CA1074332A - Phenoxypropylamine derivatives and the preparation thereof - Google Patents
Phenoxypropylamine derivatives and the preparation thereofInfo
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- CA1074332A CA1074332A CA163,292A CA163292A CA1074332A CA 1074332 A CA1074332 A CA 1074332A CA 163292 A CA163292 A CA 163292A CA 1074332 A CA1074332 A CA 1074332A
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Abstract
ABSTRACT OF THE DISCLOSURE
This invention discloses a process for the preparation of phenoxypropylamine derivatives having the formula:
This invention discloses a process for the preparation of phenoxypropylamine derivatives having the formula:
Description
I ~) ?~
The present invention relates to phenoxypropylamine derivatives, pharmaceutically-acceptable acid addition salts thereof, and to a process for the preparation thereof. The invention is also concerned with pharmaceutical compositions containing such compounds.
In accordance with the present invention there is provided a phenoxy-propylamine derivative having the general formula:
X - NH - C - N~ (I) 3)n-~~ \R2 O - CH - CH - CH - NHR
OH
in which X is an unbranched or branched alkylene group containing up to four carbon atoms, Rlisa hydrogen atom or a lower alkyl group containing up to six carbon atoms, R2 is a hydrogen atom or an alkyl or alkenyl group, in each case containing up to six carbon atoms, a hydroxyalkyl or alkoxyalkyl group, in which the alkyl group in each case contains up to three carbon atoms or a phenyl or benzyl group, provided that where at least one of R
and R2 is lower alkyl, X is other than -CH2CH2, R3 is an alkyl, alkenyl, alkoxy group ineach casecontaining up to four carbon atoms, a halogen atom, a nitro, amino or .
The present invention relates to phenoxypropylamine derivatives, pharmaceutically-acceptable acid addition salts thereof, and to a process for the preparation thereof. The invention is also concerned with pharmaceutical compositions containing such compounds.
In accordance with the present invention there is provided a phenoxy-propylamine derivative having the general formula:
X - NH - C - N~ (I) 3)n-~~ \R2 O - CH - CH - CH - NHR
OH
in which X is an unbranched or branched alkylene group containing up to four carbon atoms, Rlisa hydrogen atom or a lower alkyl group containing up to six carbon atoms, R2 is a hydrogen atom or an alkyl or alkenyl group, in each case containing up to six carbon atoms, a hydroxyalkyl or alkoxyalkyl group, in which the alkyl group in each case contains up to three carbon atoms or a phenyl or benzyl group, provided that where at least one of R
and R2 is lower alkyl, X is other than -CH2CH2, R3 is an alkyl, alkenyl, alkoxy group ineach casecontaining up to four carbon atoms, a halogen atom, a nitro, amino or .
2 -10~ 33Z
aliphatic acylamino group, and R4 is a branched alkyl group, a hydroxyalkyl group or a cycloalkyl group containing up to six carbon atoms, and n is 0 or 1, and the pharmaceutically acceptable acid addition salts thereof.
The compounds of the present invention possess ~-receptor-blocking properties and are therefore suitable for the therapy and prophylaxis of heart diseases such as Angina pectoris, cardiac arrhythmias and similar illnesses.
Amongst the substances having a blocking action on the ~-receptors, urea derivatives have also already been dis-closed because of their favourable properties, according to DOS 2,040,441. They are phenylurea derivatives which carry the 2-hydroxy-propylamine group, which is characteristic with ~-blocking properties, in any desired position, preferably in the 4-position, relative to the ureido group.
Surprisingly, it has now been found that compounds according to the present invention, which differ from the known phenylurea derivatives above all in that they possess an optionally branched alkylene group between the aromatic nucleus and the ureido group, are distinguished by a sub-stantially stronger ~-receptor-blocking action. Thus it has been found, for example, that the ~-receptor-blocking action of the compound N-4-l(3'-tert.-butyl-amino-2'-hydroxy)-propoxyl-benzylurea, as demonstrated by the increase in fre-quency of the heart-beat of dogs after administration of iso-proterenol with or without prior administration of the com-pound to be tested, is more than 5 times greater than that of the analogous compound N-4-~(3'-tert.-butyl-amino-2'-10 ï1~33.'~
hydroxy)-propoxy]-phenylurea (Example 4 of DOS 2,040,441), the action of which is particularly singled out in the publication mentioned. The toxicity values, found in mice, are approximately the same for the compounds of formula I
as for the known phenylurea derivatives, so that the compounds of formula I have a considerably more favourable ratio of effective dose to toxic dose. Finally, some of the compounds of formula I are also distinguished by a particularly long-lasting action, as, for example, N-3-nitro-4-~(3'-tert.-butylamino-2'-hydroxy~-propoxy]-benzylurea.
In comparison to known ~ - blocking agents such as, for example, propranolol, the compounds of formula I show no, or only a slight, cardiodepressive action, so that the danger of producing a cardiac insufficiency by the medication is less.
Thus, no changes in the ECG were detectable in dogs even at high doses, for example of 2 mg/kg. In rats, again, high doses only occasionally showed a slight reduction in the pulse rate. Equally the dose of aconitine required to trigger disturbances of the cardiac rhythm, for example in rats, is not increased by pretreatment with a compound of formula I, and this is also a measure of the slight occurrence of un-desired cardiodepressivity.
A particularly favourable action is shown by com-pounds of formula I in which each of Rl and R2 is a hydrogen atom, n is 0, X is a methylene or ethylidene group and R4 is a branched alkyl group containing three, four or five carbon atoms, or compounds in which each of Rl and R2 is a hydrogen ~'7~33.'~
atom, R3, which is in the m-position to X and in the o-position to the ether side-chain, is a lower alkoxy group, a nitro group, a chlorine atom or a bromine atom, a lower alkyl group containing up to three carbon atoms, an amino group or a lower acylamino group, n is 1 and X is a methylene or ethylidene group, and R4 is a branched alkyl group containing three, four or five carbon atoms, or compounds in which R
is a hydrogen atom or an alkyl group and R3 is a hydrogen atom, R2 is a lower alkyl group, a hydroxy-lower alkyl group, a phenyl group or a benzyl group, n is 0 and X is a methylene or ethylidene group and R4 is a branched alkyl group contain-ing three, four or five carbon atoms. As examples of such compounds there may be mentioned, inter alia9 in addition to the compounds already mentioned above, N-1-~4'-13"-tert.-butylamino-2"-hydroxy)-propoxy]-phenyl}-ethyl-(1)-urea, N-
aliphatic acylamino group, and R4 is a branched alkyl group, a hydroxyalkyl group or a cycloalkyl group containing up to six carbon atoms, and n is 0 or 1, and the pharmaceutically acceptable acid addition salts thereof.
The compounds of the present invention possess ~-receptor-blocking properties and are therefore suitable for the therapy and prophylaxis of heart diseases such as Angina pectoris, cardiac arrhythmias and similar illnesses.
Amongst the substances having a blocking action on the ~-receptors, urea derivatives have also already been dis-closed because of their favourable properties, according to DOS 2,040,441. They are phenylurea derivatives which carry the 2-hydroxy-propylamine group, which is characteristic with ~-blocking properties, in any desired position, preferably in the 4-position, relative to the ureido group.
