HK1074446B

HK1074446B - 3-phenyl substituted pyridoindolone, preparation and therapeutic use thereof

Info

Publication number: HK1074446B
Application number: HK05108402.0A
Authority: HK
Inventors: Bernard Bourrie; Pierre Casellas; Paola Ciapetti; Jean-Marie Derocq; Samir Jegham; Yvette Muneaux; Camille-Georges Wermuth
Original assignee: 赛诺菲-安万特
Priority date: 2002-10-23
Filing date: 2003-10-21
Publication date: 2008-08-15

Description

The present invention relates to pyridoindolone derivatives substituted in -3 by a phenyl, their preparation and therapeutic application.

Early art

French patent 276 5581 describes compounds with formula: - What? wherein: x represents a hydrogen or chlorine atom or a methyl or methoxy group; r1 represents a hydrogen atom or a methyl or ethyl group; r2 represents a methyl or ethyl group; or r1 and r2 together form a group (CH2); r3 represents either a phenyl group possibly substituted by a halogen atom or a methyl or methoxy group or a thienyl group. The description of this patent states that compounds of formula (A) having an affinity for the GABAA receptor-associated omega modulatory sites can be used in the treatment of conditions related to gabaergic disorders associated with GABAA receptor-types, such as sleep apnea, sleep apnea, sleep apnea, etc.

International application WO-A-01 09129 describes compounds for which the basic skeleton is different from that of the claimed pyridoindolones.

International application WO-A-02 087574 describes pyridoindolones which differ from the compounds of the invention by the substituent r3. r3 may be a phenyl group R3 possibly monosubstituted or a thienyl group (formulas (I) and (Ibis)).

The present invention relates to compounds having anticancer activity, as follows: in which: R1 represents a hydrogen atom, a (C1-C4) alkyl group or a group (CH2) nOH, (CH2) n-O-tetrahydropyran-2-yl, (CH2) nNR'6R'7, (CH2) nCN, (CH2) nCO2 ((C1-C4) Alk or (CH2) nCONR6R7;R2 represents a hydrogen atom or a (C1-C4) alkyl group or R1 and R2 together form a (CH2) ph3 group;R3 represents a monosubstitute of a hydroxyl group, hydroxymethyl, carboxy, (C1-C4) hydroalcano, azido, (C1-C4) hydroxyl, hydroxycarbonyl, hydroxyfluoroethylene, (C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C2-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C2-C1-C1-C1-C1-C1-C1-C1-C1-C2-C1-C1-C1-C1-C1-C1-C2-C1-C1-C1-C1-C2-C1-C1-C1-C1-C1-C1-C2-C1-C1-C2-C1-C1-C1-C2-C1-C1-C2-C1-C2-C1-C1-C2-C2-C1-C2-C2-C1-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-C2-CFluoromethyl, hydroxyl, hydroxymethyl, (C1-C4) alcosi, carboxy, (C1-C4) alcanoyl, azide, (C1-C4) alcoksycarbonyl, hydroxy iminomethyl, thiol, (C1-C4) alcylthio, (C1-C4) alcylsulfonyl, a phenyl, cyano or by a grouping (CH2) mNR'7R10, CONR6R8 or OCH2nR9 ; or R3 represents a benzodioxol group not substituted or substituted on the phenyl by a halogen atom; R4 and R5 are identical or different and each independently represent a hydrogen atom or a heterogeneous hydroxyl group, or hydroxy group, (CH1-CNR4); or trihydroxycyl, trihydroxycyl, trihydroxycyl or trihydroxycyl (CH1-CNR64); or trihydroxycyl, trihydroxycyl, trihydroxycyl or trihydroxycyl (CH6C71-CR64); or trihydroxycyl, trihydroxycyl, trihydroxycyl or trihydroxycyl (CH6C71-C64); or trihydroxycyl, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy (C6C6C74-C64); or trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy (C6C6C64); or trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydroxy, trihydMorpholinyl, pyrrolidinyl, piperazinyl or 4-methylpiperazine-1-yl;R'6 represents the hydrogen or a (C1-C4) alkyl group;R'7 represents the hydrogen or a (C1-C4) alkyl group;or R'6 and R'7 together with the nitrogen atom to which they are bound constitute a heterocyclic radical chosen from among morpholinyl or pyrrolidinyl;R8 represents the hydrogen, a (C1-C4) alkyl group or a -nCH2-group;or R6 and R8 together with the nitrogen atom to which they are linked constitute a heterocyclic radical chosen from amongst 4-carnitol, morphine, piperyl or cyclenol;or R6 or R7 represents a pyrrolidinyl or a 4-methyl or 4-pyrolidine group;or R6 or R7 represents a pyrrolidine, a 4-carnitol or a 4-methyl or 4-pyrolidine radical;or R10 represents a pyrrolidine, a 4-methyl or a 4-methyl group;or R6 or R7 represents a pyrrolidine, a 4-methyl or a 4-methyl or a 4-methyl group;or R6 or R7 represents a pyrrolidine, a 4-methyl or a 4-methyl or a 4-methyl or a 4-methyl group;orphine, a pyrrolidine, a 4-methyl or a 4-methyl or a 4-methyl or a 4-methyl or 4-methyl or a 4-methyl group;orphine, or a pyrrolidine, a 4-methyl or a 4-methyl or a 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl group;orphine;orphine, R7 represents a 4-methyl or R6 or R7 represents a 4-methyl or a 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-methyl or 4-meth2 or 3;m is 0 or 1.Alk is an alkyl.

The compounds of formula (I) may exist as bases or as additive salts to acids. These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other useful acids, e.g. for purification or isolation of compounds of formula (I) are also part of the invention.

The compounds of formula (I) may also exist as hydrates or solvates, i.e. as associations or combinations with one or more water molecules or with a solvent.

For the purposes of this invention, the following definitions shall apply: a halogen atom : a fluorine, a chlorine, a bromine, or an iodine ; a (C1-C4) alkyl group: a linear or branched saturated aliphatic group containing 1 to 4 carbon atoms. Examples include the methyl, ethyl, propyl, isobutyl, butyl, isobutyl, tert-butyl groups; a (C1-C4) alcoxy group: an O-alkyl radical where the alkyl group is as previously defined.

The present invention is particularly concerned with compounds of formula (I) in which: R1 represents a hydrogen atom, a (C1-C4) alkyl group or a group (CH2) nCO2 ((C1-C4) Alk or (CH2) nCONR6R7 ;R2 represents a hydrogen atom or a (C1-C4) alkyl group ;R3 represents a phenyl monosubstituted by a hydroxyl group, hydroxymethyl, carboxy, (C1-C4) alcoxycarbonyl, hydroxyiminomethyl, (C1-C4) alkyulfonyl, trifluoromethyl, (C1-C4) alkyulfonyl, (C1-C4) alkyulfonyl, cyano or by a group (CH2) CONNR6m or (C1-C4) CONR6m or by a phenyl substitute substituted by 5 different or identical groups; or (C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-(C1-C4) alkyl, trifluoromethyl, cyano, (C1-C4) alcoxy, (C1-C4) alcoxycarbonyl or an O- ((CH2) nNR6R7 group;R6 represents the hydrogen or a (C1-C4) alkyl group;R7 represents the hydrogen or a (C1-C4) alkyl group;or R6 and R7 together with the nitrogen atom to which they are bound constitute a heterocyclic radical chosen from among: piperidyl, morpholinyl, pyrrolidinyl, piperazine or 4-methylpiperazine-1-cyl;R8 represents the hydrogen, a (C1-C4) heterocyclic group or a group -nCH2 nR6R67;R8 and R8 together with the nitrogen or the 4-methylpyrrolide, or a radical chosen from amongst them;R1 represents the pyrrolidinyl, or a 4-methylpyrrolide, or a 2-methylpyrrolide.

The compounds of formula (I) covered by the invention include the preferred compounds defined as follows: R1 represents a hydrogen atom, a methyl group, cyanomethyl, (C1-C4) alcoxycarbonyl methyl, (C1-C4) aminomethyl, aminoethyl, aminopropyl, pyrrolidinoethyl; and/or R2 represents a methyl group; and/or R1 and R2 together form a group (CH2) 3; and/or R3 represents a phenyl monosubstituted by a hydroxyl group, (C1-C4) alcoxycarbonyl, methylsulfonyl, trifluoroethyl, methylthio, cyanomethoxy, aminoethyl, aminoethyl, acetylated, hydroxymethyl, cyano, amino, azido, azomethylene, hydroxy substitute group (CHNR2) or a phenylethene group (R710 or R710 or R710-hydroxy, representing a group identical to a pyrroxy, or a 4-methyl or 2-methyl group, wherein R710 or R710 is a phenylethene or a phenylethene or a 2-hydroxy group, or a pyrroxy, representing a group of atoms, respectively, containing a 4-hydroxy or a 2-hydroxy group, and a pyrroxy, representing a methyl or a 2-hydroxy group, and a 2-hydroxy, respectively, respectively, but not including the pyrroxy, and R7 and R710-hydro.methyl, methoxy, methylthio, trifluoromethyl, hydroxyl, (C1-C4) alcoxycarbonyl, methylsulfonyl, cyanomethoxy, aminoethy, acetyl, hydroxymethyl, cyano, amino, azido, aminomethyl, hydroxyiminomethyl or a group (CH2) mNR'7R10 in which R'7 represents a hydrogen atom or a methyl, R'10 represents a hydrogen atom or a phenyl, pyridyl, pyrimidyl or R'7 and R'10 together with the nitrogen atom are linked to form a piperazine group or a 4-thyperazine-1-methoxy and constitute a substituent or a zethylene or a benzene or a methyl group; R'3 represents a benzene or a phenol, R'4 represents a substituent or a methyl, R'4 represents a substituent or a substituent of a methoxy, R'4 represents a substituent or a methyl group.

In particular, the following compounds are preferred: The following substances are to be classified in the same heading as the active substance: 3-(2,4-dichlorophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one ;3-(1,6-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-3-dihydro-3-yl-benzonitrile ;3-(4-Aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;3-(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((( The following substances are to be classified in the same heading as the additive:

In the following, protective group Gp or G'p means a group that allows, on the one hand, to protect a reactive function such as a hydroxy or an amine during a synthesis and, on the other hand, to regenerate the intact reactive function at the end of synthesis.

A leaving group is a group that can be easily cleaved from a molecule by breaking a heterolytic bond, leaving an electron pair, and can be easily replaced by another group during a substitution reaction, for example, halogens or an activated hydroxy group such as a mesyl, tosyl, triphlate, acetyl, etc. Examples of leaving groups and references for their preparation are given in Advances in Organic Chemistry , J. March, 3rd Edition, Wiley Interscience, p. 310-316.

According to the invention, compounds of general formula (I) can be prepared by the following process.

This process is characterised by: We react a 2-amino-indole with the formula: - What? wherein R1, R2, R4 and R5 are as defined for a compound of formula (I) with an ester of formula: - What? where R3 is as defined for a compound of formula (I) and Alk represents an alkyl in C1-C4.

The reaction is carried out in a polar and preferably basic solvent, e.g. pyridine, at a temperature between ambient and solvent reflux temperature.

In general, a compound of formula: wherein the substituents R'1, R'2, R'3, R'4, R'5 are precursors of the substituents R1, R2, R3, R4, R5 as defined for a compound of formula (I), and then, using methods known to man of the art, transform these substituents to obtain the desired substituents R1, R2, R3, R4, R5 for the compound of formula (I).

From a compound of formula (I) in which R1 or R2 is hydrogen, a compound of formula (I) in which R1 and/or R2 is an alkyl group is prepared by the action of an alkyl iodide in the presence of NaH.

Compounds of formula (I) in which the substituent R1 is a group -(CH2)nCO2(C1-C4)Alk or -(CH2)nCONR6R7 are prepared from the corresponding compounds of formula (I) ' in which R1 = H and R2, R3, R4, R5 have the same values.

For example, a compound of formula (I) in which R1 = H can be substituted by a group (CH2) 2CN by acting a compound of formula Br(CH2) nCN in the presence of sodium hydride.

In addition, to prepare a compound of formula (I) in which R1 represents a group (CH2) nNR'6R'7, a brominated compound of formula Br(CH2) nNR'6R'7 may be acted upon a compound of formula (I) in which R1 = H.

More generally, to prepare a compound of formula (I) in which R1 represents a group (CH2) nNR'6R'7, one can act on a compound of formula (I) in which R1 = H, a compound of formula X ((CH2) nNGp in which X represents a leaving group such as a bromine atom, a mesyl or tosyl group, for example, and Gp represents a protective group of nitrogen; after deprotection of nitrogen, the amine formed can, if necessary, be alkylated using the methods known to man of the art.

To prepare a compound of formula (I) in which R1 represents a group (CH2) nOH, one can act a compound of formula X(CH2) nO-G'p in which X is a starting group and G'p is a protective group of oxygen on a compound of formula (I) in which R1 = H, then treat the compound thus obtained to remove the protective group by methods known to man of art.

To prepare a compound of formula (I) in which the substituents R3 and/or R4 and/or R5 contain a hydroxymethyl, hydroxyiminomethyl, alkylaminomethyl or dialkylaminomethyl group, the corresponding compound of formula (I) containing a substituent R3 and/or R4 and/or R5 containing a cyano group is transformed by methods known to the art.

To prepare a compound of formula (I) in which the substituents R3 and/or R4 and/or R5 contain a hydroxyl group, an analogue compound of formula (I) in which the substituents R3 and/or R4 and/or R5 contain a protected hydroxyl group may first be prepared and then, in a later step, this group may be converted to a hydroxyl by methods known to man of the trade. As a protective group for the hydroxyl, a benzyl, a benzoyl or a (C1-C4) alkyl may be used, for example.

Compounds of formula (I) in which R4 and/or R5 represents one Br atom or the substituent on the phenyl group R3 represents one or more bromine atoms can be used as precursors to prepare other compounds of the invention e.g. compounds bearing amine substituents such as (CH2) nNR6R7, (CH2) mNR'7R10 using reactions known to man of the art.

Compounds containing a brominated substituent are also useful for the preparation of compounds containing an alkoxycarbonyl substituent.

Aminoindoles of formula (II) can be prepared by methods such as those described in Khim. Geterosikl. Soedin., 1973, 12, 647-652 and in J. Heterocycl. Chem., 1975, 12, 135-138.

Some 2-aminoindole derivatives of formula (II) are known and described in Khim. Geterotsikl. Sweden, 1973, 4, 511-515; Eur. J. Med. Chem. Chim. Ther., 1992, 27 (9), 908-918; Chem. Heterocycl. Compd., 1970, 6, 338-343; Tetrahedron, 1971, 27, 775-785; Pharm. Chem. J., 1990, 24 (11), 810-812; Tetrahedron, Lett., 1996, 37 (28), 4931-4932.

