HK1135378A - New 1h-indol-1-yl-urea compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Novel 1H-indol-1-yl-urea compounds, process for their preparation and pharmaceutical compositions containing them

Technical Field

The present invention relates to novel 1H-indol-1-yl-urea compounds, processes for their preparation and pharmaceutical compositions containing them.

Background

The literature provides numerous examples of compounds having the structure ebony (eburnane), in particular in patent specification US 3454583, this document describes vincamine ((3 α, 14 β, 16 α) - (14, 15-dihydro-14-hydroxy-eburnamenine-14-carboxylic acid methyl ester) and its derivatives in terms of vasodilating properties patent applications FR 2433528 and FR 2381048 provide novel 20, 21-didemethyleburnamenine compounds, and patent application EP 0287468 provides novel 17-aza-20, 21-didemethyleburnamenine compounds patent application EP 0658557 describes compounds of the ebony type modified at the 14-and 15-positions of the ebony skeleton patent application EP0563916 describes 1H-indole-cyclohexanecarboxamide compounds.

Disclosure of Invention

In addition to the fact that they are novel compounds, the compounds of the present invention also have very valuable pharmacological properties. In particular, they have been found to be strongly selective or non-selective inducers of tyrosine hydroxylase.

More particularly, the present invention relates to compounds of formula (I), their enantiomers and diastereomers, and also to their addition salts with a pharmaceutically acceptable acid or base:

wherein:

R₁and R₂May be the same or different and represents a hydrogen atom or a linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

R₃represents a hydrogen or halogen atom, linear or branched (C)₁-C₆) Alkyl radicals or linear or branched (C)₁-C₆) An alkoxy group, a carboxyl group,

het represents a pyridyl, pyrimidinyl, piperidinyl, 2-methylpyridyl, 3-methylpyridyl, 4-methylpyridyl, phenyl, benzyl, quinolinyl, pyridazinyl or indolyl group, each of which may optionally be substituted by one or more groups selected from halogen, linear or branched (C)₁-C₆) Alkyl and straight or branched chain (C)₁-C₆) An alkoxy group,

represents a single bond or a double bond,

it is to be understood that R₃May be attached to any carbon atom of the indole/indoline core which allows attachment thereof.

Among the pharmaceutically acceptable acids, mention may be made, without implying any limitation, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, etc.

Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, lysine and the like may be mentioned, without implying any limitation.

Detailed Description

An advantageous embodiment relates to the compounds wherein R₁、R₂And R₃All represent a hydrogen atomA compound (I) is provided.

An even more advantageous embodiment of the present invention relates to compounds of formula (I) wherein Het is a pyridinyl, pyrimidinyl or piperidinyl group.

Another particular aspect of the invention relates to compounds of formula (I) wherein Het is a pyridyl group.

Even more particularly, the present invention relates to compounds of formula (I) which are:

n- (1H-indol-1-yl) -N' - (3-pyridyl) urea,

n- (2, 3-dihydro-1H-indol-1-yl) -N' - (3-pyridyl) urea.

Addition salts of preferred compounds with pharmaceutically acceptable acids or bases form part of the invention.

The invention also relates to a process for the preparation of a compound of formula (I), characterized in that: taking the compound of the formula (II) as a starting material,

wherein Het is as defined for formula (I),

thermolysis of the Compound of formula (II) liberates N₂Leading to the formation of isocyanate compounds of formula (III), which can be isolated:

Het—N＝C＝O (III)

the compound of formula (III) is then reacted with a compound of formula (IV):

wherein R is₃As defined in formula (I),

the compounds of formula (I) according to the invention are obtained, which can be purified according to conventional separation techniques, converted into their addition salts, if desired with pharmaceutically acceptable acids or bases, and, where appropriate, separated into isomers according to conventional separation techniques.

The compounds of formula (II) and formula (IV) are commercially available or obtained according to conventional organic synthesis methods well known to those skilled in the art.

The compounds of formula (I) have valuable pharmacological properties, in particular as potent Tyrosine Hydroxylase (TH) inducers. Tyrosine hydroxylase is known to be the rate-limiting enzyme that controls, inter alia, the synthesis of neurotransmitters in central catecholaminergic and dopaminergic neurons (Zhu M. -Y. et al, Molecular Brain Research 133, (2005), 167-175). The rate of synthesis of these neurotransmitters is particularly relevant to the manifestation of tonic (tonic) brain dysfunction, which constitutes the majority of behavioral pathologies in humans, such as anxiety, psychosis, depression, stress, and the like. (Schloss P. et al, Pharmacology & Therapeutics)102, (2004), 47-60; Morilack D.A. et al, neuropsychology International Journal (International Journal of neuropsychopharmacology)7, (2004), 193-218). Deficiency of norepinephrine and dopamine in the prefrontal cortex is the source of negative and cognitive symptoms, especially in schizophrenia (Pira l. et al, European Journal of Pharmacology 504, (2004), 61-64).

Due to their ability to induce tyrosine hydroxylase, the compounds of the invention are useful for the treatment of depression, anxiety, memory disorders during aging and/or neurodegenerative disorders, for palliative treatment of parkinson's disease, and for adapting to stress.

