DE1593762A1 - Process for the preparation of new substituted 1-phenoxy-2-hydroxy-3-alkylaminopropanes - Google Patents

Description

Case 1/275
Dr.Ve/Ba

Dr. F Zumetein sen. - Dr. E. Aesmann Dr.ILKoenigtberger - Dipl. Phys. R. Holzbauer

Dr. F. Zumttein jun. Pqtentanwfllte

8 Munich 2, Bräuhauutraß 4 / III

New complete registration documents

CH. BOEHRINGEH SOHN, Ingelheim am Rhein

Process for the preparation of new substituted 1-phenoxy

2-hydroxy-3-alkylaminopropanes

The invention relates to the preparation of new substituted 1-phenoxy-Z-hydroxy-i-alkylaminopropanes of the general formula

^E l

^R 3

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New documents (Art .; § 1 from. 2 No. 1 Sentence 3 of the amendment from 4 September 1967)

In this formula mean

R is the isopropyl or t-butyl group; R _{1 is} a radical with the partial formula - (0Η ₂ ) _χ -0Ν, (ΟΗ ₂ ) _χ -ΝΗ ₂ or ( ⁰ Hp) _{x +} -I-OH (where χ means zero or an integer from 1-3), - COOH or -COOCH ₅ ; Rp is an alkoxy, alkenyl, alkynyl or thioalkyl group with 1-4 carbon atoms or a cyano (= -CN) group, or hydrogen if R ₁ is different from a cyano group and an amino group;

R, hydrogen, a halogen atom, or an alkyl or alkoxy group with 1-4 carbon atoms.

The new connections can be made in the following ways:

1.) Implementation of a compound of the general formula

'/ \> - OOH, -Z II

^S 3

in which R ₁ - R _{5 are} as defined in formula I and Z is the group -CH-CH ₂ or -CHOH-CH ₂ -HaI (Hal = halogen atom), with

0
a Ν, Ν'-dialkylurea of the general formula

RHN - J - NHR III

in which R is as defined in formula I.

It creates the desired connection in one step of formula I.

The reaction was allowed best in a high boiling inert organic solvent such as tetralin, decalin, benzonitrile above or in the melt at temperatures between 150-220 ⁰ C, preferably 180-220 ⁰ C, to proceed. The use of not

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offers water-miscible solvents such as tetralin the advantage that the basic components can be isolated directly by extraction with acidic aqueous solutions. the Reaction is not or only very difficult to carry out, if heat-sensitive groups (e.g. unsaturated radicals or amino groups) are present in the starting material of the formula II.

The new compounds can also be prepared by other customary methods, the following processes having proven particularly useful to have:

2.) Reaction of compounds of the formula II with isopropyl or t-butylamine in common for such reactions.

3.) Implementation of a compound of the general formula

-OKt IV

in the R ^ - R are as defined in formula I and in the Kt represents a hydrogen atom or a cation, for example the ion of an alkali metal, with a compound of the formula

Z - CH ₂ - NHR

in which Z is as defined in formula II and R as in formula I,

4.) Introduction of the radical R into a primary amine of the formula

R-,

// Xs-OCH ₉ -CHOH-CH ₉ -NH ₉ VI

V /

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in which R ^ - R, as defined in formula I, on usual Manner, for example by reaction with isopropyl or t-butyl halides or when the isopropyl radical is introduced, also by reductive alkylation using hydrogen and acetone.

5.) Cleavage of a protective group from a tertiary amine the formula

^ -U, Sch

// v \ I

// \\ - QCH ₀ -CHOH-CH ₀ -N - R VI Ί

in which R and R, - R ~ have the meaning given above and Sch an easily split off group, for example the benzyl or carbobenzoxy radical.

6.) Reduction of the oxo group of a compound of the general formula

R ₂

'/ \> - 00H ₂ -X-NHR VIII

R ₃

in which R and R ^ - R are as defined for formula I and X is the group -CO-CH ₂ - or -CHOH-CHO-. The reduction can be carried out in the usual way, for example by means of aluminum isopropoxide or sodium amalgam.

7.) hydrolysis of an oxazolidinone of the formula

// X ^ -OCH ₀ -CH CH ₀ IX

/ 2 ι ι <L

R ₀ -η C

2 R ₃ , ι

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or »ines urea derivatives of the formula

-UOHo-CHOH-CH ₀ -NC-NR, Rc X

² I Il ^{4 5}

R ₂ Λ - t - 'R 0

in which formulas R and R-, - R, are defined as in formula I and R, as well as R ₁ - *, which can be the same or different, an alkyl radical, preferably lower alkyl, an aralkyl radical or an aryl radical, preferably the phenyl radical, mean, for example by means of strong sodium or potassium hydroxide solution.

ii.) Another process for the preparation of the compounds of the formula I consists in the fact that, in the case of compounds which already have the 3-alkylaminopropanol (2) chain, but in which one of the substituents R, R 'or R is in the phenyl nucleus is not yet present, but rather means a group which can easily be converted into the radical in question, this group being converted into the radical R ₁ or Rg or R 1 by customary methods. So you can, for example, compounds of the formula

XS ₁ -OCH ₂ -CHOh-CH ₂ -NHR XIa

in which R, R ₂ and R are as defined in formula I and A is a group which can be converted _{into R 1 by customary methods such as CONH 2} -, -CH = NOH, - (CH ₂ ) ^ - Hal (Hai = halogen) or NOg group, or compounds of the general formula

20 9 824/109 6 6 »

^R l

// \> - OCH ₀ -CHOH-CH ₀ -NHr

_o - VJIl ¹ UiL - \ Jiirt -HiUl XXb

in which R, R- and R ^ are as defined in formula I and B is a _{group which can be converted into R 2} by customary methods, such as a hydroxyl, hydroxyalkyl or haloalkyl group, or compounds of the general formula

-OCH ₂ -CHOh-CH ₂ -NHR XIc

in which R, R- and Rp are as defined in formula I and C _{denotes a group such as the hydroxyl or aldehyde group which can easily be converted into E 5} by customary methods, can be converted into compounds of the formula I by using the customary method required in each case ( Dehydration, reduction, exchange reaction, alkylation).

