Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-21
2003-05-20
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S554000, C549S555000, C549S556000, C549S558000, C549S559000, C549S560000, C514S475000
Reexamination Certificate
active
06566541
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to agents which inhibit type 2 methionine aminopeptidase (MetAP2), including novel ovalicin and fumagillin derivatives, and to the identification and use of such agents for treating and diagnosing diseases involving abnormal angiogenesis or immune reactions which result in pathology.
BACKGROUND OF THE INVENTION
Angiogenesis is the process of new blood vessel formation. It has been shown to play a pivotal role in certain normal physiological reactions, e.g., wound healing, corpus luteum formation and embryonic development. It has also been reported to play a pivotal role in a variety of pathological conditions, e.g., tumors, diabetic retinopathy, inflammatory diseases and arteriosclerosis. For example, it has been reported that without access to sufficient vasculature, tumor growth is restrained as a result of widespread cell death.
Further, while immune reactions are required to protect animals from deleterious foreign antigens, certain immune reactions can result in pathological conditions, e.g., autoimmune diseases, allergies or tissue graft rejection.
Fumagillin and certain types of fumagillin analogs have been reported to exhibit anti-angiogenic activity, and ovalicin has been reported to exhibit anti-angiogenic and immunosuppressive activity.
There is a need for inhibitors which are more potent, less neurotoxic, more stable, and/or have longer serum half-lives.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds which can be used in treating and/or diagnosing diseases involving abnormal angiogenesis or immune reactions resulting in pathology, which are potent, stable, have long serum half-lives, and/or which are polar, thereby being unable to penetrate the blood/brain barrier and thus resulting in low neurotoxicity.
It is yet another object of the invention to provide compounds which inhibit MetAP2 activity.
It is yet another object of the invention to provide compounds which inhibit endothelial cell proliferation.
It is yet another object of the invention to provide a method for identifying agents which are anti-angiogenic or immunosuppressive.
Still another object of the invention is to utilize MetAP2 to aid in identifying agents useful for the treatment and/or diagnosis of diseases involving abnormal angiogenesis or immune reactions which result in pathology.
In one aspect, the invention features a compound of the formula:
and pharmaceutically acceptable salts thereof,
wherein
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
can be the same or different from each other, and are hydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether;
R
7
is hydrogen or an hydroxy group; and
R
8
is
(1) a subtituted alkyl, allyl or alkyne group; or
(2) a substituted alkoxyl or thioalkoxyl group, or methylene or ethylene alkoxyl or thioalkoxyl group, wherein the methylene or ethylene can be optionally substituted; or
(3) an aroyl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(4) an aryl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(5) an amino, alkylamino, dialkylamino, halogen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, carboxylic acid, carboxyl ester, carboxyl salt; or
(6) an alkyl group which can be optionally substituted with N
+
P
1
P
2
P
3
X
−
or S
+P
1
P
2
X
−
, wherein P
1
, P
2
, and P
3
can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and X
−
is a counter anion; or
(7) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with hydroxyl, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, alky, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl or alkylthioether; or
(8) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with N
+
P
1
P
2
P
3
X
−
, S
+
P
1
P
2
X
−
, wherein P
1
, P
2
and P
3
can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and X
−
is a counter anion; or
(9) a benzenesulfonyl, methylsulfonyl or alkyl sufonyl group, with or without a methylene or ethylene substituent, or the corresponding amide or ester, which can be optionally substituted; or
(10) an alkoxycarbonyl or phenoxycarbonyl group with or without a methylene or ethylene substituent, which can be optionally substituted.
A preferred embodiment is a compound having the formula:
Another aspect of the invention features a compound of the formula:
and pharmaceutically acceptable salts thereof,
wherein
Z is an oxygen and can have R or S configuration;
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
can be the same or different from each other and are hydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether;
R
7
and R
8
can be the same or different from each other and are:
(1) hydrogen or a subtituted alkyl, allyl or alkyne group;
(2) a substituted alkoxyl or thioalkoxyl group, or methylene or ethylene alkoxyl or thioalkoxyl group, wherein the methylene or ethylene can be optionally substituted;
(3) an aroyl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
Griffith Eric C.
Liu Jun O.
Su Zhuang
Baker C. Hunter
Choate Hall & Stewart
Herschbach Jarrell Brenda
Massachusetts Institute of Technology
Trinh Ba K.
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