MXPA98004717A - Use of triciclic derivatives of 1,4-dihydro-1,4-dioxo-1h-naftalene, new compounds obtained and therapeutic application - Google Patents

Use of triciclic derivatives of 1,4-dihydro-1,4-dioxo-1h-naftalene, new compounds obtained and therapeutic application

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MXPA98004717A
MXPA98004717A MXPA/A/1998/004717A MX9804717A MXPA98004717A MX PA98004717 A MXPA98004717 A MX PA98004717A MX 9804717 A MX9804717 A MX 9804717A MX PA98004717 A MXPA98004717 A MX PA98004717A
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dihydro
dioxo
thiazole
product characterized
new product
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MXPA/A/1998/004717A
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Spanish (es)
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Boutherinfalson Odile
Desquandbilliald Stephanie
Favrou Anita
Finet Michel
Tembo Olivier
Torregrosa Jeanluc
Yannicarnoult Sylvie
Domagalale Marquer Florence
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Laboratoire Innothera Societe Anonyme
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Abstract

The invention relates to the therapeutic use of tricyclic derivatives and their pharmaceutically acceptable salts which correspond to the general formula: (See Formula) wherein: A is either a sulfur atom, an oxygen atom, or is a R3N radical wherein R3 is a hydrogen atom, a C1 to C5 alkyl radical or a substituted or unsubstituted or heteroaromatic, substituted or unsubstituted aromatic ring, R1 is an alkyl radical of C1 to C5 or a radical R4NH where R4 is a hydrogen atom , a C1 to C5 alkyl radical or a substituted or unsubstituted or substituted or unsubstituted aromatic ring or heteroaromatic ring or a ring substituted or unsubstituted by one or more acceptor or donor groups, or a heteroaromatic ring with one or more heteroatoms, substituted or unsubstituted by the acceptor or donor groups. R 2 is a hydrogen atom, a halogen atom, a C 1 to C 5 alkyl radical of oxygen substituted or unsubstituted by an alkyl radical of C 1 to C 5, or a radical NR 5 R 5, where R 5 and R 5 are independently from each other hydrogen atom, Oxygen or monovalent organic radicals of C1 to

Description

UTILIZATION OF TRIICHCLIC DERIVATIVES OF 1,4-DIHIDR0-1,4-DI0X0-1H-NAFTALEN0, NEW COMPOUNDS OBTAINED AND THEIR THERAPEUTIC APPLICATION The present invention refers to the use of cyclic derivatives and their pharmaceutically acceptable salts. for obtaining a medicament for the treatment of diseases related to an alteration of venous function and / or inflammatory edema and with the new compounds thus obtained. It relates more particularly to the tricyclic derivatives of 1,4-dihydro-l, 4-dioxo-lH-naphthalene. The invention also comprises the therapeutic application of all said compounds. In J. Heterocycl. Chem. , 6 (6), 909-916, 1969, by Carroll FI, Blackwell JT, describes the synthesis of lH-naft [2, 3-d] imidazole-4, 9diones substituted in position 2. In addition, the work of Zh. Org. Khim. , 3 (1), 162-168, 1967, by Efimova G.A. , Efros L.S., refers to the preparation of 1,2-dimethyl-lH-napht [2,3-d] imidazole-4,9-dione. Finally, the publication J. Am. Chem. Soc. 76, 4148-4152, 1954, of Hoover JRE, Day AR, describes the preparation of derivatives of lH-naphthimidazole-4,9-dione from 2, 3 -dichloro-l, 4-dihydro-l, 4-dioxo-naphthalene. The article -7. Prakt. Chem. 319 (2), 254-258, 1977, by Hammam Ahmed S., Osman Abdel-Magid, describes the synthesis of 2-amido-3-chloro-1,4-dihydro-1,4-dioxo-naphthalenes a from 2,3-dichloro-1,4-dihydro-1,4-dioxo-naphthalene, which compound can serve as an intermediate for the subsequent synthesis of substituted naphth [2,3-d] oxazole-4,9-diones or not in position 2. The US patent 3,039,925, of June 19, 1962 and a DE patent application of April 24, 1967 by Gerhard Domagk, Karl W. Schellhammer, Siegfried Petersen, Hans B. Koenig refer to the synthesis of 2-methyl-naft [2 , 3-d] oxazole-4,9-dione performed by Fries K. and Ochwat P. (Berichte 56, 1926 [1923]). Japanese Patent JP 61,251,675 of S. Hiroyuki, as well as the article Collect. Czech Chem. Commun. , 50 (1), 71-79, 1985. de Hammam A. S. , Bayoumy B. E. and the document J. Heterocyclíc Chem. 25, 901-906, 1988, by Katritzky A.R. , Fan .Q., Describe the preparation of naphtho [2,3-d] thiazole-4,9-diones. The tricyclic derivatives and their pharmaceutically acceptable salts of the present invention correspond to the general formula wherein A is either a sulfur atom, an oxygen atom, or is an R3N radical where R3 is a hydrogen atom, an alkyl radical of C? to Cs or a substituted or unsubstituted aromatic ring, or substituted or unsubstituted heteroaromatic. R-L is an alkyl radical of C? to C5 or a radical R4NH where R4 is a hydrogen atom, an alkyl radical of C to C5 or substituted or unsubstituted aromatic ring, or substituted or unsubstituted heteroaromatic, or an aromatic ring substituted or unsubstituted by one or more acceptor or donors, or a heteroaromatic ring with one or more heteroatoms, substituted or unsubstituted by the acceptor or donor groups. R2 is a hydrogen atom, a halogen atom, an alkyl radical of C to Cs, an oxygen atom substituted or unsubstituted by an alkyl radical of Ci Cs, a radical NR5RS, where R5 and Rs, are independently of each other a hydrogen, oxygen atom or organic monovalent radicals of C-1 to C5. In the present invention, by "acceptor or donor groups", is meant an alkyl radical of C1 to C5, or a halogen atom, an oxygen atom substituted or not by an alkyl radical in C? to C5, or a radical NR6R6, where R6 and R6, are independently from each other a hydrogen, oxygen atom or monovalent organic radicals of C-L to C5. The invention also concerns the following new products: 4,9-dihydro-4,9-dioxo-l, 2-dimethyl-lH-naft [2 -3-d] imidazole -4,9-dihydro-4-sulfate, 9-dioxo-2 - (2-f luorofenyl) -lH-napht [2 -3-d] imidazole -4,9-dihydro-4,9-dioxo-2 - (2-fluorophenyl) -naft- [2 -3-d] oxazole -4, 9 ~ dihydro-4, 9-dioxo-2 - (3-fluorophenyl) -naft- [2 -3-d] oxazole -4, 9 -dihydro-4, 9-dioxo-2 - (4-f luorofenil) ) -naft- [2 -3-d] oxazole -4,9-dihydro-4,9-dioxo-2- (2-methylphenyl) -napht- [2-3-d] oxazole -4,9-dihydro- 4,9-dioxo-2- (3-methylphenyl) -naft- [2-3-d] oxazole -4,9-dihydro-4,9-dioxo-2- (4-methoxyphenyl) -naft- [2- 3-d] oxazole -2- (2-chlorophenyl) -4,9-dihydro-4,9-dioxo-napht- [2-3-d] oxazole -2- (4-chlorophenyl) -4,9-dihydro -4,9-dioxo-napht- [2-3-d] oxazole -4,9-dihydro-4,9-dioxo-2- (2-thienyl) -naft [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-difluoro-phenyl) - 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 -4,9-dihydro-4,9-dioxo-2- sulphate ( 3-furyl) -naphtho [2-3-d] thiazole -2- (5-chloro-furan-2-yl) -4,9-dihydro-4,9-dioxo-naph or [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-bromo-furan-2-yl) -4,9-dihydro-4,9-dioxo-naf or [2-3-d] thiazole -2- ( 4, 5-dibromofuran-2-yl) -4,9-dihydro-4,9-di-oxo-naphtho [2,3-d] thiazole -2- (3-bromo-furan-2-yl) -4 , 9-dihydro-4,9-dioxo-naph or [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-nitro-furan-2-yl) -naphtho [2, 3-d] thiazole -2- (5-amino-furan--yl) -4,9-dihydro-4,9-dioxo-naphtho [2,3-d] thiazole -2- (5-acetamidophuran) -2-yl) -4,9-dihydro-4,9-di-oxonaphto [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-, 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-oxazoli1) -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-d-oxo-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-fluoyl) naphtho [2,3-d] thiazole -4,9-dihydro-4,9-dioxo-6-fluoro-2- (4-fluoro-phenyl) naphtho [2,3-d] thiazole -4,9-dihydro-4,9-dioxo-7- fluoro-2- (4-fluoro-fe nil) aph [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-napht [2, 3-d] ] thiazole -4,9-dihydro-4,9-dioxo-2- (2-furyl) -8-methoxy-naph to [2, 3-d] thiazole -4,9-dihydro-4,9-dioxo- 2- (2-furyl) -5-hydroxy-naph to [2, 3-d] thiazole -4,9-dihydro-4,9-dioxo-2- (2-furyl) -8-hydroxy-napht [ 2,3-d] thiazole -4,9-dihydro-4,9-dioxo-2- (2-furyl) -6-methoxy-naph to [2,3-d] thiazole -4,9-dihydro-4 , 9-dioxo-2- (2-furyl) -7-methoxy-naph to [2,3-d] thiazole -4,9-dihydro-4,9-dioxo-2-furyl-6-methylnaph to- [ 2,3-d] thiazole -4,9-dihydro-4,9-dioxo-2-fur il-7-methylnaf to- [2,3-d] thiazole -4,9-dihydro-4,9-dioxo-6-methyl-2-f-enylnaph- [2,3-d] thiazole -4, 9 -dihydro-4, 9-dioxo-7-methyl-2-f-enylnaph- [2, 3-d] thiazole -4, -dihydro-4, 9-dioxo-2-f-uryl-5-methylnaf- [, 3-d] thiazole -4,9-dihydro-4,9-dioxo-2-furyl-8-met i Inaf o- [2,3-d] iazole -4,9-dihydro-4,9- dioxo -5-methyl-2-f enylnaph to- [, 3-d] thiazol-4, 9-dihydro-4, 9-dioxo-8-methyl-2-f-enylnaph- [2, 3-d] thiazole The invention also comprises the following intermediates: -1, 4-dihydro-l, 4-dioxo-5-methoxy-naphthanne, -2, 3-dibromo-l, 4-dihydro-l, 4-dioxo-5- methoxy-naphthalene, -2-amino-3-bromo-1,4-dihydro-1, -dioxo-5-methoxy-naphthane-2-amino-3-bromo-1,4-dihydro-l, 4-dioxo- 8-methoxy-naphthane-2, 3-dibromo-l, 4-dihydro-l, 4-dioxo-6-f luoro-naphne-2-amino-3-bromo-6-f luoro-1,4-dihydro- l, 4-dioxo-naphthalen-2-amino-3-bromo-7-f luoro-1,4-dihydro-1,4-dioxo-naphne-2, 3-dibromo-l, 4-dihydro-l 4-dioxo-5-f lu oro-naf taleno -2-amino-3-bromo-l, 4-dihydro-1,4-dioxo-5-f luoro-naf-taleno-2-amino-3-bromo-1,4-dihydro-1,4 -dioxo-8-fluoro-naphthalene-2-amino-3-chloro-l, 4-dihydro-1,4-dioxo-6 -met and Inaf taneno-2-amino-3-chloro-l, 4-dihydro- 1, 4-dioxo-7-methylnaph-2, 3-dibromo-1,4-dihydro-1, -dioxo-5-methyl-naphthalene--amino-3-bromo-1,4-dihydro-1, 4 -dioxo-5-methyl-naphthalene -2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-8-methyl-naphthalene The invention also comprises the use of tricyclic derivatives and their acceptable salts for pharmaceutical use which correspond to the general formula (I) for obtaining a medicine intended for: -the treatment of functional or organic venous insufficiency; -the treatment of hemorrhoidal pathologies; -the treatment of migraine; -the treatment of osteoarticular, dermatological and cardiovascular inflammations; -the treatment of shock states constituted by a significant drop in blood pressure and more particularly in the states of septic shock. Specifically, the compounds of the present invention correspond to the general formula (I) illustrated below A = -NH, -N- CSH5, -N-CH ,, 0, S, N R, = -CH3, -NH2, R2 = H, -OCH3, -OH, -F, Cl, CH3 The present invention further comprises the salts of the salifiable compounds of the formula (I). Said salts comprise the addition salts of mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, or nitric acid and the addition salts of organic acids such as acetic, propionic, oxalic, citric, maleic, fumaric, succinic, tartaric The invention is illustrated by means of the following non-limiting examples. The examples identified by numbers correspond to new compounds, while the examples identified by letters correspond to known compounds. In all the examples, the analyzes are carried out as indicated below: Melting points: they were made in a "Bank of Kofler" type device LEICA - REICHERT model WME. - Thin layer chromatographies: They were obtained on silica gel plates with UV254 fluorescence indicator of 0.25 mm thickness of type MACHEREY-NAGEL (Reference 805 023). The elution solvents are those indicated for each compound. - Mass spectra: They were carried out either in an AEI MS-50 type spectrometer, or in a FISONS VG PLATFORM type spectrometer. The form of ionization is indicated for each analysis. - NMR spectra: The NMR spectra of XH and 13C were performed either on a JEOL type spectrometer at 270 M Hz and at 68 M Hz respectively, or on a BRUCKER type spectrometer at 400 M Hz and at 100 M Hz. respectively The deuterated solvents used are indicated for each analysis. - Infrared spectra: They were obtained in a NICOLET 205 FT-IR type spectrometer. They were made 1% (m / m) in dispersion in Kbr. Use 1 Sulfate of 4,9-Dihydro-4,9-dioxo-1,2-dimethyl-1H-naphth [2, 3-d] imidazole To a solution of 2g (8.84 mmol) of 4,9-dihydro- 4,9-dioxo-1,2-dimethyl-lH-napht [2,3-d] imidazole in 300ml of a mixture (2/1) methanol / dichloromethane maintained at 70 ° C, lml of concentrated sulfuric acid was added. The reaction mixture was stirred at 70 ° C for two hours, concentrated under reduced pressure and the pale yellow precipitate produced was filtered, washed with dichloromethane and then with ethyl ether to obtain 2 g of 4,9-dihydroxy sulfate. 4,9-dioxo-l, 2-dimethyl-lH-naphth [2,3-d] imidazole in the form of yellow crystals. Rdt: 70% F: > 260 ° C Rf: 0.50 (CH2Cl2 / Methanol, 97.5 / 2.5) XK NMR (DMSO d6): d (ppm) 8.05 (dd, 2H, H-5, H-8, JH5 -H6 = JH7-H8 = 8.85 Hz; JHS_H7 = H6-HS 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) NMR of 13 C (DMSO, d6): d (ppm) 177.22, 175.44 (2 C, C-4, C-9) 153.46 (C, 2 C) 138.96 (C, 3 C) 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 (IC, CH3) IR (KBr): v (cm "1) Between 3414 and 2400 (long band NH +); 1674 (C = 0) ) Example 2 4, 9-Dihydro-4,9-dioxo-2- (2-fluorophenyl) -iH-napht- [2,3-d] imidazole To a suspension of 1.37g (7.29 mmoles) of 2,3- diamino-1,4-dihydro-l, 4-dioxo-naphthalene in 50 ml of water, a solution of 0.77 ml (7.29 mmoles) of 2-fluorobenzaldehyde in 5 ml of glacial acetic acid was added, after 5 hours of reflux the The black solid obtained was filtered, then washed three times with 30 ml of water.The solid is then recovered with 2 liters of dichloromethane and the organic phase was washed three times with water, dried in calcium chloride and then evaporated to dry to get 1.50g of brown crystals. The product was purified on a flash column (support: silica, conditioning: heptane, eluents: dichloromethane / heptane, 95/5 then dichloromethane / methanol, 99/1), this is how they were obtained after the evaporation of the solvents under reduced pressure O.OOg of 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -lH-naft [2, 3-d] -imidazole in the form of yellow crystals. Rdt: 47% F: > 260 ° C Rf: 056 (CH2Cl2 / ethyl acetate, 92/8) SM (EI): m / z 292 (M +.) NMR of XH (DMSO d6): d (ppm) 14.28 (s, lH, NH) 8, 12 (m, 2H, H-5, H-8) 8.00 (m, 1H, H-6 ') 7.86 (m, 2H, H-6, H-7) 7.60 (m, 1H , H-3 ') 7.44 (m, 2H, H-4', H-5 ') 13 C NMR (DMSO d6): d (ppm) 179.13, 175.03 (2C, C-4, C-9) 157.41 (IC, C-2 ') 147.88 (IC, C-2) 133.85 (2C, C-6, C-7) 132.67 (3C, C-6', C-9a, C-3a) 130.62 (2C, C-4a, C-8a) 126.24, 124.82 (3C, C-5, C-8, C-5 ') 116.62, 116 , 31 (2C, C-11, C-31) IR (KBr): v (cm "1) 3339 (NH); 1683.1665 (C = 0) Example 3 4, 9-Dihydro-4, 9-dioxo-2- (2-fluorofissil) -naft [2,3-d] oxazole To a solution of 6. Og (28.8 mmol) of 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-naphthalene in 120 ml of nitrobenzene was added under cover of light 17.10 ml (144.0 mmoles) of 2-fluorobenzoic acid chloride.
After 10 minutes of stirring at 80 ° C, it was added 0. 20ml of concentrated sulfuric acid. The reaction mixture was refluxed for 18 hours. After complete cooling, ether was added to obtain a yellow precipitate which was filtered on sintered glass and washed with ether. This solid is then purified on a flash column (support: silica, conditioning: heptane, eluent: dichloromethane / heptane, 60/40) to obtain 2.5 g of 4,9-dihydro-4,9-dioxo-2- (2 -fluorophenyl) -naft [2, 3-d] -oxazole in the form of yellow crystals Rdt: 30% F: > 260 ° C Rf: 0.60 (CH2C12) SM (IE): m / z 293 (M +.) H-NMR (DMSO ds): d (ppm) 8.25 (m, 2H, H-5, H- 8) 8.19 (m, 1H, H-6 ') 7.95 (m, 2H, H-6, H-7) 7.76 (m, 1H, H-4') 7.52 (m, 2 H, H-3 ', H-5 •) 13 C NMR (DMSO d 6): d (ppm) 178.22, 173.06 (2 C, C-4, C-9) 161.88 (C, C- 2) 158.08 (IC, C-2 ') 150.67, 142.83 (2C, C-3a, C-9a) 135.37 (1C, C-6') 134.64 (2C, C- 6, C-7) 132.31, 131.94 (2C, C-4a, C-8a) 130.65 (IC, C-4 ') 126.79, 126.47 (2C, C-5, C -8) 125.62 (IC, C-5 ') 117.32 (IC, C-31) 113.21 (IC, C-1') IR (KBr): v (cm "1) 1693, 1680 ( C = 0) Example 4 4, 9-Dihydro-4, 9-dioxo-2- (3-fluorophenyl) -naft [2,3-d] oxazole To a solution of 5.00g (24 mmoles) of 2-amino- 3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 50ml of nitrobenzene, 14.6ml (120mmol) of 3-fluorobenzoic acid chloride was added to shelter from light and after 5 minutes of stirring 0.50ml of concentrated sulfuric acid After 24 hours of reflux and complete cooling, it was added to the 200ml reaction mixture of ether. The formed precipitate was filtered and then taken up in 200 ml of dichloromethane to which 100 ml of a glacial solution of sodium hydroxide was added. After 6 hours under stirring at this temperature, the organic phase was extracted, washed several times with water and dried in calcium chloride. The solid obtained after evaporation of the solvent was purified on a medium pressure column (support: silica, conditioning: heptane, eluent: dichloromethane / heptane, 50/50). The yellow crystals obtained are decolorized, recrystallized in a (v / v) dichloromethane / heptane mixture to obtain 0.50g of 4,9-dihydro-4,9-dioxo-2 (3-fluorophenyl) -naft [2, 3-d ] oxazole in the form of yellow crystals.
