WO1999050248A1 - Pyridazinone hydrochloride compound and method for producing the same - Google Patents
Pyridazinone hydrochloride compound and method for producing the same Download PDFInfo
- Publication number
- WO1999050248A1 WO1999050248A1 PCT/JP1999/001629 JP9901629W WO9950248A1 WO 1999050248 A1 WO1999050248 A1 WO 1999050248A1 JP 9901629 W JP9901629 W JP 9901629W WO 9950248 A1 WO9950248 A1 WO 9950248A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrochloride
- compound
- solvent
- pyridazinone
- mixture
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
- C07D237/22—Nitrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
- C07D237/12—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a 3/2-hydrochloride of a pyridazinone compound having a bronchodilacion function, an antiallergy function and/or an antiplatelet function, and a method for producing the same.
- a pyridazinone compound of the formula (1) i.e. 4- chloro-5- [3- (4-benzylpiperazin-l-yl ) carbonylmethoxy-4- methoxybenzyla ino] -3 (2H) -pyridazinone is disclosed in O95/01343 laid open on January 12, 1995 and JP-A-8-
- the above patent publications disclose a hydrochloride of the pyridazinone compound (1) and a method for producing the same, and a 2 -hydrochloride (see Reference Example 1) obtained by the above preparation method has an excellent pharmaceutical effect.
- the 2 -hydrochloride is highly hygroscopic and is easily 2 decomposed and is rapidly decomposed in a methanol solvent.
- the 2-hydrochloride is unstable, and is therefore not suitable as a starting material for a pharmaceutical product.
- the present inventors have intensively studied, and have discovered that the pyridazinone compound (1) takes a 3/2-hydrochloride form (2) in addition to a 2- hydrochloride form. Further, as proved by the following Test Example 1, the present inventors have discovered that the pyridazinone compound (1) in the form of 3/2- hydrochloride (2) is clearly excellent in hygroscopicity and stability.
- the 3/2-hydrochloride (2) were compared with regard to biological dynamics in a dog. As this result, it was found that as compared with the compound (1), the 3/2-hydrochloride has 5.4 times higher maximum concentration in blood (Cmax) and is 2.3 times more preferable in respect of area under the curve (AUC) of time-concentration in blood (O- ⁇ ) . Thus, it was proved that the 3/2-hydrochloride (2) is excellent as 3 a starting material for a pharmaceutical product as compared with the compound (1) .
- the method for producing the 3/2 -hydrochloride (2) includes the following features.
- a 2-hydrochloride of pyridazinone compound (1) obtained from a three component solvent system of chloroform-methanol-diethyl ether disclosed in WO95/01343 and JP-A-8-041033 can be obtained also from a two component system solvent of ethyl acetate-methanol as shown in Reference Example 2.
- hydrogen chloride is added in the form of a methanol solution, but if this is replaced by a solution of 35% hydrochloric acid diluted with methanol, a 3/2-hydrochloride (the compound of the present invention) can be obtained, as shown in Example 1.
- the presence of water plays an important role.
- the compound (1) used as a starting material in the production method of the present invention may be a 2- hydrochloride, a 1-hydrochloride or other salts.
- Examples of a solvent usable in the present invention include ethyl acetate-ethanol of Example 2 and ethanol 6 alone of Example 3 in view of a production process of a starting material for a pharmaceutical product, but the solvent is not specially limited and other alcohol type or ester type solvents may be used.
- Examples of the alcohol type solvent include methanol, propanol, isopropanol, ethylene glycol or the like, and examples of the ester type solvent include methyl acetate, isopropyl acetate, ethyl propionate or the like.
- An amount of a solvent used is not specially limited, but if the amount of a solvent is smaller, there is a tendency that a time required for crystallization is reduced. However, if the amount of a solvent is smaller than 1.5 times weight to the compound, stirring becomes difficult and causes a problem during mass production.
