SK187399A3 - 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 - Google Patents

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

Maleic acid addition salt of 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine, process for its preparation, pharmaceutical composition containing it and its use

Technical field

The present invention relates to a maleic acid addition salt of 5- (2-ethyl-2H-tetrazol-5-yl) 1-methyl-1,2,3,6-tetrahydropyridine, to pharmaceutical compositions containing said addition salt, and to its use in the treatment of diseases or disorders caused by malfunctioning of the choline or muscarinic system.

BACKGROUND OF THE INVENTION

U.S. Patent 4,866,077 discloses a series of piperidine and tetrahydropyridine compounds substituted with a 1,2,3-triazole or tetrazole group at the 5-position. These compounds have a high affinity for central AcCh receptors, including muscarinic A1 receptors, and are considered useful in the treatment of disorders caused by choline system malfunction, such as treatment of Alzheimer's disease, senile dementia and impaired learning ability and impaired memory ability.

The structure and properties of these compounds have been described by Molten et al., In Med. Chem. 37. 4085-4099 (1994). The 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine compound having the formula and object of the present invention is said to be a partial muscarinic M1 agonist and the muscarinic M2 and M3 receptor antagonist (Subtypes of Muscarinic Receptor, The Sixth International Symposium, 9-12).

-2 November 1994, Fort Lauderdale). Ligands of muscarinic receptors with this pharmacological profile pay particular attention to the treatment of Alzheimer's disease.

Furthermore, it has been shown that 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine may be useful in the treatment of traumatic brain injury (TBI) and psychoses , or other schizophrenia diseases (WO97 / 17 074 and the dependent PCT application claiming priority of DK 620/97).

TBI can be caused by a variety of physical and neurological events or diseases, such as conditions associated with brain or spinal cord trauma, for example, by physical spinal forces, ischemia, defeat, respiratory arrest, cardiac arrest, cerebral thrombosis or embolism, neurologic AIDS, cerebral hemorrhage, encephalomyelitis, hydrocephalitis, post-operative events, cerebral infections, concussions, or increased intracranial pressure.

The term psychosis includes all forms of psychosis such as organic psychoses, drug-induced psychoses, Alzheimer's related psychoses and psychoses or related conditions associated with other mental disorders such as paranoid personality disorder and the like.

The term schizophrenia and schizophrenia diseases encompasses all types of these diseases, such as catatonic, paranoid, undifferentiated and residual schizophrenia, and all conditions associated with these diseases, including their positive and negative symptoms.

However, said compound 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine is a liquid in the free base form and is not suitable as such

Also solid pharmaceutical preparations such as tablets or capsules. For oral administration, the use of solid doses is preferred as the most convenient way of administering pharmaceuticals; therefore, the solid form of 5- (2-ethyl-2/7-tetrazole-

5-yl) -1-methyl-1,2,3,6-tetrahydropyridine, suitably in the form of a pharmaceutically acceptable salt thereof, which could be mixed with various excipients and formulated into tablets or filled into capsules.

Oxalic acid 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine addition salt is specifically disclosed in U.S. Patent 4,866,077.

The oxalic acid addition salt may be very suitable in terms of crystallization and purification process, but is not suitable for the preparation of pharmaceutical preparations for the toxic properties of said acid.

The pharmaceutically acceptable salt of 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine tartrate is described by Moltzen et al. J. Med. Chem. 37, 4085-4099 (1994). However, tartrate is difficult to precipitate and recrystallize in large scale production. Accordingly, the tartaric acid salt is not suitable for industrial production of solid pharmaceutical preparations.

Unexpectedly, it has now been found that the maleic acid addition salt conveniently precipitates and recrystallizes in bulk.

SUMMARY OF THE INVENTION

The present invention provides a solid, pharmaceutically acceptable form of 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine, suitable for the industrial manufacture of solid pharmaceutical preparations, for example tablets or capsules.

The invention includes a maleic acid addition salt of said compound, and further pharmaceutical compositions comprising said addition salt.

The maleic acid addition salt of the present invention can be prepared by treating 5- (2-ethyl-2/7-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine or its maleic acid salt in an inert solvent; followed by precipitation, isolation and optionally recrystallization by known methods and, if desired, micronization of the crystalline product; the precipitation of the maleic acid salt is carried out in an inert aprotic solvent, preferably tetrahydrofuran (THF).

The maleic acid addition salt of the invention may be administered by any of the conventional methods, for example, orally or parenterally; compositions suitable for administration may be in the form of tablets, capsules, powders, syrups, or solutions or dispersions for injection. The maleic acid salt of the invention is preferably in accordance with the purpose of the invention administered in the form of a solid pharmaceutical preparation, suitably as a tablet or capsule.

Methods for preparing solid pharmaceutical preparations are well known in the art. Tablets may be prepared by mixing the active ingredients with the usual ingredients,

By auxiliary substances and / or carriers, followed by compression of the mixture in conventional tabletting machines. Examples of additives or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, gums and the like. Any other ingredient or excipient such as coloring agents, flavors, preservatives and the like may also be used, provided that they are compatible with the active ingredients of the formulation.

