CA2293324A1 - 5-(2-ethyl-2h-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate - Google Patents
5-(2-ethyl-2h-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate Download PDFInfo
- Publication number
- CA2293324A1 CA2293324A1 CA002293324A CA2293324A CA2293324A1 CA 2293324 A1 CA2293324 A1 CA 2293324A1 CA 002293324 A CA002293324 A CA 002293324A CA 2293324 A CA2293324 A CA 2293324A CA 2293324 A1 CA2293324 A1 CA 2293324A1
- Authority
- CA
- Canada
- Prior art keywords
- acid addition
- addition salt
- ethyl
- methyl
- maleic acid
- 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.)
- Abandoned
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
Landscapes
- 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
The present invention relates to a maleate acid addition salt of 5-(2-ethyl-2H-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 disorders caused by a malfunction of the acetylcholine (AcCh) or muscarinic system.
Description
5-(2-Ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate The present invention relates to a malefic acid addition salt of 5-(2-ethyl-2H-tetrazol-s 5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, phamnaceutical compositions containing s 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.
Background of the Invention ~o 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 tetrazoie group. These compounds have high affinity to central AcCh receptors, including muscarinic receptors, and are considered useful for the treatment of disorders involving mal-function of the cholinergic system, e.g. Alzheimer's disease, senile dementia, and ~s impaired teaming or memory function.
The structure-activity relationship of these compounds has been described by Moltzen et al., in Med. Chem. 1994, 37, 4085-4099. The compound, 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine having the formula N~
~N~
which is the subject of the present invention, has been reported to be a partial ago-nist at muscarinic M1 receptors and an antagonist at muscarinic M2 and M3 re-ceptors (Subfypes of Muscarinic Receptors, The sixth International Symposium, zs Nov. 9-12, 1994, Fort Lauderdale). Ligands at muscarinic receptors with this phar-macological profile are considered of particular interest for the treatment of Alz-heimer's disease.
CONFIRMATION COPY
Background of the Invention ~o 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 tetrazoie group. These compounds have high affinity to central AcCh receptors, including muscarinic receptors, and are considered useful for the treatment of disorders involving mal-function of the cholinergic system, e.g. Alzheimer's disease, senile dementia, and ~s impaired teaming or memory function.
The structure-activity relationship of these compounds has been described by Moltzen et al., in Med. Chem. 1994, 37, 4085-4099. The compound, 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine having the formula N~
~N~
which is the subject of the present invention, has been reported to be a partial ago-nist at muscarinic M1 receptors and an antagonist at muscarinic M2 and M3 re-ceptors (Subfypes of Muscarinic Receptors, The sixth International Symposium, zs Nov. 9-12, 1994, Fort Lauderdale). Ligands at muscarinic receptors with this phar-macological profile are considered of particular interest for the treatment of Alz-heimer's disease.
CONFIRMATION COPY
Further, it has been demonstrated that 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 (W097117074 and co-pending PCT application claiming priority from DK 620197).
TB1 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 ~o caused by AIDS, cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operative events, cerebral infections, concussions, or elevated intracraniai pressure.
Psychosis means to include all forms of psychoses such as organic psychoses, drug induced psychoses, Alzheimer related psychoses, and psychoses or related ~s conditions associated with other mental disorders, such as paranoid personality disorder, ect.
The terms schizophrenia and schizophreniform diseases include all types of such disorders, e.g. catatonic, disorganised, paranoid, undifferential and residual schizo-Zo phrenia, and all conditions associated with such diseases, including the positive and negative symptoms thereof.
Unfortunately, the 5-(2-ethyl-2H tetrazol-5-yl)-1-methyl-1,2,3,8-tetrahydropyridine free base is a liquid and as such not suitable for the production of solid pharmaceu-2s tical preparations, such as tablets or capsules. As oral administration a solid entity is the preferred and most convenient method for the administration of a pharma ceutical, 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 so sules, is highly desirable.
The oxalic acid addition salt of 5-(2-ethyl-2H-tetrazo!-5-yl)-1-methyl-1,2,3,6-tetra-hydropyridine is specifically disclosed in US patent No. 4,866,077. However, while 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.
s A pham~aceutically 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.
Chem.1994, 37, 4085-4099. Unfortunately, the tartrate is difficult to precipitate and recrystallize in large scale productions. Accordingly, the tartrate salt is not suitable ~o for commercial production of solid pharmaceutical preparations.
