AU2001248656A1 - Therapeutically useful new salts of cck inhibitors, process for the preparation thereof and pharmaceutical preparations containing them - Google Patents
Therapeutically useful new salts of cck inhibitors, process for the preparation thereof and pharmaceutical preparations containing themInfo
- Publication number
- AU2001248656A1 AU2001248656A1 AU2001248656A AU4865601A AU2001248656A1 AU 2001248656 A1 AU2001248656 A1 AU 2001248656A1 AU 2001248656 A AU2001248656 A AU 2001248656A AU 4865601 A AU4865601 A AU 4865601A AU 2001248656 A1 AU2001248656 A1 AU 2001248656A1
- Authority
- AU
- Australia
- Prior art keywords
- ethanolamine
- solvates
- diethylamine
- diethanolamine
- polymoφhs
- 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
- 150000003839 salts Chemical class 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 12
- 238000000034 method Methods 0.000 title claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 title description 6
- 239000003112 inhibitor Substances 0.000 title description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000012453 solvate Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 9
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 4
- 210000003169 central nervous system Anatomy 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 210000005095 gastrointestinal system Anatomy 0.000 claims description 4
- 239000003586 protic polar solvent Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 235000013350 formula milk Nutrition 0.000 claims 10
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- NGRZTKIMIMIZMN-UHFFFAOYSA-N 2-aminoethanol;2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-diethylindol-1-yl]acetic acid Chemical compound NCCO.C=1C2=CC(CC)=CC(CC)=C2N(CC(O)=O)C=1C(=O)NC(S1)=NC(C=2C(=CC(Cl)=C(OC)C=2)OC)=C1CCC1CCCCC1 NGRZTKIMIMIZMN-UHFFFAOYSA-N 0.000 claims 2
- 230000002496 gastric effect Effects 0.000 claims 2
- FYSRSSNLDCOZDJ-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-diethylindol-1-yl]acetic acid Chemical compound C=1C2=CC(CC)=CC(CC)=C2N(CC(O)=O)C=1C(=O)NC(S1)=NC(C=2C(=CC(Cl)=C(OC)C=2)OC)=C1CCC1CCCCC1 FYSRSSNLDCOZDJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000725 suspension Substances 0.000 description 10
- 239000013078 crystal Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- NFDFTMICKVDYLQ-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-dimethylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC NFDFTMICKVDYLQ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 101710150887 Cholecystokinin A Proteins 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- YJKHKHDMOPQPHB-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-dimethylindol-1-yl]acetic acid;2-(2-hydroxyethylamino)ethanol Chemical compound OCCNCCO.C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC YJKHKHDMOPQPHB-UHFFFAOYSA-N 0.000 description 1
- PMLNAIGXYMGPBR-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-dimethylindol-1-yl]acetic acid;n-ethylethanamine Chemical compound CCNCC.C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC PMLNAIGXYMGPBR-UHFFFAOYSA-N 0.000 description 1
- COILIDFWUDVRLY-UHFFFAOYSA-N 2-aminoethanol;2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-dimethylindol-1-yl]acetic acid Chemical compound NCCO.C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC COILIDFWUDVRLY-UHFFFAOYSA-N 0.000 description 1
- WDUJZHOCJPEEHB-UHFFFAOYSA-N 2-aminoethanol;2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-dimethylindol-1-yl]acetic acid;hydrate Chemical compound O.NCCO.C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC WDUJZHOCJPEEHB-UHFFFAOYSA-N 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- 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
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
THERAPEUΗCALLY USEFUL NEW SALTS OF CCK INHIBITORS. PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
The invention relates to the therapeutically useful new salts of the general formula (I) (Figure 1 ). their solvates. polymorphs and pseudopolymorphs. to the process for the preparation thereof and to the pharmaceutical preparations containing them, wherein in the formula
X means ethanolamine. diethanolamine or diethylamine. The compound of the formula (II) (Figure 2) is a cholecystokinin A (CCK- A) agonist, which can be used for the treatment of the disorders of the gastrointestinal system, and of the central nervous system.
The following salts of the compound of the formula (II) and the processes for their preparation are described in publication WO 99/15525 : salt with trifluoroacetic acid, salt with hydrochloric acid, mono- and di-sodium salts, mono- and di-potassium salts. The salt with trifluoroacetic acid and its hydrate, because of the strong toxicity of the trifluoroacetic acid, are not suitable for therapeutic use. The composition of the salt with hydrochloric acid is not stochiometric, it is not reproducible.
