Note: Descriptions are shown in the official language in which they were submitted.
~ ~4,~,~Z36
This invention relates to a process for the preparation of pheno~y-
propylamine derivatives.
Sub~tance~ with a blocking action on the ~-receptors are becoming increas-
ingly ~mportant in the therapeutic treatment of v~rious cardiac illness -
whose aeti.ology or 3ymptom~ may be explained by an unde~irably high
content of endogenou3 catecholamines in the circulation. In this connec-
tion a significant advance has been achieved by the discovery of so-called
cardio~elective ~-blocking agents, these being age~t~ which mainly act
only on the ~-receptors of the heart but have little effect o~ ~-receptors
-:, .
of other organ~, since by using such agents undesirable side effects,
such as for e~ample the spastic effect on the respiratory trac~39 ~ay be
avoided. ~owever, o~ the~e selective agents hitherto only one compound9
namely 1'-(4-acetamino-phenoxy(2'-hydroxy-3~ i~opropylamino))-propane,
which i9 described in Au~trian Patent Specification No.261,582, has been
used in practice, and accordingly there is still a great need to ~ind
actually usable cardiosele¢tive ~-blocking agent3. However, many ~-
blocking agents have the drawback of an undesirable cardiodepressant
action which is often coupled with the ~-blocking action.
The patent llterature ha~ also disclosed cardioselective phenoxypropyl-
0 amine derivative~ with a ~ureido group in the p-po~ition relative to the
propylamine side chain (D~OS ~o.2,100,323), which may be substituted in
the nucleu~ by hydro¢arbon groups, ether groups, halogen atoms,
trifluoromethyl group~ or nitrile groups and also cardioselective
phenoxypropylamine derivative~ with an alkanoylamide group in the ~
position and acyl groups, for example the acetyl group, in the o-position
relative to the propylamine side chain, see Austrian Patent Specificstl~n
No.292,671.
.
Surprisingly,. it has now b~en found that phenoxypropylamine derivatives
which carry a ureido group in the ~-po~ition to the phenoxypropylamine -
- I ,
,~ ',
1 chain and an ac~l. group, prefera~l~ a lower alkanoyl group or an
oxime group in the o-position, and which have the general formula:
. R ~ : -
NII-CO-N~R ,~ ; ' '
.~ ~1
:ll ~ C~R2 (I)
~' . I X "; "'
.~; . OCH2--CH-CH2--NH-R3
~:f ~.
in which R is a hydrogen ato.m or an ~lk~l group and R1 i5 an alkyl,
cycloalkyl, aralkyl or aryl group, or R and R1 together represent
a di~alent, optionally ~ranched ~ydrocar~on group with 4 to 7 car-
,~ ,,
~ bon atoms in the main chain, ~herein one or t~o of these carbon ~ :
.~ atoms may be replaced by oxy~en, sulphur or nitrogen, R~ is a
hydrogen atom or an alkyl, aralkyl or ar~l group, R3 is a prefer~ :
ably branched alkyl group, or a hydroxyalkyl, cycloalkyl or cyano-
alkyl group, and X is an ox~gen atom or the group -NOR~, wherein
,:. . ~ . ,- .
.. in the case where X is oxygen R2 is not hydrogen, and R4 is a
'l ,
.~ hydrogen atom, a lower alkyl group or an aralkyl group, and also .~ ~.
the salts of these derivatives, have outstanding card.ioselective7 .
~ : B-blocking properties which are coupled with a very good and
3i reliable activity when administered orally. The activity of the ~; m .
. derivatives of formula ~I) may be determined on awake dogs accord- .
ing ta the method o~ 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, Cardio-
.,.~ ,
logla Suppl. II r 491 11 (1966) carried out on narcotised dogs, the
increase in pulse rate produced by isoprenaline is more strongly
inhibited by prior administration of these compounds than is the
~: ~0 , ~ :
.'1 ;
:
, .,
,.. .
~o4~Z36
1 hypotensive effect of isoprenaline. This effect also may be seen
in rats from a ~lockin~ action on the increase in unesterified
fatt~ acids caused by isoprenaline ~Bl-effect~, whexeas hardly any
influence was detected on the increased lactate and glucose values
caused by isopre-
., ~
. ~
' 10 ~ ~
.,,~ :
,'! . . :
.i : :
,)
~ 20
.~ , .
, ~
: :` ~
;,~: :
9 -.