The invention also relates to pharmaceutical compositions which may comprise, as active ingredient, at least one compound of formula (I), an enantiomer or diastereomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base; or further comprises one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.

The pharmaceutical compositions thus obtained are generally in the form of dosage forms, for example they may take the form of tablets, dragees, capsules, suppositories, or injectable or drinkable solutions, and may be administered by the oral, rectal, intramuscular or parenteral routes.

In the pharmaceutical compositions according to the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transcutaneous, intravaginal, rectal, nasal, lingual, buccal, ocular or respiratory administration.

For parenteral injection, the pharmaceutical compositions according to the invention include, inter alia, aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions as well as sterile powders for the reconstitution of injectable solutions or dispersions.

For solid oral administration, the pharmaceutical compositions according to the invention include, inter alia, tablets or dragees, sublingual tablets, sachets, capsules and granules; for liquid oral, intranasal, buccal or ocular administration, emulsions, solutions, suspensions, drops, syrups and aerosols are included, inter alia.

Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories or ovules (ovules), those for transdermal or transdermal administration including in particular powders, aerosols, creams, ointments, gels and patches.

The above-mentioned pharmaceutical compositions are intended to illustrate the invention without, however, limiting it in any way.

Among inert, non-toxic, pharmaceutically acceptable excipients or carriers, mention may be made (by way of example and without representing any limitation) of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retarding agents, lubricants, absorbents, suspending agents, colorants, flavoring agents, and the like.

The effective dosage will vary with the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the condition, and any associated treatment administered. The dosage is 0.1-100mg per day, and is administered once or more times.

The following examples serve to illustrate the invention without any limitation.

The starting materials used are known products or prepared according to known methods. The following various preparations produce synthetic intermediates useful in the preparation of the compounds of the present invention.

The structures of the compounds described in the examples and preparations are determined according to the usual spectroscopic techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).

Melting points were measured using a tottoloi instrument (no emergency column calibration). When the compound is in the form of a salt, the melting point is the melting point of the compound in the form of a salt.

Preparation 1:nicotinoyl azides

To 2.4ml of concentrated hydrochloric acid (37%) was added 2g of nicotinhydrazide at 0 ℃ followed by 2.02g of sodium nitrite in 3.6ml of water. The reaction mixture was stirred at 0 ℃ for 30 minutes and then treated with saturated sodium bicarbonate solution. After 3 extractions with ether, the organic phase is washed successively with water and saturated sodium chloride solution and then dried over magnesium sulfate. After concentration under reduced pressure, the expected product is obtained (g. papeo et al, Synthesis, (2004), 2886).

2178(v_N3)；1685(v_CO)。

Preparation 2:2-pyridinecarbonyl azides

This compound was obtained according to a similar manner to that of preparation 1, using 2-pyridinecarbohydrazide in place of nicotinhydrazide.

Preparation 3:isonicotinoyl azides

This compound was prepared according to a similar method to that of preparation 1, substituting isonicotinyl hydrazide for nicotinyl hydrazide.

Preparation 4;1-methyl-3-piperidinecarbonyl azide

This compound was obtained according to a similar manner to that of preparation 1, substituting 1-methyl-3-piperidinecarboxhydrazide for nicotinhydrazide.

Preparation 5:1-methyl-2-piperidinecarbonyl azide

This compound was obtained according to a similar manner to that of preparation 1, substituting 1-methyl-2-piperidinecarboxhydrazide for nicotinhydrazide.

Preparation 6:1-methyl-4-piperidinecarbonyl azide

This compound was obtained according to a similar manner to that of preparation 1, substituting 1-methyl-4-piperidinecarboxhydrazide for nicotinhydrazide.

Preparation 7:5-methoxy-2, 3-dihydro-1H-indol-1-ylamine

Step A: 5-methoxy-2, 3-dihydro-1H-indoles

0.991g of 5-methoxy-1H-indole was dissolved in 67ml of glacial acetic acid at ambient temperature. 1.37g of sodium cyanoborohydride are added in portions. After stirring for 1 hour 30 minutes at ambient temperature, the reaction mixture was dried; the residue was treated with 50ml of water and extracted twice with dichloromethane. With saturated NaHCO₃The organic phase is washed with the solution and then with saturated NaCl solution, dried over magnesium sulfate and concentrated to give the expected product.

And B: 5-methoxy-1-nitroso-2, 3-dihydro-1H-indole

To 10ml of 50% acetic acid solution at 0 ℃ were added 0.499g of the above compound of step A in a lump. 0.232g of sodium nitrite dissolved in 5ml of water is added dropwise at 0 ℃. When the dropwise addition was complete, the reaction mixture was stirred at 0 ℃ for 1 hour 30 minutes. After addition of water, the aqueous phase was extracted 3 times with dichloromethane; the combined organic phases were washed with water and dried over magnesium sulfate. Evaporation to dryness gives the expected product, which can be used for subsequent reactions without purification.

