We claim as our invention:
1. A surface processing method comprising: forming a carrier gas stream containing submicron particles having average particle size in the range between 0.01 and 3.0 m, blowing said carrier gas stream against a surface of a work.
2. A surface processing method according to claim 1, said carrier gas stream is blown against the surface of the work with an incident angle less than 40 to cause deposition of a layer which comprises a material forming said particles.
3. A surface processing method according to claim 2, said incident angle is not more than 10.
4. A processing method according to claim 2 or 3, said particle has a hardness larger than a hardness of the surface of the work.
5. A processing method according to claim 1, said carrier gas stream is blown against the surface of the work with an incident angle between 40 and 90to cause etching of the surface of said work.
6. A processing method according to claim 1, said particles are blown against the surface of the work with velocity not less than 50 msec.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A 2,6-substituted-3-nitropyridine derivative compound represented by of formula 1:
wherein:
R1 is hydrogen, fluoro, a C1-C6 linear or branched alkyl group, a methoxy group, a methylsulfanyl group, a nitrile group, a hydroxyl group or NR3R4, wherein R3 and R4 each independently is H, a methyl group or an ethyl group, or R3 and R4 taken together form a saturated or unsaturated 5-, 6- or 7-membered heterocyclic amino compound that contains 1 to 3 hetero atoms selected from among N, O and S and is unsubstituted or substituted by a C1-C3 alkyl group, a hydroxyl group, a C1-C3 hydroxyalkyl group, an amino group, a carboxyl group or a carbamoyl group; with the proviso that when R1 represents a thiazolyl group
Y is substituted by a C1-C5 linear or branched alkyl group, a C1-C3 alkylamine or dialkylamine group or a C5-C6 saturated or unsaturated cyclic amine group, and Z is hydrogen or a C1-C3 alkyl group; and
R1 optionally contains an asymmetric carbon atom;
R2 is NR5(CH2)nR6a wherein R5 is H, a C1-C6 linear or branched alkyl group or an unsubstituted or substituted C3-C6 cyclic alkyl group, and R6 is H, a hydroxyl group, a phenyl group, a C1-C2 alkoxy group, a C1-C6 linear or branched alkylamine group, or a C1-C6 linear or branched alkyl group that is terminally substituted by a saturated or unsaturated 5 to 7-membered heterocyclic compound containing 1 to 3 hetero atoms selected from among N, O and S, or R5 and R6 taken together form a saturated or unsaturated 5 to 7-membered heterocyclic amine compound which contains 1 to 3 hetero atoms selected from among N, O and S and is unsubstituted or substituted by a C1-C3 alkyl group, an amine group, a hydroxyl group or a C1-C2 hydroxyalkyl group,
n is an integer of 0 to 3, and
X is hydrogen, a fluoro group, a hydroxyl group, an amino group, an acetyl group or a nitrile group;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein;
R1 is hydrogen, fluoro, a methyl group, an n-butyl group, a t-butyl group, a methoxy group, a methylsulfanyl group, a nitrile group, a hydroxyl group or NR3R4, wherein R3 and R4 each independently is H, a methyl group or an ethyl group, or R3 and R4 taken together form a heterocyclic compound that is morpholine, thiomorpholine, piperazine, piperidine, methylpiperidine, hydroxypiperidine, hydroxymethylpiperidine, aminopiperidine, 3- or 4-carbamoylpiperidine, carboxylicpiperidine, imidazol-1-yl or a thiazol-4-yl derivative
wherein Y is methyl, isopropyl, cyclohexyl or dipropylamino, and Z is hydrogen or a C1-C3 alkyl group,
R2 is NR5(CH2)nR6, wherein R5 is H, methyl, ethyl, isopropyl, cyclopropyl, n-butyl, isobutyl or t-butyl, and R6 is H, a hydroxyl group, a morpholinyl group, a phenyl group, a pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, imidazol-1-yl or 1,3-dioxolan-2-yl, or R5 and R6 taken together form a heterocyclic compound that is morpholine, piperazine, methylpiperazine, aminopiperidine, 2-methyl-4,5-dihydroimidazol-1-yl, 2-methylimidazol-1-yl or isopropylimidazol-1-yl,
n is an integer of 0 to 3, and
X is hydrogen, a fluoro group, an amino group, an acetyl group or a nitrile group.
