EP0000306A1 - Substituted hexahydrobenzopyrano(3,2-c)pyridines, process for their preparation and medicines containing them - Google Patents

Abstract

The hexahydro benzopyrano [3,2-C] pyridines of the formula <IMAGE> in which R is hydrogen or a saturated or unsaturated, linear or branched lower alkyl radical, aralkyl, acyl, dialkylaminoalkyl, alkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl or aryl ; R1 is hydrogen, halogen or a lower alkoxy radical; R2 is hydrogen or halogen; R3 is hydrogen, halogen, lower alkyl, alkoxy, nitro, amino or forms naphthalene with R4 and the benzene ring; R4 is hydrogen, halogen or forms naphthalene with R3 and the benzene ring; R5 is hydrogen, a lower alkyl radical or arylalkyl, can be used as antidepressant drugs. They are prepared according to the following reaction scheme: <IMAGE>

Description

The present invention relates to substituted hexahydro benzopyrano [3,2-C] pyridines,

By the publication of A. Sammour and M. Alkady (Indian Journal of Chemistry vol. 12, p. 51-53), it is known to condense ketones, such as cyclohexanone on 3-carbethoxy coumarins to obtain 2-amino-2 , 3 cyclohexanchroman-4 α carbamido acetic acid lactam.

dans laquelle R est l'hydrogène ou un radical alcoyle inférieur saturé ou insaturé, linéaire ou ramifié, aralkyle, acyle, dialkylaminoalkyle, alkylcarbonyle, alcoxycarbonyle, halogénoalcoxycarbonyle ou aryle ; R₁ est l'hydrogène, un halogène ou un radical alcoxy inférieur ; R₂ est l'hydrogène ou un halogène ; R₃ est l'hydrogène, un halogène, un radical alcoyle inférieur, alcoxy, nitro, amino ou forme le naphtalène avec R₄ et le cycle benzénique ; R₄ est l'hydrogène, un halogène ou forme le naphtalène avec R₃ et le cycle benzénique ; R est l'hydrogène, un radical alcoyle inférieur ou arylalkyle.Hexahydro benzopyrano [3,2-C] pyridines have been found represented by the formula:

in which R is hydrogen or a saturated or unsaturated, linear or branched lower alkyl radical, aralkyl, acyl, dialkylaminoalkyl, alkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl or aryl; R ₁ is hydrogen, halogen or a lower alkoxy radical; R ₂ is hydrogen or halogen; R ₃ is hydrogen, halogen, lower alkyl, alkoxy, nitro, amino or forms naphthalene with R ₄ and the benzene ring; R ₄ is hydrogen, halogen or forms naphthalene with R ₃ and the benzene ring; R is hydrogen, a lower alkyl or arylalkyl radical.

The salts of these new compounds with mineral and organic acids acceptable in human therapy form part of the invention. These compounds have remarkable pharmacological properties which make them interesting in human medicine, in particular for the treatment of depressive states and mental disorders.

The polycyclic structure of the compounds suggests for a given compound the existence of several stereoisomers. Examination in thin layer chromatography of the reaction products reveals the existence of two stereoisomers A and B. Recrystallization from an adequate solvent is sufficient to isolate in the pure state the majority stereoisomer of the crude reaction product. The minority stereoisomer can be obtained by concentration of the mother liquors. It is possible to transform the minority stereoisomer by acid treatment into the majority stereoisomer.

The existence of the two stereoisomers A and B has been demonstrated for certain compounds. Consequently, two modes of synthesis of these compounds are used, making it possible to access either the A series or the B series.

The preparation methods are illustrated in the following sequence where R, R ₁ , R ₂₉ R ₃ , R ₄ and R ₅ have the meanings previously given.

The addition according to Michaêl of a piperidone-4 N - substituted on a coumarin ethyl carboxylate-3 and the opening of the resulting adduct by ammonium acetate generating ammonia or by a primary amine R ₅ -NH _{2 is} carried out by heating the compounds together at temperatures between 20 and 200 ° C in the presence or not of an alcoholic solvent for a time varying from 3 to 70 hours. Treatment with concentrated hydrochloric acid at the boil gives access to the Ⓐ series of compounds by dehydrating cyclization. On the other hand, treatment with concentrated cold hydrochloric acid allows the isolation of a B-ketone ester hydrolyzable by the potassium-alcohol pair in corresponding acid.

Decarboxylation by heating in sodium hydrogen carbonate makes it possible to isolate the compounds belonging to the Ⓑ series. The transition from the compounds of the Ⓑ series to the corresponding compounds of the Ⓐ series is achievable by treating with hot hydrochloric acid the said compound of the Ⓑ series.

According to a variant of the process, when R is hydrogen, it is possible to treat by catalytic hydrogenation a compound previously obtained in particular R = benzyl, then to replace the hydrogen with a saturated or unsaturated, linear or branched alkyl radical, aralkyl, dialkylaminoalkyl.

According to another variant, one can treat a compound where R is alkyl such as methyl or aralkyl such as benzyl with a chlorbcarbamate at boiling point in an aromatic solvent and thus isolate the compounds where R is an alkoxycarbonyl

In particular when R ₁ or R ₂ or R ₃ or R ₄ is a halogen, it is advantageous to treat a compound where, R = benzyl with benzyl chloroformate and to hydrolyze the carbonate obtained by hydrobromic acid in order to be able to access the compounds where R is H when R ₁ or R ₂ or R ₃ or R ₄ is a halogen. It is then convenient to replace this hydrogen with a saturated or unsaturated, linear or branched, aralkyl, dialkylaminoalkyl alkyl radical.

The halo coumarin ethyl carboxylate-3, synthetic intermediates such as fluero-6, chloro-5 and chloro-7 ethyl coumarin carboxylate-3 are new and as such fall within the scope of the invention.

The new hexahydro benzopyrano [3,2-C] pyridines substitutedea have excellent properties which make them drugs used in depressive states and peychic disorders This mood-modifying activity can be determined by standardized tests well known to specialists. Thus, the compounds of the invention have been found to be potent inhibitors of reserpine ptosis.

On the Swiss mouse, a PO compound is given simultaneously with IP reserpine at 5 mg / kg. The ptosis, rated according to Rubin B, and Coll. (J. Pharmacol. Exp. Therap., 1957, 120-125) at 1 h, 1 h 30 min and 2 h later allows the dose inhibiting the average ptosis to be determined by 50%. The effective doses 50 (ED.50) obtained for a few products and those obtained for standard substances well known to specialists, such as Imipramine [N- (3-dimethylaminopropyl) iminodibenzyl hydrochloride and Amitripthyline, are recorded in Table 1. [3-dimethylamino propylidene) -5 dibenzo (a, d) 1,4-cycloheptadiene hydrochloride].

Toxicity is evaluated on the Swiss mouse. The oral lethal doses 50 (LD 50) are given in the following table:

The medicament containing as active ingredient a compound of the invention, associated with an acceptable pharmaceutical vehicle or excipient, is presented in a form suitable for oral or parenteral administration.

The dosage forms are unitary such as tablets, capsules, capsules, ampoules ... These dosage forms contain from 0.05 to 100 mg of active substance and allow daily administration of 1 to 200 mg.

Examples - Composition of a 100 mg tablet, possibly coated:

Among the observations collected in a clinical trial of the drug containing the active ingredient of Example 5.A.

