.80
(m,1H),6.98(d,1H),7.58(dd,1H),7.60(s,1H),8.20(s,2H); IR spectrum:
strong peak at 1508 cm.sup.-1, with no peaks at or near 1661
cm.sup.-1 or 3244 cm.sup.-1, which would have been characteristics
of the starting material].
[0443] By proceeding in a similar manner, but using the appropriate
quantity of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide
(that is described as in Example 1) instead of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,
there is prepared sodium salt of
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide.
EXAMPLE 12
Compounds CC-CG
[0444] By proceeding in a similar manner as in Example 1, but using
the appropriate quantities of the appropriate benzoic acid instead
of 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid are
prepared:--
(.+-.)N-(3,5-dichloropyrid-4-yl)-3-exonorbornyloxy-6-fluoro-4-methoxyben-
zamide, m.p. 139-140.degree. C. [Elemental analysis:--C, 56.6; H,
4.5; N, 6.6; Cl, 16.6%; calculated:--C, 56.5; H, 4.5; N, 6.6; Cl,
16.7%].
N-(3,5-dichloropyrid-4-yl)-2-fluoro-5-isopropyloxy-4-methoxybenzamide,
m.p. 154.5-156.degree. C. [Elemental analysis:--C, 51.8; H, 4.2; N,
7.4; Cl, 18.7%; calculated:--C, 51.5; H, 4.05; N, 7.5; Cl,
19.0%].
(.+-.)N-(3,5-dichloropyrid-4-yl)-2-fluoro-4-methoxy-5-(tricyclo[2.2.1.0]-
hept-2-yloxy)benzamide hemihydrate, m.p. 149-151.degree. C.
[Elemental analysis:--C, 55.7; H, 4.0; N, 6.2%; calculated:--C,
55.6; H, 4.2; N, 6.5%].
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobe-
nzamide, m.p. 96-99.degree. C. [Elemental analysis:--C, 50.1; H,
3.8; N, 6.6; Cl, 16.6%; calculated:--C, 49.7; H, 3.5; N, 6.4; Cl,
16.3%].
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenz-
amide, m.p. 105-108.degree. C. [Elemental analysis:--C, 47.0; H,
3.2; N, 6.8; Cl, 17.4%; calculated:--C, 47.0; H, 3.2; N, 6.85; Cl,
17.3%].
EXAMPLE 13
Compound CH
[0445] A solution of oxalyl chloride (0.05 mL) in dichloromethane
(3 mL) is cooled to -60.degree. C. and dimethylsulfoxide (1 mL)
added. After stirring at this temperature for 0.25 hours, a
solution of
2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)e-
thanol (0.2 g) in dichloromethane (5 mL) is added dropwise. After
stirring at -60.degree. C. for 0.25 hours, triethylamine (0.33 mL)
is added dropwise and the solution stirred for 0.25 hour at
-60.degree. C. and then at room temperature overnight. The solution
is then poured into water (30 mL), extracted with ethyl acetate
(3.times.50 mL) and the combined organic extracts washed with brine
(30 mL), dried (magnesium sulfate), and concentrated to give a
yellow-brown oil. The oil is subjected to mplc on silica gel, using
petroleum ether: ethyl acetate (3:1 v/v) as eluent to give
2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)e-
thanone (0.14 g). m.p. 115-116.5.degree. C. [Elemental
analysis:--C, 57.7; H, 4.7; N, 3.5%; calculated:--C, 57.3; H, 4.6;
N, 3.5%].
EXAMPLE 14
Compounds CI-CN
[0446] A stirred solution of
N-(3,5-dichloropyrid-4-yl)-2-fluoro-5-isopropyloxy-4-methoxybenzamide
(0.5 g) in glacial acetic acid (10 mL) is treated dropwise with an
aqueous solution of hydrogen peroxide (2 ml; 27.5%). The mixture is
stirred for 3 hours at 70-80.degree. C., treated with a further
portion of aqueous hydrogen peroxide (2 mL), and the solution
stirred for a further 12 hours. The solution is then cooled,
basified by treatment with 2 N sodium hydroxide solution (50 mL)
and extracted with ethyl acetate (3.times.150 mL). The combined
organic extracts are washed with brine (50 mL), dried (magnesium
sulfate) and concentrated to give a brown oil. The oil is subjected
to mplc on silica gel using ether as eluent to give
N-(3,5-dichloro-1-oxido-4-pyridinio)-2-fluoro-5-isopropyloxy-4-methoxyben-
zamide (0.25 g). m.p. 142-144.degree. C. [Elemental analysis:--C,
48.6; H, 3.9; N, 7.0; Cl, 17.6%. calculated:--C, 48.3; H, 4.05; N,
7.0; Cl, 17.8%].
[0447] By proceeding in a similar manner, but using the appropriate
quantities of the appropriate benzamide or ethanone there are
prepared:--
(.+-.)N-(3,5-dichloro-1-oxido-4-pyridinio)-3-exonorbornyloxy-6-fluoro-4--
methoxybenzamide, m.p. 101-106.degree. C. [Elemental analysis:--C,
53.9; H, 4.5; N, 6.3; Cl, 15.5%. calculated:--C, 53.9; H, 4.4; N,
6.3; Cl, 15.9%].
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-6-fluoro-4-methoxy-
benzamide, m.p. 143-144.degree. C. [Elemental analysis:--C, 52.9;
H, 4.5; N, 6.4; Cl, 16.2%. calculated:--C, 52.1; H, 4.1; N, 6.75;
Cl,17.1%].
N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-4-difluoromethoxy--
6-fluorobenzamide, m.p. 129-130.degree. C. [Elemental analysis:--C,
47.6; H, 3.4; N, 6.0; Cl, 15.3%. calculated:--C, 47.9; H, 3.35; N,
6.2; Cl, 15.7%].
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxy-2-fluoro-5-isopro-
pyloxybenzamide, m.p. 196-198.degree. C. [Elemental analysis:--C,
45.2; H, 3.0; N, 6.5; Cl, 16.6%. calculated:--C, 45.2; H, 3.1; N,
6.6; Cl, 16.7%].
2-(3,5-Dichloro-1-oxido-4-pyridinio)-1-(3-cyclopentyloxy-6-fluoro-4-meth-
oxyphenyl)ethanone, m.p. 159-162.degree. C. [Elemental
analysis:--C, 54.9; H, 4.4; N, 3.5; Cl, 16.9%. calculated:--C,
55.1; H, 4.4; N, 3.4; Cl, 17.1%].
EXAMPLE 15
Compound CO
[0448] Thionyl chloride (0.78 mL) is added to a solution of
5-cyclopentyloxy-6-methoxynicotinic acid (850 mg) and
dimethylformamide (1 drop) in toluene (60 mL). The mixture is
heated and stirred at reflux for 1 hour. The mixture is cooled and
concentrated to give crude acid chloride.
[0449] Meanwhile, sodium hydride (320 mg of a 60% dispersion in
oil) is added to a stirred solution of 4-amino-3,5-dichloropyridine
(649 mg) in dry dimethylformamide (20 mL) under a nitrogen
atmosphere. The mixture is stirred at room temperature for 30
minutes. The crude acid chloride is dissolved in dry
dimethylformamide (10 mL) and the solution is added dropwise to the
mixture. After 3 hours, the mixture is diluted with water and the
mixture extracted with ethyl acetate. The ethyl acetate extracts
are washed with water and dried (MgSO.sub.4). Concentration of the
extracts gave a buff solid which is triturated with methyl t.butyl
ether to give
5-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide
(500 mg) as a white solid, m.p. 182-183.degree. C. [Elemental
analysis:--C,53.4; H,4.45; Cl,18.6; N,10.9% calculated:--C,53.4;
H,4.48; Cl,18.55; N,10.99%.]
EXAMPLE 16
Compound CP
[0450] Thionyl chloride (0.46 mL) is added to a solution of
5-cyclopentyloxy-6-methoxynicotinic acid (500 mg) and
dimethylformamide (1 drop) in toluene (10 mL). The mixture is
heated and stirred at reflux for 1 hour. The mixture is cooled and
concentrated to give crude acid chloride as a yellow oil which
slowly crystallised.
[0451] Meanwhile, sodium hydride (128 mg of a 60% dispersion in
oil) is added to a stirred solution of 2,6-dichloroaniline (263 mg)
in dry tetrahydrofuran (10 mL) under a nitrogen atmosphere. The
mixture is stirred at room temperature for 45 minutes. The crude
acid chloride is dissolved in dry tetrahydrofuran (5 mL) and the
resulting solution added dropwise to the mixture. After 3 hours the
mixture is concentrated, treated with water, and extracted with
ethyl acetate. The extracts are dried (MgSO.sub.4) and concentrated
to give a brown oil. Trituration of the oil with methyl t.butyl
ether gave
N-(2,6-dichlorophenyl)-5-cyclopentyloxy-6-methoxynicotinamide (250
mg) as a white solid, m.p. 145-6.degree. C. [Elemental
analysis:--C,56.7; H,4.79; Cl,18.5; N,7.4% calculated:--C,56.7;
H,4.76; Cl,18.6; N,7.35%.]
EXAMPLE 17
Compound CQ
[0452] Thionyl chloride (0.46 mL) is added to a solution of
5-cyclopentyloxy-6-methoxynicotinic acid (500 mg) and
dimethylformamide (1 drop) in toluene (10 mL). The mixture is
heated and stirred at reflux for 1 hour. The mixture is cooled,
concentrated, and the residue dissolved in dichloromethane (5 mL).
This solution is added dropwise to a solution of
4-amino-3,5-dimethylisoxazole (168 mg) and triethylamine (0.21 mL)
in dichloromethane (20 mL). The resulting mixture is stirred at
room temperature for 2 hours then at reflux for 1 hour. The cooled
mixture is washed with water, 2 M aqueous hydrochloric acid, water,
then dried (MgSO.sub.4). After concentration the yellow oily
residue is triturated with a mixture of n-pentane and methyl
t.butyl ether to give
5-cyclopentyloxy-N-(3,5-dimethylisoxazol-4-yl)-6-methoxynicotinamide
(240 mg) as a buff solid, m.p. 139-40.degree. C. [Elemental
analysis:--C,61.3; H,6.40; N,12.4% calculated:--C,61.6; H,6.39;
N,12.68%.]
EXAMPLE 18
Compound CR
[0453] Thionyl chloride (0.46 mL) is added to a solution of
5-cyclopentyloxy-6-methoxynicotinic acid (500 mg) and
dimethylformamide (1 drop) in toluene (10 mL). The mixture is
heated and stirred at reflux for 1 hour. The mixture is cooled and
concentrated to give crude acid chloride.
[0454] Meanwhile, sodium hydride (128 mg of a 60% dispersion in
oil) is added to a stirred solution of 4-amino-3,5-difluoropyridine
(208 mg) in dry tetrahydrofuran (10 mL) under a nitrogen
atmosphere. The mixture is stirred at room temperature for 60
minutes. The crude acid chloride is dissolved in dry
tetrahydrofuran (5 mL) and the resulting solution added dropwise to
the mixture. After 3 hours the mixture is treated with water and
concentrated. The residue is diluted with water and the mixture
extracted with ethyl acetate. The extracts are dried (MgSO.sub.4)
and concentrated to give a white solid. The solid is triturated
with n-pentane and methyl t-butyl ether to give
5-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-6-methoxynicotinamide
(230 mg), as a white solid, m.p. 210-11.degree. C. [Elemental
analysis:--C,58.4; H,4.93; N,11.8% calculated:--C,58.45; H,4.91;
N,12.03%.]
EXAMPLE 19
Compound CS
[0455] Thionyl chloride (0.45 mL) is added to a solution of
6-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (510 mg) and
dimethylformamide (1 drop) in toluene (6 mL). The mixture is heated
and stirred at reflux for 2.5 hours. The mixture is cooled and
concentrated to give crude acid chloride.
[0456] Meanwhile, sodium hydride (51 mg of a 60% dispersion in oil)
is added to a stirred solution of 4-amino-3,5-dichloropyridine (350
mg) in dry tetrahydrofuran (10 mL) under a nitrogen atmosphere. The
mixture is stirred at room temperature for 30 minutes. The crude
acid chloride is dissolved in dry tetrahydrofuran (6 mL) and the
resulting solution added dropwise to the mixture. The mixture is
stirred for 4.5 hours and then allowed to stand at room temperature
for 72 hours. The mixture is treated with water, concentrated and
the residue extracted with ethyl acetate. After washing with water
the extracts are dried (MgSO.sub.4) and concentrated. The residue
is purified by flash chromatography (alumina, pentane/ethyl acetate
9:1 v/v as eluent) to give
6-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-5-methoxypyridine-2-carboxami-
de (750 mg) as a white solid, m.p. 164-6.degree. C. [Elemental
analysis:--C,53.6; H,4.56; Cl,18.4; N,11.2% calculated:--C,53.4;
H,4.48; Cl,18.55; N,10.99%.]
EXAMPLE 20
Compound CT
[0457] n-Butyl lithium (4.9 mL of a 2.5M solution in hexanes) is
added dropwise to a stirred solution of diisopropylamine (1.7 mL)
in dry tetrahydrofuran (20 mL) at -78.degree. C. under a nitrogen
atmosphere. After 30 minutes. a solution of
3,5-dichloro-4-methylpyridine (1.95 g) in dry tetrahydrofuran (10
mL) is added dropwise and the solution stirred at -78.degree. C.
for a further 30 minutes. A solution of methyl
5-cyclopentyloxy-6-methoxynicotinoate (1.5 g) in dry
tetrahydrofuran (15 mL) is added and the red mixture stirred and
allowed to warm to room temperature during 4 hours. After stirring
overnight at room temperature the mixture is treated with saturated
aqueous ammonium chloride. The tetrahydrofuran layer is separated
and the aqueous phase is extracted with ethyl acetate. The combined
organic layers are washed with saline and dried over anhydrous
magnesium sulphate. Concentration gives a light brown oil which is
triturated with a mixture of n-pentane and methyl t-butyl ether to
give
1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)etha-
none (1 g) in the form of a beige solid, m.p. 118-9.degree. C.
[Elemental analysis:--C,56.8; H,4.82; Cl,18.5; N,7.40%
calculated:--C,56.7; H,4.76; Cl,18.6; N,7.35%.]
EXAMPLE 21
Compound CU
[0458] Thionyl chloride (0.55 mL) is added to a solution of
5-cyclopentyloxy-6-methylthionicotinic acid (0.6 g) in dry toluene
(10 mL) containing dimethylformamide (1 drop) and the mixture
stirred at reflux for 1.5 hours. The solution is evaporated in
vacuo, redissolved in toluene and evaporated again to give the
crude acid chloride.
[0459] Meanwhile sodium hydride (220 mg of a 60% dispersion in
mineral oil) is added to a stirred solution of
4-amino-3,5-dichloropyridine (445 mg) in dry tetrahydrofuran (10
mL) under an atmosphere of nitrogen, and the mixture is stirred at
room temperature for 1 hour. The crude acid chloride is dissolved
in tetrahydrofuran (10 mL) and added to the mixture and the mixture
stirred at room temperature for 3 hours. The mixture is evaporated,
the residue diluted with water and the product extracted into ethyl
acetate. The extracts are dried (MgSO.sub.4), evaporated, and
triturated with a mixture of n-pentane and t-butyl methyl ether to
give
5-cyclopentyloxy-N-(3,5-dichloro-4-pyridyl)-6-methylthionicotinamide
(500 mg) as a cream solid, m.p. 144-5.degree. C. [Elemental
analysis:--C,51.50; H,4.42; Cl,17.7; N,10.5; S,8.1%
calculated:--C,51.26; H,4.30; Cl,17.8; N,10.55; S,8.05%].
EXAMPLE 22
Compound CV
[0460] By proceeding in a similar manner to example 21 but
replacing the 5-cyclopentyloxy-6-methylthionicotinic acid by the
appropriate quantity of 5-isopropyloxy-6-methylthionicotinic acid
there is obtained:--
N-(3,5-dichloro-4-pyridyl)-5-isopropyloxy-6-methylthionicotinamide
as a white solid, m.p. 167-8.degree. C. [Elemental
analysis:--C,48.20; H,4.02; Cl,19.30; N,11.30%
calculated:--C,48.40; H,4.06; Cl,19.05; N,11.29%].
