Phenyl acetamides as sPLA2 inhibitors

Details Phenyl acetamides as sPLA2 inhibitors Phenyl acetamides as sPLA2 inhibitors

1997-11-24

2002-03-05

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S039000, C562S041000, C562S051000, C558S049000, C558S173000, C514S534000, C514S568000, C514S617000

Reexamination Certificate

active

06353128

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel substituted phenyl acetamides useful for inhibiting sPLA
2
mediated release of fatty acids for conditions such as septic shock.
The structure and physical properties of human non-pancreatic secretory phospholipase A
2
(hereinafter called, “sPLA
2
”) has been thoroughly described in two articles, namely, “Cloning and Recombinant Expression of Phospholipase A
2
Present in Rheumatoid Arthritic Synovial Fluid” by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.;
The Journal of Biological Chemistry
, Vol. 264, No. 10, Issue of Apr. 5, pp. 5335-5338, 1989; and “Structure and Properties of a Human Non-pancreatic Phospholipase A
2
” by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake;
The Journal of Bioloaical Chemistry
, Vol. 264, No. 10, Issue of Apr. 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA
2
is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA
2
mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA
2
; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and etc.
It is desirable to develop new compounds and treatments for sPLA
2
induced diseases.
This invention provides compounds known as phenyl acetamides of the formula I
wherein:
R
1
is —H or —O(CH2)
n
Z;
R
2
is —H or —OH;
R
3
and R
4
are each independently —H, halo or —(C
1
-C
4
)alkyl;
One of R
5
and R
6
is —YR
7
and the other is —H, where Y is —O— or —CH
2
— and R
7
is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, —(C
1-C
4
)alkyl, (C
1
-C
4
)alkoxy, phenyl or phenyl substituted with one or two halo groups;
Z is —CO
2
R, —PO
3
R
2
or —SO
3
R where R is —H or —(C
1
-C
4
)alkyl; and
n is 1-8;
or a pharmaceutically acceptable salt, racemate or optical isomer thereof;
provided that when R
6
is YR
7
, R
1
is hydrogen; and
when R
1
, R
2
, R
3
, R
4
and R
6
are hydrogen and R
5
is YR
7
where Y is —O—, R
7
cannot be phenyl; and
when R
1
, R
2
, R
3
, R
4
and R
6
are hydrogen and R
5
is YR
7
where Y is CH
2
, R
7
cannot be phenyl substituted with one methoxy or two chloro groups.
This invention is also a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
This invention is also a method of inhibiting sPLA
2
comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II.
wherein:
R
1
is —H or —O(CH
2
)
n
Z;
R
2
is —H or —OH;
R
3
and R
4
are each independently —H, halo or —(C
1-C
4
)alkyl;
one of R
5
and R
6
is —YR
7
and the other is —H, where Y is —O— or —CH
2
— and R
7
is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, —(C
1-C
4
)alkyl, (C
1
-C
4
)alkoxy, phenyl or phenyl substituted with one or two halo groups;
Z is —CO
2
R, —PO
3
R
2
or —SO
3
R where R is —H or —(C
1-C
4
)alkyl; and
n is 1 to 8;
or a pharmaceutically acceptable salt, racemate or optical isomer thereof.
According to a further aspect of the present invention, there is provided a method of inhibiting SPLA
2
in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula (II).
According to a further aspect of the present invention, there is provided a method of selectively inhibiting sPLA
2
in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula (II).
This invention also provides a method of alleviating the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula II in an amount sufficient to inhibit sPLA
2
mediated release of fatty acid and to thereby inhibit or prevent the arachidonic and cascade and its deleterious products.
Other objects, features and advantages of the resent invention will become apparent from the subsequent description and the appended claims.
Definitions:
As used herein, the term, “alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl and the like.
The term “halo” means chloro, fluoro, bromo or iodo.
The term “(C
1
-C
4
) alkoxy”, as used herein, denotes a straight or branched alkyl chain having one to four carbon atoms attached to the remainder of the molecule by an oxygen atom. Typical C
1
-C
4
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.
The salts of the above phenyl acetamides are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., “pharmaceutical Salts,”
J. Phar. Sci
., 66: 1-19 (1977)).
Examples of pharmaceutically acceptable organic bases which may be used to prepare pharmaceutically acceptable salts include ammonia, amines such as triethanolamine, triethylamine, ethylamine, and the like. Examples of pharmaceutically acceptable alkali metal bases include compounds of the general formula MOR
12
, where M represents an alkali metal atom, e.g. sodium, potassium, or lithium, and R
12
represents hydrogen or C
1
-C
6
alkyl.
The term “acid protecting group” is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an acid group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed when it is desired to do so. Such groups are discussed by T. W. Greene in chapter 5 of
Protective Groups in Organic Synthesis
, John Wiley and Sons, New York, 1981, incorporated herein by reference in its entirety.
Examples of acid protecting groups includes esters and substituted esters such as methyl, methoxymethyl, methyl-thiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenylaryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, t-butyl, cyclopentyl, triphenylmethyl, p-bromobenzyl and trimethylsilyl. A preferred acid-protecting group is methyl.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. For example, compounds where R
2
is —OH have a chiral center and form a racemate. The R— and S— isomers and mixtures thereof, including racemic mixtures are contemplated by this invention. If

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