Title of Invention

AMINO ACID DIAMIDES IN NON ALPHA POSITION WHICH ARE USEFUL AS ADJUVANTS FOR ADMINISTRATION OF BIOLOGICAL ACTIVE AGENTS

Abstract

Amino acid diamides in non &#945; position of formula (1), wherein R<sub>1</sub> is selected from amongst the group consisting of the functional groups alkyl, halogen, NO<sub>2</sub>, OH, OCH<sub>3</sub> alone or associated and R<sub>2</sub> is selected from the group consisting of functional groups H, alkyl, halogen, NO<sub>2</sub>, OH, OCH<sub>3</sub>, which are useful as adjuvants for the administration of biological active agents, as well as pharmaceutical compositions containing these diamides of formula (1) and the use thereof for the manufacture of antithrombotic medications and for the manufacture of a medication for the treatment of a disease selected from amongst the group consisting of inflammation, cancer and allergy.

Full Text

AMINO ACID DIAMIDES IN NON a POSITION WHICH ARE USEFUL AS ADJUVANTS FOR ADMINISTRATION OF BIOLOGICAL ACTIVE AGENTS FIELD OF THE INVENTION r- The present invention relates to new amino acid diamonds in no a position which are useful as adjutants for administration of biological active ingredients. The compounds under the invention facilitate the oral, intraduodenal, interact logic and pulmonary administration of heparin, low-molecular-weight heparins, very-low-molecular-weight heparins, and other glycosaminogiycans and derivatives. Primarily those derivatives relative to n=2 and n=5 (WO 97/35480) are claimed as agents that facilitate the oral absorption of biological products. The applicant has also discovered that the derivatives that have the CI or NO2 substituents in position 3 are at least as active as the derivatives.; that have an OH in position 1. Figure 3 shows the intracolonic absorption in the rat of the association of the pharmaceutical composition RO-14 with the product of example 4. Example 2, 6-[4-{2-hydroxybenzoylamino}benzoylamino]humanoid acid, (compound 2). To a solution of 2.60 g (11.00 mom) of methyl 4-(3-aminobenzoylamino)botanists dissolved In 25 ml of ethyl acetate, very lovely add 1 40 g (10.00 mole) of 2-hydroxybenzoyl chloride dissolved in 5 ml of ethyl acetate. Then add 1.00 g (10.00 (compound 4) To a suspension of 20.36 g (91.71 mmol) of 4-(2-aminobenzoylamino)botanic acid in 200 ml of dry methylene chloride, add 42.33 g (391.92 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an^ ice bath and add 11.87 g (117.57 mmol) of triethylamine and a solution of 15.52 g (78.38 (compound 5) To a suspension of 1.61 g (6.81 mmol) of 5-(2-aminobenzoylamino)pentanoic acid in 20 ml of dry methylene chloride, add 1.41 g (11.94 mmol) of trimethylsllyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.88 g (8.73 mmol) of triethylamine and a solution of 1.15 g (5.82 mmol) of To a suspension of 2.00 g (7.20 mmol) of 8-(2-aminobenzoylamlno) actinic acid in 25 ml of dry methylene chloride, add 1.36 g (12.60 mmol) of trlmethylsllyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and To a suspension of 0.30 g (1.20 mmol) of 6-(2-amJnoben2oylamino)hexanoic acid in 5 ml of dry methylene chloride,. add 0.23 g (2.10 mmol) of trimethylsllyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.15 g (1.53 mmol) of triethylamine and a solution of 0.20 g (2.05 mmol) of 2- To a suspension of 3.90 g (17.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry ethyl acetate, add 3.26 g (17.56 mmol) of 2-nltrobenzoyl chloride dissolved In 5 ml of dry ethyl acetate and 1.76 g of triethylamine. Allow the reaction allow the reaction to reflux under argon during 2 hours. Then place the flask in an ice bath and add 0.31 g (3.07 mmol) of triethylamine and a solution of 0.40 g (2.05 mmol) of 2-acetylsalicycoyl chloride dissolved in 5 ml of dry ethylene swirled. Allow the reaction to stir for 30 minutes in an ice bath and 24 nouns at room temperature. Eliminate the solvent at low pressure, add 30 m\ of 10% Noah to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and ether. Purify the reaction product by recrystallization (EtOH/HzO). This yields 0.37 g (56%) of 3-[2-(2-hydroxybenzoyl-amino)benzoylamino]pyromaniac acid as a white solid. M.P.: 200-202 °C IR(ATR): V 3331. 