TWI454464B - 哌衍生物的製備方法 - Google Patents
哌衍生物的製備方法 Download PDFInfo
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- TWI454464B TWI454464B TW098142940A TW98142940A TWI454464B TW I454464 B TWI454464 B TW I454464B TW 098142940 A TW098142940 A TW 098142940A TW 98142940 A TW98142940 A TW 98142940A TW I454464 B TWI454464 B TW I454464B
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- 238000000034 method Methods 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title description 6
- 150000004885 piperazines Chemical class 0.000 title 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 150000005621 tetraalkylammonium salts Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- -1 tetra-n-butylammonium halide Chemical class 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012467 final product Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- YODQESWJUQGRPE-UHFFFAOYSA-N 4-(2,3-dichlorophenyl)piperidine Chemical compound ClC1=CC=CC(C2CCNCC2)=C1Cl YODQESWJUQGRPE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical group CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
Classifications
-
- 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
- C07D295/12—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 or doubly bound nitrogen atoms
- C07D295/135—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
本發明係有關一種製備通式(I)之反式N-{4-{2-[4-(2,3-二氯苯基)-哌-1-基]-乙基}-環己基}-脲衍生物的新穎方法。
通式(I)化合物原來係揭示於匈牙利專利說明書編號P0302451中作為D3/D2受體拮抗劑。P0302451說明書中列出三個用以製備式(I)化合物的反應路徑(A、B、C方法)。根據方法,A”，胺衍生物與(硫代)胺甲醯氯化合物反應。P0302451方法A之實施例3中，胺於無水條件下，在三乙胺存在下，與N,N-二甲基-胺甲醯氯反應。
就工業觀點而言，前述"A"程序之缺點係為長反應時間(48小時)及較差產率(65%)。此外，所得最終產物應以額外再結晶步驟純化。
吾人目標係提供一種缺少先前方法之缺點的方法，即藉易於單離純化之方式在較短反應時間及較佳產率下製備式(I)化合物。
吾人於實驗過程中，驚異地發現當式(III)化合物
或其鹽及/或水合物及/或溶劑合物與通式(II)胺甲醯氯
(其中R1
及R2
係獨立地表示
- 選擇性經芳基取代之直鏈或分支鏈C1
-6
烷基，或
- 含有1至3個雙鍵之C2-7
烯基，或
- 單環性、雙環性或三環性芳基，選擇性經一或多個以下基團所取代：C1-6
烷氧基、三氟-C1-6烷氧基、C1-6烷氧基羰基、C1-6烷醯基、芳基、C1-6烷硫基、鹵素或氰基，或
- 選擇性經取代之單環性、雙環性或三環性環烷基，或R1
及R2
連同相鄰氮原子一起可形成選擇性經取代、飽和或不飽和、單環性或雙環性之雜環性環，其可含有其他選自氧、氮或硫原子之雜原子)
於溶劑與濃鹼性水溶液之混合物中，在作為相轉移除觸媒之四烷基銨鹽存在下進行反應，通式(I)化合物
(其中R1
及R2
係如前所述)係以高產率(高於90%)及短反應時間下製得。
應用本發明方法時，單離純化過程變得較簡易：分離有機相及水相，之後在將有機相水洗後，藉蒸餾移除溶劑，得到最終產物。
本發明係有關一種製備通式(I)化合物之新穎方法
其中R1
及R2
係獨立地表示
- 選擇性經芳基取代之直鏈或分支鏈C1
-6
烷基，或
- 含有1至3個雙鍵之C2-7
烯基，或
- 單環性、雙環性、或三環性芳基，選擇性經一或多個以下基團所取代：C1-6
烷氧基、三氟-C1-6烷氧基、C1-6烷氧基羰基、C1-6烷醯基、芳基、C1-6烷硫基、鹵素或氰基，或
- 選擇性經取代之單環性、雙環性或三環性環烷基，或R1
及R2
連同相鄰氮原子一起可形成選擇性經取代、飽和或不飽和、單環性或雙環性之雜環性環，其可含有其他選自氧、氮或硫原子之雜原子。
本發明優點係為反應時間變得較短，可在無進一步純化下以高純度自反應混合物回收最終產物，其中產率超過90%。
當R1
及R2
表示芳基時，芳基部分可為選自苯基、甲苯基、萘基及菲基。
在本發明程序中，式(III)化合物
或其鹽及/或水合物及/或溶劑合物與通式(II)胺甲醯氯
(其中R1
及R2
係描述於前文)於溶劑與濃鹼性溶液之混合物中，在相轉移觸媒存在下進行反應。如此，於較短反應時間(9至10小時)及良好產率(高於90%)下得到最終產物。
本發明較佳具體實施態樣中，濃鹼為鹼金屬氫氧化物之(例如NaOH或KOH)水溶液。
相轉移觸媒係為四烷基銨鹽，其中該烷基部分可具有C1-6直鏈或分支鏈。適當之相轉移觸媒的選擇中，易於操作可為重要因素。較佳相轉移觸媒係為四-正丁基銨鹽或四甲基銨鹽，其中該形成鹽之陰離子可為硫酸根、氯或溴陰離子。
可使用於本發明方法之適當溶劑係包括中性水不可溶混溶劑，例如甲苯、二氯甲烷、氯苯或二甲苯。本發明較佳具體實施態樣中，較佳係可使用二氯甲烷作為溶劑。
本發明方法之單離純化步驟中，分離有機相及水相，之後在將有機相水洗後，藉蒸餾移除溶劑，得到所需最終產物。
藉由以下非限制性實施例進一步說明本發明。
