US3175945A

US3175945A - Antihypertensive quaternary ammonium salts of 1:2:3:4-tetrahydroisoquinoline

Info

Publication number: US3175945A
Application number: US93874A
Authority: US
Inventors: Wiggins Leslie Frederick; Temple Richard William; Gittos Maurice Ward
Original assignee: Aspro Nicholas Ltd
Current assignee: Aspro Nicholas Ltd
Priority date: 1960-03-08
Filing date: 1961-03-07
Publication date: 1965-03-30
Anticipated expiration: 1982-03-30
Also published as: GB984361A; FR1453802A

Description

, represent methyl, propargyl or Z-hydroxyethyl groups and X represents This invention relates to quaternary ammonium salts and pharmaceutical preparations containing them.

It has been found that there is a class of quaternary ammonium salts of l:2:3:4 tetrahydroisoquinoline Whose members modify the actions of the sympathomimetic amines, for example adrenaline, in animals, and

i which class of salts is therefore, of pharmaceutical and veterinary importance.

Accordingly, one aspect of the present invention provides a pharmaceutical or veterinary composition which United States Patent essentially contains a pharmacologically active quaternaryammonium salt of 1:2:3:4-tetrahydroisoquinoline having the structural formula:

(I) t r wherein R and R which may be the same or different, ethyl, n-propyl, iso-propyl, alkyl,

a non-toxic anion,for example a chloride, bromide or iodide radical, or an alkyl sulphonate or a substituted or unsubstituted aryl sulphonate group.

Most of such quaternary ammonium salts are believed to benovel compounds and such of the salts as have been mentioned in the literature have not had anypharmacological activity attributed to them. The novel salts provided by the present invention are quaternary ammonium salts of 122:3:4-tetrahydroisoquinoline as defined above except when one of the groups R, or R con tains one carbon atom and the other group contains from one to three carbon atoms or is hydroxyethyl and X is an iodine anion.

As has already been mentioned, the quaternary ammonium salts as defined above have been found to modify the actions of sympathomimetic amines.

The following compounds are of particular interest in that they have been shown to be eitective in causing in animals a selective block of the peripheral sympathetic (adrenergic) nervous system Without affecting the peripheral parasympathetic nervous system and without causing ganglion block:

Others of the compounds defined above also modify the actions of thesympathomimetic amines. Examples of such compounds which exert a hypotensive effect are quaternary ammonium salts of:

2 2-dimethyl-1 :2 3 24-tetrahydroisoquinoline, for example the iodide; and

3,175,945 Patented Mar. 30, 1965 Z-methyl-Z-n-propyl-l :2 3 :4 tetrahydroisoquinoline, for

example the iodide.

Other examples of such compounds may exert a mildly hypertensive effect.

The pharmacologicallyactive quaternary ammonium salts of 1:2z324-tetrahydroisoquinoline as defined above may be provided as a pharmaceutical or veterinary composition in a suitable form for dosage, which composit1on contains essentially at least one pharmacologically active salt and which also comprises a pharmaceutical carrier base which may be a liquid, semi-solid or solid. Thus for example, the composition may be in a form suitable for parenteral administration which may be sterile solutions, suspensions in water or other liquids,

with or Without the addition of soluble or insoluble diluents and/ or solid or liquid excipients.

In clinical practice the compounds of the present invention will normally be administered orally and in consequence, the preferred formulations are of the kind which are most suitable for oral ingestion.

Preparations for oral administration can be liquids or solids or any combination of these forms such as solutions, suspensions, emulsions, elixirs, syrups, powders or tablets.

Pharmaceutical preparations for administration of the active therapeutic agents in unit dose form can take the form of compressed powders or of a powder enclosed in a suitable capsule of absorbable material such as gelatin. These compressed powders or tablets can take the form of the active material admixed with suitable excipients and/ or diluents such as starch, lactose, stear-ic acid, magnesium stearate, dextrin or the like.

The pharmacologically active salt may be presented in the form of a resinate to give a relatively slow and even release of the drug when acted upon by the normal contents of the gastro-intestinal tract, as described in for example United Kingdom patent specifications No. 857,- 193 and 857,194.

According to another'aspect of the invention, there is provided a method of preparing the quaternary ammonium salts having the formula defined above, which method comprises heating a N-substituted-1:22324-tetrat hydroisoquinoline having the formula:

N-Rt NRg Ol i Q Q wherein R and R have the meanings defined above, with an allrylating agent of the formula R X or R X respectively, preferably in the presence of an appropriate organic solvent, such as for example acetone or methyl ethyl ketone. The product either separates and can be filtered off, or is precipitated for example by the addition of ether.

