US2909526A - Aminoalkoxyalkylpiperidines - Google Patents
Aminoalkoxyalkylpiperidines Download PDFInfo
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- US2909526A US2909526A US709459A US70945958A US2909526A US 2909526 A US2909526 A US 2909526A US 709459 A US709459 A US 709459A US 70945958 A US70945958 A US 70945958A US 2909526 A US2909526 A US 2909526A
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- bis
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- methylpiperidine
- hypotensive
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Definitions
- A is a secondary amino group containing not more than 4 carbon atoms and suitably represented by such moieties as dirnethylamino, diethylamino and pyrroliding, and -(CH is a straight chain alkylene linkingelement joining the oxygen and the nitrogen of A, said alkylene element containing 2-3 carbon atoms.
- the compounds of this invention are thus unsymmetrical bis-tertiary amines and can be represented as 2- (dialkylaminoalkoxymethyl) -1-n1ethylpiperidines. These new compounds possess specific pharmacologic actions, particularly as agents which lower blood pressure, and diifer from the agents in clinical use by virtue of their potent hypotensive effect in the formof the histertiary amine.
- hypotensive agents of the type hexamethonium and pentapyrrolidinium require that they be in the form of the bis-quaternary ammonium salt to promote an effective hypotensive response.
- certain undesirable factors such as poor absorption of the drug when administered orally, side effects, and development of tolerance and cross-tolerance (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 2nd edition, The Macmillan Co., New York, N. Y., 1955, p. 636).
- the new unsymmetrical bis-tertiary amines are high boiling liquids which are distillable under vacuum and which may be converted to their diacid salts by simple neutralization with the required amount of acid.
- Suitable salts for use by oral administration in the form of tablets are hydrochlori'cles, hydrobromides, sulfates, phosphates, acetates, tartrates, malates and the like.
- sterile solutions can be processed from the water-soluble diacid salts for use as parenteral therapeutic agents.
- the compounds of this invention being bis-tertiary amines will also form bis-quaternary ammonium salts, and as quaternating agents there may be used, for example, alkylating agents such as methyl bromide, paratoluene-sulfonic acid methyl ester, diethylsulfate and allyl bromide.
- alkylating agents such as methyl bromide, paratoluene-sulfonic acid methyl ester, diethylsulfate and allyl bromide.
- the new compounds are conveniently prepared by reaction of Z-hydroxymethyl-l-piperidine and a dialkylaminoalkyl halide in the presence of an alkaline condensing agent following the equation below.
- 2-hydr0xymethyl-l-methylpiperidine hydrochloride 2-(2'-dimethylaminoethoxymethyl) -1-methylpiperidine 2 hydroxymethyl 1 methylpiperidine hydrobromide (16.8 g., 0.08 mole) was dissolved in water, made basic with 40% sodium hydroxide, salted with potassium carbonate and extracted with 15 ml. portions of toluene. The combined extracts were dried over magnesium sulfate.
- 15.8 g. (0.11 mole) of 2-dimethylarninoethyl chloride hydrochloride was converted to a dry toluene solution of the base.
- Sodium sand was prepared in the usual manner from 1.8 g. (0.08 mole) of sodium in 50 ml. of dry toluene and treated over 3 hours,
- the bis-tertiary amines were converted to their water-soluble dihydrochloric acid salts and these in turn were administered intravenously to anesthetized (Nembutal, 30 mg./kg.) normal dogs.
- the eifect on blood pressure response was characterized as 3+ (profound and sustained hypotension), 2+ (moderate and sustained hypotension), 1+ (a suggestion of hypotensive response), and (no hypotensive response).
- the dosage used was A of the LD
- the LD (the minimum lethal dose) was in turn established by the subcutaneous injection of the compounds in mice. In those instances where the LD,,,,,, was greater than 500 mg./kg., the dosage used for the intravenous tests with dogs was mg./kg.
- sexamethonium bromide hexamethylenebis-[trimethylammonium bromide1
- A is selected from the group consisting of dimethylamino, diethylamino and pyrrolidino and n is a small whole number consisting of 2 and 3.
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent ANHNOALKOXYALKYLPIPERIDINES Seymour L. Shapiro, Hastings on Hudson, Louis Freedman, Bronrrville, and Harold Soloway, Yonkers, N.Y., assignors to US. Vitamin 8; Pharmaceutical Corporation, a corporation of Delaware No Drawing. Application January 17, 1958 Serial No. 709,459
Claims. (Cl. 260-2945) This invention relates to aminoalkoxyalkylpiperidines which are represented by the formula N an.
in which A is a secondary amino group containing not more than 4 carbon atoms and suitably represented by such moieties as dirnethylamino, diethylamino and pyrroliding, and -(CH is a straight chain alkylene linkingelement joining the oxygen and the nitrogen of A, said alkylene element containing 2-3 carbon atoms.
The compounds of this invention are thus unsymmetrical bis-tertiary amines and can be represented as 2- (dialkylaminoalkoxymethyl) -1-n1ethylpiperidines. These new compounds possess specific pharmacologic actions, particularly as agents which lower blood pressure, and diifer from the agents in clinical use by virtue of their potent hypotensive effect in the formof the histertiary amine.
In contrast to the compounds of this invention, the hypotensive agents of the type hexamethonium and pentapyrrolidinium require that they be in the form of the bis-quaternary ammonium salt to promote an effective hypotensive response. Associated with the hypotensive response of such bis-quaternary ammonium salts are certain undesirable factors such as poor absorption of the drug when administered orally, side effects, and development of tolerance and cross-tolerance (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 2nd edition, The Macmillan Co., New York, N. Y., 1955, p. 636).
It is also unique with regard to the unsymmetrical bistertiary amines of this invention, that slight variations from the preferred structures as described above are associated with disappearance of hypotensive properties. Thus, if the alkylene element, (CH is varied as CHCH CH or if the l-methylpiperidine group is varied as a l-methylpyrrolidine group, or if the 2-dialkylaminoalkoxymethyl group on the piperidine ring is replaced as a. Z-dialkylaminoalkoxyethyl group, there are obtained unsymmetrical bis-tertiary amines which are ineffective as hypotensive agents. It is apparent, therefore, that critical structural requirements are indicated for the desired pharmacologic effect.
2,909,526 Patented Oct. 20, 1959 The new unsymmetrical bis-tertiary amines are high boiling liquids which are distillable under vacuum and which may be converted to their diacid salts by simple neutralization with the required amount of acid. Suitable salts for use by oral administration in the form of tablets are hydrochlori'cles, hydrobromides, sulfates, phosphates, acetates, tartrates, malates and the like. In turn, sterile solutions can be processed from the water-soluble diacid salts for use as parenteral therapeutic agents.
The compounds of this invention being bis-tertiary amines will also form bis-quaternary ammonium salts, and as quaternating agents there may be used, for example, alkylating agents such as methyl bromide, paratoluene-sulfonic acid methyl ester, diethylsulfate and allyl bromide.
The carbon in the 2-position of the piperidine ring of the compounds of this invention bears four different substituents and is accordingly asymmetric, and the compounds herein described and prepared are d1 mixtures. It is intended that the individual d and 1 forms which are separable by standard techniques be considered with in the purview of this invention.
The new compounds are conveniently prepared by reaction of Z-hydroxymethyl-l-piperidine and a dialkylaminoalkyl halide in the presence of an alkaline condensing agent following the equation below.
I CH
The following examples will illustrate in detail how the compounds of this invention may be prepared by this method, though it is not to be construed as limiting in any manner, save as described in the appended claims.
EXAMPLE I Z-hydroxymethyl-l-methylpyridinium bromide A solution of 30.5 g. (0.28 mole) of Z-pyridylcarbinol in ml. of acetonitrile was maintained at 10 C. during the addition of 54 g. (0.56 mole) of methyl bromide. After standing 20 hours, the product, 54 g. (94%) was separated.
A sample recrystallized from ethanol, melted at 166 169 C.
Anal.--Calcd. for C H BrNO: C, 41.2; H, 4.9; N, 6.9. Found: C, 40.9; H, 4.9; N, 6.7.
2-hydr0xymethyl-l-methylpiperidine hydrochloride 2-(2'-dimethylaminoethoxymethyl) -1-methylpiperidine 2 hydroxymethyl 1 methylpiperidine hydrobromide (16.8 g., 0.08 mole) was dissolved in water, made basic with 40% sodium hydroxide, salted with potassium carbonate and extracted with 15 ml. portions of toluene. The combined extracts were dried over magnesium sulfate. In a similar manner, 15.8 g. (0.11 mole) of 2-dimethylarninoethyl chloride hydrochloride was converted to a dry toluene solution of the base. Sodium sand was prepared in the usual manner from 1.8 g. (0.08 mole) of sodium in 50 ml. of dry toluene and treated over 3 hours,
with stirring with the toluene solution of 2-hydroxymethyl-l-methylpiperidine while keeping the temperature below 90 C. At the end of this period, the stirred mixture was brought to reflux temperature and the toluene solution of Z-dimethylaminoethyl chloride added dropwise, over 1 hour, and then reflux was continued for 7 hours. After removal of sodium chloride, the filtrate concentrated at reduced pressure, yielded a residue of 13.8 g. Distillation gave a fraction of 8.1 g., boiling at 5870 C. at 0.3-0.4 mm., which on redistillation yielded 5.1 g. (32%) of product, boiling at 6466 C. at 0.25 mm.
Anal.Ca1cd. for CHI-124N201 C, H, N, 14.0. Found: C, 66.0; H, 12.1; N, 13.9.
EXAMPLE II 2-(3'-dimefhylaminopropoxymethyl) -1-methylpiperidine! This compound was prepared by the procedure illustrated above for 2-(2'-dimethylaminoethoxymethyl)-1- methylpiperidine from 21 g. (0.1 mole) of 2-hydroxymethyl-l-methylpiperidine bromide, 20.6 g. (0.13 mole) of B-dirnethylaminopropyl chloride hydrochloride and 2.3 g. (0.1 mole) of sodium. Workup and distillation gave 4.1 g. (19%) of the product, boiling at 9093 C. at 0.6 mm.
Anal.-Calcd. for C H N O: C, 67.2; H, 12.2; N, 13.1. Found: C, 66.7; H, 12.0; N, 12.7.
EXAMPLE III 2-(2'-trimethylammoniumethoxymethyl) -1-dimethylpiperidinium dibromide A solution of 3.0 g. (0.015 mole) of 2-(2dimethylaminoethoxymethyl)-1-methylpiperidine in 25 m1. of acetonitrile was cooled in a pressure bottle and 3.8 g. (0.04 mole) of methyl bromide added. Precipitation began within an hour. After standing 20 hours, the product was separated, 5.1 g. (86%), MP. 253-255 C. A sample recrystallized from ethanol melted at 254-255" C.
Anal.CalCd. for C13H30BI'2N2OI C, H, 7.8. Found: C, 40.4; H, 7.9.
Typical compounds prepared for this invention have been gathered in Table I, wherein their physical properties are reported, along with the hypotensive response obtained in normal dogs.
For pharmacologic testing, the bis-tertiary amines were converted to their water-soluble dihydrochloric acid salts and these in turn were administered intravenously to anesthetized (Nembutal, 30 mg./kg.) normal dogs. The eifect on blood pressure response was characterized as 3+ (profound and sustained hypotension), 2+ (moderate and sustained hypotension), 1+ (a suggestion of hypotensive response), and (no hypotensive response). The dosage used was A of the LD The LD (the minimum lethal dose) was in turn established by the subcutaneous injection of the compounds in mice. In those instances where the LD,,,,,, was greater than 500 mg./kg., the dosage used for the intravenous tests with dogs was mg./kg.
As a control for comparison, sexamethonium bromide (hexamethylenebis-[trimethylammonium bromide1) was used.
In addition, compounds closely allied to the preferred structures of this invention have been prepared and in- '4 cluded in Table I to indicate the specificity of structural effects required for the hypotensive response.
TABLE I.PHYSIOAL AND HYPOIENSIVE PROPERTIES CF AMINOALKOXYALKYLPIPERIDIN ES 2-[3-dimethylarninopropoxymethyll-l-methylpyrrolidine.
It will be noted that the compounds encompassed by this invention (Nos. 1-4) aiford a pronounced hypotensive response, and as the bis-tertiary amines, show efifects comparable to the bis-quaternary ammonium compound, hexamethonium (No. 9). On the other hand, 'compounds closely related to the compounds of this invention (Nos. 5-8) show little or no hypotensive response as the bis-tertiary amines.
Having described our invention, what we claim as new and desire to secure by Letters Patent is:
1. The compound in which A is selected from the group consisting of dimethylamino, diethylamino and pyrrolidino and n is a small whole number consisting of 2 and 3.
2. The compound 3. The compound CHz-OCHzOH -N 4. The compound References Cited in the file of this patent 5. The compound
Claims (1)
1. THE COMPOUND
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US709459A US2909526A (en) | 1958-01-17 | 1958-01-17 | Aminoalkoxyalkylpiperidines |
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US709459A US2909526A (en) | 1958-01-17 | 1958-01-17 | Aminoalkoxyalkylpiperidines |
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US2909526A true US2909526A (en) | 1959-10-20 |
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US709459A Expired - Lifetime US2909526A (en) | 1958-01-17 | 1958-01-17 | Aminoalkoxyalkylpiperidines |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US2773876A (en) * | 1953-06-04 | 1956-12-11 | Sterling Drug Inc | Tertiary-aminoalkoxymethyl-1-(lower alkyl) piperidines and preparation thereof |
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1958
- 1958-01-17 US US709459A patent/US2909526A/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US2773876A (en) * | 1953-06-04 | 1956-12-11 | Sterling Drug Inc | Tertiary-aminoalkoxymethyl-1-(lower alkyl) piperidines and preparation thereof |
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