Surprisingly, it has now been found that compounds according to the present invention, which differ from the known phenylurea derivatives above all in that they possess an optionally branched alkylene group between the aromatic nucleus and the ureido group, are distinguished by a sub-stantially stronger ~-receptor-blocking action. Thus it has been found, for example, that the ~-receptor-blocking action of the compound N-4-l(3'-tert.-butyl-amino-2'-hydroxy)-propoxyl-benzylurea, as demonstrated by the increase in fre-quency of the heart-beat of dogs after administration of iso-proterenol with or without prior administration of the com-pound to be tested, is more than 5 times greater than that of the analogous compound N-4-~(3'-tert.-butyl-amino-2'-10 ï1~33.'~
hydroxy)-propoxy]-phenylurea (Example 4 of DOS 2,040,441), the action of which is particularly singled out in the publication mentioned. The toxicity values, found in mice, are approximately the same for the compounds of formula I
as for the known phenylurea derivatives, so that the compounds of formula I have a considerably more favourable ratio of effective dose to toxic dose. Finally, some of the compounds of formula I are also distinguished by a particularly long-lasting action, as, for example, N-3-nitro-4-~(3'-tert.-butylamino-2'-hydroxy~-propoxy]-benzylurea.
In comparison to known ~ - blocking agents such as, for example, propranolol, the compounds of formula I show no, or only a slight, cardiodepressive action, so that the danger of producing a cardiac insufficiency by the medication is less.
Thus, no changes in the ECG were detectable in dogs even at high doses, for example of 2 mg/kg. In rats, again, high doses only occasionally showed a slight reduction in the pulse rate. Equally the dose of aconitine required to trigger disturbances of the cardiac rhythm, for example in rats, is not increased by pretreatment with a compound of formula I, and this is also a measure of the slight occurrence of un-desired cardiodepressivity.
A particularly favourable action is shown by com-pounds of formula I in which each of Rl and R2 is a hydrogen atom, n is 0, X is a methylene or ethylidene group and R4 is a branched alkyl group containing three, four or five carbon atoms, or compounds in which each of Rl and R2 is a hydrogen ~'7~33.'~
atom, R3, which is in the m-position to X and in the o-position to the ether side-chain, is a lower alkoxy group, a nitro group, a chlorine atom or a bromine atom, a lower alkyl group containing up to three carbon atoms, an amino group or a lower acylamino group, n is 1 and X is a methylene or ethylidene group, and R4 is a branched alkyl group containing three, four or five carbon atoms, or compounds in which R
is a hydrogen atom or an alkyl group and R3 is a hydrogen atom, R2 is a lower alkyl group, a hydroxy-lower alkyl group, a phenyl group or a benzyl group, n is 0 and X is a methylene or ethylidene group and R4 is a branched alkyl group contain-ing three, four or five carbon atoms. As examples of such compounds there may be mentioned, inter alia9 in addition to the compounds already mentioned above, N-1-~4'-13"-tert.-butylamino-2"-hydroxy)-propoxy]-phenyl}-ethyl-(1)-urea, N-
3-methoxy-4[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-urea, N-3-nitro-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy3-benzylurea, N-3-chloro-4-1(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea, N-4-1(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-N'-benzylurea, N-4-~(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzyl-N'-phenylurea, N-4-~(3'-isopropyl-amino-2'-hydroxy)-propoxy]-benzylurea, N-4-[(3'-tert.-butyl-amino-2'-hydroxy)-propoxy]-benzyl-N'-dimethylurea, N-3-methyl-
4-~(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea, N-3-amino-4-[(31-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-urea, N-3-acetylamino-4-~(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea, N-3-ethoxy-4-1(3'-tert.-butylamino-2'-10'7~33~
hydroxy)-propoxy]-benzylurea, N-3-bromo-4-~(3'-tert.-butyl-amino-2'-hydroxy)-propoxyI-benzylurea and N-4-~(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-N'-methyl-N'-(3-hydroxy)-ethylurea.
In accordance with the invention there is also provided a process for the preparation of a compound of formula I herein, which comprises reacting a phenoxypropane derivative having the general formula:
/ R
X - NH - C - N
~ I \ R2 ( 3)n ~ (II) in which Y is the group ~ CH -/CH2 or ~ CH - CH2 - Hal in which Hal is a chlorine, bromine, or iodine atom, and ~1' R2, R3, X and n are as defined above for formula I, or a mixture of such compounds in which Y has both the possible meanings, at room temperature or at an elevated temperature with ammonia or an amine having the general formula:
H2N - R5 (III) in which R5 is a hydrogen atom or the group R4, and when R5 is a hydrogen atom it may be converted to the group R4 by reaction of the reaction product with a carbonyl compound having the general formula :
1-3 7 ~3'~
_R
,, 6 \
C = 0 (IY) " R7 / ``
in which R6 is a hydrogen atom or a lower alk~l ~roup and R7 is an alkyl group or a hydroxyalkyl group containin~ up to four carbon atoms~ or R6 and R7 taken together may form an alkylene group containing up to five carbon atoms, and the product is reduced simultaneously or subsequently.
If the reaction product thereby produced is a salt, the base may be liberated therefrom and the compound of formula I may be isolated as a base or after having again been converted into a salt.
It is thus possible, according to the process of the invention, to react an epoxy derivative of formula II, i~l which Y is C~ / H2 , simpl~ with hn amine of the for~ula H?N-R4, with R4 having the abovementioned meaning, ~he re-~ction may be carried out in the presence or absence of asolvent. Preferred solvents are polar solvents, such as, for exam~le, lower alcohols or N,N-dimethylacetamide. Excess amine of the formula H2N-R4 may also serve as the solvent.
Particularly good results are o~,tained if water is added to the reaction mixture, ~his measure achieves a notable increase in the reaction speed, so that complete conversion is achie~ed in a relatively short time even at room temper-ature.
If instead of the epoxide compound the halohydrin of for~u~ , in ~hich Y is -ICH - CH2 - Hal is e l d 0~
~ 3 3'~
the starting material, the reaction again may be carried out with or without solve~t. ~ecause of ~he low~r reaction speed it i5 in t`nis case advisable to perform the reaction at an elevated temperature, preferably at 50 to 120C. If the amino compound of formula II is-~olatile at tLis temperature, it is necessary to work in a closed apparatus. A~ain, excess amine of formula III may serve as the solvent.
Tf ammonia is employed as the reactant of formula III, it is necessary subse~uently to replace a hydrogen atom of the prir~ary amino group formed, by the group R4. This is preferably achieved by reductive al~ylation with the aid of an oxo compound of the formula IV. The objective is achieved if first the primary amine is reacted with the oxo compound and then the reduc'ion is carried out, or if the reduction is simply carried out in the presence of the oxo compound o~
- formula IV. A catalytic hydrogenation for example with palladium on charcoal as the catalyst, or a reduction with ~odium borohydri~e, is preferred as the reduction method.
~he compounds of formula I herein are isolated from the reaction mixture in a customary manner. A very good tendency to crystallise is shown, for example, by the salts of the compounds of formula I w~th dicarboxylic acids such as, ~or example, the fumarates, oxalates or succinates, so that a conversion o~ the compounds into such salts is parti-cularly preferred for the purpose of isolation.
- ~he compo~nds of formula I may be used in pharma-ceutical compositions either as bases or as pharmaceutically-~?7433'2 acceptable salts. As examples of such pharmaceutically acceptable salts there may be ~.entioned the hydrohalides, especially the hydrochlorides and hydrobromides, and also the sulphates, phosphates, acetates, i~umarates, succinates, cyclohexylsulphamates, tartrates and citrates. The prepara-tion of such salts is achieved, for example, by reacting the bases with stoichiometric amounts of the appropriate acid.