And C: 5-methoxy-2, 3-dihydro-1H-indol-1-ylamine

At ambient temperature, 0.353g of 5-methoxy-1-nitroso-2, 3-dihydro-1H-indole was dissolved in 17mL of ethanol and 8.5mL of water were added. 1.42g of zinc was added followed by 1.89g of ammonium carbonate. After vigorous stirring for 1 hour at ambient temperature, the reduction reaction was complete. The zinc was removed by filtration through celite and washed with methanol. After evaporation to dryness, the residue was taken up in water and extracted 3 times with dichloromethane. The organic phase was washed with saturated NaCl solution, dried over magnesium sulfate and evaporated to dryness to give the expected product, which was used in the next step without purification.

Preparation 8:1H-indol-1-yl-carbamic acid phenyl ester

3g of 1H-indol-1-ylamine are dissolved in 28ml of anhydrous dichloromethane. 2.8g of 4- (dimethylamino) pyridine are added and the reaction mixture is cooled to 0 ℃. 2.85ml of phenyl chloroformate are added dropwise and the reaction mixture is stirred at 0 ℃ until complete conversion to the carbamate. After removal of the solvent by evaporation, the residue was dissolved in a pentane/dichloromethane mixture (50/50) and the insoluble material (4- (dimethylamino) pyridinium chloride) was separated by filtration. The filtrate was concentrated to dryness and the resulting residue was taken up in dichloromethane. The organic phase was washed 3 times with 0.1M hydrochloric acid solution and then with saturated NaCl solution. After evaporation of the solvent, the residue obtained is triturated in a pentane/diethyl ether mixture and then dried over phosphorus pentoxide in vacuo to give the expected product.

144.5℃。

Preparation 9:quinolin-3-ylcarbamic acid phenyl ester

1.01g of 3-aminoquinoline are dissolved in 20ml of anhydrous dichloromethane. 1.12g of 4- (dimethylamino) pyridine was added and the reaction mixture was cooled to 0 ℃. 1.14ml of phenyl chloroformate are added dropwise and the reaction mixture is stirred at ambient temperature under an argon atmosphere for 1 hour. After removal of the solvent by evaporation, 50ml of water were added to the residue. After 15 minutes, the carbamate formed a white precipitate which, after filtration, was dried to give the expected product.

196℃。

Preparation 10:(1H-indol-1-yl) -N-methylcarbamic acid phenyl ester

To a solution of 200mg of phenyl N- (1H-indol-1-yl) carbamate in 20ml of freshly distilled tetrahydrofuran under inert atmosphere is added 48mg of sodium hydride. After stirring for 10 minutes, 49. mu.l of methyl iodide were added. The reaction mixture was stirred under an inert atmosphere for 4 hours. After evaporation of the tetrahydrofuran, extraction was carried out 3 times with dichloromethane, washing was carried out with saturated NaCl solution and the organic phase was evaporated to dryness. The carbamate was purified by flash chromatography (ethyl acetate/cyclohexane: 1/9). After removal of the solvent by evaporation, the expected product is obtained.

112℃。

Example 1: n- (1H-indol-1-yl) -N' - (3-pyridinyl) urea

A solution of 1.14g of the compound of preparation 1 in 38ml of toluene was heated under reflux under an argon atmosphere until complete disappearance of the starting material (2 hours). 3-pyridylisocyanate was obtained as intermediate, cooled to 0 ℃ and added thereto a solution of 995mg of 1H-indoleamine in 38ml of dichloromethane. Stirring was continued at ambient temperature for 24 hours. The precipitate formed was filtered off and then stirred in water (10ml) for 12 hours. After filtration and washing with pentane, the solid was taken up in a dichloromethane/methanol mixture (90/10). After filtration, the solid was dried over phosphorus pentoxide in vacuo to give the desired product.

202.5℃。

Example 2: n- (2, 3-dihydro-1H-indol-1-yl) -N' - (3-pyridinyl) urea

A solution of 942mg of preparation 1 in 30ml of toluene was heated under reflux under an argon atmosphere until complete disappearance of the starting material (1 hour 30 minutes). The resulting 3-pyridylisocyanate as an intermediate was cooled to 0 ℃ and 824mg of 1-indoleamine dissolved in 30ml of dichloromethane were added. Stirring was then continued at ambient temperature for 15 hours. The precipitate formed was filtered off and washed with diethyl ether to form the first batch. The mother liquor was concentrated. The residue was taken up in a small amount of dichloromethane and then diethyl ether was added. The precipitate formed, which then formed a second batch, and was recrystallized from ethyl acetate.

197℃。

Example 3: n- (5-chloro-2, 3-dihydro-1H-indol-1-yl) -N' - (3-pyridinyl) urea

This compound was obtained according to a similar manner to example 2 except for using 5-chloro-1-indoleamine in place of 1-indoleamine.

Example 4: n- (5-methoxy-1H-indol-1-yl) -N' - (3-pyridinyl) urea

This compound was obtained according to a similar manner to example 1 by substituting 5-methoxy-1H-indol-1-amine for 1H-indoleamine.

A solution of 0.281g of the compound of preparation 1 in 9.25ml of toluene is heated under reflux under an argon atmosphere until complete conversion to the isocyanate takes place (2 hours). To this solution, cooled to 0 ℃, 0.300g of 5-methoxy-1H-indol-1-ylamine dissolved in 9.25ml of dichloromethane was added. Stirring was continued at ambient temperature for 24 hours. After filtration, the precipitate formed was dissolved in dichloromethane and the organic phase obtained was washed 3 times with water. After drying over magnesium sulfate, evaporation to dryness, the residue was triturated with pentane and dried over phosphorus pentoxide in vacuo to give the expected product.

