CA1149819A - Process for the manufacture of new amines - Google Patents
Process for the manufacture of new aminesInfo
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- CA1149819A CA1149819A CA000101368A CA101368A CA1149819A CA 1149819 A CA1149819 A CA 1149819A CA 000101368 A CA000101368 A CA 000101368A CA 101368 A CA101368 A CA 101368A CA 1149819 A CA1149819 A CA 1149819A
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- 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
-
- 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
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- 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
- C07C275/32—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 singly-bound oxygen atoms
- C07C275/34—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 singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
CIBA-GEIGY AG 4-6930/1+2 Basel Canada A PROCESS FOR THE MANUFACTURE OF NEW AMINES
Abstract of the Disclosure Compounds of the formula
Abstract of the Disclosure Compounds of the formula
Description
38~
The invention relates to a process for the manu-facture of new amines of the formula Rl\ OH
/ N-C-NH-Ph-O-CH2-CI-I-CH2-NH-R3 (I~
wherein Rl represents hydrogen or lower alkyl; R2 represents lower alkyl; R3 represents lower alkyl, and Ph represents a meta- or para-phenylene radical, unsubstituted or sub-stituted once by alkyl or alkenyl withup to 4 C-atoms or by halogen, and pharmaceutically acceptable salts thereof.
The term lower rad.tcals is used to describe those con-taining up to 7 C-atoms. .
Lower alkyl radicals are for example methyl, ethyl, n-propyl or isopropyl, or straight-chain or branched buty~, pentyl or hexyl, which can be bonded in any desired posi-tion.
: ` ~
Alkenyl radicals with 2: to 4 C-atoms are for ex- ~.
ample allyl or methallyl. :
: ~alagen atoms are especially fluorine, chlorine :~.
or bromine.
Meta- or para-phenylene radicals Ph can be unsub- .
stituted or have one substituent. Substituents are alkyl radicals ~ith 1 to ~``C-atoms, or alkenyl~ra~icals with 2 to 4 C-atoms.
~: :
The invention relates to a process for the manu-facture of new amines of the formula Rl\ OH
/ N-C-NH-Ph-O-CH2-CI-I-CH2-NH-R3 (I~
wherein Rl represents hydrogen or lower alkyl; R2 represents lower alkyl; R3 represents lower alkyl, and Ph represents a meta- or para-phenylene radical, unsubstituted or sub-stituted once by alkyl or alkenyl withup to 4 C-atoms or by halogen, and pharmaceutically acceptable salts thereof.
The term lower rad.tcals is used to describe those con-taining up to 7 C-atoms. .
Lower alkyl radicals are for example methyl, ethyl, n-propyl or isopropyl, or straight-chain or branched buty~, pentyl or hexyl, which can be bonded in any desired posi-tion.
: ` ~
Alkenyl radicals with 2: to 4 C-atoms are for ex- ~.
ample allyl or methallyl. :
: ~alagen atoms are especially fluorine, chlorine :~.
or bromine.
Meta- or para-phenylene radicals Ph can be unsub- .
stituted or have one substituent. Substituents are alkyl radicals ~ith 1 to ~``C-atoms, or alkenyl~ra~icals with 2 to 4 C-atoms.
~: :
- 2 - ~ :-.
- : ::.. , . :
~9~
The new compoun~s possess valuable pharmacological properties. Thus they inhibit cardioselective ~-receptors as is found in animal experiments, for example on intra-venous administration of 0.1 - 1 mg~kg to pen-tobarbital narcotized cats in the isoproterenol-tachycardia test, on intravenous administration of more than 10 mg/kg in narcotized cats through inhibition of the isoproterenol vasodilation, on the isolated guinea pig heart (according to Langendorff) in a concentration of approximat~ly 0.3 - 3 y~ml through inhibition of the isoproterenol tachy-cardia (blocking of cardial ~-receptors), as also on intravenous administration of approximately 5 - 30 mg~kg in narcotized cats through blocking o~ vascular ~-receptors.
The new compounds can there~ore he used as cardioselective ~-receptor blocking agents. The new com-pounds are however also valuable intermediate products for the manufacture of other use~ul substances, especial-ly pharmaceutically active compounds.
Particularly valuable compounds because o~ theix outstanding pharmacological properties are l-[(p-N',N'-dimethyl-ureido)-phenoxy~-2-hydroxy-3-isopropylamino propane, l-~lm-N',N'-dimethyl-ureido~-phenoxy]-2-hydroxy-
- : ::.. , . :
~9~
The new compoun~s possess valuable pharmacological properties. Thus they inhibit cardioselective ~-receptors as is found in animal experiments, for example on intra-venous administration of 0.1 - 1 mg~kg to pen-tobarbital narcotized cats in the isoproterenol-tachycardia test, on intravenous administration of more than 10 mg/kg in narcotized cats through inhibition of the isoproterenol vasodilation, on the isolated guinea pig heart (according to Langendorff) in a concentration of approximat~ly 0.3 - 3 y~ml through inhibition of the isoproterenol tachy-cardia (blocking of cardial ~-receptors), as also on intravenous administration of approximately 5 - 30 mg~kg in narcotized cats through blocking o~ vascular ~-receptors.
The new compounds can there~ore he used as cardioselective ~-receptor blocking agents. The new com-pounds are however also valuable intermediate products for the manufacture of other use~ul substances, especial-ly pharmaceutically active compounds.
Particularly valuable compounds because o~ theix outstanding pharmacological properties are l-[(p-N',N'-dimethyl-ureido)-phenoxy~-2-hydroxy-3-isopropylamino propane, l-~lm-N',N'-dimethyl-ureido~-phenoxy]-2-hydroxy-
-3-isopropylamino-propane, l-[lo-allyl-p-N',N'-dimethyl-ureidoj-phenoxy]-2-hydroxy-3-isopropyl-amino-propane, F
. . . .
` . ~ .`
.
8~
and especially l-[(o-chloro-p-N'-,N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane which, for example, when intravenously administered 0.1 - 1 mg/kg to pentobarbital-narco-tized cats inhibit the isoproterenol tachycardia (0.5 Y/kg administered intravenously) and on intravenous administration of over 10 mg/kg to pentobarbital-narcotized cats inhibit the isoproterenol-vasodilatation (0.5 y,~kg administered intravenously) and also, in concentrations of 0.3 - 3 ~/ml, inhibit the iso-proterenol-tachycardia (0.005 ~/ml) blocking of cardial ~-receptors) on the isolated , . . ~ , .
. - ~, . . . ~ , .
- ~ , - ' ' : ' guinea pig heart (according to Langendorff), and hlock vascular ~-receptors on intravenous administration of 5-30 mg/kg on narcotized cats.
The new compounds of formula I are obtained according to methods which are in themselves known, and comprise;
a) reacting a compound of formula V
1 \ " ,1 N - C - NH - Ph - O - CH2 - CH - CH2 - Z ~V) ~herein Rl, R2 and Ph have the above significance, Xl represents the hydroxyl group and Z represents a halogen atom or a reactive esterified hydroxyl group, or Xl and Z together form an epoxy group~ with an amine of the formula ~herein R3 has the above significance; or b) reacting a compound of formula VI
2.
N - C - NH - Ph - O - CH2 - CH - CH2 - NH2 ~VI) wherein Rl, R2 and Ph have the above significance, with a compound of the formula wherein Z and R3 have the above significance; or c) reacting a compound of formula VIII
1 \ "
/ N - C - NH - Ph - OH ~VIII) wherein Rl, R2 and Ph have the above significance, with a compound of formula IX
~1 .
.