The compounds of formula II required as starting product~ are in many cases new. Where they are halohydrins or epoxides they may ~e obtained by reaction of the corres-ponding phenols with epihalohydrins. ~Iainly epoxides of formula II are obtained if the phenolates are reacted with the epihalohydrin either in a~ anhydrous medium, for example in dimethylformamide or hexamethy~phosphoric acid trisam de as the solvent, or i~ water or an aqueous-alcoholic solution.
On the other hand, mainly halohydrins of formula II are produced i~ the reaction starts from the corresponding free phenols and is carried out at a temperature of 100C, the epihalobydrin is employed in excess and a ba~ic catalyst, for example piperidine, is added. ~he epoxides of formula II
obtained in the manner described may contain a certain amount of halohydrin of formula II, which of course does not inter-fere with the further reaction to give the compounds of formula I.
~ he phenols with a previously formed side chain carrying the ureido group, which are required for the manu-_9_ , 10'7 ~33~
facture of the compo~lds of formula II, also may be preparedaccording to known methods. ~hus, for example, the reaction of hydroxy-substituted phenylalkyl~mine salts with potassium cyanate yields urea derivatives which may serve as the start-ing material for the preparation of compounds of formula IIin which each of R~ and R2 is a hydrogen atom. If it is desired to prepare compounds of formula II in which ~1 and/or R2 are not hydrogen, the corresponding ureidoalkyl-substituted phenol is obtained by reaction of the corresponding isocyan-ate, of which the phenolic hydroxyl group is protected by anacyl or benzyl ~roupS with ar amine of the formula ~R1R2.
~he group which protects the phenolic hydroxyl group then may be split off easily.
It is also possible to synthesise the ureidoalkyl-substit~ted phenols from carb~mic acid chlorides.
~ or administration, the compounds of formula I maybe mixed with any customary pharmaceutically-acceptable ex-cipient. Accordingly the invention also provides a pharma-ceutical composition comprising, as an active ingredient, a phenoxypropylamine derivative havi~g the general formula I
herein, or a pharmaceutically-acceptable acid addition salt thereof, in admixture with a pharmaceutically-acceptable excipient. ~he excipient is chosen in a conventional manner in accordance with the form in which the composition is to be administered. It is possible to produce both mixtures which may be converted into tablets or dra~ees, and stable solu-tions containing, for example, salts of the compounds of .. . . . . ... ..
l~}7~
formula I. Also, the active compounds of formula I may be included in capsules.
Th~ examples which follow illustrate the compounds according to the invention and the preparation thereof.
Example 1 8.0 G. of N-4-~(2',3'-epoxy)-propoxy~-benzylurea are allowed to react for 4 hours at room te~perature with a mix-ture of 60 ml. of tertiary butyl~mine ar.d 60 ml. of water.
~he reaction mixture is then evaporated in vacuo and the residue is subjected to a further distillation with ethanol/
benzene in order to remove water completely. ~.5 G. o~ N-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea, re-pr~senting 79.~/o of theory, are thus obtained.
~he ojly base is dissolved in ethanol, the soLution is fil~ered and the filtrate is treated with a solution o~
the equivalei.~ amount of fumaric acid in acetone. ~he fumarate crystallises out and is filtered off after some time. After recrystallisation from eth~nol, the product shows a melting point of 171 to 173C.
~he N-4-[(2't3'-epoxy)-propoxy~-benzylurea required as a starting material was obtained by reaction of N-(~-hydrox~)-benzylurea in aqueous solution with epichlorohyd~in, the calculated amount of NaOH being added. It ~elts at 150 to 157C.
; 25 ~ ExamPle 2 13.0 G. of N-3-~(2',3'-epoxy)-propoxy~-benzylurea are reacted with a mixture of 40 ml. of tert.-butylam ne and . .
~7~33~
40 ml. of water for 2 hours at room temperature. After working-up in a manner analogous to that used in EXample 1, 15.0 g. of crude N-3-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea are obtained~ ~he fumarate obtained from the base analogously to Example 1 has a .~elting point of 157 to 161C.
~ he N-3-t(2',3'-epoxyj-propoxy]-benzylurea which serves aq the startin~ product W8S obtained by reaction of the sodium salt of N-(m-hydroxy)-benzylurea ~lith epichloro-hydrin at 50C in hexamethylphosphoric acid trisamide as the~olventO It is an oi1y product.
Example 3 - 10.0 G. of N-2-[(2',3'-epoxy)-propoxy]-benzylurea are reacted with tert.-butylamine as described in Example 2.
This yields 13.0 g. of ~-2-[(3'-tert.-butyla~ino-2'-hy~roxy)-propoxy~-benzylurea as an oily producl;. Melting point of the fumarate (from ethanol) 125 to i280C.
xample 4 10 G. of N-4-[(2',3'-epoxy)-propoxy]-benzylurea are reacted with 80 ml. of a 1:1 mixture of isopropylamine and water for 4 hours at room temperature. 12.4 G. of N-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzylurea are thus - obtaine~t the melti~g poirit of th~ va~ b~ iO3 ~o 1C6C.
Example 5 2.0G. of N-3-methoxy-4-r(3'-chloro_2'_hydroxy)-propoxy] benzylurea and 20 ml. of tert.-butylamine are warmed to 100C for 2 hours in a closed vessel. After .
.
107433~
cooling, the excess tert.-butylamine is distilled off in vacuo, and the residue is treated with a little acetone and seeded. A substance crystallises out and is filtered off after some time. 1.7 G. of N-3-methoxy-4~(3'-tert.-butyl-amino-2'-hydroxy)-propoxy]-benzylurea are thus obtained, corresponding to a yield of 75.5% of theory. Melting point:-134 to 137C. Melting point of the neutral fumarate is 198 to 200C.
The N-3-methoxy-4-l(3'-chloro-2'-hydroxy)-propoxy]-benzylurea used as the starting material is obtained from 3-methoxy-4-hydroxy-benzylurea by reaction with epichloro-hydrin at 100C, the reaction time being 3 hours and piperi-dine being added as a catalyst.
Example 6 1.0 G. of N-4-r(2',3'-epoxy)-propoxy]-benzylurea and 1.64 g. of tert.-butylamine in 20 ml. of ethanol are heat-ed to the boil for 2 hours. The clear solution thereby obtain-ed is concentrated in vacuo and the residue is completely freed of the solvent. 0.95 G. of the crude N-4-~(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea are thus obtained.
After conversion to the fumarate, the product has a melting point of 171 to 173& .
The following compounds are obtained in a manner analogous to Examples 1 to 6:
7. N-4-1(3'-Isopropylamino-2'-hydroxy)-propoxy3-benzyl-N'-methylurea, melting point of the neutral fumarate 170 to 172C.
107433~
8. N-4-[(~'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-~'-methylurea, melting point of the fumarate 146 to 9. N-4-~(3'-Isopropylamino-2'-hydro~y)-propoxy3-benzyl-N'-isopropylurea, melting point of the fumara`te 149 to ~53C.
10. N-4-t(3'-tert.-Butylamino-2'-hydroxy~-propoxy~-benzyl-I~ isopropylurea, melting ~oint of the base 1~5 tc 138C.
11. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-N'-allylurea, melting point of the base 73 to 76C.
