CH635335A5 - 2,3-Diphenylchromone derivatives, process for their preparation and their therapeutic application - Google Patents

Description

The present invention relates to new 2,3-phenyl-chromone derivatives, to their process of preparation, as well as to their application as medicament.

The new 2,3-diphenyl chromone derivatives according to the invention correspond to the following general formula

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4 "

CH..0 î

3

(D

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ÇH,

FL

R,

(H)

in which

R3 has the meaning given for formula I, with one in which

Ri and R2 are alkyl groups, or the two groups Ri and R2 form, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocycle 55 which may optionally contain another heteroatom,

R3 is a phenyl or phenyl group para substituted by groups selected from an alkyl group, a halogen atom, a nitro group or an amino group.

According to a preferred embodiment of the invention, the groups Ri and R2 are alkyl groups having from 1 to 4 carbon atoms, or the groups Ri and R2 form with the nitrogen atom to which they are attached a piperidino, morpholino or pyrrolidino group, R3 is a sub-65 phenyl group formed in para by a group chosen from an alkyl group having at least two carbon atoms, a halogen atom, a nitro or amino group.

The invention also includes the addition salts of

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compounds of formula I above with pharmaceutically acceptable mineral or organic acids.

A subject of the invention is also a process for preparing the compounds of formula I above, characterized in that a compound of formula II is reacted,

CHaCI

in which

Rj has the meaning given above, with a secondary amine of formula NR1R2, in which Ri and R2 are as defined above, in the presence of a solvent, at a temperature between room temperature and the reflux temperature of the mixture, and with stirring.

The solvent used is a solvent inert with respect to the reactants and can be, for example, benzene or ethanol.

The reaction between the compound of formula II and the secondary amine is preferably carried out in a molar ratio of 1: 2.

After reaction, the mixture is filtered and the filtrate is concentrated to dryness. The residue is taken up with water and the insoluble part is extracted using a solvent. The organic extract is washed with water and, after drying, for example over sodium sulfate, the solvent is removed. The residue is recrystallized from a suitable solvent. The free base obtained which is the product of the invention can be transformed into a pharmaceutically acceptable salt soluble in water such as for example a hydrochloride, citrate, tartrate, maleate, etc.

The following nonlimiting examples are given by way of illustration of the preparation of the compounds of the invention.

Example 1

Preparation of 8-dimethylaminomethyl-7-methoxy-2-p-tolyl-3-phenyl-chromone of formula reaction mixture in a separating funnel, dried over anhydrous sodium sulfate and evaporated in vacuo until to dryness. The residue is taken up in a little water and the undissolved part is extracted with a solvent such as chloroform. The chloroform layer is washed several times with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed to obtain a residue which is in the form of an oil and can be recrystallized from a solvent such as ligroin. 4.8 g of a white solid are thus obtained, the melting point of which is 128-130 ° C.

Analysis: C26H25NO3

Calculated%: C 78.17; H 6.31; N 3.51 Found%: C 78.16; H 6.25; No. 3.48

From the free base, the following water-soluble salts can be prepared: Hydrochloride: white crystals recrystallized from ethanol, m.p. = 218-220 ° C

Analysis: C26H26CINO3

Calculated%: Cl 8.07; N 3.15 25% found: Cl 8.13; N 3.21

Citrate: white crystalline solid, without net P.F. (ethanol-ether)

Analysis: C32H33NO10

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Calculated%: C 64.96; H 5.62; N 2.37 Found%: C 64.80; H 5.48 N 2.12

Tartrate: white crystalline solid, without net P.F. (ethanol-35 ether)

Analysis: C30H31NO9

Calculated%: C 65.56; H 5.69; N 2.55 40 Found%: C 65.48; H 5.70; N 2.35

Maleate: white crystalline solid, m.p. = 157-160 ° C (ethanol-ether)

45 Analysis: C30H29NO7

0

Is introduced into a flask with two tubes with a capacity of 500 ml provided with an agitator and a stopper retained on its seat by a light spring 4.8 g of 8-chloromethyl-7-methoxy-2-p- tolyl-3-phenyl-chromone dissolved in benzene and 5 ml of dimethylamine are quickly added. The flask is closed and stirred for 12 hours. After filtration, the organic phase is separated from the

