CA1061342A

CA1061342A - Process for the preparation of phenoxypropylamine derivatives and salts thereof

Info

Publication number: CA1061342A
Application number: CA239,428A
Authority: CA
Inventors: Gerhard Zolss
Original assignee: Chemie Linz AG
Current assignee: Patheon Austria GmbH and Co KG
Priority date: 1974-11-20
Filing date: 1975-11-12
Publication date: 1979-08-28
Also published as: JPS51125248A; ATA930874A; PL96643B1; YU255975A; LU73817A1; AT335465B; JPS549195B2; RO70441A; CH615905A5; ES442813A1; SU613715A3; DD122082A1; YU39335B; CS183825B2

Abstract

ABSTRACT OF THE DISCLOSURE
This invention discloses a new and commercially useful process for the preparation of phenoxypropylamine derivatives of the general formula (I) (I) and the acid addition salts thereof wherein R is a hydrogen atom or an alkyl group and R1 is a hydrogen atom or an alkyl, cycloalkyl, aralkyl or aryl group or R and R1 together represent a divalent optionally branched hydrocarbon group, optionally substituted, R2 is a hydrogen atom or an alkyl, aralkyl or aryl group, R3 is an alkyl, hydroxyalkyl, cycloalkyl, or cyanoalkyl group and X is an oxygen atom or the group -NOR4 wherein, when X is oxygen, R2 is not hydrogen and R4 is hydrogen, a lower alkyl group or an aralkyl group. This process comprises reacting a carbonic acid or thiocarbonic acid derivative of the general formula (II) (II) in which Y is an alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, or aralkylthio group, with an amine of the general formula (III)

Description

342 ` ~: -1 This invention relates to a process for the preparation of phenoxypropylamine derivatives.
Substances with a blocking action on the ~-receptors ; -are becoming increasingly important in the therapeutic treatment ~;
of various cardiac illness whose aetiology or symptoms may be explained by an undesirably high content of endogenous -catecholamines in the circulation. In this connection a signifi- ;
cant advance has been achieved by the discovery of so~called cardioselective ~-blocking agents, these being agents which mainly act only on the ~-receptors of the heart but have little effect on ~-receptors of other organs, since by using such agents undesirable side effects, such as for example the spastic effect on the respiratory tracts, may be avoided. However, of these selective agents hitherto only one compound, namely ~ 4-acetamino-phenoxy(2'-hydroxy-3'-isopropylamino))-propane, which is described in Austrian Patent Specification No. 261r582, has been used in practise, and accordingly there is still a great need to find actually usable cardioselective ~-blocking agents. However, many ~-blocking agents have the dra~back of an -20 undesria~le cardiodepressant action which is often coupled with -the ~-blocking action.
The patent literature has also disclosed cardioselective phenoxypropylamine d~rivatives with a ureido group in the p-position relative to the propylamine side chain (DT-OS No.

2,1~0,323), which may be substituted in the nucleus by hydrocarbon groups, ether groups, halogen atoms, trifluoromethyl groups or nitrile groups and also caraioselective phenoxypropylamine derivatives with an alkanoylamide group in the _-position and acyl groups, for example the acetyl group, in the _-position relative to the propylamine side chain, see Austrian Patent-Specification ~o. 292,671.

..

`` ~.. OG,~.3~Z
1 Surprisingly, it has now been found that phenoxy-propylamine derivatives which carry a ureido grou~p in the p-position to the phenoxypropylamine chain and an acyl group, preferably a lower alkanoyl group or an oxime group in the o-position, and which have the general formula~

NH - C.O - N

~ ~ 2 (I) ~; ~
~.: . ,, OCH2 - fH - CH~ - NH - R
OH .

in which R is a hydrogen atom or an alkyl group and Rl is a .~
hydrogen atom, an alkyl, cycloalkyl, aralkyl or aryl group, or .
R and R~ together represent a divalent, optionally branched hydrocarbon group with 4 to 7 carbon atoms in the main chain, wherein one or two of these carbon atoms may be replaced by oxygen, sulphur or nitrogen, R2 is a hydrogen atom or an alkyl, .
aralkyl or aryl group, R3 is a preferably branched alkyl group, a hydroxyalkyl, cycloalkyl or cyanoalkyl group, and X is an oxygen ~`~
atom or the group -NOR4, wherein when X is oxygen R2 is not ..
hydrogen, and R4 is hydrogen, a lower alkyl group or an aralkyl group, and also the salts of these derivatives, have outstanding cardioselective, ~-blocking properties which are coupled with a ~:
very good and reliable activity when administered orally.
The activity of the derivatives of formula (I) may be ~.

