Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-02-08
2002-12-10
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C556S413000, C562S426000, C562S431000, C562S471000, C562S463000, C560S011000, C560S017000, C560S053000, C560S060000, C560S140000, C560S226000, C560S190000, C560S180000, C560S174000, C514S506000, C514S557000, C514S567000
Reexamination Certificate
active
06492550
ABSTRACT:
BACKGROUND OF THE INVENTION
I. Field of the Invention
The present invention relates to certain alpha-substituted thio and oxo trifluoromethylketone compounds, their salts, hydrates and derivatives thereof, a process for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and such ketone compounds as inhibitors of phospholipase A2 enzymes that are involved in the human inflammatory diseases and are thus useful agents in the treatment of inflammatory diseases such as asthma, arthritis, inflammatory bowel disease and neurodegenerative diseases.
II. Background of the Invention and Description of the Prior Art
Inflammatory diseases of the skin, such as psoriasis and atopic dermatitis, afflict greater than 5% of the population. And the inflammatory disease such as asthma affects more than 10 million people in U.S. alone. Currently, the treatment of these disorders typically involves topical use or inhalation of corticosteroids and bronchodilators. However, these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy. In addition, topical application of a drug is difficult for many patients where the affected area may be very large.
Phospholipase A
2
(PLA
2
) is the common name for phosphatide 2-acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids. When the fatty acid is arachidonic acid, further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma. Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.
PLA
2
enzymes exist as secreted forms (MW~12,000-15,000) and cytosolic forms (MW~85,000). The cytosolic or cPLA
2
enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.
Inappropriate activation of the cytosolic PLA
2
enzymes, therefore, can result in a variety of chronic and acute conditions including asthma, cerebral ischemia [Clemens et al.,
Stroke
, 1996, 27: 527-535], Alzheimer's Disease [Stephenson et al.,
Neurobiology of Stroke
, 1996, 3: 51-63 and see also U.S. Pat. No. 5,478,857], rheumatoid arthritis, neutrophil and platelet activation [Huang et al.,
Mediators of Inflammation
, 1994, 3: 307-308], chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light [Gresham et al.,
American Journal of Physiology
, 1996, 270
; Cell Physiology
, 39: C1037-C1050] and macrophage activation [Balsinde et al.,
Journal of Biological Chemistry
, 1996, 271: 6758-6765].
Inhibitors of the cPLA
2
enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases. The literature describes a significant number of compounds said to be phospholipase A
2
inhibitors.
Biochemistry
, 1993, 32: 5935-5940, discloses a trifluoromethyl ketone analog of arachidonic acid having the formula
as a selective inhibitor of cPLA
2
.
Bioorganic Med. Chem. Lett
., 1995, 5: 519-522, discloses selective cPLA2 inhibitors of the formula
where R is either H or OH.
Japanese published Patent Application JP09268153A (Derwent No. 97-554679/51) discloses cPLA
2
inhibitors of the formula RCOCF
3
where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid. The compounds are said to be useful as antiinflammatory or antiallergic drugs.
Certain trifluoromethylketone have been disclosed as inhibitors of fatty acidamide hydrolase in
Bioorg
. &
Med. Chem. Lett
., 1999, 9: 265-270.
Published PCT Application WO 98/25893 discloses arylsulfonamide compounds of the general formula
wherein:
A represents a C
4
-C
10
alkyl group, an aryl group, an arylalkyl group, radicals selected from the group consisting of —CH═CH—B, —O—B, —S—B, and —NH—B, or radicals of formula —CH
2
—X,
wherein:
B represents a non-aromatic C
3
-C
8
carbocycle, a C
3
-C
8
alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and
X is a member selected from the group consisting of a halogen atom, —S-aryl, —S-heterocycle, and —PO
3
R
2
wherein each R is independently selected from the group consisting of a hydrogen atom and C
1
-C
3
alkyl;
R
1
and R
2
each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: —(CH
2
)
q
—A′ wherein q is an integer of 2 to 4, and A′ is a member selected from the group consisting of a hydroxyl group, a group represented by the formula:
wherein R
5
and R
6
each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula:
wherein R
7
represents a hydrogen atom, a lower alkyl group, or a group represented by the formula:
wherein s is an integer of 2 to 5; or
R
1
and R
2
each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula:
wherein g and h are each an integer of 1 to 4, and B′ stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or
R
1
and R
2
may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R
1
and R
2
are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
R
3
represents a hydrogen atom, a lower alkyl group, or a C
3
-C
8
cycloalkyl group;
R
4
represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom;
n is an integer of 1 to 4, provided that when n is 2, the two R
4
groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A
2
activity, particularly cPLA
2
.
The published PCT Application WO 98/08818 discloses Inhibitors of phospholipase enzymes of formulae I, II and III.
or a pharmaceutically acceptable salt thereof, wherein:
A is independent of any other group and is selected from the group consisting of —CH
2
— and —CH
2
—CH
2
—;
B is independent of any other group and is selected from the group consisting of —(CH
2
)
n
—, —(CH
2
O)
n
—, —(CH
2
S)
n
—, —(OCH
2
)
n
—, —(SCH
2
)
n
—, —(CH═CH)
n
—, —(C≡C)
n
—, —CON(R
6
)—, —N(R
6
)CO—, —O—, —S—and —N(R
6
)—;
R
1
is independent of any other R group and is selected from the group consisting of —X—R
6
, —H, —OH—, halogen, —CN, —NO
2
, C
1
-C
5
alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R
2
is independent of any other R group and is selected from the group consisting of —H, —COOH, —COR
5
, —CONR
5
R
6
, —(CH
2
)
n
—W—(CH
2
)
m
—Z—R
5
, —(CH
2
)
n
—W—R
5
, —Z—R
5
, C
1
-C
10
alkyl, alkenyl and substituted aryl;
R
3
is independent of any other R group and is selected from the group consisting of —H, —COOH, —COR
5
, —CONR
5
R
6
, —(CH
2
)
n
—W—(CH
2
)
m
—Z—R
5
, —(CH
2
)
n
—W—R
5
, —Z—R
5
, C
1
-C
10
alkyl, alkenyl and substituted aryl;
R
4
is i
Balasubramanian Neelakantan
Banville Jacques
Gai Yonghua
Plamondon Serge
Bristol--Myers Squibb Company
Killos Paul J.
Morse David M.
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