FI58326B - FOERFARANDE FOER FRAMSTAELLNING AV SOM BETA-ADRENERGISKT STIMULERANDE MEDEL ANVAENDBARA ALFA-AMINOMETHYL-4-HYDROXI-3-METHYLSULFONYL-METHYL-BENZYL ALCOHOL - Google Patents

Description

—I rRl .... ANNOUNCEMENT r Α7Λ / Μα (11) UTLÄGGN I NGSSKRIFT 5 8 3 2 6 v ^ (51) Kv.ik? / In ».a.3 C 07 C 14-7 / 12 FINLAND —FINLAND (21) P «MnttIi» k.mu »-P» tt »K« öknln | 77Ö / 73 (22) HakemttpUvi - AfMttknln | * d «| 1 ^ .03.73 (23) AlkupCIvi — Gl (tl | h * t * dt * 1 ^ .03.73 (41) Tullut lulklMlal - BIMt offmtllg 21.09.73 PUmtt j. R.kllttrll »Uttu · NBrtMkilpwonJ. LariJ.M», ...

Patent · och ragisteratyralaan 'Anaeiun utiagd och uti. »Krtft * n pubiicmd 30.09.80 (32) (33) (31) found utuolkuu * —B« gtrd priority 20.03.72 USA (us) 236177 (71) Smith Kline & French Laboratories, 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, USA (72) Carl Kaiser, Haddon Heights, New Jersey, Stephen Torey Ross, Berwyn, Pennsylvania, USA (7 ^) Berggren Oy Ab (5M Method Useful as 0-adrenergic stimulants

Or-aminomethyl-1 + -hydroxy-3-methylsulfonyl-methylbenzyl for the preparation of alcohols - For the preparation of β-adrenergic stimuli with a further preparation of β-aminomethyl-U-hydroxy-3-methylsulfonyl-methylbenzyl alcohol

The present invention relates to a process for the preparation of novel α-aminomethyl-4-hydroxy-3-methylsulfonylmethylbenzyl alcohols having useful pharmacodynamic activity. More specifically, the compounds of the invention can be used as 3-adrenergic stimulants with relatively higher activity in respiratory smooth muscle than in cardiac muscle. As a result, these compounds have a direct bronchodilator effect and a very low cardiovascular effect, which has been found in conventional pharmacological experiments.

Two in vitro test systems were used to determine selective 3-stimulus activity: (1) effect on the spontaneous state of the guinea pig tracheal chain to measure the effect of 3-stimulus (immediate relaxant) on airway smooth muscle, and (2) effect on guinea pig right-sided 3-stage atrial spontaneous to measure the effect on the heart muscle. The compounds of the invention have a selective bronchodilator property because they are active in the above-mentioned Experiment (1) at a lower dose than that required in the above-mentioned Experiment (2), thus obtaining a positive separation ratio.

58326

The compounds of the invention can be represented by the following general structural formula

B

/ X 0

H

H0-X''1 wherein R1 is tert-butyl, cyclobutyl, 2- (4-hydroxy-phenyl) -1-methylethyl or 2- (4-methoxyphenyl) -1,1-dimethyl.

The compounds of the invention may be used in the form of a pharmaceutically acceptable acid addition salt having the same utility as the free base. Such salts, which are prepared by methods well known in the art, can be formed with both inorganic and organic acids, e.g. ,, propionic acid, tartaric acid, salicylic acid, citric acid, glyconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, p-aminobenzoic acid, glutamic acid, benzoic acid, benzenesulfonic acid, benzene sulphonic acid,

The compounds of the invention further contain at least one asymmetric carbon atom which can be redissolved into the d- and 1-optical isomers.

A preferred compound of the invention is tert-butylaminomethyl-4-hydroxy-3- (methylsulfonylmethyl) benzyl alcohol, which soothes the spontaneous state of the guinea pig tracheal ring preparation at an ED 2 of 0.0051 mcg / ml, while increasing guinea pig right atrial rate at an ED 2 of 8.28 mcg / ml. These activities give an absolute separation ratio of 1620, which is a 33- to 0-fold improvement over the corresponding activity of d, l-isoproterenol (absolute separation ratio = 0.5) in similar in vitro preparations. According to the invention, R'f 1 la combines steel] »j. a- /? With - (4-hydroxyphenyl) -1-methylaminaminomethyl) -4-hydroxy-3-methylsulfonylmethylbenzyl alcohol, the aforementioned ratio of the above is 254, which is a 508-fold improvement over d, 1-isoproterenol.

3 58326

The compounds of the invention are prepared as shown in the following sequence of reactions: 0 ϋΓ-ΓΗ / v \\ CH SO Na 3 C ™ fft -CH 3 2 CH 3 SO 2 Mg 0 0 Br

/ v II / v Il I

h3cso2ch2- | ^ N- 6-ch3 c6h5ch2ci h3cso2ch2_ | ^ N_ c-ch2 H0 ~ ^ J PHT 06Η50Η2Ο - ^ / o il H ^ CSO-CH2 - ^ N - C-CH5-NR, p, r _ 3 2 7-, 1 Ja-0 y ^ C6H5CH2O1 ^ / J 2 6 5 3H2 is

H3CSO2CH2-ki2N1-CH-CH2-NHR1 Formula II

HO -% / in which formulas R 1 is as defined in formula I. Thus, as shown above, 4-hydroxyphenol is chloromethylated with formaldehyde and hydrochloric acid and treated with the sodium or magnesium salt of methylsulphinic acid to give a methylsulphonylmethyl derivative. The latter is brominated and the resulting α-bromophenol is reacted with N-benzylamine to give the corresponding α-benzylaminophenone. This derivative is catalytically hydrogenated with palladium on carbon to give a debenzylated alkylsulfonylmethylbenzyl alcohol product.

It has been found that the aminoketone derivatives of formula II in the above reaction series are useful intermediates.

The compounds of the invention may be administered orally or parenterally in conventional unit dosage forms such as tablets, capsules, injectables, aerosols, etc., by combining an appropriate dose of a compound of formula I with a carrier in accordance with accepted pharmaceutical practice.

11 58326

The foregoing is a general description of how the compounds of the invention may be prepared. The following examples illustrate the preparation of specific compounds with β-adrenergic stimulant activity.

Example 1

To a mixture of 260 ml of $ 37 formaldehyde and 1800 ml of concentrated hydrochloric acid is added 400 g of p-hydroxyacetophenone at a temperature of about 45 ° C. The mixture is kept at 50 ° C for two hours, filtered and washed with water to give 3-chloromethyl-4-hydroxyacetophenone, m.p. 154 ° C, decomp.

A mixture of 40 g of 3-chloromethyl-4-hydroxyacetophenone and 26 g of magnesium methylsulphinate in 500 ml of ethanol is heated under reflux with stirring for 3 hours. The reaction mixture is then concentrated in vacuo. The resulting oil is redissolved in chloroform and washed with water. The chloroform is dried and evaporated to give 4-hydroxy-3-methylsulfonylmethylacetophenone, m.p. 206.5 to 208.5 ° C.

A mixture of 14.0 g of 4-hydroxy-3-methylsulfonylmethylacetophenone, 9.3 g of potassium carbonate, 7.8 ml of benzyl chloride and a catalytic amount of sodium iodide in 250 ml of acetone and 250 ml of water is heated to reflux and stirring for 16 hours. The acetone is removed and the aqueous phase is extracted with chloroform, washed with water, dried and evaporated to give an oil which is recrystallized from isopropyl alcohol to give crystalline 4-benzyloxy-3-methylsulphonylmethylacetophenone, m.p. 94-97 ° C.

To a stirred solution of 7.7 g of 4-benzyloxy-3-methylsulfonylmethylacetophenone and 2.15 g of 2-pyrrolidone in 300 ml of tetrahydrofuran is added 12.5 g of pyrrolidone hydrotribromide (PHT) and stirring is continued for 56 hours at room temperature. The mixture is filtered into tea and the filtrate is concentrated in vacuo to give an oil which crystallizes on standing. The crystals are redissolved in chloroform. The chloroform solution is washed with water, dried and concentrated to give a solid which is recrystallized from acetonitrile to give 4-benzyloxy-α-bromo-3-methylsulfone, dimethylacetophenone, m.p. L43-L44 ° C. The latter (100 g) is dissolved in 1 liter of acetonitrile and 82 g of M-benzyl-N-t-butylamine are added. The mixture is stirred and refluxed for 4 hours, cooled and diluted with ether. Crystalline N-benzyl-N-t-butylamine hydrobromide is filtered off. The filtrate is acidified with ethereal hydrochloric acid and ether is then added to give 4-benzyloxy-α (N-benzyl-N-t-butylamino) -3-methylsulfonylmethylacetophenone hydrochloride, m.p. 152-15 ^ 0.

A mixture of 20 g of 4-benzyloxy-α (N-benzyl-Nt-butylamino) -3-methylsulfonylmethylacetophenone hydrochloride, 10 g of 5% palladium on carbon and 125 ml of ethanol is hydrogenated in a Parr apparatus at room temperature. using an initial hydrogen pressure of H, 2 kp / cm. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from ether-ethanol to give α- (t-butylaminomethyl) -4-hydroxy-1'-methylsulfonylmethylbenzyl alcohol hydrochloride, m.p. 219-220 ° C.

Example 2 Using the procedure of Example 1, 4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone is reacted with N-benzyl- [5-benzyloxyphenyl-isopropyl] -amine to give α- [2- (4-hydroxy-phenyl) -1-methyl] after hydrogenation. -etyyliaminometyyli7-i4-hydroxy-3-metyylisulfonyylime-tyylibentsyylialkoholi. The compound is an amorphous substance without a clear melting point.

Example 3

Following the procedure of Example 1, 4-benzyloxy-α-bromo-3-methylsulfonylmethylacetophenone is reacted with N-benzyl- [5-methoxyphenyl-t-butyl] -amine, followed by hydrogenation to give α- [2- (4-methoxyphenyl) -1,11]. -dimethylethylaminomethyl-14-hydroxy-3-methylsulfonylmethylbenzyl alcohol.

The alcohol is treated with hydrogen chloride in methanol-ether to give α-Z1-C4-methoxyphenyl-1H-dimethylethylaminomethyl-4- (4-hydroxy-3-methylsulfonylmethylbenzyl alcohol hydrochloride) as colorless crystals, m.p. L80-L82 ° C.

Similarly, the use of N-benzylcyclobutylamine in the above reaction followed by hydrogenation and treatment of the resulting alcohol with hydrogen chloride in methanol-ether gives α- (cyclobutylaminomethyl) -4-hydroxy-3-methylsulfonylmethyl benzyl alcohol hydrochloride, m.p. 193 ~ 19i * 0C.

Claims (4)

6 58326 A process for the preparation of methylsulfonylmethylbenzyl alcohols or pharmaceutically acceptable salts thereof useful as β-adrenergic stimulants having the formula H H 3 CSO 2 CH 2-γ> -CH-CH 2 - ΝΗΚλ HO - wherein R 1 is tert-butyl, cyclobutyl, 2- - phenyl) -1-methylethyl or 2- (4-methoxyphenyl) -1,1-dimethylethyl, characterized in that the compound of the formula 0 h3cso2ch2 -—c-ch2-n-r1 .CHpCrH. C6H5CH2O - where R is as defined above, is hydrogenated from the catalytic Pd / C catalyst. Process for the preparation of α- (tert-butylaminomethyl-4-hydroxy-3-methylsulfonylmethylbenzyl alcohol) according to Claim 1, characterized in that 4-benzyloxy-α- (N-benzyl-N-tert-butylamino) -3-methylsulfonylmethylacetophenone is hydrated In the presence of a Pd-C catalyst. A compound for the preparation of a β-adrenergic stimulant comprising a methylsulfonylmethylbenzyl alcohol or a pharmaceutically acceptable acid addition salt, preferably a compound having the formula H W 0 H ^ CSO ^ H ^ - | -R-HO-CH2 -