3051, 2657, 1718, 1649, 1626, 1593, 1523, 1269. 1225. 904, 853, 749 cm*' ^H-NMR (400 MHz, DMSO): .5 2.52 (t, 2 H, J = 7.4 Hz, -CH2-CO-), 3.46 (m, 2 H, - CH2-NH-), 6.97 (m. 2 H, aromatic), 7.18 (m. 1 H, aromatic), 7.41 (m, 1 H. aromatic), 7.51 (m, 1 H, aromatic). 7.65 (m. 1 H. aromatic). 7.85 (m. 1 H. aromatic). 8.45 (m. 1 H, aromatic). 8.79 (Scrod. 1 H. -NH-CH2-), 11.61 (s, 1H. -OH). 12.15 (s, 1 H, -COOH). 12.25 (s, 1 H,-NH-Ph).ppm ^^C NMR (200 MHz, DMSO): 5 35.4, 35.5, 117.2. 118.02, 119.3, 121.7. 123.1. 123.2. 128.0, 129.4, 131.4, 131.7, 137.8, 157.9. 165.3, 168.1, 172.7 ppm MS m/z (%): 328 (M"". 6). 293 (3). 250 (5). 239 (100), 208 (20). 119 (65), 92 (50). 65 (60). 44 (42) Elemental analysis of C17H16N2O5 Calculated: % C = 62.19; % H = 4.91; % N = 8.53 Found: % 0 = 61.82; % H = 4.72; % N = 8.39 Example 10. 2-[2-(2-hydroxybenzoylamino)benzoylamino]ethnic acid;.(compound 10). To a suspension of 4.74 g (24.44 mmol) of 2-(2-amlnobenzoylamino)ethanoic acid in 40 ml of dry methylene chloride, add 5.05 g (4.28 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 3.16 g (31.32 mmol) of triethylamine and a solution of 4.13 g (20.88 mmol) of acetylsalicyloyi chloride dissolved In 10 ml of dry ethylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 40 ml of 10% Noah to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H20). This yields 3.54 g (54%) of 2-[2-(2-hydroxybenzoylamino) benzyls-amino]ethanoic add as a white solid. M.P.: 222-224 °C IR(ATR): V 3286. 2978. 1730, 1650, 1627, 1598, 1584. 1526,' 1242. 900, 835. 752 cm"^ ^H-NMR (400 MHz, DMSO): .53.95 (d, 2 H, J = 4.9 Hz. -CH2-). 6.97 (m, 2 H, aromatic), 7.21 (m. 1 H, aromatic). 7.41 (m. 1 H, aromatic), 7.55 (m, 1 H, aromatic), 7.80 (m. 2 H, aromatic). 8.52 (m, 2 H. aromatic). 9.07 (Scrod. 1 H. -NH-CH?-). 11.58 (s. 1 H, -OH), 12.18 (s, 1 H, -COOH), 12.70 (s. 1 H. -NH-Ph) ppm "C-NMR (200 MHz, DMSO); 5 41.2. 117.2. 118.0. 119.3. 121.8. 122.3. 123.2, 128.1, 129.3, 131.8, 133.7, 138.1. 157.9, 165.4, 168.4,171.0 ppm. MS m/z (%): 278 (M*-36. 16), 239 (37) 234 (17), 195 (14), 107 (9), 119 (100). 92 (36). 77(22)65(28). 50(19) Elemental analysis of C20H22N2O5 Calculated: % C = 61.14; % H = 4.49; % N = 8.91 Found: % C = 60.90; % H = 4.42; % N = 8.98 Example 11. 4-[2-(2-hydroxy-4-nitrobenzoylamino)benzoylamino]butanoic acid, (compound 11). To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethylamine and a solution of 0.77 g (38.50 mmol) of 2- hyclroxy-4-nitrobenzoyl chloride dissolved In 10 ml of dry ethylene chloride. Allow the reaction to stir for. 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOl4.to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated Hull, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H20). This yields 0.50 g (34%) of 4-(2-(2-hydroxy-4-nitro-benzoylamino)ben2oylamlno]butanoic acid as a yellow solid. M.P.: 209-211 °C IR(ATR): V 3378, 2939, 1702, 1592, 1520, 1449, 1420, 1347, 1326, 1300, 1259, 1232, 1215, 1162, 813, 748, 737 cm'"' ^H-NMR (400 MHz, DMSO): .51.75 (m, 2 H, -CH2-CH2-CH2-), 2.28 (t, t H, J = 7.3 Hz, -CH2-CO-). 3.26 (m, 2 H, -CH2-N-), 7.20 (m, 1 H, aromatic), 7.52 (m, 1 H. aromatic). 7.66 (m, 1 H, aromatic), 7.74 (m, 2 H, aromatic), 8.10 (m, 1 H, aromatic). 8.49 (m, 1 H, aromatic), 8.71 (t, J = 5.4 Hz, -NH-CH2-), 12.12 (s, 2 H, -OH, -COOH). 12.30 (s, 1 H, -NH) ppm ^*C-NMR (200 MHz, DMSO): 5 24.2, 31.1, 38.7, 111.4, 113.6,\121.1, 123.5, 124.0, 125.4, 128.1. 131.2 132.1. 137.4, 149.9, 156.8, 162.5, 167.8, 174.2 ppm MS m/z (%): 284 (M*-103, 55), 253 (4), 238 (16). 222 (1), 211 (2), 182 (8), 154 (9). 