GB1561679A

GB1561679A - 3,3 - diphenylpropylamine derivatives

Info

Publication number: GB1561679A
Application number: GB22681/78A
Authority: GB
Original assignee: Alfa Farmaceutici SpA
Current assignee: Alfa Farmaceutici SpA
Priority date: 1977-06-17
Filing date: 1978-05-25
Publication date: 1980-02-27
Also published as: DK144064C; NO145097B; FR2394527B1; IT1080455B; ATA430078A; DE2825447A1; PT68122A; SE7806945L; NO782101L; BE867570A; GR73140B; NO145097C; ES470845A1; DK144064B; DK269278A; NL7805617A; FR2394527A1; JPS5430142A; AT357141B

Description

(54) 3,3-DIPHENYLPROPYLAMINE DERIVATIVES (71) We, ALFA FARMACEUTICI S.P.A., of Via Ragazzi del '99, No. 5, 40133 Bologna, Italy, an Italian body corporate, do hereby declare 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: The present invention relates to certain derivatives of N - (3 - phenylthiopropyl)3,3 - diphenylpropylamine which have pharmacological activity and are particularly useful as anti-ulcer, anti-spastic and spasmolytic agents.

N - (3 - phenylthiopropyl) - 3,3 - diphenylpropylamine itself and its pharmaceutically acceptable salts are described in U.K. Patent Specification No. 1,345,319, in which it is shown to possess good anti-ulcer activity.

We have now discovered that certain derivatives of N - (3 - phenylthiopropyl) - 3,4 - diphenylpropylamine and pharmaceutically acceptable salts thereof also possess valuable pharmacological activity.

The compounds of the invention have the formula:

in which: R represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; and Rl, R2, R3 and R4 are the same or different and each represents a hydrogen atom or a hydroxyl group, provided that, when Rl, R2, R3 and R4 all represent hydrogen atoms, R does not represent a hydrogen atom.

When R represents an alkyl group, it is preferably a methyl group.

Examples of compounds according to the present invention are: 1. N - (3 - p - hydroxyphenylthiopropyl)3,3 - diphenylpropylamine; 2. N - (3 - phenylthiopropyl) - N - (3 - phydroxyphenyl - 3 - phenylpropyl)amine; 3. N methyl - N - (3 - phenylthiopropyl) N - (3 - p - hydroxyphenyl - 3 - phenylpropyl)amine; 4. N - methyl - N - (3 - p - hydroxyphenylthiopropyl) - 3,3 - diphenylpropylamine; 5. N - methyl - N - (3 - phenylthiopropyl)3,3 - diphenyl - propylamine; 6. N - (3 - p - hydroxyphenylthiopropyl) N - (3 - p - hydroxyphenyl - 3 - phenylpropyl)amine; and their pharmaceutically acceptable salts.

The compounds of the invention may be prepared by any of the following processes: Process 1 Reaction between a primary amine and a suitable halo compound. An example is the reaction of 3,3 - diphenylpropylamine or a derivative thereof having a hydroxy substituent in one of its benzene rings with a 1 - halo - 3phenylthiopropane or a derivative thereof having a hydroxy substituent in its benzene ring. Alternatively, the same compounds could be prepared by reacting 3 - phenylthiopropylamine or a derivative thereof having a hydroxy substituent in its benzene ring with a 1 - halo3,3 - diphenylpropane or a derivative thereof having a hydroxy substituent in its benzene ring.

Process 2 Hydrogenation of the Schiff's base obtained by condensation of a primary amine with an aldehyde.

Process 3 Reaction of a secondary amine with a suitable halo compound, particularly reaction of a compound of the invention in which R represents a hydrogen atom with a compound of formula R'X (in which R' represents an alkyl group having from 1 to 4 carbon atoms and X represents a halogen atom) to produce a compound of the invention in which R repre sents an alkyl group. An example is the reaction of N - (3 - phenylthiopropyl) - N - (3 p - hydroxyphenyl - 3 - phenylpropyl)amine with methyl iodide.

Process 4 Reaction of a N - (3,3 - diphenylpropyl) N - (3 - halo - propyl)amine with a thiophenyl or with an active derivative thereof.

Process 5 Dealkylation of a compound having a formula similar to that given above but in which anv of R', R2, R3 and R4 is replaced by an alkoxy group, to produce the corresponding compound in which Rl, R2, R3 or R4 represents a hydroxy group. An example is the demethylation of N - (3 - phenylthiopro pyl) - N - (3 - p - methoxyphenyl - 3phenylpropyl)amine.

