US2819998A - Nxchjcoschs - Google Patents

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US2819998A
US2819998A US2819998DA US2819998A US 2819998 A US2819998 A US 2819998A US 2819998D A US2819998D A US 2819998DA US 2819998 A US2819998 A US 2819998A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

  • R is either a lower hydrocarb-onoxy 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.
  • L is a lower alkyl group containing up to about three carbon atoms such as methyl, ethyl or propyl.
  • lower hydrocarb-onoxy group is meant groups such as the methoxy group, the ethoxy group, the butoxy group, the isobutoxy group and the hexoxy group.
  • hydrocarbonoxy groups are substantially saturated but they maycontain 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 I 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 containing up to about six carbon atoms. Some examples of such groups appear above.
  • X is a pharmacologically acceptable anion.
  • 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.
  • quaternizing agents include aliphatic hydrocarbon halides, sulfates, and sulfonates in which the organic portion of the molecule corresponds to in the above structural formulas.
  • useful quaternizing agents include methyl iodide, vdimethylsulfate, ethyl bromide, diethyl sulfate, m-methoxybenzyl bromide, 3,4-dichlorobenzyl bromide, 3,4-dimethoxybenzyl p-toluene sulfonate, p-methoxy-benzyl chloride, pethoxybenzyl methanesulfonate, etc.
  • the nitrogen compounds employed in preparing this mono-quaternary is prepared synthetically by the cyclodehydration, decarboxylation, and dehydrogenation of N-acetyl-dl-tryptophan by methods well known in the art employing various dehydrating agents such as phosphoryl chloride, polyphosphoric acid, etc. This process is illustrated by the following equation wherein 3 4. 5. e nd R have the same meanings as above.
  • Py-N-methyl-1,2,3,4-tetrahydroharman was prepared by the reduction of harman methobromide or the anhydronium base py-N-methylharman by a standard known procedure.
  • anhydronium base catalytic hydrogenation employing a platinum catalyst was the most satisfactory method for carrying out the reduction while sodium borohydride was the most satisfactory agent for reducing
  • the parent bases in the tetrahydro series (Formula III wherein R is a lower hydrocarbonoxy group are readily CHzCHCOzH prepared by analogous procedures from the O-alkylated NHCOCH' harmalol derivatives which are known compounds. Harmalol is obtained by demethylation of harmaline, one of g g I the Harmala alkaloids. This series is illustrated below 11, wherein R stands for the lower hydrocarbonoxy group of P of Formula III.
  • the anion X is usually either a halogen anion such as chloride, bromide or iodide or an organic sulfate or sulfonate anion such as methosulfate, ethosulfate, benzenesulfonate, or paratoluenesulfonate.
  • halogen anion such as chloride, bromide or iodide
  • organic sulfate or sulfonate anion such as methosulfate, ethosulfate, benzenesulfonate, or paratoluenesulfonate.
  • These anions may be replaced by other pharmaceutically acceptable anions such as the phosphate, succinate, citrate, or tartrate by various processes well known in the art.
  • the salt may be converted to the quaternary ammonium hydroxide by treatment with silver oxide or.by passage through a column of a strongly basic union exchange resin on the hydroxide cycle.
  • Examples of useful ion exchange resins are Dowex l, 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 arrimonium hydroxide corresponding to one of the salts of this invention is then neutralized with the acid corresponding to the desired anion.
  • one of the above 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 canulating the carotid artery and recording the blood pressure on a kymogrlaphafter subjecting the cat to various stimuli.
  • the ganglionic blocking activity was determined by measconvenient to employ the compounds in the form of.dilute uring 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 eflected a significant reduction in the animals blood pressure.
  • 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 d-tubocurarine.
  • 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 of 0.5-4.0 mg./ kg. were found to be'effective. Doses of the order of 1 mg./kg. or less were commonly used. Thus the therapeutic index is sufliciently high to make these materials safe to use.
