US3471573A

US3471573A - Choleretic nuclear-substituted phenylalkyl carbinols

Info

Publication number: US3471573A
Application number: US492877A
Authority: US
Inventors: Giancarlo Bramanti; Luigi Turbanti
Original assignee: Individual
Current assignee: Individual
Priority date: 1965-10-04
Filing date: 1965-10-04
Publication date: 1969-10-07
Anticipated expiration: 1986-10-07

Description

United States Patent 3,471,573 CHOLERETIC NUCLEAR-SUBSTITUTED PHENYL- ALKYL CARBINOLS Giancarlo Bramanti, Via Zerboglio 25, and Llllgl Turbanti, Via Bonaccorso da Padule 10, both of Pisa, Italy No Drawing. Filed Oct. 4, 1965, Ser. No. 492,877 Int. Cl. C07c 43/20, 39/02 US. Cl. 260-613 4 Claims ABSTRACT OF THE DISCLOSURE This invention relates to compounds exhibiting marked choleretic activity. These compounds of the invention are phenyl-alkyl carbinols and phenyl-cycloalkyl carbinols whose aromatic rings are substituted by at least one hydroxyl and/oralkoxy group.

The main purpose of this invention consists in the provision of a novel series of compounds of the above type, having a marked choleretic activity.

The invention covers also a method for producing said compounds. The compounds according to the invention may be expressed by the following formula:

Patented Oct. 7, 1969 benzene ring. The compounds according to the invention show a high choleretic activity, which is unusually marked within the first two hours after the administration of the drug, while an appreciable attenuation of said activity is noticed in the following hours.

Such course of the activity during the course of time, is of fundamental importance, since it is preferable that the choleretic action be exerted in the course of digestion, and not beyond it; thus, the drug will simulate the physiological behaviour.

Owing to the above-mentioned properties, the compounds according to the invention may be viewed as drugs useful in the therapy of intestinal dysfunctions originating from slight or middle hepatic insufiiciencies.

The choleretic activity of the products of the invention has been ascertained by means of pharmacological tests uonducted on rats and dogs by the method of extemporary biliary fistula, the drugs having been administered by oesophagic and intestinal scoop. The minimal doses, ascertained as efiicacious for the above-stated two animal species, are of ab. 25 mg./kg. of body weight.

The acute toxicity of the compounds in question, as tested on rats for the different administration routes, is significantly low, since doses 20 10 times greater than the efiicacious one are needed to cause the death of 50% of animals to which the drug was given by month, while the subacute toxicity tests, continued through a time of 3 weeks, and with doses 5-6 times greater than the effective dose, did not result in any detrimental effect.

A confirmation of the expected pharmacologic-therapeutic properties has been found by clinical experimentation, since the compounds according to the invention have permitted the obtention of significant beneficial effects in the treatment of morbid conditions of liver and hepatic ducts.

In order to demonstrate the effective pharmacologic activity of the compounds according to the invention, when compared with the traditional and conventional drugs, the absolute values of increments in the biliary se- HO HO l I cretion, in respect of controls-and above all in the first CHEOQ, G or HOQ two hours after the administration of drugs, are tabulated below:

TABLE Increments in respect of initial value (1111.) Z increment in Dose, after the respect of control mgJkg.

Compound per 05 151; hr. 2nd hr. 3rd hr. 4th hr. 5th hr. 1-2 hrs. Total Controls (blank) 04 02 ll 0. 10 13 0 3,5-dimethoxy-4-hydroxyphenyl-n-butyl-carbmol. 28 12 04 08 13 46 58 3-ethoxy-4-hydroxyphenyl-n-butyl-carbinol 50 36 +0. 17 0 07 07 59 79 3-hydroxy-4-methoxyphenyl-carbinol 07 03 06 11 36 50 3-methoxy-4-hydroxyphenyl-cyclohexyl-carbmol- 24 24 0 07 54 1. ()5 4-hydroxyphenyl-n-butyl-carbinol 28 07 09 02 74 1. 15 3,4-dihydroxyphenyl-nbutyl-carbinol 0 03 09 12 29 42 Cholipin-l-phenyl-pentanol-verecolen 50 22 07 06 10 18 35 40 (l-hydroxy-4-phenyl-cyclohexyl)butyuic acid. 50 11 18 08 01 05 35 75 Phenylamyl Flubilar-sodium camphoratm. 50 22 14 01 06 11 42 58 Oragallin-diethylamide of the a-chloro-pyn'daz acid 60 +.14 02 05 0 14 .22 .38

and when R is 60 The compounds in question were obtained by causing a substituted aromatic aldahyde to react with the suitable alkylmagnesium halogenide in ether or tetrahydrofuran, whereupon the resulting complex compound is decomposed by means of diluted, aqueous mineral acids, or by a solution of ammonium chloride, the reaction solvent is evaporated, and aryl-alkyl carbinol is isolated by crystallization or distillation.

A particular feature of this invention consists in that the aryl-alkyl carbinols having phenolic OH can be obtained, by the above-described method, starting from the CHaO R The main feature of compounds according to the invention consists in that the biological activity is strictly de- 70 pendent on the presence of the substituent OH in the then corresponding aldehydes, which phenolic groups are either free, or esterified, as shown in the diagram below:

I HOG-@H-alkyl The following, non restrictive examples, are only intended to provide for a better understanding of the invention.

3-ethoxy 4-hydroxy-phenyl-butyl-carbinol Formula I, wherein OCzH R l and wherein R is --C H n.

38 g. (1.56 mole) of Mg and one iodine crystal were put into a three-liters, round-bottomed, four-necked flask, fitted with a reflux condenser having a CaCl stopper, sealed stirrer, dropping funnel and pipe for inert gas; then, while stirring, 80 ml. of an ether solution containing 86 ml of n-butyl-bromide were added in two or three portions, allowing the same time a flow of dry N to pass through with water, and additional ether solution of n-butyl bromide was added at a rate such as to keep the ether at its boiling point, until attaining a total addition of 213.6 g. (1.56 mole) of butyl bromide, in 300 ml, of ether. After the end of such addition, the stirring was continued for one hour more, then, a solution of 44 g. of ethyl-vanillin in 880 ml. of ether was added dropwise through the funnel, in a time of 90 min., again While stirring and under an atmosphere of dry nitrogen.

After the end of the ethyl-vanillin addition, the stirring was continued for one hour more, whereupon the reaction mixture was slowly poured on 3 kg. of crushed ice, and finally acidified with diluted H 80 using Congo red as indicator.

The supernatant ether layer was decanted, and the aqueous layer was repeatedly extracted with ether; the ether extracts were put together, washed with an aqueous solution of bicarbonate, dried on Na SO and evaporated. The solid residue thus obtained was recrystallized from a little benzene: M.P. 75 C. (Kofler).

Formula I, wherein:

3-hydroxy-4-methoxy-phenyl-carbinol 80.16 g. (0.585 mole) of n-butyl-bromide dissolved in 300 ml. of ether were added to 14.2 g. (0.585 mole) of Mg. in the same manner as stated in the preceding example, and then a solution of 25.6 g. (.1 mole) of 3-benzoyloxy-4-methoxy-benzaldehyde in 400 ml. of ether was added in the reaction flask, again by the same procedure. The reaction mixture was finally slowly poured on ab. 1 kg. of ice-water and then acidified with diluted H 50 The supernatant ether layer was decanted, the aqueous layer was repeatedly extracted with ether, the ether extracts were put together, and repeatedly shaken with a 5% solution of NaOH; the alkaline solutions were put together and saturated with CO and the supernantant oily layer was extracted with ether; the oily residue left by the washed dehydrated and evaporated ether extract, was crystallized from petroleum ether, and after the subsequent purification by crystallization from benzene and petroleum ether, gave colorless crystals M.P. 44 C. (Kofler).

By the above described general methods, and following the precedures as stated in the foregoing examples, the following products have been obtained;

( 1) 3,5 -dimethoxy-4-hydroxyphenyl-n-butyl-carbinol Formula I, wherein:

Q 1. H0 H0 OH; and R, iS C4H9I1.

crystals, M.P. 102 C.

(2) 3,4-dihydroxyphenyl-n-butyl-carbinol Formula I, wherein:

Q is H0 H0 and R is --C H n.

Crystals: M.P. C.

(3) 3-methoxy-4-hydroxyphenyl-cyclohexyl-carbinol Formula I, wherein:

CHaO

Crystals: M.P. 139 C.

(4) 4-hexydroxyphenyl-n-butyl-carbinol Formula I, wherein:

R Q HO and wherein R is C H n. Colorless crystals, M.P. 76-7 C.

and R is References Cited UNITED STATES PATENTS 7/ 1958 Norton et al. 1/ 1967 Week 260-625 XR OTHER REFERENCES Kharasch et al.: Grignard Reactions of Non metallic Substances 1954), pages 276, 282.

Loev et al.: J.A.C.S., vol. 78 (1956), pages 40834086.

Loev et al.: J.A.C.S. vol. 78 (1956), pages 6095-6098.

BERNARD HELFIN, Primary Examiner US. Cl. X.R. 260-624, 625, 999