CA1044236A - Process for the preparation of phenoxypropylamine derivatives and salts thereof - Google Patents
Process for the preparation of phenoxypropylamine derivatives and salts thereofInfo
- Publication number
- CA1044236A CA1044236A CA239,750A CA239750A CA1044236A CA 1044236 A CA1044236 A CA 1044236A CA 239750 A CA239750 A CA 239750A CA 1044236 A CA1044236 A CA 1044236A
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- hydroxy
- phenyl
- tert
- carbon atoms
- propoxy
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/38—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention discloses a new and commercially useful process for the preparation of phonoxypropylamine derivatives of the general formula (I):
(I) and the acid addition salts thereof wherein R is a hydrogen atom or an alkyl group, R1 is 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 x is an oxygen atom or the group -NOR4, wherein in the case where X is oxygen R2 is not hydrogen and R4 is a hydrogen atom, a lower alkyl group or an aralkyl group. This process comprises reacting a urea derivative of the general formula (II):
with an amine of the general formula (III):
This invention discloses a new and commercially useful process for the preparation of phonoxypropylamine derivatives of the general formula (I):
(I) and the acid addition salts thereof wherein R is a hydrogen atom or an alkyl group, R1 is 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 x is an oxygen atom or the group -NOR4, wherein in the case where X is oxygen R2 is not hydrogen and R4 is a hydrogen atom, a lower alkyl group or an aralkyl group. This process comprises reacting a urea derivative of the general formula (II):
with an amine of the general formula (III):
Description
~ ~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 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. ~
' ~ .
; 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 - . : , ,, ~'' ' ' `' 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-
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 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. ~
' ~ .
; 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 - . : , ,, ~'' ' ' `' 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 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.
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 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'--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~
' ' 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
~;~ 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'--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~
' ' 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
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
Claims (7)
- Claim 1 continued....
(II) in which 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 an elevated temperature, and then isolating the reaction product as the free base or a salt thereof. - 2. A process as claimed in claim 1, in which the reaction is carried out at a temperature within the range of 50° to 200°.
- 3. A process as claimed in claim 2, in which the reaction is carried out at a temperature from 50° to 150°C.
- 4. A process as claimed in claim 1, in which the amine of formula (III) is employed in excess relative to the urea derivative of formula (II).
- 5. A process as claimed in claim 4, in which the amine of formula (III) simultaneously serves as solvent.
- 6. A process as claimed in claim 1, in which a mixture of an aliphatic alcohol with water is used as solvent.
- 7. A process as claimed in claim 1, in which the amine of formula (II) is used in the form of one of its salts, and a stoichiometric amount of an aqueous alkali solution is added to the reaction mixture.
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 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 a hydrogen atom or 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 hydroxy alkyl group containing up to 6 carbon atoms, a cycloalkyl group con-taining 3 to 7 carbon atoms or a cyanoalkyl group containing up to 6 carbon atoms and X is an oxygen atom or the group -NOR4, wherein in the case where X is oxygen, R2 is not hydrogen, and R4 is a hydrogen atom, a lower alkyl group with up to 4 carbon atoms or benzyl and the pharmaceutically-acceptable acid addition salts thereof, which comprises reacting a urea derivative of the general formula:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT943674A AT335467B (en) | 1974-11-25 | 1974-11-25 | A PROCESS FOR THE PREPARATION OF NEW 3- (P-UREIDOPHENOXY) -2-HYDROXY-AMINOPROPANES AND THEIR ACID ADDITION SALTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1044236A true CA1044236A (en) | 1978-12-12 |
Family
ID=3614119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA239,750A Expired CA1044236A (en) | 1974-11-25 | 1975-11-13 | Process for the preparation of phenoxypropylamine derivatives and salts thereof |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5231046A (en) |
| AT (1) | AT335467B (en) |
| CA (1) | CA1044236A (en) |
| CH (1) | CH615906A5 (en) |
| CS (1) | CS181692B2 (en) |
| DD (1) | DD122081A1 (en) |
| ES (1) | ES442895A1 (en) |
| LU (1) | LU73858A1 (en) |
| PL (1) | PL96061B1 (en) |
| RO (1) | RO72484A (en) |
| YU (1) | YU39538B (en) |
-
1974
- 1974-11-25 AT AT943674A patent/AT335467B/en not_active IP Right Cessation
-
1975
- 1975-10-10 YU YU2581/75A patent/YU39538B/en unknown
- 1975-10-14 CH CH1331275A patent/CH615906A5/en not_active IP Right Cessation
- 1975-10-31 CS CS7500007351A patent/CS181692B2/en unknown
- 1975-11-12 RO RO7583898A patent/RO72484A/en unknown
- 1975-11-13 CA CA239,750A patent/CA1044236A/en not_active Expired
- 1975-11-21 JP JP50139371A patent/JPS5231046A/en active Granted
- 1975-11-21 DD DD189614A patent/DD122081A1/xx unknown
- 1975-11-22 PL PL1975184945A patent/PL96061B1/en unknown
- 1975-11-24 ES ES442895A patent/ES442895A1/en not_active Expired
- 1975-11-24 LU LU73858A patent/LU73858A1/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| LU73858A1 (en) | 1976-09-06 |
| ATA943674A (en) | 1976-07-15 |
| CH615906A5 (en) | 1980-02-29 |
| AT335467B (en) | 1977-03-10 |
| CS181692B2 (en) | 1978-03-31 |
| DD122081A1 (en) | 1976-09-12 |
| YU258175A (en) | 1982-05-31 |
| PL96061B1 (en) | 1977-12-31 |
| JPS5231046A (en) | 1977-03-09 |
| ES442895A1 (en) | 1977-04-16 |
| JPS5312508B2 (en) | 1978-05-01 |
| YU39538B (en) | 1984-12-31 |
| RO72484A (en) | 1981-11-24 |
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