OBSERVATION N ° 1

Name: Dac ... Agnes, Age: 78 years old Sex: F Diagnosis: pre-senile depression. Associated treatments: NOZINAN - SUREPTIL. Dosage and duration of treatment: 5 mg / day for 30 days.

Activity:

Weight regain. Improved mood and social inclusion.

Tolerance

OBSERVATION N ° 2

Name: LAR ... Gineste Age: 58 years old Sex: M

Diagnostic :

Post-neuroleptic depression in a schizophrenic. Associated treatments: NOZINAN - ARTANE - GARDENAL. Dosage and duration of treatment: 20 mg / day for 30 days

Activity:

Weight gain. Improved mood and sleep. Decreased anxiety. Improvement of hypochondriac disorders.

Tolerance:

_{. R} .AS biological clinic

OBSERVATION N ° 3

Name: JAC ... Marcel Age-: 55 years old Sex: M Diagnosis:

Severe hypochondriac depressive syndrome Associated treatments: MEPRONIZINE. Dosage and duration of treatment: 10 mg / day for 20 days

Activity:

The patient is less concerned with his body. Reduction of washing rites. Improvement of social behavior.

Tolerance:

. R.A.S. biological clinic. organic

OBSERVATION N ° 4

Name: MIC ... Louise Age: 55 years Sex: F Diagnosis: Depressive relapse of melancholic type. Associated treatments: NOZINAN 25 mg. Dosage and duration of treatment: 25 mg / day for 45 days

Activity:

Improved mood. Less pessimistic attitude. Less frequent crying. Less pronounced sense of guilt.

Tolerance:

biological R.A.S.

OBSERVATION N ° 5

Name: TIL ... François Age: 47 years old Sex: M Diagnosis: Depressive syndrome in a melancholic type of ethyl. Associated treatments: Polyvitamin infusions - NOZINAN 50 mg -ARTANE 5. Dosage and duration of treatment: 5 mg / day for 30 days.

Activity:

Improved mood. Less frequent crying. Increased appetite.

Tolerance:

• . clinical: some dizziness and nausea;
• . biological: R.A.S.

OBSERVATION N ° 6

Name: BEL ... André Age: 45 years Sex: M Diagnosis: Hypochondriac delirium with anxiety. Associated treatments: ARTANE 10 mg - ANTASTHENE. Dosage and duration of treatment: 25 mg / day for 30 days

Activity:

Decrease in hypochondriac disorders. Sick less irritable and fearful.

Tolerance:

• . clinical: some dizziness;
• . organic: R.A.S.

Examples of the preparation of the compounds of the invention are given below.

EXAMPLE I

Acid lactam [amino-4a methyl-2 hexahydro-1,2,3,4,4a, 10a [10H] (benzopyrano) (3-.2-C) (pyridine)] -yl-10, acetic ( formula ¹ ), C ₁₅ H ₁₈ N ₂ 0 ₂ PM = 258.31

Chlorhydrate : PF_G = 250 - 252° C (éthanol) C.C.M. plaque alcaline 0,1 N gel de silice, éluant : méthanol-chloroforme - cyclohexane (1-3-5) : 1 spot. Par concentration des eaux-mères on obtient un produit B : PF_G ⁼ 232 - 234° C, IR C=O : 1680 cm^-1 Analyse :

Solubilized in 34 liters of anhydrous ethanol, 2.182 kg (10 moles) of ethyl coumarin-3 carboxylate, 1.144 kg (10 moles) of N-methyl 4-piperidone, 1.544 kg (20 moles) of acetate are added of ammonium hydroxide and the reaction medium is stirred for 72 hours at ambient temperature. The mixture is refluxed for one hour and about 25 liters of ethanol are evaporated. The resinous mass is taken up in 8.9 liters of concentrated hydrochloric acid and the mixture is brought to reflux for half an hour. The reaction medium is cooled by means of an ice bath and the mixture is brought to alkaline pH with 9 liters of NaOH 30 %. The solid obtained is drained, which is in the form of a cream product, melting at 228 ° C. It is recrystallized from 10 liters of isopropanol. 2.083 kg (yield 70%) of lactam of [amino-4a, 2-methyl-hexahydro-1, 2, 3, 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine) is obtained. )] - yl - 10 acetic (product A) PF _G = 224 ° C, IR ν _{C = O} : 1690 cm ^-1 Analysis:

Hydrochloride: mp _G = 250 - 252 ° C (ethanol) TLC alkaline plate 0.1 N silica gel, eluent: methanol-chloroform - cyclohexane (1-3-5): 1 spot. By concentration of the mother liquors, a product B is obtained: PF _G ⁼ 232 - 234 ° C, IR C = O: 1680 cm ^-1 Analysis:

Transition from B to A: One refluxed for one hour, 10 grams of B in 100 ml of concentrated hydrochloric acid. After cooling, it is basified with 30% NaOH, extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , the solvent is evaporated. A white solid is obtained whose physicochemical characteristics are identical in all respects to those of A.

EXAMPLE 2

Acid lactam [4-amino-2-benzyl hexahydro-1. 2. 3, 4. 4a. 10 a [10 H] (benzopvrano) (3,2-C) (pyridne)] -yl-10 acetyl (formula 2) C ₂₁ H ₂₂ N ₂ O ₂ 'PM = 334.42 Prepared according to Example 1, from 47.6 g (0.218 mole) of ethyl coumarfin-3 carboxylate, 33.4 g (0.218 mole) of N-benzyl 4-piperidone, 34.8 g (0.436 mole) of ammonium acetate , in 1.9 liters of anhydrous ethanol. 43.7 g (yield = 60%) of lactam of 4-amino acid, 2-benzyl-hexahydro-1,2,3,4,10 a [10H] (beasopyrano) (3,2-C) are obtained. pyridine] yl-1a acetic as a solid. White. MP _G = 192 ° C (ethanol) Hydrochloride: C ₂₁ H ₂₃ ClN ₂ O ₂ , PM = 370.87, PP _G = 254-255 ° C (methanol) IRν _{C = O} 168 ₀ cm ^-1

EXAMPLE 3

Eamino-4a acid lactam 2-methyl-6-methoxy-hexahydro-1, 2, 3 _. 4. 4a. 10a. [10 H] (benzopyrano) (3.2-C) (pyridine)] -yl-10 acetic (formula 3) C ₁₆ H ₂₀ N ₂ O ₃ , PM = 288.35 Prepared according to Example 1 from 93 g (0.375 mole) methoxy-8 carbethoxy-3 coumarin, 30.6 g (0.375 mole) N-methyl 4-piperidone, 41.4 g (0.75 mole) ammonium acetate and 3.6 liters alcolle. 48.6 g (yield = 45%) of lactam of [amino-4a-2-methyl-6-methoxy-1,2-hexahydro-1,2,3,4,4a, 10a, [10 H] (benzopyrano) acid are obtained (3, 2-C) (pyridine)] yl-10 acetic in the form of a white solid, PF _G = 258 ° C Hydrochloride, monohydrate: C ₁₆ H ₂₃ ClN ₂ O ₄ PM = 342.82 PF _G = 265 ° C ( methanol) IR ν _{C = 0} : 1680 cm ^-1 IRν _-OH

