EP0988036A1 - Use of diketone tetracycles derivatives, novel compounds obtained and their application in therapy - Google Patents

Abstract

The invention concerns the use of teracyclic derivatives of general formula (I) in which independently of one another: R1 is a hydrogen atom, a halogen atom, a C1-C5 alkyl radical, a C1-C5 alkoxy radical or OH, a nitro radical, an amino radical, a C1-C5 amino alkyl radical, a C1-C5 amino dialkyl radical, a C1-C5 thioalkyl radical or SH; R2 is a hydrogen atom, a halogen atom, a C1-C5 alkyl radical, a C1-C5 alkoxy radical, or OH, a nitro radical, an amino radical, a C1-C5 alkyl amino radical, a C1-C5 amino dialkyl radical, a C1-C5 thioalkyl radical or SH; R3 is a hydrogen atom, a halogen atom, a C1-C5 alkyl radical, a C1-C5 alkoxy radical or OH, a nitro radical, an amino radical, a C1-C5 amino alkyl radical, a C-C amino dialkyl radical, a C1-C5 amino thioalkyl radical or SH; n and m are either equal to 0 or to 1, but not independently of each other such that if n is equal to 1 then m is equal to 0, and if n is equal to 0 then m is equal to 1, for obtaining a medicine for treating functional and organic venous insufficiency.

Description

 Use of derivatives of diketonic tetracycles, new compounds obtained and their application in therapy

The present invention relates to the use of tetracyclic derivatives and their pharmaceutically acceptable salts for obtaining a medicament intended for the treatment of diseases linked to impaired venous function and / or edema. inflammatory and the new compounds obtained. It relates more particularly to derivatives of tetracyclic compounds comprising a 1,4-dihydro-1,4-dioxonaphthalene unit. The invention relates to the therapeutic application of all these compounds.

The document Che. Rev. , 63, 279-296 (1963), by Sartori MF, describes the synthesis of heterocyclic quinones from 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalenes, in particular the naphthimidazopyridines diones and their derivatives.

The article J. Amer. Chem. Soc. 79, 5708-5710 (1957) by Truitt P., Cooper JE, ood FM, Jr, describes a reverse synthesis of 6, ll-dihydro-6, 11-dioxonaphth [2 ', 3': 4, 5 ] -imidazo [1,2-a] pyridine. While the do- ent ent J. Org. Chem., 24, 374-380 (1959), by Mosby WL, Boyle RJ, discusses the theoretical possibility of obtaining three types of compounds with different structures: 5, 6-dihydro-5, 6-dioxo-naphth- [ 1 ', 2': 4, 5] - imidazo [l, 2-a] pyridine, 5, 6-dihydro-5, 6-dioxo-napht- [1 ', 2': 4,5] imidazo [2, 3-a] pyridine, 6, ll-dihydro-6, 11-dioxo-naphth [2 ', 3': 4, 5] imidazo [1, 2-aJpyridine, the authors demonstrate obtaining the first type of structure. On this same problem, the article J. Org. Chem., 26, 1316-1318

(1961), by Mosby WL, describes the possibility of obtaining two types of products with similar reactions: 5, 6-dihydro-5, 6-dioxo-napht [1 ', 2': 4, 5] imidazo [ 1, 2-a] - pyridine (so-called angular form) and 6,11-dihydro-6,11-dioxo-naphth [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine (so-called linear form). The authors note that the formation of the linear structure is obtained less easily than the angular structure. More drastic conditions are therefore necessary for the formation of this structure (reflux at high temperature). The “angular” structure of the family is demonstrated in the synthesis of 5,6-dihydro-5,6-dioxo-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine using a specific reagent for orthodiketones in the document J. Org. Chem. 28, 1019-1022 (1963) by Van Allan JA, Reynolds GA

U.S. Patent 2,970,146; Jan. 31, 1961 (Cl. 260- 256.4), Boyle R. J., Birsten 0. G., Mosby W. L., describes the synthesis of new heterocyclic orthoquinones. The document Indian J. Chemistry 18B, 236-239 (1979) by Ayyangar NR, Lugade AG, Tilak BD describes the unequivocal synthesis of 6, ll-dihydro-6, 11-dioxonaphth [2 ', 3': 4 , 5] imidazo [1, 2-a] pyridine. The document J. Indian Chem. Soc. 68 (9), 529-531 (1991) by Yanni AS, describes the synthesis and the bactericidal and fungicidal activity of 6, ll-dihydro-6, 11-dioxopyrido [l ', 2': 1, 2 ] -imidazo [5, 4-g] quinoline. Finally the DE patent. 1,108,699 (C1.12p). Appl. Sept. 25, 1959 by Schellhammer CW, Domagk G., describes the cytostatic and bacteriostatic activity of 5,6-dihydro-5,6-dioxo-pyrido derivatives [l ', 2': 1, 2] imidazo [4, 5-f] quinoline.

The invention relates to the use of tetracyclic derivatives and their pharmaceutically acceptable salts corresponding to the general formula:

(I) in which independently of each other: R. is a hydrogen atom, a halogen atom, a Cη to C5 alkyl radical, a C ₁ to C ₅ alkoxy radical or OH, a nitro radical, an amino radical, alkyl radical C _x -C ₅ amino, dialkyl radical C ₁ -C ₅ amino, a thioalkyl radical, C ₂ -C ₅ or SH

R ₂ is a hydrogen atom, a halogen atom, a C ₁ to C ₅ alkyl radical, a C ₁ to C ₅ alkoxy radical or

OH, nitro, amino, alkyl radical C _λ -C ₅ amino, dialkyl radical C _x -C ₅ amino, thioalkyl radical C _x -C ₅ or SH

R ₃ is a hydrogen atom, a halogen atom, a C ^ to C5 alkyl radical, a C ^ to C ₅ alkoxy radical or

OH, nitro, amino, alkyl radical C ₁ -C ₅ amino, dialkyl radical -C ₅ amino, thioalkyl radical C _x -C ₅ or SH with the exception of derivatives for which: R _j is a hydrogen atom and R ₂ is a hydrogen atom and R ₃ is a hydrogen, a halogen atom, a nitro radical or a C ^ to C ₅ alkyl radical

R _{j ^} is a hydrogen atom and R ₂ is a halogen atom and R ₃ is a hydrogen, a halogen atom, a nitro radical or a C _t to C ₅ alkyl radical

R _x is a halogen atom and R ₂ is a hydrogen atom and R ₃ is hydrogen, a halogen atom, a nitro radical or a C _t to C ₅ alkyl radical R- is a C _x to C ₅ alkyl radical and R ₂ is a hydrogen atom and R ₃ is a hydrogen, a halogen atom, a nitro radical or a C _x to C ₅ alkyl radical

R ₂ is a C _x to C ₅ alkyl radical and R _x is a hydrogen atom and R ₃ is a hydrogen, a halogen atom, a nitro radical or a C ₁ to C ₅ alkyl radical n and m are either equal to 0 or 1, but not independently of each other so that if n is equal to 1 then m is equal to 0, and if n is equal to 0 then m is equal to 1, to obtain a drug intended for the treatment of functional and organic venous insufficiency.

The invention also relates to the following new products, namely: 4-amino-5, 6-dihydro-5, 6-dioxonapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine, 7-amino-2-chloro-6, ll-dihydro-6, 11-dioxo-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine, 10-amino -2-chloro-6, ll-dihydro-6, 11-dioxo-napht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine, 2-amino-5, 6-dihydro -5, 6-dioxo-napht [1 ', 2': 4, 5] - imidazo- [1, 2-a] pyridine, 3-amino-5, 6-dihydro-5, 6-dioxo-napht [ 1 ', 2': 4, 5] - imidazo- [1, 2-a] pyridine, 5, 6-dihydro-5, 6-dioxo-4- (methylamino) naphth- [1 ', 2': 4 , 5] -imidazo [1, 2-a] pyridine, 5, 6-dihydro-2-dimethylamino-5, 6-dioxo-napht- [1 ', 2': 4, 5] -imidazo [1,2 -a] pyridine, 5, 6-dihydro-3-dimethylamino-5, 6-dioxo-napht- [1 ', 2': 4,5] -imidazo [1,2-a] pyridine, 4-amino -9-chloro-5, 6-dihydro-5, 6-dioxo-napht- [1 ", 2 ': 4, 5] imidazo [1, 2-a] pyridine, 9-chloro-5, 6-dihydro -5, 6-dioxo-4- (methylamino) - napht- [l ', 2': 4, 5] imidazo [1, 2-a] pyridin e, 9-bromo-5, 6-dihydro-5, 6-dioxo-1-methoxynapht [l, 2 ': 4, 5] imidazo [l, 2-a] -pyridine, 9-bromo-5, 6 -dihydro-5, 6-dioxo-4-methoxynapht [l ', 2': 4, 5] imidazo [l, 2-a] -pyridine, 9-chloro-5, 6-dihydro-5, 6-dioxo -l-methoxy-napht-

[1 ', 2': 4, 5] imidazo [l, 2-a] pyridine, 9-chloro-5, 6-dihydro-5, 6-dioxo-4-methoxy-napht- [1 ', 2' : 4, 5] imidazo [l, 2-a] pyridine, 9-chloro-5, 6-dihydro-5, 6-dioxo-2-methoxy-napht- [1 ', 2': 4,5] imidazo [l, 2-a] pyridine, 9-chloro-5, 6-dihydro-5, 6-dioxo-3-methoxy-napht- [1 ', 2': 4, 5] imidazo [l, 2-a ] pyridine, 9-chloro-5, 6-dihydro-5, 6-dioxo-l-hydroxynapht-

[1 ', 2': 4, 5] -imidazo [1,2-a] pyridine, 9-chloro-5,6-dihydro-5,6-dioxo-4-hydroxynapht-

[1 ', 2': 4, 5] -imidazo [l, 2-a] pyridine, 5, 6-dihydro-5, 6-dioxo-10-methoxynapht [1 ', 2': 4, 5] - imidazo [1, 2-a] yridine, 5,6-dihydro-5,6-dioxo-ll-methoxynapht [1, 2 ': 4.5] - imidazo [1,2 -a] pyridine, 5 , 6-dihydro-5,6-dioxo-10-hydroxynapht [l ', 2': 4,5] - i idazo- [1, 2 -a] pyridine, la 5,6-dihydro-5,6-dioxo -ll-hydroxynapht [l ', 2': 4.5] - imidazo- [1, 2 -a] pyridine, 5,6-dihydro-5,6-dioxo-ll-nitronapht [l ', 2': 4,5] - imidazo- [1, 2 -a] pyridine, ll-amino-5, 6-dihydro-5, 6-dioxonapht [1 ', 2': 4, 5] - imidazo- [1, 2 -a] pyridine, 5, 6-dihydro-ll-dimethylamino-5, 6-dioxonapht- [102 ': 4, 5] -imidazo [1, 2-a] pyridine, 9 -amino- 5, 6- dihydro-5, 6-dioxo-napht [1 ', 2': 4, 5] - imidazo- [1, 2 -a] yridine, la 5, 6-dihydro-9-dimethylamino-5, 6-dioxonapht-

[1 ', 2': 4.5] -imidazo [1,2-a] pyridine, 5,6-dihydro-5,6-dioxo-10-methylthionapht- [1 ', 2': 4, 5] -imidazo [1,2-a] pyridine, 5, 6-dihydro-5, 6-dioxo-9-methylthionapht-

[1 ', 2': 4, 5] -imidazo [1, 2-a] pyridine, la 9, ll-dichloro-5, 6-dihydro-5, 6-dioxo-napht- [l ', 2': 4,5] -imidazo [1, 2-a] pyridine, la 9, ll-dibromo-5, 6-dihydro-5, 6-dioxo-napht- [1 ', 2': 4, 5] -imidazo [ 1, 2-a] pyridine, 5,6-dihydro-5,6-dioxo-9-methoxynaphth [1, 2 ': 4,5] imidazo [1, 2-a] pyridine, 9-chloro- 5, 6-dihydro-5, 6-dioxo-2-hydroxy-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine, 9-chloro-5, 6-dihydro-5 , 6-dioxo-3-hydroxy-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine, la 10, ll-dichloro-5, 6-dihydro-5, 6-dioxonaphth [ 102 ': 4, 5] imidazo [1,2-a] pyridine, 5,6-dihydro-5, 6-dioxo-9-hydroxynaphth [l', 2 ': 4, 5] imidazo [1, 2- a] pyridine, 5, 6-dihydro-5, 6-dioxo-11-methylthionaphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine. The present invention also relates to the salts of the salifiable compounds mentioned above. These salts include 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 acid, random, fumaric, succinic, tartaric.

The present invention relates in particular to the use of the abovementioned compounds for obtaining a medicament intended for the treatment of hemorrhoidal pathologies and migraine. The invention is illustrated by the nonlimiting examples below.

The examples indicated by a number correspond to new compounds while the example comprising a letter corresponds to a known compound.

- Melting points: They were made on a LEICA - REICHERT WME model "Kofler bench".

- Thin layer chromatographies: They were obtained on silica gel plates with 0.25 mm thick UV ₂₅₄ fluorescence indicator of the MACHE-REY-NAGEL type (Reference 805 023). Elution solvents are indicated for each compound.

- Mass spectra: They were carried out with a spectrometer of type AEI MS-50 or on a spectrometer of type FISONS VG PLATFORM. The ionization mode is indicated for each analysis. - NMR spectra: The NMR spectra of H and ¹³ C were carried out either on a spectrometer of the JEOL type respectively at 270 MHz and at 68 MHz, or on a spectrometer of the BRUCKER type respectively at 250 MHz and at 62.5 MHz or 400 MHz and 100 MHz. The deuterated solvents used are indicated for each analysis.

- Infra-Red Spectra: They were obtained on a NICOLET 205 FT-IR type spectrometer or of NICOLET IMPACT 410 type. They are carried out at 1% (m / m) in dispersion in KBr.

Example 1

4-amino-5_ 6-dihydro-5.6-dioxonapht [1 ^/ .2 ': 4,53- i idazoT1,2-alpyridine

To an orange suspension of 700 g (2.39 mmol; 1 eq) of 5, 6-dihydro-5, 6-dioxo-4-nitronapht [! ' , 2 ': 4, 5] - imidazo [1, 2-a] pyridine in ethanol under argon, a catalytic amount of palladium on carbon at 10% is added and the mixture is brought to reflux. 230 μl of hydrazine monohydrate (2.39 mmol; 1 eq) are then added. The reaction mixture immediately turns purple. After 30 minutes, 230 μl of hydrazine monohydrate (2.39 mmol; 1 eq) are added. After 1 hour of reaction, the reaction mixture is allowed to return to room temperature and the brown-purple precipitate is filtered through cotton and then washed with ethanol to give 610 mg of 4-amino-5,6-dihydro-5,6 dioxonapht [1 ', 2': 4, 5] imidazo [1,2- a] pyridine.

