Note: Descriptions are shown in the official language in which they were submitted.
~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
NOR4
OCH2-CH-CH2-NH-R3
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
O-CH2 -X
,, , : , ~ ,- : .'
1060450
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:-
NH2
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,
1060450
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
CH2-X
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.
1060450
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
8 --
~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:-
-- 10 --
:
10604S0
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.
-- 11 --
1060450
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%
- 12 -
1060450
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-
- 13 -
1060450
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.
- 14 -
1060450
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.
- 15 -
.
.
10604S0
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.
- 16 -
.. .
~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
88C
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.
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