Stereoisomeric indole compounds, method of their production and their use

 

(57) Abstract:

The present invention discloses new stereoisomeric indole compounds of formula (1) where Y, X, R1, R2and R described in the description, the method of their production and use. The above compound can be obtained by the condensation of tryptophan with stereoisomeric-amino acid or carboxylic acid to obtain an amide form and subsequent cyclization of amide forms of education oxazoline rings. The compounds possess physiological activity, such as inhibiting effect against perechisleniya lipids and can be used as inhibitors perechisleniya lipids that contain the specified active ingredient. 5 S. and 2 C.p. f-crystals.

The invention relates to new stereoisomeric indole compounds or their salts, to a process for the preparation of such compounds and their use.

Description of the achieved level of technology

Known indole compound Metafragen A (Martefragin A), which was isolated from an extract of seaweed ("Ayanishiki") (Martensia fragilis Harvey) and which belongs to the family Congregatocarpus [Proceedings of the Japan Pharmaceutical Society, the 116thannual meeting, page 2215 (1996)].

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It is known including pharmaceutical. However, the synthetic method of preparation and stereochemistry specified indole compounds are still unknown.

The authors of the present invention tried, first, to synthesize the stereoisomers of the above compounds with the purpose of clarifying its spatial structure, determination of physiological activity, mechanism of action and other Strategy of synthesis of the stereoisomers of the compounds selected by the authors, involves the synthesis of an intermediate product of L-tryptophan (2) and stereoisomeric-amino acids (3A') (hereinafter stereoisomeric-amino acid is called as homosalate).

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(where R, R1and R2have the following values, and the symbol * indicates the position of an asymmetric carbon atom).

Because the stereoisomers of the above homosalate are not commercially available compounds, the authors have also developed a method of synthesis of the stereoisomers of homosalate specified below, and because of this were able to successfully synthesize stereoisomeric indole compound (1A') of the above L-tryptophan (2) and stereoisomeric of homosalate (3A').

In addition, on the basis of the fact that it was developed the way of sin is alatina (3A'), the same way that the stereoisomeric homosalate as raw materials with the aim of finding compounds with more potent physiological activity than the specified connection (3A'), can be synthesized new indole alkaloids from L-tryptophan and various amino acids, non-stereoisomeric of homosalate, and in this regard have been received various connections.

The inventors have also found that dezaminirovanie form of the above compound (1A') has a greater inhibitory activity against perechisleniya lipids than any of the four isomers of the above Marcapagina And such as (1"S,3"S) form, (1"R,3"S) form, (1"R,3"R) - form and (1"S,3"R) form, and have also developed methods for their synthesis.

Disclosure of the invention

Thus, the present invention relates to a stereoisomeric indole compounds of the following formula (1) or their salts:

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where Y denotes the group:

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where X denotes an alkyl group containing 1-5 carbon atoms (the alkyl group may be optionally substituted hydroxyl group, carboxyl group, amino group, methylthiourea, mercaptopropyl, guanidino group, it is Yes, alkyl group, aracelio group, cycloalkyl group or aryl group, or Y represents a group

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R denotes a hydrogen atom, alkyl group, aracelio group, cycloalkyl group, aryl group, atom monovalent metal, amine or ammonium; and the symbol * indicates the position of an asymmetric carbon atom.

Especially can be specified aminoformic the compounds of formula (la):

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or its salts, as well as dezaminirovanie form the compounds of formula (1A): having the formula (1b) or its salt:

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where R, R1, R2and X have the same meanings as in the formula (1).

For compounds of the above formula (1), (la) and 1(b) may specify the following specific examples of suitable substituents.

So, in addition to the fact that the substituent R denotes a hydrogen atom, typical examples of the substituents R is an alkyl group with straight or branched chain, containing 1-12, preferably 1-6 carbon atoms, such as methyl group, ethyl group, through the group, isopropyl group, n-bucilina group, tertiary bucilina group, pencilina group, exilda group, anjilina group decile group and Godzilla group; the cycle is nilina group, tsiklogeksilnogo group and methylcyclohexyl group; aryl group of 6-16 carbon atoms, and kalkilya group including from 7 to 16 carbon atoms, such as phenyl group, naftalina group, benzyl group and phenylethylene group which may be substituted by a halogen atom, a hydroxyl group, alkoxygroup, amino group, etc. in Addition, the substituent R may be a monovalent metal such as sodium and potassium, amine or ammonium.

In addition, acceptable substituents R1and R2can be an alkyl group with straight or branched chain, containing from 1 to 12, in particular 1 to 6, carbon atoms, such as methyl group, ethyl group, through the group, isopropyl group, n-bucilina group, tertiary bucilina group, pencilina group, exilda group, anjilina group decile group and Godzilla group; cycloalkyl group containing 5 or 6 carbon atoms in the ring, such as cyclopentene group, methylcyclopentadienyl group, tsiklogeksilnogo group and methylcyclohexyl group; aryl group containing 6 to 16 carbon atoms, and aracelio group, includes 7-16 carbon atoms, such as phenyl group, drakeley group, alkoxygroup, amino group, etc.

As an example, salts of compounds of formula (1), (1a) and (1b) can be mentioned salts of inorganic acids and organic acids. Especially preferred are hydrochloride.

Indole compounds of the present invention include one or more asymmetric carbon atoms and therefore exist S-form or R-form isomers, depending on their position. For example, in the case aminoformic compound (1A'):

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the specified connection contains asymmetric carbon atoms at positions 1 and 3". In this regard, the compounds of the present invention are 4-isomer, respectively, the position of an asymmetric carbon atom, i.e., (1"S,3"S) form, (1"R, 3"S) form, (1"R,3"R) - form and (1"S,3"R) form. In addition, dezaminirovanie form (1b):

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indole compounds of the present invention contain an asymmetric atom in position 3". In this regard, the connection of the present invention has two isomers, respectively, the position of an asymmetric carbon atom, i.e., S-form and R-form.

The present invention includes all of these isomers and mixtures of such isomers.

In the illustration below indole soedinenie relates to a method of obtaining stereoisomeric indole compounds of formula (1):

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the condensation of tryptophan formula (2):

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with the acid of formula (3):

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obtaining the compounds of formula (4):

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followed by cyclization of the compounds of formula (4), where Y denotes the group:

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where X denotes an alkyl group comprising 1-5 carbon atoms (the alkyl group may be substituted with hydroxyl group, carboxyl group, amino group, methylthiourea, mercaptopropyl, guanidino group, imidazolidine group or benzyl group), and R1and R2each independently represents a hydrogen atom, alkyl group, aracelio group, cycloalkyl group or aryl group, or Y represents the group:

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R denotes a hydrogen atom, alkyl group, aracelio group, cycloalkyl group, aryl group, atom monovalent metal, amine or ammonium; and the symbol * indicates the position of an asymmetric carbon atom.

In accordance with this method aminoformic stereoisomeric indole compounds of the above formula (1A) can be obtained by condensation of tryptophan above formula (2) with an acid of the formula (3A):

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obtaining the compounds of formula (4A):

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and then the cycle is ukazannoi formula (1b) can be obtained by condensation of tryptophan above formula (2) with an acid of the formula (3b):

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obtaining the compounds of formula (4b):

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followed by cyclization of the compounds of formula (4b), where R, R1, R2and X have the above values.

For compounds of the above formulas (2) to(4), (2A)-(4A) and (2b) to(4b) can be specified the same specific examples of suitable substituents as in the case of formula (1), (la) and (1b).

As noted above, the acid used for the synthesis of stereoisomeric compounds of the present invention, is a stereoisomeric-amino acid in the case of obtaining aminoformic, and in the case of obtaining dezaminirovanie form connections 4-methylcarbonate acid, which is a stereoisomeric carboxylic acid.

Typical stereoisomeric-amino acids include, for example, 4 stereoisomer (+) - alanine, (+)valine, (-)leucine, (+)isoleucine, (+)lysine, (-)serine, (-)threonine, (-)phenylalanine, (-)tyrosine, (-)aspartic acid, (+)glutamic acid, (-)methionine, (+)arginine, (-)histidine, (+)ornithine, (+)norleucine, (+)oxipurinol acid, (-)cysteine and homosalate. Due to the fact that 4 stereoisomer of homosalate not commercially available, examples of synthesis are also described in section I of the Examples 1-4 get is that get as intermediate products, accordingly, in the synthesis of (2S,4S)-homotaurine in the Example of a 1 and in the synthesis of (2S,4R)-homotaurine in the Example of a 3, described below.

In accordance with the present invention stereoisomeric indole compound obtained when (1) the condensation of tryptophan with stereoisomeric-amino acid or 4-methylcarbonate acid with the formation of amide and then (2) when conducting the oxidative cyclization with the formation of amide immediately, on a new method of synthesis, oxazoline rings. By condensation of tryptophan with stereoisomeric-amino acid or 4-methylcarbonate acid, it is preferable to carry out the protection of the amino group in the amino acid. It can be noted in this context, such as dialkylamino, preferably demethylation, tert-butoxycarbonylamino and others, but to protect the amino group is preferred as the protecting group tert-butoxycarbonyl group (BOC group), since, in particular, in this case, the more efficient is the condensation of tryptophan with stereoisomeric-amino acid and subsequent cyclization of the amide.

At the same time, especially if the oxidative cyclization of the amide is carried out in the presence of 2,3-dichloro-5,6-diziani.

In the case of compounds of formula (1) according to the present invention can be of various types of compounds by varying the group Y, choosing an appropriate source material, for example, using stereoisomeric-amino acid and carboxylic acid, and by varying the substituents R, R1, R2when selecting the appropriate ester groups in the source material, for example by using sophisticated tryptophan ester, and the selection of aminosalicylates in stereoisomeric-amino acid or when replacing the substituents in the compounds obtained after synthesis, the other substituents R, R1, R2other than the above.

New stereoisomeric indole compounds of the present invention are alkaloids containing indole ring and oxazoline ring, which have inhibitory action against perechisleniya lipids, and in this regard they can be used as a prophylactic drugs and medicines for the treatment of circulatory disorders, such as atherosclerosis, hypertension, thrombosis, inflammatory conditions such as nephritis; liver diseases such as alcoholic hepatitis; diseases of the gastrointestinal tract such as ulcer is a doctrine, and, in addition, they can be used as a means of protection from destruction by UV radiation in cosmetic products etc.

In this regard, the present invention also relates to inhibitors perechisleniya lipids containing as the active ingredient stereoisomeric indole compounds or their salts, which have the above-mentioned formula (1), and examples of which can be of the formula (1A) and (1b).

Best mode for carrying out the present invention

I. Synthesis lineform stereoisomeric indole compounds (Marcapagina and its salts or esters)

The following examples illustrate the method of synthesis lineform indole compounds of the present invention. Before the synthesis of compounds of the present invention provide a synthesis of stereoisomeric homotaurine, which is a starting material, by the method given in the Examples get 1-4 and Examples 1-5 are given the options of synthesis of stereoisomeric indole compounds and their use.

[Example of obtaining 1] Synthesis of (2S,4S)-homotaurine (see scheme 1).

(2S, 4S)-homosalate can be synthesized by using as starting materials Cesky active methylbutanol (step 1 in Scheme 1)

1 g (11.3 mmol) of (S)-2-methyl-1-butanol: (S)-1 (Tokyo Kasei) and 30 ml of anhydrous pyridine are placed in a flask type "eggplant" volume of 100 ml in an argon atmosphere and stirred at 0oWith, and then add or 4.31 g (to 22.6 mmol) of p-toluensulfonate and stirred at 0oC for 30 minutes, then stirred at room temperature for 5 hours. Add ice water and adjusted the pH of the aqueous layer to a value of 2-3 3N hydrochloric acid and then extracted with diethyl ether. After that, the extract washed with saturated sodium bicarbonate solution and saturated saline solution, dried with anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain a colorless oily substance. Specified substance purified column chromatography (75 g of SiO2, hexane/ethyl acetate = 10:1) to obtain 2.5 g totalrevenue form (S)-2 (colorless oily substance: output - 91,4%).

C12H18SO3(M. C. 242,10), a colorless oily substance []20D+5,66 (=1,060, Meon).

2. Iodination totalrevenue form (S)-2 (stage 2 in Scheme 1)

of 1.94 g (8 mmol) totalrevenue form (S)-2 and 30 ml of anhydrous acetone are placed in a flask type "eggplant" volume of 100 ml in an argon atmosphere, in 2 days add pentane to dilute the reaction solution and cooled to deposition of sodium salt. After removal of the specified sodium salt by filtration on a glass filter, the extraction is carried out with water to remove acetone, dried with anhydrous magnesium sulfate and distilled pentane at normal pressure to obtain 1.08 g (yield - to 68.0%) iodirovannoi form (S)-3. The structure of the obtained substance is confirmed by comparison with commercially available drug.

3. The synthesis of complex malonic ester using iodirovannoi form (S)-3 (step 3 in Scheme 1)

to 1.38 g of metallic sodium and 50 ml of anhydrous ethanol are placed in a three-neck flask with a volume of 200 ml in an argon atmosphere at 0oWith and mix. After dissolution only add sodium to 9.45 ml of diethylmalonate dropwise with a syringe and then added dropwise to 6.5 ml iodirovannoi form (S)-3 and stirred at room temperature overnight. Then add 100 ml of an aqueous solution of ammonium chloride, removing the ethanol by distillation under reduced pressure and the residue extracted with diethyl ether. The ether layer was washed with saturated saline, then dried it with anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to obtain a colorless oily substance. Specified substance cleanse column chromium is the author of diapir (S)-4.

C12H22O4(M. C. 230,15), a colorless oily substance []20D/+15,3 (=1,060, Meon).

4. The hydrolysis of complex devernay form (S)-4 (stage 4 in Scheme 1)

6,90 g complex devernay form (S)-4 and 20 ml of ethanol are placed in a flask type "eggplant" with a volume of 300 ml, and mix. Add 5,71 mg (102 mmol) of potassium hydroxide previously dissolved in 100 ml of water, and heated to the boiling temperature under reflux. The temperature of the solution is again brought to room temperature and the ethanol is distilled off under reduced pressure, and then remove the impurities by extraction with ethyl acetate. Then, to the aqueous layer add 3N model HC1 to bring the pH to 1-2 and the specified layer is extracted with ethyl acetate. The organic layer vymalivayut the addition of sodium chloride, dried with anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure to get 5,22 g (yield - 100%) of target compound in the form of dicarboxylic acid (S)-5.

C8H1404(M. C. - 174,09), white powder, []26D+16,9 (=1,10, Meon).

5. Decarboxylation of dicarboxylic acid (S)-5 (step 5 in Scheme 1)

of 5.05 g (29 mmol) of the dicarboxylic acid (S)-5, 16 ml of a 7% aqueous solution of DMSO and of 1.87 g (32 mmol) of CHL is hours. The temperature of the solution is again brought to room temperature, twice extracted with diethyl ether and washed the organic layer with water. The layer was dried with magnesium sulfate and the solvent is distilled off under reduced pressure to obtain a colorless oily substance. Specified substance purified column chromatography (120 g of SiO2, pentane/diethyl ether = 5:1) to obtain the 2,82 g (yield - 75%) of the target carboxylic acid (S)-6. The specified carboxylic acid (S)-6 is the starting material for the synthesis of desamination described below.

WITH7H14ABOUT2(M. C. - 130,10), a colorless and oily substance []26D+RS 9.69 (s=1,042, Meon).