  • These compounds may be combined with various phar maceutical carriers the choice of which depends upon the properties of the particular compounds and upon the route of administration.
  • phar maceutical carriers the choice of which depends upon the properties of the particular compounds and upon the route of administration.
  • intravenous administration it is solutions either in Water or in aqueous solutions isotonic in glucose or sodium chloride.
  • Example I Substituted ammonium salts
  • the bulk of the substituted ammonium salts referred to herein were prepared by refluxing the base with the quater-- results obtained for each of the compounds prepared by this type of procedure are summarized in the accompanying table. bases employed in preparing these quaternary salts were harman, 1,Z-dimethyl-1,2,3,4-tetrahydro-B-carboline, and 1,2-dimethyl-7-methoxy-1,2,3,4tetrahydro- 8-carboline.
  • Example II -1,2-dimethyl-7-meth0xy-1,2,3,4-teirahydrofi-carboline Harmaline methosulfate, 6.77 g.', dissolved in 120 ml. of methanol was added to a solution of 3.7 8 g. of sodium borohydride and 1.33 g. of sodium hydroxide dissolved in 40 ml. of methanol. The mixture was refluxed for 2 hours and a further 1.99 g. of sodium borohydride and 20 ml. 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.
  • Example ,IIl.1-methyl-2-(m-methoxybenzyl)-1,2,3,4- tetrahydro-fl-carboline hydrochloride A solution of 12.1 grams of sodium borohydride in ml. of methanol was slowly added to a slurry of 16 g.
  • Example IV --1-methyl-2-(Z-diethylaminoethylcarbamylmethyD-B-carbolinium bromide 2-carbomethyoxymethyl harmanium bromide (Exampie I-ccmpound No. 2 in the table), 2.01 g. was reflexed 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. Its melting point was 189-190 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States QUATERNARY SALT DERIVATIVES OF AN William M. McLamore, Kew Gardens, N. Y., assignor to Chas. Pfizer & Co., Brooklyn, N. Y., a corporation of Delaware 4 Claims. (Cl. 167--65) This invention is concerned with a unique group of substituted ammonium salts useful as therapeutic agents. In particular, they are monosalts and are derivatives of barman 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-quaternary 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 pharmacohynamic properties which makes them useful for this purpose.
Many compounds will lower the blood pressure of an animal upon injection. However, their hypotensive effect is a result of mechanisms which are harmful to the host such as the impairing of cardiac output due to cardiac depression or actual cardio-toxicity. This type of activity is of course undesirable. The valuable substituted monoammonium salts of this invention has been found to possess a unique combination of peripheral eflects 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 effects including the cardiac effects referred to above.
The valuable mono-ammonium salts of this type have the following structural formulas atent O 2,819,998 Patented Jan. 14, 1958 lCe 69x9 i N-CHzC-Rt H .N-CHa- R4. R
H OH R In] (III) This application is a divisional application of copending application Serial Number 562,026 filed January 30, 1956 in which the salts of Formula [II are claimed. Those materials represented by Formula I are claimed in the present application. In the foregoing structural formulas R is either a lower hydrocarb-onoxy 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 hydrocarb-onoxy group is meant groups such as the methoxy group, the ethoxy group, the butoxy group, the isobutoxy group and the hexoxy group. These hydrocarbonoxy groups are substantially saturated but they maycontain 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 I 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 containing 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 in the above structural formulas. Examples of useful quaternizing agents include methyl iodide, vdimethylsulfate, ethyl bromide, diethyl sulfate, m-methoxybenzyl bromide, 3,4-dichlorobenzyl bromide, 3,4-dimethoxybenzyl p-toluene sulfonate, p-methoxy-benzyl chloride, pethoxybenzyl methanesulfonate, etc.
The treatment of harman with methyl bromoacetate to yield one of these valuable substituted mono-ammonium salts is represented in the accompanying equation which illustrates the quaternization process.
