WO1999001448A1 - 5-(2-ethyl-2h-tetrazol-5-y1)-1-methyl-1,2,3,6-tetrahydropyridine maleate - Google Patents
5-(2-ethyl-2h-tetrazol-5-y1)-1-methyl-1,2,3,6-tetrahydropyridine maleate Download PDFInfo
- Publication number
- WO1999001448A1 WO1999001448A1 PCT/DK1998/000294 DK9800294W WO9901448A1 WO 1999001448 A1 WO1999001448 A1 WO 1999001448A1 DK 9800294 W DK9800294 W DK 9800294W WO 9901448 A1 WO9901448 A1 WO 9901448A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid addition
- addition salt
- ethyl
- maleic acid
- methyl
- Prior art date
Links
Classifications
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
Definitions
- the present invention relates to a maleic acid addition salt of 5-(2-ethyl-2/-/-tetrazol- 5-yl)-1 -methyl-1 ,2,3,6-tetrahydropyridine, pharmaceutical compositions containing the acid addition salt and the use thereof for the treatment of diseases or disorders caused by a malfunction of the cholinergic or muscarinic system.
- US patent No. 4,866,077 discloses a series of piperidine and tetrahydropyridine compounds substituted in position 5 with a 1 ,2,3-triazoie or a tetrazole group. These compounds have high affinity to central AcCh receptors, including muscarinic M1 receptors, and are considered useful for the treatment of disorders involving malfunction of the cholinergic system, e.g. Alzheimer's disease, senile dementia, and impaired learning or memory function.
- 5-(2-ethyl-2H-tetrazol-5-yl)-1 -methyl-1 , 2,3,6- tetrahydropyridine may be useful for the treatment of traumatic brain injury (TBI) and psychosis or other schizophreniform diseases (WO97/17074 and co-pending PCT application claiming priority from DK 620/97).
- TBI may be caused by various physical and neurological conditions or diseases such as conditions associated with trauma to the brain or spinal cord e.g. caused by physical forces acting on the scull or spinal column, ischaemia, stroke, arrested breathing, cardiac arrest, cerebral thrombosis or embolism, neurological problems caused by AIDS, cerebral hemorrhage, encephaiomyelitis, hydrocephalus, postoperative events, cerebral infections, concussions, or elevated intracranial pressure.
- conditions associated with trauma to the brain or spinal cord e.g. caused by physical forces acting on the scull or spinal column, ischaemia, stroke, arrested breathing, cardiac arrest, cerebral thrombosis or embolism, neurological problems caused by AIDS, cerebral hemorrhage, encephaiomyelitis, hydrocephalus, postoperative events, cerebral infections, concussions, or elevated intracranial pressure.
- Psychosis means to include all forms of psychoses such as organic psychoses, drug induced psychoses, Alzheimer related psychoses, and psychoses or related conditions associated with other mental disorders, such as paranoid personality disorder, ect.
- schizophrenia and schizophreniform diseases include all types of such disorders, e.g. catatonic, disorganised, paranoid, undifferential and residual schizo- phrenia, and all conditions associated with such diseases, including the positive and negative symptoms thereof.
- the 5-(2-ethyl-2/-/-tetrazol-5-yl)-1 -methyl-1 ,2,3,6-tetrahydropyridine free base is a liquid and as such not suitable for the production of solid pharmaceu- tical preparations, such as tablets or capsules.
- oral administration a solid entity is the preferred and most convenient method for the administration of a pharmaceutical, a solid form of 5-(2-ethyl-2H-tetrazol-5-yl)-1 -methyl-1 , 2,3,6- tetrahydropyridine, suitably a pharmaceutically acceptable salt thereof, which can be mixed with various adjuvants or diluents and formed into tablets or filled in cap- sules, is highly desirable.
- oxalic acid addition salt of 5-(2-ethyl-2/-/-tetrazol-5-yl)-1 -methyl-1 ,2,3,6-tetra- hydropyridine is specifically disclosed in US patent No. 4,866,077.
- oxalic acid addition salts may be particularly useful for crystallization and purification purposes, they are not suitable for the preparation of pharmaceuticals due to the toxicity of oxalic acid.