Rdt: 7% F: 230 ° C Rf: 0.50 (CH2Cl2 / Heptane, 95/5) SM (IE): m / z 293 (M +.) NMR of XH (CDC13): d (ppm) 8.31 (m, lH, H-6 ') 8.27 (m, 2H, H-5, H-8) 8.02 (s, 1H, H-2') 7.83 (m, 2H, H-6) , H-7) 7.63 (m, 1H, H-5 ') 7.31 (m, 1H, H-4') 13 C NMR (DMSO d6): d (ppm) 178,173 (2C, C-4, C-9) 162.53 (IC, C-3 ') 149.37 (IC, C-9a) 143.47 (IC, C-3a) 134,85,134.46 (2C , C-6, C-7) 132. 45, 132.08 (2C, C-4a, C-8a) 131.06 (IC, C-5 ') 127.52, 127.11 (2C, C-5, C-8) 124.74 (IC. , C-6 ') 117.46, 117.15 (2C, C-2, C-4') IR (KBr): v (cm "1) 1695, 1680 (C = 0) Example 5 4, 9-Dihydro- 4, 9-dioxo-2- (4-fluorophenyl) -naft [2,3-d] oxazole To a solution of 6.22g (30 mmol) of 2-amino-3-chloro-1,4-dihydro-1, 4-dioxo-naphthalene in 60ml of nitrobenzene was added while protecting light from ld.OOml (150mmol) 4-fluorobenzoic acid chloride.After 10 minutes of stirring at reflux, 0.20ml of concentrated sulfuric acid was added. After 12 hours and complete cooling, ether was added to obtain a yellow precipitate which was filtered on fritted glass, washed with ether and purified on a flash column (support: silica, conditioning: heptane, eluent: dichloromethane / heptane, 60/40) The yellow powder obtained after evaporation of the solvent was decolorized, recrystallized from dichloromethane to obtain 2.90g of 4,9-dihi dro-4, 9-dioxo-2 - (4-fluorophenyl) -naft [2,3-d] oxazole in the form of yellow crystals. Rdt: 33% F: > 260 ° C Rf: 0.60 (CH2Cl2 / Heptane, 80/20) SM (EI): m / z 293 (M +.) 1 H NMR (CDC13): d (ppm) 8.33 (m, 2H, H -2 ', H-6') 8.28 (m, 2H, H-5, H-8) 7, 82 (m, 2H, H-6, H-7) 7.26 (m, 2H, H-3 ', H-5') 13 C NMR (CDC13): d (ppm) 166.89 (IC, C-4 ') 143.45 (IC, C-3a) 134.42 (2C, C-6, C-7) 132.86, 132.55 (2C, C-4a, C-8a) 130.78 (2C, C-2 ', C-6') 127.52, 127.07 (2C, C-5, C-8) 121.50 (IC, C-1 ') 116.82, 116.50 ( 2C, C-3 ', C-5') IR (KBr): v (cm "1) 1689, 1669 (C = 0) Example 6 4, 9-Dihydro-4.9-dioxo-2- (2-methylphenyl) -naft [2, 3-d] oxazole To a solution of 5.00g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-l, 4-dioxo-naphthalene in 37ml (280mmol) of chloride of acid-2-methylbenzoic acid, 8 drops of concentrated sulfuric acid were added to the light after 7 hours of reflux and complete cooling, the ocher precipitate that formed, was filtered on sintered glass, washed with ether and purified on a flash column (support: silica; conditioning: heptane; eluent: dichloromethane / heptane, 50/50). The yellow powder obtained after evaporation of the solvent was decolorized, and recrystallized from dichloromethane to obtain 2. 34g of 4,9-dihydro-4,9-dioxo-2- (2-methylphenyl) -naft [2,3-d] oxazole in the form of yellow crystals. Rdt: 34% F: 212 ° C Rf: 0.50 (CH2Cl2 / Heptane, 80/20) SM (IE): m / z 289 (M +.) NMR of ^ (CDC13): d (ppm) 8.30 (m, 1H, H-6 ') 8.27 (m, 2H, H-5, H-8) 7.81 (m, 2H, H-6, H-7) 7.47 (m, 1H, H-4 ') 7.37 (m, 2H, H-3', H-5 ') 2.84 (s, 3H, CH 3) RN of 13C (CDCl 3): d (ppm) 179.05, 173, 50 (2C, C-4, C-9) 140.81 (IC, C-21) 134.77 (2C, C-6, C-7) 133.50 (IC, C-3) 132.50 ( IC, C-4 ') 130.80 (IC, C-61) 127.91, 127.49 (2C, C-5, C-8) 125.60 (IC, C-5') 123.45 ( ÍC, C-1 ') 22.50 (ÍC, CH3) IR (KBr): V (cm "1) 1668, 1678 (C = 0) Example 7 4, 9-Dihydro-4.9-dioxo-2- (3 methylphenyl) -naft [2,3-d] oxazole To a solution of 5 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphne in 70 ml of dioxane, 32.00ml (240 mmoles) of 3-methylbenzoic acid chloride were added to the light and, after 5 minutes of stirring, 0.50ml of concentrated sulfuric acid, after 45 minutes of reflux and complete cooling, added 200ml of ether and the precipit The formation that was formed was eliminated by filtration. The red filtered liquid was evaporated to dryness, extracted into dichloromethane, washed several times with water, dried and purified on a flash column (support: silica, conditioning: heptane, eluent: dichloromethane / heptane, 50/50). The yellow crystals formed after evaporation of the solvent were decolorized, recrystallized from dichloromethane to obtain 3g of 4,9-dihydro-4,9-dioxo-2- (3-methylphenyl) -naft [2,3-d] -oxazole in the form of yellow crystals. Rdt: 43% F: 255 ° C Rf: 0.43 (CH2Cl2 / Heptane, 80/20) SM (IE): m / z 289 (M +.) NMR of XH (CDC13): d (ppm) 8.26 (m, 2H, H-5, H-8) 8.17 (s, 1H, H-2 ') 8.13 (m, 1H, H-5') 7.82 (m, 2H, H-6) , H-7) 7.43 (m, 2H, H-4 ', H-6') 2.48 (s, 3H, CH3) 13 C NMR (CDC13): d (ppm) 179.13, 173, 72 (2C, C-4, C-9) 166.95 (IC, C-2) 150.65, 144.17 (2C, C-3a, C-9a) 139.62 (IC, C-3 ' ) 134,81, 134,77; 134.32 (3C, C2 ', C-6, C-7) 132.86, 132.55 (2C, C-4a, C-8a) 129.54, 129.26 (2C, C-4 ', C-5') 127.91, 127.49 (2C, C- 5, C-8) 125.86 (IC, C-6 ') 125.44 (IC, C-11) 21.71 (IC, CH3) IR (KBr): v (cm "1) 1693.1678 ( C = 0) Example 8 4, 9-Dihydro-4, 9-dioxo-2- (4-methoxyphenyl) -naft [2,3-d] oxazole To a solution of 5.Og (24 mmoles) of 2-amino -3-chloro-1,4-dihydro-l, 4-dioxo-naphthalene in 80ml of dichloromethane, 16ml (120mmol) of 4-methoxybenzoic acid chloride was added to the light and at room temperature, and then 0.003ml of concentrated sulfuric acid After 3 hours of reflux the reaction mixture was evaporated to dryness, and the obtained black oily residue was extracted with 300ml of dichloromethane, washed with a 10N sodium hydroxide solution, and then with water and finally dried in calcium chloride, the product was then purified on a flash column (silica 6-35 mm, conditioning: heptane, eluent: dichloromethane / heptane, 60/40), to obtain 4. lg of 4,9-dihydro-4,9-dioxo-2- (4-methoxyphenyl) -naft [2,3-d] oxazole in the form of yellowish-orange crystals after recrystallization and decoloration with animal black. Rdt: 56% F: > 260 ° C Rf: 0.44 (CH2Cl2 / Ethanol, 99/1) SM (IE): m / z 305 (M +.) NMR of XH (CDC13): d (ppm) 8.28 (dd, 2H, H -5, H-8, JH5_H6, = 8.85 Hz, '-'H5-H7 - "H = 1.73 Hz) 8.24 (d, 2H, H-2', H-6 ', JH2, .H3, = JH5.-H6 '= 8-60 Hz) 7.80 (m, 2H, H-6, H-7) 7.05 (d, 2H, H-3', H-5 ', JH2.-H3. = JHS.-H6- = 8.60 Hz) 3.92 (s, 3H, CH3) IR (KBr): v (cm "1) 1750.1680 (C = 0) Example 9 2- (2-Chlorophenyl) ) -4,9-dihydro-4,9-dioxo-naft [2,3-d] oxazole To a solution of 5g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4 -dioxo-naphthalene in 60 ml of dioxane, 15.3 ml (120 mmoles) of 2-chlorobenzoic acid chloride was added and, after 5 minutes of stirring, 0.5 ml of concentrated sulfuric acid. The reaction mixture was refluxed for 4 hours and the precipitate obtained after evaporation of the dioxane under reduced pressure was dissolved in 200 ml of dichloromethane. To this solution, 100 ml of a 10 N sodium hydroxide solution was added cold. It was allowed to stir for 2 hours. The organic phase was then extracted, washed several times with water and dried in calcium chloride. The solid residue obtained after evaporation of the solvent was purified on a medium pressure column (support: silica; eluent: dichloromethane / heptane, 40/60). The product obtained was recrystallized after decolorization of the mixture (l / l) heptane / dichloromethane to obtain 5 g of 2- (2-chlorophenyl) -4,4-dihydro-4,9-dioxo-naft [2, 3- d] -oxazole in the form of light yellow crystals. Rdt: 67% F: 216 ° C Rf: 0.42 (CH2Cl2 / Heptane, 80/20) SM (IE): m / z 309.311 (M +.) NMR of Í (CDC13): d (ppm) 8 , 26 (m, 3H, H-5, H-8, H-6 ') 7.82 (m, 2H, H-6, H-7) 7.53 (m, 3H, H-3', H -4 ', H-5') 13 C NMR (CDC13): d (ppm) 134.99, 134.87 (3 C, C-2 ', C-6, C-7) 133.78, 132.84 , 132.18 (4C, C-3 ', C-41, C-51, C-61) 132.38, 132.04 (2C, C-4a, C-8a) 128.04, 127.63 ( 2C, C-5, C-8) 124.80 (IC, C-1 ') IR (KBr): v (cm "1) 1691.1674 (C = 0) Example 10 2- (4-Chlorophenyl) - 4,9-dihydro-4,9-dioxo-naphth [2,3-d] oxazole To a solution of 5. Og (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4. dioxane-naphthalene in 60 ml of dioxane was added at room temperature 15.3 ml (120 mmol) of 4-chlorobenzoic acid chloride and 0.5 ml of concentrated sulfuric acid.The reaction mixture was refluxed for 4 hours, then evaporated to dry, extracted with 200 ml of dichloromethane and neutralized cold with 100 ml of 10 N sodium hydroxide. The organic phase was then washed three times with water and dried in calcium chloride. The red powder thus obtained was purified on a flash column (support: silica, conditioning: heptane, eluent: dichloromethane / heptane, 70/30). The yellow crystals obtained after evaporation of the solvent were decolorized, and recrystallized from dichloromethane to obtain 2.5 g of 2- (4-chlorophenyl) -4,9-dihydro-4,9-dioxo-lH-naft [2, 3- d] oxazole in the form of yellow crystals. Rdt: 34% F: > 260 ° C Rf: 0.40 (CH2Cl2 / Heptane, 80/20) SM (IE): m / z 309.311 (MH +) NMR of ^ (CDC13): d (ppm) 8.28 (m, 4H, H- 5, H-8, H-2 ', H-61) 7.82 (m, 2H, H-6, H-7) 7.55 (d, 2H, H-3', H-5 ', JH2 , _H3 = JH5, .H6 8.34 Hz) 13 C NMR (CDC13): d (ppm) 178.55, 173.21 (2C, C-4, C-9) 165.31 (lC, C-2 ) 150.35, 144.03 (2C, C-3a, C-9a) 139.55 (IC, C-4 ') 134.48, 134.43 (2C, C-6, C-7) 132, 38, 132.04 (2C, C-4a, C-8a) 129.65, 129.49 (4C, C-2 ', C-3', C-5 ', C-6') 127.55, 127.09 (2C, C-5, C-8) 123.63 (IC, C-1 ') IR (KBr): v (cm "1) 1695, 1675 (C = 0) Example 11 4, 9- Dihydro-4, 9-dioxo-2- (2-thienyl) -naft [2,3-d] -oxazole To a solution of 5. Og (24 mmol) of 2-amino-3-chloro-1,4-dihydro- l, 4-dioxo-naphthalene in 50 ml of dichloromethane, 12.9 ml (120 mmoles) of 2-tenoyl chloride and then 3 μl of concentrated sulfuric acid were added at room temperature and at room temperature. reflux, the reaction mixture was evaporated to dry and the oily residue black or The residue was extracted with 100 ml of dichloromethane and washed with a 10 N sodium hydroxide solution, then with water and finally dried in calcium chloride. Then, the product was purified on a flash column (silica 6-35 μm, conditioning: heptane, eluent: dichloromethane / heptane, 60/40), to obtain 5.3 g of 4,9-dihydro-4,9-dioxo2- (2-thienyl) -naft [2,3-d] oxazole in the form of yellowish-orange crystals after recrystallization and decoloration with animal black.
Rdt: 78% F: > 260 ° C Rf: 0.41 (CH2C12) SM (IE): m / z 281 (M +.) 1 H NMR (CDC13): d (ppm) 8.22 (dd, 2H, H-5, H-8 , JHS-H6. = 8.85 Hz, JHS.H7 = 1.73 Hz) 8.06 (dd, 1H, H-5 ', JH5, -H41 = 3.49 Hz, JH5, _H3. = 1/00 Hz) 7 , 83 (m, 2H, H-6, H-7) 7.73 (dd, 1H, H-3 ', JH3, -H4, = 4.88 Hz, JH3, -H5, = 1.00 Hz) 7.27 (dd, 1H, H-4 ', JH4, -H3, = 4.88 Hz, JH4, -H5. = 3.49 Hz) IR (KBr): v (cm "1) 1687.1667 ( C = 0) Example 12 4, 9-Dihydro-4, 9-dioxo-2- (2-fluorophenyl) -naphtho [2,3-d] thiazole To a suspension of 5. Og (24 mmoles) of 2-amino 3-Chloro-1,4-dihydro-1,4-dioxo-naphthalene in 80 ml of water was added 8.4 g (35 mmol) of sodium sulphide nonahydrate The reaction mixture was refluxed for approximately 20 minutes. minutes, then 20ml of an aqueous solution containing 2.Og of sodium sulfide was added.When the medium changed completely to the blue coloration, 1.95ml (24mmol) of 2-fluorobenzaldehyde and 6.36ml of glacial acetic acid were successively added. After an hour of reflux, the obtained black semi-solid product was filtered, dried and then purified on a flash column (support: silica; conditioning: heptane; eluent: dichloromethane / heptane, 50/50). The greenish crystals formed after the evaporation of the solvent were washed several times with ethanol and ether and then decolorized and recrystallized from dichloromethane to obtain 2. Og of 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -naphtho [2,3-d] -thiazole in the form of yellow crystals. Rdt: 27% F: > 260 ° C Rf: 0.60 (CH2C12) SM (IE): m / z 309 (M +.) 1 H NMR (CDC13): d (ppm) 8.62 (m, 1H, H-6 ') 8, 30, 8.21 (2dd, 2H, H-5, H-8, JHS-H6 = ^ HV-HS = 8.85 Hz, JHS-HS = JHS-H7 = 1-73 Hz) 7.81 (m, 2H, H-6, H-7) 7.56 (m, 1H, H-4 ') 7.29 (m, 2H, H-3) ', H-5') RM? of 13 C (CDC13): d (ppm) 179.17 (2 C, C-4, C-9) 169.20 (1 C, C-2 ') 153.47 (C, 2 C), 134.43, 134 , 09 (2C, C-6, C-7) 133.70, 133.56 (2C, C-4a, C-8a) 130.02 (IC, C-6 ') 127.86, 126.97 (2C, C-5, C-8) 124.99 (IC, C-4') 120 , 00 (ÍC, C-5 ') 116.48, 115.90 (2C, C-1', C-3 ') IR (KBr): v (cm "1) 1683, 1661 (C = 0) Example 13 4, 9-Dihydro-4, 9-dioxo-2- (3-fluorofissil) -naphtho [2,3-d] thiazole To a suspension of 5. Og (24 mmol) of 2-amino-3-chloro- 1, 4-dihydro-l, 4-dioxo-naphthalene in 50 ml of water was added a solution containing 8.4 g (35 mmol) of sodium sulphide nonahydrate in 50 ml of water.The reaction mixture was refluxed For approximately 20 minutes, at the time when the reaction medium turned blue, 2.50 ml (24 mmol) of 3-fluorobenzaldehyde and 6.36 ml of glacial acetic acid were successively added, after two hours of reflux, the black product obtained filtered, dissolved in dichloromethane, washed with distilled water, dried in calcium chloride, filtered and evaporated under reduced pressure.The obtained black-green solid was then purified. n in a flash column (support: silica; conditioning: heptane; eluent: dichloromethane / heptane, 50/50, then dichloromethane, then dichloromethane / methanol, 99/1). The solid obtained after evaporation of the solvent was washed several times with methanol, ethanol and ether then decolorized and recrystallized from dichloromethane to obtain 4. Og of 4,9-dihydro-4,9-dioxo-2- (3- fluorophenyl) -naphtho [2, 3-d] -thiazole in the form of yellow crystals. Rdt: 54% F: > 260 ° C Rf: 0.56 (CH2C12) SM (IE): m / z 309 (M +.) NMR of ^ (CDClj): d (ppm) 8.37, 8.25 (2dd, 2H, H-5 , H-8, JH JH = 8.85 Hz, JH 7.95 (m, 2H, H-2 ', H-6') 7.84 (m, 2H, H-6, H-7) 7.55 ( m, 1H, H-5 ') 7.25 (m, 1H, H-4 *) IR (KBr): v (cm "1) 1676, 1661 (C = 0) Example 14 4.9-Dihydro-4 , 9-dioxo-2- (4-fluorofissil) -naphtho [2,3-d] thiazole To a suspension of 5. Og (24 mmoles) of 2-amino-3-chloro-1,4-dihydro-l, 4-dioxo-naphthalene in 130ml of water, 8.4g (35mmol) of sodium sulphide nonahydrate was added.The reaction mixture was refluxed for 20 minutes, then 50ml of an aqueous solution containing 1ml was added. .Og of sodium sulfide.
The medium became completely blue in color. 2.60 ml (24 mmol) of 4-fluoro-benzaldehyde and 6.36 ml of glacial acetic acid were successively added. After one hour of reflux, the greenish precipitate obtained was filtered, dried, and then purified on a flash column (support: silica, conditioning: heptane, eluent: dichloromethane / heptane, 60/40). The yellow crystals formed after evaporation of the solvent were successively washed with isopropanol and ether and then decolorized and recrystallized from dichloromethane to obtain 2. Og of 4,9-di-hydro-4,9-dioxo-2- (4-fluorophenyl) -naphtho [2,3-d] -thiazole in the form of yellow crystals. Rdt: 27% F: > 260 ° C Rf: 0.51 (CH2Cl2 / Heptane, 90/10) SM (IE): m / z 309 (M +.) NMR of ^ (CDCl;,): d (ppm) 8.30, 8.21 (2dd, 2H, H-5, H-8, JHS-H6 'H8-H7 = 8.85 Hz, JH JH8-H6 = 1.73 Hz) 8.12 (m, 2H, H-2 ', H-6') 7.83 (m, 2H, H-6, H-7) 7.22 (m, 2H , H-3 ', H-5') 13 C NMR (CDC13): d (ppm) 179.17 (2C, C-4, C-9) 165.21 (IC, C-4 ') 134.46 , 134.04 (2C, C-6, C-7) 132.78, 132.43 (2C, C-4a, C-8a) 130.08, 129.96 (2C, C-2 ', C- 6 ') 127.88, 126.98 (2C, C-5, C-8) 116.74, 116.42 (2C, C-3', C-5 ') IR (KBr): v (cm " 1) 1678, 1659 (C = 0) Example 15 2- (2,4-Difluorophenyl) -4,9-dihydro-4,9-dioxo-naphtho- [2,3-d] thiazole A 5. Og (24.15 mmoles) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxanephthalene in 150 ml of water was added 150 ml of an aqueous solution containing 29. Og. (120.00 mmoles) of sodium sulphide nonahydrate. The reaction mixture was refluxed for 20 minutes. The medium completely turned to a blue coloration. 2. Oml (18.00 mmoles) of 2,4-difluorobenzaldehyde and 6.3 ml of glacial acetic acid were successively added.
After 3 hours of reflux, the solid formed was filtered, washed with distilled water, dried and then purified on the cake (support: silica, eluent: dichloromethane). The yellow crystals obtained after the evaporation of the solvents were recrystallized from dichloromethane, decolorized with animal black to obtain 3.9 g of 2- (2,4-difluorophenyl) -4,9-dihydro-4,9-dioxo-naphtho [ 2, 3-d] thiazole.
Rdt: 97% F: > 260 ° C Rf: 0.40 (CH2C12) SM (IE-): m / z 327 (M +.) 1 H NMR (CDC13): d (ppm) 8.55 (m, 1H, H-3 ') 8 , 28, 8.24 (2dd, 2H, H-5, H-8, J, H5-H6 = k-lH7-H8 8.85 Hz, JH JH6-H8 = 1-73 Hz) 7.84 (m, 2H , H-6, H-7) 7.10 (m, 2H, H-5 ', H-6') 13 C NMR (CDC13): d (ppm) 178.88, 177.93 (2C, C- 4, C-9) 163.45 (IC, C-2) 134.87, 134.52 (2C, C-6, C-7) 133.44, 133.10, 131.61 (4C, C- 3a, C-4a, C-8a, C-9a) 127.95, 127.18 (2C, C-5, C-8) 123.45 (IC, C-1 ') 113.53, 113.21 (2C, C-2 ', C-4') 105.56, 105.18, 104.79 (3C, C-3 ', C-5', C-6 ') IR (KBr): v (cm "1) 1681, 1658 (C = 0) Example 16 4, 9-Dib.idro-4, 9-dioxo-2- (3-pyridyl) -naphtho [2,3-d] -thiazole To a suspension of 10 .OOg (48.2 mmoles) of 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-naphthalene in 100 ml of water was added 13.88 g (74.5 mmoles) of sodium sulphide nonahydrate. of reaction, brought progressively to reflux, turned to blue coloration at 60 ° C. The addition of 4.00g (16.7 mmol) of concentrated sodium sulfide of water was necessary to complete the change in coloration. Then 6ml (60.6 mmol) of 3-pyridine carboxaldehyde and lOml of glacial acetic acid were successively added. After two hours of reflux, and complete cooling, 300ml of ethanol was added. The formed precipitate was removed by filtration. The filtrate was evaporated to dryness, extracted into dichloromethane, washed several times with ether and then with water, dried and purified on a medium pressure column (support: silica, conditioning: heptane, eluent: dichloromethane / methanol, from 100/0 to 99/1). The yellow crystals formed after evaporation of the solvent were washed with ethanol and then decolorized, recrystallized from dichloromethane to obtain l.OOg of 4,9-dihydro-4,9-dioxo-2- (3-pyridyl) -naphtho [2, 3-d] thiazole in the form of yellow crystals.
Rdt: 7% F: 256 ° C Rf: 0.50 (CH2Cl2 / Methanol, 98/2) SM (IE): m / z 292 (M +.) K NMR (CDC13): d (ppm) 9.33 (d, 1H, H-2 ', J = 1, 83 Hz) 8.80 (d, 1H, H-6f, JH5, -H6. = 3.36 Hz) 8.49 (d, 1H, H- 4 ', JH4, -H5, = 7.93 Hz) 8.36, 8.26 (2dd, 2H, H-5, H-8, JH5-HS = JH7-H8! 5 Hz, J. H5-H7 JHS-H8 = 1-73 Hz) 7.84 (m, 2H, H-6, H-7) 7.50 (dd, 1H, H-5 ', JH4, -H5, = 7.93 Hz, JH5 , -H6, = 3.36 Hz) 13 C NMR (CDC13): d (ppm) 178.13, 177.78 (2C, C-4, C-9) 177.67 (IC, C-2) 155 , 18 (IC, C-3a) 152.87, 148.58 (2C, C-2 'C-6') 142.18 (IC, C-9a) 134.77, 134.31 (2C, C- 6, C-7) 134.18 (IC, C-4 ') 132.74, 132.01 (2C, C-4a, C-8a) 128.36 (IC, C-3') 128.04, 127.16 (2C, C-5, C-8) 124.56 (IC, C-5 ') IR (KBr): v (cm "1) 1680, 1660 (C = 0) Example 17 Sulfate of 4, 9-Dihydro-4, 9-dioxo-2- (4-pyridyl) -naphtho [2,3-d] thiazole To a suspension of 500 mg (1.71 mmol) of 4,9-dihydro-4,9-dioxo -2- (4-pyridyl) -naphtho [2,3-d] thiazole in 60 ml of methanol, 60 ml of a methanolic solution containing O.ldml (1.74 mmol) of 98% sulfuric acid was added. After one hour of refluxing and complete cooling, the yellow precipitate obtained was filtered, rinsed several times with ethyl ether and then dried, thus obtaining 500 mg of 4,9-dihydro-4,9-dioxo-2-sulfate. (4-pyridyl) -naphtho [2,3-d] thiazole, in the form of yellow crystals. Rdt: 75% F: > 260 ° C Rf: 0.50 (CH2Cl2 / Methanol, 96/4) IR (KBr): v (cm "1) of 3100 and 2725 (NH +); 1686, 1668 (C = 0) Example 18 4.9- Dihydro-4,9-dioxo-2- (3-furyl) -naphtho [2,3-d] -thiazole A 6. Og (29 mmol) of 2-amino-3-chloro-l, 4-dihydro-1 , 4-dioxo-naphthalene, was added lOOml of a freshly prepared aqueous solution containing 34.8g (145 mmol) of sodium sulphide nonahydrate.The reaction mixture was stirred at 70 ° C for 20 minutes, until the A bluish color was then added 2.5 ml (29 mmoles) of 3-furaldehyde and 7.6 ml (133 mmoles) of glacial acetic acid, after two hours of stirring at 50 ° C, and then 1 hour 40 minutes at room temperature At this time, the dark yellow precipitate obtained was filtered and washed twice with 500 ml of water, thus obtaining 7. Og of crystals that were extracted with 500 ml of dichloromethane, washed three times with 750 ml of water and then dried in ethyl chloride. calcium and filtered. After evaporation of dichloromethane under reduced pressure, the orange solid obtained was purified by filtration on a silica pad (dichloromethane / heptane, 80/20) to obtain 3.5 g of 4,9-dihydro-4,9-dioxo-2- (3-furyl) -naphtho [2,3-d] thiazole as yellow crystals which were recrystallized from ethyl acetate after discoloration with animal black. Rdt: 43% F: 245 ° C Rf: 0.58 (CH2Cl2) SM (IE): m / z 281 (M +.) NMR of XH (CDC13): d (ppm) 8, 34 (dd, 1H, H - 5h H- 8, JH5.H6 = JH7.H8 = 8. 85 Hz, JH5_H7 = JH6.H8 = 1 . 73 Hz), 28 (dd, 1H, H-2., = 1.50 Hz, JH = 0.90 Hz) 8.23 (dd, 1H, H-5ou, H-8, J, H5-H6 ~ '-' H7-H8 = 8.85 Hz, '-'HS-H? - "-? S-H8 = 1.73 Hz) 7.81 (m, .2H, .H-6, .H-7) 7.56 (t, .1H, .H-5 ', .JH2, -H5, = 1.50 Hz) 6.98 (dd, .1H, .H-4', .JH2, .H4, = 0.90 Hz, .JH4, _H5, = 1.80 Hz) 13 C NMR (CDC13): d (ppm) 178.28, 177.83 (2C, C-4, C-9) 167.28 (IC, C-2) 155.05 (IC, C- 3a) 144.77, 143.90 (2C, C-2 ', C-5') 140.77 (IC, C-9a) 134.39, 134.06 (2C, C-6, C-7) 133.04, 132.63 (2C, C-4a, C-8a) 127.86, 126.90 (2C, C-5, C-8) 120.80 (IC, C-3 ') 109.19 (ÍC, C-4 ') IR (KBr): v (cm "1) 1678.1656 (C = 0) Example 19 2- (5-Chloro-furan-2-yl) -4, 9-dihydro-4 , 9-dioxo-naphtho [2,3-d] thiazole To a solution of 1.78g (6.3 mmoles) of 4,9-dihydro-4,9-dioxo-2- (2-furyl) -naphtho [2, 3 -d] thiazole in 600ml of chloroform, was injected at 0 ° C of chlorine gas for two minutes. The reaction mixture was stirred for 10 minutes until a light yellow solution was obtained. The excess chlorine was removed by passing a stream of argon. The yellow solid product obtained after evaporation under reduced pressure was then purified on a flash column (silica 6-35 μm; conditioning: heptane; eluent: dichloromethane / heptane, 50/50), to obtain 0.43g of pale yellow crystals. After filtering on a silica pad, 0.40 g of 2- (5-chloro-furan-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [2,3-d] thiazole was obtained in the form of yellow crystals after recrystallization and discoloration with animal black. Rdt: 20% F: 257.7 ° C Rf: 0.42 (CH2C12) SM (IE): m / z 315 (M +.) NMR of ^ (CDC13): d (ppm) 8.33 (dd, 1H, H -5ou H-8, JH5-H6 = 8.85 Hz, JH5_H7 = 1.73 Hz) 8.23 (dd, 1H, H-5ou H-8, JH5-H6 = 8.85 Hz, JH5-H7 = 1.73 Hz) 7.81 (m, 2H, H-6, H-7) 7.43 (d, 1H, H-3 ', JH3, -H4, = 3.58 Hz) 6.45 (d, 1H, H-4', J H3 , _H4, = 3.58 Hz) 13 C NMR (CDC13): d (ppm) 178.10, 177.92 (2C, C-4, C-9) 163.94 (IC, C-2) 141.10 ( IC, C-2 ') 140.78 (IC, C-3a) 139.58 (IC, C-9a) 134.40, 134.17 (2C, C-6, C-7) 133.10, 132 , 68 (2C, C-4a, C-8a) 127.86, 126.95 (2C, C-5, C-8) 115.65 (IC, C-3 ') 113.34 (IC, C- 4 ') IR (KBr): v (cm "1) 1678, 1652 (C = 0) Example 20 4, 9-Dihydro-4, 9-dioxo-2- (2-thienyl) -naphtho [2, 3- d] -thiazole To 4.00g (19 mmoles) of 2-amino-3-chloro-l, 4-di-hydro-1,4-dioxo-naphthalene, 150ml of a freshly prepared aqueous solution containing 22.80g was added. (95 mmoles) of sodium sulphide nonahydrate The reaction mixture was kept at 80 ° C for 20 minutes until it was obtained of a bluish color. 1.8 ml (19 mmoles) of thiophene-2-carboxaldehyde and 5. Oml (87 mmoles) of glacial acetic acid were then added successively. After two hours of stirring, the obtained black-brown precipitate was filtered, and was dissolved in 350 ml of dichloromethane. The organic phase was washed three times with 150 ml of water, dried in calcium chloride and filtered.
