CA2392362A1 - Novel methods and compositions involving opioids and antagonists thereof - Google Patents
Novel methods and compositions involving opioids and antagonists thereof Download PDFInfo
- Publication number
- CA2392362A1 CA2392362A1 CA002392362A CA2392362A CA2392362A1 CA 2392362 A1 CA2392362 A1 CA 2392362A1 CA 002392362 A CA002392362 A CA 002392362A CA 2392362 A CA2392362 A CA 2392362A CA 2392362 A1 CA2392362 A1 CA 2392362A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- hydrogen
- substituted alkyl
- cycloalkyl
- cycloalkenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 172
- 239000000203 mixture Substances 0.000 title claims abstract description 75
- 229940005483 opioid analgesics Drugs 0.000 title abstract description 23
- 239000005557 antagonist Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 239
- 230000002093 peripheral effect Effects 0.000 claims abstract description 68
- 230000000694 effects Effects 0.000 claims abstract description 65
- 239000002623 mu opiate receptor antagonist Substances 0.000 claims abstract description 60
- 206010028813 Nausea Diseases 0.000 claims abstract description 20
- 230000008693 nausea Effects 0.000 claims abstract description 20
- 206010047700 Vomiting Diseases 0.000 claims abstract description 19
- 206010010774 Constipation Diseases 0.000 claims abstract description 18
- 230000008673 vomiting Effects 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 397
- 239000001257 hydrogen Substances 0.000 claims description 371
- 229910052739 hydrogen Inorganic materials 0.000 claims description 371
- 125000003342 alkenyl group Chemical group 0.000 claims description 204
- 150000002431 hydrogen Chemical group 0.000 claims description 198
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 164
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 145
- 125000003107 substituted aryl group Chemical group 0.000 claims description 99
- 125000003118 aryl group Chemical group 0.000 claims description 95
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 93
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 80
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 80
- 125000002947 alkylene group Chemical group 0.000 claims description 75
- 125000000623 heterocyclic group Chemical group 0.000 claims description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims description 72
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 71
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 229960005181 morphine Drugs 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 39
- -1 morphinan compound Chemical class 0.000 claims description 34
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 32
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 32
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 32
- 239000000651 prodrug Substances 0.000 claims description 32
- 229940002612 prodrug Drugs 0.000 claims description 32
- 150000003797 alkaloid derivatives Chemical class 0.000 claims description 29
- 239000008896 Opium Substances 0.000 claims description 26
- 229960001027 opium Drugs 0.000 claims description 26
- 150000001204 N-oxides Chemical class 0.000 claims description 23
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical group NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 17
- 229960000482 pethidine Drugs 0.000 claims description 17
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 16
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims description 16
- 229960004126 codeine Drugs 0.000 claims description 16
- 229960004193 dextropropoxyphene Drugs 0.000 claims description 16
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 claims description 16
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 claims description 16
- 229960000920 dihydrocodeine Drugs 0.000 claims description 16
- 229960002428 fentanyl Drugs 0.000 claims description 16
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims description 16
- 229960000240 hydrocodone Drugs 0.000 claims description 16
- 229960002085 oxycodone Drugs 0.000 claims description 16
- 229960004380 tramadol Drugs 0.000 claims description 16
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims description 16
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims description 16
- 208000002193 Pain Diseases 0.000 claims description 15
- 125000002252 acyl group Chemical group 0.000 claims description 15
- 230000036407 pain Effects 0.000 claims description 15
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Chemical group CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 11
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Chemical group CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 11
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 claims description 9
- 125000004450 alkenylene group Chemical group 0.000 claims description 9
- 229960005118 oxymorphone Drugs 0.000 claims description 9
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims description 8
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 claims description 8