EXAMPLE 4

Acid lactam [amino-4a hexahydro-1, 2, 3. 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 (3,2- C) (pyridine)] -yl-10 acetic (formula 4) C ₁₄ H ₁₆ N ₂ O ₂ , PM = 244.30 Solubilized 34.3 g of the product of Example 2 in 320 ml of ethanol and door 5 hours at 60 ° C, under an initial hydrogen pressure of 60 kg, in the presence of 4.7 g of Pd / C 10%

After cooling, filtration of the catalyst and evaporation of the solvent, the lactam of the acid [amino-4a hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) is obtained. (pyridine)] yl-10 acetic in the form of a white solid, melting at 212 ° C. Weight obtained = 20 g (Yield: 80%) IR υ _{C = O} : 1680 cm ^-1 Hydrochloride C ₁₄ H ₁₇ ClN ₂ O ₂ , PM = 280.76 PF _G = 292-294 ° C (methanol) Analysis

EXAMPLE 5

Acid lactam [amino-4a chloro-8 methyl-2 hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl- 10 acetic (formula 5) C ₁₅ H ₁₇ ClN ₂ O ₂ PM = 292.77 5.1. Product A

Chlorhydrate : C₁₅H₁₈Cl₂N₂O₂ P.M. = 329,22 PF_G = 260 - 262° C (éthanol) Méthanesulfonate On solubilise 10 g du produit de l'exemple 5.1 dans la quantité nécessaire de chloroforme à 60° C. On refroidit à 41° C et on ajoute 2,5 ml d'acide méthane sulfonique en solution dans 7,5 ml de chloroforme. Par refroidissement on obtient un produit blanc que l'on essore et que l'on recristallise dans le méthanol PF_G = 265-267° C Analyse

Is refluxed for 8 hours 101.06 g (0.4 mole) of 6-chloro-coumarin-3 ethyl carboxylate, 45.76 g (0.4 mole) of N-methyl piperidone-4, 61.7 g (0.8 mole) of ammonium acetate and 12 liters of ethanol. The solvent is evaporated off and the residue is taken up in 320 ml of concentrated hydrochloric acid and the solution obtained is brought to reflux for half an hour. Then basified with 30% NaOH, cooling the medium with an ice bath. It is then diluted with H ₂ 0 and extracted with chloroform. After drying over Na ₂ SO ₄ and evaporation, 148 g of a beige solid are obtained. Recrystallized from the acetone-methanol mixture. 55 g of lactam are obtained from the acid [4-amino-8-chloro-2-methyl-hexahydro-1, 2, 3, 4, 4a, lOa [10 H] benzopyrano) (3,2-C) (pyridine)] yl-10 (Yield: 47%) PF _G = 245 ° C IRν _{C = O} : 1680 cm ^-1 Analysis

Hydrochloride: C ₁₅ H ₁₈ Cl ₂ N ₂ O ₂ PM = 329.22 PF _G = 260 - 262 ° C (ethanol) Methanesulfonate 10 g of the product of Example 5.1 are dissolved in the necessary quantity of chloroform at 60 ° C The mixture is cooled to 41 ° C. and 2.5 ml of methane sulphonic acid dissolved in 7.5 ml of chloroform are added. By cooling, a white product is obtained which is wrung out and which is recrystallized from methanol PF _G = 265-267 ° C. Analysis

5.2 Product B 5.2.1 .: Lactam of the ethyl monoester of acid [amino-4a, 8-chloro-2-methyl-hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3 , 2-C) (pyridine)] yl-1Q malonic C ₁₈ H ₂₁ ClN ₂ O ₄ PM = 364.827

80 g (0.31 mole) of ethyl chloro-6 coumarin-3 carboxylate are brought to reflux for 8 hours 35.8 g (0.31 mole) of N - methyl piperidone-4, 48.8 g (0 , 62 mol) of ammonium acetate and 1240 ml of ethanol. After evaporation, the residue is taken up in 600 ml of concentrated hydrochloric acid, when cold, and the mixture is stirred for 1 hour. It is adjusted to alkaline pH by the addition of 600 ml of 30% sodium hydroxide and 600 g of ice while maintaining the temperature below 25 ° C. It is extracted with 2 times 1 liter of chloroform. The organic phase is dried over sodium sulfate and evaporated. By recrystallization from ethanol of the residue obtained, 63 g of the expected product are isolated with a yield of 56% PF _G = 190 ° C

5.2.2. Acid lactam [amino-4a, chloro-8, 2-methyl hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] - yl-10 malonic.

To a suspension of 53 g (0.15 mole) of the product of Example 5.2.1 in 400 ml of ethanol is added a solution of 21 g (0.375 mole) of potassium hydroxide in 400 ml of water. It is then brought to reflux for 1 hour. Then cooled to 12 ° C and adjusted to pH 5-6 by addition of hydrochloric acid N. It is left to stand overnight and the precipitate is filtered off. 35 g of the expected product are obtained with a yield of 75.5%, mp = 210-215 ° C. with decomposition.

5.2.3. Product B

To a solution of 2.5 g (0.03 mole) of sodium bicarbonate in 100 ml of water, 10 g (0.03 mole) of product 5.2.2 is added. and the reflux is brought to 1 hour A precipitate is gradually formed. Then cool and spin. By recrystallization from ethyl alcohol 4.1 g of Product B PF _G = 246 ° C IRν _{C = O} 1700 cm ^-1 are obtained

EXAMPLE 6

Acid lactam [4-amino-8-bromo-2-methylhexahydro1,2,3,4,4a, 10a, [10 H] (bezopyrano) (3,2-C) (pyridine)] -yi-10 acetic (formula 6) C ₁₅ H ₁₇ BrN ₂ O ₂ PM = 337.23 prepared according to Example 5.1 from 47 g (0.158 mole) of 6-bromo-coumarin-3 ethyl carboxylate, 18.1 g (0.158 mole) of N-methyl piperidone-4, 24.4 g (0.316 mole) of ammonium acetate and 3 liters of ethanol. After recrystallization from acetone-ethanol, 26 g of lactam of [amino-4a-bromo-8-methyl-2-hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) are obtained. (3,2-C) (pyridine)] -yl-10 acetic. (Yield = 49%) PF _G = 237 - 239 ° C 1690 cm ^-1 IR ν _{C = O} : 1690 cm ^-1 Analysis:

EXAMPLE 7

Lactam of amino-4a-dimethyl-2, 8 hexahydro-1, 2, 3. 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C (pyridine) yl-10 acetic (formula 7) C ₁₆ H ₂₀ N ₂ O ₂ PM = 272.3 ⁴ Prepared according to Example 5.1 from 60 g (0.258 mole) of methyl 6-coumarin-3 ethyl carboxylate, 29.6 g (0.258 mole ) of N-methyl piperidone-4, 39.9 g (0.516 mol) of ammonium acetate and 2 liters of ethanol. After recrystallization from acetone-ethanol, 39.3 g of lactam are obtained. acid [amino-4a-dimethyl-2,8 hexahydro-1, 2, 3, 4, 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] yl- ¹ acetic (yield ₌ 56 %) PF _G = 241 - 243 ° C IR ν _{C = O} : 1680 cm ^-1

EXAMPLE 8

Acid lactam [amino-4a fluoro-8 methyl-2 hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl- 10 acetic (formula 9) C ₁₅ H ₁₇ FN ₂ O ₂ PM = 276.31