EXAMPLE 23
Compound CW
[0461] n-Butyl lithium (3.73 mL of a 2.5 M solution in hexanes) is
added dropwise to a stirred solution of diisopropylamine (1.29 mL)
in dry tetrahydrofuran (15 mL) at -75.degree. C. under a nitrogen
atmosphere. After stirring for 30 minutes, a solution of
3,5-dichloro-4-methylpyridine (1.48 g) in dry tetrahydrofuran (8
mL) is added dropwise and the mixture stirred for a further 30
minutes. A solution of methyl
5-isopropyloxy-6-methylthionicotinoate (1.1 g) in dry
tetrahydrofuran (10 mL) is added dropwise at -75.degree. C. and the
mixture allowed to warm to room temperature during 4 hours. The
reaction is quenched by the addition of saturated aqueous ammonium
chloride and then the solvent is removed in vacuo. The aqueous
residue is extracted with ethyl acetate, the extracts washed with
water and dried (MgSO.sub.4). After treating with decolourising
charcoal and removing the solvent, a dark yellow oil is obtained.
The oil is dissolved in a minimum amount of n-pentane/methyl
t-butylether and allowed to crystallise.
2-(3,5-dichloro-4-pyridyl)-1-(5-isopropyloxy-6-methylthio-3-pyridyl)ethan-
one (450 mg) is obtained as a white solid, m.p. 124-5.degree. C.
[Elemental analysis:--C,51.8; H,4.34; Cl,19.10; N,7.50%
calculated:--C,51.76; H,4.34; Cl,19.10; N,7.55%].
EXAMPLE 24
Compound CX
[0462] Hydrogen peroxide (3 mL of strength 27.5%) is added to a
stirred suspension of
1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloropyrid-4-yl)ethano-
ne (470 mg) in glacial acetic acid (5 mL) and the mixture heated at
75.+-.5.degree. C. for 3 hours. More hydrogen peroxide (1 mL of
strength 27.5%) is added and the mixture heated for a further 2
hours. After cooling, the mixture is basefied with 6 M aqueous
sodium hydroxide and extracted with ethyl acetate. The extracts are
washed with water, dried (MgSO.sub.4) and evaporated. The residue
is triturated with diethyl ether to afford
1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloro-1-oxid-
o-4-pyridinio)ethanone hemihydrate (100 mg) as a white solid, m.p.
171-2.degree. C. [Elemental analysis:--C,53.5; H,4.51; N,7.0%
calculated:--C,53.20; H,4.71; N,6.90%].
EXAMPLE 25
Compounds CY-CZ
[0463] Diisopropyl azodicarboxylate (1.67 mL) is added to a stirred
solution of triphenylphosphine (2.22 g) in dry tetrahydrofuran (20
mL) at 0-5.degree. C. under a nitrogen atmosphere. After 30
minutes, methyl 5-hydroxy-6-methoxynicotinoate (1.55 g) and a
solution of a mixture of (.+-.)-endo- and
(.+-.)-exo-(8,9,10-trinorborn-5-en-2-ol) (0.94 g) in dry
tetrahydrofuran (5 mL) are added successively and the mixture
refluxed for 24 hours. After cooling to room temperature the
mixture is diluted with water and extracted with ethyl acetate. The
extracts are washed with water, dried (MgSO.sub.4) and evaporated.
Purification by flash chromatography (n-pentane/ethyl acetate 9:1
v/v on silica) affords a mixture of methyl
(.+-.)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinoate
and methyl
(.+-.)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)nicoti-
noate, (950 mg) [Elemental analysis:--C,65.50; H,6.35; N,5.14%
calculated:--C,65.44; H,6.22; N,5.09%].
[0464] The mixture of methyl
(.+-.)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinoate
and methyl
(.+-.)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)nicoti-
noate, (900 mg), dissolved in methanol (20 mL) is treated with a
solution of potassium hydroxide (380 mg) in water (5 mL) and
stirred at 45.degree. C. for 3 hours. After cooling the bulk of the
solvent is removed in vacuo, the resdue dissolved in water and the
solution acidified to pH 2 with concentrated aqueous hydrochloric
acid. The products are extracted into ethyl acetate, the extracts
dried (MgSO.sub.4) and evaporated to give a mixture of
(.+-.)-6-methoxy-5-exo (8,9,10-trinorborn-5-en-2-yloxy)nicotinic
acid and
(.+-.)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.]-hept-2-yloxy)nicotinic
acid, (670 mg), as a white solid. [Elemental analysis:--C,64.50;
H,5.76; N,5.53% calculated:--C,64.36; H,5.79; N,5.36%].
[0465] The mixture of
(.+-.)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinic
acid and
(.+-.)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)nicotinic
acid, (670 mg), is stirred in a mixture of dichloromethane (10 mL)
and dimethylformamide (1 drop) and oxalyl chloride (487 mg) is
added and the resulting mixture stirred at room temperature for 30
minutes. The mixture is concentrated in vacuo to give a mixture of
the acid chlorides.
[0466] Meanwhile sodium hydride (160 mg of a 60% dispersion in
mineral oil) is added to a solution of 4-amino-3,5-dichloropyridine
(445 mg) in dry tetrahydrofuran (10 mL) under a nitrogen
atmosphere. The mixture is stirred for 30 minutes at room
temperature and then a solution of the foregoing mixture of acid
chlorides in dry tetrahydrofuran (5 mL) is added and stirring is
continued for a further 3 hours. The reaction mixture is
evaporated, the residue diluted with water and extracted into ethyl
acetate. The extracts are dried (MgSO.sub.4) and evaporated to give
a pale yellow oil. The oil is partially purified by flash
chromatography (n-pentane/ethyl acetate 4:1 v/v as eluent on
silica) to give a mixture of
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-5-
-en-2-yloxy)nicotinamide and
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)nicotinamide, (340 mg), as a white solid. This
mixture is purified into the individual constituents by reversed
phase high pressure liquid chromatography to give
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-
-2-yloxy)nicotinamide (195 mg) as a white solid, m.p. 191-3.degree.
C., [.sup.1Hnmr in D.sub.6-DMSO shifts relative to
Me.sub.4Si:--1.42, 1H, m; 1.56, 1H, m; 1.75, 1H, m; 1.81,1H, m;
2.91, 1H, m; 3.03, 1H, m; 3.96, 3H, s; 6.07, 1H, m; 6.35, 1H, m;
7.70, 1H, d; 8.42, 1H, d; 8.77, 2H, s; 10.61, 1H, br. s.].
[Elemental analysis:--C,55.9; H,4.24; N,10.2% calculated:--C,56.17;
H,4.22; N,10.34%], and
(.+-.)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)nicotinamide monohydrate (74 mg) as a white
crystalline solid, m.p. 213-4.degree. C. [1 Hnmr in D.sub.6-DMSO
shifts relative to Me.sub.4Si:--1.30, 2H,m; 1.36, 3H, m; 1.55, 1H,
m; 1.83, 1H, m; 2.16, 1H, m; 3.96, 3H, s; 4.49, 1H, m; 7.78, 1H, d;
8.42, 1H, d; 8.77, 2H, s; 10.62, 1H, br. s.]. [Elemental
analysis:--C,53.5; H,4.01; N,9.70% calculated:--C,53.79; H,4.51;
N,9.90%]
EXAMPLE 26
Compounds DA-FE
[0467] Thionyl chloride (0.5 mL) is added to a stirred mixture of
4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (500 mg) in
dry toluene (10 mL) containing dimethylformamide (1 drop). The
mixture is stirred at gentle reflux for 1 hour, cooled and
concentrated in vacuo to give the acid chloride, which is dissolved
in dimethylformamide (10 mL).
[0468] Meanwhile sodium hydride (160 mg of a 60% dispersion in
mineral oil) is added to a solution of 4-amino-3,5-dichloropyridine
(665 mg) in dry dimethylformamide (10 mL), the mixture stirred for
1 hour and then added to the solution of the acid chloride. The
resulting mixture is stirred for 6 hours, concentrated in vacuo,
the residue diluted with water and the product extracted into ethyl
acetate. The dried (MgSO.sub.4) extracts are concentrated to a
yellow/brown solid which is purified by flash chromatography
(dichloromethane/methanol 50:1 v/v as eluent on silica) to give
N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de, (220 mg) as a white solid, m.p. 129-30.degree. C. [Elemental
analysis:--C,53.1; H,4.44; N,11.1% calculated:--C,53.42; H,4.48;
N,10.99%]
[0469] By proceeding in a similar manner, but replacing
4-amino-3,5-dichloropyridine by the appropriate quantities of the
corresponding aniline or aminopyridine derivatives and acid
chlorides there are prepared: [0470]
N-(2,6-difluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0471]
N-(2-chloro-6-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2--
carboxamide; [0472]
N-(2-trifluoromethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0473]
N-(2,4,6-trichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0474]
N-(2,6-dibromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0475]
N-(2-chloro-6-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2--
carboxamide; [0476]
N-(2,6-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0477]
N-(2-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0478]
N-phenyl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide; [0479]
N-(2-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0480]
N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0481]
N-(3-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0482]
N-(4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0483]
N-(2,6-dimethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0484]
N-(2-methylthiophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0485]
N-(2-bromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0486]
N-(2-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0487]
N-(2-aminosulfonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0488]
N-(2-benzoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0489]
N-(2-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0490]
N-(2,5-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0491]
N-(3-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0492]
N-(2-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0493]
N-(2-dimethylaminophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-ca-
rboxamide; [0494]
N-(2-acetylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0495]
N-(2-hydroxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxam-
ide; [0496]
N-(4-chloropyrid-3-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0497]
N-pyrid-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0498]
N-pyrazin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0499]
N-pyrimidin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide-
; [0500]
N-(3-methylpyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-car-
boxamide; [0501]
N-pyrid-3-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0502]
N-(3-chloropyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0503]
N-(3-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0504]
N-pyrid-4-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0505]
N-(3,5-dimethylisoxazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide; [0506]
N-(3,5-dibromopyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0507]
N-(3,5-dimethylpyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0508]
N-(2,6-dichloro-4-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0509]
N-(2,6-dichloro-4-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridi-
ne-2-carboxamide; [0510]
N-(2,3,5-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbox-
amide; [0511]
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridin-
e-2-carboxamide; [0512]
N-(2,6-dichloro-4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0513]
N-(3,5-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de; [0514]
N-(3-bromo-5-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carbo-
xamide; [0515]
N-(2,4,6-trifluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamid-
e; [0516]
N-(2,6-dichloro-4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-car-
boxamide; [0517]
N-(4,6-dichloropyrimid-5-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxa-
mide; [0518]
N-(2,3,5,6-tetrafluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-ca-
rboxamide; [0519]
N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridin-
e-2-carboxamide; [0520]
N-(5-cyano-3-methylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2--
carboxamide; [0521]
N-(2,6-dichloro-4-carbamoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-c-
arboxamide; [0522]
N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-
-2-carboxamide; [0523]
N-(4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
[0524]
N-(3-methyl-5-bromoisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyr-
idine-2-carboxamide; and [0525]
N-(3,5-dimethylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carb-
oxamide.
EXAMPLE 27
Compound FF
[0526] A mixture of
N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxami-
de (360 mg) and aqueous hydrogen peroxide (3 mL of strength 27.5%)
in glacial acetic acid is heated at 75.+-.5.degree. C. for 3 hours.
After cooling, the mixture is basefied with 6 M aqueous sodium
hydroxide and extracted with ethyl acetate. The extracts are washed
with water, dried (MgSO.sub.4) and evaporated to give a white
solid. The solid is purified by flash chromatography (gradient
elution with pentane/ethyl acetate 7:3 v/v changing to
pentane/ethyl acetate 1:1 v/v on silica) to give
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxypyridine-2-
-carboxamide as a white solid, m.p. 206-7.degree. C. [Elemental
analysis:--C,51.6; H,4.37; N,10.40% calculated:--C,51.27; H,4.30;
N,10.55%].
EXAMPLE 28
Compound FG
[0527] Oxalyl chloride (50 mL) in dry dichloromethane (1.5 mL) is
cooled to -30.degree. C. under a nitrogen atmosphere. Dimethyl
sulphoxide (80 mL) is added, the mixture stirred for 10 minutes
then a solution of
(.+-.)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin--
4-yl)ethanol (210 mg) in dichloromethane (2.5 mL) is added and the
mixture stirred for 3 hours. Triethylamine (0.2 mL) is added and
the mixture is allowed to warm to room temperature. After pouring
into water the organic phase is extracted into dichloromethane, the
extracts washed sequentially with 1% aqueous sulphuric acid, water,
saturated aqueous sodium bicarbonate and water. The extracts are
dried (MgSO.sub.4) and evaporated to give a solid. The solid is
triturated with pentane, collected and dried to give
1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)et-
hanone (60 mg), as an off-white solid, m.p. 132.degree. C.
[Elemental analysis:--C,56.80; H,4.92; N,7.10%
calculated:--C,56.71; H,4.78; N,7.35%].
EXAMPLE 29
Compounds FH-FI
[0528] Thionyl chloride (0.4 mL) is added to a stirred solution of
(.+-.)-6-methoxy-5-exo-(8,9,10-trinorborn-2-yloxy)nicotinic acid
(0.4 g) in toluene (10 mL) containing dimethylformamide (1 drop).
The mixture is refluxed for 1 hour, cooled and evaporated to give
the acid chloride which is dissolved in dimethylformamide (10
mL).
[0529] Meanwhile sodium hydride (80 mg of a 60% dispersion in
mineral oil) is added to a solution of 4-amino-3,5-difluoropyridine
(0.26 g) in dimethylformamide (10 mL) and the mixture stirred for 1
hour. The mixture is then added to the solution of the acid
chloride and stirring continued for 6 hours. After evaporation of
the solvent the residue is partitioned between ethyl acetate and
water. The ethyl acetate phase is separated, washed with water,
dried (MgSO.sub.4) and evaporated to give an oil. The oil is
purified by flash chromatography (n-pentane/ethylacetate 3:2 v/v as
eluent on silica) to give an oil which upon triturating with
n-pentane gave
(.+-.)-N-(3,5-difluoropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-
-2-yloxy)nicotinamide, (0.19 g) as a solid, m.p. 120-1.degree. C.
[Elemental analysis:--C,61.3; H,5.33; N,11.3% calculated:--C,60.80;
H,5.10; N,11.19%].
[0530] By proceedind in a similar manner, but replacing
4-amino-3,5-difluoropyridine with the appropriate quantity of
4-amino-3,5-dichloropyridine, there is prepared:--
(.+-.)-N-(3,5-dichloropyridin-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-2-
-yloxy)nicotinamide, m.p. 169-170.degree. C. [Elemental
analysis:--C,55.90; H,4.73; N,10.30% calculated:--C,55.90; H,4.69;
N,10.29%].
EXAMPLE 30
Compounds FJ-FN
[0531] Thionyl chloride (0.65 mL) is added to a stirred solution of
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid (0.4 g) in toluene (10 mL) containing
dimethylformamide (1 drop). The mixture is refluxed for 2 hours,
cooled and evaporated to give the acid chloride which is dissolved
in dimethylformamide (5 mL).
[0532] Meanwhile sodium hydride (116 mg of a 60% dispersion in
mineral oil) is added to a solution of
N-(3,5-dichloropyridin-4-yl)acetamide (449 mg) in dimethylformamide
(15 mL) and the mixture stirred for 2 hours. The mixture is then
added to the solution of the acid chloride and stirring continued
for 3 hours. After evaporation of the solvent the residue is
partitioned between ethyl acetate and water. The ethyl acetate
phase is separated, washed with water, dried (MgSO.sub.4) and
evaporated to give a brown oil. The oil is diluted with
dimethylformamide (10 mL) and treated with piperidine (0.61 mL) for
18 hours. After concentrating the residue is partitioned between
water and ethyl acetate. The ethyl acetate phase is washed with
water, dried (MgSO.sub.4) and evaporated. The residue is purified
by flash chromatography (n-pentane/ethylacetate 7:3 v/v as eluent
on silica) to give
(.+-.)-N-(3,5-dichloropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.-
]hept-2-yloxy)pyridine-2-carboxamide, (0.35 g) as a white solid,
m.p. 161-2.degree. C. [Elemental analysis:--C,56.14; H,4.29;
Cl,17.67; N,10.13% calculated:--C,56.17; H,4.22; Cl,17.45;
N,10.34%].
[0533] By proceeding in a similar manner, but replacing
4-amino-3,5-dichlororopyridine with the appropriate quantity of
4-amino-3,5-difluoropyridine, there is prepared:--
(.+-.)-N-(3,5-difluoropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6-
.]hept-2-yloxy)pyridine-2-carboxamide hydrate, m.p. 64-5.degree. C.
[Elemental analysis:--C,60.34; H,4.63; N,11.18%
calculated:--C,60.39; H,4.67; N,11.12%].
[0534] By proceeding in a similar manner, but replacing
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid with the appropriate quantity of
(.+-.)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylic
acid, there is prepared:--
(.+-.)-N-(3,5-dichloropyridin-4-yl)-5-methoxy-4-(tetrahydrothiophen-3-yl-
oxy)pyridine-2-carboxamide, m.p. 171-2.degree. C. [Elemental
analysis:--C,48.4; H,3.88; N,10.63% calculated:--C,48.01; H,3.78;
N,10.50%].
