EXAMPLE 1
Synthesis of (S,S)-N-acetyl-S-(6-methoxy-α-methyl-2-naphthalen acetyl)cisteine 4-(nitroxy)butyl ester (NCX 2101) having formula
The precursor is naproxene (Formula VI), the precursor of B is N-acetylcisteine (formula CVIII)
To a solution of 6-methoxy-α-methyl-2-naphthalenacetic acid (10 g, 43.4 mmoles) in chloroform (100 ml) and N,N-dimethylformamide (6 ml), 1,1′-carbonyldiimidazole (CDI) (7.04 g, 43.4 mmoles) is added. After 15 minutes the obtained solution is treated with (S)-N-acetylcisteine (7.08 g, 43.4 mmoles) and left at room temperature for 12 hours. The reaction mixture is washed with HCl 5%, then with water and lastly with brine. The organic phase is anhydrified with sodium sulphate and then evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with ethyl acetate. 11.66 g of the expected product in the form of a white solid m.p.: 122°-1260° C., is obtained.
1H-NMR (CDCl3): 7.71-7.65 (3H, m), 7.34, (1H, dd), 7.16-7.09 (2H, m), 6.36 (1H, d), 4.67 (1H, m), 4.00 (1H, q), 3.90 (3H, s) 3.32 (2H, t), 1.84 (3H, s), 1.59 (3H, d).
b) Synthesis of (S,S)-N-acetyl-S-(6-methoxy-α-methyl-2-naphthalen acetyl)cisteine 4-(bromobutyl) ester
To a solution of (S,S)-N-acetyl-S-(6-methoxy-α-methyl-2-naphthalenacetyl)cisteine (11.3 g, 30.1 mmoles) in tetrahydrofuran (200 ml), triphenylphosphine (23.7 g, 90.3 mmoles) and carbon tetrabromide (28.85 g, 90.3 mmoles) are added. The reaction mixture is left under stirring for 24 hours at room temperature. The solvent is removed by evaporation at reduced pressure. The obtained crude product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 4 g of the ester in the form of a white solid with m.p. 67°-71° C., are obtained.
c) Synthesis of (S,S)-N-acetyl-S-(6-methoxy-α-methyl-2-naphthalen acetyl)cisteine 4-(nitroxy)butyl ester
To a solution of the ester obtained at the end of the previous step (1 g, 1.96 mmoles) in acetonitrile (20 ml), silver nitrate (0.66 g, 3.92 mmoles) is added. The reaction mixture is heated for 7 hours under reflux away from light. The formed salt is removed by filtration and the solution is evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 0.47 g of (S,S)-N-acetyl-S-(6-methoxy-α-methyl-2-naphthalenacetyl)cisteine 4-(nitroxy)butyl ester in the form of a white solid m.p. 56-59° C., are obtained.
1H-NMR (CDCl3): 7.80-7.68 (3H, m), 7.37(1H, d), 7.20-7.13 (2H, m), 6.12 (1H, d) 4.40 (2H, dd), 4.26 (1H, m), 4.15-3.87 (3H, m), 3.92 (3H, s), 2.33 (2H, d), 1.6 (3H, d), 1.74-1.67 (4H, m), 1.61 (3H, d).
Elementary analysis:
EXAMPLE 4
Synthesis of (S)-N-acetyl-[2-fluoro-α-methyl-(1,1′-biphenyl)-4-acetyl]cisteine 4-(nitroxy)butyl ester (NCX 2131) having formula
The precursor is flurbiprofen (Formula IX), the precursor of B is N-acetylcisteine (formula CVIII)
The NCX 2131 compound is synthetized according to the process described in Example 1. The substance appears as an oil. Yield: 26%
1-NMR (CDCl3): 7.41-7.38 (6H, m), 7.10 (2H, m), 6.22 (1H, d), 4.78 (1H, m), 4.46 (2H, t), 4.13 (2H, t), 3.92 (1H, q), 3.36 (2H, d), 1.93 (3H, d), 1.76 (4H, d), 1.55 (3H, d).