YId: 97%

F:> 260 ° C Rf: 0.30 (CH ₂ Cl ₂ / Methanol, 98/2)

SM (APcI-): m / z 263 (M ^" )

'H NMR (CD ₂ C1 ₂ , 270 MHz): δ (pp)

9.22 (d, 1H, H-8, J _H8.H9 = 6.59Hz)

7.92 (s, 2H, NH ₂ ) 7.75 (d, 1H, Hl, J _H1.H2 = 8.23Hz)

7.61 (t, 1H, H-10, J _H10.HU = 6.62Hz)

7.50 (d, 1H, H-ll, J _Hl0.HU = 6.59Hz)

7.33 (t, 1H, H-2, J _H1.H2 = 8.23Hz)

7.14 (t, 1H, H-9, J _H8 . _H9 = 6.60Hz) 6.88 (d, 1H, H-3, J _{M. H3} = 8.22Hz)

IR (KBr): v (cm ¹ )

3580, 3260 (NH ₂ ), 1615 (C = 0)

Example 2 7-amino-2-chloro-6. ll-dihvdro-6, 11-dioxo-napht- [2 ', 3' t4, 5] imidazo [1,2-a] pyridine or

10-amino-2-chloro-6, l-dihydro-6, ll-dioxo-napht- [2 *, 3 ': 4, 5] imidazo [1.2-alpyridine

To a suspension of 6.55 g (20.0 mmol, 1 eq) of 2-chloro-6, ll-dihydro-6, ll-dioxo-7-nitronapht [2 ', 3': 4.5] imidazo- [1, 2-a] pyridine (described in the patent: filing number: PCT / FR96 / 01974) or 2-chloro-6, ll-dihydro-6, 11-dioxo-10-nitronapht- [2 ', 3': 4, 5] imidazo [1, 2-a] pyridine (described in the patent: filing number: PCT / FR96 / 01974) in 1 1 of ethanol, a catalytic amount of palladium is added to coal at 10%. The reaction mixture is brought to reflux. 2.55 ml (52.5 mmol, 2.6 eq) of hydrazine are added in three installments every 60 minutes. The suspension changes from orange to green. After evaporation to dryness of the reaction medium, 5.54 g of crude product are obtained which is purified on a medium pressure column (support: silica 6-35 μ; eluent: dichloromethane / ethyl acetate, 98/2). The purple precipitate is washed hot with dichloromethane. 0.24 g of 7-amino-2-chloro-6,11-dihydro-6,11-dioxo-naphth- [2 ', 3': 4, 5] imidazo is obtained after filtration on micropores in dichloromethane [1, 2-a] pyridine or 10-amino-2-chloro-6, 11-dihydro- 6, 11-dioxo-napht [2 ', 3': 4, 5] -imidazo [1, 2-a] pyridine in the form of dark purple crystals. Yid: 24%

F:> 260 ° C

Rf: 0.4 (CH ₂ Cl ₂ / AcOEt, 96/4) SM (APCI +): m / z 298 (M + H) ^* 1 H NMR (Pyridine-d ₅ , 270 MHz): δ (ppm ) 9.40 (d, 1H, Hl, J _H1.K3 = 1.7 Hz) 7.84 (ls, 2H, NH ₂ )

7.78 (dd, 1H, H-4, J _{H <} _ _H3 = 9.5 Hz, J _{H <.H1} = 0.8 Hz) 7.69 (t, 1H, H-8 or H-9, in β of the amino, J „_ _m = J, H8-H9 or J„ _{8. H9} = J _H9 _ _H10 = 4.2 Hz) 7.54 (dd, 1H, H-3, ^ _. ^ = 2.1 Hz)

7.26 (d, 2H, H-8 or H-9 in α of the mino, H-7 or H-

10, J „ ₈ -„ ₉ or J _H9 . _Hl0 = J _{W. M} or J _H10 . _H9 = 4.6 Hz) IR (KBr): v (cm ¹ ): 3423, 3317 (NH ₂ ), 1633 (C = 0). Example 3

2-amino-5, 6-dihvdro-5, 6-dioxo-napht [1 ', 2'; .51 - imidazo [1,2-alpyridine or

3-amino-5, 6-dihvdro-5, 6-dioxo-napht 11 '.2': 4, 51- imidazo [1,2-alpyridine

To a suspension formed of 150 mg (0.51 mole; 1 eq) of 5, 6-dihydro-5, 6-dioxo-2-nitronapht [1 ', 2': 4, 5] - imidazo [1, 2 -a] pyridine (described in the patent: filing number: PCT / FR96 / 01974) or 5,6-dihydro-5,6-dioxo-3-nitronapht [1 ', 2': 4, 5] imidazo [1,2-a] pyridine (described in the patent: filing number: PCT / FR96 / 01974), with a catalytic amount of palladium on charcoal in ethanol and under argon, 49 μl are added (0, 51 mmol; 1 eq) of hydrazine monohydrate. After 30 minutes, 49 μl (0.51 mmol; 1 eq) of hydrazine monohydrate are again added. The reaction mixture is a green suspension. After returning to room temperature, the precipitate is filtered to provide 30 mg of 2-amino-5,6-dihydro-5,6-dioxo-naphth- [1 ', 2': 4, 5] imidazo [1, 2- a] pyridine or 3-amino-5, 6-dihydro-5, 6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine in the form of green crystals.

Yid: 22%

F:> 260 ° C

Rf: 0.40 (CH ₂ Cl ₂ / Methanol, 80/20) SM (APcI +): m / z 264 (M + H0

"H NMR (CD ₂ C1 ₂ , 270 MHz): δ (ppm)

9.27 (d, 1H, H-8, J _Hβ . _H9 = 6.23Hz)

8.00 (d, 1H, H-ll, J _H10 . _H11 = 7.89Hz)

_7.80 (d, 1H, Hl or H-4, J _H1 . _H2 or J _H3.H4 = 8, 30Hz, in β of

NHJ

7, 63 (d, 1H, H-10, J _H10 . _Hll = 6.23Hz)

7.40 (d, 1H, Hl or H-4, J _M or J _H3. = 2.49Hz, in α of

NHJ

7, 21 (t, 1H, H-9, J _H8.H9 = J _H9 . _Hl0 = 6, 65Hz) 6, 98 (dd, 1H, H-2 or H-3, J _Λ . _N or J _m . _Hi = 8, 31Hz, j _≈ _ _M or J _H1 . _ω = 2.49Hz, in α of NH ₂ ) IR (KBr): v (cm ^"1 )

3420 (NH ₂ ), 1635 (C = 0)

Example 4

5.6-dihydro-5, 6-dioxo-4- (methylamino) naphth- [! ' .2 ': 4, 51 imidazo [1,2-alpyridine

To a solution of 0.3 g of 4-amino-5,6-dihydro-5,6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine (1,14 mmol, 1 eq) in 60 ml of ethanol dried on a sieve at -5 ° C under argon, 0.127 g of sodium cyanoborohydride (2.02 mmol, 1.7 eq) is added, then 0.17 ml of acetic acid (3.02 mmol, 2.64 eq) then 0.11 ml of 37% formaldehyde in water (3.81 mmol, 3.34 eq) drop by drop. The reaction is followed by TLC (eluent: CH ₂ Cl ₂ / MeOH, 9/1). The reaction mixture is allowed to cool to room temperature. The reaction is allowed to stir at this temperature for 18 hours to provide the crude after evaporation of the solvent. This is purified on a flash column (support: silica 6-35 μm, h = 20 cm, d = 4 cm; packaging: dichloromethane; eluent: dichloromethane / methanol, 9/1) to provide 50 mg of 5, 6-dihydro-5, 6-dioxo-4- (methylamino) naphth- [1 ', 2': 4, 5] imidazo [1, 2- a] pyridine in the form of purple crystals. Yid: 13% F:> 260 ° C

Rf: 0.6 (CH ₂ Cl ₂ / Methanol, 9/1) SM (APcI +): m / z 278 (M +) "H NMR (CD ₂ C1 ₂ , 270 MHz): δ (ppm) 9.78 (bs, 1H, NH)

9.22 (d, 1H, H-8, J _Hβ . _H9 = 6, 93Hz) 7.85 (d, 1H, Hl, J _Λ ^ = 7, 91Hz) 7.78 - 7.46 (m, 3H , H-2, H-10, H-ll) 7.14 (t, 1H, H-9 _H8 _ _H9 = 6, 92Hz) 6.92 (d, 1H, H-3, J _m _ _m = 7 , 92Hz) 3.08 (d, 3H, N-ÇH ^ J ^^ ≈ 5.44Hz) ¹³ C NMR (CD ₂ C1 ₃ , 67.5 MHz): δ (pp)

136.9 (1C, C-2)

131.7 (1C, C-10) 129.0 (1C, C-ll)

118.2 (1C, C-8) 116.1 (1C, C-9) 115.9 (1C, C-3)

113.8 (1C, Cl) 29.8 (1C, CH ₃ )

IR (KBr): v (cm ¹ ) 3510 (NH), 1620 (C = 0)

Example 5 5, 6-dihvdro-2-dimethylamino-5, 6-dioxo-naphth- [1 ', 2'; 4, 51 -imidazo [1,2-alpyridine or

5, 6-dihydro-3-dimethylamino-5, 6-dioxo-naphth- [1 ', 2'; 4,51 -imidazo [1,2-al yridine

At 150 mg (0.57 mmol, 1 eq) of 5, 6-dihydro-5, 6-dioxo-2-nitronapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine or 5, 6-dihydro-5, 6-dioxo-3-nitronapht [1 ', 2': 4, 5] imidazo [1, 2- a] pyridine suspended in 40 ml of dry ethanol under argon at -5 ° C, 65 mg (1.77 eq) of NaBH ₃ CN, 85 μl (2.65 eq) of acetic acid and 55 μl (3.34 eq) of 37% formaldehyde in l are added dropwise 'water. After returning to ambient temperature over a period of 4 hours, the solvent is evaporated to dryness to give 320 mg of a crude green mixture. This is then purified on a flash column (support: silica 6-35 μm, h = 7 cm, d = 5 cm; eluent: dichloromethane / methanol; 99/1) to provide 32 mg of 5,6-dihydro -2-dimethylamino-5, 6-dioxo-naphth [1 ', 2': 4,5] - imidazo [1,2-a] pyridine or 5, 6-dihydro-3-dimethylamino- 5, 6-dioxo- naphth- [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine, in the form of carmine crystals. YId: 60% F: 258-260 ° C

Rf: 0.6 (CH ₂ Cl ₂ / MeOH, 9/1)

SM (APcI +): m / z 292 (M + H) ⁺

^X H NMR (CDC1 ₃ , 270 MHz): δ (ppm) 9.33 (d, 1H, H-8, J _H8 . _H9 = 6.6Hz)

8.04 (d, 1H, H or H-4, J _{H1. Œ} or J ^ = 8.8 Hz)

7.82 (d, 1H, H-ll, J _HX0 . _H11 = 8.7Hz)

7.60 (syst, AB, 1H, H-10, J _H10 . _H11 ≈ 8.7Hz, J _H9 . _H10 ≈ 7.5Hz)

7.42 (d, 1H, Hl or H-4, J _H1 . _H3 or J _H2 . _H4 = 2.9Hz) 7.17 (syst, AB, 1H, H-9, J _H8 . _H9 = 6.6Hz , J _H9 . _H10 = 7.1 Hz)

6.64 (dd, 1H, H-2 or H-3, J _H1 . _H2 or J _H3 . _H4 = 8, 7Hz, J _H1 _ _H3 or J _H2 - _H. = 2.4HZ)

3.23 (s, 6H, -N (CH ₃ ) ₂ )

¹³ C NMR (CDC1 ₃ , 67.5 MHz): δ (ppm) 179.7 (IC, C-5)

170.3 (CI, C-6a)

154.9 (IC, C-2 or C-3, carrying dimethylamino)

154.3 (IC, C-12a)

150.1 (IC, C-lla) 133.6 (IC, C-10)

133.4 (IC, C-4a) 131.8 (IC, C-8)

129.2 (IC, C-l or C-4) 119.4 (IC, C-12b) 118.2 (IC, C-ll)

116.6 (IC, C-9)

112.2 (IC, C-2 or C-3, in α of dimethylamino)

107.2 (IC, C-1 or C-4)

40.3 (2C, -N (CH ₃ ) ₂ ) IR (KBr): v (cm ^"1 )

1638 (C = 0)

Example 6

A --_ τtfi_rιo-9-chloro-5.6-dihvdro-5,6-dioxo- τιanht \ 1 '.2'; 4.51 imidazor .2-a _ yridine ΛVO 98/56374

PCT / FR98 / 01143

14

To a suspension of 1.00 g (3.0 mmol, 1.0 eq) of 9-chloro-5, 6-dihydro-5, 6-dioxo-4-nitronapht [1 ', 2': 4, 5] - imidazo- [1, 2-a] pyridine (described in the French patent: filing number: 95 14 684) in 150 ml of ethanol, a catalytic amount of 10% palladium on carbon is added. The reaction mixture is brought to reflux and then 0.28 ml (5.8 mmol, 1.9 eq) of hydrazine is added, in four batches, every 30 minutes, for 2.5 hours. The suspension changes from orange to burgundy. After cooling, the bordeaux precipitate is filtered, washed with ethanol and then with dichloromethane. 447 mg of 4-amino-9-chloro-5,6-dihydro-5,6-dioxonaphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form is obtained after filtration through micropores burgundy crystals. Yid: 45%

F:> 260 ° C

Rf: 0.15 (CH ₃ CN / H ₂ 0, 50/50)

SM (APcI +): m / z 298 (M + H) ^*

1 H NMR (CDC1 ₃ , 270 MHz) s δ (ppm) 9.44 (d, 1H, H-8, J _H8 . _H10 = 2.0 Hz)

7.93 (d, 1H, Hl, J _H1.K2 = 6.9 Hz)

7.90 (d, 1H, H-ll, J _H11 . _H10 = 9.8 Hz)

7.63 (dd, 1H, H-10, J _H10 . _H8 = 2.0 Hz, J _H10 . _H11 = 9.4 Hz)

7.51 (dd, 1H, H-2, J ^ ≈ 6.9 Hz, J _H2.K3 = 8.4 Hz) 7.22 (d, 1H, H-3, J _H3 . _H2 = 9.8 Hz)

IR (KBr): v (cm ¹ )

3297 (NHJ, 1617 (C = 0), 1587 (C = N),

Example 7 9-chloro-5, 6-dihvdro-5, 6-dioxo-4- (methylamino) - napht [1 ', 2' 14, 51 imidazo [1.2-alpyridine

To a solution of 2.71 g of 4-amino-9-chloro-5,6-dihydro-5,6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine (9.10 mmol, 1 eq) in 400 ml of absolute ethanol under argon, at -20 ° C., 1.10 g of cyanoborohydride of sodium are added. dium (17.50 mmol, 1.9 eq) then 1.8 ml of acetic acid (31.50 mmol, 3.5 eq) and 1.2 ml of 37% formaldehyde in water (43.00 mmol, 4.7 eq) drip. The reaction is followed by TLC (eluent: CH ₂ Cl ₂ / AcOEt, 96/04). After the end of the addition of the last reagent, the reaction mixture is allowed to rise to ambient temperature. After 8 hours of reaction, the medium is filtered and the filtrate is evaporated under reduced pressure. A crude product is obtained which is purified on a cake (support: silica 6-35 μm, h = 20 cm, d = 6 cm; eluent: dichloromethane / ethyl acetate, 99.5 / 0.5) to provide 141 mg 9-chloro-5,6-dihydro-5,6-dioxo-4- (methylamino) - naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form of crystals purple. Yid: 5%

