IL27406A - Stable acid addition salts of bis-(4-hydroxyphenyl)-(quinolyl-2)-methane and their preparation - Google Patents

Stable acid addition salts of bis-(4-hydroxyphenyl)-(quinolyl-2)-methane and their preparation

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Publication number
IL27406A
IL27406A IL2740667A IL2740667A IL27406A IL 27406 A IL27406 A IL 27406A IL 2740667 A IL2740667 A IL 2740667A IL 2740667 A IL2740667 A IL 2740667A IL 27406 A IL27406 A IL 27406A
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IL
Israel
Prior art keywords
bis
methane
hydroxyphenyl
quinolyl
compositions
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Application number
IL2740667A
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Thomae Gmbh Dr K
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Priority to IL2740667A priority Critical patent/IL27406A/en
Publication of IL27406A publication Critical patent/IL27406A/en

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

27406/2 onjam Stable acid addition salts of bis ( -h droxy henyl)-(quinol 1-2)- methane and their preparation DR. KARL THOMAE G.m.b.H.
C: 5996 27406/2 The invention consists in novel acid addition salts of bis-(4-bydroxyphenyl)-(quinolyl-2)-methane having pharmaceutical properties.
The German Patent Specification Ho. 1,081,014 and the British Patent Specification No. 735,683 describe the preparation of bis-(4-hydrophenyl)-quinolyl or iso-quinolyl methanes of the formula wherein Y is a hydroxy, alkoxy or acyloxy group, to are hydrogen or alkyl, aryl, aralkyl, hydroxy, acyloxy or alkoxy groups, R1 is hydrogen or alkyl, and Quin is an unsubstituted or optionally alkyl substituted quinolyl or isoquinolyl radical attached in its 1- or 3- position to the methane carbon atom.
One of the compounds of formula I above thus described is bis-(4-hydroxyphenyl)-(quinolyl-2)«methane which has an excellent laxative activity and also a very low toxicity.
These compounds are prepared by the reaction of a compound of the formula 27406/2 with a phenol or a phenol derivative of the formula Y in the presence of a water removing agent which may be an acid such as sulfuric4 ydrochloric or phosphoric acid, or, for example, zinc chloride, a phosphorus halide, or phosphorus pentoxide, tin tetrachloride, brron trifluoride or aluminium chloride.
These patent specifications do not disclose the existence of salts of the compounds of formula I or the preparation of such salts.
The aforesaid bis-(4-hydroxyphenyl)-(quinolyl-2)~ methane which, in the freshly prepared state, exists as a colourless substance, becomes discoloured on prolonged storage. This decoloration, which is due to a slow modi* fication in the molecule, occurs very rapidly upon treatment with polar solvents, e.g. mixtures of ethanol and water, such as those normally used, for example, for granulation, the preliminary step of the tablet-making process. Formulation of pharmaceutical preparations is thus made very difficult.
It has now been found according to the invention that certain acid addition salts of this compound are considerably more stable than the free base.
The invention, therefore, consists in stable physiologically compatible acid addition salts of bis- 4-h drox hen l - uinol l-2 -methane with inor anic or 27406 2 strong organic acids. These salts are considerably more ^ stable than the free base and possess very good stomach compatabilit . They have a very good laxative action.
Thus, for example, bis-(4-hydroxyphenyl)-(quinolyl-2)-methane hydrochloride has a laxative action on humans at a dose of only 30 mg.
Preferred inorganic acida for the salt formation are hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, and preferred strong organic acid methanesulphonic acid, jg-toluenesulphonic acid and benzene-sulphonic acid.
The new salts are prepared by reacting the free base with the selected acid.
This reaction is conveniently carried out in an inert organic liquid, preferably a ketone such as acetone, or an alcohol, such as methanol or ethanol.
The invention also consists in pharmaceutical compositions comprising as active ingredient one or more stable physiologically compatible acid addition salts of bis-(4-h droxyphen 1)-( uinoly1-2)-methane together with one or more pharmaceutical carriers or excipients. Such compositions are preferably in the form of dosage units such as tablets, capsules, cachets and suppositories; or otherwise in liquid forms, e.g. syrups, suspensions or elixirs; such liquid forms preferably containing 0.1 to 1.0$ w/v (g/ml) of active ingredient. Since the bis-( -h drox p enyl)-( uinol 1-2)-methane salts are compatible with the stomach, there is no necessity to coat tablets containing these salts to form dragees. Tablets may, however, be therefore advantageously contain 10 to 250 mg. of the active ingredient. Dosage forms for oral administration preferably contain 10 to 60 mg, advantageously 20-40 mg. of active ingredient, while forms for rectal administration preferably contain 50 to 250 mg, for example about 150 mg, of active ingredient.
The following examples illustrate the invention:-Example 1 Bis-(4-hydroxyphenyl)-(quinolyl-2)-methane hydrochloride 40 g. of bis-(4-hydroxyphenyl)-(quinolyl-2)-methane are suspended in 200 ml. of acetone. Hydrogen chloride is passed into the suspension with stirring and cooling until it is saturated. The light-yellow mass of crystals formed is filtered with suction and dried. 39 g. of hydrochloride of m.pt. 205°C are obtained.
The salts stated herebelow were obtained by reaction of bis-(4-hydroxyphenyl)-(quinolyl-2 )methane-in acetone ·ore^lmQl with the corresponding acids: a) acid sulphate m.pt. = 238°C b) methanesulphonate m.pt. = 224°C c) toluenesulphonate m.pt. = 136°C d) benzenesulphonate m.pt. = 138°C e) hydrobromide m.pt. = 218°C f) acid phosphate m.pt. = 226°C The following examples describe the production of several forms of pharmaceutical preparations.
Example 2 Tablets with 40 mg. of bis-(4-hydrox phenyl)-(quinolyl-2 )- bis-(4-hydroxyphenyl)-(quinolyl-2)- ethane hydrochloride 40.0 mg lactose 118,0 mg potato starch 50.0 mg polyvinyl pyrrolidone 9.0 mg tartaric acid 1.0 mg magnesium stea ate 2.0 mg 220.0 mg Method of preparation; A mixture of active substance, lactose and potato starch is granulated through a 1.5 mm sieve with a 15$ aqueous polyvinyl pyrrolidone solution containing the dissolved tartaric acid, dried at 45°C and again granulated through a 1.5 mm sieve. The granulate is mixed with magnesium stearate and then pressed into tablets.
Tablet weight : 220 mg. Die : 9 mm.
Example 3 Suppositories with 150 mg. of bis-(4-hydroxyphenyl)- ( quinoly1-2 )-methane hydrochloride 1 suppository contains: bis-( 4-hydrophenyl) -( quinolyl-2)-methane hydrochloride 150.0 mg suppository base (e.g. Witepsol W 45) 1550.0 mg 1700.0 mg Method of preparation: The suppository base is melted, and brought to a temperature of 37°C. The finely powdered active subs is added thereto with stirring, the mixture cooled to 35°C and the melt poured into pre-cooled suppository Example 4 Suspension with 20 mg. of bis-( 4-hydroxyphenyl )-(quinolyl-2)-methane hydrochloride per 5 ml.
Composition: 100 ml. of suspension contain: bis-( 4-hydroxyphenyl )-( quinolyl-2 )-methane hydrochloride Aerosil Carboxymethyl cellulose (highly viscous) Methyl j)-hydroxybenzoate n-Propyl jD-hydroxybenzoate Cocoa essence Glycerol Sugar Dist. water 115.0 g Method of preparation: The jo-hydroxybenzoates are dissolved in water heated to 80°C, the Aerosil is suspended in this solution and then a mixture of carboxymethyl cellulose and sugar dissolved therein. The mixture is then cooled to room temperature and the finely powdered active substance suspended therein. Glycerol and cocoa essence are then added. 5 ml. of this suspension contain 20 mg. of bis- ( 4-hydroxyphenyl )-( quinolyl-2 )-methane hydrochloride . 27406/2

Claims (4)

1. Stable physiologically compatible acid addition salts of bis-(4-hydroxyphenyl)-(qidjaolyl-2)-methane with inorganic or strong organic acids.
2. Bis-(4-hydroxyphenyl)-(quinolyl-2)-methane hydrochloride
3. Bis-(4-hydrophenyl)-( uinolyl-2 )-me hane hydrogen sulphate.
4. Bis-(4-hydroxyphenyl)-(quinolyl-2)-raethane methane-sulphonate.
5. is-(4-hydroxyphenyl)-(quinolyl-2)-methane toluene-sulphonate.
6. Bis-(4-hydroxyphen 1)-( uinolyl-2)-methane benzenesulphonate.
7. Bis-(4-hydroxyphenyl)-( uinolyl-2)-me hane hydrobromide.
8. Acid bis-(4-hydroxyphenyl)-(quinolyl-2)-methane phosphate.
9. A process for the preparation of physiologically compatible stable acid addition salts of bis-( -hydroxyphenyl)-(quinolyl-2)-methane which comprises treating bis-(4-hydroxyphenyl)-(quinolyl-2)-methane with an inorganic or strong organic acid ^ an inert organic liquid.
10. A process as claimed in Claim 9, in which the organic liquid is ethanol, methanol or acetone.
11. A process as claimed in Claim 9 substantially as 27406/2 herein described with reference to Example 1.
12. Pharmaceutical compositions comprising as an active ingredient one or more acid addition salts as claimed in any one of Claims 1 to 8.
13. Compositions as claimed in Claim 12 in the form of dosage units, e.g. pills, tablets, coated tablets, capsules, cachets, or suppositories.
14. Compositions as claimed in Claim 13, in which each dosage unit contains 10 to 250 mg. of active ingredient. 1^· Orally-administrable compositions as claimed in Claim 14, containing from 10 to 60 mg., preferably 20 to 40 mg., of active ingredient per dosage unit.
16. Compositions as claimed in Claim 14 in the form of suppositories containing from 50 to 250 mg. of active ingredient per dosage unit.
17. Compositions as claimed in Claim 12 in the form of syrups, suspensions or elixirs.
18. Compositions as claimed in Claim 17 containing from 0.1 to 1.05* (w/v « g/ml) of active ingredient. 19> Compositions as claimed in Claim 12 substantially as herein described with reference to Examples 2, 3 or 4. PARTNERS
IL2740667A 1967-02-08 1967-02-08 Stable acid addition salts of bis-(4-hydroxyphenyl)-(quinolyl-2)-methane and their preparation IL27406A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
IL2740667A IL27406A (en) 1967-02-08 1967-02-08 Stable acid addition salts of bis-(4-hydroxyphenyl)-(quinolyl-2)-methane and their preparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IL2740667A IL27406A (en) 1967-02-08 1967-02-08 Stable acid addition salts of bis-(4-hydroxyphenyl)-(quinolyl-2)-methane and their preparation

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IL27406A true IL27406A (en) 1971-02-25

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