CN1176079C - 制备哌嗪衍生物甲磺酸盐的方法 - Google Patents
制备哌嗪衍生物甲磺酸盐的方法 Download PDFInfo
- Publication number
- CN1176079C CN1176079C CNB028016858A CN02801685A CN1176079C CN 1176079 C CN1176079 C CN 1176079C CN B028016858 A CNB028016858 A CN B028016858A CN 02801685 A CN02801685 A CN 02801685A CN 1176079 C CN1176079 C CN 1176079C
- Authority
- CN
- China
- Prior art keywords
- formula
- group
- mesylate
- compound
- tool
- 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.)
- Expired - Fee Related
Links
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims abstract description 7
- 150000004885 piperazines Chemical class 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- 125000006187 phenyl benzyl group Chemical group 0.000 claims 1
- -1 m-phenyl benzyl Chemical group 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 125000004193 piperazinyl group Chemical group 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical group ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及哌嗪衍生物甲磺酸盐以及以经济的、高产率和高纯度制备这些甲磺酸盐的方法。根据本发明方法,哌嗪环的合成以及甲磺酸盐的形成可以合并为单一反应步骤。本发明涉及式(I)化合物的甲磺酸盐,其中X为双环杂环苯基,并且Y为甲基、乙基(任选地被氟取代)、C3-C7-环烷甲基、苄基或间-苯基苄基。
Description
本发明涉及制备哌嗪衍生物的甲磺酸盐的新方法。
发明背景
日本专利No.3,044,383描述由伯胺与取代的二(羟乙基)胺的反应性酯反应可以获得哌嗪衍生物。此反应性酯衍生物可由取代的二(羟乙基)胺化合物与具通式R1SO2-Hal(其中R1代表烷基或芳基,及Hal是一个卤原子)的磺酰卤反应获得。使用此方法获得所需要的哌嗪衍生物的盐酸盐或氢溴酸盐。为了获得相应的甲磺酸盐必须将获得的盐转化成为自由碱,使用甲磺酸盐可以自其制备所需的甲磺酸盐。
已发现根据本发明的方法可以以一种经济方式以高产率及高纯度直接获得此类哌嗪衍生物的甲磺酸盐。
本发明涉及用于制备具式(1)
化合物的新颖方法,其使式(2)的胺
X-NH2 (2)
与式(3)
的化合物及甲磺酸酐反应,其中式X代表具式(4)基团
其中
-R1是氢或氟
-R2是氢,C1-C4-烷基,C1-C4-烷氧基或一个氧代基团,
-A代表一个具有5-7环原子的杂环基团,其中有1-3个选自O,N及S的杂原子存在,
-Y是甲基,乙基,被一或多个氟原子取代的乙基,选择性被一或多个氟原子取代的C3-C7-环烷基甲基,或具式(5)的基团
(5)
其中Z是氢,苯基,被1-3个取代基选自羟基、卤素、C1-C4-烷基、C1-C4-烷氧基或氰基取代的苯基,并且R3是氢或1-3个选自卤素、羟基、C1-C4-烷基或C1-C4-烷氧基的取代基。
本发明涉及制备具式(1)的化合物的甲磺酸盐,其中X是具式(6)的基团
并且Y的意义同上。
本发明尤其涉及制备具式(1)的化合物的甲磺酸盐的方法,其中X是具式(6)的基团,并且Y代表间-苯基苄基,苄基或甲基。
根据本发明的方法,哌嗪环的合成及甲磺酸盐的生成并合于一个单一步骤,其具有很大优势。
通过其与甲磺酸酐的反应生成具式(3)的化合物的反应性酯,优选在碱诸如三乙胺的存在下进行。可以在一种有机溶剂中于温度0-150℃、优选回流温度进行此反应。
适当的溶剂例如是单氯苯及甲乙酮。
具式(2)及(3)的起始化合物是已知的化合物或可用与之结构上相关的已知化合物相同的方式制备。
具式(1)的化合物的甲磺酸盐是新颖化合物。此类化合物的一些游离碱、盐酸加成盐及富马酸盐是已知者。
本发明也涉及具式(1)的化合物的新颖的甲磺酸盐。
本发明特别涉及具式(1)的化合物的甲磺酸盐,其中X是式(6)的基团
并且Y有以上的意义。
本发明更特别涉及具式(1)的化合物的甲磺酸盐,其中X是具式(6)的基团并且Y代表间-苯基苄基、苄基或甲基。
本发明特别涉及具式(1)的化合物的甲磺酸盐,其中X是具式(6)的基团并且Y代表间-苯基苄基。
具式(1)的化合物的盐酸加成盐连同其引人注意的药理学性质可从WO 97/36893获知。此已知的HCL-盐的缺点是其在水中溶解度较差。在25℃下于2,4,8及24小时后的溶解度介于0.18与0.20mg/ml之间。
已发现此化合物的甲磺酸盐在水中的溶解度约8-10倍于盐酸盐,即25℃下是1.7mg/ml。此较高溶解度具有重要意义因为其导致该有效化合物较佳的生物利用度。
