CA1061341A - Process for the preparation of phenoxypropylamine derivatives and salts thereof - Google Patents
Process for the preparation of phenoxypropylamine derivatives and salts thereofInfo
- Publication number
- CA1061341A CA1061341A CA239,398A CA239398A CA1061341A CA 1061341 A CA1061341 A CA 1061341A CA 239398 A CA239398 A CA 239398A CA 1061341 A CA1061341 A CA 1061341A
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- formula
- hydroxy
- carbon atoms
- phenyl
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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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- 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 disclosed a new and commercially useful process for the preparation of phenoxypropylamine derivative of the general formula (I):
(I) and the acid addition salts thereof, wherein, R is a hydrogen atom or an alkyl group, R1 is a hydrogen atom or an alkyl, cycloalkyl, aralkyl or aryl group or R and R1 together represent a divalent, optionally branched hydrocarbon group, optionally sub-stituted, R2 is an alkyl, aralkyl, or aryl group and R3 is an alkyl, hydroxyalkyl, cycloalkyl or cyanalkyl group. This process comprises reacting an alkali metal salt of a phenol of general formula (II) (II) with a compound or mixture of compounds of the general formula (III) (III) in which X is a group or
This invention disclosed a new and commercially useful process for the preparation of phenoxypropylamine derivative of the general formula (I):
(I) and the acid addition salts thereof, wherein, R is a hydrogen atom or an alkyl group, R1 is a hydrogen atom or an alkyl, cycloalkyl, aralkyl or aryl group or R and R1 together represent a divalent, optionally branched hydrocarbon group, optionally sub-stituted, R2 is an alkyl, aralkyl, or aryl group and R3 is an alkyl, hydroxyalkyl, cycloalkyl or cyanalkyl group. This process comprises reacting an alkali metal salt of a phenol of general formula (II) (II) with a compound or mixture of compounds of the general formula (III) (III) in which X is a group or
Description
139~1 . . ` ~
1 This invention relates to a process for the preparation ..
of phenoxypropylamine derivatives. .
- Substances with a blocking action on the ~-receptors ~ .
are becoming increasingly important;in the therapeutic treatment ;
of various cardiac illness whose aetiology or symptoms may be explained by an undeslrably high content o endogenous catechol- .
amines in the circulation. In this connection a significant .. .
advance has been achieved by the discovery of so-called cardio~
selective ~-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 undesir-able 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, namel~ l'-(~-acetamino-phenoxy(2'-hydroxy-3'-isopropylamino))-propane, which is described 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. However, many - ~-blocking agsnts have the drawback of an undesirable cardio-.:
depressant action which is often coupled with the ~-blocking action. I!
The patent literature has also disclosed cardioselective ~:
phenoxypropylamine derivatives with a ureido group in the p-position relative to the propylamine side chain (DT-OS No. .
1 This invention relates to a process for the preparation ..
of phenoxypropylamine derivatives. .
- Substances with a blocking action on the ~-receptors ~ .
are becoming increasingly important;in the therapeutic treatment ;
of various cardiac illness whose aetiology or symptoms may be explained by an undeslrably high content o endogenous catechol- .
amines in the circulation. In this connection a significant .. .
advance has been achieved by the discovery of so-called cardio~
selective ~-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 undesir-able 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, namel~ l'-(~-acetamino-phenoxy(2'-hydroxy-3'-isopropylamino))-propane, which is described 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. However, many - ~-blocking agsnts have the drawback of an undesirable cardio-.:
depressant action which is often coupled with the ~-blocking action. I!
The patent literature has also disclosed cardioselective ~:
phenoxypropylamine derivatives with a ureido group in the p-position relative to the propylamine side chain (DT-OS No. .
2,lOO,323), which may be substituted in the nucleus by hydro- .
carbon groups, ether groups, halogen atoms, trifluoromethyl groups or nitrile groups and also cardioselective phenoxy- ~;
propylamine derivatives with an alkanoylami~e group in the p-position and acyl groups, for example the acetyl group, in the ~.
30 o-position relative to the propylamine side chain, see ~ustrian ~~
Patent Specification No. 292,671. :
--1-- ~.
- ~6:~L341 1 Surprisingly, it has now been found that phenoxy~
propylamine derivatives which carry a ureido group in the p~
position to the phenoxypropylamine chain and an acyl group, ~.
preferably a lower alkanoyl group, in the o-position, and which .. :
have the general formula~
NH - CO - N - R~
Ri r.'; ;: "
Cl - R2 (I) O '~ .'~' .,~.
OCH2 - CH - CH2 N~I 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 represen~t 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 an alkyl, aralkyl or aryl ..
group and R3 is a preferably branched alkyl group, a hydroxy~
alkyl, cycloalkyl or cyanoalkyl group, and also the salts of 20 these derivatives, have outstanding cardioselective, ~-blocking :.
properties which are coupled with a very good and reliable activity when administered orally. The activity of the deriva- ~ .
tives c formula ~I) may be determined on awake dogs by the .
method of Dunlop ~ Shanks, Brit. J Pharmacol 32, 201-18, 1968.
The cardioselective action may be recognised for example by the ~ :
fact that according to the method of Shanks et al, Cardiologia suppl. II, 49, 11 (1966) carried out on narcotised dogs, the . ..
increase in pulse rate produced by isoprenaline is more strongly inhi.bited by prior administration of the above compounds than is `' the hypotensive effect of isoprenaline. This effect also may be -2- .
.
i3~i ~
1 seen in rats from a blocking erfect on the increase in unesteri-fied fatty acids caused by isoprenalina (~l-effect), whereas hardly any effect 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), lO which indicates that the compounds of the formula (I) do not .
exhibit any undesired and in some cases dangerous cardio- ~
depressant action. The toxicity of the compounds of the ;.
formula (I) in mice is the same as, or even lower than that of :~
the commercially available ~-blocking agents. .