The N-allyl-l 2:3 :4-tetrahydroisoquinoline starting material may be prepared from 1:2:3:4-tetrahydroisoquinoline by reaction with an allyl halide in the presence of a base, such as for example potassium carbonate, either alone or in a suitable solvent, such as for example acetone. The tertiary amine product is often contaminated with the unsubstituted tetrahydroisoquinoline and in this case may be separated either by fractional distillation or by the Hinsberg technique. The tertiary amine starting material prepared in this manner may then be quaternized in the above described manner.

'The N-propargyl-l:213:4-tetrahydroisoquinoline starting material, which is a new compound, may itself be prepared from 1:2: 3:4-tetrahydroisoquinoline by reaction with 2:3-dibromoprop-l-ene, followed by dehydrohalogenation with a suitable base of the N-(Z-bromoprop-Z- ene)-1:2:3:4-tetrahydroisoquinoline so formed. The resulting tertiary base may then be quaternized in the manner already described.

Example 1 Example 2 A mixture of 2-methyl-l:2z3:4-tetrahydroisoquinoline (25 g.) ethyl-p-toluenesulphonate (37.2 g.) and methyl ethyl ketone (75 ml.) was heated on a steam bath for 2 /z hours. On prolonged standing at room temperature the solution deposited crystals. These were filtered off, washed with methyl ethyl ketone, to give 2-ethyl-2-methyl- 1 :2 3 i4-tetrahydroisoquinolinium p-toluene sulphonate, M.P. 102-106 C.. Analysis.C, 65.67%; H, 7.26%; N, 4.10%. C1gH1gN.C7H7SO requires C, H, 7.25%; N, 4.03

Example 3 Allyl bromide (12.1 g.) was added slowly to a solution of 2-methy1-1:2:3:4-tetrahydroisoquinoline (14.7 g.) in methyl ethyl ketone (50 ml.) and the mixture heated on a steam bath for 1 hour. The syrup which separated was crystallized by trituration and was recrystallized from isopropanol-ether to give '2-ally1-2-methyl-1:22324-tetrahydroisoquinolinium bromide M.P. l58-l60 C. Analysis.- C, 58.4%; H, 6.79%; N, 5.26%; Br, 29.72%. C H NBr requires C, 58.22%; H, 6.76%; N, 5.22%; Br, 29.80%.

Example 4 Propargyl bromide (11.9 g.) was slowly added to a solution of Z-methyl 1:2: 3 :4 tetrahydroisoquinoliue (14.7 g.) in methyl ethyl ketone (100 ml.). A syrup settled out immediately and crystallized on cooling. The resulting product was filtered off and recrystallized from ethanol to give 2-methy1-2-propargyl-122:324-tetrahydroisoquinolinium bromide, M.P. 195197 C. Analysis.- C, 58.82% H, 6.18%; N, 5.58%. C H NBr requires C, 58.65%; H, 6.06%; N, 5.26%.

Example 5 Ethyl iodide (8 g.) was slowly added to a solution of 2-ethy1-1:2:3:4 tetrahydroisoquinoline (8 g.) in methyl ethyl ketone (40 ml.) and the mixture heated on a steam bath for 1 hour. The crystalline product was filtered off and recrystallized from isopropanol to give 2:2-diethy1- 1:2:3:4-tetrahydroisoquinolinium iodide, M.P. 158-160 C. Analysis.C, 49.28%; H, 6.41%; N, 4.05%. C H NI requires C, 49.21%; H, 6.35%; N, 4.42%

. Example 6 A mixture of 2ethyl-l:2;3.:4-tetrahydroisoquinoline (10. g.), n-propyliodide (11 g.) and methyl etheyl ketone (40 ml.) was heated on a steam bath for 3 hours, cooled and ether added. The precipitated syrup crystallized on triturating with ether. Recrystallization from isopropanol- 41 gave 2-ethyl-2-n-propyl-l:2:3:4: tetrahydroisoquinolinium iodide, M.P. 108-1l1 C. Analysis.C, 50.83%; H, 6.63%; N, 4.45%; l, 37.87%. C I-1 511 requires C, 50.76%; H, 6.695%; N, 4.23%; I, 38.31%.

