Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1998-08-21
2001-05-08
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C548S324500, C548S323500, C548S200000, C548S215000, C548S254000, C548S261000, C548S512000, C562S443000, C562S446000, C562S447000, C562S448000, C562S449000, C562S455000, C562S457000, C562S430000, C560S034000, C560S041000, C544S171000, C544S263000, C544S325000, C544S400000, C546S116000, C546S121000, C546S175000, C546S199000, C546S215000, C546S316000
Reexamination Certificate
active
06229011
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 VLA-4 (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 surival 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 chronic inflammatory diseases such as RA, 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, X′, Y and Z are as defined below, inhibit the binding of VCAM-1 to VLA-4 and so would be useful in treating inflammatory diseases in which such binding contributes to the disease process.
DETAILED DESCRIPTION OF THE INVENTION
As used in this specification, the term “lower alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like. Lower alkyl groups may be unsubstituted or substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl, hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and substituted amino. Examples of substituted lower alkyl groups include 2-hydroxylethyl, 3-oxobutyl, cyanomethyl, and 2-nitropropyl.
The term “cycloalkyl” means an unsubstituted or substituted 3- to 7-membered carbacyclic ring. Substitutents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower allcanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino.
The term “lower alkoxy” means a straight-chain or branched-chain alkoxy group containing a maximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
The term “lower alkylthio” means a lower alkyl group bonded through a divalent sulfur atom, for example, a methyl mercapto or a isopropyl mercapto group.
The term “aryl” means a mono- or bicylic aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted by conventional substituent groups. Preferred substituents are lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, aryl alkynyl, lower alkynyl and lower alkanoylamino. The especially preferred substituents are lower alkyl, lower alkoxy, hydroxy, halogen, cyano and perfluoro lower alkyl. Examples of aryl groups that may be used in accordance with this invention are phenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, m-hydroxy phenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-naphthyl and the like.
The term “arylalkyl” means a lower alkyl group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl or heteroaryl group as herein defined. Any conventional aralkyl may be used in accordance with this invention, such as benzyl and the like.
The term “heteroaryl” means an unsubstituted or substituted 5- or 6-membered monocyclic hetereoaromatic ring or a 9- or 10-membered bicyclic hetereoaromatic ring containing 1, 2, 3 or 4 hetereoatoms which are independently N, S or O. Examples of hetereoaryl rings are pyridine, benzimidazole, indole, imidazole, thiophene, isoquinoline, quinzoline and the like. Substitutents as defined above for “aryl” are included in the definition of heteroaryl.
The term “lower alkoxycarbonyl” means a lower alkoxy group bonded via a carbonyl group. Examples of alkoxycarbonyl groups are ethoxycarbonyl and the like.
The term “lower alkylcarbonyloxy” means lower alkylcarbonyloxy groups bonded via an oxygen atom, for example an acetoxy group.
The term “lower alkanoyl” means lower alkyl groups bonded via a carbonyl group and embraces in the sense of the foregoing definition groups such as acetyl, propionyl and the like.
The term “lower alkylcarbonylamino” means lower alkylcarbonyl groups bonded via a nitrogen atom, such as acetylamino.
The term “aroyl” means an mono- or bicyclic aryl or heteroaryl group bonded via a carbonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, 2-naphthtyl and the like.
The term “aryloxy” means an aryl group, as hereinbefore defined, which is bonded via an oxygen atom. The preferred aryloxy group is phenoxy.
The present invention comprises a compound of the formula:
and the pharmaceutically acceptable salts and esters thereof.
In accordance with the invention, Z is hydrogen or lower alkyl (preferably hydrogen), one of X and X′ is hydrogen, halogen, or lower alkyl (X′ is preferably hydrogen), and the other (preferably X) is a group X-6, X-7 or X-10 as described below. Y is a group Y-1 or Y-2 as described below.
The group X-6 is of the formula:
wherein:
R
1
is hydrogen or lower alkyl,
R
15
is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkyithio, hydroxy lower alkyl, alkoxy lower alkyl, alkylthio lower alkyl, alkylsulfinyl lower alkyl, alkylsufonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy or a group of the formula R
17
—C≡C—,
R
16
is H, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio,
R
17
is H, aryl, heteroaryl, or lower alkyl which is unsubstituted or substituted by OH, aryl, or heteroaryl, and
a is 0 or 1.
The groups R
15
and R
16
are preferably independently hydrogen, lower alkyl, nitro, halogen (especially chloro or fluoro), perfluoromethyl, cyano or phenoxy. R
1
is preferably hydrogen and a is preferably 0.
X-7 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;
a, R
1
, R
15
and R
16
are as above, and
R
30
is absent or is hydrogen or lower alkyl.
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 halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R
30
, when present, is preferably hydrogen or lower alkyl.
The group X-10 is of the formula:
wherein:
R
18
is hydrogen, substituted or unsubstituted lower alkyl, aryl, heteroaryl, a
Chen Li
Guthrie Robert William
Huang Tai-Nang
Hull Kenneth Gregory
Sidduri Achyutharao
Higel Floyd D.
Hoffman-La Roche Inc.
Johnston George W.
Tramaloni Dennis P.
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