F:> 260 ° C

Rf: 0.45 (CH ₂ C ethyl acetate, 96/4)

SM (APcI-) m / z 311 (M ^" )

1 H NMR (CDC1J: δ (ppm) 9.94 (bs, 1H, NH)

9.34 (s, 1H, H-8)

7.73 (d, 1H, H-ll, J _H11 . _H10 = 9.55Hz)

7.57-7.49 (m, 2H, H-10, H-l)

7.30 (t, 1H, H-2) 6.93 (d, 1H, H-3, ^ ≈ 7.89Hz)

3.20 (d, 3H, N-ÇH ^ J ^ _. ^ ≈ Hz)

IR (KBr): V (cm ^-1 )

1726 (C = 0)

Example 8

9-bromo-5, 6-dihydro-5, 6-dioxo-1-methoxynapht- [1 '.2'; 4.5 ^" ] imidazo [l, 2 -a ^" | -pyridine or

9-bromo-5, 6-dihydro-5.6-dioxo-4-méthoχynapht- [1 '.2' t4.5limidazori.2 -a] -pyridine A suspension of 2.00 g (5.78 mmol, 1 eq ) of 2, 3-dibromo-1,4-dihydro-5-methoxy-1,4-dioxo-naphthalene (described in the French patent: filing number: 95 14 684) in 200 ml of ethanol are added 1.10 g (6.36 mmol, 1.1 eq) of 2-amino-5-bromo pyridine. This mixture is brought to reflux for 16 hours. After cooling to room temperature, the ethanol is removed by evaporation under reduced pressure. The crude product is purified on a flash column (support: silica 6-35 μm; packaging: CH ₂ C1 ₂ / Heptane, 90/10; eluent: gradient CH ₂ Cl ₂ / AcOEt, 100/0 to 40/60) to provide 0.42 g of 9-bromo-5, 6-dihydro-5, 6-dioxo-l-methoxy-napht [l ', 2': 4,5] - imidazo [l, 2-a] pyridine or 9- bromo-5, 6-dihydro-5, 6-dioxo-4-methoxy-naphth [l ', 2': 4, 5] imidazo [l, 2-a] pyridine in the form of dark burgundy crystals. Yid: 20.3%

F:> 260 ° C

Rf: 0.20 (CH ₂ Cl ₂ / AcOEt, 60/40)

S, M, (APσl-): m / z 359 (M-)

"H NMR (CD ₂ C1 ₂ , 270 MHz): δ (ppm) 9.51 (m, 1H, H-8)

7.71 (m, 3H, H-ll, H-10, H-l or H-4)

7.50 (dd, 1H, H-2, J ^ - ^ # J _M - _H1 = 2.94 Hz)

7.31 (d, 1H, H-3, J _H3 - _H2 = 2.93 Hz)

4.05 (s, 3H, ÇH _j O in 1 or 4) IR (KBr): v (cm ^"1 )

3092, 2921 (C-H); 1637 (C = N); 1579 (C-C)

Example 9

9-chloro-5, 6-dihvdro-5, 6-dioxo-l-methoχy-napht- [1 '.2' 14.5 ~ | imidazo [l .2 -a ^" ) pyridine or

9-chloro-5,6-dihydro-5.6-dioxo-4-methoxy-napht- [1 ', 2': 4, 5] imidazo [l .2 -aloyridine

To a suspension of 2.00 g (5.78 mmol, 1 eq) of 2, 3-dibromo-1,4, dihydro-1,4, dioxo-5-methoxynaphthalene (described in the French patent: filing number : 95 14 684) 1.48 g (11.50 mmol, 2 eq) of 2-amino-5-chloro-pyridine are added to 310 ml of methoxyethanol. This mixture is brought to reflux for 5 hours and then stirred at room temperature for 18 hours. The methoxyethanol is removed by evaporation under reduced pressure. The crude product is purified on two successive cakes (the ^1st cake provides 0.80 g of 9-chloro-5, 6-dihydro-5, 6-dioxo-1-methoxy-napht [l ', 2': 4, 5] imidazo [l, 2-a] pyridine or 9-chloro 5, 6-dihydro-5, 6-dioxo-4-methoxy-napht [l ', 2': 4, 5] imidazo- [1, 2 -a] pyridine, support: silica 6-35 μm, height = 17 cm, diameter = 4.8 cm; packaging: CH ₂ Cl ₂ / AcOEt, 90/10; eluent: gradient CH ₂ Cl ₂ / AcOEt, 90 / 10 to 0/100) (2 * "cake, support: silica 6-35 μm, height≈lδ cm, diameter = 4.8 cm; packaging: CH ₂ Cl ₂ / AcOEt, 90/10; eluent: gradient CH ₂ Cl ₂ / AcOEt, 85/15 to 0/100). After filtration on micropores 0.30 g of 9-chloro-5, 6-dihydro-5, 6-dioxo-1-methoxynapht [l ', 2' : 4, 5] imidazo [l, 2-a] pyridine or 9-chloro- 5, 6-dihydro-5, 6-dioxo-4-methoxynapht [l ', 2': 4, 5] imidazo [l, 2 - a] pyridine are obtained in the form of orange-red crystals.

YId: 44%

F:> 260 ° C

Rf: 0.12 (CH ₂ Cl ₂ / AcOEt, 50/50)

S,, (APcI ^* ): m / z 313-315 (M + H) ⁺ S, M, (APcl ^" ): m / z 312-314 (M) ^"

^X H NMR (CD ₂ Cl _a , 270 MHz): δ (ppm)

9.42 (d, 1H, H-8, J _H8 - _H10 = 2.14 Hz)

7.82 (d, 1H, H-ll, J _H10 - _H11 = 9.46 Hz)

7.78 (d, 1H, Hl or H-4, J ^ or J _H3.H1 = 7.93 Hz)) 7.61 (dd, 1H, H-10, J _H8 - _H10 = 2.13 Hz, J _H10 - _H11 = 9.46 Hz)

7.50 (dd, 1H, H-2 or H-3 in β of OCH ₃ , J _H2 - _H3 = 8.54 Hz, J _H1 - _M or J ^ ≈ 7.78 Hz)

7.33 (dd, 1H, H-3 or H-2 in α of OCH ₃ , J ^ - ^ = 8.54 Hz, J _K1 - _H3 or J _∞ - _M = 1.22 Hz) 4.05 ( s, 3H, OÇΑ_ in 1 or 4) "C NMR (CDC1 ₃ , 67.5 MHz): δ (ppm)

182.13 (CI, C = 0)

167.75 (IC, C-6a)

158.13 (IC, C-l or C-4) carrying methoxy 148.71 (IC, C-lla)

133.24 (IC, C-10)

132.98 (IC, C-4a or C-12b)

132, 21 (IC, C-2 or C-3) in β of 0CH ₃

126.96 (IC, C-8) 125.47 (IC, C-9)

123, 85 (IC, Cl or C-4) in γ of OCH ₃

119, 50 (IC, C-2 or C-3) in α of 0CH ₃

119, 09 (IC, C-ll)

57, 20 (IC, 0-ÇH ₃ in 1 or 4) IR (KBr): v (cm ^"1 )

1640 (C = 0)

Examples 10 and 11

9-chloro-5, 6-dihydro-5, 6-dioxo-2-methoxynapht- [1 ', 2'; 4,5] imidazo [1,2-a] pyridine and

9-chloro-5, 6-dihvdro-5, 6-dioxo-3-methoxynapht- [1 ', 2'; 4,5] imidazo [l, 2-a] pyridine

To a suspension of 2.30 g (6.30 mmol, 1 eq) of 2,3-dibromo-1,4-dihydro-1,4, dioxo-6-methoxynaphthalene in 200 ml of isopropanol, are added 1, 30 g (9.97 mmol, 1.5 eq) of 2-amino-5-chloro-pyridine. This mixture is brought to reflux for 55 hours. Then 100 ml of ethanol are added to the reaction medium maintained at reflux for another 137 hours. After returning to ambient temperature, the precipitate which has formed is filtered through a frit and washed with water and heptane. The raw product is purified on cake (support: silica 6-35 μm, height = 17 cm, diameter = 4.8 cm; packaging: CH ₂ Cl ₂ / Ac0Et, 90/10; eluent: gradient CH ₂ Cl ₂ / Ac0Et , 100/0 to 50/50). 0.60 g of the mixture of 9-chloro-5, 6-dihydro-5, 6-dioxo-2-methoxy- naphth [l ', 2': 4, 5] imidazo [l, 2-a] pyridine and 9-chloro-5,6-dihydro-5,6-dioxo-3-methoxy-napht [l ', 2' : 4, 5] imidazo [l, 2-a] - pyridine are obtained in the form of orange-red crystals (ratio: 62/38). Yid: 29%

Least polar product

The isomer is purified by three successive recrystallizations from acetic acid, then washing with water and filtration through micropores. F:> 260 ° C

Rf: 0.62 (CH ₂ Cl ₂ / Me0H, 95/5)

HPLC: Nucleosil 100-5C18 column, id = 4.6 mm, 1 = 250 mm, Eluent: Methanol / Water, 75/25, flow rate: 1 ml / min, TR = 27.5 min SM (APcI ^* ): m / z 313-315 (M + Hj

"H NMR (CD _a Cl ₂ , 270 MHz): δ (ppm)

9.32 (d, 1H, H-8, J _H8 - _H10 = 2.14 Hz)

8.07 (d, 1H, Hl or H-4, in β of methoxy, J _Hl - _H2 or J _H3 - _H <= 8.85 Hz) 7.76 (d, 1H, H-ll, J _H10 - _H11 = 9.76 Hz)

7.66 (d, 1H, Hl or H-4, in α of methoxy, J _H2 - _H4 or,

J _H1 - _H3 = 2.44 Hz)

7.61 (dd, 1H, H-10, J _H8 - _H10 = 2.13 Hz, J _H10 - _H11 = 9.46 Hz)

7.00 (dd, 1H, H-2 or H-3, in α of 0CH ₃ , J ^ - ^ or J _H3 - _H. = 8.85 Hz, J _H2 - _H4 or J ,,, - ^ = 2.44 Hz)

¹³ C NMR (CDC1 ₃ , 67.5 MHz): δ (ppm)

165.55 (IC, C-2 or C-3, methoxy carrier)

133.51 (CI, C-4a or C-12b) 133.11 (CI, C-1 or C-4, in β of methoxy)

132.93 (IC, C-10)

126.80 (IC, C-8)

124.92 (IC, C-9)

118.28 (IC, C-ll) 116.78 (IC, C-2 or C-3, in α of methoxy) 109.18 (IC, C-lou C-4 in α of OCH ₃ ) 55.99 (IC, 0-ÇH ₃ ) IR (KBr): v (cm ¹ )

1646 (C = 0), 1596 (C-Car) Most polar product (not separated from the least polar product)

Rf: 0.62 (CH ₂ Cl ₂ / MeOH, 95/5)

HPLC: Nucleosil 100-5C18 column, i.d. = 4.6 mm, 1 = 250 mm, Eluent: Methanol / Water, 75/25, flow rate: 1 ml / min, TR = 26.3 min

MS (APd ^* ): m / z 313-315 (M + H0 ^X H NMR (CDC1 ₃ , 270 MHz): δ (ppm) 9.32 (d, IH, H-8, J _H8 - _H10 = 2 .07 Hz)

8.07 (d, IH, Hl or H-4, in β of methoxy, J _H1 - _H2 or J _H3 - _H4 = 8.30 Hz)

7.71 (d, IH, H-ll, J _H10 - _H11 = 9.55 Hz) 7.63 (m, IH, Hl or H-4, in α of methoxy) 7.57 (dd, IH, H -10, J _H8 - _H10 = 2.08 Hz, J _H10 - _H11 = 9.55 Hz) 7.21 (dd, IH, H-2 or H-3, in methoxy α, J _H1 - _H2 or J _H3 - _H , = 8.31 Hz, J _a - _M or J _H1 - _H3 = 2.50 Hz)

3.93 (s, 3H, OCH ..)

"C NMR (CDC1 ₃ , 67.5 MHz): δ (ppm) 180.11 (IC, C-5 or C-6) 167.31 (IC, C-6a) 162.23 (IC, C- 2 or C-3, methoxy carrier) 155.16 (IC, C-12a) 148.19 (IC, C-11a) 133.67 (IC, C-4a or C-12b) 133.10 (IC, C-10) 127.10 (IC, C-lou C-4, in β of methoxy) 126.99 (IC, C-8) 124.90 (IC, C-9)

122.04 (IC, C-2 or C-3, in α of methoxy) 118.27 (IC, Cl or C-4, in α of methoxy) 114.65 (IC, C-ll) 56.11 (IC, 0-ÇH ₃ )

Example 12

9-chloro-5, 6-dihvdro-5, 6-dioxo-l-hvdroxynapht- fl '.2' 14, 5 imidazori .2-a] pyridine or

9-chloro-5.6-dihvdro-5, 6-dioxo-4-hydroxynapht- [1 ', 2'; 4.5] imidazo [l, 2-a] pyridine

To a solution of 200 mg (0.64 mmol, 1 eq) of 5,6-dihydro-5,6-dioxo-1-methoxy-napht [1 ', 2': 4, 5] imidazo [1, 2- a] pyridine or 5, 6-dihydro-5, 6-dioxo-4-methoxy-napht- [l ', 2': 4, 5] imidazo [1, 2-a] pyridine in 120 ml of chloroform is added to ambient temperature 427 mg (3.2 mmol, 5 eq) of aluminum chloride. After 15 hours of reflux (76 ° C), and return to room temperature, the reaction medium is poured into 100 ml of ice water. The organic phase is separated and the aqueous phase is reextracted with 200 ml of dichloromethane.

The organic phases after having been combined are washed with 200 ml of water, dried over magnesium sulfate, filtered and evaporated to dryness. 150 mg of red-brown solid are thus obtained which are purified on silica cake (silica: 6-35 μm, 0: 5 cm, h: 10 cm, packaging: CH ₂ Cl ₂ / AcOEt, 1/1; eluent CH ₂ Cl ₂ / AcOEt, 1/1). After washing with water and petroleum ether, 45 mg of 9-chloro-5, 6-dihydro-5, 6-dioxo-1-hydroxy-napht [l ', 2': 4, 5] - imidazo [l, 2-a] pyridine or 9-chloro-5, 6-dihydro-5, 6-dioxo-4-hydroxy-napht [l ', 2': 4, 5] imidazo [l, 2-a] pyridine are obtained in the form of red orange crystals. Yid: 23% F:> 260 ° C

Rf: 0.18 (CH ₂ Cl ₂ / MeOH, 20/80) SM (APcI ⁺ ): m / z 298/300 (M + Hj ^X H NMR (270 MHz, CDC1 ₃ ): δ (ppm) 10 , 64 (s, IH, OH in 1 or 4) 9.37 (d, IH, H-8, J _H8 - _H10 = 1.83 Hz)

7.77 (d, IH, H-ll, J _H10 - _H11 = 9.46 Hz)

7.73 (dd, IH, Hl or H-4, J ,, .- ^ _or „_„ _, = 7.63 Hz, J _H1 - _{H3 or} “-.- _“ = 0.91 Hz) 7, 67 (dd, IH, H-10, J _Hl0 - _κll = 9.46 Hz, J _H8 - _H10 = 1.83 Hz)

7.43 (t, IH, H-2 or H-3 in β of OH, J _H1 - _{H2 or H3} _ _H4 #J _H2 - _H3 = 7.63 Hz)

7.27 (dd, IH, H-3 or H-2 in α of OH, J ^ -,., = 7.63 Hz,

^J H1 ~ H3 OR H2-H4 = ° ^{'91 Hz} ) IR (KBr): V (cm ^"1 )

1633 (C = 0), 1584 (C-Car)

Example 13

5, 6-dihydro-5, 6-dioxo-10-methoxynapht [1 ', 2'; 4,51 imidazo [1,2-alpyridine

5.58 g of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (24.60 mmol; 1.0 eq) and 3.66 g of 2-amino-4-methoxypyridine (29 , 50 mmol; 1.2 eq) are dissolved in 250 ml of ethanol. After 48 hours of reflux, the reaction mixture is filtered through sintered glass and purified on a flash column (support: silica 6-35 μm, eluent: Dichloromethane / Methanol, 100/0 to 90/10) to provide after evaporation of the solvents 0, 98 g of 5,6-dihydro-5,6-dioxo-10-methoxy-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form of red crystals.

