Method for producing pyrazoles, novel pyrazoles and applications thereof

Abstract

A method for preparing a pyrazole of formula (I) in which R,R′ and R″ have different meanings, characterised in that it involves reacting a sydnone of formula (II) in which R and R′ have the meanings already indicated, with an alkyne of formula (III) in which R″ has the meaning already indicated, in the presence of copper, to obtain a pyrazole compound of formula (I) that is then isolated and salified if desired. ##STR00001##

Claims

1. A process for preparing a pyrazole of formula I ##STR00032## in which R represents a hydrogen atom; a halogen atom; a thio or -thioalkyl group; a hydroxyl or alkoxy group; an amino or -aminoalkyl group; an alkyl radical containing from 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with F, Cl, Br, I , CN, OH, NH2, NH—(C1-C8 alkyl), N—(C1-C8 alkyl)2, SH; an aryl radical containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times with an alkyl or alkoxy radical containing 1 to 8 carbon atoms; a heterocycle; an amino acid; a polypeptide; a protein; a nucleic acid; a DNA molecule; a polysaccharide; a polymer; a nanoparticle; a dendrimer; R′ represents a hydrogen atom; a halogen atom; a thio or -thioalkyl group; a hydroxyl or, alkoxy group; an amino or -aminoalkyl group; an alkyl radical containing from 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with F, Cl, Br, I, CN, OH, NH2, NH—(C1-C8 alkyl), N—(C1-C8 alkyl) 2, SH; an aryl radical containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times with an alkyl or alkoxy radical containing 1 to 8 carbon atoms; a heterocycle; R″ represents a hydrogen atom; a halogen atom; a thio group; a hydroxyl group; an amino group; a hydrocarbon-based group or a hydrocarbon-based group containing from 1 to 100 heteroatoms; wherein a sydnone of formula II ##STR00033## in which R and R′ have be meanings already indicated, is reacted with an alkyne of formula III ##STR00034## in which R″ has the meaning already indicated, in the presence of copper salt complexed with a nitrogenous ligand used as a catalyst metal, so as to obtain a pyrazole compound of formula I which is isolated and salified if desired.

2. A process as claimed in claim 1, wherein R represents an unsubstituted or substituted aryl or heteroaryl radical.

3. A process as claimed in claim 1, wherein R′ represents a hydrogen atom.

4. A process as claimed in claim 1, wherein R″ represents a hydrogen atom; a halogen atom; a thio or -thioalkyl group; a hydroxyl or alkoxy group; an amino or -aminoalkyl group; an alkyl radical containing from 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with F, Cl, Br, I, CN, OH, —O-heterocycle which is substituted or unsubstituted, NH2, —NH—(C1-C8 alkyl), —N—(C1-C8 alkyl)2, —NH—R′″ or —(C1-C3 alkyl)—NH—R″′ where R″′ represents a sulfonated group, SH; an aryl radical containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times with an alkyl or alkoxy radical containing 1 to 8 carbon atoms; a heterocycle; an amino acid; a. polypeptide; a protein; a nucleic acid; a DNA molecule; a polysaccharide; a polymer; a nanoparticle; a dendrimer.

5. A process as claimed in claim 4, wherein R″ represents a heteroaryl radical or an aryl radical or an alkyl radical containing from 1 to 8 carbon atoms.

6. A process as claimed in claim 1, wherein the nitrogenous ligand is chosen from phenanthrolines, triazoles, pyridines, imidazoles and benzimidazoles.

Description

EXAMPLES 1 TO 6

(1) Compounds of the pyrazole of formula I in which R represents a phenyl radical, R′ represents a hydrogen atom and R″ represents a benzyl radical were prepared in accordance with the reaction below,

(2) ##STR00008##
according to the procedures of the invention set out below:
Procedure A

(3) 200 μl of a freshly prepared aqueous solution of copper sulfate pentahydrate (5 mg, 0.02 mmol) (0.2 eq.) in bathophenanthrolinedisulfonic acid disodium salt trihydrate (11.8 mg, 0.02 mmol) and triethanolamine (15 mg, 0.1 mmol) were added to a solution of sydnone (0.1 mmol), of alkyne (0.1 mmol), of sodium ascorbate (39.6 mg, 0.2 mmol) and of triethanolamine (15 mg, 0.1 mmol) in 1.8 ml of water. The resulting mixture was brought to 60° C. for 16 h with stirring, and then cooled with 2 ml of a 0.05 M solution of HEDTA and extracted with 3×5 ml of methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and concentrated so as to obtain the expected product, which was subjected to a further purification by flash chromatography.

(4) Procedure B

(5) A solution of sydnone (0.5 mmol), of alkyne (0.5 mmol), of triethylamine (0.5 mmol) and of 1,10-phenanthroline (0.1 mmol) in 10 ml of anhydrous dimethylformamide were poured into a flask containing copper iodide (0.1 mmol) under argon. The resulting mixture was brought to 60° C. under argon for 16 h, with stirring, and then concentrated. The residue was dissolved in 10 ml of methylene chloride and washed with 10 ml of a 0.05 M solution of HEDTA. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the expected product, which was subjected to a further purification by flash chromatography.

