CA1238326A - Pyrrolo ¬3,2,1-hi|indole derivatives, their preparation and pharmaceutical compositions containing them - Google Patents
Pyrrolo ¬3,2,1-hi|indole derivatives, their preparation and pharmaceutical compositions containing themInfo
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- CA1238326A CA1238326A CA000469792A CA469792A CA1238326A CA 1238326 A CA1238326 A CA 1238326A CA 000469792 A CA000469792 A CA 000469792A CA 469792 A CA469792 A CA 469792A CA 1238326 A CA1238326 A CA 1238326A
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- pyrrolo
- hydrogen
- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
ABSTRACT
"PYRROLO[3,2,1-hi]INDOLE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
Pyrrolo[3,2,1-hi]indole derivatives, in the form of racemates or optically active isomers, of formula (I)
"PYRROLO[3,2,1-hi]INDOLE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
Pyrrolo[3,2,1-hi]indole derivatives, in the form of racemates or optically active isomers, of formula (I)
Description
~2383Z6 "PYRROLO[3,2,1-hi]INDOLE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
The present invention relates to pyrroloindole derivatives, their preparation and pharmaceutical compositions containing them.
The invention provides pyrrolo[3,2,1-hi]indole derivatives, in the form of racemates or optically active isomers, of the formula (I) N
~ ~ NH
~ (I) in which R is hydrogen or a linear or branched Cl 4 alkyl group, and Rl and R2 which may be the same or different, are hydrogen, halogen or Cl 4 alkyl, and their pharmaceutically acceptable acid addition salts.
According to the invention, the compounds (I) can be prepared by following the reaction scheme given in the Appendix.
The starting ester (II), in which R' is an alkyl group, in particular ethyl, can be obtained from N-aminoindole according to the method described by H. Rapoport et al.
(J.A.C.S. [1958], _ , 5574-5), the N-aminoindole itself being prepared according to the method described by A.N. ~ost et 30 al. (C.A. 54, 1964).
According to the invention, the starting ester (II) is $l~
3Z~;
hydrogenated by means of hydrochloric acid in the presence of tin at ambient temperature to provide a compound (III).
Then - either the compound (III) is reacted with ethylenediamine in the presence of trimethylaluminium to obtain a compound (I) in which R is hydrogen, or the compound (III) is alkylated by reaction with an alkyl halide ~X, in which R is Cl-C4 alkyl and X is halogen (preferably iodine), for example in the presence Gf diisopropylamine and butyllithium in a solvent, and the alkylated compound (IV) thus obtained is reacted with ethylenediamine in the presence of trimethylaluminium to obtain a compound (I) in which R is a Cl-C4 alkyl group. The compound (I) thus obtained can be converted into an acid addition salt by any known method.
The Examples which follow illustrate the invention. The structure of the compounds obtained was confirmed by analysis and IR and NMR spectra.
Example 1 2-(4,5-Dihydro-l_-imidazol-2-yl)-1,2,3,4,5-tetrahydropyrrolo[3,2,1-hi]indole and its fumarate.
1. In a l,000-ml three-necked flask equipped with a magnetic stirrer, hydrogen chloride gas inlet, air-cooled condenser with calcium chloride guard tube and thermometer, placed in a bath of dry ice and isopropyl alcohol, 15.8 g (0.073 mol) of ethyl 4,5-dihydropyrrolo[3,2,1-hi]indole-2-carboxylate are introduced with 150 ml of ethanol.
The mixture is cooled to -20C and hydrogen chloride gas is condensed in at this temperature until a solution is obtained. 26.1 g (0.22 gram-atom) of granulated tin are then added in a single portion, the cold bath is removed and stirring is maintained for 20 hours at room temperature.
A yellow suspension is obtained, and this is ~2i;;~3;2~
concentrated on the water bath and taken up in 550 ml of absolute ethanol. The mixture is cooled, ammonia is bubbled in until the pH equals 9 to 10 to precipitate the tin salts, the latter are drained while being washed with 5 iced ethanol and the filtrate obtained is evaporated to dryness. The residue is subjected to chromatography on a silica column, eluting with methylene chloride. 11.65 9 of an oily yelLow product are finally collected.
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
The present invention relates to pyrroloindole derivatives, their preparation and pharmaceutical compositions containing them.
The invention provides pyrrolo[3,2,1-hi]indole derivatives, in the form of racemates or optically active isomers, of the formula (I) N
~ ~ NH
~ (I) in which R is hydrogen or a linear or branched Cl 4 alkyl group, and Rl and R2 which may be the same or different, are hydrogen, halogen or Cl 4 alkyl, and their pharmaceutically acceptable acid addition salts.
According to the invention, the compounds (I) can be prepared by following the reaction scheme given in the Appendix.
The starting ester (II), in which R' is an alkyl group, in particular ethyl, can be obtained from N-aminoindole according to the method described by H. Rapoport et al.
