CA1041491A - Process for the manufacture of new amines - Google Patents

Abstract

Process for the manufacture of new amines Abstract of the Disclosure 1-Phenoxy-2-hydroxy-3-amino-propanes of the formula I

Description

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The invention relates to new l-phenoxy-2 hydroxy-3-amino-propanes of the formula I
Rl-0 _ - ~ -CH2cHHcH2-NH-R2 wherein Rl is a l-glucop~ranosidyl residue and R2 is isopropyl, tert -butyl or ~-methyl-phenethyl or l-methyl-3-phenyl-propyl which are optionally sub-stituted in the phenyl part, and to processes for their manufacture The compounds of formula I can be made by a process wherein a) a phenol of the formula II

- , .
Rl-0 __ ~ OH ~II) lQ wherein Rl has the above meaning, is reacted with a compound of the formula III X
Il :: .: .
Z - CH2 - CH - CH2 - NH R2 ~III) ; i! ;

wherein R2 has the above meaning, Z is reactive esterified hydroxyl and Xl is hydroxyl or Z and Xl together are epoxy, or Z and thè hydrogen of the amino ~. , ~ ...
group together are a direct bond, or b) a compound o~ the formula IV
,. , X .: .:
l- ~ 0-CH2-CH-CH2 Zl ~IV) ;
wherein Rl has the above meaning is reacted with a compound of the formula V

2 R2 tv) ~: .
;wherein R2 has the above meaning, one of the radicals Zl and Z2 is aminQ and thé~other l~ reactiv. esterlfied hydroxyl and Xl is hydroxyl~, or Zl together with Xl are epoxy and Z2 is amino, or c) in a compound of the formula I, except that the compound -carries a radical which can be split off on the amino group and/or on the hy- -droxyl group, this~radical or these radicals is or are split off, d) a compound corl~esponding to the formula I, wherein the nitro-gen is doubly bonded to one of its substituents, or wherein a C atom bonded to the nitrogen carries a hydroxyl group~ is reduced, or /': ,: .

49~
e) a compound of formula I in which Rl contains one or more protective groups is subjected to solvolysis or hydrogenolysis to remove the protective group or groups, and if desired, resulting racemate mixtures are separated into the pure racemates and/or resulting racemates are separated into the optical antipodes and/or resulting salts are converted into other pharmaceutically acceptable salts or into the free compounds or resulting free compounds are converted into their pharmaceutically acceptable salts.
The l-glucopyranosidyI residue can contain protective groups on the hydroxyl groups.
As protective groups there are in particular to be understood those substituted hydroxyl groups which can be converted into free hydroxyl ~ -groups, for example as described below.
Subs~ituted hydroxyl groups are, in particular, etherified or esterified hydroxyl groups.
Etherified hydroxyl groups are, for example, aliphatically or araliphatlcally etheri~ied hydroxyl, such as lower alkoxy~ for example those with up to 7 and in particular with up to 4 C atoms, such as ethoxy and es- ~
pecially methoxy or n-propoxy, or phenyl-lower alkoxy optionally substituted ` -in the phenyl part, wherein the ~:

~;~
'' c: ~ :

~ _ 2a -B~ :~
; .:

`` 1~41~
lower alkoxy part in particular corresponds to the ahove lower alkoxy and is preferably methyleneoxy and wherein examples of substituents which may be mentioned are lower alkyl such as lower alkyl wi.th up to 7, in particular with up to 49 C atoms, such as i- or n-propyl, ethyl or especially methyl, lower alkoxy, such as mentioned above9 .;:~
trifluoromethyl and especially halogen, such as bromine and ;.
above all chlorine, as well as lower alkylbenzyl, for example methylbenzyl, lower alkoxybenzyl, for example methoxybenzyl, trifluoromethylbenzyl or in particular ~
benzyl or halogenobenzyl, for example chlorobenzyl. ~ `-.: :; . `
Etherified hydroxyl groups, for example also .; .
include those in which two adJacent or sterically adjacent hydroxyl groups are together replaced by an ylidenedioxy . ;
radical. Ylidenedioxy is, in particular, lower alkylidene- ::
dioxy, such as lower alkylidenedioxy with up to 7, above . .;;
all with up to 4 C atoms, such as, in particular,~iso~
propylidenedioxy or optionally substituted:benzylidenedloxy, ~:
such as benzylidenedioxy substituted by lower.alkyl, .... ..
lower alkoxy or halogen, for example methylbenzylidene-dioxy, methoxybenzylidenedioxy or chlorobenzylidenedioxy ~ ~.
and especially benzylidenedioxy. .~
. . .
. ~ Esterified hydroxyl groups are, for ex~nple~ lower : aIkanoyloxy, for example with up to 7, especially with up ~, . .. .
: to:4~,~C atoms~ such as propionyloxy or especially acetoxy, or~optionally~:substltuted~benzo~loxy, wherein examples of ~ ; i : `substi-tuents which may~be mentioned are lower alkyl, such ..
as~mentioned above:, lower alkoxy, such as mentioned above, : . . . . . .