(6) Procedure C

(7) Copper sulfate pentahydrate (5 mg, 0.02 mmol) (0.2 eq.) was added to a solution of sydnone (0.1 mmol), of alkyne (0.1 mmol), of sodium ascorbate (39.6 mg, 0.2 mmol), of triethylamine (0.1 mmol) and of 1,10-phenanthroline (0.02 mmol) in 2 ml of a tert-butanol/water mixture (1:1). The resulting mixture was stirred for 16 h at 60° C. and then cooled with 2 ml of a 0.05 M solution of HEDTA and extracted with 3×5 ml of methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and concentrated so as to obtain the expected product, which was subjected to a further purification by flash chromatography.

(8) Procedure C′

(9) 200 μl of a freshly prepared aqueous solution of copper sulfate pentahydrate (5 mg, 0.02 mmol) (0.2 eq.) in bathophenanthrolinedisulfonic acid disodium salt trihydrate (11.8 mg, 0.02 mmol) and triethanolamine (15 mg, 0.1 mmol) were added to a solution of sydnone (0.1 mmol), of alkyne (0.1 mmol), and of sodium ascorbate (39.6 mg, 0.2 mmol) in 1.8 ml of a tert-butanol/water mixture (55:45). The resulting mixture was stirred for 16 h at 60° C. and then cooled with 2 ml of a 0.05 M solution of HEDTA and extracted with 3×5 ml of methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and concentrated so as to obtain the expected product, which was subjected to a further purification by flash chromatography.

(10) Procedure D

(11) The process was carried out as in procedure C, but by performing the reaction at ambient temperature.

(12) Procedure E

(13) The process was carried out as in procedure B, but without triethylamine.

(14) Procedure F

(15) The process was carried out as in procedure C, but without copper ligand (without 1,10-phenanthroline) and at 100° C. in place of 60° C.

(16) Procedure G

(17) The process was carried out as in procedure C, but using the ligand 3,10-diphenyldiimidazo[1,2-a:2′,1′-c]quinoxaline (VIIIa) in place of 1,10-phenanthroline.

(18) ##STR00009##

3,10-diphenyldiimidazo[1,2-a:2′,1′-c]quinoxaline

(19) The results obtained are reported in table 1 below.

(20) TABLE-US-00001 TABLE 1 % yield 3a/3a′ ratio Procedure A 99 100/0 Procedure B 92 100/0 Procedure C 99 100/0 Procedure C′ 99 100/0 Procedure D 67 100/0 Procedure E 62 100/0 Procedure F 16 100/0 Procedure G 40 100/0

(21) Thus, an excellent yield is obtained, in particular using the protocols A, B, C and C′, and in addition the regioselectivity of the reaction is complete in favor of the compound 3a, this being in very varied aqueous, organic or mixed media.

COMPARATIVE EXAMPLE 1

(22) By way of comparison, the same reagents were also used to react them by the thermal route according to the prior art, under the following conditions: Solvent=DMF−Reflux (153° C.)−reaction time=16 h.

(23) A yield of only 15% and a mixture of isomers 3a and 3a′ in a 3a/3a′ ratio=25/75 were obtained.

EXAMPLES 7 AND 8

4-phenethyl-1-phenyl-1H-pyrazole

(24) ##STR00010##

(25) The product of the title of example 7 was prepared from 3-phenylsydnone and 4-phenyl-1-butyne using procedure C, with purification by flash chromatography (ethyl acetate (EtOAc)/cyclohexane=20/80). The product was obtained in the form of a yellow oil with a yield of 96%.

(26) By carrying out the process under the conditions of procedure B, the product was obtained with a yield of 90%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 7.67 (s, 1 H), 7.65 (s, 2 H), 7.56 (s, 1 H), 7.46 (t, J=8.0 Hz, 2 H), 7.20-7.37 (m, 6 H), 2.93-3.00 (m, 2 H), 2.86-2.93 (m, 2 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 141.6, 141.0, 140.3, 129.5, 128.6, 128.5, 126.2, 125.0, 123.1, 118.9, 37.2, 26.3.

EXAMPLE 9

(1-phenyl-1H-pyrazol-4-yl)methyl benzoate

(27) ##STR00011##

(28) The product of the title of example 9 was prepared from 3-phenylsydnone and prop-2-yn-1-yl benzoate using procedure C, with purification by flash chromatography (EtOAc/cyclohexane=20/80). The product was obtained in the form of a yellow oil with a yield of 93%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 8.05 (m, 3 H), 7.82 (s, 1 H), 7.68 (d, J=7.7 Hz, 2 H), 7.56 (t, J=7.5 Hz, 1 H), 7.49-7.38 (m, 4 H), 7.30 (t, J=7.5 Hz, 1 H), 5.34 (s, 2 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 166.7, 141.7, 140.1, 133.2, 130.2, 129.8, 129.6, 128.5, 127.7, 126.9, 119.4, 118.6, 57.8.