8.1 -Fluoro-6 coumarin-3 ethyl carboxylate (formula 8) C ₁₂ H ₉ FO ₄ PM = 236.19

• 3 H à 1,4 (triplet)
• 2 H à 4,35 (quartet)
• 3 H de 7,2 à 7,6 (massif)
• 1 H à 8,5 (singulet)

77 g (0.55 mole) of 4-fluoro-2-hydroxy-benzaldehyde, 96.6 g (0.604 mole) of ethyl malonate, 220 ml of ethanol, 2.9 ml of piperidine and 0.3 ml of glacial acetic acid. It is poured into 600 ml of giaceae water. Filter and recrystallize from ethanol the 6-fluoro-coumarin-3 ethyl carboxylate, PF _G = 108 ° C, IR ν _{C = O} : 1710 cm ^-1 (lactone), 1730 cm ^-1 (ester) NMR (CDCl ₃ ) δ ppm compared to TMS

• 3 Hrs at 1.4 (triplet)
• 2 H at 4.35 (quartet)
• 3 H from 7.2 to 7.6 (massive)
• 1 H at 8.5 (singlet)

8.2 - Lactam of 4-amino-8-fluoro-2-methylhexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl -10 acetic (formula 9) G ₁₅ H ₁₇ FN ₂ O ₂ PM = 276.31

Prepared according to Example 5.1 from 80 g (0.339 mole) of fluoro-6 coumarin-3 ethyl carboxylate, 38.8 g (0.339 mole) of N-methyl piperidone-4, 52.4 g (0.678 mole ) ammonium acetate and 2 liters of ethanol. After recrystallization from isopropanol, 37.5 g of lactam from [amino-4a-fluoro-8-methyl-2-hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) are obtained. (3,2-C) (pyridine)] -yl-10 acetic (yield = 40%) PF _G = 226-228 ° C IRν _{C = O} : 1680 cm ^-1

EXAMPLE 9

Acid lactam [amino-4a acetvl-2 hexahydro-1, 2, 4, 4a, 10a, [10 H] (benzopyano) (3.2-C (pyridine)] - yl-IO acetic (formula 10) C ₁₆ H ₁₈ N ₂ O ₃ PM = 286.32 12.2 g (0.05 mole) of the product of Example 4 are dissolved. in 200 ml of chloroform. 14 ml (0.1 mole) of triethylamine are added and 4.3 ml (0.06 mole) of acetyl chloride are added dropwise at 20 ° C. The mixture is left stirring for 6 hours at room temperature. Washed with 400 ml of water, dried over sulphate, evaporated and recrystallized from a methanol-chloroform mixture. 7.1 g of lactam of [amino-4a-2-acetylhexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine) are obtained. ] -yl -10 acetic (yield = 50%) PF _G = 284 - 287 ° C IR ν _{C = O} : 1680 cm ^-1

EXAMPLE 10

Acid lactam [amino-7a methyl-10 hexahydro-7a, 8, 9, 10. 11, 11a, [12 H] (benzo) (f) (benzopyrano) (3,2-C) pyridine] -yl -10 acetic (formula ¹¹ ) C ₁₉ H ₂₀ N ₂ O ₂ , PM = 308.39

Prepared according to Example 5.1 from 70 g (0.261 mole) of benzo (f) ethyl coumarin-3 carboxylate, 30 g (0.261 mole) of N-methyl piperidone-4, 40.4 g (0.522 mole) ammonium acetate, and 1500 ml of ethanol. After recrystallization from an ethyl acetate-methanol mixture, 44.2 g of lactam of [amino-7a-methyl 10-hexahydro-7a, 8, 9, 10, 11, 11a, [12 H] are obtained ( benzo) (f) (benzopyrano) (3,2-C) pyridine] yl-10 (Yield = 55%) PF _G = ₂₆ 3 - 265 ° C IR ν _{C = O} : 1680 _cm - ¹

EXAMPLE 11

Lactam of the acid [amino-4a n-propyl-2 hexahydro-1,2, 3, 4. 4a. 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl -10 acetic (formula 12) C ₁₇ H ₂₂ N ₂ O ₂ , PM = 286.38 It is brought to 10 hours at 80 ° C a solution of 15 g (0.061 mole) of the product of Example 4 in 300 ml of dimethylformamide with 7.9 g (0.064 mole) of propyl bromide and 9.1 g (0.66 mole) of potassium carbonate. The insoluble material is filtered, the solvent is evaporated under vacuum. We purify in ethyl acetate. 9.9 g of lactam are obtained from the acid [amino-4a n-propyl-2 hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) ( pyridine)] yl-10 acetic (yield = 56.7%) PF _G = 182 - 184 ° C IRν _{C = O} : 1680 cm ^-1

EXAMPLE 12

Acid lactam [amino-4a (phenylpropyl) -2 hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 13) C ₂₃ H ₂₆ N ₂ O ₂ PM = 36 ² , 4 ⁷ Prepared according to example 11 from the product of example 4 (15 g, 0.061 mole), 12.8 g (0.064 mole ) of phenylpropyl bromide, 12.1 g of lactam from [amino-4a (phenylpropyl) -2 hexahydro-1, 2, 3, 4, 4a, 10a [10 H] (benzopyrano) are obtained ( 3,2-C) (pyridine)] yl-10 acetic (yield = 54.7%) PF _G = 154 - 156 ° C (ethyl acetate) IR ν _{C = O} 1690 cm ^-1

EXAMPLE 13

Lactam of 2-amino-4a-dimethylaminopropyl-hexahydro-1 acid _. 2. 3, 4, 4a, 10, H] (benzopyrano) (3.2-C) (pyridine)] -yl-10 acetic (formula 14) C ₁₉ H ₂₇ N ₃ O ₂ PM = 329.44 Prepared according to Example 11 from the product of Example 4, 12.1 g (0.049 mole), 6.3 g (0.0516 mole) of 2-chloro-2-dimethylamino propane. 7.6 g of lactam are obtained from the acid [amino-4a 2-dimethylaminopropyl-hexahydro-1, 2, 3, 4, 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] yl -10 acetic. (Yield = 47%) PF _G = 149 - 150 ° C (ethyl acetate), IR ν _{C = O} : 1680 cm ^-1

EXAMPLE14

Acid lactam [amino-4a chloro-7 methyl-2 hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl- 10 acetic (formula 16) C ₁₅ H ₁₇ ClN ₂ O ₂ PM = 292.77

14.1 Chloro-7 coumarihe-3 ethyl carboxylate (formula 15) C ₁₂ H ₉ ClO ₄ PM = 252.5

• 3 H à 1,3 (triplet)
• 2 H à 4,35 (quartet)
• 3 H de 7,1 à 7,6 (massif)
• 1 H à 8,45 singulet

11.2 g (0.071 mole) of 4-chloro-2-hydroxy-benzaldehyde, 12.5 g (0.072 mole) of ethyl malonate, 30 ml of ethanol, 0.4 ml of piperidine are refluxed for 5 hours. and 0.1 ml of acetic acid. The reaction medium is cooled to 0 ° C. and the precipitate formed is filtered off. Washed with hexane and dried ethyl chloro-7 coumarin-3 carboxylate obtained PF _G = 122 - 3 ° C, IRν _{C = O} : 1760 cm ^-1 (lactone and ester) NMR (CDCl ₃ ) 5p .pm compared to TMS