Calculated%: C 69.89; H 5.67; N 2.37 Found%: C 69.75; H 5.46; N 2.28

50 Hemisuccinate: white solid, without characteristic P.F. (ethanol-ether)

Analysis: C30H31NO7

55 Calculated%: C 69.61; H 6.04; N 2.71 Found%: C 69.50; H 5.81; N 2.53

Example 2

preparation of 8-diethylaminomethyl-7-methoxy-2-p-60 tolyl-3-phenyl chromone. The procedure is as in Example 1, starting from 8-chloromethyl-7-methoxy-2-tolyl-3-phenyl-chromone and ditehylamine. The yield is 78% of a white crystalline product. M.p. = 179-181 ° C

65 Analysis: C28H29NO3

Calculated%: C 78.66; H 6.84; N 3.28 Found%: C 78.65; H 6.78; N 3.21

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4

Hydrochloride: white crystalline product, m.p. = 212-214 ° C

Analysis: C28H30CICNO3

Calculated%: Cl 7.65; N 3.02 Found%: Cl 7.65; N 2.88

Example 3

Preparation of 8-piperidinomethyl-7-methoxy-2-p-tolyl-3-phenyl-chromone.

The procedure is as in Example 1, starting with 8-chloro-methyl-7-methoxy-2-p-tolyl-3-phenyl-chromone and piperidine. The yield is 69% of a white crystalline product. M.p. = 217-219 ° C

Analysis: C29H29NO3

Calculated%: C 79.24; H 6.65; N 3.19 Found%: C 79.23; H 6.38; N 3.15

Hydrochloride: white crystalline product, m.p. = 226-228 ° C

Analysis: C29H30CICNO3

Calculated%: Cl 7.45; N 2.94 Found%: Cl 7.31; N 2.88

Example 4

Preparation of 8-pyrrolidinomethyl-7-methoxy-2-p-tolyl-3-phenyl-chromone.

The procedure is as in Example 1, starting from 8-chloro-methyl-7-methoxy-2-p-tolyl-3-phenyl-chromone and Pyrrolidine. The yield is 81% of a white crystalline product, m.p. = 197-199 ° C.

Analysis: C28H27NO3

Calculated%: C 79.03; H 6.40; N 3.29 Found%: C 78.85; H 6.31; N 3.25

Hydrochloride: white crystalline product, m.p. = 210-212 ° C

Analysis: C28H28CINO3

Calculated%: Cl 7.70; N 3.04 Found%: Cl 7.55; N 2.88

Example 5

Preparation of 8-morpholinomethyl-7-methoxy-2-p-tolyl-3-phenyl-chromone.

The procedure is as in Example 1, starting from 8-chloro-methyl-7-methoxy-2-p-tolyl-3-phenyl-chromone and morpholine. The yield is 71% of a white crystalline product, m.p. = 226-228 ° C.

Analysis: C28H27NO4

Calculated%: C 76.17; H 6.16; N 3.17 Found%: C 76.20; H 6.09; N 3.08

Hydrochloride: white crystalline product, m.p. = 243-245 ° C

Analysis: C28H28CINO4

Calculated%: Cl 7.42; N 2.93; N 2.93 Found%: Cl 7.31; N 2.85

Example 6

Preparation of 8-dimethylaminomethyl-7-methoxy-2,3-diphenyl-chromone.

The procedure is as in Example 1, starting from 8-chloro-methyl-7-methoxy-2,3-diphenyl-chromone and dimethylamine. The yield is 85% of a white crystalline product. M.p. = 177-179 ° C

Analysis: C25H23NO3

Calculated%: C 77.90; H 6.01; N 3.63 Found%: C 77.85; H 5.98; N 3.58

Hydrochloride: white crystalline product, m.p. = 205-207 ° C

Analysis: C25H24CINO3

Calculated%: Cl 8.41; N 3.32 Found%: Cl 8.35; N 3.27

Example 7

Preparation of 8-diethylaminomethyl-7-methoxy-2,3-diphenyl-chromone.

The procedure is as in Example 1, starting from 8-chloro-methyl-7-methoxy-2,3-diphenyl-chromone and diethylamine. The yield is 75% of a white crystalline product, m.p. = 142-144 ° C.

Analysis: C27H23NO3

Calculated%: C 79.19; H 5.66; N 3.42 Found%: C 79.12; H 5.65; N 3.37

Hydrochloride: white crystalline product. M.p. = 228-230 ° C.

Analysis: C27H24CINO3

Calculated%: Cl 7.73; N 3.14 Found%: Cl 7.74; N 3.10

Example 8

Preparation of 8-piperidinomethyl-7-methoxy-2,3-diphenyl-chromone.

The procedure is as in Example 1, starting from 8-chloro-methyl-7-methoxy-2,3-diphenyl-chromone and piperidine. The yield is 64% of a white crystalline product, m.p. = 197-200 ° C.

Analysis: C28H27NO3

Calculated%: C 79.03; H 6.39; N 3.29 Found%: C 78.85; H 6.31; N 3.18

Hydrochloride: white crystalline product, m.p. = 208-210 ° C

Analysis: C28H28CINO3

Calculated%: Cl 7.68; N 3.03 Found%: Cl 7.65; N 2.91

Example 9

Preparation of 8-pyrrolidinomethyl-7-methoxy-2,3-diphenyl-chromone.

The procedure is as in Example 1, starting with 8-chloro-methyl-7-methoxy-2,3-diphenyl-chromone and Pyrrolidine. The yield is 58% of a white crystalline product, m.p. = 179-181 ° C.

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635335

Analysis: C27H25NO3

Calculated%: C 78.80; H 6.12; N 3.40 Found%: C 78.62; H 5.91; N 3.38

Hydrochloride: white crystalline product, m.p. = 238-240 ° C.

Analysis: C27H26CINO3

Calculated%: Cl 7.92; N 3.13 Found%: Cl 7.68; N 2.85

Example 10

Preparation of 8-morpholinomethyl-7-methoxy-2,3-diphenyl-chromone.

The procedure is as in Example 1, starting from 8-chlo-romethyl-7-methoxy-2,3-diphenyl-chromone and morpholine. The yield is 61% of a white crystalline product, m.p. = 238-241 ° C.

Analysis: C27H25NO4

Calculated%: C 75.85; H 5.89; N 3.28 Found%: C 75.80; H 5.71; N 3.25

Hydrochloride: white crystalline product, m.p. = 223-225 ° C

Analysis: C27H20CINO4

Calculated%: Cl 7.65; N 3.02 Found%: Cl 7.68; N 2.81

Example 11

Preparation of 8-dimethylaminomethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone.

The procedure is as in Example 1, starting from 8-chlo-romethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone and dimethylamine. The yield is 91% of a white crystalline product, m.p. = 168-170 ° C.

Analysis: C25H22FNO3

Calculated%: C 74.41; H 5.50; N 3.47 Found%: C 74.35; H 5.40; N 3.21

Hydrochloride: white crystalline product, m.p. = 243-245 ° C.

Analysis: C25H23FCINO3

Calculated%: Cl 8.06; N 3.19 Found%: Cl 7.95; N 3.18

Example 12

Preparation of 8-diethylaminomethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone.

The procedure is as in Example 1, starting from 8-chloro-methyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone and diethylamine. The yield is 78% of a white crystalline product, m.p. = 173-175 ° C.

Analysis: C27H26FNO3

Calculated%: Cl 75.14; H 6.08; N 3.25 Found%: Cl 75.08; H 5.91; N 3.15

Hydrochloride: white crystalline product, m.p. = 238-240 ° C.

Analysis: C27H27CIFNO3

Calculated%: Cl 7.58; N 2.99 Found%: Cl 7.60; N 3.10

Example 13

Preparation of 8-piperidinomethyl-7-methoxy-2-p-fluo-rophenyl-3-phenyl-chromone.