Example 7 Allyl bromide (8 g.) was added slowly to a solution of 2-ethyl-1:2:3:4-tetrahydroisoquinoline (10 g.) in methyl ethyl ketone (40 ml.) and the mixture heated on the steam bath for 1 hour. The syrup which separated was crystallized by trituration with ether. Recrystallization from ethanol-ether gave 2allyl-2-ethyl-1:2:3:4-tetrahydroisoquinolinium bromide, M.P. 100 C.

Example 8 Allyl bromide (36.6 g.) was added slowly to 1:2:3:4- tetrahydroisoquinoline (39.9 g.) with cooling. Potassium carbonate (41.4 g.) was then added and the mixture heated on a steam bath for 4 hours. Water ml.) was added to the cooled mixture followed by 10 N sodium hydroxide (20 ml.). The oil which separated was isolated by ether extraction. The oil distilled at 114-l22 C/l2 mm., and from the infra-red spectra thereof was shown to be a mixture of 2-allyl-1:21324-tetrahydroisoquinoline and 1:223 :4-tetrahydroisoquinoline. The oil was submitted to a Hinsberg separation using sodium hydroxide and benzene sulphonyl chloride. The 2-allyl-1:2:3:.4- tetrahydroisoquinoline did not form a benzene sulphonaniide and remained soluble in dilute hydrochloric acid. Basification of the acidic solution with 10 N sodium hydroxide liberated the 2-allyl-l:2z3z4-tetrahydroisoquinoline which distilled at 118122 C./ 12 mm.

Allyl bromide (8 g.) was slowly added to a solution in methyl ethyl ketone (40 ml.) of 2-allyl-lz2z3z4-tetrahydroisoquinoline (9 g.) prepared in the above manner, and the resulting mixture was heated on a steam bath for 2 hours. The precipitated syrup slowly crystallized on trituration with ether. Recrystallization from isopropanol ether gave 2: 2-diallyl-1 :2: 3 :4tetrahy-droisoquinolinium bromide, M.P. 1l5-1l8 C. Analysis.-C, 60.77%; H, 6.69%; N, 4.59%; Br, 27.7%. C H NBr requires C, 61.24%; H, 6.85%; N, 4.76%; Br, 27.16%.

Example 9 A mixture of 2-ethyl-122:3:4-tetrahydroisoquinoline (10 g.), ethylene bromohydrin (10 g.) and methyl ethyl ketone (40 ml.) was heated on a steam bath for 3 hours, cooled, and ether added. The resulting precipitated syrup crystallized on trituration with ether. Recrystallization from ethanol-ether gave 2-ethyl-2-(2'-hydroxyethyl)-l:2:

Y 3 :4-tetrahydroisoquinolinum bromide, M.P. 65-70 C.

Example 10 l22:3:4-tetrahydroisoquinoline (26.5 g.) was added slowly whilst cooling to 80% formic acid (13 g.). 38% formalin solution (20 g.) was then run in and the resulting mixture was heated on a steam bath. When the evolution of CO had almost ceased, 3 mls. formic acid and 3 mls. formalin were added and heating was continued for a further 2 hours.

The mixture was then cooled and water (50 mls.) was added, Whereafter, the solution was rendered strongly basic by the addition of KOH solution. The oil which separated was extracted with ether three times and the combined ether extracts were washed twice with water, dried and distilled. The N-methylated compound distilling at 108l12 C./ 16 mm. was collected in a yield 0 17.0 g.

Ethyl iodide (10 mls.) was added to a solution in acetone (40 mls.) of 2-methy1-1:2:3 :S-tetrahydroisoquinoline prepared as described above and the resulting mixture was then heated on a steam bath until reaction Was complete. Ether was then added to the mixture and the solid which then formed was collected in a yield of 17.0 g., M.P. 139- 142 C.

Recrystallization from alcohol-ether with charcoaling gave 2 methyl-Z-ethyl-l:2z3:4-tetrahydroisoquinolinum iodide, MP. 140-14l C. Analysis.C, 47 9%; H, 6.0%; N, 4.7%. C N NI requires C, 47.5%; H, 6.0%; N, 4.6%.

Example 1] Methyl iodide g.) was added slowly to a solution of 2-methyl-1:2:3 :4-tetrahydroisoquinoline (14.7 g.) in methyl ethyl ketone (50 ml. and the mixture heated .on a steam bath for l-hour. The crystalline product which formed was filtered off and recrystallized from ethanol to give 2:2- dimethyl-1:2:3:4-tetrahydroisoquinolinium iodide (15.0 g.) having M.P. 194196 C.