6. Synthesis of acid chloride of (S)-7 (step 6 in Scheme 1)

2,82 g of carboxylic acid (S)-6 and 18.0 ml of anhydrous benzene and 9.0 ml of thionyl chloride are placed in a flask type "eggplant" volume of 50 ml and heated at boiling temperature under reflux for 3 hours. The temperature of the solution is again brought to room temperature and the solvent is distilled off under reduced pressure obtaining of 2.92 g (yield - 91%) of acid chloride of (S)-7. (S)-7 is subjected to condensation with an asymmetric auxiliary group (S)-8, without any treatment after the floor is"ptx2">

WITH7H13C1 (M century 148,55), a colorless and oily substance.

7. Condensation asymmetric auxiliary group (S)-8 (stage 7 in Scheme 1)

of 3.85 g (21,7 mmol) of (4S)-benzyloxypyridine and 50 ml of anhydrous THF are placed in a three-neck flask with a volume of 200 ml in an argon atmosphere and cooled to -78oC. Then add to 13.6 ml of a 1.6 M solution of n-utility/n-hexane and stirred at -78oC for 40 minutes, then add of 2.92 g (19,7 mmol) of acid chloride of (S)-7 and stirred at -78oC for 1.5 hours. Then add an aqueous solution of ammonium chloride and extracted with a solution of diethyl ether, washed with saturated saline, dried with anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure to obtain a colorless oily substance. Specified substance purified column chromatography (45 g SiO2, hexane/ethyl acetate = 5:1) to obtain the 4,93 g (yield - 86,5%) of target compound (S)-9 in the form of colorless crystals.

WITH17H23NO3(M. C. 289,29), white powder, []27D+59,3 (=1,088, SMS3).

8. Direct sideropenia to carboximide (stage 8 in Scheme 1)

1,03 g (5,19 mmol) titrimetrically potassium and 10 ml besplat via cannula 1 g (3.46 mmol) of (S)-9, pre-dissolved in 10 ml of anhydrous THF, and stirred at -78oC for 30 minutes. After that, using the cannula added 1.35 g (4,36 mmol) triisopropylbenzenesulfonyl, pre-dissolved in 6 ml of anhydrous THF, and stirred for 2 minutes and then add of 0.91 ml (15.9 mmol) of glacial acetic acid. All this was stirred at room temperature for 7 hours. The reaction solution was diluted with ethyl acetate, add to it a saturated saline solution and extracted twice with ethyl acetate. Specified the extract was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure to obtain 1.85 g of a yellow oily substance. Specified substance purified column chromatography (60 g of SiO2for the flash-chromatography, hexane/dichloromethane =3:1) to obtain 893 mg (yield - 78,1%) target azide forms (2S,4S)-10.

C17H22N4ABOUT3(M. C. 330,39), colorless crystals, So pl.: 71,5-72,5oC []24D+to 112.2 (C=1,032, SMS3).

9. Removing asymmetric auxiliary group [Synthesis-carboxylic acid azide (2S,4S)-11] (stage 9 in Scheme 1)

850 mg azide forms UP>oWith, then add 216 mg of the monohydrate of lithium hydroxide and stirred for 1 hour. Add aqueous saturated sodium bicarbonate solution, distilled THF under reduced pressure, and then extracted with ethyl acetate. An ethyl acetate layer is dried with anhydrous sodium sulfate and then the solvent is distilled off under reduced pressure to obtain 450 mg (yield - 99%) (S)-8. Bring the pH value of the aqueous layer to 1-2 3N hydrochloric acid and extracted with ethyl acetate, an ethyl acetate layer is dried with anhydrous sodium sulfate and then the solvent is distilled off under reduced pressure to obtain 425 mg (yield - 96,7%) target-carboxylic acid azide ((LK 23: 43)-11 in the form of a colorless oily substance.

WITH7H13N3ABOUT2(M. C. 171,101), a colorless oily substance []23D+3,26 (=0,982, SMS3).

10. Recovery-azide carboxylic acids: synthesis of (2S,4S)-homotaurine (stage 10 in Scheme 1)

378 mg (2.21 mmol) -carboxylic acid azide (2S,4S)-11, 4,0 ml of anhydrous ethanol and 37.8 mg of 10% Pd-C is placed in a flask type "eggplant" is a volume of 25 ml in an argon atmosphere at carrying out substitution with hydrogen and stirred at room temperature for 2.5 hours. Pd-C is removed by filtration and dissolve the crystals.

C7H15NO2(M. C. 145,1103), colorless crystals, IR: [cm-1] 2962, 2920, 1584, 1513, 1405, 669, 554, 471.

LREIMS m/z (%) 154 (M+, 1), 100 (100).

HREIMS calculated for C7H15NO2: 145,1103 found: 145,1127.

[Example getting 2] Synthesis of (2R,4S)-homotaurine (see Diagram 2).

Synthesis prior to receipt of the acid chloride (S)-7 coincide with those identified in the Example of obtaining 1. The asymmetric auxiliary group has the R-configuration. The reaction phase after condensation with an asymmetric auxiliary group is performed according to the procedure similar to that described in the Example of obtaining 1. The reaction stage from the moment of condensation with an asymmetric auxiliary group to the synthesis of (2R,4S)-homotaurine [(2R, 4S)-23] and physical data for the (2R,4S)-homotaurine below.

[Example of getting 3] Synthesis of (2S,4R)-homotaurine (see Diagram 3).

(2S, 4R)-homosalate synthesized by using (S) of citronellol as the source material.

1. Metilirovanie (S)-citronellol (step 1 in Scheme 3)

5 g (32,0 mmol) of (S)-citronellol, 180 ml of dichloromethane and a 4.86 g (35,2 mmol, 1.1 EQ.) of triethylamine are placed in a three-neck flask of 500 ml in the atmosphere is A. After stirring the reaction solution at a temperature of from -10oWith 0oWith over 2.5 hours it is washed with ice water, 5% hydrochloric acid and water, dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure to obtain a colorless oily substance (S)-30. Specified substance is subjected to a recovery in the next stage without any further purification.

2. Recovery nelfinavir (S)-30 (stage 2 in figure 3)

400 ml of diethyl ether and of 1.80 g (47,3 mmol, 1.4 EQ.) of lithium aluminum hydride are placed in a three-neck flask with a volume of 200 ml, provided with a tube with calcium chloride and reflux, and then cooled with ice. Add dropwise a solution of a 7.92 g (33.8 mmol) of (S)-30 in diethyl ether and heated at boiling temperature under reflux for 3 hours. After completion of the reaction, the reaction solution is cooled with ice and add 3.6 ml of water and stirred for 1 hour, then add another 2,88 ml of 10% aqueous sodium hydroxide solution and stirred for 1 hour, and then filtered through celite to remove lithium aluminum hydride and the solvent is distilled off under reduced pressure to obtain 4.5 g (98%) of colorless oily substance (R acetone (acetone:water = 70:105) placed in a three-neck flask of 500 ml in an argon atmosphere and suspended. Add dropwise a solution of 4.5 g (32.1 mmol) of (R)-31 in acetone and bring the temperature up to 5oC. Immediately added dropwise 40 ml of a solution 0,86 g (5.46 mmol, 0,17 EQ.) potassium permanganate in water and 40 ml of acetone. Everything is stirred at a temperature of from 5oWith up to room temperature for 20 hours. Reddish-brown residue is removed by filtration through celite, and the acetone is distilled off at normal pressure. Then to the residue add 1N sodium hydroxide until alkaline reaction, and then extracted with diethyl ether to remove soluble components. The aqueous layer was acidified with 3N hydrochloric acid, extracted with diethyl ether, dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure to obtain a colorless oily substance. Specified substance purified column chromatography (50 g of SiO2, hexane/ethyl acetate = 5:1) to obtain 2,389 g (57%) (R)-32. (R)-32 is a starting material for the following synthesis desamination.

4. Stage (4)-(8) in Scheme 3

Stage (4)-(8) in Scheme 3 is carried out similarly to the stages of (6)-(10) in the Example of obtaining 1. Below are the physical data obtained (2S,4R)-homotaurine [(2S,4R)-37].

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WITH7H15NO2(M. C. 145,1103) b is-homotaurine (see diagram 4).

The stage of obtaining the acid chloride (R)-33 coincide with those that were given above in the Example of a 3. Stage coming after condensation with an asymmetric auxiliary group, when using asymmetric auxiliary group in the (R) -configuration is performed similarly to the stages indicated in the Example of obtaining 1.

The stage from the moment of condensation with an asymmetric auxiliary group to the synthesis of (2R, 4R)-homotaurine [(2R,4R)-47] and physical data (2R,4R)-homotaurine below.

In addition, examples of the synthesis of stereoisomeric indole compounds from complex tryptophan ester and stereoisomeric of homosalate (see scheme 5).

[Example 1] Synthesis of (1 S,3"S)-indole

1. tert-Butoxycarbonylamino (2S,4S)-homotaurine (stage 1 in figure 5)

1285 mg (1,96 mmol) (2S,4S)-homotaurine received in the Sample receiving 1, and 2.5 ml of 1N aqueous sodium hydroxide solution, 1.5 ml water, 1.5 ml of dioxane and 643 mg (2,95 mmol) Vos2About placed in a flask type "eggplant" is a volume of 25 ml and stirred at room temperature for 16 hours. Then add aqueous saturated sodium bicarbonate solution and the resulting mixture was washed with diethyl ether, then water wodnym sodium sulfate and the solvent is distilled off under reduced pressure to obtain 456 mg (yield - 95%) of (2S,4S)-13 [Re-form (2S,4S)-homotaurine] as a colorless oily substance.

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C12H23NO4(M. C. 245,32) colorless oil.

IR (pure): [cm-1] = 2965, 1724, 1516, 1456, 1252, 1165, 1051, 1024, 852, 779.

2. Condensation complex tryptophan-0-benzyl ether and Re-forms (2S, 4S)-homotaurine (stage 2 Scheme 5)

325 mg complex benzyl ester of L-tryptophan, 30 ml of anhydrous THF and 265 mg of the BOC-shaped homosalate [(2S,4S)-13] placed in dvuhgolosy flask type "eggplant" volume of 100 ml in an argon atmosphere and bring the temperature tooC. Then, a syringe is added dropwise 0.3 ml condensing agent DEFC (diethylacrylamide) and 0.33 ml of triethylamine and stirred at 0oC for 1 hour, then at room temperature during 1 hour. Then add ethyl acetate, dried with saturated sodium bicarbonate solution and the solvent is distilled off under reduced pressure to obtain a brown oily substance. Specified substance purified column chromatography (20 g of SiO2, hexane/ethyl acetate = 2:1) to obtain the 493,7 mg (yield 97% of the target condensate-dipeptide-15 in the form of an amorphous substance. Specified substance re-crystallized from ethyl acetate[]6D]D6+5,28 (c=0,985,CHCl3).

IR (KBR) [cm-1]=3365, 2962, 1734, 1684, 1647, 1520, 1458, 1437, 1275, 1256, 1160, 741.

13C-NMR (400 MHz, CDCl3): 172,15 (C), 171,42 (c), 155,44 (c), 136,24 (c), 135,32 (c), 128,50 (c), 128,32 (c), 127,72 (c), 123,07 (c), 122,19 (c), 119,67 (c), 118,65 (c), 111,23 (c), 109,84 (c), 80,01 (c), 67,13 (c), 53,08 (c), 39,59 (c), 30,07 (c), increased by 28.70 (c), 28,29 (c) 27,79 (c), 19,27 (c), 10,84 (c).

LRFABMS: m/z (%) 522 (M+N+, 20), 130 (100) HRFABMS Calculated for C30H39N3O5+H: 522,2968. Found: 522,2957

1H-NMR (400 MHz, CDCl3):

to 8.14 (1H, s, 1-H)

7,51 (1H, d, J=7,6, 7-H)

7,28-6,85 (N, m, aromatic H)

of 6.52 (1H, d, 2-N)

5,04 (2H, s, 4'-H)

is 4.93 (1H, m, 2'-H)

4,82 (1H, W, 9"H)

4,07 (1H, s, 3"-H)

3,29 (2H, m, 1'-H)

1,72 (1H, m, 5"-H)

1,40 (N, s, BOC-H s)

of 1.28 (2H, m, 4"-H)

of 1.07 (1H, m)

0,84 (6N, m, 6"-H, 7"-H)

3. DDH oxidation of kt-15 (stage 3 in figure 5)

300 mg (0,60 mmol) of kt-15, 30 ml of anhydrous THF and 313 mg (1.38 mmol) DH (2,3-dichloro-5,6-dicyanobenzoquinone) is placed in a flask type "eggplant" volume of 100 ml in an argon atmosphere and heated at boiling temperature with back in the refrigerator for 1 hour. The temperature of the solution again bring to room temperature and distilled THF under reduced pressure, after which water is added and extracted with ethyl acetate. This is the ass then dried with anhydrous magnesium sulfate. The solvent is distilled under reduced pressure to obtain brown solid substance. Specified substance purified column chromatography (10 g of SiO2for the flash-chromatography, hexane/ethyl acetate = 3: 1) to give 224 mg (yield - 62,5%) of the target cyclic form (1"S,3"S)-16.

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C30H35N3O5(M. C. 517,6261) colourless powder, So pl. 210,5-of 211.5 [[]6D]D6-39,01 (c=0,810,CHCl3).

IR (KBr): [cm-1] = 3278, 2964, 1689, 1593, 1280, 1245, 1188, 1074, 741, 696.

1H-NMR (400 MHz, CDCl3):

8,66 (1H, s, l N-N)

at 8.60 (1H, s, 2'-H)

8,13 (1H, d, J=7,8, 7'-H)

was 7.45 (3H, m, 4'-6'-H)

7,24-7,38 (5H, and-Ph)

5,32 (2H, DD, J=12,5, 16,4, -CH2Ph)

5,28 (1H, d, 1"-H)

5,10 (1H, d, N-H)

of 1.74 (1H, m, 2"-H)

of 1.52 (2H, m, 4"-H)

1,45 (N, s, BOC-H)

1,22 (1H, m, 3"-H)

0,99 (3H, d, J=6,6, 6"-H)

to 0.88 (3H, t, J=7,3, 5"-H)

LRFABMS: m/z (%) 518 (M+H, 100) HRFABMS Calculated for C30H35N3O5+H: 518,2655. Found: 518,2639.

Elemental analysis for C30H35N305:

Calculated: To 69.61; H 6,82; N 8,12.

Found: 68,35; N 6,83; N 7,74.

4. De-tert-butoxycarbonylamino cyclic form (1"S, 3"S)-16 (stage 4 in figure 5)

Ls 16.80 mg (0.15 mmol) of the cyclic form (1"S,3"S)-16 and 2 ml disater add 0.5 ml triperoxonane acid, stirred at a temperature of 0oC for 1 hour and then stirred at room temperature until disappearance of starting material. The specified product is cooled again to 0oWith water and neutralize with saturated sodium bicarbonate solution, and then removing the solvent by distillation under reduced pressure and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate and then the solvent is distilled off under reduced pressure to obtain 59 mg (yield - 91%) of amine form (1"S, 3"S)-17 as a brown solid. Specified substance is recrystallized from an ethyl acetate ether and hexane.

< / BR>
C25H27N3O3(M. C. 417,5081) brown crystals, So pl. 169~170,5, []20D-16,4 (c=0,68, CHCl3).

IR (KBR): [cm-1] = 3143, 2962, 1707, 1593, 1280, 1244, 1074, 741, 698.

1H-NMR (400 MHz, CDCl3):

to 9.20 (1H, s, 1'N-H)

8,67 (1H, d, J=2,7, 2'-H)

8,11 (1H, m, 7'-H)

7,42 (3H, m, 4'~6'-H)

7,29 (5H, m, -Ph)

5,42 (2N, c, -CH2Ph)

4.26 deaths (1H, s, 1"-H)

2,03 (1H, m, 2"-H)

of 1.76 (2H, s, N-H)

was 1.69 (1H, m, 4"-H)

1,51 (H, m, 4"-H)

to 1.21 (1H, m, 3"-H)

to 0.97 (3H, d, J=6,6, 6"-H)

to 0.97 (3H, t, J=7,5, 5"-H)

LRFABMS: m/z (%) 417 (the ptx2">

Elemental analysis for C25H27N3O3:

Calculated: 71,92; N. Of 6.52; N 10,06.

Found: 71,99; N 6,62; N Of 10.25.

5. Demethylation of amine form (1"S, 3"S) -17 (stages 5 in Scheme 5)

85 mg (0.20 mmol) of amine form (1"S,3"S)-17, 3.4 ml of 37% formaldehyde solution, 1.7 ml of acetic acid and 3.0 ml of 1,4-dioxane are placed in a flask type "eggplant" is a volume of 25 ml in an argon atmosphere and add back 85 mg of 10% Pd-C under ice cooling. Hold the replacement of hydrogen and continue stirring at room temperature until disappearance of starting materials (approximately 1.5 hours). Add the ethanol is removed by filtration Pd-C and distilled off under reduced pressure, the solvent is getting 466 mg of colorless oily substance. Specified substance purified column chromatography (15 g of silica gel for flash chromatography, hexane/ether = 1:5) to give 4,7 mg (yield of 53%) dimethyl form (1"S,3"S)-18 in the form of a colorless oily substance.

< / BR>
C27H31N3O3(M. C. 445,5617) colorless oil.

IR (pure): [cm-1] = 3300, 2962, 1701, 1589, 742, 702.

1H-NMR (400 MHz, CDCl3):

9,36 (1H, s, l N-N)

8,71 (1H, d, J=2,9, 2'-H)

is 8.16 (1H, m, 7'-H}

7,42 (3H, m, 4'~6'-H)

7,28 (5H, m, -Ph)
/BR>1,72 (1H, m, 2"-H)

of 1.39 (1H, m, 4"-H)

of 1.26 (1H, m, 4"-H)

1,19 (1H, m, 3"-H)

of 0.93 (3H, d, J-6,6, 6"-H)

from 0.84 (3H, t, J=7,3, 5"-H)

LAFABMS: m/z (%) 446 (M+H, 15), 401 (100).

HRFABMS Calculated for C27H31N3ABOUT3+N: 446,2444. Found: 446,2449.

6. Dibenzylamine dimethyl form (1S",3"S)-18 (step 6 in Scheme 5)

44 mg (0,0988 mmol) dimethyl form (1S",3"S)-18 and 4 ml of ethyl acetate are placed in a flask type "eggplant" is a volume of 25 ml in an argon atmosphere and cooled with ice, and then add 44 mg of 10% Pd-C. carry out the replacement of hydrogen and continue stirring at room temperature until disappearance of starting materials. Then add ethanol and removed by filtration Pd-C, and then the solvent is distilled under reduced pressure to obtain a colorless solid. Specified substance purified column chromatography (1 g Si02, l3/Meon/NH4IT = 7:3:0,3) to obtain 10 mg (yield - 57,4%) (1"S, 3"S)-19.

< / BR>
C20H25N3O3(M. C. 355,4373) white powder, So pl. 163-164.

IR (KBr): [cm-1] = 3430, 2962, 1595, 1458, 1389, 744.

1H-NMR (400 MHz, D13):

at 8.60 (1H, s, 2'-H)

8,01 (1H, d, 7'-H)

7,33 (1H, DD, J=1,0, 7,6, 4'-H)

7,05 (2H, m, 5', 6'-H)

4,24 (1H, DD, J=4,5, 11,0, 1"-H)

of 2.36 (1H, BR> from 0.84 (3H, t, J=7,1, 5"-H)

[Example 2] Synthesis of (1"R,3"S)-indole (see diagram 6).

By the procedure similar to that shown in Example 1, get (1"R,3"S)-indole from a complex ester of tryptophan and (2R,4S)-homotaurine mentioned in Example getting 2. Below is the method of synthesis of these compounds.

Below are the physical data for the respective compounds.

(Compound 25)

< / BR>
C30H39N3O5(M. C. 521,66) white powder.

1H-NMR (400 MHz, D13):

to 7.99 (1H, s, 1N-N)

7,52 (1H, d, J=7,3, 7-H)

7,20 (N, m, aromatic H)

6,85 (1H, s, 2-H)

of 6.65 (1H, s, 1"N-H)

of 5.06 (2H, s, 4'-H)

is 4.93 (1H, d, J=7,5 2'-H)

4,70 (1H, W, 9"H)

of 4.12 (1H, q, J=7,0, 3"-H)

of 3.32 (2H, m, 1'-H)

was 1.58 (1H, DD, J=4,1, 12,9, 5"-H)

of 1.47 (2H, m, 6"-H)

1,40 (N, s, BOC-H s)

1,25 (1H, t, J=7,0 4"-H)

of 1.16 (1H, s, J=7,0 4"-H)

from 0.84 (3H, d, J=6,6, 8"-H)

of 0.83 (3H, t, J=7,5, 7"-H)

(1"R,3"S)-26

< / BR>
C30H35N3O5(M. C. 517,6261) brown powder,

1H-NMR (400 MHz, SO3):

8,67 (1H, sh, 1'N-H)

8,53 (1H, s, 2'-H)

to 8.14 (1H, d, J=7,9, 7'-H)

7,24-of 7.48 (8H, m, aromatic H)

of 5.29 (2H, DD, J=11,9, 17,0, -CH2Ph)

5,12 (1H, m, 1"-H)

5,10 (1H, s, N-H)

of 1.87 (2H, m, 2"-H)

of 1.53 (2H, m, 4"-H)

1,46 (N, s, BOC-H s)

1,28 (>(M. C. 445,5617) colorless oil,

1H-NMR (400 MHz, D13):

to 9.15 (1H, s, 1'N-H)

to 8.70 (1H, d, J=3,0, 2'-H)

of 8.15 (1H, m, 7'-H)

the 7.43 (3H, m, 4'~6'-H)

7,29 (5H, m, -Ph)

5,43 (2H, DD, J=12,5, 14,6, -CH2Ph)

Android 4.04 (1H, t, J=7,5, 1'-H)

2,39 (6N, s, N(CH3)2)

is 2.05 (1H, m, 2"-H)

of 1.84 (1H, m, 2"-H)

of 1.46 (2H, m, 4"-H)

1,22 (1H, m, 3"-H)

to 0.89 (3H, d, J=6,6, 6"-H)

to 0.88 (3H, t, J=7,4, 5"-H)

(1"R,3"S)-29

< / BR>
C20H25N3O3(M. C. 355,4373) colorless powder.

IR (KBr): [cm-1] = 3421, 2962, 1597, 1385, 754.

1H-NMR (400 MHz, CDCl3):

8,67 (1H, s, 2'-H)

of 8.09 (1H, d, J=7,5, 7'-H)

7,42 (1H, d, J=7,6, 4'-H)

7,14 (2H, m, 5', 6'-H)

3,91 (1H, DD, J=6,3, 8,8, 1 H)

of 2.36 (6H, s, N(CH3)2)

a 1.96 (2H, m, 2"-H)

for 1.49 (1H, m, 4"-H)

of 1.41 (1H, m, 4"-H)

to 1.21 (1H, m, 3"-H)

of 0.90 (3H, d, J=6,8, 6"-H)

to 0.89 (3H, t, J=7,4, 5"-H)

13C-NMR (400 MHz, CDCl3): 163,71 (C), 160,71 (C), 159,13 (C), 152,42 (C), 137,73 (C), 131,49 (C), 130,10 (C) of 129.6 (C), 123,19 (C), 121,60 (C), 121,46 (C), 112,74 (C), 61,99 (C), 42,21 (C), 42,10 (C), 38,74 (C), 32,92 (C), 29,96 (C), 19,78 (C), 11,37 ().

[Example 3] Synthesis of (1 S,3"R)-indole (see diagram 7).

By the procedure similar to that shown in Example 1, get (1"S,3"R)-indole from a complex ester of tryptophan and (2R,4S)-homotaurine indicated in the Example of a 3, according to the connection.

(Compound 39)

< / BR>
C30H39N3O5(M. C. 521,66) white powder, []24D-5,92 (c=0.950, and CHCl3).

1H-NMR (400 MHz, D13):

8,02 (1H, s, 1N-(H)

7,52 (1H, d, J=7,8, 7-H)

7,21 (N, m, aromatic H)

6,86 (1H, s, 2-H)

is 6.54 (1H, s, 1"N-H)

of 5.06 (2H, s, 4'-H)

4,94 (1H, d, J=7,8, 2'-H)

4,74 (1H, s, 9'-H)

4,10 (1H, s, 3"-H)

of 3.32 (2H, d, J=4,9, 1'-H)

of 1.56 (1H, m, 5"-H)

1,46 (N, s, BOC-H s)

of 1.26 (1H, t, J=7,0, 4"-H)

of 1.16 (1H, s, J=7,0, 4"-H)

of 0.85 (3H, d, J=6,6, 8"-H)

of 0.83 (3H, t, J=7,4, 7"-H)

(1"S,3"R)-40

< / BR>
C30H35N3O5(M. C. 517,6261) brown powder, []23D-48,0 (c=1,038, CHCl3).

IR (KBR): [cm-1] = 3276, 2962, 1685, 1593

(1"S,3"R)-41

< / BR>
C25H27N3O3(M. C. 417,5081) brown crystals, []22D-30,9 (c=0.950, and CHCl3).

IR (KBR): 2958, 1707, 1593

(1"S,3"R)-42

< / BR>
WITH27H31N3O0(M. C. 445,5617) colorless oil.

1H-NMR (400 MHz, D13):

to 9.15 (1H, s, 1'N-H)

to 8.70 (1H, d, J=2,9, 2'-H)

is 8.16 (1H, m, 7'-H)

the 7.43 (3H, m, 4'-6'-N)

7,30 (5H, m, -Ph)

5,43 (2H, DD, J=12,3, 15,2, -CH2Ph)

a 4.03 (1H, t, 1"-H)

2,39 (6N, s, N(CH3)2)

to 2.06 (1H, m, 2"-H)

of 1.80 (1H, m, 2"-H)

of 1.50 (1H, m, 4"-H)

OF 1.43 (1H, B>N3O3(M. C. 355,4373) colorless powder, []23D-21,1 (c=0,870, MeOH).

IR (KBr) [cm-1] = 3400, 2960, 1591, 1458, 1389, 744.

[Example 4] Synthesis of (1"R,3"R)-indole (see diagram 8).

By the procedure similar to that shown in Example 1 (1"R,3"R)-indole obtained from mentioned in Example 4 of ester of tryptophan and (2R, 4R)-homotaurine in accordance with the following synthesis scheme.

[Example 5] Synthesis of stereoisomeric indole compounds from a complex ester of tryptophan and L-isoleucine (see diagram 9).

1. tert-Butoxycarbonylamino L-isoleucine (stage 1 in figure 9)

3,00 mg (22,87 mmol) of L-isoleucine (S)-11 placed in a flask type "eggplant" with a volume of 300 ml and dissolved by adding 21 ml of 1N NaOH. Then add 15 ml of water, 15 ml of dioxane and 5,49 mg (to 25.15 mmol) Vos2Oh and stirred at room temperature for 5 hours, then add 2,70 mg (12,37 mmol) Vos2Oh and stirred at room temperature for 13 hours. The reaction solution is washed with 3 times 30 ml of ether, adjusted pH to 2-3 by adding to the aqueous layer in an ice bath of citric acid and then twice washed with 50 ml of diethyl ether, extracted with 30 ml ethyl acetate, washed 5 times with 20 ml of water, with escitalo oil.

2. Condensation complex tryptophan-0-benzyl ether with BOC-L-isoleucine (stage 2 in figure 9)

After placing it in a flask type "eggplant" volume of 100 ml of 0.60 g (is 1.81 mmol) of the hydrochloride complex tryptophan-benzyl ester and carrying out substitution with argon add 30 ml of anhydrous THF and stirred. Then in another flask is also put to 0.48 g (1.94 mmol) of the BOC-form (S)-12 L-isoleucine, spend substitution with argon and dissolved in 10 ml of anhydrous THF, and then added to the flask type "eggplant" volume of 100 ml. Specified product is cooled to 0oC in an ice bath and added dropwise of 0.58 ml (3.88 mmol) of the condensing agent DEFC (diethylacrylamide) and of 0.60 ml (3,59 mmol) of triethylamine and stirred at 0oC for 1 hour and then at room temperature for 1 hour. To the reaction solution was added 50 ml of ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated saline, dried with anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. Thus obtain 1.28 g of brown oil, which was purified on a column of silica gel (60 g SiO2, ethyl acetate/hexane = 1: 2) and then recrystallized from ethyl acetate and hexane to obtain 888,4 mg (behoefte (S)-13 (stage 3 in figure 9)

1.50 g (2,94 mmol) condensate - dipeptide (S)-13 placed in a flask type "eggplant" volume of 200 ml, spend in it replacement with argon and dissolved product by adding 75 ml of anhydrous THF. Then add 1,31 g (5,77 mmol) DH (2,3-dichloro-5,6-dicyanobenzoquinone), recrystallized from benzene, and heated at boiling temperature under reflux for 3 hours. The solvent is distilled off from the reaction solution and the residue is added 200 ml of ethyl acetate and 20 ml of water for carrying out the extraction, and then the reaction solution was washed with aqueous saturated sodium bicarbonate solution and saturated saline solution, dried with anhydrous magnesium sulfate and the solvent is distilled off. Obtain 1.52 g of residue, which is purified on a column of silica gel (90 g Si02, ethyl acetate/hexane =1:3), with the receipt of 1.46 g (yield - 98,3%) of crude crystals. These crystals are recrystallized from ethyl acetate and n-hexane to obtain 746,9 mg (50,2%) of the target cyclic form (S)-14 in the form of white crystals.

4. De-tert-butoxycarbonylamino cyclic form (S)-14 (stage 4 in figure 9)

200 mg (0.40 mmol) of the cyclic form (S)-14 placed in dvuhgolosy flask type "eggplant" volume 30 ml, dissolved in 5.0 ml (of 6.49 mmol) dichloromethane and ohney temperature until disappearance of starting materials. The reaction solution is cooled again to 0oC, neutralized aqueous saturated sodium bicarbonate solution, distilled dichloromethane and extracted with ethyl acetate and then the organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate and magnesium sulfate and the solvent is distilled off under reduced pressure to get 185,8 mg of residue. The specified residue is purified on a column of silica gel (15 g SiO2, ethyl acetate/hexane = 1:3), with 143,5 mg (93,3%) cyclic form (S)-15, which is then recrystallized from ethyl acetate and n-hexane to obtain 109,0 mg (68,0%) of white crystals.

C24H25N303(M. C. 403,48), So pl. 137-138oC.

[]21,5D-41,6 (=0,58, SMS3).

IR (KBr) [cm-1] = 3282, 2962, 1707, 1593, 1458, 1389, 1360, 1281, 1244, 1192, 1144, 1074, 958, 744, 698, 418.

5. Demethylation of cyclic form (S)-15 (stage 5 in figure 9)

298,0 mg (0,74 mmol) cyclic form (S)-15 placed in a flask type "eggplant" volume of 100 ml and dissolved by adding 14 ml of 37% formaldehyde, 8.0 ml of acetic acid and 6.0 ml of 1,4-dioxane, and to this mixture is added 300 mg of 10% Pd-C under cooling in an ice bath and then spend the substitution of hydrogen. Then remove the add ethanol, Pd-C is removed by filtration and the filtrate concentrated. You get 967,7 mg of residue, which is purified on a column of silica gel (45 g SiO2, ethyl acetate/hexane = 1: 2), getting to 216.2 mg (yield - 67,9%) of the target white amorphous dimethyl form (S)-16.

WITH26H29H3ABOUTC, []19D-60,4 (C=0,33, SMSC).

IR (KBr) [cm-1] = 3406, 2964, 2931, 2875, 2829, 2783, 1707, 1589, 1458, 1389, 1331, 1281, 1244, 1190, 1136, 1074, 958, 744, 698.

6. Dibenzylamine dimethyl form (S)-16 (step 6 in Scheme 9)

of 87.0 mg dimethyl form (S)-16 placed in a flask type "eggplant" volume of 50 ml and dissolved by the addition of 4.0 ml of ethyl acetate, and then to the resulting mixture is added 170 mg of 10% Pd-C under ice cooling, carry out the replacement of hydrogen and stirred at room temperature for 2 hours. To the reaction mixture ethanol, Pd-C is removed by filtration and the filtrate concentrated to obtain and 64.3 mg (yield - 93,5%) of almost pure target compound in powder form. Next to the residue add dichloromethane and the insoluble fraction was washed with ethyl ether to obtain 24,8 mg (yield - 36,0%) of the pure target compound (S)-17.

C19H23N3O3, []20D-61,0 (C=0,30, Meon).

IR (KBR) [cm-1] = 3 is s (desamination)

Examples of the synthesis of desalinators indole compounds of the present invention are given below. Before the synthesis of the compounds of the present invention provide a synthesis of source material - 4-methylcarbonate acid, as shown in the Examples get 5 and 6, as in Example 6 examples of synthesis using it.

In the description below, Datamonitor indole compounds of formula (1) are referred to as compounds 55 and 56; tryptophan formula (2) is denoted as compound 14; 4-Metelkova acid of the formula (3) is denoted as compound S-6, R-32; and amide form the compounds of formula (4) is denoted as the connection 54.

[Example of getting 5] Synthesis of optically active (S)-4-methylcarbonate acid (S-6)

Optically active (S)-4-methylcarbonate acid derived from optically active methylbutanol used as source material in the implementation of the Scheme 1, according to the above scheme of the synthesis of (2S,4S)-homotaurine (I. Synthesis lineform indole compounds, an Example of obtaining 1) to the reaction stage (5).

[Example of obtaining 6] the Synthesis of optically active (R)-4-methylcarbonate acid (R-32) (see Scheme 10).

Optically active (R)-4-methylcarbonate acid th above scheme of synthesis of (2S,4R)-homotaurine (I. Synthesis lineform indole compounds. An example of obtaining 3) to the reaction stage (3).

(S)-4-Metelkova acid can also be obtained by the procedure similar to that shown in the Example of a 6, in the case when the source material is (R)-citronellol.

The following is an example of the synthesis of indole compounds, dezaminotisteinil (connections 55 and 56) of a complex ester of tryptophan (compound 14) and 4-methylcarbonate acid (compound S-6).

[Example 6] Synthesis desamination (see diagram 10).

1. Synthesis of compound 54

To a solution of hydrochloride complex benzyl ester of L-tryptophan (2,31 g, 7.0 mmol) in THF (100 ml) is added (S)-4-methylcarbonate acid (1.0 g, 1.1 equivalent) and diethyl-phosphoricacid (DAFT, 2,07 ml, 2.0 equivalents) and stirred at 0oWith, then add triethylamine (2,34 ml, 2.4 equivalents) and stirred at 0oWith a further 1 hour. After concentrating the reaction mixture under reduced pressure, to the residue is added ethyl acetate. An ethyl acetate solution is washed by the addition of saturated sodium bicarbonate solution, then washed with 10% hydrochloric acid and saturated saline. The organic layer was dried the i.i.d. product is recrystallized from a mixed solvent of ethyl acetate:n-hexane (1:1) to give compound 54 (2,54 g, output - 89%).

< / BR>
C25H30N2O3(M. C. 406,23); colourless powder; So pl. 80-81oWith (ethyl acetate: n-hexane, 1:1).

[]23D:-5,03 (=1,09, SMS3).

IR (clean) [cm-1] = 3300 (NH), 3112, 2959, 1732 (-COO), 1651 (-CONH), 1519, 1456, 1379, 1354, 741, 697.

1H-NMR (400 MHz, CDCl3): 8,59 (1H, Shir, 1N-(H), 7,53 (1H, d, J=7,8, 7-H), 7,21 (M, aromatic-H), 6,74 (1H, d, J=1,7, 2-H), 6,12 (1H, d, J= 7,8, 1"N-H), 5,09 (2H, DD, J=12,2, 19,5, 4'-H), to 5.03 (1H, m, 2'-H), of 3.32 (2H, DD, J= 2.0 A, 5,4, 1'-H), to 2.13 (2H, m, 3"-H), to 1.61 (1H, m, 4"-H), to 1.38 (1H, m, 4"-H) of 1.29 (2H, m, 6"-H), 1,10 (1H, m, 5"-H), FROM 0.84 (3H, d, J=7,1, 8"-H) OF 0.82 (3H, t, J=6,2, 7"-H).

2. Synthesis of compound 55 [desalinators indole compounds of formula (1), where R is a benzyl group]

Compound 55 (500 mg, of 1.23 mmol) dissolved in THF (50 ml) solution was added 2,3-dichloro-5,6-dicyanobenzoquinone (DH, 698 mg, 2.5 equivalents) and heated at boiling temperature under reflux for 1 hour. After cooling the reaction mixture, water is added and the THF is distilled off under reduced pressure. To the obtained residue is added ethyl acetate to conduct extraction. The organic layer was washed with saturated sodium bicarbonate solution, then with saturated saline and then dried with anhydrous sodium sulfate. Dissolve silicagel, the ethyl acetate: n-hexane, 1: 5) to give the pure compound 55 (232 mg, yield -47%). Then the connection 55 is recrystallized from ethyl acetate.

< / BR>
C25H26N2O3(M. C. 402,19); colourless powder; So pl. 138,5-139,5oWith (ethyl acetate).

[]23D:+7,14 (C=1.00, it SNS3).

IR (pure): [cm-1] = 3323, 2960, 1684 (WITH), 1604, 1570, 1280, 1246, 1203, 1140, 1076, 785, 746.

1H-NMR (400 MHz, CDCl3): 8,71 (1H, d, J=2,9, 2'-H), 8,59 (1H, Shir., 1N-(H), (8,18-8,13 (1H, m, 7'-H), WAS 7.45 (3H, m, 4',5',6'-H), 7,31 (5H, m, -Ph), 5,43 (2H, s, -CH2Ph), of 2.92 (2H, m, 1"-H) of 1.93 (1H, m, 2"-H), 1,71 (1H, m, 2"-H), TO 1.45 (2H, m, 4"(H) to 1.23 (1H, m, 3"-H) to 0.96 (3H, d, J=6,5, 6"-H) OF 0.91 (3H, t, J=7,3, 5"-H).

3. Synthesis of compound 56 (desalinators indole compounds of formula (1) in which R denotes H)

Compound 55 (100 mg, 0.25 mmol) dissolved in 10 ml of ethyl acetate, to the specified solution was added 100 mg of 10% palladium on coal and stirred at room temperature in an argon atmosphere for 2 hours. To the reaction solution add ethanol, filtered off the catalyst and then concentrate the filtrate under reduced pressure to get crude product (95,4 mg), which is then purified by chromatography on a column (silica gel, ethyl acetate: methanol, 10:1) with Poluchenie; So pl. 181,0-USD 183.0oWith (aqueous ethanol).

IR (pure): [cm-1] = 3161, 2960, 1676, 1603, 1560, 1458, 1414, 1278, 1130, 1082, 949, 741.

1H-NMR (400 MHz, CDCl3): 8,64 (1H, s, 2'-H), OF 8.04 (1H, d, J=8.0 a, 7'-H), 7,42 (1H, d, J=7,3, 4'-H), 7,20-7,13 (2H, m, 5' and 6-H), 2,88-TO 2.74 (2H, m, 1"-H), 1,90 AND 1.80 (1H, m, 2"-H), 1,66-OF 1.57 (1H, m, 2"-H), 1,45 is 1.34 (2H, m, 4"-H), 1,25-OF 1.13 (1H, m, 3"-H) TO 0.92 (3H, d, J=6,6, 6"-H) OF 0.87 (3H, t, J=7,2, 5"-H).

III. The biological activity of stereoisomeric indole compounds

[Example 7] : Action stereoisomeric indole compounds against perechisleniya lipids in liver microsomes of rats

(1) determining the level peroxidizing lipid

10 μl of microsome fraction (protein concentration of 30-50 mg/ml) obtained from the liver of rats, and 10 μl of a solution of test compound in ethanol is added to 0.5 ml of 0.1 M Tris-cleaners containing hydrochloride buffer (pH 7.5) containing 14 mm MgCl2, mixed and pre-incubated at 37oC for 5 minutes. Then add 10 ál of 0.2 M ADP, 10 μl of 12 mm FeSO4, 40 ál of NADPH-reproducing system and bring the volume of the mixture to 1 ml of distilled water, mix, and conducting the reaction at 37oC for 10 minutes. After completion of the reaction, add 2 ml of 15% solution of trichloroacetic acid containing 0,375% thiobarbiturates absorption at a wavelength of 535 nm, determine the number of substances capable of reacting with thiobarbituric acid, including malonic dialdehyde formed during the reaction. Based on these values determine the amount of 50% inhibitory effect against perechisleniya lipids (value IR50).

(2) test Results

By determining the inhibitory effect against perechisleniya lipids corresponding stereoisomeric compounds were obtained value IR50for the corresponding stereoisomeric indole compounds: (1"S,3"S)-19 Example 1, (1"R,3"S)-29 from Example 2 (1"R,3"R)-53 of Example 4, (1"S, 3"R') -43 in Example 3 and (S)-17 from Example 5 for connection type homosalate (S,S)-form, (R,S)-form, (R,R)-form and (S,R)-forms, which are respectively 1,07, 1,10, 1.24 and 1,10 µg/ml, respectively, as shown in the Table below. In addition, the value IR50for (S)-form of homotaurine is 1.89 µg/ml, indicating that the specified connection has somewhat weaker activity.

The connection is Inhibitory concentration (IC50µg/ml)

(1"S,3"S)-19 - 1,07

(1"R,3"S)-29 - 1,10

(1"R,3"R)-53 - 1,24

(1"S,3"R)-43 - 1,10

(S)-17 - 1,89

[Example 8]: the Action of indole compounds against perenne determination performed according to the method described in Example 7.

(2) test Results

Was the comparison and study of inhibitory effect against perechisleniya lipids corresponding indole compounds, i.e. desamination (compound 56) from Example 6 and synthetic (1'S,3"S) Marcapagina And (above-mentioned compound 19). As a result, as shown in the Table below, data were obtained for values IR50consider and synthetic (1'S, 3"S) Marcapagina And level of 0.33 mg/ml and 1.35 mcg/ml, respectively, which confirm that desamination shows higher activity.

The connection is Inhibitory concentration (IC50µg/ml)

Desamination (compound 56) - 0,33

Synthetic Metafragen And [compound (1"S,3"S)-19] - 1,35

The effectiveness of the invention

By using a new method of synthesis involving the condensation of tryptophan with stereoisomeric-amino acid or 4-methylcarbonate acid with the formation of amide form during the subsequent oxidative cyclization aminoformic education immediately oxazoline rings, it is possible to obtain various new indole compounds of the present invention.ewnetu, such as inhibitory effect against perechisleniya lipids, and therefore can be used as material for the production of pharmaceutical and cosmetic products, etc. moreover, desalinators indole compounds have a higher than aminoformic, physiological activity, such as inhibiting effect against perechisleniya lipids.

1. Synthetic indole compound in the R-form or S-form of formula (1) or its salt

< / BR>
where Y denotes a group

< / BR>
where X represents an alkyl group containing 1-5 carbon atoms;

R1and R2each independently represents a hydrogen atom or alkyl group

or Y represents a group

-(CH2)2-(CH3)H-CH2CH3,

R represents a hydrogen atom, aracelio group or aryl group;

the symbol (*) denotes the position of an asymmetric carbon atom.

2. Synthetic indole compound under item 1 in the R-form or S-form of the formula (1A) or its salt

< / BR>
where X represents an alkyl group containing 1-5 carbon atoms;

R1and R2each independently represents a hydrogen atom or alkyl group;

R represents a hydrogen atom, tx2">

3. Stereoisomeric indole compound under item 1 of the formula (1b) or its salt:

< / BR>
R represents a hydrogen atom, aracelio group or aryl group;

the symbol (*) denotes the position of an asymmetric carbon atom.

4. A method of obtaining a stereoisomeric indole compounds of formula (1)

< / BR>
the condensation of tryptophan formula (2)

< / BR>
with the acid of formula (3):

< / BR>
obtaining the compounds of formula (4)

< / BR>
followed by cyclization of the compounds of the formula (4), where Y denotes the group

< / BR>
where X represents an alkyl group containing 1-5 carbon atoms;

R1and R2each independently represents a hydrogen atom or alkyl group

or Y represents a group

-(CH2)2-(CH3)H-CH2CH3,

R represents a hydrogen atom, aracelio group or aryl group;

the symbol (*) denotes the position of an asymmetric carbon atom.

5. A method of obtaining a stereoisomeric indole compounds of formula (1A)

< / BR>
the condensation of tryptophan formula (2)

< / BR>
with stereoisomeric-amino acid of formula (3A)

< / BR>
obtaining the compounds of formula (4A)

< / BR>
with posleduyushego carbon;

R1and R2each independently represents a hydrogen atom or alkyl group;

R represents a hydrogen atom, aracelio group or aryl group;

the symbol (*) denotes the position of an asymmetric carbon atom.

6. A method of obtaining a stereoisomeric indole compounds of the formula (1b)

< / BR>
the condensation of tryptophan formula (2)

< / BR>
with a carboxylic acid of the formula (3b)

< / BR>
obtaining the compounds of formula (4b)

< / BR>
followed by cyclization of the compounds of formula (4b),

R represents a hydrogen atom, aracelio group or aryl group;

the symbol (*) denotes the position of an asymmetric carbon atom.

7. The inhibitor perechisleniya lipids, comprising as active ingredient a synthetic indole compound or its salt according to any one of paragraphs. 1-3.

Priority points:

05.09.1997 - PP. 1-7;

09.02.1998 - PP. 1-7 (clarification radicals).

 

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71 cl, 2 tbl, 3 ex

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