FR2722195A1 - Novel di:hydro-pyrrolo-pyridin-2-ones and oxazolo-pyridin-2-ones - Google Patents

Abstract

1,3-Di-hydro-2H-pyrrolo2,3-bpyridin-2-one and oxazolo-4,5-bpyridin-2(3H)-one derivs. of formula (I) and their geometric and/or optical isomers and acid or base addn. salts, are new. R1 = H, alkyl, alkenyl, cyanoalkyl or arylalkyl; W = -A-R2 or -(A)m-(CH2)n-N(R3)R4; R2 = alkyl, cycloalkyl, cycloalkylalkyl, etc.; R3, R4 = H, alkyl, phenyl, phenylalkyl, cycloalkyl or cycloalkylalkyl; A = -C(=O)- or -C(OH)H-; Y = O or -C(R5)R6; R5, R6 = H, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl; n = 1-4; m = 0 or 1.

Description

The present invention relates to novel 1,3-dihydro-2H-derivatives.

pyrrolo [2,3-

  b] pyridin-2 ones and oxazolo [4,5-b] pyridin-2 (3H) -ones, process for their preparation and

  pharmaceutical compositions which contain them.

  Numerous derivatives of 1,3-dihydro-2H-pyrrolo [2,3-b] pyridin-2-ones and oxazolo [4,5-

  b] pyridin-2 (3H) -ones are described therapeutically as having activities such as

  cardiotonic, insecticidal or anti-inflammatory.

  With regard to 1,3-dihydro-2H-pyrrolo [2,3-b] pyridin-2-ones, EP 436

  333 claims, in particular, 3-aminocarbonyl-1,3-dihydro-2H-pyrrolo [2,3b] pyridin-2-

  described as possessing interesting anti-inflammatory properties.

  1,3-Dihydro-2H-pyrrolo [2,3-b] pyridin-2-ones substituted in the 3-position with alkyls and aryls are also described as anti-inflammatory in an article of the

  Journal of Medicinal Chemistry (1990) 33 2697-2706.

  As regards oxazolo [4,5-b] pyridin-2 (3H) -ones, and more particularly compounds substituted at the pyridine ring, EP 357 675 and US 486 674 claim a number of compounds substituted at 6 by pyridines and described

as being cardiotonic.

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  The compounds of the present invention have a high structural originality by the acyl or hydroxyl groups which substitute them on the pyridine part of the heterocycle. No oxazolo [4,5-b] pyridin-2 (3H) -one of this type is described or claimed in the literature, and the only pyrrolo [2,3-b] pyridin-2-ones substituted on the nucleus pyridine are only by halogens, alkyls or nitriles and are described as being

  essentially anti-inflammatory.

  The new compounds discovered by the Applicant differ from all the derivatives mentioned above by their powerful analgesic properties.

  associated with a virtual absence of anti-inflammatory properties.

  Most non-morphine analgesic substances known to date also have an anti-inflammatory activity and thus intervene on the processes related to the phenomena of inflammation (this is the case, for example, of salicylated derivatives such as aspirin, pyrazoles such as phenylbutazone, arylacetic or heteroarylacetic acids such as indomethacin ...). Being anti-inflammatory, these substances inhibit cyclooxygenase which causes a blocking of the biosynthesis of many chemical mediators (prostaglandins, prostacyclin, thromboxane A2 ...). As a result, there are multiple side effects, including inhibition of platelet aggregation associated with coagulation disorders and gastrointestinal toxicity with the possibility of ulceration and hemorrhage due to decreased prostaglandin biosynthesis. PG E2 and PG F1 are cytoprotective of the gastric mucosa. In addition to the inconvenience they cause, these side effects can, in many subjects who are particularly sensitive, make it impossible to prescribe substances.

  analgesics with anti-inflammatory properties.

  The compounds of the present invention not mediating

  inflammation are therefore devoid of the side effects mentioned above.

  This characteristic, coupled with their lack of toxicity and high level of activity, renders the compounds of the present invention useful as analgesics without the usual use restrictions for most products of this invention.

class.

  More specifically, the invention relates to the compounds of general formula (I): ## STR2 ## in which: R 1 represents a hydrogen atom or an alkyl, alkenyl, cyanoalkyl or arylalkyl group; - R 2 represents an alkyl or cycloalkyl group; cycloalkylalkyl, phenyl, phenylalkyl, naphthyl or naphthylalkyl, R.sub.1 / R.sub.3 represents an oxygen atom or a group C in which R.sub.3 and R.sub.4 represent R.sub.4 independently of one another a hydrogen atom or an alkyl group cycloalkyl, cycloalkylalkyl, phenyl or benzyl, X represents a hydrogen atom and W represents a hydroxyl radical, or X and W together with the carbon atom carrying them a carbonyl group,

  it being understood that when describing formula (1):

  the terms "alkyl", "alkenyl" and "alkoxy" denote linear or branched groups containing from 1 to 6 carbon atoms and which may be unsubstituted or substituted with one or more alkoxy radicals, - the term "aryl" means groups phenyl, naphthyl or pyridine, the phenyl, benzyl, naphthyl and pyridine groups may be unsubstituted or substituted by one or more halogen atoms or hydroxyl, alkyl, alkoxy, trifluoromethyl or nitro radicals; the term cycloalkyl denotes Cyclic system having 3 to 8 carbon atoms, the terms "cycloalkylalkyl", "arylalkyl", "phenylalkyl" and "naphthylalkyl" denote cycloalkyl, aryl, phenyl or naphthyl attached through a linear carbon chain or branched having from 1 to 6 carbon atoms,

4 2722195

  their isomers, enantiomers, diastereoisomers, in pure form or in the form of

  mixture, and their addition salts with a pharmaceutically acceptable acid or base.

  More particularly, the invention relates to the compounds of formula (I) for which Y represents an oxygen atom, compounds which are oxazolo [4,5-b] pyridin-2 (3H) -one of formula (IA): w X \ /

2R-C O

C C = O (IA)

N N N R1

  wherein R1, R2, X and W are as defined for formula (I).

  their diastereoisomeric enantiomeric isomers in pure form or in the form of a mixture, as well as their addition salts with an acid or a pharmaceutically acceptable base, RP3, as well as the compounds of formula (I) for which Y represents the group C R4 compounds which are 1,3-dihydro-2H-pyrrolo [2,3-b] pyridin-2-one of formula (IB): w \ X R3 R4 RC

R2 C

l C = O (lB)

LN. NOT

  Wherein R 1, R 2, R 3, R 4, W and X are as defined for formula 1, their diastereoisomeric enantiomeric isomers in pure form or in the form of a mixture

  as well as their addition salts with an acid or a pharmaceutically acceptable base.