~ 14~
or halogen, such as mentioned above, such as methylbenzoyl 9 methoxybenzoyl, chlorobenzoyl or especially benzoyl.
~ -Methylphenethyl or l-methyl-3--phenyl-propyl R2 optionally substituted in the phenyl part is, for example, a-methylphenethyl or l-methyl~3-phenyl-propy substituted in the phenyl par-t by hydroxyl or lower alkoxy. Lower alkoxy is therein in particular lower alkoxy with up to 7 C a-toms9 above all with up to 4 C atoms, such as ethoxy, n- or iso-propoxy, n-, sec.- or tert.-butoxy or above all methoxy~ m us, a-methyl-phenethyl optionally substituted .
in the phenyl part is, for example, o-, m- or p-hydroxy~
methyl-phenethyl, o-, m- or p-methoxy-a-methyl-phenethyl and above all a-methylphenethyl unsubs-tituted in -the phenyl part. Equally, l-methyl-~-phenyl-propyl optionally sub-stituted in the phenyl part is, for exa~ple 1-methyl-3-phenyl-propyl substituted in the phenyl part by hydroxyl ~-br methoxy in the o-, m- or p-position, and above all l-methyl-3-phenyl-propyl unsubstituted in the phenyl part.
i.. ; , .
~ The new compounds possess advantageous pharmaco-.
logical properties. Thus they show a positively chrono~
tropic and in particular a positively inotropic action, as can above all be demonstrated by an increase in the myo-cardiac contractibility (probably due to direct stim~a-tion o~ the ~-receptors~ and of the pulse rate9 for -example as can be demonstrated on~non-narcotised dogs by recording various contractibility parameters, such as maxi-mum acceleration of the blood ~low m the aorta and of the pulse~rate on oral a~ministration in doses of about 0.1 to ~ 4 ~ ~

,;
- . . . . ... .

:~L()41491 ::
abou-t 10 mg/kg. The new compounds can therefore be used as positively inotropic agents, especially in the treat- -ment of insufficiency of the cardiac muscle.
,, ! ' They can furthermore also be used as valuable intermediate products for the manufacture of other useful substances, especially of pharmaceutically active compounds. ` -Compounds to be singled out are l-phenoxy 2-hydroxy-

3-amino-propanes Ia o~ the formula I, wherein R1 is optionally O-lower alkylated, O-aryl-lower alkylated, O-lower alkanoylated, O-benzoylated or O,O-ylideneylated l-glucopyranosidyl and R2 is isopropyl, tert.-butyl or . .
a-methylphenethyl or l-methyl-3-phenyl-propyl which are optionally substituted in the phenyl part.
. .
Compounds to be particularly singled ou-t are , .. . ...
l-phenoxy-2-hydroxy-3-amino-propanes Ib of the formula I, wherein Rl is O-me-thyl-l-glucopyranosidyl, O-benzyl-l-gluco-pyranosidyl, O-chlorobenzyl-l-glucopyranosidyl, O-acetyl-l- `
glucopyranosidyl, O-benzoyl-l-glucopyranosidyl, 2,4-0-iso-propylidene-l-glucopyrànosidyl, Z,4-0-benzylidene-1-gluco-pyranosidyl or l-glucopyranosidyl and R2 is isopropyl, .
tert.-butyl or ~-methylphenethyl or l-methyl-3-phenyl-propyl which are optionally substituted in -the phenyl part by hydroxyl or lower alkoxy.
~-Above all there should be mentioned l-phenoxy-2- ` -;
hydroxy-3-amino-propanes Ic of the ~ormula I, wherein Rl i9 ~ ~
glucopyranosidyl and R2 is isopropyl or tert.-butyl. ~ -Compounds to be singled out by name are in particu lar l-[p~ D-glucopyranosidyloxy)--phenoxy~-2-hydroxy~3- -,, ~ . .