The orange solid obtained after evaporation of dichloromethane under reduced pressure was decolorized with animal black and recrystallized from dichloromethane to obtain 2.71g of 4,9-dihydro-4,9-dioxo-2- (2-thienyl) -naphtho [ 2, 3-d] thiazole in the form of red-orange crystals. Rdt: 48% F: > 260 ° C Rf: 0.58 (CH2C12) SM (IE): m / z 297 (MH +.) NMR of ^ (CDCl ^: d (ppm) 8.32 (dd, 1H, H-5ou H-8, JH5.H6 = JH 8.85 Hz, JH = J " = 1.73 Hz) 8.21 (dd, 1H, H-5ou H-8, JHS.H6 = JH = 8.85 Hz, "-? 5-H7 '-'H = 1.73 Hz) 7.82 (m, 3H , H-6, H-7, H-5 ') 7.62 (dd, 1H, H-3', JH3, _H4, = 4.88 Hz, JH3, -H5, = 1.00 Hz) 7.18 (dd, 1H, H-4 ', JH3, -H4, = 4.88 Hz, JH4, -H5, = 3.49 Hz) 13C NMR (CDC13): d (ppm) 178.32, 177.92 (2C, C-4, C-9) 169.34 (IC, C-2) 155.14 (IC, C-3a) 135.50 (IC, C-9a) 134.37, 134.02 (2C, C-6, C- 7) 132.78, 132.43 (2C, C-4a, C-8a) 130.19 (IC, C-4 ') 128.50 (IC, C-3') 127.84, 127.61 ( 2C, C-5, C-8) 126.86 (C-5 ') IR (KBr): v (cm "1) 1676, 1654 (C = 0) Example 21 4.9-Dihydro-4.9- dioxo-2- (3-thienyl) -naphtho [2,3-d] -thiazole A 4. Og (19 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene , 90ml of a freshly prepared aqueous solution containing 22.8g (95mmol) of sodium sulphide nonahydrate was added. The reaction mixture was kept at 90 ° C for 20 minutes, until obtaining a bluish coloration. Then 1.8 ml (19 mmol) of thiophene-3-carboxaldehyde and 5. Oml (87 mmol) of glacial acetic acid were added successively. After two hours of stirring at 90 ° C, the yellow-green precipitate obtained was filtered, washed three times with 400 ml of water and dried. The crystals were taken up in 200 ml of isopropanol, stirred at room temperature for one hour and then filtered, dried and recrystallized from dichloromethane after decolorization with animal black to obtain 4. Og of 4,9-dihydro-4 , 9-dioxo-2- (3-thienyl) -naphtho [2,3-d] thiazole in the form of yellow-ocher crystals. Rdt: 70% F: 258 ° C Rf: 0.55 (CH2Cl2 / Methanol, 99.5 / 0.5) SM (IE): m / z 297 (MH +.) XH NMR (CDC13): d (ppm ) 8.37 (dd, 1H, H-5 or H-8, JH5-HS or JH7-H8 = 8.85 Hz, JH5-H7 or JH6_H8 1. 73 Hz) 8.23 (m, 2H, H-5 or H-8, H-2 ') 7.81 (m, 2H, H-6, H-7) 7.71 (d, 1H, H- 5 ', H4, _H5, = 4.88 Hz) 7.48 (dd, 1H, H-4', JH4, -H5, = 4.88 Hz, JH2, -H4. = 2.99 Hz) 13 C NMR (CDC13): d (ppm) 178.32, 177.92 (2C, C-4, C-9) 169.34 (C, 2 C) 155.14 (C, 3a, C) , 69 (IC, C-9a) 134.36, 134.04 (2C, C-6, C-7) 133.09, 132.71 (2C, C-4a, C-8a) 128.23 (IC. , C-4 ') 127.84 (1C, C-5') 127.61, 126.89, 126.59 (3C, C-5, C-8, C-2 ') IR (KBr): n (cm_1) 1674.1655 (C = 0) Example 22 4, 9-Dihydro-4,9-dioxo-2-phenylamino-naphtho [2,3-d] -thiazole To a solution of 200 mg (0.8 mmol) of 2- Chloro-4,9-dihydro-4,9-dioxo-naphtho [2,3-d] thiazole in 100 ml of ethanol, 730 μl (8 mmol) of aniline was added at 80 ° C. The reaction mixture was refluxed for 3.5 hours and the red precipitate obtained was filtered after cooling and then purified on the cake (support: silica 6-35 μm, eluent: dichloromethane / heptane, 20/80 at 100/0 then dichloromethane / ethyl acetate, 99, from 5 / 0.5 to 0/100). The proper fractions were pooled, filtered on micropores and the solvent was evaporated under reduced pressure to obtain 196 mg of 4,9-dihydro-4,9-dioxo-2-phenylamino-naphtho [2,3-d] thiazole in the form of red crystals. Rdt: 80% F: > 260 ° C Rf: 0.44 (CH2Cl2 / Ethyl acetate, 90/10) SM (EI): m / z 306 (M +.) NMR of XH (DMSO d6): d (ppm) 11.34 (s, NH, NH) 8.09 (m, 2H, H-5, H-8) 7.86 (m, 2H, H-6, H-7) 7.70 (m, 2H, H-2 ', H -6 ') 7.44 (m, 2H, H-3', H-5 ') 7.14 (m, 1H, H-4') 13 C NMR (DMSO d6): d (ppm) 178.04 , 177.31 (2C, C-4, C-9) 167.72 (IC, C-2) 154.61 (IC, C-3a) 145.95 (IC, C-9a) 139.49 (IC. , C-1 ') 134.02, 133.93 (2C, C-6, C-7) 132.79, 132.06 (2C, C-4a, C-8a) 129.36 (2C, C- 3 ', C-5') 126.76, 125.73 (2C, C-5, C-8) 123.68 (IC, C-4 ') 118.60 (2C, C-2', C- 6 ') IR (KBr): v (cm "1) 3228 (NH); 1677, 1632 (C = 0) Examples 23 and 24 4, 9 -Dihydro-4, 9-dioxo-8-methoxy-2-phenyl -naphtho [2, 3-d] thiazole and 4, 9 -Dihydro-4, 9-dioxo-5-methoxy-2-phenyl-naphtho [2,3-d] thiazole Intermediates of the synthesis: 1,4-Dihydro-1,4-dioxo-5-methoxy- Naphthalene To a solution of 26.45 g (0.147 mol) of 1,4-dihydro-1,4-dioxo-5-hydroxy-naphthalene in 1300 ml of dichloromethane, 39 ml (0.303 mol) of iodomethane was added dropwise then 73.50 g. of silver oxide. The reaction mixture was stirred for 72 hours then filtered. The filtrate was dried in calcium chloride, then evaporated under reduced pressure. 28.50 g of orange crystals were obtained which were purified on the cake (support: silica 40-60 mm, eluent: heptane / ethyl acetate, from 70/30 to 0/100) to obtain 23.80 g of 1,4-dihydro- 1,4-dioxo-5-methoxy-naphne. Rdt: 86% F: 188 ° C Rf: 0.50 (Ethyl acetate / Heptane, 50/50) 1 H NMR (CDC13): d (ppm) 7.72 (m, 2H, H-6, H-8) 7.32 (dd, 1H, H-7, JH = JH = 7.63 Hz) 6.88 (m, 2H, H-2, H-3) 4.01 (s, 3H, OCH3) 2, 3 -Dibromo-1,4-dihydro-1,4-dioxo-5-methoxy-naphthalene To a solution of 3.5g (18.6 mmoles) of 1,4-dihydro-1,4-dioxo-5-methoxy-naphthalene in 135ml of chloroform, 3.05g (37.2 mmoles) of sodium acetate and 3ml (58.4 mmoles) of bromine were added. The reaction medium was stirred for 48 hours. The acetate salts formed were filtered. The filtrate was washed with distilled water, dried in calcium chloride, then evaporated under reduced pressure to obtain 7.3 g of 1,4-dihydro-1,4-dioxo-2,3-dibromo-5-methoxy-naphthalene. in the form of orange crystals.
Rdt: 100% F: 190 ° C NMR of * H (DMSO d6): d (ppm) 7.80 (dd, 1H, H-8, JH7_H8 = 7.85 Hz, J, H6-H8 1.53 Hzl 7, 73 (dd, 1H, H-7, JH6.H7 = 8.34 Hz, JH6.H8 = 7.85 Hz) 7.37 (m, 1H, H-6) 3.95 (s, 3H, OCH3) 2 - Amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxy-naphthalene and 2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxy-naphthalene A A solution of 500.0 mg (1.5 mmol) of 2,3-dibromo-1,4-dihydro-l, 4-dioxo-5-methoxy-naphthalene in 25 ml of tetrahydrofuran was added with one drop of ammonia. it took a black coloration, then a current of ammonia was passed for 2 hours at 20 ° C. The crude product obtained after the evaporation of the solvents was purified on the cake (support: silica, eluent: dichloromethane / heptane, 80/20) to obtain 347.3mg of a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxy-naphthalene and of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxy-naphthalene. Overall Rdt: 82% 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxy-naphthalene NMR of XH (DMSO d6): d (ppm) 7.78 (d, 1H, H-8, JH7.H8 = 7.94 Hz) 7.67 (dd, 1H, H-7, JH6_H7 = 8.54 Hz, JH7.H8 = 7.94 Hz) 7.25 (d, 1H, H -6, JH6-H7 = 8.54 Hz) 3.99 (s, 3H, OCH3) 1.73 (s, 2H, NH2) 2-amino-3-bromo-1,4-dihydro-1,4- dioxo-5-methoxy-naphthalene NMR of XH (DMSO d6): d (ppm) 7.73 (d, 1H, H-8, JH7.H8 = 8.57 Hz) 7.61 (t, 1H, H-7, JH7.HS JH7_H8 = 8.57 Hz) 7.34 (d, 1H, H-6, JH6.H7 = 8.57 Hz) 3.97 (s, 3H, OCH3) 1.73 (s, 2H, NH2) 4, 9- Dihydro-4, 9-dioxo-8-methoxy-2-phenyl-naphtho [2,3-d] thiazole (Example 23) and 4,9-Dihydro-4,9-dioxo-5-methoxy-2-phenyl- Naphtho [2,3-d] thiazole (Example 24) To a solution of 93.70g (389.00 mmoles) of sodium sulphide nonahydrated in 400ml of water, 18.30g (64.87 mmoles) of a mixture (l / l) was added. of 2-amino-3-bromo-5-methoxy-l, 4-dihydro-l, 4-dioxo-naphthalene and 2-amino-3-bromo-8-methoxy-1,4-dihydro-1,4-dioxo-naphne. The reaction medium was refluxed until a bluish color was obtained. Then 6.6 ml (64.87 mmoles) of benzaldehyde were added successively and 22.3 ml of glacial acetic acid were dropwise added.
After 1 hour of reflux, and complete cooling, the precipitate obtained was filtered, washed with ethanol and recovered in chloroform. The organic phase was washed with water, then dried in calcium chloride. 16.50 g of yellow crystals were obtained after evaporation of the solvents under reduced pressure which were purified on a flash column (support: silica 40-60 mm, eluent: dichloromethane / ethyl acetate, 100/0 to 97/3) obtain after decolorization and recrystallization from dichloromethane 8.90g of 4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-naphtho [2,3-d] -thiazole (Example 23) and 2.29g of 4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-naphtho [2,3-d] thiazole (Example 24) in the form of yellow crystals. 4, 9-Dihydro-4, 9-dioxo-8-methoxy-2-phenyl-naphtho- [2,3-d] thiazole (Example 23): 42% F: >; 260 ° C Rf: 0.55 (CH2Cl2 / Ethyl acetate, 90/10) SM (EI): m / z 321 (M +.) NMR of XH (CDC13): d (ppm) 8.14 (dd, 2H, H -2 ', H-6', JH2, -H3, = JH5, -H6. = 6.10 Hz, JH2, _H4, = 7.90 (d, 1H, H-5, JH5.H6 = 7.63 Hz) 7.73 (dd, 1H, H-6, JH5.H6 = 7.60 Hz, JH6.H7 = 8.50 Hz) 7.52 (m, 3H, H-3 ', H-4', H-5 ') 7.39 (d, 1H, H-7, JH6.H7 = 8.50 Hz) 4.06 (s, 3H, OCH3) 13 C NMR (CDCl 3): d (ppm) 177.95 (IC, C-9) 177.58 (IC, C-4) 161.00 (IC, CWat) 135.98 (1C, CCat) 135.01 (IC, C-6) 132.23 (1C, C -4 ') 129.20 (2C, C-3', C-5 ') 127.79 (2C, C-2 •, C-6') 119.78, 119.02 (2C, C-5, C-7) 56.74 (OCH3) IR (KBr): v (c "1) 1671 (C = 0) 4,9-Dihydro-4,9-dioxo-5-methoxy-2-phenyl-naph or- [2, 3-d] thiazole (Example 24) Yield: 11% F: 245 ° C Rf: 0.47 (CH2Cl2 / Ethyl acetate, 98/2) SM (IE): m / z 321 (M +.) XH NMR (CDC13): d (ppm) 8.15 (dd, 2H, H-2 ', H-6', JH2, -H3, = JH5, -HS, 7.98 Hz, J H.2 '-H4' 7.92 (d , 1H, H-8, JH7.H8 = 7.60 Hz) 7.73 (t, 1H, H-7, JH7.H8 = JH6_H7 = 8.00 Hz) 7.53 (m, 3H, H-3 ', H-4', H-5 ') 7.39 (d, 1H, H-6, JH6.H7 = 8.00 Hz) 4.03 (s, 3H, OCH3) 13C NMR (CDC13): d (ppm) 161.50 (1C, C-5) 135.50 (CCI, Cat) 135.08 (C, C-7) 132.20 (C, 4 'C) 129.70 (2C, C -3 ', C-5') 127.80 (2C, C-2 ', C-6') 119.75 (IC, C-6) 119.02 (IC, C-8) 57.00 (IC. , OCH3) IR (KBr): v (c "1) 1678.1651 (C = 0) Examples 25 and 26 4, 9 -Dihydro-4, 9-dioxo-7-methoxy-2-phenyl-naphtho [2, 3-d] thiazole and 4, 9 -Dihydro-4, 9-dioxo-6-methoxy-2-phenyl-naph or [2,3-di-thiazole To a solution of 9.9 g (41.0 mmol) of sodium sulphide nonahydrated in 27 ml of water, he added 1.9g (6.7 mmoles) of a mixture (l / l) of 2-amino-3-bromo-6-methoxy-1,4-dihydro-1,4-dioxo-naphthalene and of 3-amino-2-bromo-6- methoxy-l, 4-dihydro-l, 4-dioxo-naphthalene. The reaction medium was then maintained at 50 ° C until obtaining a bluish coloration. Then, 0.685ml (6.7 mmoles) of benzaldehyde and 2.300ml of glacial acetic acid were successively added. After 3 hours of heating and complete cooling, the green crystals obtained were filtered, washed with ethanol, then dissolved in 300 ml of chloroform. The organic phase was washed with 100 ml of water, dried in calcium chloride and evaporated under reduced pressure. 4. Og of yellow crystals were obtained, which were purified on a medium pressure chromatography column (support: silica 6-35 mm, internal diameter: 3.0 cm, height: 40 cm, pressure: 30 bars, eluent: heptane / dichloromethane, 100/0 to 65/35). The yellow crystals obtained were decolorized and recrystallized from dichloromethane to obtain 0.2g of 4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-naphtho [2,3-d] thiazole (Example 25) and 1.2g of 4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-naphtho- [2,3-d] thiazole (Example 26). 4,9-Dihydro-4,9-dioxo-7-methoxy-2-phenyl-naphtho- [2,3-d] thiazole (Example 25): 1.5% F: > 260 ° C Rf: 0.47 (CH2C12) SM (I.E.): m / z 321 (M +.) NMR of?. (270 MHz, CDC13): d (ppm) 8.20 (s, 1H, H-8) 8.15 (dd, 2H, H-2 ', H-6', JH2, _H3, = JHS, -H6 7.21 Hz, JH JH4.-H6. = 1.93 Hz) 7.78 (d, 1H, H-5, JH5_H6 = 8.65 Hz) 7.53 (m, 3H, H-3 ', H-4', H-5 ') 7, 24 (d, 1H, H-6, JH5.H6 = 8.65 Hz) 4.01 (s, 3H, 0CH3) 13 C NMR (270 MHz, CDC13): d (ppm) 132.68 (IC, C-5) ) 129.84 (IC, C-4 ') 129.69 (2C, C-3', C-5 ') 128.20 (2C, C-21, C-6') 120.64 (1C, C-6) ) 111.99 (IC, C-8) 56.58 (0CH3) IR (KBr): v (cm "1) 1679 (C = 0) 4, 9-Dihydro-4,9-dioxo-6-m -toxhoxy- 2- phenyl-naphtho [2,3-d] thiazole (Example 26) Yield: 9% F: 221 ° C Rf: 0.65 (CH 2 Cl 2 / Ethyl acetate, 98/2) SM (IE): m / z 321 (M +.) NMR of XH (270MHz, CDC13): d (ppm) 8.29 (d, 1H, H-8, JH = 8.65 Hz) 14 (d, 2H, H-2 ', H-6 'H2' -H3 '= J "= 7.21 Hz, 7.67 (d, 1H, H-5, JH5.H7 = 2.67 Hz) 7.52 (m, 3H, H-3 ', H-4', H-5 ') 7.25 (dd, 1H, H-7, JH7.H8 = 8.65 Hz, JH5_H7 = 2.67 Hz) 4.01 (s, 3H, OCH3) 13 C NMR (270 MHz, CDC13): d (ppm) 164.21 (IC, C-6) 155.88 (1C, Ccuat) 135.87 (IC, Cat) 132.31 (IC, C-5) 130.30 (IC, C-4 ') 129.25 (2C, C-3', C-5 ') 127.79 (2C, C-2', C-61) 127.40 (1C, C cuat) 120.27 (IC, C-7) 110.09 (IC, C-8) 56.05 (0CH3) IR (KBr): v (cm "1) 1667 (C = 0) Example 27 4, 9 -dihydro-4, 9-dioxo-8-hydroxy-2-phenyl-naphtho [2,3-d] thiazole A suspension of 1.OOg (0.003 mole) of 4,9-dihydro-4,9-dioxo-8 -methoxy-2-phenyl-naphtho [2,3-d] -thiazole (Example 23) in 67ml (1160 moles) of acetic acid and 67ml (0.570 moles) of hydrobromic acid was refluxed for 5 hours and 30 minutes. After cooling to 10 ° C, the reaction medium was filtered on fritted glass. The precipitate was dissolved in 200 ml of chloroform. The organic phase was washed with a 3% ammonia solution (3 x 40 ml) and dried in calcium chloride. The yellow solid obtained after evaporation under reduced pressure of the solvent was purified on a medium pressure column (support: silica 6-35 mm, eluent: toluene / dichloromethane, 100/0, 50/50, 0/100) was then recrystallized 3 times in a toluene / heptane mixture, 50/50 to obtain 0.302g of 4,9-dihydro-4,9-dioxo -8-hydroxy-2-phenyl-naphtho [2,3-d] thiazole. Rdt: 33% F: 263, 5 ° C Rf: 0.51 (heptane / ethyl acetate, 70/30) SM (IE): m / z 307 (M +.) XH NMR (CDC13): d (ppm ) 8.08 (dd, 2H, H-2 ', H-6', JH2, .H3, = JH5.-H6 '= 8/4 Hz / JH2.-H4.
J "= 1.4 Hz) 7.81 (dd, 1H, H-5, JH5.H7 7, 6 Hz, JH = 1.4 Hz) 7.67 (t, 1H, H-7) 7.55 (m, 3H, H-3 ', H-4', H-5 ') 7.35 (dd, 1H, H-6, JH6.H7 = 8.4 Hz) 13 C NMR (CDC13): d ( ppm) 163.11 (IC, C-8) 136.57 (IC, C-6) 132.53 (IC, C-4 ') 129.32 (2C, C-3', C-5 ') 127 75 (2C, C-2 ', C-6') 125.62 (IC, C-7) 120.17 (IC, C-5) IR (KBr): v (cm "1) 1650 (C = 0) Example 28 4, 9-Dihydro-4, 9-dioxo-2- (1-pyrrolyl) -naphtho- [2,3] -thiazole To a suspension of 2.30g (0.01 mol) of 2-amino-4, 9-dihydro-4,9-dioxo-naphtho [2,3-d] thiazole in 25 ml of acetic acid, 1.3 ml (0.01 mol) of hot 2,5-dimethoxy-tetrahydrofuran was added to it. reflux for 2 hours.The brown precipitate obtained was filtered, dissolved in dichloromethane, then washed three times with 200 ml of distilled water.The organic phase was dried in calcium chloride, filtered and evaporated under reduced pressure to obtain 1.80g. of a yellow solid that was purified in u na column flash (support: silica 6-35 mm, conditioning: heptane, eluent: dichloromethane / heptane, 90/10). 0.90 g of 4,9-dihydro-4,9-dioxo-2- (1-pyrrolyl) -naphtho [2,3] -thiazole was obtained as yellow crystals, then recrystallized and decolorized with animal black. Rdt: 64% F: > 260 ° C Rf: 0.41 (CH2C12) SM (IE): m / z 280 (M +.) E NMR (CDC13): d (ppm) 8.29, 8.20 (2dd, 1H, H-5 , H-8, JH5.H6 .85 Hz, J, H5-H7 = 1.73 Hz) 7.79 (m, 2H, H-6, H-7) 7.48 (m, 2H, H-2 ', H-5') 6.42 (m, 2H, H-3 ', H -4 ') RM? of 13 C (CDCl 3): d (ppm) 177.89, 177.47 (2 C, C-4, C-9) 165.60 (C, 2 C) 153.00 (C, 3a) 137, 14 (IC, C-9a) 134.30, 134.06 (2C, C-6, C-7) 132.87, 132.38 (2C, C-4a, C-8a) 127.75, 126, 69 (2C, C-5, C-8) 120.52 (2C, C-2 ', C-5') 114.23 (2C, C-3 ', C-4') IR (KBr): v (cm "1) 1680.1665 (C = 0) Examples 29 and 30 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 10. Og (35.6 mmol, 1 eq) of 4.9 -dihydro-4, 9-dioxo-2- (furan-2-yl) naphtho [2, 3-d] thiazole was solubilized in 750 ml of dichloromethane previously dried on molecular sieve, the solution was cooled to 0 ° C, by small fractions 11.2g (81.9 mmoles, 2.3 eq) of aluminum chloride The reaction mixture was brought to reflux, 8. Oml (126.0 mmoles, 3.5 eq) of bromine in solution were added dropwise. in 20ml of dichloromethane, and the reaction was allowed to rest for 5 hours.The solution was cooled and turned over c Gently in a saturated solution of sodium hydrogencarbonate. The organic phase was washed several times with water until a neutral pH, then dried in calcium chloride. 10.5 g of solid crude product (brown-orange) was obtained after evaporation of the solvent, and then it was purified on a flash column (support: silica 6-35 mm, eluent: CH2C12 / Heptane: 50/50, CH2C12: 80 / 20), to obtain, after evaporation, 4.5 g of 2- (5-bromofuran-2-yl) -4,9-dihydro-4,9-dioxonaf or [2,3-d] -thiazole, in the form of orange crystals and 380 mg of 2- (4,5-dibromofuran-2-yl) -4,9-dihydro-4,9-dioxonaphto [2,3-d] thiazole in the form of yellow crystals. 2- (5-Bromo-furan-2-yl) -4,9-dihydro-4,9-dioxonaf to- [2, 3-d] thiazole Rdt: 42.8% F: > 260 ° C Rf: 0.47 (CH2C12) SM (IE): m / z 359-361 (M +) XH NMR (CDC13): d (ppm) 8.34 (m, 1H, H-5 or H- 8) 8.23 (m, 1H, H-5 or H-8) 7.81 (m, 2H, H-6, H-7) 7.40 (d, 1H, H-3 ', JH3, - H4, = 3.74 Hz) 6.59 (d, 1H, H-4 ', JH3, -H4, = 3.67 Hz) 13C NMR (CDC13): d (ppm) 178.28,177.99 (2C , C-4, C-9) 162.67 (C-2) 162.06 (C-2 ') 155.35 (C-3a) 149.88 (C-9a) 140.88 (C-51) 134.58, 134.27 (2C, C-6, C-7) 133.30,132.83 (2C, C-4a, C-8a) 127.24, 127.13 (2C, C-5, C- 8) 115.23, 115.50 (2C, C-31, C-41) IR (KBr): V (cm "1) 1682 and 1656 (C = 0) 2- (4.5-Dibromofuran-2-yl) -4,9-dihydro-4,9-dioxo-naf or [2,3-d] thiazole Rdt: 2.4% F:> 260 ° C Rf: 0.63 (CH2C12) SM (APcl-): m / z 438 (MH) K NMR (CDC13): d (ppm) 8.35 (m, 1H, H-5 or H-8) 8.24 (m, 1H, H-5 or H-8) 7.82 (m, 2H, H-6, H-7) 7.46 (s, 1H, H-3 ') 13 C NMR (CDC13): d (ppm ) 134.54, 134.25 (2C, C-6, C-7) 127.92,127.03 (2C, C-5, C-8) 117.59 (IC, C-3 ') IR (KBr) : v (cm'1) 1685 and 1655 (C = 0) Example 31 2- (3-Bromo-furan-2-yl) -4,9-dihydro-4,9-dioxonaf to- [2,3-d] thiazole To 150ml of a sodium hydroxide solution (pH = 10.7), 5.33g (22.2 mmoles, 1 eq.) Of sodium sulphide nonahydrate was added. The solution was brought to 90 ° C and stirred under an argon atmosphere. 4.61g (22.2 mmoles, 1 eq.) Of 2-amino-3-chloro-l, 4-dihydro-1,4-dioxanephthalene were added, the solution was stirred until obtaining a bluish coloration. The solution was cooled between 20 and 25 ° C and 3.89g (22.2 mmoles) of 3-bromo-2-furaldehyde (CAS No. 14757-789) was added to the reaction medium. After five minutes the bubbling of argon was replaced by compressed air for 1 hour, then 5 ml of acetic acid was added dropwise, and the medium turned brown-red. The stirring was maintained for five minutes, the black precipitate formed was filtered on fritted glass, washed with water and dried to give 9.30g of product that was purified several times on a flash column (support: silica 6-35mm; 0 4.5cm, h 30cm eluent: Dichloromethane / Heptane: 50/50). After evaporation of the solvent, 2.15 g of 2- (3-bromo-2-furan-2-yl) -4,9-dihydro-4,9-dioxo-naphtho- [2,3-d] thiazole was obtained in the form of orange crystals. Rdt: 26.9% F: > 250 ° C Rf: 0.30 (CH2C12) SM (APcl +): m / z 361 (M + H +) NMR of ^ (CDClj): d (ppm) 8.36 (m, 1H, H-5 or H- 8) 8.25 (m, 1H, H-5 or H-8) 7.82 (m, 2H, H-6, H-7) 7.65 (d, 1H, H-5 ', JH4, - H5, = 2.14 Hz) 6.75 (d, 1H, H-4 ', JH4, -HS, = 2.14 Hz) 13 C NMR (DMS0-d6): d (ppm) 147.95 (IC. , C-5 ') 134.82, 134.42 (2C, C-6, C-7) 127.24, 126.44 (2C, C-5, C-8) 117.50 (IC, C- 4 ') IR (KBr): v (cm "1) 1680 and 1655 (C = 0) Example 32 2- (4-bromofuran-2-yl) -4,9-dihydro-4,9-dioxonaphtho- [2.3 -d] thiazole To 0.257g (1.24 mmol, 1 eq) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 9ml of water, 1.19g (4.96 mmol, 4 eq) of sodium sulphide nonahydrate The mixture was refluxed until the coloration of the reaction medium became completely bluish, then 0.26 g (1.48 mmol, 1.19 eq) of 4-bromo-2-furaldehyde at ° C. The reaction medium was cooled to room temperature before adding 0.28 ml of acetic acid. A precipitate formed. The reaction medium was stirred one hour at room temperature.