Elementary analysis
EXAMPLE 5
Preparation of trans-3-[4-[α-methyl-[4-(-2-methylpropyl)benzene] acetyloxy)-3-methoxyphenyl]-2-propenoyl 4-(nitroxy) butyl ester (NCX 2210) having formula:
The precursor is ibuprofen (Formula VII), the precursor of B is ferulic acid (formula DII):
To a solution of α-methyl-[4 (2-methylpropyl)benzene acetic acid (5.03 g, 24.4=moles) in tetrahydrofuran (100 ml) and N,N-dimethylformamide (5 ml) 1,1-carbonyldiimidazole (4.25 g, 24.8 mmoles) is added. After 1 hour the obtained solution is treated with ferulic acid (4.90 g, 25 mmoles), sodium ethylate (89 mg) is added and left at room temperature under stirring for 12 hours. The reaction mixture is washed with HCl 5%, then with water and lastly with brine. The organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure.
The obtained residue is purified by chromatography on silica gel, eluting with ethyl acetate/n-hexane 7/3. 5.1 g of trans-3-[4-[α-methyl-[4-(-2-methylpropyl)benzene] acetyl)-3-methoxyphenyl]-2-propenoic acid as white solid, with m.p. 131°-137° C., are obtained.
1H-NMR (CDCl3): 7.72 (1H, d), 7.32 (2H, dd), 7.26 (1H, m), 7.16-7.07 (4H, m), 6.98 (LH, d), 6.37 (1H, d), 3.99 (1H, q), 3.73 (3H, s), 2.47 (2H, d), 1.88 (1H, m), 1.63 (3H, d), 0.92 (6H, d).
b) synthesis of trans-3-(4-[α-methyl-[4-(−2-methylpropyl)benzenelacetyloxy]-3-methoxyphenyl]-2-propenoyl 4-bromobutyl ester
To a solution of trans-3-[4-[α-methyl-[4-(2-methylpropyl)-benzene]acetyloxy]-3-methoxyphenyl]-2-propenoic acid (5.33 g, 14 mmoles) in N,N-dimethylformamide (130 ml), sodium ethylate (1.2 g. 16 mmoles) is added under stirring. After 1 hour to the obtained mixture 1,4-dibromobutane (10 g, 46 mmoles) is added and let react at room temperature for 12 hours. The reaction mixture is washed with HCl 5%, then with water and lastly with brine, the organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 8/2. 4.46 g of trans-3-[4-hydroxy-[α-methyl-[4-(-2-methylpropyl)benzene]acetyl]-3-methoxyphenyl]-2-propenoyl 4-bromobutyl ester are obtained.
c) Synthesis of trans-3-[4-[α-methyl-[4-(-2-methylpropyl)benzene)acetyloxy]-3-methoxyphenyl]-2-propenoyl 4-(nitroxy) butyl ester
To a solution of trans-3-[4-[α-methyl-[4-(-2-methylpropyl)benzene]acetyloxy]-3-methoxyphenyl]-2-propenoyl 4-bromo-butyl ester (4 g, 7.72 mmoles) in acetonitrile (70 ml) silver nitrate (2.58 g, 15 mmoles) is added. The reaction mixture is heated under reflux for 2 hours away from light. At the end the formed salt is removed by filtration and the solution is evaporated at reduced pressure. The recovered residue is purified by chromatography on silica gel, eluting with n-hexane/ethyl acetate 8/2. 2.4 g of trans-3-(4-[α-methyl-[4-(-2-methylpropyl)benzene)acetyloxy)-3-methoxyphenyl]-2-propenoyl 4-(nitroxy) butyl ester as an oil, are obtained.
1H-NMR (CDCl3): 7.62 (1H, d), 7.32 (2H, d), 7.15 (2, d), 7.16-7.05 (2H, m), 6.96 (1H, d), 6.35 (1H, d), 4.51 (2, t), 4.24 (2H, t), 3.99 (1H, q), 3.74 (3H, s), 2.48 (2H, d), 1.89-1.83 (5H, m), 1.62 (3H, d), 0.92(6H, d).
