CS215065B2 - Method of making the derivatives of the oxadiazolotetrahydrochinoline - Google Patents

Abstract

Way production derivatives oxadiazolo- tetrahydroisoohinoline, general formula AND or II and jejioh pharmaceutically usable addition salts with acids, characterized by se team. that se diazotuje 2-acetyl-8 (7) ami- no-7 (8) -chlorine- 1.2 , 3,4-tetrahydroisochi- nolin, reaction mixture se neutralizes from resulting product se hydrolysis from # cleaves acetyl group and gained merges # nina se optionally Converts reaction with orga # technical or inorganic acid on svo # her non-toxic pharmaceutically usable addition salt with acid. Produced compounds report pharmaco- logical efficiency, especially they inhibit enzyme phenylethanolamine-N-methyltransferesis, and can Yippee use like drugs.

Description

The present invention relates to novel oxadiazolotetrahydroisoquinoline derivatives. These compounds exhibit pharmacological activity, in particular they inhibit the enzyme phenylethanolamine-N-methyltransferase.

Epinephrine is a hormone synthesized in the adrenal medulla that releases into the blood stream in stressful situations and causes profound physiological changes that prepare the animal to cope with a stressful situation. For example, epinephrine causes anxiety. blood pressure, heart rate acceleration and increase in heart volume.

These changes are susceptible to patients with certain diseases such as angina, myocardial infarction and anxiety neurosis.

Phenylethanolamine-N-methyltransferesis catalyzes the final degree of epinephrine biosynthesis, ie, transfer of the methyl group from S-adenosylmethionine to norepinephrine, to produce epinephrine.

The compounds of the invention inhibit phenylethanolemin-N-methyltransferesis and thereby suppress epinephrine production. The compounds are therefore useful in situations in which epinephrine overproduction or epinephrine production is detrimental.

The compounds of the invention may exist in the form of isomers, which are generally within the scope of the invention. These isomers are illustrated by the following I-II

N = N <7

(II)

The oxadiazolotetrahydroisoquinolines of the formulas I-II are prepared according to the invention from 2-acetyl-8 (7) -amino-7 (8) -chloro-1,2,3,4-tetrahydroisoquinoline by diazotization and neutralization of the resulting solution to give an oxadiazole residue. The acetyl group is then removed by hydrolysis.

Likewise useful as the free bases are the non-toxic, pharmaceutically acceptable acid addition salts of the compounds of Formulas I and II. These salts are readily prepared by methods known in the art. The base is reacted with an organic or inorganic acid in a water-miscible solvent such as acetone or ethanol to isolate the salt by concentration and cooling, or in a water-immiscible solvent such as ethyl ether or chloroform, with the desired salt directly excluded. Examples of salts within the scope of the invention are maleates, fumaretes, benzoes, ascorethes, pamoates, succinates, bis (methylene) salicylates, methanesulfonates, ethanesulfonates, benzenesulfonates, acetates, propionates, tartrates, salicylates, salts, citrates, gluconates malic acid, mandelic acid salts, cinnamic acid salts, citraconates, aspartic acid salts, stearates, palmitates, itaconates, glycolates, p-aminobenzoates, glutamates, thaophyllineateates, hydrochlorides, hydrobromides, sulfates, cyclohexylsulfamates, phosphates and nitrates.

The efficacy of the compounds of formulas I and II is demonstrated by the in vitro inhibition of phenylethanolamine-N-methyltransferesis using the assay described by Pendleton and Snow [Molecular Pharmacology, 9: 718-725 (1973)] at various concentrations of the test compound.

In addition, the efficacy of the compounds of the invention can be demonstrated by in vivo administration to mice at a dose of 50 mg / kg daily for 7 consecutive days. Male mice are dosed orally twice daily for 7 consecutive days with either test compound or vehicle (as a control). On the morning of the following day, the mice are re-administered the test substance or vehicle and after 2 hours the animals are sacrificed by decapitation.

The adrenal glands of the animals are removed and subjected to fluorometric analysis for both epinephrine and norepinephrine. A test compound is considered to be effective as an inhibitor of phenylethanolamine-N-methyltransferesis if it significantly decreases the epinephrine / norepinephrine ratio in the adrenal glands [R. G. Pendleton et al., J. Fharmacol. Exp. Ther. 190, 55-562 (1974) and R. G. Pendleton et al., J. Fharmacol. Exp. Ther. 197, 623-632 (1976)].

