Derivative-carboline, methods for their preparation and drug

 

Describes the new derived-carboline General formulas Ia' and Ia", where R2- C1-C6CNS radical, preferably methoxyethyl; R3is a hydrogen atom or a C1-C6alkyl radical, preferably a methyl radical; R8- C1-C6alkyl radical, optionally substituted by alkyl, phenyl radical, unsubstituted or substituted C1-C6by alkyl, halogen, the nitro-group, di(C1-C6) alkylaminocarbonyl,1-C6alkoxygroup or amino group, alkoxycarbonylmethyl or pyridylethyl; X is a bivalent radical of the formula; R11is oxygen atom or sulfur; R14is a hydrogen atom or a C1-C6alkoxycarbonyl; R15is a hydrogen atom or a C1-C6alkyl, or their racemic mixtures, pure enantiomers, mixtures thereof and their therapeutically acceptable salts, methods for their production and obtain the intermediate compounds and the drug having hypnotic and sedative activity. 10 S. and 2 C.p. f-crystals, 4 PL.

The invention concerns new derivatives

Thus, investigated the application of melatonin and its analogues, in particular for the treatment of depression and psychiatric disorders, particularly stress, anxiety, depression, insomnia, schizophrenia, psychosis and epilepsy, and sleep disorders associated with travel ("the delay in the response" = "jet lag"), neurodegenerative diseases of the Central nervous system such as Parkinson's disease or Alzheimer's disease, for the treatment of cancer or in other cases, use as a contraceptive or analgetika.

However, direct application of melatonin in vivo does not provide a truly satisfactory results due to the fact that on the first pass through the liver extracted more than 90% of the active principle, and not shown obvious hypnotic effects of melatonin.

Describes the different analogues of melatonin, showing two ways of research, co replacement indolines group naftilos group (FR-A-2658818, FR-A-2689124).

The authors showed that melatonin does not show hypnotic action, but is bioresistant acetylated metabolites that cause sleep.

The present patent application provides a new way of developing new derivatives carboline, which are analogues of endogenous acetylated metabolites of melatonin.

The present invention relates to new derivatives Carolina General formula I (I' and I")in which X represents a bivalent radical of the formulaor-R6C=CR7-; R1, R2, R3and R4each independently represents a hydrogen atom, a hydroxyl radical, lower alkyl, lower cycloalkyl, lower alkoxy, aryloxy, lower aralkylated, halogen or retrorectal or unsaturated aliphatic chain, formyl, lower alkylsulphonyl, lower alkylcarboxylic, halogen(lower)alkylaryl, halogen(lower)alkylcarboxylic, halogen(lower)alkyl, halogen(lower) alkyloxy, lower alkoxycarbonyl, carboxyl, optionally substituted carboxamide, two adjacent radicals R1, R2, R3and R4may is, 3and R4represent independently from each other peralagan(lower)alkyl, aryl, aralkyl, lower cycloalkane, POLYHALOGENATED, thiol radical, a lower alkylthio, lower cycloalkyl, mono - or POLYHALOGENATED, aaltio, Uralkali, formate, lower cycloalkylcarbonyl, arylcarboxylic, aralkylamines, lower dialkylaminoalkyl, aminoalkyl, lower acylaminoalkyl, alluminati, diarylamino, arylalkylamines, amino, alkylamino, dialkylamino, arylamino, diarylamino, aralkylamines, dialkylamino, formamide, lower alkylcarboxylic, lower cycloalkylcarbonyl, halogen(lower)alkylcarboxylic, polyhalogen(lower)alkylcarboxylic, arylcarboxamide, lower aralkylamines, lower cycloalkylcarbonyl, polyhalogen(lower)alkylaryl, arylcarbamoyl, aralkylamines, lower cycloalkylcarbonyl, halogenosilanes, aryloxyalkyl, Uralelectromed, lower alkylsulfonyl, lower cycloalkylcarbonyl, halogen(lower)alkylsulfonyl, peralagan(lower)alkylsulfonyl, arylsulfonyl, aralkylamines, ceanorhaditis.

R5represents a hydrogen atom, lower alkyl, cycloalkyl, aryl, lower aralkyl, lower alkoxyimino, alkylamino, diarylamino, halogen(lower)alkylsulfonyl, alkylsulfonyl or arylsulfonyl.

R5also represents a halogen(lower)alkyl, peralagan(lower)alkyl, hydroxyl radical, a lower cycloalkane, aryloxy, aralkylated, thiol radical, a lower alkylthio, lower cycloalkyl, aaltio, Uralkali, dialkylaminoalkyl, arylamino, aralkylamines, dialkylamino, optionally substituted carboxamide, formamid, formyl, lower cycloalkylcarbonyl, peralagan(lower)alkylaryl, arylcarbamoyl, aralkylamines, lower cycloalkylcarbonyl, halogenosilanes, aryloxyalkyl, Uralelectromed, lower cycloalkylcarbonyl, peralagan(lower)alkylsulfonyl, aralkylamines, ceanorhaditis.

R6, R7, R9, R10, R12, R13, R14and R15represent independently each other a hydrogen atom, lower alkyl, lower cycloalkyl, halogen(lower)alkyl, peralagan(lower)alkyl, aryl, aralkyl, lower alkoxy, lower cycloalkane, mono - or POLYHALOGENATED, aryloxy, aralkylated, hydroxyalkyl, alkyloxyalkyl, lower alkylthio, lower cycloalkyl, mono - or POLYHALOGENATED, aaltio, Uralkali, formate, lower alquiler is yloxy, dialkylaminoalkyl, dialkylamino, diarylamino, dialkylamino, optionally substituted carboxamide, formamide, lower alkylcarboxylic, lower cycloalkylcarbonyl, halogen(lower)alkylcarboxylic, peralagan(lower)alkylcarboxylic, lower arylcarboxamide, lower aralkylamines, formyl, lower alkylsulphonyl, lower cycloalkylcarbonyl, halogen(lower)alkylaryl, peralagan(lower)alkylaryl, arylcarbamoyl, aralkylamines, carboxyl, lower alkoxycarbonyl, lower cycloalkylcarbonyl, halogenosilanes, aryloxyalkyl, Uralelectromed, lower alkylsulfonyl, lower cycloalkylcarbonyl, halogen(lower)alkylsulfonyl, peralagan(lower)alkylsulfonyl, arylsulfonyl, aralkylamines, halogen, cyano - or microradian.

R8represents lower alkyl, lower cycloalkyl, hydroxyalkyl, alkyloxyalkyl, halogen(lower)alkyl, peralagan(lower)alkyl, aryl, lower alkylaryl, halogenared, lower alkoxyaryl, nitroil, aminoaryl, di(lower)alkylamino, pyridyl, aralkyl, lower alkoxy, lower cycloalkane, mono - or POLYHALOGENATED, aryloxy, aralkylated, lower alkylthio, lower cycloalkyl, mono - or polyalkylacrylate, arylcarboxylic, aralkylamines, dialkylaminoalkyl, dialkylamino, diarylamino, dialkylamino, optionally substituted carboxamide, formamide, lower alkylcarboxylic, lower cycloalkylcarbonyl, halogen(lower)alkylcarboxylic, polyhalogen(lower)alkylcarboxylic, arylcarboxamide, lower aralkylamines, formyl, lower alkylsulphonyl, lower cycloalkylcarbonyl, halogen (lower)alkylaryl, peralagan(lower)alkylaryl, arylcarbamoyl, aralkylamines, carboxyl, lower alkoxycarbonyl, lower cycloalkylcarbonyl, halogenosilanes, aryloxyalkyl, Uralelectromed, lower alkylsulfonyl, lower cycloalkylcarbonyl, halogen(lower)alkylsulfonyl, peralagan(lower)alkylsulfonyl, arylsulfonyl, aralkylamines, halogen, cyano or microradian.

R6, R7, R8, R9, R10, R12, R13, R14and R15can be a, but not both R8and R15, R9and R10, R12and R13, hydroxyl radical, chiaradia, amino, alkylamino, arylamino, aralkylamines, alkoxy, lower cycloalkane, mono - or POLYHALOGENATED, aryloxy, aralkylated, lower alkylthio, lower �p://img.russianpatents.com/img_data/63/631889.gif">

can also be a carbonyl group C=O, thiocarbonyl group (C=S, the radical C=N-R16or radical

R11represents an oxygen atom or sulfur;
R16represents a hydrogen atom, lower alkyl, lower cycloalkyl, aryl, aralkyl, hydroxyl radical, lower alkoxy, alkylsulphonyl, arylcarbamoyl, aralkylamines, amino, alkylamino, dialkylamino, arylamino, diarylamino, aralkylamines, alkylcarboxylic, arylcarboxamide.