(J.A.C.S. [1958], _ , 5574-5), the N-aminoindole itself being prepared according to the method described by A.N. ~ost et 30 al. (C.A. 54, 1964).
According to the invention, the starting ester (II) is $l~
3Z~;
hydrogenated by means of hydrochloric acid in the presence of tin at ambient temperature to provide a compound (III).
Then - either the compound (III) is reacted with ethylenediamine in the presence of trimethylaluminium to obtain a compound (I) in which R is hydrogen, or the compound (III) is alkylated by reaction with an alkyl halide ~X, in which R is Cl-C4 alkyl and X is halogen (preferably iodine), for example in the presence Gf diisopropylamine and butyllithium in a solvent, and the alkylated compound (IV) thus obtained is reacted with ethylenediamine in the presence of trimethylaluminium to obtain a compound (I) in which R is a Cl-C4 alkyl group. The compound (I) thus obtained can be converted into an acid addition salt by any known method.
The Examples which follow illustrate the invention. The structure of the compounds obtained was confirmed by analysis and IR and NMR spectra.
Example 1 2-(4,5-Dihydro-l_-imidazol-2-yl)-1,2,3,4,5-tetrahydropyrrolo[3,2,1-hi]indole and its fumarate.
1. In a l,000-ml three-necked flask equipped with a magnetic stirrer, hydrogen chloride gas inlet, air-cooled condenser with calcium chloride guard tube and thermometer, placed in a bath of dry ice and isopropyl alcohol, 15.8 g (0.073 mol) of ethyl 4,5-dihydropyrrolo[3,2,1-hi]indole-2-carboxylate are introduced with 150 ml of ethanol.
The mixture is cooled to -20C and hydrogen chloride gas is condensed in at this temperature until a solution is obtained. 26.1 g (0.22 gram-atom) of granulated tin are then added in a single portion, the cold bath is removed and stirring is maintained for 20 hours at room temperature.
A yellow suspension is obtained, and this is ~2i;;~3;2~
concentrated on the water bath and taken up in 550 ml of absolute ethanol. The mixture is cooled, ammonia is bubbled in until the pH equals 9 to 10 to precipitate the tin salts, the latter are drained while being washed with 5 iced ethanol and the filtrate obtained is evaporated to dryness. The residue is subjected to chromatography on a silica column, eluting with methylene chloride. 11.65 9 of an oily yelLow product are finally collected.
2. In a 100-ml Keller flask equipped ~ith a mag-1n netic stirrer, reflux condenser with calcium chlorideguard tube, thermometer, argon inlet, dropping funnel and Dean-Stark apparatus, there are successively introduced, under argon, 16 ml of toluene, 10.3 ml (0.025 mol) of tri-methylaluminium at 25.2% strength in hexane and, while 15 cooling, 1.6 ml (equivalent to 1.43 9 or 0.024 mol) of ethylenediamine dissolved in 4.5 ml of toluene.
The mixture is stirred for 5 minutes and then heated to 50C, and at this temperature there are added
The mixture is stirred for 5 minutes and then heated to 50C, and at this temperature there are added
3.3 9 (0.015 mol) of the product previously obtained, 20 dissolved in 15 ml of toluene. The mixture is then heated under reflux for 6 hours and then allowed to cool. After the mixture has been cooled to between -10 and -15C, it is hydrolysed with 10.2 ml of water while stirring, and is then extracted ~ith ethyl acetate. The organic frac-25 tions are combined, washed with sodium chloride solution,dried, filtered and evaporated. There remain approxi-mately 3 g of a fatty yellow solid from which the fumarate ~23~
is prepared directly~ For this purpose, the solid is taken up in 50 ml of ethanol and the solution is filtered, and a filtered solution of 1.5 9 (O.û13 mol) of fumaric acid in 1ûO ml of ethanol is added to it. The solution 5 obtained is stirred and concentrated to dryness, and the residue is taken up in acetone, filtered, dried under vacuum and recrystallised in ethanol. 1.65 9 of the fuma-rate is collected which melts at 184.5 - 186C.
~ 2-Methyl-2-(4,5-dihydro-1H-imidazol-2-yl)-10 1,2,4,5-tetrahydropyrrolo~3,2,1-hi]indole and its fumarate.
2 1. Ethyl 2-methyl-1,2,4,5-tetrahydropyrrolo¦3,2,1~hil-.
indole-2-carboxylate.
In a 25û-ml Keller flask equipped with a magnetic stirrer, thermometer, argon inlet and dropping funnel and 15 placed in a cold bath, there are introduced, under argon, 5.6 ml ~0.04 mol~ of diisopropylamine and 35 ml of tetra-hydrofuran (THF). The reaction mixture is cooled to bet-ween -70 and -75C and there are then introduced, in the course of 20 minutes, 25 ml (O.û4 mol) of butyllithium in 20 1.6 molar solution in hexane.