176℃。

Example 5(ii) a N- (2, 3-dihydro-1H-indol-1-yl) -N' - (2-pyridinyl) urea

This compound was obtained according to a similar method to that of example 2, substituting preparation 2 for preparation 1.

Example 6: n- (1H-indol-1-yl) -N' - (4-pyridinyl) urea

This compound was obtained according to a similar method to that of example 1, substituting preparation 3 for preparation 1.

A solution of 0.305g of preparation 3 in 8.8ml of toluene is heated under reflux under an argon atmosphere until complete conversion to isocyanate takes place (2 hours). The reaction mixture was cooled to 0 ℃ and 0.265g of 1H-indol-1-ylamine in 8.8ml of dichloromethane was added thereto. Stirring was continued at ambient temperature for 5 days. The precipitate formed was filtered and purified by column chromatography over silica gel (ethyl acetate/cyclohexane: 60/40). After evaporation of the solvent, the residue was washed with pentane, dried at 70 ℃ in vacuo and then dried at ambient temperature in vacuo over phosphorus pentoxide for 12 hours to give the expected product.

138℃。

Example 7: n- (1H-indol-1-yl) -N' - (1-methyl-3-piperidinyl) urea

This compound was obtained according to a similar method to that of example 1, substituting preparation 4 for preparation 1.

Example 8: n- (1H-indol-1-yl) -N' - (1-methyl-2-piperidinyl) urea

This compound was obtained according to a similar method to that of example 1, substituting preparation 5 for preparation 1.

Example 9: n- (1H-indol-1-yl) -N' - (1-methyl-4-piperidinyl) urea

This compound was obtained according to a similar method to that of example 1, substituting preparation 6 for preparation 1.

Example 10: n- (2, 3-dihydro-1H-indol-1-yl) -N' - (1-methyl-3-piperidinyl) urea

This compound was obtained according to a similar method to that of example 2, substituting preparation 4 for preparation 1.

Example 11: n- (5-methyl-1H-indol-1-yl) -N' - (3-pyridinyl) urea

A solution of 0.598g of preparation 1 in 20ml of toluene is heated to reflux under an argon atmosphere until complete conversion to isocyanate takes place (1 hour and 30 minutes). The reaction mixture was cooled to 0 ℃ and 0.620mg of 5-methyl-1H-indol-1-ylamine in 5ml of dichloromethane was added thereto. Stirring was continued at ambient temperature for 24 hours. The precipitate formed is filtered off, washed with dichloromethane and then with pentane. Dissolving it in hot ethanol; the crystals obtained were dried over phosphorus pentoxide at 70 ℃ under vacuum for 6 hours to give the expected product.

197.5℃。

Example 12: n- (5-methoxy-2, 3-dihydro-1H-indol-1-yl) -N' - (3-pyridinyl) urea

0.270g of a solution of the compound of preparation 1 in 9ml of toluene are heated under reflux under an argon atmosphere until complete conversion to the isocyanate takes place (1 hour). The reaction mixture was cooled to 0 ℃ and 0.300g of the Compound of preparation 7 in 5ml of dichloromethane was added thereto. Stirring was then continued at ambient temperature and after 24 hours, complete conversion to urea was achieved. The precipitate formed is filtered off, washed with dichloromethane and then with pentane. The crude product was purified by preparative plate chromatography (ethyl acetate/methanol: 95/5). Warp beamAfter 0.45 μm filtration of the eluted product at GHP, the crystals of the desired product were obtained by washing with hot ethanol.

177.5℃。

Example 13: n- (5-chloro-1H-indol-1-yl) -N' - (4-pyridinyl) urea

A solution of 0.500g of preparation 3 in 17ml of toluene is heated under reflux under an argon atmosphere until complete conversion to isocyanate takes place (1 hour 30 minutes). The reaction mixture was cooled to 0 ℃ and 0.562g of 5-chloro-1H-indol-1-ylamine in 17ml of dichloromethane was added thereto. Stirring was then continued at ambient temperature for 24 hours. The precipitate formed was filtered and purified by column chromatography on silica gel (ethyl acetate/cyclohexane/methanol: 60/40/5). After evaporation of a portion of the solvent, isPSF 0.45 μm filtration, washing of the residue with pentane and drying at 70 ℃ under vacuum over phosphorus pentoxide for 6 hours gave the expected product.

267.5℃。

Example 14: n- (5-chloro-1H-indol-1-yl) -N' - (2-pyridinyl) urea

2.45g of carbonyldiimidazole are dissolved in 12ml of tetrahydrofuran at 0 ℃. 1.023g of 5-chloro-1H-indol-1-ylamine dissolved in 50ml of tetrahydrofuran are added dropwise. The reaction mixture was stirred at 0 ℃ until complete conversion to the imidazolium compound (imidazolide) (48 hours). After removal of the solvent, the residue was dissolved in dichloromethane; the resulting organic phase was washed twice with water and once with saturated NaC1 solution and then dried over magnesium sulfate. After evaporation of the solvent, the imidazolium compound was obtained as a viscous oil, which was unstable at ambient temperature. To a solution of 0.510g of the imidazolium compound in 5ml of dichloromethane was added dropwise 0.500g of 2-aminopyridine under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature. After 24 hours, a precipitate was observed and stirring was continued. After 72 hours, ether was added and the solid was separated by filtration. The solid and filtrate were purified by flash chromatography separately and fractions containing the desired product were combined.

