Iridoid derivatives and neovascularization inhibitors...

Details Iridoid derivatives and neovascularization inhibitors... Iridoid derivatives and neovascularization inhibitors...

1999-09-13

2001-05-01

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S387000, C549S553000, C549S562000

Reexamination Certificate

active

06225478

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel iridoid derivatives and a vascularization inhibitor having for its active ingredient said derivative.
BACKGROUND ART
Although vascularization occurs in the normal physiological state of humans and animals, such as during blastogenesis and ovulation or placenta formation in accordance with the female estrus cycle, as well as in the normal state during wound healing and in the healing process. of inflammations and so on, it is also known to occur in numerous pathological states that cause rapid increases and expansion of capillaries resulting in serious tissue damage. For example, it is described in N. Engl. J. Med., 285: 1182, 1971 that the growth of tumor cells occurs dependent on an increase in capillary vascularization of tumor tissue. In addition, Matsubara, et al. reported in Jpn. J. Inflammation, Vol. 10, No. 4, July 1990, p. 241-245 that, during the course of an inflammation, there is a correlation between neogenesis of small blood vessels such as capillaries and postcapillary venules and cellular invasion by monocytes and lymphocytes, and neogenesis of small blood vessels as nutrient vessels is essential for granulation growth.
In addition, known examples of other diseases related to abnormal acceleration of vascularization include diabetic retinopathy, retrolental fibroplasia, vascularization accompanying corneal transplant, glaucoma, ophthalmic tumor and trachoma in the field of ophthalmology, angioma and fibrous angioma in the field of pediatrics, hypertrophic cicatrix and granulation in the field of surgery, rheumatoid arthritis and edemic scleroma in the field of internal medicine, and atherosclerosis and various types of tumors in the case of heart diseases.
Consequently, the use of. drugs that inhibit vascularization as pharmaceuticals for the treatment of various types of the above diseases has recently attracted attention. Namely, neogenesis of small vessels is known to occur during the course of disease. For example, drugs having vascularization inhibitory effects are useful in the treatment of various diseases such as cancer, chronic inflammations such as chronic rheumatoid arthritis, diabetic retinopathy, pronatal retinopathy, various thrombotic diseases within the retina, arteriosclerosis, angioma, angiofibroma and psoriasis.
Tetrahydrocortisol is disclosed in, for example, the above-mentioned Jpn. J. Inflammation, Vol. 10, No. 4. July 1990, p. 241-245 as an example of a drug having vascularization inhibitory effects. In addition, several anti-rheumatic agents used in the treatment of chronic rheumatoid arthritis, are disclosed as also having vascularization inhibitory effects. Examples of these anti-rheumatic agents include SH compounds such as gold sodium thiomaleate, auranofin and D-penicillamine.
However, drugs having vascularization inhibitory effects as described above also have various clinical problems. For example, it is necessary for tetrahydrocortisol to be used concomitant to heparin, which has vascularization promotion effects, in order for it to demonstrate vascularization inhibitory effects.
On the other hand, many of the anti-rheumatic agents having the vascularization inhibitory effects described above have serious adverse side effects, making their application difficult in terms of managing their administration.
In consideration of these problems of the prior art, the present invention provides a novel compound having remarkable vascularization inhibitory effects unaccompanied by serious adverse side effects, which is useful for the treatment and prevention of various diseases accompanied by abnormal acceleration of vascularization, along with a vascularization inhibitor having for its active ingredient said compound.
DISCLOSURE OF THE INVENTION
