GB1602087A

GB1602087A - 2,3-diphenylchromone derivatives and their preparation and therapeutic applications

Info

Publication number: GB1602087A
Application number: GB2237878A
Authority: GB
Original assignee: SECUREF AG
Current assignee: SECUREF AG
Priority date: 1977-05-27
Filing date: 1978-05-25
Publication date: 1981-11-04
Also published as: BE867031A; FR2392018A1; CH635335A5; AR227615A1; JPS5436265A; FR2392018B1; LU79701A1

Abstract

The 2,3-diphenylchromone derivatives correspond to the formula: <IMAGE> in which R1 and R2 are alkyl groups, or the two groups R1 and R2 form, with the nitrogen atom on which they are fastened, a 5- or 6-membered heterocycle which can optionally contain another heteroatom, R3 is a phenyl group or a phenyl group para-substituted by groups chosen from an alkyl group, a halogen atom, a nitro group or an amino group. They also relate to the addition salts with pharmaceutically acceptable inorganic or organic acids. These compounds have a stimulating action on the central nervous system and a respiratory analeptic action.

Description

(54) 2,3-DIPHENYL-CHROMONE DERIVATIVES, AND THEIR PREPARATION AND THERAPEUTIC APPLICATIONS (71) We, SEUREF A.G., a Liechtenstein Body Corporate, residing at Liechtenstein, Vaduz (Liechtenstein), do hereby deciare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to new 2,3 - diphenyl - chromone derivatives, to a process for their preparation and to their therapeutic applications.

The new 2,3 - diphenyl - chromone derivatives of this invention have the general formula:

in which: R, and R2 are each a C14 alkyl group or, together with the nitrogen atom to which they are attached, form a piperidino, morpholino or pyrrolidino group, R3 is a phenyl group para-substituted with an alkyl group containing at least 2 carbon atoms, a halogen atom, a nitro group or an amino group.

The invention includes also within its scope the pharmaceutically acceptable acid addition salts of the compounds of the formula (I) above, with inorganic or organic acids.

This invention relates also to a process for the preparation of compounds of the formula (I), comprising reacting a compound of the formula (II):

in which R3 has the above-defined meaning, with a secondary amine having the formula HNR,R2 in which R1 and R2 have the above-defined meanings. 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 reagents and may be, ror example, benzene or ethanol.

The reaction between the compound of the formula (II) and the secondary amine is preferably effected at a molar ratio of 1/2.

On completion of the reaction, the mixture is filtered and the filtrate is concentrated to dryness. The residue is taken up into water and the insoluble portion is extracted with a solvent. The organic extract is washed with water and.

after drying over sodium sulfate, for example, the solvent is removed. The residue is recrystallized from a suitable solvent. The resulting free base, which is the product of this invention, may be converted to a water soluble pharmaceutically acceptable salt, such as the hydrochloride, the citrate, the tartrate or the maleate.

The following non-limiting Examples are given to illustrate the preparation of compounds of this invention. Example A illustrates the general preparative method used.

EXAMPLE A Preparation of 8 - dimethylaminomethyl - 7 - methoxy - 2 - p - tolyl - 3 phenyl - chromone having the formula:

In a two-necked flask having a capacity of 500 ml, provided with a stirrer and with a stopper maintained in its place with a light spring, is added 8 chloromethyl - 7 - methoxy - 2- p- tolyl - 3 - phenyl - chromone (4.8 g) dissolved in benzene, and dimethylamine (5 ml) is then rapidly added thereto. The flask is closed and stirring is maintained for 12 hours. After filtration, the organic phase is separated from the reaction mixture in a separating funnel; it is then dried over sodium sulfate and evaporated to dryness in vacuo. The residue is taken up into a small amount of water and the undissolved portion is extracted with a solvent such as chloroform. The chloroform layer is washed repeatedly with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed, to give an oily residue which may be recrystallized from a solvent such as ligroin. The resulting white solid (4.8 g) has a melting point of 128 1300C.

Analysis: C26H2sNO3 C H N Calculated% 78.17 6.31 3.51 Found % 78.16 6.25 3.48 EXAMPLE 1 Preparation of 8-Dimethylaminomethyl-7-methoxy-2-p-fluorophenyl 3-phenyl-chromone The procedure of Example A is used, starting from 8 - chloromethyl - 7 methoxy - 2 - p - fluorophenyl - 3 - phenyl - chromone and dimethylamine. A white crystalline material is obtained in a yield of 91to. M.P.=168--170"C.

Analysis: C25H22FNO3 C H N Calculated Ó 74.41 5.50 3.47 Found /O 74.35 5.40 3.21 Hydrochloride: white crystalline material. M.P.=243--245"C.