R17and R18represent independently each other a hydrogen atom, lower alkyl, lower cycloalkyl, aryl, aralkyl, lower alkoxy, lower cycloalkane, aryloxy, aralkylated, lower alkylthio, aaltio, Uralkali, lower alkylcarboxylic, lower cycloalkylcarbonyl, arylcarboxylic, aralkylamines, dialkylamino, arylalkylamine, diarylamino, optionally substituted carboxamide, formamide, lower alkylcarboxylic, lower cycloalkylcarbonyl, arylcarboxamide, formyl, lower alkylsulphonyl, lower cycloalkylcarbonyl, arylcarbamoyl, aralkylamines, carboxyl, lower alkoxycarbonyl, aryl>and R3-R4can be part of another aromatic or non-aromatic ring, with or without heteroatom thereof, and optionally bearing a carbonyl or thiocarbonyl group.

Compounds corresponding to the present invention may contain from one to three centers of asymmetry, such compounds will exist as optical isomers (enantiomers).

The present invention relates to racemic mixtures, pure enantiomers or mixtures of such compounds in any ratio, and their therapeutically acceptable salts.

More specifically, the carbon atom carrying the group R8can be a centre of asymmetry, the present invention includes all such enantiomers and mixtures.

The expression "lower alkyl", "lower alkoxy" or "pagelogin(lower)alkyl" is usually understood as referring to the radicals, the alkyl residue of which contains from 1 to 6 carbon atoms.

Preferably a linear or branched C1-C4alkyl residues, more specifically selected from methyl, ethyl, n-sawn, ISO-propyl, n-butilkoi, isobutylene and tert-butilkoi groups. The expression "unsaturated aliphatic chain" is preferably understood as from the institutions and heteroaromatic groups, in particular arily selected from phenyl, thienyl, fernilee, peredelnoj and naftilos groups. Aryl radicals can also be substituted with one group or more, in particular selected from a hydrogen atom, lower alkyl, lower cycloalkyl, halogen(lower)alkyl, peralagan(lower)alkyl, aryl, aralkyl, hydroxyl radical, lower alkoxy, lower cycloalkane, mono - or POLYHALOGENATED, aryloxy, aralkylated, thiol, lower alkylthio, lower cycloalkyl, mono - or POLYHALOGENATED, aaltio, Uralkali, formate, lower alkylcarboxylic, lower cycloalkylcarbonyl, halogen(lower)alkylcarboxylic, arylcarboxylic, aralkylamines, dialkylaminoalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, aralkylamines, dialkylamino, optionally substituted carboxamide, formamide, lower alkylcarboxylic, lower cycloalkylcarbonyl, halogen(lower)alkylcarboxylic, peralagan(lower)alkylcarboxylic, lower arylcarboxamide, lower aralkylamines, formyl, lower alkylsulphonyl, lower cycloalkylcarbonyl, halogen (lower)alkylsulphonyl, peralagan(lower)alkylsulphonyl, arylcarbamoyl, arylchlorosilanes, orelkinoservisa, lower alkylsulfonyl, lower cycloalkylcarbonyl, halogen(lower) alkylsulfonyl, peralagan(lower)alkylsulfonyl, arylsulfonyl, Arakishvili, halogen, cyano or microradians.

The expression "lower aralkyl" will be understood as referring to the combination of lower alkyl and aryl, as defined above. It is preferably a benzyl radical, which optionally has a substituent.

Halogenation preferably selected from fluorine atoms, chlorine, bromine and iodine. Perhalogenated preferably are perforazione.

If R1-R2, R2-R3and R3-R4be part of another aromatic ring, the heteroatom or without, this is another aromatic ring preferably represents an optionally substituted benzene ring or optionally substituted peregrinae ring.

If R1-R2, R2-R3and R3-R4be part of another dearomatizing ring, they preferably form together a bivalent radical of formula-O-(CH2)m-, where m = 2 or 3, which is optionally substituted, or a bivalent radical of formula-O-(CH2)p-O-, where p = 1 or 2,the present invention relates to a corresponding racemic mixtures, and their pure enantiomers in any proportions.

Therapeutically acceptable salt derivatives corresponding to this invention, are common to this area of organic or inorganic salts, in particular hydrochloride, tozilaty, mesylates and citrates, and a solvate such as a hydrate or polyhydrate compounds of General formula I.

Compared to the derivatives described in WO 96/08490, derivatives, corresponding to the present invention, are characterized in that they contain a group R8that significantly improves the stability of such compounds in the acidic environment of the stomach and allows for oral administration.

Not bound by any theory, now discovered that the group responsible for the widespread effects of the compounds of the present invention, is adamidou or dihydroindeno group. This enomena or dehydroalanine group is a group, denoted as Ca-N-Cbin formula I.

Derivatives disclosed in this invention and of particular interest are those in which:
R11preferably is an oxygen atom or sulfur,
R2is hydroxyl or is Orada or lower alkoxycarbonyl group.

More specifically, the present invention relates to derivatives of the General formula Ia (Ia' and Ia")


If Ia is a Ia', R8represents an alkyl radical, optionally substituted by alkyl, halogen, amino, alkoxygroup, allyloxycarbonyl; aryl radical, optionally substituted by alkyl, halogen, the nitro-group, dialkylamino, alkoxygroup, allyloxycarbonyl, alkylaminocarbonyl, while the aryl radical is, for example, phenyl group, pyridium.

If Ia is a Ia and if R15is a hydrogen atom, R8preferably represents the radical ethyl, hexyl, isopropyl, phenyl, forfinal, methoxyphenyl, AMINOPHENYL, dimethylaminophenyl, nitrophenyl, tolyl, etoxycarbonyl, pyridyl.

If R15is different from a hydrogen atom, R8and R15identical and represent alkyl or aryl radicals, optionally substituted by alkyl, halogen, amino, alkoxygroup.

X represents a bivalent radical of the formula

or-HC=CH-,
(R5=R6=R7=H)
R11predpochtu, preferably metacircular.

R3is a hydrogen atom or alkyl radical, preferably a methyl radical.

In particular, the present invention relates to derivatives of the General formula Ib

in which R2, R3, R8, R14and X is defined above.

Derivative of the formula Ib can be obtained directly by the reaction of compounds of General formula IIA

in which R2, R3, R8, R14and X are defined above, with a carboxylic acid (such as acrylic acid) in the presence or in the absence of diphenylphosphinite or Acrylonitrile.

To obtain the derivative of General formula IIa are reaction Bichler-Napieralski (Bischler-Napieralski) by reaction of compounds of General formula IIIa

in which R2, R3, R8, R14and X are defined above, with phosphorus pentoxide (P2O5) or oxychloride of pentavalent phosphorus (l3) in a suitable solvent, for example toluene, xylene, dichloromethane.

These derivatives IIa can also be obtained by oxidation with permanganate derivatives of the General formula IIb

for which R2, R3, R14and X are defined above, with compounds of formula R8-CH2-CHO or their chemical equivalents, such as ketal, simple enol ether, ester of enol or nitrile of the formula R8-CH2-CN, in reducing conditions, with R8such as defined above.

Derivatives of formula IIIa may be obtained by acylation using Alliluyeva agent (carboxylic acid, acid anhydride, ether complex) derivative of the formula IIIb, for which R2, R3, R14and X is defined above.

Also, if X=NR5then derivatives of the formula IIIa can be obtained by the reaction of Fischer with a suitable substituted phenyl General formula IV and comfortable aldehyde or latent aldehyde, such as ketal, the General formula V


for which R2, R3, R14and X is defined above, and R5represents hydrogen or lower alkyl.

In the specific case of derivatives of the General formula IC

for which R2, R3, R8, R14and X is defined above, is a derivative of the formula IC can be obtained put the Les.

In the specific case of derivatives of the General formula Id

for which R2, R3, R8, R14and X is defined above, such derivatives of the General formula Id can be obtained by the direct impact of the reagent Lawesson (Lawesson) or P2S4the compounds of General formula Ib.

