CA1050032A - Amines and processes for their manufacture - Google Patents
Amines and processes for their manufactureInfo
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- CA1050032A CA1050032A CA190,087A CA190087A CA1050032A CA 1050032 A CA1050032 A CA 1050032A CA 190087 A CA190087 A CA 190087A CA 1050032 A CA1050032 A CA 1050032A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- 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
-
- 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
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Epoxy Compounds (AREA)
Abstract
Abstract of the Disclosure Process for the preparation of new amines of the formula I
(I) wherein Alk1 is lower alkyl, alk2 is lower alkylene, Ph is optionally substituted p-phenylene and R is lower alkyl or aryl-lower alkyl, and their condensation products with alde-hydes, ketones or carbonic acid. The new amines are valuable cardioselective antagonistic agents of adrenergic .beta.-receptor stimulants.
The new amines of the formula I can be obtained by methods known per se and suitable with methods are described.
(I) wherein Alk1 is lower alkyl, alk2 is lower alkylene, Ph is optionally substituted p-phenylene and R is lower alkyl or aryl-lower alkyl, and their condensation products with alde-hydes, ketones or carbonic acid. The new amines are valuable cardioselective antagonistic agents of adrenergic .beta.-receptor stimulants.
The new amines of the formula I can be obtained by methods known per se and suitable with methods are described.
Description
03;~
The invention relates to new amines of the formula I
Alkl - S - alk2 - O ~ O - CH2 - A ~I) wherein A represents the group -CH~OH) - CH2 - NH - R (Ia) or represents the ~roup \ X / ~Ib) wherein Alkl denotes lower alkyl, alk2 denotes lower alkylene, R is lower alkyl or phenyl-lower-alkyl, wherein phenyl is unsubstituted or mono-- substituted by lower alkylJ lower alkoxy, halogen or trifluoromethyl, Rl is hydrogen J lower alkyl, lower alkenyl, lower alkenyloxy, lower alkanoyl, halogen or trifluoromethyl, X denotes the methylene or carbonyl group, in the form of isomer mixtures (racemate mixtures) or pure racemates or optical antipodes or pharmaceutically accep~able acid addition salts thereof, as well as to processes for their manufacture.
In the preceding and following text, a lower radical is in particular understood as a radical with up to 7 C atoms, above all with up to 4 C atoms.
Thus, lower alkyl Alkl preferably has up to 7 C atoms, such as iso-propyl or n-propyl, straight or branched butyl, pentyl, hexyl or heptyl, bonded in any desired position, above all up to 4 C atoms, and especially ethyl and above all methyl.
, . ~'' ~6JS~d Lower alkylene alk2 is branched or above all straight-chain lower alkylene, preferably with at least 2 C atoms in the alkylene chain and ~ith especially 2 or 3 C atoms in the alkylene chain, such as propylene-1,3 or above all ethylene-1,2.
The Rl-substituted para-phenylene radical is referred to here-inafter as Ph.
Suitable values for Rl on the para-phenylene radical are, for example, hydrogen, trifluoromethyl, fluorine, bromine and especially chlorine, the lower alkyl radicals given for Alkl, vinyl, methallyl and especially allyl, ethoxy, iso- or n-propoxy and especially methoxy, methallyloxy and above all allyloxy, butyryl, propionyl and above all acetyl. It is preferred that the p-phenylene radical is substituted in the ortho-position to the 2-hydroxy-propoxy radical, or especially that the p-phenylene radical is unsubstituted.
The lower alkyl R is unbranched or preferably branched, in particular branched at the a-C atom, and is, for example, sec.-butyl or especially tert.-butyl or above all isopropyl.
The phenyl-lower alkyl R preferably has up to 12 C atoms, above all up to 10 C atoms, and is unbranched or preferably branched in the lower alkyl part, in particular branched at the a-C atom of the lower alkyl part. The phenyl part is in particular monosubstituted by lower alkyl as indicated for Alkl, or lower alkoxy, halogen or trifluoromethyl as indicated, but is preferably unsubstituted. Examples _ 3 _ , ~
of phenyl-lower alkyl R are l-methyl-3-phenyl-propyl and especially l-methyl-2-phenyl-ethyl.
Condensation products of compounds of the formula I wi~h formaldehyde are those of the formula Iba Al~l - S - alk2 - O ~ O - CH2 - CH - CH (Iba) ~X /
wherein Alkl, alk2~ Rl and R have the above meanings and X represents the methylene group.
Condensation products of compounds of the formula I with car-bonic acid are those of the formula Ibb .
, 50~)3Z
Rl Alkl - S - alk2 - 0 ~ O - CH2 - CH - fH2 O ~ - R (Ibb~
wherein Alkl, alk2, Rl and R have the above meanings.
The new compounds possess valuable pharmacological properties. Thus, they block cardiac ~-receptors, as can be shown in determining the antagonism of tachycardia after 0.5 ~g/kg of d/l-isoproterenol sulphate administered intravenously in narcotised cats on intravenous administration of 0.02 to 2 mg/kg, they block vascular ~-receptors, as can be shown in determining the antagonism of vaso-dilation after 0.5 ~g/kg of d/l-isoproterenol sulphate administered intravenously in narco~ised cats on intravenous administration of 3 or more mg/kg, and they block cardiac ~-receptors as can be shown in determining the tachycardia after O.OOS ~g/ml of d/l-isoproterenol sulphate on isolated guineapig hearts in vitro at a concentration of 0.02 to 2 ~g/ml.
The new compounds can therefore be used as cardio-selective antagonistic agents of adrenergic ~-receptor s~imulants, for example for the treatment of arrhythmias and angina pectoris.
However, they can also be used as valuable intermediate products for ~he manufacture of other useful substances, especially of phar-maceutically active compounds.
,1~ - 5 -1~003;~
Amongst the amines of the formula I, those wherein Alkl has the above meanings, alk2 is 1,2-ethylene or 1,3-propylene, R
is ~-branched lower alkyl or phenyl-lower alkyl with an a-branched lower alkyl part and Rl has the above meanings, should be singled out particularly.
Amines of the formula I to be singled out very especially are those wherein Alkl is lower alkyl with up to 4 C atoms, especially me~hyl, alk2 is 1,3-propylene or especially 1,2-ethylene, R is phenyl-lower alkyl with up to lO C atoms and an ~-branched lower alkyl part, 10especially 1-methyl-2-phenyl-ethyl, or above all ~-branched lower alkyl with up to 4 C atoms, such as tert.-butyl or above all isopropyl, and Rl is lower alkyl with up to 4 C atoms, especially methyl) lower alkenyl with up to 4 C atoms, especially methallyl or above all allyl, lower alkoxy with up to 4 C atoms, especially methoxy, lower alkenyloxy with up to 4 C atoms, especially methallyloxy or above all allyloxy, lower alkanoyl with up t~ 4 C atoms, especially acetyl, halo~en, " ~
~ . - 6 -~ ,.
, .
~6~5i(;~3~
especially chlorine, or above all hydrogen.
The compounds mentioned not condensed with formaldehyde or car-bonic acid are preferred.
1-[4-(2-Me~hylthio-ethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane and the compounds mentioned in the examples should be mentioned particularly.
The new compounds can be obtained according to methods which are in themselves known.
For example, a compound of the formula II
Xl Alkl - S - alk2 - O ~ 0 - CH2 - CH - CH2 ~ Z (II) wherein Alkl, alk2 and Rl have the abo~e meanings, Xl represents the hydroxyl group and Z represents a reactive esterified hydroxyl group, or Xl and Z
together form an epoxy group, can be reacted with an amine of the formula NH2-R (III), wherein R has the above meaning.
A reactive, esterified hydroxyl group is in particular a hydroxyl group esterified by a strong inorganic or organic acid, above all a hydrogen halide acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, or sulphuric acid or a strong organic sulphonic acid, such as a strong aro-matic sulphonic acid, for exam~le benzenesulphonic acid, 4-bromobenzenesul-phonic acid or 4-toluenesulphonic acid. Thus Z in particular represents chlorine, bromine or iodine.
This reaction is carried out in the usual manner. If a reactiv~
ester is used as the starting material, the reaction is preferably carried out in the presence of a basic condensation agent and/or with an excess of amine. Suitable basic condensation agents are, for example, alkali metal hydToxides, such as sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as potassium carbonate, and alkali metal alcoholates, such as sodium methylateJ potassium ethylate and potassium tertiarybutylate.
It is also possible to react a compound o the formula IIb - 7 _ 105003;~
Rl OH
Alkl - S - alk2 - O - ~ ~ O - CH2 - CH - CH2 - NH2 (IIb) wherein Alkl, alk2 and Rl have the above meanings, or a condensation product thereof with formaldehyde, i.e. a compound of the formula IIc Alk - S - alk - O ~ O - CH2 - IH I 2 (llc) wherein Alkl, alk2 and Rl have the above meanings, or a condensation product thereof with carbonic acid, i.e. a compound of the formula IId .,, ~1 Alk - S - alk - O ~ 2 IH lH2 (IId) O NH
wherein Alkl, alk2 and Rl have the above meanings, with a compound of the formula Z-R (IIIa), wherein Z and R have the above meanings.
This reaction is carried out in the usual manner, preferably in the presence of a basic condensation agent and/or with an excess of amine.
; Examples of suitable basic condensation agen~s are alkali metal alcoholates, especially sodium alcoholates or potassium alcoholates, or alkali metal car-bonates, such as sodium carbonate or potassium carbonate.
It is also possible to react a compound of the formula IV
~Ikl - S - alk2 ~ O~OH ~IV) wherein Alkl, alk2 and Rl have the above meanings, with a compound of the formula V
Xll Z - CH2 - CH - CH2 - NH - ~ (V) wherein ZJ X1 and R have the above meanings, or with a condensation product of a compound of the formula V, wherein Xl represents hydroxyl and Z repre-- : ' ~Losv~3~
sents a reactive esterified hydroxyl group, with formaldehyde, for exampLe a compound of the formula Va Z - CH - C~ CH
The invention relates to new amines of the formula I
Alkl - S - alk2 - O ~ O - CH2 - A ~I) wherein A represents the group -CH~OH) - CH2 - NH - R (Ia) or represents the ~roup \ X / ~Ib) wherein Alkl denotes lower alkyl, alk2 denotes lower alkylene, R is lower alkyl or phenyl-lower-alkyl, wherein phenyl is unsubstituted or mono-- substituted by lower alkylJ lower alkoxy, halogen or trifluoromethyl, Rl is hydrogen J lower alkyl, lower alkenyl, lower alkenyloxy, lower alkanoyl, halogen or trifluoromethyl, X denotes the methylene or carbonyl group, in the form of isomer mixtures (racemate mixtures) or pure racemates or optical antipodes or pharmaceutically accep~able acid addition salts thereof, as well as to processes for their manufacture.
In the preceding and following text, a lower radical is in particular understood as a radical with up to 7 C atoms, above all with up to 4 C atoms.
Thus, lower alkyl Alkl preferably has up to 7 C atoms, such as iso-propyl or n-propyl, straight or branched butyl, pentyl, hexyl or heptyl, bonded in any desired position, above all up to 4 C atoms, and especially ethyl and above all methyl.
, . ~'' ~6JS~d Lower alkylene alk2 is branched or above all straight-chain lower alkylene, preferably with at least 2 C atoms in the alkylene chain and ~ith especially 2 or 3 C atoms in the alkylene chain, such as propylene-1,3 or above all ethylene-1,2.
The Rl-substituted para-phenylene radical is referred to here-inafter as Ph.
Suitable values for Rl on the para-phenylene radical are, for example, hydrogen, trifluoromethyl, fluorine, bromine and especially chlorine, the lower alkyl radicals given for Alkl, vinyl, methallyl and especially allyl, ethoxy, iso- or n-propoxy and especially methoxy, methallyloxy and above all allyloxy, butyryl, propionyl and above all acetyl. It is preferred that the p-phenylene radical is substituted in the ortho-position to the 2-hydroxy-propoxy radical, or especially that the p-phenylene radical is unsubstituted.