在500毫升四頸燒瓶內添加180毫升二氯甲烷、40毫升40%氫氧化鈉、0.54克(0.002莫耳)之溴化四-正丁基銨及3.12克(0.029莫耳)之N,N-二甲基胺甲醯氯。混合物在介於20至25℃間之溫度攪拌歷經30分鐘，之後添加6.24克(0.0145莫耳)之反式4-{2-[4-(2,3-二氯苯基)-哌-1-基]-乙基}-環己胺二鹽酸鹽。在劇烈攪拌下，將反應混合物置入預熱至45至50℃之油浴中，且於氮氣下加熱至沸騰溫度經10小時。之後，將反應混合物冷卻至室溫，分相，且有機層以3×80毫升水、之後80毫升10%氯化鈉溶液洗滌。於真空下移除溶劑；所得殘留物在最高50℃溫度下進一步乾燥，直至其重量為定值。
乾重：5.7克(92%)。
熔點：212-214℃。
在500毫升四頸燒瓶內添加180毫升二氯甲烷、40毫升40%氫氧化鈉、0.54克(0.002莫耳)之溴化四-正丁基銨及3.12克(0.029莫耳)之N,N-二甲基胺甲醯氯。混合物在介於20至25℃間之溫度攪拌歷經30分鐘，之後添加6.50克(0.0145莫耳)之反式4-{2-[4-(2,3-二氯苯基)-哌-1-基]-乙基}-環己胺二鹽酸鹽單水合物。在劇烈攪拌下，將反應混合物置入預熱至45至50℃之油浴中，且於氮氣下加熱至沸騰溫度經10小時。之後，將反應混合物冷卻至室溫，分相，且有機層以3×80毫升水、之後80毫升10%氯化鈉溶液洗滌。於真空下移除溶劑；所得殘留物在最高50℃溫度下進一步乾燥，直至其重量為定值。
乾重：5.7克(92%)。
熔點：212-214℃。
在500毫升四頸燒瓶內添加400毫升二氯甲烷、40毫升40%氫氧化鈉、1.2克(0.0036莫耳)之溴化四-正丁基銨及11克(0.074莫耳)之N,N-二甲基胺甲醯氯。混合物在介於20至25℃間之溫度攪拌歷經30分鐘，之後添加15.5克(0.036莫耳)之反式4-{2-[4-(2,3-二氯苯基)-哌-1-基]-乙基}-環己胺二鹽酸鹽。在劇烈攪拌下，將反應混合物置入預熱至45至50℃之油浴中，且於氮氣下加熱至沸騰溫度經4小時。之後，將反應混合物冷卻至室溫，分相，且有機層以3×80毫升水、之後150毫升10%氯化鈉溶液洗滌。於真空下移除溶劑；所得殘留物在最高50℃溫度下進一步乾燥，直至其重量為定值。
乾重：15.2克(90%)。
熔點：203-205℃。
Claims (7)
- 一種製備通式(I)化合物之方法
- 如申請專利範圍第1項之方法，其中該相轉移觸媒係為四烷基銨鹽。
- 如申請專利範圍第2項之方法，其中該四烷基銨鹽係為鹵化四正丁基銨。
- 如申請專利範圍第3項之方法，其中該四烷基銨鹽係為溴化四烷基銨。
- 如申請專利範圍第1項之方法，其中該溶劑係為惰性水不溶混溶劑。
- 如申請專利範圍第1項之方法，其中該溶劑係為甲苯、二氯甲烷、氯苯或二甲苯。
- 如申請專利範圍第1項之方法，其中該反應係於介於45至50℃間之溫度進行。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0800766A HUP0800766A2 (en) | 2008-12-18 | 2008-12-18 | Process for the preparation of piperazine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201035057A TW201035057A (en) | 2010-10-01 |
| TWI454464B true TWI454464B (zh) | 2014-10-01 |
Family
ID=89988675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW098142940A TWI454464B (zh) | 2008-12-18 | 2009-12-15 | 哌衍生物的製備方法 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US8569497B2 (zh) |
| EP (1) | EP2367807B1 (zh) |
| JP (1) | JP5583689B2 (zh) |
| CN (1) | CN102256955B (zh) |
| EA (1) | EA019521B1 (zh) |
| HK (1) | HK1160847A1 (zh) |
| HU (1) | HUP0800766A2 (zh) |
| TW (1) | TWI454464B (zh) |
| WO (1) | WO2010070371A1 (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0700353A2 (en) * | 2007-05-18 | 2008-12-29 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| US7875610B2 (en) * | 2007-12-03 | 2011-01-25 | Richter Gedeon Nyrt. | Pyrimidinyl-piperazines useful as D3/D2 receptor ligands |
| EP2251011B1 (en) * | 2008-02-21 | 2012-04-04 | Richter Gedeon Nyrt. | Solid preparation for oral administration |
| AP2975A (en) | 2008-07-16 | 2014-09-30 | Richter Gedeon Nyrt | Pharmaceutical formulations containing dopamine receptor ligands |
| HU230067B1 (hu) | 2008-12-17 | 2015-06-29 | Richter Gedeon Nyrt | Új piperazin só és eljárás előállítására |
| HUP0800765A2 (en) | 2008-12-18 | 2010-11-29 | Richter Gedeon Nyrt | A new process for the preparation of piperazine derivatives and their hydrochloric salts |
| HUP0900790A2 (en) * | 2009-12-17 | 2011-09-28 | Richter Gedeon Nyrt | A new process for the preparation of piperazine and their hydrochloric salts |