The precipitate was then filtered, washed with water.
The brown precipitate (0.35 g) was purified on a flash column (support: alumine, conditioning: dichloromethane / heptane 70/30, eluent: dichloromethane / heptane 70/30, then 80/20 then 100/00 then dichloromethane / methanol 99.6 / 0.4) to obtain 0.145g of 2- (4-bromofuran-2-yl) -4,9-dihydro-4,9-di-oxaphtho [2,3-d] thiazole in the form of orange crystals Rdt: 32% F: > 260 ° C Rf: 0.23 (dichloromethane / heptane, ratio 70/30) with support of alumina SM (IE): m / z 360 (M +) NMR of XH (CDCl 3): d (ppm) 8.34 (m , 1H, H-5 or H-8) 8.25 (m, 1H, H-8 or H-5) 7.83 (m, 2H, H-6, H-7) 7.64 (d, 1H , H-5 ', JH3, -Hs, = 0/95 Hz) 7.46 (d, 1H, H-3', JH3, -H5, = 0.95 Hz) 13C NMR (CDC13): d ( ppm) 143.76 (IC, C-5 ') 134.48, 134.17 (2C, C-6, C-7) 127.89, 126.99 (2C, C-5, C-8) 116 , 07 (ÍC, C-3 ') IR (KBr): v (cm "1) 1680, 1657 (C = 0) Example 33 4,9-Dihydro-4,9-dioxo-2- (5-nitro) furan-2-yl) naphtho- [2,3-d] thiazole A 5g (17.8 mmoles) of 4,9-dihydro-4,9-dioxo-2- (furan-2-yl) naphtho [2, 3d] thiazole was added at room temperature 20ml of fuming nitric acid and 20ml of concentrated sulfuric acid.The reaction mixture was brought to reflux for 72 hours and the formed precipitate was filtered on sintered glass, washed with water and rinsed with ether .
The dark yellow powder obtained was recrystallized from DMF after decolorizing with animal black. They were obtained like this 2g of 4,9-dihydro-4,9-dioxo-2- (5-nitro-furan-2-yl) naphtho- [2,3-d] thiazole as a dark yellow solid. Rdt: 34% F: > 300 ° C Rf: 0.30 (CH2C12) S.M. (APCl-): m / z 326 (M-) NMR of '? (CDC13): d (ppm) 8.39 (m, 1H, H-5 or H-8) 8.27 (m, 1H, H-5 or H-8) 7.85 (m, 2H, H- 6, H-7) 7.59 (d, 1H, H-4 ', JH3, -H4, = 3.73 Hz) 7.50 (d, 1H, H-3', JH3, -H4, = 3 , 74 Hz) IR (KBr): V (cm "1) 1675, 1656 (C = 0) Example 34 2 - (5-Amino-furan-2-yl) -4,9-dihydro-4,9-dioxonaphtho - [2,3-d] thiazole In a trichol, 2g (6.10 mmol, 1 eq) of 4,9-dihydro-4,9-dioxo-2- (5-nitrofuran-2-yl) -naphtho [2] was solubilized. 3-d] -thiazole in 1500 ml of absolute ethanol.The assembly was placed under an inert atmosphere, a carbon spatula tip with 30% palladium was added.The solution was brought to reflux and 360ml (7.36mmol) was added five times. 1.2 eq) of hydrazine The reaction was maintained for one hour, the solution was changed from yellow-green to black-violet.The solution was cooled and filtered on celite, 1.65g of a black solid was obtained after the evaporation of the solvent in a rotary evaporator This solid was purified in a flash column (support: silica 6-35 mm, gradient of latent: dichloromethane then dichloromethane / methanol, 98/2), to obtain 0.36 g of 2- (5-amino-furan-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [2, 3 - d] thiazole in the form of bluish crystals.
Rdt: 20% F: > 260 ° C Rf: 0.29 (Dichloromethane / Ethyl acetate, 99/1) SM (APcl +): m / z 297 (M + H +) XH NMR (DMS0-d6): d (ppm) 8.24 (m, 1H, H-5 or H-8) 8.18 (m, 1H , H-5 or H-8) 7.99 (m, 2H, H-6, H-7) 7.60 (d, 1H, H-3 ', JH3, _H4, = 3.97 Hz) 7, 36 (s, 2H, NH2) 5.47 (d, 1H, H-4 ', JH3, -H4, = 3.97 Hz) 13 C NMR (DMSO-d6): d (ppm) 177.8, 177 , 2 (2C, C-4, C-9) 161.0 (IC, C-5 ') 155.0 (1C, C-2) 138.0 (IC, C-2') 134.3, 134 , 1 (2C, C-6, C-7) 133.1, 132.4 (2C, C-4a, C-8a) 127.0, 126.0 (2C, C-5, C-8) 122 , 1 (ÍC, C-3 ') 87.5 (ÍC, C-4') IR (KBr): v (cm "1) 3350 (NH2); 1680 and 1625 (C = 0) Example 35 2- ( 5-Acetamidofuran-2-i]) -4,9-dihydro-4,9-dioxo-naphtho [2,3-d] thiazole In a trichol, 0.300g (1.01 mmol, 1 eq) of 2- (5-aminofuran-2-yl) -4,9-dihydro-4,9-dioxo-naphtho- [2,3-d] -thiazole, dropwise and at room temperature 200ml (2.02 mmol, 2 eq) of acetic anhydride and then 60 μl (1.01 mmol, 1 eq) acetic acid. The suspension obtained was heated to 50 ° C and turned red-borravino. After 2 hours of reaction, the suspension was cooled and solubilized in 500 ml of dichloromethane. The solution was washed twice with a saturated solution of sodium hydrogen carbonate, and then several times with water until obtaining a neutral pH of the aqueous phase. After the drying of the organic phase in calcium chloride and the evaporation of the solvents, 0.330 g of solid crude product were obtained (red-borravino). This solid was purified on a flash column (support: silica 6-35mm, eluent: Dichloromethane / Methanol, 98/2). The obtained compound was solubilized in dichloromethane, filtered in micropores. The filtrate was concentrated and the formed precipitate was filtered on fritted glass to obtain 0.145g of 2- (5-acetamidoofuran-2-yl) -4,9-dihydro-4,9-dioxonaphtho [2, 3-d] thiazole in the form of red-brick crystals. Rdt: 42% F: > 260 ° C Rf: 0.34 (Dichloromethane / Methanol, 95/5) SM (APCl +): m / z 339 (M + H +) * NMR * (DMSO-d6): d (pprn) 11.75 (s, 1H, NH) 8.28 (m, 1H, H-) 5 or H-8) 8.23 (m, 1H, H-5 or H-8) 8.03 (m, 2H, H-6, H-7) 7.69 (d, 1H, H-3 ' , JH3, _H4, = 3.73 Hz) 6.62 (d, 1H, H-4 ', JH3, _H4, = 3.74 Hz) 2.22 (s, 3H, CH3) 13 C NMR (DMSO-d6): d (ppm) 177.9, 176.5 (2C, C-4, C-9) 167.5 (C, 51 C) ) 155.2 (IC, C-2) 139.0 (IC, C-2 ') 134.6, 134.4 (2C, C-6, C-7) 132.7, 132.6 (2C, C-4a, C-8a) 127.2, 126.4 (2C, C-5, C-8) 118.1 (IC, C-31) 97.0 (IC, C-4 ') 23.4 (IC, CH3 ) IR (KBr): V (cm "1) 3033 (NH); 1682 and 1655 (C = 0) Example 36 4,9-dihydro-4,9-dioxo-2- (5-hydroxymethylfuran-2-yl) naphtho [ 2,3-d] thiazole 17.36g (72.2 mmoles, 5 eq) of sodium sulphide nonahydrate were solubilized in 70 ml of water.The solution was heated to 60 ° C, then 3.00g (14.4 mmol, 1 eq) of 2-amino-3-chloro-1,4-dihydro-l, 4-dioxo-naphthalene After 30 minutes of stirring at 60 ° C, the solution was cooled to room temperature and added to the reaction medium - it turned blue - 2.43 g (14.5 mmol, 1 eq) of 5-acetoxymethyl-2-furaldehyde, and after 5 minutes, 3 ml of acetic acid was added dropwise.The medium turned brownish-orange and the precipitate formed was fi ltered in fritted glass, washed with water and dried to obtain 3.30 g of crude product that was purified on a flash column (support: silica 6-35 μm; 0 5 cm, h 15 cm, eluent: CH 2 Cl 2 / MeOH, 96/4). The orange product obtained was recrystallized from dimethylformamide, decolorized with animal black and filtered on celite and micropores to obtain 0.80g of 4,9-dihydro-4,9-dioxo-2- (5-hydroxymethyl-furan-2-yl). ) Naphtho [2, 3-d] thiazole in the form of ocher crystals. Rdt: 17% F: > 260 ° C Rf: 0.60 (CH2Cl2 / MeOH, 96/4) SM (EI): m / z 311 (M +) XH NMR (DMSO-dg): d (ppm) 8.20 (m, 1H, H-5 or H-8) 8.11 (m, 1H, H-5 or H-8) 7.91 (m, 2H, H-6, H-7) 7.46 (d, 1H, H- 3 ', JH3, -H4, = 3.1 Hz) 6.65 (d, 1H, H-4 ', JH3, .H4, = 3.1 Hz) .55 (t, 1H, OH, Joa-cH2 = 5.6 Hz) 4.54 (d, 2H, CH2, J ^ -OH = 5.6 Hz) 13 C NMR (DMSO-d 6): d (ppm) 177.6, 176.6 (2C, C-4, C-9) 160.0 (IC, C-5 ') 158.4 (IC, C-) 2) 146.6 (IC, C-2 ') 134.4 (2C, C-6, C-7) 132.3, 132.1 (2C, C-4a, C-8a) 127.0, 126.2 (2C, C-5, C-8) 114.9 (IC, C-3 ') 110.5 (IC, C-4') 55.6 (IC, CH2) IR ( KBr): v (cm "1) 3374 (OH), 1677 and 1656 (C = 0) Example 37 2- (5-Acetoxymethylfuran-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [ 2, 3-d] thiazole To 5.00g (24 mmoles) of 2-amino-3-mercapto-1,4-dihydro-1,4-dioxonaphthalene, 40ml of N- was added at 0 ° C under argan atmosphere Methylpyrrolidone The reaction mixture was stirred for 10 minutes and then 4.10 g (24 mmol) of 5-acetoxymethyl-2-furaldehyde were added at 0 ° C. After stirring for 5 hours at this temperature, the The mixture was stirred at room temperature, the trichol content was poured into 250 ml of water and the brown precipitate formed was dissolved in ethyl acetate, the organic phase was extracted, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The brown solid obtained was purified a first time per column (support: silica 6-35μ, eluent: CH 2 Cl 2 / MeOH / AcOEt, 97/1/2) to give 3. 29g of product A sample of 0.500g was separated then purified a second time by plates (support: silica; eluent: CH2Cl2 / MeOH / AcOEt, 97/1/2), to obtain 0.107mg of 2- (5-acetoxymethylfuran-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [2,3- d] thiazole in the form of yellow crystals. Rdt: 38% F: 204 ° C Rf: 0.52 (Heptane / AcOEt, 50/50) SM (I.E.): m / z 353 (M +) NMR of ^ (CDCl 3): d (ppm) 8, 34 (m, 1H, H-5 or H-8) 8.24 (m, 1H, H-5 or H-8) 7.81 (m, 2H, H-6, H-7) 7.41 (d, 1H, H-3 ', JH3, -H4. = 3.74 Hz) 6.64 (d, 1H, H-4', JH4, -H3, = 3.32 Hz) 5.15 (s) , 2H, CH2) 2.14 (s, 3H, CH3) 13 C NMR (CDC13): d (ppm) 134.39, 134.14 (2C, C-6, C-7) 133.30, 132, 83 (2C, C-4a, C-8a) 127.86, 126.94 (2C, C-5, C-8) 114.52, 113.77 (2C, C-3 ', C-4') 57.67 (IC, CH2) 20.83 (IC, CH3) IR (KBr): v (cm "1) 1734.1686 and 1669 (C = 0) Example 38 4, 9-Dihydro-4, 9-dioxo -2- (5-methyl-2-furyl) apho- [2,3-d] thiazole To a buffer solution pH 11 (containing 6.2g of H3B03 and 4g of NaOH per liter), was added 4.6g (19.3 mmoles) of sodium sulphide nonahydrate. The mixture was stirred at 15 ° C under argon atmosphere until complete dissolution, then 2 g (9.6 mmoles) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene was added. After 20 minutes, 0.96 ml (9.6 mmol) of 5-methyl-2-furfural was added to the reaction medium. After stirring for 4 hours, the trichol content was poured into 100 ml of ethyl acetate and the trichol was rinsed with 50 ml of water. The organic phase was washed three times with 80 ml of water and dried in magnesium sulfate. It was obtained after evaporation of the solvent under reduced pressure lg of orange product that was purified on the cake (support: silica 6-35 μm, eluent: CH2Cl2 / Heptane: 50/50, 90/10 and 100) to obtain 0.560 g of orange crystals that were recrystallized in an AcOEt / CH2Cl2: 70/30 mixture then decolorized with animal black. Rdt: 35% F: 254 ° C Rf: 0.48 (CH2C12) SM (IE): m / z 295 (M +) XH NMR (CD2CL2): d (ppm) 8.22 (dd, 1H, H- 5 or H-8, JH5_H6 or JH7"H8 = 8.85 Hz, JH5_H7 or JH6.H8 = 1. 73 Hz) 8.16 (m, 1H, H-5 or H-8) 7.80 (m, 2H, H-6, H-7) 7.28 (d, 1H, H-3 ', JH3. -H4, = 3.35 Hz) 6.29 (d, 1H, H-4 ', JH3, -H4, = 3.35 Hz) 2.44 (s, 3H, CH3) 13C NMR (CDC13): d (ppm) 178.43, 178.12 (C-4, C-9) 164, 07 (C-2) 157.79 (C-5 ') 155.00 (C-3a) 146, 92 (C -2 ') 140.60 (C-9a) 134.54, 134.32 (C-6, C-7) 133.50, 133.04 (C-4a, C-8a) 127.72, 126, 94 (C-5, C-8) 115.43, 110.16 (C-3 ', C-4') 14.09 (CH3) IR (KBr): v (cm "1) 1684 and 1653 (C = 0) Example 39 4, 9 -Dihydro-2- (4,5-dimethyl-2-furyl) 4,9-dioxonaphtho- [2,3-d] thiazole To 200ml of a sodium hydroxide solution (pH = 10.66), 6.94g (28.9 mmoles) of sodium sulphide nonahydrate was added. The mixture was stirred at 15 ° C under argon atmosphere until complete dissolution, then 3.00g (14.4 mmoles) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene was added. After 3 hours of stirring at room temperature, 1.80 g (14.4 mmoles) of 4,5-dimethyl-2-furaldehyde was added to the reaction medium, which turned blue, and after five minutes, drop was added to the reaction medium. 5ml drop of acetic acid, the medium turned orange. The stirring was maintained for five minutes, then the bubbling of argon was replaced by compressed air for three minutes. The black precipitate formed was filtered on fritted glass, washed with water and dried to give 4.00g of product which were purified on a flash column (support: silica 6-35, eluent: Heptane / AcOEt: 85/15). The orange product obtained after evaporation of the solvent was decolorized with animal black, then ethyl acetate was recrystallized to obtain 2. 50g of 4,9-dihydro-2- (4,5-dimethyl-2-furyl) -4,9-dioxonaphtho [2,3-d] -thiazole in the form of orange crystals.
Rdt: 90% F: 250 ° C Rf: 0.2 (CH2C12) SM (IE): m / z 309 (M +) NMR of ^ (CDCls): d (ppm) 8, 31 (dd, 1H, H- 5 or H- 8, JH5-H6 or JH5_H7 = 8, 85 Hz, JH5_H7 or JH6-H8 = 1 73 Hz) 8.22 (dd, 1H, H-5 or H-8, JH5-H6 or JH5-H7 = 8.85 Hz, JH5_H7 or JH = 1.73 Hz) 7.80 (m, 2H, H-6, H -7) 7.23 (s, 1H, H-3 ') 2.35 (s, 3H, CH3 at 5') 2.17 (s, 3H, CH3 at 4 ') 13 C NMR (CDC13): d (ppm 178.43, 178.12 (2C, C-4, C-9) 172 (C-2) 164.21 (C-2 ') 155.35 (C-3a) 153.18 (C-5' ) 145.32 (C-9a) 134.13, 133.97 (2C, C-6, C-1) 133.24, 132.89 (2C, C-4a, C-8a) 127.72, 126 79 (2C, C-5, C-8) 118.78 (C-41) 117.51 (C-3 ') 12.50 (CH3 at 5') 10.00 (CH3 at 4 ') IR ( KBr): v (c "1) 1682 and 1656 (C = 0) Example 40 4, 9-Dihydro-4, 9-dioxo-2- (5-phenyl-2-oxazolyl) -naphtho [2, 3- d] thiazole To 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene (0.21 g, 1.0 mmol) in distilled water (7 ml) was added under argon sodium sulphonate nonahydrate atmosphere (0.98 g) , 4.1 mmol) The mixture was refluxed under an argon atmosphere until the coloration of the reaction medium became completely bluish, then 5-phenyl-2-oxazolecarbaldehyde (CAS No. 96829-89-9) was added (0.21. g, 1.4 mmol) in solution in tetrahydrofuran (6 ml) as well as acetic acid (0.25 ml). The reaction medium was stirred under argon atmosphere at room temperature for one hour. An orange precipitate formed. The precipitate was filtered, washed with water. The orange precipitate (0.28 g) was partially solubilized in diethyl ether (21 ml). After filtering the insolubles, the filtrate was concentrated in vacuo and chromatographed on a flash column (support: silica 6-35).; eluent: dichloromethane / methanol: 98/2). The orange product obtained after evaporation was decolorized with animal black, then filtered in micropore. From this menera orange crystals (0.17 g) of 4,9-dihydro-4,9-dioxo-2- (5-phenyl-2-oxazolyl) naphtho [2,3-d] thiazole were obtained after evaporation. Rdt: 79% F: > 260 ° C Rf: 0.64 (reversed phase acetonitrile) 0.76 (dichloromethane / methanol, 98/2) SM (I.E): m / z 358 (M +), 330 (M + - CO) XH NMR (CDC13): d (ppm) 8.36 (m, 1H, H-5 or H-8) 8.26 (m, 1H, H-5 or H-8) 7.85 (m, 4H , H-6, H-7, H-2", H-6") 7.60 (d, 1H, H-4 ', J = 0.9 Hz) 7.55-7.35 (m, 2H , H-3", H-5") 7.27 (d, 1H, H-4", J = 0.9 Hz) 13 C NMR (CDC13): d (ppm) 178.23, 177.36 ( 2C, C-4 and C-9) 160.34 (IC, C-2) 155.20 (IC, C-2 ') 154.60 (IC, C-3a) 154.37 (IC, C-5) ') 142.98 (1C, C-9a) 134.71, 134.27 (2C, C-6 and C-7) 133.04, 132.77 (2C, C-4a and C-8a) 129, 92 (IC, C-8 or C-5) 129.15 (2C, C-2"and C-6") 128.02 (IC, C-5 or C-8) 127.16 (IC, C- 4 ') 126.51 (IC, C-1") 125.22 (2C, C-3" and C-5") 124.66 (IC, C-4") IR (KBr): V cm "1 1681 and 1654 (C = 0), 1589 (N = C-0) Example 41 4, 9-Dihydro-4, 9-dioxo-2- (2-thiazolyl) naphtho [2,3-d] thiazole A 1.12 g (5.39 mmoles) of 2-amino-3-chloro-l, 4-dihydro-1,4-dioxanephthalene in 38 ml of water, 5.18 g (21.56 mmoles) of sodium sulphide nonahydrate were added. The mixture was refluxed until the coloration of the reaction medium became completely bluish. 0.73 g (6.46 mmoles) of 2-thiazolecarboxaldehyde then 1.3 ml (22.75 mmoles) of acetic acid at 90 ° C were added. The reaction medium was immediately cooled to 0 ° C by means of an ice bath. Then a precipitate formed. The reaction medium was stirred one hour at 0 ° C. The precipitate was then filtered and washed with water. The precipitate was partially solubilized in dichloromethane. From the filtration and the solubilization in dichloromethane, a change in coloration occurred: the brown precipitate became a yellow-tan color. After filtration of insolubles and evaporation of the solvent, 0.3 g of 4,9-dihydro-4,9-dioxo-2- (2-thiazolyl) naphtho [2,3-d] thiazole was obtained in the form of crystals. yellow-toasted.
