DE1593928A1 - Diphenyl compounds and processes for their preparation - Google Patents

Description

Dr. Hans-Heinrich Willrath Dr. Dieter Weber

PATENT LAWYERS Telegram address! WILLPATENT Postal check: Frankfurt / Main 6763 Bank: Dresdner Bank AG. Wiesbaden

Account No. 876 807

D-62 WIESBADEN ^"the 25/11/1969 PostfaA 1327

Gustav-Fr «ytag-Str * Se 25 9 (MlJl) 17 27 20

Il / Doe

LIPHA Lyonnaiae Industrielle Pharmaceutique, 115 »Avenue Lacassagne Lyon (France)

Diphenyl compounds and processes for their preparation

Priority : 1st of April 18, 1966 based on the French application PV No. 57 987 2nd of February 23, 1967 based on the French registration P.7. No. 96 227

The invention relates to the production of new diphenyl derivatives, in particular amino alcohol derivatives of phenolic ones Diphenyl compounds. The compounds to be prepared are represented by the following formula.

OCH ₂ - OH - CH ₂ - NH - O - CH ₂ - R OH

INSPECTED 0098ΛΛ / 1780

Here, R denotes hydrogen or the hydroxyl group. According to the invention, one can also use the salts of the derivatives with inorganic or organic acids.

The compounds according to the invention can be prepared by reacting tert-butylamine or 2-amino-2-methylpropanol with (2,3-epoxypropoxy) -diphenyl of the following Formula made "

OCH ₂ - OH - OH ₂

You ·· intermediate product «let yourself be implemented Clay epiohlorohydrin is obtained with an aqueous solution of an alkali metal of the corresponding phenylphenols.

Aaino alcohol derivatives to be obtained according to the invention of diphenyl, all intermediate products can be used in chemical synthesis. You also own have a strong blocking effect on the ß-adrenergic effect and are therefore of particular importance for the Treatment of angina pectoris in humans and also of faohyarythmia.

. We already know · several connections which the · «JLkti-

0098U / 17 80 ow «nal inspected

vity, namely 1- (2'-naphthyl) -isopropylaminoethanol-2-chlorohydrate under the trade name Methalid and 3-isopropylamino-1- (2 ^l -naphthyl-1) -propanol-2-chlorohydrate under the trade name Propanolol . It has now been found that in this series of diphenyl derivatives the optionally hydraylated tertiary butylamine group reduces the toxicity of the compounds of this same series which are substituted by other amines, such as isopropylamine, to a considerable extent and consequently increases their therapeutic range of application considerably.

The activity of the facings made according to the invention was determined in different ways. In the first method, nan examines the substances in isolation Rabbit hearts kept to survive according to Langendorf's technique. Tachycardia evidence are obtained by injecting a standard dose of adrenaline into the aorta, the perfusion then being with Locke-Ringer's fluid takes place, which contains different concentrations of products to be examined, whereupon the Renewed adrenaline injection.

One more is observed for the ß-preventive substances or less complete inhibition of tachycardia in epinephrine, and the results are in the following Table I listed in the first column. Examine after returning to normal Locke-Ringer perfusion

0098U / 1780

a new adrenaline injection reduces the duration of the product's effect, i.e. a certain lack of effectiveness of the investigated prevention product. These results are recorded in Table I in the second column. That The comparison product is Nethalid (1- (2'-naphthyl) -isopropylaminoethanol-2-chlorohydrate). ■

0098U / 1780

TABLE I.

Pro.dukt concentrations and percentage of Taohycardieverhinder ung

1o minutes naoh
Perfusion of the
Product (1)

10 minutes naoh Looke-Ringer normal (2)

Nethalid 5 x (5 mg / 1)

-6 72

86

3-tert-butylamino-1- (2 ^f -phenylphenoxy) -propanol-2 2.5 x 10 " ⁵

(2.5 mg / l) 100

100

3-tert -Butylamino-1 - (2'-phenylphenoxy) propanol-2-1.25 x 10 "" ⁶ (1.25 mg / 1) 100 <f>

100

3-tert-Butylamino-1 -C 2 * -phenylphenoxyl) ■ propanol-2 0.625 x 10 " ⁶ (0.625 mg / l) 100 Ji

100

3-tert -Butylamino-1- (4 · -phenylphenoxy) -propanol-2 5 χ 1O " ⁶ (5 mg / 1) 67

89

3- (2 "-Hydroxy-1" -dimethyl-1 "-ethylamino) 1- (2 ^H -phenylphenoxy) -propanol-2, 5 x 10 ~ ⁶ (5 mg / 1) 100 Ji

90

0098AA / 1780

The second method is to examine disinversion the tension! effects of adrenaline. Deliver intravenous adrenaline injections to the anesthetized cat Hypertenaions. Naoh intravenous injection of 1 mg / kg a blocking agent of the ct-methanesulfonate receptors of phentolamine plus intravenous perfusion of 2 mg / kg / h of the same compound, the adrenaline injections produce a hypotensive response. The β-blocking agents are able to restore the hypertensive activity of adrenaline after this preparation. The response values for adrenaline can be found in the following table.

TABLE II

product

before treatment

well phentolamine

after phen duration

tolamin and in

ß-blocking agents

3-tert-hyperten-butyl-amino- sion 3-4 1- (2 »-phenyl» cm Hg phenoxy) -propanol-2 2 bis 0.5 A /

Hypertension 1.5 to 2.5 om Hg

Hypertension 3 to 4 cm Hg

3-tert-butyl (

idem

(4th

phenylphenoxy) propanol-2 5 / k / l

idem

Hypertension O, 5 2 to 3 om ed

(2 "Hydroxy-1" idem di * ethyl-1 " äthylamln ·) -, 1- (2'-phenyl- 'phenoxy) -prepanel-2 5 mf / kg / day.

idem

Hypertension y 3

009844/1780

The following exemplary embodiments explain production processes and constants of various compounds to be produced according to the invention.

EXAMPLE 1 3-tert-Butylamino-1- (2 ^tt -ph.enylphenoxy) -propanol-2

CH,

OCH ₀ - CH - CH ₀ - NH - C - CH,

² I ² I ³

OH CH ₃

A mixture of 9-04 g (0.04 mol) of o- (2,3-epoxypropoxy) diphenyl and 29.2 g (0.4 mol) of tert-butylamine is used for 10 hours. heated under reflux for a long time. The transparent solution obtained is concentrated in vacuo to a resinous residue, taken up with normal hydrochloric acid, in which the resin is readily soluble, and the acidic solution is mixed with ether washed. The aqueous phase is then made alkaline with 10 4 strength sodium hydroxide solution. It turns out an ul that one extracts with ether. This ethereal solution is dried over sodium sulfate, and after evaporation of the 3-tert-Butylamino-1- (2'-phenylphenoxy) - propanol-2 rectified. 7.9 g are obtained with K _p =

0.1 mm

009844/1780

153-155 ⁰ C.

The hydrochloride is obtained by the action of hydrogen chloride gas on a solution of the baee in absolute ethanol. This solution is brought to crystallize in the refrigerator. 7 g (52.5 #) of chlorine hydrate with P = 125 ^° C. (closed tube) are obtained.

Weight analysis set C ₁₀ H ₉ ^ NO ₉ Cl Mg ■ 335.86

^C 1 ⁹²⁶ K) ₂ Cl Mg M C. * H? 6 N $> 67 , 94 7.80 4.17 68 , 18 7.60 4.32

calculatedι found t

EXAMPLE 2

3-tert -Butylamino-1- (4'-phenylphenoxy) -propanol-2 C ₁₉ H ₂₅ HO ₂

CH, I ³

OCH ₉ - CH - CH ₉ - NH - C - CH, 2.2,

OH CH ₃

009844/1780

9.04 g (0.04 mol) of ρ- (2,3-epoxypropoxy) diphenyl (P * 91 ⁰ O) are refluxed with 29.2 g (0.4 mol) of tert-butylamine for 10 hours. Excess amine is evaporated off in vacuo and the residue is made ^{yellow in 100 cm normal hydrochloric acid at 50 to 60 0} O and then made alkaline with 10% sodium hydroxide solution. The precipitated base is recrystallized from hexane and melts at 89 ^° C.

The corresponding hydrochloride is obtained by introducing hydrogen chloride gas into a solution of the base in absolute alcohol. After recrystallization from the alcohol, it melts at 197 ^° C. (capillary tube).

Weight analysis »C ₁₀ H _{01 -NO 0} HCl Mg = 335.86

C? Ί > 94 H * N 17th 67, 69 7, 80 4, 28 67, 7, 84 4,

calculated"
found :

EXAMPLE 3

3- (2 "-hydroxy-1" -dimethyl-1 ⁿ «-äthylanino) -1- ( 2 "-phenyl phenoxy ) -propanol-2

009844/1780

CH

OCH ₀ - CH - CH ₂ - HH - C - CH ₀ OH

OH CH

A mixture of 9104 (0.04 mol) o- (2,3-epoxypropoxy) -diphenyl and 35.6 g (0.4 mol) 2-amino-2-methylpropane-p is heated under reflux for 10 hours. Excess amine which passes over below 0.06 mb at 37 ^° C. is distilled off then one obtains the compound whose K ₁ , =

* 0.15 mb 197-199 0 is. Yield »9.8 g, i.e. 76? I.

3.15 g of the base dissolved in 30 cm of dry acetone A solution of 1 g of oxalic acid in 25 µm of acetone is added to the compound. After 24 hours in the refrigerator the solution separates 2.8 g of the corresponding oxalate as crystals, the naoh Wi melt (capillary tube).

Crystals from which after washing with acetone at 116 ⁰ O Weight analysis! C ₁₉ H ₂₅ FO ₃ ^C ₂ ^H ₂ ° 4 Mg - 405.43

calculatedι found 1

C ₁₉ H ₂₅ FO ₃ C ₂ H ₂ O ₄ Mg - HJi IJi 62.21 6.71 3.46 62.03 6.75 3.42

009844/1780

Claims (1)

PATENT CLAIMS 1. Dipheny! Compound of the general formula fs C OH "CH OCH ₂ - CH - CH ₂ - HH - C - CH ₂ - R wherein R is a water atom or a hydroxyl group means, and their inorganic and organic addition salts. 2. 3-tert-Butylaeino-1- (2 · -phenylphenoxy) -propanol-2 3 · 3-tert-Butylaaino-1- (4'-phenylphenoxy) -propanol-2 4. 3- (2 "-Hydroxy-1" -di «ethyl-ethyla-ino) -1- (2-phenylphenoxy) -propanol-2 5. Process for the production of τοη Diphenylrerbindungen and their inorganic and organic addition salts of the formula 009844/1780 159192G 0CH ₀ - CH ² I. OH CH .XO - R where H is Wasaeiatoff or the hydroxyl group, characterized in that an amine derivative of the formula C - CH-, CH, in what?. the meaning given above an epoxy derivative from i'ornel ];> nier.siert. 0098 ^ / 1 ^ 80 BAD ORlQINAt 6. Use of a diphenyl compound according to claim 1 as a lubricant against angina pectoria and tachyarythijaie. ORIGINAL INSPECTED 009844/1780