determined on awake dogs by the method of Dunlop & Shanks, Brit `
J Pharmacol 32,201-18, 1968. The cardioselective action may be recognised for example by the fact that according to the method of Shanks et al, Cardiologia Suppl II, 49, 11 (1966) .
-2- :

. .. : , , .:, ' ' .: . . . .

1 carried out on narcotised dogs, the increase in pulse rate caused by isoprenaline is more strongly inhibited by prior administration of the above compounds than is the hypotensive effect of isoprenaline. This effect also may be seen in rats from a blocking effect on the increase in unesterified fatty -~
acids caused by isoprenaline (~l-effect~, whereas hardly any effect was detected on the increased lactate and glucose values caused by isoprenaline (~2-effect).
Surpri~ingly, despite their marked ~-blocking action the compounds of the formula (I) do not cause any low~ring of the pulse rate after oral administrations of the substances when testing the pulse rate on awake dogs by a method based on that of Barret and Carter, ~rit J Pharmacol ~0, 373-81 (1970), which indicates that the compounds of the formula (I) do not exhibit any undesired and in some cases dangerous cardiodepressive `
action. The toxicity of the compounds of the ~ormula (I) in mice is the same as, or even lower than, that of the commercially available ~-blocking agents.
The present invention provides a process for the preparation of a compound of the formula (I) which comprises reacting a carbonic acid or thiocarbonic acid derivative of the general formula:
NH - C - Y ,-O ' ' C - R (II) 0 CH - CH - CH2 - NH.R3 bH `
in which Y is an alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio or aralkylthio group, and R~, R3 and X are as defined above for '~ .

..
,, , , ~ , ...

~L~6~3~2 1 formula (I), with an amine of the formula:

/ ` (III) Rl in which R and Rl are as defined above, at room temperature or elevated temperature, and separating the resulting compound of ~ ~
formula (I) as the free base or a salt thereof. ~ -Preferred compounds of formula ~II) used in the above process are those in which Y is an alkoxy or alkylthio group with up to 4 car~on atoms, a phenoxy or phenylthio group, or a benzyloxy or benzylthio group.
The reaction is suitably carried out in a polar solvent.
In particular, aliphatic alcohols, such as methanol and ethanol, dimethyl formamide or acetonitrile, have proved suitable as solvents. Mixtures of these solvents with water also may be used, a mixture of an aliphatic alcohol and water being especially preferred as the reaction medium, since in many cases an increase in the rate of reaction is observed. rn many cases the amines themselves are also suitable as solvents.

When sélecting the reaction conditions, the chemical nature of the carbamic acid ester is appropriately taken into account. Compounds of the formula (II) in which the group Y
is an aromatic group are more reactive than those in which Y is an aliphatic or axaliphatic group. If for example, Y is a phenylthio group, then in most cases room temperature is sufficient for the reaction. On the other hand, with compounds of the formula (II) in which Y is an aliphatic group, in most cases it is necessary to heat the reaction mixture for several hours at a temperature of 100C in order to achieve

3~ complete conversion.

`,;

~ .

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

` 10~1342 1 In order to carry out successfully the reaction ~:
according to the invention, it is not absolutely necessary ~.
- that the compounds of the formula (II) are separated as such, . :
and it is possible simply to use the reaction mixture for the ~
preparation of a compound of the formula (II~, as obtained by ~. .
reacting an anilino derivative of the formula~

~ ~ ~2 ~Iv) ~ CH2 ~ CH - ~H - NH - R ; : ..
H
with a compound of the formula:
Cl - C - Y :
Il (V) ' ' "

wherein Y is as de~ined above ~or formula (II), followed by removal of the solvent, for the further reaction. The solvent is suitably removed by distillation in vacuo. Solvents which .. ~
may be usea are for example organic bases, such as pyridine. ~.
The compound of formula (~I) may be obtained in a pure, ~.:
crystallised form by dissolving the crude reaction mixture in a suitable solvent, for example acetone, and then crystallising and separating the compound of the formula (II). . .
The compound of formula (I) may be isolated in a .
~, .
conventional manner from the reaction mixture, either as the ` ::
free bases or as a salt thereof. The compound of formula (I) .
is very conveniently isolated as a salt with a dicarboxylic acid, ~:
for example,as the fumarate, oxalate or succinate, on account of .
the good crystallisability of these salts. All normal, pharmaceutically-acceptable salts, or example the hydrohalides, such as hydrochlorides and hydrobromides, ~ulphates, phosphates, ''.