. ~
;,'~
:"
3~
naline (~2-effect)~
Surprisinvly~de~pite their marked ~-blocking action the compounds oE formula -
~ (I) do not cause any lo~ering of tha pulse rate after oral administration of
; the substances when testing tha pulse rate on awake dogs by a method ba~ed
on that of Barrett, Carter, Brit J Pharmacol. 40, 373-81 (1970)~ which
indicates that the compounds of formula (I) do not e~hibit an undesired and
in some case~ dangerous cardiodepressant action. The toxicity of the com- ;
pounds of formula (I) ln mice i9 the samé` a~, or e~en lower than, that of
the co~mercially available ~-blocking agent~.
The present invention provides a process for the preparation of a compound
of the formula (I) which comprises reacting a urea derivative of the general
formula~
;~ N~-C-NH2 - ;~
" 2 (II)
-C~2-CH-CH2-N~-
O~I
~; in whioh R2, R3 and X are as defined above for formula (~), with an amine 15 ~ of~the ~ormula--
in which R and Rl are as deflned above, at elevated temperature and then
~ isolating the reaction product as the free base or a salt thereof. The
.:! i
term elevated temperature is intended to mean a temperature within the ran~e
of from 50C to 200C, preferably ~rom 50C to 150~C.
In performing tha proce3s of the invention the amines of formula (IIT) is
J~ preferably used in exce~. This excess may be chosen to be so larg~ that
;~ - the amin6 of formula (III) may serve as a solvent for the reaction mixture.
.A '
~ 4-
3~
~urther ~olve~ts which are Ruit bl~ for the reaction are polar sol~ents such
as, ~or exam~le, alcohols 9 dimethyl formamide and hexamethyl pho~ph~ric acid
triamide. The ~olvent may be used in the anhy~rous st~te or mixed wlth water,
and in the case of a water-contai m ng reaction mixture, particularly a mix-
ture of an aliphatic alcohol with water~ an acceleration o~ the reaction isobserved in many ca3e~. If the aminP o~ formula (III) is volatile at the
reaction temperature employed, the reaction mugt either be carried out in a
closed apparatuR or, if carried out in an open vessel, suitable measures ~
muRt be adopted to recycle the amine of formula (III) ~hich ~capes from the
reaction mi~ture O
:`; .
` If a salt of an amine of formula (III) i~ used, it is recommended to add the
; calculated amount of alkali solution to the salt in concentrated aqueous
~ solution~
. ' ~
~ince the reactivity varies somewhat according to the nature of the compounds,
~ 15 this should be taken into account by ad~usting the reaction conditions. The
,! choice of suitable reaction conditions as regards reaction tempe~ature and
reaction time may be easily dete:rmined by means of a preliminary experiment
! ~
~ vhich, for example~ may be followed by thin-layer chromatogr~phy.
- The compound of formula (I) may be isolated in a conventional manner ~rom the
reaction mixture~ either as a base or as a ~alt. The compound of formula (I)
1 i8 very conveniently i~olated as a salt with a dicarboxylic acid, for
-~ ~ example as the fumarate, oxalate or ~uccinate, on account of the good crys-
~ .
~ tallisability of these salts. All normal, pharmaceutically-acceptable saltB
;;~ for example, the hydrohalides such as hydrochlorides and hydrobromides,
~ 25 3ulphates, phosphates, acetate~, cyclohexylsulphamates, tartrate~ and citrates
may be prepared.
~he compounds of ~ormula (I) have an asy~metric carbon atom. They there~ore
e~ist as the racemate and as optically active formsO The racemate may be
~^, separated into the optically active forms in the usual manner, for example
--5--
L4'~36
by forming the dia~tereomeric 3alts with optically active acidsD for example
tartaric acid, or camphorsulphonic acid.
:, ,
~- The compound~ o~ formula (II) required a9 qtartin~ mate~ial~ are in marly
cases naw. For example~ they may be obtained by reactin~ the corresponding
~- 5 phenol with epihalohydrin and then with an amine.
. ~ .
Compounds of the-formula (I) which are particularly suitable are those in
which R is a hydrogen atom or a stralght or branched chain alkyl group with
up to lO, advantageously up to 6, and pre~erably up to 4 carbon atoms.
~' `
Rl i~ mo~t suitably an optionally branched chain alkyl group with up to lO,
conveniently 6p and pre~erabl~ up to 4 carbon atoms, or a benzyl or phen~l
group. Also suitable are compounds in which R and Rl together with the
terminal N-atom of the ureido group represent a pyrrolidino, diazolidino,
~ e.g. imidazolidino~ thiazolidino, oxazolidino, piperidino, morpholino,
;l~ tetrahydrodiazino, e.g. tetrahydropyrimidino, tetrahydrothiazino or homo-
piperazino group. ~he pyrrolidino, piperidino and morpholino groups are
~ preferred. R2 is preferably an alkyl group with up to 6 carbon atoms or a
., ,
l phenyl group, and when X i9 an oxime group R2 is hydrogen, R3 is preferably
~ a branched chain alkyl group with ~ to 6 carbon atoms, ar a cyclopropyl,
; cyclobutyI, cyclopentyl or cyclohexyl group, and ~4 iZ~ hydrogen, an alkyl
~ ~ 20 group with up to 6 carbon atoms, or a benzyl group.
? Particularly favourable properties are exhibited, as a rule, by compound~
in which each of R and Rl, which may be the same or different is an alkyl
group with l to 6, preferably l to 4 carbon atoms, and R also may be a hydro-
Z gen atom9 or both together form a tetramethylene, pentamethylene or 3-oxa;
;~ 25 pentaméthylene group, R2 is a lower nlkyl group with l to 5 oarbon atoms and
in the case of compounds of formula (I) in which X is -NOR~, also may be a
hydrogen atom, and R3 is a tert.butyl group or an i~opropyl group. ~
' ~ .
-6-
; The compounds of for~ula (I) may be pre3ent a~ active ingredients in pharma-
ceutical com wsition3 which may be administered orally, rectally or parent-
; erally. For this purpo~e they may be mixed with conventional pharmaceuti-
cally-acceptable carriers, the nature of the carrier bein~ determined by the
method of application. They may be converted into tablets or dragees in the
usual way, and the active compoun~s themselves, optionally together with a
pharmaceutically-acceptable golvent, may bemade up into capsule~.
Pharmaceutically-acceptable soluble salts which ara capable of forming stable
~olutions may be used in the form of injectable solutionsO ~he salts for
this purpose may be obtained simply from the corresponding bases of formula
(I) by reaction ~ith the equivalent amount of acid. Both bases and salts
may be converted in the usual way into suppositoriesO
. . .
'e ~ The individual dose for humans is 100 mg in the case of oral administration~
and correspondingly lower in the case of intravenous administration.
'JI 15 ~he ~ollowing Examples illustrate the invention.
Example 1
. , .
-'~ 2.0 g of N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-
uxea is heated under reflux for 6 hours in 10 ml of piperidine. The excess
amine is then completely distilled off in vacuo, the oily residue is tri-
turated with acetone, seeded, and cooled, and after standing overnight the
crystalIine product which precipitates is filtered o~ ashed with ether
'I ' . .
and dried.
Yleld of ~-[3-acetyl-4-(3'-tert~butylamino~2'-hydroxy)-propoxy]-phenyl-N'-
pentamethylene(l,5)-urea: 1,1 g - 45.5% of theory. Melting point of the
fumarate: 211 to 213C.
.,j .
The ~umarate may be prepared by dissolving ~ g of the starting material in
20 ml of ethanol, adding 1.53 ml of piperidine, reacting the mixture in an
'i - . : , ,,
~'' ' ' `'
-7-
Z3~
autoclave for 7 hours at 1~0C and then evaporating the reaction mixture
in vacuo, dissol~ing the oily residue in acetone, acidifying it with a solu-
tion of ~umaric acid in acetone, and isolatlng the crude, precipitated N
[3-acetyl-4-(3'-tert.butylamino-2'-hydro~y)-propoxy~-phenyl-N'-pentamethyl- ^
~ne(1,5)-urea fumarate after 5eparating an în~oluble tat the boiling tempera-
ture) fraction followed by recrystallisation from alcohol, concantration of
the alcoholic filtrate and cooling, 0.85 g of the fum rate of ~-[3-acetyl
4-(3'-tert.butylamino-2' hydroxy)-propoxy] phenyl-N'-pentamethylene(1,5)-
urea i3 obtained, which corresponds to 61.1~ of theoryO
:; ' 10 Preparation of the starting compound:
80 ml of methanol is added to 20.0 g of 3-acetyl-4-hydroxy-phPnylurea, a
solution of 6.4 g of pota~qsium hydro~ide (85%) in 50 ml of water i8 sdded,
80 ml of epichlorohydrin is adde~, and the mixture is stirred for 5 houL~s
at 50C. ~he reaction mixture i~ concentrated in vacuo, water is added to
~ 15 the concentrate, the resultant solution is cooled and the crystalline pro-
,~!, duct which precipitates is filtered off, wa~hed with water and dried in air.
i Yield of N-[3-acetyl-4-(2'-,3'-epoxy)-propoxy~-phenylurea: 24.6 g = 95.
o~ theory. Melting point: 163 to 166C.
