Anti-inflammatory agents

Details Anti-inflammatory agents Anti-inflammatory agents

1999-07-21

2001-10-23

Raymond, Richard L. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S438000, C514S445000, C514S542000, C514S551000, C546S221000, C549S065000, C549S076000, C560S041000, C560S169000

Reexamination Certificate

active

06306881

ABSTRACT:

This application is a 371 of PCT/GB99/00284, filed Jan. 27, 1999.
The present invention relates to the use of certain esters and thioesters for the treatment of diseases responsive to inhibition of intracellular leukotriene-A
4
hydrolase activity.
BACKGROUND TO THE INVENTION
The leukotriene cascade of arachadonic acid is a key mechanism in many inflammatory and allergic disease states. The dihydroxy fatty acid leukotriene B
4
(LTB
4
), produced by this cascade, is a key pro-inflammatory mediator. LTB
4
stimulates adhesion of circulating neutrophils to vascular endothelium, directs their migration toward sites of inflammation, and induces secretion of further inflammatory mediators. (For reviews see R. A. Lewis et al, N. Engl. J. Med. 1990, 323, 645-655 and M. -Q. Zhang, Curr. Med. Chem. 1997, 4, 67-78.) Leukotriene-A
4
hydrolase (LTA
4
-hydrolase) (EC 3.3.2.6) is an enzyme that catalyses the final and rate limiting step in the synthesis of LTB
4
. Inhibition of LTA
4
hydrolase selectively blocks the biosynthesis of LTB
4
which may provide an advantage over current inhibitors, such as those of 5-lipoxygenase, that block earlier in the leukotriene cascade and as a result are less selective.
Disease states associated with elevated levels of LTB
4
, and which are therefore considered to be responsive to inhibition of intracellular leukotriene-A
4
hydrolase activity include asthma, inflammatory bowel disease, psoriasis and arthritis.
Peptidomimetic compounds, such as bestatin, captopril and kelatorphan exhibit LTA
4
hydrolase inhibitory activity against isolated enzyme (T. D. Penning et al, Biorg. Med. Chem. Lett., 1995, 5, p2517-2522). However, these compounds are unable to effectively penetrate cells and hence have little anti-inflammatory activity. There is therefore a need in the art for compounds which are capable of inhibiting intracellular LTA
4
hydrolase activity.
BRIEF DESCRIPTION OF THE INVENTION
This invention is based on the finding that certain esters and thioesters are capable of inhibiting intracellular LTA
4
hydrolase activity, resulting in attenuation of LTB
4
biosynthesis. Those esters and thioesters are therefore of use for the treatment of diseases responsive to such inhibiton, for example inflammatory and allergic conditions including asthma, rheumatoid arthritis, osteoarthritis, ulcerative colitis, contact and atopic dermatitis, psoriasis, inflammatory bowel disease and Crohn's disease.
In our earlier international patent application PCT/GB97/02398 (WO 98/11063), there is disclosed the use of the same class of esters and thioesters as inhibitors of the proliferation of rapidly dividing cells, and thus as agents for the treatment, inter alia, of cancer. However, the present utility as inhibitors of LTA
4
hydrolase is unrelated to and not predictable from the teaching of that application.
A few patent publications (WO 92/09563, U.S. Pat. No. 5,183,900, U.S. Pat. No. 5,270,326, EP-A-0489577, EP-A-0489579, WO 93/09097, WO 93/24449, WO 94/25434, WO 94/25435, WO 95/04033, WO 95/19965, and WO 95/22966) include within their generic disclosure carboxylate ester compounds having matrix metalloproteinase inhibitory activity. In accordance with the present invention, such compounds are now recognised to have LTA
4
hydrolase activity, but that activity is not suggested by, or predictable from, those publications.
WO 95/04033 discloses N
4
-hydroxy-N
1
-(1-(S)-methoxycarbonyl-2,2-dimethylpropyl)-2-(R)-(4-chlorophenylpropyl)succinamide as an intermediate for the preparation of the corresponding methylamide MMP inhibitor. In addition, Int.
J. Pept. Protein Res
. (1996), 48(2). 148-155 discloses the compound
Ph-CH
2
CH(CO-IIe-OtBu)CH
2
CONHOH