Rdt: 19% F: > 260 ° C Rf: 0.22 (dichloromethane) SM (APCl-): m / z 298 (M-) XR NMR (CDC13): d (ppm) 8.36 (m, 1H, H-5 or H- 8) 8.26 (m, 1H, H-8 or H-5) 8.03 (d, 1H, H-4 ', JH4, -H5, = 3.06 Hz) 7.84 (m, 2H, H-6, H-7) 7.67 (d, 1H, H-5 ', JH4, -H5, = 3.05 Hz) 13 C NMR (CDC13): d (ppm) 145.18 (1C, C -4 ') 134.91, 134.53 (2C, C-6, C-7) 128.24, 127.41 (2C, C-8, C-5) 124.59 (1C, C-5' ) IR (KBr): V (cm "1) 1675, 1652 (C = 0) Examples 42 and 43 4,9-Dihydro-4,9-dioxo-6-fluoro-2- (2-furyl) -napht [ 2, 3-d] thiazole and 4,9-Dihydro-4,9-dioxo-7-fluoro-2- (2-furyl) -naphtho- [2,3-d] thiazole Intermediates of synthesis: 2, 3 -dibromo-1,4-dihydro-1,4-dioxo-6-fluoro-naphthalene To a solution of 1,4-dihydro-l, 4-dioxo-6-fluoronaphthalene (CAS No 148541-61-1) (12.5 g , 71 mmol) in chloroform (250 ml), 36 ml (710 mmol) of bromine was added, the solution was brought to reflux for 12 hours and then brought to room temperature After a bubbling of purchased air, the solution concentrated b garlic reduced pressure and the solid obtained was washed five times with heptane. 15. Og of a beige powder of 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene was obtained. Rdt: 65% F: 158 ° C Rf: 0.80 (dichloromethane) SM (APCl-): m / z 332, 334, 336 (M ") NMR"? (CDC13): d (ppm) 8.22 (dd, 1H, H-8, JH7.H8 = 8.55 Hz, JH_F = 5.19 Hz) 7.81 (dd, 1H, H-5, JH. F = 8.55 Hz, JH5.H7 = 2.75 Hz) 7.45 (td, 1H, H-7, JH.F = JH7.H8 = 8.55 Hz, JH5.H7 = 2.75 Hz) IR (KBr): v (c "1) 1680 (C = 0) 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoro-naphthalene and 2-amino-3-bromo -1,4-dihydro-1,4-dioxo-7-fluoro-naphthalene in a solution of 6-fluoro-2,3-dibromo-1,4-dihydro-1,4-dioxanephthalene (10.00 g, 30 mmol) in tetrahydrofuran (500 ml), ammonia was bubbled at room temperature for 2 hours, then the purchased air was passed through the solution for 15 minutes, then solvent was evaporated under reduced pressure.The solid obtained was first wiped on the cake. silica gel (support: silica 6-35 μm, 0 5 cm, h = 15 cm, eluent: dichloromethane / heptane, 90/10) then purifying by three successive flash chromatographies on silica gel column (support: silica 6-) 35 μm; 0 5 cm; h 30 cm; eluent: dichloromethane / heptane, 90/10) 4.78 g of a red powder, mixture of 2-amino-3-bromo-6-fluoro-1,4-dihydro-1,4-dioxonaphthalene and 2-amino-3-bromo-7-fluoro-1, was obtained. 4-dihydro-1,4-dioxanephthalene. Rdt: 60% (isomer ratio: 75/25) F: 190-195 ° C Rf: 0.40 (dichloromethane) SM (APCl-): m / z 270 (M-) XH NMR (acetone-d6) : d (ppm) 8.27 (dd, 1H, H-5 or H-8, JH5-Hg or JH7-H8 = 8.54 Hz, JH_F = 5.18 Hz) 7.85 (dd, 1H, H -5 or H-8, JH.F = 8.54 Hz, JH5.H7 or JH6_H8 = 2.74Hz) (td, 1H, H-6 or H-7 minor isomer, JH_F = JH5_H6 or JH7-H8 = 8.54 Hz, JH5.H7 or JH6_H8 = 2.74 Hz) 7.64 (td, 1H, H-6 or H-7 major isomer, JH_F = JH5-H6 or JH7-HS = 8.54 Hz, JH5-H7 or JHS-H8 = 2.74 Hz) IR (KBr): v (c "1) 3357 (NH2), 1685 (C = 0) 4.9-Dihydro- 4,9-dioxo-6-fluoro-2- (2-furyl) naphtho- [2,3-d] thiazole and 4,9-Dihydro-4,9-dioxo-7-fluoro-2- (2-furyl) ) Naphtho- [2,3-d] thiazole A 0.50g (1.8 mmol, 1.0 eq) of a 75/25 mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6- fluoronaphthalene and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoronaphthalene, 25 ml of a sodium hydroxide solution (5.10 4 M) containing l.llg ( 4.6 mmol, 2.5 eq) of sodium sulphide nonahydrate. The red suspension was heated 30 minutes at 80 ° C until obtaining a dark blue solution. 0.3 ml (3.6 mmol, 2.0 eq) of 2-furaldehyde was then added. After 90 minutes of heating at 80 ° C, the dark red solution obtained was brought to room temperature. A few drops of glacial acetic acid were added and then the orange precipitate formed was filtered, washed three times with water and dried. 0.5 g of a mixture of two isomers of 4,9-dihydro-4,9-dioxo-6-fluoro-2- (2-furyl) naphtho [2,3-d] thiazole and 4,9-dihydro- 4,9-dioxo-7-fluoro-2- (2-furyl) naphtho [2,3-d] -thiazole in the form of red crystals. The isomers were separated by flash chromatography on silica gel column (silica 6-35 μm, 0 4.5 cm, h 30 cm, eluent: dichloromethane), then by HPLC (column: Dynamax 60 -A Si 83-141C, eluent: heptane / ethyl acetate: 80/20) to obtain 0.125 g of less polar product and 0.375 g of more polar product. Rdt: 90% (ratio of isomers: 75/25) Less polar product F: > 265 ° C Rf: 0.32 (heptane / ethyl acetate, 80/20) SM (APCl-): m / z 299 (M-) ^ H NMR. (CD2C12): d (ppm) 8,17 (dd, 1H, H-5 or H-8, JH5_H6 or JH7.H8 = 8.55 Hz, JH_F = 5.50 Hz) 7.85 (dd, 1H, H-5 or H-8, JH.F = 8.55 Hz, JHS.H7 or JH6.H8 = 2.44 Hz) 7.61 (m, 1H, H-5 ') 7.39 (td, 1H, H-6 or H-7, JH5.H6 or JH7_H8 = JH.F = 8.55 Hz, JH5_H7 O JHs-H8 = 2.44 Hz) 7.33 (d, 1H, H-3 ', JH3, -H. = 3.66 Hz) 6.61 (dd, 1H, H-4', JH3, - H4, = 3.66 Hz, JH4, -H5, = 1.83 Hz) IR (KBr): V (cm-1) 1680 and 1655 (C = 0). Most polar product F: > 265 ° C Rf: 0.25 (heptane / ethyl acetate, 80/20) SM (APCl-): m / z 299 (M-) XH NMR (CD2C12): d (ppm) 8.23 (dd, 1H, H-5 or H-8, JH5-H6 ° Jpi-ß = 8/54 Hz 'JH-F = 5.50 Hz) 7.78 (dd, 1H, H-5 or H-8, JH_P = 8.54 Hz, JH5.H7 or JH6_H8 = 2.75 Hz) 7.61 (m, 1H, H-5 ') 7.40 (td, 1H, H-6 or H-7, JH5-H6 or JH7_H8 = JH_F = 8, 55 Hz, JH5_H7 OR JHS_H8 = 2, 75 Hz) 7.33 (d, 1H, H-3 ', JH3, -H4, = 3.66 Hz) 6.60 (dd, 1H, H -4 ', JH3, -H4, = 3.66 Hz, JH4, _H5, = 1.83 Hz) IR (KBr): V (cm "1) 1680 and 1660 (C = 0) Examples 44 and 45 4 , 9-Dihydro-4, 9-dioxo-6-fluoro-2-phenylaphtho [2,3-d] thiazole and 4,9-Dihydro-4,9-dioxo-7-fluoro-2-phenylnaphtho [2,3 -] thiazole A O.dOg (2.96 mmole, 1.0 eq) of a 75/25 mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoro-naphthalene and -amino-3-bromo-l, 4-dihydro-l, 4-dioxo-7-fluoro-naphthalene, was added 40ml of an aqueous solution of sodium sulphide nonahydrate (1.78g, 7.40 mmoles, 2.5 eq) The red suspension was heated 0.5 hour at 80 ° C until obtaining a dark blue solution. 0.6 ml (5.90 mmol, 2.0 eq) of benzaldehyde was added, and the solution was continued stirring for 2 hours at 80 ° C. The brown solution obtained was brought to room temperature, then a few drops of glacial acetic acid were added. The dark green precipitate formed was filtered, washed three times with water and dried. 0.820 g of a mixture of 4,9-dihydro-4,9-dioxo-6-fluoro-2-phenylnaphtho- [2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-7 was obtained. -fluoro-2-phenylnaphtho [2,3-d] thiazole in the form of yellow crystals. The isomers were separated by three successive flash chromatographies on silica gel column (support: silica 6-35 μm, 0 9.5 cm, h 25 cm, eluent: dichloromethane / heptane, 70/30) to obtain 0.205 g of the less polar product and 0.615g of the most polar product. Rdt: 89% (ratio of isomers: 75/25) Less polar product F: 261 ° C Rf: 0.48 (dichloromethane / heptane: 80/20) SM (APcl-): m / z 309 (M-) NMR of XH (CD2C12): d (ppm) 8.20 (dd, 1H, H-5 or H-8, JHS-H6 or JH7-H8 = 8.54 Hz, JH.F = 5.18 Hz) 8.09 (m, 2H, H-2'and H-6 ') 7.90 (dd, 1H, H-5 or H-8, JH_F = 8.54 Hz, JH5_H7 or JH6_H8 = 2.74 Hz) 7.50 (m, 4H, H-6 or H-7, H-3 ', H-4'and H-5') IR (KBr): V (cm "1) 1680 and 1660 (C = 0) Most polar product F: 241 ° C Rf: 0.41 (dichloromethane / heptane: 80/20) SM (APCl-): m / z 309 (M-) XH NMR (CD2C12): d (ppm) 8.28 (dd, 1H, H-5 or H-8, JH5.H6 or JH7_H8 = 8.54 Hz, JH.F = 5.19 Hz) 8.08 (dd, 2H, H-2 'and H -6 ', JH2, - "3, = HS.-H6. = 8.05 Hz, JH4, -HS, = JH2'-H4' = 1.65 Hz) 7.81 (dd, 1H, H-5 or H-8, JH_F = 8.54 Hz, JH5_H7 or JH6.H8 = 2.44 Hz) 7.50 (m, 4H, H-6 or H-7, H-3 'and H-4' and H-5 ') IR (KBr): V (cm'1) 1680 and 1660 (C = 0). Examples 46 and 47 4, 9-Dihydro-4, 9-dioxo-6-fluoro-2- (5-methyl-2-furyl) -naphtho [2,3-d] thiazole and 4,9-Dihydro-4, 9-dioxo-7-fluoro-2- (5-methyl-2-furyl) -naphtho [2,3-d] thiazole A 0.80 g (2.96 mmol, 1.0 eq) of a 75/25 mixture of 2 - amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoro-naphthalene and 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-7-fluoro-naphthalene; they added 40 ml of an aqueous solution of sodium sulphide nonahydrate (1.78 g, 7.40 mmoles, 2.5 eq). The red suspension was heated 30 minutes at 80 ° C until obtaining a dark blue solution. 0.59 ml (5.90 mmol, 2.0 eq) of 5-methyl-2-furaldehyde was added, and the solution was continued stirring for 90 minutes at 80 ° C. The dark roasting solution obtained was brought to temperature 8 - environment, then some drops of glacial acetic acid were added. The greenish precipitate formed was filtered, washed three times with water and dried. 0.705 g of a mixture of 4,9-dihydro-4,9-dioxo-6-fluoro-2- (5-methyl-2-furyl) naphtho [2,3-d] thiazole and 4,9-dihydro- 4,9-dioxo-7-fluoro-2- (5-methyl-2-furyl) naphtho- [2,3-d] thiazole in the form of dark red crystals. The isomers were separated by three successive flash chromatographies on silica gel column (support: silica 6-35 μm, 0 5 cm, h 35 cm, eluent: dichloromethane / heptane, 90/10) to obtain 0.177 g of the less polar product and 0.528 g of the most polar product. Rdt: 76% (ratio of isomers: 75/25) Less polar product F: 260 ° C Rf: 0.40 (dichloromethane / heptane: 80/20) SM (APCl-): m / z 313 (M-) NMR of H (CD2C12): d (ppm) 8.18 (dd, 1H, H-5 or H-8, JH5-Hg or JH7-H8 = 8.54 Hz, JH.F = 5.18 Hz) 7, 86 (dd, 1H, H-5 or H-8, JH.F = 8.54 Hz, JH5-H7 or JH6-H8 = 2.75 Hz) 7.41 (td, 1H, H-6 or H-7, JH-F = JH5-H6 or JH7_H8 = 8.54 Hz, JH5_H7 or JH6-H8 = 2.75 Hz) 7.25 (d, 1H, H-3 ', JH3, -H. = 3.36 Hz) 6.24 (d, 1H, H-4', JH3, -H4, = 3.36 Hz) 2.39 (s, 3H, CH3) IR (KBr): V (cm "1) 1685 and 1650 (C = 0), more polar product F: 238 ° C Rf: 0.30 (dichloromethane / heptane, 80/20) SM (APCl-): m / z 313 (M-) NMR of XH (CD2C12): d (ppm) 8.25 (dd, 1H, H-5 or H-8, JH5-H6 or JH7-H8 = 8.54 Hz, JH_F 5.18 Hz) 7.80 (dd, 1H, H-5 or H-8, JH_F = 8.54 Hz, JH5_H7 OR JH6.H8 = 2.75 Hz) 7.42 (td, 1H, H-6 or H-7, JH5_H6 or JH7.H8 = JH.F = 8.54 Hz, JH5.H7 ° JH6-H8 = 2.75 Hz) 7.25 (d, 1H, H-3 ', JH3, _H4, = 3.36 Hz) 6.24 (d, 1H, H-4', JH3, -H4 , = 3.36 Hz) 2.39 (s, 3H, CH3) IR (KBr): V (cm "1) 1675 and 1655 (C = 0) Examples 48 and 49 4, 9-Dihydro-4, 9 -dioxo-6- fluoro-2- (4-fluorophenyl) -naphtho [2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-7-fluoro-2- (4-fluorophenyl) -naphtho [2,3-d] thiazole A 0.80g (2.96 mmole, 1.0 eq) of a 75/25 mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoro-naphthalene and 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-7-fluoro-naphthalene, was added 40 ml of an aqueous solution of sodium sulphide nonahydrate (1.7 g, 7.40 mmol; eq) The red suspension was heated for 30 minutes at 80 ° C until a dark blue solution was obtained, 0.63 ml (5.80 mmol, 2.0 eq) of 4-fluorobenzaldehyde were then added and the solution was stirred for 90 minutes at 80 ° C. The dark roasting solution obtained was brought to room temperature, then a few drops of glacial acetic acid were added. or greenish formed was filtered, washed three times with water and dried. 0.570 g of a mixture of 4,9-dihydro-4,9-dioxo-6-fluoro-2- (4-fluorophenyl) naphtho [2, 3d] thiazole and 4,9-dihydro-4,9-dioxo were obtained. -7-fluoro-2- (4-fluorophenyl) naphtho [2,3-d] thiazole in the form of living yellow crystals. The isomers were separated by three successive flash chromatographies on silica gel column (support: silica 6-35 μm, 0 5.5 cm, h 40 cm, eluent: dichloromethane / heptane, 80/20) then each fraction was washed several times with heptane to obtain 0.143 g of the less polar product and 0.427 g of the more polar product.
Rdt: 59% (ratio of isomers: 75/25) Less polar product F: > 265 ° C Rf: 0.42 (dichloromethane / heptane, 80/20) SM (APCl-): m / z 327 (M-) NMR of XH (CD2C12): d (ppm) 8.21 (dd, 1H, H-5 or H-8, JHS.H6 or JH7.H8 8.54 Hz, JH_F = 5.19 Hz) 8.10 (dd, 2H, H-2 * and H-6 ', JH2, .H3, = JHS-H6 8.85 Hz, JH2, .F = JHS, -F = 5.19 Hz) 7 , 89 (dd, 1H, H-5 or H-8, JH_F = 8.54 Hz, JH5_H7 or JH6_H8 = 2.75 Hz) (td, 1H, H-6 or H-7, JH.F = JHS_H6 or JH7.H8 = 8.54 Hz, JH5.H7 or JH6.
H8 = 2.75 Hz) 7.20 (t, 2H, H-3 'and H-5', JH.F = H2.-H3. = JHS-H6 = 8.85 Hz) IR (KBr): v (cm "1) 1675 and 1655 (C = 0) Most polar product F:> 265 ° C Rf: 0.40 (dichloromethane / heptane, 80/20) SM (APcl-): m / z 327 (M-) NMR of XH (CD2C12): d (ppm) 8.28 (dd, 1H, H-5 or H-8, JH5-H6 or JH7_H8 = 8.54 Hz, JH.F = 5 19 Hz) 8.11 (dd, 2H, H-2 'and H-6', JH2, -H3, = JHS.-H6 '= 8.85 Hz, JH2, _F = JH6.-F = 5.19 Hz) 7.81 (dd, 1H, H-5 or H-8, JH "F = 8.54 Hz, JH5-H7 or JH6-H8 = 2.75 Hz) 7.45 (td, 1H, H-6 or H-7, JH.F = JH5-HS or JH7-H8 = 8.54 Hz, JH5-H7 or JH6-H8 = 2.75 Hz) 7.20 (t, 2H, H-3 'and H-5', JH.F JH2, _H3, = H5, -H6. = 8.85 Hz) IR (KBr): v (c "1) 1675 and 1660 (C = 0) Examples 50 and 51 4, 9-Dihydro-4, 9-dioxo-6-fluoro-2- (4-methyl-phenyl) -naphtho [2 , 3-d] thiazole and 4,9-Dihydro-4,9-dioxo-7-fluoro-2- (4-methylphnnyl) -naphtho [2,3-d] thiazole A lg (3.70 mmol, 1.0 eq ) of a 75/25 mixture of 2 - . 2 - . 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoro-naphthalene, 50 ml of an aqueous solution of sodium sulphide nonahydrate (2.22 g, 9.20 mmole, 2.5 g. eq). The red suspension was heated 30 minutes at 80 ° C until obtaining a dark blue solution. It was added then 0. 87 ml (7.40 mmoles, 2.0 eq) of 4-methylbenzaldehyde, and the solution was run out for 90 minutes at 80 ° C. The dark tan solution obtained was brought to room temperature, then a few drops of glacial acetic acid were added.
The greenish precipitate formed was filtered, washed three times with water and dried. 0.623 g of a mixture of 4,9-dihydro-4,9-dioxo-6-fluoro-2- (4-methyl phenyl) naphtho [2, 3d] thiazole and 4,9-dihydro-4,9 were obtained. -dioxo-7-fluoro-2- (4-methylphenyl) naphtho [2,3-d] thiazole in the form of yellow crystals. The isomers were separated by flash chromatography on a silica gel column (support: silica 6-35 μm, 0 9 cm, h 35 cm, eluent: dichloromethane / heptane, 70/30). The combined fractions were concentrated in vacuo and the solid product formed was washed in sintered glass twice with the minimum amount of methanol and five times with heptane to obtain 0. 467 g of the most polar product and 0.156 g of the less polar product in the form of yellow crystals. Rdt: 52% (ratio of isomers: 75/25) Most polar product F: > 260 ° C Rf: 0.42 (dichloromethane / heptane: 70/30) SM (APCl-): m / z 323 (M-) NMR of XH (CD2C12): d (ppm) 8.27 (dd, 1H, H-5 or H-8, JH5-H6 or JH7-H8 = 8.54 Hz, JH.F = 5.19 Hz) 7.96 (d, 2H, H-2 'and H-6', JH2, -H3. = JH5, -H6. = 8.24 Hz) 7.80 (dd, 1H, H-5 or H -8, JH.F = 8.54 Hz, JH5_H7 or JH7-H8 = 2.75 Hz) 7.44 (td, 1H, H-ß or H-7, JH-F = JH5-HS or JH7-HS = 8.54 Hz, JH5-H7 7.30 (d, 2H, H-3 'and H-5 \ JH2'-H3- = H5 - H6' = 8.24 Hz) 2.38 (s, 3H, CH3 ) IR (KBr): v (crrf1) 1670 and 1665 (C = 0), less polar product F:> 260 ° C Rf: 0.46 (dichloromethane / heptane: 70/30) SM (APcl-): m / z 323 (M-) NMR of XH (CD2C12): d (ppm) 8.20 (dd, 1H, H-5 or H-8, JH5-H6 or JH7-H8 = 8.54 Hz, JH-F 5,19 Hz) 7.97 (d, 2H, H-2 'and H-6', JH2.-H3 '= H5 - H6- = 8.24 Hz) 7.88 (dd, 1H, H-5 or H -8, JH-F = 8.85 Hz, JH5-H7 OR JH6-H8 = 2.75 Hz) 7.42 (td, 1H, H-6 or H-7, JH-F = JH5-H6 OR JH7-H8 = 8.54 Hz, JH5-H7 7.31 (d, 2H, H-3 'and H -5 ', JH2-H3' = H5'-H6 '= 8.24 Hz) 2.39 (s, 3H, CH3) IR (KBr): v (cm "1) 1675 and 1655 (C = 0) Examples 52 and 53 4, 9-Dihydro-, 9-dioxo-5-f luoro-2- (2-furyl) napht- [2,3-d] thiazole 4,9-Dihydro-4,9-dioxo-8 -fluoro-2- (2-furyl) na to- [2, 3-d] thiazole Intermediates of synthesis 2, 3-Dibromo-l, -dihydro-1, -dioxo-5-fluorone taleno To a solution of 1 , 4-dihydro-l, 4-dioxo-5-fluoro-naphthalene (CAS No. 62784-46-7) 2.45 g (71 mmol) in chloroform (60 ml), 7.34 ml (143 mmol) of bromine was added. The solution was brought to reflux for 12 hours and then left at room temperature After an injection of compressed air, the solution was concentrated under reduced pressure and the beige solid product obtained was purified on a flash column (support: silica).; conditioning: heptane; eluent: CH2Cl2 / heptane) to obtain 3.44 g of 2,3-dibromo-1,4-dihydro-l, 4-dioxo-5-fluoronaphthalene as beige crystals. Rdt: 74% F: 100 ° C Rf: 0.63 (dichloromethane / heptane: 80/20) MS (EI): m / z 333, 335, 337 (M ++ 1) 1 H NMR (CDC 13): d (ppm) - 8.01 (d, 1H, H-8, JH7-H8 = 7.94 Hz) 7.77 (m, 1H, H-7) 7.52 (m, 1H, H-6) IR (KBr): v (crn-1) 1704 (C = 0) 2-Amino-3-bromo-1,4-dihydro-l, 4-dioxo-5-fluoroannane 2-Amino-3-bromo-1,4-dihydro-l, -dioxo-8-fluoro-nane in a solution of 2,3-dibromo-l, 4-dihydro-l, 4-dioxo-5-fluoronaphthalene (33 mg, 0.098 mmol) in tetrahydrofuran (5 ml), ammonia was injected at room temperature for 1 hour, and then compressed air was passed through the solution for 15 minutes to remove excess ammonia. After evaporation of the solvent under reduced pressure, the red solid product obtained was purified on a silica plate (eluent CH 2 Cl 2 / Heptane = 90/10). 20.5 mg of a red powder, mixture of 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-5-fluoronaphthalene and 2-amino-3-bromo-1,4-diol, were obtained. hydro-l, 4-dioxo-8-fluoronaphthalene. Rdt: 77% F: 208 ° C Rf: 0.44 (dichloromethane) SM (APCl-): m / z 269, 271 (M-) 1 H NMR (CDC13): d (ppm) 7.98 (d, 1H, H-5 or H-8, JH5-H6 or JH7-H8 = 7.63 Hz) 7, 64 (, 1H, H-6 or H-7) 7.31 (dd, 1H, H-6 or H-7, JH5-H- or JH7-H8 = JH-F = 8.55 Hz) 6.40-5.00 (sl, 2H, NH2) IR (KBr): v (cm "1) 3466, 3355 (NH2), 1778, 1633 (C = 0) 4, 9-Dihydro-4, 9-dioxo-5-luoro-2- (2-furyl) na to- [2, 3-d] thiazole 4, 9- Dihydro-4, 9-dioxo-8-fluoro-2- (2-furyl) naphtho- [2,3-d] thiazole A 0.15 g (0.55 mmol, 1.0 eq) of a mixture of 2-amino-3 -bromo-l, 4-dihydro-l, 4-dioxo-5-fluoronaphthalene and 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-8-fluoro-naphthalene in 25 ml of water 0.33 g (1.38 mmol, 2.5 eq) of sodium sulphide nonahydrate was added The red suspension was heated for 30 minutes at 80 ° C until a dark blue solution was obtained, then 0.1 ml was added ( 1.1 mmol, 2.0 eq) of 2-furaldehyde After 90 minutes of heating at 80 ° C, the dark tan solution obtained Nida was allowed to rest at room temperature. A few drops of glacial acetic acid were added and then the brown precipitate formed was filtered, washed three times with water and dried. The mixture of products obtained was purified by chromatography on a preparative bed (silica 2 mm, eluent: dichloromethane / heptane / ethyl acetate, 80/10/10), and then the isomers of the compound obtained were separated by chromatography on a preparative bed (silica 2 mm, eluent: dichloromethane) to obtain 0.020 g of a mixture of 4,9-dihydro-4,9-dioxo-5-fluoro-2- (2-furyl) naphtho [2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-8 -fluoro-2- (2-furyl) naphtho [2,3-d] thiazole in the form of orange crystals. Rdt: 12% (report isomers 47/53) Less polar isomers F: > 260 ° C Rf: 0.34 (dichloromethane) SM (APcI +): m / z 300 (M + H +) XH NMR (CD2C12): d (ppm) 8.09 (dd, 1H, H-5 or H- 8, JH5-H6 OR JH7-H8 = 8.24 Hz, JH5-H7 or JH6-H8 = 1.22 Hz) 7.75 (td, 1H, H-ß or H-7, JH5-H6 or JH7- HS = JH6-H7 = 7.94 Hz, JH-F = 4.58 Hz) 7.65 (dd, 1H, H-5 ', JH3'-H5' = 0.92 Hz, JH4'-H5 '= 1.84 Hz) 7.46 (ddd, 1H, H-6 or H-7, JH-F = 10.98 Hz, JH6-7 = 8.24 Hz, 7.35 (d, 1H, H-3 ', JH3'-H4' = 3.67 Hz) 6.63 (dd, 1H, H-4 ', JH3-H4- = 3.67 Hz, JH4'-H5' = 1/84 Hz) IR ( KBr): v (c "1) 1680 and 1655 (C = 0) .more polar isomers F:> 260 ° C Rf: 0.28 (dichloromethane) SM (APcI +): m / z 300 (M + H +) 1 H NMR (CD2C12): d (ppm) 8.02 (dd, 1H, H-5 or H-8, JH5-HβO JH7-H8 = 7.63 Hz, JH5-H7 O JHe- H8 = 1, 22 Hz) 7.73 (td, 1H, H-6 or H-7, JH5-H6 OR JH7-H8 = JH6-H7 = 8.24 Hz, JH-F = 4.58 Hz) 7.64 (dd, 1H, H-5 ', JH3'-H5' = 0.91 Hz, JH4.