CA1060450A

CA1060450A - Process for the preparation of phenoxypropylamine derivatives and salts thereof

Info

Publication number: CA1060450A
Application number: CA239,424A
Authority: CA
Inventors: Gerhard Zolss
Original assignee: Chemie Linz AG
Current assignee: Patheon Austria GmbH and Co KG
Priority date: 1974-11-22
Filing date: 1975-11-12
Publication date: 1979-08-14
Also published as: SU612621A3; ATA939174A; JPS549196B2; RO73530A; ES442867A1; CS181690B2; CH616657A5; RO73530B; LU73840A1; AT335466B; PL96542B1; DD123522A1; JPS51125249A

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 or an alkyl group, R1 is a hydrogen atom, an alkyl, cycloalkyl, aralkyl or aryl group or R and R1 together represent a divalent, optionally branched hydrocarbon, optionally substituted, R2 is a hydrogen atom or an alkyl, aralkyl or aryl group, R3 is an alkyl, hydroxyalkyl, cycloalkyl or cyanoalkyl group and R4 is a hydrogen atom, a lower alkyl group or an aralkyl group. This process comprises reacting a p-aminophenol derivative or mixture of derivatives of the general formula (II) (II) wherein R5 is a hydrogen atom or the group and X is or , with an amine of general ABSTRACT OF THE DISCLOSURE cont.:

formula (III) (III) and when R5 is the group the product of the formula I
is isolated as the free base or acid addition salt thereof. When R5 is hydrogen, it is converted to the group by addition of a carbamic acid halide of general formula IV

Description

~060450 1This invention relates to a process for the prepara-tion of phenoxypropylamine derivatives.
Substances with a blocking action on the ~-receptors are becoming increasingly important in the therapeutic tre~tment -~
of various cardiac illness whose actiology or symptoms may be explained by an undesirably high content of endogenous catechol-amines in the circulation. In this connection a significant 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 1'-(4-acet-amino-phenoxy(2'-hydroxy-3'-isopropylamino))-propane, which is de~cribed in Austrian Patent Specification No. 261,582, has been used in practice, and accordingly there is still a great need to find actually usable cardioselective ~-blocking agents. ~owever, many ~-blocking agents have the drawback of an undesirahl~
cardiodepressant action which is often coupled with the ~-blocking action.
The patent literature has also disclosed car~ioselec-tive phenoxypropylamine derivatives with a ureido group ~n the p-position relative to the propylamine side chain (DT-~No. 2,100,323), which may be substituted in the nucleus hy hydrocarbon groups, ether groups, halogen atoms, trifluoromethyl groups or nitrile groups and also cardioselective phenoxypropyl-amine derivatives with an alkanoylamide group in the ~-position and acyl groups, for example tne acetyl group, in the o-po~sition relative ~o the propylamine side chain, see Austrian Patent Specification No. 292,671~

.

~06~)450 Also known are ~-blocking agents having a phenoxy-propylamine structure, which also bear an oxime side chain in the o-position to the propylamine side chain and may be substitu-titecl on the nucleus in any position by one or more halogen atoms, nitro groups, or aryl, alkanoylamino, alkyl or alkanoylamino, alkyl or alkoxy groups; see Austrian Patent Specification No. 286,963.
Surprisingly it has now been found that phenoxy-propylamine derivatives which carry a ureido group in tlle p-position to the phenoxypropylamine chain and an optiona~ly sub-stituted oxime group in the o-position, and which have the general formula:- / R~
NH-CO-N ~
,J~, Rl ( I ) 1~ C-R2 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 Rl 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 radical, a hydroxyalkyl, cycloalkyl or cyanoalkyl group, and R4 is a hydrogen atom, a lower alkyl group or an aralkyl group, and also the salts of these derivatives, have out5tanding cardio-selective, ~-blocking properties which are coupled with a very good and relia~le activity when administered orally.

il~6~)450 ~
The activity of the derivatives of formula (I) may be determined on awake dogs by the method of Dunlop & Sh~nks, Brit J Pharmacol 32, 201-18, 1968. The cardioselective action may be recognized for example by the fact that according to the method of Shanks et al, Cardiologia Suppl II, 49, 11 (1966) -carried out on narcotized dogs, the increase in pulse rate pro-duced by isoprenaline is more strongly inhibited by prior admini-stration of these compounds than is the hypotensive effect of isoprenaline. This effect can also be seen in rats from a block-ing effect on the increase in unesterified fatty acids caused by isoprenaline (~2-effect), whereas hardly any influenca was detected on the increased lactate and glucose values caused by isoprenaline (~-effect).
Surprisingly, despite their marked ~-blocking action the compounds of the formula ~I) do not cause any lowering of the pulse rate after oral administration of the substances when testing the pulse rate on awake dogs by a method based on that of Barrett and Carter, Brit J Pharmacol 40, 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 formula (I) in mice is the same as or even less 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 ~-aminophenol derivative of the general formula:-NH-~5 ~II) I~J C-R2 30 ¦ NOR4 ,, , : , ~ ,- : .' 1 in which R2 and R4 are as defined above for formula (I), R5 is a hydrogen atom or the group R_ and X is the group -Co-N

-CH-/H2 or -CH-CH2-Hal, where Hal is a chlorine, bromine or O OH
iodine atom and R and Rl are as defined above, or a mixture of compounds of formula (II) in which X has both the given definitions, with a compound of the formula:-H2N.R3 (III) in which R3 is as defined above, at room temperature or elevated temperature, and, if desired, introducing the ureido group into the resulting compound of the general formula:-

2 (IV~
. . NOR4 O-cH2-cH-cH2-NH~R3 OH
where R2, R3 and R4 are as defined above, either by means of a carbamic acid halide of the general formula:-/ R _~ (V) Hal-CO-N
R
where R and Rl are as defined above and Hal is a halogen atom, or by means of an isocyanate of the general formula:-O'C=N--Rl (VI)where Rl is as defined above,and separating the resulting compound of formula (I) as the free base or a pharmaceutically-acceptable acid addition salt thereof.

- 106~450 1 By elevated temperature is understood a temperature within the range of 30 to 150C, preferably from 30 to 120C.
The reaction is conveniently carried out in a polar solvent in the presence of water. The addition of water produces a marked increase in the reaction rate, with the result that it is possible to reduce the reaction time or lower the reaction tem~erature.
Particularly suitable polar solvents are aliphatic alcohols, such as methanol or ethanol, and dimethylformamide, lC dioxane, tetrahydrofuran and acetonitrile. It is also possible to employ the amine of the formula (III) as the solvent.
The amount of water added, referred to the polar sol-vent, may range from a few percent up to that amount at which the reaction mixture is still homogeneous during the reaction.
Thus, for example, an addition of water of approximately 1:1 referred to the solvent may generally be made, though the amount of water is in principle governed by the hydrophilic properties of the starting material and the end products.
If an elevated temperature is to be employed, the reaction is preferably carried out at the boiling point of the reaction mixture. If the solvent of the amine of formula ~III) is volatile at the reaction temperature employed, the reaction must be carried out in a closed system.
When selecting the reaction conditions it is expedient to take into account the fact that the epoxides of formula (II) are more reactive than the halohydrins of formula (II). For the latter compounds more severe reaction conditions must be used than for the epoxides, for example extending the reaction time and/or raising the reaction temperature.
When it is necessary subsequently to convert the amino group in compound of formula ~II) into the ureido group, 1 it is recommended to operate in a basic solvent, for example pyridine.
The compound of formula ~I) may be isolated in a con-ventional manner from the reaction mixture, either as the free base 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, pharma-ceutically-acceptable salts, for example the hydrohalides such as hydrochlorides and hydrobromides, sulphates, phosphates, acetates, cyclohexyl sulphamates, tartrates and citrates may be prepared.
The compounds of the 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 optica~ly active forms in a con~entional manner, for example by forming the diastereomeric salts with optically active acids, for example tartaric acid, or camphorsulphonic acid.
The compounds of formula ~ used as starting compounds are new. They may be prepared by reacting compounds of the general formula:-/ R ~

~ Rl- (VII) ~-R2 in which R, Rl and R2 are as defined above in formula (1), and X
is as defined in formula (II) with hydroxylamine derivatives of the general formula:-H2N-0-R4 (VIII) ~060450 1 in which R4 is defined as in formula (I). An epoxide of general formula (II) is obtained if an epoxide of general formula (VII) is reacted with a hydroxylamine base of general formula (VI~I) or with a salt thereof in the presence of an equivalent alkali, and a halohydrin of formula (II) is formed if a halohydrin or epoxide of formula (VII) is reacted with a hydrohalic acid salt of a hydroxylamine derivative of general formula (VIII). If an epoxide of formula (VII) is used the hydrohalic acid liberated in the oximation reaction with the hydroxylamine hydrohalides opens the epoxide ring to form a halohydrin of formula ~II).
The compounds of general formula (VII) may be prepared by conventional methods. Thus, for example, it may be prepared by reacting an appropriate N-(3-acyl-4-hydroxy)-phenylurea with an upihalohydrin in the presence of an alkali metal hydroxide solution.
To prepare a compound of general formula (VII~ in which R2 is a hydrogen atom, the reaction is conveniently carried out starting with the 5-nitro-salicylaldehyde, protecting the aldehyde group by forming the acetal reducing the compound to the corresponding aminoaldehyde acetal, and converting with the desired carbamic acid derivative to form the urea. The reaction is then carried out with epihalohydrin, and finally the aldehyde group is liberated.
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, conveniently up to 6 and preferably up to 4 carbon atoms, or a benzyl or phenyl group.

1 ~lso suitable are compounds in which R and Rl together with the terminal N-atom of the ureiao group represent a pyrrolidino, diazolidino, e.g. imidazolidino, thiazolidino, oxazolidino, piperidino, morpholino, tetrahydrodiazino, e.g. tetrahydro-pyrimiclino, tetrahydrothiazino or homopiperazino group. The pyrrolidino, piperidino and morpholino radicals are preferred.
R2 is preferably a hydrogen atom, an alkyl group with up to 6 carbon atoms, or a phenyl group. R3 is preferably a branched chain alkyl group with 3 to 6 carbon atoms or a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and R4 is hydrogen, an alkyl group with up to 6 carbon atoms, or a benzyl radical.
Particularly favourable properties are exhibited, as a rule, by compounds in 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 caxbon atoms, or both together form a tetramethylene, pentamethylene or 3-oxapentamethylene group, R2 is a hydrogen atom or a lower alkyl group with 1 to 5 carbon atoms,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 administered orally, rectally or parenterally. For this purpose they may be mixed with conventional pharmaceutically-acceptable carriers, ~he 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 toyether 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 ~060450 1 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 oral administration, and correspondingly lower in the case of intravenous administration.
The following Examples illustrate the invention.

EXAMRLE 1:

3.0 g of N-[3-(1'-hydroximino )-ethyl-4-(3'-chloro-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea, melting point: 123 to 125C, is reacted with a mixture of 7.5 ml of tert.butylamine and 7.5 ml of water for 16 hours at room temperature. The excess amine is then distilled off in vacuo, the oily residue i5 triturated with water, and the crystalline product formed is filtered of~, washed with water and dried over phosphorus pentoxide. 2.4 g of product are thus obtained, which is 72.5% of theory, A crystalline fumarate may be prepared from the base by adding the calculated amount of fumaric acid. Melting poi.nt:
209 to 212C.
The chlorohydrin serving as the starting material is prepared in the following manner:-10.0 g of N-[3-acetyl-4-~3'-chloro-2l-hydroxy)-propoxy]-phenyl-N'-diethylurea tmelting point: 144 to 146C) is dissolved in 170 ml of methanol, a solution of 2,2 g of hydroxylamine hydro-chloride in 10 ml of water is added~ and the mixture is left to react for 15 hours at room temperature. The methanol i5 then distilled off in vacuo, water and a small amount of ether are added, the mixture is seeded, and the crystalline product which _ g _ 106~450 precipitates is filtered, washed in wàter, and dried over phosphorus pentoxide.
Yield of N-[3-(1'-hydroximino )-ethyl-4-(3'-chloro-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea: 9.0 g = 86.3~ of theory, melting point: 123 to 125C.
It also may be prepared in the following way:-1.0 g of N-13-acetyl-4-(2',3'-epoxy)-propoxy]-phenyl-N'-diethylurea (melting point: 72 to 74C) is dissolved in 10 ml of methanol, 0.25 g of hydroxylamine hydrochloride dissolved in 1 ml of water is added, and the mixture is left to react for 17 hours at room temperature. The methanol is distilled off in vacuo, the oily residue is triturated with water, with the addition of methylene chloride, and the crystalline product formed is filtered off, washed with water and dried over phosphorus pentoxide. Yield of N-[3-~1'-hydroximino)-ethyl-4-~3'-chloro-2"-hydroxy)-propoxy]-phenyl-N'-diethylurea:
0.7 g z 60~ of theory. Melting point: 123 to 125 C.

EXAMPLE 2:

3.2 g of N-~3-~1'-hydroximino)-ethyl-4-(2',3'-epoxy)-propoxy]-phenyl-N'-diethylurea is reacted in a mixture of 10 ml of water and 10 ml of tert.-butylamine for 4 hours at room - temperature. The excess amine is then distilled of~ in vacuo, water is added to the oily residue, the mixture is seeded and left to stand overnight at room temperature, and the crystalline product formed is filtered off, washed with water and dried over phosphorus pentoxide.
Yield of N-[3-~ hydroximino)-ethyl-4-(3'-tert.butyl-amino-2'-hydroxy~-propoxy~-phenyl-N'-diethylurea: 2.7 g = 68.7%

of theory; melting point of the fumarate: 209 to 212C.

The starting material may be prepared in the following manner:-:

1 3.05 g of N-[3-acetyl-4-(2',3'-epoxy)-propoxy]-phenyl-N'-diethylurea is dissolved in 30 ml of methanol and a solution of 0.8 g of hydroxylamine hydrochloride in 3 ml of water is added. Sodium hydroxide solution (lN) is then added while stirring, so that a pH of 6 is maintained in the reaction mixture. The addition of the sodium hydroxide is complete after 2 hours, the stoichiometric amount of sodium hydroxide then having been consumed. The solution is then stirred for a further hour, the methanol is distilled off _ vacuo, the aqueous solution is extracted with ethyl acetate, and the organic phase is dried with anhydrous sodium sulphate and evaporated in vacuo.
Yield: 3.2 g of N-[3- ~'-hydroximino)-ethyl-4-(2',3'-epoxy)-propoxy]-phenyl-N'-diethylurea.

EXAMPLE 3:

0.2 g of N-[3-~1'-hydroximino)-ethyl-4-(3'-chloro-2'-hy~roxy)-propoxy~-phenyl-N'-methylurea is reacted in a mixture of 2 ml of tert.-butylamine and 2 ml of water for 16 hours at room temperature and then worked up in the way described in the preceding Examples.
Yield of N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methylurea; 0.2 g =
89.4% of theory, melting point: 104 to 106C.
The starting material is prepared as follows:-0.4 g of hydroxylamine hydrochloride (in 3 ml of water)is added to 1.3 g of N-[3-acetyl-4-~2',3'-epoxy)-propoxy]-phenyl-N'-methylurea and allowed to react for 18 hours at room temperature. The methanol is distilled off in vacuo, water is added to the residue, the residue is extracted with ethyl acetate, and the organic phase is dried with anhydrous sodium sulphate and evaporated in vacuo. Yield: 0.8 g.

1 The crystallised N-[3-(1'-hydroximino)-ethyl-4-(3'-chloro-2'-hydroxy)-propoxy]-phenyl-N'-methylurea is obtained therefrom by trituration with acetone. Melting point: 147 to 151C.

EXAMPLE 4:

1.0 g of N-[3-(1'-hydroximino)-ethyl-4-(3'-chloro-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea is reacted in 5 ml of sec.butylamine and 5 ml of water for 23 hours at room temperature.
The reaction mixture is then evaporated in vacuo, acetone is added to the oily residue, the mixture is allowed to stand overnight at room temperature, a small amount of ethanol is added, and the crystalline product thus obtained is filtered off.
Yield of N-[3-~1'-hydroximino)-ethyl-4-(3'-sec.butyl-amino-2'-hydroxy)-propoxy~-phenyl-N'-dimethylurea: 0.45 g = 40.5%
of theory, melting point of the fumarate: 192 to 195C.

EXAMPLE 5: -1.85 g of N-t3-(1'-hydroximino)-propyl-4-(2',3'-epoxy)-propoxy]-phenyl-N'-diethylurea is dissolved in a mixture of 10 ml of ethanol and 10 ml of water, 2.02 g of tert.butylamine is added, and the mixture is heated for 30 minutes at boiling point. The solvent is then distilled off, water is added to ~
the residue, the residue is acidified with lN hydrochloric ;;
acid, extracted several times with ethyl acetate, and aqueous solution is made alkaline with lN sodium hydroxide and extracted again with ethyl acetate. The organic phase is dried with sodium sulphate, filtered, and distilled in vacuo.
Yield of N-[3- ~'-hydroximino)-propyl-4-~3'-tert.butyl-amino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea: 1.45 g - 64.5%

1 of theory. The fumarate may be crystallised from the base in acetone solution by adding fumaric acid. Melting point: 210 to 212C.

EXAMPLE 6:

1.0 g of 3~ hydroximino)-ethyl-4-(3'-chloro-2'-hydroxy)-propoxy-aniline is reacted with 4.0 ml of tert.~utyl-amine and 3 ml of water for 7 hours, the excess amine is dis-tilled off in vacuo, the residue is extracted several times with ethyl acetate, and the organic phase is dried with anhydrous sodium sulphate and concentrated in vacuo. The oily residue crystallises after trituration with ether.
, Yield of 3-(1'-hydroximino)~ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy-aniline: 0.95 g = 83.2% of,theory; melting point ~in acetone): 138 to 140C.
0~25 of diethylcarbamic acid chloride is added to 0.5 g of the 3-(1'-hydroximino)-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy-aniline thus obtained, in 5 ml of pyridine, and reacted for 48 hours at room temperature. The solvent is distilled off in vacuo, the xesidue is taken up in water and extracted with, ethyl acetate, and the organic phase is dried with anhydrous sodium sulphate and distilled in vacuo.
Yield of N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.butyl-amino-2'-hydroxy)-propoxy]-phenyl-N'-die,thylurea: 0.3 g = 45.0%
of theory.
The fumarate may be obtained from the base in the usual way. Melting point: 209 to 212C.
The starting material may be prepared in the following way:-302.55 g of hydroxylamine hydrochloride in 3 ml of water is added to 3.0 g of 3-acetyl-4-(3'-chloro-2'-hydroxy)-propoxy-1 aniline in 30 ml of methanol and reacted for 17 hours at room temperature. The methanol is then distilled off in vacuo, 10 ml of water are added to the residue, the clear solution is made alkaline with 9.0 ml of 4N sodium hydroxide, the base which precipitates is seeded and the crystalline product formed is filtered off after a short time.
Yield of 3-~1'-hydroximino)-ethyl-4-(3'-chloro-2'-hydroxy)-propoxy-aniline: 2.45 g = 76.9~ of theory; melting point (in ethanol/ether): 114 to 117C.

EXAMPLE 7:

0.5 g of 3-(1'-hydroximino)-ethyl-4(3'-tert.butylamino-2'-hydroxy)-propoxy-aniline prepared according to Example 6 is reacted in 20 ml of absolute ethanol with 0.22 g of phenyl isocyanate for 4 days at room temperature. The reaction mixture is evaporated in ~acuo, the residue is dissolved in acetone, the calculated amount of fumaric acid is added and the solution is concentrated and digested with ether. The crystalline product formed is extracted at boiling point with ethanol and the in-soluble fraction is filtered off.
2~
Yield of N-13~ hydroximino)-ethyl-4-~3'-tert.butyl-amino-2'-hydroxy)-propoxy]-phenyl-N'-phenylurea fumarate:
0.35 g = 43.8~ of the theory. Melting point: 167 to 170C.
The following compounds may be obtained in an analogous manner to Examples 1 to 7.
N-[3~ hydroximino~-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea: melting point of the hydrochloride: 208 to 211C.
N-~3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)propoxy]-phenyl-N'-tetramethylene-(1,4)-urea. Melting point: 185 to 188C.

1 N- [ 3- (1 ' -hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene(1,5)-urea. Melting point of the fumurate: 170 to 173C.
N-[3-(1'-hydroximino)-ethyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point of the fumurate: 175 to 178C. -N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenylurea. Melting point of the fumarate:
217 to 220C.

N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-ethylurea. Melting point: 108 to 110C. -N-[3-(1'-hydroximino)-ethyl-4-[3'-(2''-hydroxy-1'',1''-dimethylethyl-amino)-2'-hydroxy]-propoxy]-phenyl-N'-dimethylurea.
Melting point: 174 to 176~C.
N-t3~ butoximino)-ethyl-4-(3'-tcrt.butylamin~-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point of the fumarate: 163 to 166C.
N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dipropylurea. Melting point of the fumarate: 163 to 166C.
N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-sec.butylurea. Melting point of the fumarate: 225 to 228C.
N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxyl-phenyl-N'-n-butylurea. Melting point: 93 to 95C.
N-13-('-hydroximino)-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-tert.butylurea. Melting point of the fumarate: 222 to 225C.

.

.

1 N-[3-~ hydroximino)-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy~-phenyl-N'-dibutylurea. Melting point of the fumarate: 171 to 174C.
N-[3-(1'-hydroximino)-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-isopropylurea. Melting point:
189 to 191C.
N-[3-~1'-methoximino)-ethyl-4-~3'-tert.butylamino-2'-hydxoxy~-propoxy]-phenyl-N'-dimethylurea. Melting point of the fumarate: 163 to 167C.
N-[3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-isopropylurea. Melting point: 145 to 148C.
N-~3-(1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-butylurea. Melting point of the fumarate: 137 to 139C.
N-13-(1'-hydroximino)-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy~-phenyl-N'-methyl-N'-ethylurea. Melting point of the fumarate 212 to 216C.

N-[3-(1'-hydroximino)-ethyl-4-~3'-isopropylamino-2'-hydroxy)-propoxyl-phenyl-N'-diethylurea. Melting point:
127 to 128C.
N-[3-(1'-benzyloximino)-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Melting point of the fumarate: 164 to 167C.
N-13-(1'-hydroximino)-methyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethyurea. Melting point:
169 to 172C
N-[3-(1'-hydroximino)-methyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxyl-phenyl-N'-diethylurea. Melting point:
158 to 161C.

.. .

~060450 1 N-[3-~1'-hydroximino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-dipropylurea. Melting point of the fumarate: 205 to 206C.
N-[3-(l~-hydroximino)-butyl-4-(3'-tert.butylamino-2l- -hydroxy)~propoxy]-phenyl-N'-diethylurea. Melting point of the fumarate: 178 to 180C.
N-[3-(1'-hydroximino)-propyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene-(1,5)-urea. Melting point of the fumarate: 156 to 158C.
N-[3-(1'-hydroximino)-propyl-4-(3'-tert.butylamino-2'-hydroxy)propoxy]-phenyl-N'-dimethylurea. Melting point: 86 to N-[3-(1'-hydroximino)-butyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-pentamethylene-(1,5)-urea. Melting point of the fumarate: 148 to 150C.
N-[3-~ hydroximino)-ethyl-4-~3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-cyclohexylurea. Melting point of the fumarate: 166 to 168C.

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 of less than 5 carbon atoms, R1 is a hydrogen atom, a straight-chain or branched lower alkyl group of 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 a hydrogen atom or an alkyl group containing up to 6 carbon atoms or a benzyl or phenyl group, 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 R4 is a hydrogen atom, an alkyl group containing up to 6 carbon atoms or a benzyl group, and the pharmaceutically-acceptable salts thereof, which comprises reacting a p-aminophenol derivative of the general formula:
(II)

Claim 1 continued....

in which R2 and R4 are as defined above, R5 is a hydrogen atom or the group and X is the group or , where Hal is a chlorine, bromine or iodine atom and R and R1 are as defined above, or a mixture of compounds of formula (II) in which X has both the given definitions, with an amine of the general formula:
H2N.R3 (III) in which R3 is as defined above, at room temperature or at elevated temperature and i) when R5 in the resulting compound is the group said compound is isolated or ii) when R5 in the resulting compound is hydrogen it is converted to the group by reacting the said resulting compound (a) with a carbamic acid halide of the general formula:
(V) wherein R and R1 are as defined above and Hal is a halogen atom or (b) in order to obtain compounds of formula I in which R is hydrogen with an isocyanate of the general formula O = C = N - R1 (VI) wherein R1 is as defined above and the compound of formula I obtained is isolated (c) by separation as a base or (d) by adding an acid and separating the salt thereby formed.
2. A process according to claim 1, in which the reaction of the compound of formula (II) with the compound of formula (III) is carried out at a temperature of 30° to 120°C.
3. A process according to claim 1, in which the reaction of the compound of formula (II) with that of formula (III) is carried out in a mixture of a polar solvent with water, the amount of water with respect to the amount of solvent being chosen so that a homogeneous reaction mixture is achieved.
4. A process according to claim 1, in which the amine of formula (III) is used as solvent.