The present invention provides a process for the preparation of a compound of the formula (I) which comprises ~
reacting an alkali metal salt of a phenol of the general formula: ;
NH - 5 N = I ~:
~ _ li R2 (II) OH
in which R, Rl and R2 are as defined above for formula (I), with a compound of the formula:
/ 3 ~ :
X - CH2 - N (III) in which X is a group Hal-CH2-CH or / , wherein Hal OH CH2 - CH- ~:
carbon groups, ether groups, halogen atoms, trifluoromethyl groups or nitrile groups and also cardioselective phenoxy- ~;
propylamine derivatives with an alkanoylami~e group in the p-position and acyl groups, for example the acetyl group, in the ~.
30 o-position relative to the propylamine side chain, see ~ustrian ~~
Patent Specification No. 292,671. :
--1-- ~.
- ~6:~L341 1 Surprisingly, it has now been found that phenoxy~
propylamine derivatives which carry a ureido group in the p~
position to the phenoxypropylamine chain and an acyl group, ~.
preferably a lower alkanoyl group, in the o-position, and which .. :
have the general formula~
NH - CO - N - R~
Ri r.'; ;: "
Cl - R2 (I) O '~ .'~' .,~.
OCH2 - CH - CH2 N~I 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 represen~t 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 an alkyl, aralkyl or aryl ..
group and R3 is a preferably branched alkyl group, a hydroxy~
alkyl, cycloalkyl or cyanoalkyl group, and also the salts of 20 these derivatives, have outstanding cardioselective, ~-blocking :.
properties which are coupled with a very good and reliable activity when administered orally. The activity of the deriva- ~ .
tives c formula ~I) may be determined on awake dogs by the .
method of Dunlop ~ Shanks, Brit. J Pharmacol 32, 201-18, 1968.
The cardioselective action may be recognised for example by the ~ :
fact that according to the method of Shanks et al, Cardiologia suppl. II, 49, 11 (1966) carried out on narcotised dogs, the . ..
increase in pulse rate produced by isoprenaline is more strongly inhi.bited by prior administration of the above compounds than is `' the hypotensive effect of isoprenaline. This effect also may be -2- .
.
i3~i ~
1 seen in rats from a blocking erfect on the increase in unesteri-fied fatty acids caused by isoprenalina (~l-effect), whereas hardly any effect 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), lO which indicates that the compounds of the formula (I) do not .
exhibit any undesired and in some cases dangerous cardio- ~
depressant action. The toxicity of the compounds of the ;.
formula (I) in mice is the same as, or even lower than that of :~
the commercially available ~-blocking agents. .
The present invention provides a process for the preparation of a compound of the formula (I) which comprises ~
reacting an alkali metal salt of a phenol of the general formula: ;
NH - 5 N = I ~:
~ _ li R2 (II) OH
in which R, Rl and R2 are as defined above for formula (I), with a compound of the formula:
/ 3 ~ :
X - CH2 - N (III) in which X is a group Hal-CH2-CH or / , wherein Hal OH CH2 - CH- ~:
-3- .
~a6~3~
1 is chlorine, bromine or iodine and ~4 is hydrogen or a group which can split off hydrogenolytically, and R3 is as defined above, or with a mixture of compounds of formula (III), and splitting off by hydrogenation any groups present in the reaction product which can split off hydrogenolytically, and :isolating the reaction proauct as the free base or a salt thereof.
It is not necessary for the reaction to use an alkali metal salt of the phenol of formula (II) in isolated form. It is equally possible to produce the salt in situ from the free phenol of the formula (II) by adding an equivalent amount of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, to the reaction mixture.
The reaction is suitably carried out in a solvent~ In addition to dimethylformamide and acetonitrile, aliphatic alcohols in particular, such as methanol and ethanol, have proved suitable. The reaction also may be carried out in a mixture of such solvent with water. -The reaction is accelerated by raising the temperature.
The reaction is therefore conveniently carried out at a moderately elevated temperature, for example at the boiling point of the solvent used.
If the reaction starts from a compound of formula (III) in which R~ is a group which can be split off hydrogeno-lytically, this group must be subsequently split off. This splitting off is achieved simply by catalytic hydrogenation with a catalyst such asr for example, Raney nickel, platinum oxide or palladium charcoal. Solvents which may be used for the hydrogenation are, for example, aliphatic alcohols, such as for example, methanol or ethanol, or fatty acids, such as for e~ample, glacial acetic acid. The splitting off of the protective group ',' .
~a6~3~
1 is chlorine, bromine or iodine and ~4 is hydrogen or a group which can split off hydrogenolytically, and R3 is as defined above, or with a mixture of compounds of formula (III), and splitting off by hydrogenation any groups present in the reaction product which can split off hydrogenolytically, and :isolating the reaction proauct as the free base or a salt thereof.
It is not necessary for the reaction to use an alkali metal salt of the phenol of formula (II) in isolated form. It is equally possible to produce the salt in situ from the free phenol of the formula (II) by adding an equivalent amount of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, to the reaction mixture.
The reaction is suitably carried out in a solvent~ In addition to dimethylformamide and acetonitrile, aliphatic alcohols in particular, such as methanol and ethanol, have proved suitable. The reaction also may be carried out in a mixture of such solvent with water. -The reaction is accelerated by raising the temperature.
The reaction is therefore conveniently carried out at a moderately elevated temperature, for example at the boiling point of the solvent used.
If the reaction starts from a compound of formula (III) in which R~ is a group which can be split off hydrogeno-lytically, this group must be subsequently split off. This splitting off is achieved simply by catalytic hydrogenation with a catalyst such asr for example, Raney nickel, platinum oxide or palladium charcoal. Solvents which may be used for the hydrogenation are, for example, aliphatic alcohols, such as for example, methanol or ethanol, or fatty acids, such as for e~ample, glacial acetic acid. The splitting off of the protective group ',' .
-4-. ..
I also may be carried out in the presence of a mineral acid, for example, hydrochloric acid.