[0535] By proceeding in a similar manner, but replacing
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid with the appropriate quantity of
4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylic acid, there is
prepared:--
N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-ca-
rboxamide, m.p. 132-132.5.degree. C. [Elemental analysis:--C,52.12;
H,4.12; Cl,19.03; N,11.40% calculated:--C,52.19; H,4.11; Cl,19.26;
N,11.41%].
[0536] By proceeding in a similar manner, but replacing
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid with the appropriate quantity of
4-isopropyloxy-5-methoxypyridine-2-carboxylic acid, there is
prepared:--
N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-carboxam-
ide, m.p. 142-3.degree. C. [Elemental analysis:--C,50.3; H,4.20;
Cl,20.10; N,11.85% calculated:--C,50.58; H,4.25; Cl,19.91;
N,11.80%].
EXAMPLE 31
Compounds FO-FS
[0537] Thionyl chloride (0.84 mL) is added to a stirred solution of
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid (0.7 g) in toluene (10 mL) containing
dimethylformamide (1 drop). The mixture is refluxed for 2 hours,
cooled and evaporated to give the acid chloride which is dissolved
in dimethylformamide (5 mL).
[0538] Meanwhile sodium hydride (150 mg of a 60% dispersion in
mineral oil) is added to a solution of
N-(3,5-dichloro-1-oxido-4-pyridinio)acetamide (663 mg) in
dimethylformamide (20 mL) and the mixture stirred for 2 hours. The
mixture is then added to the solution of the acid chloride and
stirring continued for 3 hours. Piperidine (0.26 mL) is added and
stirring continued for a further 4 hours. After concentrating in
vacuo the residue is dissolved in dichloromethane, the mixture
filtered, the filtrate treated with decolourising charcoal and
refiltered. Evaporation in vacuo gives a brown oil which is
purified by reverse phase high pressure liquid chromatography
(methanol/water 4:1 v/v) to give
(.+-.)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0-
..sup.2.6.]hept-2-yloxy)pyridine-2-carboxamide (60 mg) as a solid,
m.p. 235-6.degree. C. [Elemental analysis:--C,54.16; H,4.21;
N,10.58% calculated:--C,56.04; H,4.06; N,9.95%].
[0539] By proceeding in a similar manner, but replacing
N-(3,5-dichloro-1-oxido-4-pyridinio)acetamide with the appropriate
quantity of N-(3,5-difluoro-1-oxido-4-pyridinio)acetamide, there is
prepared:--
(.+-.)-N-(3,5-difluoro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.-
0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxamide, m.p. 290.degree.
C. [Elemental analysis:--C,58.27; H,4.57; N,10.58%
calculated:--C,58.61; H,4.40; N,10.79%].
[0540] By proceeding in a similar manner, but replacing
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid with the appropriate quantity of
4-isopropyloxy-5-methoxypyridine-2-carboxylic acid, there is
prepared:--
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxypyridine-2--
carboxamide, m.p. 220-1.degree. C. [Elemental analysis:--C,48.65;
H,4.10; Cl,19.24; N,11.40% calculated:--C,48.40; H,4.06; Cl,19.05;
N,11.29%].
[0541] By proceeding in a similar manner, but replacing
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid with the appropriate quantity of
4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylic acid, there is
prepared:--
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxypyrid-
ine-2-carboxamide hemihydrate, m.p. 206-8.degree. C. [Elemental
analysis:--C,49.12; H,3.94; Cl,18.04; N,10.61%
calculated:--C,48.87; H,4.11; Cl,18.03; N,10.69%].
[0542] By proceeding in a similar manner, but replacing
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid with the appropriate quantity of
(.+-.)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylic
acid, there is prepared:--
(.+-.)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tetrahydrothiop-
hen-3-yloxy)pyridine-2-carboxamide, m.p. 223-5.degree. C.
[Elemental analysis:--C,45.90; H,3.61; Cl,17.23; N,10.07%
calculated:--C,46.16; H,3.63; Cl,17.03; N,10.09%].
EXAMPLE 32
Compounds FT-FV
[0543] 3-Chloroperoxybenzoic acid (2.16 g, of 50-60% grade peracid)
is added to a solution of
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxa-
mide (0.8 g) in dichloromethane (80 mL) and the mixture refluxed
for 8 hours. Another quantity of 3-chloroperoxybenzoic acid (0.5 g,
of 50-60% grade peracid) is added and refluxing continued for 1
hour. After cooling the mixture is washed with saturated aqueous
sodium bicarbonate, dried (MgSO.sub.4) and evaporated. The residue
is purified by flash chromatography (ethyl acetate/methanol 19:1
v/v as eluent on silica) to give
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-ox-
idopyridinium-2-carboxamide, (740 mg), as an off-white solid, m.p.
154.5-155.5.degree. C. [Elemental analysis:--C,49.44; H,4.17;
Cl,17.04; N,10.07% calculated:--C,49.29; H,4.14; Cl,17.12;
N,10.14%].
[0544] By proceeding in a similar manner, but replacing
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxa-
mide with the appropriate quantity of
N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-car-
boxamide, there is prepared:--
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-ox-
idopyridinium-2-carboxamide, m.p. 239-40.degree. C. [Elemental
analysis:--C,48.2; H,3.93; N,10.13% calculated:--C,48.01; H,3.78;
N,10.53%].
[0545] By proceeding in a similar manner, but replacing
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxa-
mide with the appropriate quantity of
N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-carboxami-
de, there is prepared:--
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyr-
idinium-2-carboxamide, m.p. 236-8.degree. C. [Elemental
analysis:--C,46.38; H,3.91; N,10.48% calculated:--C,46.41; H,3.89;
N,10.82%].
EXAMPLE 33
Compounds FW-FX
[0546] n-Butyllithium (10.6 mL of a 1.6 M solution in hexane) is
added dropwise to a stirred solution of diisopropylamine (2.55 mL)
in tetrahydrofuran (30 mL) at -78.degree. C. under a nitrogen
atmosphere. After stirring for 30 minutes a solution of
3,3-dichloro-4-methylpyridine (2.93 g) in tetrahydrofuran (15 mL)
is added. After a further 30 minutes the resulting yellow
suspension is treated with a solution of (.+-.)-methyl
5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxyla-
te (2.32 g) in tetrahydrofuran (25 mL), stirred for 30 minutes at
-78.degree. C. then allowed to warm to room temperature during 4
hours. After standing overnight the mixture is treated with aqueous
ammonium chloride and the bulk of the tetrahydrofuran removed in
vacuo. The residue is diluted with water and extracted with ethyl
acetate. The extracts are washed with saline, dried (MgSO.sub.4)
and evaporated to give an oil. The oil is purified by flash
chromatography (n-pentane/ethyl acetate 4:1 v/v eluent on silica)
to give
1-(5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridin-2-yl)-2-(-
3,5-dichloropyridin-4-yl)ethanone (1.0 g), as a white solid, m.p.
156-7.degree. C. [Elemental analysis:--C,59.10; H,4.34; Cl,17.37;
N,7.04% calculated:--C,59.27; H,4.48; Cl,17.50; N,6.91%].
[0547] By proceeding in a similar manner, but replacing
(.+-.)-methyl
5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxyla-
te with the appropriate quantity of (.+-.)-methyl
5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylate,
there is prepared:--
(.+-.)-1-(5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridin-2-yl)-2-(3,5-d-
ichloropyridin-4-yl)ethanone as a white solid, m.p. 168-70.degree.
C. [Elemental analysis:--C,51.16; H,4.06; Cl,17.68; N,7.04%
calculated:--C,51.14; H,4.04; Cl,17.76; N,7.02%].
EXAMPLE 34
Compound FY
[0548] A solution of
(.+-.)-1-(4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)-5-methoxypyridin-2--
yl)-2-(3,5-dichloropyridin-4-yl)ethanone (340 mg) in
dichloromethane (20 mL) is treated with 3.63 mL of a solution of
50% m-chloroperbenzoic acid (2 g) in dichloromethane (25 mL). The
mixture is stirred at room temperature for 2 hours then refluxed
for 6 hours. After cooling to room temperature the mixture is
washed with saturated aqueous sodium bicarbonate, dried
(MgSO.sub.4) and evaporated to give a yellow solid. The solid is
purified by flash chromatography (gradient elution pentane/ethyl
acetate 7:3 v/v to neat ethyl acetate on silica) to give
1-(4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)-5-methoxypyridin-2-yl)-2-(-
3,5-dichloro-1-oxido-4-pyridinio)ethanone (160 mg) as a white
solid, m.p. 196-8.degree. C. [Elemental analysis:--C,57.15; H,4.47;
N,6.59% calculated:--C,57.02; H,4.31; N,6.65%].
EXAMPLE 35
Compounds FZ-GA
[0549] Diphosphorus tetraiodide (53 mg) is added to a stirred
solution of
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxi-
dopyridinium-2-carboxamide (150 mg) in dichloromethane (3 mL) under
a nitrogen atmosphere. The brown solution is stirred for 10 minutes
and the inorganic decomposed by the addition of aqueous sodium
sulphite. The mixture is made alkaline by the addition of 30%
aqueous sodium hydroxide. The dichloromethane layer is separated
and the aqueous phase extracted with dichloromethane. The combined
dichloromethane phases are dried (MgSO.sub.4) and evaporated to
give a white solid. The solid is purified by flash chromatography
(ethyl acetate as eluent on silica) to afford
N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridi-
nium-2-carboxamide (80 mg) as a white solid, m.p. 178-80.degree. C.
[Elemental analysis:--C,49.97; H,3.94; N,10.94%
calculated:--C,50.01; H,3.94; N,10.94%].
[0550] By proceeding in a similar manner, but replacing
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxi-
dopyridinium-2-carboxamide with the appropriate quantity of
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyri-
dinium-2-carboxamide, there is prepared:--
N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxy-1-oxidopyridinium--
2-carboxamide, m.p. 174-6.degree. C. [Elemental analysis:--C,53.17;
H,4.14; N,7.27% calculated:--C,53.28; H,4.21; N,7.31%].
EXAMPLE 36
Compound GB
[0551] A solution of chlorotrimethylsilane (0.18 mL) in
acetonitrile (6 mL) is added dropwise to a stirred mixture of
sodium iodide (648 mg), zinc dust (157 mg) and
N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-oxidopy-
ridinium-2-carboxamide (600 mg) in acetonitrile with cooling to
0-5.degree. C. The mixture is stirred for 3 hours at 0-5.degree.
C., diluted with diethyl ether, filtered and concentrated to give a
yellow solid. The solid is purified by flash chromatography (ethyl
acetate/n-pentane 7:3 v/v as eluent on silica) to give a white
solid (200 mg), m.p. 259-60.degree. C. which is an iodine adduct.
The solid is dissolved in ethyl acetate containing a few drops of
methanol and the solution stirred with 10% aqueous sodium
thiosulphate (1.5 mL). After 3 hours the organic phase is
separated, dried (MgSO.sub.4) and evaporated to give
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxy-1-oxidopy-
ridinium-2-carboxamide hemihydrate (100 mg), as a white solid, m.p.
204-5.degree. C. [Elemental analysis:--C,49.95; H,4.19; N,10.10%
calculated:--C,50.13; H,4.46; N,10.3%].
EXAMPLE 37
Compound GC-GE
[0552] A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (5 g)
and 2-chloroaniline (2.5 mL) in toluene (60 mL) is heated at reflux
under a Dean and Stark water trap for 3 hours. After concentration,
the residue is dissolved in methanol (60 mL) and the stirred
solution is treated at 0.degree. C. with sodium cyanoborohydride
(2.1 g). The temperature is allowed to rise to room temperature,
and the stirring is continued for 2 hours, before dilution with
ethyl acetate (100 mL) and washing with saline (100 mL). The
organic layer is dried and concentrated, to give a brown oil. This
oil is subjected to flash chromatography on silica gel, eluting
with a mixture of ethyl acetate and hexane (1:4 v/v), to give
N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine (0.64 g),
in the form of an oil. [Elemental analysis: C,69.5; H,6.8; N,4.1;
Cl,10.6%; calculated: C,68.8; H,6.7; N,3.2; Cl,10.7%].
[0553] By proceeding in a similar manner, but using
3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde instead of
3-cyclopentyloxy-4-methoxybenzaldehyde, there is prepared
N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzylamine.
[0554] By proceeding in a similar manner, but using
4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde instead of
3-cyclopentyloxy-4-methoxybenzaldehyde, there is prepared
N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxy-2-aminomethylpyridine.
EXAMPLE 38
Compound GF-GJ
[0555] A stirred suspension of
2,6-dichlorobenzyltriphenylphosphonium bromide (2.5 g) in dry
tetrahydrofuran (30 mL) is treated dropwise with a solution of
potassium t-butoxide (0.56 g) in dry tetrahydrofuran (32 mL) at
0.degree. C. After stirring at this temperature for 1 hour, it is
treated with a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde
(1.1 g) in dry tetrahydrofuran (15 mL). The reaction mixture is
stirred from 0.degree. C. to 5.degree. C. for 1.5 hours, and then
allowed to warm to room temperature. After stirring overnight, the
mixture is concentrated and the resulting residue is treated with
ethyl acetate (200 mL). The resulting organic solution is filtered.
The filtrate is concentrated and the resulting residue is subjected
to flash chromatography, eluting with dichloromethane, to give
trans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethene
(1.16 g), m.p. 47-49.degree. C. [Elemental analysis: C,66.4; H,5.6;
Cl,19.4%, calculated: C,66.1; H,5.55; Cl,19.5%].
[0556] By proceeding in a similar manner, but using
3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde instead of
3-cyclopentyloxy-4-methoxybenzaldehyde, there is prepared
trans-2-(2,6-dichlorophenyl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxy)pheny-
lethene.
[0557] By proceeding in a manner similar, but using
3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde and
2,6-difluorobenzyltriphenylphosphonium bromide, there is prepared
trans-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)-2-(2,6-difluorophenyl-
)ethene.
[0558] By proceeding in a similar manner, but using
4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde instead of
3-cyclopentyloxy-4-methoxybenzaldehyde, there is prepared
trans-2-(2,6-dichlorophenyl)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)ethe-
ne.
[0559] By proceeding in a manner similar, but using
4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde and
2,6-difluorobenzyltriphenylphosphonium bromide, there is prepared
trans-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(2,6-difluorophenyl)ethe-
ne.
EXAMPLE 39
Compound GK-GM
[0560] Pyridinium dichromate (3.6 g) in dry dichloromethane (40 mL)
under nitrogen is treated with
(.+-.)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol
(2.0 g), in one portion. The resulting mixture is stirred for 1.5
hours, and then filtered through a pad of diatomaceous earth, and
the pad is washed with diethyl ether. The combined filtrate and
ethereal washings are washed with saturated aqueous cupric sulfate
solution (2.times.30 mL), followed by water (30 mL), and then dried
over magnesium sulfate. The solvent is removed under reduced
pressure, and the resulting oily residue is subjected to flash
chromatography on silica gel, eluting with ethyl acetate, to give
1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethane-1,2-dione
(0.4 g), in the form of a yellow solid, m.p. 117-119.degree. C.
[Elemental analysis: C,70.1; H,6.0; N,4.1%; calculated: C,70.1;
H,5.9; N,4.3%].
[0561] By proceeding in a similar manner, but using
(.+-.)-1-(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl)-2-(pyrid-4-yl)ethan-
ol instead of
(.+-.)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol,
there is prepared
1-[(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl]-2-(pyrid-4-yl)ethane-1,2--
dione.
[0562] By proceeding in a similar manner, but using
(.+-.)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethanol
instead of
(.+-.)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol,
there is prepared
1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethane-1,2-dione.
EXAMPLE 40
Compound GN
[0563] By proceeding in a similar manner as in Example 26, but
replacing 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid by
the appropriate quantity of
5-cyclopentyl-6-methoxypyridazine-3-carboxylic acid chloride there
is prepared:
N-(3,5-dichloropyrid-4-yl)-5-cyclopentyloxy-6-methoxypyridazine-3-carbox-
amide.
EXAMPLE 41
Compound GO
[0564] Thionyl chloride (0.25 mL) is added to a stirred suspension
of 4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxylic acid
(0.23 g) in toulene (5 mL) containing dry dimethylformamide (1
drop). The mixyure is refluxed for 1 hour under a nitrogen
atmosphere, cooled and evaporated to give the acid chloride which
is dissolved in dimethylformamide (5 mL).