The procedure is as in Example 1, starting with 8-chlo-romethyl-7-methoxy-2-p-fluorophenyl-2-phenyl-chromone and piperidine. The yield is 64% of a white crystalline product, m.p. = 238-240 ° C.

Analysis: C28H26FNO3

Calculated%: C 75.81; H 5.91; N 3.16 Found%: C 75.75; H 5.86; N 3.08

Hydrochloride: white crystalline product, m.p. = 179-183 ° C.

Analysis: C28H27CIFNO3

Calculated%: Cl 7.39; N 2.92 Found%: Cl 7.42; N 3.15

Example 14

Preparation of 8-pyrrolidinomethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone.

The procedure is as in Example 1, starting with 8-chlo-romethyl-7-methoxy-2- * p-fluorophenyl-3-phenyl-chromone and Pyrrolidine. The yield is 81% of a white crystalline product, m.p. = 210-212 ° C.

Analysis: C27H24FNO3

Calculated%: C 75.49; H 5.64; N 3.26 Found%: C 75.48; H 5.63; N 3.18

Hydrochloride: white crystalline product, m.p. = 238-240 ° C

Analysis: C27H25CIFNO3

Calculated%: Cl 7.61; N 3.01 Found%: CI 7.61; N 2.88

Example 15

Preparation of 8-morpholinomethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone.

The procedure is as in Example 1, starting from 8-chlo-romethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone and morpholine. The yield is 57% of a white crystalline product. M.p. = 258-260 ° C.

Analysis: C27H24NO4

Calculated%: C 72.78; H 5.43; N 3.15 Found%: C 72.80; H 5.41; N 3.05

Hydrochloride: white crystalline product, m.p. = 240-242 ° C

Analysis: C27H25CIFNO4

Calculated%: Cl 7.36; N 2.91 Found%: Cl 7.31; N 2.90

The results of the toxicological and pharmacological tests which are reported below demonstrate the properties of the derivatives of the invention, in particular a stimulating action s

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on the central nervous system and, in particular, on the medulla oblongata with a remarkable respiratory analeptic action.

A further subject of the invention is therefore a medicament having in particular a stimulating action on the central nervous system and an respiratory analeptic action, characterized in that it contains, as active principle, a derivative of formula I or an addition salt with a pharmaceutically acceptable acid thereof.

The active principle is generally associated with a therapeutically administrable vehicle or excipient.

Toxicological study

The compound of Example 1 is remarkably little toxic compared to the products having an analogous pharmacological action.

The LD 50, evaluated according to the Lichtfïeld and Wil-coxon method, is equal for oral administration in mice at 80 mg / kg and for intraperitoneal administration at 55 mg / kg.

The death of animals treated with toxic doses occurs after excitability and generalized tonicoclonic convulsions.

With regard to the evaluation of the chronic toxicity of the product, it was found that, even after the administration in the rat, for two months, of two daily doses of the product equal to 3 mg / kg and to 5 mg / kg , the animals subjected to the treatment showed no sign of toxicity or intolerance linked to the administration of the product.

The examinations carried out on the animals treated in this way, in particular concerning the weight gain, the blood formula, the glycemia, the azotemia, the transaminations and the urinary excretion, did not reveal any alteration compared to the values. found for the group of control animals. Similarly, no alteration was revealed by the anatomo-pathological and physiological examination carried out on the main organs of the animals treated.

Pharmacological study

A) Action on respiration and on blood pressure

Intravenous administration, in rats or rabbits, of doses of the product varying between 2 and 5 mg / kg results in a significant increase in amplitude and respiratory rate, as well as a modest increase in pressure blood.

B) Protective action vis-à-vis the respiratory depression induced by morphine.

The respiratory depression induced in rabbits by 10 mg / kg of morphine injected intravenously and the breathing of the Cheyne-Stokes type which often occurs in anesthetized ranimai, were eliminated by the administration of 2.5-5 mg / kg by intravenously of the product of Example 1.

C) Action on sleep induced by barbiturates.

The prior administration by the intraperitoneal route in mice of 1 mg / kg of the product of Example 1 is capable of reducing the sleep time produced by the injection in these animals by 100 mg / kg i.p. sodium amital. The administration of 4 mg / kg of the product of Example 1 is able to reduce the sleep time induced by barbiturates by 50%.