Analysis: C2sH23FCINO3 Cl N Calculated % 8.06 3.19 Found V 7.95 3.18 EXAMPLE 2 Preparation of 8-Diethylaminomethyl-7-methoxy-2-p-fluorophenyl- 3-phenyl-chromone The procedure of Example A is used, starting from 8 - chloromethyl - 7 methyl- 7- methoxy - 2- p- fluorophenyl - 2- phenyl - chromone and diethylamine. A white crystalline material is obtained in a yield of 78%.

M.P.=173--175"C.

Analysis: C27H26FNO3 C H N Calculated % 75.14 6.08 3.25 Found V 75.08 5.91 3.15 Hydrochloride: white crystalline material. M.P.=238-240"C.

Analysis: C27H27CIFNO3 Cl N Calculated V 7.58 2.99 Found V 7.60 3.10 EXAMPLE 3 Preparation of 8-Piperidinomethyl-7-methoxy-2-p-fluorophenyl 3-phenyl-chromone The procedure of Example A is used, starting from 8 - chloromethyl - 7 methoxy - 2 - p - fluorophenyl - 3 - phenyl - chromone and piperidine. A white crystalline material is obtained in a yield of 64%. M.P.=238-2400C.

Analysis: C28H26FNO3 C H N Calculated V 75.81 5.91 3.16 Found V 75.75 5.86 3.08 Hydrochloride: white crystalline material. M.P.=179-183 C.

Analysis: C28H27CIFNO3 Cl N Calculated V 7.39 2.92 Found % 7.42 3.15 EXAMPLE 4 Preparation of 8-Pyrrolidinomethyl-7-methoxy-2-p-fluorophenyl 3-phenyl-chromone The procedure of Example A is used, starting from 8 - chloromethyl - 7 methoxy - 2 - p - fluorophenyl - 3 - phenyl - chromone and pyrrolidine. A white crystalline material is obtained in a yield of 81%. M.P.=210-212 C.

Analysis: C27H24FNO3 C H N Calculated V 75.49 5.64 3.26 Found V 75.48 5.63 3.18 Hydrochloride: white crystalline material, M.P.=238-240 C.

Analysis: C27H2sCIFNO3 Cl N Calculated V 7.61 3.01 Found % 7.61 2.88 EXAMPLE 5 Preparation of 8-morpholinomethyl-7-methoxy-2-p-fluorophenyl 3-phenyl-chromone The procedure of Example A is used, starting from 8 - chloromethyl - 7 methoxy - 2 - p - fluorophenyl - 3 - phenyl - chromone and morpholine. A white crystalline material is obtained in a yield of 570,. M.P.=258-2600C.

Analysis: C27H24FNO4 C H Calculated V 72.78 5.43 3.15 Found V 72.80 5.41 3.05 Hydrochloride: white crystalline material, M.P.=240--2420C.

Analysis: C2,H2sCIFNO4 Cl N Calculated V 7.36 2.91 Foundd 7.31 2.90 The results of toxicological and pharmacological tests indicate a stimulant action on the central nervous system, typically on the medulla obiongata. together with an outstanding analeptic respiratory action.

Thus, this invention relates to a therapeutic composition having in particular a stimulant action on the central nervous system and an analeptic respiratory action.

comprising as active ingredient a derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The active ingredient is generally combined with a therapeutically administrable carrier or excipient.

The compositions may be used in human medicine, particularly for the curative and preventive treatment of respiratory insufficiencies subsequent to all types of lesions, i.e. toxic, medicinal or infectious lesions.

For oral administration, the therapeutic compositions of this invention may be formulated as tablets, capsules, ampoules or syrups. For rectal administration, it may be formulated as suppositories and, for parenteral administration, it may be formulated as injectable solutions. For all such routes of administration, the active ingredient is combined with carriers suitable for the selected type of pharmaceutical formulation.

Non-limiting Examples of pharmaceutical formulations of the therapeutic compositions of this invention are given below.

Tablets or capsules: containing off40 mg active ingredient together with usual excipients.

Aqueous solutions for oral administration, formulated as drops, containing 1 50 mg active ingredient per ml of solution.

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

Ampoules containing 25-80 mg active ingredient, together with a suitable sterile injectable solution.

Suppositories containing 50100 mg active ingredient, together with a suitable excipient.

Thus, the compositions may be presented in unit dosage form, each unit containing 10100 mg of the active ingredient.

The daily dosage regimen varies as a function of the application contemplated.