EXAMPLE 10

2-(1-phenyl-1H-pyrazol-4-yl)propan-2-ol

(29) ##STR00012##

(30) The product of the title of example 10 was prepared from 3-phenylsydnone and 2-methyl-3-butyn-2-ol using procedure C, with purification by flash chromatography (EtOAc/cyclohexane=10/90). The product was obtained in the form of a white solid with a yield of 83%. .sup.1H NMR (400 MHz, Methanol-d.sub.4, δ ppm): 8.12 (s, 1 H), 7.75-7.65 (m, 3 H), 7.47 (t, J=8.1 Hz, 2 H), 7.31 (t, J=7.3 Hz, 1 H), 1.59 (s, 6 H). .sup.13C NMR (100 MHz, Methanol-d.sub.4, δ ppm): 141.6, 139.7, 135.0, 130.7, 127.8, 125.7, 120.4, 68.7, 31.9.

EXAMPLE 11

1,4-diphenyl-1H-pyrazole

(31) ##STR00013##

(32) The product of the title of example 11 was prepared from 3-phenylsydnone and phenylacetylene using procedure C, with purification by flash chromatography (EtOAc/cyclohexane=20/80). The product was obtained in the form of a white solid with a yield of 80%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 8.19 (s, 1 H), 8.04 (s, 1 H), 7.77 (d, J=8.1 Hz, 2 H), 7.59 (d, J=7.7 Hz, 2 H), 7.51 (t, J=7.8 Hz, 2 H), 7.44 (t, J=7.7 Hz, 2 H), 7.37-7.27 (m, 2 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 140.2, 138.9, 132.2, 129.6, 129.1, 127.0, 126.7, 125.8, 125.0, 123.5, 119.2.

EXAMPLE 12

4-heptyl-1-phenyl-1H-pyrazole

(33) ##STR00014##

(34) The product of the title of example 12 was prepared from 3-phenylsydnone and 1-nonyne using procedure C′, with purification by flash chromatography (EtOAc/cyclohexane=20/80). The product was obtained in the form of a yellow oil with a yield of 61%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 7.70 (s, 1 H), 7.66 (d, J=7.7 Hz, 2 H), 7.55 (s, 1 H), 7.43 (t, J=7.9 Hz, 2 H), 7.25 (t, J=7.3 Hz, 1 H), 2.52 (t, J=7.7 Hz, 2 H), 1.61 (quin, J=7.4 Hz, 2 H), 1.38-1.28 (m, 8 H), 0.89 (t, J=6.8 Hz, 3 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 141.1, 140.4, 129.5, 126.1, 124.8, 124.2, 118.9, 32.0, 30.9, 29.4, 29.3, 24.3, 22.8, 14.2.

EXAMPLE 13

4-(4-phenethyl-1H-pyrazol-1-yl)benzoic acid

(35) ##STR00015##

(36) The product of the title of example 13 was prepared from 3-(4-carboxyphenyl)sydnone and 4-phenyl-1-butyne using procedure C′. The product was obtained in the form of a white solid with a yield of 99%. .sup.1H NMR (400 MHz, DMSO-d.sub.6, δ ppm): 12.98 (br. s., 1 H), 8.40 (s, 1 H), 8.04 (d, J=8.6 Hz, 2 H), 7.90 (d, J=8.6 Hz, 2 H), 7.63 (s, 1 H), 7.32-7.21 (m, 4 H), 7.17 (t, J=6.8 Hz, 1 H), 2.90 (t, J=7.7 Hz, 2 H), 2.79 (t, J=7.7 Hz, 2 H). .sup.13C NMR (100 MHz, DMSO-d.sub.6, δ ppm): 166.7, 142.8, 141.8, 141.4, 130.9, 128.3, 128.3, 127.7, 126.0, 125.9, 123.6, 117.4, 36.0, 25.6.

EXAMPLES 14, 15, 16

4-(4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)benzoic acid

(37) ##STR00016##

(38) The product of the title of example 14 was prepared from 3-(4-carboxyphenyl)sydnone and 2-methyl-3-butyn-2-ol using procedure A, with the process being carried out at 37° C. The product was obtained in the form of a white solid with a yield of 93%.

(39) By carrying out the process under the conditions of procedure A but using human blood plasma as solvent, the product was obtained with a yield of 88%.

(40) By carrying out the process under the conditions of procedure C, the product was obtained with a yield of 91%. .sup.1H NMR (400 MHz, Methanol-d.sub.4, δ ppm): 8.27 (s, 1 H), 8.14 (d, J=8.8 Hz, 2 H), 7.87 (d, J=8.8 Hz, 2 H), 7.77 (s, 1 H), 1.61 (s, 6 H) .sup.13C NMR (100 MHz, Methanol-d.sub.4, δ ppm): 169.2, 144.8, 140.7, 135.7, 132.5, 125.6, 119.4, 68.7, 31.9.

