Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-05-23
2002-10-01
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S567000, C514S562000, C514S557000, C564S074000, C562S506000, C562S553000, C562S556000
Reexamination Certificate
active
06458844
ABSTRACT:
BACKGROUND OF THE INVENTION
Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated, but not resting, endothelium. The integrin VL4 (a
4
b
1
), which is expressed on many cell types including circulating lymphocytes, eosinophils, basophils, and monocytes, but not neutrophils, is the principal receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes, as well as melanoma cells, to activated endothelium in vitro. Antibodies to either protein have been effective at inhibiting leukocyte infiltration and preventing tissue damage in several animal models of inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell emigration in adjuvant-induced arthritis, prevent eosinophil accumulation and bronchoconstriction in models of asthma, and reduce paralysis and inhibit monocyte and lymphocyte infiltration in experimental autoimmune encephalitis (EAE). Anti-VCAM-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. Recent studies have demonstrated that anti-VLA-4 mAbs can prevent insulitis and diabetes in non-obese diabetic mice, and significantly attenuate inflammation in the cotton-top tamarin model of colitis.
Thus, compounds which inhibit the interaction between &agr;
4
-containing integrins and VCAM-1 will be useful as therapeutic agents for the treatment of inflammation resulting from chronic inflammatory diseases such as rheumatoid arthritis, multiple sclerosis (MS), asthma, and inflammatory bowel disease (IBD).
SUMMARY OF THE INVENTION
It has been discovered that compounds of the formula:
and the pharmaceutically acceptable salts and esters thereof wherein X and Y are as defined below, inhibit the binding of VCAM-1 to VLA-4 and are useful in treating inflammation associated with chronicinflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis, (MS), asthma, and inflammatory bowel disease (I BD).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the discovery that compounds of the formula:
and the pharmaceutically acceptable salts and esters thereof, inhibit the binding of VCAM-1 to VLA-4 and are useful in treating inflammation associated with chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis, (MS), asthma, and inflammatory bowel disease (I BD).
In accordance with the invention, X is a group X-1, X-2 or X-3 as described below. Y is a group Y-1, Y-2 or Y-3 as described below.
The group X-1 is of the formula:
wherein:
R
15
is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy;
R
16
is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio.
The groups R
15
and R
16
are preferably independently hydrogen, lower alkyl, nitro, halogen (especially chloro or fluoro), perfluoromethyl, or cyano for R
16
, and lower alkyl, nitro, halogen (especially chloro or fluoro), perfluoromethyl, or cyano for R
15
.
It is preferred that groups selected as R
15
, or R
15
and R
16
, be electron-deficient as defined below.
X-2 is a group of the formula:
wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N,O, and S, or
Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
R
15
and R
16
are as above, and
R
30
is hydrogen or lower alkyl; and p is an integer from 0 to 1.
Het is preferably a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen. When Het is a bicyclic heteroaromatic ring, it preferably contains from 1 to 3 nitrogens as the heteroatoms. R
15
is preferably, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl (especially unsubstituted phenyl); R
16
is preferably hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R
30
, when present, is preferably hydrogen or lower alkyl.
The group X-3 is of the formula:
wherein:
R
18
is aryl, heteroaryl,
R
19
is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and
R
20
is substituted or unsubstituted lower alkanoyl or aroyl
R
18
is preferably phenyl. R
19
is preferably lower alkyl, which is unsubstituted or substituted by pyridyl or phenyl. R
20
is preferably lower alkanoyl
Y is a group of formula Y-1, Y-2, or Y-3 wherein:
Y-1 is a group of the formula:
wherein:
R
22
and R
23
are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R
22
and R
23
is other than hydrogen, and
R
24
is hydrogen, lower alkyl lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen
Y-2 is a group of the formula
Het is a five or six membered heteroaromatic ring bonded via a carbon atom wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and R
30
and R
31
are independently hydrogen, lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of R
30
and R
31
is adjacent to the point of attachment, p is an integer of from 0 to 1.
Y-3 is a 3-7 membered ring of the formula:
wherein:
R
25
is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R
26
—(CH
2
)
e
—, R
26
is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R
26
is a group of formula —NR
28
R
29
,
wherein
R
28
is H or lower alkyl,
R
29
is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower akanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl,
or
R
28
and R
29
taken together form a 4, 5 or 6-membered saturated carbocyclic ring optionally containing one heteroatom selected from O, S, and N with the carbon atoms in the ring being unsubstituted or substituted by lower alkyl or halogen,
Q is —(CH
2
)
f
O—, —(CH
2
)
f
S—, —(CH
2
)
f
N(R
27
)—, or —(CH
2
)
f
—,
R
27
is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, e is an integer from 0 to 4, and f is an integer from 0 to 3; the dotted bond is optionally hydrogenated.
This invention is directed to a compound of the formula:
wherein X is a group of the formula
wherein:
R
15
is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy;,
R
16
is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio; or
X is a group of formula X-2
wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N,O, and S, or
Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
R
15
and R
16
are as above;
R
30
is hydrogen or lower alkyl; and p is an integer from 0 to 1
or X is a group of formula X-3
wherein:
R
18
is aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl
R
19
is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and
R
20
is substituted or unsubstituted lower alkanoyl or aroyl;
and Y is a group of formula Y-1
wherein:
R
22
and R
23
are independentl
Hull Kenneth Gregory
Sidduri Achytharao
Tilley Jefferson Wright
Desai Rita
Dubberley F. Aaron
Hoffmann-La Roche Inc.
Johnston George W.
Tramaloni Dennis P.
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