146 (13), 119 (90), 92 (47), 63 (48), 53 (21), 30 (100) Elemental analysis of C18H17N3O7 Calculated: % C = 55.81; % H = 4.42; % N = 10.85 Found: % C = 55.79; % H = 4.44; % N = 10.74 Example 12. 4-[2-(2-hyclroxy-5-nltrobenzoylamino)benzoylamino]butanoic acid, (compound 12). To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminoben2oylamino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethyiamine and a solution of 0.77 g {38.50 mmol) of 2-hydroxy-5-nitrobenzoyl chloride dissolved In 10 ml of dry ethylene chloride. Allow the reaction to stir for 30 minutes in an Ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the cmde product and continue stinking the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times water and with ether. Purify the reaction product by recrystallization In dioxane/HaO. This yields 0.99 g (67%) of 4-[2-(2-hydroxy-5-nltrobenzoylamino) benzoylamlno]butane acid as a cream-colored solid. M.P.: 239-241 "C IR(Arm: y3315. 3079, 2626. 1695, 1651, 1631, 1584, 1373, 1334, 1218. 831, 756, 746 cm-"* ^H-NMR (400 MHz, DMSO): .51.75 (m, 2 H, -CHT-CHT-CH O. 2.28 (t, 1 H, J = 6.8 Hz. -CH2-CO-). 3.26 (m, 2 H. -CH2-N-). 7.15 (m, 1 H, aromatic), 7.18 (m, 1 H, aromatic), 7.53 (m, 1 H, aromatic), 7.65 (m, 1 H, aromatic), 7.26 (m. 1 H, aromatic), 8.45 (m, 1 H, aromatic). 8.70 (m, J = 5.4 Hz. -NH-CH2-). 8.76 (m. 1 H, aromatic), 12.09 (s, 2 H. -OH, -GOOH). 12.90 (s. 1 H, -NH) ppm ^^C-NMR (200 MHz. DMSO): 5 24.2. 31.1. 38.7. 117.9. 119.8.-122.2. 123.5. 124.3, 127.2, 128.1, 128.5. 131.1. 137.3. 139.7. 162.0. 162.3, 167.8. 174.2 ppm MS m/z (%): 369 (M*-18, 1), 352 (10). 335 (1), 311 (3). 296 (3). 284 (31). 253 (11). 237 (3). 209 (6). 166 (6). 137 (8), 119 (74), 92 (55), 63 (43).:42 (56). 41 (72), 30 (100) Elemental analysis of C18H17N3O7 Calculated: % C = 55.81; % H = 4.42; % N = 10.85 Found: % C = 55.89; % H = 4.50; % N = 10.80 Example 13. ;.. 4-[2-(2-hydroxy-4-methoxybenzoyiamino)benzoylamino]butajioic acid, (compound 13). To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethylamine and a solution of 0.71 g (38.5 mmol) do 2-hydroxy-4-methoxybenzoyl chloride dissolved in 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Noah to-the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/HaO). This yields 0.54 g (38%) of- 4-[2-(2-hydroxy-4-methoxybenzoylamino)benzoylamino]buttonhole acid as a white solid. M.P.:201-203*'C IR(ATR): V 3306, 2939. 1711, 1643, 1622, 1582, 1524, 1508, 1438, 1383, 1244, 1208, 1178, 1144, 964, 830, 751, 671 cm ^H-NMR (400 MHz, DMSO): § 1.76 (m. 2 H, -CHAP.-CH –CH ). 2.29. (t. 1 H. J = 7.3 Hz, -CH2-CO-), 3.29 (m. 2 H. -CH2-N-), 3.78 (s, 3 H, -CH3 ). 6.48 (m. 1 H, aromatic). 6.58 (m, 1 H. aromatic), 7.17 (m, 1 H, aromatic), 7.50 (m, 1 H, aromatic), 7.71 (m, 1 H, aromatic), 7.76 (m. 1 H, aromatic), 8.45 (m, 1 H, aromatic), 8.77 (t, J = 5.4 Hz, -NH- CH2-), 12.05 (s, 2 H. -OH, -NH), 12.22 (s, 1 H, -COOH) ppm "C-NMR (200 MHz, DMSO): 5 24.2, 31.1, 38.7, 55.4, 101.3, 106.7, 109.9, 121.5, 122.6, 122.9. 128.1, 129.9, 131.5. 138.1, 160.9, 163.8.166.0.168.2, 174.2 ppm ^ MS m/z (%): 372 (M*. 3). 353 (2). 269 (84), 228 (16), 222 (17). 182 (4). 151 (100), 120 (58), 119 (59), 92 (47). 65 (24). 52 (12). 30 (53) Elemental analysis of C19H20N2O6 Calculated: % C = 61.28; % H = 5.41; % N = 7.52 Found: % C = 60.89; % H = 5.37; % N = 7.40 Example 14. 4-[2-(2-hydroxy-5-methoxybenzoylamlno)benzoyiamino]butahoicacid. (compound 14). To a suspension of 1.00 g (4.50 mmol) of 4-(2-aminobenzoyIam,ino)butanoic acid in 20 ml of dry methylene chloride, add 4.50 g (38.50 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.58 g (5.70 mmol) of triethylamine and a solution of 0.71 g (38.5 mmol) of 2-hydroxy-5-methdxybenzoyl chloride dissolved in 10 mL of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Noah to the nude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H20). This yields 0.791 g (56%) of>: 4-[2-(2-hydroxy-5-methoxybenzoylamino)benzoylamino]butanoic acid as a cream-colored solid. M.P.: 191-193 °C IR(ATR): V 3330, 2877, 1702, 1593. 1523, 1494, 1473, 1449, 1419, 1356, 1328. 1306, 1266, 1205, 1188, 1174, 1047, 931, 792, 746, 687 cm-"" ^H-NMR (400 MHz, DMSO): 5 1.76 (m, 2 H, -CH^-CH^-CH^-). 2.28 (t, 1 H, J = 7.3 Hz, -CH2-CO-), 3.27 (m. 2 H, -CH2-N-), 3.73 (s, 3 H, -CH3 ). 6.91 (m, .1 H, aromatic), 7.04 (m, 1 H, aromatic), 7.18 (m, 1 H, aromatic), 7.38 (m, 1 H, aromatic), 7.50 (m, 1 H, aromatic), 7.76 (m, 1 H. aromatic), 8.46 (m, 1 H, aromatic). 8.70 (t, J = 5.4 Hz, -NH-CH2-), 11.10 (s, 1 H, -OH), 12.03 (s, 1 H, -NH), 12.09 (s, 1 H, -COOH) ppm "C-NMR (200 MHz, DMSO): 6 24.2, 31.1, 38.7. 55.4. 112.8, 118.1, 118.3, 120.5, 121.7, 123.1, 123.8, 128.0, 131.2, 137.7. 151.6, 151.9, 164.8,168.0, 174.2 ppm MS m/z (%): 372 (M , 5), 353 (3), 269 (100), 254 (88), 198 (11). 150 (20). 120 (55), 119 (45), 92 (50), 79 (33), 65 (29). 52 (21), 30 (51) Elemental analysis of CigH2oN206 Calculated: % 0 = 61.28; % H = 5.41; % N = 7.52 Found: % 0 = 61.21; % H = 5.40; % N = 7.47 Example 15. 4-[2-(4-nitrobenzoyiamino)benzoyiamino]butanoic acid, (compound ^5). To a suspension of 2.14 g (9.63 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry methylene chloride, add 1.83 g (16.87 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.24 g (12.33 mmol) of triethylamine and a suspension of 1.53 g (8.22 mmol) of 4-nitrobenzoyl chloride in 10 ml of dry ethyl acetate. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and with etiier. Purify the reaction product by recrystallization in dioxane/H20. This yields 1.33 g (43%) of 4-[2-(4-nitrobenzoylamino) benzoylamino] butanoic acid as a cream-colored solid. M.P.: 206-208 "C IR(ATR): V 3282, 3090, 1731, 1655, 1626, 1597, 1558, 1517, 1444, 1417. 1399, 1350. 1326, 1297, 1258. 1227, 1166, 854. 836, 766, 715 cm-"" ^H-NMR (400 MHz, DMSO): 6 1.77 (m, 2 H, -CHrCH -CHH, 2.29 (t, 1 H, J = 7.3 Hz, -CH2-CO-). 3.31 (m, 2 H. -CH2-N-), 7.24 (m, 1 H, aromatic), 7.58\(m, 1 H, aromatic), 7.85 (m. 1 H, aromatic), 8.14 (d, 2 H, J = 8.7 Hz, aromatic). 8.42 (d. 2 H, J = 8.7 Hz, aromatic), 8.58 (m, 1 H, aromatic), 8.46 (m. 1 H, aromatic), 8.91 (t, J = 5.4 Hz, -NH-CH2-). 12.06 (s, 1 H, -NH). 12.72 (s, 1 H, -COOH) ppm "C-NMR (200 MHz, DMSO): 5 24.1, 31.0, 38.9, 120.5, 120.8, 123.4, 124.1, 128.2, 128.5, 132.2,138.8, 140.1, 149.4, 162.7, 168.5, 174.2 ppm MS m/z (%): 371 (M*, 5), 353 (3), 334 (1), 269 (22), 268 (29). 253 (6). 238 (59), 224 (9), 150 (23), 146 (23), 120 (50), 119 (100), 104 (39), 92 (69), 76 (48), 64 (29). 50 (27), 30 (50) Elemental analysis of C18H17N3O6 Calculated: % C = 58.22; % H = 4.61; % N = 11.32 Found: % C = 58.15; % H = 4.65; % N = 11.10 Example 16. 4-[2-(4-methoxybenzoilamino)benzoilamino]butanolc abid. (compound 16). To a suspension of 2.14 g (9.63 mmol) of 4-(2-aminobenzoylanr|ino)butanoic acid in 20 ml of dry methylene chloride, add 8.90 g (82.39 mmol) of trimethylsilyl chloride and place the reaction at reflux for 5 hours. Then place the flask in an ice bath and add 1.25 g (12.36 mmol) of triethylamine and a solution of 1.4Q g (8.24 mmol) of 4-methoxybenzoyl chloride dissolved 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Another the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/HaO). This yields 2.32 g (79%) of 4-[2-(4-methoxybenzoyl-amino)benzoylamino]butanoic acid as a cream-colored solid. M.P.: 172-174 °C IR(ATR): y 3320, 2960, 2837, 1720, 1630, 1592. 1532, 1509, 1446, 1301. 1254, 1167, 1096, 1025. 841, 748 cm" ^H-NMR (400 MHz, DMSO): 5 1.79 (m, 1 H, -CHi-CH2i-CH2r).: 2.31 (t. 0 H, J = 7.4 Hz, -CH21-CO-), 3.33 (m, 1 H, -CH2i-N-), 3.83 (s, 2 H, -CH22), 7.11 (d, 1 H, J =8.8 Hz aromatic), 7.16 (m, 0 H, aromatic). 7.53 (m. 0 H, aromatic), 9 (m. 1 H. aromatic), 7.89 (d, 2 H. J = 8.8 Hz, aromatic). 8.65 (m, 1 H. aromatic), 8.87 (t, J = 5.4 Hz, -NH- CH32-), 12.08 (s, 1 H. -NH). 