下列实施例将说明本发明。
实施例
于氮气下将27.14g(100mmol)的二(羟乙基)间-苯基苄基胺在150ml甲乙酮(MEK)中的溶液送入至一个配备温度计、回流冷凝器及机械搅拌器的1000ml圆底烧瓶中。在搅拌下于室温溶解42.50g(240mmol)的甲磺酸酐于该溶液中。冷却该反应混合物至0-5℃,并在30-45分钟期间滴加入44.77g(440mmol)的三乙胺的50ml MEK溶液,保持该温度在10℃以下。于0-5℃下另加入40ml的MEK同时搅拌15分钟。在10-25分钟期间滴加入23.08g(240mmol)的甲磺酸在30ml MEK中的溶液同时维持温度低于10℃。用30ml MEK洗涤同时搅拌15分钟后,停止冷却,及加入具式(2)其中X是式(6)基团的化合物15.01g(100mmol)。用130ml的MEK洗涤该混合物,并加温至20-25℃为时1小时。过滤该清澈溶液至另一个烧瓶中并用60ml MEK洗涤。加热该混合物直至回流,并且约有60ml MEK馏出。继续回流8-24小时并加入140ml MEK。然后馏出150ml水/MEK,并冷却该混合物至0-5℃,并于此温度另外搅拌2小时。过滤该产物,即是所需的甲磺酸盐,用75ml冷MEK(0-5℃)洗涤两次,并于氮气下于50℃(100mbar)干燥。产量33.3g;熔点范围263-275℃。
以相似方式制备具式(1)的化合物的甲磺酸盐,其中
1)X是式(6)的基团并且Y是苄基
2)X是式(6)的基团并且Y是甲基。
Claims (12)
1.制备哌嗪衍生物的方法,其特征在于具有式(1)的化合物的甲磺酸盐
是通过式(2)胺
X-NH2 (2)
与式(3)
化合物及甲磺酸酐反应获得的,在其中X代表式(4)基团
其中
-R1是氢或氟
-R2是氢,C1-C4-烷基,C1-C4-烷氧基或氧代基团,
-A代表具有5-7个环原子的杂环基,其中有1-3个选自O,N及S的杂原子存在,
-Y是甲基,乙基,被一或多个氟原子取代的乙基,任选地被一或多个氟原子取代的C3-C7-环烷基甲基或式(5)基团
其中Z是氢,苯基,被1-3个选自羟基、卤素、C1-C4-烷基、C1-C4-烷氧基或氰基取代的苯基,并且R3是氢或1-3个选自卤素、羟基、C1-C4-烷基或C1-C4-烷氧基的取代基。
2.权利要求1的方法,其特征在于制备了具式(1)化合物的甲磺酸盐,其中X是具式(6)的基团并且Y的定义同权利要求1。
3.权利要求2的方法,其特征在于制备了式(1)化合物的甲磺酸盐,其中Y代表间-苯基苄基、苄基或甲基。
4.权利要求3的方法,其特征在于制备了式(1)化合物的甲磺酸盐,其中X代表具式(6)的基团并且Y是间-苯基苄基。
5.权利要求3的方法,其特征在于制备了式(1)化合物的甲磺酸盐,其中X代表具式(6)的基团并且Y是苄基。
6.权利要求3的方法,其特征在于制备了式(1)化合物的甲磺酸盐,其中X代表具式(6)的基团并且Y是甲基。
7.具式(1)的化合物的甲磺酸盐,其中符号的含义同权利要求1。
8.权利要求7的甲磺酸盐,其中符号的含义同权利要求2。
9.权利要求8的甲磺酸盐,其中符号的含义同权利要求3。
10.权利要求9的具式(1)化合物的甲磺酸盐,其中X是具式(6)的基团并且Y是间-苯基苄基。
11.权利要求9的具式(1)化合物的甲磺酸盐,其中X是具式(6)的基团并且Y是苄基。
12.权利要求9的具式(1)化合物的甲磺酸盐,其中X是具式(6)的基团并且Y是甲基。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01200534 | 2001-02-16 | ||
EP01200534.4 | 2001-02-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1463268A CN1463268A (zh) | 2003-12-24 |
CN1176079C true CN1176079C (zh) | 2004-11-17 |
Family
ID=8179894
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028016858A Expired - Fee Related CN1176079C (zh) | 2001-02-16 | 2002-02-14 | 制备哌嗪衍生物甲磺酸盐的方法 |
Country Status (35)
Country | Link |
---|---|
US (1) | US7030241B2 (zh) |
EP (1) | EP1362040B1 (zh) |
JP (1) | JP4328528B2 (zh) |
KR (2) | KR101000733B1 (zh) |
CN (1) | CN1176079C (zh) |
AR (1) | AR034206A1 (zh) |
AT (1) | ATE284875T1 (zh) |
AU (1) | AU2002250962B2 (zh) |
BG (1) | BG66101B1 (zh) |
BR (1) | BR0205683A (zh) |
CA (1) | CA2422703C (zh) |
CZ (1) | CZ301780B6 (zh) |
DE (1) | DE60202261T2 (zh) |
DK (1) | DK1362040T3 (zh) |
DZ (1) | DZ3489A1 (zh) |
ES (1) | ES2230481T3 (zh) |
