NO179791B - Analogous Process for Preparation of Therapeutically Active 1,2,5,6-Tetrahydropyridine Compounds - Google Patents

Description

The present invention relates to a preparation of therapeutically active 1,2,5,6-tetrahydropyridine compounds. The new compounds are useful as stimulants for the cognitive function of the forebrain and hippocampus in mammals, and especially in the treatment of Alzheimer's disease.

In the generally improved health situation in the Western world, age-related diseases are much more common now than in the past, and will probably become even more common in the future.

One of the age-related symptoms is a reduction in cognitive functions. This symptom is particularly pronounced in the pathophysiological disease known as Alzheimer's disease. This disease is combined with, and also very likely caused by, an up to 90% degeneration of the muscarinic cholinergic neurons in the nucleus basalis, which is part of the substantia innominata. These neurons project to the frontal cortex and the hippocampus, and they have a generally stimulating effect on the cognitive functions of the forebrain, as well as the hippocampus, namely learning, association, consolidation and cognition.

It is a characteristic of Alzheimer's disease that although the cholinergic neurons degenerate, the postsynaptic muscarinic receptors still exist in the forebrain and hippocampus. Muscarinic cholinergic agonists are therefore useful in the treatment of Alzheimer's disease and for improving the cognitive functions of elderly people.

It is well known that arecoline (methyl-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is such a cholinergic agonist.

However, Arecolin has a very short biological half-life and a small separation between central and peripheral muscarinic effects. Also, arecoline is a rather toxic compound.

The new compounds produced according to the invention have the general formula I:

where

R<1> is H or C 1 -alkyl,

where R' is C4-8 cycloalkyl or methoxybenzyl, and R4 is H, C1-alkyl or Cl,

or pharmaceutically acceptable salts thereof.

Examples of such salts include inorganic and organic acid addition salts, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts. ■ -

The compounds are produced according to the invention by an analogous method which is characterized in that a reactive derivative of a compound of formula II

where R<1> and R4 have the meanings defined above, is reacted with a compound of formula III

where R' has the meaning defined above.

The pharmacological properties of the compounds prepared according to the invention can be illustrated by determining their ability to inhibit the specific binding of <3>H-QNB (3H-quinuclidinyl benzilate) by 50%. The inhibitory effect of a substance after 3H-QNB binding to brain membranes reflects the substance's affinity for muscarinic acetylcholine receptors.

(Yamamura, H.I. and Snyder, S.H., Proe. Nati. Acad. Sei, 71, 1725-29 (1979). The test is performed as follows:

Freshly removed whole forebrains from male Wistar rats (200-250 g) are homogenized using an Ultra-Turrax homogenizer (5-10 seconds) in volumes with 0.32 M sucrose. The homogenate is centrifuged at 4300 x g for 5 minutes. The pellet is discarded and the supernatant is centrifuged at 40,000 x g for 15 minutes. The final pellet is rehomogenized in 15 mM KI^PO^, pH 7.1 (1000 ml per g of original tissue), and this crude preparation of membrane is used for binding analyses. To 2.5 ml of tissue suspension, add 25 µl test solution<*> and 25 µl <3>H-QNB (1 nM final concentration). Samples are mixed thoroughly and incubated at 37°C for 20 minutes. After incubation, the samples are poured directly onto GF/C glass fiber filters under suction and immediately washed twice with 10 ml of buffer at 0°C. Non-specific binding is determined in duplicate using atropine (1 µg/ml, final concentration) as test substance. The amounts of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding. ;<*> Test compound is dissolved in 10 ml of 96% ethanol (if necessary, acidified with 25 µl IN HC1 and heated on a steam bath for less than 5 minutes) at a concentration of 0.22 mg/ml. Three dilutions are made in 48% ethanol (1.1 µg/ml, 11 µg/ml and 110 µg/ml). Concentrations of 10, 100 and 1000 ng/ml (final concentration) are added to the duplicate analyses. 25 - 75% inhibition of specific binding must be achieved before calculation of IC5Q.

The test value will be indicated as IC50 (the concentration (ug/ml) of the test substance that inhibits the specific binding of <3>H-QNB by 50%).

where C is specific binding in control analyzes and C is the specific binding in the test analysis (the calculation assumes normal mass action interaction).

The table below contains comparable biological data for inhibition of the specific binding of <3>H-QNB. The comparison is made for the structurally most closely related compounds produced according to the present invention and according to the countermeasure. It appears from the table that the compounds prepared according to the present invention inhibit the specific binding of <3>H-QNB by at least a factor of 2 stronger than the structurally most closely related compounds prepared according to Norwegian patent no. 169439. This means that the compounds prepared according to the invention binds by at least a factor of 2 stronger to the muscarinic receptors compared to the compounds produced according to Norwegian patent no. 169439.

The compounds produced according to the invention can, together with a common adjuvant, a common carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, be placed in the form of pharmaceutical preparations and single doses thereof, and in such form can be used as solid substances, as tablets or filled capsules or liquids, such as solutions, suspensions, emulsions, elixirs or capsules filled with such, all for oral use, in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical preparations and single-dose forms thereof may comprise common ingredients in usual amounts, with or without additional active compounds or principles, and such single-dose forms may contain any suitable effective muscarinic cholinergic agonist amount of the active ingredient in accordance with the intended daily intake. dosage range to be used. Tablets containing 10 mg of the active ingredient or, more generally, 1 - 100 mg, per tablet are therefore suitable representative end forms.

The compounds produced according to the invention can thus be used for the production of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals, including humans, in accordance with conventional methods of galenic pharmacy.

Common excipients are those pharmaceutically acceptable organic or inorganic carriers which are suitable for parenteral or enteral application and which do not react with the active compounds in a deleterious manner.

Examples of such carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, penta-erythritol fatty acid esters, hydroxymethyl cellulose and polyvinyl pyrrolidone.

The pharmaceutical preparations can, if desired, be sterilized and mixed with auxiliaries, emulsifiers, salt to affect osmotic pressure, buffers and/or dyes and the like which do not react in a harmful way with the active compounds.

For parenteral application, injectable solutions or suspensions are particularly preferred, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Ampoules are suitable single-dose forms.

Tablets, dragées or capsules with talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are particularly suitable for oral application.

A syrup, elixir or the like can be used in cases where a sweetened carrier can be used.

In general, the compounds prepared according to the invention are dispensed in a unit dose form comprising 1 - 100 mg in a pharmaceutically acceptable carrier per end.

The dosage of the compounds prepared according to the invention is 1-100 mg/day, preferably 10-70 mg/day, when administered to patients, e.g. people, as a medicine.

A typical tablet that can be prepared using conventional tableting techniques contains:

Due to the strong muscarinic cholinergic receptor agonist activity, the compounds produced according to the invention are very useful for treating symptoms associated with a reduction in the cognitive functions of the brain in mammals when they are administered in an amount that effectively stimulates the cognitive functions of the forebrain and hippocampus. The important stimulating activity of the compounds produced according to the invention includes both activity against the pathophysiological disease, Alzheimer's disease, as well as against normal degeneration of brain function. The compounds produced according to the invention can therefore be administered to an individual, e.g. a living animal body, including a human, in need of stimulation of the cognitive functions of the forebrain and hippocampus, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride or sulfate, in all cases prepared by conventional or conventional means, e.g. evaporating to dryness the free base in solution with the acid), usually side by side with, simultaneously with or together with a pharmaceutically acceptable carrier or diluent, particularly and preferably in the form of a pharmaceutical preparation thereof, either by the oral, rectal or parenteral (including subcutaneous) route, in an effective forebrain and hippocampal stimulating amount, and in all cases in an amount that effectively improves cognitive function in mammals due to their muscarinic cholinergic receptor agonistic activity . Suitable dose ranges are 1 - 100 mg daily, 10 - 100 mg daily and especially 30 - 70 mg daily, as usual depending on the exact route of administration, the form of administration used, the indication for which the administration is directed, in the individual involved and the body weight of the individual involved, and the preference and experience of the attending physician or veterinarian.

The invention will be described in more detail below with reference to the following examples:

Example 1

A) 3-(3-cyclobutyl-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridine oxalate

To a solution of matriumethoxyide (prepared from 34 mg (1.48 mmol) sodium, 20 ml distilled ethanol and 4 g molecular sieves) was added 169 mg (1.48 mmol) cyclo-butanecarboxamidoxime. The mixture was stirred at room temperature for 10 minutes and 175 mg (0.74 mmol) arecoline hydrobromide was added. The reaction mixture was stirred at 80°C for 18 hours, filtered and evaporated. 10 ml of water was added to the residue and the solution was extracted with 3 x 30 ml of ether. The combined ether phases were dried and evaporated, whereby the impure product was obtained as an oil. Crystallization as the oxalate salt from absolute ethanol gave the title compound in a yield of 60 mg. Sm.p. 148-149°C.

In exactly the same way, the following compounds were prepared:

B) 3-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridine oxalate, m.p. 132-133°C.

C) 3-(3-(2-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridine oxalate, m.p. 76-77°C.

Using norarecoline instead of arecoline, the following compounds were prepared in exactly the same manner as described above:

D) 3-(3-cyclobutyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-pyridine-oxalate, m.p. 202-205°C.

E) 3-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro-pyridine-oxalate, m.p. 152-158°C.

Example 2

A) 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1,5-dimethyl-1. 2, 5, 6- tetrahydropyridine oxalate

54.4 mg (2.37 mmol) of sodium was dissolved in 10 ml of absolute ethanol. 1 g of molecular sieves (type 4A) and 236 mg (2.37 mmol) of cyclopropanylcarboxamidoxime were added, and the resulting mixture was stirred vigorously for 15 minutes before the addition of 200 mg (1.18 mmol) of 1,4-dimethyl -3-methoxycarbonyl-1,2,5,6-tetrahydropyridine oxalate. The reaction mixture was heated at 80°C for 18 hours. The solution was then filtered from the molecular sieves and the solvent removed under vacuum. 40 ml of ether was added to the residue followed by 15 ml of water, and the organic phase was separated. The aqueous phase was extracted with 3 x 40 ml of ether and the combined ether phases were dried (Na 2 SO 4 ) and evaporated to give the title oxadiazole as an oil. The product was further purified as the oxalate salt. Sm.p. 152-153°C.

B) In exactly the same way the following compound was prepared: 3-(3-butyl-1,2,4-oxadiazol-5-yl)-1,4-dimethyl-1,2,5,6-tetrahydropyridine oxalate, sm .p. 147-148°C.

Claims (1)

Analogous process for the preparation of therapeutically active 1,2,5,6-tetrahydropyridine compounds of the general formula I where R<1> is H or C 1 -alkyl, where R' is C4-8-cycloalkyl or methoxybenzyl, and R4 is H, C1-8-alkyl or Cl, or pharmaceutically acceptable salts thereof, characterized in that a reactive derivative of a compound of formula II where R<1> and R<4> have the meanings defined above, is reacted with a compound of formula III where R' has the meaning defined above.