-H5- = 1.83 Hz) 7.46 (ddd, 1H, H -6 or H-7, JH-F = 11.29 Hz, JH5-H6 OR JH7-H8 = 8.54 Hz, JH5-H7 OR JH6-H8 = 1.22 Hz) 7.37 (d, 1H, H-31, JH3'-H4 '= 3.66 Hz) 6.64 (dd, 1H, H -4 ', JH3'-H4' = 3.66 Hz, JH4-H5 '= 1.83 Hz) IR (KBr): v (cm "1) 1680 and 1655 (C = 0) Examples 54 and 55 6 -Chloro-, 9-dihydro-, 9-dioxo-2- (2-furyl) -naphtho- [2,3-d] thiazole 7-Cl? Ro-4,9-dihydro-, 9-dioxo-2- (2-furyl) -naphtho- [2,3-d] thiazole A 435 mg (1.79 mmole) of a mixture of 2-amino-3,6-dichloro-l, 4-dihydro-1,4-dioxonaphthalene and of 2-amino-3,7-dichloro-l, 4-dihydro-l, 4-dioxonaphthalene was added at room temperature and under argon 1.72 g (7.16 mmol) of sodium sulphide nonahydrate in solution in 15 ml of caustic soda pH 10.6 After 30 minutes at 60 ° C and under argon, 296 μl (3.58 mmoles) of 2-furaldehyde was added to the completely blue reaction medium. After 15 minutes of reflux, the argon inlet was removed and the reaction mixture was diluted with 250 ml of water and extracted 3 times with 150 ml of dichloromethane. The organic phase was then washed with 300 ml of water and evaporated to dryness to obtain 450 mg of a mixture of 6-chloro-4,9-dihydro-4,9-dioxo-2- (2-furyl) -naphtho [ 2, 3-d] thiazole and 7-chloro-4,9-dihydro-4,9-dioxo-2- (2-furyl) -naphtho [2,3-d] thiazole in the form of orange crystals. The isomers were separated from the silica cake (silica 40-60 m, diameter 7 cm, height 14 cm, eluent: dichloromethane / heptane, 90/10) and 80 mg of less polar product and 150 mg of more polar product were obtained. Less polar product Rdt: 40% Ref: not described from 1920 to 1995 (vol 123) F: > 260 ° C Rf: 0.42 (CH2Cl2 / MeOH, 99/1) S.M. (APCl-): m / z 315 and 317 (M-) XH NMR (CDC13): d (ppm) 8.28 (d 1H, H-5 or H-8, JH5-H-7 or JH6-H8 = 2.08 Hz) 8.17 (d, 1H, H-5 or H-8, JH7-H8 or JH5-H6 = 8.31 Hz) 7.75 (dd, 1H, H-6 or H-7 , JH7-HS OR JH5-H6 = 8.31 Hz, JH5-H7 OR JH6-HS = 2.07 Hz) 7.65 (m, 1H, H-5 ') 7.46 (d, 1H, H-3', JH3'-H4 '= 3.74 Hz) 6.66 (dd, 1H, H-4', JH3 < -H4 '= 3.74 Hz, JH3'-H5' = 1.66 Hz) 13 C NMR (CDC13): d (ppm) 146.81 (C-5 '), 13.72 (C-6) or C-7) 129.31, 128.53 (2C, C-5, C-8) 114.75 and 114.11 (2C, C-3 ', C-4') IR (KBr): v ( cm "1) 1675, 1665 (C = 0) Most polarproduct Rdt: 26% F:> 260 ° C Rf: 0.36 (CH2Cl2 / MeOH, 99/1) SM (APcI +): m / z 316 and 318 (MH +) 1 H NMR (CDC13): d (ppm) 8.28 (d 1 H, H-5 or H-8, J "7-HB or JH5-H6 = 8 Hz) 8.18 (d, 1H, H-5 or H-8, JH5-H7 or JH6-H8 = 1.84 Hz) 7.77 (d, 1H, H-6 or H-7, JH7-H8 OR JH5-H6 = 8.04 Hz, JH5 -H-7 O JHe-Hβ = 1.84 Hz) 7.67 (ls, 1H, H-5 ') 7.47 (d, 1H, H-3', JH3'-H4 '= 3.45 Hz) 6, 66 (, 1H, H-4 ') 13 C NMR (CDC13): d (ppm) 178.50, 177.90 (2C, C-4, C-9) 148.5 (C-2') 146.8 (C-5 ') 141.8 (C-6 or C-7) 134.9 (C-6 or C-7) 131.8 (2C, C-4a, C-8a) 130.09, 127, 64 (2C, C-5, C-8) 114.80 (C-3 ') 114.11 (C-4') IR (KBr): v (cm-1) 1675, 1650 (C = 0) Example 56 4, 9-Dihydro-4, 9-dioxo-2- (2-furyl) -5-methoxy-naphtho- [2,3-d] thiazole or 4,9-Dihydro-4,9-dioxo-2- (2 -furyl) -8-methoxine to- [2, 3-d] thiazole In an interte atmosphere, to 3.64 g (12.9 mmol) of a mixture of 2-amino-3-bromo-1,4-dihydro-l, 4 -dioxo-5-methoxynaphthalene and of 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-8-methoxynaphthalene were added 140 ml of an aqueous solution containing 7.74 g (32.2 mmoles) of sodium sulfate. sodium nonahydrat ado. The suspension thus obtained was carried out 82 ° C until obtaining an "inky blue" solution. Then 2.1 ml (25.8 mmoles) of 2-furaldehyde was added to the reaction medium. The mixture became progressively brick red. After 1.25 hour, 6.73 g (38.7 mmoles) of sodium hydrosulfite was added to the reaction mixture, and a brown precipitate appeared progressively. The precipitate was filtered hot by sintered glass and washed with water. The crude product was recrystallized from DMF. A second recrystallization was carried out in dichloromethane. The filtrate, after evaporation under reduced pressure, was purified on the cake (support: silica 6-35 μm, conditioning: CH 2 Cl 2 / heptane, 80/20, eluent: CH 2 Cl 2 / MeOH, 100/0 to 90/10). The solid obtained was washed with heptane, decolorized with animal black in dichloromethane, then filtered in a micropore to obtain after evaporation under reduced pressure 0.32 g of 4,9-dihydro-4,9-dioxo-2. (2-furyl) -5-methoxynaphtho [2,3-d] thiazole or of 4,9-dihydro-4,9-dioxo-2- (2-furyl) -8-methoxynaphtho [2,3-d] thiazole in the form of orange crystals. Rdt: 8% F: > 260 ° C Rf: 0.60 (CH2Cl2 / MeOH, 98/2) SM (APcI +): m / z 312 (MH +) NMR of XH (CD2C12): d (ppm) 7.78 (dd, 1H, H- 8 or H- 5, J H7-H8 = 7, 63 Hz, J H6-H8 = 1, 22 Hz) 7, 65 (t, 1H, H- 7 or H- 6, JH7-H8 # J H6"H7 = 7.62 Hz) 7.60 (dd, 1H, H-5 ', JH4'-H5' = 1.53 Hz, JH3'-H5 '= 0.92 Hz) 7.33 (dd, 1H, H -6 or H-7 in the methoxy group, JH6 ~ H7 = 8.24 Hz, JH6-H8 OR JH5-H7 = 0.92 Hz) 7.31 (s, 1H, H-3 ') 6.59 ( dd, 1H, H-4 ', JH3'-H4' = 3.67 Hz, JH4'-H5 '= 1.83 Hz) 3.96 (s, 3H, OCH3) IR (KBr): v (cm " 1) 3112 (CH); 1674 (C = 0); 1655 (C = N) Example 57 4, 9-Dihydro-4, 9-dioxo-2- (2-furyl) -5-hydroxynaphtho- [2,3-d] thiazole or 4,9-Dihydro-4, 9 -dioxo-2- (2-furyl) -8-hydroxyne to- [2,3-d] thiazole To a solution of 4,9-dihydro-4,9-dioxo-2- (2-furyl) -5- methoxy-naphtho [2, 3-d] thiazole or of 4,9-dihydro-4,9-di-oxo-2- (2-furyl) -8-methoxy-naphtho [2,3-d] thiazole (230 mg, 0.73 mmol) ) 0.90 ml of 47% hydrobromic acid (7.69 mmol) were added to 20 ml of acetic acid. The reaction mixture was stirred under reflux for 5 hours. After returning to room temperature, the water (30 ml) reaction was added. This solution was then extracted into dichloromethane. The organic phase was washed in water until a neutral pH was achieved. After drying under calcium chloride, the organic phase was evaporated under pressure xeducide. The crude product of the reaction was purified on the cake (support: silica 6-35 μm; eluent CH2C12). The product, dissolved in dichloromethane, was decolorized with animal black. After washing with heptane, 110 mg of 4,9-dihydro-4,9-dioxo-2- (2-furyl) -5 (ou 8) -hydroxynaphtho [2,3-d] thiazole was obtained in the form of orange powder. Rdt: 50% F: 257 ° C Rf: 0.50 (CH2C12) S.M. (APcI +): m / z 298 (M + H +) XH NMR (CD2C12): d (ppm) 12.25 (s, 1H, OH) 7.77 (dd, 1H, H-8 or H-5, JH7-HS OR JH5-Hß = 7.63 Hz, JH5-H7 = 1.22 Hz) 7.70 (dd, 1H, H-5 ', JH' -H5- = 1.84 Hz, JHS'-HS- = 0.92 Hz) 7.68 (t, 1H, H-7 or H-6 in b of the hydroxy group, JH7 ~ H8 O JH5_H6 = 7.63 Hz, JH6-H7 = 8.23 Hz) 7.41 (d, 1H, H-3 ', JH3 - H4- = 3, 67 Hz) 7.34 (dd, 1H, H-6 or H-7 in a of the hydroxy group, JH6_H7 = 8.23 Hz, JH6-H8 OR JH5-H7 = 1.22 Hz) 6.69 (dd, 1H, H-4 ', JH3'-H4' = 3.66 Hz, JH4-H5 '= 1.83 Hz) 13 C NMR (CD2C12): d (ppm) 183.72 (IC, C-4 or C-9) 177.73 (IC, C-9 or C-4) 164.31 (IC, C-5 or C-8) 163.45 (IC, C-2) 155.15 (IC, C-21) 148.41 ( IC, C-3a) 146.68 (IC, C-5 ') 142.00 (IC, C-9a) 137.07 (IC, C-7 or C-6 in β of the hydroxy group) 133.76 ( ÍC, C-8a or C-4a) 125.74 (ÍC, C-8 or C-5) 120, 32 (ÍC, C-6 or C-7 in a of the hydroxy group) 115, 69 (ÍC, C-4a or C-8a) 113.75 and 114.07 (2C, C-3 * and C-4 ') IR (KBr): v (cpf1) 3400 (OH); 3124 (C-H); 1644 (C = 0); 1584 (CC) Examples 58 and 59 4, 9-Dihydro-, 9-dioxo-2- (2-furyl) -6-methoxy-naphtho- [2,3-d] thiazole and 4,9-dihydro-, 9-dioxo -2- (2-furyl) -7-methoxy-naphtho- [2,3-d] thiazole. In an inert atmosphere, 2.00 g (7.1 mmol) of a mixture of 2-amino-3-bromo-l, 4- was added. dihydro-l, 4-dioxo-6-methoxynaphthalene and 3-amino-2-bromo-l, 4-dihydro-1,4-dioxo-6-methoxynaphthalene 75 ml of an aqueous solution containing 4.25 g (17.7 moles) of Sodium sulfide nonahydrate. The suspension thus obtained was brought to 80 ° C, the naphthoquinone was progressively dissolved until it gave an "inky blue" solution. Then 1.2 ml (14.2 mmol) of 2-furaldehyde was added to the reaction medium. The mixture became progressively brick red. After an hour and a half and cooling to 50 ° C, 2.45 g (14.2 mol) of sodium hydrosulphite was added to the reaction mixture, giving a brown precipitate. The precipitate was filtered hot on fritted glass and washed with water until the washing water came out colorless. After drying in a vacuum oven, the crude product was purified on a cake of silica gel (silica 6-35 mm, eluent CH 2 Cl 2 MeOH, 98/2), 1.15 g (3.7 mmol) of the mixture of 4,9- dihydro-4, 9-dioxo-2- (2-furyl) -6-methoxy-naphtho- [2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-2- (2-furyl) -7-methoxynaphtho [2,3-d] thiazole. The separation of the isomers was carried out by means of three successive chromatographies under pressure of the mixture (silica 6-35 μm, eluent CH2Cl2 / AcOEt, 99/1). After decolorization and recrystallization in dichloromethane from each isomer, 0.210 g of orange crystals were obtained from the more polar product and 0.300 g of orange crystals from the less polar product. Most polar product Rdt: 9.5% F: > 260 ° C 10Í Rf: 0.58 (CH2Cl2 AcOEt, 90/10) S.M. (I.E.): m / z 311 (M +) R.M.N. of XH (CD2C12): d (ppm) 8.22 (d, 1H, H-8 or H-5, JH5-H6 OR JH7-H8 = 8.85 Hz) 7.69 (sl, 1H, H-5 ') 7.66 (d, 1H, H-5 or H-8 in a methoxy group, JHs-H7 O JH6-HS = 2. 74 Hz) 7.40 (d, 1H, H-3 ', JH3'-H4' = 3.66 Hz) 7.27 (dd, 1H, H-7 or H-6, JH5-H6 or JH7-HS = 8.55 Hz, JHS-H8 OR JH5-H7 = 2.45 Hz) 6.68 (dd, 1H, H-4 ', JH3'-H4' = 3.66 Hz, JH4'-H5 '= 1 , 83 Hz) 3.98 (s, 3H, CH30 in 6 or 7) IR (KBr): v (cm "1) 1675 (C = O), 1650 (C = N), 1589 Less polar product Rdt: 13.5% F:> 260 ° C Rf: 0.68 (CH2Cl2 / AcOEt , 90/10) SM (EI): m / z 311 (M +) NMR of XH (CD2Cl2: d (ppm) 8.15 (d, 1H, H-8 or H-5, JH5-H6 O JH7-H8 = 8.55 Hz) 7.73 (d, 1H, H-5 or H-8 in a methoxy group, JH5-H7 OR JH6-HS = 2. 75 Hz) 7.68 (d, 1H, H-5 ', JH4'-H5' = 1.83 Hz) 7.38 (d, 1H, H-3 ', JH3'-H4' = 3.67 Hz ) 7.25 (dd, 1H, H-7 or H-6, JH5-H6 OR JH7-H8 = 8.55 Hz, JH6-HS or JH5-H7 = 2.75 Hz) 6.68 (dd, 1H , H-4 ', JH3'-H4' = 3.66 Hz, JH4'-H5 '= 1.83 Hz) 3.99 (s, 3H, CH30 in 6 or 7) IR (KBr): v (crn-1) 1681 (C = 0), 1645 (C = N), 1586 Examples 60 and 61 4, 9-Dihydro-4, 9-dioxo-2-furyl-6-methylna to [ 2, 3-d] -thiazole and, 9-Dihydro-4, 9-dioxo-2-furyl-7-methylna to [2,3-d] -thiazole Intermediates of synthesis: 2-Amino-3-chloro- l, 4-dihydro-l, -dioxo-6-methyl-naphthalene and 2-Amino-3-chloro-l, 4-dihydro-l, 4-dioxo-7-methyl-naphthalene To a solution formed of 6.00 g ( 25 mmol, 1.0 eq) of a mixture of 2-chloro-l, 4-dihydro-l, 4-dioxo-6-methyl-naphthalene (CAS No. 87 170-60-3) and 2- chloro-l, 4-dihydro-l, 4-dioxo-7-methylnaphthalene (CAS No. 87 170-61-4) and 250 ml of glacial acetic acid, was added at one time, 2. 60 g (40 mmol, 1.6 eq) of sodium nitride in solution in 16 ml of distilled water. The medium was heated at 80 ° C for 5 hours; the color changed from yellow to orange.
After cooling, the reaction medium was evaporated to dryness and the crude product obtained was purified on a silica pad (support: silica 6-35 μm, d = 10 cm, h = 5 cm, solid deposit, eluent: Heptane / Acetate of ethyl, 92/8) to obtain after evaporation of the solvents 0.44 g of a mixture of 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-6-methylnaphthalene and 2-amino- 3-chloro-l, 4-dihydro-l, 4-dioxo-7-methylnaphthalene in the form of red crystals. Rdt: 8% Rf: 0.38 (Heptane / Ethyl acetate, 70/30) SM (APcI +): m / z 222/224 (MH +) XH NMR (CDC13): d (ppm) 7.99 and 7 , 95 (2d, 2H, protons in b of CH3, J = 7.93 Hz) 7.87 (s, 2H, protons in a of CH3) 7.56 and 7.48 (2d, 2H, protons in a of CH3 ) 2.49 and 2.47 (2s, 6H, 2 x CH3) 4, 9-Dihydro-4, 9-dioxo-2-furyl-6-methylnaphtho [2,3-d] -thiazole and 4, 9-Dihydro-4,9-dioxo-2-furyl-7-methylnaphtho [2,3-d] -thiazole (Examples 60 and 61) To a solution formed by 1.3 g (5.4 mmol, 6.0 eq) of sodium sulphide nonahydrate and 3.2 ml of a previously prepared sodium hydroxide solution at pH 10.7, was added 0.2 g (0.9 mmol, 1.0 eq) of a mixture of 2-amino-3-chloro-l , 4-dihydro-l, 4-dioxo-6-methylnaphthalene and 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-7-methyl-naphthalene. This suspension, heated to 45 ° C, produced a bluish solution in 30 minutes. Then 149 μl (1.8 mmol, 2.0 eq) of 2-furaldehyde was added and, after 15 minutes, 97 μl (1.7 mmol, 1.9 eq) of glacial acetic acid 55 ° C. The reaction medium turned brown and 6 x 100 ml of dichloromethane was extracted. The aqueous phases were stripped, dried over magnesium sulfate, filtered and evaporated to dryness. The product obtained was purified on a silica pad (support: silica 6-35 μm, h = 15 cm, d = 5 cm, solid deposit, eluent: heptane / ethyl acetate, 90/10) to obtain after evaporation the solvents 0.13 g of 4,9-dihydro-4,9-dioxo-2-furyl-6-methylnaphtho- [2,3-d] -thiazole and 4,9-dihydro-4,9-dioxo-2 mixture -furyl-7-methylnaphto- [2,3-d] thiazole of the isomers in the form of orange crystals. The isomers were then separated on preparative plates (Support: alumina, eluent: dichloromethane / heptane, 70/30). Rdt: 48.8% (mixture of two isomers) Most polar product Rf: 0.42 (dichloromethane / heptane, 70/30, alum) SM (APcI +): m / z 296 (M + H +) 1 H NMR (CD2C12 ): d (ppm) 8,20 (d, 1H, H-5 or H-8 in b of CH3, JH5-H6 or JH7-HS = 7.93 Hz) 8.05 (m, 1H, H-5 or H-8 in a of CH3) 7.73 (dd, 1H, H-5 ', JH' -H5 '= 1.83 Hz, JH3'-H5' = 0.61 Hz) 7.67 (d, 1H, H-6 or H-7, JH5-H6 OR JH7-H8 = 7.94 Hz, in a of CH3) 7.44 (dd, 1H, H-3 ', JH3'-H4' = 3.67 Hz, JH3'-H5 <= 0.61 Hz) 6.72 (dd, 1H, H-4 ', JH3 '-H4' = 3.66 Hz, JH4'-H5 '= 1.83 Hz) 2.57 (s, 3H, CH3) 13 C NMR (CD2Cl2): d (ppm) 146.41 (IC, C- 5 ') 135.31 (IC, C-6 or C-7, in a of CH3) 127.99 (IC, C-5 or C-8) 127.55 (IC, C-5 or C-8) 113.70 (IC, C-3 ') 113.59 (1C, C-4') 21.94 (IC, CH3) Less polar product Rf: 0.50 (Dichloromethane / heptane, 70/30, alumina) SM (APcI +): m / z 296 (M + H +) NMR of XH (CD2C12): d (ppm) 8.01 (m, 2H, H-5, H-8) 7.60 (dd, 1H, H- 5 ', JH4'-H5' = 1.83 Hz, JH3'-H5 '= 0.61 Hz) 7.53 (d, 1H, H-6 or H-7, JH5-H6 OR J 7-HS = 7.33 Hz, in a of CH3) 7.31 (dd, 1H, H-3 ', JH3'-H4 < = 3, 66 Hz, JH3 < -H5' = 0.61 Hz) 6.60 (dd, 1H, H-4 ', JH3'-H4' = 3.66 Hz, JH4'-H5 '= 1.83 Hz) 2.46 (s, 3H, CH3) 13 C NMR (CD2C12 ): d (ppm) 176.28 (2C, C = 0) 145.99 (IC, C-5 ') 134, 64 (IC, C-6 or C-7, in a of CH3) 127.94 ( IC, C-5 or C-8) 126, 83 (IC, C-5 or C-8) 113.24 (IC, C-3 ') 113.18 (IC, C-4') 21.74 ( ÍC, CH3) Examples 62 and 63 4, 9-Dihydro-4, 9-dioxo-6-methyl-2-enylnaphto [2,3-d] thiazole and 4,9-Dihydro-4,9-dioxo-7- methyl-2-phenyl or [2, 3-d] thiazole To a solution formed by 1.3 g (5.4 mmol, 6.0 eq) of sodium sulphide nonahydrate and 3.2 ml of a sodium hydroxide solution previously prepared at pH 10.7, 0.5 g (0.9 mmol, 1.0 eq) of a mixture of 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-6-methyl-naphthalene and 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-7-methylnaphthalene. This solution, heated to 45 ° C, turned blue in 30 minutes. 184 μl (1.8 mmole, 2.0 eq) of benzaldehyde was then added to the reaction medium. The mixture, heated to 55 ° C, turned green in 30 minutes. After the addition of 291 μl (5.0 mmol, 5.5 eq) of glacial acetic acid, a brown precipitate formed which was filtered on sintered glass and then washed with dichloromethane. The obtained crude product was purified on a silica pad (support: silica 6-35 μm, d = 5 cm, h = 5 cm, solid deposit, eluent: Heptane / ethyl acetate, 90/10) to obtain after evaporation of the solvents 90 mg of 4,9-dihydro-4,9-dioxo-6-methyl-2-phenyl-naphtho [2,3-d] -thiazole and 4,9-dihydro-4,9-dioxo- 7-methyl-2-phenyl-naphtho [2,3-d] thiazole in the form of yellow crystals. The isomers were separated on preparative plates (eluent: dichloromethane / heptane, 70/30). Rdt: 33% (mixture of two isomers) Producer more polar Rf: 0.50 (Dichloromethane / Heptane, 70/30, alumina) SM (APcI +): m / z 306 (MH +) XH NMR (CD2C12): d ( ppm) 8.10 (d, 1H, H-5 or H-8, JH5-H6 OR JH7-H8 = 7.63 Hz) 8.03 (m, 2H, H-2 'and H-6') 7 , 93 (bs, 1H, H-5 or H-8, in a of CH3) 7.55 (d, 1H, H-6 or H-7, JH5-HS or JH7-H8 = 7.93 Hz) 7 46 (m, 3H, H-3 ', H-4', H5 ') 2.45 (s, 3H, CH3) 13 C NMR (CD2C12): d (ppm) 135.36 (IC, C-6 or C-7) 132.60 (IC, C-4 ') 129.65 (2C, C-2', C-6 ') 128.01 (IC, C-5 or C-8) 127.90 ( 2C, C-3 ', C-5') 127.55 (IC, C-5 or C-8) 21.93 (IC, CH3) Less polar product R: 0.62 (Dichloromethane / Heptane, 70/30 , alumina) SM (APcI +): m / z 306 (M + H +) 1 H NMR (CD2C12): d (ppm) 8.09 to 8.00 (m, 4H, H-5, H-8, H- 2 ', H-6') 7.53 (d, 1H, H-6 or H-7, JH5-H6 OR JH7-H8 = 7.93 Hz) 7.46 (m, 3H, H-3 ', H-4 ', H-5') 2.46 (s, 3H, CH 3) 13 C NMR (CD 2 C 12): d (ppm) 134.98 (C, 6 or C-7) 132.59 (C , C-4 ') 129.66 (2C, C-2', C-6 ') 128.36 (IC, C-5 or C-8) 127.90 (2C, C-3', C -5 ') 127.25 (IC, C-5 or C-8) 22.0 (IC, CH3) Examples 64 and 65, 9-Dihydro-4,9-dioxo-2-f ryl-5-methylnapht [ 2, 3-d] -thiazole and 4, 9-Dihydro-, 9-dioxo-2-furyl-8-methylna to [2, 3-d] -thiazole Intermediates of synthesis 2, 3-Dibromo-1,4-dihydro-l, 4-dioxo- 5-methylnane-tadane To 14.5 g (84 mmol, 1 'eq) of 1,4-dihydro-l, 4-dioxo-5-methylnaphthalene, 200 ml of carbon tetrachloride and then 17.2 ml (337 mmol, 4 g) were added thereto. eq) of bromoi. The solution turned red, then 22.94 g (168 mmol, 2 eq) of sodium acetate was added. After 96 hours at reflux, the reaction medium was filtered, washed with carbon tetrachloride and evaporated to dryness. The product was purified on the cake (f = 6.5 cm, height = 5 cm, deposit = solid, support = silica, eluent CH2C12); obtaining then the evaporation to dry a brown-orange paste. With a first crystallization with dichloromethane, 8.25 g of 2,3-dibromo-1,4-dihydro-l, 4-dioxo-5-methylnaphthalene were obtained in the form of yellow crystals; and a second recrystallization from acetonitrile afforded 11.90 g of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene as yellow crystals. Rdt: 72% Rf: 0.70 (ethyl acetate / heptane, 50/50) SM (APCl-): m / z 328, 330, 332 (M-) XH NMR (CDC13): d (ppm) 8 , 11 (dd, 1H, H-8, JH7-H8 = 7.02 Hz, JH6-H8 = 1.53 Hz) 7.63 (m, 2H, H-6, H-7) 2.76 (s) , 3H, CH3) IR (KBr): v (cm "1) 1670 (C = 0); 1570 (C = C) 2-amino-3-bromo-l, 4-dihydro-l, -dioxo-5- methyl-naphthalene 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-8-methyl-naphthalene A 8 g (24 immoles, 1 eq) of 2,3-dibromo-1,4-dihydro-1, 4-dioxonaf taleno, was added 200 ml of glacial acetic acid (3.5 mmoles, 6.85 eq) then 2.52 g (38 mmoles) of sodium nitride in solution in 17.5 ml of water. After 12 h at 70 ° C, the solution turned red. The reaction medium was cooled and evaporated to dryness. The product was purified on a cake (f = 5 cm, h = 5 cm, deposit = solid, support = silica, eluent = gradient concentration of ethyl acetate / heptane 10/90 then 20/80). 525 mg of mixture of 2-amino-3-bromo-1,4-dihydro-l, 4-dioxo-5-methylnaphthalene and of 2-amino-3-bromo-1,4-di-hydro-l were obtained, 4-dioxo-8-methylnaphthalene in the form of red-orange crystals. Rdt: 8% Rf: 0.58 (Ethyl acetate / heptane, 50/50) SM (APCl-): m / z 264 266 (M-) 1 H NMR (CDCl 3): d (ppm) 8.12 ( d, 1H, H-5 or H-8, JH7-H8 or JH5-H6 = 7.32 Hz) 7.58 (t, 1H, H-6 or H-7, JH5-H6 OR JH7-HS = 7 , 63 Hz) 7.44 (d, 1H, H-6 or H-7, JH5-HS or JH7-H8 = 7.63 Hz) 2.74 (s, 3H, CH3), 9-Dihydro-, 9 -dioxo-2-furyl-5-methylnaphtho [2,3-d] -thiazole and 4,9-dihydro-4,9-dioxo-2-furyl-8-methylna to [2,3-d] -thiazole A a solution formed by 1.35 g (5.63 mmoles) of sodium sulphide nonahydrated and of 3.38 ml (1.8.10"1 mol) of a sodium hydroxide solution previously prepared at pH = 9, 0.25 g (0.93 mmol) was added. of a mixture of 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-5-methyl-naphthalene and of 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo -8-methylnaphthalene Each suspension was heated to 45 ° C and turned blue after 40 minutes, then 156 ml (1.87 mmol) of 2-furaldehyde was added and after 15 minutes, 102 μl (1.78 mmole) of glacial acetic acid at 55 ° C. The medium of The reaction turned brown, then extracted with 2 x 100 ml of dichloromethane, dried with magnesium sulfate, filtered, and evaporated to dry, yielding an alumina cake (eluent: concentration gradient: between 50/50 and 70/30 in dichloromethane / heptane. Then 51 mg (18%) of a mixture of 4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphto [2,3-d] thiazole and 4,9-dihydro-4 were obtained, 9-dioxo-2-furyl-8-methylnaphtho [2,3-d] -thiazole. The separation of the isomers in a preparative plate (support: alumina, eluent: dichloromethane / heptane) produced a more polar product and a less polar product Less polar product Rf: 0.61 (dichloromethane / heptane, 70/30, alumina) SM (APcI +): m / z 296 (M + H +) 1 H NMR (CD2C12): d (ppm) 8.07 (d, 1H, H-5 or H-8 in g of CH3, JH5-H6 or JH7- HS = 9, 55 Hz) 7, 58 (m, 3H, H-6 and H-7 in a and b of CH3 and H-5 ') 7.32 (d, 1H, H-3', JH3'-H4 ' = 3.32 Hz) 6.60 (dd, 1H, H-4 ', JH3'-H4' = 3.1 Hz, JH4'-H5 <= 1/2 Hz) 2.77 (s, 3H, CH3) 13 C NMR (CD2C12): d (ppm) 145.24 (1C, C-5 ') 137.82-132.24 (2C, C-6 and C-7) 124, 90 (IC, C- 5 or C-8) 112.54 and 112.44 (2C, C-3 'and C-4') Most polar product Rf: 0.53 (dichloromethane / heptane, 70/30, alumina) SM (APcI +): m / z 296 (M + H +) XH NMR (CD2C12): d (ppm) 8.07 (d, 1H, H-5 or H-8, JH5-H6 OR JH7-H8 = 4.98 Hz, JH5 -H7 OR JH6-HS = 1.5 Hz) 7.60 (m, 3H, H-6 and H-7 in a and b of CH3 and H-5 ') 7.32 (d, 1H, H-3', JH3'-H4 '= 3.73 Hz) 6.45 (dd, 1H, H-4', JH '-H 4 '= 3.32 Hz, JH' -H5 '= 1.66 Hz) 2.77 (s, 3H, CH3) 13 C NMR (CD2C12): d (ppm) 189.69 and 184.57 (2C, C-4 and C-9) 145.38 (IC, C-5 ') 129.29 (IC, C-6 or C-7 in b of CH3) 126.04-142.24 (IC, C-6 or C-7 in a of CH3) 123.45 (iC, C-5 or C-8 in d of CH3) 113.67 and 113.57 (2C, C-3 'and C-4') 23.39 (IC, CH 3) Examples 66 and 67 4,9-Dihydro-4,9-dioxo-5-methyl-2-phenyl-aceto [2,3-d] thiazole and 4,9-Dihydro-4,9- dioxo-8-methyl-2-phenylnaphtho [2,3-d] thiazole To a solution formed by 1.35 g (5.63 mmol, 6 eq) of sodium sulphide nonahydrate and 3.38 ml (890 mmol, 193 eq) of a solution of sodium hydroxide previously prepared at pH = 9, 0.25 g (0.93 mmole) of mixture of 2-amino-3-bromo-1,4-dihydro-l, 4-dioxo-6-methylnaphthalene and of 2 -amino-3-bromo-l, 4-dihydro-l, 4-dioxo-7-methylenenaphthalene. This suspension was heated to 45 ° C and turned blue after 30 minutes. 191 ml (1.87 mmole) was added, 2 eq) of benzaldehyde and after 15 min 102 ml (1.78 mmole) of glacial acetic acid at 55 ° C. The reaction medium was turned brown and then extracted 3 times with 100 ml of dichloromethane, washed until neutral and dried over magnesium sulfate to obtain 38 mg (13%) of crude product. After separation of the isomers in a preparative plate (alumina support, eluent 70/30 dichloromethane / heptane), two products were obtained, 4,9-dihydro-4,9-dioxo-5-methyl-2-phenylnaphtho [2, 3-d] -thiazole and 4,9-dihydro-4,9-dioxo-8-methyl-2-phenyl-naphtho [2,3-d] thiazole.