• 3 Hrs to 1.3 (triplet)
• 2 H at 4.35 (quartet)
• 3 H from 7.1 to 7.6 (massive)
• 1 H at 8.45 singlet

14.2 Acid lactam [amino-4a, 7-chloro-2-methyl-hexahydro-1, 2, 3, 4, 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl -10 acetic

Prepared according to Example 5.1 from 6.5 g (0.026 mole) of 7-chloro-coumarin-3 ethyl carboxylate, 2.9 g (0.026 mole) of N-methylpiperidone-4, 4 g (0.052 mole) of ammonium acetate and 150 ml of ethanol. After recrystallization from ethanol, 3 g of the expected lactam are obtained (yield = 40%). PF _{G =} 256-258 ° C IRν _{C = O} : 1675 cm ^-1

EXAMPLE 15

Acid lactam [4-amino-8-nitro-2-methylhexahydro -1, 2, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] - yl -10 acetic (formula 17) C ₁₅ H ₁₇ N ₃ O ₄ PM = 3 ⁰³ , 3 ² Prepare according to Example 5.1 from 70 g (0.27 mole) of 6-nitro-coumarin-3 ethyl carboxylate, 30, 6 g (0.27 mole) of N-methyl-piperidone-4, 41.3 g (0.54 mole) of ammonium acetate and 1.5 liters of ethanol. We get after re crystallization from ethanol 38.8 ^g lactam of the acid [amino-4a, nitro-8 methyl - 2 hexahydro - 1, 2, 3, 4, 4a, 10a [10 H] (benzopyrano) (3.2 -C) (pyridine)] -yl-10 acetic (yield = 47.4%) PF _G = 240-242 ° C IRν _{C = O} : 1680 cm ^-1

EXAMPLE 16

Acid lactam [diamino-4a, 8, 2-methylhexahydro-1. 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) 3,2-C) (pyridine)] yl-10 acetic (formula 18) C ₁₅ H ₁₉ N ₃ O ₂ PM ⁼ 273.34 On ice 19.9 g (0.065 mole) of the product of Example 15 in an autoclave with 300 ml of ethanol and 1 g of Pd / C at 10%. The autoclave is charged under an initial hydrogen pressure of 60 kg / cm ² and left for 3 hours at room temperature, with stirring, then 2 hours at 50 ° C. After cooling, the palladium is filtered, evaporated and the product is recrystallized. solid obtained in the ethyl acetate-ethanol mixture, 8.1 g of lactam of the acid [diamino-4a, 8, methyl-2 hexahydro-1, 2, 3, 4, 4a, 10a, are obtained [10 H] (benzopyrano) (3,2-C) (pyridine)] - yl-10 acetic (yield = 45.6%) PF _G = 230-232 ° C IRν _{C = O} : 1680 cm ^-1

EXAMPLE 17

Acid lactam (6,8-dichloro, 4-amino, 2-methyl, 1,2-hexahydro, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) 3,2-C) (pyridine) ] -yl-10 acetic (formula 19) C ₁₅ H ₁₆ Cl ₂ N ₂ O ₂ PM = 327.22

Prepared according to Example 5.1 from 17.8 g (0.062 mole) of dichloro-6,8, ethyl coumarin-3 carboxylate, 7.1 g (0.062 mole) of N-methyl-piperidone-4,9 , 5 g (0.124 mol) of ammonium acetate and 800 ml of ethanol. After recrystallization from ethyl acetate, 7.7 g of lactam from [dichloro-6, 8, amino-4a, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H ] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (yield = 38%) PF _G = 212 - 216 ° C IRν _{C = O} : 168 ₀ cm ^-1

EXAMPLE 18

Lactam of amino acid 4a, methoxy-8. methyl-2, hexahydro-1, 2, 3, 4 _,. 4a, 10a, [10 H] (benzopyrano) 3,2-C) (pyridine)] - yl-10 acetic (formula 20) C ₁₆ H ₂₀ N ₂ O ₃ PM = 288.35 Prepared according to Example 5.1 to from 35.5 g (0.143 mole) of 6-methoxy-3-coumarin ethyl carboxylate, 16.4 g (0.143 mole) of N-methyl-piperidone-4, 22.1 g (0.286 mole) of acetate of ammonium and 400 ml of ethanol. Is obtained by recrystallization from isopropanol 26 g of lactam, acid [amino-4a, methoxy-8, methyl-2, hexahydro-1, 2, 3, 4, 4a, lOa, [10 H] (benzopyrano ) (3,2-C) (pyridine)] -yl-10 acetic (yield = 63%) PF _G = 210 - 212 ° C IRν _{C = O} : 1680 cm ^-1

EXAMPLE 19

Acid lactam [4-amino-chloro-9, methyl-2, hexahydro -1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] - yl-10 acetic (formula 22) C ₁₅ H ₁₇ Cl ₂ N ₂ O ₂ PM = 292.77

19.1 5-Chloro-3 coumarin ethyl carboxylate (formula 21) C ₁₂ H ₉ ClO ₄ PM = 252.5

• 3H à 1,45 (triplet)
• 2H à 4,5 (quartet)
• 3H de 7,1 à 7,7 (massif)
• 1H à 8,8 (singulet)

The mixture is brought to reflux for 5 hours 15 g (0.0958 mole) of 2-chloro, 6-hydroxy, benzaldehyde, 16.7 g (0.105 mole) of ethyl malonate, 40 ml of ethanol, 0.6 ml of piperidine and 0.1 ml of acetic acid. After cooling, the product obtained is drained. It is dried and 14 g of chloro-5, coumarin-3 ethyl carboxylate are obtained (yield ₌ 58%) PF _G = 142-144 ° C IR ν _{C = O} : 1720 cm ^-1 ν _{C = O} : 1760 cm ^-1 NMR (CDCl ₃ ) δ ppm compared to TMS

• 3H to 1.45 (triplet)
• 2H to 4.5 (quartet)
• 3H from 7.1 to 7.7 (massive)
• 1H to 8.8 (singlet)

19.2 Acid lactam [amino-4a, chloro-9, methyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] benzoprano) (3,2-C) (pyridine)] -yl-10 acetic (formula 22) C ₁₅ H ₁₇ Cl ₂ N ₂ O ₂ PM = 292.77

Prepared according to Example 5.1 from 13.6 g (0.054 mole) of 5-chloro-coumarin-3 ethyl carboxylate, 6.1 g (0.054 mole) of N-methyl piperidone-4, 8.3 g ( 0.108 mol) of ammonium acetate and 250 ml of ethanol. After recrystallization from ethanol, 6.7 g of lactam of the acid [amino-4a, chloro-9, methyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] are obtained ( benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic. (Yield = 42.4%) PF _G = 241-243 ° C IR√ _{C = O} : 1680 cm ^-1

