US3457354A - Treatment of hypertension with 2-hydroxy (or amino) - 4,5 - dihydroxyphenethylamine derivatives - Google Patents

Description

TREATMENT OF HYPERTENSION WITH Z-HY- DROXY (R AMINO) 4.5 DIHYDROXYPHEN- ETHYLAMINE DERIVATIVES Clement A. Stone, Blue Bell, Pa., assignor to Merck & (30.,

Inc., Rahway, N..I., a corporation of New Jersey No Drawing. Continuation-impart of application Ser. No. 205,227, June 26, 1%2. This application Sept. 21, 1965, Ser. No. 489,058

Int. Cl. A611: 27/00 U.S. Cl. 424330 4 Claims ABSTRACT OF THE DISCLOSURE A method of treatment of hypertension in warmblooded vertebrates is described wherein 2-hydroxy (or amino)-4,5-dihydroxy phenethylamine, optionally substituted with a methyl or ethyl group on the a-carbon is administered by one of several different routes.

This invention relates to pharmaceutical compositions and particularly to compositions for the reduction of blood pressure in hypertensives.

This application is a continuation-in-part of copending application, Ser. No. 205,227, filed June 26, 1962, now abandoned.

Hypertension is a disorder in which the arterioles exhibit abnormal resistance to the flow of blood, usually associated with an abnormal increase in systolic, diastolic and mean arterial pressures, and symptomatically evidenced by fatigue, nervousness, dizziness, palpitation, insomnia, weakness and headaches at some time in the course of the disorder. Angina pectoris and myocardial infarction due to coronary artery disease are frequent complications, while congestive failure may occur as a result of coronary insufficiency, or cardiac hypertrophy, or both factors in combination. It is a serious disease. For example, in humans, average life expectancy probably is close to twenty years from onset, with extremes of several years or several decades.

Etiologically, the cause of hypertension is not known and consequently, its therapy is uncertain. There is no treatment now known that consistently and completely reverses the cause of hypertesion. Many symptoms of uncomplicated hypertension respond to the combination of reassurance by the doctor and time, but in most instances medicinal administration must be undertaken. Many antihypertensive drugs are now available, such as the alkaloids of rauwolfia, the thiazides and ganglionic blocking agents, e.g., mecamylamine, but they are not uniformly effective in their action. Their degree of effectiveness and the severity of induced side reactions varies considerably from patient to patient. Consequently, an additional hypertensive agent offers the possibility of filling the gaps which exist at present among the available medicines.

In accordance with the present invention, it has been found that high blood pressure is reduced by the administration of a compound selected from those represented by the formula States Patent 0 3,457,354 Patented July 22, 1969 vention. For oral administration, the compound may simply be placed in gelatin capsules so that one or two of them will carry a unitary dosage into the patient. Or, tablets may be made up, using conventional tableting agents and procedures, so that one or two tablets will contain the amount of active compound to constitute a unitary dosage. In addition, the invention contemplates pharmaceutical preparations in the forms of elixirs and aqueous solutions and suspensions of such concentrations that the usual teaspoonful or two will serve as a unit dose.

Although the hypotensive agents of this invention find particular utility in the treatment of hypertensive disorders in man, these agents, in addition, have use in the veterinary field for treatment of blood pressure abnormalities in domestic warm-blooded vertebrates. For example, the hypotensive compositions of this invention find particular use in the treatment of hypertensive disorders in domestic fowl, such as turkeys, or mammals, such as domestic large animals, for example, in horses to control nosebleed, or to control capillary bleeding during surgery in cats, dogs and other small animals.

The daily dose for humans is from to 200 milligrams and this preferably is given to the patient in fractional amounts at intervals throughout the day. For example, a capsule would contain ten milligrams of the compound and one or two of them would be taken at a time, from one to four times a day. If larger daily doses are required, it would be preferable to put into a single capsule up to 200 mg. of the compound. This plan would be carried out with tablets although the smaller dosage single tablet could contain say 20 to milligrams as the tablet can be stored to break it up into two or four pieces to be taken at a time. In like manner a conventional liquid pharmaceutical preparation may be prepared either for needle injection or oral consumption. The concentration per ml. or liquid ounce may be varied so that the doctor can adjust the dosage for the individual patient.

Dosages for veterinary administtation vary, depending on the animal to be treated, but in general, fall in a range of about 0.1 to 10 mg./kg. per day. Formulations, as discussed above, are employed.

The compounds in which R is hydrogen are known in the art and may be made by the process described by J. Harley-Mason in J. Chem. Soc. (1953), page 200. The compounds in which R is methyl or ethyl are new and therefore constitute a distinct part of this invention.

Processes for making them will be clear from the following examples.

EXAMPLE I.2 AMINO 4,5 DIHYDROXY a METHYLPHENETHYLAMINE DIHYDROCHLO- RIDE 3,4 dimethoxy a methylphenethylamine (4.0 g., 0.0205 mole) was added dropwise to a mixture of 32 ml. of concentrated nitric acid (d. 1.4) and 12 ml. of water, while stirring and maintaining the temperature at 12- 15 C. by external cooling. When the addition was complete, the solution was stirred at 1015 C. for 3 hours. After standing an additional 30 minutes at this temperature, it was cooled to 0 C. and poured into ml. of an ice-water mixture. The pale yellow solid that separated was collected and air dried.

The solid, the nitrate salt of 2-nitro-4,5-dimethoxy-otmethylphenethylamine was suspended in water, the mixture rendered alkaline with sodium carbonate and the base extracted into chloroform. After washing with water, the chloroform extract was dried over sodium sulfate and the solvent distilled under reduced pressure. The brown oily residue solidified on cooling.

The base, 2.72 g. was dissolved in absolute alcohol and the solution treated with 3.5 ml. of a 4.1 N solution of dry hydrogen chloride in absolute alcohol. The hydrochloride was recrystallized from a methanol-ether mixture and twice from ethanol-ether mixtures to give product, M.P. 215.5-2165 C.

Analysis.-Calcd. for C H O N -HCl: C, 47.74; H, 6.19; N, 10.13. Found: C, 47.75; H, 6.22; N, 9.88

The base was prepared from the hydrochloride by dissolving the salt in water, rendering the solution alkaline with sodium hydroxide and extracting the base into benzene. Distillation of the benzene left the yellow base that crystallized on cooling and melted at 81.5-84.5" C.

Step B.-Preparation of 2amino-4,5-dimethoxyamethylphenethylamine dihydrochloride The product of Step A, 2-nitro-4,5-dimethoxy-a-methyl phenethylamine (35.5 g., 0.148 mole) was dissolved in 200 ml. of absolute alcohol and hydrogenated over Raney nickel at 22 C. with an initial hydrogen pressure of 42 pounds per square inch. The catalyst was separated by filtration through a mat of diatomaceous earth. The filtrate was cooled in an ice-bath and a stream of dry hydrogen chloride passed in until an excess was present. Ether was added and the precipitated solid was collected and recrystallized from a methanol-ether mixture. The hydrochloride of 2-amino-4,S-dimethoxy-a-methylphenethylamine was obtained as a tan crystalline solid. The M.P. was highly dependent on the rate of heating. After drying over phosphorus pentoxide at room temperature, analyses were consistent with a formula containing methanol and water of crystallization.

Analysis.-Calcd. for C11H1302N2'2HC1% CH3OH' /2 H O: C, 44.81; H, 7.52; N, 9.09. Found: C, 44.67; H, 7.73; N, 8.96.

Step C.Preparation of 2-amino-4,5-dihydroxy-a-methylphenethylamine dihydrochloride The product of Step B (7.92 g., 0.028 mole) was divided into four equal portions. Each was dissolved in 20 ml. of concentrated hydrochloric acid. These solutions were sealed in glass tubes and heated to 150 C. for 2 hours. The tubes were cooled, opened, and the liquid distilled under reduced pressure from a bath at 4555 C. in an atmosphere of nitrogen. After concentrating the solution to near dryness, alcohol was added and the solution cooled. The gray crystalline product, obtained in two crops weighed 5.83 g. Recrystallization from mixtures of methanol and ether gave the product, M.P., 240241 C. with decomposition.

Analysis.-Calcd. for C H O N -2HCl: C, 42.36; H, 6.32; N, 10.98. Found: C, 42.34; H, 6.24; N, 10.89.

EXAMPLE II.2 AMINO 4,5 DIHYDROXY a ETHYLPHENETHYLAMINE DIHYDROCHLORIDE By using 3,4 dimethoxy a ethylphenethylamine in place of 3,4 dimethoxy oz methylphenethylamine and following the process of Example I, this compound was obtained.

EXAMPLE III.-2,4,5 TRIHYDROXY oz METHYL- PHENETHYLAMINE Step A.Preparation of 1 (2,4,5 trimethoxyphenyl)- 2-oximino propane 2,4,S-trimethoxyphenylacetone (25.0 g., 0.111 mole), hydroxylamine hydrochloride (9.3 g., 0.134 mole) and potassium acetate (15.6 g., 0.158 mole) were added to 400 ml. of 70% ethyl alcohol contained in a liter flask fitted with a reflux condenser. The mixture was heated on a steam bath to gentle refiux for 3% hours. The cooled reaction mixture was evaporated to dryness under reduced pressure and the residue extracted four times with 150 ml. portions of benzene. The combined benzene extracts were washed twice with 75 ml. portions of water and then dried over anhydrous MgSO Evaporation of the benzene under reduced pressure left a tan oil (26.8 g), which was redissolved in benzene and diluted by dropwise addition of petroleum ether until white crystals appeared. After completion of the crystallization, filtration yielded 20.1 g.; M.P. -85 C. Recrystallization from benzene-petroleum ether yielded 18.1 g. white crystals, MP. 91.5- 93 C.

Analysis.-Calcd. for C12H17O4NZ C, 60.23; H, 7.16; N, 5.85. Found: C, 60.22; H, 7.21; N, 5.84.

Step B.Preparation of 2,4,5 trimethoxy a methylphenethylamine hydrochloride 1 (2,4,5 trimethoxyphenyl) 2 oximino propane (18.1 g., 0.075 mole) was dissolved in 200 ml. of methyl alcohol and subjected to hydrogenation in the presence of one teaspoon of Raney nickel at C. and 1700 p.s.i. Observed pressure drop at 20 C. was 100 p.s.i.

The reaction mixture was filtered to removethe catalyst and the solvent evaporated under reduced pressure to leave a dark yellow residue. The residual oil was dissolved in excess ether and sufficient 4 N alcoholic hydrochloric acid added to precipitate the hydrochloride of the product. The amine hydrochloride was filtered and washed with ether. It weighed 17.5 g. and melted at 178181 C. Recrystallization from isopropyl alcohol yielded 14.9 g. of white crystals, M.P. 186.5-l87.2 C.

Analysis.Calcd. for C H O NCl: C, 55.06; H, 7.70; N, 5.35. Found after drying in vacuo/P O at 100 C. for 5 hours; C, 55.26; H, 7.71; N, 5.41.

Step C.-Preparation of 2,4,5 -trihydroxy-a-methylphenethylamine hydrobromide 2,4,5 trimethoxy a methylphenethylatnine hydrochloride (3.0 g., 0.0115 mole), 65 ml. of bromine free 48% hydrobromic acid and 65 ml. of glacial acetic acid were mixed under an N atmosphere and refluxed for 16 hours under N The solvent was removed under reduced pressure and hot water bath. Methyl alcohol containing S0 was added to the residue and removed under reduced pressure. The latter process was repeated and the residue dissolved in 50 ml. of Water containing S0 The solution was treated with acid washed Norit and filtered through an acid washed Norit pad on a porcelain filter while protecting it from oxygen with a nitrogen atmosphere. The filtrate was evaporated to dryness under reduced pressure and hot water bath to leave a glassy residue. This material was treated with ethyl alcohol containing S0 four times and the solvent removed under reduced pressure each time. Repeated attempts to obtain a crystalline material from butyl alcohol-ether were unsuccessful.

Analysis.Calcd. for C H O NBr: C, 40.92; H, 5.34; N, 5.30; Br, 30.26. Found after drying in vacuo over phosphorus pentoxide at C. for 21 hours: C, 42.22; H, 5.58; N, 5.32; Br, 29.20; OCH;,, 0.00.

Paper chromatography in sec-butyl alcohol (75%) formic acid (15%), H 0 (10%) (S0 atmosphere) (ascending) showed a major component of R 0.29 and a minor component of R 0.41 which appeared to be forming during the course of the chromatography.

The glassy hydrobromide crystallized after several months refrigeration under nitrogen.

EXAMPLE IV.-2,4,S-TRIHYDROXY-u-ETHYL- PHENETHYLAMINE HY DROBROMIDE Step A.Prepa1ati0n of 1-(2,4,5-trimethoxyphenyl)-2- nitrobutene-l 2,4,5 -trimethoxybenzaldehyde (30.0 g., 0.152 mole), n-butyl amine (3.2 g., 0.044 mole), l-nitropropane (15.7 g., 0.176 mole) and 50 ml. of toluene were placed in a 500 ml. flask fitted with a stirrer, reflux condenser and Dean-Stark water collecting apparatus. The dark solution was heated for 20 hours while stirring and refluxing. On cooling an orange solid separated and was collected by filtration-28.6 g.M.P. 97-109 C. The solid was recrystallized from 300 ml. of methyl alcohol to yield 22.8 g. of material melting at 112113 C.

AnaZysis.-Calcd. for C13H17O5NZ C, 58.41; H, 6.41; N, 5.24. Found: C, 58.63; H, 6.63; N, 5.42.

Step B.Preparation of 2,4,5-trimethoxy-u-ethylphenethylamine hydrochloride A solution of 1 (2,4,5 trimethoxyphenyl) 2 nitrobutene 1 (26.7 g., 0.1 mole) dissolved in 250 ml. of dry THF was added dropwise to a stirring, refluxing solution of lithium aluminum hydride (18 g.) in two liters of reagent grade ether over a period of 1 /2 hours. The reaction mixture was refluxed with stirring and calcium chloride tube protection for an additional two to three hours and the excess lithium aluminum chloride decomposed by dropwise addition of ethyl alcohol. Sodium potassium tartrate solution (600 ml. of 40%) and 250 ml. of water were added. The mixture was transferred to a large separatory funnel and the ether phase separated. The aqueous phase was extracted three times with ether and the combined ether phase dried over potassium hydroxide. Evaporation of the ether under reduced pressure left a white oily solid which was dissolved in alcohol, treated with charcoal and filtered. The clarified alcohol solution was treated with 30 ml. of 5.8 N alcoholic hydrochloric acid and the solution diluted with ether and chilled to give white crystals-l6.0 g.M.P. 206- 207 C.

Analysis.Calcd. for C H O NCl: C, 56.61; H, 8.04; N, 5.08. Found, after drying in vacuo/P O at 100 C. for 2 /2 hours: C, 56.63; H, 7.88; N, 5.00.

Step C.-Preparation of 2,4,5-trihydroxy-a-ethylphenethylamine hydrochloride 2,4,5 tn'methoxy or. ethyl phenethylamine hydrochloride (5.52 g., 0.02 mole), 100 ml. of Br free 48% hydrobromic acid were treated by the same procedure described for the preparation of the a-methyl analog and a clear amber glassy product was obtained which did not crystallize.

Analysis.Calcd. for C H O NBrz C, 43.18; H, 5.80; N, 5.04; Br, 28.73. Found, after drying at 140 C. in vacuo/P O for 21 hours: C, 43.84; H, 5.89; N, 5.09; Br, 27.95; OCH 0.00.

Chromatography in the same system described for the a-methyl-isomer showed a major component of R, 0.37 and a minor component of R 0.52 which appeared to be forming during the chromatography.

EXAMPLE V.SINGLE DOSE PREPARATION CON- TAINING 2,4,5 TRIHYDROXY PHENETHYL- AMINE One gram of 2,4,5 -trihydroxyphenethylamine, made according to the aforementioned journal article, is equally subdivided into fifty parts and each part Weighing milligrams is placed in a hard elastic capsule. One or two of these capsules may be taken at a time, once a day or if required, up to four times a day.

If the desired clinical response requires larger dosages, larger capsules would be used so that each would contain up to 200 milligrams.

EXAMPLE VI.SINGLE DOSE PREPARATION CON- TAINING 2 AMINO 4,5 DIHYDROXY-PHEN- ETHYLAMINE One gram of 2 amino 4,5 dihydroxyphenethylamine made according to the aforementioned journal article, is equally subdivided into fifty parts and each part weighing 20 milligrams is placed in a hard elastic capsule. One or two of these capsules may be taken at a time, once a day or if required, up to four times a day.

If the desired clinical response requires larger dosages,

larger capsules would be used so that each would contain up to 200 milligrams.

The products of Examples 1 to 4 can be put up in unit dosage form as in Examples 5 and 6.

EXAMPLE VII.-TABLETS CONTAINING 2,4,5- TRIHYDROXYPHENETHYLAMINE One gram of 2,4,5 trihydroxyphenethylamine is combined with conventional tableting ingredients according to known procedures and the mixture is subdivided into 25 parts. Each part, weighing 40 milligrams is compressed into a scored tablet so that a fractional tablet may be taken or one or several tablets may be taken at a time.

Tablets containing larger amounts of this active agent may be made up, or one of the other active agents contemplated by this invention may be substituted.

I claim:

1. A method for the treatment of hypertension which comprises administering to a hypertensive patient a hypotensively effective amount of a compound having the formula:

I OHzCHNHz in which R is selected from the group consisting of-OI-I and -NH and R is selected from the group consisting of H, CH and C H or the pharmaceutically acceptable salts thereof.

3. A method for treatment of hypertension, which comprises administering to a Warm-blooded mammal an effective amount of 2,4,5 trihydroxy a methylphenethylamine or the pharmaceutically acceptable salts thereof.

4. The method of claim 3 wherein said warm-blooded mammal is a human.

References Cited UNITED STATES PATENTS 2,858,312 10/1958 Olin 200570.8

FOREIGN PATENTS 7/1961 Germany.

OTHER REFERENCES Harley-Mason Journal of the Chemical Society (London) for 1953, pp. 200203.

Horner et al., Justus Liebigs Annalen der Chemie, vol. 608, pp. 128-139 (1957).

Senoh et al., Journal of the American Chemical Society, vol. 81, pp. 6236- 6240 (1959).

Hazard et al., Chemical Abstracts, vol. 55, column 20193(c) and Subject Index for Volume 55, p. 18405 (1961).

ALBERT T. MEYERS, Primary Examiner I. GOLDBERG, Assistant Examiner