3. The compound of claim 2, wherein the compound is selected from among:
2-(4-methylphenylamino)-6-(methylamino)-3-nitropyridine,
2-(4-methylphenylamino)-6-(isopropylamino)-3-nitropyridine,
2-(4-methylphenylamino)-6-(isobutylamino)-3-nitropyridine,
2-(4-methylphenylamino)-6-(N-1,3-dioxolan-2-ylmethyl)methylamino-3-nitropyridine,
2-(4-methylphenylamino)-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(4-methylphenylamino)-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(4-methylphenylamino)-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(4-methylphenylamino)-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(4-methylphenylamino)-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-(4-methylphenylamino)-6-2-(3-pyridyl)ethylamino-3-nitropyridine,
2-(4-methylphenylamino)-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-(4-methylphenylamino)-6-(piperazin-1-yl)-3-nitropyridine,
2-(4-methylphenylamino)-6-(4-aminopiperidino)-3-nitropyridine,
2-(4-methylphenylamino)-6-morpholino-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(methylamino)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(isopropylamino)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(isobutylamino)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(N-1,3-dioxolan-2-ylmethyl)methylamino-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(t-butylamino)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(N-methyl-2-hydroxy)ethylamino-3-nitropyridine,
2-(4-methoxyphenyl amino)-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(piperazin-1-yl)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-(4-aminopiperidino)-3-nitropyridine,
2-(4-methoxyphenylamino)-6-morpholino-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(methylamino)-3-nitropyridine,
2-4-(t-butypphenylamino-6-(isopropylamino)-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(N-1,3-dioxolan-2-ylmethyl)methylamino-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-4-(t-butypphenylamino-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-4-(t-butypphenylamino-6-2-(2-pyridyl)ethylamino-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-4-(t-butyl)phenylamino-6-morpholino-3-nitropyridine,
2-(4-cyanophenylamino)-6-(methylamino)-3-nitropyridine,
2-(4-cyanophenylamino)-6-(isobutylamino)-3-nitropyridine,
2-(4-cyanophenylamino)-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(4-cyanophenylamino)-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(4-cyanophenylamino)-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(4-cyanophenylamino)-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(4-cyanophenylamino)-6-(N-ethyl-2-hydroxy)ethylamino-3-nitropyridine,
2-(4-cyanophenylamino)-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-3-cyanophenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-(4-hydroxyphenylamino)-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-4-(methylsulfanyl)phenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-4-(n-butyl)phenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-4-(amino)phenylamino-6-(methylamino)-3-nitropyridine,
2-4-(amino)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-4-(amino)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-4-(amino)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-4-(amino)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-4-(amino)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-4-(amino)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-4-(amino)phenylamino-6-morpholino-3-nitropyridine,
2-4-(amino)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-4-(amino)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-4-(amino)phenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-4-(amino)phenylamino-6-2-(morpholin-1-yl)ethylamino-3-nitropyridine,
2-4-(amino)phenylamino-6-3-(morpholin-1-yl)propylamino-3-nitropyridine,
2-3-(amino)phenylamino-6-(methylamino)-3-nitropyridine,
2-3-(amino)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-3-(amino)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-3-(amino)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-3-(amino)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-3-(amino)phenylamino-6-(2-isopropypimidazol-1-yl-3-nitropyridine,
2-3-(amino)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-3-(amino)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-3-(amino)phenylamino-6-morpholino-3-nitropyridine,
2-3-(amino)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-3-(amino)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-3-(amino)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-3-(amino)phenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-3-(amino)phenylamino-6-2-(morpholin-1-yl)ethylamino-3-nitropyridine,
2-3-(amino)phenylamino-6-3-(morpholin-1-yl)propylamino-3-nitropyridine,
2-3-(amino)phenylamino-6-(2-methypimidazol-1-yl-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(methylamino)-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(N-1,3-dioxolan-2-ylmethyl)-methylamino-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(2-isopropypimidazol-1-yl-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-4-(imidazol-1-yl)phenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-(3-acetylphenylamino)-6-(methylamino)-3-nitropyridine,
2-(3-acetylphenylamino)-6-(isopropylamino)-3-nitropyridine,
2-(3-acetylphenylamino)-6-(isobutylamino)-3-nitropyridine,
2-(3-acetylphenylamino)-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(3-acetylphenylamino)-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(3-acetylphenylamino)-6-(2-isopropypimidazol-1-yl-3-nitropyridine,
2-(3-acetylphenylamino)-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(3-acetylphenylamino)-6-(4-pyridypmethylamino-3-nitropyridine,