[0565] Meanwhile sodium hydride (44 mg of a 60% dispersion in
mineral oil) is added to stirred solution of
N-(3,5-dichloropyridin-4-yl)acetamide (172 mg) in dimethylformamide
(10 mL) and the mixture stirred for 1 hour. The mixture is then
added to the solution of the acid chloride and the stirring
continued for 1.5 hours at room temperature under a nitrogen
atmosphere. Piperidine (0.23 mL) is added and the stirring
continued for a further 1.5 hours. After evaporating the solvent,
the residue, a brown oil, is purified by flash chromatography
(n-pentane/ethyl acetate 7:3 v/v as eleunt on silica) to give
N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-difluoromethoxypyrid-
ine-2-carboxamide, (0.14 g) as a white solid, m.p. 131-2.degree. C.
[Elemental analysis:--C, 48.85, H, 3.57; N, 9.91%, calculated:--C,
48.82; H, 3.62; N,10.05%], [.sup.1Hnmr in CDCl.sub.3 with
Me.sub.4Si as standard:--1.71, 2H, m: 1.83, 2H, m; 1.93, 2H, m;
2.03, 2H, m; 5.03, 1H, m; 6.64, 1H, t, J=74 Hz; 7.90, 1H, s; 8.37,
1H, s; 8.58, 2H, s: 9.88, 1H, br s.].
REFERENCE EXAMPLE 1
[0566] A mixture of 3,4-dimethoxy-6-fluorobenzaldehyde (3.7 g) and
concentrated sulphuric acid (30 mL) is heated on a steam bath for
19 hours. The mixture is cooled, treated with ice-water (100 g) and
stirred at 0.degree. C. for 30 minutes. The mixture is extracted
with chloroform (5.times.100 mL). The combined organic extracts are
extracted with aqueous sodium hydroxide solution (2.times.200 mL; 2
N). These aqueous extracts are acidified, by treatment with
concentrated hydrochloric acid, with cooling, and the rust coloured
solid formed is subjected to flash chromatography [using a solvent
gradient of 3:1 to 2:1 v/v petroleum ether (b.p. 60-80.degree. C.)
and ethyl acetate as eluent on a silica gel column], to give
6-fluoro-3-hydroxy-4-methoxybenzaldehyde (1.67 g) in the form of a
white solid, m.p. 153-154.degree. C. [NMR (DMSO):--9.56(s,1H),
7.12(d,1H,J=8 Hz),7.01 (d,1H,J=12 Hz), 3.88(s,3H)].
[0567] By proceeding in a similar manner, but using
5,6-dimethoxypyridazine-3-carboxaldehyde instead of
3,4-dimethoxy-6-fluorobenzaldehyde, there is prepared
5-hydroxy-6-methoxypyridazine-3-carboxaldehyde.
REFERENCE EXAMPLE 2
[0568] A mixture of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde (2 g),
potassium carbonate (1.66 g) and anhydrous dimethylformamide (20
mL) is treated with cyclopentyl bromide (1.62 mL) and heated on a
steam bath for 43 hours. The mixture is cooled, poured into water
(200 mL) and extracted with diethyl ether (3.times.100 mL). The
combined ethereal extracts are washed with sodium hydroxide
solution (2.times.50 mL; 2 N), and brine (2.times.50 mL), dried
over magnesium sulphate and concentrated. The residual brown oil is
subjected to flash chromatography [a solvent gradient of 9:1 to 4:1
v/v petroleum ether (b.p. 60-80.degree. C.) and ethyl acetate is
used as eluent on a silica gel column] to give
3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.42 g) in the
form of a yellow oil. [NMR (CDCl.sub.3):--10.22(s,1H),7.27(d,1H,J=8
Hz),6.63(d,1H,J=16 Hz), 4.81-4.76(m,1H),3.91
(s,3H),2.01-1.57(m,8H)].
[0569] By proceeding in a similar manner but using the appropriate
quantities of the appropriate alkyl halides there are
prepared:--
2-Fluoro-5-isopropoxy-4-methoxybenzaldehyde, [NMR
(CDCl.sub.3):--10.21 (s, 1H), 7.30 (d, 1H, J=8 Hz), 6.64 (d, 1H,
J=12 Hz), 4.55 (m, 1H), 3.92(s, 3H), 1.36 (d, 6H, J=7 Hz)];
3-cyclohexyloxy-6-fluoro-4-methoxybenzaldehyde;
3-butoxy-6-fluoro-4-methoxybenzaldehyde; and
3-propoxy-6-fluoro-4-methoxybenzaldehyde.
[0570] By proceeding in a similar manner, but using the appropriate
quantity of 5-hydroxy-6-methoxypyridazine-3-carboxaldehyde instead
of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde, there is prepared
5-cyclopentyl-6-methoxypyridazine-3-carboxaldehyde.
REFERENCE EXAMPLE 3
[0571] A solution of
3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.4 g) in glacial
acetic acid (20 mL) is treated with sulfamic acid (0.82 g) at room
temperature and stirred for 10 minutes. The resulting yellow
solution is cooled to 0.degree. C. and treated with a solution of
sodium chlorite (0.69 g of an 80% pure sample) in water (20 mL)
during 10 minutes. The resulting yellow suspension is stirred at
room temperature for 3 hours, poured into water (100 mL) and
filtered to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid
(0.88 g), in the form of a white solid. [NMR
(CDCl.sub.3):--7.46(d,1H,J=8 Hz),6.65(d,1H,J=12 Hz), 4.80-0.76
(m,1H), 3.90(s,3H), 2.01-1.58(m,8H)].
[0572] By proceeding in a similar manner but using the appropriate
quantities of the appropriate benzaldehydes there are prepared:--
[0573] 2-Fluoro-5-isopropoxy-4-methoxybenzoic acid; [0574]
3-cyclohexyloxy-6-fluoro-4-methoxybenzoic acid; [0575]
3-butoxy-6-fluoro-4-methoxybenzoic acid; [0576]
3-propoxy-6-fluoro-4-methoxybenzoic acid; and [0577]
5-cyclopentyl-6-methoxypyridazine-3-carboxylic acid.
REFERENCE EXAMPLE 4
[0578] A solution of 3-hydroxy-4-methoxybenzaldehyde (14.20 g) in
dry dimethylformamide (300 mL) is treated portionwise with sodium
hydride (60% dispersion in oil; 3.70 g) at room temperature under
nitrogen. 3-Chlorocyclo-pentene (9.6 mL) is added and the resulting
mixture is stirred overnight. The solvent is then removed under
reduced pressure and the residue is partitioned between water (500
mL) and dichloromethane (500 mL) and the aqueous layer is further
extracted with dichloromethane (500 mL). The combined organic
extracts are dried and evaporated under reduced pressure and the
residue is subjected to flash chromatography on silica gel, eluting
with a mixture of ethyl acetate and pentane (1:1 v/v), to give
3-cyclopent-2-enyloxy-4-methoxybenzaldehyde, in the form of a pale
brown oil (11.2 g).
[0579] By proceeding in a similar manner, but using the appropriate
quantity of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde, there is
prepared 3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzaldehyde.
REFERENCE EXAMPLE 5
[0580] A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde
(7.70 g) in t-butanol (160 mL) and 2-methyl-2-butene (40 mL) is
treated dropwise with an aqueous solution (150 mL) containing
sodium chlorite (80% technical grade; 4.39 g) and sodium dihydrogen
phosphate (38.49 g), and left to stand overnight. The resulting
mixture is extracted with dichloromethane (2.times.250 mL), and the
combined organic layers are dried over sodium sulfate, the solvent
is removed under reduced pressure, and the resulting residue is
recrystallized from ethyl acetate, to give
3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form
of a colorless solid. m.p. 160-163.degree. C. [Elemental analysis:
C,66.4; H,6.0%; calculated: C,66.7; H,6.0%].
[0581] By proceeding in a similar manner, but using the appropriate
quantity of 3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzaldehyde,
there is prepared 3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoic
acid.
REFERENCE EXAMPLE 6
[0582] A solution of 3-cyclopent-2-enyloxy-4-methoxybenzoic acid
(5.89 g) in dry dichloromethane (50 mL) under nitrogen at room
temperature is treated with triethylamine (10.50 mL), followed by
oxalyl chloride (2.40 mL). The resulting mixture is stirred for 2.5
hours, then most of the solvent is removed under reduced pressure,
and the resulting residue is taken up in dry tetrahydrofuran (50
mL) and filtered through a pad of diatomaceous earth. The resulting
solution, containing 3-cyclopent-2-enyloxy-4-methoxybenzoyl
chloride, is used immediately without further purification.
[0583] By proceeding in a similar manner, but using the appropriate
quantity of 3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoic acid,
there is prepared 3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzoyl
chloride.
REFERENCE EXAMPLE 7
[0584] A stirred suspension of sodium hydride (60% in oil, 0.88 g)
in dry dimethylformamide (44 mL) under nitrogen at between
5-10.degree. C. is treated with a solution of 3-hydroxy-4-methoxy
benzaldehyde (3.35 g) in dry dimethylformamide (6.3 mL). The
resulting mixture is allowed to warm to room temperature and
stirred for 40 minutes before recooling to between 5-10.degree. C.
A solution of 4-(p-toluenesulfonoxy)cyclopentene (5.24 g) in dry
dimethylformamide (12.6 mL) is added dropwise maintaining the
temperature below 10.degree. C. The resulting mixture is allowed to
warm to room temperature, left to stand for 46 hours, and then
poured into 5% aqueous potassium carbonate (305 mL). t-Butyl methyl
ether is added (150 mL), and the layers are thoroughly stirred and
separated. The aqueous layer is further extracted with t-butyl
methyl ether (2.times.75 mL), the combined organic extracts are
washed with water (3.times.30 mL) and dried over magnesium sulfate.
The solvent is removed under reduced pressure and the resulting
residue is subjected to flash chromatography on silica gel, eluting
with mixtures of ethyl acetate and pentane (1:10 to 3:10), to give
3-cyclopent-3-enyloxy-4-methoxybenzaldehyde as a pale amber viscous
oil that slowly crystallizes on standing (1.75 g).
Recrystallization of a portion (0.5 g) from cyclohexane gives an
analytically pure sample (0.4 g), m.p. 60-62.degree. C. [Elemental
analysis: C,71.8; H,6.5%; calculated: C,71.5; H,6.8%].
[0585] By proceeding in a similar manner, but using the appropriate
quantity of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde, there is
prepared 3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzaldehyde.
REFERENCE EXAMPLE 8
[0586] A stirred solution of
3-cyclopent-3-enyloxy-4-methoxybenzaldehyde (1.75 g) in t-butanol
(36.5 mL) and 2-methyl-2-butene (9.0 mL) is treated dropwise with
an aqueous solution (34 mL) containing sodium chlorite (80%
technical grade; 1.0 g) and sodium dihydrogen phosphate (8.75 g).
The resulting mixture is further stirred for 5 hours, the layers
are separated and the aqueous layer is extracted with t-butyl
methyl ether (3.times.30 mL). The combined organic layers are
washed with water (2.times.15 mL), dried over sodium sulfate and
the solvent removed under reduced pressure. The resulting residue
is recrystallized from ethyl acetate to give
3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.31 g), in the form
of a colorless solid, m.p. 171-173.degree. C. [Elemental analysis:
C,66.6; H,6.0%; calculated: C,66.7; H,6.0%].
[0587] By proceeding in a similar manner, but using the appropriate
quantity of 3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzaldehyde,
there is prepared 3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoic
acid.
REFERENCE EXAMPLE 9
[0588] A solution of 3-cyclopent-3-enyloxy-4-methoxybenzoic acid
(1.33 g) in dry tetrahydrofuran (20 mL) under nitrogen at room
temperature is treated with triethylamine (2.36 mL), followed by
oxalyl chloride (0.70 mL). The resulting mixture is stirred for 1
hour and then filtered through a pad of diatomaceous earth. The
solid collected is washed with dry tetrahydrofuran (10 mL). The
resulting combined filtrates, containing
3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride, is used
immediately without further purification.
[0589] By proceeding in a similar manner, but using the appropriate
quantity of 3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoic acid,
there is prepared 3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzoyl
chloride.
REFERENCE EXAMPLE 10
[0590] A mixture of 2-fluoro-5-hydroxy-4-methoxybenzaldehyde (3 g),
endonorborneol (1.33 g) and triphenylphosphine (4.62 g) are
dissolved in dry tetrahydrofuran (3.5 mL) and treated with
diisopropylazodicarboxylate (3.6 g). The mixture is heated with
stirring at reflux for 24 hours, cooled and treated with water (75
mL). The mixture is extracted with dichloromethane (3.times.100 mL)
and the combined organic extracts washed with 2 N sodium hydroxide
(2.times.75 mL), brine (75 mL), dried (magnesium sulfate) and
concentrated to give
3-exonorbornyloxy-6-fluoro-4-methoxybenzaldehyde as a brown oil
(2.1 g). [NMR (CDCl.sub.3):--10.24 (s, 1H), 7.23 (d, 1H, J=7 Hz),
6.64 (d, 1H, J=12 Hz), 4.22 (d, 1H, J=8 Hz), 3.92 (s, 3H), 2.5 (d,
1H, J=5 Hz), 2.33 (bs, 1H), 1.86-1.1 (m, 10H)].
REFERENCE EXAMPLE 11
[0591] To a solution of diisopropylamine (0.16 g) in
tetrahydrofuran (2 mL) at -78.degree. C. is added a 2.5 N solution
of n-butyl lithium in hexanes (0.62 mL). The solution is allowed to
warm to -10.degree. C. and cooled back to -78.degree. C. A solution
of 3,5-dichloro-4-methylpyridine (0.25 g) in dry tetrahydrofuran (4
mL) is added, stirred for 0.5 hours at -60.degree. C. and treated
with 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (0.25 g) in
dry tetrahydrofuran (4 mL). The reaction mixture is allowed to warm
to room temperature over 1 hour and stirred overnight. The mixture
is treated with 2N ammonium chloride (50 mL) and extracted with
ethyl acetate (3.times.50 mL). The combined organic extracts are
washed with brine (50 mL), dried (magnesium sulfate) and evaporated
to give
2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)e-
thanol (0.22 g). [NMR (CDCl.sub.3):--8.44 (s, 2H), 6.97(d, 1H, J=7
Hz), 6.56 (d, 1H, J=12 Hz), 5.34 (m,1H), 4.74 (m,1H), 3.83 (s, 3H),
3.5 (dd,1H, J=8 Hz, 8 Hz), 3.32 (dd, 1H, J=5 Hz, 6 Hz), 2.07 (d,
1H, J=6 Hz), 1.93-1.55 (m, 8H)].
REFERENCE EXAMPLE 12
[0592] A mixture of 2-fluoro-5-isopropoxy-4-methoxybenzoic acid
(7.2 g) and lithium iodide (24 g) in collidine (120 mL) is heated
at 150.degree. C. overnight, cooled and dissolved in 2 N sodium
hydroxide (200 mL) and washed with ethyl acetate (3.times.150 mL).
The aqueous solution is acidified to pH 1 with concentrated
hydrochloric acid and extracted with ethyl acetate (3.times.100
mL). The combined organic layers are dried (magnesium sulfate) and
concentrated to give an oil. The oil is subjected to mplc on silica
gel using petroleum ether:ethyl acetate (2:1 v/v) as eluent to give
2-fluoro-4-hydroxy-5-isopropylbenzoic acid (5.7 g). [NMR
(DMSO):--7.32 (d, 1H, J=8 Hz), 6.67 (d, 1H, J=12 Hz), 4.47 (m, 1H),
1.24 (d, 6H, J=6 Hz)].
[0593] By proceeding in a similar manner, but using the appropriate
quantities of the appropriate acid, is prepared
3-cyclopentyloxy-6-fluoro-4-hydroxybenzoic acid, [NMR
(CDCl.sub.3):--7.44 (d, 1H, J=8 Hz), 6.73 (d, 1H, J=12 Hz), 4.86
(m, 1H), 2.05-1.63 (m, 8H)].
REFERENCE EXAMPLE 13
[0594] 2-Fluoro-4-hydroxy-5-isopropyloxybenzoic acid (5.7 g) is
dissolved in methanol (200 mL) and concentrated sulfuric acid (1
mL) and heated at 70.degree. C. for 5 hours. The solution is
concentrated and the resultant oil subjected to mplc on silica gel
using petroleum ether: ethyl acetate (4:1 v/v) as eluent to give
methyl-2-fluoro-4-hydroxy-5-isopropyloxybenzoate (5.7 g). [NMR
(CDCl.sub.3) 7.38 (d, 1H, J=7 Hz), 6.67 (d, 1H, J=12 Hz), 4.85 (m,
1H), 3.9 (s, 3H), 1.3 (d, 6H, J=7 Hz)].