The temperature is maintained at be~ween -70 and -75C for 1 hour, and a solution of 7 9 (0.0322 mol~ of ethyl 1,2,4~5-tetrahydropyrrolo~3,2,1-hi]indole-2-car~oxy-late in 25 ml of THF is added in the course of 15 minutes.
The temperature is still maintained at between -70 and -75C for 1 hour and a solution of 12.4 ml (0.2 mol) of methyl iodide in 20 ml of THF is then added ~2~33'~6 in the course of 20 minutes.
The reaction mixture is maintained at between -70 and -75C for 1 hour, and then left at room temperature for 3 hours 30 minutes. The reaction mixture is poured into iced ~ater. It is extracted with diethyl ether in the presence of saturated sodium chloride solutionO The extract is washed ~ith water and dried over NA2S04.
The organic phase is separated. It is evaporated to dryness under vacuum on the ~ater bath. An oil is obtained which is purified by passage through a silica column with methylene chloride as eluent.
2.2. ~ -~4,5-d~y~ 1H-imidazol-2-yl)-1~2~4 tetrahydropyrrolo~3,2,1-hi]indole and its fumarate.
In a 50-ml Keller flask equipped ~ith a magnetic stirrer, reflux condenser, thermometer, argon inlet, drop-ping funnel and Dean-Stark apparatus, there are introduced successively, under argon, 10 ml of toluene, 5.4 ml (0.013 mol) of trimethylaluminium at 25.2X strength in hexane and, ~hile cooling to 0C, 0~9 ml ~equivalent to 0.013 mol) of ethylenediamine dissolved in 3 ml of toluene.
The mixture is stirred for 10 minutes and then heated to 50C, and at this temperature there ~s added 1.9 9 (0.0082 mol) of the product previously obtained, dissolved in 10 ml of toluene. The mixture is then heated under reflux for 6 hours and then allowed to cool. After the mixture has been cooled to between -10 and -15c, it is hydrolysed with 5.4 ml of water, while being stirred, ~2~ 2S
~, and is then extracted with ethyl acetate. The organic fractions are combined, washed with sodium chloride solu-tion, dried, filtered and evaporated. There remains a yellow solid from ~hich the fumarate is prepared directly.
For this purpose the solid is taken up in 25 ml of ethanol and the solution is filtered, and a filtered solution of 0.7 9 (0.006 mol) of fumaric acid in 50 ml of ethanol is added to it. The solution obtained is stirred and concentrated to dryness, and the residue is taken up in acetone, filtered, dried under vacuum and recrystal-lised in ethanol. The fumarate is collected which melts at 192 - 194C.
Example 3 2-n-Propyl-2-~4,5-dihydro-1H-imidazol-2-yl)-7-methyl-1~2,4,5-tetrahydropyrroloC3,2,1-hi]indole and its fumarate.
3.1. 5-Methyl-1-nitroso-2,3-dihydro-1H-indole In a 500-ml three-necked flask equipped with a magnetic stirring system, there are introduced 5-methyl-2-indoline ~prepared according to G.W. Gribble and J.H.
Hoffman, Synthesis, 1977, 859-860 from indole, described by J.E. Nordlander et al. J. Org. Shem. 46, 778-782, C1981]) to the extent of 18 9 ~0.14 mol) and 300 ml of 20X sulphuric acid.
The solution is cooled to C and sodium nitrite (9.7 9; 0.14 mol) dissolved in water (30 ml) is added.
The reaction mixture is maintained at C during the addition.
After 30 minutes of stirring at 0C, the aqueous phase is extracted with ether (500 ml). The ether phase is washed with water and then with saturated NaCl solution and dried over magnesium sulphate. The solvents are evaporated under vacuum. The compound obtained is used, as it is, in the following stage.
3.2. 5-~ethyl-2,3-dihydro-lH-indol-l-amine In a 2-1 three-necked flask equipped with a mechan-ical stirring system, condenser, dropping funnel and thermometer, and under argon, there are introduced lithium aluminium hydride (6.08 g; 0.16 mol) and tetrahydrofuran (THF) (300 ml). The compound obtained above (22 g;
0.14 mol?, dissolved in THF (300 ml) is added to the suspension. The temperature is maintained at 35C.
The reaction mixture is stirred for 4 hours at 20C and then hydrolysed (H20, 10 ml). 10 ml of lN
NaOH solution are then added, followed by 20 ml of water.
The suspension is stirred at 20C for 30 minutes, then filtered and the residue rinsed with ether. The organic phase is dried over sodium sulphate. The solvents are evaporated under vacuum. The compound obtained is used, as it is, in the following stage.
3.3.Ethyl 2~(~5-methyl-2,3-dihydro-lH-indol-l-yl]imino-propanoate In a 500-ml single-necked flask equipped with a magnetic stirring system and condenser, and under argon~
~3~ 6 there are introduced the above compound (20 9; 0.13 mol), ethyl pyruvate (16.24 g; 0.14 mol~, ethanol ~200 ml) and acetic acid (0.5 ml).