YId: 14.3%

F:> 260 ° C

Rf: 0.66 (Dichloromethane / Methanol, 90/10) SM (APCI +): m / z 279 (M + Hj

"H NMR (CD ₂ Cl _a , 270 MHz): δ (ppm)

9.06 (d, IH, H-8, J _H8.H9 = 7.32 Hz)

8.12 (dd, IH, Hl, J _Λ1B = 7.63 Hz; J _M = 1.22 Hz)

8.06 (dd, IH, H-4, J _M _ _m = 7.63 Hz; J _H4.K = 1.53 Hz) 7.69 (dt, IH, H-2, J ^ ≈ J _H2 . _H1 = 7.63 Hz, J _n _ _m = 1.22 Hz) 7.51 (dt, IH, H-3, J _H3 _ „, = ^. ^ ≈ 7.63 Hz, J _β _ _H1 = 1.53 Hz) 7.14 (d, IH, H-ll, J _H11 . „ ₉ = 2.44 Hz) 6.86 (dd, IH, H-9, J _H9 . _H8 = 7.32 Hz, J _H9.H11 = 2.44 Hz) 3.98 (s, 3H, CH ₃ ) 1R: v (cm ^{* 1} )

1645, 1622 (C = 0)

Example 14

5,6-dihydro-5,6-dioxo-ll-méthoxynapht [l'2 ^# ; 4,51 - imidazo [1.2-alpyridine

2.36 g (10 mmol, 1 eq) of 2, 3-dichloro-l, 4-dihydro-1, 4-dioxo-naphthalene and 1.29 g (10 mmol, 1 eq) of 2-amino-3- methoxypyridine are dissolved in 150 ml of ethanol. After 19 hours of reflux, the reaction mixture is evaporated under vacuum and 3.68 g of a dark red powder are obtained which is purified on cake (support: silica 6-35 μm, h = 22 cm, d = 5 cm; packaging: dichloromethane; eluent: dichloromethane). The second fraction provides 0.70 g of 5.6 dihydro-5,6-dioxo-11-methoxynapht [l'2 ': 4, 5] imidazo [1, 2-a] -pyridine in the form of orange crystals.

Yid: 25%

F:> 300 ° C

Rf: 0.82 (dichloromethane / methanol, 98/2) MS (APCI +): m / z 279 (M + H) ^*

^X H NMR (CDC1 ₃ , 270 MHz): δ (ppm)

8.95 (d, IH, H-8, J _H8 . _H9 = 6.60 Hz)

8.34 (d, IH, Hl, J _H1 . _H2 = 7.80Hz)

8.14 (dd, IH, H4, J _{H3. H4} = 7,80Hz, J _{4. Œ} = 1,20Hz) 7.70 (dt, IH, H-2, J ^ J ^ ≈ ≈ 7, 80 Hz, J ^ ≈ 1.20Hz)

7.52 (dt, IH, H-3, J ^ ≈ J, _m = 7.80 Hz, J ^ ≈ 1.20Hz)

7.13 (dd, IH, H-9, J _H9 _ _H8 ≈ 6.60 Hz, J _H9 . _H10 = 7.80 Hz) 6.98 (d, IH, H-10, J _H10 . _H9 = 7.80Hz )

13 NMR d "C (CDC1 ,, 67.5 MHz): δ (ppm) 182.37 (IC, C-5)

168.21 (IC, C-6a)

153.34 (IC, C-12a)

149.67 (IC, C-ll) 144.38 (IC, C-lla)

135.73 (IC, C-2)

131.91, 131.08 (2C, C-4a, C-12b)

130.98 (IC, C-3)

130.53 (IC, C-4) 125.35 (IC, C-1)

121.90 (IC, C-8)

117.29 (IC, C-9)

109.10 (IC, C-10)

56.49 (IC, OCH3) IR (KBr): v (cm ^"1 ):

1646 (C = 0)

Example 15

5, 6-dihydro-5, 6-dioxo-10-hydroxynapht [1 '2'; 4, 51 - imidazo [1, 2-al -pyridine

After prior assembly in argon, a mixture containing 2.49 g (18.7 mmol, 10 eq) of aluminum chloride, 0.52 g (1.87 mmol, 1 eq) of 5 is heated to reflux. , 6 dihydro-5, 6-dioxo-10-methoxynapht- [l'2 ': 4, 5] imidazo [1,2-a] pyridine in 150 ml of anhydrous chloroform. After 2 hours and 45 minutes of reflux, the mixture is allowed to cool and then the reaction medium is poured into 400 ml of ice-cold distilled water. The aqueous phase is extracted with 2 times 250 ml of dichloromethane. A precipitate appears in the aqueous phase. This is filtered on a frit and dried under vacuum. 482 mg of a red powder of 5.6 dihydro-5,6-dioxo-10-hydroxynapht [1 '2': 4, 5] - imidazo [1, 2-a] -pyridine are obtained. Yid: 97.6% F:> 260 ° C Rf: 0.52 (dichloromethane / methanol, proportion 90/10)

SM (APcI +): m / z 265 (M + H) ⁺

^ NMR (DMSO-d _s , 270 MHz): δ (ppm)

11.63 (s, IH, OH)

9.06 (d, IH, H-8, J _H9 _ _H8 = 6.65 Hz)

8.09 (d, IH, Hl, J _H1.E = 7.48 Hz)

8.01 (d, IH, H-4, J _H3.H4 = 7.47 Hz)

7.82 (t, IH, H-2, J _H2.H1 = J _H2.H3 = 7.47 Hz)

7.64 (t, IH, H-3, J _H2.H3 = J _H4.H3 = 7.48 Hz)

7.16 (s, IH, H-ll)

7.05 (d, IH, H-9, J _H8 _ _H9 = 7.05 Hz)

"C NMR (DMSO-d ₆ , 67.5 MHz): δ (ppm)

182.20 (IC, C-5)

165.14 (IC, C-6a)

161.87 (IC, C-10)

153.99 (IC, Cquat)

152.52 (IC, Cquat)

135.01 (IC, C-2)

131.25, 130.92 (2C, Cquat)

130.57 (IC, C-3)

129.87 (IC, C-4)

128.98 (IC, C-8)

124.04 (IC, C-1)

119.86 (IC, Cquat)

110.20 (IC, C-9 or C-ll)

99.79 (IC, C-9 or C-ll)

IR (KBr): v (cm ¹ )

3424 (OH); 1660, 1621 (C = 0)

Example 16

5.6-dihydro-5, 6-dioxo-11-hydroxynapht ['2' 14.51 - imidazo [1,2-alpyridine

After prior assembly in argon, a mixture containing 1.44 g (4.5 mm- , 2.5 eq) of aluminum chloride in 20 ml of anhydrous chloroform. Then adding a solution of 0.5 g (1.80 mmol, 1 eq) of 5,6-dihydro-5,6-dioxo-ll-methoxynapht [l'2 ': 4, 5] imidazo [1, 2 -a] pyridine in 70 ml of anhydrous chloroform. After 3 hours of reflux, the mixture is allowed to cool and then the reaction medium is poured into 500 ml of ice-cold distilled water. The aqueous phase is extracted with 4 liters of dichloromethane. After drying over magnesium sulphate and evaporation under vacuum of the solvent, the residue is purified on a cake (support: silica 6-35 μm, h = 15 cm, d = 5 cm; packaging: dichloromethane; eluent: dichloromethane then CH ₂ Cl ₂ / MeOH 99/1). 192 mg of a red powder of 5,6-dihydro-5,6-dioxo-11-hydroxynaphth- [1'2 ': 4, 5] imidazo [1, 2-a] pyridine are obtained. YId: 40.4%

F:> 260 ° C

Rf: 0.37 (dichloromethane / methanol, proportion 90/10)

MS (APCI +): m / z 265 (M + H) ^* 1 H NMR (DMSO-d ₆ , 270 MHz): δ (ppm)

11.23 (s, IH, OH)

8.75 (d, IH, H-8, J _H8.H9 = 5.40Hz)

8.12 (d, IH, Hl, J _M = 7.48Hz)

7.97 (d, IH, H-4, J _H3 . _H4 = 7.89Hz) 7.78 (dd, IH, H-2, J ^ ≈ 7.48 Hz, J _tt2 _ _m = 7.05 Hz )

7.58 (dd, IH, H-3, J _H2 . _Ω = 7.06 Hz; J _H4 . _H3 = 7.48 Hz)

7.21 (dd, IH, H-9, J _H9 . _H8 = 6.23 Hz, J _H9 . _H10 = 6.65 Hz)

7.07 (d, IH, H-10, J _H10 . _H9 = 7.89 Hz)

¹³ C NMR (DMF-d ,, 67.5 MHz): δ (ppm) 181.45 (IC, C-5)

166.78 (IC, C-6a)

151.16 (IC, C-12a)

147.48 (IC, C-ll)

143.57 (IC, C-lla) 134.71 (IC, C-2) 131.48, 130.69 (2C, C-4a, C-12b) 129.97 (CI, C-3)

128.68 (IC, C-4)

123.69 (IC, Cl) 119.55 (IC, C-8) 117.77 (IC, C-9) 113.40 (IC, C-10) IR (KBr): v (cm ¹ ) 3443 (OH) ; 1639 (C≈O)

Example 17

5.6-dihydro-5.6-dioxo-ll-nitronapht [1 '.2'; 4,51 imidazo- [1,2-al -pyridine

6.12 is added to a suspension of 5 g (22 mmol; 1.0 eq) of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in 150 ml of 2-methoxy-1-ethanol g (44 mmol, 2 eq) of 2-amino-3-nitropyridine. The reaction mixture is brought to reflux of the solvent for 72 hours and then brought to room temperature. The beige-orange precipitate formed is filtered and washed thoroughly with ethanol and then with heptane. The solid obtained is purified by flash chromatography on a column of silica gel (support: silica 6-35 μm; 0 8.5 cm; h 35 cm; eluent: dichloromethane / ethyl acetate, 95/5, then 50/50 after 5 1 of elution). 4.38 g of 5,6-dihydro-5,6-dioxo-11-nitronapht [1 ', 2': 4, 5] imidazo [1,2-a] -pyridine are obtained in the form of orange-red crystals . Yield: 68% F:> 260 ° C Rf: 0.63 (dichloromethane / ethyl acetate, 80/20) MS (JVPcI-): m / z 293 (M-) "H NMR (CD _a Cl _a , 270 MHz): δ (ppm) 9.51 (dd, IH, H-8, J _H8 _ _H9 » ⁶ , 55Hz, J _H8 . _H10 = 1, 22Hz) 8.46 (dd, IH, H-10 , J _{M. HM} = 7, 94Hz, J _M ^ _αo = 1.22Hz) 8.29 (dd, IH, Hl, J _H1 . _Ffi = 7, 63Hz, _{Λ → B} = 1, 22Hz) 8.09 (dd, IH, H-4, J _ω . _H4 = 7, 63Hz, J _B ^ = l, 22Hz) 7.74 (td, IH, H-2, J _M = J _HMD = 7.63Hz , J _{H2 ^ l4} = 1.22Hz) 7.56 (td, IH, H-3, J _M ^ = J _H , ^ = 7.63Hz, J _H1 . _Ω = l, 22Hz) 7.30 (dd, IH, H-9, J _H9 . „ ₁₀ = 7.94Hz, J _H8 . _H9 >> 6.55Hz) IR (KBr): v (cm ¹ )

1657 (C = 0), 1643 (C = 0), 1595 (C = N), 1519 (NOJ, 1296 (C-N0 ₂ ), 1269 (C-N0 ₂ )

Example 18 l-amino-5, 6-dihvdro-5, 6-dioxonapht [l ', 2'; 4.51- imidazo [1.2-al -pyridine

To a suspension of 1.2 g (4.09 mmol; 1.0 eq) of 5, 6-dihydro-5, 6-dioxo-ll-nitronapht [1 ', 2': 4, 5] imidazo [1, 2- a] pyridine in 60 ml of absolute ethanol, 24 mg (2% m / m) of palladium on carbon (10% Pd) are added. The assembly is placed under a hydrogen atmosphere and the suspension is stirred at room temperature for 2 hours 45 minutes. The assembly is then purged with argon and the purple suspension obtained is filtered through celite. The solid is washed with 3 l of hot ethanol and then with 50 ml of dimethylformamide. The filtrate is concentrated under reduced pressure. 1.077 g of a purple compound is obtained which is purified by two successive flash chromatographies on a column of silica gel (support: silica 6-35 μm; 0 5 cm; h 25 cm; eluent: dichloromethane / ethyl acetate, 90 / 10 then 50/50), then by passing over silica gel cake (support: silica 6-35 μm; 0 5 cm; h 20 cm; eluent: dichloromethane / ethyl acetate, 90/10 then 80/20 ), to provide 0.435 g of ll-amino-5, 6-dihydro-5, 6-dioxonapht [1 ', 2': 4, 5] -imidazo [1, 2-a] pyridine in the form of purple crystals. Yield: 100% F:> 260 ° C

Rf: 0.45 (dichloromethane / ethyl acetate, 80/20) MS (APC1 +): m / z 264 (M + H) ⁺ SM (APcX-): m / z 263 (M) ^"

"H NMR (DMSO-d ,, 270 MHz): δ (ppm)

8.51 (d, IH, H-8, J _H8 . _H9 = 7.63Hz)

8.11 (d, IH, Hl, .1, ^ = 7.63 ^) 7.97 (d, IH, H-4, J _ω.H4 = 7, 63Hz)

7.78 (t, IH, H-2, J _H1.H2 = J _H2.H3 = 7.63Hz) 7.13 (t, IH, H-9, J _H9.H10 = J _H8 . _H9 = 7.63Hz) 6.81 (d, IH, H-10, J _H9.H10 = 7, 63Hz) 6.24 (s, 2H, NHJ

1R (KBr): v (cm ^"1 )

3480 (NH ₂ ), 3335 (NH ₂ ), 1683 (C = 0), 1648 (C = 0), 1603 (C = N)

Example 19

5, 6-dihydro-ll-dimethylamino-5, 6-dioxonapht- [l ^f .2 '; 4.51 imidazo- [1,2-alpyridine