  The present invention also relates to the process for the preparation of the compounds of formula I characterized in that a compound of formula (II) is reacted as follows: Br y S) = O (II)

-N IN

  R'1 in which Y is as defined in formula I and R'1 has the same definition as R1 with the proviso that R'1 can not represent a hydrogen atom, ie in the presence of 1,2-bis ( diphenylphosphino) ethane and palladium (II) acetate with an unsaturated ether of formula (III): Alk-O-CH = CH-R'2 (11) in which Alk represents an alkyl of 1 to 4 carbon atoms and R'2 represents a hydrogen or a linear or branched alkyl of 1 to 5 carbon atoms optionally substituted with a phenyl, naphthyl or cycloalkyl so as to obtain the compounds of formula (IV): R'2-CHi-C

0 1 (IV)

he

WN X N - CZO

  R'1 in which R'1, R'2 and Y are as defined above, * in the presence of Pd (P03) 4 and lithium chloride with a compound of formula (V): AIk3Sn

CH = CH-R'2 (V)

  In which R'2 and Alk have the same definition as above so as to also access the compounds of formula (IV): R'-CHi-C y Il

O I 1 ≥O (IV)

_N N

  R'1 * is in the presence of Zinc with a halogenated derivative of formula (VI): Ar-CH-Hal (VI) in which Hal represents a halogen atom and Ar a phenyl or naphthyl group optionally substituted so as to obtain the compounds of formula (VII): ## STR1 ## in which Ar is as defined above and R 1 is as defined in formula 1, which is subjected to an oxidation reaction with an oxidizing agent such as for example, chromium oxide or N-bromosuccinimide for access to compounds of formula (VIII): ## STR2 ##

N N

  R 1 in which Ar, Y and R 1 are as defined above, with the case where N-bromo succinimide is used and where Y represents the CH 2 group, requires following the oxidation reaction of a debromination step with of Zinc, the compounds of formulas IV and VIII may if desired: - in the case where R1 or R'1 represent a benzyl group to be debenzylated in the presence of palladium on carbon and hydrogen to access the compounds of formula (IX) and (X) o R'-CH-C y Y O: = O (lx) Ar "≥ Yo Mx)

N N

  in which Y, Ar and R'2 are as defined above, in the case where R1 or R'1 represent a cyanomethyl group to be decyanomethylated in the presence of platinum oxide and hydrogen to access these same compounds of formulas (IX) and (X), all of these compounds (IV), (VIII), (IX), (X) constituting the compounds of formula (Xl): o R2 y (J) ≥O

N N

  Wherein R1, R2 and Y are as defined above, compounds (X1) which may if desired be reduced by a reducing agent, such as sodium borohydride to the alcohol of formula (XII):

R2 I001 (I)

N N

  R 1 in which R 1, R 2 and Y are as defined above, the compounds of formulas (X 1) and (XII) forming part of the invention and constituting the

compounds of formula (1).

  The pharmacological study of the compounds of the invention has shown that they are not very toxic, endowed with a high pure analgesic activity and therefore free from the disadvantages inherent to the anti-inflammatory component of the non-morphine compounds exhibiting

  this type of activity (ulcerogenic action, disruption of coagulation processes ...).

  This pure analgesic activity makes the compounds of the present invention very interesting in many indications such as: rheumatic arthritis, lumbosciatic neuralgia, cervico-brachial neuralgia, traumatic pain such as sprains, fractures, dislocations, post-traumatic pain, post-traumatic pain. operative, dental pain, neurological pain such as facial neuralgia, visceral pain such as nephritic colic, dysmenorrhea, proctologic surgery, pain of the sphere

  O.R.L., pancreatitis, various pain, headache, cancer pain.

  The present invention also relates to pharmaceutical compositions containing one of the compounds of formula (I) in base form or salified with a pharmaceutically acceptable acid, alone or in combination with one or more excipients

  or non-toxic pharmaceutically acceptable inert carriers.

  Also included in the invention are pharmaceutical compositions containing one of the compounds of formula 1, in basic or salified form, combined with caffeine and in combination with one or more non-toxic inert excipients or carriers

pharmaceutically acceptable.

  Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal, rectal, perlingual, ocular or respiratory administration and in particular injectable preparations, aerosols, eye or nasal drops, single or coated tablets,

8 2722195

  sublingual tablets, sachets, packets, capsules, glossettes, tablets,

  suppositories, creams, ointments, dermal gels etc ...

  The dosage varies depending on the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatments and is between 5 mg and 4 g per 24 hours.

  The following examples illustrate the invention and do not limit it in any way.

  PREPARATION 1: 6-BROMOOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE After dissolution of oxazolo [4,5-b] pyridin-2 (3H) -one (5 g, 23.25 mmol ) in the

  N, N-dimethylformamide (100 mL), bromine (1.28 mL, 25.58 mmol) is slowly added.

  Stirring is maintained at room temperature for 2 hours. Then water (50 ml) is added to the reaction medium; the product of the title is isolated after being filtered, rinsed with a

  little water and dried under vacuum. The yield obtained is 90%.

Br N N H

F: 229-230 ° C

  IR (KBr): 1750 cm-1 (CO carbamate) 1H NMR (CDCl3 + D2O), δ (ppm): 7.54 (d, H7, 1H, J5.7 = 2.4 Hz); 8.17 (d, H5, 1H, J5.7 = 2.4 Hz) PREPARATION 2: 6BROMO-3-METHYLOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE 6-Bromooxazolo [4,5b ] Pyridin-2 (3H) -one of Preparation 1 (530 mg, 2 mmol) is dissolved in N, N-dimethylformamide (10 ml), then sodium hydride (80% in oil) is added (66 mg, 2.20 mmol). Stirring is maintained at room temperature for 1 hour and then methyl iodide (426 mg, 3 mmol) diluted with N, N-dimethylformamide (0.5 ml) is added dropwise. The reaction mixture is refluxed for 2 hours. When the solution is cooled and the solvent evaporated under reduced pressure, the residue is taken up with water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate (MgSO4), filtered and the solvent is evaporated. The title product is purified by chromatography on silica gel (elution: CH 2 Cl 2). The yield

obtained is 85%.

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Br _N N CH3

F: 125-127 ° C

  IR (KBr): 1770 cm-1 (CO carbamate) 1H NMR (CDCl3), δ (ppm): 3.47 (s, NCH3, 3H); 7.52 (d, H7, 1H, J5.7 = 2.2 Hz); 8.16 (d, H 5, 1H, J 5, 7 = 2.2 Hz). PREPARATION 3: 6-BROMO-3- (CYANOMETHYL) OXAZOLO [4,5-b] PYRIDIN-2 (3H) -one The 6-bromooxazolo [4,5-b] pyridin-2 (3H) -one of the preparation 1 (215 mg, 1.0 mmol) is added to a solution of sodium ethanolate prepared with sodium (28 mg, 1.2 mmol) in anhydrous ethanol (6 ml). The reaction mixture is stirred at room temperature for 1 hour, then the ethanol is evaporated under reduced pressure. The anion is then dissolved in N, N-dimethylformamide (DMF) (6 ml) and then bromoacetonitrile (0.1 ml, 1.5 mmol) diluted with a little solvent is added dropwise. The reaction mixture is refluxed for 2 hours. When the solution is cooled and the solvent evaporated

  under reduced pressure, the residue is taken up with water and extracted with dichloromethane.

  The organic phase is dried over magnesium sulphate (MgSO4), filtered and the solvent is evaporated. The title product is purified by chromatography on silica gel (elution

  CH2Cl2). The yield obtained is 82%.

Br

N N

CH-CN

F: 127-129C

  IR (KBr): 1780 cm -1 (carbamate CO), 1H NMR (CDCl3), δ (ppm): 4.81 (s, NCH2, 2H); 7.66 (d, H7, 1H, J5.7 = 1.5 Hz); 8.28 (d, H5, 1H, J5.7 = 1.5 Hz) PREPARATION 4: 2- (BENZYLOXY) -6-BROMOOXAZOLO [4,5-b] PYRIDINE The procedure is the same as that used during of the synthesis of the compound of Preparation 2. Benzyl bromide is used in place of methyl iodide. The

yield obtained is 60%.

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Br o

X /> OCH23

"N N

F: 222-224C

  IR (KBr): 1740 cm -1 (-C = N-) 1H NMR (CDCl3), δ (ppm): 5.40 (s, NCH2, 2H); 7.16 (d, H7, 1H, J5 = 1.5 Hz); 7.34 (s, H arom, 5H); 7.42 (d, H5, 1H, J5.7 = 1.5 Hz). MS (IC / NH 3): m / z = 307 (M + 1) PREPARATION 5: 6-BROMO 3- (2-PHENYLTHYL) OXAZOLO [4,5-b] PYRIDIN-2 (3H) ONE * Method A: Proceeding from the same way as for the synthesis of the compound of Preparation 2, but replacing the methyl iodide by (2-bromoethyl) benzene, we obtain the

  composed of the security with a yield of 63%.