9.) Cleavage of an easily removable protective group from compounds the general formula

R-,

// XV-OCH ₀ -CHOB-Ch ₀ NHR XII

in which R and R-, - R are as defined in formula I and G is a 13th

easily hydrolytically cleavable group (for example a Acetal group).

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'/ V ^ -OCH ₂ -CHOH-CH ₂ -NHr XIII

- 7 -

10.) introduction of a halogenate; Ef? in compounds of the formula

^E l

R ₂

in which R, R, and R _{2 are} as defined in formula I, for example with hydrohalic acid / hydrogen peroxide at elevated temperature. This gives compounds of the formula I in which R 1 denotes a halogen atom.

The starting compounds of processes 1-10 are for the most part already known. They can generally be produced according to the usual methods will.

The substituted l-phenoxy-2,3-epoxypropanes of Forael II, which are mostly used as starting material, can, for example by reacting a phenol or phenolate of the formula IV correspondingly substituted on the benzene nucleus with l-halogen-2,3-epoxypropanes, e.g. epichlorohydrin, obtained under alkaline conditions will.

The compounds of the formula IV can, if they are not already known are to be obtained by conventional methods. So can the cyanophenols (especially those with additional alkyl and alkoxy groups) by dehydration from appropriately substituted phenolic benzaldoximes, which in turn are obtained from the corresponding (known) phenolic benzaldehydes are accessible. They can be reduced to the corresponding amino methylphenols be convicted.

Cyanophenols with an additional alkyl group on the benzene nucleus are best by reacting the simple cyanophenol with allyl bromide with rearrangement of the allyl ether formed as an "intermediate stage" obtained into the compound allylated on the nucleus. Cyanophenols with additional halogen on the benzene nucleus can also expediently through

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Halogenation of the simple cyanophenols with hydrohalic acid / HpC ^ be won. Gyanome allyl phenols are made from the appropriate Benzyl nitriles by introducing a nitro group and their conversion into a hydro,. ", ig / .uppe in the usual way (reduction, -Diazotizing and boiling) accessible, they can by reduction in the usual way into the corresponding amino-thy-phenols be convicted.

With regard to the production of starting materials, reference is also made to Belgian patent 641 133, British patent 894 189 and the following literature references:

Journal of pharm. med. Ghem. 5 / S. 69-76 (1962 Journal pharm. pharmacol. 5 / S. 359-369 (1963) Chemical Abstracts 58 / S. 3337 c (1962) and that Handbook by Houben-Weyl, 1. u; 2nd Edition.

The compounds of general formula I have on the -CHOIJ group an asymmetric carbon atom and therefore occur in the form of racemates as well as optically active antipodes. The optically active compounds can be obtained by either of starts out optically active starting compounds or the racemates obtained in a conventional manner, for example by means of dibenzoyltartaric acid or bromocamphorsulfonic acid, into their optical antipodes.

The 1-phenoxy - ^ - aininopropanols according to the invention of the general; v. Formula I can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid or 8-chlorotheophylline.

The compounds of the general formula I or their physiological Compatible acid addition salts have valuable therapeutic, in particular ß-adrenolytic properties and can therefore, for example for the treatment or prophylaxis of diseases of the

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Coronary vessels and for the treatment of cardiac arrhythmias, in particular of tachycardia, are used in human medicine. Also the blood pressure sands properties of the compounds are therapeutic Interesting.

Compounds of the general formula I which have proven to be particularly effective are those in which -R denotes an isopropyl group; preferably including those substances of the formula I in which R, a cyano group (preferably in the 2-position on the benzene nucleus), Rg an alkoxy (preferably methoxy) or an alkenyl (preferably AlIyI) group and R, hydrogen, Mean chlorine, bromine or methyl. Also compounds of the general formula I in which R is an isopropyl group and R ^ is a hydroxymethyl group | and R ₂ and R, have one of the meanings mentioned for it in the definition of the formula I (but preferably hydrogen), have proven to be valuable. Examples of particularly valuable compounds are 1- (2-methoxy-6-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 1- (2-allyl-4-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride , l- (2-allyl-6-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and l- (3-hydroxymethylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride.

The isopropylamino compounds described in the previous paragraph corresponding t-butylamino compounds in general similar to those, but are usually somewhat less effective.

The egg dose of the compounds according to the invention depends on -.Effectiveness "between 1 and 300 mg, with the particularly effective ■ Compounds between 1 and 150 mg (oral) and 1 - 20 mg (parenteral).

The pharmaceutical processing of the compounds of the general formula I to the usual application forms such as solutions, emulsions, Tablets, coated tablets or depot forms can be prepared in a known manner using the pharmaceutical auxiliaries customary for this purpose take place.

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The following examples explain the invention without terminating it restrict:

example 1

1- (2-methoxy-4-cyanophenoxy) -2-hydroxy-3-iBopropylaminopropane. HCl

15.4 g (0.075 mol) of 1- (2-methoxy-4-cyanophenoxy) -2,3-epoxypropane are dissolved in 100 ml of ethanol, 17.7 g (0.3 mol) of isopropylamine are added and the mixture is set to 50 - 60 C heated. The mixture is then refluxed for two hours, the solvent is distilled off (in vacuo) and ether is added to the residue. After adding dilute hydrochloric acid, the mixture is shaken vigorously, the aqueous phase is separated off and made alkaline with NaOH. The oily base which precipitates is taken up in ether, the ethereal phase is separated off, washed with water and dried over MgSO 4. The ether is then distilled off and the solid residue is recrystallized from ethyl acetate / petroleum ether. The thus purified base is Dissolved in ethanol, ethereal HCl was added and filtered off with suction the precipitated hydrochloride: Pp: 135-137 ⁰ C.
Yield 8.2 g = 37 ^ of theory

Example 2

1- (2-methoxy-5-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane · HCl 20 g (~ 0.1 mol) 1- (2-methoxy-5-cyanophenoxy) -2,3-epoxypropane are used Dissolved in 150 ml of methanol, added 17.7 g (0.3 mol) of isopropylamine and, after standing for one hour at room temperature, for two hours. Reflux heated to boiling. The solvent is then distilled off in vacuo, the residue is digested with dilute HCl and the not completely clear solution is filtered through Celite. The aqueous phase purified in this way is made alkaline with NaOH, the precipitating base is extracted with ether, the ethereal phase is washed with water and, after drying with MgSO, concentrated in vacuo. The solid residue is recrystallized from ethyl acetate / petroleum ether. Yield 10.5g

The base is dissolved in ethanol, acidified with ethereal HCl, filtered hot and then a little ether is added. The crystalline rotting hyarroliloride is filtered off and dried. Pp: 127-130 ⁰ C. Yield 10.7 g = 36 # of theory

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Example 3

1- (2-Methoxy-6-cyanophenoxy) -2-hyaroxy-3-isopropylaminopropane · HCl

In accordance with the preceding example, 19.5 g (0.095 mol) of 1- (2-methoxy-6-cyanophenoxy) -2,3-epoxypropane in methanol are reacted with 17.7 g (0.3 mol) of isopropylamine. Pp - by dissolving the purified, solid base in ethanol the Io j.stalline hydrochloride with the melting point is after the addition of ethereal HCl: 148-151 ⁰ C obtained. Yield 14.4 g = 50 $> d.Th.

Example 4

1- (2-cyano-5-methoxyphenoxy) -2-hyaroxy-3-isopropylaminopropane · HCl

Analogously to Example 2, 17.5 g (0.088 mol) of 1- (2-cyano-5-methoxy) -phenoxy) -2,3-epoxypropane in 100 ml of methanol are reacted with 20 ml of isopropylamine. 9.5 g of the recrystallized solid base of Pp: 71-73 ⁰ C are dissolved in ethanol, mixed with ethereal hydrochloric acid and the pure white 3
38% of the total

pure white hydrochloride isolated. Mp: 147-149 ° C. Yield 9.8 g =

Example 5 1- (2-Allyl-4- cyanophenoxy) -2-hydroxy-3-isopropylamino) ropane · HCl

16 g (0.0745 moles) of 1- (2-allyl-4-cyanophenoxy) -2,3-epoxypropane become reacted according to example 2 with isopropylamine in ethanol. The purified base (13 g), melting point: 92 ° -94 ° C., is dissolved in ethanol and acidified with essential HCl. There are 12.5 g of hydrochloride = 54 S * d.Th. isolated. Mp: 140-142 ° C.

Example 6 l ~ (4-Cyanomethylphenoxy) ~ 2-hydroxy-3-isopropylaminopropane * HCl

21.2 g (0.112 mol) of 1- (4-cyanomethylphenoxy) -2,3-epoxypropane are reacted with isopropylamine in methanol as in Example 2. The solid base (22.2 g) is mixed with ethereal HCl in ethanol. The hydrochloride melts at 155 - 158 ⁰ C.

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Example 7 . I- (2-Gyanome thy! Phenoxy) -2-hydroxy-3-isoprop.ylaininopropai · HCl

7.8 g (0.041 mol) of 1- (2-cyanomethylphenoxy) -2,3-epoxypropane are reacted according to Example 2 with isopropylamine in ethanol. The isolated solid base (7.0 g) is dissolved in ethanol and the hydrochloride is precipitated with ethereal hydrochloric acid. Pp: 119 - 121 ⁰ C.

Example 8 1- (2-Amino-5-methoxyphenoxy) -2-hydroxy-5-isopropylaminopropane ... 2 HCl

5.68 g (0.02 mol) of 1- (2-nitro-5-methoxyphenoxy) -2-hydroxy-3-isopropylaminopropane are dissolved in 200 ml of methanol and hydrogenated at room temperature over Raney nickel. The catalyst is filtered off with suction The clear solution is concentrated in vacuo, 5.6 g of basic residue being obtained. This is dissolved in ethanol, ethereal HCl is added and the dihydrochloride which precipitates in crystalline form is isolated. It is recrystallized from ethanol with the addition of ether, 3.5 g = 53 1 ° of theory are obtained, mp. 223-225 ⁰ C.

Example 9 1- (4-aminomethylphenoxy) -2-hydroxy-3-isopropyl aminopropane >> 2 HCl

22.2 g (0.95 mol) of l- (4-cyanophenoxy) -2-hydroxy-3-isopropylaminopropan are dissolved in 200 ml of methanol, ammonia and stirred at 20 ⁰ C and 20 atmospheres over Raney Niekel hydrogenated. After filtering off the catalyst, the solvent is distilled off in vacuo, the oily residue is dissolved in ethanol and acidified with alcoholic HCl. The solution is filtered hot, then cooled. The dihydrochloride separates out as colorless crystals. Yield: 18.1 g = 61.5 # of theory Mp 241-244 ⁰ C

Example 10 1- (3-aminomethylphenoxy) -2-hydroxy-3-isopropylaminopropane, 2 HBr

13 g (0.055 mole) 1- (3-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane are hydrogenated and worked up as in the previous example. The basic residue is dissolved in isopropanol, mixed with HBr and the colorless dihydrochloride is filtered off.

Th. Mp: 178-181 ⁰ C ...,

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Yield: 12.5 g = 57 # of theory Mp: 178 --181 ⁰ C

- LL "5 -
Example 11

-; »· .—-», τ mti, - Α »"'· -. · Iiwiinr ιιι ιβ ». -.

tr L j £ ~ 'ΐ lyl "~ 6 ~ cyano phenoxy) -2-hydroxy-3-isopropylaminopropane ♦ HCl

According to Example 2, the amino alcohol is obtained by reacting 1- (2-allyl-6-cysnoTueno2: y) -2, 3-epoxypropane with isopropylamine. The base melts at 52-54 ⁰ C

-Be .Lsp ;, ; .1 1.2 1 - (2-A . LIyl-5-cyanophenoxy) - ^ - hydroxy - ^ - isop'ropylaminopropane · HGl

1- (2-Allyl-5-cyanophenox "y) -2,3-epoxypropane is reacted with Isdpröpylamiii in analogy to Example 2. The hydrochloride is ^{hardened by precipitation of the base with HOl:} VÖm ^ p: 150-152 ° C. -

1- (3-Hydroxymethylphenoxy) -2-hydroxy-3-isoj> ropyiaminopropane ♦ HCl

23.4 g (0.13 mol) of 1- (3 ^ Hydroxyinethylphenöxy} -2v3-epoxypropane are reacted in analogy to "Example 2 with 23.6 g (O, Q4 MbI) isopropylamine. After working up and recrystallization 18.6 g of base, mp:. - 80 receive ⁰ C. The precipitated with ethereal HCl in ethanol hydrochloride schmilztbei98 - 79 101 ⁰ C.

Beispiel'14 '' ^ ^'-:' ■ '- ^"■■;.

1- (3-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane. HCl

20.8 : g ; - {p -, X moles) 1- (- 3-methoxycarbonylphenoxy) -2,3-epoxypropane. are implemented as in Example 2 with isopropylamine. After work-up and recrystallization, 13.6 g of base are obtained, mp: 75-76 ° a. The hydrochloride has an mp; from 117 - 119 ⁰ C

Example 15 ■■■ "

- (3-H: / 'droxycarbonylphehoxy) -2-hydroxy-3-isopropylaminopropane »HCl

2.5 / g (01 mol Ö _f) - (^ r-Methoxycärbonyl phenoxy) ^{-2-hydroxy-3-!} ^ -Isopropylaaainop OPAN is dissolved in 25 ml of 2.5 η NaOH for 30 minutes at 95 ⁰ C with stirring heated) whereby at the end a clear, solution is obtained. After cooling, it is acidified with HCl; aas. Water in the botation evaporator ^ m% kuunt ab ^ dj ^^ is recrystallized from acetonitrile. Oiji, gilHydiochlorid of the m.p .:. . .

154 - 156 ⁰ C won. ". _{(Λ1 (} ,, _Α ι

^% 8 ^ ^ %%% S BAD ORIGINAL

__ _1A _ 16937-62.

Example 16

1- (2-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane. HGl

55.2 g (0.17 mol) of 1- (2-methoxycarbonylphenoxy) -2,3-epoxypropane are reacted with isopropylamine as in Example 2. This gives 31 g of base, mp: 93-95 ⁰ C. The hydrochloride is isolated from ethanol with the addition of ethereal HCl. Mp: 78-81 ^0C.

Example 17

1- (4-methoxycarbonylphenoxy) ~ 2-hydroxy-3-isopropylaminopropane · HCl

107 g (0.515 mol) of 1- (4-methoxycarbonylphenoxy) -2,3-epoxypropane are reacted with isopropylamine in analogy to Example 2. The recrystallized from Essigester base (67.8 g) melts at 85-87 ⁰ C by means of the essential HGL from Ithanol / ether reprecipitated hydrochloride melts at 171 -172 ⁰ _C.;

Example 18 .

1- (2-Hydroxycarbonyl-4-chlorophenoxy) -2-hydroxy-3-isopropyl ^ aminopropane. HCl

4 g (0.015 mol) of 1- (2-hydroxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane are concentrated in 25 ml. HCl dissolved, 1.7 g (0.015 mole) of 32 # peroxide H ₂ O ₂ is added dropwise within 2 minutes at 45 ⁰ C. The exothermic reaction would braked by cooling so that the temperature does not exceed 65 ⁰ C increases. The mixture is kept at 65 ° C. for 30 minutes, then concentrated in vacuo. The crystalline residue is recrystallized from ethanol with the addition of ether. C. 183 ^0-181: to give 2 g of pure substance of mp

Example 19 - "

1- (2-Hydroxycarbonyl-4-bromopheiioxy) -2-hydroxy-3-isopropylaminopropane «HBr

8 g (~ 0.03 mol) of 1- (2-hydroxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane is reacted in analogy to Example 18, but in HBr and H ₂ O ₂ . 4 g of hydrobromide of melting point 188 - won 189 ^0C. .

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:: ■: - -.,; ■; . ; 1593782

Example 20

1- (2,4-dicyanophenoxy) -2-hydroxy-3-isopropylaminopropane. HCl

Analogously to Example 2, 3.9 g (0.0195 mol) of 1- (2,4-dicyanophenoxy)-2,3-epoxypropane are obtained in 50 ml of methanol with isopropylamine implemented. After work-up, 2.6 g of Eoh base are isolated, which after recrystallization from ethyl acetate with the addition of petroleum ether melts at 108 - 110 ° C.

Example 21

1- (2-chloro ~ 4 ~ iBetho3qrcarbonylpheno3qr) - 2-hydroxy-3-isopropylaminopropane »HCl

Prepared by chlorinating the geittäß Example 17 l- (4-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropans analogously to Example 18 "treating ijiit essential HGL and ümlcrlstallisieren one obtains the title of this example from the substance Pp: 163 ^ 165 ° G _V

Example 22

1- (2-methoxy ~ 4-amiiLOPhenoxy) -2-hydroxy-3-isopropylaminopropane oxalate

Analogously to Example 8, 1- (2-methoxy-4-nitrophenoxy) -2-hydroxy-3-isopropylaniinopropane is obtained by catalytic hydrogenation the substance mentioned in the title of this example (base). The oxalate is obtained by treating the base with essential oxalic acid. Mp: 146-147 ° C.

Example 23

1- (3 ~ Amino-4 ~ methoxyphenoxy) - ^ - hydroxy ^ -igopropyiaminopropane »2 HCl

An analogous example 8 is obtained by catalytic reduction of 1- (3-nitro-4-methoxy) -2-hydroxy-3-isopropylaminopropane, treatment with ethereal hydrochloric acid and recrystallization of the substance mentioned in the title of this example.
Mp: 215-217 ° C.

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Example j el 24

1- (4-Hydroxycarbonylphenoxy) -2-hydro3cy-3-isopropylaminopropane. HCl

Analogously to Example 14, from 1- (4-hydroxycarbonylphenoxy) -2,3-epoxypropane and isopropylamine, treatment with ethereal HCl and recrystallization of the substance mentioned in the title of this example is obtained. Mp 214-217 ⁰ C.

Example 25 1- (2-hydroxymethylphenoxy) -2-hydroxy-3-isopropylaminopropane »HCl

Analogously to Example 13, mp can be prepared from l- (2-hydroxymethylphenoxy) -2,3 "epoxypropane and isopropylamine, represent treatment with ethereal hydrochloric acid and recrystallizing the said substance in the title of this example. 111-113 ⁰ C.

Example 26

1- (2-Bromo-4-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane * HBr

The hydrochloride of the substance mentioned in the title is obtained by brominating the 1- (4-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane prepared according to Example 17 analogously to Example 19, treating with ethereal HCl and recrystallization. Mp 157-158 ⁰ C.

Example 27

1- (4-Hydroxymethylphenoxy) ~ 2-hydroxy-3-iBopropylaminopropane · HCl

Analogously to Example 13 Treat obtained from 1- (4-hydroxymethylphenoxy) -2,3-epoxypropane and Isopropylaain with ethereal hydrochloric acid, and recrystallizing said Xitel in this example substance of melting point: 105-108 ⁰ C.

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Example 28

1- (2-Hydroxycarbonyl) -2-hydroxy-3-iBopropylaminopropane · HCl

Analogously to Example 15, 1- (2-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane is used by heating with NaOH, treatment with HGl and recrystallization as indicated in the title of this example Substance from Pp: 155 - 157 ° C obtained.

Example 29

1- (2-Methoxy-4-cyanophenoxy) -2-hydroxy-3-tert-butylaminopropane «HQl

9 »9 g (0.048 mole) 1- (2-methoxy-4-cyanophenoxy) -2,3-epoxypropane are tert in 100 ml of ethanol with 14.6 g (0.02 mol) = 21 ml. Butylamine heated in a water bath for 3 hours. After distilling off of the solvent in vacuo, the residue is digested with dilute HCl and separated from the insolubles. The aqueous phase is made alkaline with NaOH, the precipitating base is extracted with ether, washed with Η «0 and the organic phase over MgSO, dried. After distilling off the ether, the oily residue is dissolved in ethanol, ethereal HCl is added and the precipitating crystals of the hydrochloride sucked off. They are recrystallized from ethanol with the addition of ether. Yield: 7.1 g, pp: 210-213 ° C

Example 30

1- (2-aminomethyl-4-chlorophenoxy) -2-hydroxy-3-tert-butylaminopropane «2 HOl

6.3 g IhO, 02 mol) 1- (2-cyano-4-chlorophenoxy) -2-hydroxy-3-tert. butylaminopropane · HCl are dissolved in 100 ml of methanol with the addition of 10 ml of NH and ^{hydrogenated under normal pressure at 20 °} C. over Raney nickel. After the catalyst has been separated off, the solvent is distilled off in vacuo and ether and water are added to the residue. After adding some NaOH, the aqueous phase is separated off, the organic phase is _{washed with H 2} O and dried over MgSO ^. After the ether has been distilled off, a solid residue remains, which is recrystallized from ethyl acetate with the addition of petroleum ether. The base is dissolved in ethanol, ethereal HCl is added and the precipitating crystals of the hydrochloride are isolated. Yield 3 * 1g. Pp; des Hydrochloride 118 - 120 ⁰ C.

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- ie -

Were prepared analogously the l- (2-Methox ^ -4-aTinonietl: 'YL3> henoxy) -2-hydroxy-3-tert.butylaminopropan: - by hydrogenation of l- (2 (Pp of the dihydrochloride 235 238 ⁰ C). -Methoxy-4-cyanophenoxy) -2-hydroxy-3-tert-butylaminopropane. HCl; the l- (2-Aminomethyl-phenoxy) -2-hydroxy-3-tert.butylaminopropan (Pp of the dihydrochloride 220 -. 222 ⁰ C) by hydrogenation of l- (2-cyanophenoxy) -2-hydroxy-3-tert.butylaminopropan * HCl and the l- (2-Aminomethyl-phenoxy) -2-hydroxy-3-isopropylaminopropan (Pp of the Dihydrochloride. 176 -179 ⁰ C) by hydrogenation of l- (2-cyanophenoxy) -2-hydroxy-3-isopropylaminopropan. HCl.

Example 31

1- (2-Methoxycarbonylphenoxy) -2 ~ hydroxy-3-tert-butylaminopropane * HCl

Analogously to Example 16 or 2, starting from 1- (2-methoxycarbonylphenoxy) -2,3-epoxypropane and tert. Butylamine, the l- (2-methoxycarbonylphenoxy) -2-hydroxy-3-tert.butylaniinopropan (Pp of the HCl salt. 144-146 ⁰ C).

Example 32 1- (2-Hydroxycarbonylphenoxy) ~ 2 ~ h.vdroxy »3-tert-butylaaiinopropane · HCl

Analogously to Example 28 or 15, starting from 1- (2-methoxy carbonylphenoxy) -2-hydroxy-3-tert-butylaminopropane (β. Example 31), 1- (2-hydroxycarboxylphenoxy) -2-hydroxy was obtained by saponification with NaOH -3-tert.butylaminopropan (Pp of the HCl Salzee. 138-140 ⁰ C).

Example 33

1- (2-methoxy-5-cyanophenoxy) -2-hydroxy-3-tert-butylaainopropane · HCl

Analogously to example 2, starting from l- (2-methoxy-5-cyanophenoxy) -2,3-epoxpropane and tert-butylamine, l- (2-methoxy-5-cyanophenoxy) -2-hydroxy-3-butylaminopropane (pp. of the hydrochloride: 149-152 ⁰ C).

209824/1096

Example 34

l ~ (4 ~ methoxycarbony! phenoxy) -2 ~ hydroxy-3 - tert. butylaminopropane. HCl

17 and 2 was analogous to Example, starting from l- _(4-i Methoxycarbo iylphenoxy) -2,3-epoxypropane, and the t-butylamine, 1- (4-methoxycarbonylphenoxy) -2-hydroxy-3-tert.butylaminopropan (mp. of the HCl salt: 205-207 ° C).

Example 35

1- (2-hydroxymethylphenoxy) -2-hydroxy - 3-tert. butylaminopropane oxalate

Analogously to Example 13, one obtains from 1- (2-hydroxymethylphenoxy) -2,3-epoxypropane and tert. Butylamine the l- (2-hydroxymethylphenoxy) -2-hydroxy-3-tert.butylaininopropan (Pp of oxalates. 180-183 ⁰ C).

Example 36

1- (2-chloro-4-methoxycarbonylphenoxy) -2-hydroxy-3-tert-butylaminopropane «HCl

Analogously to Example 18, by chlorinating 1- (4-methoxycarbonylphenoxy) -2-hydroxy-3-tert-butylaminopropane (prepared according to Example 34) there is obtained l- (2-chloro-4-methoxycarbonylphenoxy) -2-hydroxy-3- tert.butylaminopropan HCl (Pp .: 208-210 ⁰ C).

Example 37

1- (4-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane. HCl

2.08 (0.01 mol) of 1- (4-methoxycarbonylphenoxy) -2,3-epoxypropane are mixed with 2.88 g (0.02 mol) of N, N'-diisopropylurea in the presence of 10 g of lithium hydroxide in 20 ml of tetralin for two hours heated 200 ⁰ C - to 190th After cooling, 20 ml of ether are added and the whole thing is extracted by shaking with 50 ml of 10% HCl. The aqueous solution is separated off and extracted again with ether. The aqueous phase is made alkaline with NaOH and the basic component which precipitates out is taken up in ether. The ethereal phase is _{washed with H 2} O over MgSO. dried and concentrated in vacuo. The desired amino alcohol can be detected by comparative thin layer chromatography. The residue (1 g) is recrystallized from ethanol with the addition of ether, whereupon a strong accumulation occurs. A small amount of pure substance is obtained by column chromatography, which crystallizes out after adding oxalic acid in ether.

209824/1096

Example 38

1- (4-methoxycarbonylphenoxy) -2 ~ hydroxy ~ 3-isopropylaminopropane. HCl

0.3 g of 1- (4-methoxycarbonylphenoxy) -2-hydroxy-5-isopropylaminopropaii ⁱ tetrahydropyranyl ether oxalate are heated in 20 ml of 10 ^ HCl in a water bath for 10 minutes. Night cooling is made alkaline with NaOH and the precipitating base is taken up in ether. The pure base can already be detected in the thin-layer chromatogram. The ethereal solution is concentrated and ethereal HCl is added. There are isolated about 0.1 g pure white crystals after recrystallization from ethanol / ether at 171 - 172 ⁰ C melt. The tetrahydropyranyl ether is produced as follows:

7.6 g (0.09 mol) of dihydropyran are slowly added dropwise to 8.67 g (0.03 times) of 1- (4-methoxycarbonylphenoxy) -2-hydroxy-3-bromopropane with the addition of a spatula tip of p-toluenesulfonic acid. The temperature rises to about 50 ⁰ O with an exothermic reaction. It is stirred for half an hour at this temperature and then dissolved in 100 ml of ethanol. After adding 5.9 g (0.1 mol) of isopropylamine, the mixture is refluxed for five hours and then concentrated in vacuo. By dissolving the residue in ethanol and adding 3 g of oxalic acid in ether, the oxalate is obtained in crystalline form. After separation, it is recrystallized from isopropanol / ether and subjected to the hydrolysis described above.

Example 39 1- (2-Hydroxymethylphenoxy) -2-hydroxy-3-isopropylaminopropane * HCl

21 g (0.064 mole) of l- (2-hydroxymethylphenoxy) -2-hydroxy-3-N-benzyl-N-isopropylaminopropan atti be hydrogenated in 100 ml of methanol over palladium-protochloride at 80 ⁰ C and 5. FIG. After the hydrogen has been taken up, the catalyst is separated off and the solution is concentrated in vacuo. After the residue has been dissolved in ethanol, the hydrochloride is precipitated in crystalline form by adding ethereal HCl. Bs is recrystallized twice from isopropanol. Yield 8 g, Pp: 111-113 ⁰ C.

BATH ORIGINAL

209824/1096

158376-2

■ - 21 -

Example 40

1- (4-H. Hydroxycarbonylphenoxy) ^ - hydroxy ^ -isopropylaminopropane · HCl

5> 85 g (0.02 mol) of 3-isopropylamino-5- (4-methoxycarbonylphenoxymethyl-oxazolidinone) dissolved in 50 ml of ethanol and after adding a solution of 10 g of KOH in 15 ml of water for two hours Refluxed. Then the solvent is distilled off in vacuo and the residue is acidified with HCl several times with ether extracted. The aqueous phase is concentrated to dryness in vacuo and with abs. Digested ethanol. The insoluble parts are filtered off, the ethanol solution is evaporated in vacuo. The residue is dissolved in a little ethanol, filtered and ether added. The hydrochloride crystallizes out and is filtered off with suction. Yield 1.4 g, m.p .: 205-2O7 ° G. .: "" ""

Example 41

1- (4-methoxycarbonylphenoxy) -2-hydroxy-3-isopropylaminopropane * HCl

2.25 g (0.01 mol) of 1- (4-methoxycarbonylphenoxy) -2-hydroxy-3-aminopropane are dissolved in 60 ml of ethanol and, after addition of 2 ml of acetone, 1.52 g (0.04 mol) of NaBH. , dissolved in 50 ml of ethanol, added dropwise. After the exothermic reaction has subsided, the mixture is ^{heated to 50 to 60 °} C. for a further two hours. It is then acidified with HCl and the solvent is distilled off in vacuo. The residue is dissolved in HpO, made alkaline with NaOH and the precipitated base is extracted with ether. The separated organic phase is washed with water, dried over MgSO «and the ether is distilled off. The solid base is recrystallized from ethyl acetate with the addition of petroleum ether and then twice more from ethyl acetate. Ausbeu-cö'0.9 g »mp: 82-84 ° C

Example 42

1- (3-HydroxymethylT) henoxy) -2-hydroxy-3-tert.butylamino-propane * HCl

According to Example 2, 20 g of l- (3-hydroxymethylphenoxy) -2,3-epoxypropane with 18.5 g of tert. Butylamine put in methanol. Mp: 82-84 ⁰ C--

«AD OBiG> NAL 209824/1096 ^BAD

Examples of pharmaceutical applications

a) tablets

Rac. 1- (2-cyano-6-methoxyphenoxy) -2-hydroxy-3-isopropylaminopropane · HCl 4OyO g

Corn starch 164.0 g

Calcium phosphate 240.0 g

Magnesium stearate 1.0 κ

445.0 g

The individual components are intensively mixed with one another and the mixture is granulated in the usual manner. The granulate is compressed into 1000 tablets of 445 mg weight, each tablet corresponds to * holds 40 mg of the active ingredient.

b) gelatin capsules

The contents of the capsule are made up as follows:

(-) - 1- (2-Cyano-6-methoxyphenoxy) -2-hydroxy-3-isopropylaminopropane · HCl 25.0 mg

Corn starch 175.0 mg

200.0 mg

The ingredients are intensively mixed and 200 mg Portioneji the mixture are filled into gelatin capsules of a suitable size Each capsule contains 25 mg of the active ingredient.

c) solution for injection

The solution is made from the following components:

Rac. 1- (2-cyano-6-allyl-phenoxy) -2-hydroxy-3- 2.5 parts isopropylaminopropane · HCl

Sodium salt of EDTA (ethylenediaminetetra- 0.2 parts acetic acid

distilled water to 100.0 parts

ORIGINAL BATHROOM 209824/1098

The active ingredient and the EDTA salt are in enough water solved and. made up to the desired volume with water. The solution is filtered free of suspended particles and filled into 1 cc ampoules under aseptic conditions. Finally, the ampoules are sterilized and sealed. Each ampoule contains 25 mg of active ingredient.

d) depot dragees
Core;

Kac. 1- (2-Allyl-4-cyano-phenoaqr) -2-hydroxy-isopropylaminopropane maleate 25 to g

Carboxymethyl cellulose 295- _f .O g

Stearic acid 20.0 g

Cellulose acetate phthalate 40.0 g

380.0 g

The active ingredient, the carboxymethyl cellulose and the stearic acid are mixed intensively and the mixture is granulated in the usual way, building a solution of cellulose acetate phthalate used in 200 Al of a mixture of ethanol and ithylacetate. Bas granules are then compressed into 380 mg cores, which are more commonly used Way with a sugary 5% solution of polyvinylpyrrolidone coated in water. Each coated tablet contains 25 mg of active ingredient.

e) tablets. .

1- (3-Hydroxymethyl-phenoxy) -2-hytooacy-3-iβopΓopylaminopropane sulfate 50.0 parts

Milk sugar 164.0 parts

Corn starch 194.0 parts

colloidal silica 14.0 parts

Polyvinylpyrrolidone 6.0 part "

Magnesium stearate 2.0 parts

soluble starch 10.0 parts

440.0 parts

BAD OBSG'NAL

209824/1096

The active ingredient, the milk sugar, the maize starch, the colloidal Silicic acid and the polyvinylpyrrolidone are mixed intensively and the mixture is granulated, an aqueous one Soluble starch solution used. The granules will mixed with the magnesium stearate and made into tablets of 440 mg Weight and 50 mg active ingredient content pressed.