The compound of the invention is most conveniently administered orally in unit dosage form such as tablets or capsules containing the active ingredient in an amount of from about 10 pg / day and kg to 15 mg / day and kg body weight, preferably 25 pg / day and kg to 10 mg / day and kg, most preferably 4-5 mg / day and kg of body weight. Accordingly, a suitable daily dose is 500 µg to 1000 mg / day, preferably 1.0 to 500 mg / day, and most preferably 300 to 400 mg / day.

The maleic acid addition salt of the present invention is well soluble in water, alcohol and other polar solvents and, if desired, can be used to prepare injectable solutions.

Injectable solutions may be prepared by dissolving the active ingredient and possible ingredients in a portion of the solvent, preferably sterile water, adjusting the solution to the required volume, sterilizing the solution, and filling into suitable ampoules or vials. Any suitable excipients commonly used in the art, such as, for example, agents for adjusting the osmotic pressure, preservatives, antioxidants, and the like, can be used in the injectable solutions.

The invention is further illustrated by the following examples. The examples are not to be construed as limiting the scope of the invention.

The starting material, 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine oxalate, may be prepared as disclosed in U.S. Patent 4,866,077.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine

5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine oxalate (5.6 kg) was dispersed in demineralized water (22 liters). Ethyl acetate (17 liters) and a cooled solution (15-20 ° C) of potassium hydroxide (2.8 kg) in demineralized water (12.5 liters) were added; during mixing the batch was stirred and cooled. The pH was adjusted to 10 by addition of aqueous potassium hydroxide solution. The aqueous layer was further extracted with ethyl acetate (2 x 11 L). The combined organic extracts were dried over sodium sulfate (3.8 kg) and evaporated in vacuo to a boiling point of 75-80 ° C. The residue was dissolved in tetrahydrofuran (11 liters) and a solution of maleic acid (2.4 kg) in tetrahydrofuran (11 liters) was added with stirring. The solution was cooled to about 15 ° C and stirred for at least an hour.

The precipitate was collected by suction filtration, washed with tetrahydrofuran (2 x 2 L). The wet cake was recrystallized once from tetrahydrofuran (13 L). The recrystallized material was isolated by suction on a filter, washed with tetrahydrofuran (5 L) and finally dried under vacuum at 65 ° C overnight. The product yield was 5.0 kg (83% of theory) of the monomaleate. Mp 116 ° C.

Example 2

5- (2-ethyl-2 / - / - tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine

Unleashing a free principle

62-64 kg of 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2 _L- 3,6-tetrahydropyridine oxalate, water and toluene were charged to a nitrogen bubbling reactor. The mixture was stirred and cooled to below 10 ° C; Upon cooling, potassium hydroxide pellets dissolved in water were added until pH > 12. The layers were separated, the aqueous layer re-extracted with toluene and poured out after extraction. The combined organic layers were washed with water. Toluene was distilled off under vacuum at a temperature not higher than 50 ° C.

precipitation

The toluene distillation residue was redissolved by the addition of THF and maleic acid (26.5 to 27.5 kg) by heating to reflux.

The temperature of the reaction mixture was then adjusted to about 50 ° C. The solution was allowed to cool and slowly crystallize with slow stirring. The solution with the crystalline fraction was cooled to below 20 ° C and the crystalline fraction was separated. The product was washed with tetrahydrofuran and dried under vacuum to give 5- (2-ethyl-2/7-tetrazole-

5-yl) -1-methyl-1,2,3,6-tetrahydropyridine.

recrystallization

Prepared 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine maleate and tetrahydrofuran were charged to the reactor. The solution was heated to reflux and then allowed to cool to crystallize. The product was isolated, washed several times with tetrahydrofuran and dried under vacuum.

Note * If required, the solution can be seeded with germs of 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine maleate from a previous batch.

Claims (8)

PATENT CLAIMS Maleic acid addition salt of 5- (2-ethyl-2H-tetrazol-5-yl) -1-methyl-1,2,3,6-tetrahydropyridine. The maleic acid addition salt of claim 1, wherein the addition salt is monomaleate. ' A process for the preparation of a maleic acid addition salt according to claims 1 to 2, characterized in that the acid addition salt is precipitated from a solution of 5- (2-ethyl-2/7-tetrazol-5-yl) -1-methyl-1. 2 _{L of} 3,6-tetrahydropyridine, THF and maleic acid. A pharmaceutical composition comprising the maleic acid addition salt of claims 1 to 2, together with at least one pharmaceutically acceptable carrier or diluent. The maleic acid addition salt of claims 1 to 2 for use in the treatment of a disorder or disease caused by malfunction of the acetylcholine (AcCh) or muscarinic system. ^ς The maleic acid addition salt of claim 3, wherein the disease or _r disorder is Alzheimer's disease, traumatic brain involvement, or psychotic disorders. 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. The use according to claim 5, wherein the disease or disorder is Alzheimer's disease, traumatic brain involvement, or psychotic disorders.