SU728716A3 - Method of preparing condensed indoles and indenes derivatives - Google Patents

Abstract

(thio)pyrano-indole derivs with antidepressant and antiulcer activity

Description

where R is hydrogen or lower alkyl, R is lower alkyl and R is hydrogen, lower alkyl, windows, lower alkoxy, lower alkanoyloxy or halogen, which exhibit a high biological activity. The proposed method consists in the fact that a compound of the formula B-CR RSCR R Y., where B is a monovalent radical of the formula where R and R and also R, R, R and R have the indicated values Y-O SI-, mercapto-S- SOjNa or -S-SOjK, is treated with a compound of formula E,. where R - has the indicated value Z - represents; a) Dec - NR R where AKk, R have the indicated meanings; c) COOR and A K-COOR, where R is hydrogen or alkyl, and DRc is alkyl in the form, or 5R "R CR ° R CR R; where RS, R,, and R are hydrogen or lower alkyl c) and AEK-CONR R where R ° and R have the indicated values d) CH OCOR and Abk -, 1 iwn. V-O20 R is hydrogen or lower alkyl and a has the indicated meanings; e), where AEk is alkylene in the form, CR "RJCR ° RCHR% LI CReRaR R CRVcHRn where R, R, R R R, R and R is the same as above, L is halo; f) AEK-NR COR, where DEC and R are the same as above, and R is hydrogen or lower alkyl with 1--5 carbon atoms; , e), where A has the indicated values, in the presence of an acid catalyst, with isolation of the compound of the formula (c) obtained in this way. .at . where A, R, P, H-, R, R% X are the indicated values, and Z is where R and R have the indicated values, or with the nearest transformation of the compound of formula 1a into a compound of the formula for the remaining values Radical Z are known -sh techniques. The term lower alkyl refers to straight chain alkyl radicals with 1-6 carbon atoms and branched alkyl radicals with 3-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and the like. The term lower alkoxy means straight and branched alkoxy radicals with 1-4 carbon atoms, for example, methoxy, ethoxy, isopropoxy. The term lower alkanoyloxy refers to straight and branched alkanoyl oxyl radicals with 2-6 carbon atoms, for example acetoxy, propionyloxy, hexanoyloxy. The term halo means fluoro, chloro / bromo and iodo. The compounds FOU) mules 1 are capable of forming salts. Salts are obtained by reacting the corresponding base of a compound of formula I with 1 to 2 equivalents, depending on the number of basic nitrogen in the compound, or better, with an excess of the corresponding acid in an organic solvent, for example ether or an ethanol-ether mixture. The invention also includes stereohygmic isomers of the compounds of formula 1, which are formed from the asymmetric centers contained therein. These isomeric forms can be obtained by various methods, they are easily purified by cristae: by plization or by chromatography. Included are also individual optical isomers that can be separated by fractional crystallization of diastereomeric salts, for example, those formed with d- or {- succinic acid or D - (+) - d-bromocorphonsulfonic acid. When condensation is carried out (2. + III), it is more advantageous to use equimolar amounts of the starting compound I and agmnoketone of formula III in the presence of an acid catalyst. Typically, a solvent is used as the condensation reaction medium. Such solvents include aromatic hydrocarbons, such as benzene or toluene, ethers and cyclic ethers, such as diethyl ether, dioxane or tetrahydrofuran, halogenated hydrocarbons, such as methylene dichloride or carbon tetrachloride, and the like. Benzene and toluene are the most appropriate and practical dates for this purpose. Various acids can be used for this condensation: 1-: catalysts, for example, catalysts used in Friedel Crafts reactions, for example p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid acid, sulfuric acid, etc. The best acid catalysts are p-toluenesulfonic acid, aluminum chloride, boron trifluoride and phosphorus pentoxide. The amount of acid catalyst may be 0.01-100 molar equivalents; however, it is preferred that this amount be 0.1-10 molar equivalents. It should also be noted that if the reagents P and / or III contain a basic nitrogen atom (other than indole nitrogen), then the amount of acid catalyst should be in excess to the amount required for neutralizing such nitrogen. The reaction time can be from 10 minutes to 60 hours, preferably from 0.5 to 24 hours. The reaction temperature can be from -20 ° C to the boiling point of the reaction mixture. It is better to work in the temperature range of 20-170 ° C.

Example 1. 1-Methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetic acid. (1a, A A, where R and R H, R CHg; R, R, R, and R H, X 0, Z)

Ethyl acetate (23.4 g, 0.18 mol) was added to a solution of the starting compound II, tryptophol (10.0 g, 0.06 mol) in 200 ml of benzene. After settling, p-toluenesulfonic acid (1.3 g) and about hydrated alkaline alumina silicate (molecular sieve 4) are added over 10 minutes. The mixture was heated under reflux for 30 minutes, another 600 mg of p-toluenesulfonic acid was added and heated under reflux for another 2.5 hours. Molecular sieves were collected, the benzene solution was washed successively with 5% sodium bicarbonate solution and water, dried over sodium sulfate , evaporated in a zakuum to dryness and receive butter. . The oil is chromatographed on silica gel. Elution with 5% ether in benzene gives 1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetic acid ester ethyl ester as an oil 1715 cm.

The hydrolysis of this ester to the target compound is carried out as follows: the ester is dissolved in 230 ml of methanol, 10 g of KOH in 30 4 liters of water are added and the solution is allowed to stand overnight at room temperature. The methanol is distilled off, water is added and the solution is washed with benzene. The aqueous phase is acidified with 6N. NHCt and extracted. benzene. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness; get a gauze

which is crystallized from benzene containing traces of petroleum ether and get the target compound with j so pl. 150-152C, 3325 and 1705 cm,

In this example, methyl acetoacetate can be replaced with an equivalent amount of ethyl acetoacetate. In this case, in the form of an ether, after recrystallization from benzene-hexane, 1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole acetic acid ethyl ester is obtained. 87-90 ° c.

An equivalent amount of propyl acetoacetate can replace the ethyl acetoacetate in this example. In this case, propyl is obtained in the form of ether.

1-methyl-1,3,4,9-tetrahydropyran- (3,4-in) -indole-1-acetic acid new ester.

In this example, an equivalent amount of N-methyltryptophol may

0 replace tryptophol. In this case, after recrystallization from benzene, 1,9-dimethyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetic acid with m.p. 105-108 ° C. This

5, the product is identical to the product of the same name from Example 65. Similar replacement with N-ethyltryptophol gives 9-ethyl-1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetic acid acid.

Example 2. 1-Methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-propionic acid. (1a, A A, where R. H; R CH3; R E

5 R and R H; X OK Z CHiCHjCOOH).

A mixture of the starting compound i, tryptophol (500 mg), levulinic acid (580 mg), 75 ml of benzene, 1.7 g of phosphorus pentoxide and about

0 0.5 g of diatomaceous earth (Divides) is stirred with a magnetic stirrer at room temperature for 15 minutes, then at 70 ° C for 1.5 hours. The reaction mixture is filtered, the filtrate is washed three

5 times 5 n. The NaOH, aqueous phases are combined, washed twice with ether and acidified with a cold 50% solution. The aqueous phase is extracted with chloroform, the chloroform extract is dried over sodium sulfate and evaporated to dryness.

