Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-07-23
2001-09-25
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S242000, C514S255030, C514S212010, C514S274000, C514S340000, C514S018700, C514S019300, C540S524000, C544S182000, C544S316000, C544S360000, C544S393000, C544S405000, C546S122000, C546S194000, C546S273400, C546S277400, C546S300000, C546S309000, C546S331000
Reexamination Certificate
active
06294549
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates generally to &agr;v&bgr;5 antagonists useful for inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation and tumor growth.
The method of the invention can inhibit neovascularization by acting as antagonists of the integrin receptor &agr;v&bgr;5. A monoclonal antibody for &agr;v&bgr;5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model; M. C. Friedlander, et al.,
Science
270, 1500-1502, 1995. Thus, compounds that antagonize &agr;v&bgr;5 are useful for treating and preventing macular degeneration, diabetic retinopathy, tumor growth and for inhibiting vascular restenosis, angiogenesis, and inflammation.
SUMMARY OF THE INVENTION
The invention is a method for eliciting an &agr;
v
&bgr;
5
or dual &agr;
v
&bgr;
3
/&agr;
v
&bgr;
5
antagonizing effect in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of the formula:
and pharmaceutically acceptable salts thereof, wherein
X is
a 5- or 6-membered monocyclic aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S and either unsubstituted or substituted with R
1
or R
2
, or
a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S and either unsubstituted or substituted with R
1
or R
2
,
wherein R
1
and R
2
are independently selected from the group consisting of
hydrogen, F, Cl, Br, I,
C
1-10
alkyl,
C
3-8
cycloalkyl,
aryl,
aryl C
1-8
alkyl,
amino,
amino C
1-8
alkyl,
C
1-3
acylamino,
C
1-3
acylamino C
1-8
alkyl,
C
1-6
alkylamino,
C
1-6
alkylamino C
1-8
alkyl,
C
1-6
dialkylamino,
C
1-6
dialkylamino C
1-8
alkyl,
C
1-4
alkoxy,
C
1-4
alkoxy C
1-6
alkyl,
carboxy,
carboxy C
1-6
alkyl,
C
1-3
alkoxycarbonyl,
C
1-3
alkoxycarbonyl C
1-6
alkyl,
carboxy C
1-6
alkyloxy,
hydroxy, and
hydroxy C
1-6
alkyl;
Y is
where Z is O, NR
8
, or S; and R
8
is defined as R
1
above;
R
3
and R
4
are independently
hydrogen,
a five or six membered mono or nine or ten membered polycyclic unsaturated, partially or fully saturated ring system containing 0, 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C
1-3
alkoxy, C
1-5
alkylcarbonyloxy, C
1-5
alkoxycarbonyl, C
1-5
alkyl, aminoC
1-5
alkyl, hydroxycarbonyl, hydroxycarbonylC
1-5
alkyl, or hydroxycarbonylC
1-5
alkoxy,
—(CH
2
)
n
-aryl, wherein n=1-4 and aryl is defined as a five or six membered unsaturated or partially saturated monocyclic ring system, or nine or ten membered polycyclic ring system wherein at least one of the rings is unsaturated or partially saturated and each of the other rings may be unsaturated, partially saturated or fully saturated, said aryl group containing 0, 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C
1-3
alkoxy, C
1-5
alkylcarbonyloxy, C
1-5
alkoxycarbonyl, C
1-5
alkyl, aminoC
1-5
alkyl, hydroxycarbonyl, hydroxycarbonylC
1-5
alkyl, or hydroxycarbonylC
1-5
alkoxy,
halogen,
hydroxyl,
C
1-5
alkylcarbonylamino,
arylC
1-5
alkoxy,
C
1-5
alkoxycarbonyl,
aminocarbonyl,
C
1-5
alkylaminocarbonyl,
C
1-5
alkylcarbonyloxy,
C
3-8
cycloalkyl,
oxo,
amino,
C
1-3
alkylamino,
aminoC
1-3
alkyl,
arylaminocarbonyl,
arylC
1-5
alkylaminocarbonyl,
aminocarbonyl,
aminocarbonyl-C
1-4
alkyl,
hydroxycarbonyl,
hydroxycarbonyl C
1-5
alkyl,
C
1-6
alkyl, either unsubstituted or substituted, with one or more groups selected from halogen, hydroxyl, C
1-5
alkylcarbonylamino, arylC
1-5
alkoxy, C
1-5
alkoxycarbonyl, aminocarbonyl, C
1-5
alkylaminocarbonyl, C
1-5
alkylcarbonyloxy, C
3-8
cycloalkyl, oxo, amino, C
1-3
alkylamino, aminoC
1-3
alkyl, arylaminocarbonyl, arylC
1-5
alkylaminocarbonyl, aminocarbonyl, aminocarbonyl-C
1-4
alkyl, hydroxycarbonyl, or hydroxycarbonyl C
1-5
alkyl, provided that the carbon atom to which R
3
and R
4
are attached bears only one heteroatom,
—(CH
2
)
m
C≡CH,
—(CH
2
)
m
C≡C—C
1-6
alkyl,
—(CH
2
)
m
C≡C—C
3-7
cycloalkyl,
—(CH
2
)
m
C—C≡ aryl,
—(CH
2
)
m
C≡C—C
1-6
alkyl aryl,
—(CH
2
)
m
CH═CH
2
,
—(CH
2
)
m
CH═CH≡C
1-6
alkyl,
—(CH
2
)
m
CH═CH—C
3-7
cycloalkyl,
—(CH
2
)
m
CH═CH aryl,
—(CH
2
)
m
CH═CH C
1-6
alkyl aryl,
—(CH
2
)
m
SO
2
C
1-6
alkyl, or
—(CH
2
)
m
SO
2
C
1-6
alkylaryl;
R
5
is
hydrogen,
fluorine,
C
1-8
alkyl,
hydroxyl,
hydroxy C
1-6
alkyl,
carboxy,
carboxy C
1-6
alkyl,
C
1-6
alkyloxy.
C
3-8
cycloalkyl,
aryl C
1-6
alkyloxy,
aryl,
aryl C
1-6
alkyl,
C
1-6
alkylcarbonyloxy,
amino,
C
1-6
alkylamino,
amino C
1-6
alkyl,
C
1-6
alkylamino C
1-6
alkyl,
aryl amino,
aryl amino C
1-6
alkyl,
aryl C
1-6
alkylamino,
aryl C
1-6
alkylamino C
1-6
alkyl,
aryl carbonyloxy,
aryl C
1-6
alkylcarbonyloxy,
C
1-6
dialkylamino,
C
1-6
dialkylamino C
1-6
alkyl,
C
1-6
alkylaminocarbonyloxy,
C
1-8
alkylsulfonylamino,
C
1-8
alkylsulfonylamino C
1-6
alkyl,
aryl sulfonylamino C
1-6
alkyl,
aryl sulfonylamino,
aryl C
1-6
alkylsulfonylamino,
aryl C
1-6
alkylsulfonylamino C
1-6
alkyl,
C
1-8
alkyloxycarbonylamino,
C
1-8
alkyloxycarbonylamino C
1-8
alkyl,
aryl C
1-8
alkyloxycarbonylamino,
aryl oxycarbonylamino,
aryl oxycarbonylamino C
1-8
alkyl,
aryl C
1-8
alkyloxycarbonylamino C
1-8
alkyl,
C
1-8
alkylcarbonylamino,
C
1-8
alkylcarbonylamino C
1-6
alkyl,
aryl carbonylamino C
1-6
alkyl,
aryl carbonylamino,
aryl C
1-6
alkylcarbonylamino,
aryl C
1-6
alkylcarbonylamino C
1-6
alkyl,
C
1-8
alkylaminocarbonylamino,
aminocarbonylamino,
aminocarbonylamino C
1-6
alkyl,
C
1-8
alkylaminocarbonylamino C
1-6
alkyl,
aryl aminocarbonylamino C
1-6
alkyl,
aryl aminocarbonylamino,
aryl C
1-8
alkylaminocarbonylamino,
aryl C
1-8
alkylaminocarbonylamino C
1-6
alkyl,
aminosulfonylamino C
1-6
alkyl,
aminosulfonylamino,
C
1-8
alkylaminosulfonylamino,
C
1-8
alkylaminosulfonylamino C
1-6
alkyl,
aryl aminosulfonylamino C
1-6
alkyl,
aryl aminosulfonylamino,
aryl C
1-8
alkylaminosulfonylamino,
aryl C
1-8
alkylaminosulfonylamino C
1-6
alkyl,
C
1-6
alkylsulfonyl,
C
1-6
alkylsulfonyl C
1-6
alkyl,
aryl sulfonyl,
aryl sulfonyl C
1-6
alkyl,
aryl alkylsulfonyl,
aryl C
1-6
alkylsulfonyl,
aryl C
1-6
alkylsulfonyl C
1-6
alkyl,
C
1-6
alkylcarbonyl,
C
1-6
alkylcarbonyl C
1-6
alkyl,
aryl carbonyl C
1-6
alkyl,
aryl carbonyl,
aryl C
1-6
alkylcarbonyl,
aryl C
1-6
alkylcarbonyl C
1-6
alkyl,
C
1-6
alkylthiocarbonylamino,
C
1-6
alkylthiocarbonylamino C
1-6
alkyl,
aryl thiocarbonylamino C
1-6
alkyl,
aryl thiocarbonylamino,
aryl C
1-6
alkylthiocarbonylamino,
aryl C
1-6
alkylthiocarbonylamino C
1-6
alkyl,
aminocarbonyl C
1-6
alkyl,
aminocarbonyl,
C
1-8
alkylaminocarbonyl,
C
1-8
alkylaminocarbonyl C
1-6
alkyl,
aryl aminocarbonyl C
1-6
alkyl,
aryl aminocarbonyl,
aryl C
1-8
alkylaminocarbonyl,
aryl C
1-8
alkylaminocarbonyl C
1-6
alkyl,
wherein alkyl groups and aryl groups may be unsubstituted or substituted with one or more substituents selected from R
1
and R
2
; and
R
6
, R
7
, and R
9
are independently
hydrogen,
C
1-8
alkyl,
aryl,
aryl C
1-8
alkyl,
hydroxy,
C
1-8
alkyloxy,
aryloxy,
aryl C
1-6
alkyloxy,
C
1-8
alkylcarbonyloxy C
1-4
alkyloxy,
aryl C
1-8
alkylcarbonyloxy C
1-4
alkyloxy,
C
1-8
alkylaminocarbonylmethyleneoxy, or
C
1-8
dialkylaminocarbonylmethyleneoxy,
and wherein m and n are integers 0-6.
The invention is also a method for inhibiting a condition selected from the group conistsing of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, and tumor growth in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound defined above.
In a class of methods of the invention, the compounds of the formula are
and pharmaceutically acceptable salts t
Duggan Mark E.
Hartman George D.
Merck & Co. , Inc.
Owens Howard
Parr Richard S.
Wilson James O.
Winokur Melvin
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