The results of these studies highlight the low toxicity and the interesting respiratory analeptic and central nervous system stimulation activities of the derivatives of the invention which make them useful in human medicine, in particular in the therapy and prevention of respiratory failure consecutive to all types of lesions, namely toxic, medicinal or infectious.

The medicament of the invention can be presented, for oral administration, in the form of tablets, capsules, capsules, ampoules, syrups. It can be presented, for rectal administration, in the form of suppositories and, for parenteral administration, in the form of injectable solutions. In all these modes of administration, the active principle is associated with vehicles suitable for the chosen mode of pharmaceutical presentation.

A few pharmaceutical formulations of the medicament of the invention will be given below, by way of nonlimiting examples.

Tablets or capsules containing 10 to 40 mg of active principle in combination with usual excipients.

Aqueous solutions for oral administration in the form of drops containing 15 to 40 mg of active principle per ml of solution.

Syrups containing 2 to 5 g of active ingredient per 100 g of syrup.

Ampoules containing 25 to 80 mg of active ingredient in combination with an appropriate sterile injectable solution.

Suppositories containing 50 to 100 mg of active ingredient with an appropriate excipient. The doses likely to be administered daily vary depending on the intended application.

For example, the dose is one to two tablets or capsules every 3 or 4 hours. For the same period of time, it is 10 or 20 drops orally or 1 to 2 spoonfuls of syrup. By intramuscular or intravenous route, it is 1 to 2 or more ampoules per day, depending on the therapeutic need.

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Claims (9)

635335 2 CLAIMS 1. Therapeutically active 2,3-diphenyl-chromon derivatives of general formula (I) in which Ri and R2 are alkyl groups, or the two groups Ri and R2 form, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocycle which may optionally contain another heteroatom, R3 is a phenyl or phenyl group substituted by groups chosen from an alkyl group, a halogen atom, a nitro group or an amino group, as well as their addition salts with pharmaceutically acceptable mineral or organic acids. 2. Derivatives according to claim 1, characterized in that the groups Ri and R2 are alkyl groups having from 1 to 4 carbon atoms, or the groups Ri and R2 form with the nitrogen atom on which they are attached a piperidino, morpholino or pyrolidino group, R3 is a phenyl group substituted in para by a group chosen from an alkyl group having at least 2 carbon atoms, a halogen atom, a nitro or amino group. 3. Derivatives according to claim 1, chosen from 8-dimethylaminomethyl-7-methoxy-2-p-fluoro-phenyl-3-phenyl-chromone, 8-diethylaminomethyl-7-methoxy-2-p-fluorophenyl-3-phenyl -chromone, 8-piperidinomethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone, 8-pyrrolidi-nomethyl-7-methoxy-2-p-fluorophenyl-3-phenyl-chromone, 8-morpholino-methyl -7-methoxy-2-p-fluorophenyl-3-phenyl-chromone. 4. Process for the preparation of compounds of formula I according to claim 1, characterized in that a compound of formula II is reacted, CHgCl secondary amine of formula NR1R2, in which R1 and R2 are as defined for formula I, in the presence of a solvent, at a temperature between room temperature and the reflux temperature of the mixture, and under agitation fi tation. 5. Method according to claim 4, characterized in that the solvent is ethanol or benzene. 6. Method according to claim 4 or 5, characterized in that the molar ratio between the compound of formula II and 10 the secondary amine is 1: 2. 7. Medicinal product having in particular a stimulating action on the central nervous system and an respiratory analeptic action, characterized in that it contains, as active principle, a derivative according to one of claims 1 to 3 or a salt Addition with a pharmaceutically acceptable acid thereof. 8. Medicament according to claim 7, characterized in that it is presented in a form suitable for oral, parenteral or rectal administration, the active principle being 20 associated with a therapeutically acceptable vehicle. 9. Medicament according to claim 7 or 8, characterized in that it is presented in the form of unit doses containing from 10 to 100 mg of active principle. 25