EXAMPLE 20

Lactam of acid [amino-4a, chloro-6, methyl-2 hexahydro-1, 2, 3 4, 4a, 10a, [10 H] (benzopyrano (3.2-C) pyridine) -yl -10 acetic (formula 23) C ₁₅ H ₁₇ ClN ₂ O ₂ PM = 292.77 Prepared according to Example 5.1 from 12 g (0.048 mole) of chloro-8, coumarin-3, ethyl carboxylate, 5.5 g (0.048 mole) of N-methylpiperidone-4, 7.4 g (0.096 mole) of ammonium acetate and 140 ml of ethanol. 6 g of lactam of mino-4a acid are obtained after recrystallization from isopropanol, chloro-6, methyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 h] (benzopyrano) (3,2-C) (pyridine)] - ^yl-10 acetic (yield = 43% ) PF _G = 206-208 ° C IR√ _{C = O} : 1680 cm ^-1

EXAMPLE 21

Préparé selon l'exemple 11 à partir de g (0,05 mole) du produit de l'exemple 4, 9,35 g (0,055 mole) d'iodure d'isopropyle.On obtient 7,1 g de lactame de l'acide [amino -4a, isopropyl-2, hexahydro-1, 2, 3, 4, 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acétique (Rdt = 49,5 %) PF_G = 214-216° C IR√_C=O : 1680 cm^-1

Acid lactam [amino-4a, isopropyl-2, hexahdro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 24) C ₁₇ H ₂₂ N ₂ O ₂ PM = 286.37

Prepared according to Example 11 from g (0.05 mole) of the product of Example 4, 9.35 g (0.055 mole) of isopropyl iodide. 7.1 g of lactam are obtained. acid [amino -4a, isopropyl-2, hexahydro-1, 2, 3, 4, 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (Yield = 49 , 5%) PF _G = 214-216 ° C IR√ _{C = O} : 1680 cm ^-1

EXAMPLE 22 _-

Acid lactam [amino-4, ethoxalyl-2, hexahydro-1, 2, 3, 4. 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 25) C ₁₈ H ₂₀ N ₂ O5 PM = 344.37 To a solution of 17.1 g (0.07 mole) of the product of Example 4, 19.6 ml of triethylamine in 280 ml of chloroform, while keeping the temperature below 35 ° C., a solution of 11.4 g (0.084 mol) of ethoxalyl chloride in 40 ml of chloroform is added. It is left for 6 hours at room temperature. After washing with water, the organic phase is dried over Na ₂ SO ₄ , the solvent is then evaporated off and the residue is recrystallized from methanol. 13.4 g of lactam are obtained from the acid [amino-4a, ethoxalyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) ( pyridine)] -yl-10 acetic (yield = 55.5%) PF _G = 210-212 ° C IR _{√C = O} : 1680 cm ^-1 (lactam): 1730 cm ^-1 (ester)

EXAMPLE 23

4-amino acid lactam ethocarbonylmethyl-2, hexahdro-1, 2 3 4 4a 10a, [10 H] benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 26) C ₁₈ H ₂₂ N ₂ O ₄ MW = 330.39 Prepared according to Example 11 from 15 g (0.061 mole) of the product of Example 4 and 7.2 ml (0.064 mole) of ethyl bromacetate. We obtain after recrystallization in ethanol 12 g of lactam of acid [amino-4a, ethoxycarbonylmethyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) ( pyridine)] -yl-10 acetic (yield = 59.5%) PF _G = 198 - 200 ° C IR√ _{C = O} : 1680 cm ^-1 (lactam): 1720 cm ^-1 (ester)

EXAMPLE 24

Acid lactam [amino-4a - allyl-2, hexahydro-1, 2. 3, 4. 4a. 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 27) C ₁₇ H ₂₀ N ₂ O ₂ PM = 284.36 Prepared according to Example 11 from 15 g (0.061 mole) of the product of Example 4 and 8.1 g (0.067 mole) of allyl bromide. After recrystallization from isopropanol 4.2 g of lactam of the acid [amino-4a, allyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) are obtained. (3,2-C) (pyridine)] -yl-10 acetic (yield = 25%) PF _G = 206 - 208 ° C IR _{√C = O} : 1680 cm ^-1

EXAMPLE 25

Acid lactam [amino-4a, cinnamoyl-2, hexahydro-1, 2, 3. 4. 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl -10 acetigue (formula 28) C ₂₃ H ₂₁ N ₂ O ₃ PM = 374.943 Prepared according to Example 9 from 8.5 g (0.035 mole) of the product of Example 4 and 7 g (0.042 mole) of chloride cinnamoyle. After recrystallization from ethanol, 7.4 g of lactam of the acid [amino-4a, cinnamoyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) are obtained (3 , 2-C) (pyridine)] -yl-10 acetic (yield = 56.5%) PF _G = 248 - 250 ° C IR √ _{C = O} : 1680 cm ^-1

EXAMPLE 26

Acid lactam [amino-4a, benzyl-2, chloro-8, hexahydro -1 _. 2. 3, 4. 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 29) C ₂₁ H ₂₁ ClN ₂ O ₂ PM = 368.88 Prepared according to Example 5.1 from 292 g (1.15 mole) of chloro-6, coumarin-3, ethyl carboxylate, 219 g (1.15 mole) of N-benzyl-piperidone-4, 178 g (2.31 mole) of ammonium acetate and 4 liters of ethanol. After recrystallization from ethanol, 220.7 g of lactam of the acid [amino-4a, 2-benzyl, chloro-8, hexahydro-1, 2, 3, 4, 4a, 10a [10 H] are obtained (benzopyrano ) (3,2-C) (pyridine)] -yl-10 acetic (yield = 52%) PF _G = 137-139 ° C IR _{√C = O} : 1680 cm ^-1

EXAMPLE 27

Acid lactam [amino-4a, chloro-8, ethoxycarbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 30) C ₁₇ H ₁₉ ClN ₂ O ₄ PM = 350.81 A solution of 21.7 g (0.2 mole) of ethyl chloroformate in 20 ml of benzene is brought to reflux. A solution of 22 g (0.06 mole) of the product of Example 26 in 150 ml of benzene is then added dropwise. The reflux is continued for 6 hours. After cooling, washing is carried out with water and then with 3N HCl and with water. After drying over Na ₂ SO _4, the solvents are evaporated. The residue is recrystallized from methanol. 16 g of lactam are obtained from the acid [amino-4a, chloro-8, ethoxycarbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C ) (pyridine)] -yl-10 acetic (yield = 76%) PF _G = 226 - 228 ° C IR√ _{C = O} : 168 ₀ cm ^-1

EXAMPLE 28

Acid lactam [amino-4a, chloro-8, methoxycarbonyl-2, hexahydro-1, 2. 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine) - yl-10 acetic (formula 31) C ₁₆ H ₁₇ ClN ₂ O ₄ PM = 336.77 Prepared according to Example 27 from 22 g (0.06 mole) of the product of Example 26 and 21.7 g (0.2 mole) of methyl chloroformate. After recrystallization from ethanol, 8.3 g of lactam from [amino-4a, chloro-8, 2-methoxycarbonyl, 1,2-hexahydro-1,2,3,4,4a, 10a, [10 H] benzopyrano are obtained. ) (3,2-C) (pyridine)] - yl-10 acetic (yield = 41%) PF _{G =} 165 - 167 ° C IR√ _{C = O} : 1680 cm ^-1