Elementary analysis:
EXAMPLE 6
Synthesis of trans-3-[4-[2-fluoro-α-methyl-(1,1′-biphenyl)-4-acetyloxy]-3-methoxyphenyl]-2-propenoyl 4-(nitroxy) butyl ester (NCX 2216) having formula:
The precursor is flurbiprofen (formula IX), the precursor of B is ferulic acid (formula DII)
The NCX 2216 compound is synthetized according to the process described in Example 5. The total process yield is 32%. The substance appears as an amorphous solid.
1H—NMR (CDCl3): 7.40-7.25 (9H, m), 7.07-7.01 (2H, d), 6.98(1H, m), 6.38 (1H, d), 4.44 (2H, t), 4.46 (2H, t), 4.21 (2H, t), 4.04 (1H, q), 3.73 (3H, s), 1.72 (4H, m), 1.65 (3H, d).
Elementary analysis:
EXAMPLE 8
Preparation of N-acetyl-S-((S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)acetyl] (S)-cisceine 4-(nitroxy) butyl ester (NCX 2136)
The compound is synthetized following the procedure reported in Example 1. The yield is of 23%.
Elementary analysis:
EXAMPLE 9
Preparation of [3-methoxy-4-(4-nitroxybutyryloxy)phenyl]-2-trans-propenoyl-4-[(2-amino-3,5-dibromophenyl)methylamino] cyclohexanol ester (NCX 2161)
To a mixture of 4-[(2-amino-3,5-dibromophenyl)methylamino-]cyclohexanol (5 g, 13.22 mmoles) in dioxane (35 ml) and water (50 ml), triethylamine (3.31 ml, 23.7 mmoles) and di-ter-butyldicarbonate (3.46 g, 15.86 mmoles) are added under stirring. After 24 hours the solution is concentrated under vacuum, a HCl 1% solution until neutral pH (pM=7) is added and the organic phase is extracted with ethyl acetate. The organic phase is anhydrified with sodium sulphate and evaporated under vacuum. 4[(2-ter-butoxycarbonylamino-3,5-dibromophenyl) methyl amino]cyclohexanol is obtained which is used without further purification.
b) Synthesis of (3-methoxy-4-hydroxyphenyl)-2-trans-propenoyl-4-[(2-ter-butoxycarbonylamino-3,5-dibromo phenyl)methylamino] cyclohexanol ester
To a solution of ferulic acid (4 g, 20.5 mmoles) in tetrahydrofuran (40 ml) cooled at 0° C., 1,1′-carbonyldiimidazol (3.34 g, 20.5 mmoles) is added. After 10 minutes the solution is treated with 4-[(2-ter-butoxycarbonylamino-3,5-dibromophenyl) methyl amino]cyclohexanol (9.8 g, 20.5 mmoles) and let react at room temperature for 4 hours. The reaction mixture is concentrated under vacuum, treated with methylen chloride, washed with a HCl 1% solution and then with water. The organic phase is anhydrified with sodium sulphate and then evaporated under vacuum. The obtained residue is purified by chromatography on silica gel, eluting with n-hexane/ethyl acetate 1/1. (3-methoxy-4-hydroxyphenyl)-2-trans propenoyl 4-[(2-ter-butoxycarbonylamino-3,5-dibromo phenyl) methylamino) cyclohexanol ester, is obtained.
c) Synthesis of [3-methoxy-4-(4-bromobutyryl-oxy)phenyl]-2-trans propenoyl-4-((2-ter-butoxycarbonylamino-3,5-dibromo-phenyl) methylamino] cyclohexanol ester
To a solution of (3-methoxy-4-hydroxyphenyl)-2-trans propenoyl-4-(2-ter-butoxycarbonylamino-3,5-dibromo-phenyl) methylamino] cyclohexanol ester (4 g, 6.11 mmoles) in tetrahydrofuran (80 ml), triethylamine (0.85 ml, 6.11 mmoles) and 4-bromobutyrylchloride (0.7 ml, 6.11 mmoles) are added under stirring. It is let react at room temperature for 8 hours and then the organic solvent is evaporated at reduced pressure. The obtained crude product is treated with ethyl acetate and the organic phase washed with water. The organic phase is anhydrified with sodium sulphate and evaporated under vacuum. The residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. (3-methoxy-4-(4-bromobutyryloxy)-phenyl]-2-trans propenoyl 4-[(2-ter-butoxycarbonylamino-3,5-dibromo phenyl) methylamino] cyclohexanol ester is obtained.