[0595] By proceeding in a similar manner, but using the appropriate
quantities of the appropriate acid, is prepared:--
Methyl-3-cyclopentyloxy-4-hydroxy-6-fluorobenzoate, [NMR
(CDCl.sub.3):--7.38 (d, 1H, J=6 Hz), 6.68 (d, 1H, J=12 Hz), 4.87
(m, 1H), 3.91 (s, 3H), 2.03-1.62 (m, 8H)].
REFERENCE EXAMPLE 14
[0596] Methyl-2-fluoro-4-hydroxy-5-isopropyloxybenzoate (5.7 g) is
dissolved in dimethylformamide (150 mL) and treated with potassium
carbonate (5.1 g) and potassium iodide (2 g). Chlorodifluoromethane
is slowly bubbled through the stirred solution which is slowly
heated to 70.degree. C. After 7 hours the reaction is terminated by
cooling and quenching with water (100 mL). The solution is
extracted with ethyl acetate (4.times.100 mL) and the combined
organic extracts washed with brine (200 mL) and dried (magnesium
sulfate). The organic solution is evaporated to give an oil, which
is subjected to mplc on silica gel using petroleum ether: ethyl
acetate (9:1 v/v) as eluent to give
methyl-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzoic acid (5.8
g). [NMR (CDCl.sub.3):--7.52 (d, 1H, J=8 Hz), 6.97 (d, 1H, J=12
Hz), 6.67 (t, 1H, J=72 Hz), 4.56 (m, 1H), 3.93 (s, 3H), 1.36 (d,
6H, J=6 Hz)].
[0597] By proceeding in a similar manner, but using the appropriate
quantity of the appropriate ester is prepared:--
Methyl-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzoate. [NMR
(CDCl.sub.3):--7.50 (d, 1H, J=7 Hz), 6.97 (d, 1H, J=12 Hz), 6.65
(t, 1H, J=72 Hz), 4.83 (m, 1H), 3.94 (s, 3H), 1.98-1.62 (m,
8H)].
REFERENCE EXAMPLE 15
[0598] Methyl-2-fluoro-4-difluoromethoxy-5-isopropyloxybenzoate
(5.8 g) is dissolved in methanol (100 mL) and water (30 mL) with
potassium carbonate (3.9 g) and stirred at 70.degree. C. for 4
hours. After concentration the residue is dissolved in water (150
mL) and washed with ether (150 mL). The aqueous solution is
acidified with 2 M hydrochloric acid and the precipitate collected
as 2-fluoro-4-difluoromethoxy-5-isopropyloxybenzoic acid (5.2 g).
[NMR (CDCl.sub.3):--7.60 (d, 1H, J=7 Hz), 7.02 (d, 1H, J=12 Hz),
6.70 (t, 1H, J=72 Hz), 4.57 (m, 1H), 1.38 (d, 6H, J=7 Hz)].
[0599] By proceeding in a similar manner, but using the appropriate
quantities of the appropriate ester is prepared
3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzoic acid. [NMR
(CDCl.sub.3):--7.57 (d, 1H, J=8 Hz), 7.02 (d,1H, J=12 Hz), 6.68
(t,1H, J=72 Hz), 4.84 (m,1H), 2.0-1.6 (m, 8H)].
REFERENCE EXAMPLE 16
[0600] A stirred solution of diisopropylamine (14 mL) in dry
tetrahydrofuran (150 mL), is treated dropwise with a solution of
butyl lithium in hexanes (40 mL; 2.5 M), under nitrogen, while
keeping the temperature at below -70.degree. C. The resulting
mixture is then stirred for a further period of 30 minutes at below
-70.degree. C. The stirred mixture, while it is still maintained at
below -70.degree. C., is then treated dropwise with a solution of
4-picoline (9.3 g) in dry tetrahydrofuran (20 mL). The stirred
mixture is maintained at below -70.degree. C. for a further 45
minutes. The stirred mixture, while it is still maintained at below
-70.degree. C., is then treated with a solution of
3-cyclopentyloxy-4-methoxybenzaldehyde (22.0 g) in dry
tetrahydrofuran (100 mL), and it is stirred at below -70.degree. C.
for a further 30 minutes. The resulting mixture is then allowed to
warm to room temperature overnight, and then treated with saturated
aqueous ammonium chloride solution (200 mL). The layers are
separated and the aqueous layer is further extracted with ethyl
acetate (3.times.300 mL). The combined organic extracts are dried
over magnesium sulfate and evaporated to dryness. The resulting
residue is recrystallized from ethyl acetate, to give
(.+-.)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol
(28.5 g), in the form of a cream solid, m.p. 102-103.degree. C.
[0601] By proceeding in a similar manner using
3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (that is prepared
as in Reference Example 2) instead of
3-cyclopentyloxy-4-methoxybenzaldehyde, there is prepared
(.+-.)-1-(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl)-2-(pyrid-4-yl)ethan-
ol.
REFERENCE EXAMPLE 17
[0602] Sodium methoxide in methanol (82.65 mL of a 1 M solution) is
added slowly to a stirred solution of methyl
6-chloro-5-nitronicotinate (17 g) in anhydrous methanol (250 mL)
and the mixture stirred for 8 hours. The mixture is concentrated,
the residue treated with water and then extracted into ethyl
acetate. The extracts are washed with water, treated with
decolourising charcoal and dried (MgSO.sub.4). Concentration
afforded methyl 6-methoxy-5-nitronicotinate (9.8 g) as an orange
solid. Recrstallisation from cyclohexane afforded white needles,
m.p. 118-9.degree. C.
REFERENCE EXAMPLE 18
[0603] A solution of methyl 6-methoxy-5-nitronicotinate (5.4 g) in
ethyl acetate (120 mL) is hydrogenated using 5% palladium on carbon
(1 g) as catalyst. When hydrogen uptake ceased the mixture is
filtered through a pad of diatomaceous earth and the filtrate
evaporated. The residue is triturated with n-pentane and methyl
t-butyl ether to give methyl 5-amino-6-methoxynicotinoate (4.3 g)
as a light-brown solid, m.p. 108-9.degree. C. [Elemental
analysis:--C,52.99; H,5.49; N,15.25%. calculated:--C,52.74; H,5.53;
N,15.38%.]
REFERENCE EXAMPLE 19
[0604] Concentrated hydrochloric acid (9.06 mL of strength 36%) is
added to a stirred suspension of methyl
5-amino-6-methoxynicotinoate (3.3 g) in water (20 mL). The mixture
is cooled to 0.degree. C. and treated dropwise with a solution of
sodium nitrite (1.37 g) in water (5 mL). After 30 minutes at
0.degree. C. a solution of sodium tetrafluoroborate (2.84 g) in
water (10 mL) is added. After a further 30 minutes the precipitated
diazonium salt is collected, washed with a little ice-cold water
then with diethyl ether and sucked dry. Potassium carbonate (1.0 g)
is added to trifluoroacetic acid (32 mL) at 0.degree. C. followed
by the addition of the diazonium salt in one portion. The mixture
is stirred at reflux for 18 hours, cooled then poured into iced
water and stirred for 1 hour. The aqueous mixture is neutralised
with solid sodium bicarbonate and extracted with ethyl acetate. The
extracts are washed with water and dried (MgSO.sub.4).
Concentration afforded methyl 5-hydroxy-6-methoxynicotinoate (2.86
g) as a beige solid. This material is used without further
purification.
REFERENCE EXAMPLE 20
[0605] A mixture of methyl 5-hydroxy-6-methoxynicotinoate (250 mg),
anhydrous potassium carbonate (600 mg) and cyclopentyl bromide
(0.26 mL) in dry dimethylformamide (5 mL) is stirred and heated at
60.+-.5.degree. C. for 24 hours. The mixture is cooled to room
temperature, diluted with water and extracted with ethyl acetate.
The extracts are washed with water and dried (MgSO.sub.4).
Concentration gave methyl 5-cyclopentyloxy-6-methoxynicotinoate
(290 mg) as an oil.
REFERENCE EXAMPLE 21
[0606] A solution of potassium hydroxide (168 mg) in water (1 mL)
is added to a solution of methyl
5-cyclopentyloxy-6-methoxynicotinoate (250 mg) in methanol (3 mL)
and the mixture stirred for 4 hours then allowed to stand at room
temperature overnight. The mixture is concentrated, the residue
dissolved in water and the mixture adjusted to pH 6 by the addition
of concentrated hydrochloric acid. The mixture is extracted with
ethyl acetate, the extracts dried (MgSO.sub.4) and concentrated to
give a cream solid. The solid is dried at 100.degree. C. to give
5-cyclopentyloxy-6-methoxynicotinic acid (140 mg), m.p.
191-2.degree. C. [Elemental analysis:--C,60.7; H,6.43; N,5.78%.
calculated:--C,60.75; H,6.37; N,5.90%.].
REFERENCE EXAMPLE 22
[0607] 6-Chloro-5-methoxypyridine-2-carbonyl chloride (5.8 g) is
added to dry cyclopentanol (50 mL) and the mixture refluxed for 4
hours. The mixture is concentrated, the residue dissolved in ethyl
acetate (400 mL) and the ethyl acetate solution is washed with
water (3.times.250 mL). After drying (MgSO.sub.4) the solution is
evaporated to dryness to give cyclopentyl
6-chloro-5-methoxypyridine-2-carboxylate (6.3 g) as a buff solid,
m.p. 90-92.degree. C. [Elemental analysis:--C,55.9; H,5.47;
Cl,13.9; N,5.48%. calculated:--C,56.36; H,5.52; Cl,13.8;
N,5.48%.].
REFERENCE EXAMPLE 23
[0608] Sodium hydride (887 mg of a 60% dispersion in oil) is added
to a solution of cyclopentanol (3.35 mL) in dry tetrahydrofuran
(127 mL) and the mixture stirred for 1.5 hours. Cyclopentyl
6-chloro-5-methoxypyridine-2-carboxylate (6.3 g) is added and the
mixture is stirred at room temperature for 21 hours. The mixture is
poured into saturated aqueous ammonium chloride (500 mL) and the
resulting mixture extracted with ethyl acetate (2.times.500 mL).
The combined extracts are washed with saturated aqueous sodium
bicarbonate (500 mL) and water (500 mL). After drying (MgSO.sub.4)
the solution is evaporated to dryness to give a yellow oil which is
purified by flash chromatography (silica with pentane/ethyl acetate
9:1 v/v as eluent) affording cyclopentyl
6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) as an
oil.
REFERENCE EXAMPLE 24
[0609] Potassium hydroxide (1.98 g) in water (12 mL) is added to a
solution of cyclopentyl
6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) in
methanol (35 mL) and the mixture stirred at room temperature for
2.5 hours. The solution is concentrated to half of the original
volume and diluted with water. The solution is acidified to pH 4
with concentrated hydrochloric acid and the product extracted with
ethyl acetate. The extracts are dried (MgSO.sub.4) and concentrated
to give 6-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (1.38
g) as a yellow solid, m.p. 96-99.degree. C.
REFERENCE EXAMPLE 25
[0610] Sodium thiomethoxide (9.1 g) in dry methanol (50 mL) is
added dropwise to a stirred solution of methyl
6-chloro-5-nitronicotinoate (25.1 g) in dry methanol (400 mL) and
the mixture stirred for 4 hours. The pasty mixture is evaporated to
low volume, diluted with water and the product extracted into ethyl
acetate. The extacts are washed with water and brine, and finally
dried (MgSO.sub.4). Evaporation gave methyl
6-methylthio-5-nitronicotinoate (16.8 g) as a yellow solid. The
solid can be recrystallised from cyclohexane to give a yellow solid
m.p. 115-6.degree. C.
REFERENCE EXAMPLE 26
[0611] Iron powder (22.4 g) is added portionwise to a solution of
methyl 6-methylthio-5-nitronicotinoate (16.8 g) in a mixture of
glacial acetic acid (175 mL) and water (30 mL) whilst heating at
95.+-.5.degree. C. After the addition is complete the mixture is
heated for a further 1.5 hours. The cooled mixture is diluted with
water and extracted with ethyl acetate. The extracts are dried
(MgSO.sub.4), treated with decolourising charcoal and evaporated to
give methyl 5-amino-6-methylthionicotinoate as a dark yellow solid
(12.5 g).
REFERENCE EXAMPLE 27
[0612] Concentrated hydrochloric acid (31.2 mL) is added to a
stirred suspension of methyl 5-amino-6-methylthionicotinoate (12.5
g) in water (70 mL). The stirred mixture is cooled to 0-5.degree.
C. and treated dropwise with a solution of sodium nitrite (4.75 g)
in water (35 mL), then stirred for a further 30 minutes at
0-5.degree. C. A solution of sodium tetrafluoroborate (9.84 g) in
water (35 mL) is added and the mixture stirred for 1 hours. The
water is removed in vacuo, the solid residue triturated with
diethyl ether, collected and pumped dry. The solid is added
portionwise to a mixture of anhydrous potassium carbonate (3.5 g)
and trifluoroacetic acid (100 mL) and the resulting mixture stirred
at room temperature for 72 hours. The mixture is evaporated to low
volume, diluted with water and the product extracted into ethyl
acetate. The extracts are washed with water, dried (MgSO.sub.4) and
evaporated to afford a dark oil. The oil is triturated with
n-pentane then methyl t.butyl ether to give methyl
5-hydroxy-6-methylthionicotinoate (8.9 g) as a light brown solid,
mp. 152-3.degree. C.
REFERENCE EXAMPLE 28
[0613] Cyclopentyl bromide (0.78 mL) is added to a stirred mixture
of methyl 5-hydroxy-6-methylthionicotinoate (810 mg) and anhydrous
potassium carbonate (1.8 g) in dry dimethylformamide (15 mL). The
mixture is heated at 60.+-.5.degree. C. for 8 hours. After cooling
the mixture is concentrated in vacuo and the residue partitioned
between water and ethyl acetate. The ethyl acetate phase is
isolated, washed with water and dried (MgSO.sub.4). The solvent is
removed in vacuo to give methyl
5-cyclopentyloxy-6-methylthionicotinoate (920 mg) as a light brown
oil. [Elemental analysis:--C,58.41; H,6.41; N,5.24%.
calculated:--C,58.2; H,6.44; N,5.33%.].
REFERENCE EXAMPLE 29
[0614] A solution of potassium hydroxide (582 mg) in water (6 mL)
is added to a stirred solution of methyl
5-cyclopentyloxy-6methylthionicotinoate (920 mg) in methanol at
room temperature and the mixture stirred for 6 hours. After
concentrating in vacuo the mixture is diluted with water and
acidified to pH 1 with aqueous 2 M hydrochloric acid. The product
is extracted into ethyl acetate, the extracts treated with
decolourising charcoal, dried (MgSO.sub.4) and evaporated. The
residue is triturated with n-pentane to give
5-cyclopentyloxy-6-methylthionicotinic acid (640 mg) as a white
solid, m.p. 177-8.degree. C. [Elemental analysis:--C,56.90; H,6.02;
N,5.52%. calculated:--C,56.90; H,5.97; N,5.53%.].
REFERENCE EXAMPLE 30
[0615] A mixture of methyl 5-hydroxy-6-methylthionicotinoate (3 g),
isopropyl bromide (2.1 mL) and anhydrous potassium carbonate (3 g)
in dry dimethylformamide (35 mL) is stirred and heated at
60.+-.5.degree. C. for 18 hours. After cooling the solvent is
removed in vacuo and the residue partitioned between ethyl acetate
and water. The organic phase is washed with brine and dried
(MgSO.sub.4). Evaporation gives a brown oil which is purified by
flash chromatography (pentane/ethyl acetate 4:1 v/v as eluent on
silica) to give methyl 5-isopropyloxy-6-methylthionicotinoate (2.36
g) as a pale yellow oil. [Elemental analysis:--C,54.40; H,6.24;
N,5.88%. calculated:--C,54.75; H,6.27; N,5.81%.].
REFERENCE EXAMPLE 31
[0616] Potassium hydroxide (770 mg) in water (8 mL) is added to a
solution of methyl 5-isopropyloxy-6-methylthionicotinoate (1.1 g)
in methanol (15 mL) and the mixture stirred at room temperature for
6 hours. After concentrating in vacuo the residue is dissolved in
water and acidified to pH 1 with concentrated aqueous hydrochloric
acid. The mixture is extracted with ethyl acetate, the extracts
washed with water and dried (MgSO.sub.4). The solvent is removed in
vacuo to give 5-isopropyloxy-6-methylthionicotinic acid as a white
solid, m.p. 154-5.degree. C.