:j
` ~ 24.6 g of the epoxide i8 stirred in a mixture of 115 ml bf tert.but~lamine
! ~ and 100 ml of water for 4~hour~ at room tempersture, the reaction mixture is
evaporated in vacuo, 100 ml of water i~ added to the residue, and the resi-
due is acidified to a pH of 3 with hydrochloric acid. The acid ~olution i~ ~ -
extracted with ethyl acetate and then made alkaline. A proportion of the
base ~ormed crystalli3es and is filtered off, and the remainder i~ isolated
by extractin~ the mother liquor with ethyl acetate. Yield of N-r3-acetyl-4-
(3'-tert.butyl~mino-2'-hydroxy)-propoxy]-phenylurea: 26.8 g = 84.3~ of theory~
Melting point of the hydrochloride: 195 to 197C.
... .
.; , .
.,. !
.j ' .
" ~
" ' ' . ~ ' ' . , ' ' ` ' ' . , .: ' '
,'~:'. : . . . .', '. : . ..
,'Z36
~ E~am~le 2:
.~
20 ml of diethylamine is added to 2.0 g of N-[3-acetyl-4-(3'-t0rt.butylamino-
2'-hydroxy) propoxy]~phenylurea, 0.2 ml of ~ater i~ added, and the mixture
`~ i9 react~d in an autoclave for 3 hours at 130C. The reaction mixture i5
then evaporatsd in vacuo, the residue is digested with acetone/ether~ and
the precipitated crystalline product is filtered off after some time.
Yield o~ ~-[~-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-
`` diethylurea: 1-,3 g = 55.5~ of theory. Melting point of the ba~e: 110 to
~ 112C.
;- 10 ~blY~
~,
'! 12 ml of water is added to 1.0 g of N-[3-acetyl-4-(~'-tert.butylamino-2'-
: hydrochloride
hydroxy)-propoxy]-phenylurea and Z,l g of methylamin ~ 7.8 ml of 4N sodium
i~ hydroxide solution are added, and the whole is reacted in an autoclave for
.,1. `
i 1 hour at 130C.
~ 1 .
;, 1 5 The reaction mixture is concentrated in vacuo and extracted se~eral times
with ethyl acetate~ After the ethyl acetate solution has been dried with
anhydrou~ sodium sUlphate it i9 concentrated, the oily residue i5 digested
with ether and seeded, and the precipitated crystalline product is,after a
., .
~ period of time, ~iltered off, wa~hed and dried.
, $ ~' '
Tield of N-[3-acetyl-4-(3'_tert.butylamino-2~_hydroxy~_propoxy]_phenyl-N'-
methylurea: 0.65 g = 62.2~ of theory. Melting point ~from acetone/ether):
132 to 134C.
~' : :. ~ .
.' '~
. :: ~e~ '
0.40 g of N-[3~ hydroxyimino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-
propoxy]-phenylurea is reacted with 5.0 ml of diethylamine and 0.05 ml of
water in an autoolave for 3 hours at 130~. ~he reaction mi~ture i~ then
., .
1~: 9
36
concentrated in vacuo.
Yield of N-[3~ hyAroxyimino)-ethyl-4-(3'-tert.butylamino-2t-hydroxy)-
propoxy]-phenyl-N'-diethylurea: 0.40 g c 85. ~ of theory.
.'
The crystallised fumarate may be prepared from the base in acetone ~olution
by adding the calculated amount of fumaric acid. Melting point: 209U to
212C.
