LTA4 hydrolase inhibitor pharmaceutical compositions and...

Details LTA4 hydrolase inhibitor pharmaceutical compositions and... LTA4 hydrolase inhibitor pharmaceutical compositions and...

1994-10-11

2003-01-14

Ponnaluri, Padmashri (Department: 1627)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

C514S317000, C546S225000

Reexamination Certificate

active

06506876

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to anti-inflammatory compounds and pharmaceutical compositions, and more particularly to anti-inflammatory compounds and compositions which are capable of inhibiting leukotriene A
4
hydrolase.
LTA
4
hydrolase is a requisite enzyme in the biosynthetic pathway leading to LTB
4
formation. LTB
4
is a proinflammatory compound. R. Lewis, et al.,
N. Engl. J. Med
. 323, 645-655 (1990) have demonstrated that LTB
4
is a potent granulocyte agonist inducing chemotaxis, aggregation, degranulation, adherence and priming of inflammatory cells for induction by other agonists. Binding of LTB
4
to receptors is stereospecific with two distinct classes of binding sites. A. Lin, et al.,
Prostaglandins
28, 837-849 (1984). A high affinity site [4-5×10
−10
M] mediates chemotaxis and chemokinesis while lower affinity sites [0.6-5×10
−7
M] stimulate granular secretion and oxidative burst. The LTB
4
receptor is associated with a GTP-binding protein that regulates affinity and transduces signals. T. Schepers, et al.,
J. Biol. Chem
. 267, 159-165 (1992). Elevated LTB
4
levels have been reported for many diseases. Most prominently, elevated LTB
4
levels have been correlated to the pathology of inflammatory bowel disease (IBD) including Cohn's disease and ulcerative colitis and in psoriasis. P. Sharon, et al.,
Gastroent
. 86, 453-460; K. Lauritsen, et al.,
Gastroent
. 95, 11-17 (1989); S. Brain, et al.,
Br. J. Pharm
., 83, 313-317 (1984). Other properties of LTB
4
which may contribute to disease processes are: stimulation of mucus secretion; stimulation of cytokine production; and the ability to act synergistically with other inflammatory mediators such as prostaglandins and cysteinyl leukotrienes thereby amplifying the inflammatory process.
B. Samuelsson, et al.,
J. Biol Chem
., 264, 19469-19472 (1989) have shown that LTB
4
biosynthesis from arachidonic acid involves the action of 2 enzymes, 5-lipoxygenase [5-LO] and LTA
4
hydrolase. 5-LO transforms arachidonic acid to 5-HPETE and subsequent formation of LTA
4
, which is an unstable allylic epoxide intermediate which is enzymatically hydrolyzed by LTA
4
hydrolase to form the dihydroxy acid LTB
4
.
LTA
4
hydrolase is distinct from cytosolic and microsomal epoxide hydrolases based on strict substrate requirements, product formation [5(S),12(R) vs. 5(S),6(R) for mouse liver cytosolic epoxide hydrolase, and lack of inhibition by inhibitors of cytosolic epoxide hydrolase. LTA
4
hydrolase appears to be ubiquitously distributed in mammalian tissues even in cell types that do not express 5-LO, suggesting the importance of transcellular metabolism of LTA
4
. While peptidomimetic compounds such as bestatin and captopril have been shown to exhibit LTA
4
hydrolase inhibitory activity, they are not able to satisfy the requirement of a small organic compound which is capable of cellular penetration. It would therefore be very advantageous to be able to provide low molecular weight inhibitors of LTB
4
biosynthesis which preferably exhibit oral activity in vivo at desirably low concentrations.
SUMMARY OF THE INVENTION
Applicants have now discovered that compounds of the formula I
Ar
1
—Q—Ar
2
—Y—R—Z  (I)
and pharmaceutically acceptable salts and stereoisomers thereof possess LTA
4
hydrolase inhibitor activity, wherein:
Ar
1
is an aryl moiety selected from the group consisting of:
(i) phenyl, mono-, di-, or tri-substituted phenyl with the substituents selected from the group consisting of Cl, Br, F, CF
3
, lower alkyl, lower alkoxy, NH
2
, NO
2
and OH;
(ii) 2-, 4- or 5-thiazolyl,
(iii) 2-, 3- or 4-pyridinyl,
(iv) 2- or 3-thienyl, and
(v) 2- or 3-furyl;
Ar
2
is an aryl moiety selected from the group consisting of:
Q is selected from the group consisting of:
(i) —O—,