Surprisingly, it has now been found that precipitation and recrystallization of the cor-responding malefic acid addition salt proceed smoothly even in large scale.
~s The Invention It is the object of the present invention to provide a solid pharmaceutically accept-able form of 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine suitable for large scale production of solid pharmaceutical entities, e.g. tablets or capsules.
According to the present invention the malefic 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 malefic acid addition salt according to the invention may be obtained by treat-ment of 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine or a salt de-rivative thereof with malefic acid in an inert solvent, followed by precipitation, isola-tion and optionally recrystallization by known methods and if desired followed by micronisation of the crystalline product by wet or dry milling or another convenient 3o process, or preparation of particles from a solvent-emulsification process.
TB1 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 ~o caused by AIDS, cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operative events, cerebral infections, concussions, or elevated intracraniai pressure.
Psychosis means to include all forms of psychoses such as organic psychoses, drug induced psychoses, Alzheimer related psychoses, and psychoses or related ~s conditions associated with other mental disorders, such as paranoid personality disorder, ect.
The terms schizophrenia and schizophreniform diseases include all types of such disorders, e.g. catatonic, disorganised, paranoid, undifferential and residual schizo-Zo phrenia, and all conditions associated with such diseases, including the positive and negative symptoms thereof.
Unfortunately, the 5-(2-ethyl-2H tetrazol-5-yl)-1-methyl-1,2,3,8-tetrahydropyridine free base is a liquid and as such not suitable for the production of solid pharmaceu-2s tical preparations, such as tablets or capsules. As oral administration a solid entity is the preferred and most convenient method for the administration of a pharma ceutical, 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 so sules, is highly desirable.
The oxalic acid addition salt of 5-(2-ethyl-2H-tetrazo!-5-yl)-1-methyl-1,2,3,6-tetra-hydropyridine is specifically disclosed in US patent No. 4,866,077. However, while 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.
s A pham~aceutically 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.
Chem.1994, 37, 4085-4099. Unfortunately, the tartrate is difficult to precipitate and recrystallize in large scale productions. Accordingly, the tartrate salt is not suitable ~o for commercial production of solid pharmaceutical preparations.
Surprisingly, it has now been found that precipitation and recrystallization of the cor-responding malefic acid addition salt proceed smoothly even in large scale.
~s The Invention It is the object of the present invention to provide a solid pharmaceutically accept-able form of 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine suitable for large scale production of solid pharmaceutical entities, e.g. tablets or capsules.
According to the present invention the malefic 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 malefic acid addition salt according to the invention may be obtained by treat-ment of 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine or a salt de-rivative thereof with malefic acid in an inert solvent, followed by precipitation, isola-tion and optionally recrystallization by known methods and if desired followed by micronisation of the crystalline product by wet or dry milling or another convenient 3o 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).
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 sui-table form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. Preferably, and in accordance with the purpose of the present invention, the maleate of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule.
,o Methods for the preparation of solid pharmaceutical preparations are well known in the art. Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants andlor diluents and subsequently compressing the mixture in a conve-nient tabletting machine. Examples of adjuvants or diluents comprise: corn starch, ~5 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-2o age forms such as tablets or capsules, containing the active ingredient in an amount from about 10 wgldaylkg to 15 mgldaylkg body weight, preferably 25 p,gldaylkg to 10 mg/daylkg and most preferred 4-5- mg/kglday body weight. Ac-cordingly, a suitable daily dose is 500 p,g to 1000 mglday, preferably 1.0 to 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 so possible additives in a part of the vehicle, preferably sterile water, adjusting the so-lution to the desired volume, sterilization of the solution, and filling in suitable am-z poules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, ect.
The invention will be illustrated in the following examples. The examples may not s be construed as limiting.
The 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,fi-tetrahydropyridine, oxalate starting material can be prepared as described in US patent No. 4,86fi,077.
Example 1 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, maleate 5-(2-ethyl-2H tetrazol-5-y1~1-methyl-1,2,3,6-tetrahydropyridine, oxalate {5.6 kg) was suspended in demineralized water (22 L). Ethyl acetate (17 L) was added, and a cooled solution (15-20 °C) of potassium hydroxide (2.8 kg) in demineralized water (12.5 L) was added with stirring and cooling. pH was adjusted to 10 by adding aqueous potassium hydroxide. The aqueous layer was further extracted with ethyl ,o acetate (2 x 11 L). The combined organic extracts were dried with sodium sulphate (3.8 kg) and evaporated in vacuo until a pot temperature of 75-80 °C
was reached.