- a pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-1 -methyl-1 ,2,3,6- tetrahydropyridine, the tartrate, has been described in Moltzen et al., J. Med. C ?e .1994, 37, 4085-4099. Unfortunately, the tartrate is difficult to precipitate and recrystallize in large scale productions. Accordingly, the tartrate salt is not suitable for commercial production of solid pharmaceutical preparations.
- the maleic acid addition salt of 5-(2-ethyl-2H- tetrazol-5-yl)-1 -methyl-1 ,2,3,6-tetrahydropyridine and pharmaceutical compositions comprising said acid addition salt have been provided.
- the maleic acid addition salt according to the invention may be obtained by treatment of 5-(2-ethyl-2H-tetrazol-5-yl)-1 -methyl-1 ,2,3,6-tetrahydropyridine or a salt derivative thereof with maleic acid in an inert solvent, followed by precipitation, isolation and optionally recrystallization by known methods and if desired followed by micronisation of the crystalline product by wet or dry milling or another convenient process, or preparation of particles from a solvent-emulsification process. Precipitation of the maleate salt is carried out in an inert aprotic solvent, preferably tetrahydrofuran (THF).
- THF tetrahydrofuran
- the maleate acid addition salt of the invention may be administered in any suitable way e.g. orally or parenterally, and the compounds may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
- the maleate of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule.
- Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a convenient tabletting machine.
- adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives, etc. may also be used provided that they are compatible with the active ingredients.
- the compound of the invention is most conveniently administered orally in unit dos- age forms such as tablets or capsules, containing the active ingredient in an amount from about 10 ⁇ g/day/kg to 15 mg/day/kg body weight, preferably 25 ⁇ g/day/kg to 10 mg/day/kg and most preferred 4-5- mg/kg/day body weight.
- a suitable daily dose is 500 ⁇ g to 1000 mg/day, preferably 1.0 to 500 mg/day and most preferred 300-400 mg/day.
- the maleate acid addition salt according to the invention is readily soluble in water, alcohol and other polar solvents and may, if desired, be used for the preparation of solutions for injection.
- Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the vehicle, preferably sterile water, adjusting the solution to the desired volume, sterilization of the solution, and filling in suitable am- poules or vials.
- Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, ect.
- the 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1 ,2,3,6-tetrahydropyridine, oxalate starting material can be prepared as described in US patent No. 4,866,077.
- the precipitate was isolated on a nutche filter, and washed with tetrahydrofuran (2 x 2 L).
- the wet filtercake was recrystailized once from tetrahydrofuran (13 L).
- the recrystallized material was isolated on a nutche filter, washed with tetrahydrofuran (5 L), and finally dried in vacuo at 65 °C overnight. Yield 5.0. kg (83%) mono- maleate. M.p. 116 °C.
- Recrvstallisation A reactor was charged with 5-(2-ethyl-2H-tetrazoi-5-yl)-1-methyl- 1 ,2,3,6-tetrahydropyridine, maleate, and tetrahydrofuran. The solution was heated to reflux and then allowed to crystallize (1) . The product was isolated, washed several times with THF, and dried in vacuo.
- the solution may be seeded with 5-(2-ethyl-2H-tetrazol-5-yl)-1- methyl-1 ,2,3,6-tetrahydropyridine, maleate from a previous batch.