  * Method B: By proceeding in the same way as for the synthesis of the compound of Preparation 3, but replacing the bromoacetonitrile by (2-bromoethyl) benzene, we obtain the

  composed of the security with a yield of 78%.

Br

-N

(CH2) 2

F: 115-117 ° C

  IR (KBr): 1780 cm -1 (carbamate CO) 1H NMR (CDCl3), δ (ppm): 3.14 (dd, CH2, 2H, J1 = 8.1Hz, J2 = 7.4Hz); 4.15 (dd, NCH 2, 2H, J 1 = 8.1 Hz J 2 = 7.4 Hz); 7.18-7.34 (m, H arom, 5H); 7.55 (d, H7, 1H, J5.7 = 2.2 Hz); 8, 19 (d, H5, 1H, J5.7 = 2.2 Hz) PREPARATION 6: 3-ALLYL-6-BROMOOXAZOLO [4,5b] PYRIDIN-2 (3H) -ONE * Method A: Proceeding from same as for the synthesis of the compound of Preparation 2, but replacing the methyl iodide with allyl bromide, the compound of

title with a yield of 41%.

  i! Method B: By proceeding in the same manner as for the synthesis of the compound of Preparation 3, but replacing the bromoacetonitrile by allyl bromide, the compound of

title with a yield of 56%.

Br N N

CH-CH = CH2

F: 71-73 C

  IR (KBr): 1785 cm-1 (carbamate CO) 1H NMR (CDCl3), δ (ppm): 4.52 (d NCH2, 2H, J = 5.9 Hz); 5.29 (d, ethyl, 1H, J = 9.9 Hz); , (D, H, H, 1H, J = 17.5 Hz); 5.89-6.04 (m, H, 1H); 7.57 (d, H 7.1 H, J 5.7 = 2.2 Hz); 8, 20 (d, H 5.1 H, J 5.7 = 1.5 Hz)

  PREPARATION 7: 6-BROMO-3- (2-CYANOETHYL) OXAZOLO [4,5-b] PYRIDIN-2 (3H) -

  ONE 6-Bromooxazolo [4,5-b] pyddin-2 (3H) -one (215 mg, 1 mmol) is dissolved in N, N-dimethylformamide (15 ml). Acrylonitrile (64 mg, 1.2 mmol) and triethylamine (120 mg, 1.2 mmol) are added successively to the solution. The reaction medium is kept at reflux for 12 hours. When the solution is cooled and the solvent evaporated

  under reduced pressure, the residue is taken up with water and extracted with dichloromethane.

  The organic phase is dried over magnesium sulphate (MgSO4), filtered and the solvent is evaporated. The title product is purified by chromatography on silica gel (elution

  CH2Cl2). The yield obtained is 81%.

Br o BrO) o

-N

(CH2) 2-CN

F: 146-148 ° C

  IR (KBr): 2240 cm -1 (CN), 1785 cm -1 (carbamate CO) 1 H NMR (CDCl 3), δ (ppm): 2.97 (dd, CH 2, 2H, J 1 = 7.4 Hz, m.p. J2 = 6.6 Hz); 4.24 (dd, NCH 2, 2H, J 1 = 7.4 Hz J 2 = 6.6 Hz); 7.61 (d, H7, 1H, J5.7 = 1.5 Hz); 8.21 (d, H 5.1 H, J 5.7 = 1.5 Hz)

  PREPARATION 8: 6-BROMO-3- [2- (PYRIDIN-2-YL) ETHYL] OXAZOLO [4,5-b] PYRIDIN-

2 (3H) -ONE

12 2722195

  6-Bromooxazolo [4,5-b] pyddin-2 (3H) -one (1 g, 4.65 mmol) is suspended in 2-vinylpyridine (5 ml). The solution is heated, with vigorous stirring, until the

  complete dissolution of the brominated derivative. Reflux heating is maintained for 2 hours.

  When the solution is cooled, continue with water and extract with dichloromethane. The organic phase is dried over magnesium sulphate (MgSO4), filtered and the solvent is evaporated. The title product is purified by gel chromatography

  silica (elution: CH 2 Cl 2 / AcOEt: 9/1). The yield obtained is 87%.

Br

-N

(CH2) 2 '-

NOT-

F: 130-132 ° C

  IR (KBr): 1780 cm-1 (carbamate CO) 1H NMR (CDCl3), (ppm): 3.31 (t, CH2, 2H, J = 7.4 Hz); 4.34 (t, NCH 2, 2H, J = 7.4 Hz); 7.08-7.16 (m, H arom, 2H); 7.52 (d, H7, 1H, J5.7 = 1.5 Hz); 7.52-7.60 (t, Harom, 1H, J = 7.4

  Hz); 8.15 (d, H 5, 1H, J 5.7 = 1.5 Hz); 8.50 (d, Harom, 1H, J = 4.4 Hz).

  PREPARATION 9: 6-BROMO-3- [2- (PYRIDIN-4-YL) ETHYL] OXAZOLO [4,5-b] PYRIDIN-

1 5 2 (3H) -ONE

  By proceeding in the same way as for the synthesis of the compound of Preparation 8, but using 4-vinylpyridine in place of 2-vinylpyridine, the compound is obtained.

of the title with a yield of 65%.

Br 1 ≥O

N N

(CH2) 2 '' N

F: 139-141 ° C

  IR (KBr): 1780 cm-1 (CO carbamate) 1H NMR (CDCl3), δ (ppm): 3.17 (dd, CH2, 2H, J1 = 8.1Hz, J2 = 7.4Hz); 4.19 (dd, NCH 2, 2H, J 1 = 8.1 Hz, J 2 = 7.4 Hz); 7.17 (d, H arom, 2H, J = 5.9 Hz); 7.55 (d, H7, 1H, J5.7 = 1.5 Hz); 8.16 (d, H 5, 1H, J 5.7 = 1.5 Hz); 8.51 (d, Harom, 2H, J = 5.9

Hz).

  PREPARATION 10: 1-METHYL PYRROLO [2,3-b] PYRIDINE Pyrrolo [2,3-b] pyridine (2.00 g, 16.93 mmol) is dissolved in DMF (15.0 ml) under an atmosphere argon. The sodium hydride (60% in oil) (0.96 g, 40.0 mmol, 1.5 eq) is added at 0 ° C. over a period of 30 minutes. After stirring for 30 minutes at 0 ° C., iodomethane (1.49 ml, 24.0 mmol, 1.5 eq) is added dropwise. After returning to ambient temperature, the reaction medium is left stirring for 1 hour. The dimethylformamide is evaporated under reduced pressure, the product is taken up with water and extracted with dichloromethane. Purification on a silica column (petroleum ether / ethyl acetate 7/3) makes it possible to isolate the title compound with a yield of 99%

in the form of an oil.