The lower alkyl R is unbranched or preferably branched, in particular branched at the a-C atom, and is, for example, sec.-butyl or especially tert.-butyl or above all isopropyl.
The phenyl-lower alkyl R preferably has up to 12 C atoms, above all up to 10 C atoms, and is unbranched or preferably branched in the lower alkyl part, in particular branched at the a-C atom of the lower alkyl part. The phenyl part is in particular monosubstituted by lower alkyl as indicated for Alkl, or lower alkoxy, halogen or trifluoromethyl as indicated, but is preferably unsubstituted. Examples _ 3 _ , ~
of phenyl-lower alkyl R are l-methyl-3-phenyl-propyl and especially l-methyl-2-phenyl-ethyl.
Condensation products of compounds of the formula I wi~h formaldehyde are those of the formula Iba Al~l - S - alk2 - O ~ O - CH2 - CH - CH (Iba) ~X /
wherein Alkl, alk2~ Rl and R have the above meanings and X represents the methylene group.
Condensation products of compounds of the formula I with car-bonic acid are those of the formula Ibb .
, 50~)3Z
Rl Alkl - S - alk2 - 0 ~ O - CH2 - CH - fH2 O ~ - R (Ibb~
wherein Alkl, alk2, Rl and R have the above meanings.
The new compounds possess valuable pharmacological properties. Thus, they block cardiac ~-receptors, as can be shown in determining the antagonism of tachycardia after 0.5 ~g/kg of d/l-isoproterenol sulphate administered intravenously in narcotised cats on intravenous administration of 0.02 to 2 mg/kg, they block vascular ~-receptors, as can be shown in determining the antagonism of vaso-dilation after 0.5 ~g/kg of d/l-isoproterenol sulphate administered intravenously in narco~ised cats on intravenous administration of 3 or more mg/kg, and they block cardiac ~-receptors as can be shown in determining the tachycardia after O.OOS ~g/ml of d/l-isoproterenol sulphate on isolated guineapig hearts in vitro at a concentration of 0.02 to 2 ~g/ml.
The new compounds can therefore be used as cardio-selective antagonistic agents of adrenergic ~-receptor s~imulants, for example for the treatment of arrhythmias and angina pectoris.
However, they can also be used as valuable intermediate products for ~he manufacture of other useful substances, especially of phar-maceutically active compounds.
,1~ - 5 -1~003;~
Amongst the amines of the formula I, those wherein Alkl has the above meanings, alk2 is 1,2-ethylene or 1,3-propylene, R
is ~-branched lower alkyl or phenyl-lower alkyl with an a-branched lower alkyl part and Rl has the above meanings, should be singled out particularly.
Amines of the formula I to be singled out very especially are those wherein Alkl is lower alkyl with up to 4 C atoms, especially me~hyl, alk2 is 1,3-propylene or especially 1,2-ethylene, R is phenyl-lower alkyl with up to lO C atoms and an ~-branched lower alkyl part, 10especially 1-methyl-2-phenyl-ethyl, or above all ~-branched lower alkyl with up to 4 C atoms, such as tert.-butyl or above all isopropyl, and Rl is lower alkyl with up to 4 C atoms, especially methyl) lower alkenyl with up to 4 C atoms, especially methallyl or above all allyl, lower alkoxy with up to 4 C atoms, especially methoxy, lower alkenyloxy with up to 4 C atoms, especially methallyloxy or above all allyloxy, lower alkanoyl with up t~ 4 C atoms, especially acetyl, halo~en, " ~
~ . - 6 -~ ,.
, .
~6~5i(;~3~
especially chlorine, or above all hydrogen.
The compounds mentioned not condensed with formaldehyde or car-bonic acid are preferred.
1-[4-(2-Me~hylthio-ethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane and the compounds mentioned in the examples should be mentioned particularly.
The new compounds can be obtained according to methods which are in themselves known.
For example, a compound of the formula II
Xl Alkl - S - alk2 - O ~ 0 - CH2 - CH - CH2 ~ Z (II) wherein Alkl, alk2 and Rl have the abo~e meanings, Xl represents the hydroxyl group and Z represents a reactive esterified hydroxyl group, or Xl and Z
together form an epoxy group, can be reacted with an amine of the formula NH2-R (III), wherein R has the above meaning.
A reactive, esterified hydroxyl group is in particular a hydroxyl group esterified by a strong inorganic or organic acid, above all a hydrogen halide acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, or sulphuric acid or a strong organic sulphonic acid, such as a strong aro-matic sulphonic acid, for exam~le benzenesulphonic acid, 4-bromobenzenesul-phonic acid or 4-toluenesulphonic acid. Thus Z in particular represents chlorine, bromine or iodine.
This reaction is carried out in the usual manner. If a reactiv~
ester is used as the starting material, the reaction is preferably carried out in the presence of a basic condensation agent and/or with an excess of amine. Suitable basic condensation agents are, for example, alkali metal hydToxides, such as sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as potassium carbonate, and alkali metal alcoholates, such as sodium methylateJ potassium ethylate and potassium tertiarybutylate.
It is also possible to react a compound o the formula IIb - 7 _ 105003;~
Rl OH
Alkl - S - alk2 - O - ~ ~ O - CH2 - CH - CH2 - NH2 (IIb) wherein Alkl, alk2 and Rl have the above meanings, or a condensation product thereof with formaldehyde, i.e. a compound of the formula IIc Alk - S - alk - O ~ O - CH2 - IH I 2 (llc) wherein Alkl, alk2 and Rl have the above meanings, or a condensation product thereof with carbonic acid, i.e. a compound of the formula IId .,, ~1 Alk - S - alk - O ~ 2 IH lH2 (IId) O NH
wherein Alkl, alk2 and Rl have the above meanings, with a compound of the formula Z-R (IIIa), wherein Z and R have the above meanings.
This reaction is carried out in the usual manner, preferably in the presence of a basic condensation agent and/or with an excess of amine.
; Examples of suitable basic condensation agen~s are alkali metal alcoholates, especially sodium alcoholates or potassium alcoholates, or alkali metal car-bonates, such as sodium carbonate or potassium carbonate.
It is also possible to react a compound of the formula IV
~Ikl - S - alk2 ~ O~OH ~IV) wherein Alkl, alk2 and Rl have the above meanings, with a compound of the formula V
Xll Z - CH2 - CH - CH2 - NH - ~ (V) wherein ZJ X1 and R have the above meanings, or with a condensation product of a compound of the formula V, wherein Xl represents hydroxyl and Z repre-- : ' ~Losv~3~
sents a reactive esterified hydroxyl group, with formaldehyde, for exampLe a compound of the formula Va Z - CH - C~ CH
2 1 2 I (Va) 0~ /N - R
wherein Z and R have the above meanings, or with a condensa-tion product of a compound of the formula V, wherein Xl represents hydroxyl and Z represents a reactive esterified hydroxyl group, with carbonic acid, for example a com-pound of the formula Vb Z - CH2 - IH f 2 (Vb) 0 ~ N - R
wherein Z and R have the above meaning.
This reaction is carried out in the usual manner. If reactive esters are used as the starting material, the compound of the formula IV
can preferably be used in the form of its metal phenolate, such as alkali metal phenolate, for example sodium phenolate, or the reaction is carried out in the presence of an acid-binding agent, especially of a condensation agent which can form a salt with the compound of the formula IV, such as an alkali metal alcoholate.
It is also possible to hydrolyse a compound of the formula VI
Alkl - S - alk2 - o ~ - CH2 - IH lH2 (VI) \y/
wherein Alkl, alk2, Rl and R have the meanings defined under formula I and Y denotes a methylene or a carbonyl or a thiocarbonyl radical or a salt of such a compound.
The hydrolysis is carried out in the usual manner, for example in the presence of hydrolysing agents, for example, in the presence of acid agents such as, for example, aqueous mineral acids, such as sulphuric acid J - 9 _ 32' or hydrogen halide acid, or in the presence of basic agents, for example, alkali metal hydroxides, such as sodium hydroxide.
It is also possible to reduce a Schiff's base of the formula Rl OH
Alk - S - alk - 0 ~ 30 - CH2 - CH - CH = N - R (VII) or of the formula Rl OH
Alkl - S - alk2 - 0 ~ ~ ~ CH2 ~ CH ~ CH2 ~ N - R' (VIIIa) whèrein Alkl, alk2, Rl and R have the meanings defined under formula (I~
and R'H has the meanings of R.
This reduction is carried out in the usual manner, for example, with a di-light metal hydride, such as sodium borohydride or lithium aluminum hydride, with a hydride such as borane, with formic acid or by catalytic hydrogenation. In carrying out the reduction it is necessary to ensure that other reducible groups are not attacked.
It is also possible to react a compound of the formula Alkl - S - alk2 - Z (IX) with a compound of the formula Rl HO ~ O - CH2 - A (X) wherein Alkl, alk2, Rl and A have the meanings defined under formula (I) and Z represents a reactive esterified hydroxyl group, or with a salt of such a compound.
This reaction is carried out in the usual manner, for example, as indicated for the reaction of compounds of the formula IV and V.
Depending on the process conditions and starting materials, the end products are obtained in the free form or in the form of their acid addi-tion salts which is also encompassed by the invention. Thùs, for example, basic, neutral or mixed salts and possibly also hemihydrates, monohydrates, ~1 10-.
. .
sesquihydrates or polyhydrates thereo:f, can be obtalned. ~he 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 resul~ing free bases can form salts wit~ organic or inorganic acids.
Æ:
~ D~ 3 2 The acids used -or the manufacture of acid addition sa]-ts are in particular those wlnic~ are su;-rable for forming therapeu-tically usable salts. hs exa[nples of such acids there may be mentioned: Hydrogen halide acids, sulphuric acids, phosphoric acidsg nitric acid and aliphatic, ali-cyclic, aromatic or heterocyclic carboxylic acids or sul~
phonic acids, such as formic acid, ace-tic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, -tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, benzoic acid, p-aminobenzoic acid, an-thranilic acid, p-hydroxybenzoic acid, salicylic acid or embonic acld, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, e~hylene sulphonic acid, halogenobenzenesulphonic acids, toluene-sulphonic acid, naphthalenesulphonic acid or sulphanilic acid.
These or other salts of the new compounds such as, for example, the picrates, can also be used for the purifi-cation of the free bases obtained, by converting -the free bases into salts, isolating -these and again liberating the bases from the salts. Because of the close relationships between the new co~pounds in the free form and in the form o~ their salts, the free co~pounds, in the preceding and following text, are where appropriate also to be understood as the corresponding salts, with regard to general sense and in-tended use.
The invention also relates to those embodimen-ts of the process in which a compound obtainable as an in~ermediate Ja product at any stage of the process is used as the starting material and the missing process steps are carried out, or the process is stopped at any stage, or in which a starting material is formed under the reaction conditions or in which a reactant is present in the form of its salts, if appropriate.
Thus it is possible to react an aldehyde of the formula XI
Rl OH
Alkl - S - alk2 - O ~ O - CH2 - CH - CHO (XI) wherein Alkl, alk2 and Ph have the above meanings, with an amine of the formula H2N-R, wherein R has the above meaning, in the presence of a suitable reducing agent, such as one of those mentioned above. This gives, as the intermediate product, a compound of the formula VII, which is then reduced in accordance with the invention.
Depending on the choice of the starting materials and procedures the new compounds can be in the form of optical antipodes or racemates or, if they contain at least two asymmetrical carbon atoms, also in the form of isomer mixtures (racemate mixtures~.