- An amount of hydrogen chloride is necessary to be at least 2 mol time amount (hydrogen chloride) to the compound (1) , but the upper limit amount is not specially limited. However, when taking economic conditions, operation efficiency and risk of hydrolysis of the compound into consideration, the amount of hydrogen chloride is generally in the range of from 2 time mol to 8 time mol amounts, preferably from 2.5 time mol to 4 time mol amounts .
- Hydrogen chloride may be used in the form of a 35% hydrochloric acid solution.
- water in hydrochloric acid plays an important role in the production method of the present invention.
- the amount of water is preferably in the range of from 0.17 to 1 time weight to 4-chloro-5- [3- (4-benzylpiperazin-l- yl) carbonylmethoxy-4-methoxybenzylamino] -3 (2H) - pyridazinone used as a starting material.
- the optimum water amount varies depending on a kind and an amount of a solvent used, but concretely a 0.5 time amount is most suitable in the case of ethanol-ethyl acetate type mixture solvent.
- hydrochloric acid which is a commercially available concentrated hydrochloric acid was used, but hydrochloric acid used is not necessarily limited thereto.
- crystallization is carried out preferably in the range of from -20°C to 40°C, more preferably from 0°C to 20°C.
- a humidity conditioning solution was prepared by using a saturated aqueous solution of sodium chloride, and the solution thus prepared was placed in a humidistat, and temperature-moisture conditions at 25°C were adjusted.
- 0.4 g of 2-hydrochloride and 0.2 g of 3/2 -hydrochloride were weighed respectively in a weighing bottle to prepare test samples, and the test samples were subjected to hygroscopic test under the above adjusted temperature- moisture conditions to measure a water content and a decomposed material content as a lapse of time and to compare hygroscopicity and stability of the test samples,
- Table 2 Table 2
- each compound was subjected to powder X-ray diffraction measurement analysis to compare an X-ray diffraction pattern of each crystal.
- the measurement method was carried out in the following manner.
- 1-Hydrochloride, 3 /2-hydrochloride and 2- hydrochloride were subjected respectively to powder X-ray diffraction analysis. Further, a physically mixed sample prepared by mixing 1-hydrochloride and 2-hydrochloride in 10 an equivalent amount, was subjected to X-ray diffraction analysis in the same manner as above to compare an X-ray diffraction pattern of each crystal of each compound.
- the resultant mixture was stirred at room temperature for 5 hours, and a precipitate obtained was taken out by filtration and was dried at 60°C for 2 hours to obtain 2.41 g of a white 12 powder of the subject compound.
- the 4 mol/kg hydrochloric acid methanol solution used was prepared from 41.7 g of 35% hydrochloric acid aqueous solution and 58.3 g of methanol. Melting point: 191.6 - 196.2°C
- the 4 13 mol/kg hydrochloric acid methanol solution used was prepared from 41.7 g of 35% hydrochloric acid aqueous solution and 58.3 g of methanol. Melting point: 167.6 - 172.0°C
- EXAMPLE 2 3 /2-Hydrochloride (crystallization by 2 component system of ethyl acetate-ethanol)
- Compound (1) was used as a starting material.
- the amount of a solvent was expressed by times by weight to the starting material, and the amount of hydrogen chloride was expressed by mols to the starting material, and the amount of a seed crystal was expressed by wt% to the starting material.
- INDUSTRIAL APPLICABILITY 3/2-Hydrochloride of 4-chloro-5- [3- (4- benzylpiperazin-1-yl ) carbonylmethoxy-4- methoxybenzylamino] -3 (2H) -pyridazinone of the present invention is a compound excellent in hygroscopicity and stability which is useful as a pharmaceutical product having a bronchodilation function, an antiallergy 17 function and an antiplatelet function.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99910776A EP1066265A1 (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
KR1020007010430A KR20010042078A (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
US09/646,127 US6310065B1 (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
NZ506959A NZ506959A (en) | 1998-03-31 | 1999-03-30 | 3/2-hydrochloride of 4-chloro-5-[3-(4-benzylpiperazin-1-yl)carbonylmethoxy-4-methoxy benzylamino]-3(2H)-pyridazone |
IL13852199A IL138521A0 (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
AU29606/99A AU742553B2 (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
CA002326506A CA2326506A1 (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
SK1474-2000A SK14742000A3 (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
JP2000541153A JP2002509919A (en) | 1998-03-31 | 1999-03-30 | Pyridazinone compound hydrochloride and method for producing the same |
NO20004896A NO20004896L (en) | 1998-03-31 | 2000-09-29 | Pyridazinone hydrochloride compound and process for its preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10/85920 | 1998-03-31 | ||
JP8592098 | 1998-03-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999050248A1 true WO1999050248A1 (en) | 1999-10-07 |
Family
ID=13872231
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/001629 WO1999050248A1 (en) | 1998-03-31 | 1999-03-30 | Pyridazinone hydrochloride compound and method for producing the same |
Country Status (14)
Country | Link |
---|---|
US (1) | US6310065B1 (en) |
EP (1) | EP1066265A1 (en) |
JP (1) | JP2002509919A (en) |
KR (1) | KR20010042078A (en) |
CN (1) | CN1293661A (en) |
AU (1) | AU742553B2 (en) |
CA (1) | CA2326506A1 (en) |
IL (1) | IL138521A0 (en) |
NO (1) | NO20004896L (en) |
NZ (1) | NZ506959A (en) |
SK (1) | SK14742000A3 (en) |
TW (1) | TW499425B (en) |
WO (1) | WO1999050248A1 (en) |
ZA (1) | ZA200004927B (en) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8513264B2 (en) | 2008-09-10 | 2013-08-20 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
US8541450B2 (en) | 2004-11-05 | 2013-09-24 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines |
US8637530B2 (en) | 2005-07-30 | 2014-01-28 | Boehringer Ingelheim International Gmbh | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US8664232B2 (en) | 2002-08-21 | 2014-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8673927B2 (en) | 2006-05-04 | 2014-03-18 | Boehringer Ingelheim International Gmbh | Uses of DPP-IV inhibitors |
US8697868B2 (en) | 2004-02-18 | 2014-04-15 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
US8846695B2 (en) | 2009-01-07 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor |
US8853156B2 (en) | 2008-08-06 | 2014-10-07 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8865729B2 (en) | 2008-12-23 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Salt forms of a xanthine compound |
US8883800B2 (en) | 2011-07-15 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US9149478B2 (en) | 2010-06-24 | 2015-10-06 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
US9155705B2 (en) | 2008-04-03 | 2015-10-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US9186392B2 (en) | 2010-05-05 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
US9266888B2 (en) | 2006-05-04 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9457029B2 (en) | 2009-11-27 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US9486526B2 (en) | 2008-08-06 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US9526728B2 (en) | 2014-02-28 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Medical use of a DPP-4 inhibitor |
US9526730B2 (en) | 2012-05-14 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US9713618B2 (en) | 2012-05-24 | 2017-07-25 | Boehringer Ingelheim International Gmbh | Method for modifying food intake and regulating food preference with a DPP-4 inhibitor |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US11911388B2 (en) | 2008-10-16 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8978895B2 (en) * | 2008-10-01 | 2015-03-17 | Rickey E. Wark | Self-cleaning coal separator grids with multiple cleaning combs |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995001343A1 (en) * | 1993-06-29 | 1995-01-12 | Nissan Chemical Industries Ltd. | Pyridazinone derivatives with pharmaceutical activity |
