AU8292098A - Crystalline forms of antibiotic side chain intermediates - Google Patents
Crystalline forms of antibiotic side chain intermediates Download PDFInfo
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- AU8292098A AU8292098A AU82920/98A AU8292098A AU8292098A AU 8292098 A AU8292098 A AU 8292098A AU 82920/98 A AU82920/98 A AU 82920/98A AU 8292098 A AU8292098 A AU 8292098A AU 8292098 A AU8292098 A AU 8292098A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Description
WO 99/02492 PCT/US98/14036 -1 TITLE OF THE INVENTION CRYSTALLINE FORMS OF ANTIBIOTIC SIDE CHAIN INTERMEDIATES 5 BACKGROUND OF THE INVENTION Crystalline forms of intermediates for carbapenem antibiotics are desirable from a stability and purity standpoint. These compounds facilitate the synthesis of carbapenem antibiotics on a commercial scale. 10 In the present invention, crystalline forms of the compound 2S-cis-3- [[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino] benzoic acid have been discovered and characterized. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid and pharmaceutically acceptable salts and solvates thereof are disclosed. 15 The compounds can generally be synthesized taking into account the disclosure of U. S. Patent No. 5,478,820 granted on December 26, 1995. This patent does not disclose the side chain in crystalline form. SUMMARY OF THE INVENTION 20 Crystalline 2S-cis-3- [[(4-mercapto-2-pyrrolidinyl) carbonyl]-amino]benzoic acid as well as pharmaceutically acceptable salts and solvates thereof are disclosed. BRIEF DESCRIPTION OF THE DRAWINGS 25 The invention is described in connection with the following drawings, of which: Figure 1 is an X-Ray Powder Diffraction pattern of Compound I, in unsolvated form; Figure 2 is an X-Ray Powder Diffraction pattern of 30 Compound I as the 1-butanol solvate, and Figure 3 is an X-Ray Powder Diffraction pattern of Compound I, as the acetic acid solvate.
WO 99/02492 PCT/US98/14036 -2 DETAILED DESCRIPTION OF THE INVENTION The compound has the following structural formula: HS NC(O)NH C0 2 H N P I 5 wherein P represents H or a protecting group. The salt form of the compound can be protonated as shown in the following: HS C(O)NH\ C O 0 2 H N+f H- H 10 X wherein X represents a negatively charged counterion. The salt forms can also be present in the form of a solvate. The crystalline forms of the compound are characterized 15 below by virtue of their X-Ray Powder Diffraction (XRPD) patterns. The XRPD patterns were collected on a Philips APD 3720 automated powder diffractometer. The x-ray generator employed a copper target, an accelerating potential of 45 kV and a filament emission of 40 mA. Diffraction patterns were collected from 2 0 C to 40 0 C. 20 The hydrochloride salt of the compound (unsolvated material) was characterized as having an XRPD pattern at 5.5, 5.3, 4.9, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, 2.9, 2.6 and 2.3 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