In the specific case of derivatives of the General formula S

for which R2, R3, R8, R14and X is defined above, is a derivative of the formula I can be obtained by the direct impact of the reagent Lawesson (Lawesson) or P2S4the compound of General formula IC.

In the specific case of derivatives of the General formula If

for which R2, R3, R8, R14and X is defined above, is derived formula If can be obtained by the direct impact of oxidant (such as2in an alkaline environment) to the compound of General formula Ib or Id.

Derivatives corresponding to the formula Ia, in which R8and R15identical may be obtained by reaction of the derivatives of General formula IIIb

with compounds of the formula EtO-CO-C(R8) (R15

Stability in the acidic environment and pharmacological activity
1. Stability in the acidic environment and bioprospect for greyhounds.

To investigate the impact of group R8on the stability of the cycle And the comparison compounds (example) and (example) (R8= a hydrogen atom) with the compounds of example 1, example 4, example 7, example 8 and example 11 are dissolved 30 µl of each of these compounds in 5 ml of buffer with pH 1 or pH 2 or pH 3 or pH 7 (comparison). The solution is stirred for 15 minutes at 37oC. Then perform the determination of the quantities of non-hydrolyzed �ttp://img.russianpatents.com/img_data/63/631909.gif">
The results presented in Table I, are given as the percentage of hydrolyzed compounds, when compared with the compounds (example) and (example), which are completely hydrolyzed in the range from pH 1 to pH 3.

Compounds 1, 4, 7, 8, and 11 stable at pH 2 and above as at pH2 these compounds are hydrolyzed with less than 27 percent.

In conclusion, compounds in which the group R8(in the General formula (I) other than hydrogen atom does not undergo complete hydrolysis cycle A. the Stability of such compounds, as compounds of examples 1, 4, 8, in the acidic environment of the stomach allows their use of oral way. Pharmacokinetic studies of these compounds (table I) was carried out on hound dogs; compounds 1, 4, 8 show the absolute bioprosthetic oral usage relative to intravenous, respectively, above 35% (compound 1), 20% (compound 4) and 100% (compound 8), although the absolute bioprosthetic connections (example) and (example) below 1% (sample a) and 5% (example B).

Compound 1 (see Table II), and compounds 4 and 7 (see Table III) show a significant sedative effect in oral introduction hounds dogs.

2. Snetwork kept in a metal cage, connected through a flexible cable with 2 Schwartzer ED 24 Polygraph, software BRAINLAB.
Study and control products administered orally, or intravenously by means of a gastric tube. Registration is produced with a period of 30 seconds for active wakefulness, drowsiness, slow wave sleep (light sleep + deep sleep) and REM sleep. According to Shelton and others (SHELTON J., NISHINO , S., VAUGHT J. , DEMENT, W. C. and MIGNOT E. Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of a narcoleptic dogs. Sleep 19(1); 29-38, 1996), these criteria are based on the frequency and amplitude diagrams: cortical electroencephalogram (EEG, fronto-frontal), electromyograms (EMG of the upper neck muscles) and EOG (bilateral). During each period of 120 minutes continuously monitor the behavior of animals. Preliminary acclimatization dogs lasts 5 days; and, imitating a similar stress induced gastric tubes, together with the intravenous injection is administered orally mixture of water/glycol (PEG) {50/50 volume/volume}.

Wakefulness: includes all the episodes from the diagram at low voltage and mixed frequency in which EMG is not inhibited. During wakefulness dog stand, sit, or lie, and the eyes of them were opened.

one definition), and cortical EEG shows a number of relatively slow waves (4-7 Hz), not detecting carotid spindles. Synchronous wave at 4-7 Hz and 50 -100 µv appear on the background activity of REM sleep at a low voltage.

EMG moderately reduced in comparison with the stage of waking.

Easy deep sleep: NREM sleep (SWS) (light sleep + deep sleep): the dog is relaxed in the pose while lying prone. Graphics EEG are greater than in the previous phase, amplitude and sleepy spindle (10-14 Hz), and/or in a light sleep may be present K-complexes, as EOG shows slow eye movement or lack of movement. Deep sleep note, if slow Delta waves (<4 Hz) constitute 20 percent or more over the period during deep sleep.

REM sleep rapid eye movement note, if dogs lie, eyes closed with explicit intermittent rapid twitching of the muscles. The chart EEG at low voltage and mixed frequency see together with rapid eye movements and reduced EMG activity.

The separation and the duration of the States of wakefulness/sleep determine the hound dogs after oral (and intravenously for compounds of example 1) introduction Placebo (filler = 10 ml of a mixture of ethanol/PEG 400/water, 10/40/50;./about./vol.), connect antnee the status of each stage.

The compound of example 1, example 4 and example 7 showed a strong sedative effect, causing sleep, characterized by the high share of slow wave sleep. With regard to duration and latent States of the stages of wakefulness, sleep and slow wave sleep, these 3 compounds induce significant hypnotic effects.

3. Hypnotic and sedative effects in chickens.

Hypnotic and sedative effects obtained above derivatives corresponding to this invention (the results of the study are given below in Table IV}, 10-14-day-old Chicks (strain JA657) compared the effects of three of these products: diazepam, pentobarbital sodium and melatonin, as well as with the effects of the two compounds-stimulant with hallucinogenic properties: 10-methoxyaniline and harmaline that represent 3,4-dihydro--carboline. Animals kept in conditions of alternating light: 12 hours darkness (from 20.00 to 8.00 h) and 12 hours of light (from 8.00 to 20.00 h). The room temperature is 25oWith in the first week of the contents of chickens and 22oWith, starting from the second week onwards. Lighting during the day provides a halogen lamp (300 W) placed at a height of 30 cm from the floor vivart divided into 3 groups and placed on the same vivarian, 30 cm x 50 cm x 30 cm Investigational products intramuscularly (IM) in the pectoralis major muscle in the form of a solution in a mixture of ethanol/PEG 400/water = 25/50/25 (about./about./about.) in the amount of 0.2 ml per 100 g of live weight. Input dose of the investigational products (new compounds of this invention and comparative compounds) is from 0.25 to 2 mmol per 100 g of live weight. Placebo is a 0.2 ml mixture of ethanol/PEG 400/water = 25/50/25 (about./about./vol.).

Solutions of the products examined in a mixture of ethanol/PEG 400/water = 25/50/25 (about. /about. /about.) prepare during use by serial dilution of the basic solution obtained from 2.5 to 20 µmol accurately weighed product to which sequentially add 0.5 ml of pure ethanol and then 1 ml of PEG 400 with stirring, ultrasound, and then bring the volume of the solution to 2 ml by adding 0.5 ml of distilled water for injection. Table IV shows the results obtained after intramuscular (IM) doses of 0.25 to 2 µmol investigational products, dissolved in 0.2 ml of a mixture of ethanol/PEG 400/water = 25/50/25 (about./about./vol.), 100 g wet weight. For each chicken regulate the amount of input in relation to the actual live weight to values of 0.2 ml per 100 g of live weight.

The observed parameters Awlaki cycles of wakefulness/sleep for a chick that age, they register the camera for 90 minutes, the first 30 minutes are the time of adaptation to the device.

In the following Table IV presents hypnotic and sedative effects of the investigational products on daily activity 10-14-day-old Chicks, aged to study in conditions of continuous illumination from birth within 48 hours and then under conditions of alternating light: 12 hours of daylight (8.00 - 20.00 h) and 12 hours of darkness (20.00 - 8.00 h). Studies conducted during the day between 14.00 and 15.00 PM

For each of the investigated product carried out several series of definitions for groups of 3 animals each specified value is the average for each group of 3 Chicks. If the number of groups is greater than or equal to 2, then these numbers are average limits of the observed values.

In terms of conducting the research (the time of the introduction phase, when the animals are exposed to light, between 14.00 and 15.00 h) melatonin has no hypnotic action.

By successive exposure of chickens alternating or continuous lighting, the authors experimentally showed that melatonin has no direct hypnotic action, which is characteristic of its structure. Its sedative effect depends on the activity FEM acetylation. In the presence of the enzyme NAT in the pineal gland of the chicken intramuscular injection melatonin hypnotic effect of high-intensity (sleep time from 250 to 300 minutes for a dose of 1 µmol of melatonin per 100 g wet weight). Thus, melatonin is a precursor of the acetylated metabolites with direct soporific effect. The compounds of this invention are analogs pills acetylated metabolites of melatonin.