EXAMPLE 17

(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((1-phenyl-1H-pyrazol-4-yl)methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

(41) ##STR00017##

(42) The product of the title of example 17 was prepared from 3-(phenyl)sydnone and 2-propynyl-tetra-O-acetyl-β-D-glucopyranoside using procedure C. The product was obtained in the form of a white solid with a yield of 96%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 7.89 (s, 1 H), 7.68-7.62 (m, 3 H), 7.44 (t, J=7.9 Hz, 2 H), 7.28 (t, J=7.2 Hz, 1 H), 5.19 (t, J=9.5 Hz, 1 H), 5.10 (t, J=9.5 Hz, 1 H), 5.03 (t, J=9.1 Hz, 1 H), 4.83 (d, J=12.4 Hz, 1 H), 4.66-4.59 (m, 2 H), 4.27 (dd, J=4.8, 12.2 Hz, 1 H), 4.18 (dd, J=2.3, 12.2 Hz, 1 H), 3.76-3.66 (m, 1 H), 2.09 (s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H), 1.98 (s, 3 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 170.8, 170.3, 169.5, 169.4, 140.9, 140.0, 129.5, 126.8, 126.6, 119.2, 119.0, 99.2, 72.9, 71.9, 71.3, 69.2, 68.5, 62.1, 62.0, 20.8, 20.7, 20.6.

EXAMPLE 18

4-(4-methoxyphenyl)-1-phenyl-1H-pyrazole

(43) ##STR00018##

(44) The product of the title of example 18 was prepared from 3-(phenyl)sydnone and 1-ethynyl-4-methoxybenzene using procedure C′, with purification by flash chromatography (EtOAc/cyclohexane=20/80). The product was obtained in the form of a white solid with a yield of 64%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 8.09 (s, 1 H), 7.94 (s, 1 H), 7.73 (d, J=8.2 Hz, 2 H), 7.48 (t, J=8.2 Hz, 4 H), 7.30 (t, J=7.3 Hz, 1 H), 6.95 (d, J=8.6 Hz, 2 H), 3.85 (s, 3 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 158.8, 140.2, 138.7, 129.6, 127.1, 126.7, 124.8, 124.8, 123.0, 119.2, 114.6, 55.5.

EXAMPLE 19

2-(1-phenyl-1H-pyrazol-4-yl)pyridine

(45) ##STR00019##

(46) The product of the title of example 19 was prepared from 3-(phenyl)sydnone and 2-ethynylpyridine using procedure C′. The product was obtained in the form of a white solid with a yield of 95%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 8.62 (d, J=4.8 Hz, 1 H), 8.55 (s, 1 H), 8.20 (s, 1 H), 7.78 (d, J=7.9 Hz, 2 H), 7.72 (dt, J=1.6, 7.7 Hz, 1 H), 7.57 (d, J=8.1 Hz, 1 H), 7.50 (t, J=8.0 Hz, 2 H), 7.33 (t, J=7.3 Hz, 1 H), 7.20-7.12 (m, 1 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 151.5, 149.7, 140.0, 139.3, 136.9, 129.6, 126.9, 125.4, 125.2, 121.6, 119.9, 119.3.

EXAMPLE 20

1-phenyl-4-(thiophen-3-yl)-1H-pyrazole

(47) ##STR00020##

(48) The product of the title of example 20 was prepared from 3-(phenyl)sydnone and 2-ethynylthiophene using procedure C′. The product was obtained in the form of a white solid with a yield of 99%. .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 8.11 (s, 1 H), 7.95 (s, 1 H), 7.75 (d, J=8.0 Hz, 2 H), 7.49 (t, J=8.0 Hz, 2 H), 7.42-7.38 (m, 1 H), 7.38-7.27 (m, 3 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 140.1, 139.2, 132.9, 129.6, 126.6, 126.4, 126.2, 123.4, 120.4, 119.1, 115.1.

EXAMPLE 21

4-(4-((5-(dimethylamino)naphthalene-1-sulfonamido)-methyl)-1H-pyrazol-1-yl)benzoic acid

(49) ##STR00021##

(50) The product of the title of example 21 was prepared from 3-(4-carboxyphenyl)sydnone and 5-(dimethylamino)-N-(prop-2-yn-1-yl)naphthalene-1-sulfonamide using procedure C′, with the process being carried out at 37° C., and with purification by flash chromatography (EtOAc/cyclohexane/AcOH=49/49/2). The product was obtained in the form of a yellow solid with a yield of 59%. .sup.1H NMR (400 MHz, Methanol-d.sub.4, δ ppm): 8.40 (d, J=8.4 Hz, 1 H), 8.28 (d, J=8.6 Hz, 1 H), 8.20 (d, J=7.4 Hz, 1 H), 8.03 (d, J=8.8 Hz, 2 H), 7.59-7.42 (m, 5 H), 7.20 (s, 1 H), 7.17 (d, J=7.5 Hz, 1 H), 4.10 (s, 2 H), 2.73 (s, 6 H). .sup.13C NMR (100 MHz, Methanol-d.sub.4, δ ppm): 169.2, 153.3, 144.1, 142.3, 137.5, 132.3, 131.4, 131.1, 131.1, 130.7, 129.9, 129.2, 127.7, 124.3, 121.9, 120.5, 119.2, 116.4, 45.8, 38.0.