WO 99/02492 PCT/US98/14036 -3 TABLE 1 Tip Peak Angle Width Peak Backg D Spac I/Imax Type Sign No. (deg) (deg) (cts) (cts) (Ang) (%) Al A2 Ot 1 8.3325 0.48 10. 6. 10.6028 2.34 x x 0.83 2 9.7600 0.12 19. 7. 9.0550 4.43 x x 0.89 3 12.1375 0.36 10. 8. 7.2861 2.34 x x 1.05 4 14.1525 0.15 17. 9. 6.2529 3.85 x x 0.91 5 16.1575 0.15 46. 12. 5.4812 10.59 x x 2.09 6 16.6450 0.15 53. 12. 5.3218 12.20 x x 1.02 7 16.8200 0.15 41. 12. 5.2668 9.38 x x 0.91 8 17.6250 0.24 30. 13. 5.0280 6.93 x x 1.26 9 18.2600 0.07 154. 13. 4.8546 35.20 x x 1.38 10 18.9025 0.18 17. 14. 4.6910 3.85 x x 1.26 11 19.5625 0.12 34. 14. 4.5342 7.70 x x 0.76 12 20.5175 0.09 117. 15 4.3252 26.70 x x 1.07 13 21.6225 0.21 48. 16 4.1066 10.90 x x 2.88 14 22.6875 0.13 437. 17 3.9162 100.00 x x 5.62 15 23.4200 0.09 128. 18 3.7954 29.23 x x 0.78 16 23.8750 0.18 96. 18 3.7241 21.99 x x 3.47 17 24.4900 0.12 72. 18 3.6319 16.54 x x 3.02 18 25.0125 0.18 26. 18 3.5572 5.95 x x 0.89 19 25.7275 0.18 20. 19 3.4599 4.64 x x 0.83 20 26.6250 0.18 114. 20 3.3453 26.21 x x 2.09 21 26.9725 0.09 246. 20 3.3030 56.43 x x 1.74 22 27.9675 0.07 202. 21 3.1877 46.16 x x 1.32 23 28.5925 0.24 30. 22 3.1194 6.93 x x 1.05 24 30.8400 0.07 196. 24 2.8970 44.87 x x 1.55 25 32.1275 0.18 38. 24 2.7838 8.80 x x 1.82 26 32.6325 0.18 58. 25 2.7419 13.22 x x 2.04 27 33.9250 0.18 174. 26 2.6403 39.89 x x 5.13 28 35.1000 0.18 17. 27 2.5546 3.85 x x 1.05 29 35.7950 0.24 32. 27 2.5065 7.44 x x 3.16 30 36.8400 0.36 37. 28 2.4378 8.52 x x 2.45 31 37.3975 0.15 35. 28 2.4027 7.97 x x 1.07 32 37.8050 0.15 35. 28 2.3778 7.97 x x 1.15 33 38.5300 0.12 69. 29 2.3347 15.77 x x 1.15 Notes: Generator settings: 45kV, 40 mA Cu alphal, 2 wave lengths 1.54060, 1.54439 Ang 5 Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s Monochromator used Divergence slit Automatic (irradiated sample length 12.5 mm) Peak angle range 2.007-40.002 deg SUBSTITUTE SHEET (RULE 26) WO 99/02492 PCT/US98/14036 -4 Monochromator used Divergence slit Automatic (irradiated sample length 12.5 mm) Peak angle range 2.007-40.002 deg Range in D spacing 2.25207-43.9723 Ang 5 Peak position criterion Top of smoothed data Cryst peak width range 0.00-2.00 deg Minim peak significance 0.75 Number of peaks in file 33 (alphal: 33, amorphous: 0) Maximum intensity 437. cts, 2184.1 cps 10 The XRPD pattern corresponding to Table I is shown as Figure 1. The hydrochloride salt 1-butanol solvate was shown to exhibit patterns such as the ERPD pattern shown as Figure 2. 15 Characteristic D-spacings are 14.6, 7.3, 5.6, 4.9, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.0 and 2.9 Ang. More complete XRPD data pertaining to the solvate is shown below in Table 2.
WO 99/02492 PCT/US98/14036 -5 TABLE 2 Tip Type Peak Angle Width Peak Back D Spac I/Imax Sign g No. (deg) (deg) (cts) (cts) (Ang) (%) Al A2 Ot 1 3.0625 0.72 10 0. 28.826 1.84 x x 1.20 3 2 6.0675 0.07 557 4. 14.554 100.00 x x 5.75 8 3 9.7950 0.18 10. 5. 9.0227 1.84 x x 0.85 4 11.1825 0.15 14. 6. 7.9061 2.59 x x 1.10 5 12.0625 0.09 135. 6. 7.3312 24.16 x x 3.09 6 12.8450 0.12 19. 7. 6.8863 3.48 x x 1.12 7 15.8225 0.07 62. 8. 5.5965 11.21 x x 1.35 8 16.7900 0.30 12. 10. 5.2761 2.08 x x 0.95 9 17.9150 0.07 98. 10. 4.9473 17.60 x x 1.17 10 18.2525 0.21 119. 11. 4.8566 21.33 x x 6.46 11 18.7050 0.09 30. 11. 4.7401 5.43 x x 1.29 12 20.5575 0.09 31. 13. 4.3169 5.63 x x 1.32 13 21.3925 0.12 376. 13. 4.1503 67.57 x x 7.08 14 21.9375 0.06 159. 14. 4.0484 28.50 x x 0.81 15 22.3975 0.12 144. 14. 3.9663 25.85 x x 4.07 16 22.7650 0.06 132. 