NO325298B1 - 8-{4-[3-(5-fluor-1H-indol-3-yl)propyl]-piperazin-1-yl}-2-metyl-4H-benzo[1,4]oksazin-3-on mesylat - Google Patents
8-{4-[3-(5-fluor-1H-indol-3-yl)propyl]-piperazin-1-yl}-2-metyl-4H-benzo[1,4]oksazin-3-on mesylat Download PDFInfo
- Publication number
- NO325298B1 NO325298B1 NO20032914A NO20032914A NO325298B1 NO 325298 B1 NO325298 B1 NO 325298B1 NO 20032914 A NO20032914 A NO 20032914A NO 20032914 A NO20032914 A NO 20032914A NO 325298 B1 NO325298 B1 NO 325298B1
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- Norway
- Prior art keywords
- mesylate
- oxazin
- piperazin
- indol
- benzo
- Prior art date
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- DSARBXFENDRZNI-UHFFFAOYSA-N 8-[4-[3-(5-fluoro-1h-indol-3-yl)propyl]piperazin-1-yl]-2-methyl-4h-1,4-benzoxazin-3-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=C(F)C=C2C(CCCN3CCN(CC3)C3=CC=CC4=C3OC(C(N4)=O)C)=CNC2=C1 DSARBXFENDRZNI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 15
- 208000015114 central nervous system disease Diseases 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 230000000697 serotonin reuptake Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 2
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000020114 Schizophrenia and other psychotic disease Diseases 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- 229940123603 Dopamine D2 receptor antagonist Drugs 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- -1 mesylate compound Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000889 vertigo Toxicity 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
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D413/12—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 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
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører det nye fenylpiperazinderivatet av formel (I):
Patentsøknad nr. PCT/EP 00/08090 (enda ikke publisert) angår en gruppe nye fenylpiperaziner. Forbindelsene i denne gruppen viser høy affinitet for både dopamin D2 reseptoren og serotoningjenopptakssetet. Denne kombinasjonen er nyttig for behandlingen av schizofreni og andre psykotiske forstyrrelser, og muliggjør en mer fullstendig behandling av alle sykdomssymptomer (for eksempel positive symptomer og negative symptomer).
Forbindelsene viser aktivitet som antagonister ved dopamin D2 reseptorer siden de potensielt antagoniserer apomorfinindusert klatreadferd i mus. Forbindelsene viser også aktivitet som inhibitorer av serotoningjenopptak, siden de potensierer 5-HTP indusert adferd i mus.
Forbindelsene er aktive i terapeutiske modeller som er følsomme overfor klinisk relevante antipsykotika (for eksempel den kondisjonerte unngåelsesresponsen; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31: 61-67) og antidepressiva eller anxiolytika (for eksempel suppresjon av stressindusert vokalisering; van der Poel et al., Psychopharmacology, 1989,97: 147-148).
I motsetning til klinisk relevante dopamin D2-reseptorantagonister har de beskrevne forbindelsene en lav tilbøyelighet til å indusere katalepsi i gnagere og som sådanne er det sannsynlig at de induserer færre ekstrapyramidale bivirkninger enn eksisterende antipsykotiske midler.
Den inhiberende serotoningjenopptaksaktiviteten som er uløselig forbundet med disse forbindelsene kan være ansvarlig for de terapeutiske effektene som observeres i adferdsmodeller som er følsomme overfor enten anti-depressive eller anxiolytiske midler.
Forbindelsene kan benyttes for behandling av affeksjoner eller sykdommer i sentralnervesystemet forårsaket av forstyrrelser i enten de dopaminerge eller seratonerge systemene, for eksempel: aggresjon, angstforstyrrelser, autisme, vertigo, depresjon, kognisjons- eller hukommelsesforstyrrelser, Parkinsons sykdom og spesielt schizofreni og andre psykotiske forstyrrelser.
Det er nå funnet at mesylatet av den ovenfor angitte formelen har spesielt gunstige egenskaper sammenlignet med den frie basen (dvs. forbindelse nr. 89 i EP 99202710.2).
Mesylatforbindelsen er mye bedre oppløselig i vann enn den frie basen, hvilket resulterer i en god biotilgjengelighet.
Forbindelsen har et chiralitetssenter; både den racemiske blandingen og de individuelle enantiomerene omfattes av oppfinnelsen.
Forbindelsen kan bringes i former egnet for administrasjon ved hjelp av egnede prosesser ved bruk av hjelpestoffer slik som flytende eller faste bærermaterialer.
Den frie basen av forbindelsen kan fremstilles som beskrevet i EP 99202710.2.
Den frie basen kan omdannes til mesylater ifølge fremgangsmåter som er i og for seg kjente for saltdannelse.
Oppfinnelsen illustreres ved hjelp av følgende Eksempel.
Eksempel
2,0 g (4,7 mmol) av den frie basen som kan oppnås som beskrevet i EP 99202710.2 (forbindelse nr. 89) suspenderes i 40 ml metanol. Suspensjonen oppvarmes til 60°C og en oppløsning av 0,45 g (4,7 mmol) av metansulfonsyre i 10 ml metanol tilsettes i løpet av ca. 2 minutter. En klar oppløsning oppnås. Etter omrøring i 5 minutter ved 60°C begynner krystalliseringen. Oppløsningen avkjøles langsomt i løpet av 60 minutter til 20°C, og omrøres ved denne temperaturen i 30 minutter. Det foretas ytterligere avkjøling til 0°C i løpet av 60 minutter og omrøring i 90 minutter. Det faste materialet isoleres ved hjelp av filtrering, vaskes med 5 ml metanol og tørkes i løpet av natten ved 50°C under redusert trykk. Utbyttet 2,17 g (88%) av hvitt mesylat.
Claims (3)
1.
Forbindelse, karakterisert ved at den har formelen:
2.
Farmasøytisk preparat for behandling av CNS-forstyrrelser, karakterisert ved at det inneholder forbindelsen ifølge krav 1, som en aktiv bestanddel.
3.
Anvendelse av forbindelsen ifølge krav 1 for fremstilling av et farmasøytisk preparat for behandling av CNS-forstyrrelser.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01200610 | 2001-02-21 | ||
PCT/EP2002/001795 WO2002066473A1 (en) | 2001-02-21 | 2002-02-19 | 8’4-’3-(5-fluoro-1h-indol-3yl) propyl!-1-piperazynyl!-2-methyl-2h-1,4-benzoxazin -3 (4h)- one methanesulfonate with high affinity for the dopamine d 2 receptor and the serotonin reuptake site |
Publications (3)
Publication Number | Publication Date |
---|---|
NO20032914L NO20032914L (no) | 2003-06-24 |
NO20032914D0 NO20032914D0 (no) | 2003-06-24 |
NO325298B1 true NO325298B1 (no) | 2008-03-17 |
Family
ID=8179909
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20032914A NO325298B1 (no) | 2001-02-21 | 2003-06-24 | 8-{4-[3-(5-fluor-1H-indol-3-yl)propyl]-piperazin-1-yl}-2-metyl-4H-benzo[1,4]oksazin-3-on mesylat |
Country Status (25)
Country | Link |
---|---|
US (2) | US6958396B2 (no) |
EP (1) | EP1366044B1 (no) |
JP (1) | JP4216072B2 (no) |
KR (1) | KR100859107B1 (no) |
CN (1) | CN1284780C (no) |
AR (1) | AR032712A1 (no) |
AT (1) | ATE472545T1 (no) |
AU (1) | AU2002250983B2 (no) |
BR (1) | BR0206162A (no) |
CA (1) | CA2430707C (no) |
CZ (1) | CZ20032171A3 (no) |
DE (1) | DE60236848D1 (no) |
DZ (1) | DZ3490A1 (no) |
ES (1) | ES2347321T3 (no) |
HK (1) | HK1078569A1 (no) |
HU (1) | HUP0303330A3 (no) |
IL (1) | IL155720A0 (no) |
MX (1) | MXPA03007430A (no) |
NO (1) | NO325298B1 (no) |
NZ (1) | NZ526018A (no) |
PL (1) | PL201176B1 (no) |
RU (1) | RU2281945C2 (no) |
SK (1) | SK10412003A3 (no) |
WO (1) | WO2002066473A1 (no) |
ZA (1) | ZA200304267B (no) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL148218A0 (en) * | 1999-08-23 | 2002-09-12 | Solvay Pharm Bv | New phenylpiperazines |
AR032712A1 (es) * | 2001-02-21 | 2003-11-19 | Solvay Pharm Bv | Un mesilato de derivados de fenilpiperazina y composiciones farmaceuticas que lo contienen |
US7371769B2 (en) | 2004-12-07 | 2008-05-13 | Solvay Pharmaceuticals B.V. | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites |
JP2008523026A (ja) * | 2004-12-07 | 2008-07-03 | ソルベイ・フアーマシユーチカルズ・ベー・ブイ | ドーパミン−d2受容体に関する親和力およびセロトニン再吸収部位の組み合わせを有するフェニルピペラジン類 |
US20060122247A1 (en) | 2004-12-08 | 2006-06-08 | Solvay Pharmaceuticals B.V. | Aryloxyethylamine and phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition |
GT200600416A (es) * | 2005-09-12 | 2007-09-20 | Sales salicilato y gentisato de un compuesto de piperazina | |
GT200600414A (es) * | 2005-09-12 | 2007-09-20 | Sal de glucuranato de compuesto de piperazine | |
PE20070523A1 (es) * | 2005-09-12 | 2007-06-28 | Wyeth Corp | Formulacion de liberacion sostenida del glucuronato de (8-{4-[3-(5-fluoro-1h-indol-3-il)-propil]-piperazin-1-il}-2-metil-4h-benzo[1,4]oxazin-3-ona |
US9066903B2 (en) | 2006-02-28 | 2015-06-30 | The United States Of America As Represented By The Department Of Veterans Affairs | Pharmacological treatment of Parkinson's disease |
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-
2002
- 2002-02-18 AR ARP020100548A patent/AR032712A1/es not_active Application Discontinuation
- 2002-02-19 JP JP2002565987A patent/JP4216072B2/ja not_active Expired - Fee Related
- 2002-02-19 DZ DZ023490A patent/DZ3490A1/fr active
- 2002-02-19 IL IL15572002A patent/IL155720A0/xx not_active IP Right Cessation
- 2002-02-19 HU HU0303330A patent/HUP0303330A3/hu unknown
- 2002-02-19 SK SK1041-2003A patent/SK10412003A3/sk unknown
- 2002-02-19 DE DE60236848T patent/DE60236848D1/de not_active Expired - Lifetime
- 2002-02-19 PL PL362288A patent/PL201176B1/pl not_active IP Right Cessation
- 2002-02-19 ES ES02719880T patent/ES2347321T3/es not_active Expired - Lifetime
- 2002-02-19 CA CA2430707A patent/CA2430707C/en not_active Expired - Fee Related
- 2002-02-19 KR KR1020037010907A patent/KR100859107B1/ko not_active IP Right Cessation
- 2002-02-19 CZ CZ20032171A patent/CZ20032171A3/cs unknown
- 2002-02-19 WO PCT/EP2002/001795 patent/WO2002066473A1/en active Application Filing
- 2002-02-19 RU RU2003114440/04A patent/RU2281945C2/ru not_active IP Right Cessation
- 2002-02-19 US US10/432,225 patent/US6958396B2/en not_active Expired - Fee Related
- 2002-02-19 AU AU2002250983A patent/AU2002250983B2/en not_active Ceased
- 2002-02-19 BR BR0206162-7A patent/BR0206162A/pt not_active Application Discontinuation
- 2002-02-19 MX MXPA03007430A patent/MXPA03007430A/es active IP Right Grant
- 2002-02-19 CN CNB028029682A patent/CN1284780C/zh not_active Expired - Fee Related
- 2002-02-19 NZ NZ526018A patent/NZ526018A/en unknown
- 2002-02-19 AT AT02719880T patent/ATE472545T1/de not_active IP Right Cessation
- 2002-02-19 EP EP02719880A patent/EP1366044B1/en not_active Expired - Lifetime
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2003
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- 2003-06-24 NO NO20032914A patent/NO325298B1/no not_active IP Right Cessation
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2005
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