(s)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4h - benzo/a/hemolysin-1-yl)carbonyl]-3-ethoxypyrrolidine, (s)-1- [(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4h-benzo/a/hemolysin-1 - yl)carbonyl]-3-oxopyrrolidin as an intermediate product, the composition having a hypnotic non-sedating action


(57) Abstract:

Usage: in medicine. The inventive product (S)-1-/(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-without[a] chinolin-1-yl) carbonyl/-3-ethoxypyrrolidine (1). Yield 80%. so pl. 144 - 147oC. 3 other farm. the composition is based on the connection 1. 4 S. p. f-crystals, 1 table.

The present invention relates to connection -(S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] chinolin-1-yl)carbonyl]-3-ethoxypyrrolidine formula I

< / BR>
and also to the intermediate product to obtain -(S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] holesin-1-yl)carbonyl-3-hydroxypyrrolidine and the pharmaceutical composition having a hypnotic, non-sedating action.

The compound of formula I possess valuable pharmacological properties and can be used for treatment or prevention of diseases. In particular, it has nnegative hypnotic, i.e., sedative effect, so that it can be used to treat sleep disorders.

The compound of the formula I can be used as such or as an active start.

Corresponding to the compound of formula I of the racemate, its production method and its anticonvulsant properties operationsmile and anxiolytic properties.

As the closest analogue of the action can be called well-known in the markets of France, Germany and the United States drug Zolpidem (by ekjcvw) [Arch.Pharmacol. 330:248-251; J. Pharmacol. Exp.Ther. 245:1033-1041; J. Pharmacol. Exp. Ther. 237:649-658; Eur.J.Clin.Pharmacol. 36:461-466] which, as the claimed connection, does not apply to a number of benzodiazepine derivatives having, as a rule, anxiolytic activity. These compounds are associated in the brain with specific benzodiazepine receptors two subgroups, resulting in specific biochemical reactions leads to the inhibition of the functional activity of the cells in the Central nervous system. As the compound of formula I, and by ekjcvw, have the ability to ease cramps, aching muscles, to provide action against fear and relieve sleep disorders. It is very important to note that the hypnotic effect is not accompanied by a sedative effect.

So, we are talking about a new compound of the formula I, which has (in contrast to structural analogues, and from the well-known widely used sleeping pills from a number of benzodiazepines) resedation soporific effect. While (and this should again be twisted) closest structural analogues of EP N 183994 including the racemate discuss the connection of been no mention of the substances, with hypnotic and non-sedating action.

The compound of the formula I can be obtained by the interaction of the carboxylic acid of the formula II

< / BR>
or its reactive derivative with an amine of the formula III

< / BR>
where R is hydrogen or ethyl, to obtain the corresponding amide and, if R is hydrogen, the compound obtained of the formula

< / BR>
alkylate tool, giving ethyl residue.

The reaction of the free carboxylic acid of the formula II with the amine of formula III is carried out mainly in the presence of such a condensing means as hexaphosphate O-benzotriazol-1-yl-N,N,N, N'-tetramethylurea or iodide, N-methyl-2-chloropyridine, in an inert organic solvent and in the presence of a base. Suitable solvents are, for example, aromatic hydrocarbons such as benzene, toluene and xylene, and N,N-dimethylformamide. Suitable bases are, for example, tertiary amines, e.g. triethylamine, 4-methylmorpholine, etc., the Preferred carboxylic acid derivatives, directly reacts with the amine of formula III in the presence of a base, is the acid chloride of carboxylic acid. Suitable bases are, and in this Orodi, such as benzene, toluene and xylene, and ethers, such as dioxane. In both cases, the reaction is carried out preferably at a temperature in the range from room temperature to the temperature of reflux distilled reaction mixture.

If R Amina formula III means hydrogen, you must first obtain compound IV, which is then alkylate give ethyl residue reagent to compound I. the alkylation Reaction, it is expedient to carry out in an inert organic solvent, for example N,N-dimethylformamide, etc. and the reason it is advantageous to use a strong base, for example, hydrides or hydroxides of alkali metals, e.g. sodium hydride, potassium hydroxide and sodium hydroxide. It is advisable to conduct the reaction of alkylation in the approximate temperature range of 0oC to room temperature. As alkylating means it is preferable to use arilgalogenide, in particular ethyliodide or ethylbromide, or diethylsulfate.

The compound of formula IV is a new connection and is the subject of the present invention.

Used as the starting material the compound of formula III, where R is hydrogen, is a known compound (see the Rigidity R is ethyl, can be obtained, for example, by alkylation of (S)-1-benzyl-3-pyrrolidinone acylhalogenides, such as ethylbromide and ethyliodide, in the presence of base, followed by removal of the benzyl group by catalytic hydrogenolysis. (S)-1-benzyl-3-pyrrolidino also known compound (see J. Med. Chem. 29, 2504-2511 (1986) and Synth. Comm. 15, 587-698 (1985).

Used still sleeping pills, such as barbiturates and benzodiazepines are sedative-hypnotic agents. These tools have on only hypnotic, i.e. sleeping, but also a calming effect. Their use causes a General, nonspecific reduction of vigilance, which, for example, is reflected in the fact that a person's ability to recognize and memorize its reactivity and operability his senses and muscles and in the waking state is very limited. In certain cases, in the period between taking the drug and the onset of sleep, and in case of interruption of sleep at the time of maximum action of drugs, it can lead to dangerous situations. Nnegative same sleep AIDS are substances that induce and maintain sleep, only slightly or not at all limiting the functions of the Central nervous system watts hypnotic, but not sedative effect and, therefore, has no known weaknesses sedativehypnotics funds.

Calling sleep action of the compounds of formula I can be shown using the following experience in rabbits. In a state of deep anesthesia, the rabbits insert the electrodes in the region of the brain, amplified electrical signals which (electroencephalogram, EEG) allow to distinguish phases of wakefulness (W), slow wave sleep (NREM) and REM sleep (REM). The REM sleep (REM phase) this phase, which is associated with dreams. The name "REM" comes from the English Rapid Eye Movements, which means "rapid eye movement". The electrodes are connected with a plug, which is attached to the skull of the animal, so that during the experience electrodes through cable can be connected with amplifiers and recording device. After healing the wounds of rabbits for two days placed in soundproof boxes. During these two days from 9 to 15 hours recorded electroencephalogram (see Scherschlicht and Marias in the journal of the Brit.J.Clin. Pharmacol. 16, 28S-35S, 1983). On the first day of rabbits orally administered indifferent control fluid, and on the second day of 0.1, 0.3, and 1 or 10 mg/kg p. O. compounds of formula I. For each dose use four animals. BB is irout and expressed in percentage 60 min per hour of sleep. The results are shown in the table below.

The results show that the compound of formula I all used doses increases during slow sleep NREM up to 70 to 75% of the first hours of recorded sleep periods. Then the duration of NREM phases decreases with unequal rapidity. The higher the applied dose of a compound, the longer it continues its action. On the other hand, in the control days animals about 50% of each hour spend in the slow-wave NREM sleep. The lowest value observed in the first hour of recorded phases of sleep. On the REM phase compound of formula I has no effect.

The lack of sedative effect of compound I is confirmed, for example, test Horizontal Wire Test (HWT). In this test, mice or rats by the tail is lifted up so that the front legs they could capture horizontally stretched wire. If you omit the normal animals in this position, they immediately tighten up and grab the wire and also the hind legs. Depending on the degree of sedately sedatives lead to the fact that animals are still hanging on the wire or fall with it down. The compound of formula I in this test at doses up to 3000 mg/kg p. O. neither Marat, act like normal animals that were not injected the drug.

The object of the present invention is also a pharmaceutical composition having resedation hypnotic effect, containing the active principle and a therapeutically inert carrier. As the active agent composition contains an effective amount of (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] chinolin-1-yl)carbonyl]-3-ethoxypyrrolidine.

That is, the compound of formula 1 can be used as a drug, such as pharmaceuticals. The medications are administered orally in the form of tablets, lacquered tablets, coated tablets, for example, capsules of hard or soft gelatin solutions, emulsions or suspensions, or rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of solutions for injection.

In order to obtain pharmaceutical preparations the proposed product can be mixed with pharmaceutically inert, inorganic or organic carriers. Suitable carriers for receiving tablets, lacquered tablets, coated tablets and capsules of hard gelatin are, for example, lactose, corn starch or its derivatives, talc, stearic acid or its Spalatorie and liquid polyols, etc. Depending on the consistency of the current started to prepare capsules soft gelatin do not need to apply media. To obtain solutions and syrups as carriers are suitable, for example, water, polyols, sucrose, inert sugar, glucose, etc. To obtain the injected solutions are suitable, for example, water, alcohols, polyols, glycerol, vegetable oils, etc., and suppositories for example, natural or hydrogenated oils, waxes, fats, semi-solid and liquid polyols. Moreover, the pharmaceutical preparations may contain more and preservatives, promote the dissolution of drugs, stabilizers, wetting, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts, altering the osmotic pressure, buffers, covering substances or antioxidants. They can contain other therapeutically valuable substances. Drugs, containing proposed product and a therapeutically inert carrier, receive the usual way to obtain this kind of medicines, namely, that the proposed product and if necessary other therapeutically active principle is processed in herbal drug.

To the surface for treatment of sleep disorders, and to obtain medicines with auspiciously, hypnotic properties. The dosage of these drugs can vary within wide limits. Of course, she's in any case must be adapted to the individual needs of the patient. During oral introduction of effective dose is about 0.1 to 100 mg, in particular about 0.5 to 20 mg.

The following examples serve to further illustrate the present invention. They in no case do not limit the scope of the invention. All temperatures are in degrees Celsius.

Example 1.

a) 70,36 g of 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]chinolin-1-carboxylic acid in an argon atmosphere was dissolved in 1600 ml of N,N-dimethylformamide. Then add 45 ml of 4-methylmorpholine, 27,2 g of the hydrochloride of (S)-3-oxopyrrolidin and of 83.4 g of O-benzotriazol-1-yl-N,N,N, N'-tetramethyluronium-hexaphosphate. The mixture is stirred for 18 h at room temperature, after which the obtained yellow solution was poured into 6000 ml of water and slowly added 2500 ml of saturated sodium bicarbonate solution. The resulting product is sucked off and washed with 1000 ml of water. After drying the product under vacuum at 70oreceive and 83.3 g of crude product. In the region of the fallopian solutions through 100 g of silica gel using a mixture (9:1) of methylene chloride and diethyl ether mixture (9:1) of methylene chloride and acetone receive 74,2 g (88%) of (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]holesin - 1-yl)carbonyl]-3-oxopyrrolidin with TPL257 259o.

b) and 64.3 g (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]chinolin-1-yl)carbonyl] -3-oxopyrrolidin, slightly heating it (up to 44o), dissolved in 900 ml of N,N-dimethylformamide. The resulting solution was cooled to 13o, then added 31 ml of ethyliodide and cooled to 3 to 5o. After adding 17,1 powdered potassium hydroxide the mixture is stirred for 5 h at 0o. Then the reaction mixture was poured in 8000 ml of water and acidified with 50 ml of 25% hydrochloric acid. Received a suspension during the night stirred at room temperature. The resulting crystals are sucked off, washed with water and dried in vacuum at 80o. In the chromatography of the product through 3000 g of silica gel using mixtures(9:1), (4:1), (3: 1), (2:1) of methylene chloride and diethyl ether get 58.5 g of raw product and 4.4 g of a mixture, which is recrystallized from isopropanol. The result is 3.75 g is not quite pure product, which, together with the result of the above crude product is recrystallized from isopropanol. The result 54,7 g (80%) of (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]chinolin - 1-yl)carbonyl]-3-ethoxypyrrolidine with TPL144 147o.

Example 2.

o, and then dropwise added slowly 9.75 ml ethyliodide. Mixture is allowed to warm to room temperature and continue to stir over night. In order to destroy excess sodium hydride are added dropwise 50 ml of methanol, cooling the mixture with ice. The reaction mixture was concentrated in vacuo and the residual oil is dissolved in 200 ml of methylene chloride and twice shaken with saturated sodium chloride solution (each 100 ml). The organic phase is dried with sodium sulfate and then concentrated in vacuo. Obtain 14 g of a yellow oil. The crude product chromatographic through 140 g of silica gel with a mixture (2:1) of hexane and ethyl acetate. Obtain 9.3 g (75%) of (S)-1-benzyl-3-ethoxypyrrolidine in the form of a yellow oil.

b) 10 g of (S)-1-benzyl-3-ethoxypyrrolidine dissolved in 100 ml of methanol. To the resulting solution was added 1 g of 10% palladium on coal, after which it is stirred in hydrogen atmosphere. After 4 hours stops the absorption of hydrogen. The catalyst is filtered off through a bed of Dicalite, and the residue was concentrated in vacuo. Gain of 5.3 g of (S)-3-ethoxypyrrolidine as osphere argon weighed into 100 ml of ethyl acetate and the suspension added to 2.1 ml of oxalicacid. Then add 0.2 ml of N,N-dimethylformamide, and observed the evolution of gas. The mixture is stirred for 30 min at room temperature, and then add 0.2 ml of oxalicacid and then 0.1 ml of N,N-dimethylformamide, and then stirred the mixture for 30 min at room temperature. The reaction mass is then cooled in an ice bath to 0 5oand precipitate the crystals. Add a 13.3 ml of triethylamine and then a solution of 2.53 g (S)-3-ethoxypyrrolidine in 25 ml of ethyl acetate. Then stirred the mixture for 30 min at a temperature of about 0o. The reaction mass is washed twice with water (50 ml) and the collected aqueous phase is extracted once with 20 ml of ethyl acetate. The collected organic phases are dried with sodium sulfate, filtered and evaporated, resulting in a gain of 9.0 g of crude product. The crude product is dissolved in 50 ml of methylene chloride and filtered through 45 g of silica gel and washed with a mixture of methylene chloride and acetone (9:1), resulting in a gain of 8.6 g of yellow crystals. They are placed in 100 ml of tert.butyl methyl ether and heated for one hour at the temperature of reflux distilled. Mixture is allowed to cool to room temperature and the crystals are sucked off (of 6.95 g). 5.5 g of the resulting crude about what alizatio. After drying at 80oC/0.05 mm (18 h) gain of 4.2 g (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] chinolin-1-yl)carbonyl]-3-ethoxypyrrolidine with TPL134 136o.

To obtain a new tricyclic pyridone derivative of the formula 1 derived data element and spectral analysis, determined the optical density (OD):


Water content: 0.28% as

With(calc.) 69,56% (calc.) 69,41%

N(calc.) 5,61% N(calc.) of 5.53%

N(calc.) 6,24% N(calc.) 6,20%

Cl(calc.) of 7.90% Cl(calc.) 7,87%

MS (EL (70eV), m/e): 448 (M+0 44), 334 (100), 299 (16), 278 (10), 243 (10).

UV (EtOH)max(log ): 362,9 nm (4,29), to 298.9 nm (3,49), 258,8 nm (4,15), 247,7 nm (4,12).

IR (KBr, cm-1) 1649, 1619, 1599, 1429, 1102, 788, 746, 697.

OD: []2D0= +75,2(CH3Cl3), 0,5.

The resulting substance is not toxic. The daily dose is 100 mg/kg (rats) respectively 1200 mg/kg (dogs), and tolerance in the application within two weeks of good.

Example A. a Compound of formula I in a known manner can be used as an active start for the manufacture of pharmaceutical preparations with hypnosedatives effect of the following composition:


Tabletroute 8

Magnesium stearate 1 wt tablets 200


Capsule mg/capsule

Active principle 10

Milk sugar 30

Corn starch 8,5

Talc 1

Magnesium stearate 0.5 Weight is poured into the capsule substance 50L

1. (S)-1[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] chinolin-1-yl)carbonyl]-3-ethoxypyrrolidine formula I

< / BR>
2. (S)-1[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] chinolin-1-yl)carbonyl]-3-oxopyrrolidin as an intermediate product to obtain (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] -hemolysin-1-yl- )carbonyl]-3-ethoxypyrrolidine.

3. (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]chinolin-1-yl)carbonyl] -3-ethoxypyrrolidine with resedation hypnotic effect.

4. The composition having the hypnotic non-sedating action, containing the active principle and a therapeutically inert carrier, characterized in that the active agent IP - use effective amount of (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a] chinolin-1-yl)carbonyl] -3-ethoxypyrrolidine.


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26 cl, 2 tbl, 253 ex

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13 cl, 1 dwg, 4 tbl, 16 ex

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14 cl, 11 sch, 7 tbl, 13 ex

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42 cl, 8 tbl, 8 ex

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47 cl, 2 dwg, 1 ex

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23 cl, 12 ex, 8 tbl

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34 cl, 7 ex, 6 tbl, 4 dwg