Quinazoline derivative and pharmaceutical preparation

EXAMPLE 102

The dihydrochloride of N-isopropyl-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₂H₃₂N₆O₂/2 HCl/2 H₂O)

Calculated (%): 50,67; N - 7,34; N - 16,12.

Found (%): 50,94; N - 7,15; N - 16,38.

FAB-MC, positive ions, m/z: 413 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +127,05 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 103

The dihydrochloride of 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-foradil)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₀H₂₇N₆OF/2 HCl/2,5 H₂O)

Calculated (%): 47,62; N - 6,79; N - 16,66.

Found (Percent): C - 47,59; N - 6,56; N - 16,44.

FAB-MC, positive ions, m/z: 387 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +114,79 (c = 0,500, methanol).

Appearance: pale brown powder.

EXAMPLE 104

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆O₂/2 HCl/1,1 H₂O)

Calculated (%): 54,26; N - 7,25; N - 15,82.

Found (%): 54,27; H - EUR 7.57; N - 15,58.

FAB-MC, positive ions, m/z: 439 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +8,61 (c = 0,476, methanol).

Appearance: white powder.

EXAMPLE 105

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 425 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +79,21 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 106

The dihydrochloride of N-(cyclopropylmethyl)-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₂N₆O/2 HCl/1,4 H₂O)

Calculated (Percent): C - 55,57; N - 7,15; N - 16,20.

Found (%): 55,53; 7,00; N - 16,13.

FAB-MC, positive ions, m/z: 421 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +90,67 (c = 0,536, methanol).

Appearance: white powder.

EXAMPLE 107

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-ethylbutyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₈N₆O/2 HCl/0,9 H₂O)

Calculated (%): 57,86; N - 7,81; N - 15,57.

Found (%): 57,81; N - Of 7.90; N - 15,34.

FAB-MC, positive ions, m/z: 451 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +81,48 (c = 0,540, methanol).

Appearance: white powder.

EXAMPLE 108

The dihydrochloride of N-(cyclohexylmethyl)-4-{[(1S,R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₈N₆O/2 HCl/1,4 H₂O)

Calculated (%): 57,83; N - Of 7.69; N - 14,99.

Found (%): 58,09; N - 7,74; N - 14,70.

FAB-MC, positive ions, m/z: 463 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +78,36 (c = 0,513, methanol).

Appearance: white powder.

EXAMPLE 109

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₆N₆O/2 HCl/1,8 H₂O)

Calculated (%): 55,41; N - 7,74; N - 15,51.

Found (%): 55,41; N - 7,78; N - 15,51.

FAB-MC, positive ions, m/z: 437 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +75,72 (c = 0,486, methanol).

Appearance: white powder.

EXAMPLE 110

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-[(1R,2R)-2-methoxycyclohexyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₈N₆O₂/2 HCl/2,1 H₂O)

Calculated (%): 55,02; N - 7,56; N - 14,26.

Found (%): 55,08; N - Of 7.48; N - 14,23.

FAB-MC, positive ions, m/z: 479 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +61,50 (c = 0,517, methanol).

Appearance: white powder.

EXAMPLE 111

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cycle is hexyl]amino}-N-ethyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₂H₃₀N₆O/2 HCl/2 H₂O)

Calculated (%): 50,32; N - 7,37; N - 16,00.

Found (%): 50,40; N - 7,14; N - 15,65.

FAB-MC, positive ions, m/z: 395 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +95,73 (c = 0,539, methanol).

Appearance: white powder.

EXAMPLE 112

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-[1-(methoxymethyl)cyclohexyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₄₀N₆O₂/2 HCl/1,7 H₂O)

Calculated (%): 56,41; N - Of 7.68; N - 14,10.

Found (%): 56,45; N - The 7.65; N - At 13.84.

FAB-MC, positive ions, m/z: 493 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +57,51 (c = 0,532, methanol).

Appearance: white powder.

EXAMPLE 113

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-ethylbutyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₈N₆O₂/2 HCl/1,6 H₂O)

Calculated (%): 54,94; N - 7,66; N - 14,79.

Found (%): 55,02; N - 7,30; N - 14,58.

FAB-MC, positive ions, m/z: 467 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +114,98 (c = 0,534, methanol).

Appearance: white powder.

EXAMPLE 114

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)C is clohessy]amino}-N-[(1R)-1-(methoxymethyl)-2-methylpropyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₈N₆O₂/2 HCl/2,3 H₂O)

Calculated (%): 53,75; N - 7,74; N - 14,47.

Found (%): 53,65; N - Of 7.48; N - 14,52.

FAB-MC, positive ions, m/z: 467 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +75,61 (c = 0,529, methanol).

Appearance: white powder.

EXAMPLE 115

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-ethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₆N₆O/2 HCl/1,2 H₂O)

Calculated (%): 56,53; N - To 7.67; N - 15,82.

Found (Percent): C - 56,55; H - 7,62; N - 15,55.

FAB-MC, positive ions, m/z: 437 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +91,09 (c = 0,494, methanol).

Appearance: white powder.

EXAMPLE 116

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2,2-dimethylpropyl)-6-florinopolis-2-carboxamide

Elemental analysis data (for C₂₄H₃₃N₆OF/2 HCl/ H₂O)

Calculated (%): 54,24; N - 7,02; N - 15,81.

Found (%): 54,47; N - Of 6.71; N - 15,56.

FAB-MC, positive ions, m/z: 441 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +41,26 (c = 0,504, methanol).

Appearance: white powder.

EXAMPLE 117

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-the top-N-isobutylthiazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₁N₆OF/2 HCl/1,3 H₂O)

Calculated (%): 52,83; N - 6,86; N - 16,07.

Found (%): 52,88; N - 6,76; N - 15,74.

FAB-MC, positive ions, m/z: 427 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +48,82 (c = 0,512, methanol).

Appearance: white powder.

EXAMPLE 118

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-fluoro-N-(3-methoxy-2,2-dimethylpropyl)hinzelin-2-carboxamide

Elemental analysis data (for C₂₅H₃₅N₆O₂F/2 HCl/ H₂O)

Calculated (%): 53,48; 7,00; N - 14,97.

Found (Percent): C - 53,59; N - 6,98; N - 14,69.

FAB-MC, positive ions, m/z: 471 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +33,88 (c = 0,543, methanol).

Appearance: white powder.

EXAMPLE 119

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-[2-methoxy-1-(methoxymethyl)-1-methylethyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₈N₆O₃/2 HCl/1,9 H₂O)

Calculated (%): 52,95; N - 7,49; N - 14,25.

Found (%): 52,91; N And 7.36; N - 14,02.

FAB-MC, positive ions, m/z: 483 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +69,64 (c = 0,560, methanol).

Appearance: white powder.

EXAMPLE 120

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihyd the on-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₂N₆O₂/2 HCl/2,7 H₂O)

Calculated (%): 54,58; N. Of 6.68; N - 14,14.

Found (%): 54,47; N - 7,02; N - 14,25.

FAB-MC, positive ions, m/z: 473 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +34,84 (c = 0,683, methanol).

Appearance: yellow powder.

EXAMPLE 121

The dihydrochloride of N-n-butyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆O/2 HCl/2 H₂O)

Calculated (%): 54,23; N - To 7.59; N - 15,81.

Found (%): 54,36; N And 7.36; N 15.62 Wide.

FAB-MC, positive ions, m/z: 423 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +86,93 (c = 0,773, methanol).

Appearance: white powder.

EXAMPLE 122

The dihydrochloride of N-n-butyl-6-methyl-4-{[(1S,2R)-2-(3,4,5,6-tetrahydropyridine-2-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₂₅H₃₆N₆O/2 HCl/0,9 H₂O)

Calculated (%): 57,12; N - 7,63; N - 15,99.

Found (%): 57,25; N - Of 7.64; N - 15,79.

FAB-MC, positive ions, m/z: 437 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +100,57 (c = 0,696, methanol).

Appearance: white powder.

EXAMPLE 123

The dihydrochloride of N-n-butyl-6-methyl-4-{[(1S,2R)-2-(3,4,5,6-tetrahydro-2H-azepin-2-ylamino)cyclohex the yl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₂₆H₃₈N₆O/2 HCl/1,6 H₂O)

Calculated (%): 56,54; N - 7,88; N - 15,21.

Found (%): 56,53; N - 7,60; N - 15,28.

FAB-MC, positive ions, m/z: 451 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +85,02 (c = of 0.741, methanol).

Appearance: white powder.

EXAMPLE 124

The dihydrochloride 6-chloro-N-cycloheptyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₂₆H₃₅ClN₆O/2 HCl/2 H₂O)

Calculated (%): 52,75; N - 6,98; N - 14,20.

Found (%): 52,97; N - 6,86; N - 14,37.

FAB-MC, positive ions, m/z: 483 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +67,28 (c = 0,535, methanol).

Appearance: white powder.

EXAMPLE 125

The dihydrochloride of N-n-butyl-6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₂₃H₃₁ClN₆O/2 HCl/ H₂O)

Calculated (%): 51,84; N Is 6.61; N - 15,74.

Found (Percent): C - 51,82; N - 6,74; N - 15,71.

FAB-MC, positive ions, m/z: 443 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +88,64 (c = 0,546, methanol).

Appearance: white powder.

EXAMPLE 126

The dihydrochloride of N-cycloheptyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl shall insulin-2-carboxamide

Elemental analysis data (for C₂₇H₃₈N₆O/2 HCl/1,5 H₂O)

Calculated (Percent): C - 57,64; N - Of 7.70; N - 14,94.

Found (%): 57,52; N - 7,78; N - Of 14.90.

FAB-MC, positive ions, m/z: 463 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +67,56 (c = 0,447, methanol).

Appearance: white powder.

EXAMPLE 127

The dihydrochloride 6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₁₉H₂₃ClN₆O/2 HCl/1,3 H₂O)

Calculated (%): 47,23; N - 5,76; N - 17,39.

Found (%): 47,21; N. Of 5.99; N - 17,20.

FAB-MC, positive ions, m/z: 387 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +104,23 (c = 0,520, methanol).

Appearance: white powder.

EXAMPLE 128

The dihydrochloride 6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-methoxyindole-2-carboxamide

Elemental analysis data (for C₂₀H₂₅ClN₆O₂/2 HCl/1,3 H₂O)

Calculated (%): 46,80; N - Of 5.81; N - 16,37.