EXAMPLE 29

Acid lactam [amino-4a, chloro-8, butoxycarbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 32) C ₁₉ H ₂₃ ClN ₂ O ₄ PM = 378.85 Prepared according to Example 27 from 17 g (0.046 mole) of the product of Example 26 and 21.2 g ( 0.155 mol) of n-butyl chloroformate. After recrystallization from ethyl acetate, 10.2 g of lactam are obtained from the acid [amino -4a, chloro-8, butoxycarbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (yield ₌ 58.5%) PF _G = 144-145 ° C IR _{√C = O} : 1680 cm ^-1

EXAMPLE 30

Acid lactam [amino-4a, chloro-8, (2,2,2-trifluoroethoxy) carbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H7 (benzopyrano) (3 , 2-C) (pyridine)] - yl-10 acetic (formula 33) C ₁₇ H ₁₆ ClF ₃ N ₂ O ₄ PM = 404.78 Prepared according to Example 27 from 5.9 g (0.02 mole) of the product of Example 5.1 and 13.2 g (0.066 mole) of trifluoroethyl chloroformate. After recrystallization, yours in isopropanol 3 g of lactam of the acid [amino -4a, chloro-8 (2,2,2-trifluoroethoxy) carbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [ 10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (yield = 37%) PF _G = 194-196 ° C IR _{√C = O} : 1690 cm ^-1 (lactam): 1720 cm ^-1 (carbamate)

EXAMPLE 31

Acid lactam [amino-4a, chloro-8 (ethyl-2, hexyloxy) carbonyl-2 hexhydro-1, 2, 3 4, 4a, 10a 10 H] (benzopyran) (3,2-C) (pyridine)] - yl-10 acetic (formula 34) C ₂₃ H ₃₁ ClN ₂ O ₄ PH = 434.96 Prepared according to Example 27 from 12.2 g (0.0416 mole) of the product of Example 5.1 and 26.7 g (0.139 mole) of 2-ethylhexyl chloroformate. After recrystallization from acetone, 8.1 g of lactam from [amino-4a, chloro-8 (2-ethylhexyloxy) carbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, are obtained. [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (yield = 44.8%) PF _G = 140-142 ° C IR√ _{C = O} : 1690 cm ^-1 ( lactam): 1710 cm ^-1 (carbamate)

EXAMPLE 32

Acid lactam [amino-4a, chloro-8, cyclohexyloxycarbonyl-2, hexahydro-1, 2, 3, 4 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] - yl-10 acetic (formula 35) O ₂₁ H ₂₅ ClN ₂ O ₄ PM = 404.89 Prepared according to example 27 from 12.2 g (0.0416 mole) of the product of example 5.1 and 22.6 g (0.139 mole) of carclohexyl chloroformate. After recrystallization from ethanol, 7.2 g of lactam of the acid [amino -4a, chloro-8, cyclohexyloxycarbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] are obtained ( benxopyrano) (3,2-C) (pyridine)] - yl-10 acetic (yield = 42.7%) PF _G = 222-224 ° C IR√ _{C = O} : 1690cm ^-1

EXAMPLE 33

Acid lactam [amino-4a, chloro-8-, benzyloxycarbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine) ] -yl-10 acetic acid (formula 36) C ₂₂ H ₂₁ ClN ₂ O ₄ PM = 412.86 Prepared according to example 27 starting from 36.9 g (0.1 mole) of the product of example 26 and 56.5 g (0.33 mole) of benzyl chloroformate. Obtained after recrystallization from ethyl acetate. 19 g of lactam of acid [amino-4a, chloro-8, benzyloxycarbonyl-2, hexahydro-1, 2, 3, 4, 4a, lOa, [10 H ] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (yield = 46%) PF _G = 228 - 230 ° C IR√ _{C = O} : 1680 cm ^-1 (lactam): 1720 cm ^-1 (carbamate)

EXAMPLE 34

Acid lactam [amino-4a, chloro-8, hexahydro-1,2,3,4,4a. 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] - yl-10 acetic (formula 37) C ₁₄ H ₁₅ ClN ₂ O ₂ PM = 278.73 Solubilized 27.8 g (0 0.06 mole) of the product of Example 33 in 400 cm ³ of chloroform and bubbled hydrobromic acid (obtained by heating at 50 ° C of a 62% aqueous solution) for 30 minutes, at ambient temperature. A precipitate forms. It is filtered, it is dissolved in 31. of water and it is basified with 10% NaOH. By cooling, a precipitate is obtained. It is wrung, dried, and recrystallized from methanol. 10 g of lactam are obtained from the acid [amino-4a, chloro-8, hexahydro -1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine) ] -yl-10 acetic (yield = 59.8%) PF _G = 252 - 254 ° C IR√ _{C = O} : 1680 cm ^-1

EXAMPLE 35

Acid lactam [amino-4a, chloro-8, phenyl-2, hexahydro-1, 2, 3. 4. 4a. 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] - yl-10 acetic (formula 38) C ₂₀ H ₁₉ ClN ₂ O ₂ PM = 354.83 Prepared according to Example 5.1 from 16.9 g (0.067 mole) of chloro-6, ethyl coumarin-3 carboxylate, 11.7 g (0.067 mole) of N-phenyl piperidone-4, 10.5 g (0.134 mole) of acetate d ammonium and 480 ml of ethanol. By recrystallization from methanol, 9.5 g of lactam are obtained from the acid [amino-4a, chloro-8, phenyl-2, hexahydo-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) ( 3,2-C) (pyridine)] -yl-10 acetic (yield = 40%) PF _G = 220-222 ° C IRν _{C = O} : 1680 cm ^-1

EXAMPLE 36

Acid lactam [chloro-8, methyl-2, methylamino-4a, hexahydro-1, 2, 3. 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 39) C ₁₆ H ₁₉ ClN ₂ O ₂ PM = 306.79 33g (0.125 mol) of ethyl chloro-3 coumarin-3 carboxylate, 14.3 g of N are placed in an autoclave -methyl, piperidone-4, 24 g of methylamine (0.25 mole) in 33% solution in ethanol and 550 ml of ethanol. It is brought to 7 hours at 70-80 ° C. After cooling, treatment is carried out as in Example 5.1. After recrystallization from ethanol, 13 g of lactam of [chloro-8, 2-methyl-methylamino-4a, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) acid are obtained ( 3,2-C) (pyridine)] - yl-10 acetic (yield = 34%) PF _G = 158 - 160 ° C IRν _{C = O} : 1680 cm ^-1

EXAMPLE 37 Acid lactam [methyl-2, methylamino-4a, hexahydro-1,2,3,4,4,4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 40) C ₁₆ H ₂₀ N ₂ O ₂ PM = 272.34

Prepared according to Example 36 from 27.3 g (0.125 mole) of ethyl coumarin-3 carboxylate, 14.3 g of N-methyl, piperidone-4, 24 g (0.25 mole) of methylamine as 33% solution in ethanol and 500 ml of ethanol. A crude base is obtained which it has not been possible to recrystallize: 25 g
citrate C ₂₂ H ₂₈ N ₂ O ₉ PM = 464.48

The 25 g of crude product are dissolved in 120 ml of acetone and a solution of 19.2 g (0.1 mole) of citric acid in 200 ml of acetone is added under cooling. The product obtained is drained and recrystallized from ethanol. 14 g of lactam citrate of [methyl-2, methylamino-4a, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) are obtained ( pyridine)] -yl-10 acetic (yield = 24% PF _G = 180 - 182 ° C IR C = O: 1690 cm ^-1