The compound of formula (I) may be isolated in a conventional 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, cyclohexylsulphamates, tartrates and citrates may be prepared.
The compounds of formula (I) have an asymmetric carbon atom. They therefore exist as the racemate and as optically active forms. The racemate may be separated into the optically active forms in a conventional manner, for example by forming the diastereomeric salts with optically active acids, for example tartaric acid, or camphorsulphonic acid.
The starting compounds of formula (II) are in many cases new. They may be prepared by methods which are known per se. Thus, for example, the compounds of formula (II) in which each of R and Rl is hydrogen may be obtained by reacting the corresponding aniline salt with potassium cyanate~ If it is desired to prepare a compound of formula (II) in which R and/or Rl is/are not hydrogen, the corresponding ureido-substituted phenol is obtained by reactin~ the corresponding isocyanate whose phenolic hydroxyl group is protected by an acyl or benzyl -group, with an amine of the formula HNRRl, R and Rl being as defined above. The group protecting the phenolic hydroxyl group then may be easily split off. Synthesis of the ureido-substituted . .
1 phenol also may be effected from the corresponding aniline by using a carbamic acid chloride.
The star~ing compounds of formula ~ may be easily prepared by methods known from the literature (e.g. Tetrahedron 23, 2123 (1967)).
Compoun~s of formula (I) which are particularly suit-able 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, Also suitable are compounds in which R and Rl together with the terminal N-atom of the ureido group represent a pyrroli-dino, diazolidino, e.g. imidazolidino, thiazolidino, oxazolidino;
piperidino, morpholino, tetrahydrodiazino, e.g. tetrahydropyrimi-dino, tetrahydrothiazino or homopiperazino group. The pyrroli-dino, piperidino and morpholino groups are preferred. R2 is preferably 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, a cyanoalkyl group with up to 6 carbon atoms, or a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
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 carbon atoms, or both together for a tetrame-thylene, pentamethylene or 3-oxapentamethylene group, R2 is a lo~er alkyl group with 1 to 5 carbon atoms and R3 is a tertiary butyl group or an isopropyl group. -The compounds of formula (I) may be present as active , , .
13~L
1 ingredients in pharmaceutical compositions which may be adminis- -tered orally, rectally or parenterally. For this purpose they may be mixed with conventional pharmaceutically-acceptable carriers, the nature of the carrier being determined by the method of application. They may be converted into tablets or dragees in the usual way, and the active compounds themselves, optionally together with a pharmaceutically-acceptable solvent, may be made up into capsules.
Pharmaceutically~acceptable soluble salts which are capable of forming stable solutions may be used in the form of injectable solutions. The salts for this purpose may be obtained simply from the corresponding bases of formula (I) by reaction -with the equivalent amount of acid. Both bases and salts may be converted in the usual way into suppositories.
The individual dose for humans is 100 mg in the case of oral administration, and correspondingly lower in the case of intravenous administration.
The following Examples illustrate the invention.
Example 1 20 ml of methanol is àdded to 0.5 g of N~(3-acetyl-4- ~
hydroxy)-phenylurea, followed ~y a solution of 0.68 ~ of ~`
potassium hydroxide (85~ concentration) in 5 ml of water, and ;
2.48 g of 1-chloro-2-hydroxy-3-(N--benzyl-N-isopropylamino)-propane, and the mixture is stirred for 25 hours at boiling ~`
point. The methanol is then removed in vacuo and the residue is acidified with lN hydrochloric acid, extracted with chloro-form, and the chloroform phase is discarded. The acid aqueous solution is made alkaline with sodium hydroxide and extracted several times with chloroform. The chloroform solution is dried and evaporated. The residue is digested with ether and - the crystalline product which precipitates is filtered offD
, ~ .
:
34~L
1 Yield of N-[3-acetyl-4-(3'-N-benzyl-isopropylamino-2'-hydroxy)-propoxy]-phenylurea: 0.6 g = 58.3% of theory. After recrystallization from methyl ethyl ketone, the compound has a melting point of 127 to 130C.
156 mg of N-~3-acetyl-4-(3'-N-benzyl-isopropylamino-2'-hydroxy)-propoxy]-phenylurea is added to a pre-hydrogenated suspension of 15.6 mg of palladium-charcoal (10%) in 7.0 ml of glacial acetic acid, and hydrogenated at room temperature until the uptake of hydrogen ceases. The catalyst is removed, the ~iltrate is concentrated ln vacuo, the residue is dissolved in water, made alkaline with sodium hydroxide (pH 10) and extracted -with chloroform. The chloroform solution is dried and then concentrated in vacuo, the oily residue is digested with acetone and seeded, and the crystalline product formed is filtered of.
Yield of N-[3-acetyl-4-~3'-isopropylamino-2'-hydroxy)-propoxy]- `~
phenylurea: 72 mg ~ 59.6~ o~ theory. Melting point: 124 to 126C.
The N-(3-acetyl-4-hydroxy)-phenylurea required as a ~;
starting compound may be prepared as follows: 50.0 g of 3-acetyl-4-hydroxyaniline hydrochloride and 43.2 g of potassium cyanate are heated for 30 minutes at boiling point in 1350 ml o~ a 1:1 `~
mixture of ethanol and water, cooledr and left to stand overnight at -5C to bring about crystallisation.
Yield of N-(3-acetyl-4-hydroxy)-phenylurea: 36.7 g =
71.0% of theory. Melting point: 218 to 220C.
l-chloro-2-hydroxy-3-(N-benzyl-N-isopropylamino)- .'5' propane may be prepared as follows:
I also may be carried out in the presence of a mineral acid, for example, hydrochloric acid.
The compound of formula (I) may be isolated in a conventional 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, cyclohexylsulphamates, tartrates and citrates may be prepared.
The compounds of formula (I) have an asymmetric carbon atom. They therefore exist as the racemate and as optically active forms. The racemate may be separated into the optically active forms in a conventional manner, for example by forming the diastereomeric salts with optically active acids, for example tartaric acid, or camphorsulphonic acid.