8AD ORIGINAL

209824/109 6

Claims (14)

Patent claims 1.) Process for the preparation of new substituted, racemic or optically active 1-phenoxy ~ 2-hydroxy-3-alkylaminopropanes the general formula -OCH ₂ -CHOH-Ch ₂ -NHR in which R is the isopropyl ^ or the t-butyl group; R _{1 is} a radical with the partial formula - (CHg) _x -CN, (0Η ₂ ) _χ -ΝΗ ₂ or (CHg) _{x +} Tr-OH (where χ means zero or an integer from 1 - 5), -COOH or - COOCH ₅ ; R _{2 is} an alkoxy, alkenyl, alkynyl or thioalkyl group with 1-4 carbon atoms or a cyano (= -CN) group, or hydrogen when R is different from a cyano and an amino group; R, hydrogen, a halogen atom, or an alkyl or alkoxy group with 1 - 4 carbon atoms mean as well as their physiologically compatible acid addition salaen, characterized in that one a compound of the general formula -OCH ₂ -Z. II in which R ₁ to R are as defined in formula I and Z _{denotes the group ^ CH-GH 2} or -CHOH-CH ₂ -HaI (Hal = halogen atom), with 0
an N, N'-I) ialkylurea of the general formula. 209824/1096 BATH 0 »» "« · Documents (Art. AS IAbB. UNr. 1 S.JU 3 of the amendment »V. 4.9. T96W - 26 RHN- C - NHR III in which R is defined as in formula I, or that one ~ b) a compound of the general formula II is reacted with leopropylamine or t-butylamine, or that one c) a compound of the general formula -OKt IV in which R ₁ to R are as defined in formula I and Kt is a hydrogen atom or a cation, for example the ion of an alkali metal, with a compound of the general formula. Z-CH ₂ - NHR V in which Z is as defined in formula II and R as in formula I, implements, or that one ) . ■ ■ _d ) the radical R in a primary amine of the general formula -OCH ₂ -CHOH-CH ₂ -NH ₂ VI in which R- to R ~ are defined as in formula I, or that one SAD 209824/1096 =. '. = ■ 1533762 e) in connection with the general ■ formula NS -OCH ₂ -GHOH-CH-Im \ VII in the B and E- ^ to B, as defined in formula I and Sch an easily cleavable amino protective group means the group Sch replaced by hydrogen, or that one ± y in compounds of the general formula VS ₁ -OCH ₂ -X-NHR VIII in which R and R ^ to R are as defined in formula I and X is the group -CH-CH ₂ - or -CHOH-CO-, the oxo group is reduced, or that one g) an oxazolidinone of the formula -O0H, -0H CH, IX R, "C ³ D or a urea derivative of the formula ORIGINAL BATHROOM 209 824 / 1.0.9 6 ^R l // \\ - OCH ₂ -CHOH-CH ₂ -NC-NR ₄ R ₅ X A-C / 'RO E ₂ ^
R. in which formulas R and R ₁ to R, as defined in formula I and R, as well as R, -, which can be the same or different, denote an alkyl radical, preferably lower alkyl, an aralkyl or aryl radical, preferably the phenyl radical, a hydrolytic treatment, or that one h.) Compounds of the general formula : A -OCH ₂ -CHOH-Ch ₂ -NHR XIa in which R, R «and R ~ are as defined in formula I and A means a residue which can be converted into R-, by customary methods, or compounds of the general formula *1 XIt in which R, R ₁ and R are as defined in formula I and B denotes a radical which can be converted _{into R 2 by customary methods, or compounds of the general formula} 209 824/10 96 in which R, R ₁ and R ₂ are defined as in formula I and C denotes a group which can be converted into the radical R and which is subjected to treatment by customary methods necessary for conversion into compounds of formula I, or that he 1) in connection with the general formula / \\ - OCH ₂ -CHOH-Ch ₂ -NHR XII in which R and R- to R are as defined in formula I and G means an easily hydrolytically cleavable group which Group G replaced by hydrogen, or that one k) in compounds of the general formula R-, (/ \\ - OCh ₂ -GHOH-CH ₂ -NHR XIII R ₂ introduces a halogen atom and, if desired, those obtained by one of processes 1-10 Compounds converted into their physiologically acceptable acid addition salts. 2.) Process for the preparation of optically active compounds of the general formula I or their acid addition salts, thereby, characterized in that either when carrying out the process a) to k) starts from optically active starting material or according to, the process a) to k) obtainable racemates in a customary manner in splits its .optical antipodes. 209824/109 6 3.) Compounds of the general formula R-, // NS-OCHp-CHOH-CHp-NH-R ^E 3 in which R and R ₁ to R are as defined in formula I, as well as their physiologically acceptable acid addition salts. 4.) Pharmaceutical preparations containing as active ingredient Ver ^ Turns of the general formula I or their physiological ™ compatible acid addition salts in combination with usual Aids and / or carriers. 5.) Pharmaceutical preparations containing substances of the. general formula I or its physiologically acceptable acid addition salts in combination with other pharmaceutical products Active ingredients and customary auxiliaries and / or carriers. 6.) Method of treating Taehycardia using substances of the general formula Γ or their physiologically acceptable acid addition salts. \ 7.) Method for the treatment of hypertension using substances of general formula I or their physiologically acceptable acid addition salts. 8.) Process for the production of pharmaceutical preparations according to claim 4, characterized in that one compounds of the formula I or their physiologically acceptable acid addition salts with the usual pharmaceutical auxiliaries and / or carriers processed into common pharmaceutical application forms. SAD ORIGINAL 209824/109 6 9.) Process for the production of pharmaceutical preparations according to claim 5, characterized in that substances of the general formula I are used in combination with active ingredients as well as Their pharmaceutical auxiliaries and / or carriers are customary processing pharmaceutical application forms » 10.) Chemical or optically active 1- (2-methoxy-6-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane and the physiologically acceptable acid addition salts thereof. 11.) Chemical or optically active 1- (2-allyl-4-cyanophenoxy5 ~ 2-hydroxy-3-isopropylaminopropane and the physiologically acceptable acid addition salts thereof. 12.) Chemical or optically active 1- (2-allyl-6-cyanophenoxy) -2-hydroxy-5-isopropylaminopropane and the physiologically acceptable acid addition salts thereof. 13.) Chemical or optically active 1- (3-hydroxymethylphenoxy) -2-hydroxy-3-isopropylaminopropane and the physiologically acceptable acid addition salts thereof. 14.) Chemical or optically active 1- (2-allyl-5-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane and the physiologically acceptable acid addition salts thereof. 209824/1096 ^BA °