(ii) —CH
2
—,
(iii) —OCH
2
—,
(iv) —CH
2
O—,
(v) —NH—;
(vi) —NHCH
2
—,
(vii) —CH
2
NH—,
(viii) —CF
2
—,
(ix) —CH═CH—,
(x) —CH
2
CH
2
—, and
(xi) carbon-carbon single bond;
Y is selected from the group consisting of
(i) —O—,
(ii) —S—,
(iii) —NH—,
(iv) —S(O)—, and
(v) —S(O
2
)—;
R is selected from the group consisting of:
(i) linear or branched C
2
-C
6
alkylene; or
(ii) C(R
10
)(R
11
)—(CH
2
)
m
; and
Z is selected from the group consisting of:
(vii) a monocyclic or bicyclic heteroaromatic moiety having at least one heteroatom, wherein the heteroatom is nitrogen, and wherein the monocyclic heteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclic heteroaromatic moiety comprises a fused 9- or 10-membered ring;
wherein R
1
and R
2
are independently selected from the group consisting of:
(i) H,
(ii) lower alkyl or allyl,
(iii) benzyl,
(iv) —(CH
2
)
a
COR
15
,
(v)
(vi) —(CH
2
)
a
—OH
R
3
and R
4
are independently H or lower alkyl;
R
5
and R
6
are independently selected from the group consisting of:
R
7
is H, halogen, lower alkyl, lower alkoxy, nitro, hydroxy, or R
7
taken together with R
10
is an alkylene group having one or two carbon atoms;
R
8
and R
9
are independently H, halogen, lower alkyl, lower alkoxy, NH
2
, NO
2
or OH;
R
10
is H, lower alkyl, or R
10
taken together with R
7
is an alkylene group having one or two carbon atoms;
R
11
is H or lower alkyl;
R
12
is selected from the group consisting of:
(i) H,
(ii) —OH or ═O,
(iii) —(CH
2
)
a
COR
15
,
(iv) —(CH
2
)
a
CONH(CH
2
)
b
CO
2
R
16
,
(v) —NHR
17
;
R
13
and R
14
are independently hydrogen, —(CH
2
)
a
COR
15
, provided that at least one of R
13
and R
14
is hydrogen;
R
15
is —OR
16
, —NHR
16
or —NHNH
2
;
R
16
is H, lower alkyl or benzyl;
R
17
is H, lower alkyl, benzyl, —COR
16
or —CONH
2
;
X
1
is
 —S—, or —O—, wherein R
18
is H, lower alkyl, —CONH
2
, CSNH
2
, —COCH
3
or —SO
2
CH
3
;
a and b are independently integers of from 0 to 5;
m is 1, 2 or 3;
n is 0, 1, 2 or 3;
p is 1 or 2; and
q is 1, 2 or 3;
provided however that where R is C(R
10
)(R
11
)—(CH
2
)
m
, and R
10
taken together with R
7
forms an alkylene group having one or two carbon atoms, then —Ar
2
—Y—R is
wherein X is —CH— or —N—, and r is 1 or 2, further provided that wherein R
1
, R
2
or both R
1
and R
2
are —(CH
2
)
a
COR
15
, then a is not O.
DETAILED DESCRIPTION OF THE INVENTION
In one of its embodiments, the present invention entails compounds of the formula I
Ar
1
—Q—Ar
2
—Y—R—Z  (I)
and pharmaceutically acceptable salts and stereoisomers thereof, wherein:
Ar
1
is an aryl moiety selected from the group consisting of:
(i) phenyl, mono-, di-, or tri-substituted phenyl with the substituents selected from the group consisting of Cl, Br, F, CF
3
, lower alkyl, lower alkoxy, NH
2
, NO
2
and OH;
(ii) 2-, 4- or 5-thiazolyl,
(iii) 2-, 3- or 4-pyridinyl,
(iv) 2- or 3-thienyl, and
(v) 2- or 3-furyl;
Ar
2
is an aryl moiety selected from the group consisting of:
Q is selected from the group consisting of:
(i) —O—,
(ii) —CH
2
—,
(iii) —OCH
2
—,
(iv) —CH
2
O—,
(v) —NH—;
(vi) —NHCH
2
—,
(vii) —CH
2
NH—,
(viii) —CF
2
—,
(ix) —CH═CH—,
(x) —CH
2
CH
2
—, and
(xi) carbon-carbon single bond;
Y is selected from the group consisting of
(i) —O—,
(ii) —S—,
(iii) —NH—,
(iv) —S(O)—, and
(v) —S(O
2
)—;
R is selected from the group consisting of:
(i) linear or branched C
2
-C
6
alkylene; or
(ii) C(R
10
)(R
11
)—(CH
2
)
m
; and
Z is selected from the group consisting of:
(vii) a monocyclic or bicyclic heteroaromatic moiety having at least one heteroatom, wherein the heteroatom is nitrogen, and wherein the monocyclic heteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclic heteroaromatic moiety comprises a fused 9- or 10-membered ring;
wherein R
1
and R
2
are independently selected from the group consisting of:
(i) H,
(ii) lower alkyl or allyl,
(iii) benzyl,
R
3
and R
4
are independently H or lower alkyl;
R
5
and R
6
are independently selected from the group consisting of:
R
7
is H, halogen, lower alkyl, lower alkoxy, nitro, hydroxy, or R
7
taken together with R
10
is an alkylenyl group having one or two carbon atoms;
R
8
and R
9
are independ

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