The starting compounds of formula (II) are in many cases new. They may be prepared by methods which are known per se. Thus, for example, the compounds of formula (II) in which each of R and Rl is hydrogen may be obtained by reacting the corresponding aniline salt with potassium cyanate~ If it is desired to prepare a compound of formula (II) in which R and/or Rl is/are not hydrogen, the corresponding ureido-substituted phenol is obtained by reactin~ the corresponding isocyanate whose phenolic hydroxyl group is protected by an acyl or benzyl -group, with an amine of the formula HNRRl, R and Rl being as defined above. The group protecting the phenolic hydroxyl group then may be easily split off. Synthesis of the ureido-substituted . .
1 phenol also may be effected from the corresponding aniline by using a carbamic acid chloride.
The star~ing compounds of formula ~ may be easily prepared by methods known from the literature (e.g. Tetrahedron 23, 2123 (1967)).
Compoun~s of formula (I) which are particularly suit-able 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, Also suitable are compounds in which R and Rl together with the terminal N-atom of the ureido group represent a pyrroli-dino, diazolidino, e.g. imidazolidino, thiazolidino, oxazolidino;
piperidino, morpholino, tetrahydrodiazino, e.g. tetrahydropyrimi-dino, tetrahydrothiazino or homopiperazino group. The pyrroli-dino, piperidino and morpholino groups are preferred. R2 is preferably 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, a cyanoalkyl group with up to 6 carbon atoms, or a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
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 carbon atoms, or both together for a tetrame-thylene, pentamethylene or 3-oxapentamethylene group, R2 is a lo~er alkyl group with 1 to 5 carbon atoms and R3 is a tertiary butyl group or an isopropyl group. -The compounds of formula (I) may be present as active , , .
13~L
1 ingredients in pharmaceutical compositions which may be adminis- -tered orally, rectally or parenterally. For this purpose they may be mixed with conventional pharmaceutically-acceptable carriers, the nature of the carrier being determined by the method of application. They may be converted into tablets or dragees in the usual way, and the active compounds themselves, optionally together with a pharmaceutically-acceptable solvent, may be made up into capsules.
Pharmaceutically~acceptable soluble salts which are capable of forming stable solutions may be used in the form of injectable solutions. The salts for this purpose may be obtained simply from the corresponding bases of formula (I) by reaction -with the equivalent amount of acid. Both bases and salts may be converted in the usual way into suppositories.
The individual dose for humans is 100 mg in the case of oral administration, and correspondingly lower in the case of intravenous administration.
The following Examples illustrate the invention.
Example 1 20 ml of methanol is àdded to 0.5 g of N~(3-acetyl-4- ~
hydroxy)-phenylurea, followed ~y a solution of 0.68 ~ of ~`
potassium hydroxide (85~ concentration) in 5 ml of water, and ;
2.48 g of 1-chloro-2-hydroxy-3-(N--benzyl-N-isopropylamino)-propane, and the mixture is stirred for 25 hours at boiling ~`
point. The methanol is then removed in vacuo and the residue is acidified with lN hydrochloric acid, extracted with chloro-form, and the chloroform phase is discarded. The acid aqueous solution is made alkaline with sodium hydroxide and extracted several times with chloroform. The chloroform solution is dried and evaporated. The residue is digested with ether and - the crystalline product which precipitates is filtered offD
, ~ .
:
34~L
1 Yield of N-[3-acetyl-4-(3'-N-benzyl-isopropylamino-2'-hydroxy)-propoxy]-phenylurea: 0.6 g = 58.3% of theory. After recrystallization from methyl ethyl ketone, the compound has a melting point of 127 to 130C.
156 mg of N-~3-acetyl-4-(3'-N-benzyl-isopropylamino-2'-hydroxy)-propoxy]-phenylurea is added to a pre-hydrogenated suspension of 15.6 mg of palladium-charcoal (10%) in 7.0 ml of glacial acetic acid, and hydrogenated at room temperature until the uptake of hydrogen ceases. The catalyst is removed, the ~iltrate is concentrated ln vacuo, the residue is dissolved in water, made alkaline with sodium hydroxide (pH 10) and extracted -with chloroform. The chloroform solution is dried and then concentrated in vacuo, the oily residue is digested with acetone and seeded, and the crystalline product formed is filtered of.
Yield of N-[3-acetyl-4-~3'-isopropylamino-2'-hydroxy)-propoxy]- `~
phenylurea: 72 mg ~ 59.6~ o~ theory. Melting point: 124 to 126C.
The N-(3-acetyl-4-hydroxy)-phenylurea required as a ~;
starting compound may be prepared as follows: 50.0 g of 3-acetyl-4-hydroxyaniline hydrochloride and 43.2 g of potassium cyanate are heated for 30 minutes at boiling point in 1350 ml o~ a 1:1 `~
mixture of ethanol and water, cooledr and left to stand overnight at -5C to bring about crystallisation.
Yield of N-(3-acetyl-4-hydroxy)-phenylurea: 36.7 g =
71.0% of theory. Melting point: 218 to 220C.
l-chloro-2-hydroxy-3-(N-benzyl-N-isopropylamino)- .'5' propane may be prepared as follows:
5.0 g of N-benzylisopropylamine is stirred for 2 hours at 50C ~;
in a mixture of 12 ml of methanol and 5 ml of water, the methanol -~
is distilled off n vacuo at 30C, the base which separates out 3~1 1 is extracted with ether, and the ethereal solution is dried with anhydrous sodium sulphate and concentràted. The residue is distilled ln vacuo. Boiling point at 0.05 mm = 91 to 92C.
Yield: 7.0 g = 86.6% of theory.