15. 3.9031 23.74 x x 1.23 17 23.5475 0.07 114. 16. 3.7751 20.56 x x 1.10 18 24.2675 0.06 180. 17. 3.6647 32.24 x x 1.02 19 24.8675 0.09 149. 17. 3.5776 26.72 x x 2.04 20 25.1500 0.06 98. 18. 3.5381 17.60 x x 0.79 21 25.8000 0.07 108. 18. 3.4504 19.42 x x 1.35 22 26.7525 0.12 159. 18. 3.3297 28.50 x x 1.17 23 27.3775 0.07 77. 19. 3.2551 13.90 x x 0.93 24 28.0575 0.15 37. 20. 3.1777 6.68 x x 1.51 25 29.0475 0.15 45. 20. 3.0716 8.06 x x 1.41 26 29.5925 0.10 142. 21. 3.0163 25.43 x x 2.63 27 30.0575 0.06 117. 22. 2.9706 20.94 x x 0.78 28 30.3500 0.12 58. 22. 2.9427 10.37 x x 0.93 29 30.7375 0.24 117. 23. 2.9065 20.94 x x 7.76 30 31.3225 0.18 30. 23. 2.8535 5.43 x x 1.38 31 32.0950 0.12 35. 24. 2.7866 6.25 x x 0.87 32 32.8725 0.18 25. 24. 2.7224 4.49 x x 1.07 33 33.4025 0.24 18. 25. 2.6804 3.32 x x 0.85 34 33.9575 0.24 76. 26. 2.6379 13.59 x x 4.37 35 34.5225 0.04 42. 26. 2.5960 7.59 x x 0.76 36 34.9325 0.06 37. 27. 2.5664 6.68 x x 0.78 37 35.4450 0.09 67. 27. 2.5305 12.07 x x 1.45 38 36.2300 0.21 36. 28. 2.4774 6.46 x x 2.88 39 37.3500 0.12 49. 29. 2.4057 8.80 x x 1.38 40 38.2150 0.12 52. 29. 2.3532 9.31 x x 1.20 SUBSTITUTE SHEET (RULE 26) WO 99/02492 PCT/US98/14036 -6 Notes: 5 Generator settings: 45kV, 40 mA Cu alphal1, 2 wavelengths 1.54060, 1.54439 Ang Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s Monochromator used 10 Divergence slit Automatic (irradiated sample length 12.5 mm) Peak angle range 2.007 - 40.002 deg Range in D spacing 2.25207 - 43.9723 Ang Peak position criterion Top of smoothed data Cryst peak width range 0.00-2.00 deg 15 Minim peak significance 0.-75 Number of peaks in file 33 (alphal: 33, amorphous: 0) Maximum intensity 437. cts, 2184.1 cps 20 The XRPD pattern corresponding to Table 2 is shown as Figure 2. Solid material which was exposed to acetic acid was characterized as having an XRPD pattern at 5.4, 5.3, 5.1, 4.2, 3.8, 3.6, 3.4, 3.1, 2.7 and 2.6 angstroms. More complete XRPD data pertaining 25 to the solvate is shown below in Table 3.
WO 99/02492 PCT/US98/14036 -7 TABLE 3 Tip Peak Angle Width Peak Backg D Spac Ilmax Type Sign No. (deg) (deg) (cts) (cts) (Ang) (%) Al A2 Ot 1 3.1400 0.96 10. -1. 28.1149 2.96 x x 0.81 2 6.0350 0.24 12. 5. 14.6331 3.34 x x 0.95 3 11.4925 0.12 32. 10. 7.6935 9.39 x x 0.95 4 11.9925 0.24 48. 10. 7.3739 13.76 x x 4.47 5 12.8950 0.18 17. 10. 6.8597 4.86 x x 1.00 6 16.3050 0.21 202. 12. 5.4320 58.28 x x 7.76 7 16.6950 0.09 86. 13. 5.3060 25.00 x x 1.02 8 17.5350 0.07 130. 13. 5.0536 37.57 x x 0.95 9 18.0250 0.09 38. 14. 4.9173 11.11 x x 0.98 10 20.0125 0.24 37. 16. 4.4332 10.76 x x 1.70 11 20.4650 0.09 56. 16. 4.3362 16.26 x x 1.12 12 21.0225 0.10 149. 17. 4.2225 43.02 x x 1.95 13 21.8425 0.06 81. 18. 4.0658 23.41 x x 0.85 14 23.2675 0.33 346. 19. 3.8199 100.00 x x 21.88 15 23.9075 0.30 77. 19. 3.7191 22.38 x x 1.58 16 24.8525 0.09 216. 21. 3.5797 62.46 x x 1.02 17 25.9625 0.30 213. 22. 3.4292 61.61 x x 12.02 18 26.5600 0.30 110. 23. 3.3534 31.87 x x 2.45 19 27.3000 0.18 48. 23. 3.2641 13.76 x x 0.79 20 27.4900 0.36 42. 23. 3.2420 12.21 x x 0.85 21 28.2425 0.18 29. 24. 3.1573 8.43 x x 0.76 22 28.9025 0.09 62. 25. 3.0867 18.04 x x 1.07 23 29.7375 0.18 38. 26. 3.0019 11.11 x x 1.17 24 30.3075 0.15 28. 26. 2.9467 8.12 x x 1.00 25 31.2550 0.18 32. 