as an intermediate in the preparation of compounds which are inhibitors of neurotensin-degrading enzymes. However, those two appear to be the only specific known carboxylate ester compounds of the kind with which this invention is concerned.
DETAILED DESCRIPTION OF THE INVENTION
In its broadest aspect, the present invention provides a method for treatment of mammals suffering diseases responsive to inhibition of intracellular leukotriene-A
4
hydroiase activity, comprising administering to the mammal suffering such disease an amount of a compound of general formula (I) or a pharmaceutically acceptable salt hydrate or solvate thereof sufficient to inhibit such activity:
wherein
R is hydrogen or (C
1
-C
6
)alkyl;
R
1
is hydrogen;
(C
1
-C
6
)alkyl;
(C
2
-C
6
)alkenyl;
phenyl or substituted phenyl;
phenyl (C
1
-C
6
)alkyl or substituted phenyl(C
1
-C
6
)alkyl;
phenyl (C
2
-C
6
)alkenyl or substituted phenyl(C
2
-C
6
)alkenyl
heterocyclyl or substituted heterocyclyl;
heterocyclyl(C
1
-C
6
)alkyl or substituted heterocyclyl(C
1
-C
6
)alkyl;
a group BSO
n
A- wherein n is 0, 1 or 2 and B is hydrogen or a (C
1
-C
6
) alkyl, phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C
1
-C
6
)alkyl, phenacyl or substituted phenacyl group, and A represents (C
1
-C
6
)alkylene;
hydroxy or (C
1
-C
6
)alkoxy;
amino, protected amino, acylamino, (C
1
-C
6
)alkylamino or di-(C
1
-C
6
)alkylamino;
mercapto or (C
1
-C
6
)alkylthio;
amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, mercapto(C
1
-C
6
)alkyl or carboxy(C
1
-C
6
) alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated;
lower alkyl substituted by carbamoyl, mono(C
1
-C
6
alkyl)carbamoyl, di(C
1
-C
6
alkyl)carbamoyl, di(C
1
-C
6
alkyl)amino, or carboxy-C
1
-C
6
alkanoylamino; or
a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C
1
-C
6
alkyl, C
2
-C
6
alkenyl, halo, cyano (—CN), —CO
2
H, —CO
2
R, —CONH
2
, —CONHR, —CON(R)
2
, —OH, —OR, oxo-, —SH, —SR, —NHCOR, and —NHCO
2
R wherein R is C
1
-C
6
alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;
R
2
is a C
1
-C
12
alkyl,
C
2
-C
12
alkenyl,
C
2
-C
12
alkynyl,
phenyl(C
1
-C
6
alkyl)-,
heteroaryl(C
1
-C
6
alkyl)-,
phenyl(C
2
-C
6
alkenyl)-,
heteroaryl(C
2
-C
6
alkenyl)-,
phenyl(C
2
-C
6
alkynyl)-,
heteroaryl(C
2
-C
6
alkynyl)-,
cycloalkyl(C
1
-C
6
alkyl)-,
cycloalkyl(C
2
-C
6
alkenyl)-,
cycloalkyl(C
2
-C
6
alkynyl)-,
cycloalkenyl(C
1
-C
6
alkyl)-,
cycloalkenyl(C
2
-C
6
alkenyl)-,
cycloalkenyl(C
2
-C
6
alkynyl)-,
phenyl(C
1
-C
6
alkyl)O(C
1
-C
6
alkyl)-, or
heteroaryl(C
1
-C
6
alkyl)O(C
1
-C
6
alkyl)- group,
any one of which may be optionally substituted by
C
1
-C
6
alkyl,
C
1
-C
6
alkoxy,
halo, or
cyano (—CN);
phenyl or heteroaryl, or
phenyl or heteroaryl substituted by
C
1
-C
6
alkyl,
C
1
-C
6
alkoxy,
halo, or
cyano (—CN);
R
3
is the characterising group of a natural or non-natural &agr; amino acid in which any functional groups may be protected; and
R
4
is an ester or thioester group,
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
In another broad aspect of the invention, there is provided the use of a compound of formula (I) as defined in the immediately preceding paragraph, in the preparation of a pharmaceutical composition treatment of mammals suffering diseases responsive to inhibition of intracellular leukotriene-A
4
hydrolase activity,
In one particular aspect of the invention, the compound used is one of general formula (I) above wherein R, R
1
, R
2
, R
3
and R
4
are as defined above with reference to formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof,
PROVIDED THAT:
(i) when R and R
1
are hydrogen, R
2
is 4-chlorophenylpropyl, and R
3
is tertbutyl, then R
4
is not a methyl carboxylate ester group; and
(ii) when R and R
1
are hydrogen, R
2
is phenylmethyl, and R
3
is 1-methylprop-1-yl, then R
4
is not a tert-butyl carboxylate ester group.
In another particular aspect of the invention, the compound used is one of general formula (I) above wherein:
R, R
1
and R
4
are as defined above with reference to formula (I)
R
2
is C
1
-C
12
alkyl, C
2

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