AP889A - Use of Tricyclic 1,4-dihydro-1,4-dioxo-1h-naphthalene derivatives, resulting novel compounds and therapeutical use thereof. - Google Patents

Use of Tricyclic 1,4-dihydro-1,4-dioxo-1h-naphthalene derivatives, resulting novel compounds and therapeutical use thereof. Download PDF

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AP889A
AP889A APAP/P/1998/001275A AP9801275A AP889A AP 889 A AP889 A AP 889A AP 9801275 A AP9801275 A AP 9801275A AP 889 A AP889 A AP 889A
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dihydro
dioxo
naphtho
thiazole
substituted
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APAP/P/1998/001275A
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Odile Boutherin-Falson
Stephanie Desquand-Billiald
Anita Favrou
Michel Finet
Oliver Tembo
Jean-Luc Torregrosa
Sylvie Yannic-Arnoult
Marquer Florence Domagala-Le
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Laboratoire Innothera Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/24—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings
    • C07C225/26—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings having amino groups bound to carbon atoms of quinone rings or of condensed ring systems containing quinone rings
    • C07C225/30—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones the carbon skeleton containing carbon atoms of quinone rings having amino groups bound to carbon atoms of quinone rings or of condensed ring systems containing quinone rings of condensed quinone ring systems formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/24—Quinones containing halogen
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/60—Naphthoxazoles; Hydrogenated naphthoxazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/84—Naphthothiazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

Abstract

The invention concerns che therapeutic use of tri salts and their pharmaceutically acceptable salts having the general formula: in which: A is either a sulfur atom, an oxygen atom, or an R3N radical where R3 is a hydrogen atom, a Cj-Cj alkyl radical, or a substituted or unsubstituted aromatic ring, or a substituted or unsubsticuted heteroaromatic ring. R, is either a C-C5 alkyl radical, or an R,NH radical where R4 is a hydrogen atom, a C-C5 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 dcnor groups. R2 is a hydrogen acorn, halogen atom, a C.-C5 alkyl radical, an oxygen atom that may or may not be substituted by a C:-CS alkyl radical, or an NRiR5 radical where R5 and R5. are, independently of each other, a hydrogen atom, an oxygen atom or monovalent C-CS organic radicals.