The residue was dissolved in tetrahydrofuran (11 L), and a solution of malefic acid (2.4 kg) in tetrahydrofuran (11 L) was added with stirring. The solution was cooled to approximately 15 °C and stirred for a minimum of 1 hour.
The precipitate was isolated on a nutche filter, and washed with tetrahydrofuran (2 x 2 L). The wet filtercake was recrystallized 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 5Ø kg (83%) mono-2o maleate. M.p. 116 °C.
Example 2 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, maleate Liberation of the free base: A nitrogen purged reactor was charged with 62-64 kg 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, oxalate, water, and toluene. The mixture was stirred and cooled to below 10 °C while adding potassium hydroxide pellets dissolved in water until pH > 12 was achieved. The layers were ao separated, the aqueous layer re-extracted with toluene and subsequently dis-carded.
The combined organic phases were washed with water. Toluene was distilled off in vacuo at a temperature of not more than 50 °C.
Precipitation: The residue was re-dissolved by adding THF and malefic acid (26.5-27.5 kg) while heating to reflux. The temperature of the reaction mixture was ad-justed to approx. 50 °C. The solution was left with slow agitation and voluntary cooling for crystallization~'~. The slung was cooled to below 20 °C and isolated. The product was washed with tetrahydrofuran and dried in vacuo yielding 5-(2-ethyl-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, mono-maleate.
Recrystallisation: A reactor was charged with 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, maleate, and tetrahydrofuran. The solution was heated to reflux and then allowed to crystallize ~'~. The product was isolated, washed sev-eral times with THF, and dried in vacuo.
!5 ~'~ If necessary, the solution may be seeded with 5-(2-ethyl-2H-tetrazol-5-yl)-methyl-1,2,3,6-tetrahydropyridine, maleate from a previous batch.
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 sui-table form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. Preferably, and in accordance with the purpose of the present invention, the maleate of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule.
,o Methods for the preparation of solid pharmaceutical preparations are well known in the art. Tablets may thus be prepared by mixing the active ingredients with ordinary adjuvants andlor diluents and subsequently compressing the mixture in a conve-nient tabletting machine. Examples of adjuvants or diluents comprise: corn starch, ~5 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-2o age forms such as tablets or capsules, containing the active ingredient in an amount from about 10 wgldaylkg to 15 mgldaylkg body weight, preferably 25 p,gldaylkg to 10 mg/daylkg and most preferred 4-5- mg/kglday body weight. Ac-cordingly, a suitable daily dose is 500 p,g to 1000 mglday, preferably 1.0 to 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 so possible additives in a part of the vehicle, preferably sterile water, adjusting the so-lution to the desired volume, sterilization of the solution, and filling in suitable am-z poules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, ect.
The invention will be illustrated in the following examples. The examples may not s be construed as limiting.
The 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,fi-tetrahydropyridine, oxalate starting material can be prepared as described in US patent No. 4,86fi,077.
Example 1 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, maleate 5-(2-ethyl-2H tetrazol-5-y1~1-methyl-1,2,3,6-tetrahydropyridine, oxalate {5.6 kg) was suspended in demineralized water (22 L). Ethyl acetate (17 L) was added, and a cooled solution (15-20 °C) of potassium hydroxide (2.8 kg) in demineralized water (12.5 L) was added with stirring and cooling. pH was adjusted to 10 by adding aqueous potassium hydroxide. The aqueous layer was further extracted with ethyl ,o acetate (2 x 11 L). The combined organic extracts were dried with sodium sulphate (3.8 kg) and evaporated in vacuo until a pot temperature of 75-80 °C
was reached.
The residue was dissolved in tetrahydrofuran (11 L), and a solution of malefic acid (2.4 kg) in tetrahydrofuran (11 L) was added with stirring. The solution was cooled to approximately 15 °C and stirred for a minimum of 1 hour.
The precipitate was isolated on a nutche filter, and washed with tetrahydrofuran (2 x 2 L). The wet filtercake was recrystallized 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 5Ø kg (83%) mono-2o maleate. M.p. 116 °C.