The reaction mixture is stirred at 80C for 5 5 hours. The ethanol is evaporated under vacuum and the residue is purified by column chromatography (SiO2; elu-ent, cyclohexane/ether 2:1). The compound obtained is used, as it is, in the following stage.
3.4. ~ 7-methyl-4,5-dihydropyrroloC3,2,1-hi]indole-10 2-carboxylate.
In a 25-ml three-necked flask equipped with a mag-netic stirring system and condenser, and under argon, there are introduced the compound obtained above (7 g;
0.028 mol) and acetic acid (8 ml), and ~F3 etherate 15 (3.42 ml; 0.028 mol) is added. The reaction mixture is stirred at 90C for 50 minutes. It is cooled and hydro-lysed (H20, 40 ml). The aqueous phase is extracted with ether (3 x 200 ml). The organic phase is washed with sodium bicarbonate, and with saturated sodium chloride 20 solution, and then dried over sodium sulphate.
The solvents are evaporated under vacuum and the residue is purified by column chromatography ~SiO2; elu-ent, cyclohexane/ether 2:1). The ester (II) obtained is used in the follo~ing stage.
25 3.5. Ethyl 7-methyl-1,2,4,5-tetrahydro yrroloC3,2,1-hi~-indole-2-carboxylate.
In a 50-ml three-necked flask equipped with a ~$~,326 _ 9 _ magnetic stirring system and condenser, ethanol (21 ml) is introduced. The ethanol is saturated with hydrochloric acid at -10C. The ester obtained above (2.4 9;
0.011 mol) is added, followed by tin (3~8 9; 0.032 9-S atom). The reaction mixture is stirred at +20C for 8 hours~ The solvent is evaporated under vacuum and the residue is dissolved in ethanol (50 ml). The mixture is saturated with ammonia until the pH equals 9. The sus-pension is filtered and the ethanol is evaporated under vacuum. The residue is dissolved in water and the aque-ous phase is extracted with ether (300 ml); the ether phase is washed with saturated sodium chloride solution and then dried over sodium sulphate.
The ester (III) is obtained.
3.6. Ethyl 2-n-propyl-7-methyl-1,2,4,5-te~rahydropyrrolo-[3,2,1-hi]indole-2-carboxylate.
In a 500-ml three-necked flask equipped with a magnetic stirring system and under argon, there are intro-duced diisopropylamine (0.600 9; 0.006 mol) and THF (5 ml).
The solution is cooled to -78C and n-butyllithium is added in hexane (3.75 ml; 0.006 mol). The solution is stirred at -78C for 30 minutes, and the ester obtained above (III) (1.15 9; O.Oû5 mol) is then added in THF
(10 ml). The reaction mixture is stirred at -78C for 1 hour (bro~n coloration). 1-Iodopropane (1.02 9;
0.006 mol) in THF (5 ml) is added.
The reaction mixture is stirred at -78OC for 1~3~26 1 hour and then at 20C for 1 hour. The mixture is hydrolysed (H20, 10 ml). The aqueous phase is extrac-ted with ether. The ether phase is washed with water and with saturated sodium chloride solution, and is then dried over sodium sulphate. The ester obtained (IV) is used in the following stage.
3.7. 2-n-Propyl-2-(4,5-dihydro-1H-imidazol-2-yl)-7-methyl-1 2 4 5-tetrahydropyrroloC3,2,1-hi]indole and its fumarate.
a. In 3 5û-ml three-necked flask equipped with a magnetic stirring system and condenser, and under argon, there are introduced toluene (10 ml) and trimethylalumi-nium at 25X strength in hexane (4.5 ml; 0.011 mol). The solution is cooled to -1ûC and ethylenediamine (0.640 9;
0.011 mol) in toluene (S ml) is then added. The reaction mixture is allowed to return to 20C and the ester (IV) obtained in 3.6 (1.22 9; O.û044 mol) is added in toluene (10 ml).
The reaction mixture is stirred at 110C for 20 4 hours. It is cooled to -10C and then hydrolysed (H20, 5 ml), and ethyl acetate (50 ml) is added. The mixture is stirred for 30 minutes at 0C and then filtered. The filtrate is dried over Na2S04. The solvents are evapo~
rated under vacuum. The fumarate is prepared directly.
b. In a 250-ml single-necked flask equipped with a magnetic stirring system, the compound obtained in a.
is introduced in ethanol (20 ml), and fumaric acid ~2383:~6 (0.500 g; 0.0042 mol) in ethanol (30 ml) is added. The solution is stirred for 30 minutes, and the ethanol is then evaporated under vacuum. The residue is taken up in ether.
