US2820040A - Substituted mono-ammonium salts - Google Patents

Description

t d States Paten SUBSTITUTED MON O-AMMONIUM SALTS William M. McLamore, Kew Gardens, N. Y., assignor to Chas. Pfizer & Co., Inc., Brooklyn, N. Y., a corporation of Delaware No Drawing. Application January 30, 1956 Serial No. 562,026

8 Claims. (Cl. 260-296) This invention is concerned with a unique group of substituted ammonium salts useful as therapeutic agents. In particular, they are mono-salts and are derivatives of harman and 1,2,3,4-tetrahydroharman. They have the unique property of causing a therapeutically useful lowering of the blood pressure of an animal when administered thereto.

Various compounds have been suggested from time to time, in the past, for use in the therapy of hypertension. Some of these useful compounds are quaternary ammonium salts. However, these hypotensive quaternary ammonium salts known to the art are distinguished from the valuable substituted mono-ammonium salts of this invention in that they are bis-quaternary ammonium salts such as hexamethonium chloride which is the bis-quarternary ammonium salt, N,N,N,N'-tetramethyl-1,6-hexanediamine dimethochloride. Heretofore, substituted monoammonium salts have not been found useful in the therapy of hypertension. In fact, attempts to find useful agents among the mono-ammonium salts in the past have met with disappointment. It is therefore surprising that-it has now been found that certain substituted mono-ammonium salts have a particularly valuable combination of pharmacodynamic properties which makes them useful for this purpose.

Many compounds will lower the blood pressure of an" animal upon injection. However, their hypotensive efiect is a result of mechanisms which are harmful to the host such as the impairing of cardiac output due tocardiac depression or actual cardio-toxicity. This type of activity is of course undesirable. The valuable substituted monoammonium salts ofthis invention have been found to possess a unique combination of peripheral effects including ganglionic blocking activity, and direct vasodilator activity which makes them particularly useful as hypotensive agents. In addition, they have a remarkably low degree of troublesome side efiects including the cardiac effects referred to above.

The valuable mono-ammonium salts of this invention have the following structural formulas Rs 69x6,

ice

R: 39x9 R2 N-CHz R4 Rs- N H CH: R1 -Ru-i BB In the foregoing structural formulas R is either a lower hydrocarbonoxy group containing up to about six carbon atoms or it is the NHCH CH NL group wherein L is a lower alkyl group containing up to about three carbon atoms such as methyl, ethyl or propyl. By lower hydrocarbonoxy group is meant groups such as the methoxy group, the ethoxy group, the butoxy group, the isobutoxy group and the hexoxy group. These groups are substantially saturated but they may contain some unsaturated linkages such as in the allyloxy group. R is either a hydrogen atom or a lower aliphatic hydrocarbon group containing up to about six carbon atoms. The lower aliphatic hydrocarbon groups are such groups as methyl, ethyl, allyl, butyl and hexyl again substantially saturated but which may .contain a minor proportion of unsaturated linkages. At least two to four of the substituents R R R R and R attached to the nucleus of the benzyl group in Formulas l and III are hydrogens, and the remainder are selected from the group consisting of a halogen atom, that is a fluorine, a chlorine, a bromine or an iodine atom and a lower hydrocarbonoxy group containing up to about six carbon atoms as defined above. In other words, at least one and not more than three of these groups are substituents other than hydrogen. R is a hydrogen atom or a lower hydrocarbonoxy group containiug up to about six carbon atoms. Some examples of such groups appear above. X is a pharmacologically acceptable anion. By pharmacologically acceptable anion is meant an anion which is well tolerated in the dosages employed with the products of this invention. Examples of pharmacologically acceptable anions are chloride, bromide, sulfate, methosulfate, phosphate, citrate, tartrate, gluconate, succinate, etc.