By way of further exemplification, other compounds which have been made in accordance with the invention include:

Example 12 2:3-dibromoprop-1-ene (30 g.) was slowly aded to an ice cold solution of 1:2:3:4-tetrahydroisoquinoline (39.9 g.) in ether (160 ml.) and the mixture allowed to stand overnight at room temperature. The crystals of 122:3:4- tetrahydroisoquinoline hydrobromide were filtered off and the ethereal solution distilled. N-(2-bromoprop-2-ene)- 1:223:4-tetrahydrisoquinoline was collected at 96-l00 C./0.15 mm.

N- 2-bromoprop-2-ene) -1 22:3 z4-tetrahydroisoquinoline (31.8 g.) was slowly added (over hour) to a solution of potassium hydroxide (14 g.) in ethylene glycol (100 ml.), the temperature of the well agitated mixture being kept at 130140 C. The solution was allowed to cool to room temperature and then it was poured into water (300 ml.). The basic oil was separated by ether extracderivatives may be used in preparingthe pharmaceutical compositions instead of the 2-ethyl 2-methyl-paratoluene sulphonate derivative providing that they are within the definition of the general Formula I and that the compounds and compositions containing them modify the. action of sympathomimetic amines.

We claim:

1. ,A- method of selectivelyblocking the peripheral sympathetic nervous system of animals without affecting the peripheral parasympathetic nervoussystem, which comprises administering to the animal a nontoxic salt selected from the group consisting of salts with a nontoxic anion of Z-methyl-Z-ethyl-l :2: 3 :4-tetrahydroisoquinoline; 2 methyl-2-allyl-122z3 :4-tetrahydroisoquinoline; 2,2,-diethyl 122:3 :4-tetrahydroisoquinoline and 2-ethyl-2-(2- hydroxyethyl) -1 2: 3 :4-tetrahydroisoquinoline.

2. A method of selectively blocking the peripheral sympathetic nervous system of animalsv without affecting the peripheral parasympathetic nervous system, which tion, the ether solution being dried and distilled to give N-propargyl-1:2:3:4-tetrahydroisoquinoline, B.P. 132-8 C./15 mm. Treatment of the base with ether and ethereal hydrogen chloride gave N-propargyl-1:2:3:4-tetrahydroisoquinoline hydrochloride, M.P. 199 C. after recrystallization from ethanol. The propargyl tertiary base and its acid addition salts are new compounds and may, if desired, be incorporated into pharmaceutical preparations for administration purposes, just as described for the quaternary compounds.

To convert the tertiary base into a quaternary compound in accordance with the invention, methyl bromide (4.75 g.) was slowly added to an ice cold solution of N propargyl-1z2t3:4-tetrahydroisoquinoline (8.55 g.) in methyl ethyl ketone ml.). A syrup separated out which slowly crystallized. This was filtered 01f and recrystallized from ethanol to give 2-methyl-2-propargyl-1: 2:3:4-tetrahydroisoquinolinium bromide, M.P. 195-7 C.

Example 13 Tablets were prepared by granulating and compressing the following ingredients in accordance with known pharmaceutical techniques. Each table contained:

2 ethyl 2-methy1-1:2:3:4rtetrahydroisoquinolinium para-toluene sulphonate 200 Calcium phosphate n 280 Lactose 200 Ethyl cellulose 9 Maize starch (dried) 21 Magnesium stearate 10 Other 2 2-disubstituted-1 2: 3 4-tetrahydroisoquinoline comprises administering to the animal a salt with a nontoxic anion of Z-methyl-Z-ethyl-lz2z3z4-tetrahydroisoquinoline.

3. A method of selectively blocking the peripheral sympathetic nervous system of animals without affecting the peripheral parasympathetic nervous system, which comprises administering to the animal a salt with a nontoxic anion of 2-methyl-2-allyl-1:2,3,4-tetrahydroisoquinoline.

4. A method of selectively blocking the peripheral sympathetic nervous system of animals without affecting the peripheral parasympathetic nervous system, which comprises administering :to the animal a salt with a nontoxic anion of 2-2-diethyl-1 2:3 :4-tetrahydroisoquinoline.

5. A method of selectively blocking the peripheral sympathetic nervous system of animals without affecting the peripheral parasympathetic nervous system, which comprises administering to the animal a salt with a nontoxic anion of 2-ethyl-2- (Z'hydroxyethyl -1. z 2 z 3 :4-tetrahydroisoquinoline.