The mono- and di-sodium salts, as well as the mono- and di-potassium salts and their hydrates are highly hygroscopic and chemically not stable compounds, namely the compound of the formula (II) decomposes at the amide bond giving rise to decomposition products of formulae (IV) (Figure 6) and (V) (Figure 7).
The subjects of the present invention, the therapeutically applicable new salts of the general formula (I) and their solvates, polymorphs and pseudopolymorphs. wherein in the formula X has the meaning as given above, with special regards to the ethanolamine salt and its solvates, are chemically stable, non-hygroscopic and their preparation is well reproducible.
Preparation of the subjects of the present invention, the therapeutically applicable new salts of the general formula (I) and their solvates, polymorphs and pseudopolymorphs is carried out by reacting the 2-[[[4-(4-chloro-2.5-
dimethoxyphenyl)-5-(2-cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7- dimethyl-lH-indol-1 -acetic acid of the formula (II) with the ethanolamine of the formula (Ilia) (Figure 3) or the diethanolamine of the formula (Illb) (Figure 4) or the diethylamine of the formula (IIIc) (Figure 5). The compounds (Ilia), (Illb) or (IIIc) are preferably applied in an excess of
1,2-1,5 equivalents. The reaction is preferably carried out in protic solvents, at a temperature between 40-100°C, preferably at the boiling point of the solvent. As for protic solvents preferably ethanol, acetonitrile or ethanol-water mixture can be applied. The therapeutically applicable new salts of the general formula (I) and their solvates, polymorphs and pseudopolymorphs of the present invention are cholecystokinin A (CCK-A) agonists, which can be used for the treatment of the disorders of the gastrointestinal system, and of the central nervous system.
The agonistic effect of the compound according to the present invention was investigated as described in the publication WO/99/15525 by investigating its effect on emptying the stomac, on rat, p.o. We have found that the ED50 value, 34 μg/kg p.o, is in the same order as the ED50 value of the trifluoroacetic acid salt and of the potassium salt.
A further subject of the present invention are pharmaceutical preparations containing the salts of the general formula (I), their solvates, polymoφhs and pseudopolymorphs, as active ingredients.
The pharmaceutical preparations according to the present invention, beside the active ingredients, may contain the usual pharmaceutical excipients and may be formulated as oral, sublingual, subcutan, intramuscular, intravenous, topical, intratracheal, intra-vasal, transdermal, rectal, intraocular, etc drug products.
The daily dose may be 0.01-50 mg bodyweight kg/day depending on the severity of the illness, on the sex and weight of the patient.
Further details of the invention are demonstrated by the following examples without limiting the invention to the examples.
EXAMPLES
1. Preparation of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl-lH-indol-l- acetic acid ethanolamine salt
647.4 g (1.060 mol) of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl-lH-indol-l -acetic acid and 7000 cm3 of ethanol are mixed and the resulting suspension is heated to 72 °C.
Then 95.3 cm3 (97.2 g = 1.592 mol) of 2-aminoethanol are added to the suspension. The reaction mixture is heated to reflux temperature and refluxed for 30 minutes.
The resulting pale yellow suspension is allowed to cool to room temperature, under stirring. The crystals are filtered off, washed with ethanol, dried in vacuum drying cupboard at 60-65 °C.
Product: 694.6 g white crystals of the title compound, mp: 208-210 °C.
2. Preparation of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl-lH-indol-l- acetic acid diethanolamine salt
1.22 g (2 mmol) of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl-lH-indol-l -acetic acid and 18 cm3 of ethanol are mixed and the resulting suspension is heated to 70-75 °C and 0.4 cm (4 mmol) of diethanolamine are added to the suspension. The mixture is refluxed for 20 minutes. The resulting pale yellow suspension is allowed to cool to room temperature, under stirring. After cooling the crystals are filtered off, washed with ethanol, then with di-isopropyl ether.
Product: 1.29 g white crystals of the title compound, mp: 215.5-216.5 °C.
3. Preparation of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl-lH-indol-l- acetic acid diethylamine salt 1.22 g (2 mmol) of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl-lH-indol-l -acetic acid and 12 cm of acetonitrile are mixed, the resulting suspension is heated to 50 °C and 0.62 cm3 (4 mmol) of diethylamine are added to it. The mixture is stirred at 50 °C for 20 minutes. The pale yellow suspension is allowed to cool to room temperature, under stirring. After cooling the crystals are filtered off, washed with acetonitrile, then with di-isopropyl ether.
Product: 1.28 g white crystals of the title compound, mp: 209.4 - 210.7 °C.
4. Preparation of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl-lH-indol-l- acetic acid ethanolamine monohydrate salt
5 g (8.2 mmol) of 2-[[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)-2-thiazolyl]amino]carbonyl]-5,7-dimethyl- lH-indol- 1 -acetic acid are added to the mixture of 45 cm3 of 96 % ethanol and 30 cm' of water. The resulting suspension is heated to 82 °C, then 0.74 cm" (13.2 mmol) of ethanolamine are added to it. The mixture is refluxed for 15 minutes. The pale yellow suspension is allowed to cool to room temperature, under stirring. The crystals are filtered off, washed with 96 % ethanol. Product: 5 g white crystals of the title compound, mp: 166-167 / 198-201 °C.
Claims (1)
- What we claim is:1) New salts of the general formula (I), their solvates, polymorphs and pseudo polymoφhs -wherein X stands for ethanolamine, diethanolamine or diethylamine -.2) 2-[[[4-(4-chloro-2,5-dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)-2- thiazolyl]amino]carbonyl]-5,7-diethyl-lH-indol-l -acetic acid ethanolamine salt, its solvates, polymoφhs and pseudopolymoφhs.3) Process for the preparation of the new salts of the general formula (I), their solvates, polymoφhs and pseudopolymoφhs -wherein X stands for ethanolamine, diethanolamine or diethylamine - characterized by reacting 2- [[[4-(4-chloro-2,5-dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)-2- thiazolyl]amino]carbonyl]-5,7-diethyl-lH-indol-l-acetic acid of the formula (II) with ethanolamine of the formula (Ilia), or diethanolamine of the formula (Illb) or diethylamine of the formula (IIIc).4) Process according to claim 3 characterized by using the compounds of the formulaes (Ilia), (Illb) or (IIIc) in an excess of 1,2-1,5.5) Process according to claims 3 and 4 characterized by carrying out the reaction in a protic solvent. 6) Process according to claim 5 characterized by using as protic solvent ethanol, acetonitrile or an ethanol-water mixture.7) Process according to claims 3 to 6 characterized by carrying out the reaction at the boiling point of the solvent.8) Pharmaceutical composition containing as active ingredient a new salt of the general formula (I), its solvates, polymoφhs or pseudopolymoφhs -wherein X stands for ethanolamine, diethanolamine or diethylamine -.9) Pharmaceutical composition according to claim 8 containing as active ingredient 2-[[[4-(4-chloro-2,5-dimethoxy-phenyl)-5-(2-cyclohexyl-ethyl)-2- thiazolyl]amino]carbonyl]-5,7-diethyl-lH-indol-l -acetic acid ethanolamine salt, its solvates, polymoφhs or pseudopolymoφhs. 10)Use of the pharmaceutically acceptable new salts of the general formula (I), its solvates, polymorphs or pseudopolymorphs -wherein X stands for ethanolamine, diethanolamine or diethylamine -.for the preparation of pharmaceutical compositions suitable for the treatment of the disorders of the gastrointestinal or central nervous systems. l l)Method of treatment of the disorders of the gastrointestinal or central nervous systems using an effective amount of a new salt of the general formula (I), its solvates, polymoφhs or pseudopolymorphs -wherein X stands for ethanolamine, diethanolamine or diethylamine-.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0001417A HUP0001417A2 (en) | 2000-04-07 | 2000-04-07 | New pharmaceutically applicable salts, process for their production and medicaments containing them |
| HU0001417 | 2000-04-07 | ||
| PCT/HU2001/000039 WO2001077108A1 (en) | 2000-04-07 | 2001-04-04 | Therapeutically useful new salts of cck inhibitors, process for the preparation thereof and pharmaceutical preparations containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2001248656A1 true AU2001248656A1 (en) | 2001-10-23 |
Family
ID=89978239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001248656A Abandoned AU2001248656A1 (en) | 2000-04-07 | 2001-04-04 | Therapeutically useful new salts of cck inhibitors, process for the preparation thereof and pharmaceutical preparations containing them |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US20030176475A1 (en) |