It is filtered, dried under vacuum and recrystallised in ethanol. The fumarate is collected which melts at 178 -The Table which follows illustrates compounds prepared according to the invention.
~s Table N
H
~ (I) Compounc R1 R2 R Salt M.P-(C) _ . , 1 H H H fumarate 184-186 benzoate 146-148 2 H H CH3 fumarate 192-194 3 H H C2H5 fumarate 162-164
is prepared directly~ For this purpose, the solid is taken up in 50 ml of ethanol and the solution is filtered, and a filtered solution of 1.5 9 (O.û13 mol) of fumaric acid in 1ûO ml of ethanol is added to it. The solution 5 obtained is stirred and concentrated to dryness, and the residue is taken up in acetone, filtered, dried under vacuum and recrystallised in ethanol. 1.65 9 of the fuma-rate is collected which melts at 184.5 - 186C.
~ 2-Methyl-2-(4,5-dihydro-1H-imidazol-2-yl)-10 1,2,4,5-tetrahydropyrrolo~3,2,1-hi]indole and its fumarate.
2 1. Ethyl 2-methyl-1,2,4,5-tetrahydropyrrolo¦3,2,1~hil-.
indole-2-carboxylate.
In a 25û-ml Keller flask equipped with a magnetic stirrer, thermometer, argon inlet and dropping funnel and 15 placed in a cold bath, there are introduced, under argon, 5.6 ml ~0.04 mol~ of diisopropylamine and 35 ml of tetra-hydrofuran (THF). The reaction mixture is cooled to bet-ween -70 and -75C and there are then introduced, in the course of 20 minutes, 25 ml (O.û4 mol) of butyllithium in 20 1.6 molar solution in hexane.
The temperature is maintained at be~ween -70 and -75C for 1 hour, and a solution of 7 9 (0.0322 mol~ of ethyl 1,2,4~5-tetrahydropyrrolo~3,2,1-hi]indole-2-car~oxy-late in 25 ml of THF is added in the course of 15 minutes.
The temperature is still maintained at between -70 and -75C for 1 hour and a solution of 12.4 ml (0.2 mol) of methyl iodide in 20 ml of THF is then added ~2~33'~6 in the course of 20 minutes.
The reaction mixture is maintained at between -70 and -75C for 1 hour, and then left at room temperature for 3 hours 30 minutes. The reaction mixture is poured into iced ~ater. It is extracted with diethyl ether in the presence of saturated sodium chloride solutionO The extract is washed ~ith water and dried over NA2S04.
The organic phase is separated. It is evaporated to dryness under vacuum on the ~ater bath. An oil is obtained which is purified by passage through a silica column with methylene chloride as eluent.
2.2. ~ -~4,5-d~y~ 1H-imidazol-2-yl)-1~2~4 tetrahydropyrrolo~3,2,1-hi]indole and its fumarate.
In a 50-ml Keller flask equipped ~ith a magnetic stirrer, reflux condenser, thermometer, argon inlet, drop-ping funnel and Dean-Stark apparatus, there are introduced successively, under argon, 10 ml of toluene, 5.4 ml (0.013 mol) of trimethylaluminium at 25.2X strength in hexane and, ~hile cooling to 0C, 0~9 ml ~equivalent to 0.013 mol) of ethylenediamine dissolved in 3 ml of toluene.
The mixture is stirred for 10 minutes and then heated to 50C, and at this temperature there ~s added 1.9 9 (0.0082 mol) of the product previously obtained, dissolved in 10 ml of toluene. The mixture is then heated under reflux for 6 hours and then allowed to cool. After the mixture has been cooled to between -10 and -15c, it is hydrolysed with 5.4 ml of water, while being stirred, ~2~ 2S
~, and is then extracted with ethyl acetate. The organic fractions are combined, washed with sodium chloride solu-tion, dried, filtered and evaporated. There remains a yellow solid from ~hich the fumarate is prepared directly.
For this purpose the solid is taken up in 25 ml of ethanol and the solution is filtered, and a filtered solution of 0.7 9 (0.006 mol) of fumaric acid in 50 ml of ethanol is added to it. The solution obtained is stirred and concentrated to dryness, and the residue is taken up in acetone, filtered, dried under vacuum and recrystal-lised in ethanol. The fumarate is collected which melts at 192 - 194C.
Example 3 2-n-Propyl-2-~4,5-dihydro-1H-imidazol-2-yl)-7-methyl-1~2,4,5-tetrahydropyrroloC3,2,1-hi]indole and its fumarate.
3.1. 5-Methyl-1-nitroso-2,3-dihydro-1H-indole In a 500-ml three-necked flask equipped with a magnetic stirring system, there are introduced 5-methyl-2-indoline ~prepared according to G.W. Gribble and J.H.
Hoffman, Synthesis, 1977, 859-860 from indole, described by J.E. Nordlander et al. J. Org. Shem. 46, 778-782, C1981]) to the extent of 18 9 ~0.14 mol) and 300 ml of 20X sulphuric acid.
The solution is cooled to C and sodium nitrite (9.7 9; 0.14 mol) dissolved in water (30 ml) is added.
The reaction mixture is maintained at C during the addition.
After 30 minutes of stirring at 0C, the aqueous phase is extracted with ether (500 ml). The ether phase is washed with water and then with saturated NaCl solution and dried over magnesium sulphate. The solvents are evaporated under vacuum. The compound obtained is used, as it is, in the following stage.
3.2. 5-~ethyl-2,3-dihydro-lH-indol-l-amine In a 2-1 three-necked flask equipped with a mechan-ical stirring system, condenser, dropping funnel and thermometer, and under argon, there are introduced lithium aluminium hydride (6.08 g; 0.16 mol) and tetrahydrofuran (THF) (300 ml). The compound obtained above (22 g;
0.14 mol?, dissolved in THF (300 ml) is added to the suspension. The temperature is maintained at 35C.
The reaction mixture is stirred for 4 hours at 20C and then hydrolysed (H20, 10 ml). 10 ml of lN
NaOH solution are then added, followed by 20 ml of water.
The suspension is stirred at 20C for 30 minutes, then filtered and the residue rinsed with ether. The organic phase is dried over sodium sulphate. The solvents are evaporated under vacuum. The compound obtained is used, as it is, in the following stage.
3.3.Ethyl 2~(~5-methyl-2,3-dihydro-lH-indol-l-yl]imino-propanoate In a 500-ml single-necked flask equipped with a magnetic stirring system and condenser, and under argon~
~3~ 6 there are introduced the above compound (20 9; 0.13 mol), ethyl pyruvate (16.24 g; 0.14 mol~, ethanol ~200 ml) and acetic acid (0.5 ml).
The reaction mixture is stirred at 80C for 5 5 hours. The ethanol is evaporated under vacuum and the residue is purified by column chromatography (SiO2; elu-ent, cyclohexane/ether 2:1). The compound obtained is used, as it is, in the following stage.
3.4. ~ 7-methyl-4,5-dihydropyrroloC3,2,1-hi]indole-10 2-carboxylate.
In a 25-ml three-necked flask equipped with a mag-netic stirring system and condenser, and under argon, there are introduced the compound obtained above (7 g;
0.028 mol) and acetic acid (8 ml), and ~F3 etherate 15 (3.42 ml; 0.028 mol) is added. The reaction mixture is stirred at 90C for 50 minutes. It is cooled and hydro-lysed (H20, 40 ml). The aqueous phase is extracted with ether (3 x 200 ml). The organic phase is washed with sodium bicarbonate, and with saturated sodium chloride 20 solution, and then dried over sodium sulphate.
The solvents are evaporated under vacuum and the residue is purified by column chromatography ~SiO2; elu-ent, cyclohexane/ether 2:1). The ester (II) obtained is used in the follo~ing stage.
25 3.5. Ethyl 7-methyl-1,2,4,5-tetrahydro yrroloC3,2,1-hi~-indole-2-carboxylate.
In a 50-ml three-necked flask equipped with a ~$~,326 _ 9 _ magnetic stirring system and condenser, ethanol (21 ml) is introduced. The ethanol is saturated with hydrochloric acid at -10C. The ester obtained above (2.4 9;
0.011 mol) is added, followed by tin (3~8 9; 0.032 9-S atom). The reaction mixture is stirred at +20C for 8 hours~ The solvent is evaporated under vacuum and the residue is dissolved in ethanol (50 ml). The mixture is saturated with ammonia until the pH equals 9. The sus-pension is filtered and the ethanol is evaporated under vacuum. The residue is dissolved in water and the aque-ous phase is extracted with ether (300 ml); the ether phase is washed with saturated sodium chloride solution and then dried over sodium sulphate.
The ester (III) is obtained.
3.6. Ethyl 2-n-propyl-7-methyl-1,2,4,5-te~rahydropyrrolo-[3,2,1-hi]indole-2-carboxylate.
In a 500-ml three-necked flask equipped with a magnetic stirring system and under argon, there are intro-duced diisopropylamine (0.600 9; 0.006 mol) and THF (5 ml).
The solution is cooled to -78C and n-butyllithium is added in hexane (3.75 ml; 0.006 mol). The solution is stirred at -78C for 30 minutes, and the ester obtained above (III) (1.15 9; O.Oû5 mol) is then added in THF
(10 ml). The reaction mixture is stirred at -78C for 1 hour (bro~n coloration). 1-Iodopropane (1.02 9;
0.006 mol) in THF (5 ml) is added.
The reaction mixture is stirred at -78OC for 1~3~26 1 hour and then at 20C for 1 hour. The mixture is hydrolysed (H20, 10 ml). The aqueous phase is extrac-ted with ether. The ether phase is washed with water and with saturated sodium chloride solution, and is then dried over sodium sulphate. The ester obtained (IV) is used in the following stage.