EXAMPLE 22

2-(6-(diethylamino)-3-(diethyliminio)-3H-xanthen-9-yl)-5-(N-((1-phenyl-1H-pyrazol-4-yl)methyl)sulfamoyl)benzenesulfonate

(51) ##STR00022##

(52) The product of the title of example 22 was prepared from 3-(phenyl)sydnone and 2-(6-(diethylamino)-3-(diethyliminio)-3H-xanthen-9-yl)-5-(N-(prop-2-yn-1-yl)sulfamoyl)benzenesulfonate using procedure C′ and isolation by filtration from the reaction medium. The product was obtained in the form of a violet solid with a yield of 92%. .sup.1H NMR (400 MHz, DMSO-d.sub.6, δ ppm): 8.47 (d, J=1.6 Hz, 1 H), 8.38 (br. s., 1 H), 8.32 (s, 1 H), 7.91 (dd, J=1.6, 8.0 Hz, 1 H), 7.76 (d, J=7.9 Hz, 2 H), 7.51 (s, 1 H), 7.45 (t, J=7.9 Hz, 2 H), 7.39 (d, J=7.9 Hz, 1 H), 7.28 (t, J=7.3 Hz, 1 H), 6.98-6.86 (m, 6 H), 4.12 (d, J=2.8 Hz, 2 H), 3.69-3.56 (m, 8 H), 1.20 (t, J=7.0 Hz, 12 H).

(53) MS (ESI) m/z: 714.3 [M+H].sup.+.

EXAMPLE 23

tris((1-phenyl-1H-pyrazol-4-yl)methyl)amine

(54) ##STR00023##

(55) Copper sulfate pentahydrate (0.15 mmol) was added to a solution of 3-phenylsydnone (0.9 mmol), tripropargylamine (0.1 mmol), sodium ascorbate (1.5 mmol), triethylamine (0.9 mmol) and 1,10-phenanthroline (0.15 mmol) in 18 ml of a tert-butanol/water mixture (1:1).

(56) The resulting mixture was stirred in a closed flask at 60° C. for 16 h. The second portion of sodium ascorbate (1.5 mmol), of 1,10-phenanthroline (0.15 mmol) and of the copper sulfate pentahydrate (0.15 mmol) was then added to the mixture and the new mixture was stirred at 60° C. for a further 24 h.

(57) After cooling to ambient temperature, the mixture was diluted with 20 ml of a 0.05 M solution of HEDTA and was extracted with 3×30 ml of methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and concentrated so as to obtain 127.3 mg of the expected product in the form of a white solid, 0.26 mmol, yield 85%, which was subjected to a further purification by flash chromatography (CH.sub.2Cl.sub.2/EtOAc=80/20 to 0/100). .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 7.91 (s, 3 H), 7.73 (s, 3 H), 7.71 (d, J=8.0 Hz, 6 H), 7.47 (t, J=7.9 Hz, 6 H), 7.30 (t, J=8.2 Hz, 3 H), 3.67 (s, 6 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 141.7, 140.2, 129.6, 126.5, 126.4, 120.3, 119.0, 47.1.

EXAMPLE 24

labeling of a peptide with a fluorophore: 2-(2-(2-(4-(4-((5-(dimethylamino)naphthalene-1-sulfonamido)methyl)-1H-pyrazol-1-yl)-benzamido)acetamido)-3-(1H-indol-3-yl)propanamido)acetic acid