| EP (1) | EP1274707A1 (en) |
| JP (1) | JP2003530396A (en) |
| KR (1) | KR20020084296A (en) |
| CN (1) | CN1420885A (en) |
| AU (1) | AU2001248656A1 (en) |
| BG (1) | BG107219A (en) |
| BR (1) | BR0109890A (en) |
| CA (1) | CA2405004A1 (en) |
| CZ (1) | CZ20023671A3 (en) |
| EA (1) | EA200201076A1 (en) |
| EE (1) | EE200200582A (en) |
| HU (2) | HUP0001417A2 (en) |
| IL (1) | IL152005A0 (en) |
| IS (1) | IS6577A (en) |
| MX (1) | MXPA02009887A (en) |
| NO (1) | NO20024802D0 (en) |
| PL (1) | PL362650A1 (en) |
| SK (1) | SK15052002A3 (en) |
| WO (1) | WO2001077108A1 (en) |
| ZA (1) | ZA200207969B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI280128B (en) | 2002-05-22 | 2007-05-01 | Smithkline Beecham Corp | 3'-[(2Z)-[1-(3,4- dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine) |
| US7164383B2 (en) | 2002-09-25 | 2007-01-16 | The Board Of Regents Of The University Of Oklahoma | Navigation system using locally augmented GPS |
| ECSP077628A (en) | 2007-05-03 | 2008-12-30 | Smithkline Beechman Corp | NEW PHARMACEUTICAL COMPOSITION |
| EA024557B1 (en) | 2009-05-29 | 2016-09-30 | ГЛЭКСОСМИТКЛАЙН ЭлЭлСи | Methods of administration of thrombopoietin agonist compounds |
| CN108699094B (en) * | 2016-05-04 | 2021-05-14 | 上海研健新药研发有限公司 | Amine solvate of sodium-dependent glucose cotransporter inhibitor and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CO4970713A1 (en) * | 1997-09-19 | 2000-11-07 | Sanofi Synthelabo | DERIVATIVES OF CARBOXAMIDOTIAZOLES, THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM |
-
2000
- 2000-04-07 HU HU0001417A patent/HUP0001417A2/en unknown
-
2001
- 2001-04-04 IL IL15200501A patent/IL152005A0/en unknown
- 2001-04-04 EA EA200201076A patent/EA200201076A1/en unknown
- 2001-04-04 JP JP2001575581A patent/JP2003530396A/en not_active Withdrawn
- 2001-04-04 EP EP01921689A patent/EP1274707A1/en not_active Withdrawn
- 2001-04-04 BR BR0109890-0A patent/BR0109890A/en not_active IP Right Cessation
- 2001-04-04 CN CN01807475A patent/CN1420885A/en active Pending
- 2001-04-04 WO PCT/HU2001/000039 patent/WO2001077108A1/en not_active Application Discontinuation
- 2001-04-04 US US10/240,698 patent/US20030176475A1/en not_active Abandoned
- 2001-04-04 MX MXPA02009887A patent/MXPA02009887A/en unknown
- 2001-04-04 CZ CZ20023671A patent/CZ20023671A3/en unknown
- 2001-04-04 HU HU0204476A patent/HUP0204476A2/en unknown
- 2001-04-04 SK SK1505-2002A patent/SK15052002A3/en unknown
- 2001-04-04 PL PL01362650A patent/PL362650A1/en not_active Application Discontinuation
- 2001-04-04 CA CA002405004A patent/CA2405004A1/en not_active Abandoned
- 2001-04-04 KR KR1020027013375A patent/KR20020084296A/en not_active Application Discontinuation
- 2001-04-04 EE EEP200200582A patent/EE200200582A/en unknown
- 2001-04-04 AU AU2001248656A patent/AU2001248656A1/en not_active Abandoned
-
2002
- 2002-10-02 IS IS6577A patent/IS6577A/en unknown
- 2002-10-03 ZA ZA200207969A patent/ZA200207969B/en unknown
- 2002-10-04 NO NO20024802A patent/NO20024802D0/en not_active Application Discontinuation
- 2002-10-24 BG BG107219A patent/BG107219A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001077108A1 (en) | 2001-10-18 |
| SK15052002A3 (en) | 2003-05-02 |
| NO20024802L (en) | 2002-10-04 |
| CA2405004A1 (en) | 2001-10-18 |
| US20030176475A1 (en) | 2003-09-18 |
| IS6577A (en) | 2002-10-02 |
| CN1420885A (en) | 2003-05-28 |
| BR0109890A (en) | 2003-06-03 |
| CZ20023671A3 (en) | 2003-05-14 |
| HUP0204476A2 (en) | 2003-05-28 |
| EA200201076A1 (en) | 2003-04-24 |
| HU0001417D0 (en) | 2000-06-28 |
| KR20020084296A (en) | 2002-11-04 |
| EP1274707A1 (en) | 2003-01-15 |
| BG107219A (en) | 2003-05-30 |
| MXPA02009887A (en) | 2003-06-17 |
| IL152005A0 (en) | 2003-04-10 |
| HUP0001417A2 (en) | 2002-12-28 |
| PL362650A1 (en) | 2004-11-02 |
| ZA200207969B (en) | 2004-02-10 |
| EE200200582A (en) | 2004-04-15 |
| NO20024802D0 (en) | 2002-10-04 |
| JP2003530396A (en) | 2003-10-14 |
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