.'~' ~ . '
The etarting material employed is prepared as follows:
5.0 g of ~-[3-acetyl-4-(3'-tert.butylamino 2l-hydroxy)~propoxy~-phenyl-
urea is dissolved in 50 ml of methanol, a solution of 3.25 g of hydroxyl-
amine hydrochloride in 5 ml of water i3 added, and the mixture i9 reacted
for 20 hours at room temperature. The solvent i~ di~tilled off in vacuo)
30 ml of water is added to the oily residue, the requltant solution is made
1 alkaline with 12 ml of 4N sodium hydroxide solution, the precipitated base
i~ dissolved in ethanol and flltered, a solution containing tha calculatsd
.
amount of fumaric acid in a~etone is added, and the crystalline product,
aft~r ~tanding overnight, is filtered off.
.1~ ~
Yield of N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy3-
propoxy]-phe~ylurea ~umarate: 3.5 g ~ 57.1~ of theory. Melting point:
~ 2~7~ to 2?0C.
;3~ ;~
~ 20~ ~b~æ~ 5
Y~ 1.0 g of N-[3-(l'~hydroxyimino)-ethyl-4-(3l-tert.butylamino-2'-hydroxy)-
propox~]-phenylurea fumarate is heated in 10 ml of piperidine at boiling
point for 7 hours. The reaction mixture is evaporated in vacuo, a small
. . ~ . . .
a~ount of water is added to the residue~ the calculated amount of lN sodium
hydroxide 901ution is added, and the reaction mixture is extracted se~er~l
times with ethyl acetate~ The ethyl acetate solution i~ dried and then ;`
distilled, and the N-C3-(~ hydroxyi~ino)-ethyl-4-(3' tert.butylamino-2'-
'' : '
,, ' " ' . , ~:
10- '-': ~ -
39~ .
hydroxy)-propoxy]-phenyl-N'-~entamethylene-(1,5)-urea base formed is left
behind as a crystalli~ed re~idue~
'
.
Yield: 0.55 g - 53.7% of theory. Melting point of the fumarate: 170 to
173C~
The following compounds may be preparsd in an analogou3 manner to Examples
~' 1 to 3:-
N-C3-acetYl-4-(37-tert.butylamino-2~-hydroxy)-propoxy~-phenyl-2~?-
` dimethylurea. Melting point of the *umarate: 205 to 208C. - '
, N-C3-acetyl-4-(3'~tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-, 10 ethylurea. Melting point of the fumarate: 196 to 198C.
', N-r3-acetyl-4-(3'-tert.butylamino-2'-hydroxy~-propoxy]-phenyl-N'-
~, isopropylurea. Melting point: 87 to 90C.
~,
N-~3-acetyl-4-(3'-tert,butylamino~2'_hydroxy)_propoxy]_phenyl-N~_
~! butylurea. Melting point of the fumarate: 206 to 207C.'I 15 N-r3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N~-
~ec.butylurea. Meltin~ point of the fumar~te: 215' to 217C.
N-C3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-
E~.butylurea. ~alting point of the fumarate: 213 to,215C.
N-C3-acetyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy~-phenyl-N'-
dimethylurea. Melting point: 103 to 107DC.
-[3-acetyl-4-(3'-cyclopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-
, ' .
~,), ; dime~thylurea. ~elting point: 80 to 8~C.
3-acetyl-4-(3~-~ert.butylamino-2~-hydroxy)-propoxy]-phenyl-N~
~;~ methyl-N'-ethylurea. Melting point of the fumarate: 195 to 197C.
"3, 25 N-[3-acetyl-4-t3'_tert.butylamino-2'-hydroxy)-propoxy]-phenyl-NI-
'~ methyl-N'-butylurea. ~elting point: 84 to 86C~
~', N-C3-acetyl-4-(3~-tert.butylamino-2'-hydroxy)-propo~y]-phenyl-N'-
di-n-butylurea~ Melting point of the fumarate: 184 to 187C.
~,` N-[3-aoetyl-4-(3'-tert.butylamino-2'-hydroxy?-propoxy]-phenyl-N'--
--11--
di-n-propylurea. Melting point of th~.fumArate: 1649 to 167C.
N-~3-acetyl-4-[3'-(2"-cyanopropyl(2")-amino)-2'-hydroxy]-propoxy~-
phenyl-N'~diethylurea. Melting point: 89 to 92C.
N-~3-acetyl-4-(3'-tert.butylamino-2'~hydroxy)-propox~]-phenyl-N'-
phenylurea. Melting point: 159 to 164C.
N-r3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-pro~?ox~]-phe~rl-N'-
tetramethylene(l,4~-urea~ Mel~ing point of the fumarate: 218~ to 220C.
~-[~-propionyl-4-(3~tert,butylamino_2~_hydro~y)_propoxyJ~pheuyl-
N'-methylurea~ Melting point of the fumarate: 134 to 136~C.
~ 3-propionyl-4-(3'-tert.butylamino-2'-hydroxy)-~ropoxy~-phen~rl-Ni-
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-N'-
~ 15 tetramsthylene(l,4)-urea. Melting point of the fumarate: 208 to 211Co
'~ N-[3-propionyl-4-(3'-tert~butylamino-2'-hydroxy)-propoxy]-phenyl-N'-
3-oxa-pentamethylene(1,5)-urea. Melting point of the fumarate: 193 to
195C.
N-[3-butyryl-4-(3'-tert.butylamino-2''hydroxy)-propoxy]-phenyl-N'-
~ ~0 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 ~ 5)-ureaO Melting point: 117 to 118C.
N-[3-benzoyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-
pentamethylene(l,5)-~rea. Melting point: 120 to 123C~ -
i .
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phen~
methyl-N'-i~opropylurea. Melting point: 105 to 107C.
N-L3-acetyl-4-(3~-tert.butylamino-2~-hydroxy)-propoxyJ-phenyl-N'- ' :
ethyl-N'-n-propylurea. Melting point of the fumarate: 17~ to 178C.
'~ N-C3-bubyryl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'- .
diethylurea, Melting point: 56 to 58C~
. ~ N-~3-acetyl-4-(3~-tert.butglamino-2'-hydroxy)-propoxy]-'phenyl-Nt- ''~
,~ ~ methyl-N'-cyclohexglurea. ~Ielting point: 134 to 136C~
' '
--12--
3~
N-[3-acetyl-4_(3'_tert.butyli~mino_2'_hydroxy)_propoxy~_phenyl-N'-
m~thyl-N'-~ x_ur~a. Melting poirlt o~ the fum~rate: 211~ to 214C.
N-[3-acetyl-4-(3'-tert.butylamino-Z'-hydroxy)-propoxy3-phenyl-N'-
benzylurea, Melting point of the ~umarate: 199 to 210C,
The ~ollowing compounds may be prepared in an analogou~ manner to Exi~mpIes
4 and 5,
N-r3~ -hydroxyimino)-ethyl-4-(3'-tert.butylamino-2~-hydroxy)-
,. . .
propoxy]-phenyl-N'-dimethylurda. Melting point of the hydrochloride:
208 to 211C
,., ~ .
N-[3-(1'-hydro~yimino)-ethyl-4-(3'-tert,butylii~mino 2'~hydroxy)-
propoxy]~phenyl-N'-tetramethylene(1,4)-urea, Melting point: 185 to 1~8C.
N-C3-(1'-hydroxyimino)-ethyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy]-
phenyl~N'-dimethylurea. Melting point of the fumarate: 175 to 178C.
N-~3-(1'-hydroxyimino)-ethyl-4-(3'-tert.butyli~mino-2'~hydroxy)-
t 15 propoxy~phenyl~;N'-methylurea, Melting point: 104 to 106C.
N-r3~ hydroxyimino)-ethyl-4-(3'-tert.butylamino-2'-hydro~cy)-
propoxyJ phenyl-N9-ethylurea. Melting point: 108 to 110C.
3-(1'-hydroxyimino)-ethyl-4-(3'-~ec.butyli~mino-2'-hydroxy)-propoxy]
~ phenyl-N' dimethylurea. Melting point of the ~umarate: 192 to 195C.
i ~ 20 N-{3_(1'-hydroxyimina)-ethyl-4-~3'-(2"-hydroxymethylpropylt2")-i~mino)
2'-hydroxy]-propox~ -phenyl-N'-dimethylurea. Melting point: 174 to 176C.
N-~3-(1'-butoxyimino)-ethyl-4-(3'-tert.butylamino-2'-hydro~y~-propoxy]-
phenyl-N'-dimethylurea~ Melting point of the fumarate 163 to 16~C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.butylamino-2~-hydro~
` 25 propoxy]-phenyl-N'-dipropylurea. Melting point of the fumi~rate: 163 to
166Co
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.butylamino-2'-hydroxy)-
propoxy3-phenyl-N'-~ec.butylurea. Melting point of the fumarate: 225~ to
228C.
30~ 3-(1t-hydroxyimino)-ethyl-4-(3'-tert.butylamino-2'-hydro~y)-propoxy]-
phenyl N'-butylurea. Melting point: 93 to 95C.
' -
. ~
, -13- -
~:
:
11~442~36
,.~ N-C3~ hydroxyimino~-ethyl~4-(3'-tert.,~butyl,amino-2'-hydroxy)-
propoxy]-phenyl-N';tert.-butylurea. Malting point of the fumaratst 222 to
225C.
N-~3-(1'-hydroxyimino)-ethyl-4~ tert.-butyli~mino~ hydroxy~-
propoxy]-phenyl-N'-dibutylurea, Melting point of the ~umarRtes 171 to
.; .
174C.
N-[3-~1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-
.,. . . ~
, propoxy]-phenyl-N'-isopropylurea" Melting point: 189 to 191C,.
`t N [3-(1'-methoximino)-ethyl-4-(3'-tertO-butylamino-2'-hydroxy)-
propo~y]-phenyl-N'-dimethylurea, Melting point of the fumarate: 163 to 167C.
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-
propoxy3-phenyl-N'-methyl-N'-i~opropylurea. Melting point: 145 to 148C.
~,~ N-[3~(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-
propo~y]-phenyl-N'-methyl-N'-butylurea. Melting point of the ~um~rate:
1~7 to 139C,
N C3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino2' hydroxy)-
propoxy]-phenyl-N'-methyl-N' ethylurea. Melting point of the fumarate: ~
212 to 216C'C. :: :
N~[3~ hydroxyimino)-ethyl-4-(3~'-isQpropylamino-2'-hy~roxy)-
~20 propoxy~-phenyl-N'-diethylurea. Meltlng point: 127 to 128C,
N-[3(1'-benzyloximino)-ethyl-4-(3` tert.-butylamino-2'-hydroxy3--
propoxy]_phenyl-N'-dimethylure~. Melting point of the fumarate; 164 to
167C.
N-[3-(1~-hydroxyiminojmethyl-4-(3'-tert.-butyla~ino-2'-hydroxy)-
propoxy~-phenyl-~'-dimethylurea. Melting point: 169 to 172C,~
3-(1l-hydro~yimino)-methyl-4-(3'-tert.-butylamino-2'-hydroxy)- ~
i~ propoxy]-phen~l-N'-diethylurea. Melting point: 158 to 161~. - ;
;,a, ~ . : ' ~
s ~.~. , .. ... ..... ,.. .~ . . . . . . . . . . .
iS)4Liz36
N-[3~ hydroxyimino)-propyl_4-(31-tertA.-butylamino-2~-hydroxy)-
~ropoxy]-phenyl-N'-diethylurea. Melting point of the fumarate: 210~ to
~, 212C. .
N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-
propoxy]-phanyl-N'-dipropylurea. ~elting point of the fumarate- 205 to
206C.
N-[3-(1'-hydroxyimino)-butyl-4~ tert.-butylamino-2'-hydroxy)-
propoxy]-phenyl-N'-diethylurea. Melting point of the fumarate: 178 to
180C.
N-[~-(l'-hydroxyimino)-propyl-4-(3'-tert.-butylamino-2'-hydroxy)-
propoxy]-phenyl-N'-pentamethylene-(1,5)-urea. Melting point of the fumarate:
, 156 to 158C.
N-~3-(l~-hydroxyimino)-propyl-4-(3~-tert~-butylamino-21-hydroxy)-
propoxy]-phenyl-N'-dimethylurea. Melting point: 86 to 88C.
1~ N-~3-(1'-hydroxyimino)-butyl-4-(3'-tert.-butylamino-2'-hhdroxy)-
t propoxy]-phenyl-N'-pentamethylene-(1,5)-urea. Melting point of the
fumarate: 148 to 150C.
N-~3-tl'-hydroxyimino)-ethyl-4-(3'-ter,t.-butylamino-Z'-hydroxy)-
propoxy]-phenyl-N'-phenylurea. Melting point: 105 to 108C.
~ 20 N-[3-(1'-hydroxyimino)-ethyl-4-(3'-tert.-butylamino-2'-hydroxy)-
`f : propoxy]-phen~l N'~ethyl-N'-cyclohexylurea. Melting point of the fumarate:
~ 166 to 168C.
i, ~ . :
~; ' '
:, :
., .
.. , `
`
.~ .
., .
, ~ 15