REFERENCE EXAMPLE 32
[0617] Trityl chloride (9.43 g) is added in one portion to a
solution of 2-hydroxymethyl-5-methoxy-4-pyridone (5 g) and
4-dimethylaminopyridine (4.2 g) in dry dimethylformamide (80 mL)
and the solution stirred at room temperature for 12 hours. The
mixture is then heated on a steam bath for 3 hours and diluted with
iced water (300 mL) to give a light brown solid. The solid is
collected, washed with water and sucked dry. The solid is dissolved
in hot ethyl acetate to give a clear solution which immediately
deposits a granular off-white solid. The solid does not redissolve
on further heating. After cooling the solid is collected, washed
with ethyl acetate and diethyl ether and dried to give
5-methoxy-2-trityloxymethyl-4-pyridone (7.5 g) as an off-white
solid, m.p. 185-7.degree. C.
REFERENCE EXAMPLE 33
[0618] Diisopropyl azodicarboxylate (1.47 mL) is added to a
solution of triphenylphosphine (1.96 g) in dry tetrahydrofuran (20
mL) with cooling to 0-5.degree. C. under a nitrogen atmosphere. The
pasty mixture is stirred for a further 30 minutes and then a
solution of 5-methoxy-2-trityloxymethyl-4-pyridone (2.0 g) in dry
tetrahydrofuran (25 mL) is added followed by the addition of
cyclopentanol (0.68 mL). The mixture is stirred at reflux for 8
hours, cooled and the solvent removed in vacuo. The residue is
diluted with water and extracted with ethyl acetate. The extracts
are dried (MgSO.sub.4) and evaporated to give a brown oil. The oil
is purified by flash chromatography (n-pentane/ethyl acetate 9:1
v/v as eluent on neutral alumina) to give
4-cyclopentyloxy-5-methoxy-2-trityloxypyridine (1.24 g) as a white
solid, m.p. 132-3.degree. C. [Elemental analysis:--C,80.00; H,6.70;
N,2.70%. calculated:--C,79.97; H,6.71; N,3.00%.].
REFERENCE EXAMPLE 34
[0619] 90% Formic acid (5.5 mL) is added to a suspension of
4-cyclopentyloxy-5-methoxy-2-trityloxypyridine (1.2 g) in ethyl
acetate (8.5 mL) and the mixture stirred at room temperature for 1
hours. The mixture is diluted with ethyl acetate and washed with
brine then aqueous sodium bicarbonate until the washings are
neutral. The brine washings are neutralised with solid sodium
bicarbonate and extracted with ethyl acetate. After drying
(MgSO.sub.4) the extracts are evaporated to give
4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (360 mg) as a
white solid, m.p. 93-94.5.degree. C. [Elemental analysis:--C,64.7;
H,7.80; N,6.11%. calculated:--C,64.55; H,7.68; N,6.27%.].
REFERENCE EXAMPLE 35
[0620] Solid potassium permanganate (5.87 g) is added portionwise
during 30 minutes to a suspension of
4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (4.0 g) in water
(100 mL) at 50.+-.5.degree. C. When the addition is complete the
mixture is heated at 70.+-.5.degree. C. for 45 min and then cooled
to room temperature. A solution of potassium hydroxide (1.95 g) in
water (50 mL) is added followed by sufficient isopropanol to react
with excess potassium permanganate. After stirring for 10 minutes
the mixture is filtered through diatomaceous earth and the filtrate
concentrated to .about.70 mL. The solution is acidified to pH 2
with concentrated aqueous hydrochloric acid and extracted with
chloroform. After drying (MgSO.sub.4) the extracts are evaporated
to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.5
g) as a white solid, m.p. 184-5.degree. C. [.sup.1 Hnmr in
D.sub.6-DMSO shifts relative to Me.sub.4Si:--1.55-1.79, 6H, m;
1.95, 2H, m; 3.92, 3H, s; 5.00, 1H, m; 7.59, 1H, s; 8.24, 1H,
s.].
REFERENCE EXAMPLE 36
[0621] Hydrogen chloride gas is passed into a suspension of
5-methoxy-4-pyridone-2-carboxylic acid (60.89 g) in methanol (800
mL) with ice bath cooling to 0-5.degree. C. After 2 hours the
passage of hydrogen chloride is stopped and then the mixture is
refluxed gently for 5 hours. After cooling the solution is allowed
to stand overnight. The precipitate is collected, and the filtrate
evaporated to dryness. The collected solid and the residue are
combined, dissolved in the minimum amount of water and then
basefied to pH 8 with sodium bicarbonate. The solution is extracted
with n-butanol and the extracts evaporated in vacuo to give methyl
5-methoxy-4-pyridone-2-carboxylate (38.3 g) as a pale yellow solid,
m.p 185-6.degree. C.
REFERENCE EXAMPLE 37
[0622] Diisopropyl diazodicarboxylate (6.13 mL) is added to a
solution of triphenylphosphine (8.16 g), methyl
5-methoxy-4-pyridone-2-carboxylate (3.8 g) and cyclopentanol (2.82
mL) in dry tetrahydrofuran (200 mL) with cooling to 10-15.degree.
C. under a nitrogen atmosphere. The mixture is stirred at room
temperature for 30 minutes then at reflux for 48 hours. After
concentrating, the residue is diluted with water and extracted with
ethyl acetate and the extracts washed with water, dried
(MgSO.sub.4) and evaporated to give a yellow oil. The oil is
purified by flash chromatography (pentane/ethyl acetate 3:2 v/v as
eluent on silica) to give methyl
4-cyclopentyloxy-5-methoxypyridine-2-carboxylate (4.1 g) as a
golden oil.
By proceeding in a similar manner, but replacing cyclopentanol with
the appropriate quantity of (.+-.)-tetrahydrothiophen-3-ol, there
is prepared:--
(.+-.)-methyl
5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylate as a
solid. [1 Hnmr in D.sub.6-DMSO shifts relative to
Me.sub.4Si:--2.04, 1H, m; 2.32, 1H, m; 2.91, 3H, m; 3.20, 1H, dd;
3.85, 3H, s; 3.94, 3H, s; 5.44, 1H m; 7.68, 1H, s; 8.31, 1H,
s.].
By proceeding in a similar manner, but replacing cyclopentanol with
the appropriate quantity of cyclopropylmethanol, there is
prepared:--
methyl 4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylate as a
white solid, m.p. 93-4.degree. C.
By proceeding in a similar manner, but replacing cyclopentanol with
the appropriate quantity of isopropanol, there is prepared:--
A 2:1 mixture of ethyl
4-isopropyloxy-5-methoxypyridine-2-carboxylate and methyl
4-isopropyloxy-5-methoxypyridine-2-carboxylate as an oil.
By proceeding in a similar manner, but replacing cyclopentanol with
the appropriate quantity of
(.+-.)-tricyclo[2.2.1.0..sup.2.6.]heptan-2-ol, there is
prepared:--
A 1:1 mixture of (.+-.)-ethyl
5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxyla-
te and (.+-.)-methyl
5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxyla-
te.
REFERENCE EXAMPLE 38
[0623] A solution of potassium hydroxide (4.71 g) in water (32 mL)
is added to a solution of methyl
4-cyclopentyloxy-5-methoxypyridine-2-carboxylate (7.03 g) in
methanol (188 mL) and the mixture allowed to stand for 45 hours.
After concentrating in vacuo the residue is dissolved in water,
washed with ethyl acetate and basefied to pH 5 with concentrated
aqueous hydrochloric acid. The mixture is extracted with
dichloromethane, the extracts dried (MgSO.sub.4) and evaporated to
give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.4 g)
as a white solid.
By proceeding in a similar manner, but replacing methyl
4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the
appropriate quantity of (.+-.)-methyl
5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylate,
there is prepared:--
(.+-.)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxylic
acid, as a white solid, m.p. 190-1.degree. C. [Elemental
analysis:--C,51.3; H,5.17; N,5.53%. calculated:--C,57.7; H,5.13;
N,5.49%.]
By proceeding in a similar manner, but replacing methyl
4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the
appropriate quantity of methyl
4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylate there is
prepared:--
4-cyclopropylmethoxy-5-methoxypyridine-2-carboxylic acid as a white
solid, m.p. 146-7.degree. C. [1 Hnmr in D.sub.6-DMSO shifts
relative to Me.sub.4Si:--0.37, 2H, m; 0.60, 2H, m; 1.24, 1H, m;
3.94, 3H, s; 3.98, 2H, d; 7.58, 1H, s; 8.25, 1H, s.].
[0624] By proceeding in a similar manner, but replacing methyl
4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the
appropriate quantity of a 2:1 mixture of ethyl
4-isopropyloxy-5-methoxypyridine-2-carboxylate and methyl
4-isopropyloxy-5-methoxypyridine-2-carboxylate, there is
prepared:--
4-isopropyloxy-5-methoxypyridine-2-carboxylic acid, m.p.
172-3.degree. C. [Elemental analysis:--C,56.77; H,6.21; N,6.74%.
calculated:--C,56.87; H,6.20; N,6.63%.]
[0625] By proceeding in a similar manner, but replacing methyl
4-cyclopentyloxy-5-methoxypyridine-2-carboxylate with the
appropriate quantity of a 1:1 mixture of (.+-.)-ethyl
5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxyla-
te and (.+-.)-methyl
5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxyla-
te, there is prepared:--
[0626]
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridi-
ne-2-carboxylic acid, as a white solid m.p. 188-9.degree. C. [1
Hnmr in D.sub.6-DMSO shifts relative to Me.sub.4Si:--1.28, 2H,
br.d; 1.36, 3H, br.s; 1.59, 1H, d; 1.78, 1H, d; 1.13, 1H, br.s;
2.94, 3H, s; 4.58, 1H, br.s; 7.66, 1H, s; 8.24, 1H, s.].
REFERENCE EXAMPLE 39
[0627] Manganese dioxide (6.0 g) is added to a solution of
4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (2.0 g) in
diethyl ether (80 mL) and dichloromethane (10 mL) and the mixture
stirred at room temperature for 90 hours. After filtering the
filter pad is washed with dichloromethane and the combined filtrate
and washings are evaporated to give a white solid. The solid is
dried under high vacuum to give
4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g).
[.sup.1 Hnmr in D.sub.6-DMSO shifts relative to
Me.sub.4Si:--1.55-1.79, 6H, m; 1.97, 2H, m; 3.96, 3H, s; 5.03, 1H,
m; 7.45, 1H, s; 8.41, 1H, s; 9.83, 1H, s.].
REFERENCE EXAMPLE 40
[0628] n-Butyllithium (3.21 mL of 2.5 M solution) is added to a
solution of diisopropylamine (1.15 mL) in dry tetrahydrofuran (25
mL) with the temperature being maintained below -60.degree. C.
After 30 min a solution of 3,5-dichloro-4-methylpyridine (1.21 g)
in tetrahydrofuran (7 mL) is added dropwise and the mixture stirred
for a further 30 min. A solution of
4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g) in
tetrahydrofuran (7 mL) is added and the mixture stirred for 4 hours
whilst being allowed to warm to room temperature. After a further
18 hours at room temperature the mixture is diluted with saturated
aqueous ammonium chloride (50 mL) and extracted with ethyl acetate.
The extracts are washed with water, dried (MgSO.sub.4) and
evaporated to give a yellow oil. The oil is triturated with
n-pentane to give
(.+-.)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin--
4-yl)ethanol (1.4 g) as an off-white solid, m.p. 110-112.degree. C.
[.sup.1 Hnmr in D.sub.6-DMSO shifts relative to
Me.sub.4Si:--1.55-1.78, 6H, m; 1.95, 2H, m; 3.27, 2H, m; 3.79, 3H,
s; 4.89, 2H, m; 5.64, 1H, d; 7.07, 1H, s; 7.98, 1H s; 8.54, 2H,
s.].
REFERENCE EXAMPLE 41
[0629] Diisopropyl azodicarboxylate (0.97 mL) is added to a
solution of triphenylphosphine (1.29 g) in tetrahydrofuran (10 mL)
while cooling to 0-5.degree. C. After stirring for 45 minutes
methyl 5-hydroxy-6-methoxynicotinoate (0.9 g) followed by a
solution of (.+-.)-endo-(8,9,10-trinorbornan-2-ol) (0.552 g) in
tetrahydrofuran (5 mL) are added and the mixture refluxed for 18
hours. Water is added and the mixture is extracted with ethyl
acetate, the extracts dried (MgSO.sub.4) and evaporated to give a
yellow oil. The oil is purified by flash chromatography
(n-pentane/ethyl acetate 9:1 v/v on silica) to give methyl
(.+-.)-6-methoxy-5-endo-(8,9,10-trinorbornan-2-yloxy)nicotinoate,
(1.1 g) as a white solid, m.p. 65-7.degree. C. [Elemental
analysis:--C,64.90; H,7.00; N,4.95%. calculated:--C,64.97; H,6.91;
N,5.05%.]
REFERENCE EXAMPLE 42
[0630] Potassium hydroxide (380 mg) in water (5 mL) is added to a
solution of methyl
(.+-.)-6-methoxy-5-endo-(8,9,10-trinorbornan-2-yloxy)nicotinoate
(1.1 g) in methanol (30 mL) and the mixture stirred for 4 hours.
After concentrating, the residue is dissolved in water and the
solution acidified with concentrated aqueous hydrochloric acid. The
product is extracted into ethyl acetate, the extracts dried
(MgSO.sub.4) and evaporated to give
(.+-.)-6-methoxy-5-endo-(8,9,10-trinorbornan-2-yloxy)nicotinic acid
(0.95 g) as a white solid, m.p. 192-3.degree. C. [Elemental
analysis:--C,63.5; H,6.36; N,5.34%. calculated:--C,63.86; H,6.51;
N,5.32%.]
REFERENCE EXAMPLE 43
[0631] Diisopropyl azodicarboxylate (3.14 mL) is added to a mixture
of triphenylphosphine (4.19 g),
5-methoxy-2-trityloxymethyl-4-pyridone (5 g) and
(.+-.)-tricyclo[2.2.1.0..sup.2.6.]heptan-2-ol (1.43 g) in dry
toluene (60 mL) at 10-15.degree. C. under a nitrogen atmosphere.
The mixture is stirred for 30 minutes then heated at
60.+-.5.degree. C. for 24 hours. After cooling the solvent is
evaporated and the residue partitioned between water and ethyl
acetate. The ethyl acetate phase is washed with water then brine
and dried (MgSO.sub.4). Evaporation gives a brown oil which is
purified by flash chromatography (n-pentane/ethylacetate 9:1 v/v as
eluent on neutral alumina) to give
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)-2-trityloxym-
ethylpyridine, (2.74 g), as a white solid, m.p. 140-2.degree. C.
[Elemental analysis:--C,80.70; H,6.41; N,2.54%.
calculated:--C,80.95; H,6.38; N,2.86%.]
REFERENCE EXAMPLE 44
[0632] A solution of
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)-2-trityloxym-
ethylpyridine (17 g) in glacial acetic acid is stirred at
65.+-.5.degree. C. for 24 hours. After cooling the solvent is
removed in vacuo, the residue treated with water and the resulting
mixture extracted with ethyl acetate. The ethyl acetate extracts
are washed with 1 M aqueous hydrochloric acid, the aqueous washings
basefied to pH 8 with 6 M aqueous sodium hydroxide and extracted
with ethyl acetate. These extracts are dried (MgSO.sub.4) and
evaporated to give
(.+-.)-2-hydroxymethyl-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-ylo-
xy)pyridine as a colourless oil.
REFERENCE EXAMPLE 45
[0633] Sodium hydroxide (1.1 g) is added to a suspension of
(.+-.)-2-hydroxymethyl-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-ylo-
xy)pyridine (4.54 g) in water (70 mL). Activated manganese dioxide
(9 g) is added portionwise during 45 minutes and the resulting
mixture heated at 65.+-.5.degree. C. for 6 hours. The mixture is
filtered hot through diatomaceous earth and the filtrate
concentrated to low volume in vacuo. The mixture is acidified with
glacial acetic acid and extracted with dichloromethane. The
extracts are dried (MgSO.sub.4) and evaporated. The residue is
purified by flash chromatography (ethyl acetate/methanol 19:1 v/v
as eluent on silica) to give
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid as a solid, m.p. 182-3.degree. C.
REFERENCE EXAMPLE 46
[0634] A mixture of
(.+-.)-5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-ca-
rboxylic acid (4.3 g) and concentrated hydrochloric acid (5 mL) in
methanol (50 mL) is refluxed for 8 hours. After cooling the mixture
is concentrated to a low volume, diluted with water and neutralised
with solid sodium bicarbonate. The mixture is filtered and
extracted with dichloromethane. The combined extracts are washed
with saline, dried (MgSO.sub.4) and evaporated to give
(.+-.)-methyl
5-methoxy-4-(tricyclo[2.2.1.0..sup.2.6.]hept-2-yloxy)pyridine-2-carboxyla-
te (2.3 g). [.sup.1 Hnmr in D.sub.6-DMSO shifts relative to
Me.sub.4Si:--1.29, 2H, m; 1.47, 3H, m; 1.60, 1H, d; 1.78, 1H, d;
2.14, 1H, br.s; 3.84, 3H, s; 3.94, 3H, s; 4.59, 1H, br.s; 7.67, 1H,
s; 8.28, 1H, s.]