. ~ ~
~L49~
z - CH2 - CH - CH2 - NH 3 (IX) ~herein Z, Xl and R3 have the above meanings; or d) removing from a compound of formula I wherein Rl, R2, R3 and Ph have the above significance and which possesses a removable radical on the nitrogen atom of the amino group and/or on the hydroxyl group, said radical or radicals; or e) reducing a Schiff base of formulae XII or XIII
1 \ " OH
N - C - NH - Ph - O - CH2 - CH - CH = N - R3 ~XII) or N - C - NH - Ph ~ ~ CH2 ~ CH ~ CH2 ~ N = R3' ~XIII) or a ring-tautomer, corresponding to formula XIII, wherein Rl, R2, Ph and ~`
R3 have the above significance and R3'H is the same as R3; or f) reducing in a compound of formula XVI
1 ~ O O
N - C - NH - Ph - O - CH2 - C - CH2 - NH - R3 ~XVI) wherein R1, R2, R3 and Ph have the above significance, the 2-oxo group to a hydroxyl group; or g) reacting a reactive acid derivative of a carbamic acid of formula XVII OH
HOOC - N~ - Ph - O - CH2 - CH - CH2 - NH - R3 ~XVII) wherein Ph and R3 have the above significanceJ with an amine of formula - , : :: . : : , : ~
` - -~4~
Rl - NH - R2 wherein Rl, and R2 have the above significance; and when required, resulting racemates are resolved in~o the optical antipodes, and/or resulting free bases are converted into their pharmaceutically acceptable salts or resulting salts into the free bases or into other salts which are pharmaceutically acceptable.
Thus it is for example possible to react a compound of formula V
" ,Xl / N - C - NH - Ph - O - CH - CH - CH - Z ~V) wherein Rl, R2 and Ph have the above significance, Xl represents the hydroxyl group and Z represents a halogen atom or a reactive esterified hydroxyl group, or Xl and Z together form an epoxy group, with an amine of formula NH2-R3, wherein R3 has the above significance.
The halogen atoms mentioned with respect to the group Z include chlorineJ bromine and iodine. A reactive esterified hydroxyl group is especially a hydroxyl group esterified by a strong inorganic or organic acid, above all sulphuric acid or a strong organic sulphonic acid, such as a strong aromatic sulphonic acid, for example benzenesulphonic acid,
. . . .
` . ~ .`
.
8~
and especially l-[(o-chloro-p-N'-,N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane which, for example, when intravenously administered 0.1 - 1 mg/kg to pentobarbital-narco-tized cats inhibit the isoproterenol tachycardia (0.5 Y/kg administered intravenously) and on intravenous administration of over 10 mg/kg to pentobarbital-narcotized cats inhibit the isoproterenol-vasodilatation (0.5 y,~kg administered intravenously) and also, in concentrations of 0.3 - 3 ~/ml, inhibit the iso-proterenol-tachycardia (0.005 ~/ml) blocking of cardial ~-receptors) on the isolated , . . ~ , .
. - ~, . . . ~ , .
- ~ , - ' ' : ' guinea pig heart (according to Langendorff), and hlock vascular ~-receptors on intravenous administration of 5-30 mg/kg on narcotized cats.
The new compounds of formula I are obtained according to methods which are in themselves known, and comprise;
a) reacting a compound of formula V
1 \ " ,1 N - C - NH - Ph - O - CH2 - CH - CH2 - Z ~V) ~herein Rl, R2 and Ph have the above significance, Xl represents the hydroxyl group and Z represents a halogen atom or a reactive esterified hydroxyl group, or Xl and Z together form an epoxy group~ with an amine of the formula ~herein R3 has the above significance; or b) reacting a compound of formula VI
2.
N - C - NH - Ph - O - CH2 - CH - CH2 - NH2 ~VI) wherein Rl, R2 and Ph have the above significance, with a compound of the formula wherein Z and R3 have the above significance; or c) reacting a compound of formula VIII
1 \ "
/ N - C - NH - Ph - OH ~VIII) wherein Rl, R2 and Ph have the above significance, with a compound of formula IX
~1 .
.
. ~ ~
~L49~
z - CH2 - CH - CH2 - NH 3 (IX) ~herein Z, Xl and R3 have the above meanings; or d) removing from a compound of formula I wherein Rl, R2, R3 and Ph have the above significance and which possesses a removable radical on the nitrogen atom of the amino group and/or on the hydroxyl group, said radical or radicals; or e) reducing a Schiff base of formulae XII or XIII
1 \ " OH
N - C - NH - Ph - O - CH2 - CH - CH = N - R3 ~XII) or N - C - NH - Ph ~ ~ CH2 ~ CH ~ CH2 ~ N = R3' ~XIII) or a ring-tautomer, corresponding to formula XIII, wherein Rl, R2, Ph and ~`
R3 have the above significance and R3'H is the same as R3; or f) reducing in a compound of formula XVI
1 ~ O O
N - C - NH - Ph - O - CH2 - C - CH2 - NH - R3 ~XVI) wherein R1, R2, R3 and Ph have the above significance, the 2-oxo group to a hydroxyl group; or g) reacting a reactive acid derivative of a carbamic acid of formula XVII OH
HOOC - N~ - Ph - O - CH2 - CH - CH2 - NH - R3 ~XVII) wherein Ph and R3 have the above significanceJ with an amine of formula - , : :: . : : , : ~
` - -~4~
Rl - NH - R2 wherein Rl, and R2 have the above significance; and when required, resulting racemates are resolved in~o the optical antipodes, and/or resulting free bases are converted into their pharmaceutically acceptable salts or resulting salts into the free bases or into other salts which are pharmaceutically acceptable.
Thus it is for example possible to react a compound of formula V
" ,Xl / N - C - NH - Ph - O - CH - CH - CH - Z ~V) wherein Rl, R2 and Ph have the above significance, Xl represents the hydroxyl group and Z represents a halogen atom or a reactive esterified hydroxyl group, or Xl and Z together form an epoxy group, with an amine of formula NH2-R3, wherein R3 has the above significance.
The halogen atoms mentioned with respect to the group Z include chlorineJ bromine and iodine. A reactive esterified hydroxyl group is especially a hydroxyl group esterified by a strong inorganic or organic acid, above all sulphuric acid or a strong organic sulphonic acid, such as a strong aromatic sulphonic acid, for example benzenesulphonic acid,
4-bromobenzenesulphonic acld or 4-toluenesulphonic acid. Thus Z especially represents chlorine, bromine, iodine, the -OSO3H group or a strong aromatic sulphonic acid residue.
This reaction is carried out in the usual manner. When using a reactive ester as the starting materials, the process is preferably carried out in the presence of a basic condensation agent and/or ~i~h an excess of amine .
It is furthermore possible to react a compound of formula VI
:
~ga~9 1 \ " OH
N - C - NH - Ph - O - CH2 - CH - CH2 - NH2 (VI) wherein Rl, R2 and Ph have the above significance, witll a compound of formula Z-R3, wherein Z and R3 have the above significance.
This reaction is carried out iTI the usual manner, preferably in the presence of a basic condensation agent and/or with an excess of amine. Suitable basic condensation agents are, for example, alkali alcoholates, especially sodium or potassium alcoholate, or alkali carbonates, such as sodium or potassium carbonate.
It is furthermore possible to react a compound of formula VIII
10 - 1 N - C - NH - Ph - OH (VIII) R /
wherein Rl, R2 and Ph have the above significance, with a compound of f~rmula IX
,1 Z - CH2 - CH - CH2 - NH R3 (IX) ~herein Z, Xl and R3 have the above significance.
This reaction is carried out in the usual manner. If reactive esters are used as the starting material, the compound of formula VIII
can preferably be used in the form of its metal phenolate, such as alkali ; phenolate, for example sodium phenolate, or the process is carried out in the presence of an acid-binding agent, especially a condensation agent, ~20 which can form a salt with the compound of formula VIII, such as an alkali alcoholate.
'`' .. . . . . ~ .
,. .- , ~ . -.: - ~ . . . .
' ~. ~ , , ,, ~
It is furthermore possible, in a compound of formula I wherein Rl, R2, R3 and Ph have the above significance and which possesses a removable radical on the nitrogen atom of the amino group and/or on the hydroxyl group, to remove this radical or radicals.
Such removable radicals are especially radicals removable by hydrolysis or hydrogenolysis.
Radicals removable by hydrolysis are for example acyl radicals, for example oxycarbonyl radicals, such as alkoxycarbonyl radicals, for example the tert.-butoxy-carbonyl radical, aralkoxycarbonyl radicals, for example a carbobenzoxy radicalg and especially lower alkanoyl radicals or aryloyl radicals, for example the acetyl radical or a benzoyl radical.
