Cytokine production inhibitors

Details Cytokine production inhibitors Cytokine production inhibitors

1999-04-16

2001-03-06

Owens, Amelia (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S292000, C549S293000

Reexamination Certificate

active

06197811

ABSTRACT:

The present invention relates to 5,6-dihydro-&agr;-pyrones useful as cytokine production inhibitors, to the preparation of these compounds and to pharmaceutical and veterinary compositions containing them.
It has been found that a series of synthetic derivatives of phomalactone, a known compound obtainable inter alia by fermentation of a strain of the fungus Phomopsis sp, have activity as inhibitors of cytokine production.
Accordingly the present invention provides a compound which is a 5,6-dihydro-&agr;-pyrone of formula (I):
wherein bond a is oriented either
or
;
X is O or NH;
R
1
is selected from
a group R
3
(O)C— wherein R
3
is either (i) a group of formula R
4
—CH═CH— wherein R
4
is C
1
-C
20
alkyl, C
2
-C
20
alkenyl, an aryl group or a 5- or 6-membered unsaturated heterocyclic ring containing one or two O, N
or S atoms, (ii) C
2
-C
20
alkyl, or (iii), an aryl group or a fused ring substituent of formula (1) or (2):
 wherein each of R′ and R″, which are the same or different and may occupy any position of ring a or ring b of the fused ring system, is H or C
1
-C
6
alkyl;
a group ArCH
2
— wherein Ar is an aryl group; and
a group R
5
O—CH
2
— wherein R
5
is C
1
-C
6
alkyl optionally interrupted by one or two O atoms; and
R
2
is CH
3
or, when R
1
is a group of formula (A) as defined below, R
2
is R
6
OOC— or R
6
NOC— wherein R
6
is C
1
-C
6
alkyl; or a C
1
-C
6
pharmaceutically or veterinarily acceptable salt or ester thereof; with the exception of compounds wherein bond a is oriented
, X is O and R
1
is a group of formula (A):
 wherein R
11
and R
21
are H when R
2
in formula (I) is CO
2
H or CH
3
, or one of R
11
and R
21
is H and the other is OH when R
2
in formula (I) is CO
2
H.
In one aspect of the invention the 5,6-dihydro-&agr;-pyrone has the formula (Ia):
wherein
X is O and R
1
is a group R
3
(O)C—, ArCH
2
— or R
5
O—CH
2
— as defined above, or X is NH and R
1
is a group R
3
(O)C— or ArCH
2
— as defined above.
In one embodiment of compounds of formula (Ia), X is O and R
1
is selected from:
a group R
3
(O)C— wherein R
3
is either (a) a group of formula R
4
—CH═CH— wherein R
4
is naphthyl, furanyl or a phenyl group which is unsubstituted or substituted by C
1
-C
6
alkyl, halo, nitro or hydroxy, (b) a phenyl group which is unsubstituted or para-substitued by C
1
-C
6
alkyl or by phenyl, which phenyl is in turn unsubstituted or substituted by C
1
-C
6
alkyl or OR
7
in which R
7
is C
2
-C
10
alkyl or —C(O)CH
3
, or (c) a substituent of formula (1a), (2a) or (2b):
 and
a group ArCH
2
— wherein Ar is a phenyl group unsubstituted or para-substituted by phenyl, which phenyl is in turn unsubstituted or mono-substituted by C
1
-C
6
alkyl or OR
7
as defined above;
or X is NH and R
1
is a group R
3
(O)C— wherein R
3
is a phenyl group para-substituted by phenyl, which phenyl is in turn unsubstituted or substituted by C
1
-C
6
alkyl or OR
7
as defined above.
In another embodiment of formula (Ia) X is O, R
1
is R
4
—CH═CH—(O)C— wherein R
4
is C
2
-C
20
alkenyl and R
2
is R
6
OOC— wherein R
6
is C
1
-C
6
alkyl. A particularly preferred example of C
2
-C
20
alkenyl in this embodiment is the group —CH(CH
3
)═CH—CH(CH
3
)—(CH
2
)
5
—CH
3
. Preferred examples of R
6
in this embodiment are n-propyl and n-butyl.
In a further embodiment of formula (Ia) X is O and R
1
is either a group R
3
(O)C— wherein R
3
is a group of formula (2) as defined above or a group ArCH
2
— wherein Ar is biphenyl.
A preferred group of compounds are those wherein, in formula (Ia), X is O and R
1
is selected from:
a group R
3
(O)C— wherein R
3
is a group of formula (1a), (2a) or (2b) as defined above, a biphenyl, 4-ethyl-biphenyl, 4-pentyl-phenyl or phenylmethyl group, or a group of formula R
4
—CH═CH— wherein R
4
is a naphthyl, furanyl or 3-methylphenyl group; and
a group PhCH
2
wherein Ph is an unsubstituted phenyl group;