12.49 (s. 1 H. -COOH) ppm "C-NMR (100 MHz. DMSO): 6 24.2. 31.1, 38.7, 55.5, 114.2, 120.0, 120.1, 122.4, 126.7, 128.2. 128.8. 132.1, 139.7, 162.2, 163.9, 168.7, 174.2 ppm MS m/z (%): 356 (M*, 4). 338 (9). 319 (3), 253 (19), 252 (18), 238 (5), 209 (5), 135 (100), 119 (35), 107 (7), 92 (22), 74 (28), 64 (11), 50 (7). 41 (10) Elemental analysis of C19H20N2O5 Calculated: % C = 64.04; % H = 5.66; % N = 7.86 Found: % C == 63.97; % H = 5.63; % N = 7.79 Example 17. 4-[2-(4-chtorobenzoylamino)benzoylamino]butanoicacid. (compound 17). To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of 1.35 g (7.70 mmol) of 4-methoxybenzoyl chloride dissolved 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Noah to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting, solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/HaO). This yields 1.79 g (65%) of ' 4-[2-(4-chlorobenzoyl-amino)benzoylamino]butanoic acid as a cream-colored solid. MP.: 182-184 °C IR(ATR): V 3069, 2939, 1692, 1672, 1628, 1592, 1525, 1491, 1444, 1332, 1310, 1284. 1259, 1222. 1180. 1110, 1096, 1011, 902, 845, 756, 745 cm'^ ^H-NMR (400 MHz, DMSO): 5 1.79 (m. 2 H, -CH2-CH2-CH2-). 2.31 (t. 1 H, J =7.4 Hz. -CH2-CO-). 3.32 (m, 2 H, -CH2-N-), 7.18 (m, 1 H, aromatic), 7.54 (m, 1 H, aromatic), 7.64 (d, 2 H, J = 8.5 Hz, aromatic), 7.83 (m, 1 H, aromatic), 7.92 (d, 2 H. J = 8.5 Hz, aromatic), 8.61 (m, 1 H, aromatic), 8.89 (t, J = 5.4 Hz, -NH-CH2-), 12.07 (s, 1 H, - NH). 12.61 (s. 1 H. -COOH) ppm "C-NMR (200 MHz, DMSO): 6 24.2, 31.1, 38.7, 55.5. 114.2, 120.3, 120.4. 122.9. 128.2, 128.8. 129.0, 132.2, 133.3 136.9,139.3, 163.3, 168.6, 174.2 ppm MS m/z(%): 360 (M*, 11). 342 (4), 323 (1), 258 (30), 238 (15), 213 (6), 187 (8), 162 (6), 141 (33), 139 (100), 119 (38), 111 (56). 92 (25), 75 (20). 65 (11), 41 (11) Elemental analysis of C1BH17CIN2O4 Calculated: % C = 59.92; % H = 4.75; % N = 7.76 Found: % C = 59.71; % H = 4.77; % N = 7.72 Example 18. 4-[2-(4-chloro-2-hydroxybenzoylannino)benzoyiamino]butanoic acid, (compound 18). To a suspension of 2.00 g (9.00 mmol) of 4-(2-aminobenzoylapnino)butanoic acid in 40 ml of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.50 mmol) of triethylamine and a solution of 1.45 g (7.70 mmol) of 4-chloro-2-hydroxyben2oyl chloride dissolved in 5 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Noah to the crude product and continue stinging the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and ether. Purify the reaction product by recrystallizatlon (EtOH/H20). This yields 1.35 g (47%) of 4-[2-(4-chloro-2-hydroxybenzDyl-amino)benzoylamino]butanoic acid as a white solid. M.P.: 205-206 °C IR(ATR): V 3319. 3067, 2936, 1688, 1583, 1525, 1494, 1447, 1408, 1350, 1330, 1302. 1261, 1214. 919, 796. 755 cm""' ^H-NMR (400 MHz, DMSO): § 1.75 (m, 2 H, -CHT-Chug-CH -). 2.28 (t, 2 H, J = 7.3:Hz, -CH2-CO-), 3.26 (m, 2 H. -CH2-N-), 7.01 (m, 2 H, aromatic), 7,18 (m, 1 H, aromatic). 7.50 (m, 1 H, aromatic), 7.65 (m, 1 H, aromatic), 7.87 (m, 1 hi, aromatic). 8.46 (m, 1 H, aromatic), 8.69 (t. 1 H, J = 5.12Hz, -NHH-Chat-). 12.07 (Broad. 3 H, -OH, -COOH, - NH-Ph) ppm "C NMR (200 MHz. DMSO): .5 24.3, 31.1, 38.6, 116.6, 117.8, 119.3, 121.9, 123.2, 123.9.128.0,131.1, 131.7. 137.3, 137.6, 158.4 163.9, 167.9, 174.2 ppm. MS m/z (%): 376 (M*, 2), 273 (65), 238 (17), 222 (7). 155 (25). 146 (5). 120 (39). 119 (100). 99 (13), 92 (43), 63 (27), 30 (45) Elemental analysis of C18H17CIN2O5 Calculated: % C = 57.38; % H = 4.59; % N = 7.43 Found: % C = 57.19; % H = 4.57; % N = 7.41 Example 19. 4-[2-(5-chloro-2-hydroxybenzoyiannino)benzoylamino]butanoicacid. (compound 19). To a suspension of 2.30 g (10.4 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry methylene chloride, add 9.56 g (88.50 mmol) of.trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.34 g (13.30 mmol) of triethylamine and a solution of 1.6.7 g (8.85 mmol) of 5-chloro-2-hydroxybenzoyl chloride dissolved in 5 ml of dry methylene chloride.;: Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Noah to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/HaO). This yields 0.95 g (29%) of 4-[2-(5-chloro-2-hydroxy-benzoylamino)benzoylamino]butanoic acid as a white solid. M.P.: 222-223 °C IR(ATR): V 3315. 