CA1077506A

CA1077506A - O-(3-amino-2-hydroxy-propyl)-amidoxime derivatives, process for the preparation thereof and pharmaceutical compositions comprising the same

Info

Publication number: CA1077506A
Application number: CA285,529A
Authority: CA
Inventors: Katalin Farago; Kalman Takacs; Peter Literati Nagy; Ilona Kiss Ajzert; Antal Simay; Matyas Szentivanyi; Sandor Virag
Original assignee: Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Current assignee: Chinoin Private Co Ltd
Priority date: 1976-08-27
Filing date: 1977-08-26
Publication date: 1980-05-13
Also published as: NO772958L; ES462346A1; DK150196C; GR63623B; BE858134A; NL187478C; IL52804A; FR2362845A1; SU730296A3; DK379777A; FI68396C; DK150196B; FI772551A; YU202377A; HU177578B; SE7709482L; JPS5350131A; YU237782A; NO144793C; AU521432B2

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to compounds of the general formula I and pharmaceutically acceptable salts thereof (I) wherein R2 hydrogen or alkyl having one to five carbon atoms; R3 is alkyl having one to five carbon atoms, cycloalkyl or phenyl optionally substituted with hydroxyl or phenyl; or R2 and R3 together form a five- to eight-membered ring optionally containing also other heteroatoms and/or fused with an other ring; R4 is cycloalkyl, aromatic or heteroaromatic group, optionally substituted with one or more halogens, alkoxy or alkyl and/or fused with an other ring, preferably phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, pyrazolyl; R5 is hydrogen or alkyl having one to four carbon atom cycloalkyl or phenyl optionally substituted with halogen, alkoxy having one to four carbon atoms or alkyl having one to four carbon atoms; R6 is hydrogen, alkyl having one to four carbon atoms or phenyl; m=0, 1 or 2; n = 0, 1 or 2. It also relates to a process for the preparation of these compounds.
The compounds of formula I and their pharmaceutically acceptable salts are useful in treating diabetic angiopathy in mammals and in some instances are useful as hypotensive agents.

Description

~L~77~iO6 The present invention relates to new amidoxiTne derivatives and pharmaceutically acceptable salts thereof and to methods of preparing such compounds. In a further aspect this invention rela~es to pharmaceutical composi-tions comprising one or more of the above compounds of the invention, and to methods of treating diabetic angiopathy and in some instances hypertension in mc~mmals. Some of the compounds of the invention show also ~-blocking activity.
~iabetes mellitus is one of the most frequent metabolic diseases, and its main symptom is the disorganisa-tion of the carbohydrate metabolism balance in the organism.
This symptom is, however, often accompanied by pathologic vascular disorders, for instance extremital vascular stenoses, pathological changes in the vessels of the eye ground etc.
At the present time there are numerous compounds known in ; the art including insuline for decreasing of hyperglycaemia but in the treatment of diabetic angiopathy, which is a concomitant disease, the results are very moderate when us-ing the known, commercially available pharmaceutical pre-; parates. The reason for this is that as a consequence of diabetes mellitus the adrenergic receptor sites of the vessel undergo essential changes, and therefore the adrenergic reac-tions induced by the pharmaceutical preparates in a diabetic are different from those in a non-diabetic organism rNature New Biology, 243, No. 130, 276 (1973); Szemészet, 111~ 23 (1974); Endocrinology, 93, 752 ~1973)]. Upon quantitative increasment of the metabolism the ~ adrenergic receptor sites of the vessels are transformed into ~-receptors. The ` ~

;'`' ~077S~ ~

receptor-transformation is due to a modulator compound I LAmer. J. Physiol., 218~ 869 (1970)]. When this compound is added to an a-receptor the a-antagonists are no more effective since the receptor has been transformed into ~-receptor. The original a-sensitivity can be recalled by adding also a ~-blocker.
-~ In cases where a qualitative change appeared in the metabolism it has been found that the a-antagonists (e.g. noradrenaline) preserve their activity but their effect can be inhibited by ~-blockers. This is the first functional change appearing in a diabetic organism which can be detected already in about 24 hours after the administration of alloxan (hexahydrotetraketo-pyrimidine).
l'he source of the changes characteristic to diabetes is an imperfect a-~ receptor transformation caused by the forma-tion of an irregular modulator.
We have now discovered that certain amidoxime derivatiYes and pharmaceutically acceptable salts thereof show no or a slight effect on the adrenergic reactions of the healthy vessels while have a strong influence on the adrenergic receptors which underwent a pathologic change due to the diabetes mellitus.
In summary the compounds of this invention can be represented by the general formula I

R -(lH~m-(CH)n-C-NH2 '.. :; 11 /
. N-o-cH2-cH-cH2-N
OH R ~
. . ~

.,.,,;, ~b~
,' : ' ~

1C~775~)6 wherein R2 is hydrogen or alkyl having one to five carbon atoms;
R3 is alkyl having one to five carbon a~oms, cycloalkyl or phenyl optionally substituted with hydroxyl or phenyl; or R2 and R3 together with the nitrogen atom to which they are attached may form a five- to eight-membered ring optionally containing oxygen as an heteroatom, which ring may be fused with another ring;
~: R4 is hydrogen or a cycloalkyl, aromatic, quinolyl, isoquinolyl, pyridyl or pyrazolyl group, optionally substituted with one or more halogens, alkoxy or alkyl, which ring may be fused with another ring and preerably phenyl or naphthyl;
R5 is hydrogen or alkyl having one to four carbon atoms, cycloalkyl or phenyl optionally substituted with halogen, alkoxy having one to four carbon atoms or alkyl having one to four carbon atoms;
R6 is hydrogen, alkyl having one ~o four carbon atoms or phenyl;
m = 0, 1 or 2;
n = 0, 1 or 2, Also encompassed within the invention are pharmaceutically acceptable salts of the above compounds.
The compounds of the invention first o all show a selecti~e : ~-blocking activity, and therefore may find their application in the treatment of diabetic angiopathy. Some of the compounds within the scope of the invention are also useful hypotensive agents and/or possess an ' '' . ` :
`', . ,'; _.. ~t 7~75~6 , ~-blocking activity.
Typical illustrations of the compounds of the general formula I, and salts thereof, can be had for example, hereinbelow by reference to Examples 1 to 33. The preferred -NR2R3 group is the piperidino group, and the preferred R4 substituents are phenyl or pyridyl substituted with an alkoxy. The particularly preferred compounds of the general formula I are:
0-(3-piperidino-2-hydroxy-1-propyl3-3,~-dimethoxyphenyl-acetamidoxime dihydro-chloride; and 0-(3-piperidino-2-hydroxy-1-propyl)-nicotinamidoxime dihydrochloride.
The compounds of the general formula I and the pharmaceutically acceptable salts thereof can be prepared by reacting a) amidoximes of the general formula II

R ~(CH)m-(cH)n-lcl-NH2 (II3 N-OH
wherein R~, R5, R6, n and m are as defined above, with amines of the general formula IIIA or IIIB
~R2 ~
X-cH2-cH-cH2-N \ / (IIIA) OH R3_ ~

CH2-~H-CH2-N , (IIIB) 0/ \ R3_ , ` wherein R2 and R3 are as defined above~ and X is halogen, in the presence of a base; or b) amidoximes of the general formula II, wherein R4, R5, R6, m and n ~; are as defined above, with epichlorohydrine, and reacting the amidoximes of , ~ .
the general formula V
: -,~
, ~ - 5 -: :

`::
.

~L~775~6 :~ ~ ~ (CH)m- ~CH)n-CI-NH2 (V)

2 \ / 2 : :
, ' initially obtained, after or without separation, with amines of the general formula IV R2_ HN ~ \ (IV) R
wherein R2 and R3 are as defined above; or : c) the alkali metal salts of the amidoximes of the general formula II, wherein R4, R5, R6, n and m are as defined above, with 2-phenyl-3-substitut-ed-5-chloromethyl-oxazolidines of the general formula VI
.~ Cl-CH2 0 ~ - R (VI) wherein R has the same meaning as given for R2 and R3 except hydrogen, and hydrolysing the compounds of the general formula VII

R - (CH)m tCH)n lCI 2 N
\ O-CH~ ~VII) .!.

O~N-R

, C 6H5 ; ~ without isolation; said steps (a), (b) or (c) being optionally followed by ., .
transforming the compounds of the general formula I initially obtained into the pharmaceutically acceptable salts thereof with suitable organic or in-: .
` organic acids and/or deliberating the free bases from the salts initially ; - 6 -~7'75(316 .
; obtained.
The compounds of the general :formula III can be prepared by rcacting epichlorohydrine with amines in a manner known ~ se.
Procedure a~ can preferably be eff0cted by conducting the reaction in an aqueous medium; in an organic solvent containing water (e.g. in aqueous solution of alcohol~; or inorganic solvents, preferably at about from 0 to 1~0 C.
One can also proceed reacting the amidoximes of the general formula II with alkali alcoholates in a dry medium, and adding the alcoholic solution of the amines of the general formula III to the solution containing the amidoxime salts formed, dropwise. The reaction is preferably carried out in the range from about 0 to 100 C, under stirring.
According to a further alternative the salts of the amidoximes of the general formula II are prepared with alkali hydroxides, preferably sodium or potassium hydroxide, in a non-water miscible organic solvent, e.g. benzene, toluene, xylene. The salt formation is effected at the boiling temperature of the solvent, the water deliberated is removed from the system by azeotropic distillation, the solution of the amines of the general formula III is subse-quently added and the reaction mixture is boiled for a further definite period.
According to a further embodiment of the process a) the reaction is performed in an aqueous medium, by adding the alkaline aqueous solution or suspension of the amidoximes to the compounds of the general formula III, -~ under stirring. The reaction is preferably conducted in the range of about from a to 60C, and the amidoxime is preferably dissolved or suspended in a .
~ 5 to 20 % aqueous sodium hydroxide solution. The reaction can be accomplished `i also in an organic solvent - water mixture, for example by adding the alkaline aqueous solution or suspension of the amidoxime to the alcoholic or dioxane . solution of a compound of the general formula III, dropwise. The reaction can be carried out also in a reverse order, when to the alkaline aqueous solution or suspension of the amidoxime the other compound is added.
According to the process b) of the invention amidoximes of the ; - 7 -':'.'.~

775~6 `:
general formula II are reacted with epichlorohydrine in the presence of a base.
If desired, the epoxide compound formed during the reaction can be separa-ted, it is, however, more favourable effecting the reaction in one synthesis step, without separating the intermediate. The reaction is carried out in an aqueous or organic medium; in an organic solvent containing water; or in the co-existence of two solvent phases, at a temperature of about from -10 to about +100C.
According to an embodiment of this process the reaction is performed in an alkaline aqueous medium, by adding to the alkaline aqueous solution or suspension of the amidoximes 1 to 4 moles of epichlorohydrine. The addition - of the epichlorohydrine is accomplished at -10 to +60C, under stirring, in one or more portions, or by dropwise addition. The order of the addition can be reversed, either the alkaline aqueous solution or suspension of the amido-xime is added to the epichlorohydrine, or the amidoxime is added to the alkaline aqueous solution or suspension of the epichlorohydrine. The inter-mediate of the general formula ~ is optionally removed by extracting with a non water-miscible solvent. It is, however, more favourable to react the intermediates of the general formula ~ with the corresponding amines without previous separation.
If the oxime starting substance is slightly soluble in the alkaline ` aqueous solution, the reaction can also be effected in an organic solvent con-taining water, e.g. in aqueous alcohols or aqueous dioxane. If desired, the ~ reaction can be conducted also in the co-existence of two solvent phases or :'-' in the presence of an emulsifying agent, by dissolving the epichlorohydrine in a non water-miscible organic solvent, for example in ben~ene or ether, ~ adding the solution obtained -to the alkaline aqueous solution or suspension - of the amidoxime. The order of the addition of the reactants can be reversed also in this case.
The process b) of the invention can be effected also in dry solvents, preferably in dry alcohols. In this case an alkali metal salt of the amid-oxime is prepared, preferably by dissolving the amidoxime in the alcohol solution of an alkali alcoholate. After the addition of the epichlorohydrine ~(3775~6 the reaction mixture is allowed to stand at 0 to 20C for one to five daysJ
whereupon the suitable amine is added and the reaction is conducted at room temperature or under heating the reaction mixture. As dry solvents besides the alcohols also other organic solvents, Eor example acetone, dimethyl sulfoxide, dimethyl formamide etc. or the mixtures thereof can be employed.
When carrying out process c) as alkali metal salts of the amidoximes of the general formula II preferably sodium salts are used, and the reaction is preferably accomplished in alcanols. The hydro]ysis of the intermediates of the general formula VII is preferably carried out with acids. The com-pounds of the general VI can be prepared by applying the procedures desrribed in the DT OS-2 018 2G3.
The products of the general formula I can be separated and purified according to conventional procedures, such as for example by crystallisation or extraction when an aqueous medium is used. If an organic solvent is employed, the product is crystallized or the solvent is evaporated and the product is subsequently washed with water and dried. The products can be separated also in form of the salts thereof, or salts can be formed from the l bases separated by treating with one or two equivalents of a mineral acid or - organic acid, preferably with pharmaceutically acceptable, non-toxical acids.
l 20 Also the free bases can be deliberated from the salts obtained.
., ~~ The compounds of the general formula I have been evaluated as . ~
general ~-blockers by assay using trachearing preparates IJ. Pharmacol. Exp.

, Therap., 90, 104 ~1974)~ and papillary muscles of cats.

The assays of selective ~-blocking activity on rat aorta-spiral ;
preparates were carried out in the following way:

The thorax of the animal was opened and the thoranic aorta taken out and cut , spirally. The motions of the straightened spiral were recorded with an ~-~;. isotonic recorder on two sooted cylinders. On the first cylinder the reactions of the control and on the second one the reactions of the rat-aorta treated ~j with Streptosoticine ~2-~3-nitroso-3-methyl-ureido)-2-desoxi-D-glucose] were . .
- 30 recorded. The reaction was positive when the dose-ef:Eect curve of the noradrenaline was not influenced by the tested compound on the control pre-parate, while on the diabetic aorta the effect was inhibited. The compounds _ 9 _ ~ 77~06 of the present invention generally showed a selective acti~ity, which meant a strong ~-blocking effect on diabetic aortas and no or slight effect on normal tests. Some of the tested compounds showed ~-blocking activity on normal aortas.
Testing the product of the Example 2 I- (3-piperidino-2-hydroxy-1-propyl)-3,4-dimethoxyphenylacetamidoxime dihydrochloride] the following results were obtained:
The pD2-values (minus logarithm of the dosis corresponding to half of the maximum effectivity) were evaluated. The average of five subsequent tests calculated from the difference of the pD2-values on diabetic aorta-spiral was x = 1.31. The corresponding value on normal spiral was x = 0.52.
On guinea pig trachea 10 ~ of the tested substance decreased the effect of ; 0.01 ~ /ml. isoprenaline ~D,L-1-~3,~-dihydroxyphenyl)-2-isopropylamino-ethanol] to half of its original level. On a rat uterus pretreated with Streptosotocine the tested compound had no effect when employed in a concen-tration of 100 ~ /ml. In a concentration of 50 ~/ml. the tested compound set ; .
in motion the uterus preparate of the untreated rat, which was stopped by noradrenaline. This effect is identical with the effect of 0.5~ug/ml inderale -~ Il-isopropylamino-3-~1-naphthyloxy)-propane-2-ol]. On isolated strips of rat gastric fundus treated with Streptosotocine the tested compound showed no effect in a concentration of 10 ~/ml., in contrary to 0.01 ~/ml. of iso-prenaline, where a relaxation of 25 mm. was observed. On isolated strips of ` rat gastric fundus which has not been pretreated even 100 ~ /ml. concentration of the test compound had no effect on the dose - effect curve of the isopren-aline~ which means that it showed a strong ~-blocking effect on diabetic samples and a slight effect on normal tests.
,'.1 ~; The hypoxia survival time was extended with one order of magnitude ~ by the test compound.
`~ 30 The isoprenaline induced tachycardia was also slightly influenced by the tested compound. 5 minutes after the administration of a 10 mg./kg. i.v.
dose the heart frequency increased by 10%, and 5 minutes after the administra-tion of a 100 mg./kg. i.v. dose it decreased by 3%.

, ~L~77~iO~
:; ~

The tests carried out on the product of the Example 5 [0-(3-piperi--dino-2-hydroxy-l-propyl)-nicotamidoxime dihydrochloride] supplied the follow-ing results:
The mean-value calculated from the differences of the pD2-values on diabetic aorta-spiral was x = 1.25. The corresponding value in ~he control test was x = 0.57. The test compound used in a concentration of 50 ~/ml.
decreased the effect of 0.001 ~ /ml. isoprenaline from 16 mm. to 5 mm. When employed in a concentration of 100 ~/ml., it entirely compensated the effect of 0.001-~/ml. isoprenaline, and decreased the effect of 0.01 ~ /ml. iso-prenaline from 28 mm. to 19 mm.
Tests were carried out to determine whether the noradrenaline in-duced contractions on the aorta-spiral preparates of diabetic animals treated with Streptosotocine and untreated~ respectively could be compensated with , i.nderable. For control those animals were chosen, in which no receptor transformation took place. In case of the animals treated with Streptosotocine ~ the mean difference between the pD2-values ~before and after the administra-`; tion of inderale~ of the dose - effect curves of the noradrenaline were as follows: x = 1.0335; Sx = 0.0829; t = 3.5g85; p ~ 0.01; n = 8. On non-diabetic preparates the inderale had no effect on the noradrenaline induced contractions.
x Tests were carried out to evaluate if one can find a compound among ' the compounds structurally close to the ~-blockers which has an effect on the aorta-spiral of a diabetic animal similar to that of the inderale without exerting any substantial influence on the normal ~-reactions. In other words . ,:, . .
`~ a compound having a specific effect on the modified ~-effect appearing in .~0 diabetic vessels was searched for. In the following test the compounds of the . :1 i invention tested are as follows:
~, NP-18: 0-(3-piperidino-2-hydroxy-1-propyl)-3,4-dimethylphenyl-acetamidoxime dihydrochloride NP-51: 0-(3-piperidino-2-hydroxy-1-propyl)-nicotamidoxime dihydrochloride.
On the aorta-spiral of animals treated with Streptosotocine the difference between the pD2-values before and after administrating a 1 /ug./ml. dose of ~775~)6 , "NP-18" was: x = 0.6422; Sx = 0.129; t = ~.9783; p ~ 0.01; n = 6.
We found that if the initial receptor transformations are inhibited by adding compounds "NP-18" or "NP-51", the final histological changes do not occur. About 60% of the rats belonging to the CFY strain used during the tests were in a latent diabetic state which was detected in sugar-loading tests. On one part of these animals (weight = ~ to 500 g,~ diabetic macro-and microanthiopathy was detected. At the animals which were treated with the compounds "NP-18" or "NP-51" at weight of 200 g. the microanthiopathy did not developed till they reached the weight of 500 g, and the degree of the macroanthiopathy was also considerably smaller.
It was also found that although "NP-18" and "NP-51" inhibited the effect of isoprenaline on guinea pig trachea, they exerted an effect smaller ~
with ~ order of magnitude than inderale. These compounds did not show any -?
significant effect on the blood pressure, heart frequency, minute volume and dp./dt. value of anesthesized cats. They did not influence the effect of .j isoprenaline in respect of the above parameters and caused bradychardia and dp./dt. decrease only in dose of 1001ug.1kg. The effect was similar to ~- that of 0.5~ug./kg. inderale dose. -"J, The difference between the ~-blocking activity of the new compounds of the general formula I and the inderale on cat papillary muscle was also four order of magnitude. They exerted an influence in guinea pig ileum on the effect of barium chloride and acetylcoline only in a dose of 50 to 100~ug./ml.
' Neither the compound "NP-18" nor the compound "NP-51" had any influence on the hanging of mice on a rotating rod.
~, 50 NP-18: 165 mg./kg. i.v. mouse NP-51: 123 mg./kg. i.v. mouse The compounds of the general formula I and their pharmaceutically acceptable salts find their application in the therapy in form of pharma-ceutical preparates, in which the active ingredient is accompanied by the conventional pharmaceutical carriers. The preparations can be in form of tablets, dragèe~ injection, capsule, etc.
; Further details of the invention are to be found in the following ' :

non-limiting Examples:
Example 1 2.3 g. of sodium are dissolved in 200 ml. of abs. ethanol and 13.6 g. of benzamidoxime are added. The solution of 3-piperidino-2-hydroxy-1-chloro-propane in 50 ml. of abs. ethanol - prepared from 9.3 g. of epichloro-hydrine and 8.5 g. of piperidine in a manner known ;per se - is then added dropwise at the boiling temperature of the mixture. The reaction mixture is refluxed for eight hours, filtered, and the solvent is evaporated in vacuo.
To the residue 100 ml. of 5% sodium hydroxide solution are added, and the oily product is extracted with benzene. Upon evaporating the benzene extract 9.2 g. of 0-(3-piperidino-2-hydroxy-1-propyl)-benzamidoxime are obtained, melting at 97C (from diisopropyl ether).
Molar weight: 277.35 Elementary analysis:
Calculated: C = 64.95%; H = 8.36%; N = 15.15%;
Found: C = 64.69%; H = 8.46% N = 14.87%.
The dihydrochloride salt of the product is precipitated from iso-propanol solution by introducing hydrochloric acid gas or adding the alcohol solution of hydrochloric acid. Melting point: 212 to 214C (isopropanol).
Molar weight: 350.29 Elementary analysis for C15H25N302C12:
Calculated: Cl = 20.24%;
Found: Cl = 19.90%.
LD50 = 70 5 mg./kg. i.v. on mice.
The nicotinic acid salt of the product obtained is prepared in abs.
ethano] solution by adding benzine, when ~he salt crystallizes. Melting point: 112C (from methyl ethyl ketone).
Molar weight: 400.46 Elementary analysis for C21H28N404:
Calculated: C = 62.98%; H = 7.05%; N = 14.00%;

Found: C - 62.84%; H = 7.11%; N = 13.76%.
The dihydrochloride salt showed a slight ~-blocking activity on ~L~977506 normal objects and a strong ~-blocking activity on diabetic te~ts which were carried out as described in the introductory part of the specification.
LD50 = 70 5 mg./kg. i.v. on mice.
Example 2 Following the procedure described in Example 1 but starting from ~;

3,4-dimethoxy-phenyl-acetamidoxime and 3-piperidino-2-hydroxy-1-chloro-propane, 0-~3-piperidino-2-hydroxy-1-propyl)-3,4-dimethoxyphenyl-acetamidoxime dihydrochloride is prepared. Melting point; 202 to 203C ~from abs.
ethanol). Molar weight: 424.38 Elementary analysis for C18H31N3O4C1 Calculated: C = 50.94%; H = 7.36%; N = 9.90%; Cl = 16.71%;
Found: C = 50.80% H = 7.57%; N = 9.84%; Cl = 16.42%.
. LD50 = 165 mg./kg. i.v. ~on mice) On trachea-spiral and papillary muscle a slight ~-blocking activity can be .,( ` ~
observed. The effect on papillary muscle at a temperature of 100/ug./ml. is identical with the effect caused by 0.05~ug./ml. of inderale. On the gastric ` fundus in a concentration of 100 ~g./ml. the compound does not have any ; influence on the activity of isoprenaline. At the aorta spiral of a diabetic animal, however, an inhibition of one order of magnitude had been observed.

~1 20 Example 3 Following the procedure described in Example 1 but starting from 3,4-dimethoxyphenyl-acetamidoxime and 3-~1,2,3,4-tetrahydro-2-isoquinolyl)-2-hydroxyl-l-chloro-propane 0-~3-~1,2,3,4-tetrahydro-2-isoquinolyl)-2-hydroxy-( l-propyl~-3,4-dimethoxyphenyl-acetamidoxime dihydrochloride is prepared.

; Melting point: 189C ~from isopropanol). Molar weight: 472.40 ;Elementary analysis for C22H31N304C12:

Calculated: C = 55.93%; H = 6.61%; N = 8.89%; Cl = 15.01%; `

; Found: C = 55.89%; H = 6.82%; N = 8.64%; Cl = 14.75%.

Example 4 Following the procedure described in Example 1 but starting from 3,3-diphenyl-propionamidoxime and 3-piperidino-2-hydroxy~l-chloro-propane 0-~3-piperidino-2-hydroxy-1-propyl)-3,3-diphenyl-propionamidoxime dihydro-~L~7756~6 ~:`