Less polar product Rf: 0.58 (dichloromethane / heptane, 70/30, alumina) SM (IE): m / z 305 (M +) XH NMR (CD2C12): d (ppm) 8.07 (, 3H, H -2 ', H-6', H-5 or H-8) 7.61 (m, 2H, H-6, H-7) 7.49 (m, 2H, H-3 ', H-5' ) 7.30 (m, 1H, H-4 ') 2.76 (s, 3H, CH3) Most polar product Rf: 0.51 (dichloromethane / heptane, 70/30, alumina) SM (IE): m / z 305 (M +) NMR of ^ (CD2C12): d (ppm) 8.07 (m, 3H, H-2 ', H-6', H-5 or H-8 in g of CH3) 7.60 (m, 2H, H-6, H-7) 7.49 (m, 2H, H-3 ', H-5') 7.30 (m, 1H, H-4 ') 2.77 (s, 3H, CH3) Example a, 9-Dihydro-4, 9-dioxo-2-methyl-lH-naft [2, 3-d] -imidazole Re: CA j57 97905t Rdt: 76% F: > 260 ° C Rf: 0.44 (CH 2 Cl / Methanol, 97/3) SM (EI): m / z 212 (M +.) 1 H NMR (DMSO d 6): d (ppm) 13.74 (s, 1H , NH) 8.05 (dd, 2H, H-5, H-8, JHS-H6 = JH7-HS = 8.85 Hz, JHS-H7 = JH6-HS = 1.73 Hz) 7.82 (m , 2H, H-6, H-7) 2.45 (s, 3H, CH3) 13 C NMR (DMSO d6): d (ppm) 178.15; 176.53 (2C, C-4, C-9) 153.80 (IC, C-2) 137.14 (IC, C-3a) 133.98, 133.99 (2C, C-6, C- 7) 133.27, 133.10, 132.84 (3C, C-8a, C-9a, C-4a) 126.82 (2C, C-5, C-8) 14.01 (1C, CH3) IR (KBr): v (cm "1) from 3134 to 2897 (NH); 1678, 1672 (C = 0) Example b 4, 9-Dihydro-4, 9-dioxo-2-methyl-l-enyl-1H- na t- [2, 3-d] imidazole Reference: CA _67 97905t Rdt: 72% F: 242 ° C Rf: 0.43 (CH Cl 2 / Methanol, 99/1) SM (IE): m / z 288 ( M +.) 1 H NMR (DMSO, d 6): d (ppm) 8.23 (d, 1H, H-5 or H-8, JH5-H6 or JH7-HS = 6.71 Hz) 7.90 (d, 1H, H-5 or H-8, JH-5-H6 O JH7-H8 = 6.71 Hz) 7.68 (m, 3H, H-3 ', H-4', H-5 ') 7.60 (m, 2H, H-6, H-7) 7 , 37 (m, 2H, H-2 ', H-6 *) 2.40 (s, 3H, CH3) 13 C NMR (CDC13): d (ppm) 179.13, 175.03 (2C, C-4, C-9) 153.66 (IC, C-2) 143.14 (1C, C-1 ') 135.11 (IC, C-3a) 133 , 68, 133.51 (2C, C-6, C-7) 133.15, 133.01, 132.63 (3C, C-8a, C-9a, C-4a) 129.95, 129.69 (3C, C-3 ', C-4', C-5 ') 126.93, 126.76, 126.43 (4C, C-2', C-6 ', C-5, C-8) 13.77 (IC, CH3) IR (KBr): v (cm "1) 1674, 1663 (C = 0) E c emplo c 4,9-Dihydro-, 9-dioxo-2-methyl-l-phenyl-lH-naft sulfate [2, 3-d] imidazole Reference: CA j58 8764b Rdt: 47% F:> 260 ° C Rf: 0.53 (CH2Cl2 / Methanol, 97.5 / 2.5) 1 H NMR (DMSO, d 6): d (ppm) 8,11 (dd, 1H, H-5 or H-8, JH5-H6 or JH7-HS = 8.85 Hz, JH5-H7 or JHS-H8 = 1.73 Hz) 8.00 (dd, 1H, H-5 or H-8, JH5-H6 or JH7-HS = 8.85 Hz, JHs-H7 or JHe-HS = 1.73 Hz) 7.94 (m, 2H, H-6, H-7) 7.82 (m, 2H, H-2 ', H-6') 7.51 (m, 3H, H-3 ', H-4', H-5 *) 5.54 (s, 1H, NH + 2.30 (s, 3H, CH3) IR (KBr): V (cpf1) 3414 to 2400 (broadband NH +); 1736, 1681 (C = 0) Example d 4, 9-Dihydro-, 9-dioxo-l, 2-dimethyl-lH-naft [2,3-d] -imidazole Reference: C.A. 66 104957w Rdt: 70% F: > 253 ° C Rf: 0.49 (CH 2 Cl 2 / Methanol, 98/2) SM (EI): m / z 226 (M +.) 1 H NMR (CDCl 3): d (ppm) 8.21, 8.09 ( 2m, 2H, H-5, H-8) 7.70 (m, 2H, H-6, H-7) 4.01 (s, 3H, CH3) 2.56 (s, 3H, CH3) 13 C NMR (CDCl 3): d (ppm) 179.22, 178.44 (2 C, C-4, C-9) 154.46 (C, 2 C), 134.18, 134.11 (2 C, C -6, C-7) 133.37, 133.17 (2C, C-4a, C-8a) 127.37, 126.75 (2C, C-5, C-8) 32.74 (IC, CH3 ) 13.64 (IC, CH3) IR (KBr): v (cm "1) 1674 (C = 0) Example e 4, 9-Dihydro-4, 9-dioxo-2-phenyl-lH-naft [2,3-d] -imidazole Reference: CA 68 8764b Rdt: 34% F:> 260 ° C Rf: 0.51 (CH2Cl2 / Ethyl acetate, 90/10) SM (IE): m / z 274 (M +.) 1 H NMR (DMSO dg ): d (ppm) 14.40 (s, 1H, NH) 8.26 (m, 2H, H-5, H-8) 8.12 (m, 2H, H-2 ', H-6') 7.87 (m, 2H, H-6, H-7) 7.54 (m, 3H, H-3 ', H-4', H-5 ') 13C NMR (DMSO dg): d (ppm) 179.13, 175.03 (2C, C-4, C-9) 152.60 (IC, C-2) 133.89 (2C, C-6, C-7) 132.60 (2C, C- 9a, C-3a) 130.00 (2C, C-4a, C-8a) 129.03 (3C, C-3 ', C-4', C-5 ') 126.82, 126.32 (4C , C-5, C-8, C-2 ', C-6') IR (KBr): V (cm "1) 3232 (NH); 1681, 1664 (C = 0) Example f 4, 9-Dihydro -4,9-dioxo-2-phenyl-napht [2,3-d] oxazole Reference: CA 8_7 53134z Rdt: 75% F:> 260 ° C Rf: 0.60 (CH2Cl2 / Heptane, 80/20) SM (EI): m / z 275 (M +.) 1 H NMR (CDCl 3): d (ppm) 8.33 (d, 2H, H-2 ', H-6', JH2-H3. = HS'-HS- = 6.71 Hz) 8.27 (m, 2H, H-5, H-8) 7.82 (m, 2H, H-6, H-7) 7.58 (m, 3H, H-31, H-4 ', H -5 ') 13 C NMR (CDCl 3): d (ppm) 178.50, 173.05 (2C, C-4, C-9) 167.76 (IC, C-2) 134.52, 132.99 (2C, C-6, C-7) 129.21 ( 3C, C-3 ', C-4', C-5 ') 128.33 (2C, C-2', C-6 ') 127.50, 127.04 (2C, C-5, C-8 ) IR (KBr): v (cpf1) 1693, 1678 (C = 0) Example g, 9-Dihydro-4, 9-dioxo-2- (4-methyl enyl) -na t [2,3-d] oxazole Reference: C.A. 8_7 53134z Rdt: 44% F: > 260 ° C Rf: 0.50 (CH 2 Cl 2) SM (IE): m / z 289 (M +.) 1 H NMR (CDCl 3): d (ppm) 8.27 (m, 2H, H-5, H-8 ) - 12Í 8.23 (d, 2H, H-2 \ H-6 \ JH2.-H3 '= H5'-H6 > = 8.24 Hz) 7.81 (m, 2H, H-6, H-7) 7.38 (m, 2H, H-3 ', H-5') 2.46 (s, 3H, CH3) 13 C NMR (CDCl 3): d (ppm) 178.77, 173.80 (2C, C-4, C-9) 165.51 (IC, C-2) 143.95 (IC, C-3a) 135.80 (IC, C-4 ') 134 , 29, 132.12 (3C, C-1 ', C-6, C-7) 131.70, 131.38 (2C, C-4a, C-8a) 129.93, 128.28 (4C, C-2 ', C-3', C-5 ', C-6') 127.44, 126.99 (2C, C-5, C-8) 122.41 (IC, C-1 ') 21 , 81 (IC, CH3) IR (KBr): v (crn-1) 1668, 1678 (C = 0) Example h 4, 9-Dihydro-4, 9-dioxo-2-methyl-napht [2,3-d] thiazole Reference: C.A. 120 270267 z Rdt: 11% F: > 260 ° C Rf: 0.41 (CH 2 Cl 2 / Methanol, 99/1) SM (I.E.): m / z 229 (M +.) XH NMR (CDCl 3): d (ppm) 8.33, 8.21 (2dd, 2H, H-5, H-8, JH5-H6 = JH7-HS = 8.85 Hz. 7.80 (m, 2H, H-6, H-7) 2 91 (s, 3H, CH3) 13 C NMR (CDCl 3): d (ppm) 177.95, 176.95 (2C, C-4, C-9) 173.86 (IC, C-2) 153.10 (IC, C-3a) 142.14 (IC, C-9a) 133, 90, 133.51 (2C, C-6, C-7) 132.06, 131.72 (2C, C-4a, C-8a) 127.29, 126.47 (2C, C-5, C- 8) 19.83 (IC, CH3) IR (KBr): v (cm "1) 1677, 1655 (C = 0) Example i 2-Amino-, 9-dihydro-, 9-dioxo-naph to [2, 3-d] thiazole Reference: CA 120 270267 z Rdt: 96% F:> 260 ° C Rf: 0.24 (CH 2 Cl 2 / Methanol, 96/4) SM (EI): m / z 230 (MH +.) NMR of (DMSO dg): d (ppm) 8.56 (s, 2H, NH2) 8.03 (m, 2H, H-5, H-8) 7.83 (m, 2H, H-6, H-7) 13C NMR (DMSO dg): d (ppm) 178.04, 177.31 (2C, C-4, C-9) 173.45 (IC, C-2) 154.61 (IC, C-3a) 145.95 (IC, C-9a) 134, 34, 134.03 (2C, C-6, C-7) 133.18, 132.24 (2C, C-4a, C-8a) 126.99, 125.97 (2C, C-5, C- 8) IR (KBr): v (cm "1) 3460, 3420 (NH2), 1690, 1660 (C = 0) Example j 4, 9-Dihydro-, 9-dioxo-2-phenyl-napht [2, 3-d] thiazole Reference: CA 67 11450f Rdt: 68% F: 249 ° C Rf: 0.45 (CH2C12) SM (IE): m / z 291 (M +.) XH NMR (CDCl 3): d ( ppm) 8.30, 8.21 (2dd, 2H, H-5, H-8, JHS-H6 = JH7-HS = 8.85 Hz, JH6-HS = JHS-H7 = 1.73 Hz) 8.14 (m, 2H, H-2 ', H-6') 7.83 (m, 2H, H-6, H-7) 7.56 (m, 3H, H-3 ', H-4', H-5 ' ) 13 C NMR (CDC13): d (ppm) 178.45, 172.67 (2C, C-4, C-9) 134.82, 134.44 (2C, C-6, C-7) 133, 50, 133.24, 132.74, 132.01 (4C, C-9a, C-1 ', C-4a, C-8a) 129.75, 128.01 (5C, C-2 ', C-3', C-4 ', C-5', C-6 ') 127.94, 127.18 (2C, C-5, C -8) IR (KBr): v (cm "1) 1675, 1660 (C = 0) Example k 4,9-Dihydro-4,9-dioxo-2- (2-pyridyl) -naphtho [2, 3- d] -thiazole Reference: CA 109 130788t Rdt: 75% F:> 260 ° C Rf: 0.60 (CH2Cl2 / Methanol, 97/3) SM (IE): m / z 292 (M +.) 1 H NMR (CDCl 3): d (ppm) 8.69 (d, 1H, H-6 ', JH5'-H6' = 5.50 Hz) 8.47 (d, 1H, H-3 ', JH3'-H4' = 5.50 Hz) 8.36, 8.26 (2dd, 2H, H-5, H-8, JH5-HS = JH7-HS = 8.85 Hz, JH5-H7 = JH6-H8 = 1.73 Hz) 7.82 (m, 3H, H-4 ', H-6, H-7) 7.46 (m, 1H, H-5') 13 C NMR (CDC13): d (ppm) 178.17 , 177.43 (2C, C-4, C-9) 158.76 (IC, Cquat) 151.11 (IC, C-6 ') 147.86 (IC, C-4') 134.77, 134 , 31 (2C, C-6, C-7) 133.50, 132.74 (2C, C-4a, C-8a) 128.04, 127.16 (2C, C-5, C-8) 121 , 15 (IC, C-3 ') 118.45 (IC, C-5') IR (KBr): v (cm "1) 1688, 1667 (C = 0) Example 1 4, 9-Dihydro-4, 9-Dioxo-2- (4-pyridyl) -naphtho [2, 3-d] -thiazole Reference: C.A. 109 130788t Rdt: 75% F: > 260 ° C Rf: 0.30 (CH2Cl2 / Methanol, 97/3) SM (EI): m / z 292 (M +.) NMR of XH (CDCl3): d (ppm) 8.84 (d, 2H, H -2 ', H-6', JH2 - H3 '= JHS.-HS' = 5.50 Hz) 8.39, 8.26 (dd, 2H, H-5, H-8, JH5-H6 = JH7-H8 = 8.85 Hz, JH6-H8 7.99 (d, 2H, H-3 ', H-5', JH2'-H3- = JH5'-H6- = 5.50 Hz) 7.84 (m , 2H, H-6, H-7) 13 C NMR (CDC13): d (ppm) 178.17, 172.50 (2C, C-4, C-9) 151.11 (2C, C-2 ', C-6'), 134.77, 134 , 31 (2C, C-6, C-7) 133.50, 132.74, 132.01 (4C, C-9a, C-4 ', C-4a, C-8a) 128.04, 127, 16 (2C, C-5, C-8) 121.04 (2C, C-3 ', C-5') IR (KBr): v (cm "1) 1688, 1667 (CO) Example m 4, 9-Dihydro- 4,9-dioxo-2-pyrrolyl-naphtho [2,3-d] -thiazole Reference: CA 109 130788t Rdt: 17% F: 208 ° C (dec) Rf: 0.44 (CH2Cl2 / Ethanol, 99/1 ) SM (EI): m / z 280 (M +.) NMR of XH (CD2C12): d (ppm) 9.85 (ls, 1H, NH) 8.21, 8.17 (2dd, 2H, H-5, H -8, JHS-H6 = JH7-HS = 8.85 Hz, JH5-H7 = JH6-HS = 1.73 Hz) 7.79 (m, 2H, H-6, H-7) 7.07 (, 1H, H-5 ') 6.96 (, 1H, H-3') 6.35 (m, 1H, H-4 ') IR (KBr): v (cm "1) 3286 (NH); 1676, 1647 (C = 0) Example n 4, 9-Dihydro-4, 9-dioxo-2- (2-furyl) -naphtho [2,3-d] -thiazole Reference: C.A. 67 11450f Rdt: 48% F: > 260 ° C Rf: 0.55 (CH 2 Cl 2 / Methanol, 99.5 / 0.5) SM (I.E.): m / z 281 (MH +.) H-NMR (CDC13): d (ppm) 8.37 (dd, 1H, H-5 or H-8, JHS-H6 OR JH7-HS = 8.85 Hz, JHS-H70 JH6-HS = 1.73 Hz) 8.23 (m, 1H, H-5 or H-8) 7.81 (m, 2H, H-6, H-7) 7.65 (d, 1H, H-5 ' , JH4'-H5 '= 1.97 Hz) 7.46 (d, 1H, H-3', JH3 < -H4 '= 3.94 Hz) 6.65 (dd, 1H, H-4', JH3'-H4 '= 3.94 Hz, JH' -H5 '= 1.97 Hz) 13 C NMR (CDCl 3): d (ppm) 178.25, 177.90 (2 C, C-4, C-9) 163.94 (C, 2 C) 155.25 (C, 2 'C) 148.00 (IC, C-3a) 145.93 (IC, C-5 ') 140.62 (1C, C-9a) 134.34, 134.09 (2C, C-6, C-7) 133 , 13, 132.68 (2C, C-4a, C-8a, 127.83, 126.91 (2C, C-5, C-8) 113.80 (C, 3 ') 113.34 ( ÍC, C-4 ') IR (KBr): v (cm "1) 1683, 1658 (C = 0) Pharmacological properties: The study of the compounds of the present invention and their eventual salts has shown that they have various pharmacological properties Thus, most of the compounds are selectively venotonic, not affecting the arterial system, except at concentrations much higher than those present in the veins, except for some arteries, particularly the cerebral arteries (carotids, basilar ...). they show no affinity - at most a small affinity - with the vast majority of known receptors, they also increase capillary resistance, decrease vascular hyperpermeability given by certain inflammatory agents. These properties are evidenced in mammals such as hamsters, rats, guinea pigs and rabbits, under in vi tro conditions (vessels or isolated vascular networks) and in vivo. For in vitro studies, the compounds are solubilized in pure aqueous solution or containing DMSO (di-ethylsulfoxide). For in vivo studies, the compounds are administered intravenously or intraperitoneally in the form of an aqueous solution that may or may not contain DMSO, or orally in suspension in 1% carboxymethylcellulose, administered with the aid of a tube feeding in a volume of 10 ml / kg. Models of pharmacological studies Contractile effects The contractile effects are measured in vi tro under static conditions in the vascular rings in the capacitance or resistance of the saphenous, femoral, jugular, mesenteric, cava veins ... and in the femoral, carotid, basilar arteries , mesenteric, thoracic or abdominal aorta ... of rat (Wistar, 200 to 250 g), rabbit (New Zealand, 2 to 2.5 kg), guinea pig (Dunkin Hartley 250 to 300 g). The rings are located in an isolated organ chamber (25 ml for the vessels of capacity and 2.5 ml for the vessels of resistance according to Mulvany), maintained in isometric conditions by two rigid threads inserted inside the vessel, avoiding damaging the endothelium. The vessels are bathed in a modified Krebs solution (in mM: NaCl = 118, KCl = 4.6, CaCl = 2.5, MgSO = 1.2, KH2P0 = 1.17, NaHCO3 = 25, glucose = 11) , aerated to keep the mixture gasified with 95% 0 and 5% C02, at pH = 7.4 and maintaining the temperature at 37 ° C. The rings are brought to their optimum point of the tension-length relationship. The developed voltages generate an electrical signal through a force sensor (Wheastone bridge). This signal is amplified before being visualized in the Kipp & Zonen, or digitized to be treated by the computer (IOS, EMKA). Pharmacological studies are performed after some standardized preliminary contractile stimuli by means of a depolarizing solution (hyperpotassium obtained by replacing NaCl with KCl in equimolar quantities), rinses and periods of equilibration in pure physiological solution. The presence of endothelium is verified by the relaxation induced by increasing concentrations of acetylcholine after the stabilization of a vascular precontraction. The contraction forces developed by the vascular rings in response to the different compounds are studied in resting or electrically stimulated vessels (5-8 Hz), by a hyperpotassium depolarizing "physiological" solution (KCl: 20, 40 mM), by noradrenaline (increasing concentrations), serotonin (increasing concentrations) ... Contractions are expressed in mg strength or as a percentage of the maximum contraction in depolarization by a hyperpotassium "physiological" solution. The contractile effects are also measured in vi tro under dynamic flow conditions, by the pressure developed by vascular networks perfused at constant flow. At the mesenteric level, the venoselectivity is studied on the simultaneous and separate double perfusion model of arterial and venous networks, model developed by T. WARNER (British J. Pharmacol, 1990, 99, 427-433). The separation of the two networks is done by cutting the vessels and tissues along the intestinal border. The nets are perfused at 2 ml.min-1 by a solution of Krebs (37.5 ° C) aerated at 95% 0 and 5% C02. In vivo, arterial and venous pressures are measured in the anesthetized animal, in basal conditions and after circulatory arrest caused by the swelling of a balloon-shaped catheter inserted in the right atrium. After cardiac arrest, the tone of the vein (mean circulatory pressure of filling at constant blood volume) is calculated from venous and arterial pressures measured in equilibrium and corrected according to the relative differences in filling between these two networks (SAMAR COLEMAN, ñm. J. Physiol. 1978, 234: H94-100; Y7? MAM0T0 et al., Am. J. Physiol. 1980, 238 ¡H823-828). In the awake animal, the arterial pressures are measured according to the classic process derived from Riva Rocci, by analysis of the acoustic wave transmitted at arterial level and transformed by a piezoceramic transducer located in the tail of the rat, following an envelope inflated automatically by a pressure generator. At the microcirculatory level, section variations of the veins and arterioles are studied in vivo in the dorsal cutaneous chamber model of the awake hamster, after videomicroscopic recording (Leitz Ergolux microscope equipped with a halogen source for illumination and a video camera CDR black and white HPR 610) and computer analysis (Visicap Program, Pack ICAP) of the images. After anesthesia with sodium pentobarbital (60 mg / kg intraperitoneal), the animal's back is sheared and shaved in such a way that an observation chamber (Prof. GEBHARD, Heidelberg) can be located on the skin of the back. The two parts of the chamber are sewn after having carefully removed the skin thicknesses that may hinder the observation. A jugular catheter is placed for intravenous administration of the products, 48 hours after operation. Effects on induced capillary hyperpermeability Vascular permeability is studied in vivo by measuring albumin extravasation whose amount is determined by a dye that binds with albumin (Bleu Evans). Hyperpermeability is induced by intradermal injection of a solution of histamine, bradykinin or zymosan. The technique is a derivation of that described by BEACH & STEINETZ, J. Pharmacol. Exp. Therap., 1961, 131: 400-406.