Found (%): 46,87; N - Of 5.55; N - 16,30.

FAB-MC, positive ions, m/z: 417 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +53,81 (c = 0,524, methanol).

Appearance: white powder.

EXAMPLE 129

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(3-methoxy-2,2-dimetyl who drank)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₈N₆O₂/2 HCl/ H₂O)

Calculated (%): 56,01; N - To 7.59; N - 15,07.

Found (Percent): C - 55,96; N Is 7.85; N - 14,85.

FAB-MC, positive ions, m/z: 467 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +71,08 (c = 0,543, methanol).

Appearance: white powder.

EXAMPLE 130

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆O/2 HCl/1,2 H₂O)

Calculated (%): 55,94; N - 7,47; N - To 16.31.

Found (Percent): C - 55,89; N - Of 7.64; N - 16,24.

FAB-MC, positive ions, m/z: 423 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +93,53 (c = 0,464, methanol).

Appearance: white powder.

EXAMPLE 131

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-isopropoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₆N₆O₂/2 HCl/1,6 H₂O)

Calculated (%): 54,17; N - 7,49; N - 15,16.

Found (%): 54,27; N - 7,39; N - 15,21.

FAB-MC, positive ions, m/z: 453 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +95,25 (c = 0,527, methanol).

Appearance: white powder.

EXAMPLE 132

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]am is but}-6-methyl-N-[2-(methylthio)ethyl]hinzelin-2-carboxamide

Elemental analysis data (for C₂₃H₃₂N₆OS/2 HCl/1,3 H₂O)

Calculated (%): 51,45; N - 6,87; N - 15,65.

Found (%): 51,52; N - Of 6.96; N - 15,47.

FAB-MC, positive ions, m/z: 441 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +88,30 (c = 0,530, methanol).

Appearance: white powder.

EXAMPLE 133

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-methoxy-1,1-dimethylethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 453 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +64,62 (c = 0,489, methanol).

Appearance: white powder.

EXAMPLE 134

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-{[1-(methoxymethyl)cyclohexyl]methyl}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₉H₄₂N₆O₂/2 HCl/1,4 H₂O)

Calculated (Percent): C - 57,59; N - 7,80; N - 13,89.

Found (Percent): C - 57,64; N - 7,79; N - 13,67.

FAB-MC, positive ions, m/z: 507 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +54,23 (c = mean HDI of 0.531, methanol).

Appearance: white powder.

EXAMPLE 135

Trihydrochloride 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-(2-piperidine-1-retil)hinzelin-2-carboxamide

Elemental analysis data (for C₂₇H₃₉N_{7 O/3 HCl/2,1 H2O)}

Calculated (%): Better Than Anticipated At 51.90; H Was 7.45; N - 15,69.

Found (%): 52,10; N - To 7.77; N - 15,40.

FAB-MC, positive ions, m/z: 478 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +111,91 (c = 0,470, methanol).

Appearance: white powder.

EXAMPLE 136

The dihydrochloride of N-cyclopentyl-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₄N₆O/2 HCl/2,4 H₂O)

Calculated (%): 54,52; N - 7,47; N - 15,26.

Found (%): 54,64; N - 7,12; N - 15,07.

FAB-MC, positive ions, m/z: 435 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +86,87 (c = 0,541, methanol).

Appearance: white powder.

EXAMPLE 137

The dihydrochloride N tert-butyl 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆O/2 HCl/1,2 H₂O)

Calculated (%) : - Is 55.74; H - Of 7.48; N - 16,25.

Found (%): 55,81; N - Of 7.68; N - 16,00.

FAB-MC, positive ions, m/z: 423 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +79,42 (c = 0,491, methanol).

Appearance: white powder.

EXAMPLE 138

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Data e is cementnogo analysis (for C ₂₇H₃₈N₆O₂/2 HCl/1,5 H₂O)

Calculated (%): 56,05; N - 7,49; N - 14,53.

Found (%): 56,15; N - 7,56; N - 14, 48mm.

FAB-MC, positive ions, m/z: 479 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +77,12 (c = 0,542, methanol).

Appearance: white powder.

EXAMPLE 139

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-(tetrahydro-2H-Piran-4-yl)hinzelin-2-carboxamide

Elemental analysis data (for C₂₅H₃₄N₆O₂/2 HCl/1,4 H₂O)

Calculated (%): 54,72; N - 7,13; N - 15,32.

Found (%): 55,01; N - 7,10; N - 14,93.

FAB-MC, positive ions, m/z: 451 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +80,15 (c = 0,519, methanol).

Appearance: white powder.

EXAMPLE 140

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-isopropyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₂N₆O/2 HCl/1,3 H₂O)

Calculated (%): 54,72; N - 7,31; N - 16,65.

Found (%): 54,94; N Was 7.45; N - 16,29.

FAB-MC, positive ions, m/z: 409 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +96,16 (c = 0,547, methanol).

Appearance: white powder.

EXAMPLE 141

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(CIS-4-methoxycyclohexyl)-6-utilisaton-2-carboxamide

Elemental analysis data (for C₂₇H₃₈N₆O₂/2 HCl/2,5 H₂O)

Calculated (%): 54,36; N - 7,60; N - 14,09.

Found (%): 54,39; N - 7,31; N - 13,99.

FAB-MC, positive ions, m/z: 479 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +68,99 (c = 0,516, methanol).

Appearance: white powder.

EXAMPLE 142

The dihydrochloride of N-[(1-acetylpiperidine-4-yl)methyl]-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₉N₇O₂/2 HCl/2,2 H₂O)

Calculated (%): 54,40; N - 7,40; N - 15,86.

Found (%): 54,73; N - Of 7.48; N - 15,48.

FAB-MC, positive ions, m/z: 506 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +74,33 (c = 0,487, methanol).

Appearance: white powder.

EXAMPLE 143

The dihydrochloride of 4-[((1S,2R)-2-{[(3R)-3-hydroxy-3,4-dihydro-2H-pyrrol-5-yl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆O₂/2 HCl/0,4 H₂O)

Calculated (Percent): C - 55,57; N - 7,15; N - 16,20.

Found (Percent): C - 55,66; N - 7,39; N - 16,07.

FAB-MC, positive ions, m/z: 439 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +109,62 (c = 0,478, methanol).

Appearance: pale brown powder.

EXAMPLE 144

The dihydrochloride of 4-[((1S,2R-2-{[(3S)-3-hydroxy-3,4-dihydro-2H-pyrrol-5-yl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆O₂/2 HCl/0,9 H₂O)

Calculated (%): 54,63; N - 7,22; N - 15,93.

Found (%): 54,90; N - 7,15; N - 15,61.

FAB-MC, positive ions, m/z: 439 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +51,83 (c = 0,710, methanol).

Appearance: pale brown powder.

EXAMPLE 145

The dihydrochloride 6-chloro-N-cycloheptyl-4-({(1S,2R)-2-[(2-oxo-3,4-dihydro-2H-pyrrol-5-yl)amino]cyclohexyl}amino)hinzelin-2-carboxamide

Elemental analysis data (for C₂₆H₃₃N₆O₂Cl/2 HCl/1,5 H₂O)

Calculated (%): 52,31; N - 6.42 Per; N - 14,08.

Found (%): 52,38; N - 6,51; N - 14,11.

FAB-MC, positive ions, m/z: 497 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +133,62 (c = 0,464, methanol).

Appearance: white powder.

EXAMPLE 146

The dihydrochloride of N-(tert-butoxy)-6-chloro-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₂₃H₃₁N₆O₂Cl/2 HCl/ H₂O)

Calculated (%): 50,23; N - 6.42 Per; N - 15,28.

Found (%): 49,97; H - 6,35; N - 14,99.

FAB-MC, positive ions, m/z: 459 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +74,84 (c = 0,473, methanol).

Appearance: white powder.

EXAMPLE 147

The dihydrochloride of N-(cyclopentylmethyl)-4-{[(1S,2R)2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₆N₆O/2 HCl/ H₂O)

Calculated (%): 55,65; H - 7,62; N - 14,98.

Found (Percent): C - 55,58; N - 7,24; N - 14,84.

FAB-MC, positive ions, m/z: 449 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +51,66 (c = 0,542, methanol).

Appearance: white powder.

EXAMPLE 148

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-[3-(methylthio)propyl]hinzelin-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆OS/2 HCl/ H₂O)

Calculated (%) : - Of 52.84; H - 7,02; N - 15,40.

Found (%): 52,83; N - 7,11; N - 15,33.

FAB-MC, positive ions, m/z: 455 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +82,04 (c = 0,529, methanol).

Appearance: white powder.

EXAMPLE 149

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-N-(2-furylmethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₀N₆O₂/2 HCl/ H₂O)

Calculated (%): 55,87; N - 6,38; N - 15,64.

Found (%): 56,09; N. Of 6.66; N - 15,26.

FAB-MC, positive ions, m/z: 447 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +89,45 (c = 0,474, methanol).

Appearance: white powder.

EXAMPLE 150

The dihydrochloride of N-(tert-butoxy)-4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclo is exil]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₆O₂/2 HCl/0,7 H₂O)

Calculated (%): 55,00; N - 7,19; N - 16,04.

Found (%): 55,00; N - 7,15; N - 15,96.

FAB-MC, positive ions, m/z: 439 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +85,48 (c = 0,496, methanol).

Appearance: white powder.

EXAMPLE 151

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino}-6-methyl-N-(2,2,2-triptorelin)hinzelin-2-carboxamide

Elemental analysis data (for C₂₂H₂₇N₆OF₃/2 HCl/0,7 H₂O)

Calculated (%): 49,48; N - 5,74; N - 15,74.

Found (%): 49,37; N - 5,72; N - 15,48.

FAB-MC, positive ions, m/z: 449 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +104,62 (c = 0,541, methanol).

Appearance: white powder.

EXAMPLE 152

The dihydrochloride of 4-{[(1S,2R)-2-(3,4-dihydro-2H-pyrrol-5-ylamino)cyclohexyl]amino-N-(TRANS-4-hydroxycyclohexyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 465 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +72,65 (c = 0,490, methanol).

Appearance: white powder.