(58) ##STR00024##

(59) 200 μl of a freshly prepared aqueous solution of copper sulfate pentahydrate (0.9 mg, 3.6 μmol), bathophenanthrolinedisulfonic acid disodium salt trihydrate (2.1 mg, 3.6 μmol) and triethanolamine (1.8 mg, 12 μmol) were added to a solution of 3-(4-((2-((1-((carboxymethyl)amino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)amino)-2-oxoethyl)carbamoyl)phenyl)-1,2,3-oxadiazol-3-ium-5-olate (6 mg, 12 μmol), N-dansyl-N-propargylamine (4.5 mg, 16 μmol), sodium ascorbate (7 mg, 36 μmol) and triethanolamine (1.8 mg, 12 μmol) in 1 ml of water. The resulting mixture was stirred at 37° C. for 16 h. A liquid chromatography/mass spectrometry analysis of the resulting mixture showed complete conversion of the starting product. The mixture was concentrated and purified by high performance liquid chromatography on a C18 XBridge 19×150 mm, 5 μm column so as to give the expected product labeled with dansyl. .sup.1H NMR (400 MHz, Methanol-d.sub.4, δ ppm): 8.43 (d, J=8.4 Hz, 1 H), 8.30 (d, J=8.6 Hz, 1 H), 8.22 (d, J=6.6 Hz, 1 H), 7.86 (d, J=8.8 Hz, 2 H), 7.63-7.55 (m, 3 H), 7.54-7.46 (m, 3 H), 7.31 (d, J=8.1 Hz, 1 H), 7.22 (s, 1 H), 7.20 (d, J=7.5 Hz, 1 H), 7.16 (s, 1 H), 7.07 (t, J=7.1 Hz, 1 H), 7.00 (t, J=7.5 Hz, 1 H), 4.80 (dd, J=5.4, 7.8 Hz, 1 H), 4.12 (s, 2 H), 4.06 (d, J=16.5 Hz, 1 H), 4.01-3.83 (m, 3 H), 3.44-3.38 (m, 1 H), 3.25-3.12 (m, 1 H), 2.76 (s, 6 H).

(60) MS (ESI) m/z: 751.4 [M+H].sup.+.

EXAMPLE 25

Labeling of a Protein with a Fluorophore

(61) ##STR00025##

(62) The process was carried out as above, but using, as starting sydnone, the sydnone coupled to bovine serum albumin prepared hereinafter. The process was carried out at ambient temperature for 16 h under the following conditions:

(63) Sydnone coupled to bovine serum albumin: 1 mg/ml-0.18 μmol, 1 eq.

(64) N-dansyl-N-propargylamine: 1.8 μmol, 10 eq.

(65) CuSO.sub.4: 1.8 μmol, 10 eq.

(66) Bathophenanthroline: 1.8 μmol, 10 eq.

(67) Sodium ascorbate: 18 μmol, 100 eq.

(68) After revealing the proteins with Coomassie blue and measuring the fluorescence of the dansyl λ.sub.ex=320 nm, λ.sub.em=320 nm, it was found that an average number of dansyl residues of 1.6 were grafted onto the bovine serum albumin.

(69) Thus, the process of the invention can be carried out on starting sydnones carrying biological molecules.

EXAMPLE 26

(R)-(1-phenyl-1H-pyrazol-4-yl)methyl 2-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenoxy)propanoate

(70) ##STR00026##

(71) The product of the title of example 26 was prepared from 3-(phenyl)sydnone and clodinafop-propargyl using procedure C′ with purification by flash chromatography (EtOAc/cyclohexane=30/70). The product was obtained in the form of a white solid with a yield of 62%. .sup.1H NMR (400 MHz, Methanol-d.sub.4, δ ppm): 8.15 (s, 1 H), 7.79 (d, J=2.2 Hz, 1 H), 7.75 (dd, J=2.2, 9.5 Hz, 1 H), 7.70 (s, 1 H), 7.66 (d, J=7.9 Hz, 2 H), 7.44 (t, J=7.9 Hz, 2 H), 7.30 (t, J=7.3 Hz, 1 H), 6.99 (d, J=9.0 Hz, 2 H), 6.86 (d, J=9.0 Hz, 2 H), 5.19 (s, 2 H), 4.85 (q, J=6.8 Hz, 1 H), 1.58 (d, J=6.8 Hz, 3 H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 173.8, 156.4, 152.7, 148.6, 148.5, 142.7, 141.3, 141.2, 130.7, 129.6, 128.1, 126.5, 126.3, 123.4, 120.5, 119.8, 117.2, 74.3, 59.0, 18.9.

(72) MS (ESI) m/z: 468.0 [M(.sup.35Cl)+H].sup.+, 469.8 [M(.sup.37Cl)+H].sup.+.

EXAMPLE 27

1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetra-hydrofuran-2-yl)-5-(1-phenyl-1H-pyrazol-4-yl)pyrimidine-2,4(1H,3H)-dione

(73) ##STR00027##

(74) The product of the title of example 27 was prepared from 3-(phenyl)sydnone and 5-ethynyl-2′-deoxyuridine using procedure C′ and isolation by filtration from the reaction medium. The product was obtained in the form of a white solid with a yield of 84%. .sup.1H NMR (400 MHz, DMSO-d6, δ ppm): 8.68 (s, 1 H), 8.48 (s, 1 H), 8.05 (s, 1 H), 7.81 (d, J=7.9 Hz, 2 H), 7.50 (t, J=7.9 Hz, 2 H), 7.32 (t, J=7.9 Hz, 1 H), 6.23 (t, J=6.4 Hz, 1 H), 4.33 (br. s, 1 H), 3.84 (d, J=3.0 Hz, 1 H), 3.73 (dd, J=3.0, 11.9 Hz, 1 H), 3.66 (dd, J=3.0, 11.9 Hz, 1 H), 2.32-2.13 (m, 2 H). .sup.13C NMR (100 MHz, DMSO-d.sub.6, δ ppm): 162.1, 150.0, 139.9, 138.9, 135.8, 130.0, 126.7, 124.9, 118.7, 116.6, 106.2, 87.8, 85.0, 70.2, 61.1, 31.0.

(75) MS (ESI) m/z: 371.0 [M+H].sup.+, 741.3 [2M+H].sup.+.

EXAMPLE 28

ethyl 1-phenyl-1H-pyrazole-4-carboxylate

(76) ##STR00028##

(77) The product of the title of example 28 was prepared from 3-phenylsydnone and ethyl propionate using protocol F. The product was obtained with a yield of 84% after purification by chromatography (EtOAc/cyclohexane=10/90). .sup.1H NMR (400 MHz, CDCl.sub.3, δ ppm): 8.39 (s, 1H), 8.08 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.45 (t, J=8.0 Hz, 2H), 7.32 (t, J=7.3 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3, δ ppm): 162.9, 142.2, 139.4, 130.0, 129.6, 127.6, 119.6, 117.0, 60.5, 14.5.

(78) IR (NaCl, cm.sup.−1): 3124, 3063, 2984, 2901, 1709, 1597, 1560, 1505, 1463, 1413, 1390, 1258, 1150, 1027, 996, 951, 887, 825, 770, 757, 688, 654.

(79) MS (ESI) m/z: 217.1[M+H].sup.+.

(80) HRMS (ESI) m/z: calc. for C.sub.12H.sub.13N.sub.2O.sub.2: 217.0977; found: 217.0971.

EXAMPLE 29

5-bromo-4-phenethyl-1-phenyl-1H-pyrazole

(81) ##STR00029##

(82) The product of the title of example 29 was prepared from 3-phenyl-4-bromosydnone and 4-phenyl-1-butyne using protocol G. The product was obtained in the form of a yellow solid with a yield of 74% after purification by chromatography (heptane/ethyl acetate: 95/5). .sup.1H NMR (Chloroform-d, 400 MHz): d=7.38-7.55 (m, 6 H), 7.28-7.34 (m, 2 H), 7.19-7.25 (m, 3 H), 2.89-2.95 (m, 2 H), 2.77-2.83 (m, 2 H) ppm; .sup.13C NMR (Chloroform-d, 101 MHz): d=141.4, 140.9, 139.4, 129.0, 128.6, 128.6, 128.3, 126.3, 125.6, 122.3, 112.6, 36.3, 26.7 ppm;

(83) IR (NaCl, cm.sup.−1): 3062, 3027, 2923, 2856, 1598, 1556, 1499, 1455, 1407, 1391, 1241, 1087, 1068, 961, 911, 851, 836, 760, 694;

(84) LCMS (ESI) C.sub.17H.sub.15BrN.sub.2 (M[.sup.79Br]+H) 326.9, (M[.sup.81Br]+H) 328.8.

EXAMPLE 30

5-bromo-1-(4-methoxyphenyl)-4-phenethyl-1H-pyrazole

(85) ##STR00030##

(86) The product of the title of example 30 was prepared from 3-(p-methoxyphenyl)-4-bromosydnone and 4-phenyl-1-butyne using protocol G. The product was obtained in the form of a yellow solid with a yield of 70% after purification by chromatography (heptane/ethyl acetate: 95/5). .sup.1H NMR (Chloroform-d, 400 MHz): d=7.49 (s, 1 H), 7.39-7.44 (m, 2 H), 7.28-7.34 (m, 2 H), 7.19-7.25 (m, 3 H), 6.95-7.01 (m, 2 H), 3.86 (s, 3 H), 2.88-2.95 (m, 2 H), 2.75-2.82 (m, 2 H) ppm; .sup.13C NMR (Chloroform-d, 101 MHz): d=159.4, 141.3, 140.3, 132.4, 128.6 (2C), 128.4 (2C), 127.0 (2C), 126.1, 121.7, 114.0 (2C), 112.9, 55.6, 36.1, 26.7 ppm; LCMS (ESI) C.sub.18H.sub.17BrN.sub.2O (M[.sup.79Br]+H) 357.3, (M[.sup.81Br]+H) 359.4.

(87) The starting sydnones of formula II can be prepared as follows:

(88) Stage A: Preparation of N-Nitrosylated Amino Acids

(89) A solution of 6.90 g of NaNO.sub.2 in 100 ml of water is added dropwise, over the course of 40 minutes, to a vigorously stirred suspension of N-aryl amino acid (0.1 mol) in 10% aqueous hydrochloric acid (100 ml). The resulting mixture was stirred at ambient temperature under nitrogen for 14 h. The expected product was recovered by filtration, washed with a small amount of methanol and dried so as to produce the expected N-nitrosylated compound.