12. N-4-[(3'-Isopropylamino-2'-hydroxy)-propoxy]-benzyl-N'-benzylurea, melting point of the hydrochloride 11~ to ~ 121C.
1~. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-N'-benzylurea, melting point of the base 80 to 82C.
14. N-4-[(3'-sec.-Butylamino-2'-hydroxy)-propoxy]-benzylurea, melt ng point of the neutral fumarate 170 to 15- N-4-[(3'-Cyclopropylamino-2'-hydroxy)-propoxy]-benzylurea, melting point of the neutral fumarate 130 to 134 C.
16. N-4-~(3'-Isopropylamino-2'-hydroxy)-propoxy3-benzyl-N'-(2"-methoxy)-ethyl1lrea, melting point o~ the fumarate 132 to 13~C.
17. ~-4-~(3'-tert.-Bu~ylamino-2'-hy~roxy)-propoxy~-benzyl-N'-(2"-methoxy)-ethylurea, melting point o~ the base 76 to 107~33~
18. N~-[(3'-Isopropylamino-2'-hydxo}y)-propoxy]-benzyl-N'-(2"-hydroxy)-ethylurea, melting point of the fumarate 138 to 140C.
19. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-~'(2"-hydroxy)-ethy~urea, melting point of the neutral fwnarate 146 to 149C.
20. ~-[(3'-Isopropylamino-2'-hydroxy)-propoxy~-benzyl-N'-phenylurea, melting point of the fumarate 105 to 107C.
21. N-4-t(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-N'-phenylurea, melting point of the fumarate 134 to 138C.
22. N-4-~(3'-Isopropylamino 2'-hydroxy)-propoxy]-benzyl-N'-dime-~hylurea, melting point of the fumarate 150 to 153C.
23. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy~-benzyl-N'-dimethylurea, melting point of the base 105 to 108C.
24. N~-~(3'-tert.-Butylamino-2'-hydrox;y)-propoxy]-benzyl-N'-methyl-N'-(2"-hydroxy)-ethylurea, melting point of the ~ase 111 to 113C.
25. N~ (3'-tert.~Butylamino-2'-hydroxy)-propoxy3-benzyl-N'-diisopropylurea, meltin~ point of the neutral fumarate 141 to 146C~ ~
26. N-3~(3'-tert.-Butylamino-2'-hydroxy)-propoxy~-4-methoxy-benzylurea, melting point of the base 64 to 67C.
27. ~-3-Methoxy-5-~(3'-tert.-butylamino-2'-hydroxy)-propoxy~benzylurea, melting point of the fumarate 198 to 2~0C
~. .
28. N-3~ ethoxy-4- r (3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzyl-N'-ethylurea, melting point of the base 132 to 133C. !
29. N-2- ~4 ~ [ ( 3"-tert.-Butylamino-2"-hydroxy)-propoxy]-phenyl~-ethyl-(1)-urea, melting point of the neutral fumarate 105 to 108C.
30. N-1- ~4 ~ ( 3~-Isopropylamino-2~-hydroxy)-propoxy]-phenyl~-ethyl-(1)-urea, melting point of the base 100 to ~1. N-1-~4'-[(3"-tert.-B~tylamino-2t'-hydroxy)-propoxy~-phenyl~-ethyl-(1)-ureaS melting point of the base 105 to 107C.
32. ~-1- 4 - ~ (3"-tert.-Butylami~o-2"-hydroxy)-propoxy~-phenyl~^propy'-(2)-urea, melting point of the neutral fumarate 111 to 114C.
. . .
33. N-3-Methyl-4-[(3'-isopropylamino-2'-hydroxy)-propoxy~-benzylu~ea, melting point of the base 101 to 102C.
34. N-3-Methyl-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea, melting point of the base 70 to 72C.
35. N-3-Methoxy-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzylurea, melting point of the base 132 to 135C.
36. N-3-Chloro-4-[(3'-tert.-butylamino-2'-~ydroxy)-propoxy]-be~zylurea, melting point of the ~ase 12? to 129C.
37. N-~-Nitro-4-~3'-tert.-butylamino-2'-hydroxy)-` 25 propoxy~-benzylurea, melting point of the neutral ~umarate 173 to 175C.
10~
38. N-3-Nitro-4-[(3'-isopropyiamino-2'-hydroxy)-propoxy]-benzylure~, melting point of the fumarate 180 to 185C.
39~ N-3-hcetylc~mino-4-[(3'-isopropylamino-2'-hydrox~)-propoxy]-benzylurea, melting point of the fumarate 142 to 144C.
40. N-3-Acetylamino-4-[(3'-tert.-butylami~o-2l-hydroxy)-propoxy3-benzy urea, melting point of the base 191 to 194C.
41. N-3,5-Dichloro-4- r (3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea, melting point of the base 149 to 151C.
42. N-3-Metho~y-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzyl-N'-butylurea, melting point of the base 127 to 128C.
43. N-3-Methoxy-4-~(3'-tert.-bu~ylamino-2'-hydrox~)-propox~ benzyl-~'-dibutylure~, melting point of the hydro-chloride 74 to 77C.
44. N-3-Ethoxy-4-[(3'-tert.-butylamino-2'-hydroxy)-propox~3-benzylurea, melti~g point of the fumarate 143 to 144C .
4~. N-3-Bromo-4-{(3'-tert.-butylamino-2'-hydroxy)-propoxy~-~enzylurea, melting point of the base 1~0 to 132C.
46. N-3-Amino-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea~ melting point o~ the dihydrochloride 184 to 187C.
47. N-3-Allyl-4-~(3'-tert.-butylam~no-2'-hydroxy)-propoxy3-benzyIurea fumarate, amorphous powder, sintering range 130 to 133C.
1~74332 48. N 3-Methoxy-4-[(3'-(2t2'-hydroxymethyl-isopropyl-amino)-2'-hy~roxy-propoxy]-benzylurea fumarate, amorpho~s powder, sintering range ~5 to 90C.
-18-.
hydroxy)-propoxy]-benzylurea, N-3-bromo-4-~(3'-tert.-butyl-amino-2'-hydroxy)-propoxyI-benzylurea and N-4-~(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-N'-methyl-N'-(3-hydroxy)-ethylurea.
In accordance with the invention there is also provided a process for the preparation of a compound of formula I herein, which comprises reacting a phenoxypropane derivative having the general formula:
/ R
X - NH - C - N
~ I \ R2 ( 3)n ~ (II) in which Y is the group ~ CH -/CH2 or ~ CH - CH2 - Hal in which Hal is a chlorine, bromine, or iodine atom, and ~1' R2, R3, X and n are as defined above for formula I, or a mixture of such compounds in which Y has both the possible meanings, at room temperature or at an elevated temperature with ammonia or an amine having the general formula:
H2N - R5 (III) in which R5 is a hydrogen atom or the group R4, and when R5 is a hydrogen atom it may be converted to the group R4 by reaction of the reaction product with a carbonyl compound having the general formula :
1-3 7 ~3'~
_R
,, 6 \
C = 0 (IY) " R7 / ``
in which R6 is a hydrogen atom or a lower alk~l ~roup and R7 is an alkyl group or a hydroxyalkyl group containin~ up to four carbon atoms~ or R6 and R7 taken together may form an alkylene group containing up to five carbon atoms, and the product is reduced simultaneously or subsequently.
If the reaction product thereby produced is a salt, the base may be liberated therefrom and the compound of formula I may be isolated as a base or after having again been converted into a salt.