6. The method of reducing the blood pressure of animals without causing ganglion block which comprises administering to the animal a nontoxic salt selected from the group consisting of salts with a nontoxic anion of 2-methyl-2-ethyl-1 2: 3 :4-tetrahydroisoquinoline; 2-methyl 2 allyl 112:3 :4 tetrahydroisoquinoline; 2 2 diethyl-l :2: 3 :4-tetrahydroisoquinoline; and 2-ethyl-2-(2- hydroxyethyl) -1 2 3 4-tetrahydroisoquinoline.

7. The method of reducing the blood pressure of animals without causing ganglion block which comprises administering to the animal a salt with a nontoxic anion of 2-methyl-2-ethyl-1 :2: 3 :4-tetrahydroisoquinoline.

8. The method of reducing the blood pressure of animals without causing ganglion block which comprises administering to the animal a salt with a nontoxic anion of 2-methyl-2-allyl-l :2: 3 :4-tetrahydroisoquinoline.

9. The method of reducing the blood pressure of animals without causing ganglion block which comprises administering to the animal a salt with a nontoxic anion of 2-2-diethyl-1 :2: 3 4-tetrahydroisoquinoline.

10. The method of reducing the blood pressure of animals without causing ganglion block which comprises administering to the animal a salt with a nontoxic anion of 2 ethyl 2-(2' hydroxyethyl) 1:2: 3:4 tetrahydroisoquinoline.

11. A composition useful for the treatment of hypertension in animals, consisting essentially of a nontoxic salt selected from the group consisting of salts with a nontoxic anion of 2-methyl-2-ethyl-l:2z3z4-tetrahydroisoquinoline; 2 methyl 2 allyl 1222324 tetrahydroisoquinoline; 2-2-diethyl-1 :2: 3 :4-tetrahydroisoquinoline; and 2 ethyl 2 (2' hydroxyethyl) 122:3 :4 tetrahydroisoquinoline; and a therapeutically acceptable carrier.

12. A composition useful for the treatment of hypertension in animals, consisting essentially of a salt with a nontoxic anion of 2-methyl-2-ethyl-1z2z3z4-tetrahydroisoquinoline; and a therapeutically acceptable carrier.

145A composition useful for the treatment of hypertension in animals, consisting essentially of a salt With a nontoxic anion of 2-2-diethyl-1:2:3:4-tetrahydroisoquinoline; and a therapeutically acceptable carrier.

15. A composition useful for the treatment of hypertension in animals, consisting essentially of a salt with a nontoxic anion of 2-ethy1-2-(2-hydroxyethyl)-122:3:4- tetrahydroisoquinoline; and a therapeutically acceptable carrier.

References Cited in the file of this patent UNITED STATES PATENTS De Benneville Sept. 27, 1955 2,957,872 Huebner Oct. 25, 1960 FOREIGN PATENTS Great Britain Jan. 16, 1952 OTHER REFERENCES p Robinson: J. Organic Chem., vol. 16, pp. 1911-1919 (1951).

Hjort et at: J. Pharmacol, vol. 76, p. 71 (1942).

Torossionz Comptes Rendus, pp. 1313-14 (1952), vol. 235.

Skita: Chemische Berichte, vol. '57,- pp. 1977-1982 (1924 p Chemical Abstracts, vol. 54, entry 21150a, 1960 (citing Awe et. al., Chem. Ber., vol. 90, pages 1997-2003 (1957).

Websters New International Dictionary of the English Language, Second Edition, published'by G. andC. Merriam Co., Springfield, Mass, 1939.

Claims

11. A COMPOSITION USEFUL FOR THE TREATMENT OF HYPERTENSION IN ANIMALS, CONSISTING ESSENTIALLY OF A NONTOXIC SALT SELECTED FROM THE GROUP CONSISTING OF SALTS WITH A NONTOXIC ANION OF 2-METHYL-2-ETHYL-1-1:2:3;4-TETRAHYDROISOQUINOLINE; 2 - METHYL - 2 - ALLYL - 1:2:34 - TETRAHYDROISOQUINOLINE; 2-2-DIETHYL-1:2:3:4-TETRAHYDROISOQUINOLINE; AND 2 - ETHYL - 2 - (2'' -HYDROXYETHYL) - 1:2:3:4 - TETRAHYDROISOQUINOINE; AND A THERAPEUTICALLY ACCEPTABLE CARRIER.