Some esters of formula (III) are known and can be prepared by methods such as those described in J. Org. Chem., 1984, 49 (22), 4287-4290; J. Am. Chem. Soc., 1974, 96 (7), 2121; Tetrahedron, 1970, 26 (2), 715-719; Synth. Commun., 2000, 30 (8), 1401-1411; Zhongguo Yaowu Huaxue Zazhi, 2000, 10 (1), 9-12, 25; JP 19 680 131, EP 260 832, EP 178 826, 97-46 577, DE 3 221915.

The compounds of the invention may also be prepared by a process characterized by: We react an aminoindole with the formula: wherein R1, R2, R4 and R5 are as defined for a compound of formula (I) with an ester of formula: - What? where R3 is as defined for a compound of formula (I) and Alk represents an alkyl in C1-C4.

The reaction is carried out in a protic and polar solvent, preferably in an acid medium, at a temperature between ambient and reflux solvent temperature.

The preparation of the compound of formula (IV) is carried out by means of dimethoxy-N,N-dimethylmethanamine (V) by a method similar to that described in J. Org. Chem., 1982, 47, 2846-2851 or by means of the Bredereck reagent (tertbutoxybis ((dimethylamino) methane) according to J. Org. Chem., 1982, 15, 2846-2851 and according to the following reaction scheme: - What?

Unless otherwise specified, the proton nuclear magnetic resonance (NMR) spectra are recorded in DMSO-d6, the reference being in DMSO-d6 which is 2,50 ppm of tetramethylsilane.

The signals observed in NMR are expressed as follows: s: singlet; se: enlarged singlet; d: double; d.d.: doubled; t: triple; td: tripled; q: quadruplet; m: massive; mt: multiple .

The following examples describe the preparation of certain compounds in accordance with the invention. These examples are not exhaustive and are merely illustrative of the present invention. The numbers of the compounds illustrated refer to those given in the following table, which illustrates the chemical structures and physical properties of some compounds according to the invention.

In the preparations and examples to follow, the following abbreviations are used: The following is a list of the active substances which may be used in the preparation of the active substance: Bredereck reagent: tertbutoxybis (dimethylamino) methane TA: room temperature The following is the name of the reagent:

Preparation of compounds of formula (II).

The compounds of formula (II) can exist in 2 tautomeric forms: - What?

Preparation of the report 1.1 The chemical composition of the product is determined by the following equation: A) N'- (4-methylphenyl) acetohydrazide.

104.8 g of 1-(4-methylphenyl) hydrazine hydrochloride are suspended in 525 ml of isopropyl acetate, a solution of 104.8 g of potassium carbonate is added to 300 ml of water and then stirred until the solid disappears. While maintaining the temperature below 20°C, 77.4 g of acetic anhydride is added and then stirred at 20°C, precipitation is observed and then disappears when heated to 55-60°C. The organic phase is washed with 200 ml of water and then cooled to 0-5°C for one night. The product formed by filtration is recovered and washed 2 times every 100 ml.

RMN CDCl3 (300 MHz) : 2.02 ppm : s: 3H ; 2.29 ppm: s: 3H ; 6.14 ppm: d: 1H ; 6.73 ppm: d: 2H ; 7.03 ppm: d: 2H ; 7.72 ppm: s: 1H .

(B) N,N'-dimethyl-N'- ((4-methylphenyl) acetohydrazine.

60 g of hydrazine from the previous step and 11.8 g of tetrabutylammonium bromide are suspended in 240 ml of toluene and 292 g of 50% NaOH is added to the water and 155.6 g of methyl iodide. 83 g of soda is then added in pellets and the reaction medium is heated at 80 °C for 6 hours. It is cooled to 30-35 °C and then 500 ml of water is added. The organic phase is washed 3 times per 100 ml of water. The organic phase is dried by azotropic distillation of water under reduced pressure.

The NCR of CDCl3 (300 MHz) is as follows: 2.15 ppm : s: 3H ; 2.31 ppm: s: 3H ; 2.95 ppm: s: 3H ; 3.10 ppm: s: 3H ; 6.63 ppm: d: 2H ; 7.13 ppm: d: 2H .

(C) N,1,5-trimethyl-1H-indole-2-amine hydrochloride.

The product obtained in the previous step is dissolved in toluene and 61.5 g of phosphorus oxychloride is added and heated at 80 °C for 2 hours. 100 ml of ethyl acetate is added at 80 °C and the medium is cooled to TA. The precipitate is filtered and washed twice with 50 ml of ethyl acetate, F = 222 °C.

RMN DMSO (200 MHz) : 2.36 ppm : s: 3H ; 3.11 ppm : s: 3H ; 3.49 ppm : s: 3H ; 4.29 ppm : s: 1H ; 7.25-7.35 ppm : m: 3H ; 10.07 ppm: m: 1H .

Preparation of the product N,5-dimethyl-1H-indole-2-amine dichlorohydrate, whether or not chemically defined A) N'- (4-methylphenyl) acetohydrazide.

A further method of preparation of this compound is described below.

5 g of 1- ((4-methylphenyl) hydrazine hydrochloride is dissolved in water and then triethylamine is added until the salt is neutralized. The precipitate is extracted at AcOAnd then evaporated dry. The precipitate is dissolved in 30 ml of ether and then a 4.6 ml solution of acetic anhydride dissolved in 30 ml of ether is added, drop by drop.

(B) N-Methyl-N'- ((4-Methylphenyl) acetohydrazide.

At 0°C, add drop by drop 3.2 g of hydrazine obtained in the previous step in 20 ml of DMF. When no further gas is released, add 1.8 ml of methyl iodide and agitate at TA for 1 hour. Pour over a saturated NH4Cl solution and then extract at AcOEt. Wash several times with a saturated NaCl solution and then dry steam. Chromatographically purify on a silica column with an AcO/heptane (25/75 /v) (50/50 /v) mixture to obtain 1.0 g of the expected white powder.

The following are the main features of the CDCl3 (200 MHz) NMR: 2.21 ppm: s: 3H ; 2.32 ppm: s: 3H ; 3.15 ppm: s: 3H ; 5.88 ppm: s: 1H ; 6.64 ppm: d: 2H ; 7.12 ppm: d: 2H .

(C) N,5-dimethyl-1H-indole-2-amine dichlorohydrate, whether or not in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the solution in the form of a solution in the form of a solution in the solution in the form of a solution in the solution in the form of a solution in the solution in the solution in the solution in the form of an solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the solution in the case of the solution in the solution in the case of the solution in the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the case of the

We dissolve 1.0 g of the compound in the previous step in 20 ml of POCl3 and then heat it to 100°C for 2 hours. We cool the reaction mixture and then add ether. We filter the precipitate formed and wash it with ether to get 1.3 g of the expected compound.

RMN DMSO (300 MHz) : 2.31 ppm : s: 3H ; 3.05 ppm : s: 3H ; 4.14 ppm : s: 2H ; 7.07-7.23 ppm : m: 3H ; 10.51 ppm : s: 1H ; 12.37 ppm d: 1H .

Preparation of the report 1.3

The chemical composition of the product is determined by the following equation:

A) N'- (4-Methoxyphenyl) acetohydrazide.

10 g of 4-methoxyphenylhydrazine hydrochloride is dissolved in water and then triethylamine is added until the salt is neutralized. It is extracted at AcOAnd then evaporated dry to obtain 8 g of precipitate which is 4-methoxyphenylhydrazine. This compound is dissolved in 30 ml of ether and then added drop by drop, a 13 ml solution of acetic anhydride dissolved in 30 ml of ether. It is agitated for 15 minutes at 0 °C and then the filtered white precipitate is formed to obtain 7.4 g of the expected compound.

RMN CDCl3 (200 MHz) : 2.06 ppm : s: 3H ; 3.75 ppm: s: 3H ; 5.65 and 6.03 ppm: 2s: 2H ; 6.6-6.9 ppm: m: 4H.

(B) N,N'-Dimethyl-N'- ((4-methoxyphenyle) acetohydrazide.

4,3 g of NaH at 60% is suspended in 30 ml of DMA. Drip-by-drop, 7,4 g of the previous step compound dissolved in 20 ml of DMA is added. When no more gas is released, 10,0 ml of iodomethane is added. It is stirred at room temperature for 1 hour. It is poured over a saturated NH4Cl solution and then extracted in AcOEt. Washed several times with a saturated NaCl solution and then evaporated dry. The resulting residue is ground in petroleum ether to obtain 8,0 g of the expected compound in the form of oil.

The following are the main features of the new CDCl3 (200 MHz) NMR: 2.19 ppm: s: 3H ; 2.93 ppm: s: 3H ; 3.08 ppm: s: 3H ; 3.80 ppm: s: 3H ; 6.68 ppm: d: 2H ; 6.89 ppm: d: 2H .

(C) N,1-dimethyl-5-methoxy-1H-indole-2-amine hydrochloride.

8.0 g of the previous step compound is dissolved in 30 ml of POCl3 and heated to 80°C for 2 hours. The reaction mixture is cooled and ether is added. The resulting brown precipitate is filtered and washed with ether to obtain 5.3 g of the expected compound, F = 222°C.

The following are the main features of the new standard: the use of the standardised data for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the calculation of the data for the calculation of the calculation of the data requirements for the calculation of the calculation of the calculation of the data for the calculation of the calculation of the data requirements for the calculation of the calculation of the calculation of the calculation of the value of the value of the value of the value of the value of the value of the value of the estimated data for the value of the value of the estimated data for the estimated data for the estimated

Preparation of the programme 1.4

A) N'- (4-Chlorophenyl) acetohydrazide.

We dissolve 12.5 g of 4-chlorophenyl hydrazine hydrochloride in 100 ml of water and then add triethylamine until the salt is neutralized. We extract it in AcOAnd then dry evaporate. We dissolve the base in 100 ml of ether, cool it to 0°C and then add drop by drop, 15 ml of acetic anhydride. We stir at 0°C for 15 minutes. We filter the white precipitate formed and then wash it with ether to get 12.8 g of the expected compound in the form of a white powder.

The frequency of the measurement is determined by the frequency of the measurement.

(B) N,N'-Dimethyl-N'-(4-chlorophenyl)acetohydrazide.

7.2 g of NaH at 60% is placed in suspension in 30 ml of DMA. 12.8 g of hydrazine from the previous step dissolved in 50 ml of DMA is added by drip and then stirred at room temperature until the gas release stops. 17 ml of iodomethane is added by drip and stirred at room temperature for 1 hour.

The following are the main features of the new CDCl3 (200 MHz) NMR: 2.10 ppm: s: 3H ; 2.95 ppm: s: 3H ; 3.10 ppm: s: 3H ; 6.62 ppm: d: 2H ; 7.24 ppm: d: 2H .

(C) Hydrochloride of N,1-dimethyl-5.chloro-H-indole-2-amine.

10 g of the compound in the previous step is dissolved in 50 ml of POCl3, reflux heated for 2 hours, the reaction medium cooled, ether added, and the resulting product filtered, and the precipitate washed several times with ether to obtain 9.6 g of the expected compound in powder form.

The following are the main features of the new standard: the use of the standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standard

Preparation of the report 1.5 The following substances are to be classified in the same heading as the active substance: A) 4- (β-acetylhydrazine) methyl benzoate

5.5 g of methyl 4-hydrazinobenzoate is dissolved in 38.2 ml of AcOH containing 2.4 g of sodium acetate, heated for 18 hours at 80°C. The mineral is extracted, then evaporated and re-extracted with a minimum of Et2O.

B) 4- (α) 2-acetyl-1,2-dimethylhydrazine) methyl benzoate.

The medium is poured on a saturated solution of NH4Cl and extracted by AcOEt. The organic phase is washed with NaCl, dried, evaporated to give 5.4 g of the expected compound.

C) 1-Methyl-2- (methylamino) - 1-H-indole-5-carboxylate of methyl.

The mixture of 5.4 g of the compound in the previous step is mixed with 62 ml of phosphorus oxychloride and heated for 2 1/2 hours at 80°C. The medium is evaporated and re-used by AcOEt. The solid formed is exorcised, washed by AcOEt, and dried to give 4 g of the expected compound.

The frequency range of the measurement is defined as the frequency range of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measur

The following formula (II) compounds are prepared as described above:

TABLEAU 1

Préparations			Caractérisation F°C ou RMN
1.6	Me	H	249°C
1.7	Me	7-OMe	284°C
1.8	Me	4-OMe	103°C
1.9	Me	6-OH	103°C
1.10	Me	6-Me
1.11	Me	4,6-diMe	134°C
1.12	Me	5-OMe	222°C
1.13	Me	5-Cl	RMN
1.14	Me	6-OMe	103°C
1.15	Me	5-CN	245°C
1.16	Me	5-phényl

RMN 1.13 DMSO (300 MHz) : 3.08 ppm : d: 3H ; 3.52 ppm: s: 3H ; 7.34 ppm: d: 1H ; 7.48 ppm: d: 1H ; 7.60 ppm: s: 1H ; 10.61 ppm: s: 1H .

Preparation of the Hydrochloride of 2- (methylimino) indole-5-carboxylate of ethyl. A) 4-Hydrazinobenzoate of ethyl.

5.0 g of 4-phenylhydrazine acid is dissolved in 70 ml of ethanol and 3 ml of concentrated H2SO4. It is heated at low temperature for 5 hours, the ethanol is evaporated and then re-absorbed in a saturated solution of K2CO3 and then extracted at AcOEt. 5.9 g of the expected compound is obtained as a powder.

RMN CDCl3 (300 MHz) : 1.38 ppm : t: 3H ; 3.65 ppm: s: 2H ; 4.34 pppm: q: 2H ; 5.57 ppm: s: 1H ; 6.80 ppm: d: 2H ; 7.93 ppm: d: 2H .

B) 4-N'-acetylhydrazine ethyl benzoate.

We dissolve 5.9 g of the compound in the previous step in 50 ml of acetic acid and add 3.0 g of sodium acetate. We heat it at 80°C for 16 hours. We evaporate the acetic acid, we add it to water and then we extract it to CH2Cl2.

The following is a list of the most commonly used methods of measuring the concentration of CDCl3 in the atmosphere:

C) 4-N'-Acetyl-N'-methylhydrazine)ethyl benzoate.

Suspend in 20 ml DMF, 0.72 g NaH at 60%. Cool to 0 °C, then add 4.0 g of the previous step compound dissolved in 20 ml DMA. Shake at 0 °C for 15 minutes, then add 1.7 ml iodomethane and shake at 0 °C for 30 minutes. Pour over a saturated NH4Cl solution, extract at AcOEt, wash with a saturated NaCl solution, dry on MgSO4 and then adsorb on silica. Chromatographically purify on a silica column mixed with an AcO/petroleum ether (v/v 50/50). Get 1.8 g of oil.

The following are the main features of the new CDCl3 (300 MHz) NMR: 1.38 ppm: t: 3H ; 2.15 ppm: s: 3H ; 3.17 ppm: s: 3H ; 4.35 ppm: q (J=7.1): 2H ; 6.10 ppm: s: 1H ; 6.71 ppm: d (J=8.8): 2H ; 7.99 ppm: d: 2H .