  (C = C, Ar) 1H NMR (CDCl3), δ (ppm): 3.85 (s, 3H, CH3); 6.40 (d, 1H, H-3, J3-2 = 3.3 Hz); 7.01 (dd,

  1H, H-5, J5-4 = 7.4 Hz, J5_6 = 5.2 Hz); 7.13 (d, 1H, H-2, J 2-3 = 3.3 Hz); 7, 85 (d, 1H, H-4, J4-

  5 = 7.4 Hz); 8.29 (d, 1H, H-6, J6-5 = 5.2 Hz) PREPARATION 11: 1,3-DIHYDRO1-METHYL-5-BROMO-2H-PYRROLO [2,3-b]

PYRIDINE-2-ONE

  Step 1: 1,3-dihydro-3,3,5-tribromo-1-methyl-2H-pyrrolo [2,3-b] pyridinone A Method A:

  To a solution of the compound of Preparation 10 (5.59 g, 42.3 mmol) in the

  butanol (80 ml) is added pyridinium perbromate (40.58 g, 127.0 mmol, 3.0 eq). The medium is stirred at room temperature for 2 hours. The solvents are concentrated by evaporation under reduced pressure, the crude product is taken up with water and then extracted with water.

  ethyl acetate. After evaporation, 1,3-dihydro-3,3,5-tripropromo-1-methyl-2H- is obtained.

  pyrrolo [2,3-b] pyridin-2-one in 93% yield.

  12.46 g (40.7 mmol) of 1,3-dihydro-3,3,5-tribromo-1-methyl-2H-pyrrolo [2,3-dihydro-3,3,5-tribromo-1-methyl-2H-pyrrolo]

  b] pyridin-2-one thus obtained are dissolved in 50 ml of DMF. After adding dropwise bromine (4.17 ml, 81.4 mmol, 2 eq), the reaction mixture is stirred for hours at room temperature. After evaporation of the solvent under reduced pressure, the product is taken up in water and then extracted with dichloromethane. The solvent once evaporated,

14 2722195

  the orange solid is washed with petroleum ether. After drying, the compound of

title with a yield of 85%.

  Method B: The 1-methylpyrrolo [2,3-b] pyridine of Preparation 10 (2.00 g, 15.1 mmol) is dissolved in tert-butanol (132 ml). An equivalent amount of water (132 ml) is added slowly. Bromine (9.28 ml, 128.2 mmol 12.0 eq) is added dropwise with a dropping funnel. After stirring for 24 hours at room temperature, tert-butanol is removed by evaporation under reduced pressure. The mixture is taken up with a solution of NaHCO 3 until neutral pH, then filtered. After drying, the title compound is obtained

with a yield of 91%.

Br Br OBr N Br I CH3

F = 210 C

  IR (KBr): ν = 1747 cm-1 (C = O) 1H NMR (CDCl3): δ (ppm): 3.28 (s, 3H, CH3); 3.55 (s, 2H, CH 2), 7.59 (s, 1H, H-4); 8.25 (s, 1H, H-6) Step 2: 1,3-dihydro-5-bromo-1-methyl-2H-pyrrolo [2,3-b] pyridin-2-one The compound obtained in Step 1 (0.327 g, 0.85 mmol) is dissolved in acetic acid (8 ml). Zinc (4.3 g, 8.5 mmol, 10 eq) is added at room temperature and under argon. After stirring for 30 minutes at the same temperature, the reaction medium is filtered and then evaporated under reduced pressure. The crude product is extracted with ethyl acetate at neutral pH and then purified on a silica column (petroleum ether / ethyl acetate 7/3). The

  The compound of the title is obtained with a yield of 98%.

Br CH3

F = 149 C

  IR (KBr): ν = 1713 cm-1 (C = O) 1H NMR (CDCl3), δ (ppm): 3.28 (s, 3H, CH3); 3.55 (s, 2H, CH 2), 7.59 (s, 1H, H-4); 8.25

(s, 1H, H-6).

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  PREPARATION 12: 1,3-DIHYDRO-5-BROMO-3,3-DIMETHYL-2H-PYRROLO [2,3-b]

PYRIDINE -2-ONE

  Under argon, dissolve 3 g (13.21 mmol) of the compound of Preparation 11 in 40 ml of anhydrous tetrahydrofuran. Cool in an ice bath and add 793 mg (33.03 mmol) of sodium hydride. After stirring for 30 minutes, slowly add 2.06 ml (4.69 g, 33.03 mmol) of methyl iodide. Let it slowly return to room temperature

  for 1 hour. Evaporate the solvent. Resume the residue with water and extract with CH2Cl2.

  Dry the organic phase over MgSO4.

  After purification on a silica column, 2.09 g of title product is obtained with a

yield of 62%.

CH3 Br CH3

N N

CH3

F: 93-94C

  1H NMR (CDCl3); Δ (ppm): 1.41 (s, 6H, 2 x CH 3); 3.27 (s, 3H, CH 3), 7.50 (d, 1H, H-4);

8.23 (d, 1H, H-6).

  PREPARATION 13: 3-BENZYL-6-BROMOOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE 215 mg (1.0 mmol) of 6-bromooxazolo [4,5-b] pyridin-2 are added ( 3H) -one to a solution of sodium ethoxide prepared from 6 ml of anhydrous ethanol and 28 mg (1.2

mmol) of sodium.

  After stirring for 1 hour at ambient temperature and then dried under reduced pressure, the residue is taken up in 6 ml of N, N-dimethyl formamide and benzyl bromide.

added drop by drop.

  After 2 hours of heating under reflux, cooling and dry under pressure

  reduced, the residue is taken up in water and extracted with dichloromethane.

  The crude product obtained by dry-cleaning is purified by column chromatography.

silica (Eluent: CH2Cl2).

Yield 68%.

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Br Br> ONzC = O I, = N N CH2

Mp 78-80 ° C

  IR (KBr): 1780 cm-1 (CO carbamate) 1H NMR (CDCl3): δ (ppm): 5.12 (s, NCH2, 2H); 7.27-7.39 (m, H arom, 3H) 7.47-7.51 (m, H arom, 2H) 7.54 (d, H7, 1H, J5.7 = 2.2Hz) δ, (D, H5, 1H, J5.7 = 2.2Hz) EXAMPLE 1: 3-METHYL-6ACETYLOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE * Method A: Coupling with butylvinyl ether 6-Bromo-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one of Preparation 2 (0.50 g, 2.18 mmol) was dissolved in N, N-dimethylformamide (5 mL). Triethylamine (0.44 g, 4.36 mmol), butylvinylether (1.2 g, 12 mmol), 1,2-bis (diphenylphosphino) ethane (24 mg 0.06 mmol) and acetate palladium (II) (12 mg, 0.054 mmol) are then added in order. The solution, under an inert atmosphere, is refluxed for 8 hours. When it is cooled, it is hydrolyzed with a 10% hydrochloric acid solution, stirring is maintained for 1 hour. The N, N-dimethylformamide is evaporated under reduced pressure and the residue is taken up with water, extracted with dichloromethane; the organic phase is then dried over magnesium sulphate (MgSO4), filtered and the solvent is evaporated. The title product is purified by flash silica gel chromatography

(eluent: CH2Cl2 / AcOEt: 8/2).

The yield obtained is 90%.

  Method B: Coupling with 1-ethoxy-1- (trimethylstannyl) ethylene 6-Bromo-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one of Preparation 2 (700 mg; 05 mmol) is dissolved in tetrahydrofuran (20 ml) and then (3.14 mmol, 0.59 ml) of 1-ethoxy-1 (trimethylstannyl) ethylene is introduced. Tetrakis (triphenylphosphine) palladium (0) (180 mg, 0.15 mmol), lithium chloride (380 mg, 8.84 mmol) are then added

  in order. The solution, under an inert atmosphere, is refluxed for 8 hours.

  When this is cooled, it is hydrolyzed with a 10% hydrochloric acid solution, stirring is maintained for 1 hour. Tetrahydrofuran is evaporated under reduced pressure and the residue is taken up with water, extracted with dichloromethane; the organic phase is then dried over magnesium sulphate (MgSO4), filtered and the solvent is evaporated. The title product is purified by flash chromatography on silica gel (6luent:

  CH2Cl2 / AcOEt: 8/2). The yield obtained is 60%.

