SU1731047A3 - Method for synthesis of carbazole derivatives or theirs physiologically acceptable salts - Google Patents

Abstract

The invention relates to carbazole derivatives, in particular the preparation of compounds of the general formula Qx AA-B-l - (A, l HYKH T Hi where, C | CЈ-alkyl, C 3 -C 6 alkynyl, C C7 cycloalkyl-C-C - alkyl, phenyl-Cj-alkyl; n 2 or 3; R 2 C -Cg-alkyl; or halogen; A-B-group CH-CH - or., or their physiologically acceptable salts capable of acting on 5-hydroxytripre receptors - Tamine (5-HT), localized at the ends of the primary sensory nerves. “The goal is to create new active substances of the indicated class. but with hydroxyl or its protected derivative, to produce substance B-group: followed by hydrogenation of the double bond and obtaining the group hCH-CH -, removing, if necessary, the protective group by dividing the mixture of enantiomers into individual enantiomers, transferring the free base to the desired salt New substances effective without causing undesirable actions (low toxicity) about the following

Description

at room temperature and atmospheric pressure on 10% palladium oxide on coal 100 mg for about 5 hours. The catalyst is filtered and washed with additional ethanol 100 ml. The filtrates are combined and evaporated to give a resin of 0.4 g, which is purified by PCC extraction. System A (200: 8: 1) to obtain an oil of 0.32 g. The oil is dissolved in 15 ml of absolute ethanol and treated with a solution of maleic acid 120 mg in ethanol. The resulting solution is concentrated to approximately 5 ml and diluted with 5 ml of dry ether to precipitate targeted Oh product 0.41 g, Toplo 160 - 162 ° C.

Found,%: C 64.9; H 6.0; N 9.0

C, H2, M30-C4H404

Calculated,%: C 65.2; H 6.0; N 9.9.

Example 11 1,2,3,9-Tetrahydro-E-methyl-3-Ј (1H-imidazol-4-yl) methyl | -4H-carbazol-4-one maleate.

A solution of 1,2,3,9-tetrahydro-9-methyl-3- (1H-imidazbl-4-yl) methylene - 4H-carbazbl-4-one 1.37 g in ethanol 100 ml are hydrogenated at atmospheric pressure and room temperature on a 10% palladium on charcoal catalyst (50% aqueous paste, 130 mg) o After about 30 minutes, a precipitate forms, 30 ml is added to dissolve the precipitate again. The mixture is stirred further for 4 hours and then filtered. The filtrate is treated with maleic acid 569 mg and the resulting solution is evaporated to form a solid, which is recrystallized from a mixture of methanol and ethyl acetate to obtain the desired product 1.35 g, m.p. 175 -,.

0

stirred for 2 hours. Water 50 ml is added and the suspension is extracted with 3x25 ml dichloromethane. The United 0 dried organic extracts are evaporated to an oil of jx 800 mg, which is dissolved in a mixture of THF 10 ml, acetic acid 10 ml and water 10 ml and Heat at reflux 5 for 1.5 hours. The mixture is poured into a saturated solution of potassium carbonate 60 ml and extracted with 3x30 ml of dichloromethane. The combined dried organic extracts were evaporated to give an # 800 mg oil, which was purified by PCM extraction using System A (200: 10: 1) to form a 188 mg foam. The foam was dissolved in ethanol 3 ml and treated with a solution of maleic acid 64 mg in ethanol 0, 5 ml. Solvent 5 is removed in vacuo and the residue is dissolved in dry ether of 5x5 ml to give the desired product 195 mg, m.p. 157 - 158 ° С.

Found,%: C 61.4; H 5.7; N 11.8 „C20H-Z2N402-C4H404 Calculated,%: C 61.8; H 5.6; N 12.0.

Examples 13 and 14 are carried out in a manner similar to Example 12.

Example 13. 1,2,3; 9-Tetragde- (5-methyl-1H-imidazol-4-yl) meth- THrtJ-9- (phenylsulfonyl) -4H-carbazol-4-one maleate.

The intermediate product 7,500 mg reacts with benzenesulfonyl chloride 0.15 ml to form the desired product 215 mg, so pl. 154 - 156 ° Sa

Found,%: C 60.3; H 4.7; N 7.5. CZ3H2 "N, CyC4H404 Calculated,%: C 60.6; H 4.7; N 7.9.

Example 14. Methyl 1,2,3,4-tetrahydro-3- (5-methyl-1H-imide azol-4-aA)

0

S

0

five

nineteen

methyl-4-oxo-9H carbonol 9-acetate is less than „

The intermediate product 7 500 mg reacts with methyl chloroformate 0.09 ml with the formation of the target product 155 mg so pl. 167 - 168 ° Co

Found,%: C 60.8; H 5.0; N9.1.