To a suspension of 1.0 g (3.4 mmol; 1.0 eq) of 5, 6-dihydro-5, 6-dioxo-ll-nitronapht [1 ', 2': 4, 5] imidazo [1, 2- a] pyridine in 60 ml of absolute ethanol, 0.1 g is added

(10% m / m) of palladium on carbon (10% Pd). The assembly is placed under a hydrogen atmosphere then the suspension is stirred at room temperature for 3, 5 hours. The assembly is then purged with argon and the purple solution obtained is cooled to 0 ° C. One successively adds: 1.3 ml of formaldehyde (37% solution in water; 17.0 mmol; 5.0 eq), 0.4 ml of glacial acetic acid (6.8 mmol; 2.0 eq ) and 1.28 g of sodium cyanoborohydride (20.5 mmol; 6.0 eq). After 15 minutes of stirring at 0 ° C, the solution is brought to room temperature and then filtered through celite. The solid is washed with 200 ml of ethanol. The filtrate is concentrated under reduced pressure and the green paste obtained is taken up in 200 ml of dichloromethane and 200 ml of water. After 30 minutes of vigorous stirring and then separation of the phases, the organic phase is washed with 3x200 ml of water. The combined aqueous phases are extracted with 5 × 50 ml of dichloromethane. The combined organic phases are then concentrated under reduced pressure. The purple solid obtained is purified by passage over a silica gel cake (support: silica 6-35 μm; 0 5 cm; h 22 cm; eluent: dichloromethane / ethyl acetate, 98/2). 400 mg of 5,6-dihydro-11-dimethylamino-5,6-dioxo-naphth [l ', 2': 4, 5] -imidazo [1, 2-a] pyridine are obtained in the form of purple crystals. Yid: 40%

F:> 260 ° C

Rf: 0.6 (dichloromethane / ethyl acetate, 90/10)

SM (APCI +): m / z 292 (M + H) ^*

"H NMR (CD _a Cl _a , 270 MHz): δ (ppm) 8.73 (dd, IH, H-8, J _H8 . _H9 = 6, 41Hz, J _H8 . _H10 = 0.92Hz)

8.13 (ddd, IH, Hl, J _H1 . „ ₂ = 7, 63Hz, J _H1 . _Ω = l, 22Hz, J _H1 . _H4 = 0.61Hz)

8.00 (ddd, IH, H-4, J ^. ^ 7, 63Hz, J ^. ^ L, 22Hz, J _H1 . _H4 = 0.61Hz) 7.63 (td, IH, H-2, J _H1 . _H2 = J „_. _H3 = 7, 63Hz, J ^ ≈l, 22Hz)

7.43 (td, IH, H-3, J _H2 . _H3 = J „ _3. „ ₄ =, 63Hz, J ^ ≈l, 22Hz)

7.00 (dd, IH, H-9, J _H9 . _H10 = 7.93Hz, J _H8 . _H9 = 6.41Hz)

6.66 (dd, IH, H-10, J _H9 . _H10 = 7.93Hz, J _H8 . _H10 = 0.92Hz)

3.25 (s, 6H, 2xCH ₃ ) ¹³ C NMR (CD _a Cl _a , 67.5 MHz): δ (ppm)

135.5 (IC, C-2)

130. 6 (IC, C-3) 129, 9 (IC, C-4)

124. 8 (IC, C-1) 119.6 (IC, C-8 or C-9 or C-10) 118.2 (IC, C-8 or C-9 or C-10)

112.9 (IC, C-8 or C-9 or C-10) 42.4 (2C, CH ₃ ),

IR (KBr): v (cm ¹ ) 1686 (C = 0), 1645 (C = 0), 1629 (C = N) Example 20

9-amino-5,6-dihvdro-5,6-dioxo-napht [l, 2 ^# ; 4,51- imidazo [1,2-alpyridine A suspension formed of 200 mg (0.68 mmol, 1 eq) of 5,6-dihydro-5,6-dioxo-9-nitro-napht [l ', 2': 4, 5] - imidazo [1, 2-a] -pyridine and 250 ml of ethanol, we add in a catalytic amount of palladium on carbon at 30% then 5 times 16 μl (1.65 mmol, 2.42 eq) of hydrazine monohydrate. After 1 hour of stirring at 25 ° C, the reaction medium is filtered through celite to provide, after passage over a micropore filter, 50 mg of 9-amino-5,6-dihydro-5,6-dioxo-naphth [1 ', 2 '-.4,5] imidazo [1, 2-a] -pyridine in the form of dark purple crystals. Yid: 28%

F:> 260 ° C

Rf: 0.60 (Dichloroethane / Methanol, 90/10) MS (APcI +): m / z 264 (M + H0 ^X H NMR (DMSO-d _β , 270 MHz): δ (ppm) 8.67 ( d, IH, H-8, J _H8 . _H10 = 1.9Hz)

8.02 (d, IH, Hl, J _H1.H2 = 7.4Hz) 7.93 (d, IH, H-4, J _H3.H4 = 7.6Hz) 7.72 (dd, IH, H- 2, J _H1 . _H2 = J _H2.H3 = 7.4Hz) 7.67 (d, IH, H-ll, J _H10 . _H11 = 9.3Hz) 7.51 (dd, IH, H-3, J ^ ≈ J _M.Ht = 7.4Hz)

7.27 (dd, IH, H-10, J _H10.HU = 9.3Hz; J _H8.H10 = 1.9Hz)

5.77 (s, 2H, NH ₂ )

"C NMR (DMSO-d ~ _β 6, 67.5 MHz): δ (ppm)

182.0 (CI, C-5) 150.6 (CI, C-12a)

144.8 (IC, C-lla)

141.2 (IC, C-9)

134.8 (IC, C-2)

131.8 (IC, C-12b) 130.8 (IC, C-4a) 130.0 (IC, C-3)

128.8 (IC, C-4)

124.8 (IC, C-10)

123.4 (IC, C-l) 117.6 (IC, C-ll)

110.0 (IC, C-8)

IR (KBr): v (cm ¹ )

3385, 3323 (NH ₂ ); 1652, 1631 (C = 0)

Example 21

5,6-dihydro-9-di éthy1amino-5,6- dioxonapht [! ' .2 '; 4, 51 -imidazo [1,2-alpyridine

To a suspension of 1.0 g (3.4 mmol; 1.0 eq) of 5, 6-dihydro-5, 6-dioxo-9-nitronapht [1 ', 2': 4, 5] imidazo [1, 2- a] pyridine in 60 ml of absolute ethanol, 0.1 g (10% m / m) of palladium on carbon (10% Pd) is added. The assembly is placed under a hydrogen atmosphere then the suspension is stirred at room temperature for 3.5 hours. The assembly is then purged with argon and the purple solution obtained is cooled to 0 ° C. The following are added successively: 0.76 ml of formaldehyde (37% solution in water; 10.2 mmol; 3.0 eq), 0.4 ml of glacial acetic acid (6.8 mmol; 2.0 eq ) and 0.64 g of sodium cyanoborohydride (10.2 mmol; 3.0 eq). After 30 minutes of stirring at 0 ° C, the suspension is brought to room temperature and then filtered through celite. The solid is washed with 300 ml of ethanol. The filtrate is concentrated under reduced pressure and the green paste obtained is taken up in 200 ml of dichloromethane and 200 ml of water. After 10 minutes of vigorous stirring followed by separation of the phases, the organic phase is washed with 2 × 100 ml of water. The combined aqueous phases are extracted with 3 × 100 ml of dichloromethane. The combined organic phases are then concentrated under reduced pressure. The purple solid obtained is purified by passing over a silica gel cake (support: silica 6 35 μm; 0 5 cm; h 24 cm; eluent: dichloromethane / ethyl acetate, 90/10 then 80/20). 640 mg of 5,6-dihydro-9-dimethylamino-5,6-dioxonaphth [1 ', 2': 4.5] imidazo [1,2-a] pyridine are obtained in the form of purple-black crystals.

Yid: 64% F:> 260 ° C

Rf: 0.25 (dichloromethane / ethyl acetate, 80/20) SM (APCI +): m / z 292 (M + H) ^* SM (APσl-): m / z 291 (M) ^"

"H NMR (CD _a Cl _a , 270 MHz): δ (ppm) 8.51 (d, IH, H-8, J _H8.H10 = 2.45Hz) 8.01 (dd, IH, Hl, J _H1.H2 = 7.63Hz, J _H1.m = 1.22Hz) 7.95 (dd, IH, H-4, J ^ _. ^ 7, 63Hz, J _œ . _H4 = 1.22Hz) 7.57 ( td, IH, H-2, J _H1.H2 = J _K2.H3 = 7, 63Hz, ^ _. ^ l, 22Hz)

7.54 (dd, IH, H-ll, J _H10 . _H11 = 9, 77Hz, J _H8.H11 = 0.61Hz) 7.38 (td, IH, H-3, J _H2.H3 = J _{κ3. H4} = 7.63Hz, J ^ _. ^ L, 22Hz) 7.24 (dd, IH, H-10, J _{H10 „HU} = 9, 77Hz, J _H8.H10 = 2.45Hz) 2.95 (s, 6H, 2xCHJ ¹³ C NMR (CD ₂ Cl _a , 67.5 MHz): δ (ppm)

183.3 (IC, C-5) 167.0 (IC, C-6a) 152.6 (1C, C-12a) 145.4 (1C, C-lla or C-9) 143, 5 (IC, C- lla or C-9)

135.4 (IC, C-2)

132.7 (CI, C-4a or C-12b)

131.3 (CI, C-4a or C-12b)

130.4 (CI, C-3) 129.8 (CI, C-4)

124.4 (IC, C-1)

122.8 (1C, C-10)

118.0 (IC, C-ll)

110.8 (IC, C-8) 41.0 (2C, CH ₃ ), IR (KBr): v (cm ¹ )

1644 (C = 0), 1631 (C = 0), 1595 (C≈N)

Example 22 5, 6-dihydro-5, 6-dioxo-10-methylthionapht [1 '.2': 4, 51 imidazo [1, 2-al pyridine

To a suspension of 0.30 g (1.3 mmol; 1 eq) of 2, 3-dichloro-1,4-dioxo-naphthalene in 25 ml of 2-ethoxyethanol, 0.20 g (1.42 mmol) is added ; 1.1 eq) of 2-amino-4-methylthiopyridine. After 24 hours of reflux the mixture is cooled and the precipitate formed is filtered and dried. Recrystallization from 1,2-dichlorobenzene provides 0.27 g of 5,6-dihyro-5,6-dioxo-10-methylthionapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form of orange-red crystals. Yid: 64% F:> 260 ° C

Rf: 0.4 (Dichloroethane / Methanol, 98/2) SM (APcI +): m / z 295 (M + H) ^* "H NMR (CDCl ₃ / CF ₃ COOD, 270 MHz): δ (ppm)

9.23 (d, IH, H-8, J _H8 . _H9 = 7.63Hz)) 8.39 (d, IH, Hl, J _H1 . _H2 = 7.33Hz) 8.16 (d, IH, H -4, J _H3 . _H4 = 8.24 Hz) 7.97 (m, IH, H-2) 7.87 (m, IH, H-3) 7.77 (s, IH, H-ll) 7, 58 (d, IH, H-9, J _H8 . _H9 = 6.72Hz) 2.75 (s, 3H, CHJ

"C NMR (CDCl ₃ / CF ₃ COOD, 67.5 MHz): δ (ppm) 179.8 (IC, C-5)

168.69 (IC, C-6a) 160.22 (IC, Cquat) 142.5 (IC, C-10) 137.7 (IC C-2) 134.81 (IC C-3) 132.75 (CI, C-4) 131.9 (CI, C-4a or C-12b) 128.06 (CI, Cl) 126.54 (CI, C-8) 124.00 (CI, Cquat)

119.96 (IC, C-9 or C-ll) 104.91 (IC, C-9 or C-ll) 14.27 (IC, CH ₃ ) IR (KBr): v (cm ^"1 ) 1688, 1642 (C = 0)

Example 23

5, 6-Dihydro-5, 6-dioxo-9-methylthionapht [l ', 2'; 4,51- imidazo [1, 2-alpyridine A suspension of 3.2 g (14.0 mmol; 1 eq) of 2,3-dichloro-1,4-dioxo-naphthalene in 60 ml of 2-ethoxyethanol, 2.35 g (16.78 mmol; 1.2 eq) of 2-amino-5-methylthiopyridine are added. After 24 hours of reflux the reaction mixture is cooled and the precipitate formed is filtered and dried. Double recrystallization from ethanol provides 2.56 g of 5,6-dihyro-5,6-dioxo-9-methylthionapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form of dark red crystals. Yid: 52% F: 245 ° C

Rf: 0.33 (Dichloromethane / Methanol, 98/2) SM (APCI +): m / z 295 (M + H) ^{* X} H NMR (CDCl ₃ / CF ₃ COOD, 270 MHz): δ (ppm) 9 , 20 (s, IH, H-8) 8.35 (d, IH, Hl, J ^ = 7.32Hz) 8.15 (d, IH, H-4, J _H4 . _M = 7.63Hz) 8 , 12 (m, 2H, H-10 and H-ll) 7.96 (dd, IH, H-2, ^^ = J ^ = 7.63Hz) 7.85 (dd, IH, H-3, J _H2 . _H3 = J _u H, 3_-H4 = 7.63 Hz) 2.64 (s, 3H, CH ₃ ) 1R (KBr): V (cm ¹ )

1646 (C = 0)

Example 24 9. ll-dichloro-5, 6-dihydro-5, 6-dioxo-napht- [! ' .2 '; 4,51 imidazo [1,2-alpyridine

To a solution formed of 4.55 g (20.04 mmol, 1 eq) of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in 100 ml of ethanol, 3.92 g ( 24.05 mmol, 1.2 eq) of 2-amino-3,5-dichloropyridine. This mixture is brought to reflux for 24 hours. After complete cooling, the reaction medium is evaporated to dryness. A brown solid is obtained which is purified on a flash column (support: silica; eluent: dichloromethane / ethyl acetate, 100/0 to 99/1). The solid obtained is redissolved in dichloromethane and washed successively with a 10% hydrochloric acid solution and then with distilled water. The organic phase is then treated with animal black and then passed through a micropore filter to provide, after evaporation of the solvents, 0.46 g of 9, ll-dichloro-5, 6-dihydro-5, 6-dioxo-napht [1 ', 2' : 4, 5] imidazo [1, 2-a] pyridine in the form of yellow crystals. Yield: 7% F:> 260 ° C Rf: 0.37 (CH ₂ Cl ₂ / AcOEt, 98/2)

SM (IE): m / z 316/318/320 (M ⁺ J, 288/290/292 (M-CO)

1

9.29 (d, IH, H-8, J _H8 . _H10 = l, 20Hz)

8.30 (dd, IH, Hl, J _H1.K = 7.63Hz, J _H1 . _H3 = 1.22Hz)

8.16 (dd, IH, H-4, J _H3 . _H4 = 7.63Hz, J, ^ = l, 22Hz)

7.73 (ddd, IH, H-2 or H-3, J ^ = J ^ = 7.63Hz, ^ Hï-Hl

1.22Hz)

7.69 (d, IH, H-10, J _H8.H10 = 1.83Hz)

7.56 (ddd, IH, H-2 or H-3, J ^ _. ^ = J _H3 . _H4 = 7.63Hz, J _H1.H3 1.22Hz) R, M, N, du "c (CD ₂ C1 ₂ , 67.5 MHz): δ (ppm)

136.01 (IC, C-2) 132.10 (IC, C-10) 131.58 (IC, C-3) 131.37 (IC, C-12b) 131.19 (IC, C-4a) 130.52 (IC, C-4) 125.82 (IC, C-8) 125.46 (IC, Cl) 124.93 (IC, C-9) 124.42 (IC, C-ll) IR ( KBr): v (cm) 1652, 1636 (C = 0)

Example 25

9, ll-dibromo-5,6-dihydro-5,6-dioxo-napht [1 ', 2'; 4,5 - imidazo [1, 2-alpyridine

In a three-necked flask containing 2.27 g (10 mmol, 1 eq) of 2, 3-dichloro-l, 4-dihydro-l, 4-dioxo-naphthalene and 5.00 g (19.8 mmol, 2 eq) of 2-amino-3, 5-dibromopyridine, 50 ml of 2-ethoxyethanol are added. After 48 hours of reflux, the solvent is evaporated under reduced pressure and the brown solid residue obtained is purified on a flash column (support: silica; packaging: heptane; eluent: dichloromethane) to provide 1.83 g of 9, ll-dibromo- 5, 6- dihydro-5, 6-dioxo-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form of orange crystals. Yield: 45% F:> 260 ° C Rf: 0.59 (CH ₂ Cl ₂ / MeOH, 99/1)

S, M, (APel ^* ): m / z 405-407-409 (M + H) ⁺ "H NMR (CDC1 ₃ , 270 MHz): δ (ppm) 9.40 (d, IH, H-8 , J _H8 - _Kl0 = 1.52 Hz)

8.28 (dd, IH, Hl, J „ _rv2 = 7.63 Hz, J ^ - ^ = 1.22 Hz) 8.14 (dd, IH, H-4, J _ω.H.4 = 7, 63 Hz, J ,,, - ,,, = 1.22 Hz) 7.95 (d, IH, H-10, J _H8 - _H10 = 1.52 Hz)

7.71 (dt, IH, H-2, ^ - _H , = J _H2 - _H3 = 7.63 Hz, J _H2.H4 = 1.22 Hz)

7.55 (dt, IH, H-3, J _H1 - _H2 = ^ "" ₃ = ^{7 '63 Hz} ' J -m = 1.22 Hz)

IR (KBr) tvtcm ^{* 1} ) 1653, 1646 (C = 0)

Example 26: 5.6-Dihydro-5.6-dioxo-9-methoxynaphth [1 '.2': 4.51 imidazo [1,2-alpyridine

A yellow suspension containing 3.96 g (17.42 mmol) of 2, 3-dichloro-1,4-naphthoquinone and 2.16 g (17.42 mmol) of 2-amino-5 is brought to reflux for 24 hours. - methoxypyridine in 150 ml of absolute ethanol. After the reaction medium has cooled, the mixture is filtered on a frit and then the rust precipitate obtained (2.92 g) is dried under vacuum. This is purified by cake (support: silica 6-35 mm, h = 15 cm, d = 5 cm; packaging: dichloromethane; eluent: dichloromethane / methanol, 100/0 to 99/1). , 50 g of an orange powder of 5,6-dihydro-5,6-dioxo-9-methoxynaphth [l ', 2': 4, 5] imidazo [1, 2- a] pyridine.

Yid: 31% F:> 260 ° C

Rf: 0.45 (dichloromethane / ethanol, 98/2) MS (APCI ^*) I m / z 279 (M + H) ⁺ NMR ^X H (CDC1 _3): δ (ppm) 8.23 (s, IH, H -8) 8.07 (d, IH, Hl, J _Hl _ _M = 7.48 Hz) 8.04 (d, IH, H-4, J _H4 . _H3 = 7.89 Hz) 7.60 (m, 2H, H-2 and H-ll) 7.41 (m, IH, H-3)

7.29 (dd, IH, H-10, J _H10 . _H11 = 9.55 Hz, J _H10 . _H8 = 2.49 Hz) 3.88 (s, 3H, OCH ₃ ) IR (KBr): v (cm ¹ )

1645 (C = 0)

Examples 27 and 28: 9-chloro-5, 6-dihvdro-5, 6-dioxo-2-hvdroxy- napht [l ', 2' 14, 5limidazo [l, 2-a] pyridine or

9-chloro-5, 6-dihydro-5.6-dioxo-3-hydroxy-naphth [l ', 2' 14, 5 ^" | imidazo [l, 2-a] pyridine Synthesis intermediate: 6-acetoxy-2, 3 -dibromo-1,4-naphtoσuinone:

A solution of 12.00 g of 6-acetoxy-1,4-naphthoquinone, 18.40 g of sodium acetate (224 mmol, 4 eq) and 20 ml of bromine (392 mmol) is brought to reflux for 7 hours. , 7 eq) in 200 ml of chloroform. After returning to ambient temperature, the reaction medium is filtered through glass wool and the filtrate is evaporated under reduced pressure. The solid obtained is taken up with dichloromethane then washed with water until neutral, dried over magnesium sulfate and evaporated under reduced pressure. The crude reaction product is purified by three successive precipitations in a CH ₂ Cl ₂ / heptane mixture and 12.00 g of 6-acetoxy-2,3-dibromo-1,4-naphthoquinone are obtained in the form of yellow-colored crystals. Mp: 186 ° C yield: 58%

Rf: 0.68 (CH ₂ Cl ₂ / heptane, 90/10) SM (APcI ^' ): m / z 371-373-375 (MH ^~ ) ^X H NMR (CDC1 ₃ ): δ (ppm) 8, 23 (d, IH, H-8, J ^ _. ^ = 8.72Hz) 7.90 (d, IH, H-5, J ,, ^ = 2.08Hz)

7.52 (dd, IH, H-7, J, „. _H8 = 8.30Hz, J _H5 _ _H , = 2.08Hz) 2.37 (s, 3H, CH ₃ )" C NMR (DMSO) : δ (ppm) 175.31 and 175.07 (2C, Cl and C-4) 168.75 (CI, C = 0 acetate) 154, 79 (IC, C-6)

142.03 and 141.72 (2C, C-4a and C-8a)

132.41 and 128.32 (2C, C-2 and C-3)

129.55 and 127.81 (2C, C-7 and C-8) 120.64 (CI, C-5)

20.98 (IC, CH ₃ )

IR (KBr): vtcm ^"1 )

1763 (C = 0); 1673 (C = 0)

2-acetoxy-9-chloro-5, 6-dihydro-5, 6-dioxonapht [l ', 2'; 4, 5 imidazo [1,2-alpyridine and

3-acetoxy-9-chloro-5,6-dihydro-5, 6-dioxonapht [', 2': 4, 51 imidazo [1, 2-alpyridine

A solution of 5.80 g of 6-acetoxy-2,3-dibromo-1,4-naphthoquinone (16 mmol, leq), 3.90 g of 2-amino-5-chloropyridine (31 mmol, 2 eq) and 2.6 ml of a solution of 6N hydrochloric acid in 300 ml of ethanol is brought to reflux for four hours. After returning to room temperature, stirring is continued overnight. The reaction medium is then filtered. The precipitate is washed with water until neutral and then dried in an oven under vacuum. The filtrate is taken up in dichloromethane, washed with water until neutral, then dried over magnesium sulfate and evaporated under reduced pressure. The filtrate and the precipitate are combined to be purified by column chromatography (support: silica 35-70 mm, diameter = 7 cm, height = 35 cm, packaging: CH ₂ Cl ₂ / heptane, 80/20, eluent: CH ₂ Cl ₂ / ACOET, 95/5). 0.23 g of the least polar isomer and 0.19 g of the most polar isomer are thus separated. Yield: 12% mixture of the 2 isomers

Least polar isomer

Appearance: orange crystals

Mp:> 260 ° C (degradation from 250 ° C)

Rf: 0.46 (AcOEt / CH ₂ Cl ₂ , 10/90) SM (APcI ^" ): m / z 340-342 (M ^" ) MS (APcX ^' ): m / z 341-343 (MH0 NMR ^X H (CD ₂ Cl _a ): δ (ppm)

9.24 (d, IH, H-8, J _H8 . _H10 = 1.24 Hz)

8.05 (d, IH, Hl or H-4 in β of CH ₃ COO, J _H1 . _{H2 or H3} . _H4 =, 72Hz)

7.84 (d, IH, Hl or H-4 in α of CH ₃ COO, J _H1 . _{H3 or H2} . _H4 =, 08Hz)

7.69 (dd, IH, H-ll, J _H10 . _H11 = 9.55)

7.55 (dd, IH, H-10, J _H10 . _H11 = 9, 55Hz, J _H8 . _H10 = 2.08Hz) 7.18 (dd, IH, H-2 or H-3 in α of CH ₃ COO, J _H1 . _{H2 or H3} . _H4 =, 30Hz, J _{M βM} = 2.49 Hz)

2.27 (s, 3H, CH ₃ in 2 or 3.) "C NMR (CDC1J: δ (ppm) 180.40 (IC, C-5 or C-6) 168.42 (IC, C = 0 ester) 156.30 (IC , C-2 or C-3) 153.29 (IC, C-12a) 148.53 (IC, C-lla)

133.27 and 132.31 (2C, C-l or C-4 and C-10) 133.09 and 128.24 (2C, C-4a and C-12b) 126.91 (IC, C-8) 125.18 (IC, C-9)

123.95 (IC, C-2 or C-3 in α from OCOCHJ 118.49 and 118.21 (2C, Cl or C-4 in α from OCOCH ₃ and C- 11)

21.13 (IC, CH ₃ ) IR (KBr): v (cm ^" -)

1756 (C = 0); 1691 (C = 0); 1659 (C = 0) most polar isomer Aspect: orange crystals

Pf:> 260 ° C (degradation from 250 ° C) Rf: 0.36 (Ac0Et / CH ₂ Cl ₂ , 10/90) SM (APcI ^' ): m / z 340-342 (M ^" ) S. . (APcI ^* ): m / z 341-343 (MH0 1 H NMR (CD.Cl.): δ (ppm) 9.35 (d, IH, H-8, J _Hβ . _H10 = 2.08 Hz)

8.20 (d, IH, Hl or H-4 in β of CH ₃ COO, J _H1 . „_ _Or „. „, = 8.30 Hz)

7.86 (d, IH, Hl or H-4 in α of CH ₃ COO, J _m . _M „ _m . _M = 2.08Hz)

7.76 (dd, IH, H-ll, J _H10 . _HU = 9.55Hz, J _H8 . _HU = 0.83Hz)

7.61 (dd, IH, H-10, J _H10 . _H11 = 9.55Hz, J _H8 . _H10 = 2.08Hz)

7.46 (dd, IH, H- 2 or H- 3 in α of CH ₃ COO, J _H1 . _{H2 or H3} . _H4 = 8, 31Hz, J _H1 . _{H3 or H2} . _H4 = 2.49 Hz) 2 , 36 (s, 3H, CH ₃ in 2 or 3.)

IR (KBr): v (cm ^"1 )

1762 (C = 0); 1645 (C = 0)

9-chloro-5, 6-dihvdro-5, 6-dioxo-2-hvdroxy- naphtf1 ', 2'; 4, 5 ^" | imidazo | ^' l, 2-a] pyridine and 9-chloro-5, 6- dihydro-5, 6-dioxo-3-hvdroxy- naphtfl ', 2'; 4, 5] imidazofl, 2-a] pyridine

A solution of 0.160 g of 2-acetoxy-9-chloro-5, 6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine and 3-acetoxy-9-chloro- 5, 6-dioxo-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine (0.46 mmol, 1 eq) and 94 mg (2.3 mmol, 5eq) of hydroxide of sodium in 40 ml of ethanol is heated at 60 ° C for two hours. After returning to ambient temperature, the precipitate formed is filtered through a frit, washed with water until neutral and then washed with dichloromethane. After vacuum heating, recrystallization from ethanol makes it possible to obtain 50 mg of 9-chloro-5, 6-dihydro- 5, 6-dioxo-2-hydroxy-napht [l ', 2': 4, 5] imidazo [1,2-a] pyridine and 9-chloro-5,6-dihydro-5,6-dioxo-3-hydroxy-napht [1 ', 2': 4, 5] imidazo [1,2-a ] pyridine which can be separated.

Yid: 36% the least polar isomer

Appearance: solid orange

Mp:> 260 ° C Rf: 0.32 (CH, Cl, / MeOH, 96/4) MS (APcI ^' ): m / z 297/299 (MH) ^" 1H NMR (CDC1 ₃ + TFA): δ (ppm)

9.58 (s, 1H, H-8)

8.27 (d, IH, H-ll, J _H10 - _H11 = 8.75 Hz)

8.20 (m, 2H, H-1 or H-4 in β of OH and H-10)

7.60 (d, IH, Hl or H-4 in α of OH, J _H1 . _{H3 or H2} . _H4 = 2.24

Hz)

7.22 (dd, IH, H-2 or H-3 in α of OH, J _H1 . _{H3 or m} _ _M = 2.28 Hz) IR (KBr): v (cm ^"1 )

3290 (OH); 1640 (C = 0) most polar isomer

Appearance: solid orange

Mp:> 260 ° C Rf: 0.29 (CH ₂ Cl ₂ / MeOH, 96/4)

SM (APcI ^" ): m / z 297/299 (MH) ^"

1 H NMR (CDC13 + TFA): δ (ppm)

9.52 (s, 1H, H-8)

8.18 (m, 2H, H-10 and H-ll) 8.04 (d, IH, Hl or H-4 in β of OH, J ^ _{or H3} . _H4 = 8.3

Hz)

7.76 (d, IH, H-lou H-4 in α of OH, J ^ _{or H2} . _H4 = 2.5 Hz)

7.35 (dd, IH, H-2 or H-3 in α of OH, J _{B. B or H2} . _H4 = 2.5Hz, J _H1 . _{H2 or H3} . _H4 = 8.3 Hz)

IR (KBr): v (cm-l)

3438 (OH), 1634 and 1690 (C = 0)

Example 29: 10. ll-Dichloro-5, 6-dihvdro-5, 6-dioxonapht [1 ^" , 2 '14, 5 imidazo [1, 2-alpyridine

To a suspension of 0.334 g (1.47 mmol; 1.0 eq) of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in

10 ml of ethanol, 0.240 g (1.47 mmol, 1 eq) of aminodichloropyridine is added (50/50 mixture of 2-amino-3,4- dichloropyridine and 4-amino-2,3-dichloropyridine). The reaction mixture is brought to reflux of the solvent for 22 hours then brought to room temperature, and concentrated under reduced pressure. The orange solid obtained is purified by passing over a silica gel cake (support: silica 6- 35 mm; 0 5 cm; h 20 cm; eluent: dichloromethane / ethyl acetate, 95/5). An orange solid is recovered which is washed 5 times with 15 ml of ethanol to give 20 mg of 10, ll-dichloro-5, 6-dihydro-5, 6-dioxonapht [1 ', 2': 4, 5] imidazo [1,2-a] pyridine in the form of orange crystals.