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 claims description 8
- 229960001391 alfentanil Drugs 0.000 claims description 8
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims description 8
- 229960001736 buprenorphine Drugs 0.000 claims description 8
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 claims description 8
- 229960001113 butorphanol Drugs 0.000 claims description 8
- 229960003461 dezocine Drugs 0.000 claims description 8
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 claims description 8
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 8
- 229960001410 hydromorphone Drugs 0.000 claims description 8
- 229960003406 levorphanol Drugs 0.000 claims description 8
- 229960001797 methadone Drugs 0.000 claims description 8
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 claims description 8
- 229960000805 nalbuphine Drugs 0.000 claims description 8
- 229960005301 pentazocine Drugs 0.000 claims description 8
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 claims description 8
- ZBAFFZBKCMWUHM-UHFFFAOYSA-N propiram Chemical compound C=1C=CC=NC=1N(C(=O)CC)C(C)CN1CCCCC1 ZBAFFZBKCMWUHM-UHFFFAOYSA-N 0.000 claims description 8
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- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 claims description 8
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- PCSQOABIHJXZMR-MGQKVWQSSA-O (4r,4as,7ar,12bs)-4a,9-dihydroxy-3-methyl-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CC[N+](C)(CC=C)[C@@H]3CC5=CC=C4O PCSQOABIHJXZMR-MGQKVWQSSA-O 0.000 claims description 5
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- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 5
- JVLBPIPGETUEET-GAAHOAFPSA-O methylnaltrexone Chemical compound C[N+]1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)CC1CC1 JVLBPIPGETUEET-GAAHOAFPSA-O 0.000 claims description 5
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical group C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 claims description 5
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45080699A | 1999-11-29 | 1999-11-29 | |
| US09/450,806 | 1999-11-29 | ||
| PCT/US2000/042315 WO2001037785A2 (en) | 1999-11-29 | 2000-11-29 | Novel methods and compositions involving opioids and antagonists thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2392362A1 true CA2392362A1 (en) | 2001-05-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002392362A Abandoned CA2392362A1 (en) | 1999-11-29 | 2000-11-29 | Novel methods and compositions involving opioids and antagonists thereof |
Country Status (13)
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|---|---|
| EP (1) | EP1244447B1 (https=) |
| JP (1) | JP2003528819A (https=) |
| AU (1) | AU784541B2 (https=) |
| CA (1) | CA2392362A1 (https=) |
| CY (1) | CY1106359T1 (https=) |
| DE (1) | DE60032940T2 (https=) |
| DK (1) | DK1244447T3 (https=) |
| ES (1) | ES2278647T3 (https=) |
| IL (2) | IL149600A0 (https=) |
| MX (1) | MXPA02005335A (https=) |
| NZ (1) | NZ518562A (https=) |
| PT (1) | PT1244447E (https=) |
| WO (1) | WO2001037785A2 (https=) |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6274591B1 (en) | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
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| US5250542A (en) * | 1991-03-29 | 1993-10-05 | Eli Lilly And Company | Peripherally selective piperidine carboxylate opioid antagonists |
-
2000
- 2000-11-29 ES ES00992256T patent/ES2278647T3/es not_active Expired - Lifetime
- 2000-11-29 WO PCT/US2000/042315 patent/WO2001037785A2/en not_active Ceased
- 2000-11-29 CA CA002392362A patent/CA2392362A1/en not_active Abandoned
- 2000-11-29 PT PT00992256T patent/PT1244447E/pt unknown
- 2000-11-29 JP JP2001539402A patent/JP2003528819A/ja active Pending
- 2000-11-29 DK DK00992256T patent/DK1244447T3/da active
- 2000-11-29 DE DE60032940T patent/DE60032940T2/de not_active Expired - Lifetime
- 2000-11-29 AU AU39706/01A patent/AU784541B2/en not_active Ceased
- 2000-11-29 EP EP00992256A patent/EP1244447B1/en not_active Expired - Lifetime
- 2000-11-29 MX MXPA02005335A patent/MXPA02005335A/es active IP Right Grant
- 2000-11-29 NZ NZ518562A patent/NZ518562A/en unknown
- 2000-11-29 IL IL14960000A patent/IL149600A0/xx unknown
-
2002
- 2002-05-12 IL IL149600A patent/IL149600A/en not_active IP Right Cessation
-
2007
- 2007-03-07 CY CY20071100318T patent/CY1106359T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ518562A (en) | 2005-04-29 |
| EP1244447B1 (en) | 2007-01-10 |
| MXPA02005335A (es) | 2003-01-28 |
| CY1106359T1 (el) | 2011-10-12 |
| JP2003528819A (ja) | 2003-09-30 |
| DK1244447T3 (da) | 2007-04-23 |
| WO2001037785A9 (en) | 2002-08-29 |
| ES2278647T3 (es) | 2007-08-16 |
| WO2001037785A2 (en) | 2001-05-31 |
| DE60032940T2 (de) | 2007-11-08 |
| IL149600A0 (en) | 2002-11-10 |
| AU3970601A (en) | 2001-06-04 |
| PT1244447E (pt) | 2007-02-28 |
| WO2001037785A3 (en) | 2002-01-10 |
| EP1244447A2 (en) | 2002-10-02 |
| IL149600A (en) | 2010-06-16 |
| DE60032940D1 (de) | 2007-02-22 |
| AU784541B2 (en) | 2006-04-27 |
| EP1244447A4 (en) | 2003-06-04 |
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