CWH19N30, -C |) H404 Calculated,%: C 60.9; H 5.1; N 9.3.

Example 15 1,2,3,9-Tetragid-Ј (5 methyl 1 H-imidazbl-4-yl) Ae- (2-propylene) -4H-carbazol-4-one maleate.

A solution of the intermediate product 7 500 mg in dry DMF 10 ml is added dropwise to a stirred suspension of sodium hydride (73% oil on dispersion, 36 mg) in dry DMF under nitrogen and the resulting suspension is stirred at room temperature for 30 minutes, then the solution allyl bromide 121 mg in dry DMF 1 ml is added and the resulting solution is stirred at room temperature for 1 hour. The reaction mixture is then poured into water 500 ml and extracted with 4x100 ml dichloromethane. The combined organic extracts are washed with water 3x250 ml, dried and late triple to form an oil, which is dissolved in a mixture of THF 5 ml, water 5 ml and acetic acid 5 ml and heated with a freezer for 1.5 h. After cooling, the solution is basified with 2% sodium carbonate solution and then extracted dichloromethane (2x50 ml). The combined dried organic extracts are concentrated to an oil, which is purified by FCS and extracted with system A (150: 8: 1) to obtain the free base of the desired product 151 mg as a solid,. The solid is dissolved in dry methanol 20 ml, maleic acid is added 55 mg and the resulting solution is heated on a steam bath for 10 minutes. The solution is then cooled, tO ml of ether is added to precipitate the desired product 174 mg, m.p., 194-196 ° C

 ,

-,

ten

15

73104720

III-imidazole 4 yl) methyl 4H carbazol-4-one maleato

Boron tribromide (1M in dichloromethane; 1.4 L) is added dropwise to a cold (0 ° C) stirred solution of 1, 2,3,9-tetrahydro-A-6-methoxy 9-methyl-3-X5-methyl -1H-imidazol-4-yl) methyl-4H-carbazbl-4-one 150 mg in dry dichloromethane 15 ml under nitrogen. After 1 hour, 10 ml of methanol is added and the solution is evaporated. The residue is purified by PCH extraction system A (100: 10 : 1) to obtain a solid substance 83 mg, which is dissolved in ethanol "20 ml and treated with a solution of maleic acid 32 mg in ethanol 2 ml" The solvent is removed in vacuum and the residue is triturated to dryness D Sx 20 25 ml to give 90 mg of the title product, m.p. 197 - 199 ° C, TLC (system A 100: 10: 1) Rf 0.33

Example 17, 1,2,3,9-Tetrahydro-3-Ј (5-methyl 1H-imidazl-4-yl) 25 (phenylmethyl) -4H-carbazb4-one maleate

A solution of 1, 2,3,9 tetrahydro-iZ-Ј (5 methyl-1- (triphenylmethyl) 1H imidazol-) methyL-9- (phenylmethyl) -4H-carbaza6ll4-it 240 mg in a mixture of acetic acid 7 ml, 7 ml of water and THF 7 ml are heated under reflux for 2 hours. The mixture is poured into 40 ml of saturated potassium carbonate solution and extracted with 3x20 ml of dichloromethane. The combined dried organic extracts are evaporated to obtain a 256 mg solid, which is purified by HCl elution with A (200: 10: 1) to obtain a solid substance 99 mg ". It is dissolved in ethanol 3 ml and treated with a solution of maleic acid 33 mg in ethanol 1 ml. The solvent is removed in vacuo and the residue is triturated in dry ether to obtain the desired product 128 mg, mp 142-144 ° C. Water content found: 0.27% w / v 0.07 moth NgO.

Found,%: C 68.7; H 5.6; N 8.5.

Cr, H „M50 C4H, 0, -0.07 H20

Calculated,%: C 69.1; H 5.6; N 8.6.

thirty

35

40

45

50

Found,%: C 65.7;

and

SgoN

„N, 0-C“ H, 0,

H 6.0; N 9.3.

N

Calculated,%: C 66.1; H 5.8; 9.65.

Pr, Immer 16. 1,2,3,9-Tetragidro-6-hydroxy-9-methyl-3- (5-methyl-

55

Examples 19 and 20 were carried out in a manner similar to Example 18, from the corresponding protected intermediates.

Example 18 9- (Cyclopentylme-, thyl) -1,2,3; 9-tetrahydro-3- (5 methyl21

1H-imide green.-4-yl) methyl -AN-Csarbazbl-4-one maleate.

Deprotection of 1,2,3,9-tetrahydro 9- (cyclopentylmethyl) -3-метил5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl me tLg H-carbazbl-H-255 mg gives free base target product 127 ug Maleate form gives the target product 144 mg, Topl. 178 - 180 ° C. Found water content: 0.37% w / wU 0.1 mol H20.

Found,%: C 67.3; H 6.2; N 8.9.

 H20

Calculated,%: C 67.7; H 6.6; N 8,8.

 EXAMPLE 19 1,2,3,9-Tetrahydro-3-K5 methyl-1H-imidaebl-4-yl) methyl-9- -propinshO-H-carba ol-one maleate.

Deprotection of 1,2,3,9-tetrahydro 3 5-methyl 1- (triphenylmethyl) -1H-imidazol-4 yl3-9 (2-propynyl) -4H-carbazbl--one 90 mg and PCF purification gives the free base of the target product 30 mg. Maleate form gives the target

one

product 40 mg, so pl. 189-191 C. water holding found 1.4% w / wE 0.34 mol.

Found,%: C 65.0; H5.4; N 9

CMH, ", Ny С4Н40" 0.34 H0-0.125 OH

Calculated,%: C 65.4; H 5.5; N С2Н

and 9.4.

EXAMPLE 20 (E) -1,2,3,9-Tetrahydro-9-methyl-3-Ј (5-methyl-1H-imidazol-4-yl) methylene-4H -carbazble-4-one methanesulfonate.

Lithium diieopropylamide (from n-butyl lithium, 1.55 M in hexane; 57.3 ml) and diisopropylamine 11.64 ml in THF 45 ml are added dropwise over 15 minutes, at-5 ° C under nitrogen to 1,2,3,9-tetrahydro-E-methyl-4H-carbazole-4 mixed suspension, 15 g in THF 510 ml. After 45 minutes, intermediate 2 was added to 26.5 g in one portion and the resulting solution was transferred at -5 to 1.75 hours. The solution was treated with acetic acid at below 20 ° C and stirred for 1 hour. 34 ml of methanesulfonic acid and the mixture is stirred and heated under reflux for 16 hours. The resulting suspension is cooled to 5 ° C, stirred at lower 5 ° C for 1 hour and the solid is filtered off. The product is washed with THF (2x50 ml) and dried in a vacuum.

1047

at 50 ° C, substances 28.5 are called from

22

to obtain a solid weight, which is recrystallized - methanol to produce a

.

left product 17 g, so pl. 164 - 267 ° Co

Found,%: C 54.5; H 5.3; N 9.75

C18H, TY3OCH, 4 CH40

Calculated,%: C 54.7; H 5.35; N

ten

15

20

25

9.9,

PRI me R 21 about 1,2,3,9-Tetragde ro-E-methyl-3- (5-methyl-1H-imidazol-4-yl) -methyl / -4H-carbazole 4- he.

A solution of (E) 1,2,3,9 tetrahydro-9 methyl 3 Ј (5-methyl-1H-imidaz6l 4-yl) methylene | methanesulfonate 10 g in methanol 150 ml and triethylamine 3.6 ml are hydrogenated at room temperature. temperature and atmospheric pressure on a catalyst suspension — previously reduced 1 (1% palladium oxide on carbon (aqueous paste; 1 g) in methanol 10 ml. The mixture is then filtered, concentrated to 100 ml and heated under reflux. Water is added 50 ml and the solution is cooled to 0 ° C. The solid obtained is 6t filtered, washed with water Ј 50 ml and dried in vacuum at 50 ° C. Acquiring the desired product 3.80 g

f H-NMR and TLC of this material correspond to the same data obtained for the product of example 7.

EXAMPLE 22 1,2,3,9-Tetrahydro-3-Ј (5-methyl-1H-imide C Ol-4-yl) 35 type -9-4H-carbazol-4 - it hydrochloride monohydrate.

A suspension of 1,2,3,9-tetrahydro 3-t (5-methyl-1H-imidazbl-4-yl) methyl-9-methyl-4H-carbazol-4-one 20 g in an IMS 200 ml heated to boiling and 2 and hydrochloric acid 50 ml is added. The resulting solution is allowed to

20 ° С, obtained in suspension for 1 hour and after-° C for 2 hours.

The product is filtered and dried in vacuum at 55 ° C to obtain the desired product (20.8 g, live),

Found%: C

thirty

40

45

cool until this is stirred they are cooled by

50

getting

m.p. 290 ° C (decomposition 62, 1; H 6.25; N

12.05; C1 9.85.

C H N O-HCl-HgO

g Calculated,%: C 62.5; H 6.4; N

12.15; C1 10.25.

j EXAMPLE 23, (+) - 1,2,3,9-Tetra-, hydro 9-methyl-3- (5-methyl-1 H-imidazbl4-yl) metsh G-4H-carbazbl -4-on.

A solution of (i) -1,2,3; 9-tetrahydro-9-methyl-3 5 (5-methyl-1H-ipidazol-4-yl) methylZ 4N carbazol-4 it) 500 mg in warm methanol 30 ml is treated with a solution (+) 2} 3-bis GA-methyl-phenyl) -carboxy-LoxyT-butane acid 690 mg in methanol 10 ml and the solution is allowed to stand at 0 ° C for 3 days. Then it is filtered to isolate a solid, which is recrystallized from methanol to obtain required salt 195 mg, t pl. 146 - 148 ° C. A portion of this salt, 186 mg, is suspended in 10 ml of water and a solution of potassium carbonate 1 g in 15 ml of water is added and the mixture is extracted with 2x40 ml of dichloromethane. The collected dried organic extracts are evaporated in vacuo to isolate the desired product 79.2 mg as a solid. substances. tsi 230 - 232 ° C g °

ten

15

+ 49.7 ° (С 0.41%, СНС13)

W

25

thirty

35

40

EXAMPLE 24 0 () -1,2,3,9-Tetra-hydro-9-methyl 3 (5 methyl 1H-imidazl 4-yl) methyl-4H-carbazole-one.

A solution of (4) 1,2,3,9-tetrahydro-9-methyl-3 (5-methyl 1H) -imide azol-4-yl) methyl-4H-carbazbl-4-one 500 mg in warm methanol 30 ml is treated a solution of () 2,3-bis-G (4-methylphenyl) carbonyl-1-butanedic acid 690 mg in methanol 10 ml and maintain the solution at 0 ° C for 3 days "Then it is 6t-filtered to isolate a solid, which is recrystallized from methanol to obtain the desired salt 162 mg, t „PL„ 147 - 149 ° С. The salt is suspended in water 15 ml and a solution of potassium carbonate 1 g in 10 ml of water is added, and the mixture is extracted with 2x30 ml of cichloromethane. The collected dried organic extracts were evaporated in vacuo to isolate the desired product 72.5 mg as a solid, mp. 230 - 232 ° C, cQ 45 -47.4 ° C (C - 0.44%, СНС15).

PRI mme R 25. 1,2,3,9-Tetrahydro-9-metshKZ Ј (5-methyl-1H-imidazdl-4-yl) methyl 4H-carbazol-4-one „

A solution of the intermediate product 7 190 mg in dry DMF 1 ml is added dropwise to a stirred suspension of sodium hydride (52% dispersion in oil; 20 mg) in dry DMF 0.4 ml under nitrogen. After 15 minutes, methyl iodide is added. 0.027 ml and the mixture is stirred for 1.5 hours. Water is added to 20 ml and the suspension is extracted with 3x10 ml of dichloromethane. United

2Q

55

50

0

five

five

0

five

0

five

The dried organic extracts are evaporated to give A300 mg of an oil, which is dissolved in a mixture of THF 4 ml, acetic acid 4 ml and water 4 ml and heated under reflux for 1.5 hours. The mixture is poured into 20 ml of sodium carbonate saturated solution and extracted with dichloromethane 3x10 ml. The collected dried organic extracts are evaporated to form a semi-solid, 255 mg, which is purified by CCP with elution with System A (200: 10: 1) to form the desired product 7 mg. H-NMR and TLC of this material correspond to the analogous data obtained for the product in Example 7

EXAMPLE 26o 1,2,3; 9-Tetragid Q po-E-methyl-3- (5-methyl-1H-imidaz6l) mets1 4H-carbazol-4 on.

A solution of 1,2,3; 9-tetrahydro-9-me- (5-methyl- (triphenylmethyl) -1H-imidazol-yl) methylcarbase-it-268 mg in a mixture of glacial acetic acid 5 ml, THF 5 ml and 5 ml is heated at 100-110 ° C for 8 hours. After cooling, 2N sodium hydroxide solution is added to 50 ml and the resulting suspension is extracted with dichloromethane 2x50 ml. The collected dried organic extracts are concentrated to a foam, which is purified by PCE by elution with System A (100: 8: 1) to form the desired product 114 mg as a solid H-NMR and TLC of this material correspond to the analogous data obtained for the product in Example 7.