2-(3-acetylphenylamino)-6-(t-butylamino)-3-nitropyridine,
2-(3-acetylphenylamino)-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-(3-acetylphenylamino)-6-(piperazin-1-yl)-3-nitropyridine,
2-(3-acetylphenylamino)-6-morpholino-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(methylamino)-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(isopropylamino)-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(isobutylamino)-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(N-1,3-dioxolan-2-ylmethyl)methylamino-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(t-butylamino)-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(N-ethyl-2-hydroxy)ethylamino-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(piperazin-1-yl)-3-nitropyridine,
2-(4-morpholinophenylamino)-6-(4-aminopiperidino)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(methylamino)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(N-1,3-dioxolan-2-ylmethyl)-methylamino-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-morpholino-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-(3,4-difluoro)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(methylamino)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(N-ethyl-2-hydroxy)ethylamino-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-4-(2-methylthiazol-4-yl)phenylamino-6-morpholino-3-nitropyridine,
2-4-(2-isopropylthiazol-4-yl)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-4-(2-isopropylthiazol-4-yl)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-4-(2-isopropylthiazol-4-yl)phenylamino-6-(N-ethyl-2-hydroxyethyl)amino-3-nitropyridine,
2-4-(2-isopropylthiazol-4-yl)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-4-(2-isopropylthiazol-4-yl)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(methylamino)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(N-ethyl-2-hydroxyethyl)-amino-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(4-methyl)piperazin-1-yl)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-morpholino-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-2-(2-pyridyl)ethylamino-3-nitropyridine,
2-4-(2-cyclohexylthiazol-4-yl)phenylamino-6-(n-butylamino)-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(methylamino)-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(N-ethyl-2-hydroxyethyl)-amino-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-4-(2-dipropylaminopropylthiazol-4-yl)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-4-(2-dipropylaminothiazol-4-yl)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(methylamino)-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2(3-fluoro-4-diethylamino)phenylamino-6-morpholino-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-2-(morpholin-1-yl)ethylamino-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(3-imidazol-1-yl)propylamino-3-nitropyridine,
2-(3-fluoro-4-diethylamino)phenylamino-6-(3-morpholin-1-yl)propylamino-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(methylamino)-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-(3-fluoro-4-morpholino)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(methylamino)-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(2-methyl-4,5-dihydro)-imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-2-(3-fluoro-4-thiomorpholino)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-(3-fluoro-4-thiomorpholino)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(methylamino)-3-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(2-isopropyl)imidazol-1-yl-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-piperazino)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(methylamino)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(isopropylamino)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(isobutylamino)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(4-hydroxypiperidino)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(2-isopropyl)imidazol-1-yl-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(3-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(4-pyridyl)methylamino-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(t-butylamino)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(piperazin-1-yl)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-(4-aminopiperidino)-3-nitropyridine,
2-(3-fluoro-4-piperidino)phenylamino-6-morpholino-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(methylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(isopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino }-6-(isobutylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino }-6-(4-hydroxypiperidino)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(2-methyl-4,5-dihydro)-imidazol-1-yl-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(3-pyridyl)methyl-amino-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(4-pyridyl)methyl-amino-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(t-butylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(piperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-(4-aminopiperidino)-3-nitropyridine,
2-{3-fluoro-4-(4-hydroxypiperidino)phenylamino}-6-morpholino-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(methylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino)-6-(isopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(isobutylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(4-hydroxypiperidino)-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(2-methyl-4,5-dihydro)-imidazol-1-yl-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(piperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-morpholino-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(4-aminopiperidino-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(3-pyridyl)methylamino-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(4-pyridyl)methylamino-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-2-(morpholin-1-yl)ethyl-amino-3-nitropyridine,