In contrast to melatonin, all derivatives of the present invention, described above, have a direct hypnotic and sedative action that does not depend on the time of implementation, i.e. from the level of the enzyme N-acetyltransferase in the Central nervous system.

Obtained for the derivatives of the present invention results show that their sedative effect is stronger than the effect of the comparative products (pentobarbital, melatonin) and equivalent or even superior to the action of diazepam.

Thus, derivatives, corresponding to this invention, particularly useful for the treatment of sleep disorders and diseases associated with impaired activity of melatonin.

Examples
Example 1: ETCARBO7
Formula: C18H20N2O2; M = the-2,3,4,6,7,12-hexahydrobenzo[2,3-a]-chinolin-4-one
Receive:
Paramethoxyamphetamine sulfonate (5 g, of 20.7 mmol) and N-(4,4-diethoxybutane)butanamide (4.8 g, of 20.7 mmol) are mixed in a commercial THF (85 ml) in a flask of 500 ml. and Then the medium is heated to boiling THF under reflux and add one drop of acetic acid (25%, 35 ml). Transparent yellow mixture is stirred for 6 hours at a temperature in the range from 80 to 85oC. After cooling, the reaction mixture was transferred into an Erlenmeyer flask 2 l and alkalinized by adding a saturated solution of sodium carbonate (~100 ml), pH>7. The organic phase is decanted and the aqueous phase is twice extracted with ethyl acetate (2 x 100 ml). The combined organic phases are successively washed with a saturated solution of sodium carbonate (70 ml) and water (70 ml), the organic phase is dried over gSO4and the solvent is evaporated under reduced pressure until crystals (~5 ml ethyl acetate). After dilution with diethyl ether (50 ml) and the solution left overnight in the refrigerator. The crystals obtained by filtration, washed with diethyl ether and dried in vacuum. Then obtain N1-(2-(5-methoxy-1H-3-indolyl)ethyl)butanamide (3.3 grams, R=61%).

Bischler-Napieralski (Bischler-Napieralski) N1-(2-(5-methoxy-1H-3-indolyl)ethyl)butanamide when dobavlaut to a solution of 1-propyl-6-methoxy-3,4-dihydro-2-carboline (2,34 g) in dimethylformamide (DMF) (20 ml). Then add drop by drop diphenylphosphinite (2.1 ml, 1.06 equiv.) dissolved in DMF (3 ml) and then triethylamine (2,85 ml, 2.1 EQ.). After recrystallization from ethyl acetate receive 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one (1.6 g, 56%).

Method 2.

Acrylic acid (1 EQ.), dissolved in xylene, are added to a solution of 1-propyl-6-methoxy-3,4-dihydro-2-Karbala-in xylene. The reaction flask provided with a trap for water and heat the medium to the boiling point of xylene under reflux for 24 hours. Then the xylene is distilled off under reduced pressure. The product is cleaned, as described above.

NMR1H (CDCl3): of 1.29 (t, 3H); 2.44 and 2,54 (2 m, 6N); of 2.86 (t, 2H); 3,86 (s, 3H); 4,08 (t, 2H); 6.87 in (DD of 2.4 and 8.7 Hz, 1H); 6,95 (l to 2.4 Hz, 1H); 7,27 (l to 8.7 Hz, 1H); 8,04 (broad s, 1H).

Mass spectrum: m/z 296 (M+.), 281 (100).

Exact mass: calculated 296,1524; found 296,1545.

Melting point: 223oC.

Example 2: HECARBO7
Formula: C22H28N2O2; M = 352,47mol-1
Structure:

9-methoxy-1-hexyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N1-(2-(5-methoxy-1H-3-indolyl)ethyl)octanamide results 1-gate-heptyl-6-methoxy-3,4-dihydro-2-carboline in xylene. The reaction flask provided with a trap for water and heat the reaction medium to the boiling point of xylene under reflux for 48 hours. Then the xylene is distilled off under reduced pressure. The product is recrystallized from ethyl acetate.

NMR1H (CDCl3): to 0.92 (t, 3H); to 1.42 (m, 8H); 2.40 a (t, 2H); 2.50 each (m, 4H); of 2.56 (t, 2H); 3,86 (s, 3H); 4,08 (t, 2H); 6.87 in (DD of 2.4 and 8.7 Hz, H); 6,94 (l to 2.4 Hz, 1H); 7.23 percent (l to 8.7 Hz, 1H); 8,04 (broad s, 1H).

Mass spectrum: m/z 352 (M+.), 281 (100).

Melting point: 140oC.

Example 3: IPCARBO7
Formula: C19H22N2O2; M = 310,39mol-1
Structure:

9-methoxy-1-isopropyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] -chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N1-(2-(5-methoxy-1H-3-indolyl)ethyl)-3-methylbutylamine results 1-isobutyl-6-methoxy-3,4-dihydro-2-carboline.

Acrylic acid (1 EQ.), dissolved in xylene, are added to a solution of 1-isobutyl-6-methoxy-3,4-dihydro-2-carboline in xylene. The reaction flask provided with a trap for water and heat the reaction medium to the boiling point of xylene under reflux for 48 hours. Then the xylene is distilled off under reduced pressure. Product paracrystals is; ,87 (DD 2.4 and 9 Hz, 1H); 6,95 (l to 2.4 Hz, 1H); 7,32 (d 9 Hz, 1H).

Mass spectrum: m/z 310 (M+.), 295(100).

Melting point: 251-252oC.

Example 4: PHCARBO7
Formula: C22H20N2O2; M = 344,41mol-1
Structure:

9-methoxy-1-phenyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N1-(2-(5-methoxy-1H-3-indolyl)ethyl)-2-phenylacetamide results 1-benzyl-6-methoxy-3,4-dihydro-2-carboline.

Acrylic acid (0.75 ml, 1.1 EQ.) added to a solution of 1-benzyl-6-methoxy-3,4-dihydro-2-carboline (2.8 g) in DMF (20 ml). Then add drop by drop diphenylphosphinite (2.1 ml, 1.06 equiv.) dissolved in DMF (3 ml), and then triethylamine (2,85 ml, 2.1 EQ.). After division on silica gel (eluent chloroform/methanol) to obtain 9-methoxy-1-phenyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one (1.6 g, 56%).

NMR1H (CDCl3): a 2.71 (m, 4H); 2.91 in (t, 2H); a 3.83 (s, 3H); 4,20 (t, 2H); 6,76 (DD of 2.4 and 8.7 Hz, 1H); 6,84 (l to 8.7 Hz, 1H); 6.90 to (l to 2.4 Hz, 1H); 6,93 (broad s, 1H); 7,42 and 7.50 (m, 5H).

Mass spectrum: m/z 344 (M+.) (100), 253.

Melting point: 235oC.

Example 5: CO2ETCARBO7
Formula: C19H20N2O4; M = 340,37molholesin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) of 3-((2-(5-methoxy-1H-3-indolyl)ethyl)amino)-3-oxopropanoic leads to the corresponding Carolina.

To the solution obtained carboline (800 mg) in benzene (10 ml) add a solution of sodium hydroxide (1N, 3 ml) and then tetrabutylammonium hydrosulfate (0.1 EQ. ). After that add akriloilkhlorida (0,27 ml) at 0oC and the mixture allowed to warm to room temperature over night. The product is shared on silica gel (chloroform/methanol) and receive, thus, 1-carbethoxy-9-methoxy-2,3,4,6,7,12-hexahydrobenzo-[2,3-a]chinolin-4-one.

NMR1H (CDCl3): of 1.42 (t, 3H); 2,60 (t, 2H); to 2.85 (t, 2H); of 2.97 (t, 2H); to 3.89 (s, 3H); 4,30 (t, 2H); 4.35 the (Quartet, 2H); of 6.96 (d of 2.1 Hz, 1H); 7,01 (DD 2.1 and 7.5 Hz, 1H); 7,35 (l 7.5 Hz, 1H).

Mass spectrum: m/z 340(M+.), 294 (100).

Melting point: 174-175oC.

Example 6: 6ETETCARBO7
Formula: C20H24N2O2; M = 324,42mol-1
Structure:

9-methoxy-1,10-diethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] -chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N1-(2-(5-methoxy-6-ethyl-1H-3-indolyl)ethyl)butanamide leads to the production of 7-ethyl-1-propyl-6-methoxy-3,4-dihydro-2-carboline.

To RKV.). Then add drop by drop diphenylphosphinite (1.06 equiv.) dissolved in DMF (3 ml), and after triethylamine (2.1 EQ.). After division on silica gel (eluent chloroform/methanol) to obtain 9-methoxy-1,10-diethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one (28%).

NMR1H (CDCl3): of 1.26 (m, 6N); 2.41 and 2,58 (2m, 6N); 2,70 (Quartet, 2H); 2,87 (t, 2H); a 3.87 (s, 3H); 4,07 (t, 2H); 6,88 (1C, 1H); 7,19 (s, 1H); 8,33 (broad s, 1H).

Mass spectrum: m/z 324 (M+.), 309 (100).

Melting point: 204oC.

Example 7: ETCARBO7S
Formula: C18H20N2OS; M = 312,42mol-1
Structure:

9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-tion
Receive:
The reagent Lawesson (Lawesson) (0.5 mmol) is added by portions at 110oTo a solution of 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo [2,3-a]chinolin-4-it (300 mg, 1.01 mmol) in anhydrous toluene (15 ml). After boiling under reflux for 30 minutes and evaporation of the toluene, the product chromatographic on silica gel (eluent chloroform/methanol = 99/1) and receive, thus, 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-tion (yield 60%).

NMR1H (CDCl3): of 1.32 (t, 3H); 2,32 (t, 2H); 2,65 (Quartet, 2H); 2,98 (t, 2H); is 3.08 (t, 2H); to 3.89 (s, 3H); 4.80 to (t, 2H); RA melting point: 118oC.

Example 8: ETDHCARBO7
Formula: C18H22N2O2; M = 298,38mol-1
Structure:

9-methoxy-1-ethyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] -chinolin-4-one
Receive:
To a solution of 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-it (500 mg) in ethanol successively added sodium bicarbonate (500 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. So, get 9-methoxy-1-ethyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a]chinolin-4-one (76%).

NMR1H (CDCl3): of 0.79 (t, 3H); 1,13 (2m, 2H); 1,95 (m, 2H); of 2.20 (m, 1H); of 2.45 (m, 2H); 2,77 (m, 2H); a 3.87 (s, 3H); 4,88 (s, 1H); 5,09 (m, 1H); is 6.78 (DD of 2.4 and 8.7 Hz, 1H); 6,92 (l to 2.4 Hz, 1H); 7,25 (l to 8.7 Hz, 1H); 8,77 (broad s, 1H).

Melting point: 207oC.

Example 9: ETNAPH7
Formula: C20H21NO2; M = 307,39mol-1
Structure:

11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-he
Receive:
To boiling under reflux a solution of N - (2-(7-methoxy-naphthas-1-yl)ethyl)butanamide of 2.27 g, 11.1 m is transferred into a solution of KOH (40%). This mixture is then extracted with EtOAc (x 3). After drying the organic phase over gSO4remove the solvent. The crude reaction product is dissolved in DMF (5 ml) and added acrylic acid (0,94 ml, 1.2 EQ. ). Then add drop by drop diphenylphosphinite (2.7 ml, 1.1 equiv.) dissolved in DMF (3 ml) and then triethylamine (3,67 ml, 2.6 EQ.). By recrystallization from a mixture of EtOAc/P. E. = 20/80 get 11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f]pyrido[2,1-a] isoquinoline-8-he (329 mg).

NMR1H (CDCl3): of 1.17 (t, 3H); of 2.38 (m, 4H); of 2.58 (t, 2H); and 3.16 (t, 2H); 3,82 (t, 2H); of 3.95 (s, 3H); 7,17 (DD, 1H); 7,29 (d, 1H); 7,33 (d, 1H); 7,66 (d, 1H); 7,76 (d, 1H).

Melting point: 105-107oC.

Example 10: PHNAPH7
Formula: C24H21NO2; M = 355,43mol-1
Structure:

3-methoxy-11-phenyl-5,8,9,10-tetrahydro-6N-benzo[f] pyrido-[2,1-a] isoquinoline-8-he
Receive:
To boiling under reflux to a solution of N-(2-(7-methoxy-naphthas-1-yl)ethyl)phenylacetamide (600 mg) in toluene (100 ml) add l3(1,4 ml). After 3 hours, the toluene is removed under reduced pressure. The residue is transferred into a solution of KOH (40%). This mixture is extracted with EtOAc (x 3). After drying the organic phase over gSO4remove the solvent. The crude reaction product of rsid (0.45 ml), dissolved in DMF (1 ml) and then triethylamine (0,55 ml, 2.1 EQ. ). Get 3-methoxy-11-phenyl-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-he (170 mg, yield 25%).

NMR1H (CDCl3): 2,70 (m, 4H); of 3.32 (t, 2H); 3,88 (t, 2H); of 3.94 (s, 3H); 6,74-OF 7.60 (10H).

Melting point: 152-154oC.

Example 11: PHCARBO7S
Formula: C22H20NOS; M = 360,47mol-1
Structure:

9-methoxy-1-phenyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] [beta] chinolin-4-tion
Receive:
The reagent Lawesson (Lawesson) (180 mg, 0.47 mmol) is added by portions at 110oTo a solution of 9-methoxy-1-phenyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-it (164 mg, 0.47 mmol) in anhydrous toluene (10 ml). After boiling under reflux for 30 minutes and evaporation of the toluene, the product chromatographic on silica gel (eluent chloroform) and receive, thus, 9-methoxy-1-phenyl-2,3,4,-6,7,12-hexahydrobenzo[2,3-a]chinolin-4-tion (130 mg, yield 76%).

NMR1H (CDCl3): of 1.32 (t, 3H); 2,32 (t, 2H); 2,65 (Quartet, 2H); 2,98 (t, 2H); is 3.08 (t, 2H); to 3.89 (s, 3H); 4.80 to (t, 2H); 6,91 (DD of 2.4 and 8.7 Hz, 1H); 6,98 (l to 2.4 Hz, 1H); 7,34 (l to 8.7 Hz, 1H); 8,11 (broad s, 1H).

Melting point: 180oC.

Example 12: DEETCARBO7S
Formula: C18H18N2OS; M = 3-2,3,4,12 tetrahydroindole[2,3-a]chinolin-4-tion
Receive:
To a solution of 9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-thione (500 mg, 1.6 mmol) in DMF (42 ml) add tertbutoxide potassium (665 mg, 5.9 mmol). After drawing up of the reaction mixture in vacuum it is stirred over night under normal oxygen pressure. Then add water (15 ml) and concentrated hydrochloric acid (3 ml). This solution was stored in a refrigerator for 4 hours. After filtration will receive a 9-methoxy-1-ethyl-2,3,4,12-tetrahydroindole[2,3-a]chinolin-4-tion (150 mg, 30% yield).

NMR1H (CDCl3): to 1.38 (t, 3H); 2,93 (Quartet, 2H); to 3.06 (t, 2H); 3,90 (s, 3H); of 5.06 (t, 2H); 7.03 is (d+s, 2H); 7,19 (d, 1H), 7,38 (d, 1H); a 7.62 (d, 1H); 8,43 (broad s, 1H).

Mass spectrum: m/z 310 (M+.), 295, 155.

Melting point: 212oC.

Example 13: FPHCARBO7
Formula: C22H19N2O2F; M = 362,40mol-1
Structure:

9-methoxy-1-(para-forfinal)-2,3,4,6,7,12-hexahydrobenzo-[2,3-a] chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N-[2'-(5-methoxy-1H-3-indolyl)ethyl] -2-(para-forfinal)ndimethylacetamide (1,15 g, 3.5 mmol) to give 1-(para-terbisil)-6-methoxy-3,4-dihydro-2-carbolin (1.06 g) which is dissolved directly in anhydrous pillbox (of 0.24 ml, 3.5 mmol), drop by drop diphenylphosphinite ((PhO)2P(O)N3) (0,74 ml, 3.5 mmol) in solution in DMF (2 ml) and triethylamine (1 ml, 7.8 mmol). After division on silica gel (chloroform) to obtain 9-methoxy-1-(para-forfinal)-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one.

NMR1H (CDCl3): a 2.71 (m, 4H); 2,89 (t, 2H); is 3.82 (s, 3H); 4,19 (t, 2H); 6,77 (DD 9 Hz and 3 Hz, 1H); 6,9-7.20 and 7,38 (3 m, 7H).

Mass spectrum: m/z 362 (M+.), 319, 253.

Melting point: 191oC.

Example 14: ANCARBO7
Formula: C23H22N2O3; M = 374,43mol-1
Structure:

9-methoxy-1-(para-methoxyphenyl)-2,3,4,6,7,12-hexahydrobenzo-lo[2,3-a] chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N-[2'-(5-methoxy-1H-3-indolyl)ethyl] -2-(para-methoxyphenyl)ndimethylacetamide (800 mg, 2.1 mmol) gives 1-(para-methoxybenzyl)-6-methoxy-3,4-dihydro-2-carbolin (1.06 g) which is dissolved directly in anhydrous dimethylformamide (DMF) (10 ml).

This mixture is cooled to 0oWith and consistently add acrylic acid (0.15 ml, 2.2 mmol), drop by drop diphenylphosphinite ((PhO)2P(O)N3) (0.45 ml, 2 mmol) in solution in DMF (2 ml) and triethylamine (of 0.53 ml, 4 mmol). After division on silica gel (chloroform) to obtain the3): to 2.67 (m, 4H); 2,90 (t, 6 Hz, 2H); a 3.83 (s, 3H); 3,91 (s, 3H); 4,20 (t, 6 Hz, 2H); 6,77, 6,88,? 7.04 baby mortality and 7,33 (m, 7H).

Mass spectrum: m/z 374 (M+. 100), 359, 253, 187.

Melting point: 154-155oC.

Example 15: DMACARBO7
Formula: C24H25N3O2; M = 387,48mol-1
Structure:

9-methoxy-1-(para-dimethylaminophenyl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N-[2'-(5-methoxy-1H-3-indolyl)ethyl]-2-(para-dimethylaminophenyl)-ndimethylacetamide gives 1-(para-dimethylaminophenyl)-6-methoxy-3,4-dihydro-2-carbolin (1.06 g) which is dissolved directly in anhydrous dimethylformamide (DMF).

This mixture is cooled to 0oWith and consistently add acrylic acid, drop by drop diphenylphosphinite ((PhO)2P(O)N3) in solution in DMF and triethylamine. After division on silica gel (chloroform) to obtain 9-methoxy-1-(para-dimethylaminophenyl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-one.

NMR1H (CDCl3): 2,69 (m, 4H); 2,89 (t, 2H); 3.04 from (C, 6N); is 3.82 (s, 3H); 4,20 (t, 2H); to 6.80 (m, 3H); 6.89 in (m, 2H); to 7.25 (d, 2H); 7.29 trend (broad s, 1H).

Mass spectrum: m/z 387 (M+.), 194, 142, 134 (100).

Example 16: PYRCARBO7
Formula: C21H19N3O2; M = 345,40

NMR1H (CDCl3): 2,73 (m, 2H); to 2.85 (m, 2H); to 2.94 (t, 2H); 3,18 (s, 3H); 4,24 (t, 2H); 6,85 (DD 2.4 and 9 Hz, 1H); 6,93 (l to 2.4 Hz, 1H); 7,10 (d 9 Hz, 1H); 7,30 (DD, 1H); was 7.45 (d, 1H); 7,80 (DD, 1H); is 8.75 (d, 1H).

Mass spectrum: m/z 345 (M+., 100), 330, 316, 302.

Melting point: >260oC.

Example 17: NPHCARBO7
Formula: C23H19N3O4; M = 389,41mol-1
Structure:

9-methoxy-1-(para-nitrophenyl)-2,3,4,6,7,12-hexahydrobenzo-[2,3-a] chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N1-(2-(5-methoxy-1H-3-indolyl)ethyl)-2-(para-nitrophenyl)-ndimethylacetamide (360 mg, 1 mmol) gives 1-(para-nitrobenzyl)-6-methoxy-3,4-dihydro-2-ka(0,07 ml). Then add drop by drop diphenylphosphinite (of 0.21 ml) and then triethylamine (0.26 per ml). After division on silica gel (eluent AcOEt/EP 50/50), will receive a 9-methoxy-1-(para-nitrophenyl)-2,3,4,6,7,12-hexahydro-indolo[2,3-a]chinolin-4-one (163 mg, yield 41%).

NMR1H (CDCl3): 2,75 (m, 4H); of 2.92 (t, 2H); is 3.82 (s, 3H); to 4.17 (t, 2H); to 6.80 (DD 3 and 9 Hz, 1H); 6.90 to (d 3 Hz, 1H); 6,92 (d 9 Hz, 1H); to 7.59 (d 9 Hz, 1H); 8,32 (9 Hz, 1H).

Melting point: 138-140oC.

Example 18: TOLCARBO7
Formula: C23H22N2O2; M = 358,43mol-1
Structure:

9-methoxy-1-(para-tolyl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N1-(2-(5-methoxy-1H-3-indolyl)ethyl)-2-(para-tolyl)-ndimethylacetamide (2,12 mg, 6.6 mmol) gives 1-(para-methylbenzyl)-6-methoxy-3,4-dihydro-2-carbolin. To a solution of 1-(para-methylbenzyl)-6-methoxy-3,4-dihydro-2-carboline in DMF (15 ml) was added acrylic acid (0,46 ml). Then add one drop of diphenyl-phosphorylated (1,4 ml) and then triethylamine (1.75 ml). After division on silica gel (eluent chloroform/methanol) to obtain 9-methoxy-1-(para-tolyl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a]-chinolin-4-one.

NMR1H (CDCl3): the 2.46 (s, 3H); 2,73 (m, 4H); is 2.88 (t, 2H); is 3.82 (s, 3H); 4,20 (Tr>

Example 19: PHDHCARBO7
Formula: C22H22N2O2; M = 346,42mol-1
Structure:

9-methoxy-1-phenyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] -chinolin-4-one
Receive:
To a solution of 9-methoxy-1-phenyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-it (2.4 g) in a mixture of ethyl acetate/ethanol 1/1 (160 ml), add sodium bicarbonate (900 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. So, get 9-methoxy-1-phenyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a]chinolin-4-one (2.3 g, yield 95%).

NMR1H (CDCl3): 2,05 (m, 1H); 2,28 (m, 1H); 2,47 (m, 2H); to 2.74 (m, 1H); of 2.97 (m, 2H); 3,81 (m+s, 4H); by 5.18 (m, 2H); of 6.71 (DD 2,4 Hz and 9 Hz, 1H); 6.89 in (l and 2.4 Hz, 1H); 6,93 (d 9 Hz, 1H); 7,25 (m, 5H); 7,5 (broad s, 1H).

Mass spectrum: m/z 346 (M+.), 242, 200.

Melting point: 162oC.

Example 20: FPHDHCARBO7
Formula: C22H22N2FO2; M = 364,41mol-1
Structure:

9-methoxy-1(pair-forfinal)-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-one
Receive:
To a solution of 9-methoxy-1-(arbonet sodium (50 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. So, get 9-methoxy-1-(para-forfinal)-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-one (21 mg, yield 33%).

NMR1H (CDCl3): 2,05 (m, 1H); 2.40 a (m, 3H); to 2.74 (m, 1H); 2,90 (m, 2H); 3,80 (1C+1m, 4H); 5,19 (m, 2H); of 6.71 (DD 2.4 and 9 Hz, 1H); 6,92 (m, 3H); 6,97 (l to 8.7 Hz, 1H); 7.18 in (m, 2H); 7,52 (broad s, 1H).

Mass spectrum: m/z 346 (M+.), 242, 200.

Melting point: 162-166oC.

Example 21: PHDHNAPH7
Formula: C24H23NO2; M = 357,45mol-1
Structure:

3-methoxy-11-phenyl-5,8,9,10,11,11 a-hexahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-he
Receive:
To a solution of 3-methoxy-11-phenyl-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-it (30 mg) in ethyl acetate (15 ml), add sodium bicarbonate (20 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. Thus obtained 3-methoxy-11-phenyl-5,8,9,10,11,11 a-hexahydro-6N-benzo[f] pyrido[2,1-a]isoquinoline-8-he (25 mg, yield 83%).

NMR1H (CDCl3): and 2.14 (m, 1H); 2,48-and 3.16 (m, 5H); 3,13 (d 15.6 Hz, 1H); 3,94 (m + who+.), 329, 253, 211.

Melting point: 175oC.

Example 22: ETDHNAPH7
Formula: C20H23NO2; M = 309,40mol-1
Structure:

11-ethyl-3-methoxy-5,8,9,10,11,11 a-hexahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-he
Receive:
To a solution of 11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-she (74 mg) in ethyl acetate (25 ml), add sodium bicarbonate (30 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. Thus obtained 3-methoxy-11-ethyl-5,8,9,10,11,11 a-hexahydro-6N-benzo[f] pyrido[2,1-a]isoquinoline-8-he (50 mg, yield 67%).

NMR1H (CDCl3): 0,73 (t, 6.8 Hz, 3H); 1,08 (m, 2H); is 2.05 (m, 2H); 2,30 was 3.05 (m, 5H); and 3.16 (d, 16.0 Hz, 1H); of 3.96 (s, 3H); 5,02 (broad s, 1H); 5.17 to (DDD, and 12.4 Hz, 4.4 Hz and 16 Hz, 1H); 7,12-7,21 (m, 3H); to 7.67 (d, 8.6 Hz, 1H); 7,73 (d, 8.6 Hz, 1H).

Mass spectrum: m/z 309 (M+.), 253, 225, 211.

Melting point: 206oC.

Example 23: ANIDHCARBO7
Formula: C22H23N3O2; M = 361,45mol-1
Structure:

9-methoxy-1-(para-AMINOPHENYL)-1,2,3,4,6,7,12,12 b-is indolo[2,3-a]chinolin-4-it (91 mg) in ethyl acetate successively added sodium bicarbonate (50 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. So, get 9-methoxy-1-(para-AMINOPHENYL)-1,2,3,4,6,7,12,12 b-octahedron[2,3-a]chinolin-4-one (37 mg, yield 44%).

NMR1H (CDCl3): 1,95 (m, 1H); 2,28 (m, 1H); 2.40 a (m, 2H); 2,90 (m, 2H); 3,70 (m, 1H); of 3.80 (m, 3H); 4,20 (broad s, 2H); 5,20 (m, 2H); of 6.49 (d, 8,3 Hz, 1H); of 6.65 (DD, 8.7 Hz, 2.4 Hz, 1H); 6,83 (d, 2.4 Hz, 1H); 6.90 to (d, a 8.4 Hz, 1H); to 6.95 (d, 8.7 Hz, 1H).

Mass spectrum: m/z 361 (M+.), 242, 200, 181.

Melting point: 165-166oC.

Example 24: PHDHCARBO7S
Formula: C22H22N2OS; M = 362,48mol-1
Structure:

9-methoxy-1-phenyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] -chinolin-4-tion
Receive:
To a solution of 9-methoxy-1-phenyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-she (520 mg) in anhydrous toluene (50 ml) is added in small portions at 110oWith a reagent of Lawesson (Lawesson) (640 mg). After boiling under reflux for 30 minutes and evaporation of toluene allocate product by means of column chromatography on SiO2(eluent chloroform/methanol, 99/1), and will receive a 9-methoxy-1-phenyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a]chinolin-4-tion (160 mg, 30% yield).

NMR1H (CDCl3): 1,95 (m, 2.4 Hz, 1H); 6,83 (d, 2.4 Hz, 1H); 6,94 (d, 8.7 Hz, 1H); 7,20 (m, 5H).

Melting point: 242-244oC.

Example 25: ETNAPH7S
Formula: C20H21NOS; M = 323,45mol-1
Structure:

11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-tion
Receive:
11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f]pyrido [2,1-a]isoquinoline-8-ONU (45 mg) in anhydrous toluene (10 ml) is added in small portions at 110oWith a reagent of Lawesson (Lawesson) (70 mmol). After boiling under reflux for 30 minutes and evaporation of toluene allocate product by means of column chromatography on SiO2(eluent dichloromethane), get the 11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f]pyrido[2,1-a]isoquinoline-8-tion (32 mg, yield 70%).

NMR1H (CDCl3): 1.14 in (t, 7,3 Hz, 3H); to 2.35 (m, 4H); 3,13 (t, 7.7 Hz, 2H); 3.25 to (t, 6 Hz, 2H); 3,99 (s, 3H); 4,27 (t, 6 Hz, 2H); 7,19 (DD, 8.5 and 2.4 Hz, 1H); 7,28 (m, 2H); to 7.67 (d 8,5 Hz, 1H); 7,76 (d, a 8.9 Hz, 1H).

Melting point: 164-166oC.

Example 26: PHNAPH7S
Formula: C24H21NOS; M = 371,49mol-1
Structure:

3-methoxy-11-phenyl-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-tion
Receive:
o
With small portions of reagent Lawesson (Lawesson) (66 mg). After boiling under reflux for 30 minutes and evaporation of toluene allocate product by means of column chromatography on SiO2(dichloromethane), get 3-methoxy-11-phenyl-5,8,9,10-tetrahydro-6N-benzo [f] pyrido[2,1-a] isoquinoline-8-tion (37 mg, yield 74%).

NMR1H (CDCl3): a 2.71 (t, 7.8 Hz, 1H); to 3.36 (m, 4H); of 3.97 (s, 3H); 4,36 (t, 6.2 Hz, 1H); of 6.68 (d, 8.5 Hz, 1H); 7.18 in (m, 8H); 7,63 (d, 8.7 Hz, 1H).

Melting point: 136oC.

Example 27: ETDHCARBO7S
Formula: C18H22N2OS; M = 314,44mol-1
Structure:

1-ethyl-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] -chinolin-4-tion
Receive:
1-ethyl-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron-[2,3-a] chinolin-4-ONU (262 mg) in anhydrous toluene (20 ml) is added in small portions at 110oWith a reagent of Lawesson (Lawesson) (208 mg). After boiling under reflux for 30 minutes and evaporation of toluene allocate product by means of column chromatography on SiO2(eluent chloroform/methanol, 99/1), receive 1-ethyl-9-methoxy-1/2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-tion (30 mg, yield of 11.5%).

NMR1H (CDCl3): 0,81 (t, 3H); 1.06 a (m, 2H); 1,90 (m, 2H);

Melting point: 124oC.

Example 28: CO2ETDHCARBO7
Formula: C19H22N2O4; M = 342,39mol-1
Structure:

1 carbethoxy-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron-[2,3-a] chinolin-4-one
Receive:
To a solution of 1-carbethoxy-9-methoxy-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it (50 mg) in ethyl acetate successively added sodium bicarbonate (10 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. Thus, get 1 carbethoxy-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-one (30 mg, yield 60%).

NMR1H (CDCl3): of 1.02 (t, 3H); to 2.15 (m, 2H); 2,85 (m, 8H); to 3.35 (m, 1H); 3,85 (s, 3H); of 4.05 (t, 2H); to 5.08 (m, 2H); PC 6.82 (DD, 8.7 and 2.4 Hz, 1H); 6,92 (d, 2.4 Hz, 1H); 7,21 (d, 8.7 Hz, 1H); 8,24 (broad s, 1H).

Mass spectrum: m/z 342 (M+.), 286, 269, 240, 199.

Melting point: 213oC.

Example 29: TOLDHCARBO7
Formula: C23H24N2O2; M = 360,46mol-1
Structure:

9-methoxy-1-(para-tolyl)-1,2,3,4,6,7,12,12 b-octahedron-[2,3-a] chinolin-4-one
Policeregulations add sodium bicarbonate (50 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. So, get 9-methoxy-1-(para-tolyl)-1,2,3,4,6,7,12,12 b-octahedron[2,3-a]chinolin-4-one (32 mg, yield 58%).

NMR1H (CDCl3): 2,04 (m, 1H); of 2.23 (m, 1H); to 2.29 (s, 3H); to 2.46 (m, 2H); to 2.74 (m, 1H); to 2.94 (m, 2H); 3,70 (m, 1H); of 3.80 (s, 3H); 5,20 (m, 1H); 5,24 (d, 1H); of 6.71 (DD, 2.4 Hz and 8.7 Hz, 1H); 6.87 in (d, 2.4 Hz, 1H); 6,93 (d, to 8.7 Hz, 1H); was 7.08 (d, 8.0 Hz, 2H); 7,16 (d, 8.0 Hz, 2H); 7,2 (1H, NH).

Example 30: ANDHCARBO7
Formula: C23H24N2About3; M = 376,46mol-1
Structure:

9-methoxy-1-(para-anisyl)-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-one
Receive:
To a solution of 9-methoxy-1-(para-anisyl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a]chinolin-4-it (43 mg) in ethyl acetate successively added sodium bicarbonate (50 mg) and palladium on coal and the mixture is stirred overnight in a hydrogen atmosphere. After filtration and evaporation of the solvent the crude product is recrystallized from ethyl acetate. So, get 9-methoxy-1-(para-anisyl)-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-one (24 mg, yield 56%).

NMR1H (CDCl3): 2,05 (m, 1H); to 2.25 (m, 1H) ; to 2.46 (m, 2H); 2,74 (d, 1H); to 2.54 (m, 2H); 3,68 (m, 1H); of 3.75 (s, 3H); of 3.80 (s, 3H); 5,atur melting point: 242oC.

Example 31: DIETCARBO7
Formula: C20H26N2O2; M = 326,43mol-1
Structure:

1,1-diethyl-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-one
Receive:
5-methoxytryptamine (494 mg, at 2.59 mmol) and ethyl(4-ethyl-4-formyl)caproate (522 mg, 2,61 mmol) are mixed in a commercial toluene (27 ml) in a flask of 50 ml and Then the reaction medium is heated to boiling toluene under reflux for 2 hours. After cooling, the toluene is evaporated under reduced pressure and add acetic acid (1 ml).

Then the reaction medium is heated to boiling acetic acid under reflux for 2 hours. After cooling, add water (25 ml) and the precipitated solid. This solid was diluted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure.

After division on silica gel (eluent chloroform/methanol - 97,5/2,5) receive 1,1-diethyl-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-one (200 mg, yield 23%).

NMR1H (CDCl3): 0,73 (t, 7.5 Hz, 3H); 1,02 (Quartet 7.5 Hz, 1H); of 1.18 (t, 7.5 Hz, 3H); 1.50 in (Quartet 7.5 Hz, 1H) and 1.60 (m, 1H); 1,80, 1H).

Melting point: 229oC.

Example 32: ETCARBO7TL
Formula: C21H24N2O4; M = 368,43mol-1
Structure:

(6S)-6-carbethoxy-9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-one
Receive:
Bischler-Napieralski (Bischler-Napieralski) N1-(butyryl)-5-methoxy-(L)-tryptophan ethyl ester (2.1 g) gives (3S)-1-propyl-3-carbethoxy-6-methoxy-3,4-dihydro-2-carbolin (1.5 g). To a solution of (3S)-1-propyl-3-carbethoxy-6-methoxy-3,4-dihydro-2-carboline (1.5 g) in DMF (20 ml) are added successively drop of acrylic acid (0.35 ml), diphenylphosphoryl (1 ml) and triethylamine (2 ml). After division on silica gel (eluent ethyl acetate/petroleum ether 30/70) receive (6S)-6-carbethoxy-9-methoxy-1-ethyl-2,3,4,6, -7,12-hexahydrobenzo[2,3-a] chinolin-4-one (400 mg, yield 17%).

NMR1H (CDCl3): 1,1 (t, 3H); 1,25 (t, 3H); 2,3 (m, 1H); 2,62 (m, 5H); is 3.08 (DD, 6 and 16 Hz, 1H); of 3.53 (d, 16 Hz, 1H); 3,85 (s, 3H); is 4.03 (m, 2H); 6,00 (d, 6 Hz, 1H); 6,85 (DD, 2,3 and 8.7 Hz, 1H); 6,94 (d, 2.3 Hz, 1H); from 7.24 (d, 8.7 Hz, 1H); 8,13 (broad s, 1H).

Melting point: 192oC.


Claims

1. Derivative-carboline General formulas Ia' and Ia"

or-HC= CH-;
R11is oxygen atom or sulfur;
R14is a hydrogen atom or a C1-C6alkoxycarbonyl:
R15is a hydrogen atom, a C1-C6alkyl;
or racemic mixtures, pure enantiomers and their mixtures in all proportions and their therapeutically acceptable salts.

2. Derivatives under item 1, where R8- ethyl, hexyl, isopropyl, phenyl, forfinal, methoxyphenyl, AMINOPHENYL, dimethylaminophenyl, nitrophenyl, parameterfor, etoxycarbonyl, pyridyl.

3. Derivative according to any one of the preceding paragraphs, selected from
9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-hexyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] -chinolin-4-it,
9-methoxy-1-isopropyl-2,3,4,6,7,12-hexaoxa-9-methoxy-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1,10-diethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-thione,
9-methoxy-1-ethyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-it,
11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-it,
3-methoxy-11-phenyl-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-it,
9-methoxy-1-phenyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] -[beta] chinolin-4-thione,
9-methoxy-1-ethyl-2,3,4,12-tetrahydroindole[2,3-a] chinolin-4-thione,
9-methoxy-1-(paraterphenyl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-(parametersetter)-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-(paraveterinary)-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-(pyrid-2'-yl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-(paranitrophenyl)-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-paratool-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it,
9-methoxy-1-phenyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-it,
9-methoxy-1-(paraterphenyl)-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-it,
3-methoxy-11-phenyl-5,8,9,10,11,11 and hexahydro-6N-benzo-[f] pyrido[2,1-a] asahiklin-8-it,
11-ethyl-3-methoxy-5,8,9,10,11,11 and-hexalin-4-it,
9-methoxy-1-phenyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-thione,
11-ethyl-3-methoxy-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-thione,
3-methoxy-11-phenyl-5,8,9,10-tetrahydro-6N-benzo[f] pyrido[2,1-a] isoquinoline-8-taona,
1-ethyl-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-thione,
1 carbethoxy-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-it,
9-methoxy-1-para-tolyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-it,
9-methoxy-1-pair-anisyl-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-it,
1,1-diethyl-9-methoxy-1,2,3,4,6,7,12,12 b-octahedron[2,3-a] chinolin-4-it,
(6S)-6-carbethoxy-9-methoxy-1-ethyl-2,3,4,6,7,12-hexahydrobenzo[2,3-a] chinolin-4-it.

4. The method of obtaining derivatives of the General formula Ib

where R2, R3, R8, R14and X take the values defined in paragraph 1,
including direct interaction of the compounds of General formula IIA

where R2, R3, R8, R14and X take the values defined in paragraph 1,
with a carboxylic acid in the presence or in the absence of diphenylphosphinite or Acrylonitrile.

5. The method of obtaining derivatives of the General formula IIA

where R2, R3, R8, R14and X take the values defined in paragraph 1,
with pjatiokisi phosphorus (P2O5) or with phosphorus oxychloride (l3) in a suitable solvent.

6. The method of obtaining derivatives of the General formula IIA

where R2, R3, R8, R14and X take the values defined in paragraph 1,
including oxidation by permanganate derivatives of the General formula IIb

where R2, R3, R8, R14and X take the values defined in paragraph 1.

7. The method of obtaining derivatives of the General formula IIb

where R2, R3, R8, R14and X take the values defined in paragraph 1,
comprising the reaction of Pictet-Spengler derivatives of the General formula IIIb

where R2, R3, R8, R14and X take the values defined in paragraph 1,
with compounds of formula R8-CH2-SON, or their chemical equivalents under the reduction conditions.

8. The method of obtaining derivatives of the General formula IC

where R2, R3, R8, R14
where R2, R3, R8, R14and X take the values defined in paragraph 1.

9. The method of obtaining derivatives of the General formula Id

where R2, R3, R8, R14and X take the values defined in paragraph 1,
comprising reaction of a reagent of Lawesson or P2S4with compounds of General formula Ib

where R2, R3, R8, R14and X take the values defined in paragraph 1.

10. The method of obtaining derivatives of the General formula S

where R2, R3, R8, R14and X take the values defined in paragraph 1,
comprising reaction of a reagent of Lawesson or R2S4with compounds of General formula IC

where R2, R3, R8, R14and X take the values defined in paragraph 1.

11. The method of obtaining derivatives of the General formula If

where R2, R3, R8, R14and X take the values defined in paragraph 1,
comprising the reaction of an oxidant (such as2in an alkaline environment) with the compound of General formula Ib

12. Drug, with hypnotic and sedative activity, characterized in that it includes a derivative according to any one of paragraphs. 1-4.

 

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< / BR>
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< / BR>
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< / BR>
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