27. 2.8595 9.39 x x 0.78 26 32.9850 0.30 83. 29. 2.7134 23.94 x x 3.24 27 33.3150 0.18 62. 29. 2.6872 18.04 x x 0.81 28 33.9350 0.09 48. 30. 2.6396 13.76 x x 1.02 29 34.4175 0.15 74. 30. 2.6036 21.38 x x 1.91 30 35.0900 0.36 42. 31. 2.5553 12.21 x x 2.40 31 35.9900 0.36 40. 32. 2.4934 11.47 x x 2.14 32 37.0675 0.30 62. 34. 2.4234 18.04 x x 1.78 33 38.4225 0.24 41. 35. 2.3410 11.84 x x 0.95 Notes: 5 Generator settings: 45kV, 40 mA Cu alphal, 2 wavelengths 1.54060, 1.54439 Ang Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s Monochromator used WO 99/02492 PCT/US98/14036 -8 Divergence slit Automatic (irradiated sample length 12.5 mm) Peak angle range 2.007-40.002 deg Range in D spacing 2.25207-43.9723 Ang Peak position criterion Top of smoothed data 5 Cryst peak width range 0.00-2.00 deg Minim peak significance 0.75 Number of peaks in file 33 (alphal: 33, amorphous: 0) Maximum intensity 437. cts, 2184.1 cps 10 The XRPD pattern corresponding to Table 3 is shown as Figure 3. The crystalline compound of the present invention is useful in various pharmaceutically acceptable salt forms, for the synthesis of carbapenem compounds that are in turn useful for the 15 treatment of bacterial infections in animal and human subjects. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharmaceutical chemist. i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or 20 excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug. Typically the intermediate compound is protonated, and is 25 found in association with a negatively charged counterion, represented by the generic X-. There are various possibilities for the charge balancing counterion X- Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, 30 benzenesulfonate, bicarbonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, carbonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2-hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, WO 99/02492 PCT/US98/14036 -9 maleate, mandelate, methylenebis(salicylate), mucate, methanesulfonate, napadisylate, napsylate, pamoate, pantothenate, pectinate, phosphate/ diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, triflate, tosylate and undecanoate. Other 5 anionic species will be apparent to the ordinarily skilled chemist. The preferred form of the crystalline compound is the hydrochloride salt form. The compound can be produced in accordance with the following non-limiting examples. 10 EXAMPLE ONE A. Synthesis HS COOH HS COOH H H N HCI N BOO O acetic acid H H O 15 ClE The BOC protected sidechain 1 (prepared according to the teachings of PCT WO97/06154 published on February 20, 1997) was dissolved in 1.5 L of a 1 N solution of dry hydrogen chloride in acetic 20 acid (30 min). Gas evolution was observed and the reaction product slowly crystallized. After filtering, washing (with acetic acid and hexane) and drying 137 g of product was obtained. The crystals contain acetic acid but are not a solvate. 25 B. Recrystallization procedures 1-Propanol Solvate The above product (25 g) was dissolved in 1-propanol (500 mL) at 100oC. Upon cooling the product crystallized out. After 30 filtering, washing (with 1-propanol and hexane) and drying 20 g of the 1-propanol solvate was obtained.