EXAMPLE 153

The dihydrochloride of N-(4-methoxyphenyl)-6-methyl-4-{[(1S,2R)-2-(pyridine-2-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₂₈H₃₀N₆O₂/2 HCl/ H₂O)

Calculated (%): 58,64; N Is 5.98; N - 14,65.

Found (%): 58,44; N - 5,90; N - 14,67.

FAB-MC, positive ions, m/z: 482 [M+H]⁺.

Appearance: pale brown powder.

EXAMPLE 154

The dihydrochloride of N-isobutyl-6-methyl-4-{[(1S,2R)-2-(pyridine-2-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₂₅H₃₂N₆O/2 HCl/1,5 H₂O)

Calculated (%): 56,39; 7,00; N - 15,78.

Found (%): 56,46; N - 6,74; N - 15,84.

FAB-MC, positive ions, m/z: 432 [M+H]⁺.

Appearance: yellow powder.

EXAMPLE 155

The dihydrochloride 6-chloro-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-[2-(4-methoxyethyl)ethyl]hinzelin-2-carboxamide

Elemental analysis data (for C₃₁H₃₃N₆O₂Cl/2 HCl/2,4 H₂O)

Calculated (%): 55,30; N - 5,96; N - 12,48.

Found (%): 55,26; N - 5,72; N - 12,25.

FAB-MC, positive ions, m/z: 557 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +78,95 (c = 0,537, methanol).

Appearance: pale brown powder.

EXAMPLE 156

The dihydrochloride 6-chloro-N-(cyclopentylmethyl)-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₈H₃₃N₆OCl/2 HCl/0,8 H₂O)

Calculated (%): 56,77; N - 6,23; N - 14,19.

Found (%): 56,81; N - 6,14; N - 13,91.

FAB-MC, positive ions mz: 505 [M+H] ⁺.

Constant optical rotation [α]²⁰_D= +94,71 (c = 0,549, methanol).

Appearance: white powder.

EXAMPLE 157

The dihydrochloride 6-chloro-N-(3,3-dimethylbutyl)-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₈H₃₅N₆OCl/2 HCl/0,8 H₂O)

Calculated (Percent): C - 56,58; N - 6,55; N - 14,14.

Found (%): 56,47; N - 6,48; N - 14,26.

FAB-MC, positive ions, m/z: 507 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +103,51 (c = 0,398, methanol).

Appearance: white powder.

EXAMPLE 158

The dihydrochloride 6-chloro-N-(3-terbisil)-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₉H₂₈N₆OClF/2 HCl/1,5 H₂O)

Calculated (%): 55,20; N Is 5.28; N - 13,32.

Found (%): 55,22; N - To 5.21; N - 13,00.

FAB-MC, positive ions, m/z: 531 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +91,81 (c = 0,501, methanol).

Appearance: white powder.

EXAMPLE 159

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₂N₆O₃/2 HCl/0,9 H₂O)

Calculated (%): 54,23; N - 6,52; N - 15,18.

Found (%): 54,28; N - 6,50; N - br15.15

FAB-MC, positive ions, m/z: 465 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +76,07 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 160

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₀N₆O₃/2 HCl/1,2 H₂O)

Calculated (%): 52,89; N - 6,36; N - 15,42.

Found (%): 52,94; N - 6,28; N - 15,29.

FAB-MC, positive ions, m/z: 451 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +104,31 (c = of 0.533, methanol).

Appearance: white powder.

EXAMPLE 161

The dihydrochloride of N-(cyclohexylmethyl)-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 476 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +53,58 (c = 0,530, methanol).

Appearance: white powder.

EXAMPLE 162

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 446 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +93,55 (c = 0,543, methanol).

Appearance: white powder.

EXAMPLE 163

The dihydrochloride of N-(2-ethylbutyl)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}Ziklag the KSIL)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₆N₆O₂/2 HCl/1,5 H₂O)

Calculated (%): 56,25; N - 7,17; N - 14,58.

Found (%): 56,21; N - Of 6.96; N - 14,43.

FAB-MC, positive ions, m/z: 477 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +58,41 (c = 0,517, methanol).

Appearance: white powder.

EXAMPLE 164

The dihydrochloride of N-(2-ethylbutyl)-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₇N₇O/2 HCl/1,2 H₂O)

Calculated (%): 57,77; N - 7,17; N - Of 16.84.

Found (%): 57,88; N - 7,16; N - 16,54.

FAB-MC, positive ions, m/z: 488 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +57,76 (c = 0,554, methanol).

Appearance: white powder.

EXAMPLE 165

The dihydrochloride of N-(cyclopropylmethyl)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₀N₆O₂/2 HCl/1,2 H₂O)

Calculated (%): 55,49; N - 6,41; N - 15,53.

Found (%): 55,44; N - 6,34; N - 15,42.

FAB-MC, positive ions, m/z: 447 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +72,26 (c = 0,476, methanol).

Appearance: white powder.

EXAMPLE 166

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohex the l)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 476 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +72,40 (c = 0,511, methanol).

Appearance: white powder.

EXAMPLE 167

The dihydrochloride of N-(2,2-dimethylpropyl)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₄N₆O₂/2 HCl/0,9 H₂O)

Calculated (%): 56,60; N - 6,91; N - 15,23.

Found (%): 56,57; N - 6,74; N - 15,18.

FAB-MC, positive ions, m/z: 463 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +67,63 (c = 0,482, methanol).

Appearance: white powder.

EXAMPLE 168

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(3-methoxy-2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₆N₆O₃/2 HCl/1,4 H₂O)

Calculated (%): 54,90; N - Of 6.96; N - 14,23.

Found (%): 55,04; N - 6,90; N - 13,92.

FAB-MC, positive ions, m/z: 493 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +58,92 (c = 0,482, methanol).

Appearance: white powder.

EXAMPLE 169

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-[1-(methoxymethyl)cyclohexyl]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₉H₃₈N₆O₃/2HCl/2 H ₂O)

Calculated (%): 55,50; N - 7,07; N - 13,39.

Found (%): 55,53; N - For 6.81; N - 13,14.

FAB-MC, positive ions, m/z: 519 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +77,88 (c = 0,416, methanol).

Appearance: white powder.

EXAMPLE 170

The dihydrochloride of N-ethyl-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₂₈N₆O₂/2 HCl/2,7 H₂O)

Calculated (%): 50,96; N - To 6.58; N - 15,50.

Found (%): 50,98; N - 6,18; N - Br15.15.

FAB-MC, positive ions, m/z: 421 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +86,40 (c = 0,537, methanol).

Appearance: white powder.

EXAMPLE 171

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₃₀H₃₂N₆O₂/2 HCl/2,6 H₂O)

Calculated (%): 57,34; N - 6,29; N - 13,37.

Found (%): 57,34; N - 6,15; N - 13,47.

FAB-MC, positive ions, m/z: 509 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +12,54 (c = 0,606, methanol).

Appearance: pale yellow powder.

EXAMPLE 172

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (C ₂₇H₃₄N₆O/2 HCl/1,6 H₂O)

Calculated (%): 57,87; N - 7,05; N - 15,00.

Found (%): 57,80; N - 7,02; N - 14,82.

FAB-MC, positive ions, m/z: 459 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +75,63 (c = 0,788, methanol).

Appearance: white powder.

EXAMPLE 173

The dihydrochloride of N-n-butyl-6-methyl-4-[((1S,2R)-2-{[(methylimino)(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₈H₃₆N₆O/2 HCl/1,2 H₂O)

Calculated (%): 59,30; N - 7,18; N - 14,82.

Found (%): 59,22; N - Of 6.96; N - 14,94.

FAB-MC, positive ions, m/z: 473 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +29,53 (c = 0,684, methanol).

Appearance: white powder.

EXAMPLE 174

The dihydrochloride of N-n-butyl-4-{[(1S,2R)-2-(1H-isoindole-3-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₄N₆O/2 HCl/1,2 H₂O)

Calculated (%) : - To 59.51; H - 6,85; N - 14,87.

Found (Percent): C - 59,70; N - 6,76; N - 14,81.

FAB-MC, positive ions, m/z: 471 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +46,63 (c = 0,609, methanol).

Appearance: pale yellow powder.

EXAMPLE 175

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[(hydroxyimino)(phenyl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Data e is cementnogo analysis (for C ₂₇H₃₄N₆O₂/2 HCl/0,8 H₂O)

Calculated (%): 57,71; N - 6,74; N - 14,96.

Found (%): 57,77; N - 6,63; N - 15,03.

FAB-MC, positive ions, m/z: 475 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +3,13 (c = 0,511, methanol).

Appearance: white powder.

EXAMPLE 176

Trihydrochloride 4-[((1S,2R)-2-{[[2-(dimethylamino)phenyl](imino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₃₂H₃₇N₇O₂/3 HCl/ H₂O)

Calculated (%): 56,60; N - 6,23; N - 14,44.

Found (%): 56.78 Has; N - 6,24; N - 14,35.

FAB-MC, positive ions, m/z: 552 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +21,93 (c = 0,547, methanol).

Appearance: pale yellow powder.

EXAMPLE 177

The dihydrochloride of 4-[((1S,2R)-2-{[(3-forfinal)(imino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₃₀H₃₁FN₆O₂/2 HCl/0,8 H₂O)

Calculated (%): 58,69; N - Of 5.68; N - 13,69.

Found (%): 58,83; N - Of 5.55; N - 13,42.

FAB-MC, positive ions, m/z: 527 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +12,78 (c = 0,735, methanol).

Appearance: pale yellow powder.

EXAMPLE 178

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amine is]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₀N₆O₃/2 HCl/1,5 H₂O)

Calculated (%): 56,20; N - Of 5.89; N - 14,04.

Found (%): 56,22; N - Of 5.83; N - 13,82.

FAB-MC, positive ions, m/z: 499 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +1,86 (c = 0,642, methanol).

Appearance: pale yellow powder.

EXAMPLE 179

The dihydrochloride of N-n-butyl-6-chloro-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₆H₃₁ClN₆O/2 HCl/0.5 H₂O)

Calculated (%): 55,67; N - 6,11; N - 14,98.

Found (%): 55,68; N - 6,17; N - 14,86.

FAB-MC, positive ions, m/z: 479 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +89,76 (c = 0,684, methanol).