These compounds are readily prepared by treating the parent nitrogenous base with the appropriate quaternizing agent. Appropriate quaternizing agents include aliphatic hydrocarbon halides, sulfates, and sulfonates in which the organic portion of the molecule corresponds to II -CHaCRt, R:

3 and sulfonates according to the following equation wherein R R R R and R have the same meanings as above. 3, 1's, CHSX -CH Rs 5 R1 R:

R1 Ra N/ N CH R15 R4 H in the above structural formulas. Examples of useful 10 quaternizing agents include methyl iodide, dimethylsul- 9X9 R fate, ethyl bromide, diethyl sulfate, m-methoxybenzyl CE: bromide, 3,4-dichlorobenzyl bromide, 3,4-dimethoxyi R benzyl p-toluene sulfonate, p-methoxybenzyl chloride, p- N/'\/ 2- ethoxybenzyl methanesulfonate, etc. H R The treatment of barman with methyl bromoacetate to CH3 5 yield one of the valuable substituted mono-ammonium R5 salts of this invention as re resented in the accom an in equation illustrates the qua t ernization process. p y g Py-N-methyl-llzi3r4-tetrahydroharman w Prepared by I the reduction of harman methobromrde or the anhydronium base py-N-methylharman by a standard known procedure. With the anhydronium base, catalytic hydrogenation employing a platinum catalyst was the most N BlCHzCOaCHs satisfactory method for carrying out the reduction while N sodium borohydride was the most satisfactory agent for 3 B reducing the methobromide salt. These processes are ilaBre lustrated below.

CH2002CHS i N a N-orn Pt N-on, H 1 N N l H e 1H; 0H: Harman, the nitrogen compound employed in preparing NaBIy this mono-quaternary is prepared synthetically by the cyclodehydration, decarboxylation, and dehydrogenation 9319 of N-acetyl-dl-tryptophan by methods well known in the art employing various dehydrating agents such as phos- CH2 phoryl chloride, polyphosphoric acid, etc. This process N is illustrated by the following equation. H (I133 The parent bases in the tetrahydro series (Formula OH2CHCO2H HI) wherein R is a lower hydrocarbonoxy group are NHCOOHS readily prepared by analogous procedures from the O- l N alkylated harmalol derivatives which are known compounds. Harrnalol is obtained by demethylation of harmaline, one of the Harmaia alkaloids. This series is illustrated below wherein R stands for the lower hydrocarbon group of R of Formula 1H.

N N N OHaO N HO N R0 N H I H I H CH3 OH: H:

SOCHZ OH. 1?:

R0 N-CH: N-om R0 -CH: at

a a a CH: CH: O R R5 Similar processes are known which employ tryptophan or Two of the compounds of this invention were prepared tryptamine and acetaldehyde as starting materials. -In the by special procedures. In the barman series, for the tetrahydroharman series, Formula III wherein R3 is a preparation of the compound of Formula I! wherein hydrogen atom, py-N-methyl-l,2,3,4-tetrahydroharman v R =NHCH CH N(C H the monoquatern-ary am (1,2-dimethyl-1,2,3,4-tetrahydro-fl-carboline) was treated monium salt derived from barman and methyl bromowith a series of substituted benzyl halides, sulfates, and acetate, described above, wastreated with Z-diethylamino- ..5 ethyl amine which resulted in the formation of the desired amide as is illustrated in the following equation.

Bre

In the tetrahydroharman series, Formula III, the compound wherein R =OCH and the remaining R groups are hydrogens was prepared by treating harman with mmethoxybenzyl bromide and reducing the so-obtained material with sodium borohydride. This process is illustrated by the following equation.

CH:- OCH:

@019 /H NCH OCH: N H

through a column of a strongly basic anion exchange resin on the hydroxide cycle. Examples of useful ion exchange resins are Dowex 1, Dowex 2, Amberlite IRA-400 and Amberlite IRA-410. These resins are polyquaternary ammonium compounds in which the quaternary ammonium groups are attached to a styrene-divinylbenzene copolymer. Such resins are prepared for example, by chloromethylating the copolymer and then treating it with an alkyl halide such as trimethylamine or dimethylethanolamine. The so-obtained solution of the substituted ammonium hydroxide corresponding to one of the salts of this invention is then neutralized with the acid corresponding to the desired anion. Alternatively, one of the abov: substituted mono-ammonium halides of this invention may be treated directly with the silver salt of the acid corresponding to the desired anion in an aqueous alcoholic solution. The silver halide precipitates and can be separated from the product.

The ability of these compounds to bring about a therapeutically useful reduction in blood pressure was determined in cats anesthetized with chloralose by cannulating the carotid artery and recording the blood pressure on a kymograph after subjecting the cat to various stimuli. The ganglionic blocking activity was determined by measuring the ability of these materials to abolish or decrease the response of the nictitating membrane to a standard preganglionic electrical stimulation in the superior cervical ganglion preparation of the cat as well as their ability to block the stimulating effect on the ganglia of the tetramethylammonium ion. Stimulation of the ganglia in the latter fashion is manifested by a rise in blood pressure and a contraction of the nictitating membrane as well as other pharmacodynamic effects. All of the above compounds were found in these tests to be highly effective in reducing the blood pressure. That is each was found to possess ganglionic blocking activity, or direct vasodilator activity or a combination thereof which effected a significant reduction in the animals blood pressure.

With regard to possible side effects of these materials affecting either the heart or the neuro-muscular transmission, further tests were carried out. The cardiac effects were measured in the isolated perfused cats heart according to the Langendorf method. The coronary inflow was measured with a fiowmeter, and the contractile force and rate were recorded with the inkriting recorder. In a hypotensive drug, a decrease in any of these activities is undesirable since it reflects cardio-toxicity of the drug. While an increase in coronary inflow is desirable, it is not a necessary prerequisite for a useful drug. None of the valuable mono-ammonium salts of the present invention was found to elicit the above manifestations of cardiotoxicity to a harmful degree. Some actually had a favorable type of action. Neuro-muscular blocking or curariform activity was measured in the gastrocnemius preparation of the guinea pig. The activity of these compounds was compared with that of d-tubocurarine. None was found to possess more than 4% of the activity of dtubocurarine.

The valuable hypotensive agents of this invention may be administered by various routes. In the animal experiments described above, however, intravenous administration was found to be the most convenient. These valuable agents are relatively toxic materials exhibiting acute intravenous toxicities in the range of about 10-40 mg./kg. However, very small doses of these substances are required. Intravenous doses in the range 0.5-4.0 rug/kg. were found to be effective. Doses of the order of 1 mgJkg. or less were commonly used. Thus the therapeutic index is sufficiently high to make these materials safe to use.

These compounds may be combined with various pharmaceutical carriers the choice of which depends upon the properties of the particular compounds and upon the route of administration. For intravenous administration, it is convenient to employ the compounds in the form of dilute solutions either in water or in aqueous solutions isotonic in glucose or sodium chloride.

The following examples are given to illustrate the preparation of specific compounds of this invention. They are presented for illustrative purposes only and are not to be considered as limiting the invention in any way.

EXAMPLE I Substituted ammonium salts The bulk of the substituted ammonium salts referred to herein were prepared by refluxing the base with the quaternizing agent in acetone for from one to seven hours and then filtering the product, either immediately after cooling or after storing the mixture overnight. The cake was washed on the filter with fresh solvent and generally recrystallized from a suitable solvent. Yields of crude product so obtained were of the order of 90%. In some instances, this product was obtained directly in a pure condition and recrystallization was not necessary. Specific results obtained for each of the compounds prepared by this type of procedure are summarized in the accompanying table. In this particular series of compounds, the bases employed in preparing these quarternary salts were harman, 1,2 dimethyl 1,2,3,4 tetrahydro 8 carboline, and 1,2 dimethyl 7 methoxy 1,2,3,4 tetrahydro-p-carboline.

1 ,2 -d imethyl-7-meth0xy-1 ,2,3 ,4 -tetrahydro-fi-carboli ne Harmaline methosulfate, 6.77 g., dissolved in 120 ml. of methanol was added to a solution of 3.78 g. of sodium borohydride and 1.33 g. of sodium hydroxide dissolved in ml. of methanol. The mixture was refluxed for 2 hours and a further 1.99 g. of sodium borohydride and 20 m1. of methanol was added. The solution was refluxed for an additional three hours after which time the yellow color had faded. The solvent was removed and ether and water were added to the residue. The layers were separated and the water layer extracted several times with additional portions of ether. The combined ether SUBSTITUTED AMMONIUM SALTS PREPARED BY PROCEDURE OF EXAMPLE 1 Analysis No. Compound M. P., 0. Reeryst. solvent Calculated Found 0 H N x o H N X N-R x N/ H I CH 00H: Br 269.5-270.5 MBOH 62.67 5.00 7.31 82.56 5.18 6.07

2.--- CH1GOaCHa B1 209-210 Me0H 53.74 4.61 8.36 23.84 63.47 4.50 8.38 23.70

Compound "63 /CH; N X

R R x CH OCH; H Br -181 MeOH-MeaCO--- 62.84 6.28 6.98 62.65 6.60 6.68

-03 H 01 199-201 MeOH-MezOO.-- 70.67 7.00 7.85 0.94 70.64 7.47 7.74 10.00

OCH:

-oH, H Br 188-189 Notrecryst 62.84 6.28 6.98 62.25 6.21 6.84

oH H Br 179-180 --.--do 51.57 4.51 6.36 64.04 5.24 6.15

-OH 00111 00B: 131 177178.5 61.25 6.31 6.40 61.85 1133 6.27

EXAMPLE II extracts were washed with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated until crystals separated. The product weighed 6.32 g. and had a melting point of 177-179 C. It was a white crystalline solid which could be recrystallized from ethanol and acetone. An analytical sample so prepared had a melting point of 177.5-178.5.

Analysis.-Calculated for C H ON C, 73.01; H, 7.88; N, 12.17. Found; C, 72.99; H, 7.98; N, 12.19.

carboline hydrochloride A solution of 12.1grams of sodium borohydridein 100 ml. of methanol was slowly added to a slurry of 16 g. of the m-methoxybenzyl bromide salt of harman (Example lcompound No. 1 in the table) in 200 ml. of methanol. The mixture was refluxed with stirring for six hours, the methanol evaporated, and the residue treated with water and ether. The layers were separated and the ether and the water layer extracted with several additional portions of ether. The extracts were dried over magnesium sulfate and the solvent removed yielding 13.6 g. of crude l-methyl- 2. (In-methoxybenzyl) l,2,3,4 tetrahydro-B-carboline. This material was dissolved in dry ether and treated with an excess of methanolic hydrogen chloride. The hydrochloride salt of the base was precipitated by treating the solution with acetone. The crude product was recrystallized from a mixture of methanol and acetone yielding white needles, melting point 226226.5 C.

Analysis.Calculated for C H ON Cl: C, 70.06; H, 6.47; N, 8.17. Found: C, 69.85; H, 6.60; N, 8.19.

EXAMPLE 1V 1 methyl 2 (2 dierhylaminaethylcarbamylmethyl)18- carbolinium bromide Z-carbomethoxymethyl harmanium bromide (Example lcompound No. 2 in the table), 2.01 g. was refluxed with 3.48 g. of dry diethylaminoethylamine in 30 ml. of anhydrous methanol for 4 hours. The solution was concentrated and the product precipitated by treatment of the concentrate with benzene. It was a light yellow solid which was collected, washed with benzene and ether and recrystallized from acetone and methanol. point was 189-190 C.

Analysis.Calculated for C H ON Br: C, 57.28; H, 6.49; N, 13.36. Found: C, 56.83; H, 6.37; N, 13.19.

What is claimed is:

l. A compound having the formula:

R r S R N-CH a.

N/ H a R Its melting wherein R is selected from the group consisting of hydrogen and a lower aliphatic hydrocarbon group containing up to about six carbon atoms; at least two to four of R R R R and R are hydrogen and the remainder are selected from the group consisting of a halogen atom and a lower hydrocarbonoxy group containing up to about six carbon atoms; R is selected from the group consisting of hydrogen and a lower hydrocarbonoxy group containing up to about six carbon atoms; and X is a pharmacologically acceptable anion.

2. A therapeutic composition comprising a compound as claimed in claim 1 and a pharmaceutical carrier therefor.

3. A method for reducing the blood pressure comprising the step of administering to the host a compound as claimed in claim 1.

4. 1,2 dimethyl 2 (n1 methoxybenzyl) 1,2,3,4- tetrahydro-B-carbolinium bromide.

5. 1,2 dimethyl 2 (0 methoxybenzyl) 1,2,3,4- tetrahydro-B-carbolinium bromide.

6. 1,2 dimethyl 2 (3,4 dichlorobenzyl) l,2,3,4- tetrahydro-fl-carbolinium bromide.

7. 1,2 dimethyl 2 (p methoxybenzyl) 1,2,3,4- tetrahydro-fi-carbolinium--chloride.

8. l-methyl 2 (2-diethylaminoethylcarbamylmethyl)- fi-carbolinium bromide.

References Cited in the file of this patent UNITED STATES PATENTS Pyman et al July 21, 1936 Duschinsky June 16, 1953 OTHER REFERENCES

Claims (1)

1. A COMPOUND HAVING THE FORMULA: