Vascular-permeability suppressants

Details Vascular-permeability suppressants Vascular-permeability suppressants

1998-04-13

2001-01-30

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S227800, C514S255030, C514S314000, C514S326000, C514S336000, C514S422000, C514S475000

Reexamination Certificate

active

06180626

ABSTRACT:

TECHNICAL FIELD
This invention relates to a novel vascular permeability suppressants, more particularly a vascular permeability suppressant which prevents retention of carcinomatous pleural effusion or carcinomatous ascites through their suppressing action on vascular permeability, and to an agent which prevents carcinomatous pleural effusion or carcinomatous ascites retention, and also to the method of suppressing retention of carcinomatous pleural effusion or carcinomatous ascites by utilizing this agent.
PRIOR ART
Oxaspirooctane derivatives of the general formula (I):
wherein, R
1
represents carbamoyl group; lower alkylcarbamoyl group; hydroxy(lower)alkylcarbamoyl group; lower alkoxy(lower)alkylcarbamoyl group; lower alkylthio(lower)alkylcarbamoyl group; lower alkoxycarbonyl(lower)alkylcarbamoyl group; lower alkylcarbamoyloxy(lower)alkylcarbamoyl group; di(lower)alkylcarbamoyl group; N-[hydroxy(lower)alkyl](lower)alkylcarbamoyl group; N-[hydroxy(lower)alkyl](lower)alkylcarbamoyloxy(lower)alkylcarbamoyl group; lower alkylcarbamoyloxy(lower)alkenoyl group; N-[heterocyclic carbonyloxy(lower)alkyl](lower)alkylcarbamoyl group; cyclo(lower)alkylcarbamoyl group; arylcarbamoyl group; haloarylcarbamoyl group; protected carbamoyl group; lower alkylthiocarbamoyl group; heterocyclic carbamoyl group; ar(lower)alkenoyl group; lower alkoxycarbonyl group; heterocyclic carbonyl group which may have lower alkyl group, hydroxyl group, hydroxy(lower)alkyl group, lower alkoxy(lower)alkyl group, or lower alkoxycarbonyl group; lower alkyl group; carboxy(lower)alkyl group; protected carboxy(lower)alkyl group; ar(lower)alkyl group which may have halogen atom or lower alkoxyl group: heterocyclic(lower)alkyl group; lower alkylcarbamoyl(lower)alkyl group; hydroxy(lower)alkenoyl group; acyloxy(lower)alkenoyl group or diacyloxy(lower)alkenoyl group; R
2
represents lower alkoxyl group, and R
3
represents the formula:
the formula:
(wherein R
6
represents protected carboxyl group), the formula:
(wherein R
6
represents the same as described above), the formula:
the formula:
(wherein R
7
represents protected carboxy(lower)alkyl group or ar(lower)alkyl group which may have halogen atom), or the formula:
(wherein R
8
represents acyl group), and the process for the production thereof are publicly known as described in Japanese Patent Gazette (Kokai) No. (Hei)2-85272.
The angiogenesis-suppressing activity of the above-mentioned oxaspirooctane derivatives (I) are known as described in Japanese Patent Gazette (Kokai) No. (Hei)2-85272.
Medicines that suppress vascular permeability itself or medicines that prevent the pathological condition that can occur as the result of increased vascular permeability, for example serious symptoms due to retention of carcinomatous ascites or pleural effusion, have not yet been known. Therefore, patients with increased retention of carcinomatous ascites or pleural effusion are inevitably treated only with passive means such as removal of ascites or pleural effusion with a syringe, etc., and thus vascular permeability suppressants serving as agents which actively suppress ascites retention or pleural effusion itself have been desired. The present inventors discovered in the result of their researches that oxaspirooctane derivatives (I) have an excellent suppressing effect on vascular permeability and that they also prevent retention of carcinomatous ascites or carcinomatous pleural effusion based on the said effect. Thus the inventors completed the present invention after extensive researches.
DISCLOSURE OF THE INVENTION
This invention is concerned with a vascular permeability suppressant, such as agents which prevent retention, for example, of carcinomatous pleural effusion or carcinomatous ascites, contain an oxaspirooctane derivative (I) represented by the above-mentioned chemical formula or a pharmaceutically acceptable salt thereof as the active ingredient. The said pharmaceutically acceptable salts are exemplified by pharmaceutically acceptable conventional salts such as sodium salts, ammonium salts, and the like.
BEST EMBODIMENTS OF THE INVENTION
The substituents of an oxaspirooctane derivative (I) as the active ingredient of the vascular permeability suppressant of this invention, are defined in the following.
“Lower” means the carbon atom number 1 to 6 unless otherwise indicated.
Preferable “lower alkyl groups” in “lower alkylcarbamoyl group”, “hydroxy(lower)alkylcarbamoyl group”, “lower alkoxy(lower)alkylcarbamoyl group”, “lower alkylthio(lower)alkylcarbamoyl group”, “lower alkoxycarbonyl(lower)alkylcarbamoyl group”, “lower alkylcarbamoyl(lower)alkylcarbamoyl group”, di(lower)alkylcarbamoyl group”, “ar(lower)alkyl group”, “N-[hydroxy(lower)alkyl](lower)alkylcarbamoyl group“, ”N-[hydroxy(lower)alkyl](lower)alkylcarbamoyloxy(lower)alkylcarbamoyl group”, “lower alkylcarbamoyloxy(lower)alkenoyl group”, “lower alkylthiocarbamoyl group”, “lower alkyl group”, “hydroxy(lower)alkyl group”, “lower alkoxy(lower)alkyl group”, “carboxy(lower)alkyl group”, “protected carboxy(lower)alkyl group”, “heterocyclic(lower)alkyl group”, or “lower alkylcarbamoyl(lower)alkyl group” may include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, etc.
Preferable “lower alkoxyl groups” in “lower alkoxy(lower)alkylcarbamoyl group”, “lower alkoxycarbonyl(lower)alkylcarbamoyl group”, “lower alkoxycarbonyl group”, and “lower alkoxy(lower)alkyl group” may include methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group, etc.
Preferable “lower alkylthio groups” in “lower alkylthio(lower)alkylcarbamoyl group” may include methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group, hexylthio group, etc.
Preferable “lower alkenoyl groups” in “lower alkylcarbamoyloxy(lower)alkenoyl group”, “hydroxy(lower)alkenoyl group”, “acyloxy(lower)alkenoyl group”, “diacyloxy(lower)alkenoyl group” and “ar(lower)alkenoyl group” may include C
3
-C
6
alkenoyl groups such as acryloyl group, crotonoyl group, etc.
Preferable “cyclo(lower)alkylcarbamoyl group” is “cylco(C
3
-C
7
)alkylcarbamoyl group”, including cyclopropylcarbamoyl group, cyclobutylcarbamoyl group, cyclopentylcarbamoyl group, cyclohexylcarbamoyl group, cycloheptylcarbamoyl group, etc.
Preferable “aryl groups” in “arylcarbamoyl group”, “haloarylcarbamoyl group”, “ar(lower)alkyl group”, and “ar(lower)alkenoyl group” may include phenyl group, tolyl group, xylyl group, naphthyl group, etc.
Preferable halogens in “haloaryl group” and “halogen” may include chlorine, bromine, iodine, and fluorine.
Preferable “heterocycles” in “N-[heterocyclic carbonyloxy(lower)alkyl](lower)alkylcarbamoyl group”, “heterocyclic carbonyl group”, “heterocyclic carbamoyl group”, and “heterocyclic(lower)alkyl group” may include mono-ring heterocycles containing nitrogen atom as the heteroatom (e.g. pyridyl group, pyrrolidyl group, piperidyl group, piperazinyl group, 2-oxopyrrolidyl group, etc.), mono-ring heterocycles containing nitrogen and oxygen atoms as the heteroatoms (e.g. morpholinyl group, etc.), mono-ring heterocycles containing nitrogen and sulfur atoms as the heteroatoms (e.g. thiomorpholinyl group, etc.), benzene- condensed heterocycles containing nitrogen atom as the heteroatom (e.g. quinolyl group etc.), and the like.
Preferable “protected carbamoyl group” means carbamoyl group protected with a conventional carbamoyl-protecting group such as halo(lower)alkanoyl group exemplified by trichloroacetyl group, dichloroacetyl group, and monochloroacetyl group.
Preferable “protected carboxyl groups” in “protected carboxy(lower)alkyl group” and “protected carboxyl group” may include esterified carboxyl groups such as lower alkoxycarbonyl groups (e.g. methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, etc.), and the like.
Preferable “acyl groups” in “acyloxy(lower)alk

Affiliated with

Also associated with

Rating

Vascular-permeability suppressants does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Vascular-permeability suppressants, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Vascular-permeability suppressants will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2483358