Method of producing thiazolo/4,5-c/quinoline or its acid-additive salts

专利摘要:
The invention relates to new thiazolo[4,5-c]quinoline derivatives of the general Formula I <IMAGE> (I) and acid addition salts thereof, a process for the preparation of the same and pharmaceutical compositions comprising the said compounds. The substituent definition of the general Formula I is as follows: R stands for hydrogen; a straight or branched chained alkyl group having 2-5 carbon atoms optionally substituted by one or more halogen atom(s); phenyl or phenyl-(lower alkyl) optionally bearing one or more substituent(s) on the phenyl ring; R1 and R2 are identical or different and stand for hydrogen, halogen or lower alkyl). The compounds of the general Formula I possess valuable central nervous depressive properties.
公开号:SU1544190A3
申请号:SU864028529
申请日:1986-11-12
公开日:1990-02-15
发明作者:Кнолл Иожеф；Береньи Эдит；Будаи Каталин；Кнолл Берта；Фюртш Жужа；Тимар Юлиа；Жила Габриелла；Никлиа Илдико；Петец Луиза；Манди Аттила
申请人:Эгиш Дьедьсердьяр (Фирма)；
IPC主号:

专利说明:

The invention relates to organic chemistry, in particular, to a method for producing new chemical compounds - thiazolo [4], quinoline or its acid addition salts, which have a depressive effect on the central nervous system, which can be used in medicine.
The aim of the invention is to obtain thiazolor, 5-cG quinoline or its acid addition salts, which have a new biological effect for this heterocyclic system.
Preparation of thiazolo, 5 with quinoline and its acid addition salts.
Example 1. A mixture of 17., 62 g (0.1 mol) of 3-amino-mercaptoquinoline, 150 ml of formic acid and 1.5 g of sodium pyrosulfite are heated to boiling for 3 hours. The reaction mixture is cooled, diluted with a mixture of 800 ml of water and 0 ml of concentrated hydrochloric acid, alkalinized with a solution of sodium hydroxide to pH 10 and extracted three times with benzene, each time 200 ml. After evaporation of the benzene phase, 15.0 g of thiazolo, 5-c quinoline are obtained, yield 80%, melting point 1l4-H6 C.
SP
Ј 4
WITH

cm
The resulting base is dissolved in acetone and an equimolar amount of ethanesulfonic acid is added. The resulting thiazolo A, 5 sec. Quinoline-ethanesulfonate has a melting point of 155-157 ° C.
PRI mme R 2. A mixture of 17.62 g (0.1 mol) of 3-miner-mercaptoquinoline and 500 ml of triethyl orthoformate is heated with a continuous distillation of the ethanol formed during the reaction at 120-1 0 ° s After removing the last traces of ethanol, the reaction mixture is cooled, diluted with benzene, and acidified with ethanol with acidic acid to pH 1. The precipitated crystals are filtered. 21.5 g of thiazolor, 5 are obtained from quinoline hydrochloride, yield 96%, temperature, melting at 231-232 ° C.
The hydrochloride obtained in this way is converted by treatment with sodium hydroxide in thiazolo 4.5 with quinoline; the base has a melting point of 114-116 ° C.
Study of biological action. Thiazolo pt, 5 Lquinoline and its pharmaceutically acceptable acid addition salts have a depressive effect on the central nervous system, which is different from the depressive effect of known effective agents. In contrast to most tranquilizers, these compounds do not inhibit nonspecific activation processes and make it possible for animals to flee in an experiment with a congenital reflex and at a high dose. Known tranquilizers even in minimal doses cause complete inhibition of this reaction.
Thiazolo, 5 with quinoline and its acid addition salts do not exhibit a spasmolytic effect, but have a stronger depressive effect on the central nervous system than benzodiazepines and do not bind to benzodiazepine receptors.
The pharmaceutical activity of thiazolo, 5-sPhinolin and its pharmaceutically acceptable acid addition salts is confirmed by the following experiments.
Example Acute toxicity.
Acute toxicity was determined on CFY rats (body weight 100-160 g). Each group consisted of 10 animals. Control compounds were administered
0
orally (10 mg / kg) and subcutaneously (5 ml / / kg). Before oral administration of the rats, they were starved for 16 hours. In each group
animals were 50% male rats and 50% female rats. Recorded deaths occurring within 8 hours. LD SQ calculated on the basis of the graphical method.
Litchfield and Wilcoxon. With the introduction of thiazolo C, 5 with quinoline hydrochloride LD5o was 55 mg / kg intravenously, 2bO mg / kg subcutaneously, 350 mg / kg orally. With the introduction of thiazolo, 5 with quinoline-ethanesulfonate LDSO 51 mg / kg intravenously, 280 mg / kg subcutaneously, 290 mg / kg orally.
PRI me R. Hotplate method (heating plate for fixing preparations with dry heat).
The effect of each dose of test compounds was determined on groups consisting of each of 10 rats. The experiments were carried out on metal plates heated to 5b ° C. The latent period of pain reactions was determined within 1 hour and, 1 hour after administration of the test compound, 2.5-fold lengthening of the control value was considered as 100% effect. With the introduction of thiazolo, quinoline-hydrochloride ED5o 7.5 mg / kg subcutaneously, 60 mg / kg by mouth. With the introduction of thiazolo, 5 s | quinoline-ethanesulfonate ED5Q 8 mg / kg subcutaneously, 72 mg / kg by mouth.
PRI me R 5. Algolytic action.
The essence of the experiment is that a dose of 10 mg / kg of morphine, administered intravenously or subcutaneously, causes complete anesthesia in rats, so that laparotomy can be performed in such a way that animals do not even show the smallest signs of pain or stress. no postoperative exhaustion occurs. The feeling of pain in untreated animals was taken as 100, and the total disarray
five
casting - for
ED
00
and ED
50
five
amounts of the compound tested that completely eliminate the feeling of pain or reduce the number of punctures by 50. In this test, only narcotic painkillers were effective. The test salts of thiazolo A, 5 with quinoline generally have no effect on the surgical sense of pain.
51
PRI me R 6. Writhinp-test.
Each dose of the test compounds was administered to groups of 10 mice, and after 20 min after administration, a 0.6% acetic acid solution was injected at a dose of 60 mg / kg intraperitoneally. Under the influence of chemical irritation of the peritoneum (Peri5 1906
toneum) observed characteristic writhing in 90% of control animals. 10 treated animals after intraperitoneal administration of acetic acid for 20 minutes were monitored. The effect of individual doses was expressed as a percentage using the following equation:
writhing 1PP analgesic effect, P-TI1 Tontroln. X 1UU
Based on the control experiments, the denominator was determined as 90%.
A comparison with the results determined by the Hotplate method shows that the test compounds showed a lower activity during the Writhing test. From this it can be concluded that with the Hotplate test, which is not so selective for the analgesic action, other nonspecific effects on the central nervous system were measured, which also led to a prolongation of the reaction time.
The following results were obtained: administration of thiazolo, 5 with quinoline hydrochloride EDSQ 32 mg / kg subcutaneously, 82 mg / kg through the mouth. With thiazol4, quinoline-ethanesulfonate ED50 5 &amp; mg / kg subcutaneously, 70 mg / kg by mouth.
Example. Anesthesia enhancing action.
Sleep time was determined in male CFy rats (body weight 150-200 g). Each group consisted of 10 animals. Inaktin was injected into the tail vein at a dose of 35 mg / kg. The moments during which the animals lose or restore the righting reflex are recorded. Sleep time of control animals A25.9 ± 3.2 s (Ј 120).
Both test compounds significantly lengthened the anesthesia time of the control barbiturate. With the introduction of thiazolo, 5 C | quinoline-hydrochloride EDjXK, 22 subcutaneously, 22 through the mouth. With the introduction of thiazolor, 5 with quinoline-ethanesulfonate ED50o 22 subcutaneously, 32 through the mouth.
PRI me R 8. Modified test with jumps.
This test serves to identify the psychoactive effect. The apparatus consists of a metal plate heated to 45 ° C and a glass cylinder open at the top and bottom. Animals were placed under a glass cylinder on
plate and made it make one jump. Recorded the latent period between the installation of animals and the jump. The time required for escape (jump) was considered as an indicator of irritability of the central nervous system and was expressed in units of 0 to 10. Both test compounds were ineffective in the modified jump test.
PRI me R 9. Test with shielding.
This test serves to study the ability of the rats to learn and retain during conditioning of the device.
During conditioning, the rats were trained to jump onto the cover of a glass cylinder under the action of a 110 V shock aimed at the paw. The flight response (congenital reflex) was accompanied by a ring as a stimulus-induced response. The task was to have the animals show the acquired reflex ten times with a 10-second pause without gain. The retention of the acquired reflex was considered as positive if after 2k hours after the experiment this effect persisted. In these experiments, animals, based on their learning ability, were classified into four groups:
no learning ability if during the 20 consecutive experiments there has not been a congenital reflex;
learning ability is weak if the innate reflex, although it appears, does not have an acquired reflex,
mediocre learning ability, if the acquired reflex has appeared through a few additional combinations;
excellent learning ability if the acquired reflex appeared ten times immediately after the combination.
Both test compounds inhibited the formation of acquired reflex in this test. At a dose of 25 mg / kg, the test compounds elicited complete and at a dose of 18 mg / kg severe braking.
Haloperidol, at a small dose (0.025 mg / kg), caused a strong inhibition of the formation of the acquired reflex. Chlordiazepoxide with the same dose had no effect on the formation of the acquired reflex.
Example 10. Shuttle-Box.
Acquisition of a conditioned reflex in two directions (ATS) was analyzed in a Shuttle-Box for 5 days at a time.
The apparatus consisted of six chambers, which were separated from each other by partitions with a small hole in the middle of each partition. Animals were trained to cross the aperture during the conditioned stimulus (light signal, CS). If the animals did not achieve this task, they were punished with electric shock directed at the paw (1.3 mA, US, ultrasound). Animals were exposed to this experience a hundred times a day. Each experiment consisted of a pause of 15s, followed by 15 s of CS. The last 5 seconds with CS was overlapped by the first US second (ultrasound). During this training period, the number of ATS and podpisignal reactions (IR) were automatically calculated and evaluated using a multilateral variant analysis (ANOVA). Both test compounds at a dose of 50-25 mg / kg strongly inhibited the acquisition of a conditioned reflex in the Shuttle-Box. The number of positive reactions (F), apparently, is significantly lower than in control animals, starting from the first day of the experiment.
At a dose of 25 mg / kg, the number of negative reactions (- f) was high.
The number of sub-signal reactions (IR) showed a slight decrease. Chlordiazepoxide did not affect
c
P
five
0 5 0 5
WITH
five
the acquisition of a conditioned reflex at a dose of 10 and 5 mg / kg, this substance being a standard at a dose of 10 mg / kg increased the number of negative reactions
(f).
Example 11, Defining mobility in Shuttle-Box.
To determine the mobility of animals, the apparatus described in Shuttle-Vokh-test was used. When experiencing mobility, all stimuli were excluded, animals had to move freely from one chamber to another. The average number of intersections was determined during the observation period of 30 minutes. The value was calculated using a research t-test for two means.
At this point, the test compounds showed little effect, reducing mobility.
The results of the action of thiazolo}, 5 quinoline-ethanesulfonate (compound for the acquisition of a conditioned reflex in the Shuttle-Box experiment with subcutaneous treatment (standard - chlordiaepoxide) are listed in the table.
Example 12 A crude preparation of rat cerebral cortex shell was used to determine binding to the benzodiazepine receptors. 2mol 3H-diazepam was incubated with a membrane for 1 h at 0 ° C in tris-citrate buffer solution (pH 6.8). The specific bond was determined in the presence of 10 Schmol diazepam; Chloridiazepoxide was used as a control drug in the displacement experiments.
Chlordiazepoxide has been found to be at certain concentrations of vets from the 3H-diazepam receptors. In contrast, Compound A did not alter the specific bond of 3H-diazepam even at high concentrations.
Preparation of medicinal compositions.
Example 13. Tablets of the following composition are made, mg: Thiazolo 4, 5-c, quinoline-ethanesulfonate 25.0
Corn Starch97.0
Polyvinylpyrodidone 175.0 Magnesium Stearate 3.0
Total weight 300,0
The mixture of the active substance and corn starch is moistened with a 10-15% aqueous solution of polyvinylpyrrolidone, granulated and dried at AO-A5 ° C. The resulting granules are thoroughly dried, mixed with magnesium stearate and pressed into tablets.
Example N. Capsules of the following composition are prepared, mg: Thiazolor, 5-cP quinoline-hydrochloride 20.0
Milk sugar 60,0
Cornstarch17,0
Talc2.0
Magnesium Stearate 1.0
Total weight 100.0
The dose of the active substance can vary widely: daily at an oral dose of 20-1000 mg / kg, daily parenteral dose of 5,250 mg / kg.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining thiazolo A, quinoline of the formula
S
or its acid addition salt, characterized in that 3-amino-4-mercaptoquinoline of formula
-.
L
N
or its acid addition salt is reacted with formic acid or its reactive derivative and the desired product is isolated as the free base or acid addition salt. i

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

GB2024207A|1978-05-26|1980-01-09|Lepetit Spa|New tricyclic ortho-fused heterocyclic compounds|

---

HU196308B|1985-11-12|1988-11-28|Egyt Gyogyszervegyeszeti Gyar|Process for producing pharmaceutical compositions containing 2-methyl-thiazolo/4,5-c/quinoline as active component|HU199423B|1987-04-24|1990-02-28|Egyt Gyogyszervegyeszeti Gyar|Process for producing 3-amino-4-/ethylthio/-quinoline and pharmaceutical compositions comprising such compounds|

---

US6110929A|1998-07-28|2000-08-29|3M Innovative Properties Company|Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof|

---

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---

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---

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US20090075980A1|2003-10-03|2009-03-19|Coley Pharmaceutical Group, Inc.|Pyrazolopyridines and Analogs Thereof|

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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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HU854304A|HU197019B|1985-11-12|1985-11-12|Process for producing thiqzoloquinoline derivatives and pharmaceuticals comprising same|

---