EXAMPLE 38 Acid lactam [benzylamino-4a, methyl-2, chloro-8 hexahydro-1,2, 3, 4 _. 4a, 10a [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 41) C ₂₂ H ₂₃ ClN ₂ O ₂ PM = 382.88

Prepared according to Example 5.1 from 25.2 g (0.1 mole) of chloro-6, ethyl coumarin-3 carboxylate, 11.5 g (O, 1 mole) of N-methyl piperidone-4, 21.4 g (0.2 mole) of benzylamine and 500 ml of ethanol. After recrystallization from diisopropyl ether, 9.5 g of lactam of the acid are obtained [benzylamino-4a, chloro-8, methyl-2, hexahydro-1, 2, 3, 4, 4a, 14a, [10 H] (benzopyrano ) (3,2-C) (pyridine)] -yl-10 acetic (yield = 25%)
PF _G = 115 - 117 ° C IR C = O: 1690 cm ^-1

EXAMPLE 39

Eamino-4a acid lactam, chloro-8, (2,2,2,2-trichloroethoxy) carbonyl-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3 , 2-C) (pyridine)] -yl-10 acetic (formula ⁴² ) C ₁₇ H ₁₆ Cl ₄ N ₂ O ₄ PM = 454.14 Prepared according to Example 27 from 12.2 g (0.0416 mole) of the product of Example 5.1, and 29.5 g (0.139 mole) of trichloroethyl chloroformate. By recrystallization from ethyl acetate, 8.4 g of lactam of the acid [amino-4a, chloro-8, (2,2-trichloro-2,2,2, ethoxy) carbonyl-2, hexahydro-1 are obtained, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (yield = 44.5%) PF _C = 223 - 225 ° C IR C = O: 1695 cm ^-1 (lactam): 1720 cm ^-1 (carbamate)

EXAMPLE 40

Acid lactam [amino-4a, benzoyl-2, hexahydro-1, 2, 3. 4. 4a. lOa. [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 43) C ₂₁ H ₂₀ N ₂ O ₃ PM = 348.40 Prepared according to Example 9 from 8 , 5 g (0.035 mole) of the product of Example 4 and 5.9 g (0.042 mole) of benzoyl chloride. By recrystallization from ethanol, 8.2 g of lactam of the acid [amino-4a, benzoyl-2, hexahydro -1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) are obtained (3 , 2-C) (pyridine)] -yl-10 acetic (yield = 67%) PF _G = 253 - 255 ° C CRI = O: 1680 cm ^-1

EXAMPLE 41

Acid lactam [amino-4a, pivalovl-2, hexahvdro-1,2,3,4,4a, 10a, [10 H] (benzoprano) (3,2-C) (pyridine) -yl-10 acetic (formula 44) C ₁₉ H ₂₄ N ₂ O ₃ PM = 328.41 Prepared according to Example 9 from 8.5 g (0.035 mole) of the product of Example 4 and 5.1 g (0.042 mole) of pivaloyl chloride . After recrystallization from isopropanol, 6.6 g of lactam of the acid [amino-4a, pivaloyl-2, heaahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) are obtained (3 , 2-C) (pyridine)] -yl-10 acetic (yield = 57.5%) PF _G = 253 - 255 ° C CRI = 0: 1690 cm ^-1

EXAMPLE 42

Acid lactam [amino-4a, acetyl-2, chloro-8, hexahydro-1, 2. 3. 4, 4a. 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (formula 45). C ₁₆ H ₁₇ ClN ₂ O ₃ PM = 320.77 Prepared according to Example 9 from 4.5 g (0.016 mole) of the product of Example 34 and 2 g (0.026 mole) of acetyl chloride. After recrystallization from ethyl acetate-methanol, 27 g of lactam of the acid [amino-4a, acetyl-2, chloro-8, hexahydro-1, 2, 3, 4, 4a, 10a, are obtained [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (yield ₌ 52.6%) PF _G = 255-257 ° C IR C = O: 1670 cm ^-1 : 1690 cm ^{- 1}

EXAMPLE 43

Lactam of amino-4a acid, chloro-8, isopropyl-2, hexahydro-1, 2 3 4 4a 10a, 10 H] (benzopyrano) (3.2-C) (pyidine)] -yl-10 acetic (formula 46 ) C ₁₇ H ₂₁ ClN ₂ O ₂ PM = 320.82 Prepared according to Example 11 from 6.2 g (0.022 mole) of the product of Example 34 and 3.1 g of 2-bromo-propane. After recrystallization from ethanol, 2 g of lactam of the acid [amino-4a, chloro-8, isopropal-2, hexahydro-1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) are obtained. (3,2-C) (pyridine)] -yl-10-10 acetic (yield = 28%) _PFG = 186. - 188 ° C IR CO: ₁₆₈₀ cm ^-1

EXAMPLE 44

Acid lactam [amino-4a, chrorc-8, (methyl-2, propenyl-3) 2, hexahydro-1, 2, 3. 4, 4a, 10a, (benzopyrano) (3,2-C) ( pyridine)] -yl-10 acetic (formula 47) C ₁₈ H ₂₁ ClN ₂ O ₂ PM = 332.83 Prepared according to Example 11 from 6.2 g (0.022 mole) of the product of Example 34 and 2.6 ml (0.025 mole) of 3-chloro, 2-methyl propene, By recrystallization from ethyl acetate, 2.3 g of lactam from the acid [amino-4a, chloro-8, (methyl -2, propenyl-3) 2, hexahydro -1, 2, 3, 4, 4a, 10a, [10 H] (benzopyrano) (3,2-C) (pyridine)] -yl-10 acetic (Yield: 31 , 5%) PF _C = 202 - 204 ° C IR C = O: 1680 cm ^-1

Claims (4)

1. Hexahydro benzopyrano [3,2-C] substituted pyridines characterized by the formula

wherein R is hydrogen or a saturated or unsaturated, linear or branched lower alkyl radical, aralkyl, acyl, dialkylaminoalkyl, alkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; R ₁ is hydrogen, halogen or a lower alkoxy radical; R ₂ is hydrogen or a halogen: ^R 3 is hydrogen, a halogen, a lower alkyl radical, alkoxy, nitro, amino or forms naphthalene with R ₄ and the benzene ring; R ₄ is hydrogen, halogen or forms naphthalene with R ₃ and the benzene ring; R ₅ is hydrogen, a lower alkyl or arlalkple radical. 2. Hexahydro benzopyrano [3,2-C] pyridines according to claim 1 characterized by their salts with mineral and organic acids acceptable in human therapy. 3. A process for the preparation of hexahydro benzopyrano [3,2-C] pyridines according to claim 1, characterized in that a piperidone -4 N - substituted of formula is added

in which R has the same meaning as previously on an ethyl-3-coumarin carboxylate of formula

in which R ₁ , R ₂ , R ₃ , R ₄ have the same meanings as above, opens with ammonium acetate the resulting adduct or with a primary amine R ₅ - NH ₂ in which R ₅ has the same meaning as above, then performs a dehydrating cyclization with hydrochloric acid. 4. Medicament useful in particular as an antidepressant characterized in that it contains as active ingredient a hexahydro benzopyrano [3,2-C] pyridine according to claim 1 or 2.