The abdominal wall of the rats (Wistars, 200 to 230 g) is sheared one hour before the start of the test. The product to be tested is injected intraperitoneally or by bone, 1 to 4 hours before slaughter. The rats are anesthetized with a mixture of halothane. They then receive an intradermal injection into the abdomen of 0.10 or 0.15 ml (6.7 or 10 micrograms of histamine) of the inflammatory agent and an intravenous injection of one ml of a 0.5% Evans Blue solution into the abdomen. penis vein These injections are done 30 minutes before euthanasia. After 30 minutes of these two injections, the rats are euthanized by cervical dislocation.
At the site of the injection of the inflammatory agent, the skin is cut and placed in frosted neck glass tubes containing 3 ml of fuming hydrochloric acid. The digestion of the skin is carried out by contact for at least one hour in a water bath at 37 ° C. Three ml of benzalkonium chloride at 12.8% are then added. After allowing to stand for thirty minutes, 7 ml of dichloromethane are added. The tubes are shaken periodically for one hour. The aqueous phase is removed by aspiration and the organic phase of dichloromethane is filtered. Optical densities are quantified by absorption spectrophotometry at a wavelength of 620 nm, against a blank containing only dichloromethane. The means of the optical densities of different groups of treated or control animals are calculated, the percentage of variation of the values corresponding to the treated animals in relation to the control animals is calculated. The effect of the compounds on the hyperpermeability induced by inflammatory agents, such as histamine and bradykinin, is also studied after intravenous bolus injection in the dorsal skin chamber model of the hamster and according to the process developed by GIMENO et al., Decrito Previously (A new technique using intravital videomicroscopy for macromolecular permeability measurement ^ 18th European Congress of microcirculation, Rome 1994) by videomicroscope and image analysis by quantification of the distribution of the fluorescence intra and extravascular fluorescent tracer (FITC-Dextran) injected into bolus by the jugular catheter (63 mg / kg for a defined volume in 1 ml / kg). The microscope is equipped with a fluorescent source and with a combination of filters (excitation in blue 450-490 nm and stop filter 515 nm). Effects on capillary resistance: The increase in capillary resistance is observed by the modification of the petechial index (negative pressure that induces erythrocyte extravasation), measured by a procedure derived from the Parrot angiosterrometer. The study is carried out on male Wistar rats weighing an average of 200 g (approximately six weeks old). The lower region of the loin is shaved after depilating it with the help of a paste based on a derivative of thioglycolic acid and calcium hydroxide. After approximately thirty minutes, the skin is rinsed thoroughly and dried. During the day of the study, the rats are kept without coercion. A depression of 80 mm of mercury is applied. If the petechiae (extravasation of erythrocytes) do not appear in 15 seconds, the depression is increased to help maintain the suction cup in the same place. The minimum depression for which the petechiae appear, expressed in mm of mercury, the base capillary resistance value (before any). Two evaluations are made for each trial in different places on the spine. The rats are treated orally. After a certain time (usually 2, 4, 6 hours) of the treatment, the test is renewed in different areas of skin, until the appearance of the petechiae, establishing a new index of depression. All evaluations are done in the dark. A percentage of variation of the capillary resistances of the treated animals is calculated in relation to their basic capillary resistance., for each compound studied, at each time of treatment and compared with the control group (excipient only) or with the reference group. Effects on induced pleurisy in the rat: The anti-inflammatory activity of the compounds is also studied by mediating the inhibition of edema and leukocyte migration after the induction of a pleurisy in the rat by injection of carrageenan into the pleural cavity ( ALMEIDA et al., J. Pharmacol. Exp. Therap., 1980, 214: 74). The rats are treated by bone with the compounds 2 hours before the injection of carrageenan, as well as 2 and 4 hours of this injection. After a certain time (6 hours) of the induction of pleurisy, the rats are euthanized and the pleural fluid is recovered by aspiration and its volume is measured. The leukocyte cells are counted by a "cell counter". The results are expressed in the amount of leukocytes in the exudate per 100 g of the weight of the animal and compared with that of the control group. Effects against septic shock: The activity in septic shock was studied in the rat after the induction of shock by an intravenous bolus injection of a lipopolysaccharide endotoxin (LPS: 15 mg / kg) of E. coli, a method similar to that described by TERASHITA and al., Eur. J. Pharmacol., 1985, 109: 257-261. The arterial pressures were measured as a function of time and comparatively between the treated groups and the control groups (excipient only). The compounds were administered intravenously or by bone, 5 minutes or two hours respectively before the injection of LPS. Examples of pharmacological effects: The compounds of the invention and their optional salts selectively increase, in most cases, the contraction of the animal veins produced by noradrenaline, by electrical stimulation or by a depolarizing hyperpotassium solution. By way of illustration, the contractile effect of different compounds in the saphenous vein of the rabbit, pre-extracted by a depolarizing "physiological" solution of potassium concentration equal to 40 mM, is shown.; the maximum effect produced by each compound is expressed in the percentage of the maximum contraction induced by depolarizing hyperpotassium solutions with ED50 value): Emax Compounds (% Contr.max.) ED 0 (nM) Example f 15 + 1 21 Example j 16 + 6 30 Example k 26 + _ 9 70 Example h 29 + 6 86 Example i 18 + 1 90 Example n 24 + _ 3 110 Example 3 17 + 6 36 Example 4 29 + 11 42 Example 7 17 + 2 36 Example 13 21 + 3 57 Example 18 39 + 6 88 Example 19 20 + 8 75 Example 20 24 + 4 110 Example 28 29 + 2 37 Example 38 12 ± 1 160 Example 59 18 ± 4 53 Example 57 22 ± 3 41 By way of illustration, the oral administration of certain compounds of the invention and their eventual salts increases the capillary resistance of the rat by doses generally comprising between 0.01 and 5 mg / kg: Compounds Effects in 4 hours Effects in 6 hours (in% of the control) (in% of the control) Example 3 5 mg / kg 27 18 Example 18 5 mg / kg 25 28 Example 21 5 mg / kg 10 22 Example f 0.1 mg / kg 7 17 Example h 0.1 mg / kg 19 19 Example 1 0.1 mg / kg 37 35 Example n * 0.1 mg / kg 45 45 Example 2 0.1 mg / kg 25 28 Example 10 0.1 mg / kg 25 46 Example 15 0.1 mg / kg 20 27 Example 28 ** 0.1 mg / kg 10 13 * (granulometry: between 0.5 and 0.6 mm) ** (granulometry: between 0.6 and 0.7 mm) By way of illustration, oral administration of certain compounds of the invention and their eventual salts reduces the inflammatory hyperpermeability induced by zymosan in the rat at doses generally between 0.01 and 5 mg / kg: Compounds Effect in 2 hours Effect in 4 hours (in% of the control) (in% of the control) Example 1 5 mg / kg -28 -28 Example n 5 mg / kg 0 -21 Example 21 5 mg / kg -22 -21 Example 28 5 mg / kg -29 0 Example f 0.1 mg / kg -15 -22 Example j 0.1 mg / kg -14 -32 Example 3 0.1 mg / kg -22 -26 Example 14 0.1 mg / kg -31 -15 Example 17 0.1 mg / kg -15 -23 Example 25 0.1 mg / kg -14 -17 Example 26 0.1 mg / kg -14 -24 Example 38 0.1 mg / kg -12-3 Example 59 0.1 mg / kg -13 +21 In addition, the compounds of the invention and their eventual salts are very non-toxic. For example, after a single oral administration of 500 mg / kg in the mouse, no toxic effect or mortality was observed for most of the compounds and in particular for Example f (1 g / kg), Example j , Example h (1 g / kg, diarrhea), Example n (1 g / kg, red urines), Example 3 (mild diarrhea), Example 5, Example 6, Example 13 (1 g / kg). Most compounds are not cytotoxic (the cell viability being measured by the quantification of the neutral red cell incorporation) up to concentrations equal to its solubility in aqueous medium in the fibroblastic cell line of the mice (L929), in particular Example f, Example j, Example 3, Example 4, Example 20, Example 21 ... Among the active compounds of the invention, Example n is particularly emphasized. Example n, for example, selectively potentiates the contractile response of the rabbit saphenous vein to norepinephrine (ED50 value reduced by a factor of ten and Emax increased 30%), to electrical stimulation (increase of 200% to 0.3 micromolar), to serotonin, in addition to contractile effects observed in the presence of a response to a hyperpotassium solution, in these depolarizing hyperpotassium conditions, the product contracts , for example, rabbit jugular vein (ED50 = 16 nM), rat vein (ED50 = 50 nM), perfused rat mesenteric venous network (ED50 = 300 nM), rat carotid artery (ED50 = 300 nM) , rabbit (ED50 = 120 nM), basilar rabbit artery. In the model of dorsal cutaneous chamber in the hamster, Example n (28 micrograms / kg injected in intravenous boluses) reduces the venous but not arterial diameter after the intravenous injection of histamine (1 mg / kg) and reduces hyperpermeability vascular induced by it. The effect by bone of Example n on the capillary resistance of the rat is dose-dependent in a long range of doses and its duration of action, of at least six hours, correlates with its measured plasma concentrations. After two hours, oral administration of 0.1 mg / kg of product of Example n decreases the hypereine-induced hyperpermeability of 26 percent relative to the control group in the rat. Oral administration of 3 x 5 mg of this product significantly decreases the volume of lung exudate after the induction of pleurisy by carrageenan in the rat. Administered intravenously by bolus at a dose of 28 micrograms / kg, 5 minutes before induction of septic shock, the product of Example n increases mean arterial pressure by 20-mm of mercury relative to the group of control rats. The product of Example n does not affect the blood pressure of the anesthetized rat after injection in i.v. bolus at least up to 28 micrograms / kg, nor that of the rat wakes up after oral administration of 0.1- 5-50 mg / kg. The foregoing shows that the compounds of the invention and their eventual salts can be used in human and animal therapies. Said compounds are indicated in particular in functional and organic venous insufficiency and hemorrhoidal pathologies, for their vascular and anti-inflammatory components, as well as in the typically inflammatory conditions and in the shock states characterized by a significant drop in blood pressure. In the latter case, an improvement of the venous return is susceptible to maintain the cardiac output and consequently the arterial pressure. Functional venous insufficiency is characterized by dilatation and hyperdistension of the superficial veins of the lower limbs, edema, paresthesias. This type of pathology can evolve towards organic venous insufficiency characterized by the development of varicose veins, valvular incontinence, towards phlebothrombosis and trophic disorders that lead to ulcerative lesions. In this venous pathology, an inflammatory component is installed in the first stages and manifests more clearly in advanced stages. Due to its venoconstrictive and anti-inflammatory effects, in particular on vascular hyperpermeability and its contractile effects in the cerebral arteries, the compounds of the invention and their eventual salts are also indicated for migraine. Therefore, the present invention comprises the use of the aforementioned compounds and their optional salts, as active substances for the preparation of medicaments and pharmaceutical compositions for human and veterinary use, comprising at least one of said compounds and salts in association with a physiologically acceptable carrier or diluent. Obviously, the form of these medicaments and pharmaceutical compositions will depend on the desired administration route, particularly parenteral, topical (cutaneous) and rectal, and they can be formulated according to classical techniques, with the application of usual supports and vehicles. Thus, in the case of an oral administration, said components may be presented in the form of tablets, tablets, capsules, solutions, syrups, emulsions, suspensions, powder, granules, soft capsules, lyophilisate, microcapsules, or microgranules. Tablets, tablets and capsules containing the active substance together with a diluent (for example lactose, dextrose, sucrose, mannitol, maltitol, xylitol, sorbitol or cellulose), a lubricant (for example silica, talc or stearate), a binding agent (for example starch, methylcellulose or gum arabic), a disintegrating agent (for example alginate), are manufactured by known techniques of mixing, granulation, pastillation, coating, compression etc ... The syrups may contain, as support, glycerol, mannitol and / or sorbitol. The solutions and suspensions may comprise water and other physiologically compatible solvents and a support such as a natural gum, gelose, sodium alginate or polyvinyl alcohol. For parenteral administration, the medicaments and compositions may be presented in the form of solutions, emulsions or suspensions comprising the active substance and a suitable support or solvent, such as sterilized water or sterilized isotonic saline solutions. For cutaneous application, medications and compositions may be presented in the form of an ointment, cream or gel, "in the form of an emulsion, suspension, solution, mousse or powder." For rectal application, medications and compositions may be presented in the form of capsules, creams, emulsions, gel, mousse, ointments, or suppositories.

Claims (90)

  1. NOVELTY OF THE INVENTION Having described the present invention is considered as a novelty and therefore the content of the following claims is claimed as property. 1. the use of tricyclic derivatives and their pharmaceutically acceptable salts that correspond to the general formula:
  2. (I) characterized in that: A is either a sulfur atom, an oxygen atom, or is an R3N radical where R3 is a hydrogen atom, an alkyl radical of C] _ to C5 or a substituted or unsubstituted aromatic ring, or heteroaromatic replaced or unsubstituted. R] _ is an alkyl radical from 0 to C5 or a radical R4NH where R4 is a hydrogen atom, an alkyl radical from C ^ to C5 or a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring, or a ring aromatic substituted or unsubstituted by one or more acceptor or donor groups, or a heteroaromatic ring with one or more heteroatoms, substituted or unsubstituted by the acceptor or donor groups. R is a hydrogen atom, a halogen atom, an alkyl radical of C to C5, an oxygen atom substituted or unsubstituted by an alkyl radical of 0 to C5, or a radical NR5R5. where R5 and R5 are independently a hydrogen, oxygen atom or monovalent organic radicals of 0? to C5. which results in the obtaining of a medicine for the treatment of diseases related to an alteration of the venous function and / or inflammatory edema. 2. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-l, 2-dimethyl-lH-napht [2-3-d] imidazole sulfate.
  3. 3. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -lH-napht [2-3-d] imidazole.
  4. 4. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -naft [2-3-d] oxazole.
  5. 5. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (3-fluorophenyl) -naft [2-3-d] oxazole.
  6. 6. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (4-fluorophenyl) -naft [2-3-d] oxazole.
  7. 7. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-methylphenyl) -naft [2-3-d] oxazole.
  8. 8. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (3-methylphenyl) -naft [2-3-d] oxazole.
  9. 9. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (4-methoxyphenyl) -naft [2-3-d] oxazole.
  10. 10. New product characterized in that it comprises 2- (2-chloro-phenyl) -4,9-dihydro-4,9-dioxo-napht [2-3-d] oxazole.
  11. 11. New product characterized in that it comprises 2- (4-chloro-phenyl) -4,9-dihydro-4,9-dioxo-napht [2-3-d] oxazole.
  12. 12. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-thienyl) -naft [2-3-d] oxazole.
  13. 13. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -naphtho [2-3-d] thiazole.
  14. 14. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (3-fluorophenyl) -naphtho [2-3-d] thiazole.
  15. 15. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (4-fluorophenyl) -naphtho [2-3-d] thiazole.
  16. 16. A new product characterized in that it comprises 2- (2,4-difluoro-phenyl) -4,9-dihydro-4,9-dioxo-naphtho [2-3-d] thiazole.
  17. 17. A new product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (3-pyridyl) -naphtho [2-3-d] thiazole.
  18. 18. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (4-pyridyl) -naphtho [2-3-d] thiazole sulfate.
  19. 19. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (3-furyl) -naphtho [2-3-d] thiazole.
  20. 20. New product characterized in that it comprises 2- (5-chloro-furan-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [2-3-d] thiazole.
  21. 21. A new product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-thienyl) -naphtho [2-3-d] thiazole.
  22. 22. A new product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (3-thienyl) -naphtho [2-3-d] thiazole.
  23. 23. A new product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2-phenylamino-naphtho [2-3-d] thiazole.
  24. 24. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-naphtho [2-3-d] thiazole.
  25. 25. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-naphtho [2-3-d] thiazole.
  26. 26. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-naphtho [2-3-d] thiazole.
  27. 27. A new product characterized in that it comprises 4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-naphtho [2-3-d] thiazole.
  28. 28. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-naphtho [2-3-d] thiazole.
  29. 29. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (1-pyrrolyl) -naphtho [2-3-d] thiazole.
  30. 30. A new product characterized in that it comprises 2- (5-bromo-furan-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [2-3-d] thiazole.
  31. 31. A new product characterized in that it comprises 2- (4,5-dibromo-furan-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [2, 3-15! d] -thiazole.
  32. 32. A new product characterized in that it comprises 2- (3-bromo-furan-2-yl) -4,9-dihydro-4,9-dioxonaphto [2,3-d] thiazole.
  33. 33. A new product characterized in that it comprises 2- (4-bromofuran-2-yl) -4,9-dihydro-4,9-dioxonaphto [2,3-d] thiazole.
  34. 34. A new product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (5-nitro-furan-2-yl) naphtho [2,3-d] thiazole.
  35. 35. New product characterized in that it comprises 2- (5-amino-furan-2-yl) -4,9-dihydro-4,9-dioxonaphto [2,3-d] thiazole.
  36. 36. New product characterized in that it comprises 2- (5-acetamido-furan-2-yl) -4,9-dihydro-4,9-dioxonaphto [2,3-d] thiazole.
  37. 37. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (5-hydroxymethylfuran-2-yl) naphtho [2,3-d] thiazole.
  38. 38. New product characterized in that it comprises 2- (5-acetoxy-methyl-furan-2-yl) -4,9-dihydro-4,9-dioxo-naphtho [2,3-d] -thiazole.
  39. 39. New product characterized because it comprises 4,9-dihydro-4,9-dioxo-2- (5-methyl-2-furyl) naphtho [2,3-d] thiazole. - fifteen!
  40. 40. New product characterized in that it comprises 4,9-dihydro-2- (4,5-dimethyl-2-furyl) -4,9-dioxonaphto [2,3-d] thiazole.
  41. 41. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (5-phenyl-2-oxazolyl) naphtho [2,3-d] thiazole.
  42. 42. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-thiazolyl) naphtho [2,3-d] thiazole.
  43. 43. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-6-fluoro-2- (2-furyl) naphtho [2,3-d] thiazole.
  44. 44. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-7-fluoro-2- (2-furyl) naphtho [2,3-d] thiazole.
  45. 45. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-6-fluoro-2-phenylnaphtho [2,3-d] thiazole.
  46. 46. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-7-fluoro-2-phenylnaphtho [2,3-d] thiazole.
  47. 47. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-6-fluoro-2- (5-methyl-2-furyl) naphtho [2,3-d] thiazole.
  48. 48. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-7-fluoro-2- (5-methyl-2-furyl) naphtho [2,3-d] thiazole.
  49. 49. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-6-fluoro-2- (4-fluorophenyl) naphtho [2,3-d] thiazole.
  50. 50. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-7-fluoro-2- (4-fluorophenyl) naphtho [2,3-d] thiazole.
  51. 51. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-6-fluoro-2- (4-methylphenyl) naphtho [2,3-d] thiazole.
  52. 52. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-7-fluoro-2- (4-methylphenyl) naphtho [2,3-d] thiazole.
  53. 53. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-5-fluoro-2- (2-furyl) naphtho [2,3-d] thiazole.
  54. 54. New product characterized because it comprises 4,9-dihydro-4,9-dioxo-8-fluoro-2- (2-furyl) naphtho [2,3-d] thiazole.
  55. 55. New product characterized in that it comprises 6-chloro-4,9-dihydro-4,9-dioxo-2- (2-furyl) -naphtho [2,3-d] thiazole.
  56. 56. New product characterized in that it comprises 7-chloro-4,9-dihydro-4,9-dioxo-2- (2-furyl) -naphtho [2,3-d] thiazole.
  57. 57. New product characterized because it comprises 4,9-dihydro-4,9-dioxo-2- (2-furyl) -5-methoxynapht [2, 3-d] thiazole.
  58. 58. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-furyl) -8-methoxynaphtho [2,3-d] thiazole.
  59. 59. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-furyl) -5-hydroxynaphtho [2,3-d] thiazole.
  60. 60. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-furyl) -8-hydroxynaphtho [2,3-d] thiazole.
  61. 61. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-furyl) -6-methoxy-naphtho [2,3-d] thiazole.
  62. 62. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2- (2-furyl) -7-methoxy-naphtho [2,3-d] thiazole.
  63. 63. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2-furyl-6-methylnaphtho [2,3-d] thiazole.
  64. 64. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2-furyl-7-methylnaphtho [2,3-d] thiazole.
  65. 65. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-6-methyl-2-phenylnaphtho [2,3-d] thiazole.
  66. 66. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-7-methyl-2-phenylnaphtho [2,3-d] thiazole.
  67. 67. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphtho [2,3-d] thiazole.
  68. 68. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-2-furyl-8-methylnaphto [2,3-d] thiazole.
  69. 69. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-5-methyl-2-phenylnaphtho [2,3-d] thiazole.
  70. 70. New product characterized in that it comprises 4,9-dihydro-4,9-dioxo-8-methyl-2-phenylnaphtho [2,3-d] thiazole.
  71. 71. An intermediate product characterized in that it comprises 1,4-di-hydro-l, 4-dioxo-5-methoxy-naphthalene.
  72. 72. An intermediate product characterized in that it comprises 2,3-di-bromo-l, 4-dihydro-l, 4-dioxo-5-methoxy-naphthalene.
  73. 73. Intermediary product characterized in that it comprises 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-5-methoxynaphthalene.
  74. 74. An intermediate product characterized in that it comprises 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-8-methoxynaphthalene.
  75. 75. An intermediate product characterized in that it comprises 2,3-di-bromo-l, 4-dihydro-l, 4-dioxo-6-fluoronaphthalene.
  76. 76. An intermediate product characterized in that it comprises 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-6-fluoronaphthalene.
  77. 77. An intermediate product characterized in that it comprises 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-7-fluoronaphthalene.
  78. 78. Intermediary product characterized in that it comprises 2,3-di-bromo-l, 4-dihydro-l, 4-dioxo-5-fluoronaphthalene.
  79. 79. Intermediary product characterized in that it comprises 2-amino-3-bromo-5-fluoro-1,4-dihydro-1,4-dioxonaphthalene.
  80. 80. An intermediate product characterized in that it comprises 2-amino-3-bromo-8-fluoro-l, 4-dihydro-l, 4-dioxonaphthalene.
  81. 81. An intermediate product characterized in that it comprises 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-6-methylnaphthalene.
  82. 82. An intermediate product characterized in that it comprises 2-amino-3-chloro-l, 4-dihydro-l, 4-dioxo-7-ethylnaphthalene.
  83. 83. An intermediate product characterized in that it comprises 2,3-dibromo-1,4-dihydro-l, 4-dioxo-5-methylnaphthalene.
  84. 84. An intermediate product characterized in that it comprises 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-5-methylnaphthalene.
  85. 85. Intermediary product characterized in that it comprises 2-amino-3-bromo-l, 4-dihydro-l, 4-dioxo-8-methylnaphthalene.
  86. 86. The use of the compounds of any of clauses 1 to 70, characterized in that it leads to the obtaining of a medicament for the treatment of functional or organic venous insufficiency.
  87. 87. The use of the compounds of any of clauses 1 to 70, characterized in that it leads to the obtaining of a medicament for the treatment of hemorrhoidal pathologies
  88. 88. The use of the compounds of any of Clauses 1 to 70, characterized in that it leads to Obtaining a medication for the treatment of migraine.
  89. 89. The use of the compounds of any of clauses 1 to 70, characterized in that it leads to the production of a medicament for the treatment of osteorticular, dermatological and cardiovascular inflammations.
  90. 90. The use of the compounds of any of clauses 1 to 70, characterized in that it leads to the obtaining of a medicament for the treatment of shock states consisting of a significant drop in blood pressure and more particularly in states of septic shock. SUMMARY The invention relates to the therapeutic use of tricyclic derivatives and their pharmaceutically acceptable salts which correspond to the general formula: (I) in which: A is either a sulfur atom, an oxygen atom, or is an R3N radical where R3 is a hydrogen atom, an alkyl radical from 0 to C5 or a substituted or unsubstituted aromatic ring, or substituted heteroaromatic or unsubstituted. R is an alkyl radical of C to C5 or a radical R4NH where R4 is a hydrogen atom, an alkyl radical of 0 to C5 or a substituted or unsubstituted aromatic ring, or substituted or unsubstituted heteroaromatic, or a substituted aromatic ring or unsubstituted by one or more acceptor or donor groups, or a heteroaromatic ring with one or more heteroatoms, substituted or unsubstituted by the acceptor or donor groups. R is a hydrogen atom, a halogen atom, an alkyl radical of Cx to C5, an oxygen atom substituted or unsubstituted by an alkyl radical of Cx to C5, or a radical NR5R5. where R5 and R5 are independently a hydrogen, oxygen atom or monovalent organic radicals of 0? to C5.
MXPA/A/1998/004717A 1995-12-12 1998-06-12 Use of triciclic derivatives of 1,4-dihydro-1,4-dioxo-1h-naftalene, new compounds obtained and therapeutic application MXPA98004717A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9514683 1995-12-12
FR95/14683 1995-12-12

Publications (1)

Publication Number Publication Date
MXPA98004717A true MXPA98004717A (en) 1999-07-06

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