5~32 Resulting lsolner mix-tures (racemate mixtures) can be sep~ra-ted into the ~YiO stereomc-rio (o~ias~tereo}nerlc) pure racemates in a known marlner on t',le basis of the physico--che~i^al differencc-s of the corstituen~ts~ for exal~le by chromatography and/or fractional crystallisation Resulting racemates can be resolved in-to the dia sterevmers according to known methods, for exam~le by recrys-talllsation from an optically active solvent, with the aid of micro-organisms or by reaction with an optically active acid which for~s salts with the racemic compound and separation of the salts obtained in this manner, for example on the basis of their different solubillties, and the anti-podes can be liberated from the diastereomers by treatment with suitable agents. Particularly customary o~tically active acids are, for example, the D- ~nd L-forms o~
tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, cam~horsulphonic acid or quinic acid. AdvantageGusly, the more active o-f the antipodes is isola-ted.
Preferably, those starting materials are used ~or carrying out the reaccion according to the invention which lead to the initially particularly mentioned groups of end products and especially to the end products which have been particularly described or singled out.
The starting materials are kno~l or can, if they are new, be obtained according to methcds which are in themselves known.
The new sompounds can be used as medicaments~ for example in the form o~ pharm~ceutical preparations, in w~1ich ~Y_ ~6~S{~3~2 they or thelr ~salts ~re ~)re en-t as a mixture ~itl1 a pharma-ceutical, or~a~ic or lno~ganic, solid or li~uid excipient t~lich is sui-ta~le for, or ex~mple~ enteral or parenteral administration4 Suitable subs-tances for formlng the excipien-t are those wllich do not react w~th the ~ew com~
pounds such as, for example, ~ater, gelatine~ lac-tose, starch, magnesium stearate, talc, vege-table oils, benzyl alcohols, gum, polyalkylene glycols, white petroleum ~elly, cholesterol or other kno~l medicinal excipie-rlts. The pharmaceutical prep~ra-tions can be, for example~ in the form of tablets, dragees, capsules, suppositories, ointments or creams, or in a li~u~d form, as solutions (for example as an elixir or syru)~ suspensio~s or emulsions. ~ne~ are optionally sterilised and/or contain auxiliaries, such as preservatives, stabilising agents, wetting agents or emul-sifiers, salts for regulating the osmo-tic pressure or buffers.
They can also conialn yet other therapeutically valuable substances. The preparations, ~hich can also be used ln veterinary medicine, are formulated according to customary methods.
; The examples which follow explain the inven-tion without, however, limiting it.
Exam~
A solution of 20 g of 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-chloro-propane and 30 g o.~ isopropy]-amine in 50 ml of isopropanol is heated for 12 to 14 hours under refll~. Tne volatile constituen-ts are then evaporated off ~nder reduced pressure and the eJaporation residue is /~ :
_ ~_ . -. .
105l)(~3Z
dissolved in 300 ~1 of ethyl acetate and the solution is e~tracted ~iith 50 ml portions of 2 N hydrochloric acid.
The aqueous phase is separa~ted off and rendered s-trongly alkaline with concen-trated sodium hydroxi(le solution. The oil wllich precipitates is extracted with about 200 ml of ethyl acetate and distilled in a bulb tube at 150 to 160C/0.04 mm Hg. 1-[4-(2-me-thylthioethoxy)-phenoxy]-2-hydroxy-~-isopropylamino-propane is thus o~tained as an almost colourless oil which solidifies to crystals. Its hydrochloride melts at 102 to 103C (crystallise~ from butanone).
Exam~le 2 An analogous method to Example 1, usin~ ~5 g of t-butyla~ine, gives 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-~-t butylamino-propane of melting point 62-63C
(from ether/petroleum ether). Its hydrochloride melts at 131-133C (from acetone-ether).
1-~4-(2-Methylthioethoxy~-phenoxy]-2-hydroxy-3-chloropropane, required as the starting material can be obtained as follows:
2-(p-Hydroxyphenoxy)-tetrahydropyrane is reacted analoOously to ~xample 4 with 2-methylthioethyl chloride and is hydrolysed for 2 to 3 hours with dilute hydrochloric acid in e-thanol. p-(2~Methylthioethoxy)-phenol, thus obtained, is used in the crude form for the next stage.
20 g of crude p (2-methylthioethoxy)-phenol, 30 ml of epichloroh~drin and 0.2 ml of piperidine are heated for 1 hour ~der reflux. The excess epichlorohydrin is then ~6 distilled off at 100~ bath temperature and 10 mm Hg. The crude 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-chloropropane thus obtained is used direct for the next stage.
Example 3
wherein Z and R have the above meanings, or with a condensa-tion product of a compound of the formula V, wherein Xl represents hydroxyl and Z represents a reactive esterified hydroxyl group, with carbonic acid, for example a com-pound of the formula Vb Z - CH2 - IH f 2 (Vb) 0 ~ N - R
wherein Z and R have the above meaning.
This reaction is carried out in the usual manner. If reactive esters are used as the starting material, the compound of the formula IV
can preferably be used in the form of its metal phenolate, such as alkali metal phenolate, for example sodium phenolate, or the reaction is carried out in the presence of an acid-binding agent, especially of a condensation agent which can form a salt with the compound of the formula IV, such as an alkali metal alcoholate.
It is also possible to hydrolyse a compound of the formula VI
Alkl - S - alk2 - o ~ - CH2 - IH lH2 (VI) \y/
wherein Alkl, alk2, Rl and R have the meanings defined under formula I and Y denotes a methylene or a carbonyl or a thiocarbonyl radical or a salt of such a compound.
The hydrolysis is carried out in the usual manner, for example in the presence of hydrolysing agents, for example, in the presence of acid agents such as, for example, aqueous mineral acids, such as sulphuric acid J - 9 _ 32' or hydrogen halide acid, or in the presence of basic agents, for example, alkali metal hydroxides, such as sodium hydroxide.
It is also possible to reduce a Schiff's base of the formula Rl OH
Alk - S - alk - 0 ~ 30 - CH2 - CH - CH = N - R (VII) or of the formula Rl OH
Alkl - S - alk2 - 0 ~ ~ ~ CH2 ~ CH ~ CH2 ~ N - R' (VIIIa) whèrein Alkl, alk2, Rl and R have the meanings defined under formula (I~
and R'H has the meanings of R.
This reduction is carried out in the usual manner, for example, with a di-light metal hydride, such as sodium borohydride or lithium aluminum hydride, with a hydride such as borane, with formic acid or by catalytic hydrogenation. In carrying out the reduction it is necessary to ensure that other reducible groups are not attacked.
It is also possible to react a compound of the formula Alkl - S - alk2 - Z (IX) with a compound of the formula Rl HO ~ O - CH2 - A (X) wherein Alkl, alk2, Rl and A have the meanings defined under formula (I) and Z represents a reactive esterified hydroxyl group, or with a salt of such a compound.
This reaction is carried out in the usual manner, for example, as indicated for the reaction of compounds of the formula IV and V.
Depending on the process conditions and starting materials, the end products are obtained in the free form or in the form of their acid addi-tion salts which is also encompassed by the invention. Thùs, for example, basic, neutral or mixed salts and possibly also hemihydrates, monohydrates, ~1 10-.
. .
sesquihydrates or polyhydrates thereo:f, can be obtalned. ~he 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 resul~ing free bases can form salts wit~ organic or inorganic acids.
Æ:
~ D~ 3 2 The acids used -or the manufacture of acid addition sa]-ts are in particular those wlnic~ are su;-rable for forming therapeu-tically usable salts. hs exa[nples of such acids there may be mentioned: Hydrogen halide acids, sulphuric acids, phosphoric acidsg nitric acid and aliphatic, ali-cyclic, aromatic or heterocyclic carboxylic acids or sul~
phonic acids, such as formic acid, ace-tic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, -tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, benzoic acid, p-aminobenzoic acid, an-thranilic acid, p-hydroxybenzoic acid, salicylic acid or embonic acld, methanesulphonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, e~hylene sulphonic acid, halogenobenzenesulphonic acids, toluene-sulphonic acid, naphthalenesulphonic acid or sulphanilic acid.
These or other salts of the new compounds such as, for example, the picrates, can also be used for the purifi-cation of the free bases obtained, by converting -the free bases into salts, isolating -these and again liberating the bases from the salts. Because of the close relationships between the new co~pounds in the free form and in the form o~ their salts, the free co~pounds, in the preceding and following text, are where appropriate also to be understood as the corresponding salts, with regard to general sense and in-tended use.
The invention also relates to those embodimen-ts of the process in which a compound obtainable as an in~ermediate Ja product at any stage of the process is used as the starting material and the missing process steps are carried out, or the process is stopped at any stage, or in which a starting material is formed under the reaction conditions or in which a reactant is present in the form of its salts, if appropriate.
Thus it is possible to react an aldehyde of the formula XI
Rl OH
Alkl - S - alk2 - O ~ O - CH2 - CH - CHO (XI) wherein Alkl, alk2 and Ph have the above meanings, with an amine of the formula H2N-R, wherein R has the above meaning, in the presence of a suitable reducing agent, such as one of those mentioned above. This gives, as the intermediate product, a compound of the formula VII, which is then reduced in accordance with the invention.
Depending on the choice of the starting materials and procedures the new compounds can be in the form of optical antipodes or racemates or, if they contain at least two asymmetrical carbon atoms, also in the form of isomer mixtures (racemate mixtures~.
5~32 Resulting lsolner mix-tures (racemate mixtures) can be sep~ra-ted into the ~YiO stereomc-rio (o~ias~tereo}nerlc) pure racemates in a known marlner on t',le basis of the physico--che~i^al differencc-s of the corstituen~ts~ for exal~le by chromatography and/or fractional crystallisation Resulting racemates can be resolved in-to the dia sterevmers according to known methods, for exam~le by recrys-talllsation from an optically active solvent, with the aid of micro-organisms or by reaction with an optically active acid which for~s salts with the racemic compound and separation of the salts obtained in this manner, for example on the basis of their different solubillties, and the anti-podes can be liberated from the diastereomers by treatment with suitable agents. Particularly customary o~tically active acids are, for example, the D- ~nd L-forms o~
tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, cam~horsulphonic acid or quinic acid. AdvantageGusly, the more active o-f the antipodes is isola-ted.
Preferably, those starting materials are used ~or carrying out the reaccion according to the invention which lead to the initially particularly mentioned groups of end products and especially to the end products which have been particularly described or singled out.
The starting materials are kno~l or can, if they are new, be obtained according to methcds which are in themselves known.
The new sompounds can be used as medicaments~ for example in the form o~ pharm~ceutical preparations, in w~1ich ~Y_ ~6~S{~3~2 they or thelr ~salts ~re ~)re en-t as a mixture ~itl1 a pharma-ceutical, or~a~ic or lno~ganic, solid or li~uid excipient t~lich is sui-ta~le for, or ex~mple~ enteral or parenteral administration4 Suitable subs-tances for formlng the excipien-t are those wllich do not react w~th the ~ew com~
pounds such as, for example, ~ater, gelatine~ lac-tose, starch, magnesium stearate, talc, vege-table oils, benzyl alcohols, gum, polyalkylene glycols, white petroleum ~elly, cholesterol or other kno~l medicinal excipie-rlts. The pharmaceutical prep~ra-tions can be, for example~ in the form of tablets, dragees, capsules, suppositories, ointments or creams, or in a li~u~d form, as solutions (for example as an elixir or syru)~ suspensio~s or emulsions. ~ne~ are optionally sterilised and/or contain auxiliaries, such as preservatives, stabilising agents, wetting agents or emul-sifiers, salts for regulating the osmo-tic pressure or buffers.
They can also conialn yet other therapeutically valuable substances. The preparations, ~hich can also be used ln veterinary medicine, are formulated according to customary methods.
; The examples which follow explain the inven-tion without, however, limiting it.