. . , . . I .

: .: : . .; .

~ L~4~19~
isopropylamino~propane and the compounds named in the examples.
m e new l-phenoxy-2-hydroxy-3-amino-propanes can be manufactured according to methods which are in them-sel~es known.
It is possible to react a phenol of the formula II

Rl - O ~ OH . (II) -wherein Rl has the above meaning, with a compound of the formula III

Z - CH2 - CH - CH2 - NH - R2 . ~III) wherein R2 has the above meaning, Z is reac-tive esteri-fied hydroxy]. and Xl is hydroxyl or Z and Xl together are epoxy, o~ Z and the hydrogen of the amino group together are a direct bond.
Reactive esterified hydroxyl is, in particular a hydroxyl group esterified hy strong inorganic or organic .
acids~ above all a ~ogen halide acid, such as hydro-chloric acid9 hydrobromic acid or hydriodic acid, also sulphuric acid or an organic sulphonic acid, such as an aromatic sulphonic acid, ~or example benzenesulphonic acid, 4-bromobenzenesulphonic acid or 4-toluenesulphonic acid. ~:Thus, reactive esterifled hydroxyl in partlcular represents chlorine, bromine or iodine~ ~
: mis reaction can be carried out in the customary - :
~ ~ ,~ . .. . .. .
~ manner. If reactive esters are used as starting mater~als : , ~ : , .

... .

!.`. .

4~
o~ the formula III or compounds of the formula III wherein Z and the hydrogen o~ the amino group together form a direct bond, a co~pound of the formula II can advantage- ~:
ously be used in the form of its metal phenolate, such as : :
alkali metal phenolate, for example sodium phenolate, or the reaction is carried out in the presence of an acid-binding agent, especially of a condensation agent, ~hich can form a salt with a compound of the formula II, such as :.
in the presence of an alkali me-tal alcoholate, ~or example `
an alkali metal lower alkanolate, such as sodium me-thylate ~.:
or sodium ethylate.
It is furthermore possible~ for example, to react a compound o~ the formula IV
- . . ;,~, .. ,~ ,." .
... . ...
. 11 (IV) R~3~CH2--a~aX~ Zl ;

wherein Rl has the above meaning, with a compound of ~-the~
formula V ~ ~ -Z2 ~ R2 (V) wherein R2 h~s the above meaning, one of the radicals Zl :
and Z2 is amino and the other is reactive esterified hydroxyl and Xl is hydroxyl, or Zl toge-ther with Xl is ;:
epoxy and Z2 is amino.
Reactive esterified hydroxyl is, in partlcular,:a hydroxyl group esterified by a strong inorganic or organic aoid~ above all a hydrogen halîde acl~, such as hydro~
chloric acid~ hydrobromic acid or hydriodic acid, or :

_ 7 ~

~,1 : ' ~ : ' , ~ ...

~ \

~04~L49~ -sulphuric acid or an organic sulphonic acid, such as an aromatic sulphonic acid, for example benzenesulphonic acid, 4-bromobenzenesulphonic acid or 4-toluenesulphonic acid~
Thus, reactive esterified hydroxyl is, in particular, chlorine, bromine or iodine.
This reaction can be carried out in the usual manner. If a reactive ester of the formula IV or V is used, the reaction is preferably carried out in the pre-sence of a basic condensation agent and/or with an excess o~ amine of the formula IV. Examples of suitable basic condensation agents are alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide~ alkali metal ;
carbonates, such as potassium carbonate, and alkali metal ;~
alcoholates, such as alkali metal lower alkanolates, for example sodium methylate, po-tassium ethylate or potassium . ~ , .. .
ter-tiary butylate. ~ -;
Furthermore it is possible, in a compound of the formula I, wherein Rl and R2 have the above meanings and which possess~a removable radical~on the amino group and/or on the hydroxyl group, to spllt off this radical or these radicals. ~-Such radicals which can be spli-t off are in particu-lar radicals which can be split off by solvolysis or by reduotion. ~
Examples of radloals which can be split off by ;reduction are a-arylalkyl radicals, such as benzyl radi- ~-cals,~ and ~-aralkoxycarbonyl radicals, such as benzyloxy-carbonyl rsdic~1-, whloh can~be s 1lt off in the usua1 . .

