CA1105021A - Process for the manufacture of new 1-amino-2-hydroxy- 3-heterocyclyloxy-propanes - Google Patents

Abstract

Abstract of the Disclosure l-Amino-2-hydroxy-3-heterooyclyloxy-propanes of the formula

Description

~q~

The present invention relates to l-amino-2-hydroxy-3-heterocyclyloxy-propanes of the Eormula y ~ ~ ~2 ~ CH(O~l) - CH2 - N~ ~ C~12-CH2 ~ (I) wherein Y represents the group - CH = or the group - N = , ~`~
R~ represents hydrogen, hydroxyl, lower alkyl or lower alkoxy, R2 represents hydroxyl, lower alkoxy or~ together with Rl, o-lower alkylidenedloxy or o-lower-alkylenedioxy, ancl R3 represents lower alkyl, lower alko~y, halogen or cyano, with the radicals Rl, R2 and R3 each being bound to any one of the possible aromatic carbon atoms;
or to salts thereof; to processes for producing them, to pharmaceutical preparations containing such compounds; and to the application thereof.
The radics1 of the formula (--~ R3 represents the 2-pyridyl radical where-ln the group I~3 can be i~ the 3-, 4-, 5- or 6-positi.on, or the 2-pyraæinyl radical wherein the group~R3 can be in the 3-, 5- or 6-position.
Within the scope of the present application, the groups and

- 2 , ... ~ , . . . . .

compounds termed 'llower" have, except where o~herwise defined, up to 7 carbon atoms and in particular up to 4 carbon atoms.
Lower alkyl is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec.-butyl, tert..-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl; whilst lower alken.yl is, for example, vinyl, allyl or methallyl; and lower alkynyl is, for example, ethynyl or propargyl.
Lower alkoxy is, for example, methoxy~ ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert.-butyloxy.
Halogen is particularly halogen having an atomic number of up to 35, i.e. fluorine, chlorine or bromine.
o-Lower-alkylidenedioxy and o-lower-alkylenedioxy each have 1 to 3 carbon atoms and ar~, for example, methylenedioxy or isopropylidenedioxy, whilst lower-alkylenedioxy is, for example, 1,2-ethylenedioxy.
Salts of compounds o the formula I are primari].y acid addition salts, and in partlcular pharmaceutically acceptable non-toxic acid addition salts with suitable inorganic acids, : such as hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid; or with suitable organic acids, such as with aliphatic, cycloaliphatic, aromatic, araliphati.c or heterocyclic carboxylic acids or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acicl, glycolic acid, lactic acid, malic acid~ tartaric acid, citric acid, ascorbic acid, maleic acid, umaric acid, pyruvic acid, benzoic acid, anthranllic acid, : 3 -.
.

.. . :: -4-hydroxybenzoic ac.id, salicylic acid, phenylacetic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, ethylenesulphonic acid, 4-chlorobenzenesulphonic acid, toluenesulphonic acid, naphthalene-sulphonic acid, sulphanilic acid or cyclohexylaminesulphonic acid, and al.so ascorbic acid. By virtue of the close relation-ships between the new compounds in the free form and in the form of their salts, it is to be understood that by "free compounds" and by "salts" are accordingly meant~ with the appropriate modifications, optionally also the corresponding salts and free compounds, respectively.
The invention relates in particular to compounds of the formula I wherein Rl represents hydrogen, hydroxyl, lower alkyl or lower alkoxy each having up to 4 C atoms, R2 represents hydroxyl, lower alkoxy having up to 4 C atoms, and, together with Rl, o-lower-alkylidenedioxy having - 1 to 2 C atoms, and R3 represents lower allcyl or lower alkoxy each having up to 4 C atoms, halogen or cyano, wikh Rl and R2 each being in ~he 2-, 3- or 4-position and o-lower-alkylidenecli.oxy in the 2,3 or 3,4-position, and R3 in a pyridine ring beill, in the

3~, 4-, 5- or 6-position, or in a pyrazine ring in the 3~, 5- or 6-posi~ion;
and to their ~al~s, ~specially their pharmaceutically acc~ptable~

'~

- , . , , - , ., - . . ..

, . . . . .
..

non-toxic acid addition salts.
The invention relat-es furthermore particularly to compo-mds of the formula ~ O - CH2 - CH(OH) - CH2 - NH - CH2-CH2 ~ 2 (Ie), wherein Rl represents hydrogen, hydroxyl, methyl or methoxy, R2 represents hydroxyl, methoxy or, together with Rl~ o-me.thylenedioxy, and R3 represents methyl, methoxy, chlorine or cyano, with Rl and R2 each being in the 3- or 4-position, o-methylenedioxy in the 3,4-position, and R3 in the 3- or 4-position;
and to their salts, especially their pharmaceutically acceptable, non-toxic acid addition salts.
The invention relates in addition especially to compounds of the formula N C~12 CH(OH) - CH2-NH - C~12-C42 ~ R2 (Ib) wherein Rl represents hydrogen~ hydroxyl~ methyl or methoxy, R2 represents hydroxyl, methoxy or, together with Rl, o-methylenedioxy, and ~: R3 represents methyl, methoxy, chlorine or cyano, with Rl and R2 each being in the 3- or 4-position, o-methylenedioxy in the , ~ . . . .
: :,.... .

,,, .. ~ , ~ , . . . . . . .
.

', ' ', , ,~

3,4-position, and R3 in the 3-position;
and ~o their salts, particularly their pharmaceutically acceptable, non-toxic acid addition salts.
The invention relates in particular to the following compounds of the formula I:

2-[3'-(2-(3,4-dimethoxyphenyl~-ethylamino)-2'-hydroxy-propoxy]-3-cyanopyridine, l-(3-chloropyrazin-2-yloxy)-3-~2-(3,4-dimethoxyphenyl)-ethylamino]-2-propanol, l-[2-(3,4-dimethoxyphenyl)-ethylamino]-3 (3-methoxypyridin-2-yl-oxy)-2-propanol, l-~2-(p-methoxyphenyl)-ethylamino]-3-(3-methylpyridin-2-yloxy)-2-propanol, l-12-(3,4-methylenedioxyphenyl)-ethylamino~-3-(3-methylpyridin-2-yloxy)-2-propanol, l-12-(3,4-rnethylenedioxyphenyl)-ethylamino] 3-(4-methylpyridin-2-yloxy)-2-propanol~
l [2-(p-hydroxyphenyl)-ethylamino]-3-(3-methylpyridin-2-yloxy)-2-propanol, l-12-~p-hydroxyphenyl)-ethylamino]-3-(4-methylpyridin-2-yloxy)-2-propanol~
l-[2~(3,4-dlmethoxyphenyl)-e.thyLamino]-3-(3-me~hoxypyrazin-2-yl-oxy)-2-propanol, l-~2-(p-hydroxyphenyl)-ethylamino]-3-(3-methoxypyridin-2-yloxy)-2-propanol, l-[2-(3-methoxy-4-hydroxyphenyl)-ethylamino~-3-(3-methylpyridin-2-yloxy)-2-propanol.;
and to their salts, especially their pharmaceutically acceptable, ~, :: . . .
.
' . ~.: . - ' . ~: '' r~

non-toxic acid addition salts.
The new compounds possess valuable pharmacological properties.
They thus have in particular an adrenergic beta receptor-blocking action, which can be verified as inhibition of the isoproterenol tachycardia, for example on the isolated guinea-pig heart according to Langendorff. The concentrations required for a half-maximum inhibitory effect (EC50) are in this case 0.04 - 0.44 ~g/ml. Furthermore, for example, 2-[3'-(2-(3,4-dimethoxyphenyl)-ethylamino)-2'-hydroxy-propoxy]~3-cyanopyridine, as neutral fumarate, inhibits on the anaesthetised cat with perfused back extremity the isoproterenol tachycarclia clearly more (ED50 = 0.2 mg/kg i.v.) than it does the isoproterenol vasodilation (ED50 = 3 mg/kg i.v.). From this it follows that this compound belongs to the cardioselective beta-receptor-blocker class.
The new compounds produce moreover an inhibi~ion of the adrenergic alpha receptors, which effect can be verified, for example, as noradrenalin antagonism on the isolated vas deferens in the ra~. The concentrations necessary for a PA2 value are in this tes~ system 0.~ - 7.6 ~ , with corresponding pA~ values of 6.40 - 5.12 ~ .
The new compounds additionally possess hypotensive properties, whlch can be shown~ ~or example, by the long-lasting lowering of the ar~eriaL blood pressure in the anaesthetised cat with doses upwards of 0.1 ~g/kg i~v. By virtue of their properties -:;~ : . .

.

.

as beta-receptor blockers with additional alpha-receptor-blocking and hypotensive effects, the new compounds can be used in the treatment of the indications known for beta-receptor blockers, for example hypertonia, Angina pectoris or disturbances of the cardiac rhythm.
The new compounds of the present invention can be produced by (a) in a compound of the formula 6 N ~--O ~ ~H - CH2 - N - CH2 - ~12 ~ 'RS(II) ~ X2 Xl wherein Y and R3 have the above meanings, R4 has ~e meaning of Rl or represents the group -O-X3, R5 has the meaning of R2 or represents the yroup -O-X4, Xl represents hydrogen, an ~-aryl-lower-alkyl group an acyl radical of an organic carboxylic acid or an organic sulphonic acid or an optionally substituted l-poly-phenyl-lower-alkyl group, each of the groups X2, X3 or X4 represent hydrogen, a 1 phenyl-lower-alkyl group optionally substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or nitro, an acyl radical of an organic carboxylic acid or an organic sulphonic acid, or an optionally substituted aliphatic or araliphatic hydrocarbon radical polybranched on the linking carbon atom, or Xl and X2 together or X3 and X4 together represen~
1-phenyl-lower-alkylidene optionally substituted in the phenyl moiety by lower alkyl, hydroxyl, B

. . .
. .
. ~, . .
.- . ... .
.. . . . .

f~ '2~

lower alkoxy, halogen and/or nitro, or represent lower alkylidene or cycloalkylidene or the diacyl radical of a carboxylic acid or thiocarboxylic acid, provided that at least one of the groups Xl, X2, X3 or X4 or Xl and X2 together or X3 and X4 together is different from hydrogen, or in a salt of such a compound, split-ting off by solvolysis or reduction all gxoups X1, X2, X3 or X4 which are different fxom hydrogen or the group Xl and X2 together and/or X3 and X4 together and replacing them by hydrogen, or (b) reacting a compound of the ~ormula R3 (III) N ~ ~---- O - CH2 ~ CH2 X6 x5 or a salt thereof, ~ith a compound of the formula ~ ~ ~12 ~ ~12. - ~ (IV) or a salt thereof, wherein one of th.e groups X6 and X7 represents a reactive esterified hydroxyl group and the other represents the primary amino yroup, and X5 represents the hydroxyl group, or wherein X5 and X6 together represent the epoxy group, and X7 represents the primary amino group, and Y, Rl, R2 and R3 have the above mean1ngs, or ~ .

':

,?~ f'~

(c) in a compound of the formula .Y Rl 3 ~ ~ ~
~ N ~ O - CH2 - CH(OH~ - X8 ~ (V) wherein the group -X8- (Va) represents one of the radicals of the formulae -CH=N~CH2 CH2- (Vb), or -CH2-N=CH-CH2 ~Vc), or -C(=X9)-N-CH2-CH2- (Vd)~ or -C~2-N-C(=X9)-cH2- (Ve), wherein Xg represents the oxo or thioxo group, Y, Rl, R2 and X
have the above meanings, and R3 has the given meaning with the exception of halogen and cyano, or in a salt thereof, reducing the group -X8-, optionally by way of the intermediate containing the radical -CH2-~-CH2-CH2-, to the radical of the formula -CH2-NH-CH2-CH2- and, if required, converting a compound of the formula I, wherein R3 represents halogen by reaction with a lower : alkanol into a compound o-E the formula I, wherein R3 is lower ::
alkoxy, or converting a compound of the formula I, wherein Rl : and/or R2 xepresent(s) hydroxyl by reaction with a reactive de-rivative of a lower alkanol into a compound of the formula I, wherein Rl and~or R2 represent(s) lower alkoxy or lower alkyliaene-dioxy, and, when a salt is re~uired, converting a free compound of the ~ormula I irrto a salt, and, when a free compound of the formula I is required, converting a salt into the free compound, and when a pharmaceutically acceptable non-toxic acid addition salt is . ~ - 9a -" -~
J

~ . . , . . . ~ . ' . , , .. ' ' ' , . ', . ~

.. .

~. ' ' ~ . ~ ' . , ~,A l. L ~ ,J~;~

required, converting a free compound of the formula I into a pharmaceutically acceptable non-toxic acid addition salt, and when a racemate is required, converting a mixture of racemates into the two stereoisomeric (diastereomeric) racemates, and when an optical antipode is required, resolving a racemate into the optical antipodes.
The groups Xl and/or X2 and/or X3 and/or X4 are split off by means of solvolysis or reduction. In the stated starting materials of the formula IIy Xl is preferably a group other than hydrogen, whilst X2, X3 and X~ represent in particular hydrogen.
An especially suitable group Xl capable of being split off is particularly an ~-aryl-lower-alkyl group which can be split off by hydrogenolysis, such as an optionally substituted l-phenyl-lower-alkyl group, wherein substituents, especially of the phenyl moiety, can be, for example, lower alkyl such as methyl or tert.-butyl, hydroxyl, lower alkoxy such as methoxy, halogen, e.g.
chlorine or bromine, and/or nitro, and above all benzyl. A group Xl can also be A radical capable of being split off by solvolysis, such as by hydrolysis or acidolysis, and also by reduction, in-cluding hydrogenolysis, especially a corresponding acyl radical,such as the acyl radical of an organic carboxylic acid, ~or example lower alkanoyl such as acetyl, or aroyl such - 9b -~3 ' ':
~ ~ .
~ . , ' ' benzoyl~ also the acyl radical of a semi-ester of carboxylie acid, such as lower alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert.-bu~yloxycarbonyl, 2-halogeno-lower-alko~ycarbonyl, for example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, for example benzy]oxyearbonyl or diphenyl-methoxycarbonyl, or aroylmethoxycarbonyl, for example phenacyl-oxycarbonyl, or the acyl radical of an organic sulphonic acid, such as of an aromatic sulphonic aeid, particularIy an optionally substituted phenylsulphonyl radieal wherein substituents have, for example, the meaning given for the above l-phenyl-lower-alkyl radieal, and espeeially 4-methylphenylsulphonyl, also an optionalLy substituted l-polyphenyl-lower~alkyl group wherein substituents partieularly of the phenyl moiety have, Eor example, the above given meaning, and represent espeeially trityl.
A group X2, X3 or X4 replaeeable by hydrogen is preferably likewise a group eapable of being split of by hydrogenolysis, sueh as one of the stated, optionally substituted, l-phenyl-lower-alkyl groups, and above all benzyl~ It ean also be one o~
the aeyl groups, mentioned for the group Xl~ whieh are eapable of being split off by solvolysis, ineluding aleoholysis, or by reduetion; also an optionally substituted aliphatie or araliphatie hydroearbon radieal polybrallehed on the linking earbon atom, sueh as tert.~lower-alkyl, for example tert.~butyl, or ~rityl.
A radieal formed by Xl and X~ or X3 and X~ together and eapable of being split of, is in partieular again a group ~' :
: ~ . . . ~ . . . .. . - .
- ~ . .

- . . ~ , . ' ~

~ '2 ~

capable of being split off by hy~rogenolysis, such as optionally substi~uted l-phenyl-lower-alkylidene, wherein substituents, especially of the phenyl moiety, can be, e.g., lower alkyl such as tert.-butyl, hydroxyl~ lower alkoxy~ halogen and/or nitro, and particularly benzylidene; and also groups capable of being split off by solvolysis, especially by hydrolysis, such as lower alkylidene, for e~ample methylene or isopropylidene, or cycloalkylidene, for example cyclohexylidene. A further radical formed by the groups Xl and X2 or X3 and X~ together is the diacyl radical of carboxylic acid or thiocarboxylic acid, i.e. the carbonyl or thiocarbonyl group.
Starting materials usable in the form of salts are used principally in the form of acid addition salts, for example with mineral acids~ and also with organic acids.
Radicals Xl andlor X2 and/or X3 and/or X~ capable of being split off by hydrogenolysis, particularly optionally substituted l-phenyl-lower-alkyl groups, also suitable. acyl groups such as optionally swbstituted ~-phenyl-lower-alkoxycarbonyl, and also optionally substituted l-phenyl lower-alkylidene gl^OUpS ~ormed by the groups Xl and X2 and/or X3 and X4 together, can be split of~ by treatment~with catalytically activated hydrogen, for ; example with hyclrogen itt the presence of a nickel catalyst, such as Raney nickel, or of a suitable noble metal catalyst.
: Groups X~ and/or X2, and/or X3 and/or X4, such as acyl radicals of organic carboxylic acids, e.g. lower alkanoyl, and semi-esters ' : : - . .

~ ' . ~ : -of carboxylic acid, e.g. lower alkoxycarbonyl, also~ e.g., trityl radicals, and also lower alkylidene groups or carbonyl groups formed by the radicals Xl and X2 and/or X3 and X4 together, can be split off, depending on the type of such radicals, by trea~ment with water under acid and/or basic conditionsg for example in the presence of a minPral acicl, such as hydrochloric acid or sulphuric acid, or in the presence of a hydroxide or carbonate of alkali metals or alkaiine-earth metals.
Radicals which can be split off by acidolysis are in par-ticular certain acyl radicals of semi-esters of carboxylic acid, such as tert.-lower-alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl radicals~ also tert.-lower~alkyl radicals X2, X3 or X4; they can be split off by treatment with suitable strong organic carboxylic acids, such as loweralkanecarboxylic acids optionally substituted by halogen, especial].y by fluorine, particularly with trifluoroacetic acid (if necessary in the presence of an activating agent, such as anisole), and also with formic acid.
By radicals ~1 and/or X2 and/or X3 and/or X4 capable of being split off by reduction are meant also those groups which are split off by treatment with a chemical reducing agent (par-ticularly with a reducing metal or a reducing metal compouncl).
Such radicals are in particular 2-halogeno-lower alkoxycarbonyl or aroylrnethoxycarbonyl, which can be split off, for example, :

by treatment with a reducing heavy metal such as zinc, or with a reducing heavy metal salt such as with a chromium-II salt, e.g.
chromium-II chloride or chromium-II acetate, usually in the presence of an organic carboxylic acid, such as formic acid or acetic acid, and of water. Arylsulphonyl radicals capable of being split off by reduction, especially those denoted in partieular by the radical Xl, ean be replaeed by hydrogen by treatmen-t with an alkali metal, e.g. lithium or sodium, in ammonia, or hy means of electrolytic reduction.
The above reactions are performed in a manner known per se, usually in the presence of a solvent or solvent mixture, wlth suitable reaetants being able to simultaneously function as such, and, if necessary, with cooling or heating, e.g. in a temperature range of about -20C to about +150C, in an open or closed vessel and/or in the atmosphere of an inert gas, e.g.
nitrogen.
A reaetive esterified hydroxyl group X6 or X7 in a eompound of formula III or IV is a hydroxyl group esterified by a strong aeid, espeeially a stxong inorganic aeid such as a hydrohalie aeid, espeeially hydrochloxic aeid, hydrobromie acid or hydriodic acid, or sulphurie aeid, or by a strong organie aeid, particularly a strong organie sulphonie aeid, such as an aliphatic or aromatie sulphonic aeid, ~or example methanesul-phonie aeid, 4-methylphenylsulphonic aeid or 4-bromophenyl-sulphonie aeid, and is above all halogen, eOg. chlorine, bromine or iodine, or aliphatieally or aromatically substituted sulphonyl-oxy, for example methylsulphonyloxy or 4-methylphenylsulphonyloxy.

~ ,. . , - . . ,: .. . . :.

The reaction of compound III with compound IV is performed in a manner known per se, and is performed, part- -icularly with the use of a starting material having a reactive esterified hydroxyl group, advantageously in the presence of a basic agent, such as an inorganic base, for example in the presence of a carbonate or hydroxide of an al~ali metal or of an alkaline-earth metal, vr in the presence of an organic basic agent~ such as an alkali metal lower alkanolate, and/or of an excess of the basic reactant, and usually in ~he presence of a solvent or solvent mixture~ and, if necessary, with cooling or heating, e.~. in a temperature range of about -20C to about ~150C, in an open or closed vessel and/or in an inert-gas atmosphere, e.g. in a nitrogen atmosphere.
The reductive conversion of a radical of the formula -X8- (Va) in a compound of for~ula V into the desired grouping of the formula -CH2-NH-CH2-OEI2- can be performed i~ a manner known per se, with ~;~

- - ,. ': - :' . - . , . ` , .. . , . - . ~ .
:. . . . :.
: , . . : , ' :
.
.:
, ~he choice of the suitable reducing agents depending on the nature of the groups of the formula (Va~. Particularly suitable for the reduc~ion of groups of the formulae (Vb) and (Vc), and also of groups of the formulae (Vd) and ~Ve), wherein the radicals of the formula - C(=X9)-N-CH2-CH2- or -CM2~N-C(=X9)-CH2-contain a carbamoyl grouping, are light-metal-hydride reducing agents such as alkali metal aluminium hydrides, e.g. lithium aluminium hydride (which are particularly sultable for the reduction of carbamoyl groups), or alkali metal boron hydrides, e.g. sodium boron hydride, and also alkali metal cyanoboron hydrides, e.g. sodium cyanoboron hydride, or boron hydrides, e.g. diborane, (which serve above all to reduce alkylideneamino groups). Furthermore, groupings of the formulae (Vb) and (Vc) can be converted, optionally with simultaneous hydrogenolytic splitting-off of a radical Xl replaceable by hydrogen by means of hydrogeno].ysis, by treatment with catalytically activated hydrogen, such as with hydrogen in the presence of a heavy-metal catalyst, e.g. ~:aney nickel~ platinum oxide or palladium, into the group of the :formula -CH2-NH-CH2-CH~-. Groupings of the formulae (Vd) and (Ve), wherein X9 in each case represen~s a thiono group and optionally contains a radlcal Xl which can be split o~f by hydrogelloly~is, are converted by reductive desulphurisation, e.g. by treatrnent with a hydrogenatio~ catalyst, such as Raney nickel, into the grouping of the formuLa -CH2 NH- -CH2-CH2-. The above reducing reactions are performed in a manner : :: , .
:, , . . , . -- ,,: ~ .. . ; . :.. ~ , .. . . . ..

~ '`2 ~

known per se, customarily in the presence of an inert solvent and, if necessary, with cooling or heating, e.g. in a tem-perature range of ahout -20C to about ~150C, and/or in a closed vessel under pressure and/or in an inert-gas at~osphere~
e.g. in a nitrogen atmosphere.
Within the scope of the definition of the compounds of the formula (I)~ compounds obtained according to the process can be converted in the usual manner into other final materials, for example by exchanging a suitable substituent for another or by introducing a substituent. Thus, in a compound of the formula (I) wherein R3 represents halogen, such as chlorine, this can be exchanged, by reaction with a lower alkanol which corresponds to the meaning of R3 as lower alkoxy~ for lower alkoxy. For this there is advantageously used a basic condensing agent such as an alkali hydroxide, for instance sodium hydroxide or potassium hydroxide, or an alkali-lower-alkanolate correspond-ing to the meaning of the lower alkoxy radica]. to be introduced, such as sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide.
Furthermore, it is possible to convert in a compound of the formula (I) wherein ~1 and/or R2 represent(s) hydroxyl such hydroxyl groups into the corresponding lower alkoxy groups or into a ]ower alkylidenedioxy group. This is performed, for -example, by reacting a compound of the formula I containing a hydroxyl group with a reactive derivative of a lower alkanol .~ .
' ~,,~;

... :. .. .. ., . - . . :
- . . . . .... .. . . . .
.. . . . .. . . .. . . .. .

- . .. :: . . :
.

corresponding to the meaning of Rl as lower alkoxy~ the hydroxyl group of which, as stated in the ore~oing in the case of the groups X6 and X7, is esterified. Suitable as such are, e.g.
the corresponding lower alkyl halides, such as the chloride or bromide. The process here is advantageously performed in the presence of a basic agent, such as an inorganic base, e.g. in the presence of a carbonate or hydroxide of an alkali metal or alkaline-earth ~etal, or in the presence of an organic basic agent, such as an alkali metal lower alkanolate. Such a compound o~ the formula I containing hydroxyl groups can advantageously be converted, in the customary manner, into a salt, e.g. into an alkali metal salt, such as a sodium salt, for example by reaction with sodium methoxide; and the salt prepared in this manner subjected to the reaction with for instance a lower alkyl bromide, e.g. with methyl ~romide or ethyl bromide. There is customarily used for this purpose a solvent or solvent mixture, for example a polar solvent such as a lower alkanol, e.g~ ethanol, or a fatty acid amide, e.g. dimethylformam-Lde or N-methylacetamide or N,N-dimetllylacetamide, or an amide of phosphoric acid, such as hexamethylphosphoric acid triamide, or sulpholane, or mixtures o such solvents. The reacti.on is carried out in a range of about tl:0 to about ~160C in an open or closed vessel, optionally in an inert gas atmosphere, e.g. under nitrogen.
5uitable reactive derivatives of a lower alkanol are also the corresponding diazoalkanes such as diazomethane or diazoethane.
:: B : ~
~ ~ /7 - . .. . - . - . . .. . . .

~ r~
~ 1.~

Their reaction with a compound of the formula (I) containing hydroxyl groups ls performed in an organic solvent, for instance in an ether such as diethyl ether, or in a chlorinated hydro-carbon~ such as methylene chloride. The reaction is in this case advantageously performed in a temperature range of about -20~ to -~S0C, optionally under a prot.ective gas, such as nitrogen.
Depending on the process conditions and on the starting materials, the new compounds are obtained in the free form or in the form, likewise embraced by the invention, of their salts, and the new compounds or salts thereof can also be in the form of hemi-, mono~, sesqui or polyh.ydrates thereof. Acid addition sal~s of the new compounds can be converted, in a manner known per se, for example by treatment with basic agents such as hyclroxideg, carbonates or hydrogen carbonates of alkali metals, or ion e~changers, into the free compoundsO Alternatively, resulting free bases can form with organic or inorganîc acids, e.g. with the acids mentioned, acid addition salts, for the :
production of which are used in particular those acids that are suitable for the formation of pharmaceutically acceptable salts.
These or other salts, especially acld acldi.tion salts, of the new compouncls, such as picrates or perchloratcs, can also serve to purify the resulting free bases by converting the ~ret~ bases : into salts, separating and purifying these~ and again liberating ~ the bases from the salts.
,.".
l~

: .' ,. . ~ .

:

Depending on the choice of starting materials and procedures, the new compounds can be obtained in the form of optical antipodes or racemates or, provided they contain at least two asymmetrical carbon atoms, also in the form of mixtures of racemates. The starting ma-terials can be employed also in the form of op~ical antipodes.
Racemate mixtures obtained can, by vîrtue of the physical-chemical differences in the diastereolsomers, be separated I in a known manner~ e.g. by chromatography and/or fractional crystal-~, 5~tereO~soin~r~c llsation, into the two ~Y~ ~ (diastereomeric) racemates.
Racemates obtained can be resolved by known methods, into the antipodes, e.g. by recrys~allisation ~rom an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance, especially acid, which forms salts with the racemic compo-md, and separation of the salt mixture obtained;in this manner, e.g. by virtue o~ differing solubilities~ iIltO the diastereomeric salts from which the ~ree - antipodes can be liberated by the action o~ suitable agents.
Particularly suitable optically active acids are, for example, the D- and L-forms of tartaric acid, cli o-toluyltar~aric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspar-tic acid or quinic acid. Lt is advantageous to isolate ~he most active of the two antipodes.
The present invention relates also to those embodimen~s o~
the~processj whercin a compound occurring as an intermediate at , - ~ , . .

~ - . . .: :

` `` : `

- . . ~ , ' `: ~ :

some stage is used as starting material and the uncompleted steps are performed; or wherein the process is interrupted at some stage; or wherein a starting material is formed under the reaction conditions; or wherein a reactant is optionally present in the form of its salts.
For carrying out the reactions according to the invention there are advan~ageously used those starting materials which lead to the groups o~ final materials particularly mentioned at the beginning of the the text, and especially to the final mate-iials that have been specifically described or emphasised.
The starting materials are known or can - where they are new - be obtained by methods known per se.
Cornpounds o~ the formula (I-L) can thus be obtained, for example~ by reaction of a compound of the formula ~3 (VI) N

or of a salt thereof, wherein Y and R3 have the above meanings, with a compound Qf the formula R~

2 I C~2 1 ~ C~12 ~ ~2 ~ (VII) wherein Xl has the a~orementioned meaning, and X2 represents the group X2~ with at least one of the groups Xl and X2 having a meaning other than hydrogen, and X10 represents hydroxyl or I, ~2~ -'~ .

:

.

, ~ 2~

a reactive esterified hydroxyl group, or X2 and X10 together represent a carbon oxygen bond, or wherein Xl and X2 together represent a radical which is capable of being split off and which is replaceable by two hydrogen atoms bound to the oxygen or nitrogen atom, and X10 represents a reactive esterified hydroxyl group; or analogously to an above descri.bed process modification by trea~ment of a compound of the formula , .

~ ~ ~ ~ ~2 ~ ~H ~ CH2 X 6 ~ X2 , ~, .
with a compound of ~he formula - ... .. .

X7 ~ C~l~ ~ CD2 ~ ~ ~ (IX) uherein X2 has the meaning given above for X2~ and one of the groups X6 and X7 represents a reactive esterified hydro~yl group and the:other represents the group of ~he formula - NH(Xl), whereill Xl has the above-given meaning, provided that a~ least one of the groups Xl and X2 has a meaning other than hydrogen, or whereln X2 and X6 ~orm an oxygen-carbon bond, and X7 represents the group of the formula ~ NH(Xl!, and Xl has a meaning other than hydrogen. The above reactions are performed in a manner known per se, for example as described above.
Starting materials of the formula (VIII) wherein Y represents the gFoup - N = can b- obtained, for example, by reacting a ~/

compound of the formula (VI) described above, or a salt thereof, with a compound of the formula X~ H2 - C~ - ~I2 (X) . O
wherein Xll represents a reactive esterified hydroxyl group, and, if desired, by opening up the epoxyethyl grouping in the product obtained to give a 2-amino-1-hydroxyethyl grouping or a 2-reactive esterified hydroxy l-hydroxyethyl grouping.
These reactions can be performed in a malmer known per se.
Starting materials of the formula (VIII) wherein Y represents the group - CH -- can be obtained, for example, by reacting a compound of the formula ~ ~3 (~I), ~ X12 ..

wherein X12 represents a suitable group capable of being split off, such as halogen~ e.g. chlorine or bromine, nitro or lower a]kylsulphonyl, w-Lth 2,2-dimethyl-5-hyd~oxymethyl-1,3-dioxolane;
reacting the resulting compound by means of hydrolysis, for instance with the aid of aqueous acids such as dilute hydrochloric acid, to give the corresponding 192-propanediol derivative;
converting this by treatment with triethyl orthoacetate into ~he correspond:Lng R3-substituted 2-ethoxy-5-(2-pyridyloxymethyl)-2-methyl 1,3-dioxolane; convert:Lng thls by treatment with ~richlorosllane in a chlorina~ed hydrocarbon, such as dichloro~

t~

~ ' - ' `, ' ", , ~ : ' ` , : , ~: ' ~,~ e.,,~

methane, into the corresponding R3-substituted 2-(2 acetyloxy-3-chloropropyloxy)-pyridine; and converting this by means of a suitable base, such as tetrabutylammonium hydrogen sulphate in an alkaline solution, for example in the presence of sodium hydroxide and a chlorinated hydrocarbon such as methylene chloride, into the compound of the formula (VIII) wherein X2 and X6 represent a oxygen-carbon bond. These reactions are performed in the customary manner. Compounds of the formula ~VII) can in their turn be obtained, in a manner known per se, by for example reacting a compound of ~he Iormula X10 CH2 ~ I ~ C~2 ~ X6 (XII~
~ X2 . . .
with a compound of the formula rl~ S (XIII) HN CH - CH
Xl . .

wherein the given qualifications and meanings apply for Xl, X2 and X10, and X~ and X~ represent an oxygen-carbon bond.
Starting materials of the ~ormula (V) can be obtained by reacting amino compounds o~ the ~ormula O C112 ~ C~ CH2 ~ N112 (IIIa), wherein the hydr;oxyl group can optionally be in a protected a 3 , , , : : , . :, -.......... ~ .,, . - . ... . .

. . . . . .

form, e.g. in an es~eriEied or suitably etheri:Eied form, with o~o cornpounds oE the formula 0 = CH - CH~ - ~ 2 (XIV), or with carboxylic acid compounds of the formula ~ C - CH2 - < ~ (XIVa), or with their reactive deriva~ives, such as the halides, e.g.
the chlorides; or by reacting amino groups of the formula Rl ~ R2 (IVa) H~N - Cl-12 - CH2 -with oxo compounfls of the formula ' ' - (XV), ~1 ~ - Ctl2 - CH - C ~

wherein the group -CHO can optionally be in a suitably etherified form, or with carboxylic acicl compounds oE the ~ormula R3 / OH (XV~), ~O - CH2 - ~H - C ~
0~1 Q
wherein the hydroxyl group can optionally be in a protected -form, ~ e.gc i.n the esterified form,or in a suitably etherified Eorm.

:' ' ' -, -. ,-,: ~

.

r~ æ~-In an intermediate having a protected hydroxyl group, this group is converted into the free form. The aforementioned reactions are performed in a manner known per se.
The new compounds can be used, for example, in the form of pharmaceutical preparations which contain a pharmacologically effective amount of the active substance, optionally together with pharmaceutically applicable carrier substances whieh are suitable or enteral administration, e.g. oral or parenteral adrninistration, and which can be inorganic or organic and solid or liquid. Thexe are thus used tabl.ets or gelatine capsules which contain the active substance together with diluents, e.g.
lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerin and/or lubricants, e.g. fliatomaceous earth, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets can also contain binders, e.g. magnesium aluminium silicate, starches such as maize starch, wheat starch, rice starch or arrowroot starch~
gelatine, tragacanth, methylcellulose, sodium carboxymethyl~
cellulose and/or polyvinylpyrrolidone, and, if desired, efer-vescent agents, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyestuffs, flavourings and sweetening agents.
Furthermore, the new pharmacologi.cally effective compounds can be used in the form of preparations which can be administered parenterally, or in the ~orm of infusion solu~ions. Such . .

- ., . ... .. : , -f ~,r~r~

solutions are preEerably isotonic aqueous solutions or suspensions, and these, e.g. in the case of lyophilised preparations which contain the active substance alone or together with a carrier material~ e.g. mannitol, can be prepared before use. The pharmaceutical preparations can be sterilised and/or can contain auxiliaries, P.g. preservatives, stabilisers, wetting agents and/or emulsifying agents, agents promoting solubility, salts for regulating the osmotic pressure and~or buffers. The present pharmaceutical preparations, which can if desired contain further pharmacologically active sub-stances, are produced in a manner known per se, e.g. by means of conventional mixing, granulating, coati.ng, dissolving or lyophilising processes, and they contain from about 0.1% to 100%, particularly from about 1% to about 50%, of active substance, with lyophilised preparations containing up to 100%
of active substance.
The dosage amount can depend on various factors~ such as on mode of application, species and age and/or on the individual conditions. Thws, the dosage amounts to be administered daily in the case of oral administration to warm-blooded animals are between about 0.04~g and about 2.0 g, and for warm-blooded animals having a weight of about 70 kg the dosage amounts are preferably between a'bout 0.1 g and 1.0 g.
The following Examples serve to further il'lustrate the lnvention. Temperatures are given in degrees Centigrade.

" .

.' . ' . ' ' '. ' .
. . .
' ~ ' - - ~ - ,; ' : , .
. . . -. . . . : ~ , . ' , , : .

xample 1 100 ml of 2 N hydrochloric acid is added to a solution of 75 g of crude 2-[3' (2-(3,4-dime~hoxyphenyl)-ethyl)~2'-phenyl-oxazolidinyl-(5')]-methoxy-3-cyanopyridine in 200 ml of ethanol, and the solution is left to s~and for 2-3 hours at 20-30. The reaction mixture is subsequently concentrated by evaporation and distributed between 200 ml of ethyl acetate and 300 ml of water;
the water phase is clarified with ac~ive charcoal, filtered, and rendered alkaline with 2 N sodium hydroxide solution. The oil which has precipitated is extracted with ethyl acetate.
The crude product, obtained by concentration by evaporation~ is dissolved in 1.5 litres oE dichloromethane, and the solution is stirred for 1/2 hour with 300 g of an adsorption agent based on magnesium silicate. The mixture is then treated with active charcoal and filtered, and the filtrate is concentrated by evaporation to yield crude 2-~3'-(2-(3,4-dimetlloxyphenyl)-ethylamino)-2'-hydroxy-propoxy~-3-cyanopyridine; this is dissolved in 25 ml of methanol, and a hot so:lution of 3.0 g of fumaric acid in 20 ml of methanol is added. On cooling, the neutral fumarat~ crystallises out in the form of colourless crystals which melt at 160 - 161.
The starting material can be produced in the :Eollowing manner:
a) A mixture of 90.6 g of homoveratrylamine, 75 g of gly~erin glycide and 250 ml of isoproparlol is held for 24 hours at 50 internal temperature. Concen~ration by evapora~ion yields a ; ,,.:.~ ,~J ~7 . --.

: ~ , . . - - ,, - .

.. : . . ~ ..

mixture which consists to the extent of 75% of 3-L2-(3,4-dimethoxyphenyl)-ethylamino] 1,2-propanediol, and which can be further used in the crude form.
b) 170 g of the crude product obtained is refluxed together with 80 ml of benzaldehyde, 500 ml of toluene and 1 ml of glacîal acetic acid for 7 hours on a water separator. The solution is then washed once with 100 ml of 1 N sodium hydroxide solution and twice with 100 ml of water each time; it is subsequently dried over magnesium swlphate and concentrated by evaporation.
The unreacted benzaldehyde is removed from the residue by distillation under reduced presswre (12 Torr). The distillation residue, which cannot be distilled undecomposed, consists principally of 3-l2-(3,4-dimet`hoxyphenyl)-ethyll~S-hydroxymethyl-2-phenyl-oxazolidine, which can be further used as crude product.
c) 56 g of crude 3-[2-(3,4-dimethoxyphenyl.)-ethyl]-5-hydroxy-methyl-2-phenyl-oxazolidine is reacted in 250 ml of 1,2-cli-methoxyethane with 5.7 g of a sodium hydride dispersion (55%), and stirring is maintained for 2 hours a~ 40. Af~er the addition of 16.4 g of 2 chloro-3-cyanopyridine, the reaction mixture is stirred at 40-50 for a further 2 hours; it is subsequently filtered through a filtering auxiliary based on diatomaceous earth, and the filtrate is concentrated by evaporation. The resulting residue is distributed between 500 ml of ethyl ccetake and 100 ml of water; the organic phase is washed twice with 100 ml of water each ~ime, dried over magnesi~n sulphate, and .
.
.
.
, , . :

concentrated by evaporation to yield crude 2-[3'-(2-(39~-dimethoxy phenyl)-ethy].)-2'-pheny]-oxazolidinyl-(5')]-methoxy-3-cyanopyridine.

Example 2 A mix~ure of 9.3 g oE 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine and 9.0 g of 2-(3,4-dimethoxyphenyl)-ethylamine in 100 ml of isopropanol is stirred for 18 hours at 20 - 30;
the solvent is then evaporated off, the residue is dissolved in 50 ml of 2 N hydrochloric acid, and the solution is extracted with 50 ml of ether. The acidified phase is separated, and is rendered alkaline with concentra~ed ammonia solution. The crude base is ex~racted 3 times with lO0 ml of ethyl acetate each time, and the solvent is evaporated off after each extraction, and in this way thère is finally obtained an oil which gradually crystallises. The crude 1-(3-chloropyrazin-2-yloxy)-3-[2-(3,4-dimethoxyphenyl)-ethylamino]-2-propanol thus obtained melts at 62 - 70. It forms a hydro~hloride which, after recrystallisation from methanol, melts at 184 - 187.

Example 3 A solution of 9.2 g o~ 2-(2,3-epoxy-propoxy)-3-methoxy-pyridine and 9.0 g of 2-(3,4-dimethoxy-phenyl)-ethylamine in 100 ml o isopropanol is stirred for 6 hours at room temp~rature.
Processing analogously to Example 2 yields 7.5 g o~ crude base, which is chromatographed, as a solution in ethyl acetate, through a column of 30G g of silica gel. The by-products are extracted - - . . . ,,, . -. .
- . .
,: . .

by subsequent washing with e~hyl acetate. By elutiolL with ethyl acetate containing amo~mts of ethanol rising from 1 - 5%~
and finally with an ethyl aceta~e/ethanol mixture of 4:1, there is obtainecl l-l2-(3,4-dimethoxy-phenyl)-ethylamino]-3-(3-methoxy-pyridin-2-yloxy)-2-propanol~ which, after removal of the solvent by evaporation, is a yellow oil of which the acid oxalate, after recrystallisation from methanol/acetone, melts at 132-134.
The starting material can be produced in the ollowing manner:
a) 26.5 g of socdium hydride is added with stirring, in the course of one hour, to a mixture of 161 g o 3-methoxy 2-n-Ltro-pyridine and 144 g of 2,2-dimethyl-5-hydroxymethyl-1,3-dioxolane in 1000 ml of hexamethylphosphoric acid triamide; the temperature during t:he addition is maintained at 0 - 10 by coollng. The reaction mixture is stirred ~or a further 5 hours with ice cooling, and then for lS hours at room temperature. The reaction mixture is poured onto ice, and extracted with cliethyl ether.
- The organic extract is washed with a concentrated aqueous sodium chloride solution, dried, and concentrated by evaporation. The residue is dissolved in 1000 ml of ethanol; 100 ml of 2 N
hydrochloric acid is then acldecl and the whole is allowed to stand ~or 8 hours. After removal of the solvent by evaporation, the residue i.s made allcaline with a concentrated solutlon of sodium hydroxide in water, and extractecl wi~h ethyl acetate.

Removal of the solvent by evaporation y;elds a crude product ~ ~k ,~ 30 . . . . . .
, ' from which is obtainedJ after the addition of diethyl ether, crystall.ine 3-(3~methoxy-2-pyridyloxy)-1,2-propanediol which melts at 62 - 65.
b) To a solution of 62 g of 3-(3-methoxy-2-pyridyloxy)-1,2-propanediol in 350 ml of triethyl orthoacetate are added 2 drops of trifluoroacetic acid, and the mixture is allowed to stand for 3 hours at 20 - 30. Concentration by evaporation yields crucle 2-ethoxy-5-(3-metho~y 2-pyridyloxymethyl)-2-methyl-1~3~dioxolane in the form of oil, which is used without fur~her purification.
c) To a mixture of 85 g of 2-ethoxy-5-(3-methoxy-2-pyr:idyloxy-methyl)-2-methyl-1,3-dioxolane -Ln 500 ml o~ dichlorcmethane is aclded 45 m]. of trimethylchlorosilane, and stirring is performed at 20 - 30 for one hour. Complete concentration by evapora~ion under reduced pressure yields crude 2-(2-acetyloxy-3-chloro-propyloxy)-3-methoxy-pyridine in the form o~ oil, which is used without purification.
d) A mixture of 80 g of 2-(2-acetyloxy-3-chloropropoxy)-3-methoxy-pyridlne, 900 ml of me~hylene chloride, 500 ml of a 2 N
aqueous sodium hydroxide solution and 9.5.g of tetrabutyl-ammonium hydrogen sulphate is vigorously stirred for 16 hours at 20-3Q. The organic phase is then separated and concentrated by evaporatlon. The oi.l relllaining is dissolved în d:iethyl e~her;
the solution is filtered, treated with active charcoal, and concentrated by evapora~ion to give 2.-(2,3-epoxy-propyloxy)-3-: :
.. . . . . . . .
, , : . . .

me~hoxy-pyridine, which melts at 63 - 65.

Example 4 A mixture of 9.1 g of l~amino 3-(3-methyl-pyridi.n-2-yloxy)-2-propanol, 10.8 g of 2-(p-methoxy-phenyl)-ethyl bromide, 10 g of potassium carbonate and 100 ml of absolute ethanol is refluxed for 20 hours with stirring. The reaction mixture is filtered after cooling, concentrated in vacuo, and the residue is dissolved in 200 ml of ethyl acetate. The solution is washed once with 50 ml of water, and then extracted with 50 ml of 1 N
acetic acid. From the acidified aqueous solution is liberated the base with concentrated sodium hydroxide solution; it is then extracted with ethyl acetate, and ~he solvent is completely removed by evaporat:ion to leave crude 1-[2-(p-methoxy-phenyl)-ethylamino]-3-(3-methyl-pyridin-2-yloxy)~2-propanol in the form of a gradually crystallising oil which, after recrystallisation from isopropanol, melts at 80 - 81.

~ .

A solution of 6.65 g of 1-amino~3~(3-methyl-pyridin-2 yloxy) 2-propanol in lO0 ml. o~ methanol i9 neutralised with an approxi-mately 4 N so:lution of hydrogerl chlorLde in methanol, and after the additlon of 5.0 g of 3~4-met.hylenedioxy-phenylacetaldehyde and 2.0 g of sodi-ml c.yanoboron hydride it is stirred for about 30 hours at 20 - 30. The reaction mlxture is concentrated in vacuo, and the residue is distr;buted between 100 ml of 2 N
hydrochloric acid and 50 ml of ethy]. acetate. The acidified phase .. . , . . ~ . - - -.
.
'' ' . . :
.

is rendered alkaline with concentrated sodium hydroxide solution and there is thus obtained crude 1-~2~(3,4-methylene~
dioxy-phenyl) ethylamino]-3-(3-methyl-pyridin-2 yloxy)-2-propanol, the hydrochloride of which melts at 123 - 125 after recrystallisation from isopropanol/ether.

Example 6 A solution of 8.4 g of crude 1-[N-benzyl-N-[2-(3,4-methylenedioxy-phenyl)-ethyl]-amino]-3-(4-methyl-pyridin-2-yl oxy)~2-propanol in lO0 ml of methanol is hydrogenated, with the addition of 1 g of palladium charcoal catalyst (5%~, under normal condi~îons until the calculated amount of hydrogen has been absorbed, Removal of the ca~alyst by fil~ration and of the solvent by evaporation yie].ds crude 1-~2-(3,4-methylenedioxy-phenyl)--ethylamino~-3-(4-methyl-pyridin-2-yloxy)-2-propanol as a crystalIine compound, which melts at 80-81 after recry~tal-lisation from isopropanol.
The starting material is obtained in the ollowing manner:
a) Gl.~cerin glycide and ben~ylamine are reacted, in cl lcnown manner, to give 3-benæylamino-1,2-propanediol ~b.p. 160~170/
0.01 Torr).
b) 3~Benzylamino-1,2-propanediol is converted with benzaldehyde, by azeotropi~ distillation with benzene in a manner known per se, in.to 3-benzyl-5-hyclroxymethyl-2-phenyl-oxazolidine, b.p. 168-171/0.005 TO~rD
c) From 134 g o~ this compo~Tnd, 50.9 g of 2-chloro-4-inet~nyl--- 3* --~ , .
- . - : - ~ . . . . . . , , ~ . . .

.. ...
, . ~ . ,., ., ~ . ', ,'.. , ' , . . : , : .. '.'. , . : ; .
.. . .
.. .

pyridine and 19.1 g of a sodium hydride dispersion is produced, in the usual manner, l-benzylamino~3-(4-methyl-pyridin-2-yl-oxy)-2-propanol, which melts at 70 - 71 after recrystallisation from cyclohexane.
d) To a solution of 10.9 g of 1-benzyla~ino-3-(4-methyl-pyridin~
2-yloxy)-2-propanol and 7.0 g of triethylamine in S0 ml of chloroform i.s added dropwise, with stirring, a sol.ution of 9.6 g of 3,4-met.hylenedioxy-phenylacetyl chloride in 50 ml of chloroform, and the reaction mixture is subsequently stirred for 2 hours. The reaction solution is washed with 20 ml o:E 2 N
hydrochloric acid, then with 2 N sodium hydroxide sol.ution, and finally with water; it is dried over sodium sulphate, and the solvent is evaporated off to obtain oily N-benzyl-N-[2-hydroxy-3-(4-methyl-pyridin-2-yloxy)-propyl]-(3,4-methylenedioxyphenyl)-acetamide, which is further used without additional purification.
e~ A solution of 12 g of the resulting compound in 50 ml o~
1,2-dimethoxyethane is added dropwise~ with ice cooling and with stirring, to a suspension o~ 2.0 g o~ lithi~n alumlnium hydride in 100 ml of l,2-dimethoxyethane. The reactLon mixture is then :stirred for 3 hours at an internal temperature oE 48 - 55, and subsequently decomposed with 10 ml of water whilst cooling with ice. The organic phase is separated, concentratecl in vacuo and dissolved in about 200 ml of ethyl acetate. The solutlon :is extracted with 50 ml o~ 2 N hydrochloric acid; the acid aqueous phase is separated,~and the base is liberated with concen~rated ~,f : , ,... . . . . .. . . . . .
, ,: . ~ -: . . . . . . - . .

sodium hyclroxide solution. Ex-trac~Lon with ethyl acetate and removal of the solvent by evaporatlon yield l-[N-benzyl-N-[2-(3,4-methylenedioxy-phenyl)-ethyl]-amino}-3-(4-methyl-pyridirl-2 yloxy)-2-propanol as oil, which is further processed as such.

100 ml of a 1 M solution of diborane in tetrahydrofuran is added, while cooling with lce, to a solution of ~ g of crude N- L 2-hyclroxy-3-(3-methyl-pyridin-~-yloxy)-propyl]--~3,4-methylene-dioxy-phenyl)-acetamide in 100 ml oE tetrahydrofuxan, and the whole is allowed to stand for S hours at room temperature.
~he solution is then concentrated by evaporation; an addition o 100 ml of 2 N hydrochloric acicl is made, and the solution is left to stand for about 1 hour. It is then extracted with SO ml of ether, the acid a~ueous phase is separated, and rendered alkaline with Goncentrated sodium hydroxide solution. Extraction with ethyl aceta~e and removal of the solvetlt by evaporation yield crude 1-[2-(3,4-methylenedioxy-phenyl-ethylami~o]-3-(3-rnethyl-pyridin-2~yloxy)-2-propallol in the form of oil, the hydrochloride of which melts at 123-125 after recrystallisation from methanol/ether.
The starting material is obtained, analog~usly to Exarnple 6b), from 10 g of (3~ methylenedioxyphenyl)~acetyl chloride, 8.2 g of l-amino-3-(3-methyl-pyriclin-2-yloxy)-2-propanol and 6.1 g of trietllylamine, in the form o an oily product.

' .:

.. : .. . . . . . , . ,, . ." . , , ,. , . , -, , , ,'.: ' '' ' : : ' ~ .:, . ', " . ', . ' ''. . , : .. , ., . . .:: .

E
A mix~ure of 8.8 g of 3-cyano-2~(2~3-epoxy-propoxy)-pyridine and 9.0 g of 2-(3,~-dimethoxy-phenyl~-ethylamine in 100 ml of isopropanol is stlrred for 18 hours at room temperature.
, Working up analogously to Example 2; yields crude 3-cyano-2-i~ ef~ J~o 3-(2-(3,4-dimethoxy-phenyl)-e~ ) 2-hydroxy-propoxy]-pyridine, the neutral. fumarate of which melts at 160 - 161~ after recrystallisation from methanol.
The 3-cyano-2-(2,3-epoxy propoxy)-pyridine required as starting material is produced, in a manner analogous ~o that of the Examples 3a) - 3d), uslng 2-chloro-3-cyanopyridine, with the following crystalline intermediate products being obtained.
a) 5-[(3-cyanopyridin-2-yloxy)-methoxy]-2~2-dimethyl-1,3-dioxolane, which melts at 68-71 a~ter recrystallisation from ether/petroleum ether; ancl b) 3-cyano-2-(2,3-epoxy-propoxy)-pyridirLe, which melts at 55-58 after recrystallisati.on from ether.

A solution oE 23 g of crude 1-[N-benzyl-N-[2-(p-benzyl-oxypheny].)-ethyl]-amino]-3-(3-methyl-pyridin-2-yloxy)-2-propanol.
in 300 ml of methanol is hydrogenated, andlogously to Example 6, until 2 molar equivalents of hydrogen have been absorbed, ancl subsequen~ly proce~s~secl ~o obtain l-[2-(p-hydroxyphenyl)-ethyl-amino]~3 (3-methyl-pyridin-2-yloxy)-2-propanol, the neutral ~fumarate of which melts at 182-183 after recrystallisation _ ~ .

' : :
~: :

~ 5``~

from isopropanol.
The starting materi.al is obtained in the following manner:
a) A solution of 16.0 g of (p-benzyloxyphenyl)-acetyl chloride in 100 ml of chloroform is added, in the course of 10 minutes, to a solution o~ 13.6 g of 1-benzylamino-3-(3-methyl-pyridin-2-yloxy)-2-propanol, which melts at 77-82, and 7.6 g of triethyl-amine in 150 ml of chloroform~ with the temperature rising to about 40. The reaction mixture i5 stirred for a further 2 hours, and is subsequently worked up analogously to Example 6b) to obtain crude N-benzyl-N-[2-hydroxy-3-(3-methyl-pyridin-2-yloxy)-propyl]-~p-benzyloxy-phenyl)-ace~amide in the form of brown oil, which is further processed without ~dditional purlfication.
b) 24 g of the compound obtained is dissolved iTL 200 ml of tetrahydro:furan; 150 ml of a 1 M solution of diborane in tetra-hydrofuran is added whilst cooling with ice, and the mixture is allowed to s~and for 24 hours at room temperature. Working up analogously to Example 6c) yields crude 1-[N-benzyl-N-[2-(p-- benzyloxyphenyl~ethyl]-amino]--3-(3-methyl-pyriclin-2-yloxy)-2-propanol in the form of brown viscous o-Ll, which can be further used without additional purificatlon.

Example 10 22 g of crude l-lN~benzyl-N E 2-(p-benzyloxy-phenyl)-ethyl]-amlno~-3-(4-metllyl-pyridin-2-yLoxy)-2 propanol is debenzylated, analogously to Example 9, to give 1-12-(p-hydroxyphenyl)-ethyl-amino]-3-(4 methyl-pyriclin-2-yloxy)-2-propanol, which melts at "' ~

~; :
- - - . . . - -- , . ~ . . ,, . , ~ ~ .. ..

104-105~ after recrystallisation from isopropanol.
The starting material is produced, analogously to the Examples 9a - b, from 1-benzylamino-3-(4-me~hyl-pyridin-2-yloxy)-2 propanol.
le 11 -Analogously to Example 1 is obtained~ using 48 g o~ crude 2-[3'-(2-(3,4-dimethoxy-phenyl)~ethyl)~2'-phenyl-oxazolidinyl-(S'~-methoxy]-3-methoxy-pyrazine, 1-[2-(3,4~dimethoxyphenyl)-ethylamino]-3 (~-me~hoxy-pyrazin-2-yloxy)-2 propanol, of which the hydrochloride melts at 167-170.
The starting material is produced, analogously to Examp:le lc), using 17.1 g of 2-chloro-3-methoxy-pyrazine, with crude oily . 2-[3'-~-(3,4-dimethoxy-phenyl)-ethyl)~-2'-phenyl-oxazoliclinyl-(5')-methoxy~-3-methoxy-pyrazine being obta:ined~

Analogously to Example 1 is obtained, using 52 g o~ crude 2-chloro-3-[3'-(2-(3,4~dimethoxy-phenyl)-ethyl)~2'--phenyl-oxazolidinyl-(5')-methoxy]-pyrazine, 1-(3-chloropyrazin-2 yloxy)-3-l2-(3,4-dimethoxy-phenyl)-ethylamino~-2-propanol, o~ which the hydrochloride melts at 183-187c The starting matPrial i9 produced, analogously to Exanlple lc), with ~he use o~ 17.6 g of 2,3-dichloropyrazine. The resull:ing 2-chloro-3-[3'-(2-(3,4-dimethoxy--pherlyl)-ethyl)-2'-phenyl-oxazolidinyl-(5')-methoxy]-pyrazille is further processed in the crude form.
*~;~ 3 .. . . . .. . . . .. - . .:.
. .
.. ~ .. . . . .

~f~ 2 Exampl~ 13 A solution oE 4.5 g o~ sodium methoxide and 9.0 g of crude 1-(3-chloropyrazin-2-yloxy)-3-[2-(3,4-dimethoxyphenyl)-ethyl-amino]-2 propanol in 200 ml of methanol is refluxed for S
hours. There is obtained, after filtration and then removal of the solvent by ~vaporation, crude l-~2-(3,4-dimethoxyphenyl)- -e~hylamino~-3-(3-methoxy-pyrazin-2-yloxy)-2-propanol in the form of yellow oil, the hydrochloride of which meits at 167-170 after recrystallisa~ion ~rom methanol.

e 14 250 ml of a 1 M solution of diborane in tetrahydrofuran is added dropwise at 5-10, whllst cooling with ice, ~o a solution of 13 g of crude N-- L 2-hydroxy-3-(3-methyl-pyridin-2-yl-oxy)-propyl]-(p-hydroxy-phenyl)-acetamide in 200 ml of tetra-hydrofurarl, and the mixture is stirred for 20 hours at room temperature. After removal of the solvent by evaporatlon, there is carefully added to the residue 100 ml of 2 N hydrochloric acid, and stirring is continued ~or 1 hour. l'he crystaLs which have been precipitated are filtered off, and the solution is extracted with 50 ml of ethcr. The aqueous phase is then brought to pH 8-9 with solicl sodium bicarbonate, and extracted twice with 100 ml of ethyl acetate each time. Concen~ration of the organic phase by evaporation yields crude 1-[2-(p-hydroxyphenyl)-ethylamino]-3-(3-methyl-pyridin-2-yloxy)-2-propanol in the form o~ yellowish oil, the neutral fumarate o~ which melts at 182-1~3 .. ... .. . ... .

- :, : .. .
. .

. .

a~ter recrystallisation from isopropanol.
The starting material is procluced in the following manner:
A solution of 7.23 g of trimethylacetyl chloride in 100 ml of dichloromethane is added dropwise at 0-5, with cooling and stirring, to a solution of 7.6 g of p~hydroxyphenylacetic acid and 6.6 g of triethylamiTle in 200 ml of dioxane. The colourless suspension is stirred for 4 hours at 0-5, and then at this temperature is added dropwise a solution of 8.2 g of 1-amino-3-(3-methyl-pyridi.n-2 yloxy) 2-propanol in 50 ml of dioxane. The suspension is stirred for 2 hours at 0-5 and then for 15 hours at room tenperature. After the solvent has b~en cvaporated o~f in vacuo, the residue is distributed between 200 ml of ethyl acetate and 100 ml of water; the organic phase is extracted with twice with 200 ml of 1 N hydrochloric acid each time, the acid extracts are combined, and the pH value thereof is adjusted to abowt 8 with solid eodium bicarbonate. The oil which has been precipitated is extrac~ed with dichloromethane. The dichloro-methane is evaporated off to leave crude N-[2-hydroxy-3-(3-methyl-pyridin~2-yloxy)-propyl}-(p-hydroxyphenyl)-~acetamide in the form of light-yellow viscous oil, which can bc used wl~hout further purificatlon.

E~am~ ]5 By a procedure analogous to that described in Example 2 is obtained, using 3.6 g of 2-(2~3-epoxy~propoxy)-3~methoxy-_ ~ _ : ''' ,, .' ' ' ~ ~

.

-pyridine and 2.5 g of p-hydroxyphenethylamlne, 1-[2-(p llydroxyph2nyl)-e~hylamino]-3 (3-methoxy-pyridin-2-yloxy)-2-propanolg the neu~ral fumarate o:E which melts at 175-176 af~er recrystallisa~ion from methanol~acetone.

Example 16 A solution of 7.3 g of 1-[2-(p-benzyloxy-phenyl)-ethylamino]-3 (3-methoxy-pyridin-2-yloxy)-2-propanol in 100 ml of e~hanol is hydrogenated, in the presence of 1.5 g of a palladium charcoal catalyst (5%) and at atmospheric pressure, untiL 1 molar equivalent of hydrogen has been absorbed. After removal o~ the catalyst by fjltratlon and concentration o~ the filtrate by evaporation, there remains 1-[2-(p-hydroxy-phenyl)-ethylamino]-3-(3 methoxy-pyridin-2~yloxy)-2-propanol, of which the neutral fumarate me:Lts at 175 - 176 after recrystallisation from methanol/acetone. `
The starting material is obtained by reaction of 5.4 g of 2-(2,3-epoxy-propoxy)-3~methoxy-pyridine cmd 6.5 g of (p-benæyl-oxy-phenyl)-ethylamine in 150 ml of isopropanol, analogowsly t.o Example 2; after recrystallisation ~rom dichloromethane/et:her, it melts at 85-86.
ple 17 .
A mixture of 400 g of 2-(p-hydroxyphenyl)-ethyl bromide, 500 mg of 1 amino-3-(3-metllyl-pyridin-2-yloxy)-2-propanol and 200 mg of potassium bicar`bona~e in 10 ml of isopropanol is ; . ., . ~ - , , . . .
. ~.
:, refluxecl for 5 hours~ Processing analogously to Example 4 yields oily l-[2-(p-hydroxyphenyl)-ethylamino]-3-(3-rnethyl-pyridin-2-yloxy) 2 propanol, the neutral fumarate of which melts aL- 182-183 after recrystallisation from isopropanol.

Example 18 A solution of 14 g of crude 1-~N-benzyl-N-[2-(4-benzyl-oxy 3-methoxy-phenyl)-ethyl]-amino] 3-(3-methyl pyridin-2-yloxy~-2-propanol in 20~ ml of methanol is hydrogenated under normal conditions, with the addi~ion o~ 4.0 g of a palladi.~ charcoal catalyst (5%), until.2 molar equivalents of hydrogen ha.ve been absorbed. After removal of the catalyst by iltratl.on and concentration of the fill:rate by evaporating oEf the solvent, the residue is distributed be~ween 200 ml of ether and 100 ml of 2 N
hydrochloric acid; ~he acid aqueous solution is separated, made alkali-ne with concentrated ammon-La solution and ex~racted with 200 ml of ethyl acetate. Concentration of the dried ethyl acetate solution by evaporation yields crucle 1- E 2-~4 hydroxy-3-methoxy-phenyl)-ethylamino]-3-(3~methyl-pyridin 2~yloxy)-2 propanol in the form of yellow oil which, dissolved with hal:E the equivalent amount of fumaric acid in methanol, forms a neutral fumarate, which melts at 181-1~3.
The starting material c~n be produced ln the ollowing manner:
a) 4-Ben~yloxy 3-me~ho~y-pllerlylclce~ic acid (m.p. 87 90) i.s converted with thionyl ~chloride in dichloromethane into the acid chloride; and this is reacted, analogously to Example 6 b), with ,, ~ , . . . .

l-benzylamino-3-(3-methyl-pyrldln-2-yloxy)-2-propanol to give N-benzyl-N [2-hydroxy-3-(3-methyl-pyridin-2~yloxy)-propyl]-(4-benzyloxy-3-methoxy-pheny].)-acetamide. This forms an oil which can be further used in the crude form.
b) 22 g of the crude amide obtained is reduced, analogously to Example 9 b), with diborane, and yields crude l-[N-benzyl-N-[2-(4-benzyloxy-3-methoxy-phenyl)~ethyl]~amino]-3-(3~methyl- -.
pyridin-2-yloxy)~2-propanol in the form of yellow oil~ which can be further used as such.

Tablets containl-ng 0.1 g o:E 2-[3'-(2-(3,4-dimethoxyphenyl)-ethyl-aminQ)-2'-hydroxy-propoxy]-3-cyanopyridine as a neutral ~umarate are produced as ~ollows:
(for 10,000 tablets):

2-[3'-(2-(3,4-dimethoxyphenyl)-ethylami.no)-2'-hydroxy-propoxy]-3-cyanopyridine as a neutral fumarate 1000.00 g lactose 580.00 g maize starch 750.00 g :
colloidal silicic acid 80.00 g talcum 80.00 g magneseum stearate 10.00 g water q.s.

_roductlon The 2~[3'~(2-(3,4-dimethoxyphenyl) ethylamino)-2'-hydroxy~.
propoxy]-3-cyanopyridine as a neutral fumarate is mixed ~ith the , lactose, a portion of the maize s-tarch and with colloiclal silicic acid, and the mixture is put through a sieve. A
further portion of maiæe starch is made into a paste witll the five-fold amount of water on a water-bath, and the powder mixture is kneaded with this paste until a slightly plastic mass is formed. This is pressed through a sieve having a mesh size of about 3 mm; it is then dried and the dry granulate is again put through a sieve. The remainder of the mai~. s~arch, the talcum and the magneslum stearate are thereupon mixed in and the resulting mlxture is pressed to form tablets each weighing 0.250 g (with breaking groove).

_ ~, B ~

. . . . . . . . . .

.. .. ~ . . .. . .
~ .. . . . ~. -- . - .
1. ' ' ' ~ .

Claims (105)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing 1-amino-2-hydroxy-3-heterocyclyloxy-propanes of the formula wherein Y represents the group -CH= or the group -N=, R1 represents hydrogen, hydroxyl, lower alkyl or lower alkoxy, R2 represents hydroxyl, lower alkoxy or, together with R1, o-lower-alkylidenedioxy or o-lower-alkylenedioxy, and R3 represents lower alkyl, lower alkoxy, halogen or cyano, with the radicals R1, R2 and R3 each being bound to any one of the possible aromatic carbon atoms, in the form of mixtures of racemates, racemates, optical antipodes or salts thereof, which comprises (a) in a compound of the formula (II) wherein Y and R3 have the above meanings, R4 has the meaning of R1 or represents the group -O-X3, R5 has the meaning of R2 or represents the group -O-X4, X1 represents hydrogen, an .alpha.-aryl-lower-alkyl group an acyl radical of an organic carboxylic acid or an organic sulphonic acid or an optionally substituted 1-polyphenyl-lower-alkyl group, each of the groups X2, X3 or X4 represent hydrogen, a l-phenyl-lower-alkyl group optionally sub-stituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or nitro, an acyl radical of an organic carboxylic acid or an organic sulphonic acid, or an optionally substituted aliphatic or araliphatic hydrocarbon radical polybranched on the linking carbon atom, or X1 and X2 together or X3 and X4 together represent l-phenyl-lower-alkylidene optionally substit-uted in the phenyl moiety by lower alkyl, hydroxyl, lower alkoxy, halogen and/or nitro, or represent lower alkylidene or cycloalkyl-idene or the diacyl radical of a carboxylic acid or thiocarboxylic acid, provided that at least one of the groups X1, X2, X3 or X4 or X1 and X2 together or X3 and X4 together is different from hydrogen, or in a salt of such a compound, splitting off by solvolysis or reduction all groups X1, X2, X3 or X4 which are different from hydrogen or the group X1 and X2 together and/or X3 and X4 together and replacing them by hydrogen, or (b) reacting a compound of the formula (III) or a salt thereof, with a compound of the formula (IV) or a salt thereof, wherein one of the groups X6 and X7 represents a reactive esterified hydroxyl group and the other represents the primary amino group, and X5 represents the hydroxyl group, or wherein X5 and X6 together represent the epoxy group, and X7 represents the primary amino group, and Y, R1, R2 and R3 have the above meanings, or (c) in a compound of the formula (V) wherein the group -X8- (Va) represents one of the radicals of the formulae -CH=N-CH2-CH2- (Vb), or -CH2-N=CH-CH2 (Vc), or -C(=X9)-?-CH2-CH2- (Vd), or -CH2-?-C(=X9)-CH2- (Ve), wherein X9 represents the oxo or thioxo group, Y, R1, R2 and X1 have the above meanings, and R3 has the given meaning with the exception of halogen.and cyano, or in a salt thereof, reducing the group -X8-, optionally by way of the intermediate containing the radical -CH2-?-CH2-CH2-, to the radical of the formula -CH2-NH-CH2-CH2- and, if required, converting a compound of the formula I, wherein R3 represents halogen by reaction with a lower alkanol into a compound of the formula I, wherein R3 is lower alkoxy, or converting a compound of the formula I, wherein R1 and/or R2 represent(s) hydroxyl by reaction with a reactive derivative of a lower alkanol into a compound of the formula I, wherein R1 and/or R2 represent(s) lower alkoxy or lower alkylidenedioxy, and, when a salt is required, converting a free compound of the formula I into a salt, and, when a free compound of the formula I is required, converting a salt into the free compound, and when a pharmaceutically acceptable non-toxic acid addition salt is required, converting a free compound of the formula I into a pharmaceutically acceptable non-toxic acid addition salt, and when a racemate is required, converting a mixture of racemates into the two stereo-isomeric (diastereomeric) racemates, and when an optical antipode is required, resolving a racemate into the optical antipodes.

2. A process as claimed in Claim 1 wherein starting materials are used, in which R1 represents hydrogen, hydroxyl, lower alkyl or lower alkoxy each having up to 4 C atoms, R2 represents hydroxyl, lower alkoxy having up to 4 C atoms, and together with R1 represents o-lower-alkylidenedioxy having 1 to 2 C atoms, and R3 represents lower alkyl or lower alkoxy each having up to 4 C atoms, halogen or cyano, with R1 and R2 each being in the 2-, 3- or 4-position, and o-lower-alkylidenedioxy or o-lower-alkylenedioxy in the 2,3- or 3,4-position, and R3 in a pyridine ring being in the 3-, 4-, 5- or 6-position, or in a pyrazine ring in the 3-, 5- or 6-position, and, if required, converting a compound of the formula I, wherein R3 represents halogen by reaction with a lower alkanol into a compound of the formula I, wherein R3 is lower alkoxy, or converting a compound of the formula I, wherein 3 and/or R2 represent(s) hydroxyl by reaction with a reactive derivative of a lower alkanol into a compound of the formula I, wherein R1 and/or R2 represent(s) lower alkoxy or lower alkylidenedioxy, and, when a salt is required, converting a free compound of the formula I into a salt, and, when a free compound of the formula I is required converting a salt into the free compound, and, when a pharmaceutically acceptable non-toxic acid addition salt is required, converting a free compound of the formula I into a pharmaceutically accept-able non-toxic acid addition salt, and when a racemate is required, converting a mixture of racemates into the two stereoisomeric (diastereomeric) racemates, and when an optical antipode is required, resolving a racemate into the optical antipodes.

3. A process as claimed in Claim 1, wherein starting materials for producing a compound of the formula (Ia), are used, wherein R1 represents hydrogen, hydroxyl, methyl or methoxy, R2 represents hydroxyl, methoxy or, together with R1, represents o-methylenedioxy, and R3 represents methyl, methoxy, chlorine or cyano, with R1 and R2 each being in the 3- or 4-position, o-methylenedioxy in the 3,4-position and R3 in the 3- or 4-position, and, if required, converting a compound of the formula I, wherein R3 represents halogen by reaction with a lower alkanol into a compound of the formula I, wherein R3 is lower alkoxy, or converting a compound of the formula I, wherein R1 and/or R2 represent(s) hydroxyl by reaction with a reactive derivative of a lower alkanol into a compound of the formula I,wherein R1 and/or R2 represent(s) lower alkoxy or lower alkylidenedioxy, and, when a salt is required, converting a free compound of the formula I into a salt, and, when a free compound of the formula I is required converting a salt into the free compound, and, when a pharmaceutically acceptable non-toxic acid addition salt is required, converting a free compound of the formula I into a pharmaceutically accept-able non-toxic acid addition salt, and when a racemate is required, converting a mixture of racemates into the two stereoisomeric (diastereomeric) racemates, and when an optical antipode is required, resolving a racemate, into the optical antipodes.

4. A process as claimed in Claim 1 wherein starting materials for producing a compound of the formula (Ib), are used, wherein R1 represents hydrogen, hydroxyl, methyl or methoxy, R2 represents hydroxyl, methoxy or, together with R1, represents o-methylenedioxy, and R3 represents methyl, methoxy, chlorine or cyano, with R1 and R2 each being in the 3- or 4-position, o-methylene-dioxy in the 3,4-position and R3 in the 3-position, and, of required, converting a compound of the formula I, wherein R3 represents halogen by reaction with a lower alkanol into a compound of the formula I, wherein R3 is lower alkoxy, or converting a compound of the formula I, wherein R1 and/or R2 represent(s) hydroxyl by reaction with a reactive derivative of a lower alkanol into a compound of the formula I,wherein R1 and/or R2 represent(s) lower alkoxy or lower alkylidenedioxy, and, when a salt is required, converting a free compound of the formula I into a salt, and, when a free compound of the formula I is required converting a salt into the free compound, and, when a pharmaceutically acceptable non-toxic acid addition salt is required, converting a free compound of the formula I into A pharmaceutically accept-able non-toxic acid addition salt, and when a racemate is required, converting a mixture of racemates into the two stereoisomeric (diastereomeric) racemates, and when an optical antipode is required, resolving a racemate, into the optical antipodes.

5. A process as claimed in Claim 1, wherein the groups X1, X2, X3 or X4 being different from hydrogen, or the groups X1 and X2 together and/or X3 and X4 together are split off by hydrogenolysis.

6. A process as claimed in Claim 2, wherein the groups X1, X2, X3 or X4 being different from hydrogen, or the groups X1 and X2 together and/or X3 and X4 together are split off by hydrogenolysis.

7. A process as claimed in Claim 3, wherein the groups X1, X2, X3 or X4 being different from hydrogen, or the groups X1 and X2 together and/or X3 and X4 together are split off by hydrogenolysis.

8. A process as claimed in Claim 4, wherein the groups X1, X2, X3 or X4 being different from hydrogen, or the groups X1 and X2 together and/or X3 and X4 together are split off by hydrogenolysis.

9. A process as claimed in Claim 5, wherein hydrogeno-lysis is carried out by treatment with catalytically activated hydrogen.

10. A process as claimed in Claim 6, wherein hydrogeno-lysis is carried out by treatment with catalytically activated hydrogen.

11. A process as claimed in Claim 7, wherein hydrogeno-lysis is carried out by treatment with catalytically activated hydrogen.

12. A process as claimed in Claim 8, wherein hydrogeno-lysis is carried out by treatment with catalytically activated hydrogen.

13. A process as claimed in Claim 1, wherein hydrogeno-lysis is carried out in the presence of a nickel catalyst

14. A process as claimed in Claim 2, wherein hydrogeno-lysis is carried out in the presence of a nickel catalyst

15. A process as claimed in Claim 3, wherein hydrogeno-lysis is carried out in the presence of a nickel catalyst

16. A process as claimed in Claim 4, wherein hydrogeno-lysis is carried out in the presence of a nickel catalyst

17. A process as claimed in Claim 1, wherein hydrogeno-lysis is carried out in the presence of a suitable noble metal catalyst.

18. A process as claimed in Claim 2, wherein hydrogeno-lysis is carried out in the presence of a suitable noble metal catalyst.

19. A process as claimed in Claim 3, wherein hydrogeno-lysis is carried out in the presence of a suitable noble metal catalyst.

20. A process as claimed in Claim 4, wherein hydrogeno-lysis is carried out in the presence of a suitable noble metal catalyst.

21. A process as claimed in Claim 1, which comprises splitting off groups X1 and/or X2 and/or X3 and/or X4 being different from hydrogen, or X1 and X2 together and or X3 and X4 together by treatment with water under acid or basic conditions.

22. A process as claimed in Claim 2, which comprises splitting off groups X1 and/or X2 and/or X3 and/or X4 being different from hydrogen, or X1 and X2 together and or X3 and X4 together by treatment with water under acid or basic conditions.

23. A process as claimed in Claim 3, which comprises splitting off groups X1 and/or X2 and/or X3 and/or X4 being different from hydrogen, or X1 and X2 together and or X3 and X4 together by treatment with water under acid or basic conditions.

24. A process as claimed in Claim 4, which comprises splitting off groups X1 and/or X2 and/or X3 and/or X4 being different from hydrogen, or X1 and X2 together and or X3 and X4 together by treatment with water under acid or basic conditions.

25. A process as claimed in Claim 21, wherein X1 and/or X2 and/or X3 and/or X4 are acyl radicals of organic carboxylic acids, or X1 and X2 together and/or X3 and X4 together are lower alkylidene groups or carbonyl groups.

26. A process as claimed in Claim 22, wherein X1 and/or X2 and/or X3 and/or X4 are acyl radicals of organic carboxylic acids, ox X1 and X2 together and/or X3 and X4 together are lower alkylidene groups or carbonyl groups.

27. A process as claimed in Claim 23, wherein X1 and/or X2 and/or X3 and/or X4 are acyl radicals of organic carboxylic acids, or X1 and X2 together and/or X3 and X4 together are lower alkylidene groups or carbonyl groups.

28. A process as claimed in Claim 24, wherein X1 and/or X2 and/or X3 and/or X4 are acyl radicals of organic carboxylic acids, or X1 and X2 together and/or X3 and X4 together are lower alkylidene groups or carbonyl groups.

29. A process as claimed in Claim 1, wherein tert.-lower-alkoxycarbonyl or optionally substituted diphenylmethoxy-carbonyl and also tert.-lower-alkyl radicals X2, X3 or X4 are split off by acidolysis.

30. A process as claimed in Claim 2, wherein tert.-lower-alkoxycarbonyl or optionally substituted diphenylmethoxy-carbonyl and also tert.-lower-alkyl radicals X2, X3 or X4 are split off by acidolysis.

31. A process as claimed in Claim 3, wherein tert.-lower-alkoxycarbonyl or optionally substituted diphenylmethoxy carbonyl and also tert.-lower-alkyl radicals X2, X3 or X4 are split off by acidolysis.

32. A process as claimed in Claim 4, wherein tert.-lower-alkoxycarbonyl or optionally substituted diphenylmethoxy-carbonyl and also tert.-lower-alkyl radicals X2, X3 or X4 are split off by acidolysis.

33. A process as claimed in Claim 1, wherein 2-halogen-lower-alkoxycarbonyl, aroylmethoxycarbonyl or arylsulphonyl groups X1 and/or X2 and/or X3 and/or X4 are split off by treatment with a chemical reducing agent.

34. A process as claimed in Claim 2, wherein 2-halogen-lower-alkoxycarbonyl, aroylmethoxycarbonyl or arylsulphonyl groups X1 and/or X2 and/or X3 and/or X4 are split off by treatment with a chemical reducing agent.

35. A process as claimed in Claim 3, wherein 2-halogen-lower-alkoxycarbonyl, aroylmethoxycarbonyl or arylsulphonyl groups X1 and/or X2 and/or X3 and/or X4 are split off by treatment with a chemical reducing agent.

36. A process as claimed in Claim 4, wherein 2-halogen-lower-alkoxycarbonyl, aroylmethoxycarbonyl or arylsulphonyl groups X1 and/or X2 and/or X3 and/or X4 are split off by treatment with a chemical reducing agent.

37. A process as claimed in Claim 33, wherein a reducing heavy metal salt or an alkali metal in ammonia or electro-lytic reduction is used as a chemical reducing agent.

38. A process as claimed in Claim 34, wherein a reducing heavy metal or a reducing heavy metal salt or an alkali metal in ammonia or electrolytic reduction is used as a chemical reducing agent.

39. A process as claimed in Claim 35, wherein a reducing heavy metal or a reducing heavy metal salt or an alkali metal in ammonia or electrolytic reduction is used as a chemical reducing agent.

40. A process as claimed in Claim 36, wherein a reducing heavy metal or a reducing heavy metal salt or an alkali metal in ammonia or electrolytic reduction is used as a chemical reducing agent.

41. A process as claimed in Claim l, wherein X5 and X6 together represent the epoxy group and X7 represents the primary amino group.

42. A process as claimed in Claim 2, wherein X5 and X6 together represent the epoxy group and X7 represents the primary amino group,

43. A process as claimed in Claim 3, wherein X5 and X6 together represent the epoxy group and X7 represents the primary amino group.

44. A process as claimed in Claim 4, wherein X5 and X6 together represent the epoxy group and X7 represents the primary amino group.

45. A process as claimed in Claim 1, wherein X5 repre-sents the hydroxyl group, X6 represents a reactive esterified hydroxyl group and X7 represents the primary amino group.

46. A process as claimed in Claim 2, wherein X5 repre-sents the hydroxyl group, X6 represents a reactive esterified hydroxyl group and X7 represents the primary amino group.

47. A process as claimed in Claim 3, wherein X5 repre-sents the hydroxyl group, X6 represents a reactive esterified hydroxyl group and X7 represents the primary amino group.

48. A process as claimed in Claim 4, wherein X5 repre-sents the hydroxyl group, X6 represents a reactive esterified hydroxyl group and X7 represents the primary amino group.

49. A process as claimed in Claim 1, wherein X5 repre-sents the hydroxyl group, X6 represents the primary amino group and X7 represents a reactive esterified hydroxyl group.

50. A process as claimed in Claim 2, wherein X5 repre-sents the hydroxyl group, X6 represents the primary amino group and X7 represents a reactive esterified hydroxyl group.

51. A process as claimed in Claim 3, wherein X5 repre-sents the hydroxyl group, X6 represents the primary amino group and X7 represents a reactive esterified hydroxyl group.

52. A process as claimed in Claim 4, wherein X5 repre-sents the hydroxyl group, X6 represents the primary amino group and X7 represents a reactive esterified hydroxyl group.

53. A process as claimed in Claim 45, which is performed in the presence of a basic agent.

54. A process as claimed in Claim 46, which is performed in the presence of a basic agent.

55. A process as claimed in Claim 47, which is performed in the presence of a basic agent.

56. A process as claimed in Claim 48, which is performed in the presence of a basic agent.

57. A process as claimed in Claim 49, which is performed in the presence of a basic agent.

58. A process as claimed in Claim 50, which is performed in the presence of a basic agent.

59. A process as claimed in Claim 51, which is performed in the presence of a basic agent.

60. A process as claimed in Claim 52, which is performed in the presence of a basic agent.

61. A process as claimed in Claim 1, wherein group X8 is reduced by means of light-metal-hydride reducing agents.

62. A process as claimed in Claim 2, wherein group X8 is reduced by means of light-metal-reducing agents.

63. A process as claimed in Claim 3, wherein group X8 is reduced by means of light-metal-reducing agents.

64. A process as claimed in Claim 4, wherein group X8 is reduced by means of light-metal-reducing agents.

65. A process as claimed in Claim 61, wherein alkali metal cyanoboron hydrides are used as reducing agents.

66. A process as claimed in Claim 62, wherein alkali metal cyanoboron hydrides are used as reducing agents.

67. A process as claimed in Claim 63, wherein alkali metal cyanoboron hydrides are used as reducing agents.

68. A process as claimed in Claim 64, wherein alkali metal cyanoboron hydrides are used as reducing agents.

69. A process as claimed in Claim 61, wherein boron hydrides are used as reducing agents.

70. A process as claimed in Claim 62, wherein boron hydrides are used as reducing agents.

71. A process as claimed in Claim 63, wherein boron hydrides are used as reducing agents.

72. A process as claimed in Claim 64, wherein boron hydrides are used as reducing agents.

73. A process as claimed in Claim 1, wherein group X8 is reduced by treatment with catalytically activated hydrogen.

74. A process as claimed in Claim 2, wherein group X8 is reduced by treatment with catalytically activated hydrogen.

75. A process as claimed in Claim 3, wherein group X8 is reduced by treatment with catalytically activated hydrogen.

76. A process as claimed in Claim 4, wherein group X8 is reduced by treatment with catalytically activated hydrogen.

77. A process as claimed in Claim 73, wherein group X8 is reduced with hydrogen in the presence of a heavy-metal catalyst.

78. A process as claimed in Claim 74, wherein group X8 is reduced with hydrogen in the presence of a heavy-metal catalyst.

79. A process as claimed in Claim 75, wherein group X8 is reduced with hydrogen in the presence of a heavy-metal catalyst.

80. A process as claimed in Claim 76, wherein group X8 is reduced with hydrogen in the presence of a heavy-metal catalyst.

81. A process as claimed in Claim 1, which comprises reacting a compound of the formula I, wherein R3 repre-sents halogen, with a lower alkanol in the presence of a basic condensing agent.

82. A process as claimed in Claim 2, which comprises reacting a compound of the formula I, wherein R3 repre-sents halogen, with a lower alkanol in the presence of a basic condensing agent.

83. A process as claimed in Claim 3, which comprises reacting a compound of the formula I, wherein R3 repre-sents halogen, with a lower alkanol in the presence of a basic condensing agent.

84. A process as claimed in Claim 4, which comprises reacting a compound of the formula I, wherein R3 repre-sents halogen, with a lower alkanol in the presence of a basic condensing agent.

85. A process as claimed in Claim 81, wherein the lower alkanol is used in the form of the corresponding alkali-lower-alkanolate.

86. A process as claimed in Claim 82, wherein the lower alkanol is used in the form of the corresponding alkali-lower-alkanolate.

87. A process as claimed in Claim 33, wherein the lower-alkanol is used in the form of the corresponding alkali-lower-alkanolate.

88. A process as claimed in Claim 84, wherein the lower alkanol is used in the form of the corresponding alkali-lower-alkanols.

89. A process as claimed in Claim 1, which comprises reacting a compound of the formula I, wherein R1 and/or R2 represent(s) hydroxyl, with a lower alkanol esterified with a strong inorganic or a strong organic acid.

90. A process as claimed in Claim 2, which comprises reacting a compound of the formula I, wherein R1 and/or R2 represent(s) hydroxyl, with a lower alkanol esterified with a strong inorganic or a strong organic acid.

91. A process as claimed in Claim 3, which comprises reacting a compound of the formula I, wherein R1 and/or R2 represent(s) hydroxyl, with a lower alkanol esterified with a strong inorganic or a strong organic acid.

92. A process as claimed in Claim 4, which comprises reacting a compound of the formula I, wherein R1 and/or R2 represent(s) hydroxyl, with a lower alkanol esterified with a strong inorganic or a strong organic acid.

93. A process as claimed in Claim 89, wherein the corresponding lower alkyl halide is used.

94. A process as claimed in Claim 90, wherein the corresponding lower alkyl halide is used.

95. A process as claimed in Claim 91, wherein the corresponding lower alkyl halide is used.

96. A process as claimed in Claim 92, wherein the corresponding lower alkyl halide is used.

97. A process as claimed in Claim 89, which is performed in the presence of a basic agent.

98. A process as claimed in Claim 90, which is performed in the presence of a basic agent.

99. A process as claimed in Claim 91, which is performed in the presence or a basic agent.

100. A process as claimed in Claim 92, which is performed in the presence of a basic agent.

101. A process as claimed in Claim 89, which is performed in a polar solvent.

102. A process as claimed in Claim 90, which is performed in a polar solvent.

103. A process as claimed in Claim 91, which is performed in a polar solvent.

104. A process as claimed in Claim 92, which is performed in a polar solvent.

105. 1-amino-2-hydroxy-3-heterocyclyloxy-propanes of the formula wherein Y represents the group - CH - or the group - N =, R1 represents hydrogen, hydroxyl, lower alkyl or lower alkoxy, R2 represents hydroxyl, lower alkoxy or, together with R1, o-lower-alkylidenedioxy or o-lower-alkylenedioxy, and R3 represents lowex alkyl, lower alkoxy, halogen or cyano, with the radicals R1, R2 and R3 each being bound to any one of the possible aromatic carbon atoms, in the form of mixtures of racemates, racemates, optical antipodes or salts of such compounds whenever prepared by a process as claimed in claim 1 or by any process which is an obvious chemical equivalent thereof.