d) Synthesis of (3-methoxy-4-(4-nitroxybutyryloxy)phenyl]-2-trans-propenoyl 4-[(2-ter-butoxycarbonylamino-3,5-dibromo phenyl) methylamino] cyclohexanol ester
To a solution of [3-methoxy-4-(4-bromobutyryloxy)phenyl)-2-trans-propenoyl-4-[(2-ter-butoxycarbonylamino-3,5-dibromophenyl)methylamino) cyclohexanol ester (4 g, 4,98 mmoles) in acetonitrile (70 ml), silver nitrate (0.87 g, 4.98 mmoles) is added under stirring. It is heated under reflux for 7 hours away from light and lastly the formed salt is removed by filtration. The organic solution is evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. [3-methoxy-4-(4-nitroxybutyryloxy)phenyl]-2-transpropenoyl 4-[(2-ter-butoxycarbonylamino-3,5-dibromo-phenyl)methylamino] cyclohexanol ester is obtained.
e) Synthesis of [3-methoxy-4-(4-nitroxybutyryloxy)phenyl]-2-transpropenoyl 4-[(2-amino-3,5-dibromo phenyl) methylamino) cyclohexanol ester
To a solution of (3-methoxy-4-(4-nitroxybutyryloxy)phenyl]-2-transpropenoyl 4-[(2-ter-butoxycarbonylamino-3,5-dibromo phenil)-methylamino] cyclohexanol ester (2 g, 2.54 mmoles) in ethyl acetate (50 ml), cooled at 0° C. and maintained under stirring, a HCl 5N solution in ethyl acetate (3.17 ml) is added. The solution is left under stirring at 0° C. for 4 hours. Lastly the precipitate is filtered. The obtained crude product is treated with ethyl acetate, to which a 5% sodium bicarbonate solution is added. It is shaken and the bicarbonate solution is substituted with an equal part of water. It is shaken again, the organic phase is recovered, anhydrified with sodium sulphate and evaproated at reduced pressure. [3-methoxy-4-(4-nitroxybutyryloxy)phenyl 2-2-transpropenoyl-4-(2-amino-3,5-dibromophenyl) methylamino] cyclohexanol ester is obtained.
Yield: 36%
Elementary analysis:
EXAMPLE 10
Preparation of [4-amino-[[3-methoxy-4-(4-nitroxybutyryloxy)phenyl]-2-trans propenoyl]-1-hydroxy-butyliden]-bisphosphonic acid (NCX 2211),
To a solution of ferulic acid (1.2 g, 6.11 mmoles) in tetrahydrofuran (80 ml), triethylamine (0.85 ml, 6.11 mmoles) and 4-bromobutyrylchloride (0.7 ml, 6.11 mmoles) are added under stirring. It is let react at room temperature for 3 hours and then evaporated at reduced pressure. The obtained crude product is treated with ethyl acetate and the organic phase washed with water. The organic phase is then anhydrified with sodium sulphate and evaporated under vacuum. The obtained residue is purified by chromatography on silica gel eluting with chloroform/methanol 8/2. The [3-methoxy-4-(4-bromobutyryloxy)-phenyl]-2-trans propenoic acid is lastly isolated.
b) Synthesis of the (3-methoxy-4-4nitroxybutyryloxy)phenyl]-2-trans propenoic acid
To a solution of (3-methoxy-4-(4-brornobltyryloxy)phenyl] 2-trans-propenoic acid (1.5 g, 4.5 mmoles) in acetonitrile (70 ml) silver nitrate (0.87 g, 4.98 mmoles) is added under stirring. The mixture is heated under reflux and, under stirring, it is reacted for 3-hours sheltered from the light. The formed salt is removed by filtration and the organic phase is evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel column, eluting with chloroform/methanol 8/2. The (3-methoxy-4-(4-nitroxybutyryloxy)phenyl]-2-trans propenoic acid is recovered.
c) Synthesis of [4-amino-[(3-methoxy-4-(4-nitroxy butyryloxy)phenyl]-2-trans propenoyl]-1-hydroxy-butyliden] bisphosphonic acid
To a solution of [3-methoxy-4-(4-nitroxybutyroyloxy)-phenyl]-2-trans propenoic acid (29, 6.4 mmoles) in N,N-dimethylformamide (30 ml), cooled at 0° C., N,N′dicyclohexylcarbodiimide (1.3 g, 6.4 mmoles) and 1-hydroxybenzotriazol (1.04 g, 7.68 mmoles) are added under stirring. After 30 minutes alendronic acid (1.6 g, 6.4 mmoles) is added. The reaction mixture is left under stirring at room temperature for 7 hours. At the end it is acidified with a HCl 5% solution and the organic phase is extracted with ethyl acetate. The organic phase is washed with brine, anhydrified with sodium sulphate and evaporated at reduced pressure. The crude product is purified by chromatography on silica gel column eluting with methylene chloride/methanol 8/2, obtaining the [4-amino-[[3-methoxy-4-(4-nitroxybutyroyloxy)phenyl]-2-trans propenoyl]-1-hydroxy butyliden] bisphosphonic acid. Yield: 11%.
Elementary analysis:
EXAMPLE 11
Preparation of S-[[2-[4-(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]acetyl] penicillamine 4-(nitroxy)butyl ester (NCX 2060) having formula
The compound is prepared according to the procedure reported in Example 1, by using N-ter-butoxycarbonyl-penicillamine instead of N-acetyl cisteine.
b) Synthesis of S-[[2-[4-[(4chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetyl)-penicillamine-4-(nitroxy)butyl ester.
The compound is obtained from the previous one by following the procedure described step e) of Example 9 to remove the protective group N-ter-butoxycarbonyl and recover the aminic function. Yield: 26%.
Elementary analysis:
EXAMPLE 12
Preparation of N-acetyl-S-[((S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl)-L-prolin]cisteine 4-(nitroxy)butyl ester of formula (NCX 2134)
The compound is synthetized following the procedure reported in Example 1. Yield: 27%
Elementary analysis
EXAMPLE 13
Preparation of 3-(4-D-α-aminobenzylpenicillaminoyloxy]-3-methoxyphenyl]-2-trans propenoyl 4-(nitroxy)butyl ester (NCX 2080) having formula
The compound is synthetized following the method reported in Example 5. Yields: 11%.
Elementary analaysis
EXAMPLE 14
Preparation of 9-[[2-[-N-acetyl-S-(4-nitroxybutyroyl)cisteinyl]ethoxy]-methyl]guanine of formula (NCX 2135),
A solution containing 4-bromobutyric acid (5.1 g, 30.6 mmoles) and 1,1′-carbonyldiimidazole (5.61 g, 34.6 mmoles) in chloroform (50 ml) is prepared and it is left under stirring at room temperature for 1 hour. To the reaction mixture a solution of N-acetylcisteine (5 g, 30.6 mmoles) in N,N-dimethylformamide (5 ml) containing sodium ethylate (50 mg) is added. It is let react under stirring and after 24 hours the solution is washed with HCl 1% and then with brine. The organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained crude product is purified by chromatography on silica gel column, eluent ethyl acetate/chloroform 7/3, lastly obtaining N-acetyl-S-(4-bromobutyroyl) cisteine.
b) Synthesis of N-acetyl-S-(4-nitroxybutyroyl)cisteine
To a solution of N-acetyl-S-(4-bromobutyroyl)cisteine (3 g, 9.6 mmoles) in acetonitrile (70 ml) silver nitrate (1.7 g, 10 mmoles) is added. The reaction mixture is heated under stirring under reflux for 2 hours away from light. The formed salt is removed by filtration and the solution is evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel column eluting with ethyl acetate/chloroform 7/3, lastly obtaining N-acetyl-S-(4-nitroxybutyroyl)cisteine.
c) Synthesis of 9-([[2-[N-Acetyl-S-(4-nitroxybutyroyl)cisteinyl]ethoxy]methyl]guanine
A solution of N-acetyl-S-(4-nitroxybutyroyl)cisteine (2.8 g, 9.6 mmoles) and 1,1-carbonyldiimidazol (1.55 g, 9.6 mmoles) in tetrahydrofuran (50 ml) is prepared and left under stirring at room temperature for 1 hour. The reaction mixture is treated with aciclovir (2.16 g, 9.6 mmoles). After 6 hours of reaction at room temperature, the solution is evaporated at reduced pressure, the obtained residue treated with ethyl acetate and washed with brine. The organic phase is anhydrified with sodium sulphate and then dried under vacuum. The obtained residue is purified by chromatography on silica gel column eluting with ethyl acetate. 9-[[2-[N-acetyl-S-(4-nitroxybutyroyl)cisteinyl-]ethoxy]methyl]guanine is obtained. Yields: 9%.
Elementary analysis
EXAMPLE 15
Preparation of trans-3-[4-(5-amino-2-hydroxybenzoyl)-3-methoxyphenyl]2-propenoyl 4-(nitroxy) butyl ester (NCX 2212),
The compound is synthetized according to the procedure reported in Example 5, first protecting the primary aminic group of the mesalamine as described in Example 9, step a).
b) Obtaining of trans-3-[4-(5-amino-2-hydroxybenzoyl)-3-methoxyphenyl]2-propenoyl 4-(nitroxy)butyl ester
The final compound is obtained by hydrolizing the bond between the aminic function and the N-ter-butoxycarbonyl protective group as described in Example 9, step e). Yields: 28%.
Elementary analysis:
EXAMPLE 16
Preparation of 6-methylen-5-hydroxy-10[2-hydroxy-5-(4-nitroxybutyryloxy)benzoyl]tetracycline of formula (NCX 2163)
In a solution of 4-bromobutyrylchloride (3 g, 16.17 mmoles) in tetrahydrofuran (50 ml), cooled at 0° C., triethylamine (4.5 ml, 32.34 mmoles) and then gentisic acid (2.4 g, 16.16 mmoli) are dropped under stirring. It is let react at 0° C. for 4 hours, under stirring, hen it is evaporated at reduced pressure. The obtained crude product is treated with ethyl acetate, the organic phase is washed with HCl 1% and then brine. The organic phase is anhydrified with sodium sulphate and dried. The obtained residue is purified by chromatography on silica gel column, eluting with methylene chloride/methanol 95/5, obtaining the 5-(4-broobutyryloxy)-2-hydroxy-benzoic acid.
b) Synthesis of 5-(4-nitroxybutyroyloxy)-2-hydroxywbenzbic acid
To a solution of 5-(4-bromobutyryloxy)-2-hydroxy-benzoic acid (3 g, 9.6 mmoles) in acetonitrile (150 ml) silver nitrate (1.7 g, 10 mmoles) is added under stirring. The mixture is heated under reflux for 7 hours away from light. Lastly the formed salt is removed by Filtration and the solution is evaporated at reduced pressure. The obtained residue is purified by chromatography on silica gel column, eluting with methylene chloride/methanol 95/5. In this way the 5-(4-nitroxybutyryloxy)-2-hydroxy-benzoic acid is isolated at the pure state.
c) Synthesis of 6-methylen-5-hydroxy-10[2-hydroxy-5-(4-nitroxybutyryloxy)benzoyl)tetracycline
A solution of 5-(4-nitroxybutyryloxy)-2-hydroxy-benzoic acid (5 g, 16.4 mmoles) and 1,1′-carbonyldiimidazol (2.67 g, 16.4 mmoles) in tetrahydrofuran (70 ml) is maintained under stirring at room temperature for 1 hour. Adriamycin (7.2 g, 16.4 mmoles) is added. It is reacted under stirring for 12 hours at room temperature. The organic solution is then evaporated at reduced pressure, the obtained residue is treated with ethyl acetate and washed with brine. The organic phase, anhydrified with sodium sulphate, is dried under vacuum obtained residue is purified by chromatography on silica gel column eluting with ethyl acetate. 6-methylen-5-hydroxy-10[2-hydroxy-5-(4-nitroxybutyryloxy)benzoyl]tetracycline is obtained. Yield: 19%.