Example 2 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, maleate Liberation of the free base: A nitrogen purged reactor was charged with 62-64 kg 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, oxalate, water, and toluene. The mixture was stirred and cooled to below 10 °C while adding potassium hydroxide pellets dissolved in water until pH > 12 was achieved. The layers were ao separated, the aqueous layer re-extracted with toluene and subsequently dis-carded.
The combined organic phases were washed with water. Toluene was distilled off in vacuo at a temperature of not more than 50 °C.
Precipitation: The residue was re-dissolved by adding THF and malefic acid (26.5-27.5 kg) while heating to reflux. The temperature of the reaction mixture was ad-justed to approx. 50 °C. The solution was left with slow agitation and voluntary cooling for crystallization~'~. The slung was cooled to below 20 °C and isolated. The product was washed with tetrahydrofuran and dried in vacuo yielding 5-(2-ethyl-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, mono-maleate.
Recrystallisation: A reactor was charged with 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine, maleate, and tetrahydrofuran. The solution was heated to reflux and then allowed to crystallize ~'~. The product was isolated, washed sev-eral times with THF, and dried in vacuo.
!5 ~'~ If necessary, the solution may be seeded with 5-(2-ethyl-2H-tetrazol-5-yl)-methyl-1,2,3,6-tetrahydropyridine, maleate from a previous batch.
Claims (8)
1. A maleic acid addition salt of 2-ethyl-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole.
2. The maleic acid addition salt according to claim 1 which is the mono-maleic acid addition salt.
3. A pharmaceutical composition comprising a maleic acid addition salt according to claims 1 to 2 together with at least one pharmaceutically acceptable carrier or diluent.
4. A method for the treatment of a disorder or disease caused by malfunction of the acetylcholine (AcCh) or muscarinic system, comprising administering a therapeutically effective amount of a maleic acid addition salt according to claims 1 to 2 to a subject suffering from such a disorder.
5. The method according to claim 3 wherein Alzheimer's disease, traumatic brain injury, or psychotic disorders are treated.
6. The use of a maleic acid addition salt according to claims 1 to 2 for the preparation of a pharmaceutical composition for the treatment of a disorder or disease caused by malfunction of the acetylcholine (AcCh) or muscarinic system.
7. The use according to claim 5 wherein the disease or disorder is Alzheimer's disease, traumatic brain injury, or psychotic disorders.
8. A method for the preparation of maleic acid addition salt according to claims 1 to 2 characterized in that the acid addition salt is precipitated from a solution of 2-ethyl-5-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-2H-tetrazole, THF and maleic acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK78197 | 1997-07-01 | ||
| DK0781/97 | 1997-07-01 | ||
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2293324A1 true CA2293324A1 (en) | 1999-01-14 |
Family
ID=8097489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002293324A Abandoned CA2293324A1 (en) | 1997-07-01 | 1998-07-01 | 5-(2-ethyl-2h-tetrazol-5-yl)-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) | NO996580D0 (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) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8714789D0 (en) * | 1987-06-24 | 1987-07-29 | Lundbeck & Co As H | Heterocyclic compounds |
| HUP9901051A2 (en) * | 1995-11-06 | 2000-03-28 | H. Lundbeck A/S | Use of 5-(2-ethyl-2h-tetrazol-5-il)-1,2,3,6-tetrahydro-1-methyl-pyridine for the manufacture of pharmaceutical preparations for the 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 JO JO19982031A patent/JO2031B1/en active
- 1998-06-25 PE PE1998000563A patent/PE116099A1/en not_active Application Discontinuation
- 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 IL IL13309398A patent/IL133093A0/en unknown
- 1998-07-01 JP JP50616699A patent/JP2002507215A/en active Pending
- 1998-07-01 SK SK1873-99A patent/SK187399A3/en unknown