JPH0841033A (en) * | 1993-06-29 | 1996-02-13 | Nissan Chem Ind Ltd | Pyridazinone derivative |
-
1999
- 1999-03-30 SK SK1474-2000A patent/SK14742000A3/en unknown
- 1999-03-30 EP EP99910776A patent/EP1066265A1/en not_active Withdrawn
- 1999-03-30 WO PCT/JP1999/001629 patent/WO1999050248A1/en not_active Application Discontinuation
- 1999-03-30 TW TW088105033A patent/TW499425B/en active
- 1999-03-30 AU AU29606/99A patent/AU742553B2/en not_active Ceased
- 1999-03-30 US US09/646,127 patent/US6310065B1/en not_active Expired - Fee Related
- 1999-03-30 NZ NZ506959A patent/NZ506959A/en unknown
- 1999-03-30 KR KR1020007010430A patent/KR20010042078A/en not_active Application Discontinuation
- 1999-03-30 CN CN99804120A patent/CN1293661A/en active Pending
- 1999-03-30 IL IL13852199A patent/IL138521A0/en unknown
- 1999-03-30 JP JP2000541153A patent/JP2002509919A/en not_active Withdrawn
- 1999-03-30 CA CA002326506A patent/CA2326506A1/en not_active Abandoned
-
2000
- 2000-09-15 ZA ZA200004927A patent/ZA200004927B/en unknown
- 2000-09-29 NO NO20004896A patent/NO20004896L/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995001343A1 (en) * | 1993-06-29 | 1995-01-12 | Nissan Chemical Industries Ltd. | Pyridazinone derivatives with pharmaceutical activity |
JPH0841033A (en) * | 1993-06-29 | 1996-02-13 | Nissan Chem Ind Ltd | Pyridazinone derivative |
Cited By (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9108964B2 (en) | 2002-08-21 | 2015-08-18 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8664232B2 (en) | 2002-08-21 | 2014-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US9556175B2 (en) | 2002-08-21 | 2017-01-31 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions |
US9321791B2 (en) | 2002-08-21 | 2016-04-26 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10023574B2 (en) | 2002-08-21 | 2018-07-17 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10202383B2 (en) | 2002-08-21 | 2019-02-12 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8697868B2 (en) | 2004-02-18 | 2014-04-15 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
US8541450B2 (en) | 2004-11-05 | 2013-09-24 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines |
US9499546B2 (en) | 2004-11-05 | 2016-11-22 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
US9751855B2 (en) | 2004-11-05 | 2017-09-05 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
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US8637530B2 (en) | 2005-07-30 | 2014-01-28 | Boehringer Ingelheim International Gmbh | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
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US9815837B2 (en) | 2006-05-04 | 2017-11-14 | Boehringer Ingelheim International Gmbh | Polymorphs |
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US9493462B2 (en) | 2006-05-04 | 2016-11-15 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9173859B2 (en) | 2006-05-04 | 2015-11-03 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US10080754B2 (en) | 2006-05-04 | 2018-09-25 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US10301313B2 (en) | 2006-05-04 | 2019-05-28 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9266888B2 (en) | 2006-05-04 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Polymorphs |
US11084819B2 (en) | 2006-05-04 | 2021-08-10 | Boehringer Ingelheim International Gmbh | Polymorphs |
US11291668B2 (en) | 2006-05-04 | 2022-04-05 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US10022379B2 (en) | 2008-04-03 | 2018-07-17 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US9415016B2 (en) | 2008-04-03 | 2016-08-16 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US9155705B2 (en) | 2008-04-03 | 2015-10-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10973827B2 (en) | 2008-04-03 | 2021-04-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10034877B2 (en) | 2008-08-06 | 2018-07-31 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8853156B2 (en) | 2008-08-06 | 2014-10-07 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US9486526B2 (en) | 2008-08-06 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
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Also Published As
Publication number | Publication date |
---|---|
IL138521A0 (en) | 2001-10-31 |
AU2960699A (en) | 1999-10-18 |
KR20010042078A (en) | 2001-05-25 |
US6310065B1 (en) | 2001-10-30 |
AU742553B2 (en) | 2002-01-03 |
TW499425B (en) | 2002-08-21 |
NO20004896D0 (en) | 2000-09-29 |
ZA200004927B (en) | 2001-12-24 |
CA2326506A1 (en) | 1999-10-07 |
CN1293661A (en) | 2001-05-02 |
JP2002509919A (en) | 2002-04-02 |
SK14742000A3 (en) | 2001-03-12 |
EP1066265A1 (en) | 2001-01-10 |
NZ506959A (en) | 2002-02-01 |
NO20004896L (en) | 2000-10-12 |
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