Example 2 50 ml of ethanol is added to 1.0 g of N-~3-acetyl-4-hydroxy)-phenvlur~a, followed by 5.27 g of 1-chloro-2-hydroxy-3-(N-benzyl-N-tert.-butylamino)-propane and a solution of 1.36 g of caustic alkali ~85~ KOH). The reactiQn mixture is heated for 23 hours at boiling point and under a nitrogen atmosphere, the alcohol is distilled off in vacuo, water is added to the residue, the residue is acidified with hydrochloric acid, extracted with chloroform, and the aqueous layer is made alkaline and re-extracted with chloroform. After drying the extract over anhydrous sodium sulphate, the solvent is distilled o~f in vacuo, the residue i8 digested with ether and seeded, and the crystalline product which precipitates is filtered off after a period of time.
Yield of N-[3-acetyl-4-(3'-N-benzyl-tert.-butyl-amino-2'-hydroxy)-propoxy~-phenylurea: 1.15 g = 54.0% of theory. Melting point 20 (in acetone): 145 to 147C.
The splitting off of the benzyl group by catalytic `~
hydrogenation is carried out as described in Example 1. The N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxyl~phenyl-urea hydrochloride has a melting point of 195 to 197C.
The preparation of the starting compound is carried out in an analogous manner to Example 1.
- l-chloro-2-hydroxy-3-(N-benzyl-N-tert.-butylamino)-propane has a boiling point at 0.05 mm of 105 to 107C.
Example 3 0.5 g of N-(3-acetyl-4-hydroxy)-phenyl-N'-methylurea ....
_g_ :~
L34~ ~
1 is dissolved in methanol, a solution of 0.2 g of potassium hydroxide in 25 ml of methanol is added, followed by 0.5 g of l-chloro-2-hydroxy-3-tert.-butylamino propane hydrochloride, and the mixture is heated for 45 hours at boiling point.
The solvent is distilled off in vacuo, the residue is taken up in methylene chloride, and the organic phase is extracted with sodium hydroxide and water, dried with sodium sulphate and concentrated in vacuo.
The N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy}-phenyl-N'-methylurea thus formed crystallises after seeding and digestion with ether. Melting point: 132 to 134C.
Example 4 18 ml of methanol is added to 1.0 g of N-(3 acetyl-4-hydroxy)-phenyl-Nl-pentamethylene(l~5)-urea/ followed by 0.8 g of l-chloro-2-hydroxy-3-tert.-butylaminopropane hydrochloride, 0.5 g of potassium hydroxide (85%) and 2 ml of water, and the mixture is stirred for 27 hours at 50C.
The solvent is distilled off in ~acuo and the residue is taken up in lN hydrochloric acid and washed several times with ethyl acetate. The aqueous solution is made alkaline with ~N
sodium hydroxide, extracted several times with methylene chloride, and the organic phase is dried with sodium sulphate and distilled in vacuo. ~;
The residue, which contains the base of N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-penta-methylene(l,5)-urea is dissolved in 5 ml of acetone of the formation of the fumarate, a solution of 0.1 g of fumaric acid in 5 ml of acetone is added, the resultant solution is seeded, and the crystalline product which precipitates is filtered of, washea with acetone and ether, and dried. Melting point: 211 to 213C.
--10-- ;.
34~
... . .
1 Example 5 The preparation of N-[3-acetyl-4-(3'-N-benzyl-N-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea (melting point of the fumarate: 110~ to 112C) is carried out in an analogous manner to Example 1.
To split off the N-benzyl group by catalytic hydrogena-tion, 111 mg of N-[3-acetyl-4-(3'-N-benzyl-N--isopropylamino-2'-hydroxy)-propoxy~-~henyl-N'-diethylurea is added to a prehydro-genated suspension of Raney nickel in 6~5 ml of ethanol and hydrogenated at room temperature until the uptake of hydrogen has ceased. Duration of reaction: 5 hours.
The catal~st is separated, the solvent is distilled off in vacuo, the oily residue is triturated with ether and seeded, and the crystalline product which precipitates is ~iltered off after a period of time.
Yield of N-[3-acetyl-4-t3'-isopropylamino-2'-hydroxy~-propoxy]-phenyl-N'-diethylurea: 65 mg = 73% of theory.
Example 6 14.2 mg of palladium charcoal is prehydrogenated in 7 ml of ethyl alcohol containing 8.1 mg of hydrochloric acid.
100.8 mg of N-[3-acetyl-4-(3'-N-benzyl N'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea prepared in an analogous manner to Example 1 is added and hydrogena-tion is carried out until the uptake of hydrogen has ceased. Duration of reaction:
2 hours.
The catalyst is separated, the filtrate is concentrated n. vacuo,~ the residue is taken up in water and made alkaline with sodium hydro~ide solution, and the base formed is extracted with ethyl acetate. After drying the product with anhydrous sodium sulphate, the solvent is evaporated in vacuo, the residue .
:, '. ' .. ~ : . .
.
. :
L341 ` ~
1 is digested with ether and seeded, and the crystalline product formed is filtered off after a period of time. Yield: 62 mg =
76.6~ of theory.
The following compounds may be obtained in an analogous manner to Examples 1 to 5:-N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]- -phenyl-N'-diethylurea. Melting point of the base: 110 to 112C.
N-~3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy3-phenyl-N'-dimethylurea. Melting point o the fumarate: 205~to 208C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-ethylurea. Melting point of the ftlmarate: 196 to 198C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxv~-propoxy]-phenyl-N'-isopropylurea. Melting poin~ of the base: 87 to 90C.
N-[3-acetyl-~-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-butylurea. Melting point of the fumarate: 215 to 217C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-sec.butylurea. Meltin~ point of the fumarate: 215 to 217C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy~-phenyl-N'-tert.butylurea. Melting point of the fumarate: 213 ~o 215C.
N-[3-acetyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Meltin~ point of the base: 103 to -107C.
N-[3-acetyl-4-~3'-cyclopropylamino-2'-hydroxy~-propoxy]- -N'-dimethylurea. Melting point of the base: 80 to 83C.
N-[3-acetyl-4-(3'-tert.butylamino 2'-hydroxy)~propoxy]-phenyl-N'-methyl-N'-ethylurea. Melting point of the fumarate: ;
195 to 197C.
3~ N-[3~acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-butylurea. Melting point of the fumarate: 192 to 195C.
1 N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy~-propoxy]-phenyl-N'-di-_-butylllrea. Melting point of the fumarate: 184 to 187~C.
N~[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]- ;
phenyl-N'-di-n-propylurea. Melting point of the fumarate: 164 to 167C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-phenylurea. Melting point o~ the base: 159 to 164C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-10 phenyl-N~-tetramethylene(l~4)-urea. Melting point of the fumarate: 218 to 220C.
N-[3-propionyl-~-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenylurea. Melting point o~ the fumarate: 20~ to 207C.
N-[3-propionyl-4-(3'-tert.butylamino-2'-hydroxy)~
propoxy~-phenyl-N'-methylurea. Melting point of the fumarate:
13~ to 136C.
N-[3-propionyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point of the base:
107 to 109C.
N-[3-propionyl-~-~3'-tert.butylamino-2'-hydroxy)-propoxyJ-phenyl-N'-aimethylurea. Melting point of the fumarate:
l99~to 202C.
N-[3-propionyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy}-phenyl-N'-tetramethylene(1,4)-urea. Melting point of the fumarate:
208 to 211C.
N-[3-propionyl-~-(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-~-(3'-tert.butylamino-2'-hydroxy)-propoxy]-3~ phenyl-N'-pentamethylene(1,5)-urea. Melting point of the fumarate~
167 to 170C.
`,': ' .
6134~L
1 N-[3-phenylacetyl-4-(3'-tert.butylamino-2'-hydroxy)- -propoxy]-phenyl-N'-pentamethylene(1,5)-urea. Melting point of the base: 117 to 118C.
N-[3-benzoyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy~-phenyl-N'-pentamethylene(1,5)-urea. Melting point of the base:
120 to 1~3C.
- N- f 3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-isopropylurea. Melting point o~ the base:
105 to 107C. `
t0 N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy~
phenyl-N'-ethyle-N'-n-propylurea. Melting point of the fumarate:
176 to 178C.
N-13-butyryl-4 (3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point of the base: 56 to 58C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-benzylurea. Melting point of the fumarate:
211 to 214C.
~0 . .
, ;":
. .
;
in a mixture of 12 ml of methanol and 5 ml of water, the methanol -~
is distilled off n vacuo at 30C, the base which separates out 3~1 1 is extracted with ether, and the ethereal solution is dried with anhydrous sodium sulphate and concentràted. The residue is distilled ln vacuo. Boiling point at 0.05 mm = 91 to 92C.
Yield: 7.0 g = 86.6% of theory.
Example 2 50 ml of ethanol is added to 1.0 g of N-~3-acetyl-4-hydroxy)-phenvlur~a, followed by 5.27 g of 1-chloro-2-hydroxy-3-(N-benzyl-N-tert.-butylamino)-propane and a solution of 1.36 g of caustic alkali ~85~ KOH). The reactiQn mixture is heated for 23 hours at boiling point and under a nitrogen atmosphere, the alcohol is distilled off in vacuo, water is added to the residue, the residue is acidified with hydrochloric acid, extracted with chloroform, and the aqueous layer is made alkaline and re-extracted with chloroform. After drying the extract over anhydrous sodium sulphate, the solvent is distilled o~f in vacuo, the residue i8 digested with ether and seeded, and the crystalline product which precipitates is filtered off after a period of time.
Yield of N-[3-acetyl-4-(3'-N-benzyl-tert.-butyl-amino-2'-hydroxy)-propoxy~-phenylurea: 1.15 g = 54.0% of theory. Melting point 20 (in acetone): 145 to 147C.
The splitting off of the benzyl group by catalytic `~
hydrogenation is carried out as described in Example 1. The N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxyl~phenyl-urea hydrochloride has a melting point of 195 to 197C.
The preparation of the starting compound is carried out in an analogous manner to Example 1.
- l-chloro-2-hydroxy-3-(N-benzyl-N-tert.-butylamino)-propane has a boiling point at 0.05 mm of 105 to 107C.
Example 3 0.5 g of N-(3-acetyl-4-hydroxy)-phenyl-N'-methylurea ....
_g_ :~
L34~ ~
1 is dissolved in methanol, a solution of 0.2 g of potassium hydroxide in 25 ml of methanol is added, followed by 0.5 g of l-chloro-2-hydroxy-3-tert.-butylamino propane hydrochloride, and the mixture is heated for 45 hours at boiling point.
The solvent is distilled off in vacuo, the residue is taken up in methylene chloride, and the organic phase is extracted with sodium hydroxide and water, dried with sodium sulphate and concentrated in vacuo.
The N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy}-phenyl-N'-methylurea thus formed crystallises after seeding and digestion with ether. Melting point: 132 to 134C.
Example 4 18 ml of methanol is added to 1.0 g of N-(3 acetyl-4-hydroxy)-phenyl-Nl-pentamethylene(l~5)-urea/ followed by 0.8 g of l-chloro-2-hydroxy-3-tert.-butylaminopropane hydrochloride, 0.5 g of potassium hydroxide (85%) and 2 ml of water, and the mixture is stirred for 27 hours at 50C.
The solvent is distilled off in ~acuo and the residue is taken up in lN hydrochloric acid and washed several times with ethyl acetate. The aqueous solution is made alkaline with ~N
sodium hydroxide, extracted several times with methylene chloride, and the organic phase is dried with sodium sulphate and distilled in vacuo. ~;
The residue, which contains the base of N-[3-acetyl-4-(3'-tert.-butylamino-2'-hydroxy)-propoxy]-phenyl-N'-penta-methylene(l,5)-urea is dissolved in 5 ml of acetone of the formation of the fumarate, a solution of 0.1 g of fumaric acid in 5 ml of acetone is added, the resultant solution is seeded, and the crystalline product which precipitates is filtered of, washea with acetone and ether, and dried. Melting point: 211 to 213C.
--10-- ;.
34~
... . .
1 Example 5 The preparation of N-[3-acetyl-4-(3'-N-benzyl-N-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea (melting point of the fumarate: 110~ to 112C) is carried out in an analogous manner to Example 1.
To split off the N-benzyl group by catalytic hydrogena-tion, 111 mg of N-[3-acetyl-4-(3'-N-benzyl-N--isopropylamino-2'-hydroxy)-propoxy~-~henyl-N'-diethylurea is added to a prehydro-genated suspension of Raney nickel in 6~5 ml of ethanol and hydrogenated at room temperature until the uptake of hydrogen has ceased. Duration of reaction: 5 hours.
The catal~st is separated, the solvent is distilled off in vacuo, the oily residue is triturated with ether and seeded, and the crystalline product which precipitates is ~iltered off after a period of time.
Yield of N-[3-acetyl-4-t3'-isopropylamino-2'-hydroxy~-propoxy]-phenyl-N'-diethylurea: 65 mg = 73% of theory.
Example 6 14.2 mg of palladium charcoal is prehydrogenated in 7 ml of ethyl alcohol containing 8.1 mg of hydrochloric acid.
100.8 mg of N-[3-acetyl-4-(3'-N-benzyl N'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea prepared in an analogous manner to Example 1 is added and hydrogena-tion is carried out until the uptake of hydrogen has ceased. Duration of reaction:
2 hours.
The catalyst is separated, the filtrate is concentrated n. vacuo,~ the residue is taken up in water and made alkaline with sodium hydro~ide solution, and the base formed is extracted with ethyl acetate. After drying the product with anhydrous sodium sulphate, the solvent is evaporated in vacuo, the residue .
:, '. ' .. ~ : . .
.
. :
L341 ` ~
1 is digested with ether and seeded, and the crystalline product formed is filtered off after a period of time. Yield: 62 mg =
76.6~ of theory.
The following compounds may be obtained in an analogous manner to Examples 1 to 5:-N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]- -phenyl-N'-diethylurea. Melting point of the base: 110 to 112C.
N-~3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy3-phenyl-N'-dimethylurea. Melting point o the fumarate: 205~to 208C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-ethylurea. Melting point of the ftlmarate: 196 to 198C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxv~-propoxy]-phenyl-N'-isopropylurea. Melting poin~ of the base: 87 to 90C.
N-[3-acetyl-~-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-butylurea. Melting point of the fumarate: 215 to 217C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-sec.butylurea. Meltin~ point of the fumarate: 215 to 217C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy~-phenyl-N'-tert.butylurea. Melting point of the fumarate: 213 ~o 215C.
N-[3-acetyl-4-(3'-isopropylamino-2'-hydroxy)-propoxy]-phenyl-N'-dimethylurea. Meltin~ point of the base: 103 to -107C.
N-[3-acetyl-4-~3'-cyclopropylamino-2'-hydroxy~-propoxy]- -N'-dimethylurea. Melting point of the base: 80 to 83C.
N-[3-acetyl-4-(3'-tert.butylamino 2'-hydroxy)~propoxy]-phenyl-N'-methyl-N'-ethylurea. Melting point of the fumarate: ;
195 to 197C.
3~ N-[3~acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-butylurea. Melting point of the fumarate: 192 to 195C.
1 N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy~-propoxy]-phenyl-N'-di-_-butylllrea. Melting point of the fumarate: 184 to 187~C.
N~[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]- ;
phenyl-N'-di-n-propylurea. Melting point of the fumarate: 164 to 167C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-phenylurea. Melting point o~ the base: 159 to 164C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-10 phenyl-N~-tetramethylene(l~4)-urea. Melting point of the fumarate: 218 to 220C.
N-[3-propionyl-~-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenylurea. Melting point o~ the fumarate: 20~ to 207C.
N-[3-propionyl-4-(3'-tert.butylamino-2'-hydroxy)~
propoxy~-phenyl-N'-methylurea. Melting point of the fumarate:
13~ to 136C.
N-[3-propionyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point of the base:
107 to 109C.
N-[3-propionyl-~-~3'-tert.butylamino-2'-hydroxy)-propoxyJ-phenyl-N'-aimethylurea. Melting point of the fumarate:
l99~to 202C.
N-[3-propionyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy}-phenyl-N'-tetramethylene(1,4)-urea. Melting point of the fumarate:
208 to 211C.
N-[3-propionyl-~-(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-~-(3'-tert.butylamino-2'-hydroxy)-propoxy]-3~ phenyl-N'-pentamethylene(1,5)-urea. Melting point of the fumarate~
167 to 170C.
`,': ' .
6134~L
1 N-[3-phenylacetyl-4-(3'-tert.butylamino-2'-hydroxy)- -propoxy]-phenyl-N'-pentamethylene(1,5)-urea. Melting point of the base: 117 to 118C.
N-[3-benzoyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy~-phenyl-N'-pentamethylene(1,5)-urea. Melting point of the base:
120 to 1~3C.
- N- f 3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-isopropylurea. Melting point o~ the base:
105 to 107C. `
t0 N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy~
phenyl-N'-ethyle-N'-n-propylurea. Melting point of the fumarate:
176 to 178C.
N-13-butyryl-4 (3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-diethylurea. Melting point of the base: 56 to 58C.
N-[3-acetyl-4-(3'-tert.butylamino-2'-hydroxy)-propoxy]-phenyl-N'-methyl-N'-benzylurea. Melting point of the fumarate:
211 to 214C.
~0 . .
, ;":
. .