It is thus possible, according to the process of the invention, to react an epoxy derivative of formula II, i~l which Y is C~ / H2 , simpl~ with hn amine of the for~ula H?N-R4, with R4 having the abovementioned meaning, ~he re-~ction may be carried out in the presence or absence of asolvent. Preferred solvents are polar solvents, such as, for exam~le, lower alcohols or N,N-dimethylacetamide. Excess amine of the formula H2N-R4 may also serve as the solvent.
Particularly good results are o~,tained if water is added to the reaction mixture, ~his measure achieves a notable increase in the reaction speed, so that complete conversion is achie~ed in a relatively short time even at room temper-ature.
If instead of the epoxide compound the halohydrin of for~u~ , in ~hich Y is -ICH - CH2 - Hal is e l d 0~
~ 3 3'~
the starting material, the reaction again may be carried out with or without solve~t. ~ecause of ~he low~r reaction speed it i5 in t`nis case advisable to perform the reaction at an elevated temperature, preferably at 50 to 120C. If the amino compound of formula II is-~olatile at tLis temperature, it is necessary to work in a closed apparatus. A~ain, excess amine of formula III may serve as the solvent.
Tf ammonia is employed as the reactant of formula III, it is necessary subse~uently to replace a hydrogen atom of the prir~ary amino group formed, by the group R4. This is preferably achieved by reductive al~ylation with the aid of an oxo compound of the formula IV. The objective is achieved if first the primary amine is reacted with the oxo compound and then the reduc'ion is carried out, or if the reduction is simply carried out in the presence of the oxo compound o~
- formula IV. A catalytic hydrogenation for example with palladium on charcoal as the catalyst, or a reduction with ~odium borohydri~e, is preferred as the reduction method.
~he compounds of formula I herein are isolated from the reaction mixture in a customary manner. A very good tendency to crystallise is shown, for example, by the salts of the compounds of formula I w~th dicarboxylic acids such as, ~or example, the fumarates, oxalates or succinates, so that a conversion o~ the compounds into such salts is parti-cularly preferred for the purpose of isolation.
- ~he compo~nds of formula I may be used in pharma-ceutical compositions either as bases or as pharmaceutically-~?7433'2 acceptable salts. As examples of such pharmaceutically acceptable salts there may be ~.entioned the hydrohalides, especially the hydrochlorides and hydrobromides, and also the sulphates, phosphates, acetates, i~umarates, succinates, cyclohexylsulphamates, tartrates and citrates. The prepara-tion of such salts is achieved, for example, by reacting the bases with stoichiometric amounts of the appropriate acid.
The compounds of formula II required as starting product~ are in many cases new. Where they are halohydrins or epoxides they may ~e obtained by reaction of the corres-ponding phenols with epihalohydrins. ~Iainly epoxides of formula II are obtained if the phenolates are reacted with the epihalohydrin either in a~ anhydrous medium, for example in dimethylformamide or hexamethy~phosphoric acid trisam de as the solvent, or i~ water or an aqueous-alcoholic solution.
On the other hand, mainly halohydrins of formula II are produced i~ the reaction starts from the corresponding free phenols and is carried out at a temperature of 100C, the epihalobydrin is employed in excess and a ba~ic catalyst, for example piperidine, is added. ~he epoxides of formula II
obtained in the manner described may contain a certain amount of halohydrin of formula II, which of course does not inter-fere with the further reaction to give the compounds of formula I.
~ he phenols with a previously formed side chain carrying the ureido group, which are required for the manu-_9_ , 10'7 ~33~
facture of the compo~lds of formula II, also may be preparedaccording to known methods. ~hus, for example, the reaction of hydroxy-substituted phenylalkyl~mine salts with potassium cyanate yields urea derivatives which may serve as the start-ing material for the preparation of compounds of formula IIin which each of R~ and R2 is a hydrogen atom. If it is desired to prepare compounds of formula II in which ~1 and/or R2 are not hydrogen, the corresponding ureidoalkyl-substituted phenol is obtained by reaction of the corresponding isocyan-ate, of which the phenolic hydroxyl group is protected by anacyl or benzyl ~roupS with ar amine of the formula ~R1R2.
~he group which protects the phenolic hydroxyl group then may be split off easily.
It is also possible to synthesise the ureidoalkyl-substit~ted phenols from carb~mic acid chlorides.
~ or administration, the compounds of formula I maybe mixed with any customary pharmaceutically-acceptable ex-cipient. Accordingly the invention also provides a pharma-ceutical composition comprising, as an active ingredient, a phenoxypropylamine derivative havi~g the general formula I
herein, or a pharmaceutically-acceptable acid addition salt thereof, in admixture with a pharmaceutically-acceptable excipient. ~he excipient is chosen in a conventional manner in accordance with the form in which the composition is to be administered. It is possible to produce both mixtures which may be converted into tablets or dra~ees, and stable solu-tions containing, for example, salts of the compounds of .. . . . . ... ..
l~}7~
formula I. Also, the active compounds of formula I may be included in capsules.
Th~ examples which follow illustrate the compounds according to the invention and the preparation thereof.
Example 1 8.0 G. of N-4-~(2',3'-epoxy)-propoxy~-benzylurea are allowed to react for 4 hours at room te~perature with a mix-ture of 60 ml. of tertiary butyl~mine ar.d 60 ml. of water.
~he reaction mixture is then evaporated in vacuo and the residue is subjected to a further distillation with ethanol/
benzene in order to remove water completely. ~.5 G. o~ N-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea, re-pr~senting 79.~/o of theory, are thus obtained.
~he ojly base is dissolved in ethanol, the soLution is fil~ered and the filtrate is treated with a solution o~
the equivalei.~ amount of fumaric acid in acetone. ~he fumarate crystallises out and is filtered off after some time. After recrystallisation from eth~nol, the product shows a melting point of 171 to 173C.
~he N-4-[(2't3'-epoxy)-propoxy~-benzylurea required as a starting material was obtained by reaction of N-(~-hydrox~)-benzylurea in aqueous solution with epichlorohyd~in, the calculated amount of NaOH being added. It ~elts at 150 to 157C.
; 25 ~ ExamPle 2 13.0 G. of N-3-~(2',3'-epoxy)-propoxy~-benzylurea are reacted with a mixture of 40 ml. of tert.-butylam ne and . .
~7~33~
40 ml. of water for 2 hours at room temperature. After working-up in a manner analogous to that used in EXample 1, 15.0 g. of crude N-3-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea are obtained~ ~he fumarate obtained from the base analogously to Example 1 has a .~elting point of 157 to 161C.
~ he N-3-t(2',3'-epoxyj-propoxy]-benzylurea which serves aq the startin~ product W8S obtained by reaction of the sodium salt of N-(m-hydroxy)-benzylurea ~lith epichloro-hydrin at 50C in hexamethylphosphoric acid trisamide as the~olventO It is an oi1y product.
Example 3 - 10.0 G. of N-2-[(2',3'-epoxy)-propoxy]-benzylurea are reacted with tert.-butylamine as described in Example 2.
This yields 13.0 g. of ~-2-[(3'-tert.-butyla~ino-2'-hy~roxy)-propoxy~-benzylurea as an oily producl;. Melting point of the fumarate (from ethanol) 125 to i280C.
xample 4 10 G. of N-4-[(2',3'-epoxy)-propoxy]-benzylurea are reacted with 80 ml. of a 1:1 mixture of isopropylamine and water for 4 hours at room temperature. 12.4 G. of N-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzylurea are thus - obtaine~t the melti~g poirit of th~ va~ b~ iO3 ~o 1C6C.
Example 5 2.0G. of N-3-methoxy-4-r(3'-chloro_2'_hydroxy)-propoxy] benzylurea and 20 ml. of tert.-butylamine are warmed to 100C for 2 hours in a closed vessel. After .
.
107433~
cooling, the excess tert.-butylamine is distilled off in vacuo, and the residue is treated with a little acetone and seeded. A substance crystallises out and is filtered off after some time. 1.7 G. of N-3-methoxy-4~(3'-tert.-butyl-amino-2'-hydroxy)-propoxy]-benzylurea are thus obtained, corresponding to a yield of 75.5% of theory. Melting point:-134 to 137C. Melting point of the neutral fumarate is 198 to 200C.
The N-3-methoxy-4-l(3'-chloro-2'-hydroxy)-propoxy]-benzylurea used as the starting material is obtained from 3-methoxy-4-hydroxy-benzylurea by reaction with epichloro-hydrin at 100C, the reaction time being 3 hours and piperi-dine being added as a catalyst.
Example 6 1.0 G. of N-4-r(2',3'-epoxy)-propoxy]-benzylurea and 1.64 g. of tert.-butylamine in 20 ml. of ethanol are heat-ed to the boil for 2 hours. The clear solution thereby obtain-ed is concentrated in vacuo and the residue is completely freed of the solvent. 0.95 G. of the crude N-4-~(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea are thus obtained.
After conversion to the fumarate, the product has a melting point of 171 to 173& .
The following compounds are obtained in a manner analogous to Examples 1 to 6:
7. N-4-1(3'-Isopropylamino-2'-hydroxy)-propoxy3-benzyl-N'-methylurea, melting point of the neutral fumarate 170 to 172C.
107433~
8. N-4-[(~'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-~'-methylurea, melting point of the fumarate 146 to 9. N-4-~(3'-Isopropylamino-2'-hydro~y)-propoxy3-benzyl-N'-isopropylurea, melting point of the fumara`te 149 to ~53C.
10. N-4-t(3'-tert.-Butylamino-2'-hydroxy~-propoxy~-benzyl-I~ isopropylurea, melting ~oint of the base 1~5 tc 138C.
11. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-N'-allylurea, melting point of the base 73 to 76C.
12. N-4-[(3'-Isopropylamino-2'-hydroxy)-propoxy]-benzyl-N'-benzylurea, melting point of the hydrochloride 11~ to ~ 121C.
1~. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-N'-benzylurea, melting point of the base 80 to 82C.
14. N-4-[(3'-sec.-Butylamino-2'-hydroxy)-propoxy]-benzylurea, melt ng point of the neutral fumarate 170 to 15- N-4-[(3'-Cyclopropylamino-2'-hydroxy)-propoxy]-benzylurea, melting point of the neutral fumarate 130 to 134 C.
16. N-4-~(3'-Isopropylamino-2'-hydroxy)-propoxy3-benzyl-N'-(2"-methoxy)-ethyl1lrea, melting point o~ the fumarate 132 to 13~C.
17. ~-4-~(3'-tert.-Bu~ylamino-2'-hy~roxy)-propoxy~-benzyl-N'-(2"-methoxy)-ethylurea, melting point o~ the base 76 to 107~33~
18. N~-[(3'-Isopropylamino-2'-hydxo}y)-propoxy]-benzyl-N'-(2"-hydroxy)-ethylurea, melting point of the fumarate 138 to 140C.
19. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-~'(2"-hydroxy)-ethy~urea, melting point of the neutral fwnarate 146 to 149C.
20. ~-[(3'-Isopropylamino-2'-hydroxy)-propoxy~-benzyl-N'-phenylurea, melting point of the fumarate 105 to 107C.
21. N-4-t(3'-tert.-Butylamino-2'-hydroxy)-propoxy]-benzyl-N'-phenylurea, melting point of the fumarate 134 to 138C.
22. N-4-~(3'-Isopropylamino 2'-hydroxy)-propoxy]-benzyl-N'-dime-~hylurea, melting point of the fumarate 150 to 153C.
23. N-4-[(3'-tert.-Butylamino-2'-hydroxy)-propoxy~-benzyl-N'-dimethylurea, melting point of the base 105 to 108C.
24. N~-~(3'-tert.-Butylamino-2'-hydrox;y)-propoxy]-benzyl-N'-methyl-N'-(2"-hydroxy)-ethylurea, melting point of the ~ase 111 to 113C.
25. N~ (3'-tert.~Butylamino-2'-hydroxy)-propoxy3-benzyl-N'-diisopropylurea, meltin~ point of the neutral fumarate 141 to 146C~ ~
26. N-3~(3'-tert.-Butylamino-2'-hydroxy)-propoxy~-4-methoxy-benzylurea, melting point of the base 64 to 67C.
27. ~-3-Methoxy-5-~(3'-tert.-butylamino-2'-hydroxy)-propoxy~benzylurea, melting point of the fumarate 198 to 2~0C
~. .
28. N-3~ ethoxy-4- r (3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzyl-N'-ethylurea, melting point of the base 132 to 133C. !
29. N-2- ~4 ~ [ ( 3"-tert.-Butylamino-2"-hydroxy)-propoxy]-phenyl~-ethyl-(1)-urea, melting point of the neutral fumarate 105 to 108C.
30. N-1- ~4 ~ ( 3~-Isopropylamino-2~-hydroxy)-propoxy]-phenyl~-ethyl-(1)-urea, melting point of the base 100 to ~1. N-1-~4'-[(3"-tert.-B~tylamino-2t'-hydroxy)-propoxy~-phenyl~-ethyl-(1)-ureaS melting point of the base 105 to 107C.
32. ~-1- 4 - ~ (3"-tert.-Butylami~o-2"-hydroxy)-propoxy~-phenyl~^propy'-(2)-urea, melting point of the neutral fumarate 111 to 114C.
. . .
33. N-3-Methyl-4-[(3'-isopropylamino-2'-hydroxy)-propoxy~-benzylu~ea, melting point of the base 101 to 102C.
34. N-3-Methyl-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea, melting point of the base 70 to 72C.
35. N-3-Methoxy-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzylurea, melting point of the base 132 to 135C.
36. N-3-Chloro-4-[(3'-tert.-butylamino-2'-~ydroxy)-propoxy]-be~zylurea, melting point of the ~ase 12? to 129C.
37. N-~-Nitro-4-~3'-tert.-butylamino-2'-hydroxy)-` 25 propoxy~-benzylurea, melting point of the neutral ~umarate 173 to 175C.
10~
38. N-3-Nitro-4-[(3'-isopropyiamino-2'-hydroxy)-propoxy]-benzylure~, melting point of the fumarate 180 to 185C.
39~ N-3-hcetylc~mino-4-[(3'-isopropylamino-2'-hydrox~)-propoxy]-benzylurea, melting point of the fumarate 142 to 144C.
40. N-3-Acetylamino-4-[(3'-tert.-butylami~o-2l-hydroxy)-propoxy3-benzy urea, melting point of the base 191 to 194C.
41. N-3,5-Dichloro-4- r (3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea, melting point of the base 149 to 151C.
42. N-3-Metho~y-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzyl-N'-butylurea, melting point of the base 127 to 128C.