Elementary analysis:
EXAMPLE 17
Preparation of 5-[[3-(3-methoxy-4-(4-nitroxy)butyryloxy]phenyl-2-trans-propenoyl]amino)-1,2,3,4-tetrahydroacridine (NCX 2214)
The compound is synthetized according to the procedure reported in Example 10. Yield 7%
Elementary analysis
EXAMPLE 18
Preparation of [1S-[1α, 3α,7β,8β, (2S*,4S*)]]-2,2-dimethylbutanoic acid 1,2,3,7,8,8-hexahydro-3,7-dimethyl-8-[tetrahydro-4-[2-hydroxy-5-(4-nitroxybutyryloxy) benzoyl-oxy[-6-oxo-2H-piran-2-yl]ethyl]-1-naphthalenyl ester (NCX 2164)
The compound is synthetized following the method described in Example 16. Yield: 13%.
Elementary analysis:
EXAMPLE 21
Preparation of N-acetyl-S-(4-nitroxybutyroyl) cisteine 1-[(1-methylethyl) amino]-3-(1-naphthalen oxy)-2-propanol ester (NCX 2132)
The compound is synthetized with the process described in Example 14. Yields: 7%.
Elementary analysis:
EXAMPLE 22
Preparation of 2-(ter-butylamino)-1-[4-hydroxy-3-[N-acetyl-S-(4-nitroxybutyryl)-penicillaminoyl] oxyphenyl)ethanol (NCX 2133)
The compound is synthetized by following the procedure reported in Example 14, using N-acetyl penicillamine instead of N-acetylcisteine. Yields: 43%
Elementary analysis:
EXAMPLE 23
Preparation of 7-[2-hydroxy-3-[3-methoxy-5-(4-nitrooxybutyryloxy)benzoyl]trans-2-propenoyl]theophylline (NCX 2213)
The drug is synthetized according to the process described in Example 9. Yield: 22%
Elementary analysis:
EXAMPLE 24
Preparation of N-acetyl-S-(2-acetylbenzoyl)cisteine 4-(nitroxy)butyl ester (NCX2138) of formula
The compound is synthetized according to the process described in Example 1. Yield 36%.
Elementary analaysis
EXAMPLE 25
Preparation of 4-(3-[3-methoxy-5-(4-nitroxybutyryloxy)phenyl]-2-propenoyloxy]-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (NCX2215)
Elementary analysis
EXAMPLE 26
Preparation of S-[2-[(2,6-dichlorophenyl)amino)benzeneacetiloxy]penicillamine 4 (nitroxy)butyl ester (NCX 2061) of formula
The compound is synthetized according to the process described in Example 11. Yield 21%.
Elementary analysis
EXAMPLE 27
Synthesis of (S)-N-acetyl-S-[[1-[5-(2,5-dihydro-5-oxo-3-furanyl)-3-methyl-2-benzofuranyl]ethyloxy)-4-oxo-butanoyl) cysteine (4-nitroxy)butyl ester of formula
The compound is synthetized according to the process described in Example 4. Yield 25%.
Elementary analysis
EXAMPLE 28
Synthesis of (8S-cis)-10[(3-amino,2,3,6-tri-deoxy-α-L-lyxo-exo pyranosyl)oxy]-7,8,9,10-tetrahydro,6,8,11-trihydroxy-8-([[3-methoxy-4-(4-nitroxybutanoyl)phenyl]-2-trans-propenoyl-oxy] methyl-oxoj-1-methoxy-5,12-naohtacenedione of formula
Elementary analysis
