Cytokine production and tyrosine kinase inhibitors

Details Cytokine production and tyrosine kinase inhibitors Cytokine production and tyrosine kinase inhibitors

2001-03-27

2003-02-11

Pryor, Alton (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C568S303000, C568S306000, C568S309000, C568S312000, C568S313000, C568S326000

Reexamination Certificate

active

06518316

ABSTRACT:

The present invention relates to compounds useful as cytokine production inhibitors, to the preparation of these compounds and to pharmaceutical and veterinary compositions containing them.
It has now been found that fermentation of a strain of the fungus
Cladosporium
cf.
cladosporioides
in a nutrient medium produces biologically active novel compounds. Biologically active derivatives of those compounds, which are also novel, can be produced by standard synthetic procedures.
The present invention therefore provides a compound which is a benzofluoranthene derivative of formula (I)
wherein
X is ═O, ═N—OR
6
,
NHR or
OH wherein R
6
is H or C
1
-C
6
alkyl, bond a is oriented
or
and R is H, C
1
-C
6
alkyl which is unsubstituted or substituted by C
6
-C
10
aryl, or C
3
-C
6
cycloalkyl;
is a bond and
and
are not bonds or, when X is ═O,
and
are both bonds and
is not a bond;
R
1
and R
2
, which are the same or different, are H or a halogen;
R
3
and R
4
, which are the same or different, are H, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, a heterocyclic group or an aromatic group;
bond e is oriented
or
; and
R
5
is C
1
-C
6
alkyl;
or formula (Ib):
or formula (II)
or formula (III)
or a stereoisomer of a said derivative; or a pharmaceutically acceptable salt or ester of a said derivative or stereoisomer.
A C
1
-C
6
alkyl group is straight or branched and is typically C
1
-C
4
alkyl, such as methyl, ethyl, i-propyl, n-propyl, s-butyl, n-butyl or t-butyl. A C
3
-C
6
cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A halogen is F, Cl, Br or I. Preferably it is Cl, Br or I.
An aromatic group is typically C
6
-C
10
aryl. A C
6
-C
10
aryl group may be, for instance, phenyl or naphthyl.
A heterocyclic group is a saturated or unsaturated 5- or 6-membered heterocyclic ring which contains one or more heteroatoms selected from O, N and S and which is optionally fused to a benzene ring or to a second 5- or 6-membered heterocyclic ring. The term heterocyclic group also embraces a heterocyclyl-C
1
-C
6
alkyl group namely a saturated or unsaturated heterocyclic ring as defined above which is linked via a C
1
-C
6
alkylene chain to the point of connection in formula (1).
A saturated heterocyclic ring may be, for example, a tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, morpholine or piperazine group. An unsaturated heterocyclic group may be, for example, a furan, thiophene, indole, isoindole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, quinoline, quinoxaline, isoquinoline, thienopyrazine, pyran, pyrimidine, pyridazine, pyrazine, purine or triazine group. A heterocycyl-C
1
-C
6
alkyl group may be, for example, a furfuryl, pyridylmethyl, pyrrolidinylmethyl or tetrahydropyranylmethyl group.
The heterocyclic group may be unsubstituted or substituted by one or more substituents, for instance one or more substituents selected from OH, halogen C
1
-C
6
alkyl which is unsubstituted or substituted, for example by halogen, such as CF
3
, C
1
-C
6
alkoxy, nitro and an amino group N(R
10
R
11
) as defined above.
In a first aspect formula (I) takes the following definitions;
X is ═O; R
1
and R
2
are both H,
is a bond and
and
are not bonds; R
3
and R
4
are both H; and R
5
is C
1
-C
6
alkyl, preferably CH
3
.
In a second aspect of formula (I)
X is
NHR as defined above; R
1
and R
2
are H;
is a bond and
and
are not bonds; R
3
and R
4
are H; and R
5
is C
1
-C
6
alkyl, preferably methyl.
In a third aspect of formula (I)
X is ═O; R
1
and R
2
, which are the same or different, are H or halogen provided they are both H when R
3
is other than H;
is a bond and
and
are not bonds; R
3
is H, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, a heterocyclic group or an aromatic group; R
4
is H and R
5
is C
1
-C
6
alkyl, preferably CH
3
. Preferably R
3
is C
1
-C
6
alkyl, more preferably CH
3
.
In a fourth aspect of formula (I)
X is ═O;
is a bond and
and
are not bonds; R
1
, R
2
and R
3
are H; R
4
is C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, a heterocyclic group or an aromatic group; and R
5
is C
1
-C
6
alkyl, preferably CH
3
, C
2
H
5
OR C
3
H
7
. Preferably R
4
is C
1
-C
6
alkyl, more preferably CH
3
.
In a fifth aspect of formula (I)
X is ═O or
OH as defined above;
and
are bonds and
is not a bond; R
1
, R
2
, R
3
and R
4
are H; and R
5
is C
1
-C
6
alkyl, preferably CH
3
.
In formulae (I) and (Ib) bond e at position C
8
is preferably on the same side of the molecule as the group at position C
7
, (OR
5
or OCH
3
respectively).
In one preferred aspect of the invention the compound is of formula (I′)
wherein bond f is oriented
or
; or is a derivative of formula (II) or (III) as defined above.
In a more preferred aspect the compound of formula (I) is of formula (Ia):
The stereochemical configuration shown in formulae (I), (I′),(Ia) and (Ib) as depicted above is relative, not absolute. The bonds depicted as being oriented
at C
6
, C
7
and C
8
could therefore be
instead whilst those shown as
could be oriented
instead. Diastereoisomers of these structures represent a further aspect of the invention.
The substitution patterns of preferred compounds within formula (I) are shown in the following table:
Compound
R
1
R
2
R
3
e
OR
4
R
5
Bond d or bonds b and c present?
 Ia
═O
H
H
H
Me
d