- 1998-07-01 CN CN98806497A patent/CN1261361A/en active Pending
- 1998-07-01 EP EP98930655A patent/EP0994869A1/en not_active Withdrawn
- 1998-07-01 MA MA25155A patent/MA25138A1/en unknown
- 1998-07-01 CA CA002293324A patent/CA2293324A1/en not_active Abandoned
- 1998-07-01 TR TR1999/03283T patent/TR199903283T2/en unknown
- 1998-07-01 PL PL98337184A patent/PL337184A1/en unknown
- 1998-07-01 AU AU81020/98A patent/AU735751B2/en not_active Ceased
- 1998-07-01 EA EA200000081A patent/EA200000081A1/en unknown
- 1998-07-01 KR KR1019997012429A patent/KR20010014297A/en not_active Application Discontinuation
- 1998-07-01 WO PCT/DK1998/000294 patent/WO1999001448A1/en not_active Application Discontinuation
- 1998-07-01 BR BR9810331-8A patent/BR9810331A/en not_active Application Discontinuation
- 1998-07-01 HU HU0002876A patent/HUP0002876A2/en unknown
- 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/NO996580D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002507215A (en) | 2002-03-05 |
| IS5278A (en) | 1999-11-30 |
| PE116099A1 (en) | 1999-11-23 |
| UY25069A1 (en) | 1998-12-21 |
| SK187399A3 (en) | 2000-06-12 |
| TR199903283T2 (en) | 2000-06-21 |
| CO4940483A1 (en) | 2000-07-24 |
| AU8102098A (en) | 1999-01-25 |
| EP0994869A1 (en) | 2000-04-26 |
| AR013096A1 (en) | 2000-12-13 |
| NO996580L (en) | 1999-12-30 |
| TNSN98120A1 (en) | 2005-03-15 |
| ZA985498B (en) | 1999-01-20 |
| NO996580D0 (en) | 1999-12-30 |
| IL133093A0 (en) | 2001-03-19 |
| CN1261361A (en) | 2000-07-26 |
| EA200000081A1 (en) | 2000-08-28 |
| BR9810331A (en) | 2000-09-05 |
| JO2031B1 (en) | 1999-05-15 |
| WO1999001448A1 (en) | 1999-01-14 |
| KR20010014297A (en) | 2001-02-26 |
| AU735751B2 (en) | 2001-07-12 |
| MA25138A1 (en) | 2001-04-02 |
| UY25177A1 (en) | 2000-12-29 |
| PL337184A1 (en) | 2000-08-14 |
| BG103933A (en) | 2000-07-31 |
| HUP0002876A2 (en) | 2001-06-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106255679B (en) | As NAThe heterocyclic compound and application thereof of V channel inhibitor | |
| DE69524114T2 (en) | NAPHTHYRIDINONDERIVATE | |
| JPH09500875A (en) | 4-Phenyl-4-phenylpropyl (ethyl) -piperidine as tachykinin antagonist | |
| WO2002010172A1 (en) | Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents | |
| EP0610793A1 (en) | Tetracyclic morpholine derivatives and their use or analgesics | |
| TW201102385A (en) | Substituted triazolopyridines and analogs thereof | |
| DE69111816T4 (en) | INDOLEDERIVATIVES AND THEIR USE AS A SEROTONIN ANTAGONISTE. | |
| JPH054983A (en) | Isoquinolinone derivative, its production and 5-ht3 receptor antagonist containing the derivative as active component | |
| US4891376A (en) | 1-((2-Pyrimidinyl)aminoalkyl)piperidines, their preparation and their application in therapy | |
| JPH06510537A (en) | 5-HT4 receptor antagonist | |
| JP2022547617A (en) | IL-17A modulators and uses thereof | |
| JP7301209B2 (en) | Process and intermediates for the large-scale preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, and preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate | |
| TW202128642A (en) | Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (dlk) kinase for the treatment of disease | |
| MXPA04010313A (en) | Polymorph of acid 4-[2- [4-[1-(2- ethoxyethyl)- 1h- benzimidazole- 2-il]-1 -piperidinyl] ethyl]- alpha, alpha- dimethyl- benzeneacetic. | |
| WO1991001979A1 (en) | New aminopiperazine derivatives | |
| MXPA03005888A (en) | Amlodipine free base. | |
| JPH05506249A (en) | Bisbenzocycloheptapiperidylidene, piperidine and piperazine compounds, compositions and uses | |
| WO1989009767A1 (en) | Carbamoyl-2-pyrrolidinone compounds | |
| CA2164296C (en) | Heterocyclic chemistry | |
| CN101243074A (en) | Heterocyclic compounds | |
| AU735751B2 (en) | 5-(2-ethyl-2H-tetrazol-5-Y1)-1-methyl-1,2,3,6-tetrahydro pyridine maleate | |
| EA009460B1 (en) | Triazole compounds useful in therapy | |
| CN102770431A (en) | [4[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(1H-pyrrolo-pyridin-yl)-methanones and synthesis thereof | |
| DE69515498T2 (en) | NAPHTHYRIDINE DERIVATIVES | |
| MXPA03005884A (en) | Amlodipine hemimaleate. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |