JPS5942389A - Manufacture of 4-(1-methyl-4-piperidene)-4,9-dihydrothieno (2,3-c)-2-benzothiepine and tartrate of same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4-(1-methyl-4-biperidylidene)-4 having the following formula
, 9-dihydrocheno(2,3-C)-2-benzochepine and its (a) tartrate salt.

The compound of formula I (bipetiaden) and its (a) tartrate salt have a high degree of antihistamine, antiserotonin, antireserpine and anticataleptic activity, and furthermore, their relatively low toxicity makes them useful for the treatment of migraine. It is expected to have therapeutic uses.

Compound I was pharmacologically tested in the form of its (t)tartrate salt, which was administered orally and parenterally. Dosages were calculated relative to base. Its effects in many pharmacological tests are similar to those of the three-membered anti-inhibitors of the imipramine group: the nuclear compound acts antagonistically to reserpine in mice; −) dose significantly antagonizes reserpine's abnormal hypothermia)
and 20■/k competitively with reserpine in rats.
The compound satisfactorily and significantly suppresses the ulcerogenic effect of reserpine (starting from subcutaneous administration of 17), and also has a markedly pronounced anticataleptic effect in rats and is resistant to perphenazlne catalepsy tests. Its intermediate protective dose PD5o is 7.0T
n9/9 cm, c, ) - also antagonizes oxotremorine tremor in mice (threshold dose to significantly inhibit tremor is 1.OTv/kg (i, p-)
). In addition to this, Compound I has pronounced central antiserotonin effects; this property has been shown to influence the behavior induced by administering 5-hydroxytryptophan to rats. Kino J in rabbits? Quipazine has been shown to affect hyperthermia and, to some extent, to interact with tryptamine in rats. After administration of 5-hydroxytricytophan to rats, the intensity of the central antiserotonin effect of Compound I on behavioral symptoms was determined at a moderately protective dose (2.9 mfil/kg) against tremor (PD5o for subcutaneous administration). The effect of Compound I in this test was similar to that of cyproheptadine,9 and was also essentially similar to that of amitrizotyline. Very strong.

The antihistamine and antiserotonin effects of Compound I are the most potent of its peripheral effects. When administered orally to guinea pigs, the antihistamine effect in the histamine aerosol test, expressed as a moderate protective dose PD5°, is 0.046 Tng/)l.

In the histamine detoxification and histamine bronchial stenosis tests, compound ① belongs to the most potent known antihistamines. After administration of 5-hydroxytryptamine, the antiserotonin effect in the rat paw edema test was 0.3m97k.
There is a significant bending resistance following oral administration of g. Compound II also has a mild peripheral anticholinergic effect: the nuclear compound exhibits a pupil-dilating effect in mice and blocks the local effects of acetylcholine in guinea pigs.

Known anti-migraine drug bizotifen (Dixo
n) et al., Arzneim, -Forach, 27 +
1968 +1977), compound ■ has a clear advantage in its lower anti-inhibitory effect.

When administered orally, the compound
In an observational test by R) and Simon (5irnon), the exploration activity of mice was inhibited by IA inhibition of bizotifurun (NIJf).
(D5o of compound I is 23 m97 kg, D5o of pizotifen is 7 Tn9/kl). In a mouse locomotor activity test using the light-cell method by Dews, the inhibitory activity of Compound I was 7 times lower than that of bizotifen (D5o of Compound II was 24
．． 2■/Boiled, bizotifen D5oid 3.4
■／kl? ). In a 45-specificity study of sleep synergy of thiopencur in mice, the threshold dose of compound ■ corresponded to 10% of its oral LD5o, and the threshold dose of -10,000 pizotifen corresponded to only 2.5 of its oral LD5o.
(The oral toxicity of the two compounds in mice is similar). Compound ■ has a pronounced tendency towards behavioral stimulation in rats: animax
Compound when observing its effect on the total activity of the animal using instruments! ]0ri/yu and 30rn9/lQ9
Oral doses of zotifen have a mild stimulatory effect (the activity in animals increases to a value of 125-131% of the control group), while 3-30 μl/kl of zotifen. The oral dose clearly rejects the lateral significance of the generality of the animals (up to a value of 57-64 chi compared to the control group).

The oral toxicity of compound ■ in rats is surprisingly low:
After administration at a dosage of 1 g 7 kg (p-o,)
Only one animal from the test group of ten nearly died within seven days. Only subtle suppression was observed within 30 minutes after administration. Oral LD5o in mice is 129m9/kg
That's 6. Compounding early summer 50~】o.

A single administration to dogs at a dose of rn9/kg does not cause any behavioral changes, toxicity or death of the animals.

Compounds of formula I have been described in the literature ( R
, ajaner M., , Metya J., and
Protiua M, .

Co11ect, Czech, Chem, Con
Jmun, 32 + 2854 +1967: (Czechoslovak Patent No.]]524) The compound was prepared by combining 1-methyl-4-piperidylmagnesium chloride with cheno(2°3-c)-2-benzochepine-4 (9H) in tetrahydrofuran. )-one and the resulting formula■
: Confession below 4-(]-]methyl-4giberidyl)-4,9-dihydrocheno(2,3-j)-2-benzochepine-4-
Obtained by acid-catalyzed dehydration reaction of ol.

At that time, the following observations were made: Compound ■, said to have been obtained from the Grignard reaction with a yield of 74%, was not homogeneous and remained unchanged after subsequent acid-catalyzed dehydration (heating with dilute sulfuric acid). The final product, namely Compound I, was heavily contaminated with other compounds that remained. The dehydration yield of 95% reported in the above-mentioned paper was based on the evaporation residue, namely crude compound I, which contained the unspecified impurities mentioned above. Impurities in the resulting product were also due to the low melting point reported for compound (125°C from benzene-petroleum ether).
Furthermore, it can be explained from acetone]] from 99 to 120°C. These low melting products were thought to be solvated; however, they were actually a mixture of compound Ⅰ and the impurities mentioned above.

Cheno(2,3-and)-2-benzochain-4(9H)-one and ]-methyl-4 chloride in tetrahydrofuran
The reaction with -piperidylmagnesium has recently been studied in detail and the crude product obtained was further isolated by a combination of crystallization and chromatography methods. Using a thin layer chromatography method using silica dal, the material obtained appears to be rather heterogeneous and, in addition to the aminoalcohol, appears to contain substantial amounts of less polar components. It seemed to me. The pure amino alcohol (1) can be obtained from the crude product by extraction with ethanol; the desired compound H remains undissolved (v), and - if possible, smaller polar substances go into solution. The latter material can be isolated from the mother liquor by column chromatography on silica gel and purified by crystallization. It is most surprising that both the amino alcohol (1) and the less polar component melt exactly at the same temperature of 212-213°C. However, these mixtures melt with a considerable drop, then these are the melting points of the solvation as reported in the above literature.

Elemental analysis of components with low polarity is amino alcohol■
Although elemental analysis shows a very similar composition, the mass spectra demonstrate its exact composition: C17H46NO82, which corresponds to a component with two fewer hydrogen atoms than the amino alcohol (1). The UV spectrum of the new compound shows a high degree of conjugation, which corresponds to a diarylketone structure. The infrared spectrum confirms the diaryl ketone with a characteristic absorption band of 16]1i'.

Both infrared and 'HNMR spectra demonstrate the absence of hydroxyl groups. The differences in the 'H spectra of compound Ⅰ and less polar substances are particularly significant in the aromatic proton signal band. Although the spectrum of compound ■ shows the presence of six aromatic protons, five of the signals merge into unresolved multiple rings, and only the signal of the proton at position 5 of the backbone is clearly separated, indicating the polarity. The small compound 1HI'lV[R accounts for the presence of only 5 aromatic protons, the signals of which are all clearly distinct and can be localized to individual positions of the backbone,
There is no proton at position 7. Another proof of the structural differences between compound Ⅰ and the less polar component is given by the mass spectra in the region corresponding to the fragments.

The main fragment of compound Ⅰ has rry'n98, which corresponds to the protected ammonium ion with 71c1-methylpiperidine structure, and the main fragment of the less polar impurity has Vβ70; The atom corresponds to the methylpiperidine fragment. The first case is typical for methylpiperidyl groups attached to aliphatic carbons, and the second case corresponds to the behavior of methylpiperidyl groups attached to aromatic carbon atoms. All these spectra show that 7-(1-methyl-4-peridyl)cheno(2,3
-C) - Provides the structure of -2-benzochepin-4(9)T)-one.

The formation of compound Ⅰ can be explained by the 1,6-addition of the Grignard reagent to the three double bond system in the molecule of the starting ketone (including the double bond of the keto group C=0) or by the reaction used. This can be explained by the addition of the Grignard reagent to the dipole formed by forced enolization of the starting ketone under conditions (Ga@rtnerR,, Chem, R
ave, 45.493 +1949) 0 Such addition and subsequent hydrolysis must be carried out by elimination of two hydrogen atoms, i.e. by oxidation, possibly under the action of oxygen in the air. Ta. This is an unobserved example of a reaction that involves strongly sterically hindered aromatic ketones, such as 2,3,5,6-tetramethyl and 2,3,5,6-tetramethyl-2- Previously studied in the reaction of methoxybenzophenone with Grignard drugs (Fugen R,C.

etc.: J, Amer, Chem, Soa, 65
e 60 * 1943: E I, 2543,
] 949 a, or, Org, Chem, 1
3.

496.1948).

Yes! A: *White The subject of the present invention is to provide a method for producing compound I, which method involves removing compound I from amino alcohol H and then using it in an almost pure state in a dehydration reaction; This includes a method for removing almost all of the residue of compound (1).

These important additional operations take advantage of the good solubility of compound II in ethanol. The product of the first reaction step, ie the Grignard reaction, is suspended in ethanol, the suspension is heated to the boiling point and, after cooling, the almost pure amino alcohol 1 is filtered off with suction.

This material was obtained in approximately 50% yield; a significant amount of the compound ■
A mother liquor containing 1 does not allow the desired amino alcohol intermediate 1 to be recovered more economically. The final residue of compound (1) is removed from the final product (2) by crystallization from ethanol; this impurity remains in the mother liquor. Finally, part of the present invention is a process for preparing the new tartrate salts of compound I by neutralization with tartaric acid in aqueous ethanol.

The tartrate is moderately soluble in water, and other acid addition salts are also quite suitable for the preparation of the final dosage form; Succinic acid, fumarate and maleate have been previously disclosed (see RaJsner M, et al. 1, C). A method for preparing compound ① in pure form is not described here. Because it is not included in the present invention.

According to the invention, compound I can be conveniently prepared (by the procedure of the examples below), but this example is not intended to limit the scope of the invention in any way.

50rnl of dry tetrahydrofuran to 24ml of magnesium
fi and then 4-chloro-1-methylpiperidine (Adlsrov@at al, +Ceak, far
m, 12 +122.1963) in dry tetrahydrofuran (dried on Molecular Sheep Potaslt 4A)
A solution of approximately 25 ml dissolved in 300 ml of water is introduced and then 5
Warm the mixture in a preheated oil bath to a temperature of 0-55°C. Iodine (0,5,9) and 1,2-dibromoethane are added and the mixture is allowed to stand for about 10-30 minutes until the reaction begins. When the mixture begins to reflux vigorously, the oil bath is removed and the remainder of the 4-chloro-1-methylbi-4-lysine solution is added dropwise at such a rate that the reaction mixture continues to reflux vigorously. Once the reaction starts to start at a sufficient rate, start stirring. After about 40-50 minutes, when most of the solution has been added dropwise, the reaction mixture is allowed to warm moderately.

Reflux is continued for an additional 1.5 hours with stirring. The mixture was then cooled to 10° C. with ice water, and under constant stirring and cooling with ice water, cheno(2,3-ζ)-2-pensochepi/-4-(9H) dissolved in dry tetrahydrofuran 325me was added.
-on (Protiva M, *Raj\narM,
etc., Co11act, Czeah, Chem, Com
mun.

Name 9.2161.1964; Yu9,1366゜1974
) 155 g of solution were processed within 1 hour. The reaction mixture is maintained at a temperature of 10-15°C. Once the solution has been completely added, cooling is discontinued and the mixture is stirred for about 30 minutes until the solution comes to room temperature on its own. C) A solution of tartaric acid 225I dissolved in 2 t of water, with vigorous stirring and at such a rate that the temperature of the mixture does not exceed 20 °C (intensive external cooling is initially necessary). Process with. Thereafter, 509 m/i of toluene are added and the mixture is stirred vigorously for 10 minutes. Next, the toluene layer containing neutral substances is separated, and the aqueous layer is mixed with toluene 200%
Wash with 1 nl, add 9600 mJ of chloroform and, with vigorous stirring and cooling, make alkaline with concentrated aqueous ammonia.

Separate the chloroform layer and add 20% of the aqueous layer to chloroform.
The combined chloroform solution was extracted with water
00- and then left for 12 hours with 30 g of anhydrous potassium carbonate and 10.9 g of activated carbon. The solid t-F was then separated and washed with chloroform for 50 minutes. The chloroform is distilled off under reduced pressure (10-20 kPa), the residue is diluted with ethanol 2001, the mixture is then briefly refluxed and then cooled to 50°C. The precipitated crystals 4-(
1-Methyl-4-piperidyl)-4,9-dihydrocheno(2,3-e)-2-benzochepin-4-ol (
II) is filtered off with suction, washed successively with 100% ethanol and then 100% petroleum ether and dried under reduced pressure. The yield was 113g (51%) and the product was 2
Melts at 09-211°C. The material obtained is almost pure and quite stable for further processing. Crystallization of the sample from ethanol gives a completely pure substance with a melting point of 212-213°C.

A solution of 240 g of sulfuric acid dissolved in 1170 mA of water is treated with 166 g of the above amino alcohol (1) at 40-50 DEG C. and the mixture is refluxed for 15 minutes with stirring. After cooling, the mixture was diluted with 200 ml of water and chloroform 4
00 ml and then 22 ml of concentrated alkaline ammonia
The stirred mixture is made alkaline while adding 09. Maintain the temperature of the mixture at 20-30°C. Separate the chloroform layer, then add the aqueous layer to chloroform 2×10
Extract with 0ml. - Add the combined chloroform solution to 1 part water.
It was washed with 50 m of water, dried with 20 g of potassium carbonate, and then left to stand for a day and night, and then the desiccant was removed from door to door. The P solution was evaporated under mild vacuum (10-20 kPa) and the crystalline residue was dissolved in ethanol 90 omA! It is then dissolved by treatment with water and heating to the boiling point with stirring.

While heating the solution, the solution is decolorized by filtration using charcoal 10.9 and then the p-liquid is crystallized at 5°C. After standing for 12 hours, 4-(1-methyl-4-biperidylidene)-4,9-dihydrocheno-(2,3-ζ)-
The crystallized base of 2-benzochepine (I) was collected by suction and then added with 50 mg of ethanol and 10 mg of petroleum ether.
Wash continuously with 0ml. Dry at room temperature, product 12
Obtain 4g.

Evaporation of the mother liquor to a volume of 200 ml and standing at 5° C. gives 14 g of product (second crop) with satisfactory purity. The overall yield is 138g (88g) and the melting point is 160-161°C. The entire amount of material is suitable for subsequent conversion into salts. When the sample is further crystallized,
Completely pure base 1 is obtained with a melting point of 162 DEG -164 DEG C.

After dissolving base I (94 g) in 65 QmA' of boiling ethanol, heating is discontinued and a hot solution of 47 g of (+) tartaric acid dissolved in 85 ml of water is slowly added. The resulting solution is then cooled to 10° C. with stirring to induce crystallization. After cold welding for 12 hours, the crystals were collected by suction and then ethanol 2X50mA! Wash with The wet product is dissolved in a mixture of 1250 ml of ethanol and 1000 d of water by heating to the boiling temperature, then the solution is filtered while maintaining thermal conditions and the filtrate is stirred in a water bath for 4 hours and cooled to crystallize. . The product was then diluted with ethanol 2
Wash with 30 ml of X and dry in air at room temperature. The mother liquor is evaporated under reduced pressure (3-5 kPa) to about half of its original volume and then cooled to 5°C to obtain a second crop of product. The overall yield of the (+)tartrate salt of base I is 125,
190°C), and the salt melts (with decomposition) at 228-231°C.

, D8′)”H(1

Claims (1)

[Claims] 1. Cheno(2,3-C)-2-benzochegin-4(
91) -one is reacted with -methyl-4-piperidylmagnesium chloride in tetrahydrofuran, followed by the following formula ■: ■ 4-(1-methyl-4-piperidyl)-4,9 with H3
-Dihydrocheno(2,3,e)-2-benzochepin-4-ol is subjected to an acid-catalyzed dehydration reaction to simultaneously obtain 4-(1-methyl-4-biperidylidene) having the following formula: The following formula ■: 7-(1-methyl-4-piperidyl)cheno(2,3
-Q)-2-benzochepin-4(91()-one) is extracted with ethanol to eliminate its presence, and the pure alcohol of formula The resulting crude base of formula (1) is then crystallized from ethanol to free it from residues of said ketone of formula (2), and then, if desired, the pure base of formula (1) is dissolved in aqueous ethanol. The above-mentioned method of production is characterized in that the salt is converted into the above-mentioned salt by neutralization with tartaric acid.