CA1062717A - 1-aryloxy-2-hydroxy-3-alkinylaminopropanes and processes for production thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to novel 1-aryloxy-2-hydroxy-3-alkynylaminopropanes, the acid addition salts thereof and to processes for their preparation. The novel compounds show adrenolytic activity and may be of use in human medicine for the treatment or prophylaxis of diseases of coronary vessels and for the treatment of cardiac arrythmias, in particular tachycardia. The hypotensive properties of the compounds are also therapeutically interesting. Processes for the production of the novel compounds are described and examples of certain of the novel compounds are given. Pharmaceutical compositions containing the novel compounds are described and exemplified.

Description

-7~7 The present invention relates to novel substituted racemic and optically active l-aryloxy-2-hydroxy-3-alkynyl-amino-propanes, the acid addition salts thereof, and to processes for their production.
According to one feature of the present invention there are provided compounds of the general formula:

~ _ OC}12 - CHO}I- CH2 - NH - C - C--CH

2 \$J 5 I

wherein Rl represents a hydrogen or halog~en atom, a nitro group, or an alkyl group with 1 to 5 carbon atoms, an alkoxy group with 1 ~o 4 carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a lower alkoxyalkyl group or a group of the formula:
-~CH2)X-CN, -~CH2)X NH2 or ~C 2)x (in which x is zero or an integer from 1 to 3), the group -COOH or -COOR6, (in which R6 represents an alkyl group with 1 to 4 carbon atoms), an alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, ~ -lower alkanoyl, alkanoyloxy or alkanoylaminoJ phenacetyl substituted in the phenyl moiety by at least one halo, alkyl, nitro, cyano or carboxyl group, benzoyl substituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a cycloalkyl group with 3 to 7 carbon atoms, the group:
-Q-co~NHR7R~, (in which Q represents a single bond, an oxygen atom, a NH-, CH2- or - 2 _ .~r~s -~
~:~iJ
, " ~

~6~ L7 CH2-NH group and R7 and R8, which may be the same or different, each represents a hydrogen atom or a lower alkyl group) or phenyl or phenoxy substituted by at least one halogen atom~
alkyl, alkoxy, nitro, cyano or carboxyl group;
R2 represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 4 carbon a~oms, lower alkanoyl or alkenyl group with 2 to 4 carbon atoms, or a cyano, amino or nitro group; or Rl and R2 together represent a 3,4-methylene-dioxy group;
R3 represents a hydrogen or halogen atom, or an alkyl or alkoxy group with 1 to 4 carbon atoms; or R2 and R3, being bonded to adjacent carbon atoms in the phenyl moiety, together represent the group:
-CH=CH-CH=CH- or ~(CH2)n~
(in which n is an integer from 3 to 5); :
R4 rep~esents a hydrogen atom or an alkyl group with ~ -1 to 3 carbon atoms; and R5 represents an alkyl group with 1 to 3 carbon ? ~ ' atoms; or R4 and R5 together represent the group ~CH2 ~ p (in which p represents an integer from 4 to 6), and non-toxicJ phar-maceutically acceptable acid addition salts. ; .
The compounds according to the invention as here- ~ -inbefore defined contain an asymmetric carbon atom and thus ~ .
:

- 3 -J

'' . , ' ' ' 27~

may exist not only in racemic form but also in the form of optically active isomers. It will be appreciated tha.t all such forms of the compounds of formula I (and acid addition salts thereof) are within the scope of the present invention.
The acid addition salts useful for incorporation in pharmaceutical compositions are physiologically compatible acid addition salts, other acid addition salts may however be useful in the preparation of compounds of formula I and physiologically compatible ~cid addition salts thereof.

.

, -' .

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

. ,". I

, : ~, ,. . ~ ,:

::.. ,.,.. : .: .: : . :

~ 6~ ~7 The compounds of general formula I and their physiologically compatible acid addition salts have shown interesting pharmacological activity in animal tests on guinea pigsg particularly adrenolytic activity.
The compounds of fo~nula I may thus be useful in human medicine for the treatment or prophyla~is of diseases ; of coronary vessels and for the treatment of cardiac arrythmia, especially of tachycardia. The blood pressure decreasing properties of the compounds are also ]0 therapeutically interesting.
Compounds of fo~nula I have thus been tested and found to have a greater activity coupled with a substantially less toxic effect than known y-receptor blockers such, as, for example5 the ~e ~ product l-(l~napthyloxy)- ;~
2-hydroxy-3-isopropylaminopropane (propanolol).
Where a compound of formula I contains the group ` R8, the said group preferably represents a pyrrolidino~ ;
piperidino~ morpholino, phenyl or phenoxy group.
Where Rl represents a lower aliphatic, araliphatic or aromatic acyl, acyloxy or acylamino group the said acyl group is pre~erably an acetyl, propionyl, butyryl or isobutyryl group or a phenacetyl group optionally substituted on the phenyl moiety by at least one halogen atom or alkyl, nitro, cyano, or carboxyl group, or a - S - , .

,, ., ., . ,. - .

~ 7 17 benzoyl group optionally substituted by at least one halogen atom or lower alkyl, nitro, cyano or carboxyl group.
Preferred compounds according to the present invention by virtue of their especially favourable physiological properties include compounds of formula I
(wherein Rl represents an alkenyl, alkynyl, alkenyloxy~
alkynyloxy or cya~o group especially the allyl, ethynyl, propynyl, allyloxy or propargyloxy group) and acid addition salts thereof. Compounds according to the present invention wherein the group Rl is in the 2-position of the phenoxy group are particularly preferred.
Other preferred compounds according to the present invention include compounds of formula I Cwherein R2 represents a hydro~en atom or a lower alkyl (e.g.
methyl) groupl and acid addition salts thereof. The substituent R2 is preferably in the 5-position of the phenoxy group and R3 preferably represents a hydrogen atom.
Preferred compounds according to the invention, by virtue of their interesting physiological properties also include compounds of formula I [wherein Rl represents .

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

6;~ 7 a hydro~yalkyl group ~especially the hydro~ymethyl gTOUp) and R2 and R3 both represent hydrogen atoms~ and acid addition salts ~hereof.
Other preferred compounds according to the inven-tion, by virtue of their interesting physiological properties, include compounds of formula I [wherein Rl represents an amino or acylamino group ~especially the acetylamino group) and R2 and R3, which may be the same or different, each represent a hydrogen or halogen atom or an alkyl group]
and acid addition salts thereof.
Compounds of formula I ~wherein R4 and R5 both represent a methyl group) and acid addition salts thereof are also preferred compounds of the invention.
Especially preferred compounds of the invention include the following compounds:-1-(2-Cyanophenoxy)-3-~2-methylbut-3-yn-2--ylamino)-2-propanol and acid addition salts thereof; -1-(2-Ethynylphenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol and acid addition saltsthereof;
1-(3,5-Dibromo-4 aminophenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol and acid addition salts thereof;
' ' , .
' "''. ' - 7 - ~

,.~, .

" ~
, .

