DE2906239A1 - Doxylamine optical isomers - with antihistamine and sedative-hypnotic activity (dextro-enantiomer) or antihistamine activity (laevo-enantiomer) - Google Patents

Abstract

New cpds. are (+) - and (-)-enantiomers of 2-dimethylamino-ethyl phenyl-methyl-(2-pyridyl)-carbinol ether (doxylamine) (I), and their salts with organic carboxylic acids (esp dicarboxylic acids). In the guinea-pig isolated ileum prepn, (+)-(I) has more antihistaminic action at a lower concs than (-) - (I). (+)- (I) prolongs hexobarbital sleeping time in guinea pigs, while (-)-(I) greatly reduces this (+)-(i) is useful as an anthihistamine and/or as a sedative and hypnotic agent, while (-)-(I) is useful as an anthihistaminc for daytime use.

Description

Right-handed (+) - enantiomer and left-handed

(-) - Enantiomer of ß-dimethylamino-ethyl (phenyl methyl-2-pyridyl) carbinol ether The invention relates to dextrorotatory (+) - enantiomer and levorotatory (-) -Enantiomer of ß-dimethylamino-ethyl- (phenyl-methyl-2-pyridyl) -carbinolether as well as processes for their production and their use as active ingredients in pharmaceuticals.

It is from Ullmann's Encyclopedia of Technical Chemistry, 4th ed., Vol. 7, p. 707, Verlag Chemie, Weinheim / Bergstrasse, 1974, known that antihistamines of the dialkylaminoethane type and those of the dialkylaminopropane type into optically active ones Enantiomers can be split, see also US Pat. No. 3,061,517.

In the case of 2- (4-chloro (2-dimethylamino-ethoxy) -benzyl) -pyridine the L-enantiomer was shown to be an effective component.

In the case of antihistamines of the alkylamino-propane type such as e.g.

3-Dimethylamino-1-phenyl-1- (2-pyridyl) -propane turned out to be the D-enantiomers than more effective.

Finally, there is also 2- (α- (2-dimethylamino-ethoxy) -α-methyl) benzylpyridine succinate known, see J. Lab. Clin.

Med. 33: 325-331, however, so far neither the asymmetric carbon atom still on its cleavage into optically active enantiomers pointed out.

It has now been found that the dextrorotatory (+) - enantiomer of B-dimethylamino-ethyl (phenyl-methyl-2-pyridyl) carbinol ether of the structural formula hereinafter referred to as (+) - doxylamine for short, in many cases as an active ingredient in pharmaceuticals has a stronger effect than the doxylamine racemate and the levorotatory (-) - doxylamine enantiomer. The (-) - doxylamine antipode also shows a new effect that differs from the racemate and (+) - antipodes.

The (+) - doxylamine and the (-) - doxylamine are produced On the fractional crystallization of the diastereomeric salts of its apcemate with optically active carboxylic acids, especially tartaric acid in organic solvents.

According to a preferred method, the diastomeric salts of the Doxylamine racemates with L (+) - tartaric acid crystallized from ethanol.

Racemic doxylamine is preferred because of its antihistamine Effect used in cold preparations.

Another use is that as an active ingredient in sedatives and in hypnotics.

For the cleavage of (+) - doxylamine succinate into the optical antipodes the commercial salt of doxylamine was decomposed with sodium hydroxide and the free racemic base with L (+) - tartaric acid or with D (-) - tartaric acid to form optically active Hydrogen tartrates implemented. The diastomeric salts can be due to their different Solubility in ethanol can be separated. When cleaved with D (-) - tartaric acid could however, only the (+) - doxylamine-D (-) - hydrogen tartrate can be isolated in pure form.

The optically active hydrogen tartrates were made with sodium hydroxide solution optically active free bases obtained, which-with .succinic acid to the optically active Doxyiaiüin-succinaten were implemented. The following compounds were made according to the invention produced according to (+) - doxylamine +) - hydrogen tartrate, (-) - doxylamine-L (+) - hydrogen tartrate, (+) - Doxylamine-D (-) - hydrogen tartrate, (+) - doxylamine, (-) -doxylamine, (+) - doxylamine.succinate and (-) - doxylamine succinate. None of these compounds are described in the literature.

Doxylamine is one of its main pharmacological effects Antihistamine; in addition, like other antihistamines, it has, among other things sedative-hypnotic properties.

The experiments described below had the aim of the enantiomers of doxylamine with regard to the histamine-antagonistic and the sedative-hypnotic To check the effect based on possible stereoselective differences.

The experiments were carried out on guinea pigs (MS), an animal species which is characterized by high histamine sensitivity. The following investigations were carried out performed: A) Histamine-antagonistic effect of the enantiomers of doxylamine on the isolated MS ileum.

Histamine has a contracting effect on the isolated MS ileum; let it on this isolated organ, in a simple manner, quantitative relationships between Histamine concentration * yourself and tension development of the smooth Represent the muscles of the gut as a dose-effect curve. In the presence of a histamine antagonist the histamine concentrations necessary to induce a contraction are higher than in the control case; the resulting dose-response curve is higher in the region Histamine concentrations shifted. The measurements showed a stronger histamine-antagonistic Effect of the (+) - enantiomer of doxylamine compared to the racemate and the (-) - enantiomer.

B) Enantiomers affect the hexobarbital sleep time of MS and racemate of doxylamine.

Antihistamines have a relatively extensive pharmacodynamic Spectrum of activity; so they show in addition to the histamine-antagonistic effect - the Main effect - sedative-hypnotic effects. In many cases, these have led to that antihistamines are used therapeutically as mint sedatives, e.g. im As part of premedication before anesthesia. The sedative-hypnotic effect of Antihistamines in the range of therapeutic doses can be used in animal experiments not readily quantify; on the other hand, the sedative-hypnotic effect can be reduced the antihistamines due to the potentiation of the effect of narcotics, e.g. Barbiturates, relatively easy to quantify. For a given, it becomes narcotic effective barbiturate dose determines the assigned sleep time; after pretreatment with antihistamines in non-narcotic doses is barbiturate sleep time extended as a consequence of potentiation.

The (+) - enantiomer of doxylamine is elongated, the (-) - enantiomer greatly shortens and the racemate moderately shortens the hexobarbital sleep time of the guinea pig.

More details about the properties of the new substances, their manufacture and use are shown using the examples and the tables, example 1 Cleavage of racemic doxylamine with L (+) - tartaric acid (+) - doxylamine was turned off commercial doxylamine succinate by decomposition with sodium hydroxide solution, shaking out the free base with chloroform, removing the solvent i. V and fractionation obtain.

KP0.15 138-141 ° C nD20 1.5462 145.0 g (0.557 mol) (+) - doxylamine and 100.0 g (0.667 mol) of L (+) - tartaric acid are briefly boiled in 400 ccm of 96% ethanol and then cooled. After long standing at room temperature and frequent rubbing 110.7 g of colorless crystals with a melting point of 150-153 ° C. crystallize.

[α] D25 = - 44.00 (water, c = 5.2) From the mother liquor this Crystals crystallize on cooling and trituration from 37.2 g of colorless crystals Melting point 131-132 ° C.

[α] D25 = + 69.5 ° (water, 6 = 10.0) after concentrating the mother liquor 26.0 g of semi-crystalline resin are obtained with [α] D25 = + 67.0 ° (water, c = 10.1) The levorotatory salt is recrystallized from ethanol until it has a melting point and do not change the rotation value.

(-) - Doxylamine-L (+) - hydrogen tartrate is obtained as coarse, colorless crystals with a melting point of 156-157 ° C.

[α] D22 = -56.7 ° (water, c = 10.35) C21H28N2O7 (420.5) calc .: C 59.99; H 6.71; N 6.66; Found: C, 60.0; H 6.67; N 6.2.

The two clockwise crystallizations are also turned off Ethanol recrystallizes until the melting point and rotation value no longer match change. (+) - Doxylamine-L (+) - hydrogen tartrate is obtained as fine needles with a melting point 132-133 ° C.

[α] D22 = + 71.7 °, (water, c = 10.56) C21H28N207 (420.5) ber .: C 59.99; H 6.71; N 6.66; Found: C, 59.6; H 6.75; N 6.3 Example 2 Cleavage of doxylamine racemate with D (-) - tartaric acid 40.0 g (0.148 mol) (+) - doxylamine and 24.66 g (0.164 mol).

D (-) - tartaric acid are briefly boiled in 100 cc of 96% ethanol and then cooled. On prolonged standing and rubbing, 31.1 g of colorless crystallized Crystals with a melting point of 149-1520C.

[α] 20 = + 38.0 ° (water, c = 10.0) multiple recrystallization from ethanol gives (+) - doxylamine -D (-) - hydrogen tartrate with a melting point of 156-157 ° C.

[α] D22 = + 56.5 ° (water, c = 10.28) C21H28N2O7 (420.5) calc .: C 59.99; H 6.71; N 6.66; Found: C, 60.0; H 6.74; N 6.0 (-) - doxylamine-D (-) - hydrogen tartrate could not be isolated in pure form from the mother liquor.

Example 3 -) - Doxylamine was made from (-) - Doxylamine-L (+) - hydrogen tartrate by decomposing with caustic soda, etherifying, drying and distilling off the ether obtain.

D22 = - 9.26 ° (ethanol, c = 10.08) Example 4 (+) - Doxylamine was made from (+) - Doxylamine-D (-) - hydrogen tartrate as described in example 3 obtain.

{22 = 10.880 (ethanol, c = 10.34) Example 5 (-) - Doxylamine succinate 32.0 g (0.119 mol) (-) - doxylamine and 14.1 g (0.119 mol) succinic acid are in 40 cc of ethanol briefly boiled and still warm with 150 cc of diethyl ether until cloudy offset. You remove the cloudiness with a few drops of ethanol, cool under constant Rub off, suck off the crystals and wash with diethyl ether; Yield: 41.0 g colorless crystals, melting point 96-980C. Recrystallize from ethanol / diethyl ether increases the melting point to 98-1000C.

[α] D22 = - 41.3 ° (water, c = 10.26) C21H28N205 (388.5) calc .: C 64.93; H 7.27; N 7.21; Found: C C 65.2; H 7.13; N 6.8 Example 6 (+) - Doxylamine succinate was made from 32.0 g (+) - doxylamine and 14.1 g (0.119 mol) succinic acid as in the example 5 described produced. Yield: 34.2 g of colorless crystals with a melting point 98-1000C (from ethanol / diethyl ether).

[α] D22 = + 36.50 (water, c = 10.19) C21H28N205 (388.5) calc .: C 64.93; H 7.27; N 7.21 Found: C 65.2; H 7.07; N 6.8.

The new compounds prepared in Examples 1 to 6, their Melting points and rotation values are summarized in table 1.

Table 1 Compound F ° C [α] D22 (+) - Doxylamine-L (+) - hydro- 132-133 + 71.7 ° (water; c = 10.56) gentartrate (-) - doxylamine-L (+) - hydro- 156-157 - 56.70 (water, c = 10.35) Gentartrate (+) - Doxylamine-D (-) - hydro- 156-157 - 56.50 (water, c = 10.28) Gentartrate (+) - Doxylamine - + 10.880 (ethanol, c = 10.34) (-) - Doxylamine - - 9.260 (ethanol, c = 10.08) (+) - Doxylamine succinate 98-100 + 36.50 (water, c-10.19) (-) -Doxylamine succinate 98-100 - 41.30 (water, c = 10.26) As Table 1 shows, have (-) - doxylamine-L (+) - hydrogen tartrate and (+) - doxylamine-D (-) - hydrogen tartrate almost equal rotation values, suggesting that the two salts were optically pure. The free bases and the two succinates could not, however, be isolated in a completely optically pure manner.

The melting points were determined in the heating block and are uncorrected. The elemental analyzes were carried out by Walisch's ultra-micro-rapid method, see W. Walisch, Chem. Ber. 94, 2314/1961. The rotation values were with the photoelectric Precision polarimeter LEP A from Carl Zeiss, Oberkochen / Württ. measured.

For extrapolation of rotation angle measurements at the measurement wavelengths 546.1 and 557.8 nm on the rotation at the sodium D line 589.2 nm served the first Approximation of Drude's approach for normal rotational dispersion, see P. Drude, Textbook of Optics, 2nd edition, S. Hirzel-Verlag, Leipzig 1906.

Example 7 Methodology Guinea pigs (200-250 g body weight) were killed by a blow in the neck; the terminal ileum became a 4-5 cm long piece taken and suspended in an organ bath in Krebs-Henseleit solution (32 ° C, Carbogen-gassed, pH 7.35 # 0.11).

The development of tension was isometric using a strain gauge measured and recorded on a direct-writing, calibrated oscilloscope. After an equilibration time of 30 minutes, the suspension medium in the organ bath Histamine added in the initial concentration, left for 10 minutes and then removed by washing; after a control period of 5 minutes, histamine added in the next higher concentration; the histamine concentration was up increased to the occurrence of the maximum effect.

The enantiomers of the doxylamine were 10 minutes before the first histamine application added to the suspension medium. Histamine chloride (Merk, Darmstadt) and (+) - resp. (-) - Doxylamine @ arinate were dissolved in 0.9% NaCl solution.

The sub-bookings carried out according to the method outlined above had the following result, see Figure 1 and Table 2: It can be isolated MS ileum the intestinal contracting effect of histamine as a dose-effect relationship represent.

With a histamine concentration of 7 # 10-8 g / ccm the resulting Contraction of the ileum half maximal (ED50); at 3 # 10-3 g / com, ra5 maximum is the Contraction reached: The further increase in the histamine concentration leads to no further acceptance of the contraction.

The enantiomers of doxylamine act with respect to those that contract the bowel Antagonistic effect of histamine: they shift the dose-effect curve on the right in the area of higher histamine concentrations.

The histamine-antagonistic effect of the enantiomers is concentration-dependent: the shift to the right of the dose-response curve for histamine is at one concentration the Enantiomers of 10-6 g / ccm more pronounced than those of 10-7 g / ccm. The enantiomers of doxylamine have different quantitative stereoselectively Histamine-antagonistic activity. In both concentrations tested, this is (+) - enantiomers more potent; measured by the EC50, the (-) - enantiomer is about 5 times weaker than the (+) - enantiomer.

In the figure 1 is the influence of the enantiomers of doxylamine on the Intestinal contracting effect of histamine shown on isolated guinea pig ileum. The stress development in mg is plotted on the ordinate and the abscissa the histamine concentration in the suspension medium in g / ccm.

The curves in FIG. 1 contain the following measured values: 1 = Controls (without doxylamine) 2 = (-) - Doxylamine 10-7 g / ccm 3 = (+) - Doxylamine 10 7 g / cc 4 = (-) - Doxylamine 10-6 g / cc 5 = (+) - Doxylamine 10-6 g / ccm, see also Table 2. Table 2 The influence of the enantiomers of doxylamine on the intestinal contracting effect of histamine on the isolated guinea pig ileum.

The values given are the mean values of the maximum stress development in mg # # (mean error of the mean value). The stated concentrations of histamine or (+) - and (-) - doxylamine are the final concentrations in the suspension medium. Histamine concentration tion in g / ml 10-8 3 # 10-8 10-7 3 # 10-7 10-6 3 # 10-6 10-5 Controls 185 419 706 973 1121 1186 1183 n = 14 # # # # # # # (-) - Doxylamine 13 52 235 366 775 1032 1134 n = 12 # 10.3 # 11.8 # 23.4 # 31.4 # 48.6 # 51.4 # 54.7 10-7 g / ml (+) - Doxylamine 0 33 138 303 576 843 998 n = 11 # 16.3 # 17.4 # 31.4 # 57.6 # 63.7 # 58.3 (-) - Doxylamine 0 0 50 213 497 718 870 n = 13 # 18.4 # 16.1 # 28.4 # 38.6 # 44.7 10-6 g / ml (+) - Doxylamine 0 0 0 92 270 522 672 n = 14 # 11.3 # 23.4 # 37.8 # 44.7 EXAMPLE 8 Methodology MS of both sexes weighing 200-250 g was ip

20 mg / kg hexobarbital sodium is injected. After 3.40 + 1.10 minutes (n = 19) the animals were lying on their side; the mean sleep time was 22.40 + 2.35 minutes (n = 19). The enantiomers or the racemate of doxylamine were in a dosage of 5, 10, 20 and 30 mg / kg 30 minutes before the application of hexobarbital sodium i.p. injected; the test animals did not show any signs at any of the dosages chosen a beginning anesthesia (e.g. strengthening the positioning and holding reflexes). the The number of trials for each dose was n-10. In the presence of the enantiomers or of the racemate of doxylamine became - as in the control case - the hexobarbital sleep time certainly.

The results can be seen from FIG.

The evaluation of FIG. 2 shows: The enantiomers of the doxylamine have qualitative stereoselectively different effects: 1.) The (+) - enantiomer, which is characterized by a stronger histamine antagonistic effect (see A, Page 3/4), increases the hexobarbital sleep time depending on the dose.

2.) The (-) - enantiomer, however, leads to a dose-dependent shortening the hexobarbital sleep time; this effect is more pronounced than the sleep-lengthening effect Effect of the (+) - enantiomer.

3.) The racemate of doxylamine leads - like the (-) - enantiomer - to a dose-dependent much reduction in hexobarbital sleep time; its effectiveness is weaker than that of the (-) - enantiomer, apparently as a consequence of the simultaneous presence of the (+) - enantiomer, Figure 2 shows the influence of the enantiomers of doxylamine and racemate on the hexobarbital sleep time in intact guinea pigs.

The ordinate shows the lengthening or shortening of the hexobarbital sleep time plotted as a percentage of the control value.

The numbers above the columns indicate the dose of the enantiomers administered i.p. or of the racemate in mg / kg; black bars: (+) - doxylamine; white columns: racemate; hatched columns: (- (-) - doxylamine; vertical bars: e (mean error of Mean value); applied hexobarbital dose: 20 mg / kg i.p .; Number of trials n = 10 for each tested dose of the ena2ltiomers or the racemate.

SUMMARY The racemate of doxylamine succinate was through Reacting with sodium hydroxide converted into the free base, the salts with optically active tartaric acids through fractional crystallization from organic solvents, in particular ethanol, into the respective optically active stereoisomers of doxylamine hydrogen tartrate could be separated. By decomposing the optically active doxylamine hydrogen tartrate with sodium hydroxide the free optically active bases of the doxylamine are obtained, their reaction with succinic acid, the optically active enantiomers of doxylamine succinate results.

The dextrorotatory (+) - enantiomer of doxylamine gives the isolated Guinea pig intestines have a much stronger histamine antagonistic effect than that levorotatory (-) - enantiomers.

It extends the sleep time of guinea pigs while hexobarbital the levorotatory (-) - enantiomer greatly shortens this sleep time.

L e r s e i t e

Claims (11)

P atent claims Right-rotating (+) - enantiomer and levorotating (-) - enantiomer of ß-dimethylamino-ethyl- (phenyl-methyl-2-pyridyl) -carbinol ether of the structural formula hereinafter referred to as (+) - and (-) - doxylamine. 2.) Salts of (+) - and (-) - doxylnmin with organic carboxylic acids, especially dicarboxylic acids. 3.) Process for the preparation of (+) - and (-) - doxylamine and its Salts with organic carboxylic acids, especially dicarboxylic acids, by fractionated Crystallization of the diastereomeric salts of racemic doxylamine with optically active ones Dicarboxylic acids from organic solvents. 4.) Method according to claim 3, characterized in that salts are used of the dxylamine racemate crystallizes with the optically active ensntiomers of tartaric acid. 5.) Process according to claim 3 and 4, characterized in that one Doxyl racemate in the form of its salts with L (+) - tartaric acid through crystallization Ethanol separates. 6.) Medicines that contain (+) - doxylamine as an active ingredient. 7.) Medicines which contain (-) - doxylamine as an active ingredient. 8.) Use of (+) - doxylamine as an antihistamine. 9.) Use of (-) - doxylamine as an antihistamine. 10.) Use of (+) - doxylamine as a sedative and hypnotic. 11.) Use of (-) - doxylamine as a daily antihistamine.