~ 4~L~9~
manner by hydrogenol~sis, especially by catalytically activated hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, for example platinum, palladium or Raney nickel. Further radicals which can be split off by hydrogenolysis are, for example, 2-halogenoalkoxy-carbonyl radicals~ such as the 2,2,2-trichloroethoxy~ - -carbonyl radical or the 2-iodoethoxy-carbonyl or Z,2,2-tribromoethoxy-carbonyl radical, which can be split off in ... ~ .. .. .
the customary manner9 especially by metallic reduction (so-called nascent hydrogen). Nascent hydrogen can be ;
obtained by the action of metal or metal alloys, such as amalgams, on agents which provide hydrogen, such as weak carboxylic acids, alcohols or water, and in particular zinc or zinc alloys together with ethanol or dilute aqueous acetic acid can be used. The hydrogenolysis of 2-halogeno-alkoxycarbonyl radicals can furthermore be effec-ted by chromium-(II) compounds, such as chromium-(II) chloride or chromium-(II) acetate. A radical which can be split off by reduction can also be an arylsulphonyl group,~such as the toluenesulphonyl group, which can be : :... .
split off in the customary manner by reduction with nascent hydrogen, for example by means of an alkali metal, : ~ .
such as lithium or sodium, in liquid ammonia, and can in ~; particular be split off from a N a-tom. :
Divalent radicals which can be split of~ by reduc- -tion~and which are substituents of the hydroxyl group and the~amlno group are, ~or example, optionally substitu-ted ;~
methylene radicals9~such as arylmethylene radicals, such -~04~ ~9~ ~
as optionally substituted benzylidene radicals, possikle substituents on the phenyl nucleus being, ~or example, halogen, such as chlorine, lower alkyl such as m~thyl, or lower alkoxy, such as methoxy. Thus, arylmethylene is in particular benzylidene. The splitting off can be effected in the customary manner, for example by catalytic ally activated hydrogen, such as by hydrogen in the pre-sence of a hydrogenation catalyst, for example platinum9 palladium or Raney nickel.
A further possible procedure is to reduce a com-pound corresponding to the formula I, wherein the nitrogen is doubly bonded to one of its substituents, or wherein a C atom bonded to the nitrogen carries a hydroxyl group.
Thus, for example, a possible procedure is -to :
. ,:. . . .
reduce a Schiff's base of the formula VI or VII

., - .
- ~ ~1 ~ O-CH2CHOHCH~-N=R2 (VI) `
~: : ~ - . ' ,". :; ., .
~ 1 ~ 0-CH2CHOECH=~ R2 (VII) ~ ~
. . -: .
or a ring tautomer corresponding to the ~ormula VI, of the ~ ~
.,; : , ~ormula VIII - -~
--- . , .

R - ~ ~CU2~ 2 (VIII) wherein Rl and R2 have the~above meaning and~R2H is ;~

:: : : : ` ' ', : ., : ` ' ~ : `: : . ' .: : "

~(~4~9~9~ `:
identical to R2.
mis reduc-tion can be effec-ted in the customary manner, for example by means of a di-light me-tal hydride, such as an alkali metal borohydride or alkali metal aluminium-hydride, for example lithium aluminium hydride, by means of a hydride, such as diborane~ or by means of hydrogen in the presence of a hydrogenation catalyst, for example platinum~ palladium or nickel, such as Raney nickel.
Care must be taken in carrying out the reduction that ~other reducible groups are not attacked.
In resulting compounds it is possible, within the ;
definition of the end products, to modify, introduce or split off substituents in the usual manner; alternatively, resulting compounds can be converted into other end pro- `~
ducts in the customary manner.
Thus it is possible to split off the protective ~`
groups in resulting compounds which carry protective groups in the sugar residue Rl. For example it is pos- ~ ~
sible, in resulting compounds in which one or more hydroxyl `
groups in the sugar residue are protected by an optionally `
substituted benzyl radical or in which two adjacen-t hyd--..... : , roxyl groups in the sugar residue Rl are together pro-tected .. . ;
by an optionally substituted benzylidene radical, to split off these radicals in the usual manner. Optionally ; . . .
substituted benzyl is, for~example, halogenobenzyl, such ~-as~chlorobenzyl,~lower alkylbenzyl, such as methylbenzyl ~;
or lower alkoxybenzyl, such as ~ethoxybenzyl, and in parti- ;
cul~r unsubstitu-ted benzyl. Optionally substituted ~