Appearance: white powder.

EXAMPLE 180

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-6-methoxyquinazoline-2-carboxamide

Elemental analysis data (for C₂₇H₃₄N₆O₂/2 HCl/1,25 H₂O)

Calculated (%): 56,89; N - For 6.81; N - 14,74.

Found (%): 56,82; N - 6,65; N - 14,64.

FAB-MC, positive ions, m/z: 475 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +108,39 (c = 0,679, methanol).

Appearance: white powder.

EXAMPLE 181

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-(4-methox is phenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₃₀H₃₂N₆O₂/2 HCl/1,2 H₂O)

Calculated (%): 59,74; N Is Between 6.08; N - 13,93.

Found (%): 59,73; N. Of 5.99; N - 13,94.

FAB-MC, positive ions, m/z: 509 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +40,36 (c = 0,654, methanol).

Appearance: pale yellow powder.

EXAMPLE 182

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₉H₃₅ClN₆O/2 HCl/1,2 H₂O)

Calculated (%): 56,76; N - 6,47; N - 13,70.

Found (%): 56,84; N. Of 6.31; N - 13,66.

FAB-MC, positive ions, m/z: 519 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +100,55 (c = 0,537, methanol).

Appearance: white powder.

EXAMPLE 183

The dihydrochloride of N-cycloheptyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-6-methoxyquinazoline-2-carboxamide

Elemental analysis data (for C₃₀H₃₈N₆O₂/2 HCl/1,3 H₂O)

Calculated (%): 58,97; N - 7,03; N - Of 13.75.

Found (%): 58,95; N - 6,85; N - 13,76.

FAB-MC, positive ions, m/z: 515 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +109,66 (c = 0,538, methanol).

Appearance: white powder.

EXAMPLE 184

The dihydrochloride of N-cycloheptyl-4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cycle is hexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₃₀H₃₈N₆O/2 HCl/2 H₂O)

Calculated (%): 59,30; N - 7,30; N - 13,83.

Found (%): 59,12; N - 7,03; N - 13,99.

FAB-MC, positive ions, m/z: 499 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +85,09 (c = 0,463, methanol).

Appearance: white powder.

EXAMPLE 185

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₇H₃₃ClN₆O₂/2 HCl/2,2 H₂O)

Calculated (%): 52,17; N - 6,39; N - 13,52.

Found (%): 52,17; N - 6,15; N - 13,70.

FAB-MC, positive ions, m/z: 509 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +109,94 (c = 0,573, methanol).

Appearance: white powder.

EXAMPLE 186

The dihydrochloride of N-isobutyl-4-{[(1S,2R)-2-(1H-isoindole-3-ylamino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₄N₆O/2 HCl/1,5 H₂O)

Calculated (%): 58,94; N - 6,90; N - 14,73.

Found (%): 59,14; N - 6,88; N - 14,60.

FAB-MC, positive ions, m/z: 471 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +68,82 (c = 0,555, methanol).

Appearance: white powder.

EXAMPLE 187

The dihydrochloride of N-cycloheptyl-4-{[(1S,2R)-2-(1H-isoindole-3-ylamino)cyclohexyl]amino}-6-methylpyrazolo the-2-carboxamide

Elemental analysis data (for C₃₁H₃₈N₆O/2 HCl/2 H₂O)

Calculated (Percent): C - 60,09; N - 7,16; N - 13.56MHz.

Found (%): 59,88; N - 7,13; N - Of 13.58.

FAB-MC, positive ions, m/z: 511 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +29,96 (c = 0,534, methanol).

Appearance: pale yellow powder.

EXAMPLE 188

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₈H₃₄ClN₇O/2 HCl/2,2 H₂O)

Calculated (%): 53,16; N - 6,44; N - 15,50.

Found (%): 53,20; N - 6,59; N - 15,32.

FAB-MC, positive ions, m/z: 520 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +93,92 (c = 0,477, methanol).

Appearance: white powder.

EXAMPLE 189

The dihydrochloride of N-n-butyl-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₃N₇O/2 HCl/2,5 H₂O)

Calculated (%): 54,07; N - 6,98; N - 16,98.

Found (%): 53,87; N And 7.36; N - 16,73.

FAB-MC, positive ions, m/z: 460 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +75,62 (c = 0,521, methanol).

Appearance: white powder.

EXAMPLE 190

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(3-meth is XI-2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₇N₇O₂/2 HCl/1,6 H₂O)

Calculated (%): 55,55; N - 7,03; N - 16,20.

Found (%): 55,76; N - 6,77; N - 15,95.

FAB-MC, positive ions, m/z: 504 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +49,33 (c = 0,454, methanol).

Appearance: white powder.

EXAMPLE 191

The dihydrochloride of N-ethyl-4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₂₉N₇O/2 HCl/1,5 H₂O)

Calculated (%): 54,24; N - 6,45; N - Of 18.45.

Found (%): 54,14; N - Of 6.49; N - 18,28.

FAB-MC, positive ions, m/z: 432 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +93,78 (c = 0,499, methanol).

Appearance: white powder.

EXAMPLE 192

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(2-methoxy-1,1-dimethylethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₅N₇O₂/3 HCl/1,4 H₂O)

Calculated (%): 51,95; N - 6,59; N - 15,71.

Found (%): 52,10; N - 6,62; N - 15,42.

FAB-MC, positive ions, m/z: 490 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +88,29 (c = 0,564, methanol).

Appearance: white powder.

EXAMPLE 193

The dihydrochloride of 4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl is)amino]-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₆N₆O₃/2 HCl/ H₂O)

Calculated (%): 56,47; N - 6,77; N - 14,11.

Found (%): 56,46; N - 6,88; N - 14,11.

FAB-MC, positive ions, m/z: 505 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +78,74 (c = 0,508, methanol).

Appearance: white powder.

EXAMPLE 194

The dihydrochloride of N-(2,2-dimethylpropyl)-4-[((1S,2R)-2-{[imino(1H-pyrrol-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₅N₇O/2 HCl/0,75 H₂O)

Calculated (%): 56,98; N - 7,08; N - 17,89.

Found (%): 57,19; N - 6,85; N - 17,70.

FAB-MC, positive ions, m/z: 462 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -25,62 (c = 0,484, methanol).

Appearance: white powder.

EXAMPLE 195

The dihydrochloride 6-fluoro-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-N-(TRANS-4-methoxycyclohexyl)hinzelin-2-carboxamide

Elemental analysis data (for C₂₇H₃₃FN₆O₃/2 HCl/1,8 H₂O)

Calculated (%): 52,82; N - 6,34; N - 13,69.

Found (%): 52,94; N - 6,23; N - 13,72.

FAB-MC, positive ions, m/z: 509 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +36,36 (c = 0,495, methanol).

Appearance: white powder.

EXAMPLE 196

The dihydrochloride of 4-[((1S,2R)-2-{[3-furyl(imino)methyl]amino}C is clohessy)amino]-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₆N₆O₃/2 HCl/1,4 H₂O)

Calculated (%): 55,79; N - 6,82; N - 13,94.

Found (%): 55,94; N - Of 6.73; N - 13,69.

FAB-MC, positive ions, m/z: 505 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +88,09 (c = 0,563, methanol).

Appearance: white powder.

EXAMPLE 197

The dihydrochloride of N-(4,4-diverticulosis)-4-[((1S,2R)-2-{[2-furyl(imino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 511 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +79,24 (c = 0,530, methanol).

Appearance: white powder.

EXAMPLE 198

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 509 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -4,42 (c = 0,995, methanol).

Appearance: Golden yellow powder.

EXAMPLE 199

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-3-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₉H₃₁N₇O₂/3 HCl/1,5 H₂O)

Calculated (%): 53,92; N Is 5.77; N - 15,18.

Found (%): 53,89; N - 5,80; N - 15,14.

FAB-MC, positive ions, m/z: 509 [M+H]⁺.

Constant optical the CSOs rotation [α] ²⁰_D= -23,50 (c = 0,570, methanol).

Appearance: yellow powder.

EXAMPLE 200

Trihydrochloride 4-[((1S,2R)-2-{[imino(pyridin-4-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₉H₃₁N₇O₂/3 HCl/0,3 H₂O)

Calculated (%): 55,78; N - 5,59; N - 15,70.

Found (%): 55,76; N Is 5.77; N - 15,74.

FAB-MC, positive ions, m/z: 509 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -9,04 (c = 1,105, methanol).

Appearance: yellow powder.

EXAMPLE 201

The dihydrochloride 6-chloro-N-cycloheptyl-4-{[(1S,2R)-2-(hinzelin-4-ylamino)cyclohexyl]amino}hinzelin-2-carboxamide

Elemental analysis data (for C₃₀H₃₄N₇OCl/2 HCl/0,8 H₂O)

Calculated (%): 57,07; 6,00; N - 15,53.

Found (%): 57,06; N - 5,94; N - 15,32.

FAB-MC, positive ions, m/z: 544 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +7,06 (c = 0,764, methanol).

Appearance: white powder.

EXAMPLE 202

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₄N₆O/2 HCl/2,2 H₂O)

Calculated (%): 56.78 Has; N - 7,13; N - 14,71.

Found (%): 56,71; N - 6,82; N - 14,62.

FAB-MC, positive ions, m/z: 459 [M+H]⁺.

Kee is Naya optical rotation [α] ²⁰_D= +72,00 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 203

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[(3-forfinal)(imino)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₉H₃₄N₆OClF/2 HCl/2,5 H₂O)

Calculated (%): 53,18; N. Of 6.31; N - 12,83.

Found (%): 53,40; N - 6,14; N - 12,70.

FAB-MC, positive ions, m/z: 537 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +82,28 (c = 0,559, methanol).

Appearance: white powder.

EXAMPLE 204

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-N-(2-isopropoxyphenyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 490 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +107,86 (c = 0,534, methanol).

Appearance: white powder.

EXAMPLE 205

The dihydrochloride of 4-[((1S,2R)-2-{[imino(pyridin-2-yl)methyl]amino}cyclohexyl)amino]-6-methyl-N-[2-(methylthio)ethyl]hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 478 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +74,85 (c = 0,521, methanol).

Appearance: white powder.