(90) 4-((carboxymethyl)(nitroso)amino)benzoic acid was thus prepared in the form of a white solid with a yield of 72%. .sup.1H NMR (400 MHz, DMSO-d.sub.6, δ ppm): 8.08 (d, J=8.6 Hz, 2 H), 7.76 (d, J=8.6 Hz, 2 H), 4.81 (s, 2 H). .sup.13C NMR (100 MHz, DMSO-d.sub.6, δ ppm): 167.0, 166.6, 144.5, 130.7, 129.3, 119.0, 46.2.

(91) 2-(nitroso(phenyl)amino)acetic acid was also prepared in the form of a white solid with a yield of 89%. .sup.1H NMR (400 MHz, DMSO-d.sub.6, δ ppm): 7.62 (d, J=7.9 Hz, 2 H), 7.54 (t, J=7.9 Hz, 2 H), 7.43 (t, J=7.3 Hz, 1 H), 4.76 (s, 2 H). .sup.13C NMR (100 MHz, DMSO-d.sub.6, δ ppm): 167.2, 141.3, 129.5, 127.6, 119.9, 46.9.

(92) Stage B: Preparation of Sydnones of Formula II

(93) A mixture of 0.1 mol of N-nitrosylated amino acid and 100 ml of acetic anhydride was mixed for 3 h at 100°. The solution obtained was concentrated on a rotary evaporator. The residue was triturated with 100 ml of water. The precipitate was then recovered by filtration and recrystallized from methanol so as to obtain the expected pure product.

(94) 3-(4-carboxyphenyl)-1,2,3-oxadiazol-3-ium-5-olate was thus prepared in the form of a white solid with a yield of 52%. .sup.1H NMR (400 MHz, DMF-d.sub.7, δ ppm): 8.32 (d, J=8.5 Hz, 2 H), 8.19 (d, J=8.5 Hz, 2 H), 7.88 (s, 1 H). .sup.13C NMR (100 MHz, DMF-d.sub.7, δ ppm): 169.7, 167.1, 138.9, 135.7, 132.3, 123.1, 96.1.

(95) 3-phenyl-1,2,3-oxadiazol-3-ium-5-olate was also prepared in the form of a white solid with a yield of 55%. .sup.1H NMR (400 MHz, DMSO-d.sub.6, δ ppm): 7.94 (dd, J=1.5, 8.1 Hz, 2 H), 7.78 (s, 1 H), 7.77-7.67 (m, 3 H). .sup.13C NMR (100 MHz, DMSO-d.sub.6, δ ppm): 168.5, 132.4, 130.2, 126.6, 121.6, 94.9.

Preparation of a sydnone of formula II carrying a tripeptide: 3-(4-((2-((1-((carboxymethyl)amino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)amino)-2-oxoethyl)carbamoyl)phenyl)-1,2,3-oxadiazol-3-ium-5-olate

(96) ##STR00031##

(97) N,N′-dicyclohexylcarbodiimide (13 mg, 0.063 mmol) was added to a solution of 3-(4-carboxyphenyl)sydnone (13 mg, 0.063 mmol) and of N-hydroxysuccinimide (8.7 mg, 0.076 mmol) in anhydrous dimethylformamide (1 ml) at 0° C. The resulting solution was stirred at ambient temperature for 24 h and was then filtered. The tripeptide H-Gly-Trp-Gly-OH (20 mg, 0.063 mmol) was then added to the filtrate and the solution was stirred at ambient temperature for a further 16 h. The mixture was then concentrated and the residue was purified by semi-preparative high performance liquid chromatography on a Phenomenex Synergi Fusion-RP 21.2×150 mm, 5 μm column so as to produce 13 mg of the expected product in the form of a white solid with a yield of 41%. .sup.1H NMR (400 MHz, Methanol-d.sub.4, δ ppm): 8.05 (d, J=8.8 Hz, 2 H), 7.98 (d, J=8.8 Hz, 2 H), 7.58 (d, J=8.8 Hz, 1 H), 7.48 (s, 1 H), 7.28 (d, J=8.1 Hz, 1 H), 7.14 (s, 1 H), 7.04 (t, J=7.3 Hz, 1 H), 6.97 (t, J=7.2 Hz, 1 H), 4.79 (dd, J=5.5, 7.7 Hz, 1 H), 4.07 (d, J=16.5 Hz, 1 H), 3.97 (d, J=16.5 Hz, 1 H), 3.94-3.82 (m, 2 H), 3.36 (dd, J=5.2, 14.7 Hz, 1 H), 3.17 (dd, J=8.1, 14.8 Hz, 1 H).

(98) MS (ESI) m/z: 507.1 [M+H].sup.+.

(99) Preparation of a Sydnone of Formula II Carrying a Protein: Bovine Serum Albumin (BSA)

(100) The process was carried out as above, but using bovine serum albumin instead of the tripeptide, so as to obtain the expected product, in which the bovine serum albumin carries 12 sydnones.