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US3252860A - Antihypertensive n-picolyl-ethylene-diamine compositions - Google Patents

Antihypertensive n-picolyl-ethylene-diamine compositions Download PDF

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US3252860A
US3252860A US285618A US28561863A US3252860A US 3252860 A US3252860 A US 3252860A US 285618 A US285618 A US 285618A US 28561863 A US28561863 A US 28561863A US 3252860 A US3252860 A US 3252860A
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picolyl
ethylenediamine
pharmaceutically acceptable
antihypertensive
acid addition
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US285618A
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Mull Robert Paul
Barrett Walter Edward
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BASF Corp
Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

Definitions

  • compositions for the treatment of hypertension which contain pure chemical substances or extracts from natural sources as the pharmacologically active ingredients.
  • search for new antihypertensive drugs is continued and broadened. This is mainly due to the fact, that hypertension can have many causes, of which only a few areestablished; hypertension is, therefore, a manifestation of different disorders, which respond differently to different treatments.
  • known compounds with antihypertensive properties have different pharmacological patterns; for example, they react differently on the effects of pressor substances in anesthetized dogs.
  • the antihypertensive drug hydralazine decreases the pressor effects of amphetamine, norepinephrine and angiotensin amide and reverses the effects of epinephrine
  • guanethidine blocks the pressor effects of amphetamine, but increases the responses to epinephrine, norepinephrine and hypertensin.
  • N-picolyl-ethylenediamine compounds are those with inorganic acids, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or with organic acids, such as organic carboxylic acids, e.g., acetic, propionic, glycolic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, salicylic, 2-acetoxy-benzoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, e.g., methane sulfonic, ethane sulfonic, ethane 1,2-disulfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic acid and the like.
  • organic acids such as organic carboxylic acids, e.g., acetic, propionic, glycolic, succinic, maleic, fumaric, malic, tartaric
  • a preferred method for the treatment of hypertensive conditions comprises administering to a host requiring resuch as the compounds of the formula particularly the N-(4-picolyl)-ethylenediamine, or especially the acid addition salts of such compounds have potent antihypertensive effects.
  • pharmacological tests in which these compounds are administered intravenously or orally to anesthetized dogs, reveal that the effects on the pressor responses caused by pressor substances are basically different from those of generally accepted antihypertensive drugs; thus, they decrease the pressor responses of amphetamine, epinephrine, norepinephrine and angiotensin amide.
  • the method of treating antihypertensive conditions according to the present invention is, therefore, qualitatively different from those using known antihypertensive drugs.
  • novel pharmaceutical compositions consisting essentially of a pharmacologically effective amount of an N-picolylethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
  • compositions for the relief of hypertension are those consisting essentially of a pharmacologically effective amount of a compound of the formula bining specified proportions of the pharmacologically ac-,
  • compositions of this invention contain at most equal amounts of the active ingredient and the inert carrier; preferably, they aremade up to have from about 1 percent to at most 50 percent by weight of the pharmacologically active ingredient in the composition.
  • the percentage, by weight is from about 5 percent to at most 50 percent of active antihypertensive ingredient.
  • the percentage by weight is from about 1 percent to about 20 percent of the active antihypertensive ingredient.
  • any one of a wide variety of preparations may be manufactured, such as tablets, capsules, pills, suppositories, solutions, suspensions and the like.
  • additional substances commonly employed in the art of manufacturing pharmaceutically acceptable dosage unit compositions may include excipients, binders, fillers, lubricants, solvents, stabilizers, wetting agents, emulsifiers, buffers, and/ or other inert ingredients.
  • the tablet, capsule, dragee and the like provide for the oral form of administration.
  • These forms may be compounded to have from about 0.01 g. to about 0.1 g., especially from about 0.015 g. to about 0.05 g., of an N-picolylethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, such as a compound of the formula or especially a pharmaceutically acceptable acid addition salt thereof, and particularly N-(4-picolyl)-ethylenediamine, or especially a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, per single dosage unit, together with a pharmaceutically acceptable carrier.
  • the inert fillers, binders, lubricants and other materials normally used for the manufacture of the orally applicable pharmaceutical compositions are employed in their formulation.