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

39~2 1 acetates, cyclohexylsulphamates, tartrates and citrates may be prepared.
The compounds of formula tI) have an asymmetric carbon atom. They therefore exist as the racemate and as optically active forms. The racemate may be separated into the optically active forms in a conventional manner, for example by forming the diastereomeric salts with optically active acids, for example tartaric acid, or camphorsulphonic acid.
A compound of formula (II) in which X is NOR~ may be obtained from a corresponding compound in which X is oxygen by reaction with a hydroxylamine salt.
An anilino compound of formula (IV) may be obtained in a conventional manner by reacting the corresponding phenol in which the anilino group is protected, for e~ample, by acylation, with an epihalohydrin and then with an appropriate amine, followed by splitting off the protective acyl group.
Compounds of formula (I) which are particularly suitable are those in which R is a hydrogen atom or a straight or branched chain alkyl group with up to 10, advantageously up to 6 and preferably up to 4 carbon atoms.
Rl is most suitably a hydrogen atom, an optionally branched chain alkyl group with up to 10, advantageously up to 6 and preferably up to ~ carbon a~ms,or a benzyl or phenyl group. ~o suitable are compounds in which R and Rl togethex with the terminal N-atom of the ureido group represent a pyrrolidino, diazolidino, e.g. imidazolidino, thiazolidino, oxazolidino, piperidino, morpholino, tetrahydrodiazino, e.g. tetrahydro-pyrimidino, tetrahydrothiazino or homopiperazino group. The pyrrolidino, piperidino and morpholino groups are pre~erred.

R2 is preferably an alkyl group with up to 6 carbon atoms or a 342 ~.
',''~ ,. :. ' 1 phenyl group and, when X is the =NOR4 group, is also a hydrogen atom. R3 is preferably a branched chain alkyl group with 3 to 6 carbon atoms or a cyclopropyl, cyclobutyl, cyclopentyl or cyclo-hexyl group, and R4 is hydrogen, an alkyl group with up to 6 carbon atoms, or a benzyl group.
Particularly favourable properties are exhibited, as a rule, by compounds on which each of R and Rl, which may be the same or different, is a hydrogen atom or an alkyl group with 1 to 6, preferably 1 to 4, carbon atoms, or both together ~rom a tetramethylene, pentamethylene or 3-oxapentamethylene group, R2 is a lower alkyl group with 1 to 5 carbon atoms, and when X is ~-=NO4 may also be a hydrogen atom, R3 is a tertiary butyl group or isopropyl group, and R4 is hydrogen, an alkyl group with 1 to

4 carbon atoms or a benzyl group.
The compounds of formula (I) may be present as active ingredients in pharmaceutical compositions which may be adminis-tered orally, rectally or parenterally. For this purpose they . .
may be mixed with conventional pharmaceutically-acceptable carriers, the nature of the carrier being determined by the method of application. They may be converted into tablets or dragees in the usual way, and the active compounds themselves, optionally together with a pharmaceutically-acceptable solvent, may be made up into capsules.
Pharmaceutically-acceptable soluble salts which are ..
capable of forming stable solutions may be used in the form of injectable solutions. The salts for this purpose may be obtained simply from the corresponding bases of formula (I) by reaction with the equivalent amount of acid. Both bases and salts may be converted in the usual way into suppositories.
The individual dose for humans is 100 mg in the case of .. . . : ~ : -1 oral administration, and correspondingly lower in the case of intravenous administration.
~ he following Examples illustrate the inven-tion.
Example 1:
l.o g of N-(3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy)-phenyl-carbamic acid phenyl ester hydrochloride is dissolved in 25 ml of a 1:1 (vol) ethanol~water mixture, 0.37 g of diethylamine is added, and the reaction mixture is left to stand for 21 hours at room temperature. After the reaction is complete the alcohol is distilled off in vacuo, the aqueous residue is extracted several times with chloroform, the organic phase is dried with sodium sulphate and evaporated in vacuo. The oily residue is digested with ether, and the crystalline product formed is filtered off, washed with ether and dried.
Yield of N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea: 0.7 g = 80.7~ of theory. Melting point of the base; 110 to 112C.
The N-13-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy~-phenylcarbamic acid phenyl ester hydrochloride required as starting product may be obtained as follows: 10.0 g of 3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxyaniline is dissolved in 100 ml of pyridine, 7 g of carbamic acid phenyl ~-ester is added, and the reaction mixture is left to stand for 3 days at room temperature. The clear solution is then concen-trated in vacuo, the oily residue is taken up in 20 ml of acetone, seeded, 200 ml of water are slowly added, and the crystalline product which separates out is filtered off, washed with acetone/
water, and dried over phosphorus pentoxide. After recrystalli-sation from acetonitrile the hydrochloride melts at 176 to 180C.

1~13~2 `
~ ..
1 Example 2:
0.20 g of N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)~propoxy~-phenylcarbamic acid phenyl ester hydrocnloride is dissolved in 4 ml of a 1:1 (parts by volume) ethanol/water mixture, 0.1 g of piperidine is added, and the reaction mixture is left to stand for lg hours at room temperature. The alcohol is then distilled off in vacuo, the aqueous solution is seeded, ether is added, and crystalline product formed is filtered off :`, ~ ., and dried. Yield of N-13-acetyl-4-~3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-Nl-pentamethylene(l~5)-urea: 0.15 g =
83.6% of theory. Melting point: 132 to 135C. ~
Example 3: - ;
0.4 g of N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenylcarbamic acid phenyl ester hydrochloride is ;~
dissolved in 8 ml of a 1:1 (parts by volume) ethanol/water mixture, 0.18 g of aniline is added, and the mixture is heated for 60 minutes at boiling point while stirring. The alcohol is ~
then distilled off in vacuo, the aqueous solution is made alkaline ~ -;- .
with lN sodium hydroxide solution and is seeded, and the crystalline produck which separates out is filtered off and washed with water and ether.
~ ield o~ N-[3-acetyl-4-t3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-phenylurea: 0.35 g = 95.6~ of theory. Melting point: 159 to 164C.
Example 4~
0.5 g of N-(3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy)-phenylcarbamic acid ethyl ester is heated in 20 ml of piperidine for 24 hours at boiling point. The excess piperidine is then distilled off in vacuo, the residue is triturated with ether to which a small amount of acetone is added, ' _g_ .. ... .. ; , . . , ,: .

~i13~2 `
~ ' 1 and the crystalline product formed is ~iltered off and washed with ether/acetone.
Yield o~ N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene~1,5) urea: 0.3 g = 54.1~
of theory. After recrystallisation from acetone/ether the product has a melting point of 132 to 135C.
The N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydxoxy) propoxy]-phenylcarbamic acid ethyl ester required as startin~
compound may be obtained as follows, in an analogous way to the 10 corresponding phenyl ester: ;

5.0 g of 3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxyaniline in 50 ml of pyridine is mixed with 2.4 g o ethyl chloroformate and stirred for 1 hour at 80C. The pyridine is then distilled off in vacuo, the crystalline residue is dissolved in 30 ml of water, made alkaline with sodium hydroxide, and the crystalline product which separates out is filtered off, washed with w~ter, and dried over phosphorus pentoxide. ~ield: 6.2 g =
98.8% of theory. After recrystallisation from ethanol, the compound hasa melting point of 148 to 152C.
Example 5:
A mixture of 2.0 g of N-[3-acetyl-~-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenylcarbamic acid benzyl ester (prepared from the corresponding anilino compound with benzyl chloroformate;
melting point of the hydrochloricle; 172 to 175C) and 20 ml of piperidine is heated for 9.5 hours at boiling point while stirring.
The excess piperidine is then distilled off in vacuo, the oily residue is taken up in ether, seeded and allowed to stand at room temperature to complete the crystallisation. The N-~3-acetyl-4-t3'-tert.-butylamino-2'-hydroxy)-propoxy)-phenyl-N'-pentamethylene(l,5)-urea which separates out is filtered off, washed with ether and dried.

-10- '`' ,, :
,': .

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

1 Yield: 0.85 g = 44.9~ of theory. Melting point of the base: 132 to 135C.
Example 6:
3.0 g of 3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy~-propoxyaniline is dissolved in 15 ml of pyricline, 2.~ g of monothiocarbonic acid-s-phenyl ester chloride is added, and the ;
mixture is stirred for 1 hour at 90C. The solvent is then distilled off in vacuo. The crude N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenylcarbamic acid thiophenyl 1~ ester obtained is dissolved in 30 ml of ethanol and 15 ml of -water, 7.8 g of diethylamine is added, and the mixture is allowed l;~
to react for 23 hours at room temperature. The àlcohol is then distilleA off in vacuo, the aqueous solution is made a:Lkaline with sodium hydroxide, extracted several times with methylene chloride, and the organic phase is dried with anhydrous sOdium sulphate and evaporated ln vacuo. The residue crys-tallisss when triturated with acetone/ether. The N-(3-acetyl-4-(3'-tert~-butylamino-2'-hydroxy)-propoxy)-phenyl-N'-diethylurea thus obtained is filtered off and washed with acetone/ether.

Yield: 2.15 g = 52.9% of theory. Melting point: 110 to 112C.
Example 7:
0.76 of piperidine and 4 ml of water are added to 1.03 g of N-[3-(1'-hydroxyimino)-ethyl-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenylcarbamic acid phenyl ester, preparea by reacting N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy) propoxy]-phenylcarbamic acid phenyl ester with hydroxylamine hydro-chloride in methanol/water, and the mixture is reacted for 17 hours at room temperature. The solvent is then distilled o~f in vacuo, water is added to the residue, the oily product which ;~, .
.

. : ,, ' . ' ~

6~34;~

1 separates out is seeded, and the crystalline product formed is filtered o~f, washed with water and dried over phosphorus pentoxide.
Yield of N-[3~ hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N~-pentamethylene(1~5)-urea: 0.8 g = 86.0~ of theory. Melting point of khe fumarate:
170 to 173C.
Example 8:

.
0.81 g of diethylamine is added to 1.03 g of N-~3-tl'-10 hydroxyimino)-ethyl-(3'-tert.-butylamino-2'-hydroxy)-propoxy]- `
phenylcarbamic acid phenyl ester (prepared by reacting N-[3-acetyl-4-(3'-tert.-butylamino-2~-hydroxy)-propoxy]-phenylcarbamic acid phenyl ester with hydroxylamine hydrochloride in methanolic solution) in 10 ml o ethanol and 5 ml of water, and the mixture is allowed to react ~or 20 hours at room temperature. The solvent is distilled off in vacuo, the residue is made alkaline with lN sodium hydroxide solution, the precipitated base is extracted with ethyl acetate, and the organic phase is worked up as usual.

Yield of N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy)-phenyl-N'-diethylurea: 0.85 g =
94.15~ of theory.
The fumarate in crystallised form is obtained by dis-solving the above product in acetone and adding a solution `
of fumaric acid in acetone. Melting point 209 to 212C. -... .
The following compounds are obtained in an analogous ` -manner to Examples 1 to 6: ~

N-~3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]- ~ ~-phenylurea. Melting point of the hydrochloride: 195 to 197C.

N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxyl-propoxy~-.
phenyl-N'-dimethylurea. Melting point: 121 to 122C. ~ ~
.; :, : :

IL34;~ - ~

I N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methylurea. Melting point: 132 to 134C. ;~
N-[3-acetyl-~-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-ethylurea. Melting point of the fumarate: 196 to 198C.
N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-isopropylurea. Melting point: 87 to 90C.
N- E 3-acetyl-4-~3'-tert.-butylamino-2'-hydroxy)-propoxy]- ' phenyl-N'-butylurea. Melting point: 126 to 129C.

N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy~
phenyl-N'-sec.-butylurea. Melting point: 80 to 82C.
N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-tert.-butylurea. Melting point: 123 to 125C.
N-E3-acetyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point: 103 to 107C.
N-[3-acetyl-4-~3'-cyclopropylamino-2'-hydroxy)-propoxy]-N'-dLmethylueea. Melt1ng point. 80 to 83C.
N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]~
phenyl-N'-methyl-N'-ethylurea. Melting point: 90 to 93C.

N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-butylurea. Melting point: 84 to 86C.
N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-prapoxy]-phenyl-N'-di-n-butylurea. The base crystallises in two modi~i-cations: Melting point: (from ether: 81 to 83C) Melting point: (from methanol/water) 113 to 115C.
N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propo~y]-phenyl-N'-di-n-propylurea. Melting point 83 to 86C.
N-~3-acetyl-4-~3'-(2"-cyanopropyl(2"J-amino)-2'-hydroxy]-propoxy}-phenyl-N'-diethylurea. Melting point: 89 to .. . ................................................. . :
: ~,. . - .. . , : ::

.

1 N-[3-acetyl-4-t3'-tert.-butylamino-2'-hydroxy)-propoxyJ-phenyl-N'-tetramethylene(1,4)-urea. Melting point of the fumarate: 218 to 220C.
N-~3-propionyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenylurea. Melting point of the fumarate: 204 to 207C.
N-[3-propionyl-4-(3'-tert.-butylamino-2'-hydroxy)- - i propoxy]-phenyl-N'-methylurea. Melting point of the fumarate:
134 to 136C.
- N-~3-propionyl-4-(3'-tert.-butylamino-2l-hydroxy~-propoxyl-phenyl-N'-diethylurea. Melting point: 107 to 109C.
N-~3-propionyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point of the fumarate:
199 to 202C.
N-[3-propionyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-NI-tetramethylene(1,4)-urea. Melting point of the fumarate: 208 to 211C.
N-[3-propionyl-4-(3'-tert.-butylamino-2l-hydroxy)- ~ ~
propoxy]-phenyl-N'-3-oxa-pentamethylene(1,5)-urea. Melting point r'. ., , ,"
20 of the fumarate: 193 to 195C.
N-[3-butyryl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene(1,5)-urea. Melting point of the fumarate: 167~ to 170C.
N-[3-phenylacetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene(1,5)-urea. Melting point: 117 Q
to 118C. --.
N-[3-benzoyl-4-(3'-tert.-butylamino-2'-hydroxy)- `
propoxy]-phenyl-N'-pentamethylene(1,5)-urea. Melting point:
120 to l23C.
N-~3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-isopropylurea. Melting point: 105 to 107C.

.:

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

3 ~ ~:
N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-ethyl-N'-n-propylurea. Melting point of the fumarate:
175 to 178C.
N-[3-butyryl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point: 56 to 58C.
N-~3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-benzylurea. Melting point: 121 to 123C.
The following compounds may be obtained in an analogous manner to Examples 7 and 8.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point:
183 to 187C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-bu~ylamino-2'-hydroxy)-propoxy]-phenyl-N'-tetramethylene(1,4)-urea. Melting poink: 185 to 188C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point of the fumarate: 175 to 178C. `

N-13-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenylurea. Melting point of the fumarate:
217 to 220C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy~-propoxy]-phenyl-N'-methylurea. Melting point: 104 to 106C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-ethylurea. Melting point: 108 to 110C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-sec.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point of the fumarate: 192Q to 195C ~with decomposition).

:.

1 N-{3-ll'-hydroxyimino-ethyl-4-(3'-(2"-hydroxymethyl-propyl-(2")-amino)-2'-hydroxy~-propoxy~-phenyl-N'-dimethylurea.
Melting point: 174 to 176C.
N-[3-(1'-butoximino)-ethyl-4-~3'-te~t.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Meltiny point of the -fumarate: 163 to 166C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy~-propoxy~-phenyl-N'-dipropylurea. Melting point o the fumarate: 163 to 166C. ;;

N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy~-phenyl-N'-sec.-butylurea. Melting point of ~;
the fumarate: 225 to 228C.
N-13-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-butylurea. Melting point: 93 to 95C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino~
2'-hydroxy)-propoxy~-phenyl-N'-tert.-butylurea. Melting point of the fumarate: 222 to 225C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dibutylurea. Melting point o the fumarate: 171 to 174C. ;~
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-isopxopylurea. Melting point:
189 to 191C. ~ ;
N-[3-(1'-methoximino)-ekhyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy~-phenyl-N'-dimethylurea. Melting point of the fumarate: 163 to 167C.
N-l3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxyl-phenyl-N'-methyl-N'-isopropylurea. Melting 3~ point: 145 to 148C.
~, 6~342 1 N ~3-(1'-hydroxyimino)-ethyl-~-(3'-tert.-butylamino-2'-hydroxy)-propoxy}-phenyl-N'-methyl-N'-butylurea. Melting point of the fumarate: 137 to 13~C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-21-hydroxy)-propoxy]-phenyl-N'-methyl-N'-ethylurea. Melting point of the fumarate: 212 to 216C.
N-13-(1'-hydroxyimino)-ethyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point: 127 to 128C.

-10 N-E3-(1'-benzyloximino)-ethyl-4-(3'-tert.-butylamino- `~
2'-hydroxy)-propoxy~-phenyl-N'-dimethylurea. Melting point of `
the fumarate: 164 to 167C.
N-13-(1'-hydroxyimino)-methyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point: 169 to 172C. ;
N-E3-(1'-hydroxyimino)-methyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point:
158 to 161C.
N-[3-(1'-hydroxyimino)-propyl-4-(3'-tert.-butylamino-20 2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point o~ i the fumarate: 210 to 212C.
N-E3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dipropylurea. Melting poi~t of the fumarate: 205 to 206C.
N-E3-(1'-hydroxyimino)-butyl-4-~3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point of the fumarate: 178 to 180C.
N-[3-~1'-hydroxyimino)-propyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene-(1,5)-urea. Melting point of the fumarate: 156 to 158C.
,~ .

. .

:

.:
... ~ .. . .

L34~
1 N-[3-(1'-hydroxyimino)-propyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point:
86~ to 88C.
N-[3-(1'-hydroxyimino)-butyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene-(1,5)-urea.
Melting point of the fumarate: 148 to 150C. ~ -N-~3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-phenylurea. Melting point: 105 to 108C. ~-N-l3-(1'-hydroxyimino)-ethyl-4~(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-cyclohexylurea. Melting `
point of the fumarate: 166 to 168C.
' ""'.

','~ .

'"'~ .

,' . .

., :
.; . . .
3~

'~', ' ' '.

Claims

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 a phenoxypropylamine derivative of the general formula:

(I) in which R is a hydrogen atom or a straight-chain or branched lower alkyl group containing less than 5 carbon atoms, R1 is a hydrogen atom, a straight-chain or branched lower alkyl group containing less than 5 carbon atoms or a cyclopentyl, cyclohexyl, benzyl or phenyl group or R and R1 taken together form a divalent, straight-chain or branched hydrocarbon radical selected from the group consisting of tetra-, penta-, and oxapentamethylene, R2 is an alkyl group containing up to 6 carbon atoms or a benzyl or phenyl group and R3 is a branched alkyl group containing 3 to 6 carbon atoms, a cyanoalkyl group containing up to 6 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms, and X is an oxygen atom or the group =NOR4, and R4 is hydrogen, an alkyl group containing up to 6 carbon atoms or a benzyl group, and the pharmaceutically-acceptable salts thereof, which comprises reacting a carbonic acid or thiocarbonic acid derivative or the general formula:

(II)

Claim 1 continued ........

in which Y is an alkoxy, aryloxy, aralkyloxy,alkylthio, arylthio or aralkylthio group, and R2, R3 and X are as defined above, with an amine of the general formula:

(III) in which R and R1 are as defined above, at room temperature or elevated temperature, and separating the resulting compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1, in which, in the compound of formula (II), Y is an alkoxy or alkylthio group with up to 4 carbon atoms, a phenyloxy or phenylthio group, or a benzyloxy or benzylthio group.
3. A process as claimed in claim 1, in which the reaction is carried out in a mixture of an aliphatic alcohol and water as a reaction medium.
4. A process as claimed in claim 1 in which in the compound of formula (II), Y is a phenyloxy or phenylthio group and the reaction is carried out at room temperature.

5. A process as claimed in claim 1, in which the starting compound of formula (II) is prepared by reacting an anilino derivative of the formula:

(IV)
Claim 5 continued .......

in which X, R2 and R3 are as defined in claim 1, with a compound of the formula:

(V) in which Y is defined as in claim 1, in a solvent, and subsequently removing the solvent.