 2
—OH
H
H
H
Me
d

 3
═O
H
H
H
Me
b and c

 4
═O
H
H
Me
Me
d

 5
H
H
H
Me
d

 6
H
H
H
Me
d

 7
═N—OH
H
H
H
Me
d

 8
═O
Cl
H
H
Me
d

 9
═O
H
H
H
Me
d

10
═O
H
H
H
Me
d

11
═O
H
H
H
Me
d

10a
═O
H
H
H
Me
d

11a
═O
H
H
H
Me
d

12
═O
Br
Br
H
Me
d

13
═O
H
Br
H
Me
d
Some of these compounds are:
3-Cyclopropylamino-7-methoxy-1,2,3,6b, 7,8-hexahydrobenzo[d]fluoranthen-4,8,9-triol (compound 5);
3-Benzylamino-7-methoxy-1,2,3,6b,7,8-hexahydro-benzo[j]fluoranthene-4,8,9-triol (compound 6);
4,8,9-Trihydroxy-7-methoxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluoranthen-3-one oxime (compound 7);
5-Chloro-4,8,9-trihydroxy-7-methoxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluoranthen-3-one (compound 8);
4,9-Dihydro-7-methoxy-8-propoxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluoranthen-3-one (compound 9);
8-Ethoxy-4,9-dihydroxy-7-methoxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluoranthen-3-one (compound 10); and
4,9-Dihydroxy-7,8-dimethoxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluroanthen-3-one (compound 11).
The compounds of formulae (Ia), (Ib), (II) and (III) above have been isolated from a fungus which has been designated Culture Collection Number X20700.
This is a fungus which was isolated directly from a dead insect which had been infected by a member of the entomogenous fungus genus
Hypocrella Sacc
. The insect was collected from tropical rainforest in Thailand during 1989. A subculture of the isolated fungus was deposited by Xenova Discovery Limited of 545 Ipswich Road, Slough, Berkshire, SL1 4EQ, United Kingdom under the Budapest Treaty at the Centraalbureau voor Schimmelcultures, Baarn, The Netherlands, on Nov. 25, 1997 under reference X15/81/700. It was assigned the accession number CBS 100220.
The fungal strain CBS 100220 is a hyphomycete assigned to the widespread genus Cladosporium Link ex Fr. and no sexually reproducing state was observed in culture. Cultures incubated at 24° C. had relatively slowly extending mycelium which attained 6-7 mm diameter after 7d on both 2% MEA and potato/carrot (PCA) agar. No growth was observed on these media at 37° C. The recipes for MEA and PCA are given in Smith, D. & Onions, A. H. S., 1983; The Preservation and Maintenance of Living Fungi. Farnham Royal: CABI (using 20 g not 2 g of grated carrot).
Macroscopic characteristics were as follows:
Characters
MEA 24° C.
PCA 24° C.
Mycelial
Abundant
Low sparse
texture
dense
aerial
aerial
mycelium
mounds
Main
Olivaceous
Grey
mycelial
buff to
olivaceous
colours*
grey
to sepia
above
olivaceous
Main
Olivaceous
Se

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