Process for preparing phenothiazine compounds or lower alkyl esters thereof, or pharmaceutically acc

专利摘要:
The present invention relates to compounds of the formula (I): or a salt, ester or amide thereof; wherein R' is a C1-7 bivalent aliphatic hydrocarbon group or a single bond; R2 and R3 are the same or different and are each hydrogen, C1-4 alkyl or taken together with the nitrogen comprise a nitrogen-containing heterocyclic ring having four to six ring members; R4 is hydrogen, halogen, C1-4 alkoxy, C1-4, alkyl optionallyu substituted by one to three halogen atoms; or a group R, C02H as hereinbefore defined; and A is C1-4 alkylene orANR2R3forms a group -CH2-(CH2)2 or CH2-CH2)2 B is an acidic group other than a mono-carboxylic acid group of comparable or greater acid strength than a carboxylic acid group in a similar chemical environment, provided that any sulphonamide group contains at least one N-H bond. Also disclosed are processes for the preparation of. the compounds of the formula (I), chemical intermediates for use in their preparation, and pharmaceutical formulations containing the said compounds. The compounds have antiallergic activity as defined by blockade of anaphylactoid activity. Certain of the compounds also have good antihistaminic activity.
公开号:SU1731052A3
申请号:SU843829883
申请日:1984-12-27
公开日:1992-04-30
发明作者:Джордж Кокер Джеффри；Вилльям Эддисон Финдлей Джон；Джефферсон Лейтон Гарри
申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
IPC主号:

专利说明:

F.rN-R2
The invention relates to methods for the preparation of new biologically active phenothiazine compounds of the general formula
R, COOH,
where RJ is a -C3 alkylene group; are the same and are C, C alkyl; A - C, -Se-alkylene group, or their lower alkyl esters, or their pharmaceutically acceptable acid addition salts
The compounds of formula I exhibit an anti-histamine activity may
find application in medical practice.
The aim of the invention is to develop a method for producing new phenothiazine compounds that have not had a side sedative effect on the central nervous system,
Example 1 about 2-110- / 2-dimethyl-aminopropyl / 2-phenothiazinyl / -2 methyl propionic acid (compound P),
a) 2- / 4-Bromophenyl / -2-methylpropionic acid (compound ex-13a) „
The 2- / 4-bromophenyl / 2-methylpropionic acid ethyl ester (54.1 g) is refluxed in a solution of 50 ml of ethanol and 40 g of sodium hydroxide in 400 ml of water for 5 hours. This mixture cooled to room temperature, washed with pentane, and then acidified with concentrated hydrochloric acid (100 ml). The compound ex-13a precipitated as a white powder with a melting point of 121-124 ° C, the NMR spectrograms of which were consistent with the indicated structure.
b). 2- / 4-Bromo-3-nitrophenyl / -2-methylpropionic acid (compound oh-13c)
To a mixture of concentrated nitric acid (20 ml) and sulfuric acid (20 ml) with stirring in the form of 6-portion portions within 20 min. The compound ex-13a "is added.
the temperature of the reaction mixture is maintained at 50-55 ° C by water cooling. This mixture is then kept at 85 ° C for 10 minutes, then poured into ice and diluted with water. The resulting solid product is filtered, washed with water, dissolved in a slight excess of 2N sodium hydroxide and then re-precipitated
Suppression of excess hydrochloric acid.
The solid product is dried and recrystallized three times from benzene. As a result, the compound ex-13b is obtained as a solid product with a melting point of 167 - 171 ° C, the NMR spectrograms of which are consistent with the indicated structure,
c) Etyl2- / 4-br6m 3 1nitrophenyl / 2 methylpropionate (compound).
Compound ex-13b is suspended in a solution of 400 ml of ethanol, 25 ml of triethyl orthoformate and 2 ml of concentrated sulfuric acid, and is kept at its boiling point.
five
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0
five
Q
five
for 3 hours, the solvent is evaporated and the residue is dissolved in diethyl ether, then sequentially washed with water, a 0.5% sodium hydroxide solution and a saturated solution of sodium chloride, the diethyl ether is dried and evaporated, as a result what is obtained is an Eh-13c compound that melts at a temperature slightly above room temperature.
These NMR spectrograms are consistent with the indicated structure, it is used without prior purification.
d) Ethyl II-methyl-2- / Znitro-4-phenyl-thiophenyl / propionate (compound ex-13d).
This compound is obtained by reacting the compound ex-13c with thiophenol in ethanol in the presence of sodium biocarbonate in a stream of nitrogen at reflux for 5.5 g. The resulting reaction mixture is poured into 900 ml of an ice-cooled 5% hydroxide solution sodium and subjected to extraction treatment with 3 portions of 100 ml of diethyl ether. The diethyl ether is washed with 5% sodium hydroxide and then dried over magnesium sulfate and evaporated.
The ex-1Cc compound is produced in quantitative yield as a very viscous yellow butter-like material that cannot be converted to a solid state. Thin-layer chromatographic analysis shows almost complete homogeneity, and the NMR spectrogram data are consistent with the indicated structure, as a result of which it is used further without preliminary purification,
d) Etyl-2-methyl-2- / 2-phenothiazinyl / - propionate (compound ex-13e) „
The compound ex-13e is obtained by. cyclization of compound oh-13d under the action of triethyl phosphate in a medium of 200 ml of dry deoxygenated n-propylbenzene at reflux in a stream of nitrogen for 4 h. (thin layer chromatography on silica with aluminization with a mixture of hexane and ethyl acetate in a ratio of 10: 1) by flash chromatography. The compound does not crystallize, but its NMR spectrogram data are consistent with the indicated structure, therefore, it is used further without preliminary purification.
(e) Ethyl 2- / 10/2 dimethylaminopropyl / -2-phenothiazinyl / -2-methylpropionate (compound ex-13f or compound O).
4.1 g of the compound and 1.52 g of tert-butoxide potassium are combined in 30 ml of dry deoxygenated Toluene and stirred for 10 minutes in a stream of nitrogen. Then 1.7 g of 2-chloro-1-dimethylaminopropane are added. The reaction mixture is kept at 80 ° C for 1 h. Further additionally, 1.5 g of potassium t-butoxide and 1.7 g of 2-hlbr-1-dimethylaminopropane are added and stirring with simultaneous heating is continued for 2 h. The reaction mixture is diluted with 50 ml of toluene and washed with water and saturated sodium chloride solution "then the amines are extracted diluted hydrochloric acid, the extract is washed once with toluene, alkalinized (litmus, concentrated ammonium hydroxide) and extracted with chloroform. Evaporation of chloroform gives an oil-like product. processing on dioxide. This oil is separated by chromatographic treatment in a ffash-column with silica. , aluiru mixtures of ethyl acetate with ethanol with a gradual change in the ratio of 12: 1, 8: 1, 5: 1
The resulting free base is an oil-like product from which a crystalline maleate salt is obtained, which is recrystallized by treatment with a mixture of ethyl acetate and hexane. Acidic maleate hydrate of compound ex-13f has a melting point of 107-1 ° C. Analysis data on SNP, NMR and spectrometric analyzes consistent with the specified structure,
g) 2- / 10 (2-Dimethylaminopropyl) -2 phenothiazinyl / 2 methylpropionic acid (compound P)
The free base of ex-13f compound (0.8 g) was suspended in a mixture consisting of propylene glycol (4 ml); and sodium hydroxide (10 ml), heated at reflux for 72 hours and
0
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0
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filtered. The filtrate is evaporated to dryness, acidified with 1.00 n hydrochloric acid (9.5 ml), re-evaporated to dryness. The residue is diluted with 2-propanol, filtered to remove sodium chloride and the filtrate is evaporated to a viscous precipitate. ether (100 ml) until it is cured, after which the precipitate is filtered and recrystallized from MeOH / EtoAC to yield compound P as hydrochloride (0.414 g),. 192 - 196 ° С (expansion ,,) „
Calculated: C, 61.98; H 6.69; N 6.88.
CZfHz6N2OtS-HCl
Found: C, 61.73; H 7.62; N 6.83, The only significant ion in the mass spectrum in chemical ionization refers to M / e 371 (source element +1) „
1H NMR analysis (DMSOdg): 1.27 (d.ZN); 1.49 (s.bN); 2.75 (p. 6H); 3.40 - 3.80 (dd.1N); 4.57 (dd.1H); 6.93 - 7.30 (Mo7H) „
Example 2 2- / 10- / 3 Dimethyl-aminopropyl- / 2 phenothiazinyl / 2-cetyl-0 propionic acid (compound (f), a) Ethyl-2- / 10-3-dimethylaminopropyl / -2-phenothiazinyl / -2-methylpropionate (compound ex-14a)
Compound ex-13e (2.9 g) was dissolved in 30 ml of dry dimethylformamide, then treated with 1.13 g of potassium t-butoxin and 0.20 g of Zil. The reaction mixture was heated to 80 ° C with nitrogen and added to 1.2 g of 3-dimethyl-aminopropyl chloride, obtained from its hydrochloride salt, are added. After holding at 80 ° C for another 30 minutes, an additional 0.24 g of potassium butoxide is added.
- After 30 minutes, the reaction mixture is poured into water and subjected to extraction. Treatment with dichloromethane. After evaporation of dichloromethane, 4.3 g of a viscous oil-like product is obtained, which is subjected to a flaeh chromatographic treatment on silica, eluting with a mixture of dichloromethane and methanol in a ratio of 96: 4. As a result, an oil-like product gives 2.8 g of compound ex -14a, which seemed homogeneous upon thin-layer chromatographic analysis, and its NMR spectrogram was consistent with the indicated structure
five
b) (3-Dimethylaminopropyl: 2; - phenothiazinyl / -i2-methylpropionic acid (compound Q) „
The compound (2.1 g) was suspended in dioxane (10.0 ml) and 1.00 N NaOH (20 ml), heated at reflux for 24 hours and filtered, followed by evaporation of the filtrate to dryness. The residue is dissolved in water (60 ml), washed with ether, neutralized with 1.00 N HCl (20 ml) and filtered. Adding excess concentrated HCl to the filtrate results in precipitating a white solid, after recrystallization of which from MeoH / EtpAC, compound Q is obtained in as hydrochloride monohydrate (0.40 g), ToPL "128 ° C (decomposed 0, melt does not recover, since it largely depends on the heating rate),
Calculated: C 59.35; H 6.88; N 6.59
C2 H26N2. ° ZS HC1 HZO
Naideje: C 59.43; H 6.93; N 6.57 "INR spectrum (DMSQ-dg): 1.41 (s,
6Н) :, 2,10 (к „2Н); 2.67 (s, 6H); 3.15,
(t „2H); 6.91 - 7.40 (m 7H).
PRI me R 3 "Antihistamine
action (in vitro) 0
The longitudinal muscle is removed from the intact ileal region of the guinea pig (Hartley breed, male weighing 250-400 g) and placed in a organ bath with a tension of 300 mg. After 1 hour of equilibrium, the cumulative curves for the bc-concentration of the reaction to histamine are determined. After washing, the tissue is incubated for 1 h together with the test compound, and then repeated concentration curves are determined — reactions to histamine Shifts to the right relative to the concentration curve (agonist reactions obtained using 4 $ antagonists) are used to post the graphs Shield " Decreasing the value of log (dr-1) by log (B), where dt is an equivalent reaction in the presence and
35
40
Blood is placed in ampoules containing ethylenediamine tetraacetic acid, centrifuged, plasma of frozen decapitated pigs is frozen, plasma is placed in ampoules and frozen. The time interval between tissue sampling and their analysis does not exceed a week for the detection of compound P. The concentration of compound in plasma and brain samples tissues (homogenized in 10 ml of water) were determined by high performance liquid chromatography as follows.
The pH is adjusted to 1 ml of plasma with a pH of 2.0 and extracted with 6 ml of ethyl acetate. After shaking, 0.7 ml is evaporated to obtain a dry material and the residue is redissolved in 50 µl of methanol.
A 2 ml sample of brain homogenizer is extracted in the same manner as described above. After evaporation of the ethyl acetate to obtain a dry material, the residue is dissolved in methanol and introduced into a Varian1 / high performance liquid chromatography equipped with a column for reversed phase C, g. Through the column at a speed of 1.2 ml / min pumping
in the absence of an antagonist, (B) - polar 50 w tTechcomp ° ° solvent solvent composition consisting of 30% polyisocyanurate B $, 40% CH-jCl and 30% MeOH (fl 254, AFU S 0.04).
the concentration of the antagonist, allowed to calculate the value of the rad, t „e (negative logarithm of antagonist concentration, which shifts the 2X control curve of the reaction to histamine concentration to the right ”
The pA values for the compounds obtained in comparison with promethazine are as follows:

PA2 8.8
8.7 8.9
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0
$
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0
EXAMPLE 4 Study of distribution in brain tissue and plasma of loss of Po.
A group consisting of 5 males of Guinea pigs weighing 350-400 g orally was given compound P in the amount of 1.5 mg / kg at a time. Whole blood samples from the vena cava (3 ml) pigs euthanized with chloroform are taken before the drug is administered and after 1.2, .3, 4, 5, 8, 12, 12.24 hours after its introduction
Blood is placed in ampoules containing ethylene diamine tetraacetic acid, centrifuged, plasma removed, brain of decapitated pigs frozen, placed in ampoules and frozen. "The time interval between tissue sampling and their analysis does not exceed a week for the P compound to be collected. The concentration of the compound in plasma and samples brain tissue (homogenized in 10 ml of water) was determined by high performance liquid chromatography as follows.
The pH is adjusted to 1 ml of plasma with a pH of 2.0 and extracted with 6 ml of ethyl acetate. After shaking, 0.7 ml is evaporated to obtain a dry material and the residue is redissolved in 50 µl of methanol.
A 2 ml sample of brain homogenizer is extracted in the same manner as described above. After evaporation of the ethyl acetate to obtain a dry material, the residue is dissolved in methanol and introduced into a Varian1 / high performance liquid chromatography equipped with a column for reversed phase C, g. Through the column at a speed of 1.2 ml / min pumping
ø technical complex ° solvent solvent os
tav, comprising 30% polyisocyanurate B $, 40% CH-jCl and 30% MeOH (fl 254, AFU S 0.04).
The results are presented in Table. To SampleZo Pharmacological Effects of Compound P and Chlorprozine “
a) Groups consisting of 4 male Sprague-Dol rats were orally administered
Compound P at doses of 250 mg / kg and 500 mg / kg.
b) Groups consisting of 4 male Sprague rats. Shares were orally administered with chlorpromazine at doses of 3.10 and 30 mg / kg. The observed pharmacological phenomena are described in the scoreboard 20
As can be seen from the presented data on pharmacological tests, the compounds obtained penetrate the brain within a limited range and do not show a visible effect on the central nervous system after oral or intravenous administration, while the known antihistamines (promethazine or chlorpromazine) have undesirable side effects. due to their rapid penetration into the brain, the data given in Table 2 confirm the fact that even with the introduction of high doses (500 mg / kg) s was not observed, whereas the administration of relatively low doses chloro- promazine accompanied by considerable pharmaceutical effects "

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining phenothiazine compounds of the general formula
 s
RjCOOH,
R, N Rp
.. -.....
JQ (25 1052Y
where R is a C-C3 alkylene group; , are the same and represent
are C {-C4 alkyl, A - Cf-Cj-alkylene groups or their lower alkyl esters, or their pharmaceutically acceptable acid addition salts, as indicated by the compound
JQ (25
15
R1COOK4
where RJ has the indicated meanings;
R4 lower alkyl,
interact with an alkylating agent of the general formula
ClA-NC
R
zo
where a, r. and R, have the indicated values, at a temperature of 80 ° C in an organic solvent medium in the presence of a base, followed by deesterification of the ester group, if necessary, and isolation of the desired compounds as a free base or
in the form of a pharmaceutically acceptable acid salt additive
Table 1
eleven
Central Effects Visible effects were not observed.
at doses up to 500 mg / kg
Standalone Effects Visible Effects
not observed at doses up to 500 mg / kg
qi
No visible effects were observed at doses up to 500 gg / kg.
Visible symptoms not noted at doses of 250 - 500 mg / kg
1731052
12 Table2
Effects noted at doses of 3.10 and 30 mg / kg
Effects noted at doses of 10 mg / kg
Effects noted at doses of 10 and 30 mg / kg
Reduced muscle tone at a dose of 30 mg / kg, cyanosis at a dose of 30 mg / kg

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB848413915A|GB8413915D0|1984-05-31|1984-05-31|Phenothiazine compounds|

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