Process 6 Hydrogenation of an amide obtained by condensation of a suitable acyl halide with a primary amine. The hydrogenation may be carried out using a complex hydride of alum inium or boron, for example lithium aluminium hydride.

The processes described above are all known per se for the preparation of other compounds and may be carried out using procedures weU- known to those skilled in the art.

Preparation of a pharmaceutically accept able acid addition salt of a compound of the invention may also be carried out by a wellknown procedure, e.g. simply by reaction of the compound and a suitable acid. There is no particular limitation upon the nature of the acid employed, provided that its anion is non-toxic. Examples of suitable salts are: hydrochlorides; hydrobromides; sulphates; phosphates; nitrates; acetates; propionates; succinates; adipates; glycolates; lactates; malates; ascorbates; piruvates; tartrates; maleates; citrates; bicarbonates; palmoates; phenyl acetates; benzoates; salicylates; alkylsulphates; arylsulphates; glucuronates; and salts with methionine, tryptophan, lysine and arginine.

The preferred salts are the hydrochlorides.

The compounds of the invention have shown good pharmacological, particularly anti-ulcer, anti-spastic and spasmolytic, activity. Accordingly, they are of value for medical use. N (3 - p - hydroxyphenylthiopropyl) - 3,3 - diphenylpropylamine, particularly in the form' of its hydrochloride, possesses strong antiulcer activity combined with a low toxicity.

For example, this compound has shown, against ulcers induced by administration of phenylbutazone to rats, inhibition values of 50% and 80 ,S,, respectively, at dosages of 10 and 50 mg/kg when administered intraperitoneally ,whilst the apparent LD,,, is greater than 1000 and 150 mg/kg per os and intraperitoneally respectively.

The invention further provides a pharmaceutical composition comprising one of the compounds of the above formula or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutical carrier, diluent or excipient. The composition may be provided in a form suitable for oral or parenteral administration or for topical use.

The composition is preferably in the form of a tablet or capsule. Where it is in such a form, it may contain any one or more of: (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose or glycerol or mixtures thereof; (b) lubricants, e.g. silica, talc, stearic acid, magnesium stearate, calcium stearate or a polyethylene glycol or mixtures thereof; and, in the case of tablets, (c) binding agents, e.g. aluminium silicate, magnesium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylhellu- lose or polyvinylpyrrolidone or mixtures thereof; and optionally (d) disintegrating agents, e.g. starch, agar, alginic acid, sodium alginate, or enzymes which break down the binding agents, or mixtures thereof; and (e) absorbants and/or dyes and/or flavours and/or sweetners.

However, the composition may also be in the form of an injectable composition or a suppository or ointment. The injectable composition is preferably an aqueous or isotonic solution or suspension. The suppository or ointment is preferably an emulsion or suspension in a fatty or oily substance.

The pharmaceutical compositions of the invention may be sterilized and/or may contain an adjuvant, for example a preservative, a stabilizer, a wetting agent, an emulsifier, a solution promoter, a salt to regulate the toxicity or a buffer or any two or more thereof. It is also possible to include within the pharmaceutical composition other compounds having pharmacological activity.

The preparation of the compounds of the invention is illustrated by the following Examples. In the Examples, the thin layer chromatography (TLC) experiments were carried out on plates of silica gel Merck GF,, and using as eluent a mixture of isoamyl acetate, methanol, water and formic acid in a volume ratio of 60:20:6:5.

EXAMPLE 1 N - (3 - p - hydroxyphenylthiopropyl) - 3,3 diphenylpropylamine hydrochloride N - (3,3 - diphenylpropyl) - N - (3 - hydroxypropyl)amine hydrochloride was prepared by treatment of the free base in ethanol with gaseous hydrogen chloride, and then the resulting oil was crystallized first from ethyl acetate and then from n-butanol. 3.8 g (0.012 moles) of this N - (3,3 - diphenylpropyl) - N (3 - hydroxypropyl)amine hydrochloride in 40 ml of anhydrous benzene were then added to 0.37 ml (0.004 mole) of phosphorus tribromide. After leaving the mixture for 1 hour at room temperature, the mixture was then refluxed for 1 hour. At the end of this time, it was cooled and then poured into a cold 10% w/v aqueous solution of sodium bicarbonate.

The benzene phase was separated off, washed twice with water and then dried, after which the solvent was evaporated off Crude N - (3 - bromopropyl) - N - (3,3 - diphenylpropyl)amine was obtained in the form of an oil (Rf about 0.9) and in an amount of 3.2 g.

This crude product was used directly in the subsequent reaction.

2.49 g (0.019 mole) of 4 - mercaptophenol dissolved in 20 ml of methanol were added, with stirring, at 400C to a solution of 0.22 g (0.0096 mole) of sodium in 8 ml of methanol. The mixture was refluxed and then a solution containing 6.4 g (0.019 mole) of N - (3 - bromopropyl) - N - (3,3 - diphenylpropyl)amine prepared as described above in 10 ml of methanol was added and the refluxing was continued for 24 hours. After cooling the mixture, the solvent was evaporated off under vacuum. The resulting residue was dissolved in chloroform and then washed twice with 6N hydrochloric acid. The chloroform was evaporated off under vacuum and the residue was recrystallized, first from ethyl acetate and then from a mixture of n-butanol and diethyl ether. The desired compound was obtained in an amount of 3.64 g. The compound had a melting point of 149148 C and an Rf value on TLC of about 0.35.

EXAMPLE 2 N - '3 - p - hydroxyphenylthiopropyl) - 3,3 diphenylpropylamine hydrochloride The sodium salt of 4 - mercaptophenol was prepared by adding a solution of 1.15 g (0.05 mole) of sodium in 20 ml of methanol to a solution of 6.3 g (0.05 mole) of 4 - mercaptophenol in 20 ml of methanol and then stirring the mixed solution for 90 minutes at 40- 50"C. Meanwhile, a solution of 1.15 g (0.05 mole) of sodium in 20 ml of methanol was added, with cooling and stirring, to 6.45 g (0.05 mole) of 3 - chloropropylamine hydro chloride in 20 ml of methanol. The sodium chloride thus formed was then stirred off. To the resulting solution was gradually added the solution of the sodium salt of 4 - mercaptophenol previously prepared and the mixture was maintained for 150 minutes at 60"C.

The solids were then filtered off, solvent was evaporated off from the filtrate and the residue was dissolved in a 1:1 by volume mixture of methylene chloride and water. The solid, con sisting of crude 3 - p - hydroxyphenylthio propylamine was filtered off, dissolved in ethanol saturated with hydrogen chloride and then added to ethyl acetate to precipitate 4.6 g of the hydrochloride, melting at 174--175"C.

To a solution of 4.38 g (0.02 mole) of the 3 - p - hydroxyphenylthiopropylamine hydrochloride thus obtained in 30 ml of anhydrous ethanol was added a solution of 0.46 g (0.02 mole) of sodium in 10 ml of anhydrous ethanol. After stirring the mixture, with cooling, for 30 minutes, the solution was heated to reflux. 2.75 g (0.01 mole) of 3,3 - diphenylpropyl bromide in 20 ml of anhydrous ethanol were then gradually added and the mixture was refluxed for 24 hours. At the end of this time, the mixture was cooled and then the solvent was evaporated off under vacuum. The residue was dissolved in chloroform and the solution was washed twice with 10% w/v aqueous sodium hydroxide and then twice with 6N hydrochloric acid. The organic phase was separated off and the solvent evaporated.

The residue was dissolved in ethyl acetate and then recrystallized from a mixture of nbutanol and diethyl ether. 2.0 g of the desired compound melting at 146--149"C were obtained.

EXAMPLE 3 N - (3 - phenylthiopropyl) - N - (3 - p - hydr oxyphenyl - 3 - phenylpropyl)amine hydrochloride 11.5 ml (0.078 mole) of triethylamine were added to 9.4 g (0.039 mole) of 3 - p - methoxyphenyl - 3 - phenylpropylamine in 60 ml of toluene; the mixture was then brought to reflux. A solution of 9.0 g (0.039 mole) of 3 - phenylthiopropyl bromide in 20 ml of toluene was then gradually added. The mixture was refluxed for 15 hours and then, after cooling, the hydrobromide of triethylamine was filtered off. The residual solution was washed three times with water and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The oil thus obtained was dissolved in 50 ml of chloroform and the chloroform solution was saturated with hydrogen chloride, washed four times with warm water and dried over anhydrous sodium sulphate; the solvent was then evaporated off under vacuum. The product was then recrystallized from a 1:1 by volume mixture of ethyl acetate and diethyl ether giving 6.8 g of N - (3 - phenylthiopropyl) - N - (3 - pmethoxyphenyl - 3 phenylpropyl)amine hydrochloride, melting at 138--140"C and having an Rf value on TLC of about 0.4.

0.856 g (0.05 mole) of this compound were dissolved in 20 ml of methylene chloride and the solution was cooled to -700C; to this solution was gradually added, with stirring, a pre-cooled solution of 2.5 g (0.01 mole) of boron tribromide in 8 ml of methylene chloride. The temperature of the mixture was then allowed to increase to ambient and the mixture was stirred for 24 hours. After cooling the mixture with brine, 22 ml of water, followed by 70 ml of diethyl ether, were added and the pH was adjusted to neutrality. The diethyl ether was evaporated off and chloro form was added, after which the product was treated with hydrogen chloride. The product was filtered off and recrystallized from ethyl acetate to give 0.5 g of the desired compound melting at 113--115"C and having an Rf value on TLC of about 0.35.

EXAMPLE 4 N - methyl - N - (3 - phenylthioproyl) - N (3 - p - hydroxyphenyl - 3 - phenylpro pyl)amine To a solution of 0.8 g (0.0021 mole) of N (3 - phenyl - thiophenyl) - N - (3 - p - hydroxyphenyl - 3 - phenylpropyl)amine in 20 ml of methanol containing 0.3 ml of triethylamine were gradually added 0.13 ml (0.0021 mole) of methyl iodide. After maintaining the mixture at room temperature for 36 hours, the solvent was evaporated off under.vacuum and the residue was dissolved in 20 ml of benzene.

The benzene solution was washed three times with water and then dried, after which the solvent was evaporated off. The residual oil was purified by preparative thin layer chromatography on silica gel Merck GF,,, using as diluent a mixture of benzene, diethyl ether, acetic acid and methanol in a volume ratio of 126:60:18:1. 0.15 g of the desired compound in the form of an oil, Rf value about 3, were obtained.

EXAMPLE 5 N - methyl - N - (3 - p - hydroxyphenylthio propyl) - 3,3 - diphenyl - propylamine To a solution of 0.8 g (0.0021 mole) of N - (3 - p - hydroxy - phenylthiopropyl) - 3,3diphenylpropylamine in 20 ml of methanol containing 0.3 ml of triethylamine were gradually added 0.13 ml (0.0021 mole) of methyl iodide. After leaving the mixture at room temperature for 36 hours, the solvent was evaporated off under vacuum and the residue was dissolved in 20 ml of benzene.

The benzene solution was washed three times with water and then dried, after which the solvent was evaporated off. The resulting oil was purified by preparative TLC using the method described in Example 4, giving 0.125 g of an oil, Rf value 0.3.

This oil was dissolved in ethanol saturated with hydrogen chloride and then the solvent was evaporated off under vacuum. The residue, recrystallized from ethyl acetate, gave 0.120 g of a product, the hydrochloride of the title compound, melting at 118--120"C.

EXAMPLE 6 N - methyl - N - (3 - phenylthiopropyl) 3,3 - diphenylpropylamine hydrochloride To a 35% w/v aqueous solution of methylamine was gradually added, with stirring, a solution of 2.5 g of 3,3 - diphenylpropyl bromide in 10 ml of ethanol. The solution was stirred at room temperature for 24 hours and then the solvent was evaporated off under vacuum. The residue was dissolved in methylene chloride and the resulting solution was washed twice with a 5% w/v aqueous solution of sodium hydroxide and twice with water. The solution was dried and then the solvent was evaporated off under vacuum. The residual oil was dissolved in ethanol saturated with hydrogen chloride, after which the solvent was evaporated off under vacuum. The product was recrystallized from ethyl acetate, giving 1.6 g of N - methyl - 3,3 - diphenylpropylamine hydrochloride melting at 177 178"C.

To a solution of 3.37 g (0.015 mole) of N - methyl - 3,3 - diphenylpropylamine obtained as described above and 4.5 ml of triethylamine in 40 ml of toluene kept under reflux were added, with stirring, a solution of 3.465 g (0.015 mole) of 3 - phenylthiopropyl bromide in 10 ml of toluene. The mixture was stirred and refluxed for 15 hours. At the end of this time, the mixture was cooled and the precipitated triethylamine hydrobromide was filtered off. The remaining solution was washed three times with water and dried, after which the solvent was evaporated off. The residue was dissolved in a 97:3 by volume mixture of chloroform and methanol and purified by chromatography through a silica gel column. The solvent was evaporated from the eluted fraction corresponding to the desired product and the residue was dissolved in ethanol saturated with hydrogen chloride; the solvent was evaporated off and the residual oil was treated with diethyl ether, giving 21 g of the desired product melting at 113 114"C and having a Rf value of about 0.35.

EXAMPLE 7 N - (3 - p - hydroxyphenylthiopropyl) - N (3 - p - hydroxyphenyl - 3 - phenylpro pyl)amine hydrochloride To a stirred solution kept under reflux of 3.39 g (0.0122 mole) of 3 - p - methoxyphenyl3 - phenylpropylamine in 30 ml of toluene containing 4 ml of triethylamine was gradually added a solution of 3.18 g (0.0122 mole) of 3 - p - methoxyphenylthiopropyl bromide in 20 ml of toluene. After refluxing the mixture for 15 hours, it was cooled, filtered, washed twice with water and dried; the solvent was then evaporated off under vacuum.

The residue was dissolved in 30 ml of chloroform and the resulting solution was washed twice with 6N hydrochloric acid and three times with warm water; the solution was then dried and the solvent evaporated off under vacuum. The product was recrystallized slowly from a 1:5 by volume mixture of n-propanol and diethyl ether giving 2.4 g of a product melting at 107--109"C.

1.9 g (0.0041 mole) of this product were dissolved in 30 ml of methylene chloride and the solution was cooled to a temperature of --60"C to--70"C. A cooled solution of 2.11 ml of boron tribromide in 15 ml of methylene chloride was then gradually added. The mixture was kept at a low temperature for 1 hour and then at room temperature for 24 hours.

Whilst cooling the mixture with brine, 45 ml of water were gradually added. The aqueous phase was neutralized with 1N sodium hydroxide. The organic phase was separated, washed with water and dried and the solvent evaporated off. The residual oil was dissolved in ethanol saturated with hydrogen chloride and then the solvent was evaporated off. The residue was recrystallized from a 1:9 by volume mixture of ethanol and ethyl acetate, giving 1.1 g of the desired product melting at 15o161 C.

WHAT WE CLAIM IS: 1. Compounds of formula:

in which: R represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and Rl, R2, R3 and R4 are the same or different and each represents a hydrogen atom or a hydroxyl group, provided that, when Rl, R2, R3 and R4 all represent hydrogen atoms, R does not represent a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof.

2. N - (3 - p - hydroxyphenylthiopropyl)3,3 - diphenylpropylamine and its pharmaceutically acceptable salts.

3. N - (3 - phenylthiopropyl) - N - (3 - phydroxyphenyl - 3 - phenylpropyl)amine and its pharmaceutically acceptable salts.

4. N - methyl - N - (3 - phenylthiopropyl) N - (3 - p - hydroxyphenyl - 3 - phenylpro- pyl)amine and its pharmaceutically acceptable salts.

5. N - methyl - N - (3 - p - hydroxyphenyl hiopropyl) - 3,3 - diphenylpropylamine and ts pharmaceutically acceptable salts.

6. N - methyl - N - (3 - phenylthiopropyl)3,3 - diphenyl - propylamine and its pharmacentically acceptable salts.

7. N - (3 - p - hydroxyphenylthiopropyl) N - (3 - p - hydroxyphenyl - 3 - phenylpropyl)amine and its pharmaceutically acceptable salts.

8. A compound according to any one of the preceding Claims in which the salt is a hydrochloride.

9. A pharmaceutical composition comprising a compound according to any one of the preceding Claims, in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

10. A pharmaceutical composition according to Claim 9, in the form of a tablet or capsule.

11. A pharmaceutical composition according to Claim 9, in the form of an injectable composition, suppository or ointment.

12. A process for preparing a compound according to any one of Claims 1 to 8, substantially as hereinbefore described.

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

Claims

**WARNING** start of CLMS field may overlap end of DESC **. the solution was cooled to a temperature of --60"C to--70"C. A cooled solution of 2.11 ml of boron tribromide in 15 ml of methylene chloride was then gradually added. The mixture was kept at a low temperature for 1 hour and then at room temperature for 24 hours. Whilst cooling the mixture with brine, 45 ml of water were gradually added. The aqueous phase was neutralized with 1N sodium hydroxide. The organic phase was separated, washed with water and dried and the solvent evaporated off. The residual oil was dissolved in ethanol saturated with hydrogen chloride and then the solvent was evaporated off. The residue was recrystallized from a 1:9 by volume mixture of ethanol and ethyl acetate, giving 1.1 g of the desired product melting at 15o161 C. WHAT WE CLAIM IS:

1. Compounds of formula: