United States Patent Office Patented Jan

2,819,998 United States Patent Office Patented Jan. 4, 1958

eXe 2,819,998 N-CHC-R1 QUATERNARY SALT DERIVATIVES OF HARMAN N/NA William M. McLamore, Kew Gardens, N. Y., assignor to Chas. Pfizer & Co., Brooklyn, N. Y., a corporation of CH Delaware (II) No Drawing. Original application January 30, 1956, Serial No. 562,026. Divided and this application March O 1, 1957, Serial No. 643,254 R eX6 4 Claims. (Cl. 167-65) R N-C- R4. R NN/ This invention is concerned with a unique group of 15 substituted ammonium salts useful as therapeutic agents. EI CI R " In particular, they are monosalts and are derivatives of harman and 1,2,3,4-tetrahydroharman. They have the R6 unique property of causing a therapeutically useful lower (III) ing of the blood pressure of an animal when administered 20 thereto. Various compounds have been suggested from time to time, in the past, for use in the therapy of hypertension. This application is a divisional application of copending Some of these useful compounds are quaternary ammo application Serial Number 562,026 filed January 30, 1956 nium salts. However, these hypotensive quaternary am 25 in which the salts of Formula III are claimed. Those monium salts known to the art are distinguished from the materials represented by Formula I are claimed in the valuable substituted mono-ammonium salts of this inven present application. In the foregoing structural formu tion in that they are bis-quaternary ammonium salts such las R1 is either a lower hydrocarbonoxy group containing as hexamethonium chloride which is the bis-quaternary up to about six carbon atoms or it is the -NHCHCHNL ammonium salt, N,N,N',N'-tetramethyl-1,6-hexanedi 30 group wherein L is a lower alkyl group containing up to amine dimethochloride. Heretofore, substituted mono about three carbon atoms such as methyl, ethyl or propyl. ammonium salts have not been found useful in the therapy By lower hydrocarbonoxy group is meant groups such as of hypertension. In fact, attempts to find useful agents the methoxy group, the ethoxy group, the butoxy group, among the mono-ammonium salts in the past have met the isobutoxy group and the hexoxy group. These hydro with disappointment. It is therefore surprising that it has 35 carbonoxy groups are substantially saturated but they now been found that certain substituted mono-ammonium may contain some unsaturated linkages such as in the allyl salts have a particularly valuable combination of pharma oxy group. R2 is either a hydrogen atom or a lower cohynamic properties which makes them useful for this aliphatic hydrocarbon group containing up to about six purpose. carbon atoms. The lower aliphatic hydrocarbon groups Many compounds will lower the blood pressure of an 40 are such groups as methyl, ethyl, allyl, butyl and hexyl animal upon injection. However, their hypotensive effect again substantially saturated but which may contain a is a result of mechanisms which are harmful to the host minor proportion of unsaturated linkages. At least two such as the impairing of cardiac output due to cardiac to four of the substituents R, R R5, R6, and Rattached depression or actual cardio-toxicity. This type of activity to the nucleus of the benzyl group in Formulas I and is of course undesirable. The valuable substituted mono 45 are hydrogens, and the remainder are selected from the ammonium salts of this invention has been found to group consisting of a halogen atom, that is a fluorine, a possess a unique combination of peripheral effects includ chlorine, a bromine or an iodine atom and a lower hydro ing ganglionic blocking activity, and direct vasodilator carbonoxy group containing up to about six carbon atoms activity which makes them particularly useful as hypo as defined above. In other words, at least one and not tensive agents. In addition, they have a remarkably low 50 more than three of these groups are substituents other than degree of troublesome side effects including the cardiac hydrogen. Rs is a hydrogen atom or a lower hydrocar effects referred to above. bonoxy group containing up to about six carbon atoms. The valuable mono-ammonium salts of this type have Some examples of such groups appear above. X is a the following structural formulas pharmacologically acceptable anion. By pharmacologi 55 cally acceptable anion is meant an anion which is well R. 9Xe tolerated in the dosages employed with the products of this invention. Examples of pharmacologically accept / -CE -R able anions are chloride, bromide, sulfate, methosulfate, N phosphate, citrate, tartrate, gluconate, succinate, etc. B Y. R Rs 60 These compounds are readily prepared by treating the k parent nitrogenous base with the appropriate quaternizing (I) agent. Appropriate quaternizing agents include aliphatic 2,819,998 3 4. hydrocarbon halides, sulfates, and sulfonates in which the wherein R, R R5, Ra, and R have the same meanings as organic portion of the molecule corresponds to above. gHx -CHCR, --Rs R R R. R. - umam NM S-CH. R- R -CH- Rs E. C R. Rs eXe R CH in the above structural formulas. Examples of useful / quaternizing agents include methyl iodide, dimethylsul N-CB R fate, ethyl bromide, diethyl sulfate, m-methoxybenzyl bromide, 3,4-dichlorobenzyl bromide, 3,4-dimethoxyben CH R Rs zyl p-toluene sulfonate, p-methoxybenzyl chloride, p ethoxybenzyl methanesulfonate, etc. The treatment of harman with methyl bromoacetate to Py-N-methyl-1,2,3,4-tetrahydroharman was prepared by yield one of these valuable substituted mono-ammonium the reduction of harman methobromide or the anhydroni salts is represented in the accompanying equation which um base py-N-methylharman by a standard known proce illustrates the quaternization process. dure. With the anhydronium base, catalytic hydrogena tion employing a platinum catalyst was the most satisfac tory method for carrying out the reduction while sodium borohydride was the most satisfactory agent for reducing N - BrCF2COCs - the methobromide salt. These processes are illustrated NN/ below. E. C 69 H eBre ma N-C Pt N-CH NM N NN/ -OH,C OC ÖH, e H Naby/ s Harman, the nitrogen compounds employed in preparing this mono-quaternary is prepared synthetically by the eBre cyclodehydration, decarboxylation, and dehydrogenation N-CE of N-acetyl-dl-tryptophan by methods well known in the N art employing various dehydrating agents such as phos H phoryl chloride, polyphosphoric acid, etc. This process 40 CH is illustrated by the following equation The parent bases in the tetrahydro series (Formula III), wherein Rs is a lower hydrocarbonoxy group are readily, CHighcott ay prepared by analogous procedures from the O-alkylated NECO CH N 45 harmalol derivatives which are known compounds. Har N/ malol is obtained by demethylation of harmaline, one of B NN/N/H. the Harmala alkaloids. This series is illustrated below Cs wherein R stands for the lower hydrocarbonoxy group of Fs of Formula III.

m-m) CHO- HO RO 3 NN/YA N/ N OO-O-O-B B H CH CH . CE e6 SOCH-)

RO- N/ N-CF RO H CH

Similar processes are known which employ tryptophan or Two of the compounds were prepared by special pro tryptamine and acetaldehyde as starting materials. In the 70 cedures. In the Harman series, for the preparation of the tetrahydroharman series Formula III wherein Ra is a hy compound of Formula II wherein drogen atom, py - N - methyl - 1,2,3,4-tetrahydroharman (12 - di - methyl - 1,2,3,4 - tetrahydro - B - carboline) R=NHCH2CH2N(CH) 2 was treated with a series of substituted benzyl halides, sul the monoquaternary ammonium salt derived from harman fates, and sulfonates according to the following equations 75 and methyl bromoacetate, described above, was treated 2,819,998 5 6 with 2-diethylaminoethyl amine which resulted in the uring the ability of these materials to abolish or decrease formation of the desired amide as is illustrated in the the response of the nictitating membrane to a standard following equation. preganglionic electrical stimulation in the superior cervi cal ganglion preparation of the cat as well as their ability 9Bre to block the stimulating effect on the ganglia of the tetra --NHCHCHN (CH) - methylammonium ion. Stimulation of the ganglia in the N-CICOCs latter fashion is manifested by a rise in blood pressure and S. a contraction of the nictitating membrane as well as other CE pharmacodynamic effects. All of the above compounds eBre O 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 N-CHCONHCHCHNCCHs) or a combination thereof which effected a significant re N/ duction in the animal's blood pressure. CH 5 With regard to possible side effects of these materials In the tetrahydroharman series, Formula III, the com affecting either the heart or the neuro-muscular transmis pound wherein R4=OCH and the remaining R groups are sion, further tests were carried out. The cardiac effects hydrogens was prepared by treating harman with m-meth were measured in the isolated perfused cat's heart accord oxybenzyl bromide and reducing the so-obtained material ing to the Langendorf method. The coronary inflow was with sodium borohydride. This process is illustrated by 20 measured with a flowmeter, and the contractile force and the following equation. rate were recorded with the inkwriting recorder. In a Cl hypotensive drug, a decrease in any of these activities is undesirable since it reflects cardio-toxicity of the drug. &B, 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 cardio OJO-O-N N/ OCH toxicity to a harmful degree. Some actually had a favor H &H, able type of action. Neuro-muscular blocking or curari 30 form activity was measured in the gastrocnemius prepara eCl6 tion of the guinea pig. The activity of these compounds N-CBI OCH was compared with that of d-tubocurarine. None was N/ a-m-m- found to possess more than 4% of the activity of d-tubo B curarine. CHs 35 The valuable hypotensive agents of this invention may e Cle be administered by various routes. In the animal experi B ments described above, however, intravenous administra / tion was found to be the most convenient. These valuable -CH OCEI agents are relatively toxic materials exhibiting acute intra 40 H venous toxicities in the range of about 10-40 mg/kg. CH However, very small doses of these substances are re In the above quaternization processes the anion X is quired. Intravenous doses in the range of 0.5-4.0 mg/kg. usually either a halogen anion such as chloride, bromide or were found to be effective. Doses of the order of 1 iodide or an organic sulfate or sulfonate anion such as ng./kg. or less were commonly used. Thus the thera methosulfate, ethosulfate, benzenesulfonate, or para 45 peutic index is sufficiently high to make these materials. toluenesulfonate. These anions may be replaced by other safe to use. pharmaceutically acceptable anions such as the phosphate, These compounds may be combined with various phar succinate, citrate, or tartrate by various processes well maceutical carriers the choice of which depends upon the known in the art. For example, with the quaternary salts, properties of the particular compounds and upon the route the salt may be converted to the quaternary ammonium 50 of administration. For intravenous administration, it is hydroxide by treatment with silver oxide, or, by passage convenient to employ the compounds in the form of dilute - through a column of a strongly basic union exchange resin solutions either in water or in aqueous solutions isotonic on the hydroxide cycle. Examples of useful ion exchange in glucose or sodium chloride. resins are DoweX 1, DoweX 2, Amberlite IRA-400 and The following examples are given to illustrate the prep Amberlite IRA-410. These resins are polyguaternary am 55 aration of specific compounds of this invention. They monium compounds in which the quaternary ammonium are presented for illustrative purposes only and are not to groups are attached to a styrene-divinylbenzene copoly be considered as limiting the invention in any way. mer. Such resins are prepared for example, by chloro Example I-Substituted ammonium salts methylating the copolymer and then treating it with an alkyl halide such as trimethylamine or dimethylethanol 60 The bulk of the substituted ammonium salts referred to amine. The so-obtained solution of the substituted am herein were prepared by refluxing the base with the quater. ... monium hydroxide corresponding to one of the salts of nizing agent in acetone for from one to seven hours and this invention is then neutralized with the acid correspond then filtering the product, either immediately after cooling ing to the desired anion. Alternatively, one of the above or after storing the mixture overnight. The cake was substituted mono-ammonium halides of this invention may 65 washed on the filter with fresh solvent and generally re be treated directly with the silver salt of the acid corre crystallized from a suitable solvent. Yields of crude sponding to the desired anion in an aqueous alcoholic product obtained were of the order of 90%. In some solution. The silver halide precipitates and can be sepa instances, the product was obtained directly in a pure rated from the product. condition and recrystallization was not necessary. Specific The ability of these compounds to bring about a thera 70 results obtained for each of the compounds prepared by peutically useful reduction in blood pressure was deter this type of procedure are summarized in the accompany mined in cats anesthetized with chloralose by canulating ing table. In this particular series of compounds, the the carotid artery and recording the blood pressure on a bases employed in preparing these quaternary salts were kyrnograph. after subjecting the cat... to various stimuli. harman, 1,2-dimethyl-1,2,3,4-tetrahydro-6-carboline, and The ganglionic blocking activity was determined by meas 75 1,2-dimethyl-7-methoxy-1,2,3,4-tetrahydro-p-carboline, 7 2,819,998 Substituted Ammonium Salts Prepared by the Procedure of Example I Analysis No. Compound M. P., O. Recryst. solvent Calculated Found

e N-R xe N/ ÖH, R Xe

1---- 6 -CI OCHs Br 269.5-270.5 MeO------62.67 5.00 7.3i ------62.56 5.18 6.97 ------

2---- -CHCOOH Bre 209-20 MeOH------53.74 4,51 8.36 23.84 53.47 Compound

6 oil, R SQ Xe S. R C R R Xe

8.--- C -CH O CH Br 80-8 MeO-Me2CO.-- 62.84 6.28, 6.98 ------62.65 6.60 6.68 ------

4 -CH Cle 199-20 MeO-MeCO 70.67 7.06 7.85 9,94 70.64 7.47 7.47 0.00 O CBIs

O C3 5---- -CH H Br 188-189 Not recryst...... 62.84 6.28 6.98 ------. 62.25 6.21 6.84 ------

6 -CH H Br 179-180 ...do------54.57 4.8l 6.36 ------54.94 5.24 6.15 ------

Cl b

7- -CH OCH OCH3 Bre 177-178.5 ------6.25 6.31 6.49 ----.... 61.85 6.33 6.27.------.

Example II-1,2-dimethyl-7-methoxy-1,2,3,4-tetrahydro extracts were washed with an aqueous sodium chloride g-carboline solution, dried over magnesium sulfate and concentrated until crystals separated. The product weighed 6.32 g. Harmaline methosulfate, 6.77 g., dissolved in 120 mi. 65 and had a melting point of 177-179 C. It was a white of methanol was added to a solution of 3.78 g. of sodium crystalline solid which could be recrystallized from ethanol borohydride and 1.33 g. of sodium hydroxide dissolved and acetone. An analytical sample so prepared had a in 40 ml. of methanol. The mixture was refluxed for 2 melting point of 177.5-178.5. hours and a further 1.99 g, of sodium borohydride and Analysis.--Calculated for C14H18ON: C, 73.01; H, 20 mi. of methanol was added. The solution was re () fluxed for an additional three hours after which time the 7.88; N, 12.17. Found: C, 72.99; H, 7.98; N, 12.19. yellow color had faded. The solvent was removed and Example III.-l-methyl-2-(n-methoxybenzyl)-1,2,3,4- ether and water were added to the residue. The layers tetrahydro-3-carboline hydrochloride were separated and the water layer extracted several times A solution of 12.1 grams of sodium borohydride in with additional portions of ether. The combined ether 75 v100 ml of methanol was slowly added to a slurry of 16 g. 2,819,998 9 10 of the m-methoxybenzyl bromide salt of harman (Ex Analysis.-Calculated for CHONBr: C, 57.28; H, ample 1-compound No. 1 in the table) in 200 ml. of 6.49; N, 13.36. Found: C, 56.83; H, 6.37; N, 13.19. methanol. The mixture was refluxed with stirring for What is claimed is: six hours, the methanol evaporated, and the residue treated 1. A compound having the formula: with water and ether. The layers were separated and the ether and the water layer extracted with several additional eXe portions of ether. The extracts were dried over magne sium sulfate and the solvent removed yielding 13.6 g. of -CI R crude 1-methyl-2-(m-methoxybenzyl)-1,2,3,4-tetrahydro N 3-carboline. This material was dissolved in dry ether ) H bH, R- Rs and treated with an excess of methanolic hydrogen chlo ride. The hydrochloride salt of the base was precipitated by treating the solution with acetone. The crude product 8 was recrystallized from a mixture of methanol and acetone yielding white needles, melting point 226-226.5 C. wherein from two to four of the substituents R3, RA, R5, Analysis.--Calculated for CH3ONCi: C, 70.06; H, Rs, and R are hydrogen and each remaining substituent 6.47; N, 8.7. Found: C, 69.85; H, 6.60; N, 8.19. is selected from the group consisting of halogen and a lower hydrocarbonoxy group containing up to six carbon Example IV.-I-imethyl-2-(2-diethylaminoethylcarbamyl atoms, and X is a pharmacologically acceptable anion. methyl)-3-carbolinium bromide 2. A therapeutic composition comprising a compound 2-carbomethyoxymethyl harmanium bromide (Exam as claimed in claim 1 and a pharmaceutical carrier there ple i-compound No. 2 in the table), 2.01 g. was re for. flexed with 3.48g. of dry diethylaminoethylamine in 30 ml. 3. A method for reducing the blood pressure compris of anhydrous methanol for 4 hours. The solution was ing the step of administering to the host a compound as concentrated and the product precipitated by treatment 2 5 claimed in claim 1. of the concentrate with benzene. It was a light yellow 4. 1-methyl- 2 - (m-methoxybenzyl)-carbolinium bro- . solid which was collected, washed with benzene and ether mide. and recrystallized from acetone and methanol. Its melt ing point was 189-190 C. 30 No references cited.