~ 7~.~

1-(2-Hydroxymethylphenoxy)-3-(2-amino-2 methylbut-3-yryl)-2 propanol and acid addition salts thereof;
1-(3-Chlorophenoxy)-3-(2 amino-2-methylbut-3- ~ 1)-2-propanol and acid addition salts thereof; and ~ 5 1-(4-Acetamidophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol and acid addition salts thereof.
The compounds of formula I may, for example, be prepared by one of the following processes ~a) to (h) which processes constitute a further feature of the present invention:- -a) Reacting a compound of formula ~~ OCH2-Z II
R
~ [wherein Rl, R2 and R3 are as hereinbefore defined : and Z represents the group:- CH 5H2 or -CHOH-CH2-Hal (wherein Hal represents a halogen atom) with a compound of the formula NH2-CR4R5-C _C~
': ' ~ i271~7 wherein R4 and R5 are as hereinbefore defined.
b) Hydrolysing or hydrogenating a compound of the formula R
~ ,4 R2 ~ ~CH2-CH-CH2-NH-C-C _CH IV

wherein Rl, R2, R3, R4 and R5 are as hereinbefore defined and G represents a hydrolytically or hydrogenolytically removable group such as for example an acyl or acetal group.
c) Reacting a compound of the formula Rl Sch R
OCH 2-CHOH-CH2-N--C - C ----Cl{

~whereln Rl, R2, R3, R~ and R5 are as hereinbefore defined and Sch represents a removable protecting group) whereby a compound of formula I is obtained. The reaction is - ~:
, , .
, preferably effected by hydrolysis or hydrogenation. :
.:
Where the reaction is effected by hydrogenation the hydrogenation is such that the -C -- CH group in the compound of formula V is not reduced. A compound of _ 9 '`~'~',; "
,,, "' ' -i273.7 formula V is preferably used in which Sch represents an acyl or carbobenzoxy group.
d) Hydrolysing a compound of the Eormula:
Rl ~ OCH2-C~ IH2 14 R2 ~ X ,N - C - C - CH VI

wherein Rl, R2, R3, R4 and R5 are as hereinbefore defined and X represents the group -CO- or -CH2- or a ~ CH- lower alkyl group. The hydrolysis may conveniently be effected ` by the use of a strong alkali e.g. an aqueous sodium hydroxide or potassium hydroxide solution or an alcohol/
water mixture.
Furthermore, the compounds of general formula I -may also be produced by reacting a compound, which con-tains the basic l-phenoxy-2-hydroxy-3-hydroxy-alkylamino structure and wherein one of the substituents Rl or R2 is missing or only present in the form of an intermediate, in order to form a compound of formula I. These processes constitute stlll further featu~es of the present invention:-.
.

~6~7~L7 e~ the reaction of a compound of the formula:-A .
¦ R
~ OCH2-CHOH-CH2-NH-C-C~ CH
R2 ~ 5 VIIa . 3 .
~wherein R2, R3 and R4 are as hereinbefore defined and A represents an atom or group which may be converted into Rl) to convert the compound of formula VIIa into a compo~nd of formula I.
: A compound of formula VIIa is preferably used in which A represents a -CONH2, -CH-NOH,-COOR6 (wherein -- :
R6 is as hereinbefore defined), alkoxy, O-acyl or nitro g~oup .
: 10 Thus the reaction may9 for example, be effected by dehydration, r~duction, hydrolysis, alkylation andjor ~ -ether splitting. Thus the group A may, for example, conveniently represent such groups as the aldehyde (-CHO) group~(converts by reduction:into the -CH20H), the : --CONH2 or -CH = NOH group (converts by dehydration into ~ :
a cyano group), a halomethyl group (converts by reaction .: :, ,.

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

~ 7 with water into a hydroxymethyl group), a halogen atom (converts by reaction with Cu(I)CN and pyridine at elevated temperatures into a cyano group), a nitro group (converts by reduction into~an amino group), an alkoxy-carbonyl group (converts by saponification into a carboxyl group) or an amino group (converts by diazoti-zation and heating with copper (1) cyanide).
Thus the group A may be converted into the group Rl by applying such measures (e.g. dehydration, exchange reaction or reduction, dia~otization and heating with a copper~ salt etc.) as may be necessary.
f) the reaction of a compound of the formula Rl R

~ OCH CHOH-CH -NH-C-C= CH
B ~ 2 2 , VIIb "
(wherein R1, R3, R~ and R5 are as hereinbefore defined and ~ B represents an atom or group which may be converted into R2) to convert the compound of form~la VIIb lnto a compound of formula I. The group B may for example conven1ently :., ~ 7 ~ 7 represent such groups as a halogen atom or the group -CONH2 or -CH=NOH or the aldehyde (~CHO) group (converts by reduction into a methyl group) or an amino group (converts by diazotization and treatment with a copper (I) salt into a cyano group or a chlorine atom).
g) For the preparation of compounds of fo~mula I as hereinbefore defined (wherein R2 or R3 represents a halogen atom) the halogenation of a compound of the formula R :
,4 Ar-OCH2-CHOH-CH2-NH - C -C ~ CH VIII
RJ ;
wherein R4 and R5 are as hereinbefore defined and Ar represents the group Rl Rl :-}
R3 ::

(wherein R1~ R2 and R3 are as hereinbefore defined). ~
The halogenation is preferably effected by the .
.
use of a hydrogen halide/hydrogen peroxide mixture and advantageously at an elevated temperature.

., :. .. j .. , .. . ~ , ~ ~ ~2 7~ ~

h~ for the preparation of compounds of formula I
as hereinbefore defined (in which Rl or ~2 represents a cyano group), the reaction of a compo~md of the formula:- R
M-O-CH2-CHOH-CH2-NH- C C - CH IXa ::
R
(wherein R4 and R5 are as hereinbefore defined and M
- represents the group~
C R

R2~ C'~

(wherein Rl, R2 and R3 are as hereinbefore defined and C represents an amino group or halogen atom) to convert the compound of formula IXa into a compound of formula I.
;~ Where C represents an amino group9 the reaction is ;~ -preferably effected by diazotization and subsequent boiling in the presence of a cyanide such as KCN.
Where C represents a halogen atom the reaction is preferably effected with Cu(I)CN conveniently in the presence of a high boiling solvent.
Certain of the starting materials required for ' . ".. ~, :' '.' .

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

~63 6~7~7 carrying out processes (a) to (h) are already known, but in any case may be obtained according to known processes. Thus 9 the epoxides of formula II may, for example, be produced by reaction with a corresponding phenol or phenolate of formula ~ -.

~ OKt 2 ~ X

wherein Rl, R2 and R3 are as hereinbefore defined and Kt means hydrogen or a cation (e.g. an alkali metal cation).
The epoxides may conveniently be used for the production of further starting materials, e.g. the halohydrins of formula II which may~ for example, be produced by reacting the epoxide with a corresponding hydrogen halide.
The amines of formula III are known and, in general, represent commercial products. Compounds of formula IV
may, for example, be obtained by reacting a halohydrin of formula II with a compound (such as vinyl ether or dihydropyran) capable of introducing the protecting group G and~ subsequently, reacting the compound thus obtained of formula:-:.

"
. . .. . .. ~ .

,: ... ~; .

~iZ7~l7 .

