US2723269A - Piperidino tertiary amino alcohols - Google Patents
Piperidino tertiary amino alcohols Download PDFInfo
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- US2723269A US2723269A US125381A US12538149A US2723269A US 2723269 A US2723269 A US 2723269A US 125381 A US125381 A US 125381A US 12538149 A US12538149 A US 12538149A US 2723269 A US2723269 A US 2723269A
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- piperidyl
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- piperidino
- heptanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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Description
United States 6 Claims. (Cl. 260294.7)
The present invention is concerned with a novel group of synthetic, physiologically active basic tertiary alcohols, their acid addition and quaternary salts. As such, the present application constitutes a continuation-in-part of my copending application for United States Letters Patent, Serial No. 691,881, filed August 20, 1946.
Many different synthetic compounds, pharmacologically active as anti-spasmodics and local anesthetics, have been synthesized from time to time. The more active and apparently useful of these compounds have in general comprised fairly complex molecules containing at least one ester grouping. This grouping was generally accepted as being essential on the basis of analogy to the naturally occurring extractives which were considered esters of tropic or pseudo-tropic acids.
Unfortunately, for one reason or another, many if not most of these compounds were not wholly satisfactory. Among other factors, the presence of the ester grouping introduces a chemically labile structure which adds to the instability of the molecule. This instability creates dilriculty in the laboratory, making the preparation, purification, and handling of the materials extremely difficult. Further, modification may occur in several ways in the animal organism in which the compound is attempted to be used. For example, the compound may break down into other compounds which are ineffectual, or which are irritating, or which may even be highly toxic.
It is, therefore, the principal object of the present invention to develop a series of compounds which are physiologically active, especially as anti-spasmodics. In so doing, it is a further and added object to develop materials which are not subject to the objectionable breakdown which so frequently characterized the more active of the previously-known synthetic, pharmacologically active esters.
In the accomplishment of these objects in accordance with the present invention the surprising fact has been found that the ester grouping, previously considered essential in the prior art, is quite unnecessary. It has been found in'accordancewith the present invention that the desirable characteristics are evidenced by a group of basic nitrogenous tertiary alcohols containing no ester group- H In general, the objects of the present invention have been accomplished in the development and synthesis of basic tertiary alcohols of the general formula.
Alk wherein the groupings designated R, Alk, and Het represent varied substituents as defined immediately below.
R and Alk, by their location on the molecule, may be considered as interchangeable. In the instant application, R, for example, will usually be a phenyl, naphthyl, furyl or thienyl radical, or a monoor dilower alkyl, hydroxy, alkoxy, chloroor bromo-substituted phenyl or naphthyl radical. saturated or unsaturated aliphatic radical of about l-12 carbon atoms. The group designated as Het may be the l-piperidyl radical. v
v From the foregoing description, it will be seen that compounds in accordance with the present invention may vary quite widely in scope and structure. Typical illustrative compounds within the specific limitations of this Alk, as shown in the formula, will represent a atent O 2,723,269 Patented Nov. 8, 1955 formula are shown in the following table, in which the compounds are indicated by the values of R, Alk, and Het, in the formula given above.
TABLE r Het l-piperidyl.
Z-naphthyl 4ch1oro-1-naphthy1 Do Z-furyl 4-hydroxyphenyl z-chlorophenyl BA-dimethylphenyl 3,4-d1methoxyphenyl. 3,4-dihydroxyphenyl 2,4-dimethylphenyl 3,4-dich1orophenyL. 2, fi-dimethylphenyl In general, the basic tertiary alcohols of the present invention comprise crystalline solids, usually having a sharp melting point, although some are inclined to sinter slightly just below the melting point. Some of the compounds, however, are so difficultly crystallizable as to appear to be permanent oils and some few appear actually to be permanent oils. The crystalline compounds appear to be free from color when pure. Most of the alcohols are relatively insoluble in water but are readily soluble in ether and in alcohol-ether mixtures.
The alcohols readily form crystalline addition salts, such as hydrochloride, nitrate, citrate and the like, by reacting the alcohol in solution with the desired acid in the usual way. The hydrochlorides, for example, are readily formed and are soluble in aqueous solution. In some cases the water-solubility is so marked that the salts are extremely hygroscopic and in crystalline form must be carefully handled; They possess the markedly useful property in aqueous solution of remaining stable over long periods of time. Quaternary salts, such'as the methobromide, methiodide, ethiodide, and the like, are
also readily formed and have a number of desirable properties. Several of them also possess desirable mydriatic properties. The acid addition and quaternary salts, therefore, possess marked utility for pharmacological experiment.
It is surprising that the basic tertiary alcohols of this invention should possess anti-spasmodic properties, in view of the previously considered desirability of the ester grouping. Especially is this a surprising feature in view of the fact that secondary alcohols of similar structure, for example 3-(l-piperidyl)-1-phenyl-1-propanol and the like, also possess no appreciable pharmacological activity as spasmolytics.
It is still more surprising, in view of the fact that very closely analogous basic tertiary alcohols possess no pharmacological utility in this respect. For example, compounds in which both R and Alk are alkyl radicals have relatively little or no useful anti-spasmodic activity, and compounds in which both R and Alk are alkyl radicals, and Het is replaced by a dialkylamino radical,
v have no anti-spasmodic activity.
The basic tertiary alcohols of this invention appear to be active against both musculotropic and neurotropic spasm, being particularly effective against the latter. In addition to their surprisingly great activity, the compounds are, in general, characterized by a remarkably low toxicity. Considering the product of these two factors of activity and toxicity as a pharmacological index, many of the compounds are, therefore, considerably more useful than either atropin or Trasentin.
In addition, the compounds vary as to the rate of onset and as to duration of activity. It is, therefore, possible to select a compound from the series suitable for almost any anti-spasmodic'purpose. Their utility is, therefore, possible in a wide variety of fields.
Secondary alcohols, such as those previously noted, were prepared by catalytic hydrogenation of the corresponding ketone. The new basic tertiary alcohols of the present invention, being of entirely different type, cannot be prepared in the same way. It was found, however, that by judicious selection of reactants, the compounds of the present invention can be readily synthesized.
Perhaps the most satisfactory way was found to be the addition of a suitable Grignard reagent to the proper basic ketone in the presence of a suitable solvent for both. Heating for sufficient time to complete the reaction, followed by hydrolysis, produces the desired basic tertiary alcohol. A typical illustration of the reaction may be indicated as follows:
R OMgBr AlkMgBr \& R-COOHaCHz-Eot+ -CH2CHzHet Alk R OH I H2O CCH2-CH2Het Alk Since the first stage in this reaction must be carried out parently tends to form an insoluble-complex with the ketone.
In such cases, the chloride appears to produce the least insoluble complexes and, therefore, may be preferable. For a similar reason, in such cases the use of a higher boiling solvent, such as dibutyl ether, may become preferable in order to utilize increased temperature and thereby improve the solubility.
The amount ofGrignard reagent chosen also has an effect on the yield. Apparently, this again may be due to the formation of a complex. The latter is believed to form but to break down on hydrolysis. For this reason, it appears that some of the reagent is not available for further reaction. in any case, a-considerable increase over an equimolecular amount of the Grignard reagent ordinarily produces a definitely increased yield. Above about two molecular equivalents, however, further increase in the amount used produces a markedly diminishing return. About two moles of Grignard reagent per mole of ketone appears to be the preferable range.
The invention will be illustrated in conjunction with the following examples, which are to be taken as illustrative only and not by way of limitation. All parts are by weight, unless otherwise noted.
Example 1.I-(1-piperidyl)-3-phenyl-3-heptan0l To a chilled ether solution of n-butylmagnesium bromide (prepared from 274 parts n-butyl bromide, 48.6 parts magnesium turnings, and 800 parts by volume absolute ethyl ether) is added, with stirring, over a period of 25 minutes, a dry solution of 217 parts omega-(lpiperidyl)-propiophenone in 800 parts by volume of ether. The resulting reaction mixture is stirred for about 1 hour and allowed to stand at room temperature until reaction substantially ceases. The reacted mixture is chilled in an ice bath While it is slowly treated with 600 parts by volume of 5 N hydrochloric acid. The solid formed is collected on a filter, air-dried, redissolved in 2500 parts of water at C., the solution is treated with decolorizing charcoal and clarified by filtration. The filtrate is chilled until it starts to become cloudy and is then made alkaline with ammonia. The solid which precipitates is collected on a filter as crude l-(l-piperidyl)-3-phenyl-3-heptanol and purified by recrystallization from dilute alcohol; when pure it melts at 5656.7 C. (uncorrected) with preliminary softening at 54.4 C. It forms a hydrochloride which melts at 223-224 C. (uncorrected) with some decomposition.
By following the procedure of the above example, but by using an equivalent amount of an alkylmagnesium halide, prepared from an alkyl halide in column 1 of Table II (below) instead of n-butylmagnesium bromide, the corresponding piperidyl tertiary alcorols listed in column 2 of Table II are obtained. Column 3 lists the melting points of the piperidyl tertiary alcohol, while column 4 lists the melting points of their hydrochlorides.
TABLE II y r0- Alkyl Hallde Piperldyl Tertiary Alcohol M. P., C. chloride,
methyl chloride 4-(l-piperidyl)-2-phenyl-2-butanol 1 137-142/3 mm. 200. 3-200. 9 ethyl bromide l-(l-piperidyl)-3-phenyl-3-peuta- 82.5-83.0 185. 0-1855 n n-propyl chloride l-(l-lpiperidyl)-3-phenyl-3-hexa- 92.2-94.0 202. 0-203. 5
no isopropy1chloride 1-(l-piperidyl)-3-phenyl-4-methyl- 72.7-75.1 2
3-pentanol. allyl chloride 6-(1-t1 iperidyl)-4-phenyl-1-hexen- 180. 5-1829 4-0 isobutyl bromide -glgnperidyl)-3-pheny1-5-methyl- 53.1-56.6 218. 2-219. 7
exano sec.-butyl bromide 1-glipiperidyl)-3-pheny1=4-methyl- 210. 0-212. 5
exano tert.-butyl ch1oride- 1 (1-piperidyI)-3-pheny1-4,4-di- 228. 5-230. 0
, methyl-B-pcntanol. n-amyl bromide 1-(l-piperidyl)-3-phenyl-3-octanol 63.5-65.5 200. 0-204. 5 isoamyl bromide 1'-glgnptsridi l)-3-phenyl-6-methyl- 59.0-59.5 '240.0-?A0.'5
an arm n-heptyl bromide" l-(l-piperidyl)3-phenyl-3-decanol 63.0-65 5 207. 0-209. 5 n-duodecyl bromid l-(dl-pipesidyl)-3-phenyl-3-penta- 192. 0-193. 5
ecano Boiling point instead of melting point. Melts in approx mately 10 seconds when immersed in bath at 175 C.
By following the procedure of Example 1, but by using 1 an equivalent amount of ethylmagnesium bromide instead of n-butylmagnesium bromide, and by using an equivalent amount of beta-[2-(1,2,3,4-tetrahydroisoquinolyl)]- propiophenone instead of beta-(1-piperidyl)propiophenone, the above pentanol is obtained. When purified by recrystallization, from dilute alcohol, it melts at 92.2-93.1 C. Its hydrochloride, prepared and purified in the usual way, melts at 202.2-203.0 C.
In the above procedure, if an equivalent amount of the propiophenones and propionaphthoneslisted in column l'of Table III (below) are used instead of beta-[2- (1,2,3,4-tetrahydroisoquiuolyl)]propiophenone, the corresponding pentanols listed in column 2 are obtained. Column 3 lists the melting points of their hydrochloric'les.
Example 3.1-(4-morph0linyl) -3- (Z-naphthyl) -3- heptanol By following the procedure of Example 1, but by using an equivalent amount of beta-(4-morpholinyl)-2-propionaphthone instead of beta-(1-piperidyl)propiophenone, 1-(4-morpholinyl)-3-(2-naphthyl)-3-heptanol is obtained. Its hydrochloride, prepared and purified in the usual way, melts at 220.5-221.0 C. with decomposition.
In the above procedure, if an equivalent amount of the propiophenones and propionaphthones listed in column 1 of Table IV (below) are used instead of beta-(4- morpholinyl) 2 -propionaphthone, the corresponding heptanols listed in column 2 are obtained. Column 3 lists the melting points of the hydrochlorides of the heptanols.
TABLE IV Basie Ketone Heptanol Beta (1 piperidyl) 4 chlor 1- o- Beta (4 morpholinyl) 4-chloro-1-.
1- (1 -piperidyl) -3- (4-bromophenyl)-3-heptanol.
l (1- piperidyl) 3 (4 -ethylphenyl)-3-heptanol.
1 (1 piperidyl) -3 (2-naphthyll-3-heptanol.
1- (1-piperidyl) -3- (t-chloro- 1-naphthyD-3-heptanol.
1 (4 morpholinyl) 3 (4 chloro-l-naphthyl) -3-heptanol.
As noted above, the compounds of the present invention possess utility as anti-spasmodics. An indication of their efifectiveness may be obtained by the commonlyused test of ability to relax isolated rabbit intestinal strips which are immersed in a constant temperature test solution. In the following Table V, illustrative results are shown. In the tests shown, spasticity was induced by furfuryl trimethyl ammonium iodide in 0.1 mgm./ ml. of Tyrodes solution.- In the table, if the spasticity was counteracted to the extent that the gut assumed normal activity, relaxation is said to be 100%. If the gut shows essentially no counteractions afterthe anti-spasmodic drug, the condition is recorded as complete relaxation. The test compounds have the formula TABLE V Percent Relaxation (Average Number of Tests) Compound R 39 comp.
5 64 comp. 79 100 comp. 1 100 comp. comp. comp. comp. comp.
Trasentin ethyl n-propyl n-butyl 1 Dose, mgmJlOO cc. I Complete relaxation in several tests.
The adverse effect on the anti-spasmodic activity of the propanols of the present invention is shown in the following Table VI. The test results show the extremely poor quality of the product obtained when R in the general formula is an alkyl radical such as ethyl, and also the lack of activity when both R and Alk represent alkyl radicals and Het is replaced by a dialkylamino group.
TABLE VI Percent Relaxation of Spastic Gut Compound OH 0CH2CH2N\ H 0 5 64 comp. comp. C2115 I C211 OH O0 H2CH2N H 0 0 0 0 50 CzHs CH3 OH /CHa CCH2'CH2-N 0 0 0 0 0 CH3 CH3 1 Dose, mgm./ 100 cc.
The compounds of the present invention are also effective against barium chloride spasm. Illustrative results of testing efiectiveness in counteracting spasticity insalts thereof.
I claim: 1. A compound of the group consisting of tertiary aminoalcohols of the formula 1-( l-piperidyl -3 -phenyl-3 -heptanol.
l-( 1-piperidyl)-3-phenyl-3 -pentan0l. 1-(1-piperidyl)-3-phenyl-3 -hexano1.
l-( 1-piperidyl)-3 -phenyl-4-methyl-3 -pentanol. 1-( l-piperidyl) -3 -phenyl-6-methyl-3 -heptanol.
References Cited in the file of this patent UNITED STATES PATENTS Fourneau Aug. 14, Klarrer Oct. 30, Miescher et a1. Nov. 26,
FOREIGN PATENTS Switzerland 2. Feb. 16, France Feb. 3,
OTHER REFERENCES H OH CHz-CH2 GOH2CH2N 0111 (1938) pp. 1372-76. Alk CH2-C2 wherein R is a member of the group consisting of phenyl and naphthyl and AIR is a lower alkyl and acid addition Trefuel et al.: Chem. Abst, vol. 24 (1930) p. 3502 Mannich et a1: Chem. Abst., vol 22 (1928) pp. 590- Campbell et al.: Jour. Amer. Chem. Soc., vol. 60
Marie: Bull. Soc. Chem. (4) 3 (1908) pp. 280-86.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US125381A US2723269A (en) | 1949-11-03 | 1949-11-03 | Piperidino tertiary amino alcohols |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US125381A US2723269A (en) | 1949-11-03 | 1949-11-03 | Piperidino tertiary amino alcohols |
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| US2723269A true US2723269A (en) | 1955-11-08 |
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| US125381A Expired - Lifetime US2723269A (en) | 1949-11-03 | 1949-11-03 | Piperidino tertiary amino alcohols |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2789110A (en) * | 1953-03-14 | 1957-04-16 | Knoll Ag | Amino alcohols substituted by bicycloalkyl residues and a process of making same |
| US2945034A (en) * | 1955-03-12 | 1960-07-12 | Farmaceutici Italia | Ortho-hydroxy-n-beta-morpholino-propiophenone fungicides |
| US4110447A (en) * | 1974-10-26 | 1978-08-29 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Anti-inflammatory (halo-4-biphenylyl)-alkanolamines |
| WO1998030540A1 (en) * | 1997-01-10 | 1998-07-16 | Merck & Co., Inc. | Efficient synthesis of a chiral mediator |
| US5856492A (en) * | 1997-01-10 | 1999-01-05 | Merck & Co., Inc. | Efficient synthesis of a chiral mediator |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US828846A (en) * | 1904-03-21 | 1906-08-14 | Ernest Fourneau | Process of making alkamins. |
| FR698687A (en) * | 1929-10-07 | 1931-02-03 | Rhone Poulenc Sa | Amino-alcohols and poly-amines derived from piperazine |
| US1978539A (en) * | 1928-03-02 | 1934-10-30 | Winthrop Chem Co Inc | Basic alcohol |
| CH234785A (en) * | 1941-05-24 | 1944-10-31 | Ig Farbenindustrie Ag | Process for the preparation of N- (y, y-diphenyl-allyl) -N, N-diethylamine. |
| US2411664A (en) * | 1941-07-25 | 1946-11-26 | Ciba Pharmaccutical Products I | Amino alcohols and method of preparing the same |
-
1949
- 1949-11-03 US US125381A patent/US2723269A/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US828846A (en) * | 1904-03-21 | 1906-08-14 | Ernest Fourneau | Process of making alkamins. |
| US1978539A (en) * | 1928-03-02 | 1934-10-30 | Winthrop Chem Co Inc | Basic alcohol |
| FR698687A (en) * | 1929-10-07 | 1931-02-03 | Rhone Poulenc Sa | Amino-alcohols and poly-amines derived from piperazine |
| CH234785A (en) * | 1941-05-24 | 1944-10-31 | Ig Farbenindustrie Ag | Process for the preparation of N- (y, y-diphenyl-allyl) -N, N-diethylamine. |
| US2411664A (en) * | 1941-07-25 | 1946-11-26 | Ciba Pharmaccutical Products I | Amino alcohols and method of preparing the same |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2789110A (en) * | 1953-03-14 | 1957-04-16 | Knoll Ag | Amino alcohols substituted by bicycloalkyl residues and a process of making same |
| US2945034A (en) * | 1955-03-12 | 1960-07-12 | Farmaceutici Italia | Ortho-hydroxy-n-beta-morpholino-propiophenone fungicides |
| US4110447A (en) * | 1974-10-26 | 1978-08-29 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Anti-inflammatory (halo-4-biphenylyl)-alkanolamines |
| WO1998030540A1 (en) * | 1997-01-10 | 1998-07-16 | Merck & Co., Inc. | Efficient synthesis of a chiral mediator |
| US5856492A (en) * | 1997-01-10 | 1999-01-05 | Merck & Co., Inc. | Efficient synthesis of a chiral mediator |
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