The residue is crystallized from a mixture of ethyl acetate-petrol ether and get the specified connection with so pl. 104 IO C; NMR (CDCfj) cfl, 47 (MN), 21.8 (4H), 2.74 (2H), 3.96 (2H),

5 7.18 (4H), 7.85 (1H), 960 (1H).

This compound can also be prepared according to Example G, but replacing ethyl acetate with an equivalent amount of ethyl levulinate. In this case, before

0 hydrolysis after recrystallization from a mixture of benzene-petroleum ether get 1-methyl-1 ethyl ester, 3,4,9-tetrahydropyran- (3,4-in) -indole-1-propionic acid with so pl.

5 116-118C; J-l; -1716 cm

Example 3. 1-Methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetic acid. (1a, A A, where Rf6 JJ p-ig and, R-СНз / R, R, Н and U Н, X 5, Z)

Indole-3-ethanethiol {1.5 g) and methyl acetoacetate are mixed with 50 ml of benzene, the solution is heated for 30 minutes (bath temperature 70-80 ° C). P-Toluenesulfonic acid (0.15 g) is added and the reaction mixture is heated under reflux with stirring for 12 hours. The water formed during the reaction is collected in a trap. After cooling, the benzene solution is washed with 10% sodium bicarbonate solution, water, saturated saline solution and dried over sodium sulfate. After benzene has been distilled off, 1-methyl-1, 3,4,9-tetrahydropyran (2,) -iidol-1-acetic acid methyl ester is obtained in the form of a semi-solid j j. 1715

Then the ether is treated with a water-alcohol solution of KOH, as in examples 1 and 2 and get the target compound with so pl. 147-149 ° C NMR {CDCgg) cf 1.86 (5, -ZN), 306 and 812 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), after recrystallization, the reactions from benzene-hexane.

According to the methods of examples 1 or 3 mono to obtain other compounds formun nG

R

ly 1a, where a

and R

H

R and X are the same as above, and Z COOR or AEk-COOR, where is the same as above. Examples of such compounds i are given in table. 1 and 2. In each of these examples, an equivalent amount of the starting compound il is used instead of the starting compound (specified in examples 1 and 3). Note that in each example, the ether obtained before hydrolysis is the corresponding ester of compound W. Similarly, the procedure of example 2 is used for the products listed in Tables 1 and 2. In this case, an equivalent amount of starting compound i is used instead of starting compound 1 in example 2, and an equivalent amount of keto acid III is used instead of ketoester 31, decree anny there.

Example 43. K, K-1-Trimethyl-1, 3,4,9-tetrahydropyran- (3,4-b) f ..... f l - n 74 iip -.-.

indole-1-adetamide. (1a, A And

where

 n H, R CH3, R R and

, X 0, Z (SNe) 2)

To a stirred solution of 1-methyl-1, 3,4,9-tetragpdopiran- (3,4-in) -indole-1-acetic acid (15 g, 0.061 mol), prepared as in example 1, in dry tetrahydrofuran (300 ml), cooled to -5. ° C, triethylamine (18.5 g, 0.183 ppm), then ethyl chloroformate (16.6 g, 0.183 mol) was added. The mixture is stirred at 2 hours. This mixture, in

which now contains the mixed anhydride of these starting compounds, is added dropwise to a cooled 40% aqueous solution of dimethylamine (225 ml). The resulting mixture was stirred at room temperature for 0.5 h. Large tetrahydrofuran was evaporated, the residue was partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. Eluted with 20% ethyl acetate in benzene followed by crystallization of the eluate from ethyl acetate gave the title compound with mp. 149-15 1 ° C; 3375, 1634 cm-1

In the same way, but replacing a 40% aqueous solution of dimethanlamine with an equivalent amount of ammonium hydroxide (concentrated) —methylamine (30% aqueous solution), n-hexylamine (20% aqueous solution), diethyllagote (30% aqueous solution), isopropylamine (40% aqueous solution), ethylaginum (70% aqueous solution), pyrrolidine (50% aqueous solution), piperidine, morpholine or N-methylpiperazine, are obtained respectively:

1-methyl-1,3,4, 9-tetra1idropyran- (3, 4-v) -indole-1-acetagut, d, mp, 158-1600С;

N, 1 - dimethyl-1, 3,4, 9-tetrahydropyran- (3,4-in) -indole-1-acetamide, with so pl. , 138-140C;

N-hexyl-1-methyl-1,3,4,9-tetrahydropyran- (3, 4-in) -indole-1-acetamide

N, M-Diethyl-1-methyl-1,3,4,9-tetrahydropyran- (3, 4-v) -inol-1-acetamide, m.p. 99 ° c :; g 3350,

-, „. -j JWCS COP

1620 cm;

L-isopropyl-1-methyl-1,3,4,9-tetrahydropyran- (3,4-in) -indole-1-acetamide with so pl. 151-153C;

N-ethyl-1-meth-1, 3, 4,9-tetrac1Hydropyran- (3, 4-b) -i: ndol-1-acetz III, d with so-called pl. 152-153 ° C;

1- 1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-yl / -acetyl pyrrolidine with m.p. 119-120 ° C;

1- 1-methyl-1,3,4,9-tetrahydropyran- (3,. 4-b) -indole-1-yl) aceti / pipa (recine with m.p., 148-149 ° C;

1- (1-methyl-1,3,4,9-tetrahydropyran- (3, 4-v) -indole 1-yl-acetig Dmorfol n with mp 141-142 ° C;

1-methyl-4- (1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-yl) acetyl piperazine.

According to the method of example 43, using as the source an equivalent amount of one of the acidic compounds of formula 1a from examples 2-42, instead of 1-methyl-1,3,4,9-tetrahydropyl aH- (3, 4-b) -ingol-1 - acetic acid and, using an equivalent amount of the corresponding: amine, for example

of ammonia or a primary or secondary amine from Example 43, the corresponding amide compound 1a is obtained. Examples of such amides are given in table. 3 along with the corresponding starting materials and amines used to prepare them. In all cases, the numbers of the examples in which the starting compounds were obtained are indicated.

Example 54. (Dimethylamino) ethyl 1-methyl-1,3,4,9-tetrahydropyran- (3, 4-b) -indole (1; A A, where R and R H, R CH, R, R, R4- and RH, X O, CH2CH2Y (SN.z) 2)

A solution of N, N, 1-trimethyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetamide (5.0 g, 0.018 mol) obtained in Example 43 is added dropwise. is added to a cooled, well-mixed mixture of lithium aluminum hydride (1.4 g, 0.036 mol) in 200 ml of ether. Stirring is continued for another 1 hour at room temperature, then the mixture is heated under reflux for 2 hours. After cooling in an ice bath, 6.2 ml of water are added dropwise to decompose the excess hydride. Then another 100 ml of water is added and the ether phase is decanted. The aqueous phase is extracted once with benzene. The combined organic phases are washed with water, dried over sodium sulfate and evaporated to dryness; 5 g of oil is obtained, which crystallizes on standing. The crystalline product is crystallized from ether and the pure title compound is obtained with mp. 133-135 ° C; NMR (CDCT) (1.53 (5, H 2.07 (2H), 9.74 (1H), 10.55 (6H). The corresponding salt of oxalic acid is 1- (2-dimethylamino) ethyl) 1-methyl-1,3,4,9-tetrahydropyran- (3, 4-b) -indole has a melting point of 181-183 ° C after recrystallization from methanol-ether.

In the same way, but replacing lithium aluminum hydride with an equivalent quantity of a mixture of aluminum hydride lithium aluminum chloride, diborane and sodium borohydride - aluminum chloride, the title compound is also obtained.

In the same way, but replacing N, N, 1-trimethyl-1,3,4,9-tetrahydropyran- (3,4-in) -indole-1-acetamide with an equivalent amount of the following amides described in Example 43.

1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetamide;

N, 1-dimethyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetamide;

K-hexyl-1-methyl-1,3,4,9-tetragyropyran- (3,4-b) -indole-1-acetamide;

N, -dimethyl-l-methyl-l, 3,4, 9-tetrahydropyran- (3,4-in) -indole-1-acetamide;

K-isopropyl-1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-acetamide;

N-ethyl-1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -inol-1-acetamide;

1- | I1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole-1-yl acetyl) pyrrolidine;

1-C 1-methyl-1,3,4,9-tetrahydropyran- (3,4-B) -indole-1-yl acetyl piperidine;

0

1- | 1-methyl-1,3,4,9-tetrahydropyran- (3, 4-in) -indole-1-yl-acetyl | morpholine and

1-methyl-4 | 1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indol-1-yl ace5-tipera-piperazine; get

1- (2-aminoethyl) -1-methyl-1,3,4,9-tetrahydropyran- (3,4-b) -indole with m.p. 80-84Cjr; 33455, 3280 cm; 1-methyl-1- 2- (methylamines, 3,4,9-tetrahydropyran- (3,4-b) 0 -indole with mp 160-163 s (mp. Corresponding oxalate 140-144 C);

(Hexylamine) ethyl -1-methyl-1, 3,4,9-totrahydropyran- (3,4-b) 5 -indole;

(diethylamine) ethyl -1-methyl-1, 3,4,9-tetrahydropyran- (3,4-in) -indole, so pl. 74-76 seconds, so pl. the salts of the compound of maleic acid 98-100 ° C;

0

(Isopropylamine) ethyl -1-methyl-1, 3,4,9-tetrahydropyran- (3,4-b) -indole;

(ethylamine) -ethyl-1-methyl-1, 3,4,9-tetrahydropyran- (3,4-b) 5 -indole;

1-methyl-1- 2- (1-pyrrolidinyl) -ethyl -1, 3,4,9-tetrahydropyran- (3,4-b) -indole;

NMR (CDCI) tf 1.62 (ZN); 2.00

0 (m, 4H), 4.05 (m, 2H); m.p. maleate 190-192C;

1-methyl-1- (2-piperidinoethyl) -1, 3,4,9-tetrahydropyran- (3,4-in) -indole with so pl. 14b-148s, m.p. of the corresponding maleate 147-149 ° C;

five

1-methyl-1- (2-morpholinoethyl) -1, 3,4,9-tetrahydropyran- (3,4-b) -indole;

NMR (DMSO ds) 1.50 (3N), 6.07 (2H), 5.87-7.65 (m, 4H), 10.86

0 (1H); m.p. the corresponding maleate 192-193 C; and 1-methyl-1- 2- (4-methyl-1-piperazinyl) -ethyl -1,3,4,9-tetrahydro-pyran- (3,4-b) -indole;

NMR (CDCIj), 47 (AH), 2.58

5 (ЗН), 3.87 (t, 2Н), tpl.sootvetstvuyu dimaleat 208-210 C.

Following the procedure of Example b4, but using the initial equivalent amount of one of the amides of the formula

0 1a of examples 44-53, instead of N, N, 1-trimethyl-1, 3,4,9-tetrahydropyran- (3, 4-b) -indole-l-acetone tida, the corresponding compounds of formula I are obtained. Examples of these compounds I are listed as products in the table. 4 vmes5

those with starting compounds of the formula Ta. In all cases, examples are given in which the starting compounds are obtained.

Example 65. 1, 9-Dimethyl - 1, 3,4,9-tetrahydropyran- (3,4-in) -indole-1-acetic acid. (1a, A - A, where. CH, and R H, R

R, R, R- and H, X O and

 CH

O Z)

1-Methyl-1,3,4,9-tetrahydropyran- (3,4-in) -indole-1-acetic acid (10 g, 0.04 mol) obtained in example 1, in 150 ml of tetragol lofuran is added dropwise m is added to a stirred suspension of sodium hydride (4.4 g of a 5% dispersion) in 200 ml of tetrahydrofuran. This mixture is heated at 50 ° C with stirring for 2 hours. Methyiodide (14.2 g, 0.1 mol) is added dropwise and heating with stirring is continued for another 2 hours.

After cooling, water is added until a clear solution is obtained. The tetrahydrofuran is distilled off in vacuum, the residue is partitioned between water and benzene, the native phase is washed once with benzene, acidified. HC6 and extracted with benzene 3 times. The organic phase is washed with water, dried over sodium sulfate and treated with charcoal. The organic layer is evaporated. The residue is recrystallized from benzene, then from ether-petroleum ether, to give the title compound with mp. 105-108 ° С NMR (CDCI,) G1,73 {S, ZN), 2.88 (t, 3 5.6, 2H), 3.0 (2H), 3.63 (ZN), 4.68 (t, a 5.5, 2H), 7.34 (4H), 9.47 (1H).

In the same way, but replacing methyl iodide with an equivalent amount of ethyl- or propyl iodide, you can obtain the N-ethyl analog of the title compound 9 ethyl-1-methyl-1, 3,4,9-tetrahydropyran- (3,4-b) - indole-1-acetic acid with m.p. 134-136 C and N-propyl analogue of the same compound 1-methyl-9-propyl-1, 3,4,9-tetrahydropyran- (3,4-b) -1- acetic acid with so pl. 120122 ° С accordingly.

According to the procedure of Example 65, but using as the source of soy, zincheni an equivalent amount of an acid of formula 1a (A-A), for example, from Examples 1-42, and using an equivalent amount of the corresponding organic halogen, an N-alkyronated acid compound is obtained. as target products in the table. 5 together with compounds 1a and organic halides used to prepare them. In all cases, an example is given in which the starting compound is obtained.

According to the method of example 65, but using B as the initial equivalent amount of zo ether compound 1a (A A, where R H) obtained before hydrolysis according to example 1 and 3-42 inclusive, instead of 1-methyl-1, 3,4,9 -tetrahydropkrene- (3, 3-in J -indol-1-acetic acid and, using an equivalent amount of organic halogen, receive the corresponding N-alkylated ester compound 1a (A / P, where R is lower alkyl).