;
Claims (4)
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 hydrogen atom, a straight-chain or branched lower alkyl group containing less than 5 carbon atoms or a cyclopentyl, cyclohexyl, benzyl or phenyl group or R and R1 taken together form a di-valent, straight-chain or branched hydrocarbon radical selected from the group consisting of tetra-, penta-, and oxapentamethylene, R2 is an alkyl group containing up to 6 carbon atoms or a benzyl or phenyl group and R3 is a straight-chain or branched alkyl group containing 3 to 6 carbon atoms, a cyanoalkyl group contain-ing up to 6 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms, and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting an alkali metal salt of a phenol of the general formula:
(II)
(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 hydrogen atom, a straight-chain or branched lower alkyl group containing less than 5 carbon atoms or a cyclopentyl, cyclohexyl, benzyl or phenyl group or R and R1 taken together form a di-valent, straight-chain or branched hydrocarbon radical selected from the group consisting of tetra-, penta-, and oxapentamethylene, R2 is an alkyl group containing up to 6 carbon atoms or a benzyl or phenyl group and R3 is a straight-chain or branched alkyl group containing 3 to 6 carbon atoms, a cyanoalkyl group contain-ing up to 6 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms, and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting an alkali metal salt of a phenol of the general formula:
(II)
Claim 2 continued ......
in which R, R1 and R2 are as defined above for formula (I), with a compound of the formula:
(III) in which X is a group or wherein, Hal is chlorine, bromine or iodine and R4 is hydrogen or a group which can be split off hydrogenolytically, and R3 is as defined above, or with a mixture of compounds of formula (III), and (i) in the case where R4 is a hydrogen, isolating the reaction product or (ii) in the case where R4 is a group which can be split hydro-genolytically; splitting off this group by hydrogenation and isolating whereby (a) the product of formula I is isolated as the free base or (b) an acid is added to the reaction mixture and the product of formula I is isolated as a pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1, in which the salt of the phenol of formula (II) used in the conversion is formed in situ from the free phenol of the formula (II) and an alkali metal hydroxide.
in which R, R1 and R2 are as defined above for formula (I), with a compound of the formula:
(III) in which X is a group or wherein, Hal is chlorine, bromine or iodine and R4 is hydrogen or a group which can be split off hydrogenolytically, and R3 is as defined above, or with a mixture of compounds of formula (III), and (i) in the case where R4 is a hydrogen, isolating the reaction product or (ii) in the case where R4 is a group which can be split hydro-genolytically; splitting off this group by hydrogenation and isolating whereby (a) the product of formula I is isolated as the free base or (b) an acid is added to the reaction mixture and the product of formula I is isolated as a pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1, in which the salt of the phenol of formula (II) used in the conversion is formed in situ from the free phenol of the formula (II) and an alkali metal hydroxide.
3. A process as claimed in claim 1, in which the reaction is carried out in an aliphatic alcohol as solvent.
4. A process as claimed in claim 1, in which the reaction is carried out in a solvent at the boiling point of the solvent used.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT926674A AT335464B (en) | 1974-11-19 | 1974-11-19 | A PROCESS FOR THE PREPARATION OF NEW 3- (P-UREIDOPHENOXY) -2-HYDROXY-AMINOPROPANES AND THEIR ACID ADDITION SALTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1061341A true CA1061341A (en) | 1979-08-28 |
Family
ID=3612655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA239,398A Expired CA1061341A (en) | 1974-11-19 | 1975-11-12 | Process for the preparation of phenoxypropylamine derivatives and salts thereof |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS51125247A (en) |
| AT (1) | AT335464B (en) |
| CA (1) | CA1061341A (en) |
| CH (1) | CH617181A5 (en) |
| CS (1) | CS181691B2 (en) |
| DD (1) | DD123320A1 (en) |
| ES (1) | ES442747A1 (en) |
| LU (1) | LU73811A1 (en) |
| PL (1) | PL96050B1 (en) |
| RO (1) | RO72482A (en) |
| SU (1) | SU603333A3 (en) |
| YU (1) | YU39749B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4767784A (en) * | 1985-12-13 | 1988-08-30 | Zoelss Gerhard | Novel crystalline salts of aryloxy-propanolamines, a process for their preparation and their use |
-
1974
- 1974-11-19 AT AT926674A patent/AT335464B/en not_active IP Right Cessation
-
1975
- 1975-10-08 YU YU2558/75A patent/YU39749B/en unknown
- 1975-10-14 CH CH1331075A patent/CH617181A5/en not_active IP Right Cessation
- 1975-10-31 CS CS7500007350A patent/CS181691B2/en unknown
- 1975-11-10 RO RO7583862A patent/RO72482A/en unknown
- 1975-11-12 CA CA239,398A patent/CA1061341A/en not_active Expired
- 1975-11-17 PL PL1975184783A patent/PL96050B1/pl unknown
- 1975-11-17 DD DD189501A patent/DD123320A1/xx unknown
- 1975-11-17 LU LU73811A patent/LU73811A1/xx unknown
- 1975-11-17 SU SU752189624A patent/SU603333A3/en active
- 1975-11-18 ES ES442747A patent/ES442747A1/en not_active Expired
- 1975-11-19 JP JP50138273A patent/JPS51125247A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4767784A (en) * | 1985-12-13 | 1988-08-30 | Zoelss Gerhard | Novel crystalline salts of aryloxy-propanolamines, a process for their preparation and their use |
| US4849530A (en) * | 1985-12-13 | 1989-07-18 | Rorer Pharmaceutical Corporation | Process for the preparation of crystalline salts or aryloxy-propanolamines |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS51125247A (en) | 1976-11-01 |
| PL96050B1 (en) | 1977-12-31 |
| RO72482A (en) | 1981-11-04 |
| LU73811A1 (en) | 1976-09-06 |
| YU39749B (en) | 1985-04-30 |
| CS181691B2 (en) | 1978-03-31 |
| DD123320A1 (en) | 1976-12-12 |
| SU603333A3 (en) | 1978-04-15 |
| JPS549194B2 (en) | 1979-04-21 |
| ES442747A1 (en) | 1977-04-16 |
| AT335464B (en) | 1977-03-10 |
| ATA926674A (en) | 1976-07-15 |
| CH617181A5 (en) | 1980-05-14 |
| YU255875A (en) | 1982-05-31 |
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