  • these materials are starches, e.g., corn starch, wheat starch and the like, sugars, e.g., lactose, sucrose and the like, stearic acid, magnesium stearate, calcium stearate, aluminum magnesium silicate preparations (colloidal silica preparations), talc, tragacanth, acacia, polyethylene glycol and the like.
  • the quantities of these ingredients may vary widely and depend upon the characteristics and the size of the desired, orally applicable form, the method of its manufacture and the like. Encapsulation may be effected, using, it necessary, the same excipients as those employed for the preparation of other orally applicable forms, e.g., tablets. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used as a means of identification and the like.
  • Solutions for parenteral administration have from about 0.01 g./ml. to about 0.1 g./ml., preferably from about 0.015 g./ ml. to about 0.05 g./ ml. of an N-picolyl-ethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, such as a compound of the formula or especially a pharmaceutically acceptable acid addition salt thereof, particularly the N (4-picolyl)-ethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, a the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
  • an N-picolyl-ethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof such as a compound of the formula or especially a pharmaceutically acceptable acid addition salt thereof, particularly the N (4-picolyl)-ethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, a the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
  • Primary solvents of the solutions for injection according to this invention are water, water-miscible organic solvents, such as lower alkanols, e.g., ethanol and the like, or mixtures of water and water-miscible organic solvents, such as lower alkanols, e.g., ethanol and the like.
  • stabilizers such as anti-oxidants, e.g., thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate, mono-thioglycerol, thiosorbitol and the like, solubilizers, e.g., N,N-diethylacetamide, polyethyleneglycol, ureas, urethanes and the like, buffers and buffer combinations to maintain a preferable pH of about 7, such as, for example, acetic acid, potassium phthalate and sodium hydroxide, potassium dihydrogen phosphate and di-sodium hydrogen phosphate, potassium dihydrogen phosphate and sodium hydroxide, acetic acid and sodium acetate, and the like, salts for making isotonic solutions, e.g., sodium chloride and the like, or any other suitable auxiliary substances.
  • anti-oxidants e.g., thiourea
  • Example 1 Tablets containing 0.025 g. each of N-(4-picolyl)-ethylenediamine trihydrochloride are prepared as follows (for 800,000 tablets):
  • the N-(4-picolyl)ethylenediamine trihydrochloride, the lactose, 12,5000 g. of the corn starch, the confectioners sugar and the colloidal silica are passed through a. No. 16 screen into a mixer and blended at low speed for twenty minutes.
  • the remainder of the corn starch is suspended in a cold solution of the color FD&C Yellow No. 5 in 5,000 ml. of purified water, and a paste is formed by gradually adding 20,000 ml. of boiling purified water.
  • mixed powders are granulated with the above paste, using additional water as'required.
  • the resulting moist mass is passed through a mill, using a No. 4A screen, placed on trays and dried at 38 C. until the moisture content is between 2 percent and 3 percent.
  • the granules are broken on a mill through a No. 16 wire mesh screen, and treated with the stearic acid and the cal- Tablets containing 0.03 g. each of N-(2-picolyl)-ethylenediamine trihydrochloride are prepared as follows (for 100,000 tablets):
  • the tablets weighing 0.250 g. each, are prepared according to the procedure described in Example 1.
  • N-(2-picolyl)-ethylenediamine trihydrochloride may be replaced by another pharmaceutically acceptable acid addition salt of N-(2- picolyl)-ethylenediamine or by a pharmaceutically acceptable acid addition salt of N-(3-picolyl)-ethylenediamine.
  • Example 3 Capsules containing 0.025 g. each of N-(4-picolyl)- ethylenediamine trihydrochloride are prepared as follows (for 900 capsules):
  • Example 4 An injectable solution containing 0.02 g. per I111. of N-(4-picolyl)-ethylenediamine trihydrochloride is prepared as follows (for 1,000 ml.)-
  • N-(4-picolyl)-ethylenediamine trihydrochloride g. 20.00 Acetic acid, glacial, ml. 8.00 Water for inpection, q.s., ml. 1000.00
  • the glacial acetic acid and the N-(4-picolyl)-ethylenediamine trihydrochloride are dissolved in 900 ml. of Water for injection. The volume is adjusted to 1000 ml., and the solution is filtered through a medium porosity sintered glass filter. Portions of 1.1 ml. of the filtrate are filled into glas ampules and sterilized for thirty minutes in an autoclave at pounds steam pressure and at 115.
  • the N-(4-picolyl)- ethylenediamine trihydrochloride may be replaced by any other pharmaceutically acceptable acid addition'salt of N-(4-picolyl)-ethylenediamine, as well as by a pharmaceutically acceptable acid addition salt of N-(2-picolyl)- ethylenediamine or of N-(3-picolyl)-ethylenediamine.
  • Example A A solution of 25.0 g. of 4-picolyl chloride hydrochloride in 50 ml. of Water is treated with a saturated aqueous soltuion of an equivalent amount of potassium carbonate; the free 4-picolyl chloride, obtained as an oil, is added dropwise to 50.0 g. of ethylenediamine while maintaining the temperature below 20. After the addition is completed, the reaction mixture is heated on the steam bath for one hour while stirring. The excess of ethylenediamine is then distilled off; the residue is dissolved in 100 ml. of ethanol and an equivalent solution of potas sium hydroxide in ethanol is added. The insoluble potassium chloride is filtered off, and the filtrate is evaporated under reduced pressure. The desired N-(4- picolyl)-ethylenediamine is purified by distilling the residue and is collected at 95102/ 0.05 mm.; yield. 29.0 g.
  • the flee N-(4-picolyl)-ethylenediamine is dissolved in methanol; a methanol solution of hydrogen chloride is added and the salt is precipitated by adding diethyl ether.
  • the desired N-(4-picolyl)-ethylenediamine trihydrochloride melts at 249252 after recrystallization from methanol.
  • Example B The N-(3-picolyl)-ethylenediamine is prepared according to the procedure described in Example A, by replacing the 4-picolyl chloride hydrochloride with 25.0 g. of 3-picolyl chloride hydrochloride; the desired N-(3- icolyD-ethyIenediamine is collected at -121/0.7 mm.; yield: 15.0 g.; and is converted into its trihydrochloride as described in Example A.
  • Example C By replacing the 4-picolyl chloride hydrochloride with 50.0 g. of 2-picolyl chloride hydrochloride, converting it into the free compound and reacting the latter with ethylenediamine as described in Example A, the N-(2- picolyl)-ethylenediamine is obtained. It is purified by distillation, collected at 102-103/0.4 mm.; yield: 13.2 g.; and converted into its trihydrochloride.
  • a pharmaceutical composition consisting essentially of a pharmacologically effective amount of a member selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition consisting essentially of a pharmacologically effective amount of a member selected from the group consisting of N(4-picolyl)- ethylenediamine and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition consisting essentially of from about 1 percent to at most 50 percent by weight of a member selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition consisting essentially of from about 1 percent to at most 50 percent by weight of a member selected from the group consisting of N-(4- picolyl)-ethylenediamine and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for oral use containing as the active antihypertensive ingredient from about 0.01 g. to about 0.1 g. of a member selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically accepted carrier, per single dosage unit.
  • a pharmaceutical composition for oral use containing as the active antihypertensive ingredient about 0.01 g. to about 0.1 g. of a member selected from the group consisting of N-(4-picolyl)-ethylenediamine and a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically accepted carrier, per single dosage unit.
  • a solution for parenteral administration containing from about 0.01 g./ml. to about 0.1 g./ml. of a mem- 7 ber selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient together with a pharmacentically acceptable carrier.
  • a solution for parenteral administration containing from about 0.01 g./ml. to about 0.1 g./ml. of a member selected from the group consisting of N-(4-picolyl)- ethylenediamine and a pharmaceutically acceptable acid UNITED STATES PATENTS 5/1956 Szabo et a1 260-501 OTHER REFERENCES Chemical Abstracts, vol. 50, pp. 16849, 91956.

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Description

United States Patent 3,252,860 ANTIHYPERTENSIVE N-PICOLYL-ETHYLENE- DIAMINE COMPOSITIONS Robert Paul Mull, Florham Park, and Walter Edward Barrett, New Vernon, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed June 5, 1963, Ser. No. 285,618 8 Claims. (Cl. 167-65) The present invention concerns a novel method for the treatment of hypertension, as well as pharmaceutical compositions capable of lowering the blood pressure in hypertensiveconditions.
A great number of pharmaceutical compositions for the treatment of hypertension are known, which contain pure chemical substances or extracts from natural sources as the pharmacologically active ingredients. Despite this variety of compositions available to the practitioner, the search for new antihypertensive drugs is continued and broadened. This is mainly due to the fact, that hypertension can have many causes, of which only a few areestablished; hypertension is, therefore, a manifestation of different disorders, which respond differently to different treatments.
Furthermore, known compounds with antihypertensive properties have different pharmacological patterns; for example, they react differently on the effects of pressor substances in anesthetized dogs. Thus, while the antihypertensive drug hydralazine decreases the pressor effects of amphetamine, norepinephrine and angiotensin amide and reverses the effects of epinephrine, guanethidine blocks the pressor effects of amphetamine, but increases the responses to epinephrine, norepinephrine and hypertensin. In the same experiment, reserpine increases the pressor responses of amphetamine, epinephrine and norepinephrine, whereas ganglionic blockers useful in the treatment of severe hypertension, such as chlorisondamine chloride, also increases the pressor effects of all three pressor amines, but in addition, block the ganglia. These few examples show that there is ample room for compounds having antihypertensive properties of different pharmacological patterns, which can be exploited in the treatment of various hypertensive conditions.
We have now found a new method for the treatment of hypertensive conditions, which comprises administering to a host requiring relief from hypertension a composition consisting essentially of a pharmacologically effective amount of an N-picolyl-ethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable acid addition salts of the above-mentioned N-picolyl-ethylenediamine compounds are those with inorganic acids, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or with organic acids, such as organic carboxylic acids, e.g., acetic, propionic, glycolic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, salicylic, 2-acetoxy-benzoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, e.g., methane sulfonic, ethane sulfonic, ethane 1,2-disulfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic acid and the like.
A preferred method for the treatment of hypertensive conditions comprises administering to a host requiring resuch as the compounds of the formula particularly the N-(4-picolyl)-ethylenediamine, or especially the acid addition salts of such compounds have potent antihypertensive effects. Furthermore, pharmacological tests, in which these compounds are administered intravenously or orally to anesthetized dogs, reveal that the effects on the pressor responses caused by pressor substances are basically different from those of generally accepted antihypertensive drugs; thus, they decrease the pressor responses of amphetamine, epinephrine, norepinephrine and angiotensin amide. The method of treating antihypertensive conditions according to the present invention is, therefore, qualitatively different from those using known antihypertensive drugs.
Also included within the scope of this invention are the novel pharmaceutical compositions consisting essentially of a pharmacologically effective amount of an N-picolylethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier. 1
Preferred compositions for the relief of hypertension are those consisting essentially of a pharmacologically effective amount of a compound of the formula bining specified proportions of the pharmacologically ac-,
tive ingredient with a pharmaceutically acceptable organic or inorganic carrier. Usually, the compositions of this invention contain at most equal amounts of the active ingredient and the inert carrier; preferably, they aremade up to have from about 1 percent to at most 50 percent by weight of the pharmacologically active ingredient in the composition. In compositions for oral use (e.g., tablets, capsules and the like), the percentage, by weight is from about 5 percent to at most 50 percent of active antihypertensive ingredient. In compositions prepared for injection (e.g., solutions and the like), the percentage by weight is from about 1 percent to about 20 percent of the active antihypertensive ingredient.
In preparing pharmaceutically acceptable dosage unit forms, any one of a wide variety of preparations may be manufactured, such as tablets, capsules, pills, suppositories, solutions, suspensions and the like. In addition to the pharmacologically active component, there may be present additional substances commonly employed in the art of manufacturing pharmaceutically acceptable dosage unit compositions. These may include excipients, binders, fillers, lubricants, solvents, stabilizers, wetting agents, emulsifiers, buffers, and/ or other inert ingredients.