` ~ :
~:
~ , .

, ~ 4 ~ ~9 ~ :
benæylidene is, for example, halogenobenzylidene, such as chlorobenzylidene, lower alkylbenzylidene, such as methyl- ~
benzylidene, or lo-.le.r alkox~benzylidene such as methoxy- -benzylidene, and especially unsubstituted benzylldene.
m e splitting off can for example be effected by reduction, for example by treatment with catalytically activated hydrogen, such as hydrogen in -the presence of a hydro-genation catalyst, ~or example platinum, palladium or Raney nickel, yielding corresponding compounds with free : `
hydroxyl groups in the sugar residue Rl. :~
In resulting compounds in which one or more hydroxyl groups in the sugar residue Rl are protected by acyl, the acyl radicals can be split off in the customary ; .
manner, for example by hydrolysis or by alcoholysiæ, .~.`
preferably in the presence of a m.ild basic agent, such as -. ..
an alkali metal bicarbonate, for example sodium bicar~
bonate, giving corresponding compounds with free hydroxyl ~:
groups in the sugar residue R~
The reac-tions mentioned can op-tionally be carried i :
out simultaneously or successively and in optional sequence.
; me reactions mentioned are carried out in the : `~
usual manner in the presence or absence of : ~diluents, condensation agents and/or cataly-tic agents~ at ; .
: : lowered, ordinary or elevated temperature and if approp~
riate:in a closed vessel~
Depending on -the process conditions and starting aubstances, the end products are obta~ned in the free form or in the form o~ their acid addition salts, ~hich is also ~, . . . ..

.

encompassed by ~he inven-tion. Thus, for example, ~`
basic, neutral or mixed salts and where relevant also hemihydrates, monohydrates, sesquihydrates or poly-hydrates thereof7 can be obtained. The acid addition sal-ts o~ the new compounds can be converted into the free compo~md in a manner which is in itself known, for example by means of basic agents, such as alkalis or ion exchangers.
On -the other hand, the resulting ~ree bases can form salts with organic or inorganic acids. Acids used for the preparation of acid addition salts are in particular those which are suitable for forming therapeutically usable salts. ~ -As examples of such acids there may be mentioned, hydrogen halide acids, sulphuric acids, phosphoric acids, nitric `~ ~ ;
acid and aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid or pyruvic acid, fumaric acid, benzoic acid, anthranilic acid, p-hydroxybenzoic acid~
salicylic acid or embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid or ethylenesulphonic acid, halogenobenæenesulphonic acids, toluenesulphonic acid~ cyclohexylaminesulphonic acid or sulphanilic acid.
; These~or other salts of the new compounds such as, for example7 the picrates~ can also serve for the puri fication of ~he resul-ting ~ree bases by converting the ;
~ree~bases into salts, and isolating these and again i , ~ ~ .:. , .
:
: : . , , l - 13 - ; ~

~: ~ : ,.

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liberating the bases from the salts. Because of the close relationships between the new compounds in the free form and in the form of their salts, the free compounds are, in the preceding and following text, where appropriate also to be understood to include the corresponding salts, with regard to general sense and intended use.
m e invention also relates to those embodiments of .
the process according to which a compound obtainable as an intermediate product at any stage of -the process is used as ~he starting product and the missing process steps are carried ou-t, or the process is stopped at any sta~e, or in which a starting substance is formed under the reaction .
conditions or in which a reactant is presen-t in the form of its salts, if appropriate.
For e~ample, a possible procedure is to react an -aldehyde o~ the formula IX

~ ~ O-CH2CHO~-CHO (IX) -~

,.
with an amine H2N-R2 in the presence of a reducing agent, -- Rl and R2 having the above meaning. mis gives a compound of the formula VII as an intermediate product, which is then reduced further in accordance with the inventionO
However, another possible procedure is, for example, to` react an amine of the formula X ~

R~- ~ o-oH2cHoHc~I2-~I2 (X) ~: - . ~ . . .. .

~0~49:~
with a ketone O=R2 in the presence of a reducing agent, such as one of those mentioned above9 R2H being equivalent to R2 and Rl and ~2 having the above meaning. This gives a compound of the formula VI or VIII as an intermediate product which is then reduced further in accordance with the invention. In this case it is also possible to form i the amine X in situ, for example from one of its Schiff's bases with an optionally substituted benzaldehyde, which base is converted in situ, in particular by means of catalytic hydrogenation, into the amine X, which then --reacts further in accordance with the invention.
The new compounds can, depending on the choice of the starting substances and procedures, be in -the form of optieal antipodes or racemates or, where -they contain at least two asymmetrical carbon atoms, also in the form of isomer mixtures.
Resulting isomer mixtures ean be separated into the two stereoisomeric (diastereomeric) pure racemates ln a known manner on the basis of the physico-ehemical differences o~ the cons-tituen-ts, for example by chromato- i graphy and/or fractional crys-talllsation. i~
Resulting racemates can be resolved in-to the diastereomers according to known methods, for example by recrystallisation from an op-tically ac-tive solvent, with i ~ ....................................................................... .
the~aid of micro-organlsms or by reaction with an optically -;
aotive acid which forms sal-ts with the racemic compound and separation o~ the salts obtained in this manner, ~or example on the basis of thelr dlfferent solubillties, and ~ ; ;~

~. ..

;. : ., .. . .

, ~,.: , ~4~4~
the antipodes can be liberated from the diastereomers by ~ -treatment with suitable agen-ts. Par-ticularly cus-tomary optically ac-tive aGids are, for example, the D- and L- ~ -forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid or quinic acidO
Advantageously, the more active of the two antipodes is isolated.
Preferably, the starting substances used for carrying out the reactions according to the invention are -those which lead to the groups of end products which were particularly mentioned initially and especially to the end ~ -products which have been particularly described or singled out.
m e starting substances are known or can, i~ they `
are new, be obtainecl according to methods which are in -themselves known. Compounds IV can be prepared in the usual manner from a phenol II by reaction with a reactive ;~
derivative o~ a propanol HOCH2-CHXl-CH2Zl, such as, for example, with epichlorohydrin. Compounds I with removable ;
radicals on the amino group and/or hydroxyl group can be -:~ : ~ ..... : :
manufactured analogously to the compounds IV, as can compounds VI-X.
The new compounds can be used as medicines, for ~ ;`
example in the ~orm of pharmaceutical preparations in ~`
which they or their salts are present as a m1xture with a~pharmaceu-tical,~ organic or inorgan1c9 solid or Iiquid excip1ent~wh1ch~is su1table ~or,~ for example, enteral or-parenteral administration~ Suitable substances for 3~4~L491 ~ :
forming the excipient are those which do not react wi-th ;
the new compounds such as, for example~ water, gelatine, lactose, starch, magnesium s-teara-te, talc7 vegetable oils, benzyl alcohols, polyalkylene glycols or o-ther known medicinal excipients. The pharmaceutical preparations can for example be in the form of tablets7 dragees, capsules or suppositories or in a liquid form as solu-tions -(for example as an elixir or syrup), suspensions or emulsions. m ey are optionally sterilised and/or contain auxiliaries, such as preservati~es, stabilisers, wetting agents or emulsifiers, salts for regulating the osmotic pressure or buffers. The preparations, which can also be used in veterinary medicine, are obtained according to customary me-thods. The daily dose for a warm-blooded animal o~ about 75 kg body weigh-t is about 10-100 mg, preferably about 20-40 mg.
me examples which follow explain the invention wlthout however restricting it. ;
Example 1 -i6.4 g (0.05 mol) of 4-(2,3-epoxy-propoxy?-phenyl~
~-D-glucopyranoside and 11.8 g (0.20 mol) of isopropyl-amine are dissolved in 250 ml of methanoI and heated for

5 hours under reflux. The mixture is then completely evaporated under a waterpump vacuum. The oily residue is . ~ .
dissolved in ethanol and 8.95 g (0.05 mol) of N-cyclohexyl-sulphamic acld, dlssolved in isopropanol, are addedO m e reactlon product which precipitates in a crystall~ne form is filtered o~f whilst excluding moisture. After :~ , . ~ , ~ 17 - ~

~ . -,, . :

~4~
recrystallisa-tion ~rom ethanol-isopropanol, l-[p~ D t ' ' ' glucopyranosidyloxy)-phenoxy~-2-hydroxy-3-isopropylamino-propane-N-cyclohexyl sulphamate of melting point 70 110C
is ob-tained,[~]D - -28.8 in methanol.
m e starting material can be obtained as follows:
27.2 g (0.1 mol) of hydroquinone-~-D-gluco-pyranoside and 250 ml of epichlorohydrin are dissolved in 1 litre of e-thanol9 6.9 g (0.05 mol) of potassi~m carbonate are added and the mixture is heated ~or 6 hours under re~lux. m e precipitate which separates out is filtered off. m e ~iltrate is evaporated in a wa-terpump vacuum. m e residue is dissolved in hot ethanol and the :. . .. .
solu-tion is ~iltered. The filtrate is cooled and e-ther is added until the mixture begins to turn cloudy. me ~ .,.
reac-tion product which hereupon precipitates as crystals is ~iltered off and washed with ether. 4-(2,3-Epoxy~
propoxy)-phenyl-~-D-glucopyranoside, melting point 154~156C, [a32 - -52.4 in methanol, is thus obtained.
Exam~le 2 Analogously to -the description in Example 1, 4-(2,3-epoxy-propoxy)-phenyl-2,3,4,6-tetra-0-acetyl-~ D-glucopyranoside with isopropylamine gives l-[p-(2,3,4,6-tetra-~0-acetyl-~-D-glucopyranosidyloxy)-phenoxyJ-2- ~-.. ..
hydroxy-3 isopropylamino-propane.

AnaIogously~to the description in Example l, 4-(2,3-epoxy-propoxy)-ph~nyl-2,4-0-isopropylidene-~-D- ` -glucopyranoslde wi~h isopropylamine gives l-[p-(2,4-0-- I8 - ~ -isopropylidene ~.-D-glucopyranosidyloxy)-phenoxy]-2- :
hydroxy-3-isopropylamino-propane J

Analogously to the description in Example 1, 4-(2~3-epoxy-propoxy)-phenyl-2,4-0-benzylidene-~~D- .
glucopy.ranoside with isopropylamine gives 1-[p~(2,4-0- ..
benzylidene-~-D-glucopyr~nosidyloxy)-phenoxy~-2-hydroxy- -, .
3-isopropylamino-propane.
. Example 5 . Tablets containlng ,~0 mg of active subs-tance and .~
having the following composition are prepared in -the `
usual manner~
~ , . ~ :, . . . .
....
l-~p-(~-D~Glucopyranosidyloxy)-phenoxy]- .~;.
2-hydroxy-3-isopropylamino-propane 20 mg .. :
Wheat starch 60 mg .
Lactose 50 mg . ...
.Colloldal silica 5 mg . .-Talc 9 mg Magnesium stearate 145 mg ;. ~ -:.:. - .
Preparation :
.( . m e l-[p-(~-D~glucopyranosidyloxy)-phenoxy~-2-hydroxy-~-isopropylamino-propane is mixed with a part of the~wh~at~starch, with lactose and with colloidal sil.ica and~the mixture is forced through a sieve. : A fur~her : part of the whea-k staroh is worked in-to a paste with a ~`~
.5-fold quantity of water on~a waterbath and the powder : .

9:1.
mixture is kneaded with this paste until a slightly plastic mass has been produced. `i-m e plastic mass is forced through a sieve of approxO 3 mm mesh width and dried, and the resul-ting dry granules are again forced through a sieve. Thereafter, the residual wheat starch, talc and magnesium stearate ;.
are mixed in and the mixture is pressed to give tablets weighing 145 mg and having a breaking groove.
.
. .
- . ~ , i, . .