Exam~
A solution of 20 g of 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-chloro-propane and 30 g o.~ isopropy]-amine in 50 ml of isopropanol is heated for 12 to 14 hours under refll~. Tne volatile constituen-ts are then evaporated off ~nder reduced pressure and the eJaporation residue is /~ :
_ ~_ . -. .
105l)(~3Z
dissolved in 300 ~1 of ethyl acetate and the solution is e~tracted ~iith 50 ml portions of 2 N hydrochloric acid.
The aqueous phase is separa~ted off and rendered s-trongly alkaline with concen-trated sodium hydroxi(le solution. The oil wllich precipitates is extracted with about 200 ml of ethyl acetate and distilled in a bulb tube at 150 to 160C/0.04 mm Hg. 1-[4-(2-me-thylthioethoxy)-phenoxy]-2-hydroxy-~-isopropylamino-propane is thus o~tained as an almost colourless oil which solidifies to crystals. Its hydrochloride melts at 102 to 103C (crystallise~ from butanone).
Exam~le 2 An analogous method to Example 1, usin~ ~5 g of t-butyla~ine, gives 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-~-t butylamino-propane of melting point 62-63C
(from ether/petroleum ether). Its hydrochloride melts at 131-133C (from acetone-ether).
1-~4-(2-Methylthioethoxy~-phenoxy]-2-hydroxy-3-chloropropane, required as the starting material can be obtained as follows:
2-(p-Hydroxyphenoxy)-tetrahydropyrane is reacted analoOously to ~xample 4 with 2-methylthioethyl chloride and is hydrolysed for 2 to 3 hours with dilute hydrochloric acid in e-thanol. p-(2~Methylthioethoxy)-phenol, thus obtained, is used in the crude form for the next stage.
20 g of crude p (2-methylthioethoxy)-phenol, 30 ml of epichloroh~drin and 0.2 ml of piperidine are heated for 1 hour ~der reflux. The excess epichlorohydrin is then ~6 distilled off at 100~ bath temperature and 10 mm Hg. The crude 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-chloropropane thus obtained is used direct for the next stage.
Example 3
3.0 g of 3-isopropyl-5-[4-(2-methylthioethoxy)-phenoxy-methyl]-oxazolidine are dissolved in 20 ml of 2 N hydrochloric acid and the solution is warmed for 1 hour on a water bath (about 80~C).
After cooling, the solution is render~d alkaline with 10 ml of con-centrated sodium hydroxide solution and the mixture is extracted with 100 ml of ether. The resulting 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane is distilled at 150 - 160C/0.04 mm Hg in a bulb tube. Its hydrochloride melts at 102 to 103C
(crystallised from butanone) and is identical with the product de~
scribed in Example 1.
Example 4
After cooling, the solution is render~d alkaline with 10 ml of con-centrated sodium hydroxide solution and the mixture is extracted with 100 ml of ether. The resulting 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane is distilled at 150 - 160C/0.04 mm Hg in a bulb tube. Its hydrochloride melts at 102 to 103C
(crystallised from butanone) and is identical with the product de~
scribed in Example 1.
Example 4
4.7 g of 3-isopropyl-5-(4-hydroxyphenoxy-methyl)-oxazolidine, dissolved in 70 ml of acetone, 3 g of potassium carbonate and 2.2 g of 2-methylthio-ethyl chloride are heated for 20 hours under reflux whilst stirring. After addition of a further 1.5 g of potassium car-bonate and l.l g of 2-methylthio-ethyl chloride, the reaction mixture is heated for a further 20 to 24 hours. It is then filtered and the filtrate is evaporated under reduced pressure. The resulting oil is taken up in 100 ml of ether and extracted three times with 10 ml of concentrated sodium hydroxide at a time. The ether phase is dried, filtered and evaporated :
" ~t- I?
- . . . . . .
~ s~ z and -the e-~aporation residue is distille~ in a bulb tube at 140 to 150C/0.03 m~l Hg. 3-Isopropyl-5~[4-(2-methylthio-ethoxy)-phenoxy-methyl]-oxazolidine is thus obtained as a yellowish oil.
4.5 g of 1-(4-hydrox~phenoxy)-2-hydroxy-3-isopropylamino-propane are reacted analogously to Example 4 with a total of 3.3 g of 2~methylthio-ethyl chloride and the reaction mixture is worked up. Tnis gives 1-[4-(2-methyl-thioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane of which the hydrochloride melts at 102 to 103C (from butanone), and is identical with the product described in Example 1.
xample 6 3.7 g of 4-(2-methylthioethoxy)-phenol, 3.5 g of l-chloro-2-hydroxy-3-isopropylamino propane and 5 g of potassium carbonate in 50 ml of acetone are stirred for 5 to 7 hours at 50C. The undissolved matter is filtered off and the filtrate is evaporated under reduced pressure. The evaporation residue is taken up in 100 ml of ether and extracted 3 times with 10 ml of concentrated sodium hydroxide solution at a time. The organic phase is separated of~, dried, filtered and evaporated and gives, after distillation at 150 to 160C/0.04 mm Hg (bulb tube), 1-[4-(2-methylthio-ethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane, melting point of the hydrochloride 102 to 103C (from buta-none). The product is ide~tical with the product described in Example 1.
: -)03~
E~ 7 21 g of crude l-C~-chloro-4-(2-methylthioe-thoxy)-phenoxy]-2,3-epoxy-propane, 21 g of isopropylamine and lO0 ml of isopropanol are heated for 3 hours under reflux. The crude 1-[3-chloro 4-(2-methylthioethoxy)-phenoxy3-2-hydroxy-3-isopropylamino-propane obtained by working up as in Example l gives, on reaction with half the equivalent amount of fumaric acid, a crystalline neutral fumarate of melting point 149-150C (from isopropanol-ether).
The starting material can be prepared as follows:
43.3 g of chlorohydroquinone, 33 g of 2-methylthio-ethyl chloride ~nd 42 g of potassium hydroxide in 400 ml of acetone are heated for 20 hours under reflux whilst stirring.
The reaction mixture is cooled and filtered. After evaporating off the solvent in vacuo, the evaporation residue is taken up in 500 ml of ethyl acetate and extracted with a total of 500 ml of 2 N sodium hydroxide solution in portions.
The aqueous phase is acidified with 6 N hydrochloric acid whilst cooling with ice and the oil which separates out is extracted with ethyl acetate. The ethyl acetate is evaporated off in vacuo and the residue is distilled in a bulb tube. The fraction boiling at 140C bath temperature and 0.01 mm Hg contains 3-chloro-4-(2-methylthioethoxy)-phenol.
21.5 g of 3-chloro-4-(2-methylthioethoxy)-phenol, 15 g of epichlorohydrin and ll g of potassium carbonate in 250 ml of acetone are heated for 16 to 20 hours under reflux.
The undissolved salts are then filtered off and the filtrate :; /q 'S~3~
is evaporated in vaouo. The evaporation residue is taken up in 300 ml of ethyl acetate and washed with 100 ml of cold 2 N sodium hydroxide solution. After drying and evaporation, crude 1-[3-chloro-4-(2-methylthioethoxy)-phenoxy~-2,3-epoxy-propane is o~tained, which can be used without further purification.
~.~
18.9 g of 1,2-epoxy-3-[2-methyl-4-(2-methylthio-ethoxy)-phenoxy]-propane, 20 ml of isopropylamine and 100 ml of isopropanol are heated for 3 hours under refluxO Working up analogously to Example 1 gives 1-[2-methyl-4-(2-methyl-thioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane as an oil which with half the theoretical amount of fumaric acid forms the neutral fumarate of melting point 134-135C (from methanol-ether).
The starting material can be ~repared as ~ollows:
50 g of toluhydroquinone, 50 g of 2-methylthio-ethyl chloride and 45 g of potassium carbonate in 600 ml of acetone are heated under reflux. After 18, 33 and 55 hours, a further 9 g of 2-methylthioethyl chloride and 11 g of .
potassium carbonate are added in each case. The mixture is then heated for a further 24 hours. The reaction mixture is worked up analogously to Example 7 and gives 2-methyl-4-(2-methylthioethoxy) phenol as an oil of boiling point 130C/0.01 mm Hg~ 24 g of 2-methyl-4-(2-methylthioethoxy)-phenol, 250 ml of diethyl ketone, 18 g of epichlorohydrin and 18 g of potassium carbonate are reacted analogously to Example 7 and worked up to give the oily 1-[2-methyl-4-(2-methylthio-_ ~ _ 1~50~ethoxy)-phenoxy]-2,3-epoxy-propane. This is used in the crude form for the next stage.
Example 9 12 g ~f 1-[4-(3-methylthio-propoxy)-phenoxy]-2,3-epoxy-propane, 120 ml of isopropanol and 15 ml of isopropyl-amine are heated for 3 to 4 hours under reflux. Af-ter evaporating off the volatile constituents in vacuo, crude 1-[4-(3-methylthio-propoxy)-phenoxy]-2-hydroxy-3-isopropyl-amino-propane is obtained, which is isolated analo~ously to Example 1 and then converted into its hydrochloride. After recrystallisation from acetone-ether, the hydrochloride melts at 102-103C.
The epoxypropane required as the starting material can be obtained as follows:
- 18 g of potassium carbonate 9 2602 g of 1,3-dibromo-propane and 25 g ol~ 2-(p-hydroxyphenoxy)-tetrahydropyrane ;in 500 ml of acetone are heated for 20 hours under reflux.
The 2-[4-(3-bromopropoxy)-phenoxy]-tetrahydropyrane thus obtained, in 100 ml of ethanol, is left to stand with a solution of 42 g o~ sodium methylmercaptide in 4~0 ml of ethanol for 3 hours at 0-5Co ;After addition of concentrated hydrochloric acid until pH 1 is reached, the reaction mixture is left to stand for 2 to 3 hours at room temperature and then evaporated in vacuo, and the residue is partitioned between lOOml of water and 300 ml of ether. The ether phase lS exhaustively `extracted with 2 N sodium hydroxide solution, the aqueous phase is again rendered acid and 4-(3-methylthiopropoxy)-~ 0 ~ 2 phenol is extracted with ether. It boils at 125-128C/
0.01 mm Hg.
10 g of 4-(3-methylthio-propoxy)-phenol, 100 ml of acetone, 8 g of epichlorohydrin and 8 g of potassium carbon-ate are heated for 48 hours under reflux. After cooling, the insoluble constituents are filtered oIf and the filtrate is evaporated. Crude 1-[4-(~-methylthio~propoxy)-phenoxy~-2,3-epoxypropane is thus obtained, which is used further without additional purification.
Example 10 22 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-tert.-butyl-amino-propane, 13 g of potassium carbonate and 11 g of 2-methyl-thio-ethyl chloride in 350 ml of acetone are heated for 16 hours under reflux whilst stirring. After 24 and 48 hours, a further 13 g of potassium carbonate and 11 g of methylthio-ethyl chloride are added in each case, and heating is continued. After a total of 60 to 70 hours' reaction time the suspension is filtered, the filtrate is evaporated and the residue is dissolved in 300 ml of ether. The -ether solution is first washed 3 times wi-th 10 ml of concen-trated sodium hydroxide solution at a time and then extrac-ted twice with 75 ml of 2 N hydrochloric acid at a time.
The combined hydrochloric acid extracts are rendered alkaline with concentrated sodium hydroxide so-ution (pH about 10) and extracted twice with 200 ml of ether at a time. After distilling off the ether, crude l-C4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-tert.-butylamino-propane is obtained~
which is identical with the product from Example 2.
.!~
- , ,, , ' .
.
l~tj~32 Exam~le 11 A solution of 11.0 g of 1-[4-(2-methyl-thioethoxy)-2-allylphenoxy]-2,3-epoxy-propane and 28 g of isopropylamine in 200 ml of isopropanol is heated for 14 hours ~lder reflux.