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU81020/98A AU735751B2 (en) | 1997-07-01 | 1998-07-01 | 5-(2-ethyl-2H-tetrazol-5-Y1)-1-methyl-1,2,3,6-tetrahydro pyridine maleate |
PL98337184A PL337184A1 (en) | 1997-07-01 | 1998-07-01 | 5-(ethyl-2h-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate |
CA002293324A CA2293324A1 (en) | 1997-07-01 | 1998-07-01 | 5-(2-ethyl-2h-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate |
EA200000081A EA200000081A1 (en) | 1997-07-01 | 1998-07-01 | MALEAT 5- (2-ETHIL-2H-TETRAZOL-5-IL) -1-METHYL-1,2,3,6-TETRAHYDROPYRIDINE |
HU0002876A HUP0002876A2 (en) | 1997-07-01 | 1998-07-01 | 5-(2-ethyl-2h-tetrazol-5-y1)-1-methyl-1,2,3,6-tetrahydropyridine maleate, pharmaceutical composition containing it and its use |
BR9810331-8A BR9810331A (en) | 1997-07-01 | 1998-07-01 | 2-Ethyl-5- (1-methyl-1,2,5,6-tetrahydro-3-pyridyl-2h-tetrazole) maleic acid addition salt; pharmaceutical compositions containing said salt; method for its preparation and use treatment of diseases |
SK1873-99A SK187399A3 (en) | 1997-07-01 | 1998-07-01 | Adition salt of maleate acid and of 5-(2-ethyl-2(h)-tetrazol-5- yl)-1-methyl-1,2,3,6-tetrahydropyridine, preparation method thereof, pharmaceutical composition containing the same and use thereof |
JP50616699A JP2002507215A (en) | 1997-07-01 | 1998-07-01 | 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine maleate |
IL13309398A IL133093A0 (en) | 1997-07-01 | 1998-07-01 | 5-(2-Ethyl-2h-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate |
EP98930655A EP0994869A1 (en) | 1997-07-01 | 1998-07-01 | 5-(2-ethyl-2h-tetrazol-5-y1)-1-methyl-1,2,3,6-tetrahydropyridine maleate |
IS5278A IS5278A (en) | 1997-07-01 | 1999-11-30 | 5- (2-Ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine maleate |
BG103933A BG103933A (en) | 1997-07-01 | 1999-11-30 | 5-(2-ethyl-2h-tetrazol-5-yl)-1-methyl-1,2,3,6- tetrahydropyridine maleate |
NO996580A NO996580L (en) | 1997-07-01 | 1999-12-30 | 5- (2-Ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine maleate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK0781/97 | 1997-07-01 | ||
DK78197 | 1997-07-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999001448A1 true WO1999001448A1 (en) | 1999-01-14 |
Family
ID=8097489
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK1998/000294 WO1999001448A1 (en) | 1997-07-01 | 1998-07-01 | 5-(2-ethyl-2h-tetrazol-5-y1)-1-methyl-1,2,3,6-tetrahydropyridine maleate |
Country Status (25)
Country | Link |
---|---|
EP (1) | EP0994869A1 (en) |
JP (1) | JP2002507215A (en) |
KR (1) | KR20010014297A (en) |
CN (1) | CN1261361A (en) |
AR (1) | AR013096A1 (en) |
AU (1) | AU735751B2 (en) |
BG (1) | BG103933A (en) |
BR (1) | BR9810331A (en) |
CA (1) | CA2293324A1 (en) |
CO (1) | CO4940483A1 (en) |
EA (1) | EA200000081A1 (en) |
HU (1) | HUP0002876A2 (en) |
IL (1) | IL133093A0 (en) |
IS (1) | IS5278A (en) |
JO (1) | JO2031B1 (en) |
MA (1) | MA25138A1 (en) |
NO (1) | NO996580L (en) |
PE (1) | PE116099A1 (en) |
PL (1) | PL337184A1 (en) |
SK (1) | SK187399A3 (en) |
TN (1) | TNSN98120A1 (en) |
TR (1) | TR199903283T2 (en) |
UY (2) | UY25069A1 (en) |
WO (1) | WO1999001448A1 (en) |
ZA (1) | ZA985498B (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4866077A (en) * | 1987-06-24 | 1989-09-12 | H. Lundbeck A/S | 1,2,3-Triazole and tetrazole substituted piperidine or tetrahydropyridine compounds useful as acetylcholine agonists |