43. N-3-Methoxy-4-~(3'-tert.-bu~ylamino-2'-hydrox~)-propox~ benzyl-~'-dibutylure~, melting point of the hydro-chloride 74 to 77C.
44. N-3-Ethoxy-4-[(3'-tert.-butylamino-2'-hydroxy)-propox~3-benzylurea, melti~g point of the fumarate 143 to 144C .
4~. N-3-Bromo-4-{(3'-tert.-butylamino-2'-hydroxy)-propoxy~-~enzylurea, melting point of the base 1~0 to 132C.
46. N-3-Amino-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy~-benzylurea~ melting point o~ the dihydrochloride 184 to 187C.
47. N-3-Allyl-4-~(3'-tert.-butylam~no-2'-hydroxy)-propoxy3-benzyIurea fumarate, amorphous powder, sintering range 130 to 133C.
1~74332 48. N 3-Methoxy-4-[(3'-(2t2'-hydroxymethyl-isopropyl-amino)-2'-hy~roxy-propoxy]-benzylurea fumarate, amorpho~s powder, sintering range ~5 to 90C.
-18-.
Claims (61)
- Claim 1 continued.......
(II) in which Y is the group or in which Hal is a chlorine, bromine or iodine atom, and R1, R2, R3, X and n are as defined above, or a mixture of such compounds, in which Y has both possible meanings, at room temperature or at an elevated temperature with ammonia or an amine having the formula:
H2N - R5 (III) in which R5 is a hydrogen atom or the group R4, and i) when R5 is a hydrogen atom it is converted to the group R4 by reaction of the reaction product with a carbonyl compound having the formula:
(IV) in which R6 is a hydrogen atom or a lower alkyl group and R7 is an alkyl group or a hydroxyalkyl group containing up to four carbon atoms, or R6 and R7 taken together may form an alkylene group containing up to five carbon atoms, and the product is reduced simultaneously or subsequently after which a) the reaction product is isolated as a base or b) an acid is added to the reaction product and the salt thereby formed is isolated. - 2. A process according to Claim 1, in which a base of formula I obtained as reaction product is con-verted into a pharmaceutically-acceptable acid addition salt.
- 3. A process according to Claim 1, in which a salt obtained as reaction product is converted into another, pharmaceutically-acceptable acid addition salt.
- 4. A process according to Claim 1, in which a compound of the formula II, in which Y is the group , is reacted with an amine of formula III at room temperature, in the presence of water.
- 5. A process as claimed in claim 1, in which R1, R2 and R3 is a hydrogen atom n is O
X is a methylene, ethylene or ethylidene group and R4 is a branched alkyl group containing three, four or five carbon atoms. - 6. A process as claimed in claim 1, in which R1 and R2 is a hydrogen atom n is 1 X is a methylene or ethylidene group R3, which is in the m-position to X and in the o-position to the ether side-chain, is a lower alkoxy group, a chlorine or bromine atom or a nitro group and R4 is a branched alkyl group containing three, four or five carbon atoms
- 7. A process as claimed in claim 1, in which R1 and R2 is a hydrogen atom n is 1 X is a methylene or ethylidene group R3, which is in the m-position to X and in the o-position to the ether side-chain, is an alkyl group containing up to three carbon atoms, an amino group or an acylamino group, wherein acyl is the acyl group of an aliphatic monocarboxylic acid containing up to four carbon atoms, and R4 is a branched alkyl group containing three, four or five carbon atoms.
- 8. A process as claimed in claim 1, in which R1 and R3 is hydrogen R2 is a lower alkyl group, a phenyl or benzyl group n is O
X is a methylene or ethylidene group and R4 is a branched alkyl group containing three, four or five carbon atoms. - 9. A process as claimed in claim 1, in which R3 is hydrogen R1 is a lower alkyl group R2 is a lower alkyl group, a hydroxy lover alkyl group, a phenyl or benzyl group, n is O
X is a methylene or ethylidene group and R4 is a branched alkyl group containing three, four or five carbon atoms. - 10. The process claimed in claim 5, wherein R1, R2 and R3 is hydrogen n is O
X is methylene and R4 is tert. butyl, whereby X is in the p-position to the ether side chain. - 11. The process claimed in claim 5, wherein R1, R2 and R3 is hydrogen n is O
X is methylene and R4 is tert. butyl, whereby X is in the m-position to the ether side chain. - 12. The process claimed in claim 5, wherein R1, R2 and R3 is hydrogen n is O
X is methylene and R4 is tert. butyl, whereby X is in the o-position to the ether side chain. - 13. The process claimed in claim 5, wherein R1, R2 and R3 is hydrogen n is O
X is methylene and R4 is isopropyl, whereby X is in the p-position to the ether side chain. - 14. The process claimed in claim 5, wherein R1, R2 and R3 is hydrogen n is O
X is ethylene and R4 is tert. butyl, whereby X is in the p-position to the ether side chain. - 15. The process claimed in claim 5, wherein R1, R2 and R3 is hydrogen n is O
X is ethylidene and R4 is tert. butyl, wherein X is in the p-position to the ether side chain. - 16. The process claimed in claim 5, wherein R1, R2 and R3 is a hydrogen atom n is O
X is ethylidene and R4 is isopropyl, wherein X is in the p-position to the ether side chain. - 17. The process claimed in claim 6, wherein R1 and R2 is a hydrogen atom n is 1 R3 is methoxy X is methylene and R4 is tert. butyl.
- 18. The process claimed in claim 6, wherein R1 and R2 is a hydrogen atom n is 1 R3 is methoxy X is methylene and R4 is isopropyl.
- 19. The process claimed in claim 6, wherein R1 and R2 is a hydrogen atom n is 1 R3 is ethoxy X is methylene and R4 is tert. butyl.
- 20. The process claimed in claim 6, wherein R1 and R2 is a hydrogen atom n is 1 R3 is nitro X is methylene and R4 is tert. butyl.
- 21. The process claimed in claim 6, wherein R1 and R2 is a hydrogen atom n is 1 R3 is chlorine X is methylene and R4 is tert. butyl.
- 22. The process claimed in claim 6, wherein R1 and R2 is a hydrogen atom, n is 1 R3 is bromine X is methylene and R4 is tert. butyl.
- 23. The process claimed in claim 7, wherein R1 and R2 is a hydrogen atom, n is 1 R3 is methyl X is methylene and R4 is tert. butyl.
- 24. The process claimed in claim 7, wherein R1 and R2 is a hydrogen atom, n is 1 R3 is amino X is methylene and R4 is tert. butyl.
- 25. The process claimed in claim 7, wherein R1 and R2 is a hydrogen atom n is 1 R3 is acetylamino X is methylene and R4 is tert. butyl.
- 26. The process claimed in claim 8, wherein R1 is hydrogen R2 is benzyl n is O
R3 is hydrogen X is methylene and R4 is isopropyl. - 27. The process claimed in claim 8, wherein R1 is hydrogen R2 is benzyl n is O
R3 is hydrogen X is methylene and R4 is tert. butyl. - 28. The process claimed in claim 8, wherein R1 is hydrogen R2 is methyl n is O
R3 is hydrogen X is methylene and R4 is isopropyl. - 29. The process as claimed in claim 8, wherein R1 is hydrogen R2 is phenyl n is O
R3 is hydrogen X is methylene and R4 is tert. butyl. - 30. The process as claimed in claim 9, wherein R1 and R2 are methyl, n is O
R3 is hydrogen X is methylene and R4 is tert. butyl. - 31. The process as claimed in claim 9, wherein R1 is methyl R2 is .beta.-hydroxyethyl n is O
R3 is hydrogen X is methylene and R4 is tert. butyl. - 32. A phenoxypropylamine derivative having the general formula :
in which X, R1, R2, R3, R4 and n are defined as in claim 1, and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 1 or an obvious equivalent thereof. - 33. A compound according to Claim 32, in which each of R1 and R2 is a hydrogen atom, n is O and X is a methylene, ethylene or ethylidene group and R4 is a branched alkyl group containing three, four or five carbon atoms, and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 5 or an obvious equivalent thereof.