or X is NH and R
1
is a group R
3
(O)C wherein R
3
is a biphenyl group.
In another aspect of the invention the 5,6-dihydro-&agr;-pyrone has the formula (Ib):
wherein
X is O and R
1
is a group R
3
(O)C— as defined above, or X is —NH and R
1
is a group R
3
(O)C— or ArCH
2
— as defined above.
In one embodiment of compounds of formula (Ib), X is O and R
1
is a group R
3
(O)C— wherein R
3
is a phenyl group which is unsubstituted or substituted by C
1
-C
6
alkyl or OR
7
wherein R
7
is —C(O)CH
3
, or X is NH and R
1
is a group R
3
(O)C— wherein R
3
is a phenyl group which is unsubstituted or substituted by phenyl, which phenyl is in turn unsubstituted or substituted by C
1
-C
6
alkyl or OR
7
as defined above, or R
3
is a substituent of formula (1b):
A preferred group of compounds are those wherein, in formula (Ib), X is O and R
1
is a group R
3
(O)C— wherein R
3
is phenyl, or X is NH and R
1
is a group R
3
(O)C— wherein R
3
is biphenyl or a group of formula (1b) as defined above.
An alkyl or alkenyl group may be straight or branched. A C
1
-C
6
alkyl group may be, for example, C
1
-C
4
alkyl such as methyl, ethyl, i-propyl, n-propyl, i-butyl, s-butyl or t-butyl. A C
1
-C
20
or C
2
-C
20
alkyl group is typically a C
6
-C
18
, or C
10
-C
15
, alkyl group. A C
2
-C
20
alkenyl group is typically a C
6
-C
18
, or C
10
-C
15
, alkenyl group. An alkoxy group may be straight or branched and may be, for instance, C
1
-C
10
alkoxy, for instance C
2
-C
10
alkoxy or C
1
-C
6
alkoxy.
An aryl group is typically a C
6
-C
12
carbocyclic group containing one or two rings. When two rings are present they may be fused or bonded together. The aryl group is unsubstituted or substituted by one or more substituents. Suitable substituents include alkyl, alkoxy, OCOR
7
wherein R
7
is alkyl, nitro, hydroxy, and halo groups. Preferred examples of an aryl group are phenyl, naphthyl and biphenyl, each of which is unsubstituted or substituted as defined above.
When the aryl group is phenyl it is typically unsubstituted or substituted by one, two or three substituents selected from C
1
-C
6
alkyl, halo, nitro and hydroxy. C
1
-C
6
alkyl is preferably methyl or ethyl. Halo is preferably bromo or chloro. When R
4
is phenyl it is typically unsubstituted or substituted by 2-methyl, 3-bromo, 4-bromo, 2,3,4-trichloro, 2,3,4-trinitro or 2,3,4-hydroxy.
When, in option (iii) for R
3
the aryl group is phenyl it is typically either (a) unsubstituted, or (b) substituted by C
1
-C
6
alkyl or by phenyl which is in turn unsubstituted or substituted by C
1
-C
6
alkyl. A phenyl group which is substituted by a C
1
-C
6
alkyl or phenyl substituent is typically mono-substituted. The said substituent may occupy the 2-, 3- or 4-position of the phenyl ring, typically the 3- or 4-position and preferably the 4-position. A phenyl group mono-substituted at the 4-position by a phenyl substituent is a p-biphenyl group. When the phenyl substituent is in turn substituted by C
1
-C
6
alkyl, the alkyl group may occupy the 2-, 3- or 4- position of the phenyl substituent, preferably the 3- or 4-position and more preferably the 4-position.
When the aryl group is naphthyl it is preferably a group of formula (3):
wherein each of R′ and R″, which are the same or different and may occupy any position of ring a or ring b of the naphthyl ring system, is H or C
1
-C
6
alkyl.
When the aryl group is biphenyl it is typically unsubstituted or substituted in the second phenyl ring by C
1
-C
6
alkyl or a group —OCOR
7
wherein R
7
is C
1
-C
10
alkyl. When R
3
is biphenyl the biphenyl group is preferably unsubstituted or substituted at the 4′-position by C
1
-C
6
alkyl or —OCOR
7
as defined above.
When R
3
is a C
2
-C
20
alkyl group it is, for example, straight or branched chain C
6
-C
18
alkyl, suitably straight or branched C
10
-C
15
alkyl, preferably straight chain C
10
-C
15
alkyl. When R
4
is a C
1
-C
20
alkyl group it is, for example, straight or branched C
6
-C
15
, or C
6
-C
12
alkyl. Preferably it is a straight chain alkyl group.
When R
4
is a C
2
-C
20
alkenyl group it is, for exampl

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