US3410944A

US3410944A - Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof

Info

Publication number: US3410944A
Application number: US435344A
Authority: US
Inventors: Volkert Claassen; Jan Van Dijk; Hendrik Durk Moed
Original assignee: US Philips Corp
Current assignee: US Philips Corp; North American Philips Co Inc
Priority date: 1964-02-27
Filing date: 1965-02-25
Publication date: 1968-11-12
Anticipated expiration: 1985-11-12
Also published as: AT264502B; FR1483718A; NL6401871A; SE339481B; CH539604A; DE1293782B; CH472368A; CH503692A; DK116740B; AT270618B; GB1111451A; BE660244A; BR6567446D0; AT261590B; ES309809A1; DK118827B; AT268252B; FR4404M

Description

United States Patent ABSTRACT OF THE DISCLOSURE 1 -(4 hydroxyphenyl) 2-{2-(4-hydroxyphenyl) ethylamino} propanol and salts thereof. These compounds have uterospasmolytic activities with a minimum of hypotensive activity. This abstract is not intended to be a description of the invention defined by the claims.

The invention relates to a new compound of the FormulaI and salts thereof.

- Of these compounds an important pharmacologically activity was found. It has been found inter alia that the compound has a satisfactory uterospasmolytic and broncholytic activity, while also a considerable improvement of the muscular circulation occurs when this substance is administered.

' On the basis of the very strong uterospasmolytic activity the compound and its salts are to be considered in particular to be used, after being brought in a therapeutic form of administration known per se, in the treatment of pregnant women with threatened abortion and in the treatment of dysmenorrhea.

' Of some compounds of the Formula II in which R is an alkylene group, it is known that they also have a uterospasmolytic activity. However, this activity is far less strong in these known compounds. In addition, it is always associated with an undesired hypotension. .It has surprisingly been found that, although the compound according to the invention has a stronger uterospasmolytic activity this substance nevertheless less is considerably less hypotensive.

The uterospasmolytic activity was found inter alia in experiments in which the influence on the spasms, pro duced in the uteri of rats by the administration of pituitrin as a spasmogen, of the compound according to the invention was compared with that of that compound of Formula II in which R is an isobutyl group, which compound is the active constituent of a therapeutic which is known under the name of Dilatol. In this case it appeared that for reaching the same spasmolytic effect as with the known compound, only half of the quantity of the new compound is necessary.

The dilference in hypotensive action between the two compounds was found in experiments in which cats were used as experimental animals. It was found that the known compound has a hypotensive effect which is approximately twice as large as the compound according to the invention.

3,410,944 Patented Nov. 12, 1968 The compound according to the invention and its salts can be prepared according to methods which are known per se for the preparation of this type of compounds .and according to methods analogous thereto.

(A) A particularly suitable method is that in which a ketone of the Formula III or a salt thereof, in which formula Y and Y are possibly etherified or esterified hydroxy groups, is converted into the alcohol of the Formula I by reduction if required followed by hydrolysis or hydroge'nolysis of esterified or etherified hydroxy groups Y and/ or Y'.

The aminoketones of the Formula IH can be prepared, for example, by reaction of an amine of the Formula IV with a halogenide of the Formula V As etherified hydroxy groups Y and/or Y are to be considered preferably ar-alkoxy groups, for example, benzyloxy-, diphenyl-, methoxyor triphenylmethoxy groups. As esterified hydroxy groups Y and/or Y" are to be considered, for example, hydroxy groups esterified with lower fatty acids, for example, acetic acid, or with toluenesulphonic acid.

Very good results are obtained if start is made from the aminoketone of the Formula III in which Y and/or Y' represent benzyloxy groups which are converted intov free hydroxy groups during or after the reduction of the keto group to the carbinol group by catalytic hydrogenation.

The reduction of the keto group to the carbinol group may be carried out in any manner known for this type of reduction, for example, by catalytic hydrogenation by means of Ni, Pt or 'Pd as a catalyst, or by reduction with aluminum amalgam. Very good results are obtained also when this reduction is carried out by means of a complex metal hydride, for example, with LiAlH, or with NaBH In addition, the compounds according to the invention may be prepared by reaction of a. compound of the Formula VI with a compound of the Formula VII where Y and Y have the above indicated meanings and Z and X are groups which, during the coupling reaction,

possibly after reduction, form the secondary amino group. As examples of these reactions which may be carried out in manners known for this type of reactions may be mentioned:

(B) Alkylation of an amine of the Formula VIII or a salt thereof with a halogenide of the Formula IX 3 (C) Alkylation of an amine of the Formula X or a salt thereof with a halogenide of the Formula XI (D) Reductive alkylation of an amine of the Formula VIII with a carbonyl compound of the Formula XII (E) Reductive alkylation of an amine of the Formula X with a carbonyl compound of. the Formula XIII (F) Reaction of an amine of the Formula VIII with an acid anhydride or an acid halogenide of the Formula XIV followed by reduction of the intermediately formed acid amide in which formula Q is a radical of the Formula or a halogen atom.

The reduction of the intermediately formed acid amide to the secondary amide is preferably carried out by means of a complex metal hydride or metal alkyl hydride, for example, LiAlH or diisobutylaluminiumhydride.

As was the case with the reaction described sub A etherified or esterified hydroxy groups Y and/or Y are converted into free hydroxy groups by hydrolysis or by hydrogenolysis, if desired after the reactions described sub B to F.

Since in the compound according to the invention two asymmetric carbon atoms occur, it may be obtained in various stereo-isomeric forms.

If in this manner during the preparation two racemates are obtained, these may be separated by commonly used methods, by fractional crystallisation. Also by methods known per se the separate optical antipodes may be prepared, either by resolution of the racemates, or by choice of optically active starting substances during the synthesis.

Both the free base and salts of the compound according to the invention can be used for the preparation of new pharmaceutical compositions. As salts are to be considered, for example, acid addition salts of the base of the Formula I with hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, sul-famic acid, tartaric acid, citric acid and acetic acid.

The pharmacologically active substances may be processed in any known manner to pharmaceutical compositions by mixing with or dissolving in solid or liquid carrier materials commonly used in pharmacy, for example, starch, talcum powder, lactose, gelatin, sodium carboxy methyl cellulose, magnesium stearate and/or mixtures thereof as solid carrier materials and, for example, water rendered isotonic with blood by means of salt, or water mixed with, for example, glycerin as liquid carrier. In this manner, according to the invention, new pharmaceutical compositions such as injection liquids, powders and solid pharmaceutical dosage unit forms, such as tablets, coated tablets and suppositories, are obtained which are characterized by a content of the new compound of the Formula I or a salt thereof.

4 EXAMPLE I.--1- (4-hydroxyphenyl) -2-{2- (4-hydroxyphenyl) -ethylamino}propano1 A solution of 44 g. of 2-bromo-4'-benzyloxypropiophenone and 44 lg. of 2-(4-methoxyphenyl)ethylamine in 270 ml. of ethanol was refluxed for three hours. Then the ethanol was distilled ofi in vacuo and the concentrate mixed with ether. The resulting crystallisate was sucked off after which the filtrate was mixed with an excess of 2 N hydrochloric acid. As a result of this the hydrochloride of 4-benzyloxy-2-{2- (4-methoxyphenyl ethylamino}propiophenone slowly crystallized. This substance was also sucked off, washed with water and alcohol, and dried in vacuo. After recrystallization from dilute alcohol the yield was 25.5 g. of a product with melting point 217218 C.

12 g. of the product thus obtained were dissolved in a. mixture of 300 ml. of ethanol and m1. of water. After 42 ml. of 1% palladiumchloride solution and 3.9 g. of N orit had been added to this solution it was hydrogenated at room temperature and at a pressure of 1.1 atm. until approximately 760 ml. of hydrogen had been taken up. Then the catalyst was removed by filtration and the solvent of the filtered solution was evaporated entirely in vacuo.

The resulting residue, which consisted of the hydrochloride of 4-hydroxy-2-{2-(4-methoxyphenyl)ethylamino}propiophenone, was mixed with 30 ml. of a 48% hydrobromic acid solution and the mixture was boiled until no methylbromide developed any more, which was the case after approximately 45 minutes. Then the reaction mixture was stored in the refrigerator, after which the hydrobromide of 4'-hydroxy-2-{2-(4-hydroxyphenyl)- ethylamino}propiophenone crystallized. It was sucked olf and converted into the hydrochloride by again dissolving the resulting substance in water, discoloring the solution with a little Norit and then adding an equal volume of concentrated hydrochloric acid. As a result of this the hydrochloride crystallized. The yield was 9.6 g. of a product with melting point 136138. After this product had been recrystallized once again it was reduced to the amino alcohol.

For this purpose a solution of 3.2 g. of the hydrochloride in 160 ml. of distilled water was provided with 0.5 g. of Norit and 8 ml. of 1% palladiumchloride solution and the mixture was hydrogenated at room temperature and at a pressure of 1.1 atm. until no hydrogen was taken up any more. The catalyst was then removed by filtration, after which the filtrate was concentrated in vacuo. To the concentrated solution of the reduced product was then added an excess of dilute ammonia, as a result of which the base of the l-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino} propanol precipitated as a tough mass. After the mixture had been stored in the refrigerator for some time, the product was sucked off, washed with water and dried in vacuo. This base was a resinous mass of melting point of approximately 8890 C. Yield 2.3 g.

Example II A solution of 12.76 g. of 2-bromo-4' benzyloxypropiophenone, 9.08 g. of 2-(4-benzyloxyphenyl)ethylamine and 4.44 g. of thiethylamine in 40 ml. of ethanol was boiled for three hours. The solution was partially evaporated as a result of which some substance crystallized out. To the mixture were added ml. of water and 3 ml. of ether and the non-dissolved substance (hydrobromide of the reaction product) was removed by filtration. The two layers of the filtrate were separated, the ether layer was washed once again with water and then mixed with an excess of 4 N hydrochloric acid. After all the hydrochloride of the. reaction product had crystallized, it was sucked 01f, washed with water and ether and dried in vacuo over KOH. The yield was 10.3 g. of hydrochloride of 4'-benzyloxy-2-{2- 4-benzyloxyphenyl ethylamino} propiophenone with melting point 202204 A solution of 2.00 g. of this product in 60 ml. of 80% ethanol was hydrogenated until the two benzyl groups had been removed hydrogenolytically, which appeared from a considerable decrease of the hydrogenation rate. Then the catalyst was filtered off and the alcohol removed from the filtrate for the greater part by distilling it off the vacuo. The resulting concentrate was diluted with water and again hydrogenated until no hydrogen was taken up any longer. Then the catalyst was filtered off and the aqueous solution was evaporated in vacuo until it turned cloudy. After some time the hydrochloride of 1-(4- hydroxyphenyl)-2 {2 (4-hydroxyphenyl)ethylamino} propanol crystallized out. It was sucked off sharply and dried in vacuo. The yield was 0.55 g. of a product with melting point 183186 C. (decomposition). The char-acteristic UV. absorption spectrum showed a maximum at 267.5 m (@3310).

Example 111 3.45 g. of sodium borohydride were dissolved in a mixture of 75 ml. of ethanol and 1.5 ml. of 2 N sodium hydroxide solution. To this solution was added a solution of g. of hydrochloride of 4'-benzyloxy-2-{2-(4- benzyloxyphenyl)ethylamino}propiophen0ne (Example II) in 450 ml. of methanol, to which 1.2 g. of sodium hydroxide (in a few mls. of water) had been added. The mixture was boiled for three hours and then evaporated in vacuo to approximately 300 g. of residue. Then again 300 ml. of Water were added and once again evaporated to approximately 250 g. The separated product Was extracted with totally approximately 500 ml. of benzene (4 extractions). The solution in benzene was then dried on sodium sulphate and evaporated to approximately 15 g. of residue. By diluting this residue with ml. of diethylether 7.4 g. of 1- 4-benzyloxphenyl -2-{2- (4-benzyloxyphenyl ethylamino} propanol crystallized with melting point 97.5- 99. The product was once again crystallized from ethanol and then debenzylated hydrogenolytically. This was effected by hydrogenating a suspension of 3.88 g. in 80 ml. of approximately 60% ethanol and 2.2 ml. of 3.04 N hydrochloric acid in the above described manner. After removing the catalyst, the ethanolic solution, after dilution with 50 ml. of water, was evaporated in vacuo to 5.5

g. As a result of this the hydrochloride of 1-(4-hydroxyphenyl)-,2-{2-(4-hydrox.yphenyl)ethylamino} propanol crystallized out. By diluting a solution in approximately 9 ml. of ethanol of the crystallized product with approximately ml. of absolute ether 2.38 g. of the above hydrochloride were obtained with melting point 193195 (decomposition). The characteristic UV. absorption spectrum corresponded to that of the final product of Example II.

What is claimed is:

1. A liquid uterospasmolytic composition containing a compound selected from the group consisting of 1-(4- hydroxyphenyl -2-{2- (4-hydroxyphenyl) ethylamino} propanol and the physiologically non-toxic acid addition salts thereof and a liquid non-toxic pharmaceutical carner.

2. A solid uterospasmolytic composition containing a compound selected from the group consisting of 1-(4- hydroxyphenyl -2-{2- (4-hydroxyphenyl) ethylamino} propanol and the physiologically non-toxic acid addition salts thereof and a solid non-toxic pharmaceutical carrier.

3. A compound selected from the group consisting of 1 (4-hydroxyphenyl) 2-{2-(4-hydroxypheny1)ethylamino} propanol and the physiologically non-toxic acid addition salts thereof.

4 1-(4-hydroxyphenyl)-2-{2-(4-hydroxlyphenyl)ethylamino} propanol.

5. A physiologically non-toxic acid addition salt of 1- (4-hydroxyphenyl)-2-{2-(4 hydroxyphenyl)ethylamino} propanol.

References Cited UNITED STATES PATENTS 2,661,373 12/1953 Kulz et a]. 260570.6 3,211,792 10/1965 Osbond et al 260570.6 3,250,803 5/1966 Dijk 260570.6 XR

FOREIGN PATENTS 212,209 4/1956 Australia. 623,286 7/ 1961 Canada.

86,359 11/1956 Netherlands. 228,786 8/ 1963 Austria.

CHARLES B. PARKER, Primary Examiner. R. HINES, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,410,944 November 12, 1968 Volkert Claassen et al.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 53, cancel "less". Column 5, line 8, "distilling it off the vacuo" should read distilling it off in vacuo Signed and sealed this 17th day of March 1970.

(SEAL) Attest:

Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer WILLIAM E. SCHUYLER, JR.