HK (1) | HK1059934A1 (zh) |
HR (1) | HRP20030610B1 (zh) |
HU (1) | HUP0400772A3 (zh) |
IL (1) | IL153509A (zh) |
IS (1) | IS2417B (zh) |
ME (1) | MEP37508A (zh) |
MX (1) | MXPA03002359A (zh) |
MY (1) | MY130687A (zh) |
NO (1) | NO324460B1 (zh) |
NZ (1) | NZ524632A (zh) |
PL (1) | PL208363B1 (zh) |
PT (1) | PT1362040E (zh) |
RS (1) | RS51126B (zh) |
RU (1) | RU2272036C2 (zh) |
SI (1) | SI1362040T1 (zh) |
SK (1) | SK286143B6 (zh) |
UA (1) | UA75390C2 (zh) |
WO (1) | WO2002066449A2 (zh) |
ZA (1) | ZA200301590B (zh) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR045362A1 (es) * | 2003-08-18 | 2005-10-26 | Solvay Pharm Bv | Forma cristalina estable de mesilato de bifeprunox (monometansulfonato de 7-[4-([1,1- bifenil] -3- ilmetil) -1- piperazinil] - 2-(3h) -benzoxazolona |
US7435738B2 (en) | 2003-08-18 | 2008-10-14 | Solvay Pharmaceuticals, Inc. | Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate) |
US7405216B2 (en) | 2004-08-18 | 2008-07-29 | Solvay Pharmaceuticals, B.V. | Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate) |
US7964604B2 (en) * | 2005-02-18 | 2011-06-21 | Solvay Pharmaceuticals B.V. | Bifeprunox mesylate maintenance dose compositions and methods for using the same |
US7423040B2 (en) | 2005-02-18 | 2008-09-09 | Irene Eijgendaal | Stable crystalline form of bifeprunox mesylate, dosage forms thereof and methods for using same |
US20070275977A1 (en) * | 2006-05-02 | 2007-11-29 | Van Aar Marcel P | N-oxides of pyridylmethyl -piperazine and -piperidine derivatives |
US8106056B2 (en) * | 2006-06-16 | 2012-01-31 | Solvay Pharmaceuticals B.V. | Combination preparations comprising bifeprunox and a dopamine agonist |
US7786126B2 (en) | 2006-06-16 | 2010-08-31 | Solvay Pharmaceuticals B.V. | Combination preparations comprising SLV308 and a dopamine agonist |
US20080132520A1 (en) * | 2006-08-31 | 2008-06-05 | Winsemius Antje A | Compositions, kits and methods for administering a titration schedule comprising bifeprunox compounds |
US20090068290A1 (en) * | 2006-08-31 | 2009-03-12 | Michel Bourin | Bifeprunox doses for treating schizophrenia |
KR20090063228A (ko) | 2006-08-31 | 2009-06-17 | 솔베이 파마슈티칼스 비. 브이 | 정신분열증 치료용 비페프루녹스를 위한 적정 계획 및 이에사용하기 위한 키트 |
JP2011511011A (ja) | 2008-02-05 | 2011-04-07 | ハーバー バイオサイエンシーズ,インコーポレイテッド | 医薬的固体状態形態 |
WO2011023796A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Healthcare Products B.V. | Bifeprunox for treating addiction |
UY32934A (es) | 2009-10-12 | 2011-05-31 | Abbott Healthcare Products Bv | Monohidrato de pardoprunox |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0190472B1 (en) * | 1984-12-21 | 1989-07-12 | Duphar International Research B.V | New pharmaceutical compositions having anti-psychotic properties |
EP0189612B1 (en) * | 1984-12-21 | 1992-11-04 | Duphar International Research B.V | New pharmaceutical compositions having a psychotropic activity |
JPH0344383A (ja) * | 1989-07-12 | 1991-02-26 | Ihara Chem Ind Co Ltd | 5―トリフルオロメチル―2―ハロメチルベンゾチアゾール類の製造法 |
JP3044383B2 (ja) * | 1990-05-22 | 2000-05-22 | コニカ株式会社 | 含窒素6員環化合物の製造方法 |
ATE340173T1 (de) * | 1996-03-29 | 2006-10-15 | Duphar Int Res | Piperazin- und piperidin- derivate |
SE9702799D0 (sv) * | 1997-07-25 | 1997-07-25 | Astra Ab | New compounds |
UA71590C2 (en) | 1998-11-13 | 2004-12-15 | Duphar Int Res | Piperazine and piperidine derivatives |
US7435738B2 (en) * | 2003-08-18 | 2008-10-14 | Solvay Pharmaceuticals, Inc. | Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate) |
-
2002
- 2002-02-12 AR ARP020100460A patent/AR034206A1/es active IP Right Grant
- 2002-02-14 CZ CZ20030697A patent/CZ301780B6/cs not_active IP Right Cessation
- 2002-02-14 DZ DZ023489A patent/DZ3489A1/fr active
- 2002-02-14 CN CNB028016858A patent/CN1176079C/zh not_active Expired - Fee Related
- 2002-02-14 DK DK02719858T patent/DK1362040T3/da active
- 2002-02-14 ES ES02719858T patent/ES2230481T3/es not_active Expired - Lifetime
- 2002-02-14 KR KR1020087015071A patent/KR101000733B1/ko not_active IP Right Cessation
- 2002-02-14 EP EP02719858A patent/EP1362040B1/en not_active Expired - Lifetime
- 2002-02-14 AU AU2002250962A patent/AU2002250962B2/en not_active Ceased
- 2002-02-14 IL IL153509A patent/IL153509A/en not_active IP Right Cessation
- 2002-02-14 WO PCT/EP2002/001666 patent/WO2002066449A2/en active IP Right Grant
- 2002-02-14 NZ NZ524632A patent/NZ524632A/en not_active IP Right Cessation
- 2002-02-14 DE DE60202261T patent/DE60202261T2/de not_active Expired - Lifetime
- 2002-02-14 UA UA2003098528A patent/UA75390C2/uk unknown
- 2002-02-14 AT AT02719858T patent/ATE284875T1/de active
- 2002-02-14 US US10/468,098 patent/US7030241B2/en not_active Expired - Fee Related
- 2002-02-14 BR BR0205683-6A patent/BR0205683A/pt not_active Application Discontinuation
- 2002-02-14 KR KR1020037000026A patent/KR100859106B1/ko not_active IP Right Cessation
- 2002-02-14 SK SK309-2003A patent/SK286143B6/sk not_active IP Right Cessation
- 2002-02-14 ME MEP-375/08A patent/MEP37508A/xx unknown
- 2002-02-14 CA CA2422703A patent/CA2422703C/en not_active Expired - Fee Related
- 2002-02-14 SI SI200230061T patent/SI1362040T1/xx unknown
- 2002-02-14 JP JP2002565965A patent/JP4328528B2/ja not_active Expired - Fee Related
- 2002-02-14 PT PT02719858T patent/PT1362040E/pt unknown
- 2002-02-14 RS YUP-644/03A patent/RS51126B/sr unknown
- 2002-02-14 MY MYPI20020505A patent/MY130687A/en unknown
- 2002-02-14 HU HU0400772A patent/HUP0400772A3/hu unknown
- 2002-02-14 MX MXPA03002359A patent/MXPA03002359A/es active IP Right Grant
- 2002-02-14 RU RU2003105902/04A patent/RU2272036C2/ru not_active IP Right Cessation
- 2002-02-14 PL PL369330A patent/PL208363B1/pl unknown
-
2003
- 2003-02-26 ZA ZA200301590A patent/ZA200301590B/en unknown
- 2003-04-15 NO NO20031754A patent/NO324460B1/no not_active IP Right Cessation
- 2003-07-17 IS IS6876A patent/IS2417B/is unknown
- 2003-07-28 HR HR20030610A patent/HRP20030610B1/xx not_active IP Right Cessation
- 2003-08-13 BG BG108090A patent/BG66101B1/bg unknown
-
2004
- 2004-04-22 HK HK04102835A patent/HK1059934A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1176079C (zh) | 制备哌嗪衍生物甲磺酸盐的方法 | |
ZA200604240B (en) | Preparation of r-5-(2-(2-ethoxyphenoxyetylamino)propyl)-2-methoxybenzenesulphonamide hydrochloride of high chemical purity | |
AU2002250962A1 (en) | Process for the preparation of mesylates of piperazine derivatives | |
RU2512591C2 (ru) | Способ получения плевромутилинов | |
KR920000895B1 (ko) | 인돌의 제조방법 | |
CN1122660C (zh) | 丙酸衍生物及其制备方法 | |
US20020082277A1 (en) | Tosylate salts of 4-(p-fluorophenyl)-piperidine -3-carbinols | |
CN1812988A (zh) | 制备噻唑烷二酮衍生物的方法及其化合物 | |
JP2009185000A (ja) | フラーレン誘導体およびその製造方法 | |
JP4242937B2 (ja) | 1h−1,2,4−トリアゾール誘導体の製造方法 | |
JP2003261475A (ja) | 9,10−ジブロモアントラセン類の製造方法 | |
JPH04234350A (ja) | アクリル酸エステル類の製造方法 | |
JP2002030063A (ja) | スルファメート化合物の製造方法 | |
JP2004131414A (ja) | ニトロソウラシルの製造方法 | |
US20090247581A1 (en) | Organic Compounds | |
JPH1160559A (ja) | 3−ピラゾリジノン化合物の製造法 | |
CN1547568A (zh) | 制备4-氨基-1-萘酚醚类化合物的方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1059934 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1059934 Country of ref document: HK |
|
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20041117 Termination date: 20130214 |