(D) Hydrochloride of 2-methylimino-indoline-5-carboxylate of ethyl.

We dissolve 1.5 g of the compound in the previous step in 10 ml of POCl3, heat it to 80°C for 2 hours, cool the reaction medium, add ether, grind the precipitate and filter it, wash it with ether, and we get 1.4 g of powder.

The following is a list of the main components of the CDCl3 (300 MHz) NCR: 1.31 ppm: t J=7.1): 3H ; 3.07 ppm: d (J=4.7): 3H ; 4.25 ppm: s : 2H ; 4.31 ppm: q: 2H ; 7.58 ppm: d (J=8.8): 1H ; 7.99 ppm: m ; 2H ; 10.97 ppm: s: 1H ; 12.81 ppm: s: 1H .

Preparation of the report 1.18

Hydrochloride of 5-bromo-N-methyl-1H-indole-2-amine

(A) N'- (B) -4-bromophenyl) formic hydrazide.

Dissolve 10.0 g of 4-bromophenylhydrazine hydrochloride in 30 ml of water. Add 6.2 g of K2CO3 and 36 ml of methyl format, then reflux heat for 1 hour and then at room temperature for 12 hours. Filter the precipitate formed and wash with an isopropanol/petroleum ether mixture (v/v; 50/50).

(B) N'- ((4-Bromophenyl) N-methylacetohydrazide.

A solution of 80 ml of LAH is reflux heated in THF. 10.5 g of the previous step compound is added in suspension in 60 ml of THF. The reaction medium is refreshed for 15 hours. The reaction medium is then drip-dried with 2.3 ml of water, then 9.0 ml of NaOH 1N and then 10 ml of H2O. The salts are filtered on cellite®, washed in AcOAnd then evaporated dry. Then taken up in 80 ml of AcOAnd then 17 g of K2CO3 dissolved in 80 ml of water and then 4.0 g of acetic anhydride. Agitated at room temperature for 1 hour. The 2 phases are separated, dried on the organic MgSO4 crystals are added and evaporated. The oil is then obtained from the cotherine phase formed by the 9.0 g filter.

The following are the main components of the CDCl3 (300 MHz) NMR: 2.15 ppm: s: 3H; 3.13 ppm: s: 3H; 6.57-6.62 ppm: m: 2H; 7.32-7.40 ppm: m: 2H.

(C) Hydrochloride of 5-bromo-N-methyl-1H-indole-2-amine.

We dissolve 9.0 g of hydrazine from the previous step in 50 ml of POCl3 and then heat it at 80°C for 2 hours. We cool the reaction mixture and then add ether. We filter the precipitate and wash it with ether. We get 8.2 g of powder.

The following is the list of the most commonly used methods of measuring the frequency of the radio frequency spectrum:

Preparation of the The active substance is 8-Methyl-1,2,3,4-tetrahydropyrimide[1,2-a]indole. A) 1- (4-methylphenyl) pyrazolidine-3-one.

10 g of p-tolyylhydrazine hydrochloride is dissolved in 100 ml of anhydrous CH2Cl2. It is cooled to 0°C and added 19 ml of DBU and then 6.5 mg of 3-bromopropionyl chloride. It is agitated at room temperature for 1 hour. The reaction medium is poured over water, extracted at CH2Cl2 and then purified by chromatography of the elevated silica column with a mixture of AcOEt/petroleum ether (v/v; 50/50). 1.3 g of crystals are obtained.

RMN CDCl3 (300 MHz) : 2.35 ppm : s: 3H ; 2.54 ppm : t (J=7.9) : 2H ; 3.89 ppm : q (J=7.9) : 2H ; 6.93-7.16 ppm : m : 4H ; 8.22 ppm: s: 1H .

B) 1-acetyl-2- ((4-methylphenyl) pyrazolidine.

At 9.6 ml of a 1M solution of LAH in THF, add 1.3 g of the previous step compound dissolved in 20 ml of anhydrous THF. Reflux heating for 18 hours. Cooling to room temperature then add 2 ml of water and 7 ml of 1N soda and then filter the salts on cellite®. Evaporate the filtrate and take the residue back into 20 ml of AcOEt and add 2.6 g of K2CO3 and 5 ml of H2O then 0.6 ml of acetic anhydride. Stir at room temperature for 1 hour. Separate the 2 phases, dry on MgSO4 and the organic phase evaporates to dry.

The following are the main features of the new CDCl3 (300 MHz) NMR: 1,93-2,05 ppm: m: 2H; 2,07 ppm: s: 3H; 2,30 ppm: s: 3H; 3,50 ppm: m: 4H; 6,83-7,11 ppm: m: 4H.

C) 8-Methyl-1,2,3,4-tetrahydropyrimide[1,2-a]indole.

We dissolve 1.4 g of the compound in the previous step in 10 ml of POCl3, heat it to 80°C for 1 hour 30 minutes, cool the reaction medium, add ether, filter the precipitate and wash it with ether, and we get 1.4 g of the expected compound as a powder.

The following are the main features of the new system: the use of the DMSO (RMSO) in the DMSO: 2.06-2.14 ppm: m: 2H; 2.33 ppm: s: 3H; 3.50 ppm: m: 2H; 3.84-3.88 ppm: m: 2H; 4.15 ppm: s: 2H; 7.15-7.29 ppm: m: 3H; 10.84 ppm: s: 1H .

Preparation of intermediates of formula (III) and (IV). Preparation of the report 2.1 The following substances are to be classified in the same category as the active substance: (a) 3,5-Difluorophenyl methyl acetate.

At 0°C, a solution containing 25 ml of acetyl chloride is prepared in 250 ml of methanol, then, at room temperature, 25.5 g of 3,5-difluorophenyl acetic acid is dissolved in this solution and stirred at TA. The reaction is followed by thin-film chromatography, after the starting product has disappeared, the medium is evaporated at reduced pressure and the residue is dissolved in 250 ml of MTBE. Wash 3 times in 100 ml of water, dry on MgSO4 and then evaporate at reduced pressure.

B. 2- (3,5-Difluorophenyl) 3-dimethylamino-2-methyl propionate.

The solvent is evaporated at reduced pressure and the residue is recovered by 250 ml MTBE. The residue is washed 3 times with 50 ml of water and then dried on MgSO4 and evaporated dry. The residue recrystallizes in methylcyclohexane, the product is filtered and then washed 2 times with 25 ml methylcyclohexane to give 28 g of the expected compound, F = 97°C.

Preparation of the report The following substances are to be classified in the same heading as the active substance: A. 3,5-Difluorophenyl acetate of ethyl.

Dissolve 5 g of 3,5-difluorophenyl acetic acid in 50 ml of ethanol and 3 ml of concentrated H2SO4 and reheat at low temperature for 2 hours.

The following is the list of the most commonly used methods of measuring the concentration of CDCl3 in the sample:

B. 2- (3,5-Difluorophenyl) 3-hydroxy-2-ethyl propenoate

5.0 g of ethyl 3,5-difluorophenyl acetate is dissolved in 50 ml of ethyl formate. 2.0 g of NaH at 60% is added in small fractions. It is poured on a solution of HCl 1N and then extracted at AcOEt. The residue is crushed in petroleum ether and the remaining white precipitate is filtered and then the filtrate is evaporated to obtain 3.3 g of the expected compound in liquid form.

Preparation of the report 2.3 The following substances are to be classified in the same heading as the active substance:

Dissolve 10 ml of 2-(3,5-dimethylphenyl) ethyl acetate in 80 ml of ethyl formate. Add 5 g of NaH at 50% in small fractions and stir at TA for 12 hours. Pour onto a solution of 1N HCl and then extract by AcOEt and evaporate to obtain the expected compound, which is used as is in the next step.

Preparation of the product The substance is a mixture of two or more of the following:

8.9 ml of p-methoxyphenylacetate of ethyl is dissolved in 80 ml of ethyl formate. 4.6 g of NaH at 50% are added in small fractions, then stirred at room temperature for 12 hours. 1N HCl is poured into a solution and then extracted at AcOEt.

Preparation 2.5 2-[4-Benzyloxy) phenyl]-3-dimethylamino, methyl propenoate (IV)

After cooling at TA, ethyl acetate and 60 ml of ammonium chloride are added, stirred for 5 minutes, the organic phase is separated and the aqueous phase is extracted twice from the ethyl acetate. After evaporation of the solvent under reduced pressure, then activated charcoal treatment, 4.16 g of the expected compound is recovered after washing with pentane from the solid.

Preparation of the report 2.6 The following substances are to be classified in the same heading as the active substance: A) 3-ethyl bromophenyl acetate.

Dissolve 5 g of 3-bromophenyl acetic acid in 80 ml of ethanol, add 3 ml of concentrated H2SO4 and then reflux for 2 hours. Evaporate the ethanol, neutralize with a saturated solution of K2CO3 and then extract by AcOEt and dry on MgSO4.

B. 2- (3-bromophenyl) 3-hydroxy-2-propanoate of ethyl (III).

5,2 g of the compound in the previous step is dissolved in 70 ml of ethyl formate and 1,7 g of NaH at 60% is added in small fractions. It is stirred at TA for 5 hours. 100 ml of 1N HCl is poured over it and then extracted by AcOEt, dried on MgSO4 and then evaporated dry. 5,8 g of the expected compound is obtained as oil.

The intermediates of formula (III) are obtained by the preparations described above, as shown in the following table: - What?

TABLEAU 2

Préparations		Caractérisation RMN
2.7	2,4-diCl-phényl
2.8	3,4-diCl-phényl
2.9
2.10
2.11	1,3-benzodioxazol-5-yl
2.12	2,5-diOMe-phényl	non purifié
2.13	3,4-diOMe-phényl
2.14	3,5-diF-phényl
2.15	2,4-diF-phényl
2.16	2,3-diF-phényl
2.17	3,5-diCl-phényl
2.18
2.19	2,4-diF-phényl
2.20		huile
2.21	(4-OMe, 3,5 di-tBu)phényl	1,38 ppm : t (J=7,2) : 3H ; 1,56 ppm : s : 18H ; 3,83 ppm : s : 3H ; 4,41 ppm : q (J=7,2) : 2H ; 7,27-7,44 ppm : m : 3H ; 12,21 : d (J=12,7) : 1H.
2.22	3,4,5-triOMe-phényl
2.23	3,5-diOMe-phényl
2.24		DMSO (200 MHz) : 1,1 ppm : t : 3H ; 4 ppm : q : 2H ; 7 ppm : d : 2H ; 7,3 ppm : d : 2H ; 7,8 ppm : s : 1H ; 11 ppm : s : 1H
2.25	2,4-diOMe-phényl
2.26		DMSO (200 MHz) : 1,2 ppm : t : 3H ; 4,1 ppm : q : 2H ; 7 ppm : s : 1H ; 7,05 ppm : d : 1H ; 7,2 ppm : d : 1H; 7,35 ppm : m : 2H; 7,9 ppm : s : 1H.
2.27	2-Cl-4-F-phényl

Preparation of the report 2.28 2-Chloro-1,3-benzodioxol-5-yl)-3-hydroxyethyl acrylate (a) 5-bromomethyl-6-chloro-1,3-benzodioxol.

We dissolve 2.5 g of 6-chloropiperonyl alcohol in 80 ml of ethyl ether. We cool it to 0°C and add 1.9 ml of PBr3. We stir it at room temperature for 18 hours. We pour it on ice and then we extract it in AcOEt. We wash it with a saturated NaCl solution. We get 3.3 g of powder.

The following are the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of the values of

B. (6-Chloro-1,3-benzodioxol-5-yl) acetonitrile. It is not intended to be used in the manufacture of other products.

We dissolve 3.3 g of the compound in the previous step in 70 ml of ethanol and 15 ml of water. We add 1.8 g of KCN and then heat it back up for 5 hours. We evaporate the ethanol, we take it back in water and then we extract it in AcOEt. We dry it on MgSO4 and then we dry it off. We get 2.4 g of oil.

C) (6-Chloro-1,3-benzodioxol-5-yl)ethyl acetate.

2.4 g of the compound from the previous step is dissolved in 80 ml of ethanol and 4 ml of concentrated H2SO4. It is heated at low temperature for 48 hours. The ethanol is evaporated, re-absorbed in water and then extracted in AcOEt. It is washed with a saturated NaCl solution, dried on MgSO4 and then evaporated dry.

The following is the list of the most commonly used methods of calculating the value of the value of the assets:

D. 2-(6-Chloro-1,3-benzodioxol-5-yl)-3-hydroxyethyl acrylate.

The first step is to dissolve 2.9 g of the compound in 60 ml of ethyl formate, add 1.0 g of NaH at 60% and stir at room temperature for 5 hours, pour 100 ml of a 1N HCl solution and then extract it in AcOEt, dry on MgSO4 and evaporate dry, and then use 3.2 g of the oil as it is.

Preparation of the report 2.29 2- (hydroxyphenyle) 3-dimethylaminoacrylate of ethyl. A) (3-Hydroxyphenyl) methyl acetate

10 g of 3-hydroxyphenylacetic acid is dissolved in 60 ml of methanol and 2.5 ml of sulfuric acid. It is heated at low temperature for 2 hours. It is returned to room temperature and the methanol is evaporated. The residue is taken back into a saturated solution of K2CO3. It is extracted at AcOEt. The organic phase is dried on MgSO4, filtered and evaporated dry.

The following are the main features of the new standard:

B. (3-benzyloxyphenyle) ethyl acetate

We dissolve 3 g of the compound in the previous step in 13 ml of ethanol, add 3.75 g of K2CO3, 3.12 ml of benzyl chloride and a spatula tip of nBu4NI, reflux heat for 6 hours, return to room temperature, filter on K2CO3, evaporate dry, take back into AcOEt and wash with water, get 5 g of oil.

The following are the main features of the new system:

C) 2- (3-Hydroxyphenyle) 3-dimethylaminoacrylate of ethyl.

5 g of the compound in the previous step is dissolved in 8 ml of dimethylformamide dimethylacetal (DMFDMA). Heated at 135°C for 24 hours, adding 1 ml of DMFDMA every 3 hours or so. Dry evaporated. 6 g of oil is obtained.