17 2722195

o o

N N

  CH3 F = 162-164 ° C (i-PrOH) IR (KBr): 1790 cm -1 (CO carbamate); 1670 cm-1 (CO ketone) 1H NMR (CDCl3): δ (ppm): 2.53 (s, CH3, 3H); 3.63 (s, NCH 3, 3H); 7.91 (d, H7, 1H, J5.7 = 1.5 Hz); 8.72 (d, H5, 1H, J5.7 = 1.5 Hz) EXAMPLE 2: 3-BENZYL-6-ACETYLOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE The procedure is the following: same as that used in the synthesis of the

  Example 1 (coupling with 1-ethoxy-1- (t-methylstannyl) ethylene).

  The 6-bromo-3-benzyloxazolo [4,5-b] pyridin-2 (3H) -one of Preparation 13 being employed at the

  place 6-bromo-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one.

The yield obtained is 75%.

O o

CH I 0 =

3H C = O

N N

CH2Q3

Mp 163-164 ° C

  IR (KBr): 1780 cm -1 (carbamate CO), 1670 cm -1 (CO ketone) 1H NMR (CDCl3); ((ppm): 2.62 (s, CH3, 3H), 5.12 (s, NCH2, 2H), 7.27-7.78 (m, H arom, 3H), 7.49-7.55 ( m, H arom, 2H), 7.93 (d, H7, 1H J5.7 = 1.5 Hz), 8.77 (d, H5, 1H, J5.7 = 1.5 Hz) EXAMPLE 3: 3 -CYANOMETHYL-6-ACETYLOXAZOLO [4,5-b] PYRIDIN-2 (3H) ONE The procedure is the same as that used during the synthesis of the compound of

  Example 1 (coupling with 1-ethoxy-1- (trimethylstannyl) ethylene) 6-bromo-3-

  (cyanomethyl) oxazolo [4,5-b] pyridin-2 (3H) -one of Preparation 3 is used in place of 6-bromo-3-methyloxazolo [4,5-b] pyridin-2 (3H) - one of the preparation 2. The performance

obtained is 60%.

o

H3C> O

NOT

N N

CH "-CN

F = 170-172 ° C

  IR (KBr): 1790 cm -1 (carbamate CO), 1670 cm -1 (CO ketone) 1H NMR (CDCl3); Δ (ppm): 2.64 (s, CH 3, 3H); 4.85 (s, NCH 2, 2H); 8.03 (d, H7, 1H, J5.7 = 1.5 Hz); 8.79 (d, H5, 1H, J5.7 = 1.5 Hz) EXAMPLE 4: 6-ACETYL OXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE Method A: Decyanomethylation 3-cyanomethyl-6 -acetyloxazolo [4,5-b] pyridin-2 (3H) -one of Example 3 (1 g) is dissolved in ethanol (25 ml) and then platinum oxide (250 mg) is added. The solution is stirred at room temperature under a hydrogen atmosphere. After filtering the catalyst, the solvent is evaporated under reduced pressure. The product of the title is purified by

  flash chromatography on silica gel (elution: CH 2 Cl 2 / CH 3 OH: 95/5).

The yield obtained is 98%.

  * Method B: acetylation then debenzylation Stage 1: 6-acetyl2-benzyloxyoxazolo [4,5-b] pyridine The procedure is the same as that used during the synthesis of the compound of

  Example 1 (coupling with 1-ethoxy-1- (trimethylstannyl) ethylene), 2-benzyloxy-6-

  bromooxazolo [4,5-b] pyridine of Preparation 4 being used in place of 6-bromo-3-

* Methyloxazolo [4,5-b] pyridin-2 (3H) -one of Preparation 2.

  The yield obtained is 78% o Il -CH3

H3 v /> - o-CH2-

c NN

Mp = 180-182 ° C

  IR (KBr): 1740 cm -1 -C = N-1670 cm-1 (CO ketone) 1H NMR (CDCl3); $ (ppm): 2.50 (s, CH 3, 3H); 5.48 (s, NCH 2, 2H); 7.53 (d, H7, 1H, J5.7 = 1.5 Hz); 7, 35-7.48 (m, H arom, 5H); 7.96 (d, H5, 1H, J5.7 = 1.5Hz) Step 2: 6-acetyloxazolo [4,5-b] pyridin-2 (3H) -one 6-Acetyl-2-benzyloxyoxazolo [4, 5b] pyddine of the previous stage (1 g) is dissolved in methanol (25 ml) and then palladium on charcoal (100 mg) is added. The solution is stirred at ambient temperature under a hydrogen atmosphere. After filtering the catalyst, the solvent is evaporated under reduced pressure. The product of the title is purified by

  falsh chromatography on silica gel (elution: CH2Cl2 / CH3OH: 95/5).

The yield obtained is 95%.

o HO

H3CJ) =

N N

  HF = 222-224 ° C (H 2 O) IR (KBr): 3500-3200 cm -1 (NH), 1750 cm -1 (CO carbamate), 1670 cm -1 (CO ketone) 1 H NMR (DMSO + D 2 O), 8 2.22 (s, CH3, 3H); 7.87 (s, H, 1H); 8.66 (s, H, 1H); EXAMPLE 5: 3-METHYL-6BENZOYLOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE Step 1: 3-Methyl-benzyloxazolo [4,5-b] pyr-din-2 (3H) -one Zinc (227 mg) 3.48 mmol) is suspended in tetrahydrofuran (10 ml), 1,2-dibromoethane (0.22 ml, 0.2 mmol) is added. The mixture is heated at 60 ° C for 3 minutes, the solution is allowed to cool until the temperature is 350 ° C, the trimethylsilyl chloride (0.06 ml, 0.5 mmol) is slowly added. The agitation is

  maintained for 30 minutes and then the benzyl bromide (0.11 ml, 0.9 mmol) is added.

  Wait another 30 minutes before introducing 6-bromo-3-methyl oxazolo [4,5-b]

  pyridin-2 (3H) -one (200 mg, 0.87 mmol), tetrakis (triphenylphosphine) palladium (0) (4 mg).

  Heat at 500C for 20 minutes. After cooling the solution, the zinc is filtered, the filtrate is taken up with water and then an aqueous solution of% hydrochloric acid is added until the aqueous phase becomes clear. The extraction is carried out using dichloromethane. The organic phase is dried over magnesium sulphate (MgSO4), filtered and the solvent is evaporated off under reduced pressure. The product of the title is purified by

  silica gel chromatography (elution: CH 2 Cl 2). The yield obtained is 91%.

2722195

1'c0

[C C =

N CH3

F = 127-129C

  IR (KBr): 1780 cm-1 (CO carbamate), 1H NMR (CDCl3): δ (ppm): 3.46 (s, 3H, NCH3); 4.00 (s, 2H, CH2), 7.14-7.35 (m, 6H, H7 + 5H arom), 8.02 (d, 1H, H5, J5 = 1.5Hz) Step 2 3-methyl-6-benzoyloxazolo [4,5-b] pyridin-2 (3H) -one Chromium (VI) oxide (5 mg, 0.05 mmol) is suspended in dichloromethane (25 ml ) then tert-butyl hydrogen peroxide (1.08 ml, 8 mmol) is added dropwise. Stage 1 6-benzyl-3-methyloxazolo [4,5-b] pyridin-2-one (236 mg, 1 mmol) is slowly added to the solution. When the color of the reaction medium is yellow, the same amount of chromium oxide (VI) and tert-butyl hydroperoxide are added. Stirring is maintained for an additional 24 hours. After having filtered through Celite and the solvent evaporated under reduced pressure, the title product is purified by chromatography on silica gel (elution: CH 2 Cl 2). The

yield obtained is 82%.

o

N N ≥O

  CH3 F = 131-133 ° C (i-PrOH) IR (KBr): 1790 cm-1 (CO carbamate), 1635 cm-1 (CO ketone) 1H NMR (CDCl3); δ (ppm): 3.55 (s, NCH 3, 3H); 7.48-7.56 (m, H arom, 2H); 7.60-7.67 (m, H arom, 1H); 7.78 (d, H arom, 2H, J = 7.4 Hz); 7.89 (d, H7, 1H, J5.7 = 1.5 Hz); 8.58 (d, H5, 1H, J5.7 = 1.5 Hz) EXAMPLE 6: 6-BENZOYLOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE The procedure is the same as that used during the synthesis of the compound

  Example 5. 6-Benzyloxazolo [4,5-b] pyridin-2 (3H) -one is used in place of the 6-

  benzyl-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one. The yield obtained is 50%.

