DE1543683A1 - Optically active propanolamine derivatives and processes for their preparation - Google Patents

Description

, S. STAEGER Description | ρ

Imperial Chemical Industries Limited, London, S.W.1.,

concerning: 1543683

Optically active propanolamine derivatives and processes for their preparation

The priority of filing in Great Britain on June 16, 1965

is used xn

The invention relates to new propanolamine derivatives, some of which are useful as intermediates and the others Have healing properties.

In the applicant's UK patent 994-918, certain Propanolamine derivatives with β-adrenergic blocking properties described and claimed. These compounds are racemic, i.e., optically inactive compounds, and no optically active compounds are described in the cited patent. It has been found that some of these racemic compounds and related racemic ones Compounds can be resolved into the corresponding optically active compounds, and that latter compounds have valuable properties as indicated below.

According to the invention, there are optically active propanolamine derivatives the sormel:

O. OH ₂ . GHOH. CH ₂ .HE ¹ R ²

and their salts created, where R is an optionally substituted

2
Alkyl radical and E represents a hydrogenatable radical.

R can, for example, conveniently be an alkyl radical with at most carbon atoms, such as, for example, the n-propyl, isopropyl, sec-butyl, tert-butyl or 1-methyl-n-butyl radical or several hydroxy or alkoxy radicals _? for example alkoxy radicals with a maximum of 5 carbon atoms, such as the methoxy radical, for example. If H ^ represents a substituted alkyl radical, certain examples are the 2-hydroxynpropyl radical and the 2-hydroxy-1,1-d: i-ethylethyl radical.

BAD ORIG'NAL

E can conveniently, for example, be an a-arylalkyl radical with at most 10 carbon atoms, such as the benzyl radical, or an α, α-diarylalkyl radical with a maximum of 19 carbon atoms, such as the benzhydryl radical, or the benzyloxycarbonyl radical.

As "specific examples of the compounds according to the Invention one can use (~) -1- (N-benzyl-H-isopropylamino) -3- (i-naphthyloxy) -2-propanol and (+) - 1- (N-Benzyl-N-isopropylamino) · 3- (1-naphthyloxy) -2-propanol and their salts.

Suitable salts according to the invention can be acid addition salts, e.g. salts derived from inorganic acids such as hydrochlorides, hydrobromides, phosphates and sulfates, as well as salts derived from organic acids, such as oxalates, lactates, tartrates, ο, o-di-p-toluoyltartrates, Mention acetates, salicylates and citrates.

According to a further feature of the invention is a process for the preparation of the optically active propanolamine derivatives proposed according to the invention, which consists in that a racemic propanolamine derivative of the formula:

0.CH ₂ .CHOH.CH ₂ .NR ¹ H ²

12 ·

where E and R have the meanings given above, by means of a optically active acid dissolved / and the salts formed are isolated, whereupon isolated from these under certain circumstances Salts, the optically active bases are obtained in a conventional manner.

The racemic propanolamine derivatives used as starting materials can be found in British Patent 994,918 described and claimed manner or in an analogous manner

Way to be made.
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* £ As examples of those optically suitable for this procedure ω active acids can be (+) - or (-) - 0,0-di-p-toluoylwein- - ^ acid, (+) - or (-) - tartaric acid, (+) - or (-) - camphor-10- ■ ^ sulfonic acid and (+) - or (-) - 3-bromocamphor-8-su3.foic acid mention. The process can be carried out in a dilution or solution

^; **! ΛλΑ. Vi ^ Jm ^, ^ * &. · Β «». BATH ORIGINAL

Some of the propanolamine derivatives according to the invention are suitable as intermediates because they are after hydrogenation Right-turning products are found for the treatment of heartbeat irregularities caused by cardiac glycosides how digitalis glycoside or ouabain are induced are suitable, as described in British patent application 25 473/65. Also those propanolamine derivatives according to the invention which give levorotatory bases after hydrogenation are ß-adrenergic blocking agents and are suitable for the treatment or prophylaxis of high blood pressure, pheochromocytoma and heart diseases such as angina pectoris, irregular heartbeat and coronary inefficiency.

According to a further feature of the invention, pharmaceuticals Created masses from an optically active propanolamine derivative of the formula j

0. OH ₂ . OH OH. OH ₂ . ER ¹ E ²

Ί?

where R and E have the above meanings, that after hydrogenation gives a levorotatory base, or a pharmaceutically acceptable salt of this propanolamine derivative, and one consist of pharmaceutically acceptable diluents or carriers.

As suitable masses you can e.g. tablets, capsules, aqueous or oily solutions, aqueous or oily suspensions, Emulsions, injectable aqueous or oily

Solutions or suspensions, or dispersible powders co

ο mention.
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^ The invention is explained in more detail below with reference to execution examples, purely by way of example, where ^ j .r- all quantities are based on weight: ^

cn

Example 1 ο

18.5 parts of (±) -1- (li-benzyl-N-isopropylamino) -3- ^m (1-naphthylxy) -2-propanol are dissolved in 80 parts of methanol. Zev so obtained solution becomes a solution of 21.6 parts

The mixture is ^{kept at 3 0} O for 16 hours and then filtered. The solid residue is washed with 16 parts methanol and then dried. It consists of di - [(-) - 1- (N-nemzyl-N-isopropylamino) -3- (1-naphthylo3qy) -2-propanol] - (-) - 0,0-di-p-toluoyl tartrate, m.p. .126 ° C with decay, [*] ψ -40 ° (e, 1.472% in dimethylformamide). The product can be recrystallized from methanol and then has the following properties: mp 126-127 ° C. with decomposition, [ajjp -41 »5 ° Ce, 1.303% in dimethyl formamide).

The free base can be obtained from this salt as follows:

There are 3 parts of DiQC -) - 1- (N-Benayl-ir-isopropylamino) -3- (1-naphthylozy) -2-propanol] - (-) - 0,0-di-p-toluoyltartrate with a mixture of 25 parts of sodium hydroxide solution and 20 parts of ether are shaken. The ethereal layer is separated from the mixture, dried on magnesium sulfate, filtered and evaporated. The residue consists of (-) - 1- (N-benzyl-N-isopropylamino) -3- (1-naphthyloxy) -2-propanol, P methanol).

The (±) -1- (M "-Benzyl-ir-isopropylamino) -3- (1-naphthyloxy) -2-propanol used as starting material can be generated as in Example 7 of Applicant's UK Patent Specification 994,918 will.

Example 2

The process according to Example 1 is repeated with the difference that the 21.6 parts (-) - 0,0-di-p-toluoyltartaric acid are replaced by 21.6 parts (+) - 0,0-di-p-toluoyltartaric acid . In a similar way one thus obtains di- £ (+) - 1- (l! T-Benzyl-irisopropylamino) -3- (1 -naphthylozy) -2-propanol] - (+) -0,0-di-ptoluoyltartrate, M.p. 126 ^e 0 with decay, JaJ ψ + 41.5 ° (c, 1.3% in dimethylformamide).

Example 3 *

A mixture of 10 parts of Di-Jj +) - 1- (K-Benzyl-N-isopropylaaino) -3- (i-naphthyloaqjr) -2-propanol] - (+) - 0,0-di-p-toluoyl tartrate and 80 Parts of mannitol are passed through a 60 mesh grid. Then enough of a 10% aqueous gelatin solution is added that a thick paste is formed. The slurry is passed through a 16 mm mesh screen, then passed dried at 6O ⁰ C and passed through a 20 mesh screen. The resulting granules are 6

909837/1495

BATH

iDeile alginic acid and 2 parts magnesium te arate were added. the Mixture is pressed into tablets in a manner known per se, each containing 50 mg of active ingredient. So you get Tablets that are suitable for medicinal purposes.

909837 / U95

Claims (10)

1. Optically active propanolamine derivatives of the formula i O.CH ₂ .CHOH.GH ₂ .HE ¹ E ² 1 2 where E is an optionally substituted AITryl radical and R is and their salts
where E is a gg
represents hydrogenatable radial. 2. "Compounds according to claim 1, characterized in that R represents an alkyl radical with at most 10 carbon atoms, d optionally carries one or more hydroxy or Alkoay radicals. 3. Compounds according to claim 2, characterized in that the alkoxy substituent contains at most 5 carbon atoms. 4. Compounds according to claim 1 or 2, characterized in that R is n-propyl, isopropyl, sec-butyl, tert-butyl, 1-methyl-n-butyl, 2-hydroxy-n-propyl or 2-Hydro3cy-1,1-dimethylethyl radical represents. 5. Compounds according to any one of claims 1 to 4, characterized ρ
characterized in that R represents an oc-arylalkyl radical with a maximum of 10 carbon atoms or an α, α-siarylalkyl radical with a maximum of 19 carbon atoms or the benzylocarbonyl radical. 6. Compounds according to claim 3, characterized in that ρ
R represents the benzyl or benzhydryl radical. 7. The compounds: (-) - 1- (F-Benzyl-F-isopropylamino) -3- (1-naphthyloxy) -2-propanol and its salts. 8. The compounds (+) - 1- (BT-Benzyl-Bi-isopropylamino) -3- (i- o naphthylozy) -2-propanol and its salts, cc ^ 9. Salts according to one of claims 1 to 8, characterized in that ^ - net that they contain acid addition salts, e.g. of inorganic 4> - or salts derived from organic acids. cn
10. Salts according to claim 9, characterized in that they contain hydrochlorides, hydrobromides, phosphates, sulfates, oxalates, BATH ORIGINAL lactates, tartrates, O, O-di-p-toluoyltartrates, acetates, salicylates or citrates. 11. Process for the preparation of the compounds according to one of the Claims 1 to 10, characterized in that a racemic propanolamine derivative of the formula: where R and R are those in claim. 1 meanings given have, is dissolved by means of an optically active acid and the resulting salts are isolated, whereupon the optically active S Bases can be obtained in a conventional manner. 12. The method according to claim 11, characterized in that as optically active acid (+) - or (-) - 0,0-di-p-toluoylweins & ure, (+) - or (-) - tartaric acid, (+) ■ - or (-) - camphor-10-sulfonic acid or (+) - or (-) - 3-bromocamphor-8-sulfonic acid is used. 15. The method according to claim 11 or 12, characterized in that that it takes place in a diluent or solvent. 14. The method according to claim 13, characterized in that it takes place in methanol. 15. Pharmaceutical hates, characterized in that they are made an optically active propanolamine derivative of the formula: 0. CH ₂ . GHOH. CH ₂ . ^12th 12th °° where R and R have the meanings given in claim 1 ^. have, which after hydrogenation gives a levorotatory base, ^ or a pharmaceutically acceptable salt of this propanol- ^ amine derivative, and a pharmaceutically acceptable salt Diluents or carriers exist. BAD OBtGiNAL 16. Hassen according to claim 15, characterized in that they in the form of tablets, capsules, aqueous or oily solutions, aqueous or oily suspensions, saulsions, injectable aqueous or oily solutions or suspensions " en, or dispersible powders. PATIENT ADVOCATE DMNO. H. FINCKE DIPL.-MO. H. BOHB 909837 / U95 bad original