According to the method of example 43, using as the source an equivalent amount of one of the N-alklirovanny acid compounds Ta of examples 65-76, inclusive, instead of 1-1 methyl-1, 3, 4, 9-tetrahydropyrac- (3, 4-b) -indole -1-acetic acid and, using an equivalent amount of an amine such as ammonia, a primary or secondary amine, from Example 43, an amide of the formula Ha is obtained, where A A and R are lower alkyl. Examples of such amines are given in table. 6

Example 105. 1,9-Dimethyl-1- 2- (dimethylaminoethyl) -1, 3, 4,9-hydropyran- {3., 4-b) -indole. (G, A

"

,

 And, where R CH,

R- CH, 2.; E 4-, „about. 3

And r

 H, X Oh, Alk

H

R

R

  , N {CH,) a)

A solution of N, N, 1.9 - tetramethyl-1, 3,4, -tetrahydropyran- (3,4-in) -idol-1-acetamide (12 g) in dry tetrahydrofuran (100 ml) is added dropwise to a stirred mixture of lithium aluminum hydride (5 g) in dried tetrahydrofuran (THF, 100 ml). The mixture is heated under reflux for 20 hours under a nitrogen atmosphere. To dilute the excess hydride, a mixture of water and THF was added (1: 1.50 ml). The mixture was filtered through celite, diluted with water (300 ml) and extracted three times with ether. The organic phase of cyiuaT over sodium sulfate is filtered and evaporated to dryness in a zakuum; get named in the title compound; NMR (CDCI) J 1.66 (3N), 2.70 (6H), 3.83 (3N);

Corresponding to - 1st 1, 9-dim €; tyl-1- 2- (dimethyl-fsho) ethyl -1,3,4, 9-tetrahydropyran- (3,4-in) -indole hydrochloride with so pl. 229-230 ° C obtained after recrystallization from methylene chloride

The title compound is separated with d-- and l-dl-p-toluene of succinic acid into the optical isomer () --1 p9-d} 1-methyl-1 -2- (dimethylamino) ethyl 1,3, 4,9-tetrahydropi-41, 5 wounds-- (3, 4-в) -indole, (a,) and its antigod with (+) s (cC) f) - 34.6 °.

According to the method of example 105, based on an equivalent amount of one of the K-alkylate) AH ar "1s of the formula Ga from examples 77-104, instead of N, N, .1,9-tetramethyl-1,3,4, 9-tetrahydropyran- (3,4-b) -indole-1-acetamide, receive the corresponding N-alipylamine amine compound of the formula I Examples of such compounds in the form of target products are given in table. 7 Example 129. 1-Methyl-1,3,4, -tetrahydropyran- (3,4-b) indole-1-carboxamide (1a, A A, where R R8 H, R and RS H, X O Z CONHj, ) According to the procedure of Example 1, but using trifluoride etherate as an acid catalyst and an equivalent amount of pyruvamide instead of ethyl acetoacetate, obtained from 1-methyl-1, 3, 4.9-tetrahydropyran- (3,4-c) indole-1-cage boxamide with t .pl. 1ba-1a9S after recrystallization from benzene-hexane, identical to the product from example 46. In the same way, the products listed in Table 2 are obtained. 3 and 4, but an equivalent amount of the starting compound E is used together with the corresponding ° C, -, fi-, (G-ketoamides. For example, use typed where R and, R, B BRH, Y OH) and as fb-ketoamide S, K-dimethyl acetoamide, is obtained identical to the product from Example 43 N, N, 1-trimethyl-1,3,4,9-tetrahydropyran- (3,4-c) indole-1-acetates Example 130. 1- (Aminomethyl ) -1-methyl-1, 3; 4,9-tetrahydropyran, where R and - (3,4-in) -indole (I, A And R8 H, R CHe, R, RR and R H, X O and AIKNR-R) A solution of 1-methyl-1,3,4,9-tetrahyd rrpyran- (3,4-in) -indole-1-carboxaldehyde (547 mg) of water: hydroxylamine hydrochloride hydrochloride (2.5 ml, 5 n .) and but water about atsetatanatri (2.5 mL 5N.) and methanol (5 ml) was heated at LP-Bo C 5 min, then held straight 4C for 16 hours. The precipitate was collected and blocked tallizovyvayut from ethanol / water. Get 1-methyl-1,3,4,9-tetrahydropyra - (3,4-in) -indole-1-carboxaldehyde with so pl. 176-178s. This compound (230 mg) in dry tetrahydrofuran (10 ml) was added dropwise to a mixture of a mixture of lithium aluminum hydride (200 mg) in 15 ml of tetrahydrofuran in an ice bath. The mixture was stirred for 1 hour and allowed to warm to room temperature. The excess lithium aluminum hydride is decomposed by careful addition of H2O / THF (1: 1). The insoluble material is collected on a filter and the filtrate is concentrated, the concentrate is washed with ether. The ether solution is dried over magnesium sulphate, filtered and concentrated; a title compound is obtained that is identical to the compound of the same name from Example 57. Example 131. 1-Methyl-1- 3- (1-pyrrolidinyl) propyl -1,3,4,9t-tetrahydropyran- (3,4-b) -indole - - R (H; A A, n, CHj, R, R, AIK (CH), -N (CH2) 4) To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene is added 5 -chloro-2-pentanone (12 g, 0.10 M). The mixture is heated in the presence of 200 mg of p-toluenesulfonic acid and hydrated with alkaline aluminum silicate (molecular sieves I 4). After 1 hour of reflux, another 400 mg of acid is added. After 2 hours, the reaction mixture is cooled, filtered and washed with 5% sodium bicarbonate, water, and dried over sodium sulfate. After evaporation in vacuo, an oil is obtained. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluent afforded 1- (3-chloropropyl) -1-methyl-1,3,4, 9-tetrahydropyran- (3/4-v) -indole; NMR (CDCIg), (fl, 33 (3N), 1.93 (4H), 2.75 (2H). A solution of this compound (250 mg, 0.9 mmol) in 10 ml of tetrahydrofuran and 1.5 ml of pyrrolidine is heated 16 hours. The mixture is concentrated in vacuo and the residue is partitioned between 5% sodium carbonate and chloroform. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound, identical to the product of Example 60. According to the procedure of Example 130, but based on an equivalent amount of the starting compound 1, for example, from Examples 1-42 include Of course, instead of tryptophol, and also using an equivalent amount of an appropriate, -or C-halo lactone of formula ji, and the corresponding amine of formula HNR R, compounds of formula I are obtained, for example, from examples 54-64, inclusive. -1 - methyl-1,3,4,9-tetrahydropyran- (3, 4gv) indole (G; A A, where H, R CB, R-, RR H, X O and Aik, He) e - 86 g, E; R, gripofol (3.86 R H and X -: OH) and acetamido acetone (3.0 g) in 300 ml of dry benzene are stirred and heated under reflux; water is collected in a Dean-Stark trap. After distilling off the water, 5 drops of etheraHa boron trifluoride are added and the mixture is heated under reflux for 30 minutes with the separation of water. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. Solid precipitate is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate solution, water, and brine.

The chloroform solution is dried with g-: magnesium sulfate ad, filtered and evaporated. The residue is crystallized from benzene to give 1- (acetamidomethyl) -1-methyl-l, 3, 4, 9-tetrahydropyran-- {3, 4-b) -indole with m.p. 100-102 ° C. This product is dried under vacuum at 27 ° C. Spectroscopic and analytical data have shown that the compound is solvated by 1 mole of benzene, which can be completely removed only when swimming. The Rf values for amide and tryptophol are the same. The resulting product (2.4 g) was dissolved in 80 ml of dry tetrahydrofuran and added to a suspension of lithium aluminum hydride in 200 ml of tetrahydrofuran. Then the mixture is heated under reflux and n: e-, stirred overnight. The reaction mixture was decomposed with 22.4 ml of water, added dropwise to 3 hours with stirring and cooling. Stirring is continued for another 1 h, the precipitate is filtered off, the filtrate is dried over magnesium sulfate. After distilling off the solvent, the title compound is obtained: NMR (DMSO-d ,,) S 1.18 (t, - ZN), 1.62 (S, ZN), 2.80 (t, 2H) identical to the product from example 58.