EXAMPLE 206

The dihydrochloride of 4-[((1S,2R)-2-{[imino(4-methoxyphenyl)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (the La C ₂₈H₃₆N₆O₂/2 HCl/ H₂O)

Calculated (%): 58,03; N - Of 6.96; N - 14,50.

Found (%): 58,05; N - 6,91; N - 14,59.

FAB-MC, positive ions, m/z: 489 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +55,88 (c = 0,476, methanol).

Appearance: white powder.

EXAMPLE 207

The dihydrochloride of 4-[((1S,2R)-2-{[imino(phenyl)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₄N₆O₂/2 HCl/2,5 H₂O)

Calculated (%): 54,73; N - 6,97; N - 14,18.

Found (%): 54,71; N - 6,60; N - 14,21.

FAB-MC, positive ions, m/z: 475 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +73,66 (c = worn : 0.505, methanol).

Appearance: pale brown powder.

EXAMPLE 208

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Stage 1. 4-{[(1S,2R)-2-(Cyanoimino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

In an argon atmosphere to a solution 3,30 g of 4-{[(1S,2R)-2-aminocyclohexanol]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide in 80 ml of tetrahydrofuran at -20 ° C and successively added and 1.54 ml of triethylamine and 978 mg CYANOGEN bromide and the mixture is stirred at the same temperature for 0.5 hours. To the reaction solution was added to the DN and the mixture is subjected to extraction with ethyl acetate. The organic layer is washed with water and saturated brine and dried over magnesium sulfate. The solvent is distilled off and the residue is purified column chromatography on silica gel (chloroform: methanol = 50:1), whereby receive a 1.96 g of the desired compound as a pale yellow crystalline substance.

Stage 2. 4-[((1S,2R)-2-{[Amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

To a solution of a 1.96 g of 4-{[(1S,2R)-2-(cyanoimino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide and 8,56 g of the hydrochloride methoxyamine in 80 ml ethanol add 10,96 g of sodium carbonate and the mixture is refluxed for 1 hour. The reaction solution is added to 400 ml of a mixture of ice water and the precipitated precipitated substance is collected by filtration. After washing the collected settled the matter by water it is dried under reduced pressure. The resulting powder was washed with a mixture of solvents (chloroform: isopropyl alcohol = 1:1) and get 1,71 g of the desired compound as a white powder.

Elemental analysis data (for C₂₁H₃₁N₇O₃)

Calculated (%): 58,72; N - 7,27; N - To 22.83.

Found (%): 58,48; N - 7,17; N - 22,76.

FAB-MC, positive ions, m/z: 430 [M+H]⁺.

Appearance: white powder.

Stage 3. The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohex the l)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Suspended 1,71 g of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide in 20 ml of ethyl acetate, is added to a suspension of 5 ml of 4 n solution of hydrogen chloride in ethyl acetate and the mixture is stirred for 15 minutes. To the reaction solution was added 40 ml of diethyl ether and the resulting precipitated precipitated substance is collected by filtration, washed with diethyl ether, dried under reduced pressure and get a 2.01 g of the desired compound as a white powder.

FAB-MC, positive ions, m/z: 430 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +56,80 (c = 0,500, methanol).

In the same manner as in example 208, receive the following compounds 209-247, 249 and 250.

EXAMPLE 209

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₁N₇O₃/2 HCl/0,6 H₂O)

Calculated (%): 53,50; N - 6,14; N - 17,48.

Found (%): 53,81; N - 6,11; N - 17,14.

FAB-MC, positive ions, m/z: 478 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -20,23 (c = 0,771, methanol).

Appearance: yellow powder.

EXAMPLE 210

The dihydrochloride of 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazolo the-2-carboxamide

Elemental analysis data (for C₂₄H₂₉N₇O₃/2 HCl/ H₂O)

Calculated (%): 51,99; 6,00; N - 17,68.

Found (%): 52,23; N - 6,07; N - 17,55.

FAB-MC, positive ions, m/z: 464 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -34,15 (c = 0,650, methanol).

Appearance: pale yellow powder.

EXAMPLE 211

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₂H₃₃N₇O₂/2 HCl/2,5 H₂O)

Calculated (%): 48,44; N - 7,39; N - 17,97.

Found (Percent): C - 48,59; N - 7,05; N - 17,88.

FAB-MC, positive ions, m/z: 428 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +45,71 (c = 0,525, methanol).

Appearance: white powder.

EXAMPLE 212

The dihydrochloride of 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 414 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +33,55 (c = 0,590, methanol).

Appearance: white powder.

EXAMPLE 213

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-6-methyl-N-(n-propyl)hinzelin-2-carboxamide

Elemental analysis data (for C₂₁H₃₁N₇O₂/2 HCl/1,8 H₂O)

Calculated (%): - 48,61; N - 7,11; N - 18,90.

Found (%): 48,32; N - Of 6.71; N - 18,60.

FAB-MC, positive ions, m/z: 414 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +48,84 (c = 0,520, methanol).

Appearance: white powder.

EXAMPLE 214

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(cyclopropylmethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 426 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +46,72 (c = 0,535, methanol).

Appearance: white powder.

EXAMPLE 215

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-hydroxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₀H₂₉N₇O₃/2 HCl/3 H₂O)

Calculated (%): 44,28; N - 6,87; N - 18,07.

Found (%): 44,59; N - 6,48; N - 18,14.

FAB-MC, positive ions, m/z: 416 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +56,32 (c = of 0.625, methanol).

Appearance: white powder.

EXAMPLE 216

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₁H₃₁N₇O₂/2 HCl/2 H₂O)

Calculated (%): 48,28; N - 7,14; N - 18,77.

Found (%): 48,52; N - 6,79; N - 18,72.

FAB-MC, positive ions, m/z: 414 M+H] ⁺.

Constant optical rotation [α]²⁰_D= +43,61 (c = determined as 0.720, methanol).

Appearance: white powder.

EXAMPLE 217

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-cyclopropyl-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 412 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +49,39 (c = 0,575, methanol).

Appearance: white powder.

EXAMPLE 218

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-cyclobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₂H₃₁N₇O₂/2 HCl/1,6 H₂O)

Calculated (%): 50,11; N - 6,92; N - 18,59.

Found (%): 50,19; N - 6,69; N - 18,55.

FAB-MC, positive ions, m/z: 426 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +35,10 (c = 0,490, methanol).

Appearance: white powder.

EXAMPLE 219

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-6-methyl-N-(2,2,2-triptorelin)hinzelin-2-carboxamide

FAB-MC, positive ions, m/z: 454 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +56,92 (c = 0,520, methanol).

Appearance: white powder.

EXAMPLE 220

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-ethyl-N,6-dimethylthiazole-carboxamide

Elemental analysis data (for C₂₁H₃₁N₇O₂/2 HCl/2,3 H₂O)

Calculated (%): 47,78; N - 7,18; N - A 18.57.

Found (Percent): C - 47,80; N - 6,74; N - 18,53.

FAB-MC, positive ions, m/z: 414 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +37,14 (c = 0,490, methanol).

Appearance: white powder.

EXAMPLE 221

The dihydrochloride of 4-[((1S,2R)-2-{[imino(1,2-oxazine-2-yl)methyl]amino}cyclohexyl)amino]-N-(4-methoxyphenyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₃₅N₇O₃/2 HCl/0,8 H₂O)

Calculated (%): 55,59; N - To 6.43; N - 16,21.

Found (Percent): C - 55,89; N. Of 6.66; N $ 15.87 With.

FAB-MC, positive ions, m/z: 518 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -14,90 (c = 0,510, methanol).

Appearance: yellow powder.

EXAMPLE 222

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(1,2-oxazine-2-yl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₇H₃₈N₇O₂Cl/2 HCl/2,2 H₂O)

Calculated (%): 50,62; N - 6,99; N - 15,30.

Found (%): 50,45; N - 6,59; N - 15,19.

FAB-MC, positive ions, m/z: 528 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +57,73 (c = 0,485, methanol).

Appearance: white powder.

EXAMPLE 223

The dihydrochloride of 4-[((1S,2R)-2-{[imino(1,2-oxazine-2-is)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₅H₃₇N₇O₂/2 HCl/ H₂O)

Calculated (%): 53,76; N - 7,40; N - 17,55.

Found (%): 53,51; N - 7,20; N - 17,26.

FAB-MC, positive ions, m/z: 468 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +56,76 (c = 0,532, methanol).

Appearance: white powder.

EXAMPLE 224

The dihydrochloride of N-cycloheptyl-4-[((1S,2R)-2-{[imino(1,2-oxazine-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₈H₄₁N₇O₂/2 HCl/1,5 H₂O)

Calculated (%): 55,35; N - 7,63; N - 16,14.

Found (Percent): C - 55,67; N - 7,73; N - 15,92.

FAB-MC, positive ions, m/z: 508 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +52,47 (c = 0,404, methanol).

Appearance: white powder.

EXAMPLE 225

The dihydrochloride 6-chloro-N-cycloheptyl-4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]hinzelin-2-carboxamide

Elemental analysis data (for C₂₆H₃₆N₇O₂Cl/2 HCl/2,5 H₂O)

Calculated (%): 49,41; N - 6,86; N - 15,51.

Found (%): 49,18; N - 6,86; N - 15,41.

FAB-MC, positive ions, m/z: 514 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +76,82 (c = 0,492, methanol).

Appearance: white powder.

EXAMPLE 226

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methylamino}cyclohexyl)amino]-6-chloro-N-cycloheptylmethyl-2-carboxamide

Elemental analysis data (for C₂₄H₃₄N₇O₂Cl/2 HCl/ H₂O)

Calculated (%) : - Of 49.79; H - 6,62; N - 16,93.

Found (%): 49,66; N Is 6.54; N - 17,12.

FAB-MC, positive ions, m/z: 488 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +54,20 (c = 0,424, methanol).

Appearance: white powder.

EXAMPLE 227

The dihydrochloride 6-chloro-N-cycloheptyl-4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-hinzelin-2-carboxamide

Elemental analysis data (for C₂₅H₃₆N₇O₂Cl/2 HCl/2,5 H₂O)

Calculated (%): 48,43; N - 6,99; N - 15,81.

Found (%): 48,28; N - 6,60; N - 15,97.

FAB-MC, positive ions, m/z: 502 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +78,83 (c = 0,515, methanol).

Appearance: white powder.

EXAMPLE 228

The dihydrochloride of N-(2,2-dimethylpropyl)-4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 468 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +50,28 (c = of 0.533, methanol).

Appearance: white powder.

EXAMPLE 229

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methyl-N-[3-(methylthio)propyl]hinzelin-2-carboxamide

Elemental analysis data (for C₂₄H₃₅N_{7 O2S/2 HCl/ H2O)}

Calculated (Percent): C - 49,99; N - 6,82; N - 17,00.

Found (%): 50,05; N - 6,72; N - 16,87.

FAB-MC, positive ions, m/z: 486 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +56,42 (c = 0,514, methanol).

Appearance: white powder.

EXAMPLE 230

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-N-(3-methoxy-2,2-dimethylpropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₉N₇O₃/2 HCl/ H₂O)

Calculated (%): 53,06; N And 7.36; N - 16,66.

Found (%): 53,44; N - 7,13; N - 16,52.

FAB-MC, positive ions, m/z: 498 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +48,19 (c = 0,527, methanol).

Appearance: pale yellow powder.

EXAMPLE 231

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methyl-N-(tetrahydro-2H-Piran-4-yl)hinzelin-2-carboxamide

Elemental analysis data (for C₂₅H₃₅N₇O₃/2 HCl/2,4 H₂O)

Calculated (%): 50,23; N - 7,05; N - 16,40.

Found (%): 50,29; N - 6,88; N - 16,39.

FAB-MC, positive ions, m/z: 482 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +62,18 (c = 0,550, methanol).

Appearance: white powder.

EXAMPLE 232

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)am is but]-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₇H₃₉N₇O₃/2 HCl/2 H₂O)

Calculated (%): 52,42; N - 7,33; N - 15,85.

Found (%): 52,13; N - 7,19; N - 15,69.

FAB-MC, positive ions, m/z: 510 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +61,67 (c = 0,548, methanol).

Appearance: white powder.

EXAMPLE 233

The dihydrochloride of N-(2-ethylbutyl)-4-[((1S,2R)-2-{[imino(isoxazolidine-2-yl)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₉N₇O₂/2 HCl/ H₂O)

Calculated (%): 54,54; H - EUR 7.57; N - 17,12.

Found (%): 54,49; N - 7,38; N - 16,91.

FAB-MC, positive ions, m/z: 482 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +52,57 (c = 0,563, methanol).

Appearance: white powder.

EXAMPLE 234

The dihydrochloride of N-(2,2-dimethylpropyl)-4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₇N₇O₂/2 HCl/0.5 H₂O)

Calculated (%): 53,63; N - 7,50; N - 18,24.

Found (%): 53,63; N - 7,56; N - 17,89.

FAB-MC, positive ions, m/z: 456 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +64,07 (c = 0,518, methanol).

Appearance: white powder.

EXAMPLE 235

The dihydrochloride of 4-[((1S,2R)-2-{[imino(isoxazol the Jn-2-yl)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₄H₃₅N₇O₂/2 HCl/1,2 H₂O)

Calculated (%): 52,59; N - 7,25; N - 17,89.

Found (Percent): C - 52,55; N - 7,13; N - 17,59.

FAB-MC, positive ions, m/z: 454 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +59,96 (c = 0,507, methanol).

Appearance: white powder.

EXAMPLE 236

The dihydrochloride of 4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-N-isobutyl-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₅N₇O₂/2 HCl/0,7 H₂O)

Calculated (%): 52,41; N - 7,34; N - 18,60.

Found (%): 52,44; N - 7,22; N - 18,26.

FAB-MC, positive ions, m/z: 442 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +73,00 (c = 0,526, methanol).

Appearance: white powder.

EXAMPLE 237

The dihydrochloride of 4-{[(1S,2R)-2-({imino[methoxy(methyl)amino]methyl}amino)cyclohexyl]amino}-N-(TRANS-4-methoxycyclohexyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₆H₃₉N₇O₃/2 HCl/ H₂O)

Calculated (%): 53,06; N And 7.36; N - 16,66.

Found (%): 53,34; N - 7,17; N - 16,40.

FAB-MC, positive ions, m/z: 498 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +70,16 (c = 0,496, methanol).

Appearance: white powder.

EXAMPLE 238

The dihydrochloride of 4-{[(1S,2R)-2-({imino[m is toxi(methyl)amino]methyl}amino)cyclohexyl]amino}-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₅N₇O₃/2 HCl/2 H₂O)

Calculated (%): 48,76; N - 7,29; N - 17,31.

Found (%): 48.38 Per; N - 6,89; N - 17,14.

FAB-MC, positive ions, m/z: 458 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +66,80 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 239

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₂H₃₃N₇O₃/2 HCl/2,2 H₂O)

Calculated (%): 47,36; N - 7,15; N - 17,57.

Found (%): 47,19; N - 6,76; N - 17,50.

FAB-MC, positive ions, m/z: 444 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +47,45 (c = 0,510, methanol).

Appearance: white powder.

EXAMPLE 240

The dihydrochloride of 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 430 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +31,28 (c = worn : 0.505, methanol).

Appearance: white powder.

EXAMPLE 241

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₃N₇O₃/2 HCl/2 H₂ O)

Calculated (Percent): C - 47,83; N - 7,11; N - 17,75.

Found (Percent): C - 47,59; N - 6,94; N - 17,72.

FAB-MC, positive ions, m/z: 444 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +57,20 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 242

The dihydrochloride of 4-[((1R,2S)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 430 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -53,09 (c = 0,550, methanol).

Appearance: white powder.

EXAMPLE 243

The dihydrochloride of 4-[((1S,2R)-2-{[amino(amoxiillin)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 444 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +55,04 (c = worn : 0.505, methanol).

Appearance: white powder.

EXAMPLE 244

The dihydrochloride of 4-[((1S,2R)-2-{[amino(propoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₅N₇O₃/2 HCl/3,3 H₂O)

Calculated (%): 49,23; N - 7,26; N - 17,47.

Found (Percent): C - 48, 97mm; N - 6,88; N - 17,48.

FAB-MC, positive ions, m/z: 458 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +50,29 (c = worn : 0.505, methanol).

Appearance: white powder.

NOTE THE R 245

The dihydrochloride of 4-{[(1S,2R)-2-({amino[(2-methoxyethoxy)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₅N₇O₄/2 HCl/2,4 H₂O)

Calculated (%): 46,84; N - 7,14; N - 16,63.

Found (%): 46,82; N - 6,82; N - 16,50.

FAB-MC, positive ions, m/z: 474 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +48,40 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 246

The dihydrochloride of 4-{[(1S,2R)-2-({amino[(2-floratone)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₂H₃₂N₇O₃F/2 with HCl/2 H₂O)

Calculated (%): 46,32; N - Of 6.71; N - 17,19.

Found (%): 46,32; N - 6,36; N - 17,09.

FAB-MC, positive ions, m/z: 462 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +47,76 (c = 0,515, methanol).

Appearance: white powder.

EXAMPLE 247

The dihydrochloride of 4-({(1S,2R)-2-[(amino{[2-(methylthio)ethoxy]imino}methyl)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₂₃H₃₅N₇O₃S/2 HCl/2 H₂O)

Calculated (%): 46,15; N - 6,90; N - 16,38.

Found (%): 46,05; N - Of 6.73; N - 16,26.

FAB-MC, positive ions, m/z: 490 [M+H]⁺.

Constant optical VR is the value of [α] ²⁰_D= +39,19 (c = 0,500, methanol).

Appearance: white powder.

EXAMPLE 248

1/2 Sulfate 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide

Suspended 300 mg 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide in 9 ml of methanol and the suspension add 35.4 mg of concentrated sulfuric acid. After stirring the mixture for 15 minutes there was added 75 ml of diisopropyl ether. Precipitated precipitated substance is collected by filtration, washed with diisopropyl ether, and dried under reduced pressure and get 314 mg of the desired compound as a white powder.

Elemental analysis data (for C₂₁H₃₁N₇O₃/0,5 H₂SO₄/1,5 H₂O)

Calculated (Percent): C - 49,89; N - 6,98; N - 19,39.

Found (%): 49,78; N Is 6.61; N - MT 19 : 18.

FAB-MC, positive ions, m/z: 430 [M+H]⁺.

Constant optical rotation [α]²⁰_D= -27,63 (c = 0,550, methanol).

EXAMPLE 249

The dihydrochloride of 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-6-methylpyrazole-2-carboxamide

FAB-MC, positive ions, m/z: 372 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +57,20 (c = 0,465, methanol).

Appearance: white powder.

EXAMPLE 250

Dihydrochlor the d 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-methoxy-6-methylpyrazole-2-carboxamide

Elemental analysis data (for C₁₉H₂₇N₇O₃/2 HCl/0,8 H₂O)

Calculated (%): 46,69; N. Of 6.31; N - Grade Of 20.06.

Found (%): 46,95; N - 6,27; N - 19,87.

FAB-MC, positive ions, m/z: 402 [M+H]⁺.

Constant optical rotation [α]²⁰_D= +8,80 (c = 0,500, methanol).

Appearance: white powder.

Example test 1. Test for skin sensitization in Guinea pigs (method adjuvant and skin samples)

The back area of male Hartley Guinea pigs (n = 5) aged 7 weeks shaved with an electric razor and the next day initiate primary sensitization. During primary sensitization emulsified full beta-blockers administered intradermal dose of 0.1 ml only at the initial moment of time and in the place where entered adjuvant, causing the plaster to the skin sample in a closed condition with 0.1 g of an ointment containing 1% of tested compounds. As the basis for ointments use vaseline containing 1% sesquioleate sorbitan (surfactant). 24 hours after you have applied the adhesive tape for skin samples, the adhesive tape is removed and the application site is cleaned by wiping. The procedure of such primary sensitization is carried out every day and continue on the whole 3 days. On day 7 after the initial application of the primary sensitization work in secondary sensibili is the situation. The area subjected to primary sensitization, shaved and open put the ointment containing 10% lauryl sodium. After 24 hours the application site clean, wiping it, and in the closed state impose a cotton bandage, which is applied to 0.2 g of an ointment containing 1% of tested compounds. 48 hours after applying the bandage is removed and the application site is cleaned by wiping. The provocation carried out on day 13 after the second sensitization. Region of the back and side area is shaved and the place provocations put 0.01 g of an ointment containing 1% of the test compounds, and leave for about 24 hours. Approximately 24 hours and 48 hours after the provocation carried out the inspection of the surface of the skin to determine the presence or absence of sensibilizirovannoy. Determination carry out the evaluation according to the evaluation criteria (see table 1) according to the method of Draize (1959).

In this regard, as a positive control, using 1-chloro-2,4-dinitrobenzene (DNCB) (sensitization: 1%, provocation: 0,1%). As the test compounds are used compounds of example 58 and example 248. As a control for comparison use the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide described in example 383 in patent document 1 (sensitization: 1%induction: 0,1%)./p>

As a result of sensitization with the test compounds do not see. But see strong erythema in positive control with DNCB (score 3 in 3/5 cases, grade 2 in 1/5 of the cases and a score of 1 in 1/5 of the cases) and mild edema (score 1 in 3/5 cases and a score of 0 in 2/5 cases). In addition, in the group with connection control for comparison of swelling is not observed in all cases, while in 2/5 cases see clearly perceptible erythema (score 2).

Therefore, it is apparent that the compounds according to the invention, which do not show sensibilizirovannoy, very applicable not only to external agents, but also for drugs in other dosage forms.

Example of test 2. Test for primary skin irritation in rabbits

The back region in female rabbits Kbs: JW (n=3-32) at the age of 20 weeks shaved with an electric razor and the next day the skin of the back put a band-aid for skin samples with 0.1 g of an ointment containing the test compound (introduction). As the basis for ointments use vaseline containing 5% sesquioleate sorbitan (surfactant). 24 hours after the introduction of the adhesive tape for skin samples were removed and the application site is cleaned by wiping. Then observe the formation of erythema and swelling at the site of application. The definition of irritation carry out the evaluation according to the evaluation criteria (table 1) according to the method of Draize (1959), used in the example test 1.

As a simple primary indicator of skin irritation using the average of the sum of the assessments of erythema and edema. As control compounds for comparison, which is structurally similar to the compounds according to the invention, use of the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (A)described in example 383 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-6-methyl-N-neopentylglycol-2-carboxamide (hereinafter referred to as the control for comparison), described in example 29 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control to compare With), described in example 372 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (D)described in example 346 in patent document 1; the dihydrochloride of 4-[((1S,2R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (E), described in example 388 in patent document 1; and the dihydrochloride of 4-[((1S,R)-2-{[amino(imino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide (hereinafter referred to as the control for comparison (F), described in example 48 in patent document 1.

More specifically, the connection control for comparison And is different from the compounds of examples 211, 212, 236 and 60 according to the present invention only by the substituent in position 4; the connection to control for comparison differs from the compound of example 19 of the present invention only by the substituent in position 4; the connection to control for comparison With differs from the compounds of examples 94, 95 and 61 according to the present invention only by the substituent in position 4; the connection to control for comparison D differs from the compounds of examples 239, 240, 92, 59, 35 and 93 according to the present invention only by the substituent in position 4; the connection to control for comparison E differs from the compounds of examples 101 and 58 of the present invention only by the substituent in position 4; the connection to control for comparison F differs from the compounds of examples 208, 1 and 91 according to the present invention only by the substituent in position 4; and all other groups have the same structure. The results are given in table 2.

As can be seen from table 2, the substitution of guanidinium in the side chain in position 4 derived hintline such substituents, which are the compounds according to the invention, significantly reduces primary skin irritation. Therefore, it is apparent that the compounds according to the invention is highly applicable as external agents with less skin irritation.

Example of test 3. Impact on scratching behavior in mice, caused by the use of serotonin

On the neck and the backs of ICR male mice (n=3-6) aged 4-6 weeks put 100 μl of a solution obtained by dissolving the hydrochloride serotonin in ethanol, in a concentration of 0.1% (hereinafter referred to as serotonin), and count the count of the number of episodes of scratching at the application hind legs, taking place immediately after the application within 15 minutes after injection. The introduction of the test compounds carry the application to the skin, intravenous injection or by oral administration. In the case of application to the skin of the test compound, which is dissolved in ethanol, put in the amount of 100 μl simultaneously with serotonin. In the case of intravenous administration of the test compound dissolved in physiological solution, injected at a dose of 10 ml/kg 5 minutes before the skin is of serotonin. In the case of oral administration of the test compound, dissolved in water, injected at a dose of 10 ml/kg over 20 minutes before application of serotonin. The control group for each method of administration give the appropriate solvent and compare the magnitude of the scratching behavior between the control group and the group treated with the test compound.

The results obtained when applied to the skin of the tested compounds are given in table 3; the results obtained by intravenous injection of the test compounds are given in table 4; and the results obtained by oral administration of the tested compounds are given in table 5.

As can be seen from tables 3-5, the compounds according to the invention significantly inhibit the behavior of scratching in the neck and back caused by application of serotonin. From the obtained results it is obvious that the use of the compounds according to the invention as an external drug, intravenous drugs or drug for oral administration useful in case of itching caused by various diseases accompanied by itching.

Example of test 4. Effect on spontaneous scratching behavior in mice, caused by the destruction of the barrier of the stratum corneum

As can be seen from table 6, the compounds according to the invention is substantially the basement who have spontaneous scratching behavior, caused by destruction of the barrier of the stratum corneum. From the obtained results it is obvious that the use of the compounds according to the invention as an external drug ointment is also effective in the treatment of itching caused by xerodermia or atopic dermatitis, itching accompanying hemodialysis, and other itching.

Example of test 5. Test for acute toxicity in mice

Using male ICR mice aged 4-6 weeks. The connection according to the invention is administered intravenously at a dose of 10 ml/kg into the tail vein and then observe the behavior of the mice within 2 hours. The results are given in table 7.

As can be seen from table 7, changes in symptoms, such as sedative effect, not observed in all mice that were administered the test compound. Accordingly, the toxicity of the compounds according to the invention is extremely low, and connections can be safely used as a pharmaceutical preparation.

Sample preparation 1

Put 100 g of compound according to the invention of example 1, 292 g of D-mannitol, 120 g of corn starch and 28 g hydroxypropylcellulose with a low degree of substitution in the granulator-dryer fluidized bed (STREA; manufacturer PAUREC) and granular is to spray a quantity of aqueous 5% solution of hydroxypropylcellulose. After drying and subsequent grinding in a crusher/mill (COMIL; manufacturer PAULEC) in the mixture is mixed with a certain amount of stearate in the mixer (container mixer BOHRE, model MS; manufacturer KOTOBUKI-GIKEN), the mixture is formed into tablets with a diameter of 7 mm and a weight of 140 mg per tablet with a rotary swaging tablet press machine (CORRECT 12HUK; manufacturer KIKUSUI) and receive a tablet containing 25 mg of the compounds according to the invention.

Example product 2

Placed 75 g of compound according to the invention of example 1, 180 g of lactose, 75 g of corn starch and 18 g calcixerollic in with stirring granulator (vertical granulator, model VG-01), add a quantity of aqueous 5% solution of hydroxypropylcellulose, the mixture granularit and dried in the granulator-dryer fluidized bed (STREA; manufacturer PAUREC) and then crushed in the crusher/mill (COMIL; manufacturer PAULEC). Fill in 120 g of crushed material capsule No. 3 using capsulearava machine (filler capsules; SHIONOGI QUALICAPS) and receive capsules containing 25 mg of the compounds according to the invention.

The example of the drug 3

Weigh 2.5 g of the compounds according to the invention of example 1 and 4.5 g of sodium chloride, add 450 ml of water for injection, the mixture is stirred until dissolved and then bring the pH to 6.5 with 0.1 mol/l hydrochloric acid or 0.1 mol/l sodium hydroxide solution. Then add the keys water for injection to obtain a total volume of 500 ml Then the thus obtained solution is filtered under pressure through a membrane filter (pore size 0.22 μm). Then 5,3 ml of the filtrate is aseptically fill a 5-ml brown vial and receive a preparation for injection containing 25 mg of the compounds according to the invention. The procedure from receipt of the filling is carried out in aseptic conditions.

Sample preparation 4

At 45 º C dissolve of 99.75 g of Vihterpalu N-15 (manufactured by HIRTH), add 0.25 g of the compounds according to the invention of example 1 and dispersed by stirring. The resulting dispersion is poured into a 1-d form of suppository at high temperatures, paying attention to the prevention of the deposition, utverjdayut and removed from the form, get the suppository contains 25 mg of the compounds according to the invention.

Sample preparation 5

Weigh 0.5 g of the compounds according to the invention of example 1, and 5.2 g of sodium dihydrophosphate, 11.9 g of monohydratefast sodium, 2.5 g of sodium chloride and 0.3 g of benzalkonium chloride, add 950 ml of distilled water and the mixture is stirred until dissolution. Then add distilled water to obtain a total volume of 1000 ml of Solution, thus obtained, was filtered under pressure through a membrane filter (pore size 0.2 µm). Then 5 ml of the filtrate is filled aseptically sterilized 5-ml vial for eye drops and get eye drops (5 ml)containing 0.5 mg/ml preprogram the ia according to the invention. The procedure from receipt of the filling is carried out in aseptic conditions.

Sample preparation 6

Weigh 80 g olive oil 15 g of cetyl alcohol and 15 g of stearyl alcohol, the mixture is stirred and dissolved by heating at 70 º C in a water bath (oil phase). Separately, weigh 1 g of compound according to the invention of example 1, 10 g Polysorbate 80, 5 g of lauryl sodium, 0.25 g of methyl para-hydroxybenzoate, 0.15 g propyl-para-hydroxybenzoate and 880 g of distilled water, the mixture is stirred and dissolved by heating at 70 º C in a water bath (aqueous phase). The oil phase and the aqueous phase is placed in a vacuum emulsifier and the mixture is then emuleret under stirring with a high speed mixer-homogenizer at 70 º C in vacuum. Then, the resulting emulsion is cooled with water to 35 º C while mixing with a low speed. Then 50 ml of the resulting emulsion fill a 50-ml container of lotion and get lotion (50 ml)containing 1.0 mg/ml of the compounds according to the invention.