The intermediates of formula (IV) are obtained by following the procedure in Preparation 2.1 as shown in the following table:

TABLEAU 3

Préparations		Caractérisation RMN
3.1
3.2	2,6-diCl-phényl	DMSO (200 MHz) : 2,8 ppm : s : 6H ; 3,5 ppm : s : 3H ; 7,3-7,55 ppm : m : 3H ; 7,6 ppm : s : 1H.
3.3	3-Br, 4-OMe-phényl	125°C
3.4	2,4-diCl-phényl	DMSO (200 MHz) : 2,6 ppm : s : 6H ; 3,4 ppm : s : 3H ; 7,1-7,3 ppm : m : 2H ; 7,4-7,5 ppm : m : 2H.
3.5	2-Br-4,5-diOMe-phényl	115°C
3.6	2-Cl-4,5-diOMe-phényl	DMSO (200 MHz) : 2,6 ppm : s : 6H ; 3,4 ppm : s : 3H ; 3,6 ppm : s : 3H ; 3,65 ppm : s : 3H ; 6,65 ppm : s : 1H ; 6,85 ppm : s : 1H ; 7,4 ppm : s : 1H.
3.7	3-CN-4-OMe-phényl	125°C
3.8	2,4-diMe-phényl	-
3.9	3,4-diMe-phényl	-
3.10	4-OBn-phényl	DMSO/TFA (200 Mhz) : 2,6 ppm : s : 6H ; 3,4 ppm : s : 3H ; 5 ppm : s : 2H ; 6,8-7 ppm : m : 4H ; 7,1-7,25 ppm : m : 6H.
3.11		DMSO (300 MHz) : 2,64 ppm : s : 6H ; 3,50 ppm : s : 3H ; 3,70 ppm : s : 3H ; 4,75 ppm : s : 2H ; 6,64-7,48 ppm : m : 4H ; 7,95 ppm : s : 1H.
3.12	3,5-diOMe-phényl
		6H ; 3,64 ppm : s : 3H ; 6,81-6,86 ppm : m : 3H ; 7,54 ppm : s : 1H

Preparation of the report 3.13 The following substances are to be classified in the same heading as the active substance: The following substances are to be classified in the same heading as the product:

5.0 g of 2-chloro-4-bromotoluene is dissolved in 120 ml of CCl4, 4.3 g of NBS and 1.6 g of AIBN are added, reflux heated for 15 hours, water is added, the two phases are separated and extracted to CH2Cl2, and chromatography is performed on a silica column with petroleum ether to obtain 3.8 g of liquid.

CDCl3 (300 MHz) : 4.48 ppm: s: 2H; 7.23-7.36 ppm: m: 2H; 7.51 ppm: s: 1H. The following are the most commonly used CDCl3 concentrations:

B. (4-Bromo-2-chlorophenyl) acetonitrile. It is a white solid.

We dissolve 3.8 g of the previous step's compound in 70 ml of ethanol and 15 ml of H2O. We add 1.7 g of KCN and then heat it back up for 5 hours. We evaporate the ethanol, we add it to water and then we extract it in AcOEt. We get 2.5 g of oil.

CDCl3 (300 MHz) : 3.79 ppm: s: 2H; 7.35-7.49 ppm: m: 2H; 7.59 ppm: s: 1H. The following are the main components of the CDCl3

C) (4-Bromo-2-chlorophenyl) ethyl acetate

We dissolve 2.5 g of the compound in the previous step in 80 ml of ethanol and 4 ml of concentrated H2SO4. We heat it back for 4 days. We evaporate the ethanol, we take it back into a saturated solution of K2CO3, we dry it on MgSO4 and then we dry it. We get 2.5 g of liquid.

CDCl3 (300 MHz) : 1.28 ppm: t (J=7.1) : 3H ; 3.73 ppm: s: 2H ; 4.18 ppm: q (J=7.1) : 2H ; 7.18 ppm: m: 1H ; 7.38 ppm: m: 1H ; 7.56 ppm: s: 1H.

D. 2- (bromo-2-chlorophenyl) 3-dimethylaminoacrylate of ethyl

You dissolve 2.8 g of the compound in the previous step in 3.1 g of Bredereck's reagent, you heat it to 100°C for 15 hours, you evaporate the excess reagent, you get 2.9 g of oil.

CDCl3 (300 MHz) : 1.18 ppm: t (J=7.1) : 3H ; 2.72 ppm: s: 6H ; 4.09 ppm: q (J=7.1) : 2H ; 7.15 ppm: m: 1H ; 7.35 ppm: m: 1H ; 7.54 ppm: m: 1H ; 7.60 ppm: s: 1H .

Example 1: compound 6 The chemical is known as 3-(3,5-Difluorophenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one.

The resulting product is washed twice with 25 ml of MiBK dried at 40-45°C for 24 hours to give the expected 20.33 g of the compound after crystallization in MiBK (2033 g, F = 240°C).

The frequency of the signal is measured at the frequency of the signal .

Example 2: compound 22 The chemical is a 3-(3,5-Difluorophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one.

1.5 g of hydrochloride of Preparation 1.2 is dissolved in 50 ml of pyridine. 1.9 g of the compound of Preparation 2.2 is added and heated at 70 °C for 20 hours. It is evaporated dry and then re-absorbed in water and extracted to CH2Cl2.

The frequency range of the DMSO (MHz) is as follows: 2.51 ppm: s: 3H; 3.70 ppm: s: 3H; 7.04-8.68 ppm: m: 7H; 11.98 ppm: s: 1H.

Example 3: compound 16 The substance is classified in Annex I to Regulation (EC) No 1907/2006 as a substance of very high concern.

Dissolve 0.8 g of the compound of Preparation 1.2 obtained in 50 ml of pyridine. Add 0.8 g of the compound of Preparation 2.3 and heat at 80 °C for 20 hours. Dry evaporate and then re-substitute in water and extract to CH2Cl2.

The following are the main features of the new standard:

Example 4: compound 20 The active substance is a compound containing a mixture of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.

2.5 g of the compound of Preparation 1.3 is dissolved in 70 ml of pyridine. 3.3 g of the compound of Preparation 2.2 is added and heated at 100°C for 20 hours. Dry evaporated and then re-used in water and AcOEt. The remaining precipitate is filtered. Recrystallized in isopropanol to obtain 1.35 g of the expected compound, F = 189°C.

Example 5: compound 1 The active substance is a 3- (3,5-dimethylphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one.

This compound is prepared from the compounds in Preparations 1.1 and 2.3, F = 210°C.

Example 6: compound 2 The chemical composition of the product is determined by the following equation:

This compound is prepared from the compounds in Preparations 1.1 and 2.7, F = 170°C.

The following is the list of the most commonly used methods of measuring the concentration of CDCl3 in the atmosphere:

Example 7: compound 21 3-(2,4-Dichlorophenyl)-6-methoxy-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b] indole-2-one is a substance that is used in the manufacture of a variety of products.

This compound is prepared from the compounds in Preparations 1.3 and 2.7, F = 130°C.

The following are the main features of the new system:

Example 8: compound 32 3-(2,4-Dichlorophenyl)-1,5,7,9-tetramethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one is also used in the manufacture of other chemicals.

This compound is prepared from the compounds of Preparations 1.11 and 2.7, F = 204°C

The following are the main features of the CDCl3 (300 MHz) NMR: 2.51 ppm: s: 3H ; 2.68 ppm: s: 3H ; 4.10 ppm: s: 6H ; 6.91 ppm: s: 1H ; 7.05 ppm: s: 1H ; 7.31 ppm: dd: 1H ; 7.44 ppm: d: 1H ; 7.52 ppm: d: 1H ; 8.11 ppm: s: 1H .

Example 9: compound 66 3- ((Hydroxyphenyle)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indolone is a drug that is used in the treatment of acute and chronic pain. A) 3-(4-Methoxyphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indolone is used as a solvent for the treatment of acute and chronic pain.

Dissolve 2.0 g of hydrochloride obtained from Preparation 1.1 in 50 ml of pyridine. Add 2.1 g of formyl ester obtained from Preparation 2.4 and heat at 80 °C for 20 hours. Dry evaporate and then extract to CH2Cl2 and wash with water. Chromatograph purify on elevated silica column with a mixture of AcOEt/heptane/CH2Cl2 (50/50 v/v/v) to obtain 0.5 g of the expected compound in powder form.

The following are the main features of the new standard:

B) 3-(4-Hydroxyphenyle)-1,6,9-trimethyl-1,9-dihydro-2H-pyrido[2,3-b]indolone is a substance that is used in the manufacture of a variety of products.

The reaction medium is diluted with a mixture of DCM and MeOH. The solution is evaporated at reduced pressure. The crude is taken up into DCM and adsorbed onto 16 g of silica and chromatographed on a silica column with a mixture (97/3 g; v/v) then (95/5 g; v/v) up to (50/50 g/v) of DCM/OH. A solid is thus collected which forms a DCM/MeOH mixture. The suspension is cooled and suspended. The filter is then suspended at > 4 °C. The resulting precipitate is obtained at > 280 g.

The following are the main features of the new standard: the use of the standardised data for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the calculation of the data for the calculation of the data requirements for the calculation of the calculation of the calculation of the data requirements for the calculation of the calculation of the calculation of the data for the calculation of the calculation of the calculation of the data for the calculation of the calculation of the calculation of the data for the calculation of the calculation of the value of the value of the value of the value of the value of the value of the value of the estimated data for the estimated data for the value of the

Example 10: compound 68 1,6-Dimethyl-3- ((4-hydroxyphenyle)-1,9-dihydro-2H-pyrido[2,3-b]indolone is a substance that is used in the manufacture of a variety of products. The following substances are to be classified as:

1 g of N,5-dimethyl-1H-indole-2-amine (Preparation 1.2) is mixed with 1.4 g of the compound in Preparation 2.5 and 10 ml of acetic acid, and then heated to 100°C for 18 hours. Dry evaporated under vacuum, then 20 ml of CH2Cl2 and 5 ml of H2O are taken up again.

The following substances are to be classified as:

Mix 0.800 g of the compound in the previous step with 50 ml of TFA. Heat for 1 hour 30 minutes at 75°C. Vacuum dry evaporate and then take 15 ml of Et2O and dry, F = 186°C.

RMN DMSO (300 MHz) : 2.6 ppm : s: 3H ; 3.8 ppm: s: 3H ; 6.8 ppm: d: 2H ; 7.1 ppm: d: 1H ; 7.4 ppm: d: 1H ; 7.6 ppm: d: 2H ; 7.8 ppm: s: 1H ; 8.2 ppm: s: 1H ; 11.9 ppm: s: 1H .

Exemption 11: compound 52 The active substance is a 4- (-1,6,9-trimethyl-2-oxo-2,9-dihydro-1H-pyridone[2,3-b]indol-3-yl) benzonitrile. A) 3-(3-bromophenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one is also used.

2.5 g of the compound of Preparation 1.1 is dissolved in 40 ml of acetic acid and 60 ml of pyridine; 3.5 g of the compound of Preparation 2.6 is added and heated at 100 °C for 15 hours. The reaction medium is poured into 200 ml of water and the precipitate formed is filtered. It is picked up by CH2Cl2 and then washed with a saturated NaCl solution, dried on MgSO4 and evaporated dry. The precipitate is picked up in an AcOEt/cyclohexane mixture (20/8 v/v); then filtered. 20 g of the expected compound is obtained, F = 215-216 °C.

The following substances are to be classified in the same heading as the active substance:

Dissolve 3 g of the compound obtained in the previous step in 50 ml of 1-methyl-2-pyrrolidinone, add 1.4 g of CuCN and heat at 200 °C for 4 hours. Pour the reaction medium over 100 ml of CH2Cl2 and filter the precipitate formed. Wash the filtrate with a solution of HCl 1N and then dry on MgSO4. The resulting product is purified by silica chromatography by eluting by AcOEt/CH2Cl2 (50/50 v/v) and then AcOEt/MeOH/NH3 (90/10/1 v/ville/v). Collect 2,2 g of the expected compound as a powder.

Example 12: compound 53 3-(4-(aminomethyl)phenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one is also used in the manufacture of other chemicals.

50 mg of baking soda is dissolved in 11 ml of ethanol and 0.2 g of the compound prepared in the previous example is added and then about 100 mg of Raney's Ni is hydrogenated for 24 hours at 50 psi. The catalyst is filtered on cellite® and then rinsed with methanol and evaporated dry. The residue is taken up again in a solution of 1N HCl and the impurities are extracted with AcOEt. It is alkalinized at pH = 9 by a solution of K2CO3 and then extracted by AcOEt to obtain 90 mg of the expected compound in powder form.

Example 13: compound 84 The chemical composition of the product is determined by the following equation:

1 g of 3-(2,4-dichlorophenyl)-1,6-dimethyl-1,9-dihydro[2,3-b]indol-2-one (compound 46) is dissolved in 10 ml DMF, 0.143 g of 95% NaH is added, and after 30 minutes of agitation 0.4 ml of methyl bromate is added. After 1 hour of agitation in TA, the reaction medium is evaporated and the residue is taken up again by CH2Cl2 and washed with a solution of NaHCO3 and then a solution of NaCl.

Example 14: compound 85 2-((2,4-Dichlorophenyl)-1,6-dimethyl-2-oxo-1,2-dihydro-9H-pyrido[2,3-b] indole-9-yl-N-methylacetamide, which is a chemical compound with the formula

After 5 hours of agitation at TA, evaporate the reaction medium, take up the residue by Et2O, then strain and dry to obtain 0,260 g of the expected compound.

Example 15: compound 81 3- (Hydroxymethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one, whether or not chemically defined A) 3-(1,6-dimethyl-2-oxo-2,9-dihydro-1H-pyrid[2,3-b]indol-3-yl) benzaldehyde.

450 mg of 3-(3-cyanophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one, 10 ml of AcOH, 20 ml of pyridine, 2.6 g of sodium hypophosphite and 434 mg of Raney's Ni are mixed and heated for 4 hours at 60°C. The reaction medium is rinsed and the filtrate evaporated; the residue is then picked up in 50 ml of AcOEt/CH2Cl2 (1/1; v/v), washed with water, dried and evaporated to obtain the desired compound, F = 280°C.

B) 3-(3-Hydroxymethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one. The substance is also known as 2-indol-2-one.

280 mg of the step A compound is placed in 10 ml of CH2Cl2 and a minimum of AcOH to dissolve the compound and 375 mg of NaBH(OAc) 3 is added and then left to agitate for 18 hours in TA. The reaction medium is evaporated, the residue is taken up by AcO and then exsorted to obtain 200 mg of the expected compound.

Example 16: compound 80 1,6-Dimethyl-3-(3-((methylamino) methyl) phenyl)-1,9-dihydro-2H-pyridone[2,3-b] indole-2-one, which is a mixture of hydroxyl and dihydroxy-methyl.

280 mg of the step A compound in the previous example is placed in 10 ml of CH2Cl2 and a minimum of AcOH to dissolve the compound and then 375 mg of NaBH(OAc) 3 and 0.064 ml of methyllamine is added. After 18 hours agitation at TA, 3 times per 10 ml of water is extracted and then the aqueous phase is extracted by AcOEt. After evaporation 15 mg of the expected compound is obtained.

Example 17: compound 83 The chemical composition of the compound is determined by the following equation:

Dissolve 210 mg of the compound in step A in 5 ml of MeOH and add 46 mg of hydroxylamine hydrochloride in solution to the minimum of water and stir for 2 hours at TA. Evaporate dry and then chromatograph the residue onto silica by electrolysis by AcOEt/CH2Cl2 (2/8; v/v). 74 mg of the expected compound is obtained.