After recrystallization from isopropanol-ether, t. mp, 1- (ethyl 1 1ino) methyl -1-methyl-1,3,4,9-tetrahydropyran- {3,4-v) -indole hydrochloride 242-2430С.

Using the initial equivalent amount of the compound of formula p, for example, from Examples 1-42 inclusive, and using an equivalent amount of ketoamide of the formula R -CO-AIk-NR, secondary amines of the formula K A lM are obtained.

Example 132 a. 1-Methyl-i-nitromethyl-1, 3,4,9-tetrahydropyran- {3, 4-B) -indole (1a, A A, where. R16 and R n, R CHg, R, R, R and, CHgNO)

To a solution of 322 mg of tryptophol and 248 mg of nitro-2-propanone in 100 i-ui of benzene, add 5 drops of sterol boron fluoride and 3 drops of trifluoroacetic acid. The reaction mixture is stirred and heated under reflux with a selection of water for 18 hours. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water, sodium hydroxide solution and dried over magnesium sulfate. The solvent is distilled off, the residue is chromatographed on silica gel. After elution with chloroform, the title compound is obtained: f, - 3450, 1550 NMRSSO), b 1, b3 {S ,, 3H 2.84 (t, 2H), 4.10 (t, 2H).

By reduction of this compound with lithium aluminum hydride according to the method of Example 54, 1- (aminomethyl) -1-g of ethyl-1, 3,4, 9-tetrahydropyraH- {3, 4-b) -indole is obtained, which is identical to the product of example 57.

Poiman equiBent, electronic; the amount of the starting compound I, for example, from Examples 1-42, and using an equivalent amount of nitroketone R-CO-AlkNOo g, gives the primary amine of formula I.

- Example 133, 1 - {2-Aminoethyl) -1-methyl-1,3,4,9-tetrahydropyran- {3,) -indole (I, - A /, where

PJS H, R SNO ,, R, R

H- and R-f

 H, X 0, AlkNR CHjNH ,.).

1-Methyl-1,3,4,9-tetrahydropyran- (3,4-b) indole-1-acetamide (20 g, 0.817 mol) from ave.} Measure 43 is dissolved in dry methyl acid (400 t-ll) and, freshly prepared triethyloxo fluoroborate (17.0 g, 0.894 mol) was added to the solution at one time. The reaction mixture is interleaned at room temperature for 2 hours. The methylene chloride solution is washed with a cold aqueous solution of potassium carbonate, then with a solution of sodium chloride and the dried organic layer is evaporated in vacuo. The residue was dissolved in ether (150 ml). The solution is filtered, crystallization begins at room temperature; get ethyl-1-methyl-1, 3,4,9-tetrahydropyran- (3,4-in) indole-1-acetamide with t. square 1 39, 5-14 IC

This compound (4.79 g, 0.0176 mol) was dissolved in dry tetrahydrofuran (100 ml) and added dropwise to a stirred ice-cooled suspension of lithium aluminum hydride (1.75 g, 0.046 mol) in tetrahydrofuran (50 ml) . The reaction mixture is stirred overnight at room temperature, then dilute caustic sodium is added dropwise to decompose the excess hydride. The precipitate is filtered off, the filtrate is evaporated in vacuo and a precipitate is obtained, which is extracted with methylene chloride. The organic layer is washed with sodium chloride solution, dried over magnesium sulfate; concentration of the solvent and crystallization from ether gave the title compound with mp. 80-84 ° C; 0 J ;; 3455, 3280, identical to the compound of example 54.

Example 134. (Dimethylamino) ethyl-9-3-1-methyl-1,3,4,9-tetrahydrothiopyran- (3,4-b) -indole (1 A A, where R is C „H5- and Rle is H,

t1-1т / 1 i.

R and R 5 N,

H

- SP,

R

X S HAIk NR6R CHgCIijN (CHj) ,; ) (Dimethylamino) ethyl -1-methyl-1, 3,4,9-tetrahydrothiopyran- (3,4-b) -indole (822 mg) from example 62 is dissolved in 15 ml of tetrahydrofuran and 15 ml of benzene. Part of this benzene is distilled off to remove traces of water.

After cooling to, 140 mg of sodium hydride (suspension of 54% in mineral oil) are added and the mixture is stirred for 15 minutes. Alkylation is carried out by adding 350 mg of ethyl bromide and stirring the reaction mixture at 20 minutes. The resulting suspension was poured onto crushed ice, extracted with chloroform, the organic layer was washed several times with water and evaporated. Chromatography of the residue on silica gel (20 g) using chloroform-methanol (0-10%) yields the title compound, which, after recrystallization from ether, / hexane, has mp. 86-88 ° C ;:

, 27.65, 1600, 1568,

1537 cm; NMR (CDCIg), c 2.20 (S, 6H)

230 (w, 4H).

The hydrochloride (dimethylamino) ethyl-9-1-methyl-1,3,4,9-tetrahydropyran- (3,4-in) -indole has so pl. 220-222 C.

Using compound I (A A, where hydrogen), for example, from Examples 54-64, together with the corresponding organic halogen, other compounds of formula I are obtained (A A, where is lower alkyl).

For example, the effect on a compound of formula I with an equivalent amount of methyl bromide, instead of ethyl bromide,. gives 1,9-dimethyl-1- 2- (dimethylamino) ethyl-1,3,4,9-tetrahydrothiopyran- (3,4-b) -indole; NMR (CDCI), 72 (S, ZN), 6.40 (S, ZN), identical to the product from Example 124. M.p. 1,9-dimethyl-1- 2- (dimethyl but) -ethyl -1,3,4, 9-tetrahydrothiopyran- (3,4-b) -indole I hydrochloride I 244-246 ° C.

Similarly, using the same compound of formula 1 with an equivalent amount of propyl bromide, instead of ethyl bromide, gives (dimethylamino) ethyl 1-methyl-9-propyl-1,3,4,9-tetrahydrothiopyran- (3,4-b) -indole; NMR (CDCIj) t 1.03 (t, 3N), 1.83 (S, 3N), 2.22 (S, 6H), 4.14 (w, 2H), 7.22 (ui, 4H); m.p. the corresponding hydrochloride 243-245 ° C.

Example 135. 1-Methyl-1,3,4, 9-tetrahydro-indene (2,1-e) -pyran-1-acetic acid.

To a solution of inden-3-ethanol (8 g) and methyl acetoacetate (6 g) in 250 ml of dry benzene containing about 2 g of hydrated alkaline aluminum silicate (fJ24 molecular sieves add 1 mole of boron trifluoride etherate and the mixture is stirred at room temperature about 4 hours. Another 1 ml of boron trifluoride eterate is then added, the reaction mixture is stirred at room temperature overnight and heated under reflux for 1 hour. Hydrated alkaline aluminosilicate is collected on a filter, washed with 10% sodium bicarbonate solution and water After

drying over magnesium sulphate and benzene are distilled off in vacuo to obtain 1-methyl-1,3,4,9-tetrahydro-in- (2.1-e) -pyran-1-acetic acid methyl ester; l) 1724 cm-1

The hydrolysis of this ester to the title compound is carried out as follows. The ether (11.5 g) is dissolved in 400 ml of methanol and the solution is mixed with a solution of 12 g of sodium hydroxide in 100 ml of water, the mixture is kept overnight at room temperature, the methanol is distilled off, the residue is diluted with water. The aqueous solution is extracted several times with ether and acidified with 6 and. salty acid. The precipitate is extracted with ether. The ether extract is dried over magnesium sulfate, filtered and concentrated. The residue is crystallized from benzene and the above is obtained.

0 in the title connection with so pl. 179180С, NMR (SPS1z) (1.45 (S, 3N), 2.51 (sh, 2H), 2.73 (S, 2H), 3.25 (t, 2H), 4.02 (t, 2H ), 7.26 (sh, 4H), 9.80 (broad, 1H).

five

An equivalent amount of ethyl acetoacetate can be replaced by methyl acetoacetate in the procedure of this example; in this case, 1-methyl-1,3,4,9-tetrahydroindene (2,1-e) pyran-10-acetic acid ethyl ester is obtained as an ester.

Example 136. 1-Methyl-1,3,4,9-tetrahydro-indene (2,1-e) pyran-1-propionic acid.

A mixture of 15 g of inden-3-ethanol,

5 300 ml of dry benzene, 22.6 g of levulinic acid, 3 ml of boron trifluoride etherate and hydrated alkaline aluminum silicate (molecular sieve No. 4) are stirred at room temperature for 2 hours. The reaction mixture is filtered, the filtrate is washed three times with b, NaOH; the combined aqueous phases are washed twice with ether and acidified with cold dilute hydrochloric acid; the aqueous phases are extracted with chloroform, the extracts are dried over sodium sulfate and evaporated to dryness. The residue is crystallized from hexanether to give the title compound with mp. 97-99 ° C; x 1700 cm; NMR (CDCI) (f 1.4 (S, 3N), 2.2 (w, 4H), 2.5 (w, 2H), 3.25 (t, 2H).

Example 137. 1-Methyl-1,3,4,9-tetrahydro-indene (2,1-e) thiopyran-15-acetic acid.

A mixture of inden-3-ethanethiol (8.0 g), 6.0 g of methyl acetoacetate and 0.8 g of p-toluenesulfonic acid in 200 ml of benzene is heated under reflux for 5 hours using a water trap. After cooling, the reaction mixture was washed with 10% sodium bicarbonate solution and water. The benzene is distilled off in vacuo. The residue is methyl 1 methyl.

tyl-1,3,4,9-tetrahydro-in- (2,1-e) thiopyran-1-acetic acid g a. CM-

This ester was dissolved in 200 ml of metaiol and 100 ml of 1.25 N was added. NaOH. After stirring under reflux for 3 hours, the methanol is distilled off and the aqueous residue is extracted with ether. The aqueous layer is acidified with 6N. It is extracted with ether, the ether extract is dried over MgSO4, filtered and evaporated to dryness. The residue is crystallized from ether and the title compound is obtained. Mp. 117-121 °, with EPA 1700 cm.

La for obtaining other compounds of formula 1a, where A A, R, HF ,, R, R, X is the same as above. Z COOR or AIK -COOR °, where R and A Ik to the same as Bijuie, you can use the methods of examples 135 and 137. Examples of such compounds 1a are given in 6a, 8 BMBCTj; with and similar compounds of formulas 1 and III. In all examples, the ester obtained before hydrolysis is the corresponding ester of the compounds obtained from them.

Instead of ketoester of formula p, the equivalent amount of kego acid is used.

Table 1

N N N N NIN O.- nC, N N N N N o óoN N N N 0 un sn

H N N N about tertch :, Nd N N N N On-C.N 11N N N N 12N N N N

ABOUT

13

5-Vg

N N N, N

5-och,

N N N N

14

Formulas: 1,3,4,9-tetrahydropyran {3, 4-b) -indo.n,

end of Formula, I t, pl, ° C

one

. 1-methylcarboxylic

Sn „co acid, (see example 132) n – С„ Н

CH .; СН (СН „) С С ,, ,, Н .. С1,1 dimethylacetic - i / S acid, 154-156

(isomer A); 163-165 (isomer B}

Mr. 6-bromo-1-ethyluce

C, Nd. CH, acid, 182-184

Cn, 6-methoxy-1-methylCN .. acetic acid ,. 142-143; ,, Hj-} - ethyl acetic acid, 137-140. 1-propi-acetic acid, 148-151 s, H 1 isopropyl acetic acid, 150-152 H-methyl-1-propylacetic acid, 75-80, (isomer A), 146-148 (isomer B) CHj, CO with n 1 -fg-butylacetic l, Jn-lOO acid, .10-212 CH, iCO 5 H, 1-butylacetic acid, 121-127 - l 5 8-methyl 1-propylacetic acid, 127128 N H H H 5-OOSCH , O CH-H N H H H5-benzyl-OCH H N H N

18

6-CH „

N N N N

nineteen

N H N, H 5-NO, O CHCH (CH 3) CO H N H N O tert-CdNo SN. SO H H N O, - CHgCO H N H N

Continuation of table 1

Product, start of formula; 1,3,4,9-tetrahydropyran (3,4-v) -indole end of formula, t, mp, f С H-CjH CHjCO

He-SeN CHtCO 5 Methyl-propyl xucic acid, 157-158

HC, jH CHiCO 6-nitro-1-propylacetic acid, 119120 6-acetoxy-1-methyl acetic acid, 142-143 C H b-benzyloxy-1-methyl acetic acid, 163.5 CjHj 5-methyl-1-propylacetic acid, 177-178 with Н oL, 1-Dimethyl-acetic acid CjHj, l-gret-butylacetic acid CjHj 1-butylacetic acid 32Н Н Н Н Н7-CHj О H-CjH

5-Br O

33

N N N N

34

N N N N 5-OSN O

CH,

N N N N 5-OSOS O

35

CH.

36 N H ff H 5-ben-O

CH,

Zyloxy 37ININ4-CH O n-CH, H.J 38H AND H H6-JCHj O H-CHjH H H H H5-NO O n-C, co

40

P CH,

N N N N 41 N N N N 4-CHj O CH N N N N N 4-ce about MN SI with

44

.

(CH,), N, N, 1-trimethylpropionamide

2

NH ,, 1-methylcarboxamide,

four

47

5 ™: g,

(

48

Pyrrolone-1- {1-methyl) -propionyl 49 din-pyrrolidine

Continuation of table 2

CH with with H 6-bromo-1-ethylacetic

acid

CH 2 CHO 6-methoxy-1-methyl acetic acid

CH CO with H, 6-acetoxy-1-methyl-acetic acid

СН with С „H 6-benzyloxy-1-methyluk-2 5

succinic acid

(SI 1-methylpropionic acid

Table 3

N, 1-dimethylpropionamide, 149-15C 188-189

N-ethyl-1-methylcarboxamide

N, N-dimethyl-1-propylacetamide, 159-162 Cg HP 3 - methyl-1-propylacetic acid CH acid with 2 Well 5-methyl-1-propylacetic acid CH-CO 7-methyl-1-propylacetic acid GJ Hj 6 -nitro-1-propylacetic acid SN.CO. with H 1,5-dimethylacetic acid С Hj 5-chloro-1-methylacetic acid

25

3 3

(CHj), NH N, N, 1-tg1ime1 acetamide

24

NH

(CH) 2NH 24

44

45

46 47

48

49

50

51

52

54

728716

26

5 Affiliation t abl. 3 4N, 1-dimethylacetamide 182

1 methylcarboxamide

N, N-dimethyl-1-propylacetamide

Table4

1-methyl-1- 3- (methylamino) -propyl 5ShR (CDCIj) (1.48 (ZN), 1.87 (4HJ, 1.47 (ZN), mp. Corresponding oxalate 110 ° С

1-methyl-1- 3- (dimethylamino) propyl m.p. 114-116s; oxalate 168-172 ° C

1- (aminomethyl) -1-methyl 3465 3400, 3180, 2930, t.p. hydrochloride 251-252S

1- (ethylaminomethyl) -1-methyl NMR (DMSO-d) d 1.18 (3N), 1.62 (3N), 2.80 (2H), m.p. ; hydrochloride 242-243 0

1- (2-dimethylaminoethyl) -1-propyl, NMR (CDCI) 0.84 (i, 3N), 1.21 (3, LH), 2.79 (t, 5-5.5 cm, 2H), m.p. maleate 152-1-54 ° С

1-methyl-1- 3- (1-pyrrolidinyl) propyl, m.p. 124-127s

1-methyl-1- (2- (methylaminomethyl)

1-12- (dimethylaminoethyl) -1-methyl, m.p. 119-121 ° C

1- (aminomethyl) -1-methyl

(dimethylaminoethyl) -1-propyl

Table

Continued tab.

102 76

(CH) NH 103 72 Piperidine 104 74 Pyrrolidine 1, 9-dimethyl-1- 2- (methylamine) ethyl 1, NMR (CDCI), cf 1, 10 (IH), 1.66 (S, ЗН), 2.33 (S, ZN), so pl. bromide, 223-225 ° C 1- (2-a: minoethyl-1, 9-dimethyl-) 1570 cm (dimethylamino) ethyl-9-ethyl-1-methyl, NMR (CDCI), (5 1.39 (ZN ), 1.70 (3N), 2.75 (t, 12H), mp. 202-205 1 hydrochloride (2-dimethylamino) ethyl-9-ethyl-1-methyl-, NMR (CDCl-}); cf 1.39 (ZN), 1.70 (ZN), 2.75 (t, 12H), hydrochloride, m.p. 202-205s 9 ETHYL-1-methyl-1-2- (methylamino) ethyl NMR ( CDCI,) cG 1.6 (ZN), 2.30 1 (2-a1 danoethyl) -9-ethyl-2-methyl j NMR (CDCI), S 1.02 (t, ZN), 1.62 ( S, ZN) (dimethylamino) -ethyl -1-glutyl-9-propyl i NMR (CDCIj), cf 1.00 (t, 3N), 1.65 (S, 3N), mp. Maleate 125-126 ° C 1,9-dimethyl-1- 3- (dimethylamino) -propyl, NMR (CDCI) cf 1.60 (3N), 2.68 (6H), mp 115-118 ° C 1.9 -dimethyl-1- 3- (methylamine) propyl, MP (CDCI,)), t 1.6 (3N), 2.9 (3N), 3.6 (3N TP, mp: 194-196 julohydrate 1 2- (; 1methylamino) ethyl -1.5, 9 - trimethyl; NMR (SPSIz), if 1.63 (S, ZN), 2.20 (S, G), 2.67 (S, ZN), 2.74 (S, ZN), tg, maleate 144-145 ° C 6-benzyloxy-1- 2- (dimethylamino) methyl-9-ethyl-1-methyl-, NMR (CDCr.), Cf 1.38 (t, i7, ЗН), 1.62 ( S, ZN), 2.18 (S, 5H), so pl. hydrochloride .216-217 C

Continuation of table 6

6-MetOxy-N, N, 1,9-tetramethylacetamide

Table 7 3369, 1- (1, E-dimethyl) acetyl piperidine 1- {1-methyl-9-propyl) propionyl pyrrolidine

3372871634 11689 11790 11891 119- 92. 12093 12194 12295 12396 12497 12598 12699 127100 128101

Continuation of Table 7. 5-HLOR-1- 2- (dimethylamino) -ethyl-1,9-dimethyl NMR (CO1e), (f 1.63 (S, 3N), 2.18 (S, 6H), 3, 72 (S, 3N), mp. Maleate 148-151 with 6-benzyloxy-1,9-dimethyl. (Dimethylamine) ethyl - (NMR (CDCIa), d 1.60 (S, 3H), 2, 17 (S, 6H), 3.68 (S, 3N), 5.12 (S, 2H), mp 238-239 ° C hydrochloride 1.9 dimethyl -1-2- (dimethylamino) ethyl-6 -methoxy, NMR (CDCIg), (f 2.60 (S, 3N), 3.65 (S, 3N), mp. maleate 109-111 ° C 1.9 - dimethyl -1-2- { 1-pyrrolidinyl) ethyl NMR (COCl 3), 1.62 (S, 3N), 3.74 (S, 3N), mp 230-231 ° C hydrochloride 1,9-dimethyl-1- (2-piperidinoethyl ) -; NMR (COClS), tf 1.61 (S, 3N), 2.32 (w, 6H), 9.81 (w, 2H), mp 233-235 C hydrochloride 1.9- dimethyl-1- (2-morpholinoethyl); NMR (CDCI ,,), (f 1.62 (W H), 2.77 (2H), 2.72 (3N), mp. 230-23lC hydrochloride 1,9-dimethyl-1-G2- (4-methyl-1-piperazinyl) ethyl f NMR (CDCI, ,) rf 1,56 (S, ЗН), 2,22 (S, ЗН), 2,8 (S, 8Н), so pl. dimelate 194-195 ° С 1,9-dimethyl-1 -2- 4- (2-hydroxyethyl) -1-piperazinyl-ethyl, NMR (CDCIj), if 1.60 (S, 3N), 3.70 (S, 3N)., Mp. dichlorohydroxide 219-220C 1,9-dimethyl-1- 2- (dimethylamino) ethyl, NMR (COCl 3), (f 3.72 (S, 6H), E, 40 (S, 3N) so pl. hydrochloride 244- 246 C 1,9-dimethyl-1- 2- (methylamino) ethyl, NMR (CDCI ,,), rf 1.82 (ZN), 3.01 (sh, 4H) 1- (2-aminoethyl) -1, 9-dimethyl 1,9-dimethyl-1- 2- (hexylamino) ethyl-1 (diztilamino) ethyl-1,9-dimethyl 209

CH CO

N N N N N 210N N N N N С С С

211НН Н Н Н

BUT WITH S N he with with: N ,. H N H N H of the invention 1 Method for the preparation of derivatives of condensed indoles or indenes of the general formula Alk-NR B where R is lower alkyl, R, R are the same or different and are hydrogen or lower alkyl; R ° and R are the same or different and represent hydrogen or lower alkyl, or -H and together with the nitrogen atom to which they are attached form a heterocyclic amine radical, for example 1 pyrrolidinyl, piperidine, morpholine, pipeResin, 4- (lower alkyl) -1-piper;) or 4-hydroxy- (lower alkyl) -1-yiperidinyl: - alkylene in the form of CR "R, CR" RCR ", CReRcR V CR R - or CR R CR CR CRVcR% - ", Where S, R, RR, R R - water is a genus or lower alkyl, X is a hydroxy or thio group, A is a bivalent radical of the formula

T a b l and c a S

Product: form start (1,3,4,9 tetragndroinden (2,1-e) pyran-1 (end of formula j

S, N.- 1-methylcarboxylic

ACID, T.PL.