Example of preparation 7

Weighed 250 g white vaseline, 250 g of stearyl alcohol and 40 g polyoxyethylene hydrogenated castor oil 60, the mixture is stirred and dissolved by heating at 70 º C in a water bath (oil phase). Separately, weigh 1 g of compound according to the invention of example 1, 120 g of propylene glycol, 0.25 g of methyl para-hydroxybenzoate, ,15 g of propyl-para-hydroxybenzoate and 340 g of distilled water, the mixture is stirred and dissolved by heating at 70 º C in a water bath (aqueous phase). The oil phase and the aqueous phase is placed in a vacuum mixer and then the mixture emuleret under stirring at 70 º C in vacuum. The ointment obtained by cooling the resulting emulsion and a light mixing up until the emulsion not hardened, fill the 10-g containers for ointments or 10-g tubes for ointments and get an ointment containing 1.0 mg/g of compound according to the invention.

Example of preparation 8

Weighed 110 g of gelatin, 25 g of polyvinyl alcohol and 10 g of methyl cellulose, mix and get the powder mixture. Then it was added 13 g of glycerin and the powder was dispersed therein using a small mixer. Then to the mixture was added 100 g of distilled water and the mixture is dissolved in water when heated to 60OC. Then added to the mixture of 85 g of kaolin and dispersed therein at 60 ° C. To the resulting dispersion added to the dispersion obtained separately by mixing 20 g of glycerol and 5 g of sodium polyacrylate, and all dissolved and stirred at 60'C. Then to the mixture is added 15 g of polybutene and dispersed therein at 60 ° C. To the dispersion is added 0.5 g of compound according to the invention of example 1 and dispersed at 50 º C, getting through this pasta. Then the paste is spread on the basis of (non-woven product) (100 g/700 cm²and then covered the base cover protective Proclus is coy, made from polyethylene film (50 μm), cut and get through this sticky product. The connection according to the invention is contained in an amount of 1 mg to 7 cm²sticky drug.

Industrial applicability

As described above, the compounds according to the invention have a strong inhibitory effect on the behavior of scratching, slight irritations of the skin and not sensibiliser the skin and therefore highly applicable as external agents. Moreover, the compounds according to the invention have a overwhelming effect on the behavior of brushing not only by application to the skin, but also intravenous, subcutaneous and oral administration, and therefore highly applicable as a drug in different dosage form.

1. Derived hintline represented by the following General formula [1]or its pharmaceutically acceptable salt

where R¹represents hydrogen or alkyl;
R²represents hydrogen, alkoxy, cycloalkyl, (cycloalkyl)alkyl or alkyl where the alkoxy, cycloalkyl, (cycloalkyl)alkyl and the alkyl can be substituted one to three groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) alkoxyalkyl, (4) hydroxy, (5) alkylthio, (6) furil, (7) piperidine which may be substituted and the sludge;
R³and R⁴are the same or different and each represents hydrogen, alkyl, alkoxy or halogen;
R⁵and R⁶imagine the following:
(i) R⁵combine with R⁶that is alkylen where alkylene may condense with benzene loop;
(ii) R⁵represents hydrogen, hydroxy, alkyl or alkoxy, where alkyl and alkoxy may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen; and R⁶is (1) alkyl, (2) cycloalkyl, (3) phenyl, or (4) a 5-6-membered aromatic heterocyclic group containing one to three heteroatoms selected from the group consisting of nitrogen atom and oxygen atom, where the alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted by one to three groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furil, (6) halogen, and (7) N,N-dialkylamino;
(iii) R⁵represents hydrogen, hydroxy or alkoxy, where the alkoxy may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen; and R⁶represents-N(R⁶¹)(R⁶²), where R⁶¹is hydrogen and R⁶²represents hydrogen or alkoxy;
with the exception of compounds in which R⁵represents hydrogen, and R⁶predstavljaet a-NH ₂.

2. Derived hintline or its pharmaceutically acceptable salt according to claim 1, where
(i) R⁵combine with R⁶that is alkylen where alkylene may be condensed with a benzene cycle; or
(ii) R⁵represents hydrogen, alkyl or alkoxy; and R⁶represents (1) alkyl, (2) cycloalkyl, (3) phenyl or (4) a 5-6-membered aromatic heterocyclic group containing one to three heteroatoms selected from the group consisting of nitrogen atom and oxygen atom, where the alkyl, cycloalkyl, phenyl and aromatic heterocyclic group may be substituted by one to three groups selected from the group consisting of (1) alkoxy, (2) hydroxy, (3) phenyl, (4) pyridyl, (5) furil, (6) halogen, and (7) N,N-dialkylamino.

3. Derived hintline or its pharmaceutically acceptable salt according to claim 1, where
R²represents hydrogen, cycloalkyl, (cycloalkyl)alkyl, or alkyl, where cycloalkyl, (cycloalkyl)alkyl and the alkyl can be substituted one to three groups selected from the group consisting of (1) alkoxy, (2) halogen, (3) hydroxy, and (4) alkylthio;
R³and R⁴are the same or different and each represents hydrogen, alkyl or halogen;
(iii) R⁵represents hydrogen, hydroxy or alkoxy, where the alkoxy may be substituted by one to three groups selected from the group consisting of Sarcoxie, alkylthio and halogen; and
R⁶represents-N(R⁶¹)(R⁶²);
R⁶¹represents hydrogen;
R⁶²represents hydrogen or alkoxy;
with the exception of compounds in which R⁵represents hydrogen, and R⁶represents-NH₂.

4. Derived hintline or its pharmaceutically acceptable salt according to claim 2, where
R²represents (1) hydrogen, (2) alkoxy, (3) cycloalkyl, which can be substituted one to three groups selected from the group consisting of halogen, alkoxy, alkoxyalkyl and hydroxy, (4) (cycloalkyl)alkyl which may be substituted by one to three groups selected from the group consisting of alkoxyalkyl and hydroxy, or (5) alkyl;
(i) R⁵combine with R⁶that is alkylen where alkylene may condense with benzene loop;
(ii) R⁵represents hydrogen, alkyl or hydroxy, and R⁶is (1) alkyl which may be substituted by one to three groups selected from the group consisting of alkoxy, hydroxy, N,N-dialkylamino, phenyl, pyridyl and Furie, (2) cycloalkyl, (3) phenyl which may be substituted by one to three groups selected from the group consisting of alkoxy, halogen and N,N-dialkylamino, or (4) a 5-6-membered aromatic heterocyclic group containing one to three heteroatoms selected and the group, consisting of nitrogen atom and oxygen atom.

5. Derived hintline or its pharmaceutically acceptable salt according to claim 3, where
R²represents (1) hydrogen, (2) cycloalkyl, which may be substituted by alkoxy, (3) (cycloalkyl)alkyl or (4) alkyl which may be substituted by one to three groups selected from the group consisting of halogen, alkoxy, and alkylthio;
R³and R⁴are the same or different and each represents hydrogen, alkyl or halogen;
(iii) R⁵represents (1) hydrogen, (2) hydroxy, or (3) alkoxy which may be substituted by one to three groups selected from the group consisting of alkoxy, alkylthio and halogen; and
R⁶represents-N(R⁶¹)(R⁶²), where R⁶¹represents hydrogen, R⁶²represents hydrogen or alkoxy;
with the exception of compounds in which R⁵represents hydrogen, and R⁶represents-NH₂.

6. Derived hintline or its pharmaceutically acceptable salt according to claim 1, where the compound is chosen from the group comprising compounds (1)to(15):
(1) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(2) N-(2,2-dimethylpropyl)-4-({(1S,2R)-2-[(2-methoxy-2-methylpropanoyl)amino]cyclohexyl]amino}-6-methylpyrazole-2-carboxamide;
(3) 4-({(1S,2R)-2-[(3-methoxyp animator)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(4) 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl} amino)-N-isopropyl-6-methylpyrazole-2-carboxamide;
(5) 4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(6) 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isobutyl-6-methylpyrazole-2-carboxamide;
(7) N-(2-ethoxyethyl)-4-({(1S,2R)-2-[(3-hydroxypropylamino)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide;
(8) 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-isopropyl-6-methylpyrazole-2-carboxamide;
(9) 4-({(1S,2R)-2-[(2-hydroxy-2-methylpropanamide)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(10) 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(11) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(12) 4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(13) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide;
(14) N-(2-ethoxyethyl)-4-({(1S,2R)-2-[(2-methoxyethoxymethyl)amino]cyclohexyl}amino)-6-methylpyrazole-2-carboxamide and
(15) 4-{[(1S,2R)-2-(econimically)cyclohexyl]amino}-N-isopropyl-6-methylpyrazole-2-carboxamide.

7. Derived Chinas the Lin or its pharmaceutically acceptable salt according to claim 1, where the compound is chosen from the group comprising compounds (1)to(14):
(1) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(2) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide;
(3) 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-isobutyl-6-methylpyrazole-2-carboxamide;
(4) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(cyclopropylmethyl)-6-methylpyrazole-2-carboxamide;
(5) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-isopropyl-6-methylpyrazole-2-carboxamide;
(7) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino)-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(8) 4-[((1S,2R)-2-{[amino(hydroxyimino)methyl]amino}cyclohexyl)amino]-N-(3-methoxypropyl)-6-methylpyrazole-2-carboxamide;
(9) 4-[((1S,2R)-2-{[amino(methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-ethoxyethyl)-6-methylpyrazole-2-carboxamide;
(10) 4-[((1S,2R)-2-{[amino(amoxiillin)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(11) 4-{[(1S,2R)-2-({amino[(2-methoxyethoxy)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(12) 4-{[(1S,2R)-2-({amino[(2-floratone)imino]methyl}amino)cyclohexyl]amino}-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide;
(13) 4-({(1S,2R)-2[(amino{[2-(methylthio)ethoxy]imino}methyl)amino)cyclohexyl}amino)-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide and
(14) 4-[((1S,2R)-2-{[amino(2-methoxyimino)methyl]amino}cyclohexyl)amino]-N-(2-methoxyethyl)-6-methylpyrazole-2-carboxamide.

8. Pharmaceutical composition having activity antipruritic agent containing as an active ingredient derived hintline or its pharmaceutically acceptable salt according to any one of claims 1 to 7.

9. The pharmaceutical composition of claim 8, which is used to suppress itching caused by skin damage or skin itching.