Example 18: compound 110 1,6-Dimethyl-3- ((3-Methoxycarbonylphenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one. A) 3-(3-Bromophenyl)-1,6-dimethyl)-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one is also used.

This compound is prepared by the usual methods by the action of N,1,5-trimethyl-1H-indole-2-amine on 2-(3-bromophenyl)-3-hydroxy-2-propanoate of ethyl.

The DMSO RMN (200 MHz) is 2.42 ppm: s: 3H; 3.69 ppm: s: 3H; 7.04 ppm: d: 1H; 7.35 ppm: d: 1H; 7.05 to 7.08 ppm: m: 5H; 8.30 ppm: s: 1H; 11.91 ppm: s: 1H .

The following substances are to be classified in the same heading as the product:

500 mg of the compound in the previous step is dissolved, together with 140 mg of 1,3-bis (diphenylphosphino) propane in 20 ml of anhydrous MeOH. 1.9 ml of 99.9% triethylamine is added, 15 ml of anhydrous DMSO is added, and 60 mg of Pd (OAc) is added. CO is boiled in the reaction medium for 20 minutes and heated at 75 °C for one night in an atmosphere of CO. It is allowed to return to room temperature. The reaction medium is poured over 200 ml of water and then extracted with AcOEt. The organic phase is purified on MgSO4, filtered and evaporated dry.

The following are the main features of the newly introduced standardisation of the EMAS: the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation of the EMAS , the introduction of a new standardisation of the EMAS , the introduction of the EMAS , the introduction of the EMAS and the EMAS , the introduction of the EMAS , the introduction of the EMAS and the EMAS , the new standardisation of the EMAS , the new standardisation of the EMAS , the new standardisation of the EMAS , the new standardisation of the EMAS , the new standardisation of the new standardisation of the new standardisation of the new standardisation of the EMAS , the new and the new and the new and the new and the new and the new and the new technologies , the new technologies , the new technologies and the new technologies .

Example 19: compound 111 3-aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one is also used in the manufacture of other chemicals. A) 3-(4-Bromophenyl)-1,6-dimethyl)-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one is also used.

This compound is prepared by the usual methods by the action of N,1,5-trimethyl-1H-indole-2-amine on 2-(4-bromophenyl)-3-hydroxy-2-propanoate of ethyl.

B) 3-(4-Aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one. The substance is also known as indole-2-one.

10 ml of THF is degassed for 10 minutes, 9.2 mg of Pd2 ((dba) 3 is added under argon, then 370 mg of the previous step compound is added, then 9.4 mg of ligand (2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl and finally 2.2 ml of LiN ((TMS) 2 solution is added to the THF. The solution is agitated in a sealed tube at 90°C for 20 hours. The reaction medium is cooled, then 10 ml of HCl 1N solution is added, then agitated at room temperature for 10 minutes. The two phases are separated, the aqueous phase is washed with OAcAc solution and then precipitated with a saturated solution of K2CO3. The precipitated solution is obtained at 90 mg.

The following are the main features of the new standard: the use of the standardised data for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data requirements for the calculation of the calculation of the data for the calculation of the calculation of the data requirements for the calculation of the calculation of the calculation of the data for the calculation of the calculation of the data for the calculation of the calculation of the data for the calculation of the calculation of the data for the calculation of the calculation of the calculation of the value of the value of the value of the value of the value of the value of the value of the value of

Example 20: compound 121 The active substance is a chemical compound with the formula:

13 mg of Pd2 ((dba) 3, 500 mg of the compound in Step A, 11 mg of ligand (2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 3 ml of a LiN ((TMS) 2 solution in 1M in the THF, 127 mg of aniline, then 10 ml of anhydrous dioxane are placed under argon, stirred in a sealed tube at 65°C for 24 hours, returned to room temperature, then AcOEt added. Washed with a saturated NaCl solution. Precipitated on a column of electrolytic silica with a mixture of AcO/Ether oil (v/v 50/v 75/25/v) and precipitated in the precipitate; the compound is obtained in the form of the expected 55 mg of FETher at 188°C.

The frequency range of the DMSO (MHz) is 2.42 ppm: s: 3H; 3.68 ppm: s: 3H; 6.77-8.28 ppm: m: 14H; 12.00 ppm: s: 1H.

Example 21: composite 147 The chemical is known as 3-(2,4-Dicyanophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one.

0.6 g of 3-(2-chloro-4-bromophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one is dissolved in 15 ml of NMP. 0.27 g of CuCN is added and then reflux heated for 5 hours. The reaction medium is poured over CH2Cl2 and washed with a saturated NaCl solution.

The following is the list of the most commonly used data types: DMSO (MHz): 2.27 ppm: s: 3H ; 3.70 ppm: s: 3H ; 7.08 ppm: d (J=8.1): 1H ; 7.38 ppm: d (J=8.1): 1H ; 7.67 ppm: s: 1H ; 7.85 ppm: d (J=8.2): 1H ; 8.15 ppm: d (J=8.2): 1H ; 8.45 ppm: m: 2H: 12.11 ppm: s 1H .

Example 22: compound 143 3- (acetylphenyle)-1,6-dimethyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one is also used as a solvent.

400 mg of the compound 60 is dissolved in 20 ml of anhydrous THF. The reaction medium is cooled to 0°C, then 9.1 ml of CH3Li 1.4M is added to THF per serving. It is allowed to return to room temperature and then stirred for 2 hours. The reaction medium is poured on HCl 1N, then washed with AcOEt. The aqueous phase is basified with NaOH 5N, then the product is extracted with AcOEt. Dried on MgSO4. Filtered and dried.

The following are the main features of the new standard:

Example 23: compound 127 1,6-Dimethyl-3-(3-(pyridine-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b] indole-2-one, which is a mixture of hydroxyl and dihydroxy-methyl.

500 mg of the compound in Step A, 180 mg of 2-aminopyridine, 315 mg of NaOtBu, 50 mg of Pd2 ((dba) 3 and 95 mg of Xanthos are dissolved in 7 ml of dioxane (in a sealed tube). The reaction medium is degassed for 30 minutes, then heated at 100 °C for one night. It is returned to room temperature. After purification on a column of silica elevated with ethyl acetate, 380 mg of powder is obtained. F = 250-252 °C.

The frequency range of the DMSO (MHz) is as follows: 2.42 ppm: s: 3H; 3.70 ppm: s: 3H; 6.71-8.27 ppm: m: 12H; 9 ppm: s: 1H; 11.88 ppm: s: 1H.

Example 24: compound 94 The active substance is a polycyclic aromatic hydrocarbon with a molecular weight of less than 0,05 g/cm3 and a molecular weight of less than 0,05 g/cm3.

0.1 g of the compound 66 (example 9) is dissolved in 10 ml of DMF. 90 ml of K2CO3 is added and then 0.12 ml of bromoacetonitrile. Heat at 90°C for 48 hours. Pour the reaction medium over a saturated solution of NH4Cl, alkalize with soda, then extract to AcOEt. Chromatography is performed on an elevated silica column with a mixture of AcOEt/petroleum ether (v/v; 75/25). 20 mg of powder is obtained. F = 195-196°C

The following are the main parameters for the calculation of the data:

Example 25: composite 133 The active substance is a compound containing a mixture of hydrocarbons having carbon numbers predominantly in the range of C1 through C4. A) Benzoic acid (3-(1,6-dimethyl-2-oxo-2,9-dihydro-1H-pyrid[2,3-b] indole-3-yl) is a substance that is used in the manufacture of a product.

200 mg of the compound in sample 18 is dissolved in 10 ml of MeOH. 2 ml of water is added and then 97 mg of LiOH, H2O. Heated to 80°C for 20 hours. Recalled to room temperature. MeOH is evaporated, re-absorbed in water, then washed with AcOEt. The aqueous phase is basified with NaOH 5N, then extracted with AcOEt. The organic phase is dried on MgSO4, filtered and vaporized dry. The precipitate obtained is trampled with a mixture of oil/AcOether (2%).

The DMSO RMN (300 MHz) is as follows: 2.42 ppm: s: 3H; 3.70 ppm: s: 3H; 7.04-8.42 ppm: m: 8H; 11.93 ppm: s: 1H; 12.87 ppm: m: 1H.

The substance is classified as a substance of very high concern in the Union for the assessment of the safety and efficacy of the active substance.

200 mg of the compound in the previous step is dissolved in 20 ml of CH2Cl2 and 0.06 ml of morpholine, 340 mg of BOP and 10 ml of DMF are added. The reaction medium is stirred at room temperature for about 2 hours. The reaction medium is poured over saturated NH4Cl and extracted at AcOEt. An acid-base wash is made and then the precipitate obtained is washed with a mixture of iPrOH/petroleum ether (v/v; 50/50). 90 mg of powder is obtained. F = 296-298°C.

The DMSO NVR (300 MHz) is 2.42 ppm: s: 3H; 3.38-3.62 ppm: s: 8H; 3.69 ppm: s: 3H; 7.03-8.42 ppm: m: 8H; 11.92 ppm: s: 1H .

Example 26: compound 123 The chemical is a compound with the formula 6-Cyano-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one. A) 6-Bromo-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-1H-pyridone[2,3-b] indole-2-one is used as a solvent for the production of the following products:

This compound is prepared by the usual methods.

The DMSO NVR (300 MHz) is 2.31 ppm: s: 6H; 3.69 ppm: s: 3H; 6.91 ppm: s: 1H; 7.28-7.44 ppm: m: 4H; 8.15 ppm: d: 1H; 8.38 ppm: s: 1H; 12.30 ppm: s: 1H .

The following substances are to be classified as "methanol" and "methyl" in the respective CN codes:

The reaction medium is poured on CH2Cl2 and washed with a solution of HCl 1N. The product is adsorbed on silica and purified by elevated column chromatography with a mixture of AcOEt/petroleum ether (v/v; 50/50) then pure AcOEt and then AcOEt/MeOH 2%. 1.2 g of powder is obtained.

The following is the list of the most commonly used data types:

Example 27: compound 96 The chemical composition of the product is determined by the following equation:

600 mg of compound 46 is dissolved in 10 ml of DMF. We add 42 mg of 95% NaH. We agitate it for 30 minutes at TA and then we add 230 mg of bromoacetonitrile. We agitate it for 18 hours at TA. We concentrate it half and precipitate it by adding water. We get 200 mg of the expected product, F = 270°C.

Example 28: compound 92 The chemical composition of the product is determined by the following equation: The following substances are to be classified in the same heading as the product:

0.5 g of compound 46 is dissolved in 5 ml of DMF, 107 mg of 95% NaH is added and stirred for 10 minutes at TA. 1.25 g of 2-(3-bromopropyl) -1-H-isoindole-1,3(2H) dione is added and stirred for 18 hours at TA. Evaporation, re-substitution in CH2Cl2, washing with NaCl and then H2O. Chromatography on silica by eluting with CHCl3/MeOH (v/v ; 98/2) is obtained. 160 mg of the expected product is obtained, F = 249°C.

B) Hydrochloride of 9- ((3-Aminopropyl) -3- ((2,4-dichlorophenyl) -1,6-dimethyl-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one. The chemical is also known as indole-2-one.

180 mg of the previous step compound, 3.2 ml of THF, 5 ml of EtOH and 33 μl of hydrazine hydrate are mixed. 18 hours of reflux heating is carried out; the HCl phase is evaporated and dried. 16 mg of the expected product is obtained, F = 198°C.

Example 29: compound 91 The active substance is a 3- (2,4-Dichlorophenyl) -9- (2-hydroxyethyl) -1,6-dimethyl-1,9-dihydro-2H-pyridone. A) 3-(2,4-Dichlorophenyl)-1,6-dimethyl-9-tetrahydro-2H-pyran-2-yloxy)ethyl)-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one is also used in the manufacture of other products.

695 mg of compound 46 is dissolved in 7 ml of DMF. 99 mg of 95% NaH is added. It is agitated at TA for 15 minutes. 813 mg of 2-(2-bromoethoxy) tetrahydro-2H-pyrane is added and agitated at TA for 18 hours. It is evaporated dry, then taken up by CH2Cl2, washed by NaCl, then H2O. It is dried, then evaporated. It is chromatographed by CHCl3/MeOH (v/v ; 98/2).

B) 3-(2,4-Dichlorophenyl)-9-(2-hydroxyethyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one. The substance is also known as indole-2-one.

295 mg of the product of the previous step, 1.21 mg of p-toluene sulfonic acid and 10 ml of EtOH 95 are mixed, heated at low temperature for 8 hours, evaporated dry, washed with NaHCO3, then H2O, dried, and 198 mg of the product obtained at F = 240 °C.

Example 30: compound 102 The active substance is a 3- (2,4-dimethylphenyl)-1,6,9-trimethyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one.

400 mg of 3-(2,4-dimethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one (compound 101) is dissolved in 10 ml of DMF. 31 mg of 95% NaH is added, stirred for 30 minutes at TA. 380 μl of methyl iodide is added and stirred for 18 hours at TA. Dry evaporated. Re-used by CH2Cl2, washed by NaCl H2O, then dried, evaporated. Re-used by Et2O, boiled, dried.

Example 31: composite 57 3-(2-chloro-4-methoxyphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyridone[2,3-b]indol-2-one is also used in the manufacture of other chemicals.

A mixture of 10 ml anhydrous DMF and 0.6 ml anhydrous methanol is prepared, to which 0.5 g NaH at 60% is added. At the end of the gas release, 0.43 g of compound 59 is added and heated at 80 °C for 24 hours. The reaction medium is poured on a saturated solution of NH4Cl and the precipitate formed is filtered and washed with an isopropanol/petroleum ether mixture (v/v; 50/50).

The following table illustrates the chemical structures and physical properties of some compounds according to the invention. In this table Me represents methyl, E represents ethyl, tBu represents tert-butyl, Bn represents benzyl. - What?