- 34. A compound according to Claim 32, in which each of R1 and R2 is a hydrogen atom, X is a methylene or ethylidene group, R3, which is in the m-position to X and in the o-position to the ether side-chain, is a lower alkoxy group, a chlorine or bromine atom or a nitro group and n is 1, and R4 is a branched alkyl group containing three, four or five carbon atoms, and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 6 or an obvious equivalent thereof.
- 35. A compound according to Claim 32, in which each of R1 and R2 is a hydrogen atom X is a methylene or ethylidene group, R3, which is in the m-position to X
and in the o-position to the ether side-chain, is an alkyl group containing up to three carbon atoms, an amino group or an acylamino group, wherein acyl is the acyl group of an aliphatic monocarboxylic acid containing up to four carbon atoms, n is 1, and R4 is a branched alkyl group containing three, four or five carbon atoms, and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 7 or an obvious equivalent thereof. - 36. A compound according to Claim 32, in which each of R1 and R3 is a hydrogen atom, R2 is a lower alkyl group or a phenyl or benzyl group, n is O, X is a methylene or ethylidene group, and R4 is a branched alkyl group containing three, four or five carbon atoms, and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 8 or an obvious equivalent thereof.
- 37. A compound according to Claim 32, in which R3 is a hydrogen atom, R1 is a lower alkyl group, R2 is a lower alkyl group, a hydroxy-lower alkyl group, a phenyl or benzyl group, n is O, X is a methylene or ethylidene group and R4 is a branched alkyl group containing three, four or five carbon atoms, and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 9 or an obvious equivalent thereof.
- 38. N-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 10 or an obvious equivalent thereof.
- 39. N-3-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 11 or an obvious equivalent thereof.
- 40. N-2-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts, thereof, whenever prepared by a process as claimed in claim 12 or an obvious equivalent thereof.
- 41. N-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 13 or an obvious equivalent thereof.
- 42. N-2- {4'-[(3"-tert.-butylamino-2"-hydroxy)-propoxy]-phenyl} -ethyl-(1)-urea and the pharmaceutically-acceptab1e acid addition salts thereof, whenever prepared by a process as claimed in claim 14 or an obvious equivalent thereof.
- 43. N-1- {4'-[(3"-tert.-butylamino-2"-hydroxy)-propoxy]-phenyl} -ethyl-(1)-urea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 15 or an obvious equivalent thereof.
- 44. N-1- {4'-[(3"-isopropylamino-2"-hydroxy)-propoxy]-phenyl} -ethyl-(1)-urea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 16 or an obvious equivalent thereof.
- 45. N-3-methoxy-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 17 or an obvious equivalent thereof.
- 46. N-3-methoxy-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 18 or an obvious equivalent thereof.
- 47. N-3-ethoxy-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 19 or an obvious equivalent thereof.
- 48. N-3-nitro-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 20 or an obvious equivalent thereof.
- 49. N-3-chloro-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 21 or an obvious equivalent thereof.
- 50. N-3-bromo-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 22 or an obvious equivalent thereof.
- 51. N-3-methyl-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 23 or an obvious equivalent thereof.
- 52. N-3-amino-4[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 24 or an obvious equivalent thereof.
- 53. N-3-acetylamino-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 25 or an obvious equivalent thereof.
- 54. N-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzyl-N'-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 26 or an obvious equivalent thereof.
- 55. N-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-N'-benzylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 27 or an obvious equivalent thereof.
- 56. N-4-[(3'-isopropylamino-2'-hydroxy)-propoxy]-benzyl-N'-methylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 28 or an obvious equivalent thereof.
- 57. N-4-[3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-N'-phenylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 29 or an obvious equivalent thereof.
- 58. N-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-N'-dimethylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 30 or an obvious equivalent thereof.
- 59. N-4-[(3'-tert.-butylamino-2'-hydroxy)-propoxy]-benzyl-N'-methyl-N'-).beta.-hydroxy)-ethylurea and the pharmaceutically-acceptable acid addition salts thereof, whenever prepared by a process as claimed in claim 31 or an obvious equivalent thereof.
- 60. A process for the preparation of phenoxypropylamine derivatives having the formula:
in which X is an alkylene group containing up to four carbon atoms, R1 is a hydrogen atom or alkyl group of 1 to 4 carbon atoms, R2 is a hydrogen atom or alkyl group of 1 to 4 carbon atoms, provided that where at least one of R1 and R2 is lower alkyl, X is other than -CH2CH2-, R3 is hydrogen or halogen and R4 is alkyl containing 1 to 4 carbon atoms and the pharmaceutical-accept-able acid addition salts thereof which comprises reacting a phenoxypropane derivative having the formula in which Y is the group or where Hal is a chlorine, bromine or iodine atom and R1, R2 and R3 are as defined above with an amine having the formula NH2R4 wherein R4 is as defined above and, if desired, forming the pharmaceutical-acceptable acid addition salt. - 61. A phenoxypropylamine derivative having the formula in which X, R1, R2, R3 and R4 are as defined in claim 60, and the pharma-ceutical-acceptable acid addition salts thereof, whenever prepared by the process of claim 60.
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLLOWS:
1. A process for the preparation of phenoxypropylamine derivatives having the formula:
(I) in which X is an unbranched or branched alkylene group containing up to four carbon atoms, R1 is a hydrogen atom or a lower alkyl group containing up to six carbon atoms, R2 is a hydrogen atom or an alkyl or alkenyl group, in each case containing up to six carbon atoms, a hydroxyalkyl or alkoxyalkyl group, in which the alkyl group in each case contains up to three carbon atoms or a phenyl or benzyl group, provided that where at least one of R1 and R2 is lower alkyl, X is other than -CH2CH2-, R3 is an alkyl, alkenyl, alkoxy group, in each case containing up to four carbon atoms, a halogen atom, a nitro, amino or aliphatic acylamino group, and R4 is a branched alkyl group, a hydroxyalkyl group or a cyclo-alkyl group containing up to six carbon atoms, and n is 0 or 1 and the pharmaceutically-acceptable acid addition salts thereof which comprises reacting a phenoxypropane derivative having the formula:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT1573A AT317875B (en) | 1971-03-17 | 1973-01-02 | PROCESS FOR THE PREPARATION OF NEW 4- (4-BIPHENYLYL) -4-HYDROXYBUTTERIC ACIDS, THEIR SALT, ESTERS AND LACTONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1074332A true CA1074332A (en) | 1980-03-25 |
Family
ID=3479267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA163,292A Expired CA1074332A (en) | 1973-01-02 | 1973-02-06 | Phenoxypropylamine derivatives and the preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1074332A (en) |
-
1973
- 1973-02-06 CA CA163,292A patent/CA1074332A/en not_active Expired
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