2958, 1693, 1657, 1594, 1524, 1479, 1447, 1360, 1325.. 1303, 1272, 1213, 914, 812, 749 cm"" ^H-NMR (400 MHz, DMSO): 5 1.75 (m, 2 H, -CH?-CH?-CH?-1. 2.28 (t, 2 H, J = 7.3 Hz, -CH2-CO-), 3.26 (m, 2 H, -CH2-N-), 7.01 (m, 2 H, aromatic), 7.18 (m, 1 H. aromatic), 7.50 (m, 1 H, aromatic), 7.50 (m, 1 H, aromatic), 7.63 (m, 1 H, aromatic), 7.83 (m, 1 H, aromatic). 8.43 (m, 1 H, aromatic), 8.67 (t, 1 H, J = 5.5 Hz, -NH-CH2-), > 11.99 (Abroad. 3 H. -OH, -COOH. -NH-Ph) ppm C NMR (200 MHz, DMSO): 5 24.2, 31.1, 38.6. 118.9, 120.5, 122.3, 122.8, 123.3, 124.3,128.0, 129.4. 131.6, 132.9, 137.4, 155.8, 163.1, 167.8, 174.2 ppm. MS m/z (%): 376 (M", 3), 273 (100), 238 (22), 155 (18), 120 (40), 119 (80), 99 (13), 92 (46). 63 (26), 30 (35) Elemental analysis of C18H17CIN2O5 Calculated: % C = 57.38; % H = 4.59; % N = 7.43 Found: % C = 57.27; % H = 4.58; % N = 7.41 Example 20. 4-[2-(2-chlorobenzoylamino)benzoylamino]butanoic acid, (compound 20). ^ To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminobenzoylarnino)butanoic acid in 20 mL of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsllyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of 1.35 g (7.70 mmol) of 2-chlorobenzoyl chloride dissolved in 5 mL of dry methylene, chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Noah’s the crude product and continue stirring the mixture until. the oil has completely disappeared. Immediately acidify with concentrated HCI and extract several times with ethyl acetate. Dry the organic phase with MgS04 anhydrous and eliminate at low pressure. Wash the crude product several times with ether and finally, purify by recrystallization (EtOH/HaO). This yields 1.27 g (36%) of 4-[2-(2rChlorobenzoylamlno) benzoylamino]butanoic acid as a brown solid. M.P.: 110-112'•C IR(ATR): V 3308. 1730, 1659, 1627, 1598, 1560, 1513, 1445r. 1433, 1310. 1287, 1255.1168 cm"' ^H-NMR (400 MHz, DMSO): 5 1.73 (m, 2 H. –CH -Chug-CH -). 2.26 (t. 2 H. J = 7.0 Hz. -CH2-CO-). 3.24 (m, 2 H, -CH2-N-). 7.21 (m. 1 H. aromatic), 7.51 (m, 4 H. aromatic). 7.65 (m. 1 H. aromatic), 7.79 (m, 1 H. aromatic), 8.53 (m. 1 H, aromatic). 8.82 (Broad, 1 H. -NH-CH2-). 11.89 (s. 1 H, -COOH). 12.05 (s, 1H, -NH) ppm '. "C NMR (100 MHz. DMSO):.5 24.1, 31.1, 38.6, 120.4, 121.1,,123.3. 127.6, 128.2, 128.9, 129.8, 130.2, 131.7, 132.0, 136.3, 138.5. 164.3. 168.2, 174.1 ppm. MS m/z (%): 360 (M*. 1). 342 (7). 289 (9), 269 (8), 257 (50). 213 (57). 178 (16). 139 (97) 120 (22). 119 (100). 111 (60). 85 (67). 75 (81). 63 (32). 50 (.63), 30 (76) Elemental analysis of C18H17CIN2O4 Calculated: % C = 59.92; % H = 4.75; N = 7.76 Found: % C = 59.95; % H = 4.77; % N = 7.68 Example 21. 4-[2-(2-bromobenzoylamlno)benzoylamino]butanoic acid, (compound 21). To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 mL of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of 1.68 g (7.70 mmol) of 2-bromobenzoyl chloride dissolved in 5 mL of dry methylene, chloride./Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% Noah to the crude product and continue stirring the mixture until the oil has .completely disappeared. Immediately acidify with concentrated HCI, filter the resulting solid and wash several times with water and with ether. Finally, purify by recrystallization (EtOH/HaO). This yields 1.95 g (63%) of 4-[2-(2-bromobenzoylamino)benzoylamino] butanoic acid as a cream-colored solid. M.P.: 117-118 "C IR(ATR): V 3280. 3176. 1731. 1654. 1628, 1598, 1557. 1510, 1444, 1428, 1312, 1286, 1251, 1166, 743, 664 cm-' ^H-NMR (400 MHz, DMSO): 51.74 (m, 2 H, -CH?-CH?-CH?-l 2.26 (t, 2 H. J = 7.3 Hz, -CH2-CO-), 3.23 (m, 2 H. -CH2-N-), 7.21 (m, 1 H, aromatic), 7.45 (m, 1 H, aromatic), 7.53 (m, 2 H, aromatic, 7.61 (m, 1 H. aromatic), 8.53 (m, T H, aromatic), 8.81 (t, 1 H, J = 5.28 Hz. -NH-CH2-), 11.84(s. 1 H, -COOH). 12.03 (s, 1H, -NH) ppm C NMR (100 MHz. DMSO): 5 24.1, 31.1, 38.6, 118.6, 120.4, 121.1, 123.3, 128.1, 128.2. 128.7. 131.7. 132.0, 133.2, 138.5, 138.6, 165.2, 168.1. 174.2 ppm. MS Ci8Hi7N20/®Br m/z (%): 404 (M . 1), 303 (32). 257 (20). 238 (20), 221 (22), 185 (100). 178 (12), 157 (31) 143 (26), 119 (60), 90 (31), 76 (41), 50 (39) Elemental analysis of CieHi7BrN204 Calculated: % C = 53.35; % H = 4.23; N = 6.91 Found: % C = 53.32; % H = 4.26; % N = 6.89 Example 22. 4-[2-(3-chlorobenzoyiammo)benzoylamino]butanoic acid, (compound 22). To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminoben^oylamino)butanoic acid in 20 mL of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsiiyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of-1.35 g (7.70 mmol) of 3-chlorobenzoyl chloride dissolved In 5 mL of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at love pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCI and extract several times with ethyl acetate. Dry the organic phase with MgS04 anhydrous and eliminate at low pressure. Wash the crude product several times with ether and finally, purify by recrystallization (EtOH/HzO). This yields 0.83 g (30%) of 4-[2-(3-chlorobenzoylamino) benzoylaminojbutanoic acid as a cream-coloured solid. M.P.: 165-166 "C IR(ATR): V 3307, 3159, 1741, 1721, 1669, 1626, 1589, 1523, 1447, 1419, 1326, 1308, 1256, 1180, 759 cm'"" H-NMR (400 MHz, DMSO): 51.78 (m, 2 H, -CH -Chug-CH -):. 2.30 (t, 2 H, J = 7.0 Hz, -CH2-CO-), 3.30 (m, 2 H, -CH2-N-), 7.21 (m, 1 H, aromatic), 7.56 (m, 1 H, aromatic), 7.65 (m, 1 H, aromatic). 7.71 (m, 1 H, aromatic), 7.84 (m, 2 H, aromatic), 7.91 (m, 1 H, aromatic), 8.57 (m, 1 H, aromatic), 8.88 (t, 1 H, J = 5.3 Hz, -NH-CH2-), 12.05 (s, 1 H. -COON). 12.57 (s. 1H, -Ph-NH) ppm "C NMR (100 MHz. DMSO): .5 24.1. 31.1, 38.6. 120.4, 121.1, 123.3, 127.6, 128.2, 128.9, 129.8. 130.2, 131.7, 132.0, 136.3, 138.5, 164.3, 168.2, 174.1 ppm. MS m/z (%): 360 (M*. 8), 323 (5), 258 (38), 238 (41), 213 (19). 139 (100) 120 (64), 119 (95), 111 (96), 92 (55), 75 (40), 65 (32), 50 (28), 39 (39) Elemental analysis of C18H17CIN2O4 Calculated: % C = 59.92; % H = 4.75; % N = 7.76 Found: % C = 59.87; % H = 4.78; % N = 7.76 The activity of all compounds of the examples described above was studied in animals according to the following experimental model: 1. Purpose and rationale Evaluate the absorption of the test product when administered by intracolonic route to rats, whether or not in the presence of adjutants. The plasma concentration is measured by assaying the Factor Xa-inhibition capacity. Thei rat is used because it is one of the species commonly used in this type of test. 2. Description of the test method 2.1. Experimental system ? Description: Wister male rats, acquired from an accredited supplier. ? Weight 200-250 g ? Age 9 to 11 weeks 2.2. Mode of administration One intracolonic administration. 2.3. Dosage levels and administration volume ? Dosage level 30 mg/kg of test product + 30 mg/kg of adjuvant ? Administration volume 1 ml/kg 2.4. Vehicle 25% (v/v) propylene glycol in bidistllled water. After dissolving the test product along with the adjuvant If applicable, adjust the pH to approximately 7.4 with NaOH. 3.5. Experimental design The animals will be in fasted state for approximately 18 h with free access to water The animals will be randomized to the various experimental groups, with one remaining animal as a reserve per group: On the day of the test, the treatments will be administered by intracolonic route, following anaesthesia with examine. Administration will be done using a catheter of approximately 8 cm, connected to a 1-mi syringe. The catheter will be introduced in its entirety into, the colon through the anus and the test product will be administered levy into the colon. Following the administration of the test product, within the times established in the table, a citrated blood sample (3.8% at a ratio of 1:9) will be drawn by intracardiac puncture under anaesthesia with ketamine. Blood centrifugation: 3000 rpm, 10 minutes, 4° C. Plasma freezing (-20 + 5° C) until determining the anti-Factor Xa activity. A control group that will receive no treatment will be included, simply that one blood sample will be drawn per animal under the same conditions as the treatment group, with considered to be the baseline value of anti-Xa activity. The anti-Xa activity will be assayed by the chromomeric method (anti-Fax activity assay kit). 3, Evaluation of the results The mean, the standard deviation (RSD) and the standard error. of the mean of each experimental group will be calculated for each parameter. If considered adequate, the values obtained in the different experimental groups will be compared by a statistical analysis. CLAIMS 1) Amino acid diamonds in non a position of formula (1) wherein Rid is selected from amongst the group consisting of functional groups alkyl, halogen, NO2, OH, OCH3 either alone or associated and R2 is selected from the group consisting of functional groups H, alkyl, halogen, Nona OH, OCH3, which are useful as adjuvant for the administration of biological active agents. 2) Compounds according to claim 1, characterised in that they they present the falling structure: Compounds according to claim 1, characterised in that they they present the following conjecture: Compounds according to claim 1, characterised in that they present the following stnjcture: Pharmaceuticals compositions according to claims 1 to 4, characterised in that they comprise heparin oligosaccharides and at least one compound from formula (1) Pharmaceutical compositions according to claim 5, characterised in that they comprise compounds according to formula (2) and glycosaminoglycan oligosaccharides. Pharmaceutical compositions according to claim 5, characterised in that they comprise compounds according to formula (3) and glycosaminoglycan oligosaccharides. Pharmaceutical compositions according to claim 5, characterised in that they comprise compounds according to formula (4) and glycosaminoglycan oligosaccharides. Pharmaceutical compositions according to claims 5 and 6. characterised in that they comprise at least one compound of structure and Seminarian. Pharmaceutical compositions according to claims 5 and 7, characterised in that they comprise at least one compound of structure and Bemoaning. Pharmaceutical compositions according to claims 5 and 8, characterised in that they comprise at least one compound of structure and Bemoaning. Pharmaceutical compositions according to any of the preceding claims, characterised in that they comprise compounds according to formula (1) and at least one active agent selected from the group composed of heparin, dermas an soleplate, concretion soleplate, heparin soleplates and oligosaccharide derivatives. Use of a compound according to any of the claims 1 to 4 for the manufacture of an antithrombotic medication^ Use of a compounds according to any of the claims 1 to 4 for the manufacture of a medication for the treatment of a disease selected from the group composed of inflammation, cancer and allergy.

Documents:

344-CHENP-2006 ABSTRACT.pdf

344-CHENP-2006 CLAIMS GRANTED.pdf

344-CHENP-2006 FORM 1.pdf

344-CHENP-2006 FORM 18.pdf

344-CHENP-2006 FORM 3.pdf

344-CHENP-2006 POWER OF ATTORNEY.pdf

344-chenp-2006-abstract.pdf

344-chenp-2006-claims.pdf

344-chenp-2006-correspondnece-others.pdf

344-chenp-2006-correspondnece-po.pdf

344-chenp-2006-description(complete).pdf

344-chenp-2006-drawings.pdf

344-chenp-2006-form 1.pdf

344-chenp-2006-form 3.pdf

344-chenp-2006-form 5.pdf

344-chenp-2006-pct.pdf