21 2722195

o N N H

Mp 196-198 ° C

  IR (KBr): 1750 cm -1 (CO carbamate), 1650 cm -1 (CO ketone) 1 H NMR (DMSO + D 2 O); δ (ppm): 7.64-7.62 (m, H arom, 2H); 7.67-7.79 (m, H arom, 3H); 7.44 (d, H7, 1H, J5 = 1.5 Hz); 8.38 (d, H5, 1H, J5.7 = 1.5 Hz) EXAMPLE 7: 6-ACETYL-3- (2-PHENYLTHYL) OXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE By proceeding in the same way as for the synthesis of the compound of Example 1 (coupling with butylvinyl ether), but replacing 6-bromo-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one by the 6-bromo-3- (2phényléthyl) oxazolo [4,5-b] pyridin-2 (3H) -one

  (Preparation 5), the title compound is obtained in 75% yield.

o H3 C N

(CH2) 2

F: 210-212 ° C

  IR (KBr): 1765 cm -1 (CO carbamate), 1675 cm -1 (CO ketone) 1H NMR (CDCl3); (ppm): 2.59 (s, CH3, 3H); 3.13 (dd, CH 2, 2H, J 1 = -8.1 Hz, J 2 = 7.4 Hz); 4.18 (dd, NCH 2, 2H, J 1 = 8.1 Hz, J 2 = 7.4 Hz); 7.15-7.28 (m, H arom, 5H); 7.88 (d, H 7.1 H, J 5.7 = 1.5 Hz); 8.69 (d, H5, 1H, J5.7 = 1.5 Hz) EXAMPLE 8: 6ACETYL-3- (2-CYANOETHYL) OXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE in the same way as for the synthesis of the compound of Example 1 (coupling with butylvinyl ether), but replacing 3-methyl-6-bromooxazolo [4,5-b] pyridin-2 (3H) -one with 3- (2-cyanoethyl) 6-bromooxazolo [4,5-b] pyridin-2 (3H) -one

  (Preparation 7), the title compound is obtained with a yield of 74%.

o

H3C- - O

GNU.,

(CH2) N N

(CH2) 2- CN

22 2722195

F: 152-154 ° C

  IR (KBr): 2240 cm -1 (CN), 1780 cm -1 (carbamate CO), 1670 cm -1 (CO ketone) 1H NMR (CDCl3); Δ (ppm): 2.65 (s, CH 3, 3H); 3.01 (t, CH 2, 2H, J = 6.6 Hz); 4.81 (t, NCH 2, 2H, J = 6.6 Hz); 8.01 (d, H7, 1H, J5.7 = 1.5 Hz); 8.77 (d, H5, 1H, J5.7 = 1.5 Hz) EXAMPLE 9: 6-ACETYL-3- [2- (PYRIDIN-2YL) ETHYL] OXAZOLO [4,5-b] PYRIDIN-2 ( 3H). ONE proceeding in the same manner as for the synthesis of the compound of Example 1 (coupling with butylvinyl ether), but replacing 6-bromo-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one with 6-bromo 3- [2- (pyridin-2-yl) ethyl] oxazolo [4,5b] pyridin-2 (3H) -one

  (Preparation 8), the title compound is obtained with a yield of 25%.

o

(CH2) 2

NOT-

F: 138-140 ° C

  IR (KBr): 1790 cm-1 (CO carbamate), 1675 cm-1 (CO ketone) 1 H NMR (CDCl3): 2.62 (s, CH3, 3H); 3.34 (t, CH 2, 2H, J = 7.4 Hz); 4.40 (t, NCH 2, 2H, J = 7.4 Hz); 7.10-7.18 (m, Harom, 2H); 7.58 (t, Harom, 1H, J = 7.4 Hz); 7.91 (d, H7, 1H, J5.7 = 1.5 Hz); 8.49 (d, H arom, 1H, J = 5.2 Hz); 8, 71 (d, H5, 1H J5.7 = 1.5 Hz)

  EXAMPLE 10 6-ACETYL-3- [2- (PYRIDIN-4-YL) ETHYL] OXAZOLO [4,5-b] PYRIDIN2 (3H) -

ONE

  By proceeding in the same way as for Example 1, but using 6-bromo-3-

  [2- (pyridin-4-yl) ethyl] oxazolo [4,5-b] pyridin-2 (3H) -one (Preparation 9), the compound is obtained.

of the title with a yield of 50%.

o H3Ct \ = N

(CH2) 2'-N

F: 148-150 ° C

23 2722195

  IR (KBr): 1790 cm -1 (CO carbamate), 1675 cm -1 (CO ketone) 1 H NMR (CDCl3); δ (ppm): 2.63 (s, CH3, 3H); 3.20 (t, CH 2, 2H, J = 7.4 Hz); 4.26 (t, NCH 2, 2H, J = 7.4 Hz); 7.19 (d, H arom, 2H, J = 5.9); 7.94 (d, H7, 1H, J5, 7 = 1.5 Hz); 8.52 (d, H arom, 2H, J = 5.9); 8.72 (d, H5, 1H, J5 = 1.5 Hz) EXAMPLE 11: 3-METHYL-6-PROPIONYLOXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE Proceeding in the Same Way that for Example 1 (coupling with butylinyl ether), but replacing the butylvinyl ether by ethyl-1-propenyl ether, we obtain the

  composed of the security with a yield of 40%.

o H3c o

é C ≥

N N

  CH 3 o0 F: 110-112 C IR (KBr): 1800 cm -1 (CO carbamate), 1670 cm -1 (CO ketone) 1 H NMR (CDCl 3), δ: 1.26 (t, CH 3, 3H, J = 7.4 Hz); 3.02 (m, CH 2, 2H); 3.55 (s, NCH 3, 3H); 7.98 (d, H7, J5.7 = 1.5 Hz); 8.79 (d, H5, J5.7 = 1.5 Hz) EXAMPLE 12: 1,3-DIHYDRO-1,3,3-TRIMETHYL-5-ACETYL-2H-PYRROLO [2,3-b]

PYRIDIN-2-ONE

  Under argon, suspend 482 mg (11.37 mmol) of lithium chloride and 90 mg (7.84 10-5 mol) of tetrakis (triphenyl phosphine) palladium (0) in 10 ml of anhydrous toluene. Add to this suspension a solution of 1 g (3.92 mmol) of 1,3-dihydro-1,3,3-trimethyl-5-bromo-2H-pyrrolo [2,3-b] pyridin-2-one and 1, 46 (4.04 mmol) (1-ethoxyvinyl) tributyltin in 20 ml anhydrous toluene. After 5 hours at reflux, evaporate the solvent and take up the residue with a 10% dioxane HCl 1: 1 mixture (30 ml). After 30 minutes with agitation

  room temperature, evaporate the dioxane. Filter the tin salts obtained on celite.