Compounds with radicals which can be removed by hydrolysis are for example also compounds of formula XI
Rl O
N - C - NH - Ph - 0 - CH2 - CH - CH2 ~XI) R2 O \ N - R3 wherein Rl, R2, R3 and Ph have the above significance and Y represents a carbonyl or thiocarbonyl radical.
The hydrolysis is carried out in the usual manner by means of hydrolysing agents and, for example, in the presence of basic agents, or, especially when using compounds of formula XI as the starting material, of acid agents. Such acid agents are for example dilute inorganic acids, such as sulphuric acid or a hydrohalic acid, such as one of those mentioned above.
Radicals removable by hydrogenolysis are for example ~-aralkyl radicals, such as benzyl radicals, or aryloxycarbonyl radicals, such as ~ . .
., , , . . . :
.
phenoxycarbonyl radicals, which can be split off by hydrogenolysis in the usual manner, especially by catalytically activated hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, for example palladium or platinum. Further radicals which are removable by hydrogenolysis are for example ~-halogen-ethoxycarbonyl radicals, such as the 2,2,2-trichlorethoxy-carbonyl radical or the 2-iodoethoxycarbonyl or 2,2,2-tribromoethoxycarbonyl radical, which can be removed in the usual manner, especially by nascent hydrogen. Nascent hydrogen can herein be obtained by the action of metal or metal alloys on agents which yield hydrogen, such as carboxylic acids, alcohols or water, and in particular zinc or zinc alloys together with acetic acid can be used. The hydrogenolysis of ~-halogen-ethoxycarbonyl radicals can preferably be effected by chromium-II compounds, such as chromium-II
chloride or chomium-II acetate. In carrying out the hydrogenolysis care must be taken that other reducible groups, above all the urea group, are not attacked.
It is furthermore possible to reduce a Schiff base of formulae XII or XIII
1 " OH
R / N - C - NH - Ph - O - CH2 - CH - CH = N - R3 (XII) or N - C - NH - Ph - O - CH2 - CH - CH2 - N =R3' ~XIII) or a ring-tautomer, corresponding to formula XIII, of formula XIV
1 \ O
N - C - NH - Ph - O - CH2 - fH ICH2 ~XIV) R2 \ H
~-~ 3 . ~ ~
wherein Rl, R2, Ph and R3 have the above significance and R3'1-1 is the same as R3.
This reduction is carried out in the usual manner, for example with a di-light metal hydride, such as sodium borohydride, or by catalytic hydrogenation, such as with hydrogen in the presence of palladium, platinum oxide or Raney nickel. During the reduction, care must be taken that other reducible groups, above all the urea group, are not attacked.
It is furthermore possible to reduce the 2-oxo group in a compound of formula XVI
" ., N - C - NH - Ph - O - CH2 - C - CH2 - NH - R3 (XVI) wherein Rl, R2, R3 and Ph have the above significance, to a hydroxyl group.
This reduction is carried out in the usual manner, especially using a di-light metal hydride, such as one of those mentioned above, or according to the method of Meerwein-Pondorf-Verley or a modification thereof, especially with an alkanol as a reagent and as a solvent, such as isopropanol, and with a metal alkanolate, preferably a metal alkanolate,correspGnding to the alkanol, such as a metal isopropanolate, for exam~le aluminium isopropano-late.
It is furthermore possible to react a reactive acid derivative of a carbamic acid of formula XVII OH
HOOC - NH - Ph - O - CH2 - CH - CH2 - NH - R3 ~XVII) 1-wherein Ph and R3 have the above significance with an amine of formula Rl-NH-R2, wherein Rl and R2 have the above significance.
A reactive acid derivative of such a carbamic acid is for example a lower alkyl estsr or above all a phenyl ester, an acid halide, ~`
. .
.
- , : ~ , ~ . . :.
.: - . .
~1~9t~9 such as an acid chloride, or especially an internal anhydrlde, such as an isocyanate.
This reaction is carried out in the usual manner, especially using an excess of amine, and optionally in a solvent and at elevated temperature, preferably above 1~0C.
~ epending on the process conditions and starting substances, the final substances are obtained in the free form or in the form of their acid addition salts, which are also included in the invention. Thus for example basic, neutral or mixed salts, and where relevant also hemihydrates, mono-hydrates, sesquihydrates or polyhydrates thereof, can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner which is in itself known, for example with basic agents, such as alkalis or ion exchangers. On the other hand, the resulting free bases can form salts with organic or inorganic acids. In order to manufacture acid addition salts, such acids are especially used as are suitable for forming therapeutically usable salts. As such acids there may for example be mentioned:
hydrohalic acids, sulphuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; phenyl-acetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic and ethylenesulphonic acid; halogenobenzenesulphonic, toluenesulphonic, naphthalenesulphonic or sulphanilic acid; methionine, tryptophan, lysine or arginine.
These or other salts of the new compounds, such as for example the picrates, can also serve or the purification of the resulting , free bases, by converting the free bases into salts, separating these off and again liberating the bases from the salts. In view of the close relationships between the new compounds in the free form and in the form of their salts, the free compounds are, in the preceding and following text~ where appropriate also to be understood to include the corresponding salts as regards sense and purpose.
The invention also relates to those embodiments of the process in which a reagent is optionally present in the form of its salts.
Thus it is possible to react an aldehyde of formula XVIII
Rl O OH
., , N - C - NH - Ph - O - CH2 - CH - CHO (XVIII) wherein Rl, R2 and Ph have the above significance, with an amine of formula H2N-R3, wherein R3 has the above significance, in the presence of a suitable reducing agent such as one of those mentioned above. Here a compound of formula XII is obtained as an intermediate product and this is then reduced in accordance with the invention.
It is furthermore possible in a suitable manner to react an amine of formula VI with an aldehyde or ketone of formula O=R3', wherein R3' has the above significance, in the presence of a suitable reducing agent, such as one of those mentioned above. Here a compound of formula XIII or XIV is obtained as an intermediate product and this is then reduced in accordance with the invention.
The new compounds can, to the extent that they possess asymetric ?
carbon atoms, and depending on the choice of the starting substances and working methods, be present as optical antipodes or racemates or, to the extent that they contain at least two asymmetric carbon atoms, also as .
- :
-isomer mixtures (racemate mixtures).
Resulting isomer mixtures (racemate mixtures) can be resolved into the t~o stereoisomeric (disastereomeric) pure racemates on the basis of the physico-chemical differences of the constituents in a known manner, for example bychromatography and/or fractional crystallisation.
Resulting racemates can be resolved according to known methods, for example by recrystallisation from an optically active solvent, with the aid of micro-organisms or by reaction with an optically active acid which forms salts with the racemic compound and separation of the salts obtained in this manner, for example on the basis of their different solubilities, into the diastereomers, from which the antipodes can be liberated by the action of suitable agents. Particularly customary optically active acids are for example the D- and L-forms of tartaric acid, di-o- toluyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid or quinic acid. Advantageous-ly the more active of the two antipodes is isolated.
Appropriately, such starting substances are used for carrying out the reactions according to the invention as lead to the initially particularly mentioned groups of final substances and particularly to the final substances which have been especially described or highlighted.
The starting substances are known or can, if they are new, be obtained according to methods which are in themselves known.
The new compounds can be used as medicines, for example in the form of pharmaceutical preparations, in which they or their salts are present mixed with a pharmaceutical, organic or inorganic, solid or liquid carriers which is for example suitable for enteral or parenteral administration. Possible substances for forming the carriers are those :' .~: :`.
- . .
which do not react with the new compounds, such as for example water, gelatine, lactose, starch, magnesium stearate, talc vegetable oils, benzyl alcohols, gum, polyalkylene glycols, white petroleum jelly, cholesterol or other known medicinal carriers. The pharmaceutical preparations can for example be in the form of tablets, dragees, capsules, suppositories, ointments or creams, or in a liquid fo~m as solutions ~for example as an elixir or syrup), suspensions or emulsions. They are optionally sterilised and/or contain auxiliary substances, such as preservatives, stabilisers, wetting agents or emulsifiers, salts for regulating the osmotic pressure or buffers.
They can also contain yet further therapeutically valuable substances. The preparations, which can also be used in veterinary medicine, are formulated according to usual methods.
The examples which follow explain the invention without however restricting it.
Example 1 A solution of 40 g of l-[o-chloro-p-~N',N'-dimethyl-ureido)-phenoxyJ-2,3-epoxy-propane and 40 g of isopropylamine in 40 ml of ethanol in heated to boiling for 4 hours. Thereafter the mixture is concentrated by evaporation in vacuo and the residue is dissolved in 2 N hydrochloric acid. After extraction with ether, the hydrochloric acid layer is separated off and rendered alkaline by adding concentrated sodium hydroxide solution.
The base which has separated out is extracted by shaking with methylene chloride. After evaporation of the solvent and after recrystallisation of the residue from ethyl acetate, the l-[o-chloro-p-(N',N'dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula , F
.
(CH3)2NCONH - ~ OCH2CHCH2NIICH \ CH3 Cl 3 is obtained in crystals of melting point 130C.
The cyclohexylsulphamate melts at 146-150C.
The epoxide used as the starting product can be manufactured as follows:
50 g of dimethylcarbamic acid chloride are added dropwise at room temperature to a solution of 63 g of 3-chloro-4-hydroxy-aniline to 300 ml of pyridine, whilst stirring and the mixture is left to stand for 12 hours.
Thereafter 2 N hydrochloric acid is added until a pH value of 5 is reached, after which the N,N-dimethyl-N'-~3-chloro-4-hydroxy-phenyl)-urea precipitates.
The compound melts at 202-203C.
45 g of the phenol are now heated for 15 hours under reflux with 45 g of epichlorohydrin and 45 g of potassium hydroxide in 450 ml of acetone.
Thereafter the potassium hydroxide is filtered off and the solvent is evaporated off. The residue is dissolved in methylene chloride and extracted by shaking with 2 N sodium hydroxide solution. After evaporation of the solvent, the crude l-[o-chloro-p-~N',N'-dimethylureido)-phenoxy]-2,3-epoxy-propane remains, which is used for the above reaction.
Example 2 10 g of 1-[p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane are warmed for 4 hours at 90C with 10 g of isopropylamine in 10 ml of ~hanol.
Thereafter the excess amine as well as the solvent are evaporated off in vacuo.
F
.
... . . . . . .
- ., ~ .: .
, . . - ~ . .
The residue is dissolved in 2 N hydrochloric acid, the undissolved constituents are filtered off and the solution extracted with methylene chloride. The aqueous phase is rendered alkaline by adding 2 N sodium hydroxide solution and is thereafter extracted with methylene chloride. After evaporation of the solvent, 1-[p-~N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula (CH3)2NCONH --- ~ 2 H 2NHCH \
remains, which after recrystallisation from benzene melts at 138-139 C~
The epoxide used as the starting product can be manufactured as follows:
12 g of dimethylcarbamoyl chloride are added to a solution of 20 g of p-benzyloxy-aniline in 100 ml of pyridine and the mixture is left ~o stand for 2 days. On addition of water, the N,N-dimethyl-N'-~p-benzyloxy-phenyl)-urea precipitates; it melts at 155-158C after sublimation.
20 g of this urea are dissolved in 200 ml of ethanol and hydrogenated after addition of 2 g of palladium-charcoal ~10 per cent strength). When the uptake of hydrogen has ended, the mixture is concentrated by evaporation in vacuo and the residue is dissolved in 2 N sodium hydroxide solution. The undissolved constituents are extracted with ether and the aqueous layer is rendered acid by adding 5 N hydrochloric acid. N,N-dimethyl-N'-(p-hydroxy-phenyl)-urea precipitates; it melts at 203-205C after recrystallisation from isopropanol.
20 g of the phenol are heated for 10 hours with 20 g of potassium hydroxide and 20 g afepiclilorohydrin in 200 ml of acetone, whilst stirring.
.., . . ~ . , .
.. , :. . . . : . ~ . :
9~
Thereafter the potassium hydroxide is filtered off and the filtrate is concentrated by evaporation. The residue is dissolved in methylene chloride and extracted with 2 N sodium hydroxide solution. After evaporation of the methylene chloride, the crude l-~p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxy-propane remains as an oil.
Example 3 A solution of l-[o-allyl-p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane (15 g) and isopropylamine ~15 g) in 20 ml of ethanol is heated for 4 hours. Thereafter the reaction mixture is evaporated in vacuo, the residue dissolved in 2N-hydrochloric acid and filtered. The filtrate is rendered alkaline by addition of concentrated sodium hydroxide solution. An oil is precipitated that is extracted with methylene chloride. After the solution has been dried and the solvent evaporated, there remains l-[o-allyl-p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula )2NcoNH - ~ OCH2CHCH2NHCH /
CH2CH=CH2 CH3 which after recrystallization from benzene-petroleum ether melts at 110-112C.
The epoxide used as starting material can be prepared in the following way:
To 2-allyl-4-amino-phenol ~15 g) in 50 ml of pyridine is added dimethyl-carbamoyl chloride (12 g) and the mixture is left to stand for 12 hours at 25C. On addition of 200 ml of 2N hydrochloric acid, extraction with methylene chloride is effected. The extract is evaporated to dryness in vacuo. The residue is dissolved in 2N sodium hydroxide solution, the .
: ' '.' 9~L49~
resulting solution treated with charcoal and adjusted to a pH of 9 by addition of hydrochloric acid. The precipitated constituents are filtered off, the filtrate rendered acid. 2-Allyl-4-(N',N'-dimethylureido)-phenol is precipitated, which after recrystallization from ethyl acetate-pentane melts at 125-127C.
12 g of the phenol is heated to boiling for 12 hours with 12 g of epichlorohydrin and 12 g of potassium carbonate in 75 ml of acetone. Thereafter the solid constituents are filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in methylene chloride and extracted with sodium hydroxide solution. After evaporation of the solvent, the crude 1-[o-allyl-p-~N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane remains as an oil.
Example 4 A mixture of 30 g 1-~m-~N',N'-dimethylureido)-phenoxy]-2,3-epoxy-propane, 30 g isopropylamine and 30 ml ethanol is heated to 60 for 4 hours and then evaporated to dryness in vacuo. The residue is dissolved in 2N-acetic acid and extracted with ether. After separation of the water phase the same is rendered alkaline by addition of sodium hydroxide solution and extracted with methylene chloride. After evaporation of the solvent the l-[m-~N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of the formula ~ .
NHCON~CH3)2 .
remains, which melts after recrystalli~ation from isopropanol at 130.
- ~ .
~14~
Example 5 Tablets containing 20 mg of active substance are manufactured with the following composition:
l-[o-Chloro-p-~N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane 20 mg Starch 60 mg Lactose 50 mg Colloidal silica 5 mg Talc 9 mg Magnesium stearate 1 mg 145 mg Tablets containing 20 mg of l-[p-(N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane can be manufactured in the usual manner with the same composition.
Example 6 The following mixture is used to manufacture capsules:
l-[o-Chloro-p-(N',N'-dimethylureido)-phenoxy-2-hydroxy-3-isopropylamino-propane 2500 g Talc 80 g Colloidal silica 20 g The active substance isintimately mixed with talc and colloidal silica, and the mixture is forced through a sieve (0.5mm) and filled into hard gelatine capsules in portions of 21 mg.
Capsules can be manufactured in the same manner and with the same composition using l-~p-~N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy -3-isopropylamino-propane.
.
.. .. . ~ . ' :: ' :. , . : ~
- . ~ . .
;' .
This reaction is carried out in the usual manner. When using a reactive ester as the starting materials, the process is preferably carried out in the presence of a basic condensation agent and/or ~i~h an excess of amine .
It is furthermore possible to react a compound of formula VI
:
~ga~9 1 \ " OH
N - C - NH - Ph - O - CH2 - CH - CH2 - NH2 (VI) wherein Rl, R2 and Ph have the above significance, witll a compound of formula Z-R3, wherein Z and R3 have the above significance.