.... .
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Claims (16)

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

1. Process for the manufacture of 1-phenoxy-2-hydroxy-3-amino-propanes of the formula I
(I) wherein R1 is a 1-glucopyranosidyl residue which can contain protective groups and R2 is isopropyl, tert.-butyl or .alpha.-methyl-phenethyl or 1-methyl-3-phenyl-propyl which are optionally substituted in the phenyl part by one hydroxyl group or by one alkoxy group having up to 7 carbon atoms, characterized in that a) a phenol of the formula II
(II) wherein R1 has the above meaning, is reacted with a compound of the formula III

(III) wherein R2 has the above meaning, Z is reactive esterified hydroxyl and X1 is hydroxyl or Z and X1 together are epoxy, or Z and the hydrogen of the amino group together are a direct bond, or b) a compound of the formula IV
(IV) wherein R1 has the above meaning is reacted with a compound of the formula V
Z2 - R2 (V) wherein R2 has the above meaning, one of the radicals Z1 and Z2 is amino and the other is reactive esterified hydroxyl and X1 is hydroxyl, or Z1 together with XI are epoxy and Z2 is amino, or c) in a compound of the formula I except that the compound carries a radical which can be split off on the amino group and/or on the hydroxyl group , this radical or these radicals is or are split off, d) a compound corresponding to the formula 1, wherein the nitro-gen is doubly bonded to one of is substituents, or wherein a C atom bonded to the nitrogen carries a hydroxyl group, is reduced or e) a compound of formula I in which R1 contains one or more protective groups is subjected to solvolysis or hydrogenolysis to remove the protective group or groups, and if desired, resulting racemate mixtures are separated into the pure racemates and/or resulting racemates are separated into the optical antipodes and/or resulting salts are converted into other pharmaceutically acceptable salts or into the free compounds or resulting free compounds are converted into their pharmaceutically acceptable salts.

2. Process according to Claim 1a, characterized in that reactive esterified hydroxyl is a halogen or sulphonyloxy.

3. Process according to Claim 1b, characterized in that reactive esterified hydroxyl is a halogen or sulphonyloxy.

4. Process according to Claim 1c, characterized in that radicals which can be split off are radicals which can be split off by solvolysis or reduction.

5. Process according to Claim 4, characterized in that a monova-lent radical which can be split off by reduction is .alpha.-arylalkyl, .alpha.-aralkoxy-carbonyl, 2-halogeno-alkoxycarbonyl or arylsulphonyl.

6. Process according to Claim 4, characterized in that a divalent radical which can be split off by reduction is optionally substituted methy-lene.

7. Process according to Claim 6, characterized in that optionally substituted methylene is arylmethylene.

8. Process according to Claim 1d, characterized in that reduction is carried out with a di-light metal hydride, a hydride or hydrogen in the presence of a catalyst.

9. Process according to Claim 1, characterized in that a reactant is used in the form of its salts.

10. Process according to Claim 1, characterized in that in result-ing compounds with protective groups in the residue R1, the protective groups are split off.

11. Process according to Claim 1b, wherein R1 is 0-lower alkanoy-lated, or 0,0-ylideneylated 1-glucopyranosidyl.

12. Process according to Claim 11, wherein R1 is 0-acetyl-1-gluco-pyranosidyl, or 2,4-0-benzylidene-1-glucopyranosidyl.

13. Process according to Claim 12 wherein R1 is 2,3,4,6-tetra-0-acetyl-1-glucopyranosidyl.

14. Process according to Claim 1b, wherein R2 is isopropyl or tert.-butyl.

15. Process according to Claim 1b, characterized in that 1-[p-(.beta.-D-glucopyranosidyloxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane is prepared by reaction of 4-(2,3-epoxy-propoxy)-phenyl-.beta.-D-glucopyranoside with iso-propylamine.

16. 1-Phenoxy-2-hydroxy-3-amino-propanes of the formula I

(I) wherein R1 is a 1-glucopyranosidyl residue and R2 is isopropyl, tert.-butyl or .alpha.-methyl-phenethyl or 1-methyl-3-phenyl-propyl which are optionally sub-stituted in the phenyl part by one hydroxyl group or by one alkoxy group hav-ing up to 7 carbon atoms, whenever prepared by the process claimed in claim 1 or any process which is an obvious chemical equivalent thereof.