The volatile constituents are then evaporated off under reduced pressure and the evaporation residue is dissolved in ethyl acetate and extracted with 25 ml of 2 N hydrochloric acid at a time. Tne aqueous phase lS separated off and rendered strongly alkaline with concentrated sodium hydroxide solution. The oil which precipitates is extracted with ethyl acetate and the extract is washed with water, dried over sodium sulphate, filtered and evaporated. 1-[2-Allyl-4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane is obtained as an almost colourless oil. Its hydrogen-oxalate melts at 116-117C (when crystallised from acetone).
The epoxypropane derivative required as the starting substance can be obtained as follows:
42.0 g (0.276 mol) of 2-allylhydroquinone, dissolved in 300 ml of acetone, 39 g of potassium carbonate and 28 ml of 2-methylthioethyl chloride are heated for 20 hours under reflux whilst stirring. Filtration and evaporation of the filtrate gives 67 g of evaporation residue as a brown oil.
This is dissolved in ether, and the solution is extracted four times with a total of 300 ml of 2 N sodium hydroxide solution. The alkaline extracts are brought to pH 9 by passing in carbon dioxide and then extracted three times with ether. The ether extracts are dried with sodium ~3 ~5~ 3'~
sulphate, fil-tered and evaporated and the evapora-tlon resi-due is distilled in a bulb tube. The fraction o boiling range 110-150 C/0.05 mm Hg gives 4 (2 methylthioothoxy)-2-allyl-phenol of melting point 117-119C after crystallis~tion from carbon tetrachloride.
13.0 g of 4-(2-methylthioethoxy)-2-allyl-phenol, dissolved in 100 ml of diethyl ketone, are heated with 8.4 g of potassium carbonate and 6 ml of epichlorohydrin for ~6 hours whilst stirring under reflux. The mixture is then evaporated to dryness in vacuo and the residue is par-titioned between water and ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered and evapora-ted. 1-[4-(2-Methylthioethoxy)-2-allylphenoxy]-293 epoxy-propane is obtained as a yellowish oil.
Example 12 22.5 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-iso-propylamino-propane, 18.7 g of 2-t-butylthio-ethyl chloride and 17 g of potassium carbonate in 200 ml of acetone are stirred for 18 hours under refluxO The same amounts of potassium carbonate and 2-t-butylthio-ethyl chloride are then added once more and the mixture is heated for a further 24 hours. Working up as described in Example 10 gives 4-(2-t-butylthioethoxy)-phenoxy~ 2 hydroxy-3-isopropyl-amino-propane as an oil which distils at 150-160C/0.01 mm Hg in a bulb tube and forms a neutral fumarate of melting point 127~128QC ~from ace-tone~.
, Example 13 22.5 g of 1 ~4~hydroxyphenoxy)-2-hydroxy-3-~y ~ :
_ ~_ 3i3~ `isopropylamino-propane and a total of 40 g of potassium carbonate and 37 g of 2-ethylthio-ethyl chloride give, analogously to Example 12, 1-~4-(2-ethylthioethoxy)-phenoxy~-2-hydroxy-3-isopropylamino-propane as an oll which distils at 150-155C/0.02 mm Hg in a bulb tubeO Its hydrochloride melts at 86-88~C (from isopropanol-ether)0 xample 14 Analogously to Example 12, 22.5 g of 1-(4-hydroxy-phenoxy)-2-hydroxy-3-isopropylamino-propane 5 25 g of 2-chloropropyl methyl, sulphide and 28 g of potassium carbonate give 1-[4-~1-methyl-2-methyl-thio-ethoxy)-phenoxy]
-2-hydroxy-3-isopropylamino-propane as an oil which distils at 150-155 C/0.02 mm Hg in a bulb tube. Its neutral fumarate melts at 113C (from iso~ropanol-ether).
: Tablets containing 50 mg of active substance are prepared in the usual manner, in the following com~osition:
Composition 1-[4-(2-Methylthioe-thoxy)-phenoxy]~
2-hydroxy-3-isopropylamino-propane 50 mg Whea-t s-tarch 59 mg Lactose 70 mg Colloidal silica 10 mg Talc 10 mg Magnesium stearate - ~
200 mg _r~
The 1-[4-(2-methylthioethoxy)-phenoxy~-Z-hydroxy-~5~
3-isopropylamino-propane is mlxed with a part of -the wheat starch, with lactose and with colloidal silica and the mixture is forced through a sieve a giving a powder mixture.
A further part of the wlleat starch is worked into a paste with a five-fold amo~lnt of water on a water bath and the powder mixture is kneaded with this paste until a slightly plastic mass has been produced.
The plastic mass is pressed through a sieve of about 3 mm mesh width and dried and the resulting dry gran-ules are again forced through a sieve. The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture is pressed to give tablets weighing 200 mg and having a breaking groove.
The daily dose is about -~ to 4 tablets in the case of a warm-blooded animal of about 75 kg body weight, and the appropriate dose o~ active substance can also be administered as a single tablet of appropriate composition.
Example 16 22 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-C(l~
methyl-3-phenyl-propyl)amino]-propane, 8.5 g of 2-chloro-ethyl methyl sulphide and 11 g of potassium carbonate are heated for 6 hours at the reflux tempera-ture, whilst stirring. After adding the same amounts of 2-chloroethyl methyl sulphide and potassium carbonate, the reaction mixture is heated for a further 18 hours. Filtrationl and evapora-tion of the ~iltrate in vacuo, gives an oil ~hich is chromatographed on 600 g of silica gel. After elution with benzene containing 5% of methanol~ and subsequent ~ ~ S~ ~ 3 2 elution wlth benzene which contains 20% of methanol, the latter fraction gives pure 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-[(3'-phenyl-1'-methylpropyl)-amîno]-propane, of which the hydrochloride melts at 154-156C
(sintering at 148C) (from methanol/acetone3.
~ ' 12 g of 1-[4-(2-methylthioe-thoxy)~henoxy]-2,3-epoxy-propane~ 7.5 g of 1-methyl-3-phenyl-propylamine and 100 ml of isopropanol are heated for 4 hours under reflux.
After evaporating the volatile constituents, ultimately in a high vacuum at 130C/0.01 mm Hg, the reaction mixture is taken up in a mixture of 50 ml of ethyl acetate and 50 ml of ether, and the solution is clarified by filtration through Hy~lo and shaken with 100 ml of 2 N hydrochloric acid.
Hereupon 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-~ methyl-3'-phenyl-propyl)-amino]-propane precipitates as the crystalline hydrochloride. After recrystallisation from water, with addition of active charcoal, this substance melts at 154-156C (sintering from 148C onwards).
The epoxide used as the starting substance can be prepared as follows:
- 2-(4-Benzyloxy-phenoxy)-tetrahydropyrane is pre-pared from hydro~uinone monobenzyl ether and 2,3-dihydro-pyrane in benzene t using p-toluenesulphonic acid as the catalyst (melting point 67-69C after crystallisation from petroleum ether).
This substance is debenzylated with the addition of a palladium/charcoal catalyst, and thus gives 2-(4-hydroxy-_ ~47 .
3~
phenoxy)--tetrahydropyrane of mel~ting point 90-93C after recrystallisation from ether/petrole~n ether.
Reaction of the latter phenol with double the equivalent amount of methylthioethyl chloride and potassium carbonate in acetone for 3 days at the reflux temperature, followed by acid hydrolysis, gives 4-(2 methylthioethoxy)-phenol, an oil which boils at 120-130C/0.03 mm Hg.
A mixture of 142 g of 4-(2-methylthio-ethoxy~-phenol, 171 g of potassium carbonate and 115 g of epichloro-hydrin is heated for 40 hours under reflux, whilst stirring.
The dark suspension is cooled and filtered and the filtrate is evaporated in vacuo. The dark bro~n oil which remains is dissolved in 1,500 ml of ether and extracted twice with 500 ml of 2 N sodium hydroxide solution at a time. The ether solution is then washed three times with 500 ml o~
water at a time, dried over magnesium sulphate and evaporated.
Crude oily 1-[4-(2-methylthioethoxy)-phenoxy 3 -2,3-epoxy-propane is ob-tained, which after recrystallisation from ether/petroleum ether melts at 53-58C.
Exam~le 18 A solution of 4.2 g of 5-~[4-(2-methylthioethoxy)-phenoxy]-methyl~ -3-isopropyl-oxazolidin 2-one in 50 ml of n-butanol is boiled with 10 ml of 2 N sodium hydroxide solution for 14 hours under reflux. The solution is evaporated in vacuo, 20 ml of 2 N hydrochloric acid are added and the mixture is thoroughly shaken with 20 ml of ether. The aqueous phase is separated off and evaporated in vacuo. The crystals which precipitate are recrystallised ~osoo3z from butanone. This gives 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydrox-y-3-isopropylamino-propane as -the hydro-chloride of melting point 102-103 C.
Example 19 The Schiff's base obtained from l-amino-2-hydroxy-3-[4-(2-methylthioethoxy)-phe~oxy~-propane and benzylacetone is dissolved in 50 ml o~ isopropanol and stirred with 2 g of sodium borohydride for 16 hours. The reaction mixture is evaporated in vacuo and the residue is extracted with 50 ml of ethyl acetate. The ethyl acetate solution is washed with 20 ml of water and then brought to pH 2 with 2 N hydrochloric acid. The crystals which precipitate are filtered o~f and recrystallised from water. This gives 1-[4-(2-methylthio-ethoxy)-phenoxy]-2-hydroxy-3-[(1'-methyl-3'-phenyl-propyl)-amino~-propane as the hydrochloride of melting point 154-156C.
l-Amino-2-hydroxy-3-[4-(2-methylthioethoxy)-phenoxy]-propane, used as the starting substance is obtained by reac-tion of 1-[4-(2-methylthioethoxy)-phenoxy]-2,3-epoxy-propane and ammonia in methanol. It melts at 74-81C a~ter distillation in a high vacuum at 180C/0.05 mm Hg.
Example 20 Analogously to Example 4, 5-~4-hydroxy~phenoxy)-methyl]-3-isopropyl-oxazolidinone-(2), which is obtainable ~. , by debenzylation of 5-[(4-benzyloxy-phenoxy~-methyl~-3~iso-propyl-oxazolidinone-(2) with palladium-charcoal/hydrogen, and 2-methylthioethyl chloride gives 5-{~4-(2-methylthio-ethoxy)-phenoxy~-methyl3 -3-isopropyl-oxazolidinone-(2) of , melting point 77-78C (from e-thyl ace~tate/petrole~n ether).
. .. . ..
.
" ~t- I?
- . . . . . .
~ s~ z and -the e-~aporation residue is distille~ in a bulb tube at 140 to 150C/0.03 m~l Hg. 3-Isopropyl-5~[4-(2-methylthio-ethoxy)-phenoxy-methyl]-oxazolidine is thus obtained as a yellowish oil.
4.5 g of 1-(4-hydrox~phenoxy)-2-hydroxy-3-isopropylamino-propane are reacted analogously to Example 4 with a total of 3.3 g of 2~methylthio-ethyl chloride and the reaction mixture is worked up. Tnis gives 1-[4-(2-methyl-thioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane of which the hydrochloride melts at 102 to 103C (from butanone), and is identical with the product described in Example 1.
xample 6 3.7 g of 4-(2-methylthioethoxy)-phenol, 3.5 g of l-chloro-2-hydroxy-3-isopropylamino propane and 5 g of potassium carbonate in 50 ml of acetone are stirred for 5 to 7 hours at 50C. The undissolved matter is filtered off and the filtrate is evaporated under reduced pressure. The evaporation residue is taken up in 100 ml of ether and extracted 3 times with 10 ml of concentrated sodium hydroxide solution at a time. The organic phase is separated of~, dried, filtered and evaporated and gives, after distillation at 150 to 160C/0.04 mm Hg (bulb tube), 1-[4-(2-methylthio-ethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane, melting point of the hydrochloride 102 to 103C (from buta-none). The product is ide~tical with the product described in Example 1.