>320 ℃ C (decomposition).

Example 15: n- (1H-indol-1-yl) -N' - (2-pyrimidinyl) urea

0.408g of preparation 8 and 0.175g of 2-aminopyrimidine were heated under reflux in toluene until complete conversion to urea (72 h). The resulting precipitate was isolated by filtration and washed with a hot methanol/ethanol mixture to give the desired product.

263℃。

Example 16: n- (1H-indol-1-yl) -N' - (2-pyridinyl) urea

0.500g of preparation 8 and 0.379g of 2-aminopyridine are heated in 10ml of dry toluene at 70 ℃ for approximately 72 hours. The precipitate is isolated by filtration, washed with pentane and then dried to give the desired product.

Example 17: n- (1H-indol-1-yl) -N' - (phenyl) urea

0.300g of 1H-indol-1-ylamine was dissolved in 11ml of anhydrous dichloromethane at 0 ℃. 245. mu.l of commercially available phenyl isocyanate dissolved in 11ml of dichloromethane were added dropwise. The reaction mixture was returned to ambient temperature over 12 hours. After 4 days at ambient temperature, the precipitate observed was filtered, washed with pentane and then dried over phosphorus pentoxide at 70 ℃ under vacuum to give the expected product.

243℃。

Example 18: n- (1H-indol-1-yl) -N' - (benzyl) urea

0.308g of 1H-indol-1-ylamine was dissolved in 11ml of anhydrous dichloromethane at 0 ℃. 300. mu.l of commercially available benzyl isocyanate dissolved in 11ml of dichloromethane were added dropwise. The reaction mixture was returned to ambient temperature over 12 hours. After 4 days at ambient temperature, the precipitate observed was filtered, washed with pentane and then dried over phosphorus pentoxide at 70 ℃ under vacuum to give the expected product.

204℃。

Example 19: n- (5-chloro-1H-indol-1-yl) -N' - (benzyl) urea

0.301g of 5-chloro-1H-indol-1-ylamine is dissolved in 8ml of anhydrous dichloromethane at 0 ℃. 245 μ l of commercially available benzyl isocyanate was added dropwise. The reaction mixture was returned to ambient temperature over 12 hours. After 5 days at ambient temperature, the precipitate observed was filtered, washed with pentane and then dried over phosphorus pentoxide at 70 ℃ under vacuum to give the expected product.

218℃。

Example 20: n- (5-chloro-1H-indol-1-yl) -N' - (phenyl) urea

0.300g of 5-chloro-1H-indol-1-ylamine is dissolved in 8ml of anhydrous dichloromethane at 0 ℃. 195. mu.l of commercially available phenyl isocyanate were added dropwise. The reaction mixture was returned to ambient temperature over 12 hours. After 5 days at ambient temperature, the precipitate observed was filtered, washed with pentane and then dried over phosphorus pentoxide at 70 ℃ under vacuum to give the expected product.

247.5℃。

Example 21: n- (1H-indol-1-yl) -N' - (3-pyridylmethyl) urea

2.45g of carbonyldiimidazole are dissolved in 12ml of tetrahydrofuran at 0 ℃. 1.023g of 1H-indol-1-ylamine dissolved in 50ml of tetrahydrofuran are added dropwise. The reaction mixture was stirred at 0 ℃ until complete conversion to the imidazolium compound (48 h). After evaporation of the solvent, the residue was dissolved in dichloromethane; the resulting organic phase was washed twice with water and once with saturated NaCl solution and then dried over magnesium sulfate. After removal of the solvent, N- (1H-indol-1-yl) -1H-imidazole-1-carboxamide is obtained. To a solution of 0.600g N- (1H-indol-1-yl) -1H-imidazole-1-carboxamide in 2.5ml of anhydrous dichloromethane 135. mu.l triethylamine were added dropwise. 135. mu.l of 3- (aminomethyl) pyridine dissolved in 2.5ml of anhydrous dichloromethane are added dropwise; the reaction mixture was stirred at ambient temperature for 4 days. After removal of the solvent, the residue obtained is purified by flash chromatography (ethyl acetate/cyclohexane: 10/40, then 50/50). After removal of the solvent by evaporation, the solid obtained is washed with hot ethanol, filtered and dried to give the expected product.

159.5℃。

Example 22: NN' -bis (5-chloro-1H-indol-1-yl) -urea

0.310g of carbonyldiimidazole was dissolved in 5ml of tetrahydrofuran. 0.501g of 5-chloro-1H-indol-1-ylamine is added and the reaction mixture is stirred at ambient temperature. After 12 hours, precipitation was observed; the reaction mixture was then heated to reflux in tetrahydrofuran for 6 hours. After filtering off the precipitate, washing with dichloromethane and then with pentane, the solid is dried under vacuum to give the expected product.