2-{3-fluoro-4-(4-aminopiperidino)phenylamino}-6-(3-morpholin-1-yl)propyl-amino-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(methylamino)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(isopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(isobutylamino)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(t-butylamino)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(4-hydroxypiperidino)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(2-methyl-4,5-dihydro)-imidazol-1-yl-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(piperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-morpholino-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(4-aminopiperidino)-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(4-pyridyl)methylamino-3-nitropyridine
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(3-imidazol-1-yl)propyl-amino-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-2-(morpholin-1-yl)ethyl-amino-3-nitropyridine,
2-{3-fluoro-4-(2-methylpiperidino)phenylamino}-6-(3-morpholin-1-yl)propyl-amino-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(methylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(isopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(isobutylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(t-butylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(4-hydroxy-piperidino)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(2-methyl-4,5-dihydro)imidazol-1-yl-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(piperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(4-methyl-piperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-morpholino-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(4-aminopiperidino)-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(3-pyridyl)-methylamino-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(4-pyridyl)-methylamino-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-2-(2-pyridyl)-ethylamino-3-nitropyridine,
2-{3-fluoro-4-(3-hydroxymethylpiperidino)phenylamino}-6-(cyclopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(methylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(isopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(isobutylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(t-butylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(4-hydroxypiperidino)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(piperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-morpholino-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(4-aminopiperidino)-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(4-pyridyl)methylamino-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-(3-imidazol-1-yl)propyl-amino-3-nitropyridine,
2-{3-fluoro-4-(4-carbamoylpiperidino)phenylamino}-6-2-(morpholin-1-yl)ethyl-amino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(methylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(isopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(isobutylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(t-butylamino)-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(4-hydroxypiperidino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(piperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-morpholino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(4-aminopiperidino)-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(3-pyridyl)methylamino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(4-pyridyl)methylamino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(3-imidazol-1-yl)propyl-amino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-2-(morpholin-1-yl)ethyl-amino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(3-morpholin-1-yl)-propylamino-3-nitropyridine,
2-{3-fluoro-4-(3-carbamoylpiperidino)phenylamino}-6-(diethylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(methylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(isopropylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(isobutylamino)-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(4-hydroxypiperidino)-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(4-methylpiperazin-1-yl)-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(3-pyridyl)methylamino-3-nitropyridine, 2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(4-pyridyl)methylamino-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(3-imidazol-1-yl)propyl-amino-3-nitropyridine,
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-2-(morpholin-1-yl)ethyl-amino-3-nitropyridine, and
2-{3-fluoro-4-(4-carboxylicpiperidino)phenylamino}-6-(3-morpholin-1-yl)-propylamino-3-nitropyridine.
4. The compound of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride or methanesulfonate.
5. A method for preparing a 2,6-substituted-3-nitropyridine derivative compound of formula 1:
comprising:
a) reacting 2,6-dichloro-3-nitropyridine with an aniline compound of formula 3:
in the presence of a base to prepare a 6-chloro-3-nitropyridine derivative compound of formula 4:
and
b) reacting the compound of formula 4 prepared in Step a) with an amine compound of formula 5:
HNR5(CH2)nR6
to prepare a 2,6-substituted-3-nitropyridine derivative compound of formula 1:
wherein R1, R2, R5, R6, n and X are as defined in claim 1.
6. The method of claim 5, wherein the base of Step a) is at least one selected from among triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, N,N-dimethylaniline, 2,6-lutidine, pyridine, sodium hydroxide and sodium hydride.