: -)03~
E~ 7 21 g of crude l-C~-chloro-4-(2-methylthioe-thoxy)-phenoxy]-2,3-epoxy-propane, 21 g of isopropylamine and lO0 ml of isopropanol are heated for 3 hours under reflux. The crude 1-[3-chloro 4-(2-methylthioethoxy)-phenoxy3-2-hydroxy-3-isopropylamino-propane obtained by working up as in Example l gives, on reaction with half the equivalent amount of fumaric acid, a crystalline neutral fumarate of melting point 149-150C (from isopropanol-ether).
The starting material can be prepared as follows:
43.3 g of chlorohydroquinone, 33 g of 2-methylthio-ethyl chloride ~nd 42 g of potassium hydroxide in 400 ml of acetone are heated for 20 hours under reflux whilst stirring.
The reaction mixture is cooled and filtered. After evaporating off the solvent in vacuo, the evaporation residue is taken up in 500 ml of ethyl acetate and extracted with a total of 500 ml of 2 N sodium hydroxide solution in portions.
The aqueous phase is acidified with 6 N hydrochloric acid whilst cooling with ice and the oil which separates out is extracted with ethyl acetate. The ethyl acetate is evaporated off in vacuo and the residue is distilled in a bulb tube. The fraction boiling at 140C bath temperature and 0.01 mm Hg contains 3-chloro-4-(2-methylthioethoxy)-phenol.
21.5 g of 3-chloro-4-(2-methylthioethoxy)-phenol, 15 g of epichlorohydrin and ll g of potassium carbonate in 250 ml of acetone are heated for 16 to 20 hours under reflux.
The undissolved salts are then filtered off and the filtrate :; /q 'S~3~
is evaporated in vaouo. The evaporation residue is taken up in 300 ml of ethyl acetate and washed with 100 ml of cold 2 N sodium hydroxide solution. After drying and evaporation, crude 1-[3-chloro-4-(2-methylthioethoxy)-phenoxy~-2,3-epoxy-propane is o~tained, which can be used without further purification.
~.~
18.9 g of 1,2-epoxy-3-[2-methyl-4-(2-methylthio-ethoxy)-phenoxy]-propane, 20 ml of isopropylamine and 100 ml of isopropanol are heated for 3 hours under refluxO Working up analogously to Example 1 gives 1-[2-methyl-4-(2-methyl-thioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane as an oil which with half the theoretical amount of fumaric acid forms the neutral fumarate of melting point 134-135C (from methanol-ether).
The starting material can be ~repared as ~ollows:
50 g of toluhydroquinone, 50 g of 2-methylthio-ethyl chloride and 45 g of potassium carbonate in 600 ml of acetone are heated under reflux. After 18, 33 and 55 hours, a further 9 g of 2-methylthioethyl chloride and 11 g of .
potassium carbonate are added in each case. The mixture is then heated for a further 24 hours. The reaction mixture is worked up analogously to Example 7 and gives 2-methyl-4-(2-methylthioethoxy) phenol as an oil of boiling point 130C/0.01 mm Hg~ 24 g of 2-methyl-4-(2-methylthioethoxy)-phenol, 250 ml of diethyl ketone, 18 g of epichlorohydrin and 18 g of potassium carbonate are reacted analogously to Example 7 and worked up to give the oily 1-[2-methyl-4-(2-methylthio-_ ~ _ 1~50~ethoxy)-phenoxy]-2,3-epoxy-propane. This is used in the crude form for the next stage.
Example 9 12 g ~f 1-[4-(3-methylthio-propoxy)-phenoxy]-2,3-epoxy-propane, 120 ml of isopropanol and 15 ml of isopropyl-amine are heated for 3 to 4 hours under reflux. Af-ter evaporating off the volatile constituents in vacuo, crude 1-[4-(3-methylthio-propoxy)-phenoxy]-2-hydroxy-3-isopropyl-amino-propane is obtained, which is isolated analo~ously to Example 1 and then converted into its hydrochloride. After recrystallisation from acetone-ether, the hydrochloride melts at 102-103C.
The epoxypropane required as the starting material can be obtained as follows:
- 18 g of potassium carbonate 9 2602 g of 1,3-dibromo-propane and 25 g ol~ 2-(p-hydroxyphenoxy)-tetrahydropyrane ;in 500 ml of acetone are heated for 20 hours under reflux.
The 2-[4-(3-bromopropoxy)-phenoxy]-tetrahydropyrane thus obtained, in 100 ml of ethanol, is left to stand with a solution of 42 g o~ sodium methylmercaptide in 4~0 ml of ethanol for 3 hours at 0-5Co ;After addition of concentrated hydrochloric acid until pH 1 is reached, the reaction mixture is left to stand for 2 to 3 hours at room temperature and then evaporated in vacuo, and the residue is partitioned between lOOml of water and 300 ml of ether. The ether phase lS exhaustively `extracted with 2 N sodium hydroxide solution, the aqueous phase is again rendered acid and 4-(3-methylthiopropoxy)-~ 0 ~ 2 phenol is extracted with ether. It boils at 125-128C/
0.01 mm Hg.
10 g of 4-(3-methylthio-propoxy)-phenol, 100 ml of acetone, 8 g of epichlorohydrin and 8 g of potassium carbon-ate are heated for 48 hours under reflux. After cooling, the insoluble constituents are filtered oIf and the filtrate is evaporated. Crude 1-[4-(~-methylthio~propoxy)-phenoxy~-2,3-epoxypropane is thus obtained, which is used further without additional purification.
Example 10 22 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-tert.-butyl-amino-propane, 13 g of potassium carbonate and 11 g of 2-methyl-thio-ethyl chloride in 350 ml of acetone are heated for 16 hours under reflux whilst stirring. After 24 and 48 hours, a further 13 g of potassium carbonate and 11 g of methylthio-ethyl chloride are added in each case, and heating is continued. After a total of 60 to 70 hours' reaction time the suspension is filtered, the filtrate is evaporated and the residue is dissolved in 300 ml of ether. The -ether solution is first washed 3 times wi-th 10 ml of concen-trated sodium hydroxide solution at a time and then extrac-ted twice with 75 ml of 2 N hydrochloric acid at a time.
The combined hydrochloric acid extracts are rendered alkaline with concentrated sodium hydroxide so-ution (pH about 10) and extracted twice with 200 ml of ether at a time. After distilling off the ether, crude l-C4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-tert.-butylamino-propane is obtained~
which is identical with the product from Example 2.
.!~
- , ,, , ' .
.
l~tj~32 Exam~le 11 A solution of 11.0 g of 1-[4-(2-methyl-thioethoxy)-2-allylphenoxy]-2,3-epoxy-propane and 28 g of isopropylamine in 200 ml of isopropanol is heated for 14 hours ~lder reflux.
The volatile constituents are then evaporated off under reduced pressure and the evaporation residue is dissolved in ethyl acetate and extracted with 25 ml of 2 N hydrochloric acid at a time. Tne aqueous phase lS separated off and rendered strongly alkaline with concentrated sodium hydroxide solution. The oil which precipitates is extracted with ethyl acetate and the extract is washed with water, dried over sodium sulphate, filtered and evaporated. 1-[2-Allyl-4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane is obtained as an almost colourless oil. Its hydrogen-oxalate melts at 116-117C (when crystallised from acetone).
The epoxypropane derivative required as the starting substance can be obtained as follows:
42.0 g (0.276 mol) of 2-allylhydroquinone, dissolved in 300 ml of acetone, 39 g of potassium carbonate and 28 ml of 2-methylthioethyl chloride are heated for 20 hours under reflux whilst stirring. Filtration and evaporation of the filtrate gives 67 g of evaporation residue as a brown oil.
This is dissolved in ether, and the solution is extracted four times with a total of 300 ml of 2 N sodium hydroxide solution. The alkaline extracts are brought to pH 9 by passing in carbon dioxide and then extracted three times with ether. The ether extracts are dried with sodium ~3 ~5~ 3'~
sulphate, fil-tered and evaporated and the evapora-tlon resi-due is distilled in a bulb tube. The fraction o boiling range 110-150 C/0.05 mm Hg gives 4 (2 methylthioothoxy)-2-allyl-phenol of melting point 117-119C after crystallis~tion from carbon tetrachloride.
13.0 g of 4-(2-methylthioethoxy)-2-allyl-phenol, dissolved in 100 ml of diethyl ketone, are heated with 8.4 g of potassium carbonate and 6 ml of epichlorohydrin for ~6 hours whilst stirring under reflux. The mixture is then evaporated to dryness in vacuo and the residue is par-titioned between water and ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered and evapora-ted. 1-[4-(2-Methylthioethoxy)-2-allylphenoxy]-293 epoxy-propane is obtained as a yellowish oil.
Example 12 22.5 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-iso-propylamino-propane, 18.7 g of 2-t-butylthio-ethyl chloride and 17 g of potassium carbonate in 200 ml of acetone are stirred for 18 hours under refluxO The same amounts of potassium carbonate and 2-t-butylthio-ethyl chloride are then added once more and the mixture is heated for a further 24 hours. Working up as described in Example 10 gives 4-(2-t-butylthioethoxy)-phenoxy~ 2 hydroxy-3-isopropyl-amino-propane as an oil which distils at 150-160C/0.01 mm Hg in a bulb tube and forms a neutral fumarate of melting point 127~128QC ~from ace-tone~.
, Example 13 22.5 g of 1 ~4~hydroxyphenoxy)-2-hydroxy-3-~y ~ :
_ ~_ 3i3~ `isopropylamino-propane and a total of 40 g of potassium carbonate and 37 g of 2-ethylthio-ethyl chloride give, analogously to Example 12, 1-~4-(2-ethylthioethoxy)-phenoxy~-2-hydroxy-3-isopropylamino-propane as an oll which distils at 150-155C/0.02 mm Hg in a bulb tubeO Its hydrochloride melts at 86-88~C (from isopropanol-ether)0 xample 14 Analogously to Example 12, 22.5 g of 1-(4-hydroxy-phenoxy)-2-hydroxy-3-isopropylamino-propane 5 25 g of 2-chloropropyl methyl, sulphide and 28 g of potassium carbonate give 1-[4-~1-methyl-2-methyl-thio-ethoxy)-phenoxy]
-2-hydroxy-3-isopropylamino-propane as an oil which distils at 150-155 C/0.02 mm Hg in a bulb tube. Its neutral fumarate melts at 113C (from iso~ropanol-ether).
: Tablets containing 50 mg of active substance are prepared in the usual manner, in the following com~osition:
Composition 1-[4-(2-Methylthioe-thoxy)-phenoxy]~
2-hydroxy-3-isopropylamino-propane 50 mg Whea-t s-tarch 59 mg Lactose 70 mg Colloidal silica 10 mg Talc 10 mg Magnesium stearate - ~
200 mg _r~
The 1-[4-(2-methylthioethoxy)-phenoxy~-Z-hydroxy-~5~
3-isopropylamino-propane is mlxed with a part of -the wheat starch, with lactose and with colloidal silica and the mixture is forced through a sieve a giving a powder mixture.
A further part of the wlleat starch is worked into a paste with a five-fold amo~lnt of water on a water bath and the powder mixture is kneaded with this paste until a slightly plastic mass has been produced.
The plastic mass is pressed through a sieve of about 3 mm mesh width and dried and the resulting dry gran-ules are again forced through a sieve. The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture is pressed to give tablets weighing 200 mg and having a breaking groove.
The daily dose is about -~ to 4 tablets in the case of a warm-blooded animal of about 75 kg body weight, and the appropriate dose o~ active substance can also be administered as a single tablet of appropriate composition.