>300℃。

Example 23: n, N' -bis (1H-indol-1-yl) -urea

This compound was obtained according to a similar manner to that of example 22 except for using 1H-indol-1-ylamine in place of 5-chloro-1H-indol-1-ylamine.

>347℃。

Example 24: n- (1H-indol-1-yl) -N' - (2-pyridylmethyl) urea

0.715g of carbonyldiimidazole are dissolved in 5ml of tetrahydrofuran at 0 ℃. 0.258g of 1H-indol-1-ylamine dissolved in 25ml of tetrahydrofuran is added dropwise. The reaction mixture was stirred at 0 ℃ for 4 hours and then left at ambient temperature. To the reaction mixture was added 1.2ml of 2- (methylamino) pyridine; after stirring at ambient temperature for 48 hours, the resulting solid was filtered and washed with diethyl ether. The filtrate was concentrated to dryness and purified by flash chromatography (ethyl acetate/cyclohexane: 30/70, then 55/45). After removal of the solvent by evaporation, the solid obtained is washed with pentane and then, after filtration, dried to give the expected product.

163℃。

Example 25: n- (1H-indol-1-yl) -N' - (3-quinolinyl) urea

1.30g of preparation 9 and 0.500g of 0.500g N-amino-1H-indole are heated under reflux in acetonitrile for 20 hours under argon atmosphere. The solvent was then evaporated in vacuo and the residue taken up in 100ml of aqueous sodium carbonate solution and extracted with 3X 30ml of dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.50g of crude product. The urea was recrystallized from ethanol to give the expected product.

235℃。

Example 26: n- (1H-indol-1-yl) -N' - (2-pyridazinyl) urea

0.409g of phenyl 1H-indol-1-ylcarbamate and 0.152g of 2-aminopyridazine are heated under reflux in toluene until complete conversion to urea (72H). After filtration, the resulting precipitate was washed with hot toluene and then several times with acetone. Finally, the solid was washed with hot ethanol, then filtered and dried to give the desired product.

220℃。

Example 27: n- (1H-indol-1-yl) -N' - (4-pyridylmethyl) urea

0.499g of phenyl 1H-indol-1-yl carbamate and 0.45ml of 4- (aminomethyl) pyridine are heated in 10ml of anhydrous toluene at 70 ℃ for approximately 36 hours. The precipitate was isolated by filtration and then washed with hot pentane. After dissolution in hot ethanol and filtration, it was dried over phosphorus pentoxide at 70 ℃ under vacuum to give the desired product.

182℃。

Example 28: n- (1H-indol-1-yl) -N' - (6-quinolinyl) urea

0.502g of phenyl 1H-indol-1-yl carbamate and 0.577g of 6-aminoquinoline are heated in 10ml of anhydrous toluene at 70 ℃ for approximately 72 hours. The precipitate was isolated by filtration, washed with pentane and then dried over phosphorus pentoxide at 70 ℃ under vacuum to give the desired product.

249℃。

Example 29: n- (1H-indol-1-yl) -N' - (5-quinolinyl) urea

0.405g of phenyl 1H-indol-1-yl carbamate and 0.459g of 5-aminoquinoline are heated in 10ml of anhydrous toluene at 70 ℃ for approximately 36 hours. The precipitate was isolated by filtration, washed with hot acetone and then dried over phosphorus pentoxide at 70 ℃ under vacuum to give the desired product.

288℃。

Example 30: n- (6-chloro-3-pyridazinyl) -N' - (1H-indol-1-yl) urea

0.498g of phenyl 1H-indol-1-ylcarbamate and 1.32g of 3-amino-6-chloropyridazine are heated in 10ml of anhydrous toluene at 70 ℃ for approximately 10 days. After filtration, the precipitate was dissolved in dichloromethane. The organic phase is washed 3 times with 0.2M hydrochloric acid solution and then with saturated NaCl solution. After drying over magnesium sulfate, the organic phase is concentrated to dryness and the residue obtained is taken up in diethyl ether and then in dichloromethane. The urea was dried over phosphorus pentoxide at 70 ℃ under vacuum to give the desired product.

286(M-1)；288(M+1)。

Example 31: n- (1H-indol-1-yl) -N' - (8-quinolinyl) urea

To a solution of 0.790g of 8-aminoquinoline in 5.5ml of toluene cooled to 0 ℃ 4.5ml of a 1M solution of trimethylaluminum are added dropwise. After stirring at 0 ℃ for 10 minutes, the reaction mixture was returned to ambient temperature and stirred at this temperature for 1 hour. 0.390g of phenyl 1H-indol-1-yl carbamate are suspended in 5.5ml of toluene at 0 ℃; the aluminum complex was added to the resulting suspension using a transfer tube. After returning to ambient temperature, the reaction mixture was heated at 65 ℃ until complete conversion to urea (1 hour 30 minutes). The reaction mixture was hydrolyzed with water and the toluene was evaporated in vacuo. The residue was taken up in water and extracted with dichloromethane. The organic phase is washed 3 times with 0.5M hydrochloric acid solution and then with saturated NaCl solution and then dried over magnesium sulfate. After removal of the solvent, the residue was recrystallized from a pentane/diethyl ether mixture (90/10). After filtration, the crystals obtained are dried over phosphorus pentoxide at 70 ℃ under vacuum to give the desired product.