Description

USE OF -TRICYCLIC DERIVATIVES OF 1,4 -DIHYDRO-1,4-DIOXO-1H-NAPHTHALENE,
NOVEL COMPOUNDS OBTAINED AND THEIR APPLICATION IN THERAPY
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- I, 4 -dioxo-lH-naphthalene. The invention concerns the therapeutic application of all these compounds.
The synthesis of ΙΗ-naphtho[2,3-d]imidazole-4,9-diones, substituted in position 2, is described in J. Heterocycl. Chem., 6(6), 909-916, 1969, by F.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-l,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-l,4-dioxonaphthalene from 2,3-dichloro-l,4-dihydro-l,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. Patent No. 3,039,925, of June 19, 1962 and a German patent application of April 24, 1967 by Gerhard Domagk, Karl W. Schellhammer, Siegfried Peterson, and Hans B. Koenig concern the synthesis of 2-methyl-naphtho[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:
(I) in which: A is either a sulfur atom, an oxygen atom, or an R3N radical where R3 is a hydrogen atom, a C^Cs alkyl
radical, or a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring. RT is either a Ci-Os alkyl radical, or an R4NH radical where R4 is a hydrogen atom, a Ο,.-C5 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 . R2 is a hydrogen atom, halogen atom, a Ci~C5 alkyl radical, an oxygen atom that may or may not be substituted by a Ci-C5 alkyl radical, or an NR5R5 radical where R5 and R5. are, independently of each other, a hydrogen atom, an oxygen atom, or monovalent C1-C5 organic radicals.
In the invention the term "acceptor or donor groups" is defined as a Cx-C5 alkyl radical, a halogen atom, or an oxygen atom, which may or may not be substituted by a Cx-C5 alkyl radical, or an NR6R6, where R6 and R6, are, independently of each other, 'a hydrogen atom, an oxygen atom, or monovalent C1-Cs organic radicals.
The invention also concerns the following novel products: , - 4,9-dihydro-4,9-dioxo-l,2-dimethyl-ΙΗ-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-dioxo-naphtho[2,3-d] oxazole, - 2-(4-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[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-dioxo-naphtho [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-dioxo-naphtho [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-phenyl-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-naphtho[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-dioxo-naphtho [2,3-d]thiazole, - 2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho [2,3-d]thiazole, - 2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d] thiazole, - 2-(4-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[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-dioxo-naphtho [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- e 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-dioxo-naphtho[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, i - 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- i 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-methyl-phenyl)naphtho[2,3-d] thiazole, - 4, 9-dihydro-4, 9-dioxo-7-fluoro-2-(4-methyl-phenyl ) 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-methoxy-naphtho [2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxy-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-hydroxy-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-hydroxy-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-(2-furyl)-6-methoxy-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-(2-furyl)-7-methoxy-naphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-furyl-6-methylnaphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-furyl-7-methylnaphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-6-methyl-2-phenylnaphtho[2,3-d] thiazole, . - 4,9-dihydro-4,9-dioxo-7-methyl-2- phenylnaphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-2-furyl-8-methylnaphtho [2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-5-methyl-2- i phenylnaphtho[2,3-d] thiazole, - 4,9-dihydro-4,9-dioxo-8-methyl-2-phenylnaphtho[2,3-d] thiazole.
The invention altio concerns the following intermediate products: - 1,4-dihydro-l,4-dioxo-5-methoxynaphthalene, - 2,3-dibromo-l,4-dihydro-l,4-dioxo-5-methoxynaphthalene, - 2-amino-3-bromo-1,4-dihydro-l,4-dioxo-5-. methoxynaphthalene, - 2-amino-3-bromo-1,4-dihydro-l,4-dioxo-8-methoxynaphthalene, - 2,3-dibromo-1,4-dihydro-l,4-dioxo-6-fluoronaphthalene, • - 2-amino-3-bromo-6-fluoro-l,4-dihydro-l,4-dioxo- naphthalene, - 2 -amino-3-bromo-7-fluoro-1,4-dihydro-l,4-dioxo-naphthalene, - 2,3-dibromo-1,4-dihydro-l,4-dioxo-5-fluoronaphthalene, - 2-amino-3-bromo-1,4-dihydro-l,4-dioxo-5-fluoronaphthalene , - 2-amino-3-bromo-1,4-dihydro-l,4-dioxo-8-fluoronaphthalene , - 2-amino-3 -chloro-1,4 -dihydro-1,4-dioxo-6 -methylnaphthalene, - 2-amino-3-chloro-1,4-dihydro-l,4-dioxo-7-methylnaphthalene, - 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene, - 2-amino-3-bromo-l,4-dihydro-l,4-dioxo-5-methyl- naphthalene, ; - 2-amino-3-bromo-1,4-dihydro-l,4-dioxo-8-methyl- naphthalene.