3.7. 2-n-Propyl-2-(4,5-dihydro-1H-imidazol-2-yl)-7-methyl-1 2 4 5-tetrahydropyrroloC3,2,1-hi]indole and its fumarate.
a. In 3 5û-ml three-necked flask equipped with a magnetic stirring system and condenser, and under argon, there are introduced toluene (10 ml) and trimethylalumi-nium at 25X strength in hexane (4.5 ml; 0.011 mol). The solution is cooled to -1ûC and ethylenediamine (0.640 9;
0.011 mol) in toluene (S ml) is then added. The reaction mixture is allowed to return to 20C and the ester (IV) obtained in 3.6 (1.22 9; O.û044 mol) is added in toluene (10 ml).
The reaction mixture is stirred at 110C for 20 4 hours. It is cooled to -10C and then hydrolysed (H20, 5 ml), and ethyl acetate (50 ml) is added. The mixture is stirred for 30 minutes at 0C and then filtered. The filtrate is dried over Na2S04. The solvents are evapo~
rated under vacuum. The fumarate is prepared directly.
b. In a 250-ml single-necked flask equipped with a magnetic stirring system, the compound obtained in a.
is introduced in ethanol (20 ml), and fumaric acid ~2383:~6 (0.500 g; 0.0042 mol) in ethanol (30 ml) is added. The solution is stirred for 30 minutes, and the ethanol is then evaporated under vacuum. The residue is taken up in ether.
It is filtered, dried under vacuum and recrystallised in ethanol. The fumarate is collected which melts at 178 -The Table which follows illustrates compounds prepared according to the invention.
~s Table N
H
~ (I) Compounc R1 R2 R Salt M.P-(C) _ . , 1 H H H fumarate 184-186 benzoate 146-148 2 H H CH3 fumarate 192-194 3 H H C2H5 fumarate 162-164
4 H H nC3H7 fumarate 202-204 H H nC4H9 fumarate 171-173 6 8-C1 H H fumarate 195-196 7 a C1 H CH3 fumarate 94- 99 a 8-C1 H nC3H7 fumarate 202-204 9 7-F H H fumarate 137-141 1û 7-F H CH3 fumarate 147-150 11 .~ ___ _ _ 3 7 fumarate 200-203 ~3,B326i ~ '1 _ .~ ~
¦ 12 7-CH3 HH ¦ fumarate ¦ 168-172 13 7-CH3 HnC3H7 fumarate 178-180 14 6-CH3 8-CH3 H fum~rate 217-219 6-CH3 8-CH~CH3 fumarate 207-210 16 6-CH3 8-CH3nC3H7 fumarate 180-185 3~33~26 The compounds of the invention were subjected to pharmacologicaL tests which showed their value as ~2-antagonists.
To this end, the compounds were studied in the test of potentiality and selectivity of antagonists towards~ 2-receptors in vitro.
Determina~ion of the PA2 value in respect of the inhibi~ory effects of clonidine, a well-knownr~2-agonist~
was carried out on rat vas deferens stimulated at a fre-quency of 0.1 Hz in the presence of 30 nM prazosin and 1 ,uM cocaine, according to the method described by G.M.
Drew (European Journal of Pharmacology, 42, (1977) 123-130).
The PA2 of the compounds of ~he invention are between 7 and 9.5.
The compounds of the invention are powerful ~2-antagonists which can be used for the treatment of depres-sion (either alone or in association with a product which inhib;ts neuronal uptake mechanisms), hypotension, post-operative paralytic ileum, asthma and obesity.
The pharraceutical compositions can be in a form suitable for oral, rectal or parenteral administration, for example in the form of capsules, tablets, pellets, gelatine capsules or solutions, syrups or suspensions to be taken orally, and can contain suitable excipients.
The daily dosage can range from 0.1 to 10 mg/kg P . o .
~2~3~
Appendi~
N
r -r (I) N
R~J
P`2 React;on scheme C2R C2R ~r_C02R ' R l=~ r I r I
R2~ ~ Rl~h R
(III) tII) (IV) I
H2N-(CH2)2 NH2 . H2N-(CX2)2--~H2 (CH3)3 Al . ~(CH3)3 Al ~ here R = H(I) ~here R = aL~yl R' = alkyl, preferably ethyl X 2 halogen, preferably I
¦ 12 7-CH3 HH ¦ fumarate ¦ 168-172 13 7-CH3 HnC3H7 fumarate 178-180 14 6-CH3 8-CH3 H fum~rate 217-219 6-CH3 8-CH~CH3 fumarate 207-210 16 6-CH3 8-CH3nC3H7 fumarate 180-185 3~33~26 The compounds of the invention were subjected to pharmacologicaL tests which showed their value as ~2-antagonists.
To this end, the compounds were studied in the test of potentiality and selectivity of antagonists towards~ 2-receptors in vitro.
Determina~ion of the PA2 value in respect of the inhibi~ory effects of clonidine, a well-knownr~2-agonist~
was carried out on rat vas deferens stimulated at a fre-quency of 0.1 Hz in the presence of 30 nM prazosin and 1 ,uM cocaine, according to the method described by G.M.
Drew (European Journal of Pharmacology, 42, (1977) 123-130).
The PA2 of the compounds of ~he invention are between 7 and 9.5.
The compounds of the invention are powerful ~2-antagonists which can be used for the treatment of depres-sion (either alone or in association with a product which inhib;ts neuronal uptake mechanisms), hypotension, post-operative paralytic ileum, asthma and obesity.
The pharraceutical compositions can be in a form suitable for oral, rectal or parenteral administration, for example in the form of capsules, tablets, pellets, gelatine capsules or solutions, syrups or suspensions to be taken orally, and can contain suitable excipients.
The daily dosage can range from 0.1 to 10 mg/kg P . o .
~2~3~
Appendi~
N
r -r (I) N
R~J
P`2 React;on scheme C2R C2R ~r_C02R ' R l=~ r I r I
R2~ ~ Rl~h R
(III) tII) (IV) I
H2N-(CH2)2 NH2 . H2N-(CX2)2--~H2 (CH3)3 Al . ~(CH3)3 Al ~ here R = H(I) ~here R = aL~yl R' = alkyl, preferably ethyl X 2 halogen, preferably I
Claims (6)
1. A process for preparing pyrrolo[3,2,1-hi]indole derivatives, in the form of racemates or optically active isomers, of the formula (I) (I) in which R is hydrogen or a linear or branched C1-4 alkyl group, and R1 and R2 which may be the same or different, are hydrogen, halogen or C1-4 alkyl, and their pharmaceutically acceptable acid addition salts, which process comprises hydrogenating an ester of formula (II) (II) wherein R' is alkyl, by means of hydrochloric acid in the presence of tin at ambient temperature, and then - either reacting the resulting compound of formula (III) (III) with ethylenediamine in the presence of trimethylaluminium to obtain a compound (I) in which R is hydrogen, - or alkylating the resulting compound of formula (III) by reacting it with an alkyl halide RX, wherein R is C1-C4 alkyl and X is halogen, and then reacting the resulting compound of formula (IV) (IV) with ethylenediamine in the presence of trimethylaluminium to obtain a compound (I) in which R is an alkyl group, and if desired converting the resulting compound (I) into a pharmaceutically acceptable addition salt.
2. A process according to claim 1, wherein R is methyl, ethyl, n-propyl or n-butyl.
3. A process according to claim 2, wherein R1 and R2, which may be the same or different, are hydrogen, chlorine, fluorine, methyl, ethyl, n-propyl or n-butyl.
4. A process according to claim 3 wherein X is iodine and the compound (III) is alkylated in the presence of disopropylamine and butyllithium in a solvent.
5. Pyrrolo[3,2,1-hi]indole derivatives of formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof when prepared by a process as claimed in claim 1.
6. Pyrrolo[3,2,1-hi]indole derivatives of formula (I) as defined in claim 1 wherein R is methyl, ethyl, n-propyl or n-butyl and R1 and R2, which may be the same or different, are hydrogen, chlorine, fluorine, methyl, ethyl, n-propyl or n-butyl and pharmaceutically acceptable salts thereof when prepared by a process as claimed in claim 2 or 3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8319850 | 1983-12-12 | ||
| FR8319850A FR2556345B3 (en) | 1983-12-12 | 1983-12-12 | PYRROLO (3,2,1-HI) INDOLE DERIVATIVE, ITS PREPARATIO N AND ITS APPLICATION IN THERAPEUTICS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1238326A true CA1238326A (en) | 1988-06-21 |
Family
ID=9295079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000469792A Expired CA1238326A (en) | 1983-12-12 | 1984-12-11 | Pyrrolo ¬3,2,1-hi|indole derivatives, their preparation and pharmaceutical compositions containing them |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS60149588A (en) |
| CA (1) | CA1238326A (en) |
| FR (1) | FR2556345B3 (en) |
| ZA (1) | ZA849645B (en) |
-
1983
- 1983-12-12 FR FR8319850A patent/FR2556345B3/en not_active Expired
-
1984
- 1984-12-11 JP JP59262636A patent/JPS60149588A/en active Granted
- 1984-12-11 CA CA000469792A patent/CA1238326A/en not_active Expired
- 1984-12-11 ZA ZA849645A patent/ZA849645B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60149588A (en) | 1985-08-07 |
| JPH0447673B2 (en) | 1992-08-04 |
| ZA849645B (en) | 1985-07-31 |
| FR2556345A1 (en) | 1985-06-14 |
| FR2556345B3 (en) | 1986-07-11 |
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