Example 16 22 g of 1-(4-hydroxyphenoxy)-2-hydroxy-3-C(l~
methyl-3-phenyl-propyl)amino]-propane, 8.5 g of 2-chloro-ethyl methyl sulphide and 11 g of potassium carbonate are heated for 6 hours at the reflux tempera-ture, whilst stirring. After adding the same amounts of 2-chloroethyl methyl sulphide and potassium carbonate, the reaction mixture is heated for a further 18 hours. Filtrationl and evapora-tion of the ~iltrate in vacuo, gives an oil ~hich is chromatographed on 600 g of silica gel. After elution with benzene containing 5% of methanol~ and subsequent ~ ~ S~ ~ 3 2 elution wlth benzene which contains 20% of methanol, the latter fraction gives pure 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-[(3'-phenyl-1'-methylpropyl)-amîno]-propane, of which the hydrochloride melts at 154-156C
(sintering at 148C) (from methanol/acetone3.
~ ' 12 g of 1-[4-(2-methylthioe-thoxy)~henoxy]-2,3-epoxy-propane~ 7.5 g of 1-methyl-3-phenyl-propylamine and 100 ml of isopropanol are heated for 4 hours under reflux.
After evaporating the volatile constituents, ultimately in a high vacuum at 130C/0.01 mm Hg, the reaction mixture is taken up in a mixture of 50 ml of ethyl acetate and 50 ml of ether, and the solution is clarified by filtration through Hy~lo and shaken with 100 ml of 2 N hydrochloric acid.
Hereupon 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-~ methyl-3'-phenyl-propyl)-amino]-propane precipitates as the crystalline hydrochloride. After recrystallisation from water, with addition of active charcoal, this substance melts at 154-156C (sintering from 148C onwards).
The epoxide used as the starting substance can be prepared as follows:
- 2-(4-Benzyloxy-phenoxy)-tetrahydropyrane is pre-pared from hydro~uinone monobenzyl ether and 2,3-dihydro-pyrane in benzene t using p-toluenesulphonic acid as the catalyst (melting point 67-69C after crystallisation from petroleum ether).
This substance is debenzylated with the addition of a palladium/charcoal catalyst, and thus gives 2-(4-hydroxy-_ ~47 .
3~
phenoxy)--tetrahydropyrane of mel~ting point 90-93C after recrystallisation from ether/petrole~n ether.
Reaction of the latter phenol with double the equivalent amount of methylthioethyl chloride and potassium carbonate in acetone for 3 days at the reflux temperature, followed by acid hydrolysis, gives 4-(2 methylthioethoxy)-phenol, an oil which boils at 120-130C/0.03 mm Hg.
A mixture of 142 g of 4-(2-methylthio-ethoxy~-phenol, 171 g of potassium carbonate and 115 g of epichloro-hydrin is heated for 40 hours under reflux, whilst stirring.
The dark suspension is cooled and filtered and the filtrate is evaporated in vacuo. The dark bro~n oil which remains is dissolved in 1,500 ml of ether and extracted twice with 500 ml of 2 N sodium hydroxide solution at a time. The ether solution is then washed three times with 500 ml o~
water at a time, dried over magnesium sulphate and evaporated.
Crude oily 1-[4-(2-methylthioethoxy)-phenoxy 3 -2,3-epoxy-propane is ob-tained, which after recrystallisation from ether/petroleum ether melts at 53-58C.
Exam~le 18 A solution of 4.2 g of 5-~[4-(2-methylthioethoxy)-phenoxy]-methyl~ -3-isopropyl-oxazolidin 2-one in 50 ml of n-butanol is boiled with 10 ml of 2 N sodium hydroxide solution for 14 hours under reflux. The solution is evaporated in vacuo, 20 ml of 2 N hydrochloric acid are added and the mixture is thoroughly shaken with 20 ml of ether. The aqueous phase is separated off and evaporated in vacuo. The crystals which precipitate are recrystallised ~osoo3z from butanone. This gives 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydrox-y-3-isopropylamino-propane as -the hydro-chloride of melting point 102-103 C.
Example 19 The Schiff's base obtained from l-amino-2-hydroxy-3-[4-(2-methylthioethoxy)-phe~oxy~-propane and benzylacetone is dissolved in 50 ml o~ isopropanol and stirred with 2 g of sodium borohydride for 16 hours. The reaction mixture is evaporated in vacuo and the residue is extracted with 50 ml of ethyl acetate. The ethyl acetate solution is washed with 20 ml of water and then brought to pH 2 with 2 N hydrochloric acid. The crystals which precipitate are filtered o~f and recrystallised from water. This gives 1-[4-(2-methylthio-ethoxy)-phenoxy]-2-hydroxy-3-[(1'-methyl-3'-phenyl-propyl)-amino~-propane as the hydrochloride of melting point 154-156C.
l-Amino-2-hydroxy-3-[4-(2-methylthioethoxy)-phenoxy]-propane, used as the starting substance is obtained by reac-tion of 1-[4-(2-methylthioethoxy)-phenoxy]-2,3-epoxy-propane and ammonia in methanol. It melts at 74-81C a~ter distillation in a high vacuum at 180C/0.05 mm Hg.
Example 20 Analogously to Example 4, 5-~4-hydroxy~phenoxy)-methyl]-3-isopropyl-oxazolidinone-(2), which is obtainable ~. , by debenzylation of 5-[(4-benzyloxy-phenoxy~-methyl~-3~iso-propyl-oxazolidinone-(2) with palladium-charcoal/hydrogen, and 2-methylthioethyl chloride gives 5-{~4-(2-methylthio-ethoxy)-phenoxy~-methyl3 -3-isopropyl-oxazolidinone-(2) of , melting point 77-78C (from e-thyl ace~tate/petrole~n ether).
. .. . ..
.
Claims (52)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of amines of the formula (I) wherein A represents the group (Ia) or represents the group (Ib) wherein Alk1 denotes lower alkyl, alk2 denotes lower alkylene, R is lower alkyl or phenyl-lower-alkyl, wherein phenyl is unsubstituted or mono-substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, R1 is hydrogen, lower alkyl, lower alkenyl, lower alkenyloxy, lower alkanoyl, halogen or trifluoro-methyl, X denotes the methylene or carbonyl group, in the form of isomer mix-tures (racemate mixtures) or pure racemates or optical antipodes or pharmaceuti-cally acceptable acid addition salts thereof, which comprises reacting a) a compound of the formula (II) with an amine of the formula (III) in which Alk1, alk2, R and R1 have the meanings defined under formula (I), X1 represents the hydroxyl group and Z represents a reactive esterified hydroxyl group, or X1 and Z together the epoxy group, or reacting (b) a compound of the formula (IIb) or a condensation product thereof with formaldehyde of the formula (IIc) or a condensation product thereof with carbonic acid of the formula (IId) wherein Alk1, alk2 and R1 have the above meanings, with a compound of the formula Z-R (IIIa), wherein Z and R have the above meanings, or reacting (c) a compound of the formula (IV) with a compound of the formula (V) or with a condensation product thereof with formaldehyde of the formula (Va) or with a condensation product thereof with carbonic acid of the formula (Vb) wherein Alk1, Alk2, R and R1 have the meanings defined under formula (I), Z, and X1 or Z and X1 together have the meanings defined under formula (II).
(d) A compound of the formula (VI) wherein Alk1, alk2, R and R1 have the meanings defined under formula (I) and Y denotes a methylene or a carbonyl or a thiocarbonyl radical, or a salt of such a compound, to give a compound of the formula (I) wherein A represents the group of the formula (Ia), or reducing (e) A compound of the formula (VII) or of the formula (VIIIa) wherein Alk1, alk2, R and R1 have the meanings defined under formula (I) and R'H has the meaning of R, or reacting f) a compound of the formula (IX) with a compound of the formula (X) wherein Alk1, alk2, R1 and A have the meanings defined under formula (I) and Z represents a reactive esterified hydroxyl group, or with a salt of such a compound, and when a pure racemate of the formula I is required separating resulting isomer mixtures (racemate mixtures) into the pure racemates of the formula (I), and when an optical antipode of the formula (I) is required resolving a racemate of the formula (I) into the optical antipodes, and when a free compound of the formula (I) is required, converting a resulting salt into the free compound, and when an acid addition salt is required converting a free compound of the formula (I) into an acid addition salt.
(d) A compound of the formula (VI) wherein Alk1, alk2, R and R1 have the meanings defined under formula (I) and Y denotes a methylene or a carbonyl or a thiocarbonyl radical, or a salt of such a compound, to give a compound of the formula (I) wherein A represents the group of the formula (Ia), or reducing (e) A compound of the formula (VII) or of the formula (VIIIa) wherein Alk1, alk2, R and R1 have the meanings defined under formula (I) and R'H has the meaning of R, or reacting f) a compound of the formula (IX) with a compound of the formula (X) wherein Alk1, alk2, R1 and A have the meanings defined under formula (I) and Z represents a reactive esterified hydroxyl group, or with a salt of such a compound, and when a pure racemate of the formula I is required separating resulting isomer mixtures (racemate mixtures) into the pure racemates of the formula (I), and when an optical antipode of the formula (I) is required resolving a racemate of the formula (I) into the optical antipodes, and when a free compound of the formula (I) is required, converting a resulting salt into the free compound, and when an acid addition salt is required converting a free compound of the formula (I) into an acid addition salt.
2. Process as claimed in claim 1, wherein starting materials are used in which Alk1, alk2 and R1 have the meanings defined under formula (I) and A represents the group defined under formula (Ia), wherein R has the meaning defined under formula (I) so to obtain amines of the formula (XI) wherein Alk1, alk2, R and R1 have the meanings defined under formula (I), and when a pure racemate is required separating resulting isomer mixtures (racemate mixtures) into the pure racemate, and when an optical antipode is required resolving a racemate into the optical antipodes, and when a free compound is required converting a resulting salt into the free compound, and when an acid addition salt is required converting a free compound in an acid addition salt.
3. Process as claimed in claim 1, wherein starting materials are used in which Alk1 and R1 have the meanings defined under formula (I), alk2 denotes ethylene-1,2 or propylene-1,3 and R denotes .alpha.-branched lower alkyl or phenyl-lower-(.alpha.-branched)-alkyl so to obtain amines of the formula (XI) defined in claim 2, and when a pure race-mate is required separating resulting isomer mixtures (racemate mixtures) into the pure racemates, and when an optical antipode is required resolving a racemate into the optical antipodes, and when a free compound is re-quired converting a resulting salt into the free com-pound, and when an acid addition salt is required con-verting a free compound into an acid addition salt.
4. Process as claimed in claim 1 wherein starting materials are used in which Alk1 denotes methyl, alk2 denotes ethylene-1,2 or propylene-1,3, R
denotes isopropyl, tert.-butyl or 1-methyl-2-phenyl-ethyl and R1 denotes hydro-gen, methyl, allyl, methallyl, methoxy, methallyloxy, allyloxy, acetyl or chl-orine so to obtain amines of the formula (XI) defined in claim 2, and when a pure racemate is required separating resulting isomer mixtures (racemate mix-tures) into the pure racemates, and when an optical antipode is required re-solving a racemate into the optical antipodes, and when a free compound is required converting a resulting salt into the free compound, and when an acid addition salt is required converting a free compound into an acid addition salt.
denotes isopropyl, tert.-butyl or 1-methyl-2-phenyl-ethyl and R1 denotes hydro-gen, methyl, allyl, methallyl, methoxy, methallyloxy, allyloxy, acetyl or chl-orine so to obtain amines of the formula (XI) defined in claim 2, and when a pure racemate is required separating resulting isomer mixtures (racemate mix-tures) into the pure racemates, and when an optical antipode is required re-solving a racemate into the optical antipodes, and when a free compound is required converting a resulting salt into the free compound, and when an acid addition salt is required converting a free compound into an acid addition salt.
5. Process as claimed in claim 1 a), 1 c) and 1 f) wherein starting materials are used in which Alk1 denotes methyl, alk2 denotes ethylene-1,2, R denotes isopropyl and R1 denotes hydrogen so to obtain 1-[4-(2-methylthioeth-oxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane, and when a pure racemate is required separating resulting isomer mixtures (racemate mixtures) into the pure racemates, and when an optical antipode is required resolving a racemate into the optical anitpode and when the free compound is required converting a resul-ting salt into the free compound, and when an acid addition salt is required converting the free compound into an acid addition salt.
6. Process according to claim 1 wherein X1 and Z
together denote the epoxy group.
together denote the epoxy group.
7. Process according to claim 2 wherein X1 and Z together denote the epoxy group.
8. Process according to claim 3 wherein X1 and Z together denote the epoxy group.
9. Process according to claim 4 wherein X1 and Z together denote the epoxy group.
10. Process according to claim 5 wherein X1 and Z
together denote the epoxy group.
together denote the epoxy group.
11. Process according to claim 1 wherein X1 denotes hydroxy and Z denotes halogen.
12. Process according to claim 2 wherein X1 denotes hydroxy and Z denotes halogen.
13. Process according to claim 3 wherein X1 denotes hydroxy and Z denotes halogen.
14. Process according to claim 4 wherein X1 denotes hydroxy and Z denotes halogen.
15. Process according to claim 5 wherein X1 denotes hydroxy and Z denotes halogen.
16. Process according to claim 1, d) wherein hydrolysis is carried out in an acid medium.
17. Process according to claim 2 or claim 16 wherein hydrolysis is carried out in an acid medium.
18. Process according to claim 3 or claim 16 wherein hydrolysis is carried out in an acid medium.
19. Process according to claim 4 or claim 16 wherein hydrolysis is carried out in an acid medium.
20. Process according to claim 5 or claim 16 wherein hydrolysis is carried out in an acid medium.
21. Process according to claim 1 d) wherein hydrolysis is carried out in an alkaline medium.
22. Process according to claim 2 or claim 21 wherein hydrolysis is carried out in an alkaline medium.
23. Process according to claim 3 or claim 21 wherein hydrolysis is carried out in an alkaline medium.
24. Process according to claim 4 or claim 21 wherein hydrolysis is carried out in an alkaline medium.
25. Process according to claim 5 or claim 21 wherein hydrolysis is carried out in an alkaline medium.
26. Process according to claim 1 e) wherein an alkali metal borhydride is used as the reducing agent.
27. Process according to claim 2 or claim 26 wherein an alkali metal borhydride is used as the reducing agent.
28. Process according to claim 3 or claim 26 wherein an alkali metal borhydride is used as the reducing agent.
29. Process according to claim 4 or claim 26 wherein an alkali metal borhydride is used as the reducing agent.
30. Process according to claim 5 or claim 26 wherein an alkali metal borhydride is used as the reducing agent.
31. Process according to claim 1 wherein the reaction of a compound of the formula (IX) with a compound of the formula (X) is carried out in the presence of an alkaline condensing agent.
32. Process according to claim 2 wherein the reaction of a compound of the formula (IX) with a compound of the formula (X) is carried out in the pre-sence of an alkaline condensing agent.
33. Process according to claim 3 wherein the reaction of a compound of the formula (IX) with a compound of the formula (X) is carried out in the pre-sence of an alkaline condensing agent.
34. Process according to claim 4 wherein the reaction of a compound of the formula (IX) with a compound of the formula (X) is carried out in the pre-sence of an alkaline condensing agent.
35. Process according to claim 5 wherein the reaction of a compound of the formula (IX) with a compound of the formula (X) is carried out in the pre-sence of an alkaline condensing agent.
36. Process according to claim 31 wherein an alkali metal carbonate is used as the condensing agent.
37. Process according to claim 32 wherein an alkali metal carbonate is used as the condensing agent.
38. Process according to claim 33 wherein an alkali metal carbonate is used as the condensing agent.
39. Process according to claim 34 wherein an alkali metal carbonate is used as the condensing agent.
40. Process according to claim 35 wherein an alkali metal carbonate is used as the condensing agent.
41. Process according to claim 1 wherein the reaction of a compound of the formula (IV) with a compound of the formula (V) is carried out in the presence of an alkaline condensing agent.
42. Process according to claim 2 wherein the reaction of a compound of the formula (IV) with a compound of the formula (V) is carried out in the presence of an alkaline condensing agent.
43. Process according to claim 3 wherein the reaction of a compound of the formula (IV) with a compound of the formula (V) is carried out in the presence of an alkaline condensing agent.
44. Process according to claim 4 wherein the reaction of a compound of the formula (IV) with a compound of the formula (V) is carried out in the presence of an alkaline condensing agent.
45. Process according to claim 5 wherein the reaction of a compound of the formula (IV) with a compound of the formula (V) is carried out in the presence of an alkaline condensing agent.
46. Process according to claim 41 wherein an alkali metal car-bonate is used as the condensing agent.
47. Process according to claim 42 wherein an alkali metal car-bonate is used as the condensing agent.
48. Process according to claim 43 wherein an alkali metal car-bonate is used as the condensing agent.
49. Process according to claim 44 wherein an alkali metal car-bonate is used as the condensing agent.
50. Process according to claim 45 wherein an alkali metal car-bonate is used as the condensing agent.
51. Amines having the formula (I) as claimed in claim 1, racemates or optical antipodes or pharmaceutically acceptable acid addition salts of such compounds whenever prepared by a process claimed in claim 1 or by any process which is an obvious chemical equivalent thereof.
52. 1-[4-(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane as the racemate, or an optical antipode or a pharmaceutically acceptable acid addition salt, whenever prepared by a process claimed in claim 5 or by any process which is an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH62173A CH576438A5 (en) | 1973-01-17 | 1973-01-17 | 1-Alkylthioalkoxy-4-(3-amino-2-hydroxypropoxy) benzenes - antagonists of beta receptor stimulants prepd. e.g. by reducing corresp. Schiff base |
| CH1516473 | 1973-10-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050032A true CA1050032A (en) | 1979-03-06 |
Family
ID=25685144
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA190,087A Expired CA1050032A (en) | 1973-01-17 | 1974-01-14 | Amines and processes for their manufacture |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS49101343A (en) |
| AR (6) | AR205618A1 (en) |
| AT (2) | AT330771B (en) |
| BE (1) | BE809820A (en) |
| CA (1) | CA1050032A (en) |
| CS (1) | CS184347B2 (en) |
| DD (2) | DD110656A5 (en) |
| DE (1) | DE2400693A1 (en) |
| ES (1) | ES422301A1 (en) |
| FR (1) | FR2213771B1 (en) |
| GB (1) | GB1423073A (en) |
| HU (1) | HU168750B (en) |
| IE (1) | IE38736B1 (en) |
| IL (1) | IL44003A (en) |
| LU (1) | LU69166A1 (en) |
| NL (1) | NL7400648A (en) |
| SU (1) | SU520037A3 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0002004B1 (en) * | 1977-11-07 | 1982-03-24 | Ciba-Geigy Ag | Process for the manufacture of fluorinated cationic compounds and their use as surfactants |
| ZW9881A1 (en) * | 1980-06-02 | 1981-12-23 | Hoffmann La Roche | Substituted phenoxyaminopropanol derivatives |
| JPS5746946A (en) * | 1980-07-09 | 1982-03-17 | Sandoz Ag | 3-aminopropoxyphenyl derivative, manufacture and medicine containing same |
| DE3125870C2 (en) * | 1980-07-09 | 1994-09-15 | William John Louis | 3-aminopropoxyphenyl derivatives, their preparation and medicaments containing them |
| FR2497194B1 (en) * | 1980-08-07 | 1985-06-14 | Sandoz Sa | NEW PHENOLIC COMPOUNDS |
| US6068834A (en) | 1994-03-04 | 2000-05-30 | The Procter & Gamble Company | Skin lightening compositions |
| AU1932295A (en) * | 1994-03-04 | 1995-09-18 | Procter & Gamble Company, The | Process for making monoacetals of hydroquinone |
| US5585525A (en) * | 1994-12-16 | 1996-12-17 | The Procter & Gamble Company | Process for making monoacetals of hydroquinone |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA956632A (en) * | 1969-05-16 | 1974-10-22 | Yoshitomi Pharmaceutical Industries | Phenoxy-aminopropanol derivatives |
-
1974
- 1974-01-01 AR AR251941A patent/AR205618A1/en active
- 1974-01-01 AR AR255898A patent/AR204726A1/en active
- 1974-01-01 AR AR255900A patent/AR204105A1/en active
- 1974-01-01 AR AR255899A patent/AR204334A1/en active
- 1974-01-08 DE DE2400693A patent/DE2400693A1/en active Pending
- 1974-01-11 IE IE66/74A patent/IE38736B1/en unknown
- 1974-01-11 CS CS7700000292A patent/CS184347B2/en unknown
- 1974-01-14 CA CA190,087A patent/CA1050032A/en not_active Expired
- 1974-01-14 SU SU1985268A patent/SU520037A3/en active
- 1974-01-14 IL IL44003A patent/IL44003A/en unknown
- 1974-01-14 FR FR7401149A patent/FR2213771B1/fr not_active Expired
- 1974-01-15 DD DD176012A patent/DD110656A5/xx unknown
- 1974-01-15 LU LU69166A patent/LU69166A1/xx unknown
- 1974-01-15 ES ES422301A patent/ES422301A1/en not_active Expired
- 1974-01-15 DD DD180359A patent/DD113364A5/xx unknown
- 1974-01-16 BE BE139875A patent/BE809820A/en unknown
- 1974-01-16 HU HUCI1435A patent/HU168750B/hu unknown
- 1974-01-17 NL NL7400648A patent/NL7400648A/xx not_active Application Discontinuation
- 1974-01-17 JP JP49007590A patent/JPS49101343A/ja active Pending
- 1974-01-17 GB GB218774A patent/GB1423073A/en not_active Expired
- 1974-10-02 AR AR255896A patent/AR201704A1/en active
- 1974-10-02 AR AR255897A patent/AR201518A1/en active
-
1975
- 1975-05-26 AT AT397675A patent/AT330771B/en not_active IP Right Cessation
- 1975-05-26 AT AT397875A patent/AT330750B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DE2400693A1 (en) | 1974-07-18 |
| AR204726A1 (en) | 1976-02-27 |
| AR204105A1 (en) | 1975-11-20 |
| AU6452474A (en) | 1975-07-17 |
| AR201518A1 (en) | 1975-03-21 |
| IE38736B1 (en) | 1978-05-24 |
| CS184347B2 (en) | 1978-08-31 |
| GB1423073A (en) | 1976-01-28 |
| AT330771B (en) | 1976-07-26 |
| AR201704A1 (en) | 1975-04-08 |
| LU69166A1 (en) | 1975-12-09 |
| JPS49101343A (en) | 1974-09-25 |
| IE38736L (en) | 1974-07-17 |
| DD113364A5 (en) | 1975-06-05 |
| DD110656A5 (en) | 1975-01-05 |
| BE809820A (en) | 1974-07-16 |
| AT330750B (en) | 1976-07-12 |
| NL7400648A (en) | 1974-07-19 |
| ATA397675A (en) | 1975-10-15 |
| IL44003A (en) | 1977-05-31 |
| ES422301A1 (en) | 1976-07-01 |
| IL44003A0 (en) | 1974-05-16 |
| HU168750B (en) | 1976-07-28 |
| AR204334A1 (en) | 1975-12-22 |
| FR2213771B1 (en) | 1976-09-03 |
| ATA397875A (en) | 1975-10-15 |
| AR205618A1 (en) | 1976-05-21 |
| SU520037A3 (en) | 1976-06-30 |
| FR2213771A1 (en) | 1974-08-09 |
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