The·invention also refers to the use of tricyclic derivatives and their, pharmaceutically acceptable salts, having the above general formula (I), for the preparation ) of a drug intended for: - the treatment of functional and organic venous insufficiency; - the treatment of hemorrhoid pathologies; - the treatment of migraine; 5 - the treatment of dermatological and cardiovascular osteoarticular inflammations; - the treatment of states of shock consisting of a large drop in arterial pressure, more particularly in states of septic shock. ) Specifically, the compounds of the present invention have the general formula (I) illustrated below:
where :
A = -NH, -N-C6H5, -N-CH3, O, S, N
R2 = H, -OCH3/ -OH, -F, Cl, CH3
The present invention also relates to the salts of the compounds of formula (I) of which salts can be prepared. These salts comprise the addition salts of mineral salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or nitric acid, and the addition salts of organic salts such as acetic acid, propionic acid, oxalic acid, citric acid, maleic acid, fumaric acid, succinic acid and tartaric acid.
The invention is illustrated by the following nonlimiting examples.
The examples indicated by a number correspond to novel compounds, whereas the examples indicated by a letter correspond to known compounds.
In all the examples, the analyses are carried out as indicated below: - Melting point: The analyses are carried out using an apparatus of the "Kofler bench" type LEICA-REICHERT model WME and they are not corrected. - Thin-layer chromatographies: The thin layer chromatographies are carried out using silica gel plates with a UV2S4 fluorescence indicator, at a thickness of 0.25 mm, of the MACHEREY-NAGEL type (Reference 805 023). The elution solvents are indicated for each compound. - Mass spectra: The mass spectra are determined using a spectrometer of the AEI MS-50 type or a spectrometer of the FISONS VG PLATFORM type. The ionization mode is indicated for each example. - NMR spectra: The NMR spectra of 1H and 13C are determined using either a spectrometer of the JEOL type, at 270 MHz and 68 MHz, respectively, or a spectrometer of the. BRUCKER type, at 400 MHz and 100 MHz, respectively.
The deuterated solvents used are indicated for each analysis . - Infrared spectra: The infrared spectra are
obtained using a spectrometer of the NICOLET 205 FT-IR type. They are determined at 1% (weight/weight) in a < dispersion in KBr.
Example 1 4.9- Dihydro-4,9-dioxo-l,2-dimethyl-ΙΗ-naphtho[2,3-d]imidazole sulfate
To a solution of 2 g (8.84 mmol) of 4,9-dihydro-4,9-dioxo-1,2-dimethyl-ΙΗ-naphtho[2,3-d]imidazole in 300 mL of a methanol/dichloromethane mixture (2/1) heated at 70°C, 1 mL of concentrated sulfuric acid is added. The reaction mixture is stirred at 70“C for 2 h, then concentrated at reduced pressure, and the pale yellow precipitate that appears is filtered and washed with dichloromethane, then with ethyl ether, to produce 2 g of 4.9- dihydro-4,9-dioxo-l,2-dimethyl-ΙΗ-naphtho[2,3-d]imidazole sulfate, in the form of yellow crystals.
Yield: 70%
Melting point: >260°C
Rf: 0.50 (CH2C12/Methanol, 97.5/2.5) TH-NMR (DMSO d6) : δ (ppm) 8.05 (dd, 2H, H-5, H-8, Jhs-h6 = Uh7~h8 = 8.85 Hz; Jhs-h7 = Jh6- = 1.73 Hz) 7.85 (m, 2H, H-6, H-7) 5.44 (s, 1H, NH+) 3.98 (s, 3H, CH3) 2.53 (s, 3H, CH3) 13C-NMR (DMSO, d6) : δ (ppm) 177.22, 175.44 (2C, C-4, C-9) 153.46 (1C, C-2) 138.96 (1C, C-3a) 134.10, 134.01 (2C, C-6, C-7) 132.30, 131.93 (3C, C-8a, C-9a, C-4a) 126.24, 126.13 (2C, C-5, C-8) 32.33 (1C, CH3) 12.30 (1C, CH3) IR (KBr) : V (cm'1) 3414-2400 (broad NH+ band) ; 1674 (C=O)
Example 2 4,9-Dihydro-4,9-dioxo-2-(2-fluorophenyl)-ΙΗ-naphtho [2,3-d]imidazole * To a suspension of 1.37 g (7.29 mmol) of 2,3- diamino-1,4-dihydro-l,4-dioxonaphthalene in 50 mL of water, a solution of 0.77 mL (7.29 mmol) of 2-fluorobenzaldehyde in 5 mL of glacial acetic acid is added. After 5 h of reflux, the black solid obtained is filtered, then washed three times with 30 mL of water.
The solid is then redissolved in 2 L of dichloromethane, the organic phase is washed three times with water, dried over calcium chloride, and evaporated to dryness to produce 1.50 g of chestnut brown crystals. The product is purified on a flash column (support: silica, conditioning: heptane, eluants: dichloromethane/heptane, 95/5, then dichloromethane/methanol, 99/1), resulting in the production--after evaporation of the solvents at

Claims (1)

  1. Original document published without claims.
APAP/P/1998/001275A 1995-12-12 1996-12-10 Use of Tricyclic 1,4-dihydro-1,4-dioxo-1h-naphthalene derivatives, resulting novel compounds and therapeutical use thereof. AP889A (en)

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FR9514683A FR2742153B1 (en) 1995-12-12 1995-12-12 USE OF TRICYCLIC DERIVATIVES OF 1,4-DIHYDRO-1,4-DIOXO-1H-NAPHTALENE, NEW COMPOUNDS OBTAINED AND THEIR THERAPEUTIC APPLICATION
PCT/FR1996/001973 WO1997021684A1 (en) 1995-12-12 1996-12-10 Use of tricyclic 1,4-dihydro-1,4-dioxo-1h-naphthalene derivatives, resulting novel compounds and therapeutical use thereof

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