  Extract the filtrate with CH 2 Cl 2 and dry over MgSO 4. After purification on a silica column

  obtains 780 mg of the title product with a yield of 90%.

o

CH3 CH3

H3C -

N Me

F: 99-100C

  1H NMR (CDCl3); Δ (ppm): 1.43 (s, 6H, 2 x CH 3)); 2.62 (s, 3H, CH3-C = -O); 3.35 (s, 3H, CH3); 8.00 (d, 1H, H-4), 8.29 (d, 1H, H-6)

  EXAMPLE 13 1,3-DIHYDRO-1-METHYL-5-ACETYL-2H-PYRROLO [2,3-b] PYRIDIN-2-

ONE

  By proceeding in the same manner as for the synthesis of the compound of Example 12 but replacing 1,3-dihydro-1,3,3-trimethyl-6-bromo2H-pyrrolo [2,3-b] pyridin-2 by 1,3-dihydro-1-methyl-5-bromo-2H-pyrrolo [2,3-b] pyridin-2-one, the compound of

title with a yield of 84%.

o H3C

0

N N O

  IR: 1705, 1670 cm -1 1H NMR (CDCl3); $ (ppm): 2.58 (s, 3H, CH3-C = O); 3.32 (s, 3H, CH3); 3.58 (s, 2H, CH 2); 8.04 (s, 1H-4); 8.78 (s, 1H, H-6) EXAMPLE 14 6- (1-PHENYL-1-HYDROXYMETHYL) -3-METHYLOXAZOLO [4,5-b] 15

Pyridin-2 (3H) -ONE

  Add 42 mg (1.1 mmol) of sodium borohydride to a previously prepared solution of 254 mg (1 mmol) of 6-benzoyl-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one in

ml of anhydrous methanol.

  Dry the reaction medium under reduced pressure after stirring for 5 hours at room temperature and then take up the residue with water and isolate the product formed by

  filtration, the title product is obtained with a yield of 84%.

  EXAMPLE 15: 5-BENZOYL-1-METHYL-1,3-DIHYDRO-2H-PYRROLO [2,3-b] PYRIDIN-

  2-ONE Step 1: 5-Benzyl-1-methyl-1,3-dihydro-2H-pyrrolo [2,3-b] pyridin-2one Proceeding as in Step 1 of Example 5 but replacing the 6 bromo

  3-methyl oxazolo [4,5-b] pyridin-2 (3H) -one by 1,3-dihydro-5-bromo-methyl-2H-

  Pyrrolo [2,3-b] pyridin-2-one gives the title compound with a yield of 20%.

2722195

  CH2 CH3 1H NMR (CDCl3); Δ (ppm): 3.30 (s, 3H, N-CH 3); 3.48 (s, 2H, CH 2 C = -O); 3.94 (s, 2H,

  CH2-0); 7.15-7.33 (m, 6H, H arom + H 4); 8.08 (s, 1H, H6).

  Step 2: 5-Benzyl-3,3-dibromo-1-methyl-1,3-dihydro-2H-pyrrolo [2,3-b-pyridin-2-one Add 60 mg of N-bromosuccinimide and a dibenzoyl peroxide spatula tip to a previously prepared solution of 40 mg of the stage 1 compound in the

carbon tetrachloride.

  Reflux for 1 hour to dry and purify the crude product obtained by

  silica column chromatography (Eluent: petroleum ether / ethyl acetate: 7/3).

  The product of the title is obtained with a yield of 72%.

o = OBBr X Br

N N O

  1H NMR CH3 (CDCl3); Δ (ppm): 3.40 (s, 3H, CH 3); 7.54 (t, 2H, J = 7.35 Hz, Harom); 7.65 (d, 1H, J = 7.35 Hz, Harom); 7.80 (d, 2H, J = 7.35 Hz, Harom) 8.33 (d, 1H, J = 2.2 Hz, H4); 8.66

(d, 1H, J = 2.2 Hz, H6).

  Step 3: 5-Benzoyl-1-methyl-1,3-dihydro-2H-pyrrolo [2,3-bpyridin-2-one Add a spatula tip of zinc to a solution of 40 mg of the compound of Step 2 in 'acetic acid. After stirring for 30 minutes, dry to dryness under reduced pressure, take up with water and extract with dichloromethane. The crude product obtained by dry-cleaning is purified by chromatography on a silica column (eluent: petroleum ether / ethyl acetate,

6/4).

  The title product is obtained in the form of an oil with a yield of 60%.

  o CH3 1H NMR (CDCl3); Δ (ppm): 3.37 (s, 3H, N-CH 3); 3.64 (s, 2H, CH 2 = O); 7.53 (t, 2H, J = 7.35 Hz, Harom); 7.64 (d, 1H, J = 7.35 Hz, Harom), 7.79 (d, 2H, J = 7.35 Hz, Harom); 8.02 (d, 1H,

  J = 1.2 Hz, H4); 8.63 (d, 1H, J = 1.2 Hz, H6).

  PHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION

  A) SEARCH FOR ANALGESIC ACTIVITY

  1) Cramps induced with acetic acid The analgesic potential of these products was investigated according to the KOSTER test which is based on the counting of abdominal cramps induced in rats by intraperitoneal injection of acetic acid (Koster R. Anderson M., and De Beer EJ Fed Proc. (1959)

18, 412).

  Randomized Wistar male rats in a batch of 5 (150 + 10 g weight) receive the test products per os 30 minutes before the intraperitoneal injection of 1 cm3 of 1% acetic acid.

  The number of cramps is counted during the 25 minutes following the injection.

  The percentage of activity was evaluated for each compound (% decrease in

  number of cramps in treated compared to controls).

  2) Cramps induced with phenyl benzoquinone The analgesic potential of these products was sought according to the SIEGMUND test which is based on the counting of cramps induced in the mouse by injection

  intraperitoneal phenyl benzoquinone. (Siegmund E., Cadmus R., and L. G. Proc.

Biol. Med. (1957) 95,729).

  Male CD-1 mice randomized in batch of 5 receive the test products per os 30 minutes with the intraperitoneal injection of 0.25 cc of a 0.01% phenyl solution.

  benzoquinone in a 95-5 water-ethanol mixture.

27222195

  The number of cramps is counted between the 5th and the 15th minutes after

  the injection of phenyl benzoquinone.

  The percentage of activity was evaluated for each compound (% decrease in

  number of cramps in treated compared to controls).

  Acetic Acid PBQ PRODUCT DOSE Writhing% Whrithing% inhibition inhibition Aspirin 50 mg / kg 56% 62% 6-benzoyl-1-methyloxazolo [4,5-b] 50 mg / kg 85% 85% pyridin-2 ( 3H) -one 1,3-dihydro-1-methyl-5-acetyl-2H50 mg / kg 96% pyrrolo [2,3-b] pynridin-2-one It appears that the compounds of the invention possess an analgesic activity very

  interesting, very significantly higher than that of aspirin.

B) STUDY OF ACUTE TOXICITY

  Acute toxicity was assessed by oral administration of increasing doses of

  test compounds to batches of 3 male NMRI mice.

  The animals were observed at regular intervals during the next 24 hours

product administration.

  It appears that the compounds of the invention appear particularly non-toxic, no

  deaths were observed up to a dose of 1024 mg / kg with the compounds tested.

  EXAMPLE C COMPRESSES DOSES WITH 15 MG OF 6-BENZOYL 3-METHYL

  OXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE Preparation formula for 1000 tablets: 6-benzoyl-3-methyloxazolo [4,5-b] pyridin-2 (3H) -one ..... ........

  ............................. 15 g Wheat Starch ................ ......... DTD: ....................................... .................................. DTD: ... 15 g..DTD: 28 2722195

  Corn starch............................................... ............

  ..................................... 15 g Lactose .......... ............. DTD: ................................... ...................................... DTD: .......... ..... 65 g Steared magnesium .......................................... ............. .DTD: ................................ 1 g Silica ........................... DTD: .................... .................................................. ... DTD: ................. 1 g Hydroxypropyl cellulose ..................... DTD:. .................................................. ............... 2 g..DTD: EXAMPLE D: COMPRESSES DOSES A 5 MG OF 6-BENZOYL-3-METHYL

  OXAZOLO [4,5-b] PYRIDIN-2 (3H) -ONE Preparation formula for 1000 tablets: 6-benzoyl-3-methyloxazolo [4,5-b] pyddin-2 (3H) -one ..... .........

  .............................. 5 g Caffeine .............. DTD:. .................................................. ...................... DTD: ...................... 120 g Starch corn .............................. DTD: ................. .................................................. 66 g Lactose .............................................. ................ .DTD: ............................... ............... 305 g Steared magnesium ................................ ....................... .DTD: ........................ ........ 1 g Silica .............................. DTD: ....... .................................................. ................ DTD: .............. 1 g Hydroxy propyl cellulose ............. DTD: ................................................ ......................... DTD:. 2 g..DTD: 29 2722195

Claims (12)

  Compounds of the general formula (1): wherein R 1 represents a hydrogen atom or an alkyl alkenyl, cyanoalkyl or arylalkyl group, R.sub.2. represents an alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, naphthyl or naphthylalkyl group; R3-Y represents an oxygen atom or a group C in which R3 and R4 represent R4 independently of one another a hydrogen atom; or an alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl group, X represents a hydrogen atom and W represents a hydroxyl radical, or X and W together with the carbon atom carrying them a carbonyl group,   it being understood that when describing formula (1):   the terms "alkyl", "alkenyl" and "alkoxy" denote linear or branched groups containing from 1 to 6 carbon atoms and which may be unsubstituted or substituted by one or more alkoxy radicals, - the term "aryl" means groups phenyl, naphthyl or pyridine, the phenyl, benzyl, naphthyl and pyridine groups may be unsubstituted or substituted by one or more halogen atoms or hydroxyl, alkyl, alkoxy, trifluoromethyl or nitro radicals, the term "cycloalkyl" denotes a system cyclic having 3 to 8 carbon atoms, the terms "cycloalkylalkyl", "narylalkyl", "phenylalkyl" and "naphthylalkyl" denote a cycloalkyl, a cycloalkyl, an aryl, a phenyl or a naphthyl attached through a linear or branched carbon chain comprising from 1 to 6 carbon atoms, their isomers, enantiomers, diastereoisomers, in pure form or in the form of a mixture and their addition salts with a acid or a pharmaceutically acceptable base acceptable.   2. Compounds according to claim 1, for which Y represents an oxygen atom, compounds which are oxazolo [4,5-b] pyridin-2 (3H) -one of formula (IA): ## STR2 ## 11 010C = o (IA) N- N ' N N   In which R 1, R 2, X and W are as defined in claim 1, their isomers, enantiomers, diastereoisomers in pure form or in the form of a mixture, and   their addition salts with an acid or a pharmaceutically acceptable base.   3. Compounds according to claim 1 wherein Y represents a group R3 C, compounds which are 1,3-dihydro-2H-pyrrolo [2,3b] pyridin-2-one of formula (1B): R4 wx xX 3 4 W X R3 R4   Embedded image in which R 1, R 2, R 3, R 4, W and X are as defined in claim 1, their isomers, enantiomers, diastereoisomers in the form of a compound of formula (I); pure or in the form of a mixture and their addition salts with a pharmaceutically acid or base acceptable.   4. A compound according to claim 1 which is 3-methyl-6-acetyloxazolo [4,5-b] pyridine.   2 (3H) -one. A compound according to claim 1 which is 6-acetyloxazolo [4,5-b] pyridin-2 (3H) -one,   as well as its addition salts with a pharmaceutically acceptable base.   6. A compound according to claim 1 which is 3-methyl-6-benzoyloxazolo [4,5-b] pyridin   2 (3H) -one. A compound according to claim 1 which is 6benzoyloxazolo [4,5-b] pyridin-2 (3H) -   one, as well as its addition salts with a pharmaceutically acceptable base.   8. A compound according to claim 1 which is 5-benzoyl-1-methyl-1,3dihydro-2H-   pyrrolo [2,3-b] pyridin-2-one. 9. Process for the preparation of compounds of formula (I) according to claim 1 characterized in that a compound of formula (II) is reacted as follows: Br y N IN   R'1 wherein Y is as defined in claim 1 and R'1 has the same definition as R1 in claim 1 with the proviso that R'1 can not represent a hydrogen atom, * in the presence of 1 , 2-bis (diphenylphosphino) ethane and palladium (II) acetate with an unsaturated ether of formula (III): Alk-O-CH = CH-R'2 (III) in which Alk represents an alkyl of 1 at 4 carbon atoms and R'2 represents a hydrogen or a linear or branched alkyl of 1 to 5 carbon atoms optionally substituted with a phenyl, naphthyl or cycloalkyl so as to obtain the compounds of formula (IV): R'i-CH-CY 21 there 0 1 (IV) WN N -Co R'1   in which R'1, R'2 and Y are as defined above.   in the presence of Pd (PO 3) 4 and lithium chloride with a compound of formula (V): 32 2722195 Alk3Sn CH = CH-R'2 (V) / CH3CH20   in which R'2 and Alk have the same definition as above so as to also access the compounds of formula (IV): R'CH - C. there is N 1 (IV)   ## STR4 ## in the presence of Zinc with a halogenated derivative of formula (VI): ## STR3 ## in which Hal represents a halogen atom and Ar is a phenyl or naphthyl group; substituted so as to obtain the compounds of formula (VII): Ar-CH2 "y WNv N N   R 1 in which Ar is as defined above and R 1 is as defined in claim 1, which is subjected to an oxidation reaction with an oxidizing agent such as for example chromium oxide or N-bromo succinimide for access to compounds of formula (VIII) ## STR2 ##   wherein Ar, Y and R1 are as previously defined with, in the case where N-   bromosuccinimide is used and where Y represents the CH 2 group, it is necessary to follow the oxidation reaction of a debromination step with Zinc, the compounds of formula IV and VIII being able, if desired: 33 2722195   in the case where R 1 or R '1 represent a benzyl group, be debenzylated in the presence of palladium on charcoal and hydrogen to access the compounds of formulas (IX) and (X) II R'-CH-C iy lo, ≥ (IX ) Ar "x 0 (X N N   in which Y, Ar and R'2 are as defined above: in the case where R1 or R'1 represent a cyanomethyl group to be decyanomethylated in the presence of platinum oxide and hydrogen to access these same compounds of formulas (IX) and (X), all of these compounds (IV), (VIII), (IX), (X) constituting the compounds of formula (X1): ## STR2 ## R2> - <XI) NOT N N   Wherein R 1, R 2 and Y are as previously defined, compounds (X 1) which may, if desired, be reduced by a reducing agent, such as sodium borohydride to the alcohol of formula (XII): OH - (xI) ) y N N   In which R 1, R 2 and Y are as defined above, the compounds of formulas (XI) and (XII) forming part of the invention and constituting the   compounds of formula (1) as defined in claim 1.   10. Pharmaceutical composition containing as active ingredient at least one of the compounds according to claim 1, in base or salified form, and in combination with 34 2722195   one or more non-toxic pharmaceutically inactive excipients or carriers acceptable.   11. Pharmaceutical composition according to claim 10, characterized in that the active ingredient is combined with caffeine in combination with one or more excipients or inert non-toxic pharmaceutically acceptable.   12. Pharmaceutical composition according to claims 10 and 11 useful for the treatment of pain.