Example 27o 1,2,3,9-Tetrahydro-ro-E-methyl-3- (5-methyl-1H-imidazol-1 4 -yl) -methyl-4H-carbazol-4-one.

A solution of N, N, 5 trimethyl-4- Ј (2,3,4, i9-tetrahydrol 9-methyl-4-oxo-1H-carbazole 3 yl) methyl-1H-imidazol-1-sulfonamide 400 mg in 2 n Hydrochloric acid 30 ml and absolute ethanol 5 ml is heated at 100-110 ° C for 8 hours. Processing and PCF, as described in example 30, gives the target product 261 mg in the form of solids. The n-NMR and TLC of this material correspond to those obtained for the product in Example 7.

EXAMPLE 28 1,2,3,9-Tetragde-5 (5 methyl 1 and imidazol-4-yl) methyl} -9-methyl-4H-carbazbl-4-one.

A solution of products from the intermediate 16 0.2 g in 49% bromo-acid; 3 ml is stirred at

0

25

for 30 min. The mixture is then heated on a steam bath for 30 min and gently boiled under reflux C for 1.5 h. The mixture is diluted with water 20 ml and washed with ethyl acetate (2 x 20 ml; discarded) with acidic water. the phase is basified (to pH 9) with sodium carbonate and extracted with ethyl acetate: ethanol (20: 1-, 2x30 ml). The collected dried organic extracts are evaporated to a solid, which is triturated in dry ether with 5 ml to give the desired product 0.09 g in the form of a solid H-NMR and TS of this material correspond t to similar data obtained for the product in Example 7

PRI me R 29 "1,2,3,9-Tetragidro-3Ј (5-methyl-1H-imide z ol-4-yl) methyl 9-methyl 4H-carbazol-4-it

Solution of products from intermediate 17 0.5 g in a mixture of absolute ethanol 20 ml and 2M hydrochloric acid 10 ml is heated on a steam bath for 1 hr. The resulting solution is concentrated in vacuo to about 20 ml, diluted with water 40 ml and washed with ethyl acetate ( 2x40 ml; discarded) o

Biological research

Antagonism of the reactions caused by 5HT in neuronal 5HT receptors by the proposed compounds can be determined in vitro. The results of such tests are expressed as pAL. This value is defined as the negative logarithm of the molar concentration of the antagonist required to halve the effect of 5HT compared to AU 0 in the absence of an antagonist, the Compounds of Examples 1.5, 7, 8, 9, 18, 19, and 20 give pA2 values between 8.5 and 11.7. For example, the compound of Example 7 gives a pA2 equal to 10.2, while time, as known compounds of example 1a has pA2 8.6.

Further, the pDg for the known compound of Example 18 is 11.0 compared to

RA 8.2 for the compound of Example 4e

Antagonism of the reactions induced by 5HT in neuronal 5HT receptors by the combinations of the present invention can be determined in vivo by determining in cats the effect of the compounds on the 5HT-induced Benzold – Yarish reflex. These tests were carried out in accordance with the method of Kolins D. N. and Fortune R. Xo. The results can be expressed as

3104726

the measured dose required for a tenfold shift to the right of the response curve to the dose of 2-methyl-5-NT. In these tests, the compound of Example 7 administered intravenously corresponded to 0.2 µg / kg.

Toxicity data. Usually, cue-dineni are non-toxic in doses, with Kotora they are therapeutically effective. The compound of Example 7, for example, does not have an undesirable effect when administered orally to dogs at doses of 5 mg / kg and when administered orally to rats 10 mg / kg

ten

15

20

Claims (1)

Invention Formula The method of obtaining the derivatives of carbazole of the general formula (I) 25 where R, is hydrogen, Cf-Cg-alkyl, kinil, C3 C7-cycloalkyl — Cf — C-alkyl, phenyl-C — C-alkyl; ha 2 or 3, 1 ,, - imidazolyl formula (II) 35 40 Liu kg Where R is O-C-alkyl; Q is hydrogen or halogen; J5A-B is a group of CH-CH2- or their physiologically acceptable mudflows, characterized in that the compound of the general formula (III) is dehydrated where rf, q, m and cheni, or his 1 „have the indicated sign of protected arbitrariness 173104728 him to obtain the compound total removal of the protective group and when Formula (I), - The Form Form-Compound (I) group is obtained as , followed by hydrogenation mixture of enantiomers, if necessary to obtain a compound of the general formula, this mixture is divided and translated by (I) - a group of the formula CH of an aqueous base in physiologically SND, -, followed by the necessary, acceptable salt.