Harman, the nitrogen compounds employed in preparing this mono-quaternary is prepared synthetically by the cyclodehydration, decarboxylation, and dehydrogenation of N-acetyl-dl-tryptophan by methods well known in the art employing various dehydrating agents such as phosphoryl chloride, polyphosphoric acid, etc. This process is illustrated by the following equation wherein 3 4. 5. e nd R have the same meanings as above.
Py-N-methyl-1,2,3,4-tetrahydroharman was prepared by the reduction of harman methobromide 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 satisfactory method for carrying out the reduction while sodium borohydride was the most satisfactory agent for reducing The parent bases in the tetrahydro series (Formula III wherein R is a lower hydrocarbonoxy group are readily CHzCHCOzH prepared by analogous procedures from the O-alkylated NHCOCH' harmalol derivatives which are known compounds. Harmalol is obtained by demethylation of harmaline, one of g g I the Harmala alkaloids. This series is illustrated below 11, wherein R stands for the lower hydrocarbonoxy group of P of Formula III.
N N N on 0- 1 no R0 3 N N/ N H H CH: CH: CH;
$6 SOACH! c N-om N-CH: N w? R. RO- RO- R0 g/V \g (3112 CH: CH: RP B I Similar processes are known which employ tryptophan or Two of the compounds were prepared by special protryptamine and acetaldehyde as starting materials. In the 70 cedures. In the Harman series, for the preparation of the tetrahydroharrnan series Formula III wherein R is a hycompound of Formula II wherein drogen atom, py N methyl 1,2,3,4 tetrahydroharman l (1,2 di methyl l,2,3,4 tetrahydro B carboline) 2 2 2 s)z I was treated with a series of substituted benzyl halides, sulthe monoquaternary ammonium salt derived froni barman fates, and sulfonates according to the following equation 75 and methyl bromoacetate, described above, was treated with 2-diethylaminoethyl amine which resulted in the formation of the desired amide as is illustrated in the following equation.
QBB G N-CHzC ONHCHzCHaN(C=Hs)2 H In the tetrahydroharman series, Formula III, the compound wherein R.,: OCH and the remaining R groups are hydrogens was prepared by treating harman with m-methoxybenzyl bromide and reducing the so-obtained material H with sodium borohydride. This process is illustrated by the following equation.
' (ilH:
l l N/ N OCH:
$Cle
In the above quaternization processes the anion X is usually either a halogen anion such as chloride, bromide or iodide or an organic sulfate or sulfonate anion such as methosulfate, ethosulfate, benzenesulfonate, or paratoluenesulfonate. These anions may be replaced by other pharmaceutically acceptable anions such as the phosphate, succinate, citrate, or tartrate by various processes well known in the art. For example, with the quaternary salts, the salt may be converted to the quaternary ammonium hydroxide by treatment with silver oxide or.by passage through a column of a strongly basic union exchange resin on the hydroxide cycle. Examples of useful ion exchange resins are Dowex l, 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 arrimonium 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 above 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 canulating the carotid artery and recording the blood pressure on a kymogrlaphafter subjecting the cat to various stimuli. The ganglionic blocking activity was determined by measconvenient to employ the compounds in the form of.dilute uring 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 eflected 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 inkwriting 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 d-tubocurarine.
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 of 0.5-4.0 mg./ kg. were found to be'effective. Doses of the order of 1 mg./kg. or less were commonly used. Thus the therapeutic index is sufliciently high to make these materials safe to use.
These compounds may be combined with various phar maceutical carriers the choice of which depends upon the properties of the particular compounds and upon the route of administration. For intravenous administration, it is 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 quater-- results obtained for each of the compounds prepared by this type of procedure are summarized in the accompanying table. bases employed in preparing these quaternary salts were harman, 1,Z-dimethyl-1,2,3,4-tetrahydro-B-carboline, and 1,2-dimethyl-7-methoxy-1,2,3,4tetrahydro- 8-carboline.
In this particular series of compounds, the
Substituted Ammonium Salts Prepared by the Procedure of Example I Analysis No. Compound M. P., O. Reeryst. solvent Calculated Found H N X 0 H N X 63 l N-B x H 'CH OCH: Br 2695-2705 BIeOE 62.67 5.00 7.31 62.56 5.18 6.97
2.-.- -OH1COzCHz Br 209-210 MeOH 53.74 4.51 8.36 23.84 53.47 4.50 8.38 23.79
Compound EB /CH: N\ x N H R R R x CH OCH: H Br 180-181 MeOH-MezCO.-- 62.84 6.28 6.98 62.65 6.60 6.68
4--.. -CH H Gl 199-201 MeOH-Me:OO-- 70.67 7.06 7.85 9.94 70.64 7.47 7.47 10.00
OCH;
OCHs 5...-
-CH H Br 188-189 Not recryst 62.84 6.28 6.98 62.25 6.21 6.84
0..-- CH H B1 muse ---do 54.57 4.81 6.36 54.94 5.24 6.15
7.--. CH OCH; OCH Br 177-178.5 61.25 6.31 6.49 61.85 6.33 6.27
Example II.-1,2-dimethyl-7-meth0xy-1,2,3,4-teirahydrofi-carboline Harmaline methosulfate, 6.77 g.', dissolved in 120 ml. of methanol was added to a solution of 3.7 8 g. of sodium borohydride and 1.33 g. of sodium hydroxide dissolved in 40 ml. of methanol. The mixture was refluxed for 2 hours and a further 1.99 g. of sodium borohydride and 20 ml. 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 Analysis-Calculated for C14H18ON2: c, 73.01; H, 7.88; N, 12.17. Found: 0, 72.99; H, 7.98; N, 12.19.
Example ,IIl.1-methyl-2-(m-methoxybenzyl)-1,2,3,4- tetrahydro-fl-carboline hydrochloride A solution of 12.1 grams of sodium borohydride in ml. of methanol was slowly added to a slurry of 16 g.
of the m-methoxybenzyl bromide salt of harman (Example 1--compound 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-(m-methoxybenzyl)-1,2,3,4-tetrahydrofl-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.
AnaZysis.Calculated for c H 0N c1= C, 70.06; H, 6.47; N, 8.17. Found: C, 69.85; H, 6.60; N, 8.19.
Example IV.--1-methyl-2-(Z-diethylaminoethylcarbamylmethyD-B-carbolinium bromide 2-carbomethyoxymethyl harmanium bromide (Exampie I-ccmpound No. 2 in the table), 2.01 g. was reflexed 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. Its melting point was 189-190 C.
10 Analysis-Calculated for C H 0N Br: C, 57.28; H,
6.49; N, 13.36. Found: C, 56.83; H, 6.37; N, 13.19.
What is claimed is: 1. A compound having the formula:
Rs axe A R7- R5 4. l-methyl 2 (m-methoxybenzyl)-carbolinium bromide.
No references cited.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3071589A (en) * 1959-06-10 1963-01-01 Sterling Drug Inc 3-benzyl-4-lower-alkyl-3, 4, 5, 6-tetrahydro-4-carboline quaternary ammonium salts and preparation thereof
US3345376A (en) * 1963-11-06 1967-10-03 Upjohn Co Polyhydro-6-methoxy-1-(3, 4, 5-trimethoxyphenyl)-9h-pyrido[3, 4-b]indoles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3071589A (en) * 1959-06-10 1963-01-01 Sterling Drug Inc 3-benzyl-4-lower-alkyl-3, 4, 5, 6-tetrahydro-4-carboline quaternary ammonium salts and preparation thereof
US3345376A (en) * 1963-11-06 1967-10-03 Upjohn Co Polyhydro-6-methoxy-1-(3, 4, 5-trimethoxyphenyl)-9h-pyrido[3, 4-b]indoles

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