YId: 8.5%

F:> 260 ° C

Rf: 0.36 (dichloromethane) SM (APcI ⁺ ): m / z 317/319/321 (M + H0

¹ H NMR (CD ₂ C1J: δ (ppm)

9.10 (d, IH, H-8, J _H8.H9 = 7.06Hz)

8.26 (d, IH, Hl, ^ _. ^ = 7.89Hz)

8.11 (d, IH, H-4, J _H3.H4 = 7.89Hz) 7.75 (t, IH, H-2, J _8X.IB = J _1B.lo = 7.89Hz)

7.57 (t, IH, H-3, J _H2.H3 = J _H3.H4 = 7.89Hz)

7.27 (d, IH, H-9, J _H8.H9 = 7.06Hz) IR (KBr): v (cm ^"1 )

1655 (C = 0).

Example 30:

5, 6-Dihydro-5, 6-dioxo-9- hvdroxynaphth [1 ', 2' 14, 51 imidazo [1, 2-a pyridine

After prior assembly in argon, a mixture containing 0.4 g (1.44 mmol) of 5, 6-dihydro-5, 6-dioxo-9-methoxynaphth [l ', 2': 4 is heated to reflux. , 5] imidazo [1, 2-a] pyridine, 1.92 g (14.4 mmol) of aluminum chloride in 60 ml of anhydrous chloroform. The mixture is heated at reflux for 3 hours, then after cooling, the reaction medium is poured into 300 ml of distilled water. icy. We observe the formation of a red precipitate which is filtered on a frit. After washing with acetone and then with ethanol, and drying under vacuum; 0.33 g of 5,6-dihydro-5,6-dioxo-9-hydroxynaphth [l ', 2': 4, 5] imidazo [1,2-a] pyridine is obtained.

YId: 87%

Rf: 0.71 (dichloromethane / methanol 90/10)

SM (APcI +): m / z 265 (M + H) +

^X NMR (DMSO, 80 ° C): δ (ppm) 10.23 (s, IH, OH)

8.81 (d, IH, H-8, J _H8 . _H10 = 1.52Hz)

8.04 (d, H-4, J _H3.H4 = 7, 33Hz)

7.95 (d, H-ll, J _H10 . _H11 = 7.63Hz)

7.79-7.70 (m, 2H, Hl and H-2) 7.95 (d, H-ll, J _H3 . _H4 = 7, 33Hz)

7.41 (dd, H-10, J _H10 . _H11 = 7, 63Hz, J _H8 . _H10 = 2.14Hz)

Example 31:

5, 6-Dihydro-5, 6-dioxo-11- methylthionapht [1 ', 2' 1, 51 imidazo [1,2-alpyridine synthetic intermediate

2-amino -3-methylthiopyridine

A solution of 4 g (17.85 mmol) of 3-methylthio-2-pivaloylaminopyridine and 27 ml (556 mmol) of hydrazine monohydrate in 54 ml of dioxane is brought to reflux for 7 hours. Most of the solvent is then distilled at atmospheric pressure, the rest of the mixture is diluted in 50 ml of water and then extracted with dichloromethane (3x50 ml). The organic phases are combined and then dried with magnesium sulphate, filtered, concentrated and then dried to provide 3.82 g of unpurified 2-amino-3-methylthiopyridine.

Rf: 0.4 (Dichloromethane / Methanol, 98/2) SM (APcI +): m / z 141 (M + H) ⁺ "H NMR (CDC1: δ (ppm) 7.98 (dd, IH, H-6, J _H6 . _H5 = 4.88 Hz, J _H6 . _H4 = 1.52 Hz)) 7.55 (dd, IH, H-4, J _H5 . _H4 = 7.33 Hz, J _H6 . _H4 = 1.52 Hz)

6.64 (dd, IH, H-5, J _H5 . _H4 = 7.33 Hz, J _H6 . _H5 = 4.88 Hz) 2.52 (s, 3H, CH3) 5, 6-Dihydro-5, 6-dioxo-ll-methylthionapht [ 1 ', 2' 14, 5 imidazo [1, 2-alpyridine

To a suspension of 4.56 g (20.1 mmol; leq) of 2,3-dichloro-1,4-naphthoquinone in 150 ml of 2-ethoxyethanol, 3.10 g (22.1 mmol; l, leq) of 2-amino-3-methylthiopyridine. After 18 hours of reflux the mixture is cooled. The solvent is evaporated to dryness and the resulting solid is purified on a cake (support: silica; eluent: dichloromethane / methanol 100/0 to 98/2). The solid obtained after evaporation of the solvent under reduced pressure is recrystallized from 1,2-dichlorobenzene to give 1.30 g of 5,6-dihydro-5,6-dioxo-11-methylthionapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form of red crystals.

Rf: 0.4 (Dichloromethane / Methanol, 98/2) Yield: 22%

MS (APcI +): m / z 295 (M + H) ^* "H NMR (CDCl ₃ / CF ₃ COOD): δ (ppm) 9.24 (d, IH, H-8, J _H8.H9 = 6.71Hz) ) 8.32 (d, IH, Hl, J _H1 _ _H2 ≈7.63 Hz) 8.15 (d, IH, H-4, J _H3 . _H4 = 7.33 Hz)

7.65 (t, IH, H-2, ^ * J ^ = 7.63 Hz) 7.38 (t, IH, H-3, J _H3 . _H4 = 7.63 Hz) 7.03 (d, IH, H-10, J _H9 . _H10 = 7.63 Hz) 6.91 (t, IH, H-9, J _Hβ . _H9 = 7.02 Hz) 2.57 (s, 3H, CH3) IR (KBr): v (cm ^"1 ) 1645 (C = 0), 1624 Example 32:

9.11-Dibromo-5.6-dihvdro-5,6-dioxo-napht [l ', 2': 4,51- _m_flftgo [1, 2-alpyridine

In a three-necked flask containing 2.27 g (10 mmol, 1 eq) of 2,3-dichloro-l, 4-dihydro-l, 4-dioxo-naphthalene and 5.00 g (19.8 mmol, 2 eq) of 2-amino-3, 5-dibromopyridine, 50 ml of 2-ethoxyethanol are added. After 48 hours of reflux, the solvent is evaporated off under reduced pressure and the brown solid residue obtained is purified on a flash column (support: silica; packaging: heptane; eluent: dichloromethane) to provide 1.83 g of 9, ll-dibromo- 5, 6- dihydro-5, 6-dioxo-napht [l ', 2': 4, 5] imidazo [1, 2-a] pyridine in the form of orange crystals. Yid: 45% F:> 260 ° C

Rf: 0.59 (CH ₂ Cl ₂ / MeOH, 99/1) SM (APcl '): m / z 404-406-408 (M) ^* ' H NMR (CDC1J: δ (ppm) 9.40 ( d, IH, H-8, J _H8.H10 = 1.52 Hz) 8.28 (dd, IH, Hl, ^J _H1 - _K2 = 7.63 ^HZ ' ^J H1-H3 - 1.22 Hz)

8.14 (dd, IH, H-4, ^J _H3 - _H4 = 7.63 ^HZ ' ^J H2-H4 ⁼ 1.22 Hz) 7.95 (d, IH, H-10, ^J H8-H10 ^{= l '52} Hz) 7.71 (dt, IH, H-2, ^ H1-H2 ^- "H2-H3 = 7.63 Hz, ^J H2-H4 ⁼ !' 2 Hz) 7.55 (dt, IH, H -3, '"' iβ-.U ~ ^LJ H3-H4 = 7.63 Hz, ^J H ₁ -H3 ^{= l} '22 Hz)

"C NMR (CDC1J: δ (ppm) 136.9 (IC, C-10) 135.6 (IC, C-2) 131.3 (IC, C-3)

130.5 (3C, C-4a, C-4, C-12b) 127.8 (IC, C-8) 125.4 (IC, Cl) IR (KBr): v (cm ^"1 ) 1653, 1646 (C = 0) Example a

5.6-dihvdro-5, 6-dioxo-9-nitro-napht [l'.2 ^/ t4.51- imidazo [1,2-al -pyridine Reference: CA 55 P25998e

Yid: 2%

F:> 300 ° C

Rf: 0.15 (CH ₂ Cl ₂ / AcOEt, 96/4)

MS (IE): m / z 293 (M ⁺ ), 265 (M-CO) H NMR (DMF-d ,, 60 ° C, 270 MHz): δ (ppm)

10.07 (s, IH, H-8)

8.50 (d, IH, H-10, J _H10 . _HU = 10.00Hz)

8.25 (d, IH, Hl, J _H1 . _H2 = 7.93Hz)

8.15 (d, IH, H-ll, J _Hl0 . _H11 = 10.07Hz) 8.11 (d, IH, H-4, J _H3 . _H4 = 7.63Hz)

7.88 (dd, IH, H-2, J _H1 . _Ffi = ^ _{. "} =, 63Hz)

7.72 (dd, IH, H-3, J _H2.H3 = J _H3.H4 = 7, 93Hz)

"C NMR (DMF-d ,, 67.5 MHz): δ (ppm)

152.37, 150.51 (2C, C-11a, C-12a) 137.32 (IC, C-2)

133.50 (IC, C-4a or C-12b)

133.26 (IC, C-3)

131.52 (IC, C-4)

129.44 (CI, C-10) 127.59 (CI, C-8)

126.76 (IC, C-1)

119.71 (IC, C-ll)

IR (KBr): v (cm ^"1 )

1652, 1640 (C = 0)

Pharmacological properties

The study of the compounds of the present invention and their possible salts has demonstrated that they have various pharmacological properties. Thus, they are selectively veinotonic, affecting the arterial system only concentrations much higher than those active on the veins, except certain arteries, in particular cerebral. The compounds show no affinity or at most a very weak affinity for the large majority of known receptors. In addition, they increase capillary resistance, decrease the vascular hyperpermeability induced by certain inflammatory agents.

These properties are demonstrated in mammals such as hamsters, rats, guinea pigs and rabbits, under in vitro conditions (isolated vessels or vascular networks) and in vivo.

For in vitro studies, the compounds are dissolved in pure aqueous solution or containing DMSO (diethyl sulfoxide).

For in vivo studies, they are administered intravenously or intraperitoneally in the form of an aqueous solution containing or not DMSO, or orally in suspension in 1% carboxymethylcellulose, administered using a feeding tube under a volume of 10 ml / kg.

Pharmacological study models Contractile effects Contractile effects are measured in vitro under static conditions on vascular rings with capacitance or resistance of saphenous, femoral, jugular, mesenteric veins, cellars ... and on femoral arteries, carotids, basilars, mesenteric, thoracic or abdominal aorta ... 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 placed in an isolated organ chamber (25 ml for capacitance vessels and 2.5 ml for resistance vessels according to Mulvany), kept in isometric conditions by two rigid wires inserted inside the vessel, avoiding damage to the endothelium. The vessels are bathed in a modified Krebs solution (in πiM) NaCl = 118; KCl = 4.6; CaCl = 2.5; MgS0 = 1.2; KH2PO4 = 1.17; NaHC0 ₃ = 25; glucose = 11), permanently aerated by a gas mixture at 95% O2 and 5% ∞2, at pH = 7, 4 and thermostatically controlled at 37 ° C. The rings are brought to their optimal point of the tension-length relationship. The developed voltages generate an electrical signal via a force sensor (heastone bridge). This signal is amplified before being either viewed on a Kipp & Zonen recorder, or digitized for processing by computer (IOS, EMKA). Pharmacological studies are carried out after a few preliminary contractile stimulations standardized with a depolarizing solution (hyperpotassics obtained by replacing NaCl with KCl in equimolar quantities), rinses and equilibration periods in pure physiological solution. The presence of endothelium is verified by the relaxation induced by increasing concentrations of acetylcholine after stabilization of a vascular pre-contraction and which will then be taken into account for the study of the effects of the different compounds, the pieces of vessels whose contractile response to the preliminary stimulations and whose relaxing response dependent on the endothelium are of intensity greater than a predefined value for each type of vessel.

The contraction forces developed by the vascular rings in response to the various compounds are studied on quiescent or electrically stimulated vessels (5-8 Hz), with a hyperpotassic depolarizing "physiological" solution (KCl: 20, 40 mM), by no-radrenaline (increasing concentrations), serotonin (increasing concentrations) ... The contractions are expressed in mg force or as a percentage of the maximum contraction on depolarization by a "physiological" hyperpotassic solution.

Contractile effects are also measured in vitro under dynamic flow conditions, by the pressure developed by perfused vascular networks at constant flow. At the mesenteric level, veinoselectivity is studied on the model of double simultaneous and separate perfusion of arterial and venous networks, model developed by T. WARNER (British J. Pharmacol. 1990, 99, 427-433). The two networks are separated by cutting the vessels and tissues along the intestinal border. The networks are perfused at 2 ml.min "1 with a Krebs solution (37.5 ° C) aerated with 95% O2 and 5% C0 •

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 catheter introduced at the level of the right atrium. During cardiac arrest, the venous tone (mean circulatory filling pressure at constant blood volume) is calculated from the venous and arterial pressures measured at equilibrium and corrected according to the relative differences in compliance between these two networks. (SAMAR & COLEMAN, A. J. Physiol. 1978, 234: H94-100; YAMAMOTO et al., Am. J. Physol. 1980, 238: H823-828).

In awake animals, arterial pressures are measured according to the classic method derived from Riva Rocci, by analysis of the acoustic wave transmitted to the arterial level and transformed by a piezo ceramic transducer placed on the tail of the rat, downstream of a sleeve automatically inflated by a pressure generator.

At the microcirculatory level, variations in the venular and arteriolar sections are studied in vivo in the model of the dorsal cutaneous chamber of a vigilant hamster, after videomicroscopic recording (Leitz Ergolux microscope equipped with a halogen source for lighting and a black and white CCD video camera HPR 610) and computer analysis (Visicap software, ICAP pack) images. After anesthesia with sodium pentobarbital (60 g / kg ip), the back of the animal is shorn and depilated so as to be able to place an observation chamber (Prof. GEBHARD, Heidelberg) on the skin of the back. The two parts of the chamber are sewn after carefully removing the skin thicknesses which may hinder observation. A jugular catheter is placed for iv administration of the products 48 hours after the operation.

Effects on induced capillary hyperpermeability Vascular permeability is studied in vivo by measuring the albumin extravasation, the amount of which is determined using an albumin-binding dye (Evans Blue). Hyperpermeability is induced by intradermal injection of a solution of histamine, bradykinin or zymosan.

The technique is derived from that described by BEACH & STEINETZ, J. Pharmacol. Exp. Therap., 1961, 131: 400-406.

The rats (Wistars, 200 to 230 g) are shorn on their abdominal wall one hour before the start of the experiment. The product to be tested is injected ip or per os 1 hour to 6 hours before sacrificing. The rats are anesthetized with a mixture of halothane. Then, they receive an intradermal injection on the abdomen of 0.10 or 0.15 ml of inflammatory agent (either for histamine, 6.7 or 10 micrograms and for zymonsan 100 micrograms) and an intravenous injection 0.5 ml Evans blue solution in the vein of the penis. These injections are given 30 minutes before euthanasia. 30 minutes after 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 glass tubes with a ruffled neck 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 12.8% benzalkonium chloride is then added. After leaving 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 suction and the organic phase "dichloromethane" is filtered. The optical densities are quantified by absorption spectrophotometry at a wavelength of 620 nm, against a blank containing only dichloromethane.

The averages of the optical densities of the different batches of treated or control animals are calculated, then a percentage change in the values corresponding to the treated animals compared to those of the control animals.

The effect of the compounds on the hyperpermeability induced by inflammatory agents, such as histamine and bradykinin, is also studied after intravenous injection by bolus in the dorsal hamster skin chamber model and according to the method developed by GIMENO et al. , previously described (A new technique using investital videomicroscopy for macromolecular permeability measurement, 18th European Congress of microcirculation, Rome 1994). This technique, by videomicroscopy and image analysis, makes it possible to quantify the distribution of intra and extravascular fluorescence of the fluorescent marker (FITC-Dextran) injected as a bolus by the catheter. jugular (63 mg / kg for a volume defined at 1 ml / kg). The microscope is equipped with a fluorescent source and 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 assessed by the modification of the petechial index (negative pressure inducing extravasation of erythrocytes), measured by a method derived from the Parrot angiosterrometer.

The study is carried out on male Wistar rats weighing an average of 200 g (around six weeks old). The lower back region is shaved and then depilated using a paste based on a derivative of thioglycolic acid and calcium hydroxide. After about thirty minutes, the skin is thoroughly rinsed and dried.

On the day of the study, the rats were kept unconstrained. A vacuum of 80 mm of mercury is applied. If the petechiae (extravasation of erythrocytes) have not appeared within 15 seconds, the depression is increased step by step by keeping the suction cup in the same place.

The minimum depression for which the petechiae appear expresses, in mm of mercury, the value of basic capillary resistance (before any treatment). Two measurements are made for each test at different locations on the back.

Rats are treated orally. After a determined time (generally 2, 4, 6 or 8 hours) following the treatment, the test is repeated on different areas of skin, until the appearance of petechiae, providing a new index of depression. All measurements are made blind. A percentage of variation of the capil- The results of the treated animals with respect to their basic capillary resistance is calculated for each compound studied, at each treatment time and compared with the control group (excipient only) or the reference group.

Effects on induced pleurisy in rats

The anti-inflammatory activity of the compounds is also studied by measuring the inhibition of edema and leukocyte migration after induction of pleurisy in rats by injection of carrageenan into the pleural cavity (ALMEIDA et al., J. Pharmacol, Exp. Therap., 1980, 214: 74).

The rats are treated intravenously or gastrically with the compounds 2 hours before the injection of carrageenan. After a determined time (6 hours) following the induction of pleurisy, the rats are euthanized and the pleural fluid recovered by suction and its volume is measured. The leukocyte cells are counted by "cell counter". The results are expressed in number of leukocytes in the exudate compared to 100 g of animal weight and compared to those of the control batch.

Examples of Pharmacological Effects The compounds of the invention and their possible salts selectively increase, in the majority of cases, the contraction of the animal veins produced by norepinephrine, by electrical stimulation or by a depolarizing hyperpotassic solution. By way of illustration, the contractile effect of different compounds on the saphenous vein of rabbit precontracted by a "physiological" depolarizing solution with potassium concentration equal to 40 mM is shown; the maximum effect produced by each compound is expressed as a percentage of the maximum contraction induced by hyper- depolarizing potassium and EDso value)

Compounds Emax (% Contr.max.) EDgQ (nM)

example 8 9 78 example 9 15 20 example 13 22 20 example 14 8 50 example 17 10 30 example 19 13 10 example 20 27 14 example 21 16 40 example 24 17 150 example a 4 100

By way of illustration, the oral administration of certain compounds of the invention and their possible salts increases the capillary resistance of the rat at doses generally between 0.01 and 5 mg / kg:

Compounds Effect at 4 o'clock Effect at 6 o'clock (in% of the control) (in H of the control)

example 8 5 mg / kg + 4 + 11 example 24 5 mg / kg + 12 + 19 example a 5 mg / kg + 9 + 11

Among the preferred compounds of the invention, example 20 and example 24 are particularly retained.

The above shows that the compounds of the invention and their possible salts can be used in human and animal therapy. They are particularly indicated in functional, organic venous insufficiency and hemorrhoidal pathologies by their vascular and anti-inflammatory components, as well as in typically inflammatory conditions and in shock states consisting of a significant drop in blood pressure. In the latter case, an improvement in the venous return is likely to maintain the cardiac output and therefore, consequently, the arterial pressure.

Functional venous insufficiency is characterized by dilation and hyperdistensibility of the superficial veins of the lower limbs, edema, impatience-type paresthesias, restless leg. This type of pathology can progress towards organic venous insufficiency characterized by the development of varicose veins, valve incontinence, even towards phlebothrom- bosis and trophic disorders leading to ulcerative lesions. In this venous pathology, an inflammatory component settles in the early stages and manifests itself more clearly in the advanced stages.

By their venoconstrictor, anti-inflammatory effects, in particular on vascular hyperpermeability and their contractile effects on the cerebral arteries, the compounds of the invention and their possible salts are also indicated in migraine.

The present invention therefore comprises the use of the above-mentioned compounds and their possible 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 combination with a physiologically acceptable carrier or diluent.

The form of these drugs and pharmaceutical compositions will obviously depend on the desired route of administration, in particular oral, parenteral, topical (cutaneous) and rectal, and they can be formulated according to conventional techniques with implementation. of usual supports and vehicles.

Thus, in the case of an oral administration, they can be in the form of tablets, tablets, capsules, solutions, syrups, emulsions, suspensions, powder, granules, soft capsule, lyophilisate, microcapsule, microgranule.

Tablets, tablets and capsules contain the active substance together with a diluent (e.g. lactose, dextrose, sucrose, mannitol, maltitol, xyli- toi, sorbitol or cellulose), a lubricant (e.g. silica, talc or stearate), a binder (for example starch, methylcellulose or gum arabic), a disintegrating agent (alginate for example) and they are produced by known techniques for example of mixing, granulation, pelletizing, coating, compression, etc. Syrups may contain glycerol, mannitol and / or sorbitol as a carrier. Solutions and suspensions may include water and other physiologically compatible solvents and a carrier such as natural gum, agar, sodium alginate or polyvinyl alcohol.

For parenteral administration, the medicaments and compositions may take the form of solutions, emulsions or suspensions comprising the active substance and a suitable support or solvent such as sterile water or sterile isotonic saline solutions.

For skin application, the drugs and compositions can take the form of an ointment, cream or gel, in the form of an emulsion or suspension, solution, foam, powder.

For rectal application, the drugs and compositions can take the form of capsule, cream, emulsion, gel, foam, ointment, suppository.

Claims

1. Use of tetracyclic derivatives and their pharmaceutically acceptable salts corresponding to the general formula:

(I) in which independently of each other: Ri is a hydrogen atom, a halogen atom, a C1 to C5 alkyl radical, a C ₅ to ₅ alkoxy radical or OH, a nitro radical, a radical amino, alkyl radical C _x -C ₅ amino, dialkyl radical C ₁ -C ₅ amino, thioalkyl radical C _x -C ₅ or SH

R2 is a hydrogen atom, a halogen atom, a C1 to C5 alkyl radical, a C _x to C ₅ alkoxy radical or OH, a nitro radical, an amino radical, a C _x to C alkyl radical ₅ amino, a C ₁ -C ₅ dialkyl radical amine, a C _x C ₅ thioalkyl radical or SH

R ₃ is a hydrogen atom, a halogen atom, an alkyl radical -C 5 alkoxy radical C _x -C ₅ or OH, nitro, an amino radical, an alkyl radical in _C: to -C ₅ amino, dialkyl radical C _x -C ₅ amino, thioalkyl radical C _x -C ₅ or SH with the exception of derivatives for which: R _x is hydrogen and R ₂ is a hydrogen atom, hydrogen and R ₃ is hydrogen, a halogen atom, a nitro radical or a C _x to C ₅ alkyl radical

R _t is a hydrogen atom and R ₂ is an atom of halogen and R ₃ is hydrogen, a halogen atom, a nitro radical or a C _x to C ₅ alkyl radical

R _x is a halogen atom and R ₂ is a hydrogen atom and R ₃ is a hydrogen, a halogen atom, a nitro radical or a C ₁ to C ₅ alkyl radical

R _x is a C _x to C ₅ alkyl radical and R ₂ is a hydrogen atom and R ₃ is a hydrogen, a halogen atom, a nitro radical or a C _λ to C ₅ alkyl radical

R ₂ is an alkyl radical C_ to C ₅ and R _x is a hydrogen atom and R ₃ is hydrogen, a halogen atom, a nitro radical or an alkyl radical C _l -C ₅ n and m are either equal to 0 or to 1, but not independently of each other so that if n is equal to 1 then m is equal to 0, and if n is equal to 0 then m is equal to 1, for obtaining a drug intended for the treatment of functional and organic venous insufficiency.

2. As a new product, 4-amino-5,6-dihydro-5,6-dioxonapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

3. As a new product, 7-amino-2-chloro-6, ll-dihydro-6, 11-dioxo-napht [2 ', 3': 4, 5] imidazo [1, 2-a] - pyridine .

4. As a new product, 10-amino-2-chloro-6, ll-dihydro-6, 11-dioxo-napht [2 ', 3': 4, 5] imidazo [1, 2-a]

_* pyridine.

5. As a new product, 2-amino-5,6-dihydro-5,6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

6. As a new product, 3-amino-5,6-dihydro-5,6-dioxo-naphth [1, 2 ': 4, 5] imidazo [1,2-a] pyridine.

7. As a new product, 5,6-dihydro-5,6-dioxo-4- (methylamino) naphth [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine.

8. As a new product, 5, 6-dihydro-2-dimethylamino-5, 6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine.

9. As a new product, 5, 6-dihydro-3-dimethylamino-5, 6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine.

10. As a new product, 4-amino-9-chloro-5,6-dihydro-5,6-dioxo-napht [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine .

11. As a new product, 9-chloro-5,6-dihydro-5,6-dioxo-4- (methylamino) naphth [1 ', 2': 4, 5] imidazo- [1,2-a] pyridine.

12. As a new product, 9-bromo-5,6-dihydro-5,6-dioxo-1-methoxynapht [l ', 2': 4, 5] -imidazo [l, 2- a] -pyridine.

13. As a new product, 9-bromo-5,6-dihydro-5,6-dioxo-4-methoxynapht [l ', 2': 4, 5] imidazo [l, 2- a] -pyridine.

14. As a new product, 9-chloro-5,6-dihydro-5,6-dioxo-l-methoxy-napht [l ', 2': 4, 5] imidazo [l, 2-a] - pyridine .

15. As a new product, 9-chloro-5,6-dihydro-5,6-dioxo-4-methoxy-napht [l ", 2 ': 4, 5] imidazo [l, 2-a] - pyridine.

16. As a new product, 9-chloro-5, 6-dihydro-5, 6-dioxo-2-methoxy-napht [l ', 2': 4, 5] imidazo [l, 2-a] - pyridine .

17. As a new product, 9-chloro-5, 6-dihydro-5, 6-dioxo-3-methoxy-napht [l ', 2': 4, 5] imidazo [l, 2-a] - pyridine.

18. As a new product, 9-chloro-5,6-dihydro-5,6-dioxo-1-hydroxynapht [1 ', 2': 4, 5] imidazo [1,2-a] - pyridine.

19. As a new product, 9-chloro-5, 6-dihydro-5, 6-dioxo-4-hydroxynapht [l ', 2': 4, 5] imidazo [l, 2-a] - pyridine.

20. As a new product, 5, 6-dihydro-5, 6-dioxo-10-methoxynapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

21. As a new product, 5,6-dihydro-5,6-dioxo-11-methoxynapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

22. As a new product 5,6-dihydro-5,6-dioxo-10-hydroxynapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

23. As a new product, 5,6-dihydro-5,6-dioxo-ll-hydroxynapht [l, 2 ': 4, 5] imidazo [1, 2-a] pyridine.

24. As a new product, 5, 6-dihydro-5, 6-dioxo-11-nitronapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

25. As a new product, 11-amino-5,6-dihydro-5,6-dioxonapht [l, 2 ': 4, 5] imidazo [1,2-a] pyridine.

26. As a new product, 5, 6-dihydro-11-dimethylamino-5, 6-dioxonapht [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine.

27. As a new product, 9-amino-5,6-dihydro-5,6-dioxo-naphth [1 ', 2': 4,5] imidazo [1, 2-a] pyridine.

28. As a new product, 5, 6-dihydro-9-dimethylamino-5, 6-dioxonapht [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine.

29. As a new product, 5, 6-dihydro-5, 6-dioxo-10-methylthionapht [1 ', 2': 4, 5] imidazo [1, 2-a] - pyridine.

30. As a new product, 5, 6-dihydro-5, 6-dioxo-9-methylthionapht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

31. As a new product, 9, ll-dichloro-5, 6-dihydro-5, 6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

32. As a new product, 9, ll-dibromo-5, 6-dihydro-5, 6-dioxo-napht [1 ', 2': 4, 5] imidazo [1, 2-a] pyridine.

33. As a new product, 5, 6-dihydro-5, 6-dioxo-9-methoxynaphth [l ', 2': 4,5] imidazo [1, 2-a] pyridine.

34. As a new product, 9-chloro-5,6-dihydro-5,6-dioxo-2-hydroxy-naphth [l ', 2': 4, 5] imidazo

[1, 2-a] pyridine.

35. As a new product, 9-chloro-5,6-dihydro-5,6-dioxo-3-hydroxy-naphth [l ', 2': 4,5] imidazo [1, 2-a] pyridine.

36. As a new product, 10, 11-dichloro-5, 6-dihydro-5, 6-dioxonaphth [l ', 2': 4, 5] imidazo [1, 2-a] pyridine.

37. As a new product, 5, 6-dihydro-5, 6-dioxo-9-hydroxynaphth [l ', 2': 4, 5] imidazo [1, 2-a] pyridine.

38. As a new product, 5,6-dihydro-5,6-dioxo-11-methylthionaphth [1, 2 ': 4, 5] imidazo [1, 2-a] pyridine.

39. As a new product 9, ll-dibromo-5, 6-dihydro-5, 6-dioxo-napht [1 ', 2': 4, 5] -imidazo [1, 2-a] pyridine.

40. As an intermediate product, 6-acetoxy-2,3-dibromo-1,4-naphthoquinone.

41. As an intermediate product 2-acetoxy-9-chloro-5, 6-dihydro-5, 6-dioxo-naphth [1 ', 2': 4, 5] imidazo [1,2-a] pyridine.

42. As an intermediate product 3-acetoxy-9-chloro-5, 6-dihydro-5, 6-dioxo-napht [1 ', 2': 4, 5] imidazo

[1, 2-a] pyridine.

43. As an intermediate product, 2-amino-3-methylthiopyridine.

44. The salts of the salifiable compounds of the products according to any one of claims 1 to 39 comprising the addition salts of mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acid and the salts of addition of organic acids nics such as acetic, propionic, oxalic, citric, maleic, fumaric, succinic, tartaric acid.

45. Use of the compounds according to any one of claims 1 to 39 for obtaining a medicament intended for the treatment of hemorrhoidal pathologies.

46. Use of the compounds according to any one of claims 1 to 39 for obtaining a medicament intended for the treatment of migraine.