The tablet, capsule, dragee and the like provide for the oral form of administration. These forms may be compounded to have from about 0.01 g. to about 0.1 g., especially from about 0.015 g. to about 0.05 g., of an N-picolylethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, such as a compound of the formula or especially a pharmaceutically acceptable acid addition salt thereof, and particularly N-(4-picolyl)-ethylenediamine, or especially a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, per single dosage unit, together with a pharmaceutically acceptable carrier.
- The inert fillers, binders, lubricants and other materials normally used for the manufacture of the orally applicable pharmaceutical compositions, e.g., tablets, capsules, dragees and the like, are employed in their formulation. Examples of these materials are starches, e.g., corn starch, wheat starch and the like, sugars, e.g., lactose, sucrose and the like, stearic acid, magnesium stearate, calcium stearate, aluminum magnesium silicate preparations (colloidal silica preparations), talc, tragacanth, acacia, polyethylene glycol and the like. The quantities of these ingredients may vary widely and depend upon the characteristics and the size of the desired, orally applicable form, the method of its manufacture and the like. Encapsulation may be effected, using, it necessary, the same excipients as those employed for the preparation of other orally applicable forms, e.g., tablets. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used as a means of identification and the like.
Solutions for parenteral administration have from about 0.01 g./ml. to about 0.1 g./ml., preferably from about 0.015 g./ ml. to about 0.05 g./ ml. of an N-picolyl-ethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, such as a compound of the formula or especially a pharmaceutically acceptable acid addition salt thereof, particularly the N (4-picolyl)-ethylenediamine or especially a pharmaceutically acceptable acid addition salt thereof, a the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
Primary solvents of the solutions for injection according to this invention are water, water-miscible organic solvents, such as lower alkanols, e.g., ethanol and the like, or mixtures of water and water-miscible organic solvents, such as lower alkanols, e.g., ethanol and the like. Other ingredients are added to ensure stable solutions for injection, for example, stabilizers, such as anti-oxidants, e.g., thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate, mono-thioglycerol, thiosorbitol and the like, solubilizers, e.g., N,N-diethylacetamide, polyethyleneglycol, ureas, urethanes and the like, buffers and buffer combinations to maintain a preferable pH of about 7, such as, for example, acetic acid, potassium phthalate and sodium hydroxide, potassium dihydrogen phosphate and di-sodium hydrogen phosphate, potassium dihydrogen phosphate and sodium hydroxide, acetic acid and sodium acetate, and the like, salts for making isotonic solutions, e.g., sodium chloride and the like, or any other suitable auxiliary substances.
The following working examples are illustrative of the invention, but are in no way intended to limit the scope of the present invention.
Example 1 Tablets containing 0.025 g. each of N-(4-picolyl)-ethylenediamine trihydrochloride are prepared as follows (for 800,000 tablets):
Ingredients: G.
N-(4-picolyl) ethylenediamine trihydrochloride 20,0000 Lactose USP l43,495.0 Corn starch 17,0500 Confectioners sugar 14,0000 Colloidal silica 5,000.0 Stearic acid powder USP 2,000.0 Calcium stearate 500.0 Color FD&C Yellow No. 5 5.0
Purified water, q.s.
* Equivalent to 15,0000 g. on an anhydrous basis.
The N-(4-picolyl)ethylenediamine trihydrochloride, the lactose, 12,5000 g. of the corn starch, the confectioners sugar and the colloidal silica are passed through a. No. 16 screen into a mixer and blended at low speed for twenty minutes. The remainder of the corn starch is suspended in a cold solution of the color FD&C Yellow No. 5 in 5,000 ml. of purified water, and a paste is formed by gradually adding 20,000 ml. of boiling purified water. The
mixed powders are granulated with the above paste, using additional water as'required.
The resulting moist mass is passed through a mill, using a No. 4A screen, placed on trays and dried at 38 C. until the moisture content is between 2 percent and 3 percent. The granules are broken on a mill through a No. 16 wire mesh screen, and treated with the stearic acid and the cal- Tablets containing 0.03 g. each of N-(2-picolyl)-ethylenediamine trihydrochloride are prepared as follows (for 100,000 tablets):
Ingredients:
N-(Z-picolyl)-ethylenediamine trihydrochloride 3,000.000 Lactose USP 17,436.875 Corn starch 2,131.250 Confectioners sugar 1,750.000 Colloidal silica 625.000 Stearic acid powder USP 250.000 Calcium stearate 62.500 Color FD&C Yellow No. 5 0.625
Purified water, q.s.
* Equivalent to 1,875.000 g. on an anhydrous basis.
The tablets, weighing 0.250 g. each, are prepared according to the procedure described in Example 1.
In the above example, the N-(2-picolyl)-ethylenediamine trihydrochloride may be replaced by another pharmaceutically acceptable acid addition salt of N-(2- picolyl)-ethylenediamine or by a pharmaceutically acceptable acid addition salt of N-(3-picolyl)-ethylenediamine.
Example 3 Capsules containing 0.025 g. each of N-(4-picolyl)- ethylenediamine trihydrochloride are prepared as follows (for 900 capsules):
Ingredients: G.
N- (4-picolyl) -ethylenediamine trihydrochloride 22.50
Lactose USP 139.50
Example 4 An injectable solution containing 0.02 g. per I111. of N-(4-picolyl)-ethylenediamine trihydrochloride is prepared as follows (for 1,000 ml.)-
Ingredients:
N-(4-picolyl)-ethylenediamine trihydrochloride, g. 20.00 Acetic acid, glacial, ml. 8.00 Water for inpection, q.s., ml. 1000.00
The glacial acetic acid and the N-(4-picolyl)-ethylenediamine trihydrochloride are dissolved in 900 ml. of Water for injection. The volume is adjusted to 1000 ml., and the solution is filtered through a medium porosity sintered glass filter. Portions of 1.1 ml. of the filtrate are filled into glas ampules and sterilized for thirty minutes in an autoclave at pounds steam pressure and at 115.
In the above solution for injuection, the N-(4-picolyl)- ethylenediamine trihydrochloride may be replaced by any other pharmaceutically acceptable acid addition'salt of N-(4-picolyl)-ethylenediamine, as well as by a pharmaceutically acceptable acid addition salt of N-(2-picolyl)- ethylenediamine or of N-(3-picolyl)-ethylenediamine.
The compounds used as the active ingredients in the above compositions are prepared as followes (tempertures are given in degrees centigrade):
Example A A solution of 25.0 g. of 4-picolyl chloride hydrochloride in 50 ml. of Water is treated with a saturated aqueous soltuion of an equivalent amount of potassium carbonate; the free 4-picolyl chloride, obtained as an oil, is added dropwise to 50.0 g. of ethylenediamine while maintaining the temperature below 20. After the addition is completed, the reaction mixture is heated on the steam bath for one hour while stirring. The excess of ethylenediamine is then distilled off; the residue is dissolved in 100 ml. of ethanol and an equivalent solution of potas sium hydroxide in ethanol is added. The insoluble potassium chloride is filtered off, and the filtrate is evaporated under reduced pressure. The desired N-(4- picolyl)-ethylenediamine is purified by distilling the residue and is collected at 95102/ 0.05 mm.; yield. 29.0 g.
The flee N-(4-picolyl)-ethylenediamine is dissolved in methanol; a methanol solution of hydrogen chloride is added and the salt is precipitated by adding diethyl ether. The desired N-(4-picolyl)-ethylenediamine trihydrochloride melts at 249252 after recrystallization from methanol.
Example B The N-(3-picolyl)-ethylenediamine is prepared according to the procedure described in Example A, by replacing the 4-picolyl chloride hydrochloride with 25.0 g. of 3-picolyl chloride hydrochloride; the desired N-(3- icolyD-ethyIenediamine is collected at -121/0.7 mm.; yield: 15.0 g.; and is converted into its trihydrochloride as described in Example A.
Example C By replacing the 4-picolyl chloride hydrochloride with 50.0 g. of 2-picolyl chloride hydrochloride, converting it into the free compound and reacting the latter with ethylenediamine as described in Example A, the N-(2- picolyl)-ethylenediamine is obtained. It is purified by distillation, collected at 102-103/0.4 mm.; yield: 13.2 g.; and converted into its trihydrochloride.
What is claimed is:
1. A pharmaceutical composition consisting essentially of a pharmacologically effective amount of a member selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
2. A pharmaceutical composition consisting essentially of a pharmacologically effective amount of a member selected from the group consisting of N(4-picolyl)- ethylenediamine and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
3. A pharmaceutical composition consisting essentially of from about 1 percent to at most 50 percent by weight of a member selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
4. A pharmaceutical composition consisting essentially of from about 1 percent to at most 50 percent by weight of a member selected from the group consisting of N-(4- picolyl)-ethylenediamine and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient, together with a pharmaceutically acceptable carrier.
5. A pharmaceutical composition for oral use containing as the active antihypertensive ingredient from about 0.01 g. to about 0.1 g. of a member selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically accepted carrier, per single dosage unit.
6. A pharmaceutical composition for oral use containing as the active antihypertensive ingredient about 0.01 g. to about 0.1 g. of a member selected from the group consisting of N-(4-picolyl)-ethylenediamine and a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically accepted carrier, per single dosage unit.
7. A solution for parenteral administration containing from about 0.01 g./ml. to about 0.1 g./ml. of a mem- 7 ber selected from the group consisting of a compound of the formula and a pharmaceutically acceptable acid addition salt thereof, as the active antihypertensive ingredient together with a pharmacentically acceptable carrier.
8. A solution for parenteral administration containing from about 0.01 g./ml. to about 0.1 g./ml. of a member selected from the group consisting of N-(4-picolyl)- ethylenediamine and a pharmaceutically acceptable acid UNITED STATES PATENTS 5/1956 Szabo et a1 260-501 OTHER REFERENCES Chemical Abstracts, vol. 50, pp. 16849, 91956.
JULIAN S. LEVITT, Primary Examiner.
FRANK CACCIAPAGLIA, JR. Examiner.
MARTIN I. COHEN, Assistant Examiner.

Claims (1)

  1. 7. A SOLUTION FOR PARENTERAL ADMINISTRATION CONTAINING FROM ABOUT 0.01 G./ML. TO ABOUT 0.1 G./ML. OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3439096A (en) * 1965-09-09 1969-04-15 Unimed Inc Method of improving microcirculation and treating senility with beta-(pyridyl lower alkyl)-amines
EP0163855A1 (en) * 1984-04-13 1985-12-11 Nihon Tokushu Noyaku Seizo K.K. Nitromethylene derivatives, intermediates, and process for their preparation as insecticides
US4680294A (en) * 1984-02-16 1987-07-14 Nihon Tokushu Noyaku Seizo K.K. Pesticidal novel nitromethylene derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2739981A (en) * 1952-08-26 1956-03-27 American Home Prod Diamines and salts thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2739981A (en) * 1952-08-26 1956-03-27 American Home Prod Diamines and salts thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3439096A (en) * 1965-09-09 1969-04-15 Unimed Inc Method of improving microcirculation and treating senility with beta-(pyridyl lower alkyl)-amines
US4680294A (en) * 1984-02-16 1987-07-14 Nihon Tokushu Noyaku Seizo K.K. Pesticidal novel nitromethylene derivatives
EP0163855A1 (en) * 1984-04-13 1985-12-11 Nihon Tokushu Noyaku Seizo K.K. Nitromethylene derivatives, intermediates, and process for their preparation as insecticides
US4678795A (en) * 1984-04-13 1987-07-07 Nihon Tokushu Noyaku Seizo K.K. 1-pyridylmethyl-2-nitromethylene-1,3-diazacycloalkane insecticides
US4812571A (en) * 1984-04-13 1989-03-14 Nihon Tokushu Noyaku Seizo K.K. N-(substituted pyridyl-alkyl) alkylenediamine intermediates for insecticides

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