201℃。

Example 32: n- (1H-indol-1-yl) -1-methyl-N' - (3-pyridinyl) urea

To a solution of 100mg of phenyl N- (1H-indol-1-yl) -N-methylcarbamate in 20ml of anhydrous tetrahydrofuran were added 54mg of 3-aminopyridine and 220mg of (4-dimethylamino) pyridine. The solution was stirred in dimethylformamide at reflux for 3 days. After 3 extractions with ethyl acetate, the organic phase is washed with saturated NaCl solution and evaporated to dryness. The urea was purified via flash chromatography (ethyl acetate/cyclohexane: 3/7) to give the expected product.

289.1(M+23)。

Example 33: n- (1H-indol-1-yl) -3-methyl-3- (3-pyridyl) urea

To a solution of 313mg of phenyl (1H-indol-1-yl) carbamate in 10ml of anhydrous toluene were added 135g of 3- (methylamino) pyridine. The solution was stirred under reflux of toluene for 2 days under an argon atmosphere and then left at room temperature for 2 days. The resulting precipitate was filtered to give the desired product.

168℃。

Example 34: n- (1H-indol-1-yl) -1, 3-dimethyl-3- (3-pyridyl) urea

To a solution of 252mg of 1- (1H-indol-1-yl) -3- (pyridin-3-yl) urea in 20ml of freshly distilled tetrahydrofuran under an inert atmosphere is added 80mg of sodium hydride. After 10 minutes of agitation, 124. mu.l of methyl iodide was added. The reaction mixture was stirred under an inert atmosphere for 2 days. After evaporation of the tetrahydrofuran, extraction was carried out 3 times with dichloromethane, washing was carried out with saturated NaCl solution and the organic phase was evaporated to dryness. The urea was purified by flash chromatography (dichloromethane/methanol: 95/5) to give the expected product.

99℃。

Pharmacological study of the Compounds of the invention

Example A: induction of tyrosine hydroxylase

The study was conducted in compounds that were able to cause an increase in Tyrosine Hydroxylase (TH) protein in the blue plaque (LC) of the Balb/C mouse brain.

The animals used were male mice of pure Balb/C strain (Charles River Laboratories), which were 7-8 weeks old at the time of treatment.

A single injection of the test compound is administered to the mice by the intraperitoneal route, and if the compound is sufficiently soluble, it is dissolved in 0.04M HCl solution (corresponding control: 0.004 MHCl); alternatively, for compounds that are insoluble in aqueous media, they are dissolved in olive oil 90%/DMSO 10% (corresponding control: olive oil 90%/DMSO 10%).

All animals were decapitated and sacrificed 3 days after each compound injection. The brains were removed, then frozen in liquid nitrogen, and stored at-80 ℃.

Coronal sections 8 μm thick were taken along the posterior-anterior axis of the LC and fixed. The sections were transferred to Immobilon-P membranes. TH was determined by immunodetection and image analysis.

Results：

The results of TH induction in LC are given in table I below.

TABLE I

After intraperitoneal administration (20mg/kg), the amount of TH in various LC sections (numbered from 1 to 8 in the front-to-back direction) was determined

Results were compared to control¹Is expressed in% of the average value of (c),

％	1	2	3	4	5	6	7	8
									example 1	66	85	74	64	45	40	8	2
Example 2	63	77	64	57	34	15	8	2
									Example 6	65	81	59	33	20	13	8	2

Example 24

74

78

68

45

29

19

5

7

¹Animals treated with the same vector

Example B: predicted metabolic stability

Compounds are administered at 10 mg/ml in the presence of mouse, rat or human liver microsomes (0.33mg protein/ml)^-7M concentration was incubated to test for expected metabolic stability. Samples were taken at 0, 5, 15, 30 and 60 minutes after addition of NADPH (nicotinamide adenine dinucleotide phosphate, reduced). The enzyme reaction was stopped with methanol (V/V). The protein was precipitated by centrifugation and the supernatant was analyzed by LC-MS-MS.

The good metabolic stability of the compounds makes possible oral administration of the treatment.

TABLE II

Metabolic stability prediction by liver microsomes%

Compounds with good predicted metabolic stability in humans have the advantage that they can be administered by the oral route (between 67-82%).

Example C: predicted penetration of the Blood Brain Barrier (BBB)

The material was incubated at a concentration of 20 μ M in the apical chamber of a two-chamber container, the apical and basal chambers being separated by polycarbonate filters alone or by the same filters covered with confluent endothelial cells from bovine capillary blood vessels. After 10, 20, 30, 40 and 60 minutes, the unchanged substances in the bottom compartment were evaluated by permeation kinetics with LC-MS-MS quantification.

Test compounds generally have higher BBB penetration, which can improve the ability to reach neurological targets. The results are given in the following taxonomic form: high, medium, low. Accordingly, example 1 has high BBB penetration.

Example D: increased ERK phosphorylation in specific brain structures responsible for activity

ERK is a kinase that, in its phosphorylated p-ERK form, activates certain proteins, including tyrosine hydroxylase. The synthesis of dopamine and norepinephrine is promoted when tyrosine hydroxylase is phosphorylated, increased and activated, whereas dopamine and norepinephrine deficiency is the source of the presence of neurological or psychiatric pathologies (e.g., parkinson's disease, deficient forms of schizophrenia, depression, etc.).

