DE2458738A1 - DERIVATIVES OF L-PHENOXY-3-AMINO-PROPAN-2-OL AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Deri vate el e s 1 - V hen oxy- 3 - am j no- propan - 2 -öl s and procedures for their

The invention relates to new pharmacologically valuable Derivatives of l-phenoxy-3-aminopropan-2-ol of the general formula I.

/ J ^ -O-CH ₀ -ClI-CH ₀ NlI-X I

- I.

OH

worm X - -C =
1 CH-C-T ^
Ii CH Il
3 ° ^ OH ₃ ^CH 2 ~ p ^H T
OH mean, iA _CH ["3 fi

or

• M _O

and the phenylic nucleus I also one, two or three times, in particular by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, phenyl, halogen or the ReSt-Js ¹ R ₁ R ₉ , where R ₁ represents alkyl or acyl and R _{0 represents} hydrogen or alkyl, can be substituted, their aldehyde condensation.

509826/0976 ^BAD

- 2 - Ref. 2993

products and acid addition salts, as well as processes their manufacture. The substitutions of the phonyl nucleus I can be identical or different.

cn X

Compounds with X = -CH-CH ₀ -CH -, *** ^ are preferred.

I "■ 'il

CH OH WV'II. **

In the context of the present invention, the compounds of the general formula I also possible stereosisomers and optically active compounds and mixtures thereof, especially the racemate understood.

The substituents of the pnenylkerns- I have in particular the following meaning:

Alkyl having 1 to 4 carbon atoms, e.g. B, methyl, ethyl, propyl, tert-butyl;

Alkenyl with up to β carbon atoms, preferably vinyl, allyl, methallyl, crotyl;

Alkynyl with up to ß carbon atoms, ζ, Β. Progargyl; Cycloalkyl with a ring size of 5 to 8 carbon atoms, preferably cyclopentyl and cyclohexyl; Cycloalkenyl with a ring size of 5 to 6 carbon atoms, preferably Cyclopentenyl;

Alkoxy with up to 8 carbon atoms, alkenyloxy and alkynyloxy with each up to 5 carbon atoms, preferably methoxy, ethoxy,

509826/0976 ^{& AD}

- 3 - Ref, 2993

η- and i-propoxy, butoxy, n-pentyloxy, n-octyloxy, allyloxy, methallyloxy, proparyloxy, bonzyloxy. Halogen: preferably fluorine, chlorine or bromine. Alkyl radicals for H ₁ or R ₀ preferably have 1 to 2 carbon atoms. . .

Under the acyl residue for R., the is different from an aromatic or aliphatic carboxylic acid derived aryl or alkyl «» substituted carbonyl radical with up to 11 carbon atoms, z. B. Pormyl, Acetyl, Propionyl, Dutyryl, Benzoyl, Naphthoyl, phenylacetyl, preferably iodoch. Acetyl or Benzoyl.

The aldehyde condensation products of compounds of the general formula I are oxazolidines of the formula II

Λ -? - ο - CH ₀ ι "1 · ■"

those in the condensation of pre-bindings of the general Formula I with an aldehyde of the formula

R ₃ - CHO

509826/09 76

- 4 - Ref. 2993

in which IU is hydrogen or a lower alkyl radical represents with up to 4 carbon atoms are formed.

Inorganic and organic acids are used to form salts with the compounds of general formula I suitable. Suitable acids are, for example, hydrogen chloride, Hydrogen bromide, phosphorus, sulfur, oxalic, Milk, wine, vinegar, salicylic, benzoin, lemon, obesity Naphthalene-1,5'-disulfonic acid, pharmaceutically acceptable Acid addition salts preferred

The phenyl nuclei I of the following formulas can, as indicated above for general formula I, be substituted be.

To prepare the compounds of the general formula I, a l-phenoxy-3-aminopropan-2-ol of the general formula Formula III with a compound of the general formula IV with elimination of H-Y to give a compound according to the invention I implemented:

CH ₂ -NH ₂ + YX
OH ~ OH

III IV

ORIGINAL BATHROOM 509826/0976

-5- Ref. 2993

Here, X has the meaning already mentioned and Y · denotes halogen, in particular chlorine or bromine, and if so X for

_c - CII - C- ^ Ss' stands, also -OH, OK

CH Ä KX

³
or ONa. ·

The reaction is normally carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended. Such solvents or dispersants are, for. B. aromatic hydrocarbons such as. z. B. benzene., Toluene, xylene; Ketones e.g. B. acetone, methyl ethyl ketone; halogenated ^ hydrocarbons such. B. chloroform, carbon tetrachloride , chlorobenzene, methylene chloride; Ether such as B. tetrahydrofuran and dioxane; Sulfoxides such . B «dimethyl sulfoxide; tertiary acid amides such. B, dimethylformamide and N-methylpyrrolidone, as solvents in particular polar solvents, such as. B. related alcohols. Suitable alcohols are, for example, methanol, ethanol, isopropanol, tert-butanol, etc., The reaction is carried out at temperatures from 20 ° C to the reflux temperature of the solvent or dispersant used, The reaction often takes place at normal temperature,

509826/0976

- ^b - Ref. 2993

ClU

I - ¹

If X for -C = CII - CO-X ^X N

CIU '^ after

• i M

the reaction is accelerated by adding an acid, preferably hydrogen chloride. Examples of other suitable acids are carboxylic acids such as e.g. B. formic, acetic, propionic, butyric acid; Sulphonic acids such as, for example, benzoesulphonic acid, p-toluenesulphonic acid; Mineral acids such as B. sulfuric acid and phosphoric acid. If a compound of the general formula IV with Y = Oil is used, catalytic amounts of the acid, e.g. B. of acetic or formic acid, If compounds of the general formula IV with Y = ONa or OK are used, then about 1 mol of the acid is added. Instead of adding an acid, the compound of the general formula III can also be used in the form of a salt, e.g. B. the hydrohalide, are used. If a compound of the general formula IV is used, in which Y stands for halogen, then this compound of the general formula IV can also be reacted in the form of the hydrohalide . In the production process according to the invention, the acid addition salts of the compound I or, when an acid-binding agent such as potash or soda is added, the free amines can be formed.

509826/0976

- 7 -. Ref. 2993

The required starting compounds of the general Formula IV represent either, depending on the meaning of X Derivatives of 1- (2,4-dimethyl-5-pyrimidyl) -but-2-ene-Qns-1 of the general formula V or of 1 ~ (2,4-dimethyl-5-pyrimidyD-butan-1-ol of the general formula VI;

ι ^J

Y - C ■ «* CH-C *

I. C.

^{a [} 3

CH ₃ o

Hai - ~ CH - CH ₀ - CH - r ^^ N VI I ² I.
CH ₃ OH

Here Y has the meaning already given and Hal stands for halogen, in particular for chlorine or bromine. Starting compounds of the general formula V can be obtained by either a 2,4-dimethylpyrimidine (5) carboxylic acid ester, especially the methyl or ^ äthylester with acetone under the conditions of an alkaline ester condensation or under analogous conditions an acetic acid ester, especially methyl or acetic acid reacted ethyl ester with 2,4-dimethyl-5-acetyl-pyrimidine. The sodium or potassium salt of the formula VII or VIII: ^ ^H 3 ^ 3 is obtained in this way

CH ₃ O ^ N ^ CII ₃ CII ₃ O VII ■ VIII

509826/0976

- ^ü - Ref. 2993

The free salts are obtained from these salts by hydrolysis 2 (dimethylpyrimidoyl-1-methyl-vinyl alcohol of the formula IX, which is tautomeric with the dimethylpyrimidoyl acetone of the formula X:

™ 3 ^C , ^U 3

CII, O ^ _N > Si. ° ° ^ ^ν ^ ρϊ.

J CIi ₃ CIl ₃

IX X

By reacting the compound of the formula IX bi: w, X with suitable halogenating agents such as, for example, thionyl chloride or phosphorus tribromide, the corresponding 3-halo-1 - / ^, 4-dimethyl-pyrimidyl (5) _7-but-2 is obtained -en-on-l of the general formula XI

! ' ³

XI

509826/0976

- 9-. '"üet. 299.3

where Hal J! ur halogen, in particular i.iii _u ; ccUa · hronr, stands. Vu-rIjIndungen dei * tiil ^ enioj iit: n J'Oi / riiul VI ₁ küuuon from dun untüin'echeiKlcii compounds of the UOrniul KI uwreh hydrogenation, ^ weckiuauii / proved with kQiiip.Lu>.,>.; n hydrides, w ι · .. · ic. ii, Litüiunialudiiniuaihydrid, Natriuin!) oriiydrid ouu) · cierß'lciüheri, t be.

The connections of the general formula I'll be required as an extension (isverbi.ndun. ^: !; Cn) by using a compound of the general formula XII or XIII

/ 1 Vo-CH ₀ -CH-CH ₀ / i \ -0-ClI ₁ , -I ¹ H-CIl., -

^ """^ O ^^ ■ uli

XII XjH

where in XIII Hai is a Halou'unatom, inübeüoiidc-rt Chlov ocler bromine, or a mixture of a VerluiH.Uinf; XIl with a Vi.TO.iiicluug XIlI substituted identically in the phonyl nucleus I with compounds which split off ammonia or ammonia. etches. The reaction may be carried AtmoüijhärenJruek or under elevated pressure through at ambient temperature; oj ·: ührt and dui'ch Wärmezui'ulir, ü "Ii by heating aut Vu C ₁ accelerated or to completion (-iebraclrc...

BATH ORIGINAL

509826/0976

" ^lö " hef. 2993

The compounds of the general formulas XJI and XIII can by unisitioning a phenol of the general Formula XIV

/ \ OH XlV

with an epihalohydrin, conveniently with epihalohydrin or epibromohydrin. Depending on the reaction conditions, a compound of the general formula XII or XIII or a mixture of compounds of the general formula XII and XlII, the resulting The reaction product can be isolated before its further reaction with ammonia, but it can also be used without it Isolation can be implemented further directly.

Compounds of general formula I can also thereby be prepared that a compound of the general formula XV with a compound of the general formula XVI is implemented:

0-0-CII ₀ -Z + H ₀ NX> / I V-CII ₀ -CM-CU ₀ -NJI-X

XV XVI ^0Π 1

Here, X has the meaning already mentioned and Z denotes;

509826/0976

- 11 - Ref. 2993

-CH - CU _n or

-CIl - CH ₀ - shark

in ²

where Hai stands for a llalo <j, enatom, in particular for Chlorine or bromine,

The reaction is normally carried out in a suitable solvent or dispersant in which the reactants are dissolved or suspended. Such solvents or dispersants are, for. B. aromatic hydrocarbons such as. B. benzene, toluene, xylene; Ketones such as E.g. acetone, methyl ethyl ketone; halogenated hydrocarbons such as. B. chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; Ether such as B. tetrahydrofuran and dioxane; Sulfoxides such as dimethyl sulfoxide; tertiary acid amides such. B. dimethylformamide and N-methylpyrrolidone. In particular, polar solvents, such as. B, related to alcohols. Suitable alcohols are, for example, methanol, ethanol, isopropanol, tert-butanol, etc. The reaction is carried out at temperatures from 20 ° C. to the reflux temperature of the solvent or dispersant used. The often-reaction takes place at temperatures of 40 to 50 ⁰ C.

509826/0976

- 12 - Ref. 2993

It may be useful to have the Ausfiangsverbinduüij: der general formula XVI in an up to tenfold molar excess to use and / or the Ruaktionskoiaponente of the general formula XV in dissolved or suspended form to the dissolved or suspended reaction component to add the general formula XVI. The molar ratio between the compounds of the general formulas XV and XVI can be 1: 1 to 1:10 and optionally even more be.

When carrying out the reaction, a compound of the general formula XV can be used as a compound of the general formula XV Formula XII or the general formula XIII or a mixture of these two compounds can be used. "

In the presence of a compound of general Formula XIII, the reaction can also be carried out in the presence of acid-binding agents, such as potash, soda, etc. will. Without acid-binding agents, the hydrohalides of the compounds of the general type are usually obtained Formula I.

The production of the initial connections of the general

ι · «1 'ι

Formula XVI is described in the examples.

509826/0976

- 13 - Ref. 2993

A phenol of the general formula I can also be used to prepare the compounds of the general formula I XIV with a connection; of the general formula XVII be converted to a compound of the general formula I:

l \ -OH + Z-CII ₀ NlI-X> / 1 ^ -0-CH ₀ -ClI-CH ₀ -NH-J

λ _0II

XIV XVII I

Here X has the meaning already mentioned and Z means: .

-CII-CH _n or

-CII-CII ₀ -HaI
I 2
OH

where Hai stands for a halogen atom, in particular for Chlorine or bromine.

This reaction is also normally carried out in a suitable solvent or dispersant in which the Reaction partners dissolved or suspended. Such solvents or dispersants are, for example, aromatic Hydrocarbons such as benzene, toluene, xylene; Ketones such as E.g. acetone, methyl ethyl ketone; halogenated carbon

50 9 826/0976

" ^A * ■ Ref. 2993

Hydrogen such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; Ethers such as tetrahydrofuran and dioxane; Sulfoxides such. B. dimethyl sulfoxide; tertiary acid amides such. E. dimethylformamide and N-methylpyrrolidone. In particular, polar solvents, such as. B. related alcohols. Suitable alcohols are e.g. B. methanol, ethanol; Isopropanol, tert-butanol, etc. If Z is - -CII-CII ₀ -IIaI,

OH

the reaction is mostly in the presence of an acid-binding agent By means of such. B. potash, soda, sodium bicarbonate carried out. They can also be used in aqueous alkalis, such as B. Carry out diluted sodium or potassium hydroxide solution. The reaction temperature can be 20 to the reflux temperature of the solvent or dispersant used.

It may be advantageous to use the starting compound of the general formula XVII in up to a 10-fold molar excess use and / or the reaction component of general form XIV in dissolved or suspended form to be added to the dissolved or suspended reaction component of the general formula XVII. The molar ratio between the compounds of the general formulas XIV and XVII can be 1: 1 to 1:10 and optionally even more be.

509826/0976

Ref. 2993

When carrying out the reaction Irnnn as a compound of the general formula XVIl a compound of the general Formula XVIII or the general formula XIX or a mixture of these two compounds are used will,

• CIl ₀ -CH-CH ₀ -NH-X Hal-CH ₀ -CH-CH ₀ -NII-X O OH

XVIII XIX

The compound of the general formula XVIII and XIX can by reacting a compound of the general Formula XVI with an epihalohydrin, zv / corner-wise with epichlorohydrin or epibromohydrin. A compound is formed depending on the reaction conditions of the general formula XVIII or XIX or a mixture of compounds of the general formula XVIII and XIX, The resulting reaction product can be isolated for further conversion, it can, but also without Isolation can be implemented further directly.

The compounds of the general formula I ₁ in which X is the remainder

509826/0976

Ref. 2993

and which thus have the general formula XX l \ -0-CH ₉ -CH-CH _p -NH-CH-CH _o -CH

CiI "

OH

I.
CH.

OH ^ nA

dl «

XX

can also be prepared by a compound of the general formula XXI ₁ XXII or XXIII

-Q-CH ₀ -Ch-CH ₀ -NII-OCH-C 2 1 ώ ι κ

OH

CH ₃ 0

CH,

VO-CH ₀ -C-CH ₀ -NH-C 1 -C H-C

2 Il 2 ι H

CH ₃ O

CIl.

ι ^J

-0-

Θ ι

-0-CHo-C-CH ₀ -NH-CH-CH ₀ -CH _n ^ N 2 H 2 T 2 ι, |

O CH ^ OH ^ N- ^ C

^l 3

XXI

X-XII

XXIII

hydrogenated.

Complex hydrides such as, for example, lithium aluminum hydride, sodium borohydride and the like are advantageously used for the hydrogenation. The response is among the for

509826/0976

Ref. 2993:

dlpao Uydrido bokanntan Urnaotzuncaboüincimecu usually in alcohol or oinom alcohol / U boi room odor increased or ■ Teir.porature, 3rd B. under cooking on Reverse hydrogenation can also be used in some cases catalytic, e.g. D. untor use cinoa P.illadium-ICphlo Catalyst carried out v; ordün «

Dio Auseanßsverbindun.sen the alleomoinon lOvinol KXI are erfindunßsßomüße Yerbindunßcn dor allcoKioinon formula I,

Pll

where X is the remainder

-OCII-

^StObt ·

(t IVoCH ₂ -C-

XXIV

CH

CH

XI

XXII

XXIV

CH

VI

OH

XXIII

CH ₃ OK ™ CHj

BATH

509826/0976

- 18 - Ref. 2993

Implementation between the links of the general Formula XXIV and XI or XXIV and VI is used in solvents such as benzene, toluene, chloroform, methylene chloride, dioxane etc. at normal or elevated temperature in the presence of at least molar amounts of acid-binding agents such as potash or soda or in the absence of acid-binding agents Means carried out, in the latter case usually the hydrohalides of the compounds XXIJ or

XXIII receives. ■

The preparation of compounds of the general formula

XXIV can e.g. B. done by mild oxidation of the aminopropanols III ■

Ill XXIV

Aldehyde condensation products of the formula II are obtained by reacting compounds of the general formula I with an aldehyde of the formula R ₃ -CHO, in which R _{3 is} hydrogen or a lower alkyl radical, in a diluent or solvent, e.g. B, ethanol, preferably in the presence of an acidic catalyst, for example, JSssitjäure or hydrochloric acid and preferably at elevated temperature. The water formed during the reaction can be removed with the help of a

509826/0976

- 19 - Rei. 2993

by means of, ζ. B. benzene, by azeotropic distillation or by means of a doohydrating agent such as anhydrous potassium carbonate.

The acid addition salts of the compounds of the general Formula I can be prepared from the components in a manner known per se. Here is the application a diluent is generally advantageous, v / obei the di-salts of the compounds of general formula I are generally obtained in the case of an excess of acid. The mono-acid addition salts is obtained either by the targeted addition of only 1 mol of acid or by partial hydrolysis the di-acid addition salts.

The compounds of general formula I, their aldehyde condensation products II and their pharmaceutically acceptable acid addition salts have valuable pharmaceutical Properties. So they are z. B. suitable for the treatment or prophylaxis of heart diseases. Furthermore Some of them have pronounced ß-adrenolytic or antiarrhythmic properties. The connections can therefore on their own, in mixtures with one another or in Mixture with pharmaceutically acceptable diluents or carriers ηIs pharmaceutical preparations have been used. The pharmaceutical preparations can be in the form of e.g. B. Tablets, capsules, aqueous or oily solutions. '.. ·

509826/0976

Ref. 2993

or suspensions, emulsions, injectable aqueous or / or oil solutions or suspensions, dispersible powders or aerosol preparations. In addition to the compounds of the general formula I, the pharmaceutical preparations can also contain one or more other pharmaceutically active substances, for example Herulunir.smittel such as, for example, Luminal, Meprohamat and Chlorpromazine; Vasodilators like ζ. H. Glycerin trinitrate and Carbochronmn, diuretics such as ζ. B. chlorothiazide; the heart ionizing agents w? .ez, B. digitalis preparations; Hypotension agents such as B. Hauwolfia alkaloids; Contain bronchodilators and syrnpathomimetic agents such as 2. B, isoprenaline and kphedrine.

Of the compounds according to the invention of the general Formula I aind those particularly preferred in which X has the meaning of

-CH-CIU-CH-T ^^ N

^! il ¹ L

CH ₃ OH ^ iT ^X CH
owns.

509826/0976

The blocking effect of the compounds according to the invention on the ß 1 receptors dea Ilerzena and on, the ß2 receptors the vascular ayatema was examined as follows; At aatard dogs of both kinds, there was a laugh in one Chloraloae-urethane-morphine-anesthesia the blood pressure in the left Ventricle measured and the pressure signal continuously using Analog computer (BRUSH Instruments, Cleveland / Ohio) differentiated and among other things, the rate of pressure increase (Dp / dt) is registered. Furthermore, the blood flow to a femoral artery was measured by means of an electromagnetic clowmeter (Statham, Model M ^ OOO) according to and the blood flow recorded ml / min.

Changes in the maximum pressure increase rate (Dp / dt max.) Compared to the zero value were triggered by iv administration of Iaoproterenol (0.5 garama / kg), a known sympathomimetic (β1 reaction), while changes in the peripheral blood flow compared to the Zero values induced by intraarterial administration of iaoproterenol (0.05 gamma / kg) (ß2 reaction) (D, DUNLOP and RG Shanks "Selective blockade of adrenoceptive beta-receptors in the haart, Brit" J. Pharmac. Chemother, (1968) ^ 201-218),

The substances to be tested for their ß-receptor blockage were administered iv to the anesthetized animals stimulated with isoproterenol in increasing doses and the amount of substance was determined (at which there was a 50% inhibition of the two reactions caused by iaoproterenol (ED50),

509826/0976

- 22 - Ref. 2993

The table below shows the ED 50 values for β1 receptor inhibition (mg / kg iv) and the ED 50 values for β2 receptor inhibition (mg / kg iv). In addition, the relative ED 50 values were calculated for both cases on the basis of dea ttla Verglelchaauba tanz all reacted h- (2-hydroxy-3-isopropylamino-propoxy) acetanilide, the ED 50 values of which were set equal to 100. The quotient formed from the ED 50 of the ß2 receptor therapy and the ED 50 of the ß I receptor therapy represents a measure of the cardioselective effect of the substances under investigation. The larger this quotient, the better the cardioselective effect. If the quotient of the comparison substance k- (2-hydroxy-3-isopropylamino-propoxy) -acetanilld is set equal to 1, the relative factor indicates how much better the cardioaalective effect of the compound according to the invention is compared to the comparison substance.

Furthermore, the relative ED 50 values for the β1 receptor inhibition (Column 2 after, Tab.) A measure of the effectiveness of substances to be tested. The smaller the values, the more effective are the substances, i.e. the lower the for the for The amount needed to produce the therapeutic effect.

The used as comparison substance ^ - (2-hydroxy-3-ieopropylamino-propoxy) -acetanilide represents a preparation on the market as a ß-blocker, which has the international free designation "Practolol" carries.

509826/0976

_ p-Z _

Ref .: 2993

oil
C. 0.015 0.020 Ui
;!
1 ! (CC C c: 48 P.
Ho
U) O
^ :: ^ h
t; Tuesday
C. Oi U
3 Il : 1 ■ 11 Il , -j U) Il I.
ω I.
Ul N N • O N i j O N eptcrenh C!
U)
M.
O
4- "
U) q 1! > 0.238 4-1 μ '. Li > • Μ C N J> lti " U) 0.075 U, ύι 23 ft IU U) ω -H 4-1 _r l I 'rl
I ', JJ χ: -λ
ι. O) 4-1 I. ι ■ Ρ
ω U) <υ Ui 3 - (- 1- / p-n-pentyloxyl-phenoxy7- N U) U) ο N U) tN ■■■ • ι '* I V 2-hydroxy-propyl (3) -amino) - , Cj ω λ
K 3 cq CjQ U) U) Il * - '. butan-1-ol I. UJ U ^ - · 53 I ul ) - { Ul ■ ι- ¹ t) l
V i | t; Reference substance j Uj Ι- ^{1 night} (ν ω O
LfI O
U ") ■ ρ υ CU '- k- (2-hydroxy-3isopropyl- Ul λ; U) - S. Q c; -rl amino-propoxy) acetanilide U) U
• ■ I N U
αϊ -η W. O) Ul > u 0 !> U) U) O 53 > φ r-i I. · ' I r 1 (<; LD
I. • Η 1-1 ■ μ O σι '-ι (A.
u. | W. 4-y LH CN Q
QfJ ί-ΐ- 4-1 dl C. OJ .01 IU
rl Al
CU 505 IU M
rl U) Ul Ui
H U)>
M - - 4-1
O Sub-bookingdüuba Cdiiz 0.0036 ο, 3
'OJ 1.2 1- ( 2,4-Diniethyl-5-pyrimidyl) -
3- (i-Zp-n-propoxy-phenoxy / - • 2-hydroxy-propyl (3) -aminoj- 1.5 1.8 butan-i-ol 1- (2, hD ± methyl-5-pyrimidyl) - 133 2, ί 3- (1- / p-acetaraino-phenoxy_7-
2-hydroxy-propyl (3) -aininoJ- butan-1-ol 6.3 15.9 T- ( 2,4-dimethyl-5-pyrimidyl) -
3- (1- / pn-butoxy-phenoxy_7- 2-hydroxy-propyl (3) -amino) - 9, 287 1," butane-1 oil 1- ( 2, k -dimethyl-5-pyrimidyl) - 3 1.5 35.9 127 2, C &, k 17th 26, 1 225 100 100. 110

509826/0976

- 2h -

^ä f-4S ^ 38

A tablet with an invention compound and 100 mg total weight can e.g. B. the following composition own ι

5 »ig 1- (2,4-Diniethyl-5-pyi'iraidyl) -3- (i-Zp-acetamino phenoxy _ / - 2-hydroxy-propyl (3) -aniino) -butane-I-0I

10 mg colloidal silica (Aerosil) 72.5 mg Lactoae DAB7
1.5. mg gelatin
8.5 mg corn starch DAB7
2.5 mg Mg stearate USPXVIII

Depending on the severity of the case to be treated, for example 1 to 2 of these tablets can be administered to a patient three times a day.

The preparation of the compounds of general formula I. is explained in more detail in the following examples. The connections are often non-distillable oils, so that in some cases no melting point is given. In all However, the structure given by the Molecular analysis and / or the infrared or nuclear resonance spectrum secured.

509826/09 76

- 25 - Röf. 2993

example 1

9.6 g of 2,4-dimethyl-5-pyrimidylcarbonyl-acetone

CH

10.6 g of racemic l- (o-ethoxyphenoxy) 3-aminopropan-2-ol

0-CH ₂ -CH-CH ₂ -NH ₂

OH

° - ^C 2 ^H 5

and 100 ml of ethanol are stirred for 20 hours at room temperature. By suctioning off the ice-cold solution, 12.3 g of racemic l- (2 _# 4-Dlmethyl-5-pyrlmidyl-) 3- (l ~ / ö.-ethoxy-phenoxy- ^ 72-hydroxypropyl-3-amino- ) but-2-en-one-1 of the formula

OH CH

CH ₃ ^L1 3

M.p .: 105-106 °. A further 5.6 g of the can be obtained from the filtrate

509826/0976

- 2ό - Ref. 2993

Obtaining substance: yield 93 % of theory.

Analysis: ( ^c ₂ i ^H ₂ 7 ^N 3 ⁰ 4 ⁾

Calculated: C 65.4 H 7.1 N 10.9 0 16.6 Found: 65.3 7.1 10.8 16.7

The ^^ carbonyl acetone used as the starting substance can be obtained as follows:

222.7 g of 5 acetyl-2,4-dimethylpyrimidine, 5 liters of anhydrous Toluene, 245 g of methyl acetate and 405 g of potassium tert-butoxide are heated to 60 ° under nitrogen for 4 hours. It is poured into 2 l of ice water and 205 ml of acetic acid, and separates and by working up the toluene solution, 252.3 g of 2,4-dimethyl-5-pyrimidylcarbonyl-acetone, b.p. 112-118 ° / O, 2 Torr, Mp 65-66 ° (from ligroin)

Analysis: ( ^C _XO ^H ₁₂ ^N 2 ^O 2 ⁾

Calculated: C 62.5 H 6.3 N 14.6 O 16.6 found: 62.3 6.3 14.6 16.7

Example 2

If one treats instead of the racemic l- (o-> ethoxy ~ phenoxy-) 3-amino-propan-2-ol its levorotatory isomer

509826/0976

- 27 - Ref. 2993

-CI

I OH

OrCH ₀ -CH-CH ₀ -NH ₀

° - ^C 2 ^H 5

in the same way as described in Example 1, the levorotatory (-) - l- (2,4-dimethyl-5-pyrimidyl-) 3- (l- ^ ö-ethoxy-phenoxy ^^ - hydroxy-propyl « 3-amino-) but-2-en-one of the formula

* 0-CH ₂ -CH-CH ₂ -NH-C-Ch-CO

OH CH ₃ / _N / ^

^J CH ^LH 3

Mp: 103-105 °, cC ^ ⁵ . . ₁₀ <>

Analysis: ( ^c ₂ i ^H 27 ^N 3 ° 4 ⁾ calculated: C 65.4 H 7.1 N 10.9 0 16.6 found: 65.6 7.0 11.0 16.5

The levorotatory (-) - l- (o-ethoxy-phenoxy-) 3-amino-propan-2-ol used as the starting substance can be prepared from the racemate as follows:

20 g (o-athoxyphenoxy-) 3-aminopropan-2-ol (racemate) are dissolved in 295 ml of isopropanol and mixed with a solution of 7.1 g of L (+) - tartaric acid in 100 ml of isopropanol,

509826/0976

- 28 - Ref. 2993

a voluminous white precipitate separates out. The white product is suctioned off, well with isopropanol washed and dried in vacuo. This gives 26.7 g of the tartrate (95% of theory) of the l- (o-ethoxyphenoxv-) 3-amino-propan-2-ol with an optical rotation value · »+12

These 26.7 g are recrystallized three times from a mixture of 40 parts of dimethylformamide and 10 parts of water. The tartrate of (-) - l- (o-ethoxyphenoxy) 3-aminopropan-2-ol (2 moles of amine to 1 mole of tartaric acid) with an optical rotation value of -1 ° (melting point: 201 ° C.) is thus obtained. 4 g of this finely powdered salt are suspended in 60 ml of dioxane and NH ₃ gas is introduced for 1/2 hour at room temperature (the heat of reaction is removed by cooling). Ammonium tartrate is filtered off with suction and the dioxane filtrate is concentrated in vacuo. The solid white residue is recrystallized from ligroin. The levorotatory (-) - 1- (o-ethoxyphenoxy) 3-aminopropan-2-ol with a melting point of 87 ° C. is obtained in this way.

Yield - 2.6 g - 88% of theory (calculated on the tartrate with a rotation value of -1 °); optical rotation value »- 5.

Example 3

A mixture of 15.0 g of racemic l ~ (2,4-dimethyl-5-pyrimidyl-) 3- (l- / jö-ethoxy-phenoxy-72-hydroxypropyl-3-amino) but-2-ene -on ~ l the formula

509826/09 76

Ref. 2993

_O -CH ₂ -CH-CH ₂ -NH-C-CH-CO-I ^ n OC O H ^J _CH " ^CH 3

140 ml of ethanol, 50 ml of water and 4.0 g of sodium boronate is heated to 70 ° for 3 hours, then evaporated under reduced pressure and the residue in water and pentan-1-ol added. The clear pentanol solution is evaporated again and the residue with ethyl acetate and water at pH 6. The ethyl acetate is discarded, the aqueous solution is adjusted to pH 10 with lye and again with ethyl acetate carried out. Evaporation of this ethyl acetate gives 8.3 g of crude racemic residue as residue 1- (2,4-Dimethyl-5-pyrimidyl-) 3- (1-Zö-ethboxy-phenoxy · ^ 2-hydroxy-propyl-3-amino-) butan-l-ol of the formula

as a viscous oil, which can be further expanded by column chromatography can be cleaned.

5098 26/0 9 76

- 30 - Ref. 2993

Analysis (C ₃₁ H ₃₁ N ₃ O ₄ )

Calculated: C 64.8 H 8.0 N 10.8 0 16.4 found: 64.5 8.1 10.7 16.6

Used instead of the above racemic Starting substance your levorotatory isomer, which can be prepared according to the information in Example 2, This gives the levorotatory (-) - l- (2,4-dimethyl-5-pyrimidyl-) 3- (l-Zö-ethoxy-phenoxy ^ S-hydroxypropyl-3-ainino-) butan-l-ol the formula

* λ w 4-Jf Wn Af Wt w ** ^ ν * ·· λ

OH CH OH _x ^ -

ί ^Η 5 CH ₃ ^CH 3

as viscous oil, oCj * ⁵ ; -1.4 °

Analysis: < ^C 21 ^H 31 ^N 3 ° 4 ^

Calculated: C 64.8 H 8.0 N 10.8 0 16.4 found: 64.8 7.9 10.6 16.8

Example 4

A solution of 5.8 g of 2,4-dimethyl-5-pyrimidylcarbonyl acetone

CH ₃

509826/0976

- 31 - Ref. 2993

and 7.5 g of 1- (p-n-butoxyphenoxy) 3-aminopropan-2-ol

in 50 ml of anhydrous ethanol is left for 30 hours Stand room temperature. It is evaporated under reduced pressure, the residue is crystallized from toluene and 7.6 g of l- (2,4-dimethyl-5-pyrimidyl-) -3-l- ^ pn-butoxyphenoxy ^ 72-hydroxypropyl-3- are obtained amino-) but-2-en-one-l the formula.

,, - _{O-CH 0} -CH-CH ₀ -NH-C ₁ -C H 0 -CQ

OH CHo

CH ₃ - CH ₃

Mp: 81-83 °. From the filtrate can be another 3.3 g of Gain substance.

Analysis: ( ^C 23 ^ 3i ^N 3 ° 4 ^

Calculated: C 66.8 H 7.6 N 10.1 O 15.5 found; 66.6 7.7 10.3 15.6

When this substance is reduced with sodium boronate, as described in Example 3, 1- (2,4-dimethyl-5-pyrimidyl-) 3- (1-Zp-n-butoxyphenoxy ₌ 72-hydroxypropyl-3) is obtained -ämino -.) butanl-ol of the formula

509826/0976

Ref. 2993

0-CH _n -CH-CH ₀ -NH-CH-CH ₀ -

Δ f £ I (·

OH

CH,

as viscous oil.

A solution of this substance in about 5 volumes of ethyl acetate is stirred up with an aqueous solution of the equivalent amount of naphthalene-1,5-disulfonic acid. The pure aqueous solution (pH 4) is evaporated and the residue is stirred with anhydrous ether. The neutral naphthalene-1,5-disulfonate of 1- (2,4-dimethyl-5-pyrimidyl-) 3 is obtained in 89% yield - (l- ^ p-n-butoxy-phenoxy- ₌ 72-hydroxypropyl-3-amino-) butan-l-ols of the formula

in the form of pale yellowish crystals, mp 163-167 ° (Z.) _t

Analysis: (Cj ₈ H ₃₉ N ₃ O ₇ S)

Calculated: C 59.8 H 7.0 N 7.5 O 19.9 S 5.7

found: 59.7 7.0 7.3 20.2 5.8

50982 6/097 6

- 33 -. ^R ef ♦ 2993

Example 5

5.6 g of 1- (4-acetaminophenoxy) 3-aminopropan ~ 2-ol

QH
5.3 g of 2,4-dimethyl-5-pyrimidyl carbonyl acetone

CH ₃ ^N CII ₃

and 50 ml of anhydrous ethanol are heated to 40 ° for 20 hours. At 70 °, 3.0 g of sodium boronate are introduced in portions into the reaction mixture and the mixture is heated to 70 ° for a further 7 hours. It is then evaporated under reduced pressure and the residue is taken up in water and n-pentanol. The pentanol solution is stirred with water and the latter is adjusted to pH 6.5 by adding dilute sulfuric acid, separated off and the clear aqueous solution is stirred again with n-pentanol at pH 9.5. Evaporation of this pentanol solution gives 4.5 g of only slightly impure l- (2,4-dimethyl-5-pyrimidyl-) 3- (l- / p-acetaminophenoxy- ₌ 72-hydroxypropyl-3-amino- ) butan-l-ol of the formula

£ AO-CH ₂ -CH-CH ₂ -NH-CH-CH ₂ -Ch OH CH ₀

5 0 9 8 2 6/0976

- Vi ref. 2993

as a viscous oil that can be further purified by column chromatography.

Analysis: ^ ₂ Ao ¹ W

Calculated: C 62.7 H 7.5 N 13.9 O 15.9 found: 62.4 7.5 13.7 16.2

0.48 molar equivalents are added to a solution of the base in ethanol L - (+) - tartaric acid, the reaction mixture is evaporated under reduced pressure and the above residue is stirred several times with pure ethyl acetate. You get white hygroscopic crystals of the neutral tartrate of l- (2,4-dimethyl-5-pyrimidyl-) 3- (l- / p-acetaminophenoxy ^ 7 2-hydroxy-propyl-3-amino-) butan-l-ol of the formula

0-CH ₀ -CH-CH ₀ -NH-CH-CH ₀ -CH-TSi = ^ Tf. 1/2 (CH-CO) ₀ .2H _o 0 OH CHo ΟΗΛΝ'-Χ. OH OH

Mp 83-87 ° (T.)

Analysis: ( ^C ₂ 3 ^H 33 ^N 4 ° 7 · 2HgO) calculated; c 53.8 H 7.3 N 10.9 o 28.0

found: 53.6 7.4 10.8 28.3

509826/0976

- 35 ~ Ref. 3993

Example Q

In the same manner as in Examples 1 to 4 ¹ loading written, the following substances were prepared;

\ -O-CH ₂ -CH-CH ₂ -NH-A

OH

CH ₃

R A

2-Cl -C-CH-CO- m.p. 118-119 °

CH ₀

2-Cl -CH-CH ₀ -CH- oil

1 * 1
CH ₃ OH.

4-Cl -C-CH-CO- m.p. 103-105 °

^CH 3.

4-Cl -CH-CH ₀ -CH- oil

I ^ I CH ₃ OH

4-OCH ₃ -C-CH-CO- mp 113-115 °

CH ₃

509826/0976

Ref. 2993

4-OCU,

-CH-CH ₀ -CH-I 2 ι

CH ₀ OH

oil

-C-CH-CO-I CHo

oil

-CH-CH ₀ -CH-

I 2 ι

CH ₃ OH

oil

4-0CJßL (n)

• 3 I.

.C-CH-CQ- * I CH ₃

M.p .: 88-90

4-OC ₃ H ₇ (n)

-CH-CH ₂ -CH-CH ₃ OH

oil

4-OC ₃ H ₇ (D.

-C-CH-CO-CH ₃

Fp: 80-82 '

4-OC ₃ H ₇ (D.

.CH-CH ₀ -CH-

^{1 2} 1

CH ₃ OH

oil

2-OCH,

-C-CH-CO-CHo

M.p .: 118-119

2-OCH.

3-0C ₄ H ₉ (n)

-CH-CH ₀ -CH-CH ₃ OH

.CH-CH ₀ -CH-CH ₃ OH

oil

oil

509826/0976

- 37 - Ref. 2993

3-OC ₄ Il ₉ (η) -C-CH-CO-
3 Fp 01 2-F -C-CH-CO- ; 63-65 ° CH ₃ 2-F -CH-CH ₀ -CH-
I «ι
CH ₃ OH Fp 01 4-OC ₈ H ₁₇ (η) -C-CH-CO-
CH ₃ : 68-69 ° 4-OC ₈ H ₁₇ (n) -CH-CHo-CH- oil CH ₃ OH Fp; 4-C (CHg) ₃ -C-CH-CO- 119-120 ° CH ₃ 4-C (CH ₃ ) ₃ -CH-CH ₀ -CH-
j ^ i 1 oil CH ₃ OH Fp: 3-Cl -C-CH-CO- 121-123 ° CH ₃ 3-Cl -CH-CH ₂ -CH- oil CH ₃ OH

509826/09 76

ran. 2993

B.
3-OCH

C-CH-CQ-

CH "

oil

3-OCH.

CH-

I ₃

I 2 ι

CH ₃ OH oil

-C-CH-CO- ^l 3

M.p .: 86-87 ^p

4-Br

-CH-CB ₀ -CH CH ₃ OH

-C-CH-CO-CH ₀

Oil, naphthalene-1,5-disulfonate (according to example k) i mp 202-20if ° (z)

M.p .: 65-66 °

4-Br

• CH — CHn- CH-

I · I

CH ₃ OH oil

4-OC ₂ H ₅

-C-CH-CO- Mp: 113-115

4-OC ₂ H ₅

-CH-CS ₀ -CH-I * I

CH ₃ OH oil

4-OCH,

C-CH-CO "» 3

M.p .: 86-87 ¹

509826/0976

Ruf, 2993

4-OCH

2Λ / 7

• CH-CH _O -CH-I ² I

CH ₃ OH

The l-aryloxy-3-amino-propan.-2-ols used as starting substances

./-0-CH ₀ -CH-CH ₀ -NH ₉

OH

can be produced using conventional methods, e.g. by reacting ammonia with the l-aryloxy-2,3-epoxy propanes

- ^CH

The latter arise in a known manner from the corresponding Phenols and epichlorohydrin,

One obtains z. B .:

1- (4-n-propoxyphenoxy) 2,3-epoxypropane

Mp 43-45 ¹

1- (4-n-propoxyphenoxy - ») 3-aminopropane-2-oi. · Mp 99-101

509826/0976

- kO - Ref. 2993

l- (4-.i-propoxy-phenoxy-) 2,3-epoxy-propane oil, b.p. 112-115 ° /

0.2 torr

1- (4-i-propoxy-phenoxy-) 3-aminopropan-2-ol, m.p. 76-78 ° l- (3-n-Butoxy-phenoxy-) 2,3-epoxy »-propane oil, bp 133-137 /

O ₁ I torr

1- (3-n-Butoxy-phenoxy-) 3-aminopropane ~ 2-Ol, mp 50-60 °

l- (2-fluoro-phenoxy-) 2,3-epoxy-propane oil, bp 90-92 ° /

0.1 torr

1- (2-fluoro-phenoxy-) 3-amino-propa.n-2-ol mp 64- * 66 ^o

1- (4-n-octyloxy-phei> oxy-) 2 _# 3-epoxy-propane mp 46-48 °

1- (4-n-Octyloxy-phenoxy-) 3-aminopropane-'2TOl mp 106-107 °

1- (4-Benzyloxy-phenoxy-) 2 _# 3-epoxy-propane, mp 55 °

1- (4-Benzyloxy-phenoxy-) 3-aminopropane.-2-o ^. 143-145 °

1- (4-tert-butyl-phenoxy-) 2 _# 3-epoxy-prQpian oil, b.p. 110-112 ° /

0.2 torr

1- (4-tert-butyl-pueneoxy) 3-aminopropane-2-Ql mp 106-108 ° 1- (4-n-Pe.ntyl.oxy-phenoxy ») 2, 3» epojcy-propane mp 37-38 1- (4-n-pentyloxy-phenoxy-) 3-aminopropan-2-ol, mp 101-103 °

509826/0976

Ref. 2993

Example 7

2.2 g of 1- (2,4-dimethyl-5-pyrimidyl-) 3- (1- <£ pn-butoxy phenoxy- _z 72-hydroxypropyl -3-amino) butan-ol of the formula

are with 20 ml of ethanol and 0.55 ml of a 39% aqueous formaldehyde solution heated under reflux for 4 hours. The reaction mixture is evaporated and the The residue taken up in 200 ml of ligroin is obtained by evaporating the solution which has been clarified with a little activated charcoal 1.7 g 3- (l-hydroxy-l-Z2,4-dimethyl-5-pyrimidyl ^ 73-butyX-) 5- (4-n-butyloxy-phenoxymethyl-) oxazolidine of the formula

as colorless 01,
Analysis: (C ₂₄ H ₃₅ N ₃ O ₄ )

Calculated: C 67.1 H 8.2 N 9.8 O 14.9 found: 67.0 8.2 9.6 15.1

509826/0976

Ref. 2993

Example 8

5.0 g of 1- (2,4-dimethyl-5-pyrimidyl) -3-amino-n-butanol, 50 ml of ethanol (96%) and 9.1 g of 1- (4-n-amyloxyphenoxy ) -2,3-epoxy-propane are stirred for 20 hours at room temperature and then heated to 40 ° C. for 3 hours. By Evaporation of the reaction mixture in vacuo is obtained

13.5 g of crude l- (2,4-dimethyl-5-pyrimidyl) -3- (l- / p-n-amyloxy-phenoxy_7-2-hydroxypropy 1- (3) -amino) -butan-1-ol der formula

OH CH ₃ OH _ _N nC ₅ H _χ -0- / Vo-CHg-CH-CHg-NH-CH-CH-CH- / V-CH ₃

CH ₃

as an oil that is further purified by gel chromatography will.

Analysis: (C ₂₄ H ₃₇ N ₃ O ₄ )

Calculated C 66.8 H 8.6 N 9.7 0 14.8 found 66.6 8.6 9.6 15.0

The 1- (2,4-dimethyl-5-pyrimidyl) -3-amino-n-butanol used as the starting product above is obtained in the following way:

19.6 g (2,4-dimethyl-5-p ^ rimidylcarbonyl) acetone, 200 ml Ethanol and 0.3 g of ammonium bromide are at 50 ° C with Saturated ammonia and heated to 50 C for 20 hours with further introduction of ammonia.

509826/0976

- 4 * hr-- Rei. 2993

In the solution of 1- (2,4-dimethyl-5-pyrimidyl) -3-amino-but-2-en-one-l the formula

N = v ^CH 3
CH ₃ - / VcO-CH-C-NH ₂ (m.p. 93-94 °, recrystallized

CH ₃ . from toluene / ligroin)

8.0 g of sodium boronate are added in portions over the course of one hour and the mixture is stirred at 70 ° C. for 7 hours. The solvent is evaporated off in vacuo and the residue is taken up in aqueous potash solution (20 %) and 1-pentanol. After working up in the usual way, 18.5 g of crude 1- (2,4-dimethyl 5-pyrimidyl) -3-amino-n-butanol of the formula are obtained from the pentanol solution

as an oil, which is further purified by column chromatography can be.

Analysis: (C ₁₀ H ₁₇ N ₃ O)

Calculated: C-61.5 H 8.8 N 21.5 0 8.2 found: 61.4 8.8 21.3 8.4

50 9 8 26/0976

Ref. 2993

Example 9

In a suspension of 8.0 g of 1- (4-n-pentyloxyphenoxy) -3-aminopropan-2-ol (made from p-n-pentoxyphenol with epichlorohydrin and reacting the reaction product with ammonia) and 16.0 g of anhydrous potash in 100 ml of anhydrous toluene are 8.9 g in small portions l- (2,4-Dimethyl-5-pyrimidyl) -3-chloro-butan-l-ol hydrochloride entered. The mixture is stirred for 10 hours at room temperature and continued to heat for 5 hours in a water bath. After cooling, the salt is sucked off and the filtrate is stirred with water and sufficient hydrochloric acid to adjust the pH to 3 in the aqueous phase. The acidic solution is separated from the toluene and washed with ethyl acetate; then you make alkaline with potash and extracted several times with chloroform. 9.3 g of crude are obtained by drying and evaporating the chloroform solution 1- (2,4-Dimethyl-5-pyrimldyl) -3- (1- / p-n-pentyloxy-phenoxy-7-2-hydroxypropyl (3) -amino) -butan-1-ol the formula

OH CH _q OH

II ^J // "•vj—^.n. _O —CH «» CH _o —NH- * CH — Cn _o —un - \\

as an oil, which is further purified by column chromatography.

Analysis: ( ^C ₂ 4 ^H 37 ^N 3 ° 4 ⁾

Calculated: C 66.8 H 8.6 N 9.7 0 14.8 found: 66.7 8.6 9.6 14.9

509826/0976

- 4 ** »- Ref. 2993

The 1- (2,4-dimethyl-5-pyrimidyl) -3-chloro-butan-l-ol hydrochloride used as the starting substance is obtained as follows:

A suspension of the sodium salt of (2,4-dimethyl-5-pyrimidylcarbonyl) acetone in anhydrous toluene is saturated with hydrogen chloride and then reacted in a known manner with thionyl chloride. Which is used without further purification are obtained from the reaction product by reducing the l- (2,4 dimethyl-5-pyrimidyl) -3-chloro-butan-l-ol hydrochloride.

509826/0976

Claims (12)

Ref. 2993 Claims I. Derivatives of 1-phenoxy-3-aminopropan-2-ol of the general Formula I. I Vu-CH ₀ -CH-CII-NII-X CH., wherein X - -C = CH-C- ^ ν or CHo O k _N A
^{3 N} CHo ^Cll 3
-CH-CH _n - ^ N CH ₃ OH and the phenyl nucleus I is one, two or three times by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, AJkinyloxy, benzyloxy, phenyl, halogen or the radical -NR ₁ R ₉ , where R _{1 is} alkyl or acyl and R _{2 represents} hydrogen or alkyl, can be substituted, their aldehyde condensation products and acid addition salts, 2. Derivatives of l-phenoxy ~ 3-amino-'propan-2-ol according to claim 1, characterized in that the phenyl nucleus I is one, two or three times by alkyl having 1 to 4 carbon atoms, alkenyl and alkynyl with each with up to 6 carbon atoms, cycloalkyl and cycloalkenyl with a ring size of 5 to 8 carbon atoms each, alkoxy with up to 8 carbon atoms, alkenyloxy 509826/0976 Ref. 2993 or alkynyloxy each with up to 5 carbon atoms, phenyl, chlorine or bromine or the radical -NR ₁ R ₀ , where 'R _{1 is} alkyl with 1 to 4 carbon atoms or acyl with up to 11 carbon atoms and Rp is Are hydrogen or alkyl with up to 4 Cr atoms, is substituted. 3. Derivatives of l-phenoxy-S-amino-propan-g-ol according to the Claims 1 to 2, characterized in that the phenyl nucleus I by vinyl, allyl, methallyl or Crotyl is substituted, 4. Derivatives of l-phenoxy-3-aminopropan-2-ol according to the Claims 1 to 3, characterized in that the phenyl nucleus I is substituted by cyclopentenyl, 5. Derivatives of phenoxy-3-aminopropan-2-ol according to the Claims 1 to 4, characterized in that the phenyl nucleus I is replaced by cyclopentyl or cyclohexyl is substituted. . 6. Derivatives of l-phenoxy-3-aminopropan-2-ol according to the 50 9 826/0976 Ref. 2993 Claims 1 to 5 _# characterized in that the. Phenyl nucleus I is substituted by methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-pentyloxy, allyloxy, MethaiIyIpxy, propargyloxy, n-octyloxy. 7. Derivatives of l-PhQnoxy-3-aminopropan-2-ol according to Claims 1 to 6, characterized in that the phenyl nucleus I is represented by the radical -NlUR ₉ , where R _{1 is} methyl, ethyl, acetyl »B © n * oyl and R _{2 represent} hydrogen, methyl or ethyl, substituted, is. 8. Process for the preparation of compounds according to Claims 1 to 7, characterized in that that a compound of the general formula III on 509826/0976 with a compound of the general formula iy Y-X IV CII ₀ I where X is -C = CH-C-τ- ^ Λι 'or CH- O t CU L ³ -CII-CH ₂ -C CII ₃ OH and Y stands for halogen and, provided that X = -C = CH-C means, also door -OH, -01C, -ONa represents, is implemented, or that a compound of the general formula ' M IV-O-CH ₂ -Z''XV with a compound of the general formula XVI wherein X is -C = CH-CY ⁵ Jj or CH- 0Ii S CH, 509826/0976 Uof, OH stands and Hal halogen means, is implemented or that a Phenol of the general formula XIV OH with a compound of the general formula XVII X XVII where X is -C = CHtC-T ^ j ₁ J,. . . or CHgHj
CH, OH k _N A _{c 4} j _ w ^ W ^ CH ₃ Z -CII - CH _n or OH means, where Hai stands for a halogen atom, is reacted and that the resulting compound is optionally reacted with an aldehyde of the formula R ₃ -CHO, in which% is hydrogen or a lower ACyl radical with up to h carbon atoms to form an oxazoiidine of the formula II 509826/0976 Vo-CiI ₁₃ ^'11 -X II or optionally with an acid addition salt is implemented,. 9. Vei-drive for the preparation of derivatives of l-phenoxy-3 ~ Amino-propan-2-ols of the general formula XX et; ο OH CIL 011 CIl wherein the Phenylkerii I one, two or dreil'acb by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkeuyloxy, alkynyloxy, phenyl, halogen or the Eeate -NH ₁ K ₀ , where U ₁ Γύν alkyl or acyl and R ₂ i'ür Wassurstol or alkyl, substituted yein, whose aldehyde condensation products and acid additioniona salts, characterized in that a compound of the general formula XXI, XXlI or XXIII ff I VO-CH ₂ -ClI-CH, OH I- ₍ CH Cr-j ^ j
CU- O k _N A _t . XXI ft (f I VO-CH ₀ -C-CH ₀ -NH-C = CH-C- V "ft * Au ₃ J! ' TA XXlI I ^ O-CIL ^ C-CHg-NH-CIi-Cl ^ -Cn-j ^ 'jS Ο CU- 'OH XXIII 509826/0976 is hydrogenated and that the resulting compound is optionally reacted with an aldehyde of the formula IU-CIIQ, in which% hydrogen or a lower allryl radical with up to h carbon atoms to form an oxazolidine of the formula II or optionally with an acid to form an acid addition sulfate , 10. A pharmaceutical preparation, characterized in that it contains one or more compounds according to Claims 1 to 7 together with a pharmaceutical: impeccable diluent or contains carrier. ... 11. Pharmaceutical preparation according to claim 10, characterized in that that there is no one or more ... other pharmaceuticals contains active substances, 12. Pharmaceutical preparation according to claims 9 to 10, characterized in that - that the further pharmaceutical substance or substances from vasodilators, hypoteusion agents, Sedatives, heart ionizing agents, bronchodilators, and sympathomimetic agents ■ is selected, · '' 26/097