WO1997017074A1 (en) * | 1995-11-06 | 1997-05-15 | H. Lundbeck A/S | Treatment of traumatic brain injury |
-
1998
- 1998-06-18 AR ARP980102925A patent/AR013096A1/en not_active Application Discontinuation
- 1998-06-24 ZA ZA985498A patent/ZA985498B/en unknown
- 1998-06-25 PE PE1998000563A patent/PE116099A1/en not_active Application Discontinuation
- 1998-06-25 JO JO19982031A patent/JO2031B1/en active
- 1998-06-26 CO CO98036576A patent/CO4940483A1/en unknown
- 1998-06-29 UY UY25069A patent/UY25069A1/en not_active Application Discontinuation
- 1998-06-30 TN TNTNSN98120A patent/TNSN98120A1/en unknown
- 1998-07-01 SK SK1873-99A patent/SK187399A3/en unknown
- 1998-07-01 EP EP98930655A patent/EP0994869A1/en not_active Withdrawn
- 1998-07-01 KR KR1019997012429A patent/KR20010014297A/en not_active Application Discontinuation
- 1998-07-01 CN CN98806497A patent/CN1261361A/en active Pending
- 1998-07-01 TR TR1999/03283T patent/TR199903283T2/en unknown
- 1998-07-01 CA CA002293324A patent/CA2293324A1/en not_active Abandoned
- 1998-07-01 JP JP50616699A patent/JP2002507215A/en active Pending
- 1998-07-01 MA MA25155A patent/MA25138A1/en unknown
- 1998-07-01 WO PCT/DK1998/000294 patent/WO1999001448A1/en not_active Application Discontinuation
- 1998-07-01 IL IL13309398A patent/IL133093A0/en unknown
- 1998-07-01 AU AU81020/98A patent/AU735751B2/en not_active Ceased
- 1998-07-01 HU HU0002876A patent/HUP0002876A2/en unknown
- 1998-07-01 PL PL98337184A patent/PL337184A1/en unknown
- 1998-07-01 EA EA200000081A patent/EA200000081A1/en unknown
- 1998-07-01 BR BR9810331-8A patent/BR9810331A/en not_active Application Discontinuation
- 1998-09-10 UY UY25177A patent/UY25177A1/en not_active Application Discontinuation
-
1999
- 1999-11-30 IS IS5278A patent/IS5278A/en unknown
- 1999-11-30 BG BG103933A patent/BG103933A/en unknown
- 1999-12-30 NO NO996580A patent/NO996580L/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4866077A (en) * | 1987-06-24 | 1989-09-12 | H. Lundbeck A/S | 1,2,3-Triazole and tetrazole substituted piperidine or tetrahydropyridine compounds useful as acetylcholine agonists |
WO1997017074A1 (en) * | 1995-11-06 | 1997-05-15 | H. Lundbeck A/S | Treatment of traumatic brain injury |
Non-Patent Citations (1)
Title |
---|
J. MED. CHEM., Volume 37, 1994, EJNER K. MOLTZEN et al., "Bioisosteres of Arecoline: 1,2,3,6-Tetrahydro-5-Pyridyl-Substituted and 3-Piperidyl-Substituted Derivatives of Tetrazoles and 1,2,3-Triazoles. Synthesis and Muscarinic Activity", pages 4085-4099. * |
Also Published As
Publication number | Publication date |
---|---|
KR20010014297A (en) | 2001-02-26 |
CN1261361A (en) | 2000-07-26 |
AR013096A1 (en) | 2000-12-13 |
IL133093A0 (en) | 2001-03-19 |
JO2031B1 (en) | 1999-05-15 |
PL337184A1 (en) | 2000-08-14 |
JP2002507215A (en) | 2002-03-05 |
UY25177A1 (en) | 2000-12-29 |
EP0994869A1 (en) | 2000-04-26 |
AU8102098A (en) | 1999-01-25 |
MA25138A1 (en) | 2001-04-02 |
PE116099A1 (en) | 1999-11-23 |
TNSN98120A1 (en) | 2005-03-15 |
IS5278A (en) | 1999-11-30 |
ZA985498B (en) | 1999-01-20 |
EA200000081A1 (en) | 2000-08-28 |
BG103933A (en) | 2000-07-31 |
NO996580D0 (en) | 1999-12-30 |
CA2293324A1 (en) | 1999-01-14 |
AU735751B2 (en) | 2001-07-12 |
CO4940483A1 (en) | 2000-07-24 |
TR199903283T2 (en) | 2000-06-21 |
SK187399A3 (en) | 2000-06-12 |
BR9810331A (en) | 2000-09-05 |
HUP0002876A2 (en) | 2001-06-28 |
UY25069A1 (en) | 1998-12-21 |
NO996580L (en) | 1999-12-30 |
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