The pharmaceutical compositions according to the invention which inhibit phenylethanolamine-N-methyltransferesis comprise a pharmaceutical carrier and, as active ingredient, a tetrahydroisoquinoline derivative of the formula I or II. The active ingredient should be present in the compositions in an amount effective to inhibit phenylethanolamine-N-methyltransferase.

Preferably, the compositions of the invention contain the active ingredient of the formula I in an amount of about 50 mg to 1000 mg, preferably about 100 mg to 500 mg, per dosage unit.

For example, the pharmaceutical carrier may be a solid or a liquid. Examples of solid carriers include lactose, magnesium stearate, kaolin, sucrose, talc, stearic acid, gelatin, agar, pectin, or acacia. The amount of solid carrier may vary within wide limits, but generally ranges from about 25 mg to 1 g. Examples of liquid carriers include syrup, peanut oil, olive oil, sesame oil, propylanglycol, polyethylene glycol (molecular weight 200-400). and water. The carrier or diluent may contain a sustained release material, for example glyceryl monostearate or glyceryl distearate, either alone or together with a wax.

The compositions of the invention may be formulated for a wide variety of dosage forms. These compositions may take the form of tablets, capsules, powders, troches, lozenges, syrups, emulsions, sterile injectable liquids or liquid suspensions or solutions.

The pharmaceutical compositions are prepared by conventional techniques including such techniques as mixing, granulating, and compressing or dissolving as appropriate.

The method of inhibiting phenylethanolamine-N-methyltransferesis according to the invention comprises administering to the animal a tetrahydroisoquinoline derivative of the formula I or II in an amount sufficient to inhibit the phenylethanolamine-N-methyltransferesis.

Preferably, the compounds of Formula I or II are administered in conventional unit dosage forms prepared by combining the appropriate dose of the active ingredient with standard pharmaceutical carriers.

Preferably, the active compound of formula I or II is administered in a daily dose ranging from about 100 mg to 2000 mg, most preferably from about 200 mg to about 1000 mg. Preferably, administration is performed two to three times daily in equal doses. When administered as described above, the phenylethanolamine-N-methyltransferase is inhibited.

The pharmaceutical compositions of the invention are administered either parenterally or preferably orally, in an amount in which they exhibit the desired biological activity.

The invention is illustrated by the following non-limiting examples.

Example!

2.2 g (0.01 mol) of 2-acetyl-7-amino-8-chloro-1,2,3,4-tetrahydroisoquinoline are dissolved in a mixture of 10 ml of concentrated hydrochloric acid and 20 ml of water and diazotized at a temperature of 3 ° C by adding 0.7 g (0.01 mol) of sodium nitrite.

The mixture was stirred for 30 minutes and then 7.0 g (0.065 mol) of sodium carbonate was added to adjust the pH to 7. Extraction of the resulting mixture with chloroform and evaporation of the extract ee affords 8-acetyl- [1,2,3] oxadiazolo [4,5-h] -6,7,8,9-tetrahydroisoquinoline.

By boiling under reflux with 10% hydrochloric acid, 1,2,3 oxadlazolo [4,5-h] -6,7,8,9-trishydroisoquinoline hydrochloride is obtained from the above base.

Example 2

Using the procedure of Example 1, 2-methyl-8-araino-7-chloro-1,2,3,4-tetrahydroisoquinoline was converted to [1,2,3] oxadiazolo [5,4-h] -6,7 , 8,9-tetrahydrolaroquinoline hydrochloride.

Example 3

This example describes the composition and preparation of a tablet containing the active ingredient according to the invention.

Component Amount [1,2,3] oxadiazolo [5,4-h] -6,7,8,9-tetrahydroisoquinoline 200 mg calcium sulfate dihydrate , 50 mg sucrose 25 mg Starch 15 mg talc 5 mg stearic acid 3 mg

Calcium sulfate dihydrate, sucrose and tetrahydroisoquinoline are mixed and granulated using a 10% gelatin solution. The wet granulate is passed through a sieve, dried, blended with starch, talc and steeric acid, sieved through a sieve, and compressed into a tablet.

One such tablet is administered three times a day.

Claims (1)

A process for the preparation of oxadiazolotetrahydroisoquinoline derivatives of the general formula I or II (I) (II) and their pharmaceutically acceptable acid addition salts, characterized in that the diazotized 2-acetyl-8 (7) -amino-7 (8) -chloro-1 is diazotized. 2,3,4-tetrahydroisoquinoline, the reaction mixture is neutralized, the acetyl group is cleaved from the resulting product by hydrolysis, and the compound obtained is optionally converted by reaction with an organic or inorganic acid into its non-toxic, pharmaceutically acceptable acid addition salt.