WO 99/02492 PCT/US98/14036 -10 1-Butanol Solvate The above product (25 g) was dissolved in a mixture of 1-butanol (225 mL) and water (25 mL) at RT. The resulting solution 5 was concentrated in vacuo to a total volume of 125 mL and seeded with authentic 1-butanol solvate. The crystals were filtered, washed (with 1-butanol and hexane) and dried at RT to give 25 g of the 1-butanol solvate. 10 Acetic Acid Solvate The above product was slurried overnight in a 95/5 mixture of acetic acid and water at RT and then partially concentrated via distillation in vacuo. The crystals were filtered, washed (with acetic acid and hexane) and dried to give the acetic acid solvate. 15
Claims (7)
1. Crystalline 2S-cis-3-[[(4-mercapto-2 pyrrolidinyl)carbonyl]amino]benzoic acid or a pharmaceutically 5 acceptable salt or solvate thereof.
2. Crystalline 2S-cis-3-[[(4-mercapto-2 pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1, having an X-ray powder diffraction pattern in accordance with Figure 10 1, 2 or 3.
3. Crystalline 2S-cis-3-[[(4-mercapto-2 pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1 as the hydrochloride salt. 15
4. Crystalline 2S-cis-3-[[(4-mercapto-2 pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt unsolvated form. 20
5. Crystalline 2S-cis-3-[[(4-mercapto-2 pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt 1-butanol solvate.
6. Crystalline 2S-cis-3-[[(4-mercapto-2 25 pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt acetic acid solvate.
7. Crystalline 2S-cis-3-[[(4-mercapto-2 pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1, 30 having one of the following X-ray powder diffraction patterns: WO 99/02492 PCT/US98/14036 -12 TABLE d - Spacings (A) - HCI salt Unsolvated 1-butanol solvate Acetic acid solvate 5.5 14.6 5.4 5.3 7.3 5.3 4.9 5.6 5.1 4.3 4.9 4.2 4.1 4.2 3.8 3.9 4.0 3.6 3.8 3.9 3.4 3.7 3.8 3.1 3.6 3.7 2.7 3.3 3.6 2.6 3.2 3.5 2.9 3.3 2.6 3.0 2.3 2.9
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5219797P | 1997-07-10 | 1997-07-10 | |
| US60/052197 | 1997-07-10 | ||
| GB9800463 | 1998-01-09 | ||
| GBGB9800463.3A GB9800463D0 (en) | 1998-01-09 | 1998-01-09 | Crystalline forms of antibiotic side chain intermediates |
| PCT/US1998/014036 WO1999002492A1 (en) | 1997-07-10 | 1998-07-07 | Crystalline forms of antibiotic side chain intermediates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8292098A true AU8292098A (en) | 1999-02-08 |
| AU736136B2 AU736136B2 (en) | 2001-07-26 |
Family
ID=26312922
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU82920/98A Ceased AU736136B2 (en) | 1997-07-10 | 1998-07-07 | Crystalline forms of antibiotic side chain intermediates |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0998457A4 (en) |
| JP (1) | JP3378021B2 (en) |
| AU (1) | AU736136B2 (en) |
| CA (1) | CA2294341C (en) |
| WO (1) | WO1999002492A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4068452B2 (en) | 2000-07-19 | 2008-03-26 | エフ．ホフマン−ラ ロシュ アーゲー | Pyrrolidine derivatives as endothelin converting enzyme inhibitors |
| WO2010073706A1 (en) * | 2008-12-25 | 2010-07-01 | 株式会社カネカ | Improved process for producing intermediate for side chain of carbapenem |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9202298D0 (en) * | 1992-02-04 | 1992-03-18 | Ici Plc | Antibiotic compounds |
| WO1999002531A1 (en) * | 1997-07-09 | 1999-01-21 | Merck & Co., Inc. | Process for synthesizing carbapenem side chain intermediates |
-
1998
- 1998-07-07 CA CA002294341A patent/CA2294341C/en not_active Expired - Fee Related
- 1998-07-07 AU AU82920/98A patent/AU736136B2/en not_active Ceased
- 1998-07-07 EP EP98933212A patent/EP0998457A4/en not_active Withdrawn
- 1998-07-07 JP JP50883899A patent/JP3378021B2/en not_active Expired - Fee Related
- 1998-07-07 WO PCT/US1998/014036 patent/WO1999002492A1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| JP3378021B2 (en) | 2003-02-17 |
| JP2002504157A (en) | 2002-02-05 |
| CA2294341C (en) | 2007-09-25 |
| AU736136B2 (en) | 2001-07-26 |
| CA2294341A1 (en) | 1999-01-21 |
| EP0998457A1 (en) | 2000-05-10 |
| EP0998457A4 (en) | 2010-03-10 |
| WO1999002492A1 (en) | 1999-01-21 |
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