TABLEAU 4

Composés					Caractérisation F°C ou RMN
1	Me	Me	3,5-diMe-phényl	6-Me	210°C
2	Me	Me	2,4-diCl-phényl	6-Me	170°C
3	Me	Me	3,4-diCl-phényl	6-Me	230°C
4	Me	Me		6-Me	186°C
5	Me	Me		6-Me	248°C
6	Me	Me	3,5-diF-phényl	6-Me	240°C
7	Me	Me	3,4,5-triOMe-phényl	6-OMe	224°C dec
8	Me	Me	1,3-benzodioxol-5-yl	6-OMe	197°C
9	Me	Me	2,5-diOMe-phényl	6-Me	225°C
10	Me	Me	3,5-diMe-phényl	6-Cl	200°C
11	Me	Me	1,3-benzodioxol-5-yl	7-OMe	220°C dec
12	Me	Me	3,4-diOMe-phényl	7-OMe	190°C
13	Me	Me	3,4,5-triOMe-phényl	8-OMe	219°C
14	Me	Me	3,4-diOMe-phényl	6-Me	190°C
15	Me	Me	3,5-diOMe-phényl	6-Me	205°C
16	H	Me	3,5-diMe-phényl	6-Me	RMN
17	Me	Me	3,5-diOMe-phényl	6-Cl	229
18	Me	Me	3,5-diF-phényl	H	232°C
19	Me	Me	2,4-diF-phényl	6-Me	167°C
20	Me	Me	3,5-diF-phényl	6-OMe	189°C
21	Me	Me	2,4-diCl-phényl	6-OMe	130°C
22	H	Me	3,5-diF-phényl	6-Me	189°C dec
23	Me	Me	3,5-diMe-phényl	6-OMe	194°C
24	Me	Me		6-Me	190°C
25	Me	Me	3,5-diF-phényl	5-OMe	238°C
26	Me	Me	1,3-benzodioxol-5-yl	8-OMe	197°C
27	Me	Me	3,5-diF-phényl	7-OH	195°C
28	Me	Me	2,4-diCl-phényl	H	241 °C
29	Me	Me	2,4-diCl-phényl	7-OMe	RMN
30	Me	Me	2,4-diCl-phényl	5-OMe	228°C
31	Me	Me	2,4-diCl-phényl	7-Cl	RMN
32	Me	Me	2,4-diCl-phényl	5,7-diMe	240°C
33	Me	Me	2,4-diCl-phényl	6-Cl	258°C
34	Me	Me	3,5-diF-phényl	6-Cl	295°C
35	H	Me	3,5-diF-phényl	H	262°C
36	H	Me	2,4-diCl-phényl	H	RMN
37	Me	Me	3,5-diMe-phényl		RMN
38	Me	Me	3,5-diCl-phényl	6-Me	268°C
39	Me	Me	2,3-diF-phényl	6-Me	170°C
40	Me	Me	2,3-diF-phényl	6-OMe	179°C
41	H	Me		6-Me	270°C
42	Me	Me	3-OH-phényl	6-Me	RMN
43	Me	Me	2-Cl, 4F-phényl	6-Me	202-203°C
44	Me	Me		6-Me	245-246°C
45	Me	Me	2-Cl, 4-OMe-phényl	6-Me	196-197°C
46	H	Me	2,4-diCl-phényl	6-Me	RMN
47	Me	Me	4-OH, 3-tBu-phényl	6-Me	RMN
48	Me	Me		6-Me	194°C
49	Me	Me		6-Me	252°C
50	Me	Me		6-Me	RMN
51	Me	Me		6-Me	269°C
52	Me	Me	3-CN-phényl	6-Me	241-242°C
53	Me	Me		6-Me	213-214°C
54	H	Me		6-Me	278°C
55	H	Me	3,4,5-triOMe-phényl	6-Me	RMN
56	H	Me		6-Me	258°C
57	H	Me	2-Cl, 4-OMe-phényl	6-Me	RMN
58	H	Me	4-CN-phényl	6-Me	RMN
59	H	Me	2-Cl, 4-F-phényl	6-Me	RMN
60	H	Me	3-CN-phényl	6-Me	295°C
61	H	Me		6-Me	RMN
62	H	Me	4-COOMe-phényl	6-Me	RMN
63	H	Me	2-Cl, 4-OH-phényl	6-Me	RMN
64	H	Me		6-Me	RMN
65	H	Me	4-COOH-phényl	6-Me	RMN
66	Me	Me	4-OH-phényl	6-Me	280°C
67	Me	Me		6-Me	118°C
68	H	Me	4-OH-phényl	6-Me	186°C
69	Me	Me	2,6-diCl-phényl	6-Me	255°C
70	Me	Me		6-Me	105°C
71	Me	Me		6-Me	174°C
72	Me	Me	3-COOMe-phényl	6-Me	172-173°C
73	Me	Me	2-Cl, 4-OH-phényl	6-Me	RMN
74	Me	Me	2,4-diCl-phényl		270°C
75	H	Me	4-SMe-phényl	6-Me	280°C
76	H	Me		6-Me	280°C
77	H	Me	3,4-diOMe-phényl	6-Me	RMN
78		Me	2,4-diCl-phényl	6-Me	113°C
79	Me	Me	2,4-diCl-phényl	6-CN	290°C
80	H	Me		6-Me	RMN
81	H	Me		6-Me	RMN
82	H	Me	(3-Br, 4-OMe)-phényl	6-Me	RMN
83	H	Me	3-(CH=NOH)-phényl	6-Me	290°C
84		Me	2,4-diCl-phényl	6-Me	249°C
85		Me	2,4-diCl-phényl	6-Me	RMN
86	Me	Me	2,4-diCl-phényl	6-phényl	110°C
87	H	Me	2-Br, 4,5-diOMe-phényl	6-Me	RMN
88	Me	Me	3-CN-phényl	6-CN	> 280°C RMN
89	Me	Me	2,Cl, 3,4-diOMe-phényl	Me	250°C
90		Me	2,4-diCl-phényl	6-Me	161°C
91		Me	2,4-diCl-phényl	6-Me	240°C
92		Me	2,4-diCl-phényl	6-Me	198°C Chlorhydrate
93	Me	Me	2-Br, 4,5-diOMe-phényl	6-Me	236°C
94	Me	Me		6-Me	192°C RMN
95	Me	Me		6-Me	170°C
96		Me	2,4-diCl-phényl	6-Me	277°C
97		Me	2,4-diCl-phényl	6-Me	RMN
98	H	Me	2-Cl, 4,5-OMe-phényl	6-Me	RMN
99	Me	Me	2-Cl, 4,5-diOMe-phényl	6-Me	245°C RMN
100	H	Me	4-OMe, 3-CN-phényl	6-Me	RMN
101	H	Me	2,4-diMe-phényl	6-Me	RMN
102	Me	Me	2,4-diMe-phényl	6-Me	150°C
103	H	Me	3,4-diMe-phényl	6-Me	RMN
104	Me	Me	3,4-diMe-phényl	6-Me	211 °C
105	Me	Me		6-Me	184°C
106	Me	Me	3,4-diOMe-phényl	6-OMe	160°C
	Me	Me		6-Me	180°C Chlorhydrate
108	Me	Me	2,3-diF-phényl	6-OMe	179°C
109	Me	Me	3-tBu, 4-OMe-phényl	6-Me	231-232°C
110	H	Me	3-COOMe-phényl	6-Me	278-280°C
111	H	Me		6-Me	RMN
112	H	Me		6-Me	226°C
113	H	Me		6-Me	RMN
114	H	Me	2,4-diCl-phényl	6-Br	386°C dec RMN
115	H	Me		6-Me	267-269°C
116	H	Me	6-Cl-1,3-benzodioxol-5-yl	6-Me	RMN
117	H	Me	3,5-diOMe-phényl	6-Me	299°C RMN
118	H	Me		6-Me	237-239°C
119	H	Me		6-Me	RMN
120	H	Me	2,4-diOMe-phényl	6-Me	308-310°C
121	H	Me		6-Me	188-190°C
122	H	Me	3,5-diMe-phényl		RMN
123	H	Me	3,5-diMe-phényl	6-CN	RMN
124	Me	Me		6-Me	224°C RMN
125	H	Me	3,5-diMe-phényl	6-Br	320°C dec RMN
126	H	Me		6-Me	246°C RMN
127	H	Me		6-Me	250°C
128	H	Me	2,4-diCl-phényl	6-OMe	318°C RMN
129	H	Me		6-Me	221 °C RMN
130	H	Me	3-OH-phényl	6-Me	310°C dec RMN
131	H	Me	3,5-diCl-phényl	6-Me	300-302°C RMN
132	H	Me	3,5-diMe-phényl	6-OMe	317°C dec
133	H	Me		6-Me	296-298°C
134	H	Me		6-Me	RMN
135	Me	Me		6-Me	133-135°C
136	H	Me	3,5-diMe-phényl		238-240°C
137	H	Me		6-Me	208-209°C
138	Me	Me	3-(-COMe)-phényl	6-Me	80°C dec RMN
139	H	Me		6-Me	190°C dec
140	H	Me		6-Me	316°C dec RMN
141		Me		6-Me	225-227°C RMN
142		Me	3-OH-phényl	6-Me	216-218°C RMN
143	H	Me.	3-(-COMe)phenyl	6-Me	258-260°C
144	Me	Me	3-Br, 4-OMe-phényl	6-Me	245-247°C
145	H	Me		6-Me	RMN
146	Me	Me		6-Me	188°C
147	H	Me	2,4-diCN-phényl	6-Me	RMN
148	H	Me	2-Cl, 4-Br-phényl	6-Me	RMN
149	Me	Me	2-Cl, 4-Br-phényl	6-Me	251°C
150			2,4-diCl-phényl	6-Me	197-198°C RMN
151	Me	Me	2,4-diCN-phényl	6-Me	292°C
152	H	Me		6-Me	291 °C
153	Me	Me	2,4-diCl-phényl	6-Br	228°C
154		Me	2,4-diCl-phényl	6-Br	179-180°C dec
155		Me	2,4-diCl-phényl	6-COOEt	RMN
156	H	Me	2,4-diCl-phényl	6-COOEt	RMN
157		Me	2,4-diCl-phényl	6-Br	210°C
158	H	Me		6-Me	250°C dec
159	H	Me		6-Me	RMN
160	H	Me		6-Me	RMN
161	Me	Me		6-Me	262-264°C
162	H	Me	2,4-diCl-phényl	6-COOMe	322-324°C
163	H	Me	2,4-diCl-phényl		338-340°C
164	Me	Me	2,4-diCl-phényl		156-160°C
165	H	Me	2,4-diOMe-phényl	6-Br	207-208°C
166	H	Me	3,5-diCl-phényl	6-COOMe	RMN
167	H	Me	2-Cl, 4-Br-phényl	6-COOMe	321-323°C
168	H	Me		6-COOMe	297-298°C
169	H	Me	2,4-diOMe-phényl	6-CN	239-242°C