Thus, the therapeutic composition may be administered at a rate of one or two tablets or capsules every 3 or 4 hours. For a same period of time, it may be administered at a rate of 10 or 20 drops by the oral route, or at a rate of 1 or 2 spoonfuls of syrup. For intramuscular or intravenous administration, the therapeutic composition may be administered at a daily rate of 1 or 2 ampoules, or more, according to the therapeutic requirements.

WHAT WE CLAIM IS: 1. 2.3-Diphenyl-chromone derivatives having the general formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. Analysis: C27H24FNO4 C H Calculated V 72.78 5.43 3.15 Found V 72.80 5.41 3.05 Hydrochloride: white crystalline material, M.P.=240--2420C. Analysis: C2,H2sCIFNO4 Cl N Calculated V 7.36 2.91 Foundd 7.31 2.90 The results of toxicological and pharmacological tests indicate a stimulant action on the central nervous system, typically on the medulla obiongata. together with an outstanding analeptic respiratory action. Thus, this invention relates to a therapeutic composition having in particular a stimulant action on the central nervous system and an analeptic respiratory action. comprising as active ingredient a derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof. The active ingredient is generally combined with a therapeutically administrable carrier or excipient. The compositions may be used in human medicine, particularly for the curative and preventive treatment of respiratory insufficiencies subsequent to all types of lesions, i.e. toxic, medicinal or infectious lesions. For oral administration, the therapeutic compositions of this invention may be formulated as tablets, capsules, ampoules or syrups. For rectal administration, it may be formulated as suppositories and, for parenteral administration, it may be formulated as injectable solutions. For all such routes of administration, the active ingredient is combined with carriers suitable for the selected type of pharmaceutical formulation. Non-limiting Examples of pharmaceutical formulations of the therapeutic compositions of this invention are given below. Tablets or capsules: containing off40 mg active ingredient together with usual excipients. Aqueous solutions for oral administration, formulated as drops, containing 1 50 mg active ingredient per ml of solution. Syrups containing 2-5 g active ingredient per 100 g of syrup. Ampoules containing 25-80 mg active ingredient, together with a suitable sterile injectable solution. Suppositories containing 50100 mg active ingredient, together with a suitable excipient. Thus, the compositions may be presented in unit dosage form, each unit containing 10100 mg of the active ingredient. The daily dosage regimen varies as a function of the application contemplated. Thus, the therapeutic composition may be administered at a rate of one or two tablets or capsules every 3 or 4 hours. For a same period of time, it may be administered at a rate of 10 or 20 drops by the oral route, or at a rate of 1 or 2 spoonfuls of syrup. For intramuscular or intravenous administration, the therapeutic composition may be administered at a daily rate of 1 or 2 ampoules, or more, according to the therapeutic requirements. WHAT WE CLAIM IS:

1. 2.3-Diphenyl-chromone derivatives having the general formula:

in which: R, and R2 are each a C14 alkyl group or, together with the nitrogen atom to which they are attached, R, and R2 form a piperidino, morpholino or pyrrolidino group, R3 is a phenyl group para-substituted with an alkyl group containing at least 2 carbon atoms, a halogen atom, a nitro group or an amino group, and their pharmaceutically acceptable acid addition salts with inorganic or organic acids.

2. 8 - Dimethylaminomethyl - 7 - methoxy - 2 - p - fluorophenyl - 3 phenyl - chromone: 8- diethylaminomethyl- 7- methoxy - 2- pfluorophenyl - 3 - phenyl - chromone; 8 - piperidinomethyl - 7 - methoxy - 2 p - fluorophenyl - 3 - phenyl - chromone; 8 - pyrrolidinomethyl - 7 - methoxy 2 - p - fluorophenyl - 3 - phenyl - chromone; and 8 - morpholinomethyl - 7 methoxy - 2 - p - fluorophenyl - 3 - phenyl - chromone.

3. A process for the preparation of compounds of the formula (I) as defined in Claim 1, comprising reacting a compound of the formula:

in which R3 is as defined for formula (I), with a secondary amine having the formula HNR,R2 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 with stirring.

4. A process as claimed in Claim 3, wherein said solvent is ethanol or benzene.

5. A process as claimed in Claim 3 or 4, wherein the molar ratio of compound of the formula (II) to secondary amine is 1:2.

6. Therapeutic composition having a stimulant action on the central nervous system and an analeptic respiratory action, comprising, as active ingredient, a derivative as claimed in Claim 1 or Claim 2 or a pharmaceutically acceptable acid addition salt thereof.

7. Therapeutic composition as claimed in Claim 6, formulated in a form suitable for oral, parenteral or rectal administration, the active ingredient being combined with a therapeutically acceptable carrier.

8. Therapeutic composition as claimed in Claim 6 or 7, in unit dosage form, each unit dose containing 10-100 mg active ingredient.