Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-14
2001-07-17
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S375000, C514S393000
Reexamination Certificate
active
06262095
ABSTRACT:
The present invention concerns the use of tricyclic derivatives and the use of their pharmaceutically acceptable salts for the preparation of a drug intended for the treatment of diseases connected with an alteration of venous and/or inflammatory edema, and concerns the novel compounds obtained. It refers more particularly to the tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene. The invention concerns the therapeutic application of all these compounds.
The synthesis of 1H-naphtho[2,3-d]imidazole-4,9-diones, substituted in position 2, is described in J. Heterocyl. Chem., 6(6), 909-916, 1969, by E. I. Carroll, and J. T. Blackwell. in addition, the document Zh. Org. Khim, 3(1), 162-168, 1967, by G. A. Efimova, and L. S. Efros, concerns the preparation of 1,2-dimethyl-1H-naphth[2,3-d]imidazole-4,9-dione. Finally, the document J. Am. Chem. Soc., 76, 4148-4152, 1954, by J. R. E. Hoover, and A. R. Day, shows the preparation of derivatives of 1H-naphthoimidazole-4,9-dione from 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene.
The article in J. Prakt. Chem., 319(2), 254-258, 1977 by Ahmed S. Hammam and Osman Abdel-Magid describes the synthesis of 2-amido-3-chloro-1,4-dihydro-1,4-dioxonaphthalene from 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene, a compound that can be used as an intermediate for the subsequent synthesis of naphtho[2,3-d]oxazole-4,9-diones, which may or may not be substituted at position 2. U.S. Pat. No. 3,039,925, of Jun, 19, 1962 and a German patent application of Apr. 24, 1967 by Gerhard Domagk, Karl W. Schellhammer, Siegfried Peterson, and Hans B. Koenig concern the synthesis of 2-methylnaphtho[2,3-d]oxazole-4,9-dione carried out by K. Fries and P. Ochwat (Berichte, 56, 1926 (1923)).
Japanese Patent 61,251,675 by S. Hiroyuki, as well as the article in Collect. Czech. Chem. Commun., 50(1), 71-79, 1985 by A. S. Hammam, and B. E. Bayoumy and in the document J. Heterocyclic Chem., 25, 901-906, 1988 by A. R. Katritzky and W. Q. Fan, describe the preparation of the naptho[2,3-d]thiazole-4,9-diones.
The tricyclic derivatives and their pharmaceutically acceptable salts according to the present invention have the general formula:
in which:
A is either a sulfur atom, an oxygen atom, or an R
3
N radical where R
3
is a hydrogen atom, a C
1
-C
5
alkyl radical, or a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring.
R
1
is either a C
1
-C
5
alkyl radical,
or an R
4
NH radical where R
4
is a hydrogen atom, a C
1
-C
5
alkyl radical, or a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring,
or an aromatic ring that may or may not be substituted by one or more acceptor or donor groups, or a heteroaromatic ring having one or more heteroatoms, which may or may not be substituted by acceptor or donor groups.
R
2
is a hydrogen atom, halogen atom, a C
1
-C
5
alkyl radical, an oxygen atom that may or may not be substituted by a C
1
-C
5
alkyl radical, or an NR
5
R
5
radical where R
5
and R
5′
are, independently of each other, a hydrogen atom, an oxygen atom, or monovalent C
1
-C
5
organic radicals.
In the invention the term “acceptor or donor groups” is defined as a C
1
-C
5
alkyl radical, a halogen atom, or an oxygen atom, which may or may not be substituted by a C
1
-C
5
alkyl radical, or an NR
6
R
6′
where R
6
and R
6′
are, independently of each other, a hydrogen atom, an oxygen atom, or monovalent C
1
-C
5
organic radicals.
The invention also concerns the following novel products:
4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphtho[2,3-d]imidazole sulfate,
4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-1H-naphtho[2,3-d]imidazole,
4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]oxazole,
4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)naphtho[2,3-d]oxazole,
4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl) naphtho[2,3-d]oxazole,
4,9-dihydro-4,9-dioxo-2-(2-methylphenyl) naphtho[2,3-d]oxazole,
4,9-dihydro-4,9-dioxo-2-(3-methylphenyl) naphtho[2,3-d]oxazole,
4,9-dihydro-4,9-dioxo-2-(4-methylphenyl) naphtho[2,3-d]oxazole,
2-(2-chlorophenyl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]oxazole,
2-(4-chlorophenyl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]oxazole,
4,9-dihydro-4,9-dioxo-2-(2-thienyl)-naphtho[2,3-d]oxazole,
4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)naphtho[2,3-d]thiazole,
2-(2,4-difluorophenyl)-4,9-dihydro-4,9-dioxonaphtho [2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(3-pyridyl)-naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-naphtho[2,3-d]thiazole sulfate,
4,9-dihydro-4,9-dioxo-2-(3-furyl)naphtho[2,3-d]thiazole,
2-(5-chlorofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(2-thienyl)-naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(3-thienyl)-naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-phenylamino-naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-8-methoxy-2-phenylnaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-5-methoxy-2-phenylnaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-7-methoxy-2-phenylnaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-6-methoxy-2-phenylnaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenylnaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(1-pyrrolyl)-naphtho[2,3-d]thiazole,
2-(5-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho [2,3-d]thiazole,
2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,
2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,
2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,
2-(4-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)naphtho[2,3-d]thiazole,
2-(5-aminofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,
2-(5-acetamidofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(5-hydroxymethylfuran-2-yl)naphtho[2,3-d]thiazole,
2-(5-acetoxymethylfuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazole,
4,9-dihydro-2-(4,5-dimethyl-2-furyl)-4,9-dioxonaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(5-phenyl-2-oxazolyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(2-thiazolyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-6-fluoro-2-phenylnaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-7-fluoro-2-phenylnaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-6-fluoro-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,
6-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)naphtho[2,3-d]thiazole,
7-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)naphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-methoxynaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxynaphtho[2,3-d]thiazole,
4,9-dihydro-4,9-dioxo-2-(2-furyl) -5-hydroxynaphtho[2,3-d]thiazole,
4
Boutherin-Falson Odile
Desquand-Billiald Stephanie
Favrou Anita
Finet Michel
Marquer Florence Domagala-Le
Gerstl Robert
Kenyon & Kenyon
Laboratoire Innothera
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