Administration of ERK phosphorylation inhibitors in mice is known to produce depressive behavior (Duman c.h. et al, biopsychology (biopsychiatry) 61, (2007), 661-670).

Exposure of rats to stress is accompanied by a decrease in ERK phosphorylation (Yang C. -H., et al, J. Neuroscience (The Journal of Neuroscience)24(49), (2004), 11029-11034).

ERK is a key participant in synaptic and neuronal plasticity essential for learning and good memory function. Inhibition of its phosphorylation causes cognitive impairment (Adams J.P. et al, Annual Review of Pharmacology and Toxicology)42, (2002), 135-163).

Phencyclidine causes recurrence of schizophrenia symptoms in humans and animals and inhibits ERK phosphorylation both in vitro and in vivo (Enomoto t. et al, molecular pharmacology 68, (2005), 1765-.

The role of the compound of example 1 in ERK phosphorylation has been demonstrated in vitro experiments and ex vivo structures:

in vitro experiments

1. Method of producing a composite material

Various forms of non-phosphorylated recombinant ERK (ERK1 and ERK2) and phosphorylated recombinant ERK (p-ERK1 and p-ERK2) were immobilized on "chips", respectivelyAnd (5) researching in a system. The direct interaction of the compound of example 1 at different concentrations was studied.

2.Results

The compound of example 1 binds strongly to ERK1 and ERK2 in a dose-dependent manner. This binding is inhibited if the corresponding phosphorylated ERK is added to the medium.

Pig brain tissue in vitro experiment

1.Method

When the phosphatase of the tissue is inactivated, the various brain structures are separated, processed and suspended in a phosphate-free medium. These tissues were freed from their own ERK and p-ERK and placed in the presence of a specific recombinant form of ERK1, ERK2, p-ERK1 and p-ERK 2.

Phosphorylation ability was studied in the presence and absence of the compound of example 1 by antibodies that were evaluated for non-phosphorylated and phosphorylated ERK1 and ERK 2.

2.Results

At a concentration of 3X 10^-9M, the compound of example 1 preferentially increased phosphorylation of ERK1 and ERK2 in hippocampus and prefrontal cortex, and also increased phosphorylation of ERK2 in striatum.

Example E: pharmaceutical composition

A formulation for 1000 tablets is prepared, each tablet containing 10mg of active ingredient

The

The

.

.

.

The.

Claims (8)

1. Compounds of formula (I), their enantiomers and diastereomers, and addition salts thereof with a pharmaceutically acceptable acid or base

Wherein:

R₁and R₂May be the same or different and represents a hydrogen atom or a linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

R₃represents a hydrogen or halogen atom, linear or branched (C)₁-C₆) Alkyl radicals or linear or branched (C)₁-C₆) An alkoxy group, a carboxyl group,

het represents a pyridyl, pyrimidinyl, piperidinyl, 2-methylpyridyl, 3-methylpyridyl, 4-methylpyridyl, phenyl, benzyl, quinolinyl, pyridazinyl or indolyl group, each of which may optionally be substituted by one or more groups selected from halogen, linear or branched (C)₁-C₆) Alkyl and straight or branched chain (C)₁-C₆) An alkoxy group,

represents a single bond or a double bond,

it is to be understood that R₃May be attached to any carbon atom of the indole/indoline core which allows attachment thereof.

2. The compound of claim 1, wherein R₁、R₂And R₃Compounds of formula (I), their enantiomers and diastereomers, and their addition salts with a pharmaceutically acceptable acid or base, all of which represent a hydrogen atom.

3. Compounds of formula (I) according to claim 1, wherein Het is a pyridinyl, pyrimidinyl or piperidinyl group, their enantiomers and diastereomers, and addition salts thereof with pharmaceutically acceptable acids or bases.

4. Compounds of formula (I) according to claim 1 wherein Het is pyridinyl, their enantiomers and diastereomers, as well as addition salts thereof with a pharmaceutically acceptable acid or base.

5. Compounds of formula (I) are N- (1H-indol-1-yl) -N '- (3-pyridyl) urea and N- (2, 3-dihydro-1H-indol-1-yl) -N' - (3-pyridyl) urea.

6. A process for preparing a compound of formula (I) characterized in that: using the compound of formula (II) as a starting material,

wherein Het is as defined for formula (I),

thermolysis of the Compound of formula (II) liberates N₂Leading to the formation of isocyanate compounds of formula (III), which can be isolated:

Het——N＝C＝O (III)

the compound of formula (III) is then reacted with a compound of formula (IV):

wherein R is₃As defined in formula (I),

the compounds of formula (I) according to the invention are obtained, which can be purified according to conventional separation techniques, converted into their addition salts, if desired with pharmaceutically acceptable acids or bases, and, where appropriate, separated into isomers according to conventional separation techniques.

7. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 as active ingredient together with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

8. The pharmaceutical composition according to claim 7 for the treatment of depression, anxiety, memory disorders during aging and/or neurodegenerative disorders, for the palliative treatment of parkinson's disease, and for adapting to stress.