This reaction is carried out iTI the usual manner, preferably in the presence of a basic condensation agent and/or with an excess of amine. Suitable basic condensation agents are, for example, alkali alcoholates, especially sodium or potassium alcoholate, or alkali carbonates, such as sodium or potassium carbonate.
It is furthermore possible to react a compound of formula VIII
10 - 1 N - C - NH - Ph - OH (VIII) R /
wherein Rl, R2 and Ph have the above significance, with a compound of f~rmula IX
,1 Z - CH2 - CH - CH2 - NH R3 (IX) ~herein Z, Xl and R3 have the above significance.
This reaction is carried out in the usual manner. If reactive esters are used as the starting material, the compound of formula VIII
can preferably be used in the form of its metal phenolate, such as alkali ; phenolate, for example sodium phenolate, or the process is carried out in the presence of an acid-binding agent, especially a condensation agent, ~20 which can form a salt with the compound of formula VIII, such as an alkali alcoholate.
'`' .. . . . . ~ .
,. .- , ~ . -.: - ~ . . . .
' ~. ~ , , ,, ~
It is furthermore possible, in a compound of formula I wherein Rl, R2, R3 and Ph have the above significance and which possesses a removable radical on the nitrogen atom of the amino group and/or on the hydroxyl group, to remove this radical or radicals.
Such removable radicals are especially radicals removable by hydrolysis or hydrogenolysis.
Radicals removable by hydrolysis are for example acyl radicals, for example oxycarbonyl radicals, such as alkoxycarbonyl radicals, for example the tert.-butoxy-carbonyl radical, aralkoxycarbonyl radicals, for example a carbobenzoxy radicalg and especially lower alkanoyl radicals or aryloyl radicals, for example the acetyl radical or a benzoyl radical.
Compounds with radicals which can be removed by hydrolysis are for example also compounds of formula XI
Rl O
N - C - NH - Ph - 0 - CH2 - CH - CH2 ~XI) R2 O \ N - R3 wherein Rl, R2, R3 and Ph have the above significance and Y represents a carbonyl or thiocarbonyl radical.
The hydrolysis is carried out in the usual manner by means of hydrolysing agents and, for example, in the presence of basic agents, or, especially when using compounds of formula XI as the starting material, of acid agents. Such acid agents are for example dilute inorganic acids, such as sulphuric acid or a hydrohalic acid, such as one of those mentioned above.
Radicals removable by hydrogenolysis are for example ~-aralkyl radicals, such as benzyl radicals, or aryloxycarbonyl radicals, such as ~ . .
., , , . . . :
.
phenoxycarbonyl radicals, which can be split off by hydrogenolysis in the usual manner, especially by catalytically activated hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, for example palladium or platinum. Further radicals which are removable by hydrogenolysis are for example ~-halogen-ethoxycarbonyl radicals, such as the 2,2,2-trichlorethoxy-carbonyl radical or the 2-iodoethoxycarbonyl or 2,2,2-tribromoethoxycarbonyl radical, which can be removed in the usual manner, especially by nascent hydrogen. Nascent hydrogen can herein be obtained by the action of metal or metal alloys on agents which yield hydrogen, such as carboxylic acids, alcohols or water, and in particular zinc or zinc alloys together with acetic acid can be used. The hydrogenolysis of ~-halogen-ethoxycarbonyl radicals can preferably be effected by chromium-II compounds, such as chromium-II
chloride or chomium-II acetate. In carrying out the hydrogenolysis care must be taken that other reducible groups, above all the urea group, are not attacked.
It is furthermore possible to reduce a Schiff base of formulae XII or XIII
1 " OH
R / N - C - NH - Ph - O - CH2 - CH - CH = N - R3 (XII) or N - C - NH - Ph - O - CH2 - CH - CH2 - N =R3' ~XIII) or a ring-tautomer, corresponding to formula XIII, of formula XIV
1 \ O
N - C - NH - Ph - O - CH2 - fH ICH2 ~XIV) R2 \ H
~-~ 3 . ~ ~
wherein Rl, R2, Ph and R3 have the above significance and R3'1-1 is the same as R3.
This reduction is carried out in the usual manner, for example with a di-light metal hydride, such as sodium borohydride, or by catalytic hydrogenation, such as with hydrogen in the presence of palladium, platinum oxide or Raney nickel. During the reduction, care must be taken that other reducible groups, above all the urea group, are not attacked.
It is furthermore possible to reduce the 2-oxo group in a compound of formula XVI
" ., N - C - NH - Ph - O - CH2 - C - CH2 - NH - R3 (XVI) wherein Rl, R2, R3 and Ph have the above significance, to a hydroxyl group.
This reduction is carried out in the usual manner, especially using a di-light metal hydride, such as one of those mentioned above, or according to the method of Meerwein-Pondorf-Verley or a modification thereof, especially with an alkanol as a reagent and as a solvent, such as isopropanol, and with a metal alkanolate, preferably a metal alkanolate,correspGnding to the alkanol, such as a metal isopropanolate, for exam~le aluminium isopropano-late.
It is furthermore possible to react a reactive acid derivative of a carbamic acid of formula XVII OH
HOOC - NH - Ph - O - CH2 - CH - CH2 - NH - R3 ~XVII) 1-wherein Ph and R3 have the above significance with an amine of formula Rl-NH-R2, wherein Rl and R2 have the above significance.
A reactive acid derivative of such a carbamic acid is for example a lower alkyl estsr or above all a phenyl ester, an acid halide, ~`
. .
.
- , : ~ , ~ . . :.
.: - . .
~1~9t~9 such as an acid chloride, or especially an internal anhydrlde, such as an isocyanate.
This reaction is carried out in the usual manner, especially using an excess of amine, and optionally in a solvent and at elevated temperature, preferably above 1~0C.
~ epending on the process conditions and starting substances, the final substances are obtained in the free form or in the form of their acid addition salts, which are also included in the invention. Thus for example basic, neutral or mixed salts, and where relevant also hemihydrates, mono-hydrates, sesquihydrates or polyhydrates thereof, can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner which is in itself known, for example with basic agents, such as alkalis or ion exchangers. On the other hand, the resulting free bases can form salts with organic or inorganic acids. In order to manufacture acid addition salts, such acids are especially used as are suitable for forming therapeutically usable salts. As such acids there may for example be mentioned:
hydrohalic acids, sulphuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; phenyl-acetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic and ethylenesulphonic acid; halogenobenzenesulphonic, toluenesulphonic, naphthalenesulphonic or sulphanilic acid; methionine, tryptophan, lysine or arginine.
These or other salts of the new compounds, such as for example the picrates, can also serve or the purification of the resulting , free bases, by converting the free bases into salts, separating these off and again liberating the bases from the salts. In view of the close relationships between the new compounds in the free form and in the form of their salts, the free compounds are, in the preceding and following text~ where appropriate also to be understood to include the corresponding salts as regards sense and purpose.
The invention also relates to those embodiments of the process in which a reagent is optionally present in the form of its salts.
Thus it is possible to react an aldehyde of formula XVIII
Rl O OH
., , N - C - NH - Ph - O - CH2 - CH - CHO (XVIII) wherein Rl, R2 and Ph have the above significance, with an amine of formula H2N-R3, wherein R3 has the above significance, in the presence of a suitable reducing agent such as one of those mentioned above. Here a compound of formula XII is obtained as an intermediate product and this is then reduced in accordance with the invention.
It is furthermore possible in a suitable manner to react an amine of formula VI with an aldehyde or ketone of formula O=R3', wherein R3' has the above significance, in the presence of a suitable reducing agent, such as one of those mentioned above. Here a compound of formula XIII or XIV is obtained as an intermediate product and this is then reduced in accordance with the invention.
The new compounds can, to the extent that they possess asymetric ?
carbon atoms, and depending on the choice of the starting substances and working methods, be present as optical antipodes or racemates or, to the extent that they contain at least two asymmetric carbon atoms, also as .
- :
-isomer mixtures (racemate mixtures).
Resulting isomer mixtures (racemate mixtures) can be resolved into the t~o stereoisomeric (disastereomeric) pure racemates on the basis of the physico-chemical differences of the constituents in a known manner, for example bychromatography and/or fractional crystallisation.
Resulting racemates can be resolved according to known methods, for example by recrystallisation from an optically active solvent, with the aid of micro-organisms or by reaction with an optically active acid which forms salts with the racemic compound and separation of the salts obtained in this manner, for example on the basis of their different solubilities, into the diastereomers, from which the antipodes can be liberated by the action of suitable agents. Particularly customary optically active acids are for example the D- and L-forms of tartaric acid, di-o- toluyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid or quinic acid. Advantageous-ly the more active of the two antipodes is isolated.
Appropriately, such starting substances are used for carrying out the reactions according to the invention as lead to the initially particularly mentioned groups of final substances and particularly to the final substances which have been especially described or highlighted.
The starting substances are known or can, if they are new, be obtained according to methods which are in themselves known.
The new compounds can be used as medicines, for example in the form of pharmaceutical preparations, in which they or their salts are present mixed with a pharmaceutical, organic or inorganic, solid or liquid carriers which is for example suitable for enteral or parenteral administration. Possible substances for forming the carriers are those :' .~: :`.
- . .
which do not react with the new compounds, such as for example water, gelatine, lactose, starch, magnesium stearate, talc vegetable oils, benzyl alcohols, gum, polyalkylene glycols, white petroleum jelly, cholesterol or other known medicinal carriers. The pharmaceutical preparations can for example be in the form of tablets, dragees, capsules, suppositories, ointments or creams, or in a liquid fo~m as solutions ~for example as an elixir or syrup), suspensions or emulsions. They are optionally sterilised and/or contain auxiliary substances, such as preservatives, stabilisers, wetting agents or emulsifiers, salts for regulating the osmotic pressure or buffers.
They can also contain yet further therapeutically valuable substances. The preparations, which can also be used in veterinary medicine, are formulated according to usual methods.
The examples which follow explain the invention without however restricting it.
Example 1 A solution of 40 g of l-[o-chloro-p-~N',N'-dimethyl-ureido)-phenoxyJ-2,3-epoxy-propane and 40 g of isopropylamine in 40 ml of ethanol in heated to boiling for 4 hours. Thereafter the mixture is concentrated by evaporation in vacuo and the residue is dissolved in 2 N hydrochloric acid. After extraction with ether, the hydrochloric acid layer is separated off and rendered alkaline by adding concentrated sodium hydroxide solution.
The base which has separated out is extracted by shaking with methylene chloride. After evaporation of the solvent and after recrystallisation of the residue from ethyl acetate, the l-[o-chloro-p-(N',N'dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula , F
.
(CH3)2NCONH - ~ OCH2CHCH2NIICH \ CH3 Cl 3 is obtained in crystals of melting point 130C.
The cyclohexylsulphamate melts at 146-150C.
The epoxide used as the starting product can be manufactured as follows:
50 g of dimethylcarbamic acid chloride are added dropwise at room temperature to a solution of 63 g of 3-chloro-4-hydroxy-aniline to 300 ml of pyridine, whilst stirring and the mixture is left to stand for 12 hours.
Thereafter 2 N hydrochloric acid is added until a pH value of 5 is reached, after which the N,N-dimethyl-N'-~3-chloro-4-hydroxy-phenyl)-urea precipitates.
The compound melts at 202-203C.
45 g of the phenol are now heated for 15 hours under reflux with 45 g of epichlorohydrin and 45 g of potassium hydroxide in 450 ml of acetone.
Thereafter the potassium hydroxide is filtered off and the solvent is evaporated off. The residue is dissolved in methylene chloride and extracted by shaking with 2 N sodium hydroxide solution. After evaporation of the solvent, the crude l-[o-chloro-p-~N',N'-dimethylureido)-phenoxy]-2,3-epoxy-propane remains, which is used for the above reaction.
Example 2 10 g of 1-[p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane are warmed for 4 hours at 90C with 10 g of isopropylamine in 10 ml of ~hanol.
Thereafter the excess amine as well as the solvent are evaporated off in vacuo.
F
.
... . . . . . .
- ., ~ .: .
, . . - ~ . .
The residue is dissolved in 2 N hydrochloric acid, the undissolved constituents are filtered off and the solution extracted with methylene chloride. The aqueous phase is rendered alkaline by adding 2 N sodium hydroxide solution and is thereafter extracted with methylene chloride. After evaporation of the solvent, 1-[p-~N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula (CH3)2NCONH --- ~ 2 H 2NHCH \
remains, which after recrystallisation from benzene melts at 138-139 C~
The epoxide used as the starting product can be manufactured as follows:
12 g of dimethylcarbamoyl chloride are added to a solution of 20 g of p-benzyloxy-aniline in 100 ml of pyridine and the mixture is left ~o stand for 2 days. On addition of water, the N,N-dimethyl-N'-~p-benzyloxy-phenyl)-urea precipitates; it melts at 155-158C after sublimation.
20 g of this urea are dissolved in 200 ml of ethanol and hydrogenated after addition of 2 g of palladium-charcoal ~10 per cent strength). When the uptake of hydrogen has ended, the mixture is concentrated by evaporation in vacuo and the residue is dissolved in 2 N sodium hydroxide solution. The undissolved constituents are extracted with ether and the aqueous layer is rendered acid by adding 5 N hydrochloric acid. N,N-dimethyl-N'-(p-hydroxy-phenyl)-urea precipitates; it melts at 203-205C after recrystallisation from isopropanol.
20 g of the phenol are heated for 10 hours with 20 g of potassium hydroxide and 20 g afepiclilorohydrin in 200 ml of acetone, whilst stirring.
.., . . ~ . , .
.. , :. . . . : . ~ . :
9~
Thereafter the potassium hydroxide is filtered off and the filtrate is concentrated by evaporation. The residue is dissolved in methylene chloride and extracted with 2 N sodium hydroxide solution. After evaporation of the methylene chloride, the crude l-~p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxy-propane remains as an oil.
Example 3 A solution of l-[o-allyl-p-(N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane (15 g) and isopropylamine ~15 g) in 20 ml of ethanol is heated for 4 hours. Thereafter the reaction mixture is evaporated in vacuo, the residue dissolved in 2N-hydrochloric acid and filtered. The filtrate is rendered alkaline by addition of concentrated sodium hydroxide solution. An oil is precipitated that is extracted with methylene chloride. After the solution has been dried and the solvent evaporated, there remains l-[o-allyl-p-(N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of formula )2NcoNH - ~ OCH2CHCH2NHCH /
CH2CH=CH2 CH3 which after recrystallization from benzene-petroleum ether melts at 110-112C.
The epoxide used as starting material can be prepared in the following way:
To 2-allyl-4-amino-phenol ~15 g) in 50 ml of pyridine is added dimethyl-carbamoyl chloride (12 g) and the mixture is left to stand for 12 hours at 25C. On addition of 200 ml of 2N hydrochloric acid, extraction with methylene chloride is effected. The extract is evaporated to dryness in vacuo. The residue is dissolved in 2N sodium hydroxide solution, the .
: ' '.' 9~L49~
resulting solution treated with charcoal and adjusted to a pH of 9 by addition of hydrochloric acid. The precipitated constituents are filtered off, the filtrate rendered acid. 2-Allyl-4-(N',N'-dimethylureido)-phenol is precipitated, which after recrystallization from ethyl acetate-pentane melts at 125-127C.
12 g of the phenol is heated to boiling for 12 hours with 12 g of epichlorohydrin and 12 g of potassium carbonate in 75 ml of acetone. Thereafter the solid constituents are filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in methylene chloride and extracted with sodium hydroxide solution. After evaporation of the solvent, the crude 1-[o-allyl-p-~N',N'-dimethylureido)-phenoxy]-2,3-epoxypropane remains as an oil.
Example 4 A mixture of 30 g 1-~m-~N',N'-dimethylureido)-phenoxy]-2,3-epoxy-propane, 30 g isopropylamine and 30 ml ethanol is heated to 60 for 4 hours and then evaporated to dryness in vacuo. The residue is dissolved in 2N-acetic acid and extracted with ether. After separation of the water phase the same is rendered alkaline by addition of sodium hydroxide solution and extracted with methylene chloride. After evaporation of the solvent the l-[m-~N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane of the formula ~ .
NHCON~CH3)2 .
remains, which melts after recrystalli~ation from isopropanol at 130.
- ~ .
~14~
Example 5 Tablets containing 20 mg of active substance are manufactured with the following composition:
l-[o-Chloro-p-~N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane 20 mg Starch 60 mg Lactose 50 mg Colloidal silica 5 mg Talc 9 mg Magnesium stearate 1 mg 145 mg Tablets containing 20 mg of l-[p-(N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane can be manufactured in the usual manner with the same composition.
Example 6 The following mixture is used to manufacture capsules:
l-[o-Chloro-p-(N',N'-dimethylureido)-phenoxy-2-hydroxy-3-isopropylamino-propane 2500 g Talc 80 g Colloidal silica 20 g The active substance isintimately mixed with talc and colloidal silica, and the mixture is forced through a sieve (0.5mm) and filled into hard gelatine capsules in portions of 21 mg.
Capsules can be manufactured in the same manner and with the same composition using l-~p-~N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy -3-isopropylamino-propane.
.
.. .. . ~ . ' :: ' :. , . : ~
- . ~ . .
;' .
Claims (19)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of new amines of formula I
(I) wherein R1 represents hydrogen or lower alkyl; R2 represents lower alkyl;
R3 represents lower alkyl, and Ph represents a meta- or para-phenylene radical, unsubstituted or substituted once by alkyl or alkenyl with up to 4 C-atoms or by halogen, and pharmaceutically acceptable salts thereof, which comprises;
a) reacting a compound of formula V
(V) wherein R1, R2 and Ph have the above significance, X1 represents the hydroxyl group and Z represents a halogen atom or a reactive esterified hydroxyl group, or X1 and Z together form an epoxy group, with an amine of the formula wherein R3 has the above significance; or b) reacting a compound of formula VI
(VI) wherein R1, R2 and Ph have the above significance, with a compound of the formula wherein Z and R3 have the above significance; or c) reacting a compound of formula VIII
(VIII) wherein R1, R2 and Ph have the above significance, with a compound of formula IX
(IX) wherein Z, X1 and R3 have the above meanings; or d) removing from a compound of formula I wherein R1, R2, R3 and Ph have the above significance and which possesses a removable radical on the nitrogen atom of the amino group and/or on the hydroxyl group, said radical or radicals; or e) reducing a Schiff base of formulae XII or XIII
(XII) or (XIII) or a ring-tautomer, corresponding to formula XIII, wherein R1, R2, Ph and R3 have the above significance and R3'H is the same as R3; or f) reducing in a compound of formula XVI
(XVI) wherein R1,R2,R3 and Ph have the above significance, the 2-oxo group to a hydroxyl group; or g) reacting a reactive acid derivative of a carbamic acid of formula XVII
(XVII) wherein Ph and R3 have the above significance, with an amine of formula wherein R1, and R2 have the above significance; and, when required, resulting racemates are resolved into the optical antipodes, and/or resulting free bases are coverted into their pharmaceutically acceptable salts or resulting salts into the free bases or into other salts which are pharmaceutically acceptable.
(I) wherein R1 represents hydrogen or lower alkyl; R2 represents lower alkyl;
R3 represents lower alkyl, and Ph represents a meta- or para-phenylene radical, unsubstituted or substituted once by alkyl or alkenyl with up to 4 C-atoms or by halogen, and pharmaceutically acceptable salts thereof, which comprises;
a) reacting a compound of formula V
(V) wherein R1, R2 and Ph have the above significance, X1 represents the hydroxyl group and Z represents a halogen atom or a reactive esterified hydroxyl group, or X1 and Z together form an epoxy group, with an amine of the formula wherein R3 has the above significance; or b) reacting a compound of formula VI
(VI) wherein R1, R2 and Ph have the above significance, with a compound of the formula wherein Z and R3 have the above significance; or c) reacting a compound of formula VIII
(VIII) wherein R1, R2 and Ph have the above significance, with a compound of formula IX
(IX) wherein Z, X1 and R3 have the above meanings; or d) removing from a compound of formula I wherein R1, R2, R3 and Ph have the above significance and which possesses a removable radical on the nitrogen atom of the amino group and/or on the hydroxyl group, said radical or radicals; or e) reducing a Schiff base of formulae XII or XIII
(XII) or (XIII) or a ring-tautomer, corresponding to formula XIII, wherein R1, R2, Ph and R3 have the above significance and R3'H is the same as R3; or f) reducing in a compound of formula XVI
(XVI) wherein R1,R2,R3 and Ph have the above significance, the 2-oxo group to a hydroxyl group; or g) reacting a reactive acid derivative of a carbamic acid of formula XVII
(XVII) wherein Ph and R3 have the above significance, with an amine of formula wherein R1, and R2 have the above significance; and, when required, resulting racemates are resolved into the optical antipodes, and/or resulting free bases are coverted into their pharmaceutically acceptable salts or resulting salts into the free bases or into other salts which are pharmaceutically acceptable.
2. A process as claimed in claim 1 (a), wherein a compound of formula V is used, in which Z represents a halogen atom, the -OSO3H group or the radical of a strong aromatic sulphonic acid and wherein the reaction is carried out in the presence of a basic condensation agent.
3. A process as claimed in claim 2, wherein a compound of formula V
is used, in which Z represents chlorine, bromine or iodine.
is used, in which Z represents chlorine, bromine or iodine.
4. A process as claimed in claim 3, wherein the reaction with a compound of formula V is carried out with an excess of amine.
5. A process as claimed in claim 1(b), wherein a compound of formula is used, in which Z represents a hydroxyl group esterified by a hydrohalic acid, sulphuric acid or a strong aromatic sulphonic acid and wherein the reaction is carried out in the presence of a basic condensation agent.
6. A process as claimed in claim 1(c), wherein a compound of formula IX is used, in which Z is a halogen atom, the .OSO3H group or a radical of a strong aromatic sulphonic acid and a compound of formula VIII in the form of its metal phenolate and wherein the reaction is carried out in the presence of an acid-binding agent.
7. A process as claimed in claim 1(d), wherein the removable radicals are acyl radicals which are removed by hydrolysis or hydrogenolysis.
8. A process as claimed in claim 1(e), wherein the reduction of a Schiff base of formulae XII or XIII, or a ring-tautomer corresponding to formula XIII is carried out with a di-light metal hydride or by catalytic hydrogenation.
9. A process as claimed in claim 1(f), wherein the reduction of a compound of formula XVI is carried out with a di-light metal hydride or with an alkanol and the corresponding metal alcoholate thereof.
10. A process as claimed in claim 1(g), wherein a lower alkyl ester or phenyl ester, an acid halide or an isocyanate, is used as reactive acid derivative of a carbamic acid of formula XVII.
11. A process as claimed in claims 1 to 3, wherein compounds of formula III
(III) are prepared in which R? and R? each represents lower alkyl, R? represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1,R2 and R3 have the same values as given above for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as defined above.
(III) are prepared in which R? and R? each represents lower alkyl, R? represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1,R2 and R3 have the same values as given above for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as defined above.
12. A process as claimed in claims 4 to 6, wherein compounds of formula III
(III) are prepared in which R? and R? each represents lower alkyl, R3 represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1, R2 and R3 have the same values as given above for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as defined above.
(III) are prepared in which R? and R? each represents lower alkyl, R3 represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1, R2 and R3 have the same values as given above for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as defined above.
13. A process as claimed in claims 7 to 9, wherein compounds of formulae III
(III) are prepared in which R1' and R2' each represents lower alkyl, R3" represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1, R2 and R3 have the same values as given above for R1', R2' and R3" and Ph is a p-phenylene radical substituted by R4 as defined above.
(III) are prepared in which R1' and R2' each represents lower alkyl, R3" represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1, R2 and R3 have the same values as given above for R1', R2' and R3" and Ph is a p-phenylene radical substituted by R4 as defined above.
14. A process as claimed in claim 10, wherein compounds of formula III
(III) :
are prepared in which R1 and R2 each represents lower alkyl, R3 represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1, R2 and R3 have the same values as given above for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as defined above.
(III) :
are prepared in which R1 and R2 each represents lower alkyl, R3 represents lower alkyl, R4 represents hydrogen or chlorine or represents alkenyl with 2 to 4 C-atoms, from corresponding intermediates of the various formulae given in claim 1 in which R1, R2 and R3 have the same values as given above for R1, R2 and R3 and Ph is a p-phenylene radical substituted by R4 as defined above.
15. A process as claimed in claim 1, wherein 1-[p-N',N'-dimethyl-ureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane is prepared from the corresponding chemical intermediates defined therein in which R1 and R2 are methyl groups, R3 is isopropyl and Ph is p-phenylene.
16. A process as claimed in Claim 1, wherein 1-[o-chloro-p-N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane is prepared from the corresponding chemical intermediates defined therein in which R1 and R2 are methyl groups, R3 is isopropyl and Ph is o-chloro-p-phenylene.
17. A compound of formula I
(I) wherein R1 represents hydrogen or lower alkyl; R2 represents lower alkyl;
R3 represents lower alkyl, and Ph represents a meta- or para-phenylene radical, unsubstituted or substituted once by alkyl or alkenyl with 1 to 4 C-atoms or by halogen, or pharmaceutically acceptable salts thereof, whenever prepared according to claim 1 to 3 or by an obvious chemical equivalent thereof.
(I) wherein R1 represents hydrogen or lower alkyl; R2 represents lower alkyl;
R3 represents lower alkyl, and Ph represents a meta- or para-phenylene radical, unsubstituted or substituted once by alkyl or alkenyl with 1 to 4 C-atoms or by halogen, or pharmaceutically acceptable salts thereof, whenever prepared according to claim 1 to 3 or by an obvious chemical equivalent thereof.
18. 1-[(p-N',N'-Dimethylureido)-phenoxy]-2-hydroxy-3-isopropylamino-propane, whenever prepared according to claim 15, or by an obvious chemical equivalent thereof.
19. 1-[(o-Chloro-p-N',N'-dimethylureido)-phenoxy]-2-hydroxy-3-isopropyl-amino-propane whenever prepared according to claim 16 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH204/70 | 1970-01-08 | ||
| CH20470A CH554311A (en) | 1970-01-08 | 1970-01-08 | Cardioactive amines |
| CH16788/70 | 1970-11-13 | ||
| CH1678870 | 1970-11-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1149819A true CA1149819A (en) | 1983-07-12 |
Family
ID=25683866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000101368A Expired CA1149819A (en) | 1970-01-08 | 1970-12-23 | Process for the manufacture of new amines |
Country Status (15)
| Country | Link |
|---|---|
| JP (3) | JPS5518700B1 (en) |
| AR (6) | AR207306A1 (en) |
| AT (3) | AT318649B (en) |
| BE (1) | BE761321A (en) |
| CA (1) | CA1149819A (en) |
| CS (6) | CS155958B2 (en) |
| DE (1) | DE2100323C3 (en) |
| DK (1) | DK129650B (en) |
| ES (6) | ES387059A1 (en) |
| FR (1) | FR2081419B1 (en) |
| GB (1) | GB1311044A (en) |
| HU (1) | HU168606B (en) |
| NL (1) | NL167685C (en) |
| PL (1) | PL92434B1 (en) |
| SE (1) | SE361308B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4038313A (en) * | 1970-01-08 | 1977-07-26 | Ciba-Geigy Corporation | Cycloalkylureido phenoxy propanolamines |
| US3935259A (en) | 1970-01-08 | 1976-01-27 | Ciba-Geigy Corporation | New amines and processes for their manufacture |
| JPS5614661B2 (en) * | 1971-12-23 | 1981-04-06 | ||
| AT321315B (en) * | 1972-02-28 | 1975-03-25 | Chemie Linz Ag | Process for the preparation of new ureidophenoxypropylamine derivatives and their salts |
| JPS5013356A (en) * | 1973-06-08 | 1975-02-12 | ||
| JPS5013357A (en) * | 1973-06-08 | 1975-02-12 | ||
| JPS53105452A (en) * | 1978-02-25 | 1978-09-13 | Dresden Arzneimittel | Method for production of derivative of ureidphenoxyyalkanolamine |
| JPS53105454A (en) * | 1978-02-25 | 1978-09-13 | Dresden Arzneimittel | Method for production of derivative of ureidphenoxyyalkanolamine |
| JPS53105456A (en) * | 1978-02-25 | 1978-09-13 | Dresden Arzneimittel | Method for production of derivative of ureidphenoxyyalkanolamine |
| US4177280A (en) * | 1978-07-03 | 1979-12-04 | Syntex (U.S.A.) Inc. | Bicyclo[3.1.0]hexyl-substituted carbonylaminophenoxy cardiovascular agents |
| JPS61178357U (en) * | 1985-04-24 | 1986-11-07 | ||
| JPS63147473U (en) * | 1987-03-16 | 1988-09-28 | ||
| JPS649170U (en) * | 1988-07-15 | 1989-01-18 | ||
| DE202012101380U1 (en) | 2012-04-16 | 2012-06-15 | Fernsteuergeräte Kurt Oelsch GmbH | Cable length sensor |
-
1970
- 1970-12-23 CA CA000101368A patent/CA1149819A/en not_active Expired
- 1970-12-30 JP JP12313970A patent/JPS5518700B1/ja active Pending
-
1971
- 1971-01-01 AR AR238165A patent/AR207306A1/en active
- 1971-01-01 AR AR238164A patent/AR204685A1/en active
- 1971-01-01 AR AR238168A patent/AR203984A1/en active
- 1971-01-01 AR AR238167A patent/AR207307A1/en active
- 1971-01-01 AR AR238166A patent/AR204898A1/en active
- 1971-01-05 FR FR7100076A patent/FR2081419B1/fr not_active Expired
- 1971-01-05 DE DE2100323A patent/DE2100323C3/en not_active Expired
- 1971-01-07 GB GB79371A patent/GB1311044A/en not_active Expired
- 1971-01-07 AT AT922872A patent/AT318649B/en not_active IP Right Cessation
- 1971-01-07 PL PL1971178941A patent/PL92434B1/en unknown
- 1971-01-07 BE BE761321A patent/BE761321A/en not_active IP Right Cessation
- 1971-01-07 HU HUCI1073A patent/HU168606B/hu unknown
- 1971-01-07 CS CS9871*#A patent/CS155958B2/cs unknown
- 1971-01-07 ES ES387059A patent/ES387059A1/en not_active Expired
- 1971-01-07 AT AT922972A patent/AT318650B/en not_active IP Right Cessation
- 1971-01-07 CS CS161872A patent/CS155962B2/cs unknown
- 1971-01-07 SE SE00101/71A patent/SE361308B/xx unknown
- 1971-01-07 NL NL7100178A patent/NL167685C/en not_active IP Right Cessation
- 1971-01-07 DK DK4771AA patent/DK129650B/en unknown
- 1971-01-07 CS CS161772A patent/CS155961B2/cs unknown
- 1971-01-07 CS CS161672A patent/CS155960B2/cs unknown
- 1971-01-07 AR AR233351A patent/AR194708A1/en active
- 1971-01-07 CS CS161972A patent/CS155963B2/cs unknown
- 1971-01-07 AT AT8271A patent/AT318647B/en not_active IP Right Cessation
- 1971-01-07 CS CS161572A patent/CS155959B2/cs unknown
-
1973
- 1973-11-02 ES ES420205A patent/ES420205A1/en not_active Expired
- 1973-11-02 ES ES420201A patent/ES420201A1/en not_active Expired
- 1973-11-02 ES ES420203A patent/ES420203A1/en not_active Expired
- 1973-11-02 ES ES420202A patent/ES420202A1/en not_active Expired
- 1973-11-02 ES ES420204A patent/ES420204A1/en not_active Expired
-
1975
- 1975-06-07 JP JP6904975A patent/JPS563862B1/ja active Pending
-
1980
- 1980-06-05 JP JP7499780A patent/JPS5632305B1/ja active Pending
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