16 composed of: DMSO (300 MHz) NMR: 2.3 ppm: s: 6H; 2.4 ppm: s: 3H; 3.67 ppm: s: 3H; 6.9 ppm: s: 1H; 7 ppm: d: 1H; 7.3 ppm: m: 3H; 7.7 ppm: s: 1H: 8.26 ppm: s: 1H; 11.9 ppm: s: 1H.Composed of: 29: CDCl3 (300 MHz) NMR: 3.93 ppm: s: 3H; 4.09 ppm: s: 6H: 6.89 ppm: d: 1H; 6H: 1H: 6H92 ppm: dd: 1H ; 7.3 ppm: dd: 1H ; 7.38 ppm: d: 1H ; 7.51 ppm: d: 1H ; 7.62 ppm: d: 1H ; 7.94 ppm: s: 1H.Composed of 31: RMN DMSO (300 MHz) : 4 ppm: s: 3H ; 4.15 ppm: s: 3H ; 7.23 ppm: dd: 1H ; 7.42 ppm: d: 1H ; 7.47 ppm: dd: 1H ; 7.68 ppm: d: 1H : 7.78 ppm: d: 1H ; 7.88 ppm: d: 1H ; 8 .The following is a list of the most commonly used methods of calculating the value of the assets of the institution: (i) the total value of the assets of the institution: (ii) the total value of the assets of the institution: (iii) the total value of the assets of the institution: (iv) the total value of the assets of the institution: (v) the total value of the assets of the institution: (v) the total value of the assets of the institution: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the total value of the assets: (v) the assets: (v) the total value of the assets: (v) the assets: (v) the total value of the assets: (v) of the assets: (v) the assets: (v) the total value of the assets: (v) of the assets: (v) of the assets: the assets: (v) of the assets: (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (v) (42: composed of NMR DMSO (200 MHz) : 2.41 ppm : s: 3H ; 3.7-4.5 ppm: se: 1H ; 3.97 ppm: s: 3H ; 4.07 ppm: s: 3H ; 6.65 ppm: d: 1H ; 7-7.3 ppm: m: 4H ; 7.4 ppm: d: 1H ; 7.7 ppm: s: 1H ; 8.25 ppm: s: 1H.Composed of 46: of NMR DMSO (300 MHz): 2.5 ppm: s: 3H ; 3.7 ppm: s: 3H ; 7.1 ppm: d: 1H ; 7.3-7.5 ppm: m: 3H ; 7,0 ppm: s: 3H .7 ppm: d: 2H ; 8.1 ppm: s: 1H ; 11.9 ppm: s: 1H.Composite 47: RMN CDCl3 (300 MHz) : 1.45 ppm: s: 9H ; 2.5 ppm: s: 3H ; 4.1 ppm: s: 6H ; 6.7 ppm: d: 1H ; 7.2 ppm: d: 1H ; 7.3 ppm: d: 1H ; 7.5 ppm: d: 1H : 7.6 ppm: d: 1H ; 8 ppm: s: 1H.Composite: 50 RMN CDCl3 (300 MHz): 1.7 ppm: m: 2H ; 2,0 ppm:5 ppm: s: 3H ; 4.1 ppm: s: 6H ; 7.1 ppm: d: 1H ; 7.3 ppm: m: 2H ; 7.4 ppm: t: 1H ; 7.6 ppm: m: 2H ; 7.7 ppm: s: 1H ; 8.1 ppm: s: 1H.Composed of 55: NMR DMSO (300 MHz): 2.43 ppm: s: 3H ; 3.69 ppm: s: 6H 3.83 ppm: s: 6H ; 7.03 ppm: d: 1H .71 ppm: s: 1H ; 8.37 ppm: s: 1H ; 11.86 ppm: s: 1H.Composite 58: RMN DMSO (300 MHz) : 2.43 ppm: s: 3H ; 3.70 ppm: s: 3H ; 7.05: d: 1H ; 7.3 ppm: d: 1H : 7.73 ppm: s: 1H ; 7.8 ppm: d: 2H ; 8.03 ppm: d: 2H : 8.54 ppm: s: 1H ; 12 ppm: s: 1H.Composite 59: RMN DMSO (300 MHz): 2.40: s: 3H ; 3pm: 2H .67 ppm: s: 3H ; 7,02-7,06: m: 1H ; 7,24-7,28 ppm: m: 1H ; 7,34 ppm: d: 1H ; 7,42-7,47 ppm: m: 2H ; 7,63 ppm: s: 1H ; 8,1 ppm: s: 1H ; 11,95 ppm: se: 1H.Composed of 61: RMN DMSO (300 MHz): 2,40 ppm: s: 3H: 3,25 ppm: s: 6H ; 7,02: d: 1H ; 7,23-7,36 ppm: m: 3H ; 7,61-7,68 ppm: m [ i.e. 7,05 ppm: d (J=8,1) : 1H ]35 ppm: d (J=8.1): 1H ; 7.73 ppm: s: 1H ; 7.78 ppm: m: 4H]: 3H ; 8.3 ppm: s: 1H.Composed 62: RMN DMSO (300 MHz) : 2.43 ppm: s: 3H ; 3.70 ppm: s: 3H ; 3.88 ppm: s: 3H ; 7.05-8.50 ppm: m: 8H ; 11.97 ppm: s: 1H.Composed 63: RMN DMSO (300 MHz) : 2.41 ppm: s: 3H ; 3.66 ppm: s: 3H ; 6.75-9.80 ppm: m: 8H ; 11.87 ppm: s: 1H.The following table shows the data for the calculation of the total number of days of the monthly frequency: (i) the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency of the monthly frequency:707 ppm: s: 3H ; 7,04-8,47 ppm: m: 8H ; 11,95 ppm: s: 1H.Composed of 73: RMN DMSO (300 MHz) : 2,3 ppm: s: 3H ; 4 ppm: s: 3H ; 4,1 ppm: s: 3H ; 6,8 ppm: d: 1H ; 6,9 ppm: s: 1H ; 7,2 ppm: d: 1H ; 7,3 ppm: d: 1H: 7,5 ppm: d: 1H ; 7,7 ppm: s: 1H ; 8,1 ppm: s: 1H ; 9,9 ppm: se: 1H .77: composed of DMSO NMR (200 MHz) : 2.4 ppm : s: 3H ; 3.7 ppm: s: 3H ; 3.8 ppm: s: 6H ; 6.9 ppm: d: 1H ; 7 ppm: d: 1H ; 7.2-7.3 ppm: m: 3H ; 7.4 ppm: s: 1H: 8.3 ppm: s: 1H.Composed of 80: DMSO NMR + TFA (200 MHz): 2.4 ppm: s: 3H: 2.8 ppm: s ; 3H ; 3.8 ppm: s: 3H: 4.3-4.5 ppm: dd: 2H; 7,1 ppm: d: 1H ; 7.3-7.6 ppm: m: 3H ; 7.7 ppm: s: 1H ; 7.9 ppm: d: 1H ; 8 ppm: s: 1H ; 8.4 ppm: s: 1H.Composed of 81: RMN DMSO (200 MHz) 2.3 ppm: s: 3H ; 3.6 ppm: s: 3H ; 4.4 ppm: d: 2H ; 5.1 ppm: m: 1H 7 ppm: d: 1H ; 7.15-7.3 ppm ; m: 3H: 7,58-7.7 ppm: m: 3H ; 8.2 ppm: s: 1H ; 11 ppm:8-12 ppm: se: 1H.Composite 82: NMR DMSO (200 MHz) : 2.4 ppm: s: 3H ; 3,6 ppm: s: 3H ; 3.8 ppm: s: 3H ; 6.95 ppm: d: 1H ; 7.05 ppm: d: 1H ; 7.15 ppm: d: 1H ; 7.6-7.8 ppm: m: 2H ; 8 ppm: s: 1H ; 8.3 ppm: s: 1H 11.8 ppm: s: 1H.Composite 85: NMR DMSO (200 MHz) : 2.3 ppm: s: 3H ; 2.6 ppm: d: 3H ; 3,08 ppm: s: 3H ; 5.2 ppm: s: 2H ; 7 ppm: d: 1H ; 7.3 ppm: d: 1H ; 7.4 ppm: m: 2H ; 7.6 ppm: s: 2H ; 8.1 ppm: s: 1H ; 8.4 ppm: d: 1H.Composed of 87: RMN DMSO / TFA (200 MHz) : 2.4 ppm: s: 3H ; 3.6 ppm: s: 3H 3.95 ppm: s: 3H ; 7 ppm ; d: 1H .05 ppm: s: 1H ; 8.1 ppm: s: 1H ; 8.45 ppm: s: 1H.Composite 88: RMN DMSO/TFA (200 MHz) : 4.05 ppm: s: 3H ; 4.25 ppm: s: 3H ; 7.6-7.9 ppm: m: 4H ; 8.15 ppm: d: 1H ; 8.25 ppm: s: 1H ; 8.5 ppm: s: 1H 8.7 ppm: s: 1H.Composite 94: RMN DMSO (300 MHz): 2.73 ppm: 3H ; 4.27 ppm: s 6H ; 5.02 ppm: s: 2H ; 7,009-8,26 ppm: m: 8H.Composite 97: DMSO / TFA NMR (200 MHz) : 2,4 ppm: s: 3H ; 2,95 ppm: t: 2H ; 4 ppm: s: 3H ; 4,6 ppm: t: 2H ; 7,2 ppm: d: 1H ; 7,4-7,7 ppm: m: 3H ; 7,75 ppm: s: 2H ; 8,2 ppm: s: 1H.Composite 98: DMSO / TFA NMR (200 MHz): 2,4 ppm: s: 3H: 3H: 3,6 ppm: 3H; 3,7 ppm: s: 3H; 3,8 ppm: 3H: 6 ,95 ppm: s: 1H ; 7-7.1 ppm: m: 2H ; 7.35 ppm: d: 1H ; 7.6 ppm: s: 1H ; 8.05 ppm: s: 1H.Composed of 99: RMN DMSO/TFA (200MHz) 2.3: ppm: s: 3H ; 3.7 ppm: s: 3H ; 3.75 ppm: s: 3H ; 3.9 ppm: s: 3H ; 4.05 ppm: s: 3H : 6.85 ppm: s: 1H ; 7 ppm: s: 1H ; 7.05 ppm: s: 1H ; 7.4 ppm: d: 1H ; 7.0 ppm: s: 1H .6 ppm: s: 1H ; 8 ppm: s: 1H.Composite 100: RMN DMSO/TFA (200 MHz) : 2.4 ppm: s: 3H ; 3.65 ppm: s: 3H ; 3.7 ppm: s: 3H ; 3.8 ppm: s: 3H ; 6.95 ppm: s: 1H ; 7.05 ppm: d: 1H ; 7.2 ppm: s: 1H ; 7.35 ppm: d: 1H : 7.65 ppm: s: 1H ; 8.05 ppm: s: 1H.Composite 101: RMN DMSO/TFA (200 MHz): ppm: s: 2.2 , 2 , 3 , 3 , 3 , 4 , 5 , 6 , 6 , 6 , 7 , 8 , 8 , 10 , 10 , 10 , 10 , 10 , 10 , 11 , 11 , 11 , 11 , 11 , 11 , 11 , 11 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 13 , 13 , 13 , 14 , 15 , 16 , 19 , 19 , 19 , 19 , 19 , 19 , 20 , 20 , 20 , 20 , 20 , 20 , 20 , 20 , 20 , 20 , 20 , 20 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 21 , 22 , 22 , 22 , 22 , 22 , 22 , 22 , 22 , 22 , 22 , 22 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 23 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 24 , 243 ppm: s: 3H ; 2.4 ppm: s: 3H ; 3.75 ppm: s: 3H ; 7-7.2 ppm: m: 4H ; 7.4 ppm: d: 1H ; 7.7 ppm: s: 1H ; 8 ppm: s: 1H.Composed of 103: NMR DMSO/TFA (200 MHz): 2.3 ppm: s: 3H ; 2.45 ppm: s: 3H ; 2.5 ppm: s: 3H : 3.7 ppm: s: 3H ; 7.1 ppm ; d: 1H: 7.2 ppm: d: 1H ; 7.4 ppm: d: 1H;5 ppm: d: 1H ; 7,6 ppm: s: 1H ; 7,75 ppm: s: 1H ; 8,35 ppm: s: 1H.Composed of 112: RMN DMSO (300 MHz) : 2,41 ppm: s: 3H ; 2,46 ppm: s: 3H ; 2,69-2,72 ppm: m: 4H ; 3,19-3,28 ppm: m: 4H ; 3,19-3,28 ppm: s: 3,76 ppm: 3H 6,93 ppm: dd: 1H: 7,09 ppm: d: 1H ; 1H ; 7,15 ppm: d: 1H 7: 28 ppm: d: 1H ; 7,33 ppm: m: 2H 7,61 ppm: s: 1H ; 8.19 ppm: s: 1H.Composed 114: RMN DMSO (300 MHz) : 3.69 ppm: s: 3H ; 7.4 ppm: m: 4H ; 7.67 ppm: d: 1H ; 8.09 ppm: d: 1H ; 8.29 ppm: s: 1H ; 12.28 ppm: s: 1H.Composed 116: RMN DMSO (300 MHz): 2.41 ppm: s: 3H : 3.67 ppm: s ; 3H ; 6.12 ppm: s: 2H ; 7.02 ppm: s: 1H ; 7.10 ppm: s: 1H .19 ppm: s: 1H ; 7.36 ppm: d: 1H ; 7.63 ppm: s: 1H ; 8.05 ppm: s: 1H ; 11.92 ppm: s: 1H.Composite 117: RMN DMSO (300 MHz) : 2.42 ppm: s: 3H ; 3.68 ppm: s: 3H ; 3.78 ppm: s: 6H ; 6.41-8.37 ppm: m: 7H 11: 89 ppm: s: 1H.Composite 119: RMN DMSO (200 MHz): 2.4 ppm: s: 3H ; 3.7 ppm: s: 3H ; 7-7.2 ppm: m 3H ; 7,2:4 ppm: d: 1H ; 7.7 ppm: s: 1H ; 7.8 ppm: d: 2H ; 8.4 ppm: s: 1H.Composite 122: RMN DMSO (300 MHz) : 2.50 ppm: s: 6H ; 3.79 ppm: s: 3H ; 4.03 ppm: m 2H ; 6.92-8.28 ppm: m: 7H ; 12.46 ppm: s: 1H.Composite 124: RMN DMSO (300 MHz) : 2.43 ppm: s: 3H: 3.98 ppm: s: 3H ; 4.08 ppm: s: 3H ; 7.06-7.16 ppm: m: 8H.125: RMN DMSO (300 MHz) : 2.31 ppm : s: 6H ; 3.69 ppm : s: 3H ; 6.91 ppm : s: 1H ; 7.28-7.44 ppm : m: 4H ; 8.15 ppm : d: 1H ; 8.38 ppm: s: 1H ; 12.30 ppm: 1H.Composed 126: RMN DMSO (300 MHz) : 2.43 ppm: s: 3H : 3.70 ppm: s: 3H ; 7.05-8.88 ppm ; m: 8H ; 11.97 ppm: 1H.Composed 128: RMN DMSO (300 MHz): 3.61 ppm: 3H ;78 ppm: s: 3H ; 6.83 ppm: dd: 1H ; 7.33-7.48 ppm: m: 4H ; 7.66 ppm: d: 1H ; 8.17 ppm: s: 1H ; 11.91 ppm: s: 1H.Composed: 129: RMN DMSO (300 MHz) : 2.42 ppm: s: 3H ; 3.69 ppm: s: 3H ; 5.15 ppm: s: 2H : 6.93-8.36 ppm: m: 13H 11: 88 ppm: s ; 1H.Composed: 130: RMN DMSO (300 MHz): 2.42 ppm: s: 3H ; 3.68 ppm: s: 3H ; 6,0 ppm: s: 1H .67 ppm: dd: 1H ; 7.02 ppm: dd: 1H ; 7.03-7.24 ppm: m: 3H ; 7.34 ppm: d: 1H ; 7.68 ppm: s: 1H ; 8.25 ppm: s: 1H ; 9.26 ppm: se: 1H ; 11.85 ppm: se: 1H.Composed of: 131 RMN DMSO (300 MHz) : 2.43 ppm: s: 3H 7.05-8.61 ppm: m: 7H ; 12.00 ppm: s ; 1H.Composed of: 134 RMN DMSO (300 MHz) : 2.43 ppm: s: 3H ; 4.02 ppm: s: 3H;06 ppm: dd: 1H ; 7,29 ppm: se: 1H ; 7,35 ppm: d: 1H ; 7,72 ppm: s: 1H ; 7,84-7,94 ppm: m: 5H ; 8,45 ppm: s: 1H.Composed of 138: RMN DMSO (300 MHz): 1,71 ppm: s: 3H ; 2,44 ppm: s: 3H ; 2,64 ppm: s: 3H ; 4,02 ppm: s: 3H : 4,20 ppm: s: 3H ; 7,12 ppm: d: 1HpmThe following are the main features of the newly introduced standardisation of the EMAS: the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation procedure for the EMAS , the introduction of a new standardisation of the EMAS , the introduction of a new standardisation of the EMAS , the introduction of the EMAS , the introduction of the new standardisation of the EMAS , the new standardisation of the new standardisation of the EMAS , the new standardisation of the new standardisation of the EMAS , the new standards of the new standards of the new standards of the new standards of the new standards of the EMAS , the new standards of the new standards of the new technologies and the new technologies and the new technologies and the new technologies and the new technologies and the new technologies .Compounded 141: DMSO (300 MHz) NMR: 2.45 ppm : s: 3H ; 4.04 ppm : s: 3H ; 5.22 ppm : s: 2H ; 5.87 ppm : s: 2H ; 7.01-9.31 ppm : m: 8H.Compounded: 142 NMR DMSO (300 MHz) NMR: 2.21 ppm: s: 6H ; 2.43 ppm: s: 3H ; 2.64 ppm: t: 2H 3.99 ppm: s: 3H ; 4.62 ppm ; t: 2H: 6.67-8.29 ppm: m: 8H ; 9.27 ppm: s: 1H.Compounded 145: NMR DMSO/TFA (200 MHz): 2,4 ppm: s: 3H ; 3.7 ppm: s: 3H ; 6.9-7.1 ppm: m: 2H ; 7.3-7.45 ppm: m: 3H ; 7.5-7.7 ppm: m: 2H ; 8.35 ppm: s: 1H.Composed 148: RMN DMSO (300 MHz) : 2.40 ppm: s: 3H ; 3.67 ppm: s: 3H ; 7.04 ppm: d: 1H 7: 7.35 ppm: m: 2H ; 7.57 ppm: dd: 1H ; 7.63 ppm: s: 1H ; 7.77 ppm: d: 1H ; 8.12 ppm: s: 1H 11 .The following is a list of the Member States that have adopted the euro: the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Member States of the European Union , the Republic of the Republic of the Republic of the European Union , the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the Republic of the RepublicThe following shall be added to the list of items which are to be included in the calculation of the amount of the contribution:42 ppm: s: 3H ; 3.69 ppm: s: 3H ; 7.05 ppm: d (J=7.0) : 1H ; 7.21 ppm: d (J=7.29) : 1H ; 7.37 ppm: d (J=8.15) : 2H ; 7.51 ppm: d (J=2.6) : 1H ; 7.54 ppm: s: 1H ; 7.64 ppm: s: 1H ; 8.14 ppm: s: 1H : 8.34 ppm: d (J=7.22) : 2H ; 10.71 ppm: s: 1H 12:03 ppm: s: 1H.Composed of 160 RMN: DMSO (300 MHz): 2.40 ppm: s: 3H ; 3,017 ppm: m: 4H ; 3.66 ppm: s: 3H ; 3.75 ppm: m: 4H ; 6.94 ppm: dd (J=2.45 ; J=8.60): 1H ; 7.03 ppm: m: 2H ; 7.23 ppm: d (J=8.51): 1H ; 7.34 ppm: d (J=8.12): 1H ; 7.62 ppm: s: 1H ; 8.02 ppm: s: 1H: 11.87 ppm: s: 1H.Composed 166 ; DMSO: 3.73 ppm: s: 3H ; 3.97 ppm: s: 3H ; 7.56 ppm: d: 1H ; 7.63 ppm: d: 1H ; 7,:95 ppm: d: 1H; 8.07 ppm: m: 2H; 8.73 ppm: s: 1H; 8.92 ppm: s: 1H; 12.57 ppm: s: 1H. The following are the main factors:

The compounds of the invention have been subjected to pharmacological tests to determine their anticancer activity.

The compounds of formula (I) according to the present invention have been tested in vitro on a human breast cancer cell line: the MDA-MB-231 line available from the American Type Culture Collection (reference HTB26).

The antiproliferative effect is assessed according to J.M. Derocq et al., FEBS Letters, 1998, 425, 419-425: the rate of incorporation of [3H]thymidine into the DNA of treated cells is measured after 96 hours of incubation of a formula (I) compound.

The compounds of the invention have a CI50 generally less than 10 μM on the MDA-MB-231 line.

The compounds of formula (I) have also been tested on another human breast cancer cell line, called the multi-drug-resistant MDR line, and called MDA-A1. This line is described by E. Collomb, C. Dussert and P.M. Martin in Cytometry, 1991, 12(1), 15-25.

Err1:Expecting ',' delimiter: line 1 column 52 (char 51)

The compounds of the invention have a CI50 generally less than 10 μM on the MDA-A1 multi-resistant line.

The compounds of the invention have also been tested in vivo in mouse models of human tumour xenographs using the methods described in the literature: Mooberry SL et al., Int. J. Cancer, 2003, 104 (4), 512-521; Polin L et al., Invest. New Drugs, 2002, 20 (1), 13-22; Corbett TH et al., Invest. New Drugs, 1999, 17 (1), 17-27. Human tumour fragments of 2 to 3 mm in diameter are implanted subcutaneously in Balb/C (Iffa-Credo, Lyon, France) Severe Combined Immunodeficiency (SCID) mice.The weight of the tumours is estimated by the formula: P (tumor weight in mg) = (axb2)/2, where a and b are the length and width in mm of the tumour implant respectively. Measurement of a and b is made with a back-stage foot. The anti-tumor efficacy is assessed by comparing the mean tumour weight in the group of animals treated with the study compound (T) with that of the control group of animals treated with the soil compound (C) alone.This measurement, expressed as % of the T/C ratio, is made when C reaches approximately 1000 mg. The compounds of the invention have demonstrated antitumor activity in vivo (T/C ratio below 100%), some very significantly with a T/C ratio below or equal to 42%.

Thus, according to the present invention, it appears that compounds of formula (I) inhibit the proliferation of tumor cells including multi-resistant cells, and therefore the compounds of the present invention appear to have anticancer activity.

Thus, according to another aspect of the invention, the subject matter of the invention is medicinal products which contain a compound of formula (I), or a salt of the latter added to a pharmaceutically acceptable acid, or a hydrate or solvate of the compound of formula (I).

These drugs are used in therapeutics, particularly in the treatment or prevention of diseases caused or exacerbated by the proliferation of tumor cells.

As inhibitors of tumor cell proliferation, these compounds are useful in the treatment of solid tumours, both primary and metastatic, carcinomas and cancers, in particular: breast cancer; lung cancer; cancer of the small intestine, colon and rectum cancer; cancer of the respiratory tract, oropharynx and hypopharynx; cancer of the esophagus; cancer of the liver, stomach cancer, cancer of the bile ducts, cancer of the gallbladder, pancreatic cancer; cancers of the urinary tract including kidney, urothelium and bladder; cancers of the female genital tract including cancer of the uterus,Cervical, ovarian, chloriocarcinoma and trophoblastoma; cancers of the male genital tract including prostate, seminal vesicle, testicular, germ cell cancers; cancers of the endocrine glands including thyroid, pituitary, adrenal cancers; skin cancers including haemangiomas, melanoma, sarcomas including Kaposi' s sarcoma; tumors of the brain, nerves, eyes, meninges including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuroblastomas, neuroblastomas, schwannomas, meningiomas; solid tumors arising from malignant tumours including chloroplastomas, T-cells, lymphomas, lymphomas, lymphomas, lymphomas, lymphomas;It's called a malignant hemopathy, myeloma.

In another aspect, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a compound of the invention, containing an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of that compound, and at least one pharmaceutically acceptable excipient.

These excipients are selected according to the pharmaceutical form and the desired route of administration from among the usual excipients known to the professional.

In the pharmaceutical formulations of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active substance of formula (I) above, or its salt, solvate or hydrate, if any, may be administered as a unit of administration, in combination with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable unit forms of administration include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous, rectal and implant forms. For topical application, the compounds of the invention may be used in creams, gels, ointments or lotions.

The compounds of formula (I) above may be used at daily doses of 0.002 to 2000 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 300 mg/kg. In humans the dose may be preferentially between 0.02 and 10000 mg per day, in particular between 1 and 3000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

There may be special cases where higher or lower doses are appropriate; such doses are not outside the scope of the invention.

The present invention, in another aspect, also relates to a method of treatment of the above conditions which involves administering to a patient an effective dose of a compound of the invention or one of its pharmaceutically acceptable salts or hydrates or solvates.

According to the present invention, the compound (s) of formula (I) may be administered in combination with one or more anticancer active ingredients, in particular anti-tumor compounds such as alkylating agents such as alkyl sulfonates (busulfan), dacarbazine, procarbazine, nitrogenous mustards (chlormethane, melphalan, chlorambucil), cyclophosphamide, ifosfamide; nitrosourates such as carmustine, semustine, streptozocin; antineoplastic alkaloids such as vincline, vinblastine; taxonins such as paclitazone or taxothelium; antineoplastic analogues such as paclitazone; purine analogues, antineoplastic antagonists such as mercaptox, antineoplastic inhibitors; antimicrobial agents such as mercaptox, antineoplastic antagonists;6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine, pyrimidine analogues such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside; brequinar; topoisomerase inhibitors such as camptothecine or etoposide; anti-hormonal agonists and antagonists including tamoxifen; kinase inhibitors, imatinib; growth factor inhibitors; anti-inflammatories such as polysulfate, corticosteroids, prednisone, dexamethasone; anti-cancer drugs such as eposcopicillin, including cystomycin, platyclin, anthracin, metformin, and methylphenidate;The most commonly prescribed medications are carboplatin, oxaliplatin, alpha interferon, triphenylthiophosphoramide, ultrathamine, antiangiogenic agents, thalidomide, adjuvants for immunotherapy, and vaccines.

Claims

Compound corresponding to the formula: in which:
- R₁ represents a hydrogen atom, a (C₁-C₄)alkyl group or a (CH₂)_nOH, (CH₂)_n-O-tetrahydropyran-2-yl, (CH₂)_nNR'₆R'₇, (CH₂)_nCN, (CH₂)_nCO₂(C₁-C₄)alk or (CH₂)_nCONR₆R₇ group;

- R₂ represents a hydrogen atom or a (C₁-C₄)alkyl group;

- or R₁ and R₂ together form a (CH₂)₃ group;

- R₃ represents a phenyl monosubstituted by a hydroxyl, hydroxymethyl, carboxyl, (C₁-C₄)alkanoyl, azido, (C₁-C₄)alkoxycarbonyl, hydroxyiminomethyl, (C₁-C₄)alkylsulphonyl, trifluoromethyl, thiol, (C₁-C₄)alkylthio or cyano group or by a (CH₂)_mNR'₇R₁₀, CONR₆R₈ or O(CH₂)_nR₉ group; a phenyl substituted by 2 to 5 identical or different substituents chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, hydroxymethyl, (C₁-C₄)alkoxy, carboxyl, (C₁-C₄)alkanoyl, azido, (C₁-C₄)alkoxycarbonyl, hydroxyiminomethyl, thiol, (C₁-C₄)alkylthio or (C₁-C₄)alkylsulphonyl group, or a phenyl or cyano, or by a (CH₂)_mNR'₇R₁₀, CONR₆R₈ or O(CH₂)_nR₉ group; or R₃ represents a benzodioxolyl group which is unsubstituted or substituted on the phenyl by a halogen atom;

- R₄ and R₅ are identical or different and each independently represent a hydrogen or halogen atom or a hydroxyl, (C₁-C₄)alkyl, trifluoromethyl, phenyl, cyano, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl or (C₁-C₄)alkylsulphonyl group or an O-(CH₂)_nNR₆R₇ or (CH₂)_nNR₆R₇ group;

- R₆ represents hydrogen or a (C₁-C₄)alkyl group;

- R₇ represents hydrogen or a (C₁-C₄)alkyl group;

- or R₆ and R₇, together with the nitrogen atom to which they are bonded, form a heterocyclic radical chosen from: piperidyl, morpholinyl, pyrrolidinyl, piperazinyl or 4-methylpiperazin-1-yl;

- R'₆ represents hydrogen or a (C₁-C₄)alkyl group;

- R'₇ represents hydrogen or a (C₁-C₄)alkyl group;

- or R'₆ and R'₇, together with the nitrogen atom to which they are bonded, form a heterocyclic radical chosen from morpholinyl or pyrrolidinyl;

- R₈ represents hydrogen, a (C₁-C₄) alkyl group or a

- (CH₂)_nNR₆R₇ group;

- or R₆ and R₈, together with the nitrogen atom to which they are bonded, form a heterocyclic radical chosen from: piperidyl, morpholinyl, pyrrolidinyl, piperazinyl or 4-methylpiperazin-1-yl;

- R₉ represents a phenyl radical or an amino, morpholin-4-yl, cyano or (C₁-C₄)alkoxycarbonyl group;

- R₁₀ represents R'₆ or a phenyl, pyridyl or pyrimidinyl group or a (CH₂)_nNR'₆R'₇ group;

- or R'₇ and R₁₀, together with the nitrogen atom to which they are bonded, form a heterocyclic radical chosen from piperazinyl or 4-methylpiperazin-2-yl;

- n represents 1, 2 or 3;

- m represents 0 or 1;

- Alk represents an alkyl;
in the base form or in the form of an addition salt with an acid, and in the form of a hydrate or of a solvate.
Compound of formula (I) according to Claim 1, characterized in that:
- R₁ represents a hydrogen atom or a methyl, cyanomethyl, (C₁-C₄)alkoxycarbonylmethyl, aminomethyl, aminoethyl, aminopropyl or pyrrolidinoethyl group;

- and/or R₂ represents a methyl group;

- and/or R₁ and R₂ together form a (CH₂)₃ group;

- and/or R₃ represents a phenyl monosubstituted by a hydroxyl, (C₁-C₄)alkoxycarbonyl, methylsulphonyl, trifluoromethyl, methylthio, cyanomethoxy, aminoethoxy, acetyl, hydroxymethyl, cyano, amino, azido, aminomethyl or hydroxyiminomethyl group or a (CH₂)_mNR'₇R₁₀ group in which R'₇ represents a hydrogen atom or a methyl, R₁₀ represents a hydrogen atom or a phenyl, pyridyl or pyrimidinyl group or R'₇ and R₁₀, together with the nitrogen atom to which they are bonded, form a piperazin-1-yl or 4-methylpiperazin-1-yl group, and m represents zero or one; or R₃ represents a phenyl substituted by 2 to 3 identical or different substituents chosen from a halogen atom, a methyl, methoxy, methylthio, trifluoromethyl, hydroxyl, (C₁-C₉)alkoxycarbonyl, methylsulphonyl, cyanomethoxy, aminoethoxy, acetyl, hydroxymethyl, cyano, amino, azido, aminomethyl or hydroxyiminomethyl group or a (CH₂)_mNR'₇R₁₀ group in which R'₇ represents a hydrogen atom or a methyl, R₁₀ represents a hydrogen atom or a phenyl, pyridyl or pyrimidinyl group or R'₇ and R₁₀, together with the nitrogen atom to which they are bonded, form a piperazin-1-yl or 4-methylpiperazin-1-yl group, and m represents zero or one; or R₃ represents a benzodioxolyl group which is unsubstituted or substituted on the phenyl by a halogen atom;

- and/or R₄ represents a halogen atom or a methyl, methoxy or (C₁-C₄)alkoxycarbonyl group;

- and/or R₅ represents a hydrogen atom or a methyl group;
in the base form or in the form of an addition salt with an acid, and in the form of a hydrate or of a solvate.
Compound of formula (I) according to Claim 1, chosen from:
• 3-(2,4-dimethoxyphenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carboxylic acid;

• 3-(2,4-dimethoxyphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 3-(3-hydroxymethylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 3-(2,4-dichlorophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 3-(1,6-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]-indol-3-yl)benzonitrile;

• 3-(4-aminophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 3-(6-chloro-1,3-benzodioxol-5-yl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 1,6-dimethyl-1,9-dihydro-3-(phenylaminophenyl)-2H-pyrido[2,3-b]indol-2-one;

• 6-bromo-3-(3,5-dimethylphenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 1,6-dimethyl-3-(3-(trifluoromethyl)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 1,6-dimethyl-3-(3-(pyridin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 1,6-dimethyl-3-(3-(pyrimidin-2-ylamino)phenyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 3-(3-acetylphenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;

• 2-(2,4-dichlorophenyl)-9-methyl-5,6-dihydro-3H,4H-3a,6a-diazafluoranthen-3-one;

• methyl 9-(cyanomethyl)-3-(2,4-dichlorophenyl)-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carboxylate;
in the base form or in the form of an addition salt with an acid, and in the form of a hydrate or of a solvate.
Process for the preparation of a compound of formula (I) according to one of Claims 1 to 3, characterized in that:
a 2-aminoindole of formula:
in which R₁, R₂, R₄ and R₅ are as defined for a compound of formula (I), is reacted with an ester of formula: in which R₃ is as defined for a compound of formula (I) and Alk represents a C₁-C₄ alkyl.
Process for the preparation of a compound of formula (I) according to one of Claims 1 to 3, characterized in that:
an aminoindole of formula:
in which R₁, R₂, R₄ and R₅ are as defined for a compound of formula (I), is reacted with an ester of formula: in which R₃ is as defined for a compound of formula (I) and Alk represents a C₁-C₄ alkyl.
Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 3 or an addition salt of this compound with a pharmaceutically acceptable acid or also a hydrate or a solvate of the compound of formula (I).
Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 3, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least one pharmaceutically acceptable excipient.
Use of a compound of formula (I) according to any one of Claims 1 to 3 for the preparation of a medicament intended for the treatment and prevention of diseases caused or exacerbated by the proliferation of tumour cells.