As a result of earnest research repeatedly conducted by the inventors of the present invention on a compound having vascularization inhibitory effects in order to solve the problems of the prior art described above, a novel compound was discovered that has vascularization inhibitory effects, thereby leading to completion of the present invention. The present invention is as described below.
(1) Novel iridoid derivatives represented with the following general formula (I):
[wherein,
X represents a (C
1-5
) alkyl group or —COR
1
(R
1
is:
(a) a hydroxyl group or —OM (—OM is a pharmacologically allowed salt or M is an alkali metal atom),
(b) a (C
1-10
) alkoxyl group, (C
2-10
) alkenyloxyl group or (C
4-15
) alkedienyloxyl group (each may or may not be substituted with a phenyl group),
(c) a furfuryloxyl group, phenoxyl group or (C
3-10
) cycloalkyloxyl group, or
(d) —NR
4
R
5
(wherein R
4
and R
5
may be respectively identical or different, and each represents a hydrogen atom, (C
3-10
) cycloalkyl group, phenyl group, a five-membered or six-membered ring system containing one or a plurality of nitrogen atom (s), oxygen atom (s) or sulfur atom (s) as a heteroatom, (C
1-10
) alkyl group (which may or may not be substituted with a mercapto group, —CO
2
R
6
(wherein R
6
is a (C
1-5
) alkyl group), phenyl group or nitrogen-containing aromatic group) or R
4
and R
5
are bonded to form a heterocycloalkyl group and said heterocycloalkyl group is a five-membered or six-membered ring system that is able to contain only the nitrogen atom at which a heteroatom is bonded with R
4
and R
5
or a different nitrogen atom or oxygen atom [which may or may not be substituted with a (C
1-5
) alkyl group (which may or may not be substituted with a hydroxyl group or —OCONH —R
7
(wherein R
7
is a hydrogen atom or (C
1-5
) alkyl group)]},
Y represents a hydrogen atom or the following formula:
{wherein R
2
and R
3
may be respectively identical or different, and represent:
(a) a hydrogen atom, (C
1-10
) alkyl group (which may be a straight or branched chain), (C
2-10
) alkenyl group, (C
3-10
) cycloalkyl group, (C
1-10
) alkylamino group, (C
1-10
) alkoxyl group, (C
3-10
) heterocycloalkyl group, phenyl group, phenyl (C
1-5
) alkyl group, naphthyl group, or cyclic amino group containing a nitrogen atom, oxygen atom or sulfur atom as a heteroatom (each of which may or may not be substituted with a halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, —SO
2
NH
2
group, hydroxy (C
1-5
) alkoxyl group, (C
1-5
) alkylamino group, (C
1-5
) alkylcarbonyl group, (C
1-5
) alkylthio group, benzylthio group, halogenated (C
1-5
) alkyl group, halogenated (C
1-5
) alkoxyl group, —CO
2
R
8
(wherein R
8
is a (C
1-5
) alkyl group), (C
3-10
) cycloalkyl group or five-membered or six-membered ring system that may be condensed with a benzene ring and contains one or a plurality of nitrogen atom (s) oxygen atom (s) or sulfur atom (s) as heteroatom (s)).
(b) —COR
9
(wherein R
9
is a (C
1-5
) alkyl group (which may or may not be substituted zenith a halogen atom) or a phenyl group), or,
(c) R
2
and R
3
are bonded to form a heterocycloalkyl group or heterocycloalkenyl group, and said heterocycloalkyl group or heterocycloalkenyl group is a four-membered, five-membered or six-membered ring system that may be condensed with a benzene ring and contains either only a nitrogen atom at which a heteroatom is bonded with R
2
and R
3
or a different nitrogen atom, oxygen atom or sulfur atom (which may or may not be substituted with a (C
1-5
) alkyl group, hydroxy (C
1-5
) alkyl group, phenyl group, phenyl (C
1-5
) alkyl group, halogenated phenyl group, (C
1-5
) alkoxyphenyl group or halogenated (C
1-5
) alkylphenyl group), and A represents an oxygen atom or sulfur atom}, and
Z represents a (C
1-10
) alkyl group [which may or may not be substituted with a hydroxyl group, halogen atom, —O—R
10
, —OCO—R
11
, —OCOO—R
12
or —OCONH—R
13
(wherein, R
10
through R
13
may be a hydrogen atom or (C
1-5
) alkyl group that may be substituted with a halogen atom)] or —CO—R
14
or —CH
2
—S —R
15
(wherein R
14
and R
15
each represents with a five-membered or six-membered ring system that may be condensed with a benzene ring and can conta

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