7. The method of claim 5, wherein the compound of formula 3 is prepared by a preparation method comprising:
a) subjecting a 4-nitrophenone compound of formula 6:
to bromination at the alpha position with respect to the carboxyl group thereof to prepare a compound of formula 7:
b) reacting the compound of formula 7 prepared in Step a) with a thioamide compound of formula 8:
to prepare a compound of formula 9:
and
c) subjecting the compound of formula 9 prepared in Step b) to hydrogenation, thereby preparing the compound of formula 3:
wherein:
X, Z and Y are as defined in claim 1; and
R1 is a thiazolyl group
8. The method of claim 7, wherein the reagent used for the bromination reaction of Step a) is copper (II) bromide or bromine.
9. The method of claim 7, wherein the compound of formula 8 in Step b) is thioacetamide, thiopropionamide, thioisobutyramide, trimethylthioacetamide, thiohexanoamide, cyclohexancarbothioic acid amide, piperidine-4-carbothioic acid amide, thiourea, N-methylthiourea, N-ethylthiourea, N,N-dipropylthiourea or thiobenzamide.
10. The method of claim 7, wherein the hydrogenation reaction of Step c) is carried out under hydrogen gas in the presence of a PdC catalyst or a Raney nickel catalyst.
11. The method of claim 5, wherein the compound of formula 3 is prepared by a preparation method comprising:
a) reacting a 3,4-difluoronitrobenzene compound with a compound of formula 10:
HR1 \u2003\u2003(10)
in the presence of an organic base to prepare a nitrobenzene compound of formula 11:
and
b) subjecting the compound of formula 11 prepared in Step a) to hydrogenation, thereby preparing the compound of formula 3:
wherein:
R1 is NR3R4, wherein R3 and R4 taken together form a saturated or unsaturated 5-, 6- or 7-membered heterocyclic amino compound that contains 1 to 3 hetero atoms selected from among N, O and S and is unsubstituted or substituted by a C1-C3 alkyl group, a hydroxyl group, a C1-C3 hydroxyalkyl group, an amino group, a carboxyl group or a carbamoyl group, and
X is a fluoro group.
12. The method of claim 11, wherein the compound of formula 10 in Step a) is diethylamine, morpholine, thiomorpholine, unsubstituted or substituted piperazine, piperidine, methylpiperidine, hydroxypiperidine, hydroxyethylpiperidine, aminopiperidine, 3- or 4-carbamoylpiperidine, carboxylicpiperidine or pyrrolidine.
13. The method of claim 11, wherein the organic base of Step a) is at least one selected from among triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, N,N-dimethylaniline, 2,6-lutidine and pyridine.
14. The method of claim 11, wherein the hydrogenation reaction of Step b) is carried out under hydrogen gas in the presence of a PdC catalyst or a Raney nickel catalyst.
15. A pharmaceutical composition for the prevention or treatment of osteoporosis, comprising the 2,6-substituted-3-nitropyridine derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
16. The composition of claim 15, wherein the pharmaceutically acceptable salt is hydrochloride or methanesulfonate.
17. A method for the prevention or treatment of osteoporosis, comprising administering an effective amount of the 2,6-substituted-3-nitropyridine derivative of claim 1 or a pharmaceutically acceptable salt thereof to a mammal including a human.
18. The method of claim 17, wherein the pharmaceutically acceptable salt is hydrochloride or methanesulfonate.
19-20. (canceled)
21. The compound of claim 2, wherein the pharmaceutically acceptable salt is hydrochloride or methanesulfonate.
22. The compound of claim 3, wherein the pharmaceutically acceptable salt is hydrochloride or methanesulfonate.
23. A pharmaceutical composition for the prevention or treatment of osteoporosis, comprising the 2,6-substituted-3-nitropyridine derivative of claim 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
24. A pharmaceutical composition for the prevention or treatment of osteoporosis, comprising the 2,6-substituted-3-nitropyridine derivative of claim 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
25. A method for the prevention or treatment of osteoporosis, comprising administering an effective amount of the 2,6-substituted-3-nitropyridine derivative of claim 2 or a pharmaceutically acceptable salt thereof to a mammal.
26. A method for the prevention or treatment of osteoporosis, comprising administering an effective amount of the 2,6-substituted-3-nitropyridine derivative of claim 3 or a pharmaceutically acceptable salt thereof to a mammal.