| US11274087B2 (en) | 2016-07-08 | 2022-03-15 | Richter Gedeon Nyrt. | Industrial process for the preparation of cariprazine |
| CN110872262A (zh) | 2018-08-29 | 2020-03-10 | 上海科胜药物研发有限公司 | 一种卡利拉嗪的合成方法 |
| CN111320593B (zh) * | 2018-12-13 | 2022-04-22 | 江苏恩华药业股份有限公司 | 一种高纯度卡利拉嗪的精制方法 |
| US11547707B2 (en) | 2019-04-10 | 2023-01-10 | Richter Gedeon Nyrt. | Carbamoyl cyclohexane derivatives for treating autism spectrum disorder |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| TW200505874A (en) * | 2003-08-04 | 2005-02-16 | Richter Gedeon Vegyeszet | New compounds with therapeutic effect |
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| US4957921A (en) | 1989-12-06 | 1990-09-18 | Warner-Lambert Company | Substituted cyclohexanols as central nervous system agents |
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| US6334997B1 (en) | 1994-03-25 | 2002-01-01 | Isotechnika, Inc. | Method of using deuterated calcium channel blockers |
| AU6859096A (en) | 1995-09-22 | 1997-04-09 | Warner-Lambert Company | Substituted cyclohexylamines as central nervous system agents |
| US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
| WO1999050247A1 (en) | 1998-03-31 | 1999-10-07 | Acadia Pharmaceuticals, Inc. | Compounds with activity on muscarinic receptors |
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| US6489341B1 (en) | 1999-06-02 | 2002-12-03 | Sepracor Inc. | Methods for the treatment of neuroleptic and related disorders using sertindole derivatives |
| DK1368021T3 (da) | 2001-02-27 | 2008-02-11 | Ortho Mcneil Pharm Inc | Carbamatforbindelser til anvendelse ved forebyggelse eller behandling af bipolær sygdom |
| US6566550B2 (en) | 2001-06-21 | 2003-05-20 | Pfizer Inc | Substituted aromatic ethers as inhibitors of glycine transport |
| HU227543B1 (en) | 2001-09-28 | 2011-08-29 | Richter Gedeon Nyrt | N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them |
| SE0200301D0 (sv) | 2002-02-01 | 2002-02-01 | Axon Biochemicals Bv | Thio-carbostyril derivative |
| US6919342B2 (en) | 2003-06-05 | 2005-07-19 | Abbott Gmbh & Co. Kg | Triazole compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor |
| DE102004047517A1 (de) | 2004-09-28 | 2006-03-30 | Merck Patent Gmbh | Neuartige Kristallform von (3-Cyan-1H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, Hydrochlorid |
| HUP0500170A3 (en) | 2005-02-03 | 2007-11-28 | Richter Gedeon Nyrt | Piperazine derivatives, process for producing them and pharmaceutical compositions containing them |
| GT200600414A (es) | 2005-09-12 | 2007-09-20 | Sal de glucuranato de compuesto de piperazine | |
| HU230748B1 (hu) | 2007-05-11 | 2018-02-28 | Richter Gedeon Nyrt | Új piperazin só és előállítási eljárása |
| EA017732B1 (ru) | 2007-05-11 | 2013-02-28 | Рихтер Гедеон Нирт. | Сольватная и кристаллическая формы гидрохлорида транс-1{4-[2-[4-(2,3-дихлорфенил)пиперазин-1-ил]этил]циклогексил}-3,3-диметилмочевины, способы их получения и их применение в фармацевтических композициях и способах лечения состояний, для которых необходима модуляция дофаминовых рецепторов |
| HUP0700353A2 (en) * | 2007-05-18 | 2008-12-29 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| HUP0700369A2 (en) | 2007-05-24 | 2009-04-28 | Richter Gedeon Nyrt | Use of (thio)-carbamoyl-cyclohexane derivatives in the manufacture of a medicament for the treatment in the manufacture of a medicament for the treatment of schizophrenia |
| HUP0700370A2 (en) | 2007-05-24 | 2009-04-28 | Richter Gedeon Nyrt | Use of (thio)-carbamoyl-cyclohexane derivatives in the manufacture of a medicament for the treatment of acute mania |
| JP2011513196A (ja) | 2007-08-01 | 2011-04-28 | ハー・ルンドベック・アクチエゼルスカベット | ドーパミン作動系が破壊された障害もしくは状態の症状を軽減するためまたはその障害もしくは状態を処置するためのｋｃｎｑカリウムチャネル開口薬の使用 |
| US7875610B2 (en) | 2007-12-03 | 2011-01-25 | Richter Gedeon Nyrt. | Pyrimidinyl-piperazines useful as D3/D2 receptor ligands |
| EP2251011B1 (en) | 2008-02-21 | 2012-04-04 | Richter Gedeon Nyrt. | Solid preparation for oral administration |
| AP2975A (en) | 2008-07-16 | 2014-09-30 | Richter Gedeon Nyrt | Pharmaceutical formulations containing dopamine receptor ligands |
| HU230067B1 (hu) | 2008-12-17 | 2015-06-29 | Richter Gedeon Nyrt | Új piperazin só és eljárás előállítására |
| HUP0800765A2 (en) | 2008-12-18 | 2010-11-29 | Richter Gedeon Nyrt | A new process for the preparation of piperazine derivatives and their hydrochloric salts |
-
2008
- 2008-12-18 HU HU0800766A patent/HUP0800766A2/hu unknown
-
2009
- 2009-12-15 TW TW098142940A patent/TWI454464B/zh active
- 2009-12-18 EA EA201170809A patent/EA019521B1/ru not_active IP Right Cessation
- 2009-12-18 JP JP2011541615A patent/JP5583689B2/ja active Active
- 2009-12-18 EP EP09797147A patent/EP2367807B1/en active Active
- 2009-12-18 US US13/140,261 patent/US8569497B2/en active Active
- 2009-12-18 WO PCT/HU2009/000110 patent/WO2010070371A1/en active Application Filing
- 2009-12-18 CN CN200980150721.8A patent/CN102256955B/zh active Active
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2012
- 2012-02-08 HK HK12101189.5A patent/HK1160847A1/zh unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200505874A (en) * | 2003-08-04 | 2005-02-16 | Richter Gedeon Vegyeszet | New compounds with therapeutic effect |
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|---|---|
| CN102256955B (zh) | 2014-03-12 |
| WO2010070371A8 (en) | 2011-04-28 |
| US8569497B2 (en) | 2013-10-29 |
| EA201170809A1 (ru) | 2011-12-30 |
| HUP0800766A2 (en) | 2010-11-29 |
| US20110269959A1 (en) | 2011-11-03 |
| JP5583689B2 (ja) | 2014-09-03 |
| HU0800766D0 (en) | 2009-03-02 |
| HK1160847A1 (zh) | 2012-08-17 |
| EA019521B1 (ru) | 2014-04-30 |
| JP2012512862A (ja) | 2012-06-07 |
| EP2367807B1 (en) | 2013-02-13 |
| EP2367807A1 (en) | 2011-09-28 |
| WO2010070371A1 (en) | 2010-06-24 |
| TW201035057A (en) | 2010-10-01 |
| CN102256955A (zh) | 2011-11-23 |
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