R2~ OCH z - CH- CH 2 -Hal : with a compound of general forrnula III. ~ :~
The tertiary amines of formula V may, for example, be obtained by reacting a compound of general formula X

with a compound of general formula Sch R
. ,4 Z-CH2-N - - C-C _ GH XII

wherein R4, R5 and Sch are as hereinbefore defined.
`~ The oxazolidinones of fo~nula VII (e.g. compounds where X = CO) may be produced, for example, starting from an epoxide of formula II, by reacting the latter with a urethane (producible from chloroethyl forma~e and an 10 : amine of formula II) of formula ,4 HC_ C-C-HN-C-OC2H5 XIII
R5 ~ .

," :-- - 16 - ~

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

:, . . . . . . .. . . . . .. . . .

7~17 wherein R~ and R5 are as hereinbefore defined.
The compounds of formulae VIIa, VIIb, VIII, IXa and IXb already contain the complete l-phenoxy-2-hydroxy-3-alkynylaminopropane structure and may therefore be produced in a similar manner to process (a~ described above, starting from the corresponding phenol, which gives the corresponding l-phenoxy-2,3-epoxypropane on reaction with epichlorohydrin. The product is then reacted with an alkynylamine of form~la III in order to ; 10 give the desired starting compound.
Compounds of general formula I contain an ; asymmetric carbon atom at the -CHOH- grouping and therefore occur in the form of racemates and optically active isomers. Any racemates present may be resolved lnto their optically active forms by methods known E~ se e.g. by means of optically active acids, such as for example dibenzoyl or di-p-toluyl-D tartaric acid or D-3~bromocamphor-8-sulphonic acid. The optically active isomers may be prepared either by starting from optically active starting compounds or by resolving the racemates obtained into their optical isomers in ~ 17 -' ' ~. ' : ' . .
.. - . , . ~ .

~ 7 ~7 conventional manner.
The l-ph~noxy-2-hydroxy-3-hydroxyalkylamino-propanes according to the invention may if desired be converted into their physiologically compatible acid addition salts in the conventional way~ Acids suitable for the formulation of physiologically compatible acid addition salts include, for example 9 hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acidj lactic acid, tartaric acid, and 8-chlorotheophylline.
According to a yet still further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least ` one compound of formula I as hlereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carr;er or excipient. The compositions according to the invention ;
may also include, if desired, other physiologically active compounds, for example coronary dilators, sympathicomimetics, cardiac glycosides or tranquilizers. ~;

..

:

7 ~7 The compositions according to the invention may be presented, for example, in a form suitable for oralg parenteral or rectal administration.
The compounds according to the invention may be presented in the conventional pharmacological forms of administration, such as tablets, coated tablets, solutions, emulsions, powders, capsules or sustained release forms. Conventional pharmaceutical excipients as well as the usual methods of production may be employed for the preparation of these forms. Tablets ` ! may be produced, for example, by mixing the active ingredient or ingredîents wit:h known excipients, such as for example with diluants, such as calcium carbonate9 calcium phosphate or lactose, disintegrants `

such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talcum, and/or agents for obtaining ~ `
.
sustained release, such as carboxypolymethylene, carboxmethyl cellulose, cellulose acetate phthalate, or polyvinylacetate.

- 19 - , ~,;

~ ~ ~2 7 ~ ~

The tablets may if desired consist of several layers. Coated tablets may be produced by coating cores,obtained in a similar manner to the tablets,with agents commonly used for tablet coatings for example polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. In order to obtain sustained release or to avoid incompatibilities, the core may consist of several layers too~ The tablet-coat may also consist of several layers in order to obtain sustained release, in which case the excipients mentioned above for tablets may be used.
.
Syrups of the active ingredient according to the invention or combinations of active ingredients may additionally contain a sweetener, such as saccharin, cyclamate, glycerin or sugar, and/or taste improving agents such as flavourings e.g. vanillin or orange extract They may also contain suspension agents or thickeners, such as sodium carboxymethyl cellulose, wetting agents, such as for example condensation products of fatty alcohols with ethylene oxide, or - ~ -preservatives, such as p-hydroxybenzoates.

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

, ' ' ` '' ' '"', .. :'. ''.'.;."" ' , . - ', :, , ~i27~7 Injection solutions may, for example, be produced in the conventional manner, such as by the addition of preservation agents, such as p-hydroxybenzoates, or stabilizers, such as Complexons. The solutions are then filled into ;njection vials or ampoules.
Capsules containing one or several active ingredients may be produced for example by mixing the ~ctive ingredients with inert carriers, such as lactose or sorbitol, and filling the mixture into gelatin capsule s, . Suitable suppositories may, for example be . produced by mixing the active ingredient or active ingredient combinations with the conventional carriers . envisaged for this purpose7 such~as neutral fats or lS polyethylenegl~col or derivatives thereof. ;:~
Advantageously? the compositions may be formu'ated as dosage units, each unit being adapted:to supply .
a fixed dose of ac~ive ingredient. Tablets, coated , tablets, capsules, suppositories and ampoules are : 20 examples of suitable dosage unit fonns. Each dosage '-:
* TRADE MARK - 21 .~ .

~ ~2~ ~ 7 unit preferably contains l to 300 mg, of the said active ingredient and especially 5 to 100 mg of the said active ingredient for oral administration and 1 to 20 mg for parenteral administration.
The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients:-- ~2 ,, . ., ,,, , " , ,, " ,,, ,, , , ~.
.. ,. , ., , . , , , :,.. . . .. . . .. .. .
.. . :. . ~ . , , , .. . , .
,, . : , , . , : , .. : , .

;27~L7 l-a-Naphthoxy-3-(3-amino-3-ethylpen~4-ynyl)-2-propanol.
HCl ~accordin to rocess a) lO g (0~05 mol) of l-a-naphthoxy-2,3-epoxypropane are dissolved in 80 ml of ethanol and 5.55 g (0.05 mol) of 3-amino-3-ethylpent~4-yne are addedO The mixture is refluxed for 2 hours at the boiling temperature of the reaction mixture. After cooling the mixture, the solvent is distilled off,-the residue dissolved in ether and acidified with alcoholic HCl. The compound which crystall-ises out is isolated and recrystallized from a mixture of acetonitrile and ethanol.
Yield: 9.5 g, m.p. 195 - 196C.
Exam~le 2 .

l-m-Tolyloxy-3-(2-amino-2-methylbut-3-ynyl)-2-propanol.
~ ~' '.
8.2 g (O OS mol) of l-m-tolyloxy-2,3-epoxypropane are dissolved in 90 ml of ethanol ànd a~ter the addition of 5.25 g (0.075 mol) of 2-amino-2-methylbut-3-yne are refluxed for 2 hours. After distilling off the solvent~ the residue is recrystallized Erom ethyl acetate on the addition of `

.
': ' .. . . . . . . .
~ . . .. .
.. .. " ~'~ ',~' ' , ~ 7 petroleum ether. The crystalline base is dissolved in acetonitrile, alcoholic HCl is added and crystallization is started on the addition of ether. 6.5 g of colourless crystals are obtained, which are chromatographically pure.
M.p. 139 - 141C.
Example 3 1-(2-Allylphenoxy)-3~(2-amino-2-methylbut-3-ynyl)-2-.: .
9.5 g (0.05 mol) of 1-(2-allylphenoxy)-293-epoxy-propane are dissolved in 60 ml of methanol, 8.3 g (0.1 mol) of 2-amino-2-methylbut-3-yne are added and the mixture is refluxed for 3 hours. After distilling off the solvent, the basic residue is dissolved in acetone and a solution of 6 g of oxalic acid is added. The precipitatlng crystalline oxalate is once more recrystallized from aoetone.
Yield: 4.7 g, m.p. 144 - 146C.

1-(2-Cyanophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-' 17.5 g (0.1 mol) of 1-(2-cyanophenoxy)~2,3-epoxy . . .
propane are dissolved in 130 ml of ethanol and af-ter the addition of 16.6 g ~0.2 mol) of 2-amino-2-methylbut-3-yne - 24 _ ~;

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

~ 7 the mixture is refluxed for 2 hours. The solvent is distilled off~ the remaining residue acidified with HCl and shaken. After filtering off the insoluble particles with suction, the filtrate is made alkaline with NaOH, the precipitating base is dissolved in chloroform and the organic phase, after separation, dri~d over Na2SO4. After filtration the chloroform is distilled off and the residue ~ecrystallized from ethyl acetate on the addition of petroleum ether. The base is dissolved in acetonitrile and acidified with alcoholic HCl. The hydrochloride crystallizes out in the form of colourless crystals.
Yield: 13.9 g (uniform substance, in the thin-layer chromatogram). M.p. 169 - 171C.

~e~ :'' 1-(2-Cyanophenoxy)~3~ ethynylcyclohexylamino)-2-propanol.
HCl (accordin~ to ~rocess a) 9 g (0.05 mol) o l-ethynylcyclohexylamine~are dissolved -together with 8.7 g (0.05 mol) o 1-(2-cyano-phenoxy) 293-epoxypropane in 100 ml of ethanol and refluxed for 2 hours. After distilling off the solvent, the residue is dissolved in ethyl acetate and shaken with dilute HCl. The aqueous phase is made alkaline with , . ' , , . .. ~

~ 7 ~

NaOH, and the precipitated base extracted with ethyl acetate. The organic phase is washed, dried over MgSO4, filtered and the solvent is distilled off. The remaining residue is recrystallized from ethyl acetate in the presence of ligroine. The colourless crystalline base is dissolved in alcohol, alcoholic HCl is added and the hydrochloride is crys-talliæed out by adding ether dropwise to the mixture.
After separation, the salt is once more recrystallized from ethanol in the presence of ether.
Yield: 6.4 ga m.p. 176 - 177C.
~ The following compounds of formula I are produced according to process (a), e.g. by reacting the corre~pondingly substituted l-phenoxy 2,3-epoxypropane according -to formula II with the corresponding amine according to formula III in ethanol.

, ..
The reactions are effected in a similar manner to that set out in Examples 1 to 5.

; "' , ~ - .

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

~27~L7 m.p, of HCl-R1 R2 R3 R4 R5 salt(unless stated) 2-0-CH2-CH=CH2 H H C2H5 C2H5 112-113 2-CH2~CH=CH2 H H C2H5 C2~5 128-129 2,3-CH=CH-CH=CH- H CH3 CH3 159-161 2-0-C~2-CH=CH2 H H CH3 CH3 100-103 ::
3-GH3 H H -(CH2)5- 159-160 -: 2-cH2-cH=cH2 H H -(CH2)5- 120-122 2-Br H H CH3 CH3 138-139 ~ .

4-CN H H CH3 CH3 194-196 4-CH20H H H ~H3 CH3 108-110 (Base) : 4-COOCH3 H H CH3 CH3 127-129 3,4-(CH2)3- H CH3 CH3 139-140 .. . .
4-tert.C4Hg H H CH3 CH3 146-147 2-isoC3H7 H H CH3 CH3 157-158 2~C-CH H H CH3 CH3 165 167 4-NH-C0-NHCH3 H H CH3 CH3 (Base) ~ ~ ;

. .

. .: . : ;, ~ 7~'7 R R R R R m.p. of HCl 1 2 3 4 5 salt ~nless otherwise _ stated ) 4 NH-CO N(C2H5)2 H H CH3 CH3 125-127 4-NH-CO-NHiC3H7 2-CN H CH3 CH3 127-130 ~:~

4-CH~-CO-NH2 H H GH3 CH3 107-110 3-(C2H5)2N- H H CH3 CH3 134-137 -(dihydro- `-:
chloride) 4-NH-COCH3 H H CH3 CH3 137-1)38 ! 3 3 (Oxalate) :~

2-Cl 4~Cl H CH3 CH3 170-171 :- ~
3-Cl H H CH3 CH3 142-144 - : --2-CN 4-Cl H CH3 CH3 176-177 - 28 - .

~Z73L~

m.p. of HCl-Rl R2 R3 R~ R5 salt (unless otherwise stated~

3-Br 4-NH2 5~Br CH3 CH3 183-185~
(Dihydro-chloride) 2-C--C CH3 H H CH3 ~H3 164-166 3,4-0-(CH2)-0- H CH3 CH3 175-1760 4 CO C H H H CH3 C~13 149-151 4-OH H H CH3 CH3 136-137.5 2-Cl H H CH3 CH3 150 151 ~ ' ~ .. .
1-(2-Allyloxyphenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-2.4 g (0.025 mol) of tetrahydropyran are slowly added dropwise at 20 to 25C to 6.42 g (0,025 mol) of 1-(2~allyloxyphenoxy)-3-bromo-2-propanol and a catalytic quantity of p-toluenesulfonic acid~ The mixture is then -heated for 30 minutes to 40C, dissolved in 40 ml of benz-ene ., , ~
and 5 g (0.06 mol) of 2-amino-2-methylbut-3-yne are added thereto. The mixture is refluzed for 2 hours, then the solvent is distilled off and the residue is heated for 15 .

~ 7~ ~

minutes, with dilute hydrochloric acid 5 to 80C. After cooling the mixture is extracted with ether and the aqueous phase made alkaline with NaOH. The precipitating basic portions are taken up in ether, the organic phase dried with MgS04 and after filtering the ether is distilled off.
The residue is dissolved in a little ethanol, ethereal HCl is added and the crys~alline hydrochloride is recrystallized twice.
M.p. 99 - 102Co ~ '. .~ .
: ~.
1-(4-Nitrophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-propanol.
HCl (accordin to rocess c) 2.7 g (approximately 0.008 mol) of 1-(4-nitrophenoxy) -3-(N-acetyl-2-amino-2~methylbut--3~ynyl)-2-propanol are refluxed in 25 ml of ethanol with 1 g of KOH for 2 hours.
After distilling off the solvent, a viscous residue remains, which is treated with dllute HCl. Afker shaking with ~ -chlorofonm, the aqueous phase is made alkalîne with NaOH
and the precipitating amine is taken up in chloroform.
After drying over NaS04, the solvent is distilled off and the residue recrystallized, with the addition of petroleum ether, from ethyl ace-~ate.
Yield: 1.5 g, m.p. 125 - 127C (base). Mixed melting point with substance obtained according to process (a~:
126 - 127C.
Example 8 1-(2-Cyanophenoxy~-3~(2-amino-2-methylbut-3-yne)-2-propanol.

~ ", ~
2.84 g (0.01 mol) of 3-(2-methylbutyne-3-yl-2)-5-(2-cyanophenoxymethyl) oxazolidine-2-one are refluxed in 20 ml of ethanol~ following the addition of 3 g of KOH in 6 ml of ~ater, for 3 hours. After distilling off the solvent 9 the residue is treated with water and extracted with chloro~orm. The chloroform solution is then shaken with dilute HCl and the separated aqueous phase is made -alkaline with NaOH. The precipitating base is taken up in : ~
chloroforma the organlc phase washed with water and dried over Na2SO~ After filtration, CHC13 is distilled off and the residue recrystallized from ethyl acetate in the presence of petroleum ether.
Yield: 1.3 g, m~p. 84 ~ 86C (base). Mixed melting point with identical substance: 83 - 85C.

- 3] -:
' , ~;27~7 ~:

.
1-(4-Aminophenoxy)-3-(2-amino-2 methylbut~3-ynyl)-2-A mixture of 8.1 g of tin~ chioride in 20 ml of conccentrated HCl is heated to 60C and 2.62 g (0.01 mol) of 1-(4-nitrophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol :~
are added in portions, so that ~he temp~rature doe~ not ~.
exceed 65C. After the addit;on has been completed~ the mixture is stirred for 30 minutes and after cooling is made alkaline with NaOH. The precipitating basic portions .
are shaken with chloroform~ the chloroform solution is . -washed with water and dried over Na2SO4. After distilling .~ . ...
off the CUC13 a solid residue remains, which is recrystall-ized from ethyl acetate in the presence of petroleum !.'".,,'.. ..
ether~
Yield: 1.4 g~ mOp. 122 - 123C (base).
According to process (e) the compound 1-(4-hydroxy-phenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol was made by heating the compound 1-(4-diethylaminocarbonyloxy-phenoxy)-3-(2-amino-2~methylbut-3-ynyl)-2-propanol (m.p.
of hydrochloride: 126G) in the presence of concentrated - 32 - ..

, ', .

. ' .' .' -~;6;27~7 aqueous HCl.
M.p. of the end product (base) is 136 ~ 137.5C.

1-(2-Cyano-4-chlorophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2 propanol. HCl (according ~ rocess f) 3.87 g (0.015 mol) of 1-(2-cyanophenoxy)-3-(2 amino-2-methylbut-3-ynyl )-2-propanol are mixed with 25 ml of concentrated HCl and heated to 45Co While cooling 1.7 g (0.015 mol) of 30% H202 are added dropwise in such a way that the temperature does not rise above 65C. After the batch has been stirred for a further 30 minutes, the crystal mass is filtered off with suction and washed with water. The hydrochloride is recrystallized from ethanol.
Yield: 1.95 g. m.p. 176 - 177~G.

1-(2~Cyanophenoxy)-3-(2-amino-2-methylbut-3-ynyI)-2-propanol.

0.697 g (0.002 mol) of 1~(2-bromophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol hydrochloride are mixed with 0.376 g (0.0042 mol) of Cu(I)CN and 0.4 g of ' . :
dimethylformamide and heated for 2 hours to 190C. After cooling, the mixture is treated with water and made alkaline . . . ..... . . .............. .. ... ... .. ..
: . . . .;: , : ~ . .. .

;27~ `

with NaOH. The basic portions are taken up in CHC13 and washed with water. The chloroform is distilled off and the residue purified over a silica gel column. The pure base thus obtained is dissolved in acetonitrile and acidified with alcoholic HCl. The hydrochloride crystallizes out in colourlPss crystals.
M.p. 168 - 171C.

~ ,.
.. . ... .
1-(4-Hydroxycarbonylphenoxy)-3-(2-amino-2-methylbut-3-ynyl) _~roc_ss e)

5 g of 1-(4~ethoxycarbonylphenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol hydrochloride are refluxed in 30 ml of concentrated H~l for two hours. After cooling, the crystalline mass which is formed by hydrolysis is filtered off with suction and recrystallized twice from ethanol in the presence of ether.
Yield: 3.1 g m.p. 159 - 162C.
. ~' '.' _ 34 - ~

~iiZ7 ~L~

1-(3,5-Dibromo-4-aminophenoxy)-3-(2-amino-2-methylbut-3-4.96 g (0.02 mol) of 1-(4-aminophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol are added to a mixture of 30 ml of HBr (65%) and 10 ml of water and heated to 45C.
While stirring and cooling 4.54 g (0.04 mol) of H202 30%
are added dropwise thereto, in such a way that the temperature does not rise above 65C. After the mixture has been maintained at approximately 65C for a further 30 minutes the crystalline substance is filtered off wîth suction after cooling and is recrystallized from ethanol in the presence of ether. The ~ydrochloride is then dissolved in water, NaOH is added, the base extracted with CHC13 and after evaporation of the solvent, recrystallized from ethyl acetate in the presence of petroleum ether.
The chromatographically pure base is dissolved in ethanol, alcoholic HCl is added and the di-hydrochloride is then -~
recrystallized on the addition of ether.
Yield: 3.8 g, m.p. l83 - 185C.

~i27~

A. Tablets 1-(2-cyanophenoxy)-3-(2-amino-2-methyl-but-3-ynyl)-2-propanol. HCl 40.0 mg corn starch 164.0 mg sec. calcium phosphate 240.0 mg magnesium stearate 1 0 mg 445.0 mg Production.
The individual components are well mixed and the mixture is granulated in the usual way. The granulate is pressed into tablets each weighing 445 mg and each containing 40 mg of active ingredient.
Instead of the active ingredient mentioned in this example~ 1-(2-cyanophenoxy)-3-(1-ethynyl-cyclohexyl- ; -amino)-2-propanol. HCl and 1-(2-cyano-4-chlorophenoxy~
-3-(2~amino-2-methylbut-3-ynyl)-2-propanol may be used in the same quantity.
B. One capsulecontains 1-(2-ethynylphenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol. HCl 25.0 mg corn starch 175.0 mg 200.0 mg ,, ..

Production:
.
The active ingredien~ and the corn starch are mixed well and 200 mg portions of the mixture are filled into gelatin capsules of suitable size. Each capsule contains 25 mg of the active ingredient.
o 1 ~ "

The solution contains the following ingredients:

1-(2-cyanQ-5-methylphenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol. HCl 2.5 parts sodium salt of EDTA (ethylenediamine-tetra acetic acid) 0.2 parts distilled water ad lO0.0 parts Production:

The active ingredient ancl E~TA-salt are d;ssolved in sufficient water and then macle up to the desired volume with more water. The solution is filtered-free of suspénded particles and filled into ampoules under aseptic conditions. Finally, the ampoules are steriliæed and sealed. Each ampoule contains 25 mg of active ingred- ~ -ient. ~ -Instead of the active ingredient mentionPd in Example 1 1 (2-hydroxymethylphenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol. HCl or 1-(2-allylphenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol. HCl may be -~

~ ~Z 7 ~ 7 used in the same quantity.
D. Coated Tablets with Sustained Release ~, .
Core:

~ (2-cyanophenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol. HCl 25.0 g carboxymethyl cellulose (CMC) 295.0 g stearic acid20O0 g cellulose acetate phthalate (CAP) 40.0 g 3~0.0 g Production:
~_ , The active ingredient, CMC and stearic acid are mixed well and the mixture is gr~mulated in the usual way, using a solution of the CAP in 200 ml of a mixture of ethanol/ethyl acetate. The granulate is then pressed into 380 mg-cores~ and coated in the conventional way with a sugary 5% solution of polyvinylpyrrolidone in water.
Each coated tablet contains 25 mg of active ingredient O

- 3~ -- .

.

,, , , ,, ~, , .

27~L7 E. Tablets 1-a-naphthoxy-3-(3-amino-3-ethyl-pent-4-ynyl)-2-propanol. HCl 35.0 g 2,6 bis-(diethanolamino)-4~8-dipiperidino-pyrimido-[5,4-d~-pyrimidine 75.0 g lactose 164.0 g corn starch 194~0 g colloidal silicic acid 14.0 g polyvinylpyrrolidone 6,0 g magnesium stearate 2.0 g soluble starch 10.0 g 500.0 g Instead of the ~-adrenolytically active substances ~ ;
mentioned in this Example 1-(2-allyloxyphenoxy) 3-(2-amino-2-methylbut-3-ynyl)-2-propanol. HCl and 1-(2-propargyloxyphenoxy)-3-(2 amino-2-methylbut-3-ynyl-2-propanol. HCl may also be used in the same quantity. -.
Production: - ~
The active ingredlent together with the lactose, -corn starch, collodial sillcic acid and polyvinylpyrrolidone is granulated after thorough mixing in the usual way) using an aqueous solution of the soluble starch. The granulate is m;xed with the magnesium stearate and pressed into 1000 tablets each weighing 500 mg and each containing 35 mg of the first and 75 mg of the second active ingredient.
_ 39 ;
,"~

27~L7 r bO o~ 3 F~: h ~ O
~ I~ U~ ~ , . ~' ~) O O ~ ~ l td l 'O ~ Lr~ C~ 0~ t~l ~1 ' ' E~-~ ' ~ ~ . ~ .. _____ _ ~00 .~
E-i a,) .,1 ~ ~ H 1--1 H
t~ ~o I; ,J-) 1~ 1~ ~ ~1 , : ' O ~ > ~C
~1 Q, ~ rl ~C ~ p<~ . ..
O O O 1~ C`J ~
O .
~1 ~ ~
~d ' .~:' _ _ .. ______ _ . _ .. .~ ._. ~.
. .
I O l ~_ I ~ ~ ~ ~ ~
~? ~ ~ ~ ~ ~? ~ x L) ~1 G ~ ~ a~ O ~ O ,,~ ~ E~
O ~ .5~ ~I ~
P~ I ~ ~ I _~ p~ I f O O
O O C~ 1 ~ O ~1 r~ 1 ~1 ~ ~1 4~ ~ o ~ 1 ~ ~ o ~1 ~ 1 L~ ~ ~ ~ 0 ,~ ~ ~ 0~
~ C~ C~ C~ ~
E~i ~ ~ ) o ~ ~ ~ ~ o ~ ~ ~ o o ~ __ ~ , ~ 3 h .-1 1 3 ~

~q~627~7 The determination of the isoproterenol anatagonistic activity is effected using guinea pigs and comparing the results obtained with the standard substance DCI
(3,4-dichloroisoproterenol). The activity of the S standard substance is equivalent to 1 sedation unit.
The method is described in French Patent 8162M.
The toxicity of the test compounds is determined by subcutaneous administration of a 1-2% solution of the test compound to white mice. (Period of observation = 2 weeks). The evaluation of the results is carried out according to J. T. Litchfield jun. and F. Wilcoxon 1949 J. Pharmacol. Exptl. Therap. 96/S 99-113.
.....
' ~ , '' ~ , ' ~ .

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

Claims (52)

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

1. A process for the preparation of compounds of the general formula I

I

wherein R1 represents a hydrogen or halogen atom, a nitro group, an alkyl group with 1 to 5 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a lower alkoxyalkyl group or a group of the formula:
-(CH2)x-CN, -(CH2)x-NH2 or -(CH2)x-OH, (in which x is zero or an integer from 1 to 3), the group -COOH or -COOR6, (in which R6 represents an alkyl group with 1 to 4 carbon atoms), an al-kenyloxy or alkynyloxy group with 3 to 6 carbon atoms, lower alkanoyl, alkanoyloxy or alkanoylamino, phenacetyl substituted in the phenyl moiety by at least one halo, alkyl, nitro, cyano or carboxyl group, benzoyl sub-stituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a cycloalkyl group with 3 to 7 carbon atoms, the group:
-Q-CO-NHR7R8, (in which Q represents a single bond, an oxygen atom, a NH-, CH2- or CH2-NH group and R7 and R8, which may be the same or different, each re-presents a hydrogen atom or a lower alkyl group) or phenyl or phenoxy substituted by at least one halogen atom, alkyl, alkoxy, nitro, cyano or carboxyl group;
R2 represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 4 carbon atoms, lower alkanoyl or alkenyl group with 2 to 4 carbon atoms, or a cyano, amino or nitro group; or R1 and R2 together represent a 3,4-methylenedioxy group;

R3 represents a hydrogen or halogen atom, or an alkyl or alkoxy group with 1 to 4 carbon atoms; or R2 and R3, being bonded to adjacent carbon atoms in the phenyl moiety, together represent the group:--CH=CH-CH=CH- or -(CH2)n-in which n is an integer from 3 to 5);
R4 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and R5 represents an alkyl group with 1 to 3 carbon atoms; or R4 and R5 together represent the group ?CH2?p (in which p represents an integer from 4 to 6)?,and non-toxic, pharmaceutically acceptable acid addition salts, which process comprises;
a) reacting a compound of formula II

II

[wherein R1, R2, and R3 are as defined above and Z represents the group:
or -CHOH-CH2-Hal (wherein Hal represents a halogen atom)] with a compound of formula III
NH2-CR4R5-C?CH III
(wherein R4 and R5 are as defined above);
b) hydrolysing or hydrogenating a compound of formula IV

IV

(wherein R1, R2, R3, R4 and R5 are as defined above and G represents a hydrolytically or hydrogenolytically removable group);

c) reacting a compound of formula V

V.

(wherein R1, R2, R3, R4 and R5 are as defined above and Sch represents a removable protecting group) whereby a compound of formula I is obtained;
d) hydrolysing a compound of formula VI.

VI.

(wherein R1, R2, R3, R4 and R5 are as defined above and X represents the group:--CO-, -CH2-, or a -CH- lower alkyl group;
e) reacting a compound of formula VIIa VIIa (wherein R2, R3, R4 and R5 are as defined above and A represents an atom or group which may be converted into R1) to convert the compound of formula VIIa into a compound of formula I;
f) reacting a compound of formula VIIb VIIb (wherein R1, R2, R3, R4 and R5 are as defined above and B represents an atom or group which may be converted into R2) to convert the compound of formula VIIb into a compound of formula I;
g) halogenating a compound of formula VIII

(wherein R4 and R5 are as defined above and Ar represents a group of the formula or (wherein R1 is as defined above and R2 and R3 represent a halogen atom); or h) reacting a compound of formula IXa IXa (wherein R4 and R5 are as defined above and M represents the group in which R1, R2 and R3 are as defined above, but either R1 or R2 representing a cyano group and C represents an amino group or halogen atoms to convert the compound of formula IXa into a compound of formula I in which R1 or R2 represents a cyano group.

2. A process according to claim 1 for the preparation of compounds of the general formula I, wherein R1 represents a hydrogen or halogen atom, an alkyl group with 1 to 5 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a group of the formula:-, or (in which x is 0 or an integer from 1 to 3), the group -COOH or -COOR6 (in which R6 represents an alkyl group with 1 to 4 carbon atoms), an alkenyl-oxy or alkynyloxy group with 3 to 6 carbon atoms, lower alkanoyl, alkanoyl-oxy, or alkanoylamino, phenacetyl substituted in the phenyl moiety by at least one halo, alkyl, nitro, cyano or carboxyl group, benzoyl substituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a group of the formula:

(in which R7 and R8, which may be the same or different, each represents a hydrogen atom or a lower alkyl group), or a phenyl or phenoxy group substi-tuted by a halogen atom or an alkyl, nitro, cyano or carboxyl group; and R2, R3, R4 and R5 are as defined in claim 1 with the proviso that R2 may not represent an alkanoyl group with 2 to 4 carbon atoms, and non-toxic, pharmaceutically acceptable acid addition salts, which process comprises:
a) reacting a compound of formula II

in which R1, R2 and R3 are as defined above with a compound of formula III
NH2-CR4R5-C?CH

wherein R4 and R5 are as defined above;
b) hydrolysing or hydrogenating a compound of formula IV
in which R1 and R2 are as defined above and R3, R4 and R5 are as defined in claim 1;

c) reacting a compound of formula V

in which R1 and R2 are as defined above and R3, R4 and R5 are as defined in claim 1;
d) hydrolysing a compound of formula VI

in which R1 and R2 are as defined above and R3, R4 and R5 are as defined in claim 1;
e) reacting a compound of formula VIIa in which R2 is as defined above fo?form a compound of formula I;

f) reacting a compound of formula VIIb in which R1 is as defined above to form a compound of formula I;

g) halogenating a compound of formula VIII

in which R1 and R2 are as defined above; or h) reacting a compound of formula IXa to convert the compound of formula IXa into a compound of formula I wherein R1 or R2 represents a cyano group.

3. A process according to claim 1 wherein a compound of formula IV
is used in which G represents an acyl or acetal group.

4. A process according to claim 1.c wherein the reaction is effected by hydrolysis or hydrogenation.

5. A process according to claim 1.c wherein a compound of formula V is used in which Sch represents an acyl or carbobenzoxy group.

6. A process according to claim 1.d wherein the hydrolysis is effected by the use of an aqueous sodium hydroxide or potassium hydroxide solution or by the use of an alcohol/water mixture.

7. A process according to claim 1.e wherein A represents a -CONH2, -COOR6 (wherein R6 is as defined in claim 1), alkoxy, O-acyl or nitro group.

8. A process according to claim 1.f wherein a compound of formula VIIb is used in which B represents a halogen atom or a nitro or amino group or the group -CONH2 or -CH=NOH.

9. A process according to claim 1.g wherein the halogenation is effected by the use of a hydrogen halide/hydrogen peroxide mixture.

10. A process according to claim 1.g or 9 wherein the halogenation is effected at an elevated temperature.

11. A process according to claim 1.h wherein a compound of formula IXa is used in which C (in the definition of M) represents an amino group and the reaction is effected by diazotisation and subsequent boiling in the presence of a cyanide.

12. A process according to claim 11 wherein the cyanide is potassium cyanide.

13. A process according to claim 1.h wherein a compound of formula IXa is used in which C (in the definition of M) represents a halogen atom and the reaction is effected by the use of Cu(I)CN in the presence of a high boiling solvent.

14. Compounds of the general formula [wherein R1 represents a hydrogen or halogen atom, a nitro group, an alkyl group with 1 to 5 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a lower alkoxyalkyl group or a group of the formula -(CH2)x-CN, -(CH2)x-NH2 or -(CH2)x-OH, (in which x is zero or an integer from 1 to 3), the group -COOH or -COOR6, (in which R6 represents an alkyl group with 1 to 4 carbon atoms), an alkenyl-oxy or alkynyloxy group with 3 to 6 carbon atoms, lower alkanoyl, alkanoyloxy or alkanoylamino, phenacetyl substituted in the phenyl moiety by at least one halo, alkyl, nitro, cyano or carboxyl group, benzoyl substituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a cycloalkyl group with 3 to 7 carbon atoms, the group:
-Q-CO-NHR7R8, (in which Q represents a single bond, an oxygen atom, a NH-, CH2- or CH2-NH
group and R7 and R8, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, or phenyl or phenoxy substituted by at least one halogen atom, alkyl, alkoxy, nitro, cyano or carboxyl group);
R2 represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 4 carbon atoms, lower alkanoyl or alkenyl group with 2 to 4 carbon atoms, or a cyano, amino or nitro group; or R1 and R2 together represent a 3,4-methylenedioxy group;
R3 represents a hydrogen or halogen atom, or an alkyl or alkoxy group with 1 to 4 carbon atoms, or R2 and R3, being bonded to adjacent carbon atoms in the phenyl moiety, together represent the group:
-CH=CH-CH=CH- or -(CH2)n-(in which n is an integer from 3 to 5);
R4 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and R5 represents an alkyl group with 1 to 3 carbon atoms; or R4 and R5 together represent the group (in which p represents an integer from 4 to 6) and non-toxic, pharmaceutically acceptable acid addition salts thereof whenever prepared according to the process of claim 1.

15. A process according to claim 1 wherein compounds are used in which R1 represents lower alkanoyl, alkanoyloxy or alkanoylamino in which alkanoyl is an acetyl, propionyl, butyryl or isobutyryl group, or a phenacetyl group substituted on the phenyl moiety by at least one halogen atom or alkyl, nitro, cyano, or carboxyl group, or a benzoyl group substituted by at least one halogen atom or lower alkyl, nitro, cyano or carboxyl group.

16. Compounds according to Claim 14 wherein R1 represents low-er alkanoyl, alkanoyloxy or alkanoylamino in which alkanoyl is an acetyl, pro-pionyl, butyryl or isobutyryl group, ox a phenacetyl group substituted on the phenyl moiety by at least one halogen atom or alkyl, nitro, cyano or carboxyl group, or a benzoyl group substituted by at least one halogen atom or lower alkyl, nitro, cyano or carboxyl group, whenever prepared by the process of Claim 15.

17. A process according to Claim 1 wherein compounds are used in which R1 represents an alkenyl or alkynyl group with 2 to 5 carbon atoms, alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, or cyano group.

18. Compounds according to Claim 14 wherein R1 represents an alkenyl or alkynyl group with 2 to 5 carbon atoms, alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, or cyano group whenever prepared by the pro-cess of Claim 17.

19. A process according to Claim 17 wherein compounds are used in which R1 represents an alkyl group with 1 to 5 carbon atoms, ethynyl, pro-pynyl, allyloxy or propargyloxy group.

20. Compounds according to Claim 14 wherein R1 represents an alkyl group with 1 to 5 carbon atoms, ethynyl, propynyl, allyloxy or propar-gyloxy group, whenever prepared by the process of Claim 19.

21. A process according to Claim 19 wherein compounds are used in which R1 is present in the 2-position of the phenoxy group.

22. Compounds according to Claim 14 wherein R1 is present in the 2-position of the phenoxy group, whenever prepared by the process of Claim 21.

23. A process according to Claim 1 wherein compounds are used in which R2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms.

24. Compounds according to Claim 14 wherein R2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, whenever prepared by the process of Claim 23.

25. A process according to Claim 23 wherein compounds are used in which R2 represents a methyl group.

26. Compounds according to Claim 14 wherein R2 represents a methyl group whenever prepared by the process of Claim 25.

27. A process according to Claim 1 wherein compounds are used in which R2 is present in the 5-position of the phenoxy group.

28. Compounds according to Claim 14 wherein R2 is present in the 5-position of the phenoxy group, whenever prepared by the process of Claim 27.

29. A process according to Claim 1 wherein compounds are used in which R3 represents a hydrogen atom.

30. Compounds according to Claim 14 wherein R3 represents a hydrogen atom, whenever prepared by the process of Claim 29.

31. A process according to Claim 1 wherein compounds are used in which R1 represents a hydroxyalkyl group with 1 to 3 carbon atoms, and R2 and R3 both represent a hydrogen atom.

32. Compounds as claimed in Claim 14 wherein R1 represents a hydroxyalkyl group with 1 to 3 carbon atoms, and R2 and R3 both represent a hydrogen atom, whenever prepared by the process of Claim 31.

33. A process according to Claim 1 wherein compounds are used in which R1 represents a hydroxymethyl group, and R2 and R3 represent hydrogen atoms.

34. Compounds as claimed in Claim 14 wherein R1 represents a hydroxymethyl group, and R2 and R3 both represent hydrogen atoms, whenever pre-pared by the process of Claim 33.

35. A process according to Claim 1 wherein compounds are used in which R1 represents an amino or lower alkanoylamino group, and R2 and R3, which may be the same or different, each represents a hydrogen or halogen atom or an alkyl group of 1 to 4 carbon atoms.

36. Compounds as claimed in Claim 14 wherein R1 represents an amino or lower alkanoylamino group and R2 and R3, which may be the same or different, each represents a hydrogen or halogen atom or an alkyl group with 1 to 4 carbon atoms, whenever prepared by the process of Claim 35.

37. A process according to Claim 35 wherein compounds are used in which R1 represents an acetylamino group.

38. Compounds as claimed in Claim 14 wherein R1 represents an acetylamino group and R2 and R3, which may be the same or different, each re-presents a hydrogen or halogen atom or an alkyl group with 1 to 4 carbon atoms, whenever prepared by the process of Claim 37.

39. A process according to Claim 1 wherein compounds are used in which R4 and R5 both represent a methyl group.

40. Compounds as claimed in Claim 14 wherein both R4 and R5 represent a methyl group, whenever prepared by the process of Claim 39.

41. A process for preparing 1-(2-cyanophenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol according to Claim 1 which comprises using compounds in which R1 is a cyano group, R2 and R3 are hydrogen, and R4 and R5 are methyl groups.

42. A process according to Claim 1 for preparing 1-(2-cyano-phenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol and its hydrochloride which comprises reacting 1-(2-cyanophenoxy)-2,3-epoxypropane with 2-amino-2-methyl-but-3-yne, and where required converting the free base into its hydrochloride.

43. A process according to Claim 1 for preparing 1-(2-cyano-phenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol and its hydrochloride which comprises hydrolysing 3-(2-methylbut-3-yn-2-yl)-5-(2-cyanophenoxymethyl)-oxa-zolidin-2-one with aqueous alkali metal hydroxide solution, and where required converting the free base into its hydrochloride.

44. A process according to Claim 1 for preparing 1-(2-cyano-phenoxy)- 3-(2-methylbut-3-yn-2-ylamino)-2-propanol and its hydrochloride which comprises reacting 1-(2-bromophenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol with cuprous cyanide, and where required converting the free base into its hydro-chloride.

45. 1-(2-Cyanophenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol and the hydrochloride thereof, whenever prepared by the process of claim 42, 43 or 44, or by an obvious chemical equivalent thereof.

46. A process for preparing 1-(2-ethynylphenoxy)-3-(2-methylbut-3-yn-2-Ylamino)-2-propanol according to claim 1 which comprises using compounds in which R1 and R3 are hydrogen, R2 is an ethynyl group, and R4 and R5 are methyl groups.

47. A process for preparing 1-(2-allylphenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol according to claim 1 which comprises using compounds in which R1 and R3 are hydrogen, R2 is an allyl group, and R4 and R5 are methyl groups.

48. A process for preparing 1-(3,5-dibromo-4-aminophenoxy)-3-(2-methyl-but-3-yn-2-ylamino)-2-propanol according to claim 1 which comprises using compounds in which R2 and R3 are a bromine atom, R2 is an amino group, and R4 and R5 are methyl groups.

49. A process for preparing 1-(2-hydroxymethylphenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol according to claim 1 which comprises using compounds in which R1 is a hydroxymethyl group, R2 and R3 are hydrogen and R4 and R5 are methyl groups.

50. A process for preparing 1-(3-chlorophenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol according to claim 1 which comprises using compounds in which R1 is a chlorine atom, R2 and R3 are hydrogen atoms, and R4 and R5 are methyl groups.

51. A process for preparing 1-(4-acetamidophenoxy)-3-(2-methylbut-3-yn-2-ylamino)-2-propanol according to claim 1 which comprises using com-pounds in which R1 is an acetamido group, R2 and R3 are hydrogen atoms, and R4 and R5 are methyl groups.

52. Compounds of the general formula I according to claim 14, wherein R1 represents a hydrogen or halogen atom, an alkyl group with 1 to 5 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a group of the formula:- , or in which x is 0 or an integer rom 1 to 3, the group -COOH or -COOR6 in which R6 represents an alkyl group with 1 to 4 carbon atoms, an alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, lower alkanoyl, alkanoyloxy, or alkanoylamino, phenacetyl substituted in the phenyl moiety by at least one halo, alkyl, nitro, cyano or carboxyl group, benzoyl substituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a group of the formula:-(in which R7 and R8, which may be the same or different, each represents a hydrogen atom or a lower alkyl group), or a phenyl or phenoxy group substi-tuted by a halogen atom or an alkyl, nitro, cyano or carboxyl group; and R2, R3, R4 and R5 are as defined in claim 1 with the proviso that R2 may not re-present an alkanoyl group with 2 to 4 carbon atoms, and non-toxic, pharma-ceutically acceptable acid addition salts thereof, whenever prepared accord-ing to the process of claim 2.