LTA4 hydrolase inhibitors

Details LTA4 hydrolase inhibitors LTA4 hydrolase inhibitors

1999-05-14

2001-07-24

Kight, John (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S427000, C514S428000, C514S429000, C546S213000, C548S518000, C548S531000, C548S537000, C548S561000, C548S565000

Reexamination Certificate

active

06265433

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.
BACKGROUND OF THE INVENTION
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 Crohn'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 having the structure:
and pharmaceutically acceptable salts and stereoisomers thereof possess LTA
4
hydrolase inhibitor activity wherein
wherein . . . represents a single or double bond
q is 1 or 2, and
Y is —O—, —S—, —CH
2
—, or —CH—
B is —O—, —CH
2
— or —CH
2
O—
n is an integer from 2 to 4
R
1
is H or C
1
to C
4
alkyl
R
2
is (CH
2
)
m
R
3
wherein m is an integer from 1 to 3
R
3
is CO
2
R
4
R
4
is H alkyl, amino, alkylamino, dialkylamino or NR
1
R
2
is combined to form
wherein r is 1 or 2, p is 0 to 3 and R
3
is as defined above.
DETAILED DESCRIPTION
In one of its embodiments, the present invention entails compounds having the structure:
and pharmaceutically acceptable salts and stereoisomers thereof, wherein A, B, R
1
, R
2
, and n are as defined above.
The compounds of the present invention, in several embodiments, may comprise a carboxylic acid or ester moiety. It will be appreciated by those of ordinary skill in the art that a compound of the present invention comprising an ester moiety is readily converted, in vivo, especially when administered orally, into its corresponding carboxylic acid form. The ester-containing compounds of the present invention are therefore prodrugs of their carboxylic acid form.
In another of its aspects, the invention entails pharmaceutical composition comprising a pharmacologically effective amount of at least one of the compounds defined above and a pharmaceutically acceptable carrier.
In still another of its embodiments the present invention involves a method for treating a mammal exhibiting an LTB4 mediated inflammatory condition comprising administering to the mammal a pharmacologically effective amount of a compound of the invention.
The term “lower alkyl” means straight or branched chain alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the branched chain isomers thereof. The term “lower alkoxy” means straight or branched chain alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the branched chain isomers thereof. The term “allyl” as used herein means the 1-propenyl radical, —CH
2
—CH
2
═CH
2
. The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.
Included within the classes and subclasses of compounds embraced by this invention are isomeric forms of the described compounds including diastereoisomers, enantiomers and tautomeric forms of the described compounds. Pharmaceutically acceptable salts of such compounds are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
In the structures disclosed herein a bond drawn across a bond in a ring indicates that the bond can be to any available atom of the ring structure.
The expression “pharmaceutically acceptable salts” is intended to include those salts capable of being formed with the compounds of the present invention without materially altering the chemical structure or pharmacological properties thereof. Such salts can be inorganic and organic cations or acid addition salts, including, but not limited to sodium, potassium, calcium, ammonium, alkylammonium, quaternary ammonium, triethanolamine, lysine, hydrochloride, hydrobromide, and others well known to those of ordinary skill in the art. The foregoing salts are prepared in the conventional manner by neutralization of the compounds of this invention with the desired base or acid.
The compounds of the present invention can be administered to a subject in such oral dosage forms as tablets, capsules, pills, powders, granules, elixirs or syrups, as well as aerosols for inhalation. Likewise, administration may be effected intravascularly, subcutaneously, or intramuscularly using dosage forms known to those of ordinary skill in the pharmaceutical arts. In general, the preferred form of administration is oral. An effective but non-toxic amount of the compound is employed in treatment. The dosage regimen utilizing the present compounds is selected in accordance with a variety of factors including the type, age, weight, sex and medical condition of the patient; the severity of the condition to be ameliorated; and the route of administration. A physician of ordinary skill can readily determine and prescribe a “pharmaceutically effective amount” of at least one of the compounds defined above, that is, the effective amount of the compound required to prevent, treat or arrest the progress of the condition. Dosages of the compounds of the present invention will range generally between 0.1 mg/kg/day to about 100 mg/kg/day and preferably between about 0.5 mg/kg/day to about 50 mg/kg/day when administered to subjects suffering from allergic or hypersensitivity reactions or inflammation. The compounds may also be administered transdermally or topically to treat

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