REFERENCE EXAMPLE 47
[0635] 4-Dimethylaminopyridine (17.55 g) and trityl chloride (40.5
g) are added to a solution of
5-benzyloxy-2-hydroxymethyl-4-pyridone (30.2 g) in dry
dimethylformamide and the mixture stirred and heated at 95.degree.
C. for 2 hours. After cooling the mixture is poured into iced-water
(800 mL) and the precipitate collected, washed with water
(2.times.500 mL) and sucked dry. The solid is boiled with methanol
(500 mL) and after cooling the solid is collected, washed with
methanol (200 mL) and diethyl ether (2.times.100 mL) and dried at
80.degree. C. to give 5-benzyloxy-2-trityloxymethyl-4-pyridone
(26.5 g) as a white solid, m.p. 233-5.degree. C.
REFERENCE EXAMPLE 48
[0636] Diisopropyl azodicarboxylate (13.5 mL) is added to a mixture
of triphenylphosphine (18.15 g),
5-benzyloxy-2-trityloxymethyl-4-pyridone (21.1 g) and cyclopentanol
(6.25 mL) in dry tetrahydrofuran (600 mL) at 10-15.degree. C. under
a nitrogen atmosphere. The mixture is stirred for 30 minutes then
heated at reflux for 24 hours. After cooling the solvent is
evaporated to give a brown oil which is purified by flash
chromatography (n-pentanelethyl acetate 4:1 v/v as eluent on
silica) to give
5-benzyloxy-4-cyclopentyloxy-2-trityloxymethylpyridine as a
colourless oil.
REFERENCE EXAMPLE 49
[0637] 5% Palladium on charcoal catalyst (2 g) is added to a
solution of 5-benzyloxy-4-cyclopentyloxy-2-trityloxymethylpyridine
(24.2 g) in ethanol (500 mL) and the mixture stirred at room
temperature under a hydrogen atmosphere for 3 hours. After
filtering the filtrate is concentrated in vacuo to give a
colourless oil which is purified by flash chromatography
(n-pentane/ethyl acetate 7:3 v/v as eluent on silica) to give
4-cyclopentyloxy-5-hydroxy-2-trityloxymethylpyridine (18.8 g) as a
colourless foam. [.sup.1 Hnmr in deuterochloroform with Me.sub.4Si
as standard:--1.70, 2H, m; 1.82, 2H, m; 1.90-2.08, 4H, m; 4.25, 2H,
s; 4.93, 1H, m; 7.19, 1H, s; 7.24,7.30,7.49, 15H, Ar; 8.04, 1H,
s.].
REFERENCE EXAMPLE 50
[0638] Chlorodifluoromethane is bubbled through a suspension of
potassium carbonate (2.13 g) and potassium iodide (584 mg) in a
solution of 4-cyclopentyloxy-5-hydroxy-2-trityloxymethylpyridine (5
g) in dimethylformamide (40 mL) while heating at 70.+-.5.degree. C.
and using a cardice/acetone condenser to recycle the condensate.
After 4 hours the addition of chlorodifluoromethane is stopped and
the mixture heated for a further 16 hours. After cooling the
mixture is concentrated in vacuo, the residue diluted with water,
acidified to pH 4 with glacial acetic acid and extracted with
dichloromethane. The extracts are dried (MgSO.sub.4) and
evaporated. The residue is purified by flash chromatography
(gradient elution using n-pentane/ethyl acetate 9:1 v/v to 7:3 v/v
on silica) to give
4-cyclopentyloxy-5-difluoromethoxy-2-trityloxymethylpyridine (240
mg) as an oil. [.sup.1 Hnmr in deuterochloroform with Me.sub.4Si as
standard:--1.72, 2H, m; 1.85, 2H, m; 2.00, 4H, m; 4.31, 2H, s;
4.95, 1H, m; 6.51, 1H, t, J=74 Hz; 7.22-7.55, 16H, m;
8.19,1H,s.].
REFERENCE EXAMPLE 51
[0639] A mixture of 5,6-dimethoxy-3-methylpyridazine-2-oxide (0.5
g) in acetic anhydride (2 mL) is refluxed for 2 hours. After
cooling the mixture is diluted with water and extracted with ethyl
acetate (2.times.20 mL). The extracts are dried (MgSO.sub.4) and
evaporated to give a brown oil which is purified by flash
chromatography (ethyl acetate as eluent on silica) to give
6-acetoxymethyl-3,4-dimethoxypyridazine (0.27 g) as a colourless
oil.
REFERENCE EXAMPLE 52
[0640] A solution of potassium carbonate (0.2 g) in water 2 mL) is
added to a solution of 6-acetoxymethyl-3,4-dimethoxypyridazine
(0.27 g) in methanol (6 mL) and the mixture stirred at
60-70.degree. C. for 2 hours. After evaporating to dryness the
residue is partitioned between ethyl acetate (10 mL) and brine (10
mL). The ethyl acetate phase is evaporated to dryness and the
residue purified by flash chromatography (ethyl acetate as eluent
on silica) to give 3,4-dimethoxy-6-hydroxymethylpyridazine as a
white solid, m.p. 151-3.degree. C.
REFERENCE EXAMPLE 53
[0641] A solution of oxalyl chloride (0.61 mL) in dichloromethane
(11 mL) is cooled to -60.degree. C. and dimethylsulphoxide (0.98 g)
is added dropwise maintaining the reaction mixture at -60.degree.
C. After 15 minutes a solution of
3,4-dimethoxy-6-hydroxymethylpyridazine (1.0 g) in dichloromethane
(42 mL) is added dropwise during 45 minutes maintaining the
reaction mixture at -60.degree. C. After a further 15 minutes
triethylamine (3.96 mL) is added, the mixture stirred at
-60.degree. C. for 15 minutes then cooling is discontinued. When
the reaction mixture attains room temperature stirring is continued
for 1 hour. The reaction mixture is diluted with water (100 mL) and
dichloromethane (100 mL) and the organic phase separated. The
aqueous phase is re-extracted with dichloromethane (100 mL) and the
combined extracts are dried (MgSO.sub.4). Evaporation gave
5,6-dimethoxypyridazine-3-carboxaldehyde (0.95 g) as a white solid,
m.p. 179-81.degree. C.
REFERENCE EXAMPLE 54
[0642] n-Butyllithium (1.51 mL of a 1.6 M solution in hexane) is
added to a solution of diisopropylamine (0.34 mL) in
tetrahydrofuran (29 mL) at -10.degree. C. under a nitrogen
atmosphere. After 30 minutes the mixture is cooled to -70.degree.
C. and a solution of 3,5-dichloro-4-methylpyridine (0.39 g) in
tetrahydrofuran (4 mL) is added dropwise. After 30 minutes a
solution of 5,6-dimethoxy-pyridazine-3-carboxaldehyde (0.35 g) in
tetrahydrofuran (15 mL) is added at -70 to -60.degree. C. and
stirring continued at this temperature for 1 hour before cooling is
discontinued. After 24 hours the yellow solution is quenched by the
addition of aqueous ammonium chloride and the mixture extracted
with ethyl acetate. The dried extracts (MgSO.sub.4) are evaporated
and the residue purified by flash chromatography (ethyl acetate as
eluent on silica) to give
(.+-.)-2-(3,5-dimethylpyrid-4-yl)-1-(5,6-dimethoxypyridazin-3-yl)ethanol
(0.17 g), as a white solid, m.p. 217-8.degree. C.
REFERENCE EXAMPLE 55
[0643] Water (4 drops is added to a solution of
4-cyclopentyloxy-5-difluoromethoxy-2-trityloxypyridine (900 mg) in
glacial acetic acid (20 mL) and the mixture heated at 60.degree. C.
for 18 hours. After cooling the mixture is evaporated to dryness
and the residue partitioned between water and ethyl acetate. The
organic phase is dried over magnesium sulphate and evaporated to
give a pale yellow solid which is purified by flash chromatography
(gradient elution using n-pentane/ethyl acetate 7:3 v/v to
n-pentane/ethyl acetate 2:3 v/v on silica) to give
4-cyclopentyloxy-5-difluoromethoxy-2-hydroxymethylpyridine (250 mg)
as a white solid, m.p. 85-6.degree. C.
REFERENCE EXAMPLE 56
[0644] Solid potassium permanganate (306 mg) is added portionwise
to a stirred suspension of
4-cyclopentyloxy-5-difluoromethoxy-2-hydroxymethylpyridine (250 mg)
in water (10 mL) while heating at 50.+-.5.degree. C. The resulting
mixture is heated for 1.5 hours at this temperature, then at
70.degree. C. for minutes. A solution of potassium hydroxide (150
mg) in water (1 mL) is added followed by the addition of
isopropanol until the excess potassium permanganate is consumed.
After 15 minutes, the mixture is cooled and filtered through a pad
of diatomaceous earth and the filtrate adjusted to pH 5 with
glacial acetic acid. The white precipitate is collected, washed
with water and dried in vacuo to give
4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxylic acid (240
mg) as a white solid, m.p. 215-6.degree. C. decomp. [Elemental
analysis:--C, 52.57; H, 4.67; N, 5.18%, calculated:--52.75; H,
4.80; N, 5.13%].
[0645] The compounds of formula I exhibit useful pharmacological
activity and accordingly are incorporated into pharmaceutical
compositions and used in the treatment of patients suffering from
certain medical disorders. More especially, they are cyclic AMP
phosphodiesterase inhibitors, in particular type IV cyclic AMP
phosphodiesterase inhibitors. The present invention provides
compounds of formula I, and compositions containing compounds of
formula I, which are of use in a method for the treatment of a
patient suffering from, or subject to, conditions which can be
ameliorated by the administration of an inhibitor of cyclic AMP
phosphodiesterase. For example, compounds within the present
invention are useful as bronchodilators and asthma-prophylactic
agents and agents for the inhibition of eosinophil accumulation and
of the function of eosinophils, such as for the treatment of
inflammatory airways disease, especially reversible airway
obstruction or asthma, and for the treatment of other diseases and
conditions characterized by, or having an etiology involving,
morbid eosinophil accumulation. As further examples of conditions
which can be ameliorated by the administration of inhibitors of
cyclic AMP phosphodiesterase such as compounds of formula I there
may be mentioned inflammatory diseases, such as atopic dermatitis,
urticaria, allergic rhinitis, psoriasis, rheumatic arthritis,
ulcerative colitis, Crohn's disease, adult respiratory distress
syndrome and diabetes insipidus, other proliferative skin diseases
such as keratosis and various types of dermatitis, conditions
associated with cerebral metabolic inhibition, such as cerebral
senility, multi-infarct dementia, senile dementia (Alzheimer's
disease), and memory impairment associated with Parkinson's
disease, and conditions ameliorated by neuroprotectant activity,
such as cardiac arrest, stroke, and intermittent claudication. A
special embodiment of the therapeutic methods of the present
invention is the treating of asthma.
[0646] The compounds are also inhibitors of tumor necrosis factor,
especially a-TNF. Thus, the present invention provides compounds of
formula I, and compositions containing compounds of formula I,
which are of use in a method for treating a patient suffering from,
or subject to, conditions which can be ameliorated by the
administration of an inhibitor of a-TNF. For example compounds of
the present invention are useful in joint inflammation, arthritis,
rheumatoid arthritis and other arthritic conditions such as
rheumatoid spondylitis and osteoarthritis. Additionally, the
compounds are useful in treatment of sepsis, septic shock, gram
negative sepsis, toxic shock syndrome, acute respiratory distress
syndrome, asthma and other chronic pulmonary diseases, bone
resorption diseases, reperfusion injury, graft vs. host reaction
and allograft rejection. Furthermore, the compounds are useful in
the treatment of infections such as viral infections and parasitic
infections, for example malaria such as cerebral malaria, fever and
myalgias due to infection, HIV, AIDS, cachexia such as cachexia
secondary to AIDS or to cancer. Other disease states that may be
treated with the compounds of the present invention include Crohn's
disease, ulcerative colitis, pyresis, systemic lupus erythematosus,
multiple sclerosis, type I diabetes mellitus, psoriasis, Bechet's
disease, anaphylactoid purpura nephritis, chronic
glomerulonephritis, inflammatory bowel disease and leukemia. A
special embodiment of the therapeutic methods of the present
invention is the treating of joint inflammation.
[0647] According to a further feature of the invention there is
provided a method for the treatment of a human or animal patient
suffering from, or subject to, conditions which can be ameliorated
by the administration of an inhibitor of cyclic AMP
phosphodiesterase or of TNF, especially a-TNF, for example
conditions as hereinbefore described, which comprises the
administration to the patient of an effective amount of compound of
formula I or a composition containing a compound of formula I.
"Effective amount" is meant to describe an amount of compound of
the present invention effective in inhibiting cyclic AMP
phosphodiesterase and/or TNF and thus producing the desired
therapeutic effect.
[0648] The present invention also includes within its scope
pharmaceutical formulations which comprise at least one of the
compounds of formula I in association with a pharmaceutically
acceptable carrier or coating.
[0649] In practice compounds of the present invention may generally
be administered parenterally, rectally or orally, but they are
preferably administered by inhalation.
[0650] The products according to the invention may be presented in
forms permitting administration by the most suitable route and the
invention also relates to pharmaceutical compositions containing at
least one product according to the invention which are suitable for
use in human or veterinary medicine. These compositions may be
prepared according to the customary methods, using one or more
pharmaceutically acceptable adjuvants or excipients. The adjuvants
comprise, inter alia, diluents, sterile aqueous media and the
various non-toxic organic solvents. The compositions may be
presented in the form of tablets, pills, granules, powders, aqueous
solutions or suspensions, injectable solutions, elixirs or syrups,
and can contain one or more agents chosen from the group comprising
sweeteners, flavorings, colorings, or stabilizers in order to
obtain pharmaceutically acceptable preparations.
[0651] The choice of vehicle and the content of active substance in
the vehicle are generally determined in accordance with the
solubility and chemical properties of the product, the particular
mode of administration and the provisions to be observed in
pharmaceutical practice. For example, excipients such as lactose,
sodium citrate, calcium carbonate, dicalcium phosphate and
disintegrating agents such as starch, alginic acids and certain
complex silicates combined with lubricants such as magnesium
stearate, sodium lauryl sulfate and talc may be used for preparing
tablets. To prepare a capsule, it is advantageous to use lactose
and high molecular weight polyethylene glycols. When aqueous
suspensions are used they can contain emulsifying agents or agents
which facilitate suspension. Diluents such as sucrose, ethanol,
polyethylene glycol, propylene glycol, glycerol and chloroform or
mixtures thereof may also be used.
[0652] For parenteral administration, emulsions, suspensions or
solutions of the products according to the invention in vegetable
oil, for example sesame oil, groundnut oil or olive oil, or
aqueous-organic solutions such as water and propylene glycol,
injectable organic esters such as ethyl oleate, as well as sterile
aqueous solutions of the pharmaceutically acceptable salts, are
used. The solutions of the salts of the products according to the
invention are especially useful for administration by intramuscular
or subcutaneous injection. The aqueous solutions, also comprising
solutions of the salts in pure distilled water, may be used for
intravenous administration with the proviso that their pH is
suitably adjusted, that they are judiciously buffered and rendered
isotonic with a sufficient quantity of glucose or sodium chloride
and that they are sterilized by heating, irradiation or
microfiltration.
[0653] Suitable compositions containing the compounds of the
invention may be prepared by conventional means. For example,
compounds of the invention may be dissolved or suspended in a
suitable carrier for use in a nebulizer or a suspension or solution
aerosol, or may be absorbed or adsorbed onto a suitable solid
carrier for use in a dry powder inhaler.
[0654] Solid compositions for rectal administration include
suppositories formulated in accordance with known methods and
containing at least one compound of formula I.
[0655] The percentage of active ingredient in the compositions of
the invention may be varied, it being necessary that it should
constitute a proportion such that a suitable dosage shall be
obtained. Obviously, several unit dosage forms may be administered
at about the same time. The dose employed will be determined by the
physician, and depends upon the desired therapeutic effect, the
route of administration and the duration of the treatment, and the
condition of the patient. In the adult, the doses are generally
from about 0.001 to about 50, preferably about 0.001 to about 5,
mg/kg body weight per day by inhalation, from about 0.01 to about
100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body
weight per day by oral administration, and from about 0.001 to
about 10, preferably 0.01 to 1, mg/kg body weight per day by
intravenous administration. In each particular case, the doses will
be determined in accordance with the factors distinctive to the
subject to be treated, such as age, weight, general state of health
and other characteristics which can influence the efficacy of the
medicinal product.