14 1 -1 4 W-C

C H 1 methylcarbo. New acid H 1-proploxyacetic acid, T.PL. lai-lSS C 1-ethyl acetic acid hydrogen or lower alkyl; lower alkyl, is hydrogen, lower alkyl, hydroxy, lower alkoxy, extreme al-anoyloxy, or halogen, in that the compound of formula also R, R.; R and R have the indicated meanings. At QKCK-, mercaptogenep or -S-SO K, they are connected by a ford-W connection, where R has the indicated. value; Z is: a) AIlv-NR R, where Ab. R and R have the indicated 31 c) COOR 9 or AIk-COOR, where n is alkyl, is alhydrogen or lower R Vi cE-VV Rfle R R9, cn, kiloin. R R is hydrogen or lower alkyl c) CONR RT or Aek - CONR R. where Alk, R and R have ugchazamae otherwise) d e) where Alk - alkylene s form. CR "R CHR CR VcHir or

CR Rc / V; CR-R-CHRn where R ", R, R", k, R and R have the indicated meanings;

L is halogen;

f) AlkHR COR, where Alk and R have the indicated values, and hydrogen or lower alkyl with 1-5 carbon atoms, or

e) AIk-NO2-Alde has the indicated meanings; in the presence of an acidic catalyst with the release of the compound of formula 1a thus obtained

I r

X I; -i

A T P

with ,

R4

where A, R, R, R, R, X - have the indicated meanings, and Z - AlkNR R, where R and R have the indicated meanings or with further transformation of the compound of the formula Ha for the remaining values of the radical Z in the compound of the formula 1.

2. Method POP.1, characterized in that p-toluenesulfonic acid, boron trifluoride etherate or phosphorus pentoxide is used as a catalyst.

Priority featured

01.13.72 when: R is lower alkyl, R, R, R and R are the same or different, are hydrogen or lower alkyl, R and R are the same or different, are hydrogen or lower alkyl, or

R and R, together with the nitrogen atom to which they are attached, form a heterocyclic amine radical, for example 1-pyrrolidinyl, piperidine, morpholine, piperazine 4- (lower alkyl5) 1-piperazinyl or 4-hydroxy- (lower alkyl) -1- piperazinyl; Alk-alkylene in the form of CRR, CR RCR ° R - CR "R or

 where R, R, R, R, R, R is hydrogen or lower alkyl, X is hydroxy or thio, U is hydroxy or mercapto, A is a bivalent radical of formula A

15

where R ° is hydrogen, or lower alkyl, R is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, or halo;

14.02.72 with A - a bivalent radical of formula Aa

 BUT.

where lower alkyl, R - has the indicated meanings;

12.10.72 with A - a bivalent radical of the formula A

/ de has the indicated meanings;

12.10.72 when: Y is the group —S — SO Na or —S — SOgK.

Claims (2)

The claims ^ A method for producing derivatives of condensed indoles or indenes of the general formula R ⁵ At ⁴ J ⁵² In ¹ ΑΙΚ-ΝϊνΒ where R * is lower alkyl, R ⁴ , R ³ , R ⁴ R 'are the same or different and are hydrogen or lower alkyl; R® and R ⁷ are the same or different and represent hydrogen or lower alkyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocyclic amine radical, for example 1-pyrrolidinyl, piperidine, morpholine, piperazine, 4- (lower alkyl) -1-piperazi'NYl or 4-hydroxy- (lower alkyl) -1 “yiperazinyl: А £ к - alkylene in the form of CR ⁰ R, CR ^S R ⁹ CR ' ^, ° R' ^m , CR ^B R ⁹ CR ^No. R ^ CR ^fc R · ' ^{3 0} - * bA ^,' where R®, R ^ HR ^{* * * * * * * * * * 45 *} '- soda or radical CR ⁰ R to 'ik tc o OR CR ⁸ R ⁹ CR ^ CR ^ CR'kR ¹³ ! R ⁹ , R '* ⁰ , R *, R ¹² , R ^1? ,] genus or lower alkyl, X thio group, A - divalent formula / 6 where R is hydrogen or lower alkyl; R ⁴⁷ is lower alkyl, R ^ie is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, or halogen, characterized in that the compound of the formula C β-CR ⁴ K ⁵ CA * K ³ -T where 13 is monovalent radical form — where r '*', R ^u k R ^{, a} , as well as R ”, R ', R'” and R ⁹ have the indicated meanings, Y ~ qkck-, mercapto group S-SOgNa or -S-SOjK, processed a compound of formula W H ¹ -CO-z, where R has the indicated meaning; Z - represents: a) AIk-NR. ⁶ R ⁷ , where A ^ k, R '' and P? have the indicated values; f) COOR ⁴⁹ or Aik ¹ —COOR ', where R' is hydrogen or lower alkyl, AIK ¹ ~ alkylene in the form of CR ^e R ⁹ , CR® R ⁹ CR ^{, i?} R ^{f <} or CR. ^e R ' ^? CR ^W R ' ^t ' ⁱ CR ' ^{! 2} R' ⁱ - _f where R *, R ⁹ , K ⁴⁰ , rf *, R **, R ¹ is hydrogen or lower alkyl; c) CONR ⁶ R ⁷ or Aek ⁷ -CONR ^ R ⁷ , where A'Hk ⁴ . r6 and R have the indicated meanings ^; go go d) CH _a OCOR or -CH Aik _J OSOE where R is hydrogen or lower alkyl or Aik 'and ^ h as indicated meanings; e) Afk ^ —L *, where AEk ^x is alkylene in the form. CR * R ⁹ CHR ^ic , CpAr ⁹ CR ffCHR ⁴² or CR "R ⁹ CR ⁵ V'CR ⁷² R ¹³ CHR ⁷⁴ , where R" r 'r ⁷ ° d12. _d 13 „14 '' ^K f ^K r ^K ' ^K ' ^{R AND R} have the indicated meanings; L is a halogen; f) AIkNR ⁶ C0R, where Al.k and R ⁶ have the indicated meanings, and R ²⁷ is hydrogen or lower alkyl with 1-5 carbon atoms, or e) Aik — NO ₂ , where A1k has the indicated meanings; in the presence of an acidic catalyst, isolating the resulting compound of formula 1a where A, R, indicated where R ⁶ or compounds of I. 2. R ^{5 x} C G. V a. V R ¹ R ² , R ³ , R ⁴ , RX - have the meanings, and Z - AIkNR ° R ⁷ , and R ⁷ have the indicated meanings, by further converting the co-formulas Ta to the remaining radical Z in the compound of form U 3. Λ s' ² F The method of pop. 1, characterized in that p-toluenesulfonic acid, boron trifluoride etherate or phosphorus pentoxide are used as a catalyst. The priority according to the characteristics of 13.01.72 when: R ⁹ is lower alkyl, R ² , R ³ , and R ⁵ are the same or different, represent hydrogen or lower alkyl, R ⁶ and R ⁷ are the same or different, represent hydrogen or lower alkyl, or