[0656] The products according to the invention may be administered
as frequently as necessary in order to obtain the desired
therapeutic effect. Some patients may respond rapidly to a higher
or lower dose and may find much weaker maintenance doses adequate.
For other patients, it may be necessary to have long-term
treatments at the rate of 1 to 4 doses per day, in accordance with
the physiological requirements of each particular patient.
Generally, the active product may be administered orally 1 to 4
times per day. It goes without saying that, for other patients, it
will be necessary to prescribe not more than one or two doses per
day.
[0657] Compounds within the scope of the present invention exhibit
marked pharmacological activities according to tests described in
the literature which tests results are believed to correlate to
pharmacological activity in humans and other mammals. The following
pharmacological test results are typical characteristics of
compounds of the present invention.
1. Inhibitory Effects of Compounds on PDE Activity.
1.1 Preparation of PDE Isozymes from Pig Aorta.
[0658] The method is described fully by Souness and Scott (Biochem.
J., 291, 389-395, 1993). Briefly, aortas of freshly slaughtered
pigs are placed in Hepes buffered krebs solution, extraneous tissue
on the outside of the aorta is trimmed off and the endothelial
layer on the intimal surface is removed by rubbing with a cotton
swab. Smooth muscle strips are plucked from the aorta and 25 g are
homogenized using a Waring Blender in homogenization buffer (20 mM
Tris/HCl, pH 7.5, 2 mM MgCl.sub.2, 1 mM dithiothreitol, 5 mM EDTA
and 1 mg/ml aprotinin). The homogenate is further homogenized with
an Ultra-Turrax and then centrifuged (3000 g, 5 minutes). The
supernatant is removed, and the pellet is sonicated in a small
volume (25-50 mL) of homogenization buffer. The sonicate is
centrifuged (3000 g, 5 minutes), the pellet discarded and the
supernatant is pooled with that from the first centrifugation step.
The pooled supernatants are centrifuged (100,000 g, 1 hour), the
resulting high-speed supernatant is filtered (0.45 .mu.m) and then
applied to a DEAE-trisacryl (IBF) column (50.times.2.44 cm)
preequilibrated in column buffer (20 mM Tris/HCl, pH 7.5, 2 mM
MgCl.sub.2, 1 mM dithiothreitol, 20 .mu.M TLCK). The column is
washed with 500-700 mL of column buffer and PDE activities are
eluted with 2 successive linear gradients of NaCl (0-200 mM, 400 mL
and 200-300 mM, 200 mL) in column buffer. The fractions in the
separated peaks of activity corresponding to the different PDE
isozymes are pooled and stored at -20.degree. C. in 30% (v/v)
ethylene glycol.
1.2 Measurement of PDE Activity.
[0659] PDE activity is determined by the two-step radioisotopic
method of Thompson et al., Adv. Cyclic Nucl. Res., 10, 69-92
(1979). The reaction mixture contains 20 mM Tris/HCl (pH 8.0), 10
mM MgCl.sub.2, 4 mM 2-mercaptoethanol, 0.2 mM EGTA and 0.05 mg of
BSA/mL. The concentration of substrate is 1 .mu.M.
[0660] The IC.sub.50 values for the compounds examined are
determined from concentration-response curves in which
concentrations range from 0.1 nM -to 40 .mu.M.
1.3 Results.
[0661] Compounds within the scope of the invention produce up to
about 50% inhibition of porcine aortic cyclic AMP-specific
phosphodiesterase (PDE IV) at concentrations from about 10.sup.-9 M
up to about 10.sup.-5 M, preferably from about 10.sup.-9 up to
about 10.sup.-8 M. The compounds of the invention are from about
10,000-fold to about 50-fold more selective for cyclic AMP
phosphodiesterase IV than cyclic nucleotide phosphodiesterase types
I, III or V.
2. Inhibitory Effects of Compounds on Eosinophil Superoxide
Generation.
2.1 Preparation of Guinea-Pig Eosinophils.
[0662] The method is described fully in Souness et al (Biochem.
Pharmacol. 42, 937-945, 1991).
2.2 Measurement of Superoxide Generation.
[0663] Superoxide anion generation is determined as the superoxide
dismutase inhibitable reduction of p-iodonitrotetrazolium violet
(INTV) (Souness et al, Biochem. Pharmacol. 42, 937-945, 1991).
Briefly, cells are incubated in 96 well microtitre plates in 0.25
mL of Hanks buffered salt solution (HBSS) containing INTV (0.5
mg/mL) plus other additions for 45 minutes at 37.degree. C. The
cells are then centrifuged at 500 g for 5 minutes and the
supernatant is aspirated. The pellet is solubilized by incubation
overnight at room temperature in DMSO containing 0.6 M HCl and the
absorbance of the reduced dye is measured at 492 nm. The results
are expressed in absorbance units.
2.3 Results.
[0664] Compounds within the scope of the invention produce up to
about 50% inhibition of superoxide generation from eosinophiis
harvested from the peritoneal cavities of guinea-pigs at
concentrations from about 10.sup.-8 M to about 10.sup.-5 M,
preferably from about 10.sup.-8 M up to about 10.sup.-7 M.
3. Effects of Compounds on Tracheal Smooth Muscle
Contractility.
3.1 Preparation of Guinea-Pig Tracheal Strips and Contractility
Studies.
[0665] Organ bath studies are performed essentially according to
Tomkinson et al (Br. J. Pharmacol. 108 57-61, 1993). Briefly,
tracheas are removed from male, Dunkin-Hartley guinea-pigs (400-500
g) are placed in Krebs Ringer Bicarbonate (KRB) solution and fat
and connective tissue are dissected away. Epithelium is removed by
mechanical abrasion and the tracheal strips are suspended under an
applied load, such that they are at their optimal length, derived
from preliminary experiments, and equilibrated for 90 minutes,
washing at 15 minute intervals.
[0666] Cumulative concentration-response curves to spasmogens are
constructed and the concentration producing 30% of maximum
contraction (EC30) is determined by computerized linear regression
analysis. For relaxant studies, tissues are contracted with
spasmogens (such as methacholine, histamine, leukotriene D.sub.4)
(EC.sub.30) and when the response plateaus, PDE inhibitors (10
nM-100 .mu.M) or vehicle control (DMSO) are added cumulatively. The
concentration of relaxant producing 50% inhibition (IC.sub.50) of
the agonist response is calculated by linear regression.
Alternatively, PDE inhibitors, as above, may be added to tissues
under basal tone and the concentration producing 50% relaxation
(EC.sub.50) calculated as above.
3.2 Results.
[0667] Compounds within the scope of the invention produce about
50% relaxation of guinea-pig tracheal strips (under basal tone or
which had been contracted by treatment with spasmogens) at
concentrations from about 5.times.10.sup.-9 M to about 10.sup.-5 M,
preferably from about 5.times.10.sup.-9 M to about 10.sup.-7 M.
4. In Vivo Bronchodilator Actions of Compounds.
4.1 Measurement of Bronchodilatation.
[0668] Bronchorelaxant activity is measured in in vivo tests in the
anaesthetized guinea-pig or rat according to the method described
in Underwood et al., Pulm. Pharmacol. 5, 203-212, (1992) in which
the effects on bronchospasm induced by histamine (or other
spasmogens such as methacholine or leukotriene D.sub.4) is
determined. Nebulized aerosols generated from aqueous solutions of
compounds of the invention are each administered for one minute to
the anaesthetized animals. Alternatively, dry powder formulations
made up from compounds of the invention and lactose are blown into
the airways of the anaesthetized guinea-pigs or rats by the method
described in Underwood et al., J. Pharm. Methods, 26, 203-210,
1991.
4.2 Results.
[0669] Compounds within the scope of the invention produce from
about 30% up to about 90% decrease in bronchospasm when
administered at effective doses of about 4 to about 1000 .mu.g/kg,
preferably about 4 to about 50 .mu.g/kg, without any significant
effect on blood pressure.
5. In Vivo Actions of Compounds on Antigen (Ovalbamin)-Induced
Eosinophilia in Guinea-Pigs.
5.1 Treatment of Animals and Measurement of Eosinophil Numbers.
[0670] Male Dunkin-Hartley guinea-pigs weighing 200-250 g are
sensitized using 10 .mu.g ovalbumin in 1 mL of a 100 mg/mL
suspension of aluminium hydroxide, i.p.
[0671] Sensitized guinea-pigs are anaesthetised and dry powder
formulations of PDE inhibitors or lactose are administered (i.t.)
into the airways. In some cases PDE inhibitors are administered
orally. 23 hours later the procedure is repeated and 60 minutes
later the guinea-pigs are challenged with nebulised saline or
ovalbumin (1% in saline) for 15 seconds. 24 hours after challenge
the guinea-pigs are killed and the lungs are lavaged with warm
saline. Total and differential cell counts are made.
5.2 Results.
[0672] Compounds within the scope of the invention, administered
one hour before challenge, inhibit by at least 50%
ovalbumin-induced eosinophilia in guinea-pigs which is measured 24
hours after challenge, at oral doses of about 1 to about 50 mg/kg,
preferably about 1 to 10 mg/kg and inhaled doses of about 4 to 1000
.mu.g/kg, preferably 4 to 50 .mu.g/kg.
6 In Vitro Inhibitory Effects on TNF-Alpha Release by Human
Monocytes.
[0673] The effects of compounds on TNF-alpha production by human
peripheral blood monocytes (PBMs) are examined as follows:
6.1. Preparation of Blood Leukocytes.
[0674] Blood is drawn from normal donors, mixed with dextran, and
the erythrocytes allowed to sediment for 35 minutes at 37.degree.
C. Leukocytes are fractionated by centrifugation through a
discontinuous (18, 20 and 22%) metrizamide gradient. The
mononuclear cell fraction comprising 30-40% PBMs is suspended in
HBSS and stored at 4.degree. C. until use.
6.2. Measurement of TNF-Alpha.
[0675] Cells from the PBM-rich metrizamide fraction are spun down
(200 g for 10 minutes at 20.degree. C.), resuspended at 106 PBMs/mL
of medium; RPMI 1640 containing 1% v/v FCS, 50 U/mL penicillin and
50 mg/mL streptomycin (Gibco, U.K.), then plated out in 96 well
plates at 2.times.10.sup.5 cells/well. The medium (200 .mu.L) is
changed to remove any non-adherent cells and the remaining,
adherent PBMs left in the incubator overnight (18 hours). One hour
prior to challenge, the medium is changed to that containing
compound for test or drug vehicle. Control treatments and compounds
for test are assayed in quadruplicate wells. Compounds are tested
within the concentration range of 3.times.10.sup.-10 M to
3.times.10.sup.-6 M. Medium (50 .mu.L) with or without 10 ng/ml LPS
(E. Coli, 055 B5 from Sigma, U.K.) is then added. The incubation is
then continued for a further 4 hours. Cell supernatants are removed
for storage at -20.degree. C.
[0676] TNFa levels in cell supernatants are quantified using a
standard sandwich ELISA technique. ELISA plates (Costar, U.K.) are
coated overnight at 4.degree. C. with 3 mg/mL polyclonal goat
anti-human TNF-alpha antibody (British Biotechnology, U.K.) in pH
9.9 bicarbonate buffer. Rabbit polyclonal anti-human TNF-alpha
antiserum (Janssen Biochimicha, Belgium) at 1/500 dilution is used
as the second antibody and polyclonal goat anti-rabbit IgG
horseradish peroxidase (Calbiochem, U.S.A.) at 1/8000 dilution is
used as the detection antibody. Color development is measured by
absorbance at 450 nm using a Titek plate reader.
[0677] TNF-alpha levels are calculated by interpolation from a
standard curve using recombinant human TNF-alpha (British
Biotechnology U.K.)(0.125-8 ng/mL). Data (log-conc. vs. log-resp)
are fitted by linear regression (p>0.99) using a Multicalc
(Wallac Pharmacia, U.K.) software program. Basal TNF-alpha levels
are less than 100 pg/mL whilst LPS stimulation of the PBMs
increases TNF-alpha levels to 3-10 ng/mL.
6.3 Results.
[0678] Compounds within the scope of the invention produce 50%
inhibition of LPS-induced TNF-alpha release from human PBMs at
concentrations within the range of about 10.sup.-9 M to about
10.sup.-6 M., preferably about 10.sup.-9 M to about 10.sup.-8
M.
7. Inhibitory Effects of Compounds on Antigen-Induced
Bronchoconstriction in the Conscious Guinea-Pig.
7.1. Sensitisation of Guinea-Pigs and Measurement of
Antigen-Induced Bronchoconstriction.
[0679] Male, Dunkin-Hartley guinea-pigs (550-700 g) are sensitized
as above. Specific airways resistance (SRaw) is measured in
conscious animals by whole body plethysmography using a variation
of the method of Pennock et al., (J. Appl. Physiol., 46, 399,
1979). Test compounds or vehicle (lactose carrier) are instilled
into the airways as dry powders through a metal gavage needle. 30
minutes later, the animals are injected with mepyramine (30 mg/kg
i.p.) to prevent anaphylactic collapse and placed into the
plethysmography chambers where SRaw is determined at 1 minute
intervals. Resting SRaw is then determined. Animals are challenged
with an aerosol of ovalbumin and SRaw is determined every 5 minutes
for 15 minutes.
7.2. Results.
[0680] Compounds within the scope of the invention inhibit
antigen-induced bronchoconstriction by up to 80% at doses of
between about 1 to about 1000 .mu.g/kg (i.t.), preferably about 1
to about 20 .mu.g/kg (i.t.).
8. Inhibitory Effects of Compounds on Serum TNF-Alpha Levels in
LPS-Challenged Mice.
8.1. Treatment of Animals and Measurement of Murine TNF-Alpha.
[0681] Female Balb/c mice (age 6-8 weeks, weight 20-22 g from
Charles River, U.K.) in groups of five or more animals are dosed
p.o. with compounds suspended in 1.5% (w/v) carboxymethyl cellulose
then challenged after a minimum period of 30 min with 30 mg of LPS
i.p. After 90 min the animals are killed by CO.sub.2 asphyxiation
and bled by cardiac puncture. Blood is allowed to clot at 4.degree.
C., centrifuged (12,000 g for 5 minutes) and serum taken for
TNF-alpha analysis.
[0682] TNF-alpha levels are measured using a commercially available
murine TNF-alpha ELISA kit, purchased from Genzyme (Cat. no.
1509.00), as recommended by the manufacturer. Values for TNF-alpha
are calculated from a recombinant murine TNF-alpha standard
curve.
8.2 Results.
[0683] Compounds within the scope of the invention inhibit
LPS-induced serum TN F-alpha at doses between about 10 and about
10,000 mg/kg, preferably about 10 to about 250 .mu.g/kg.
[0684] The value of the compounds of the invention is enhanced by
their very low mammalian toxicity levels.
[0685] The following Composition Examples illustrate pharmaceutical
compositions according to the present invention.
COMPOSITION EXAMPLE 1
[0686]
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4methoxy-benz-
amide (1.0 g) (mean particle size 3.5 microns) and lactose (99 g)
(mean particle size 72 microns) are blended together for 30 minutes
in a mechanical shaker/mixer. The resulting blend is filled, to a
fill weight of 25 mg, into No. 3 hard gelatine capsules, to give a
product suitable for use, for example, with a dry powder
inhaler.
COMPOSITION EXAMPLE 2
[0687] No. 2 size gelatin capsules each containing:--
TABLE-US-00001 N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6- 20 mg
fluoro-4methoxybenzamide lactose 100 mg starch 60 mg dextrin 40 mg
magnesium stearate 1 mg
are prepared in accordance with the usual procedure.
COMPOSITION EXAMPLE 3
[0688]
5-Cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide
(1.0 g) (mean particle size 3.5 microns) and lactose (99 g) (mean
particle size 72 microns) are blended together for 30 minutes in a
mechanical shaker/mixer. The resulting blend is filled, to a fill
weight of 25 mg, into No. 3 hard gelatine capsules, to give a
product suitable for use, for example, with a dry powder
inhaler.
COMPOSITION EXAMPLE 4
[0689] No. 2 size gelatin capsules each containing:--
TABLE-US-00002 5-cyclopentyloxy-N-(3,5-dichloro-pyrid-4-yl)- 20 mg
6-methoxynicotinamide lactose 100 mg starch 60 mg dextrin 40 mg
magnesium stearate 1 mg
are prepared in accordance with the usual procedure.
[0690] Compositions similar to those above are prepared from other
compounds of formula I.
* * * * *