chloride is obtained. Melting point: 228 to 230C ~from isopropanol).
Elementary analysis for C23H33N302C12:
Calculated: C = 60.79%; H = 7.32%; M = 9.25%; Cl = 15.60%;
Found: C = 60.45%; H = 7.25%; N = 8.94%; Cl = 15.79%;
Example 5 Following the procedure described in Example 1 but starting from nicot mamidoxime and 3-piperidino-2-hydroxy-1-chloro-propane 0-~3-piperidino-2-hydroxy-1-propyl)-nicotinamidoxime dihydrochloricle is prepared. Melting point: 204C (from abs. ethanol). Molar weight: 351.27 Elementary analysis for C14H24N402C12:
Calculated: C = 47.87%; H = 6.89%; N = 15.95%; Cl = 20.19%;
Found: C = 47.59%; H = 7.00%; N = 15.64%; Cl = 19.89%.
LD50 = 123 mg./kg. i.v. ~on mice). The product of this Example showed a slight ~-blocking activity on normal test.
The nicotinic acid salt of the product is precipitated from ethyl acetate. Melting point: 111C ~from ethyl acetate). Molar weight: 401.46 Elementary analysis for C20H27N504:
Calculated: C - 59.83%; H = 6.77%; N = 17.44%;
Found: C = 59.80%; H = 6.92%; N = 17.23%. ~
., 20 LD50 = 250 mg./kg. i.v. ~on mice). The product shows a strong ~-blocking ~;
activity on a diabetic aorta spiral. ~;
Example 6 To 17.8 g. of 3-piperidino-2-hydroxy-1-chloro-propane the solution of 10.45 g. of 3,4-dimethoxyphenyl-acetamidoxime in 40 ml. of 10% sodium ~; hydroxide - prepared with heating - is added, at room temperature, under stir ring, dropwise in half an hour. The reaction mixture is stirred at room temperature for eight hours and allowed to stand overnight. The oily product obtained is extracted with benzene, the extract is dried over sodium sulfate and the solvent is evaporated. From the ethyl acetate solution of the remain-ing 10.5 g. of 0-~3-piperidino-2-hydroxy-1-propyl)-3,4-dimethoxyphenyl-acetamidoxime dihydrochloride crystallizes upon introducing hydrochloric acid gas. The product is identical with the product of the Example 2. Melting ~L0775~6 point: 201 to 203C.
Example 7 To the benzene solution of 8.8 g. of 3-piperidino-2-hydroxy-1-chloro-propane the solution of 5.2 g. of 3,4-dimethoxyphenyl-acetamidoxime in 40 ml. of 10% sodium hydroxide solution - prepared under heating - is added at room temperature, under stirring, dropwise, in half an hour. The reaction mixture is stirred at room temperature for further eight hours and allowed to stand overnight. The benzene phase is separated and the aqueous phase extracted with benzene. The benzene solution is dried over sodium sul-fate and the solvent is evaporated. From the residue using the method set forth in Example 6 for preparation of the hydrochloric acid salt, 0-~3-piperidino-2-hydroxy-l-propyl)-3~4-dimethoxyphenyl-acetamidoxime dihydro- -chlo~ide salt is obtained. The compound is identical with the product of the Example 2.
Example 8 To 8.8 g. of 3-piperidino-2-hydroxy-l-chloropropane the solution of 5.2 g. of 3,4-dimethoxyphenyl-acetamidoxime in 40 ml. of 10% sodium hydroxide solution and 40 ml. methanol is added under stirring, dropwise for half an hour, the mixture is stirred at room temperature for subsequent eight hours and allowed to stand overnight. After evaporating the methanol the extraction with benzene and the salt forming reaction is carried out as described in Example 7. 0-(3-piperidino-2-hydroxyl-1-propyl)-3,4-dimethoxy-phenyl-acetamidoxime dihydrochloride is obtained which is identical with the product of the Example 2.
Example 9 ~.
To 2.72 g. of benzamidoxime 40 ml. of benzene and 0.8 g. of powdered sodium hydroxide are added. The reaction mixture is boiled for one hour under water separator and 4.5 g. of 3-piperidino-2-hydroxy-1-chloro-propane in 10 ml. of benzene are added to the boiling mixture dropwise. After boiling for 12 hours the solvent is evaporated and 20 ml. of 10% sodium hydroxide solu-tion are added to the residue. The oily substance obtained is extracted with benzene and the benzene solution is evaporated. 3.6 g. of 0-(3-piperidino-`~

o77506 , , 2-hydroxy-1-propyl)-benzamidoxime are obtained. The compound is identical : with the product o~ the Example 1.
Example 10 To a sodium ethyla~e solution prepared from 2.3 g. of sodium and 200 ml. of abs. ethanol 15.5 g. of 4-chloro-benzamidoxime are added and subse-quently 9.3 g. of epichlorohydrine are added dropwise at 0 to ~10C. The reaction mixture is stirred at 0 to ~10C for eight hours and allowed to ~, stand overnight at this temperature. The sodium chloride precipitated isfiltered off, to the filtrate 8.6 g. of piperidine are added under stirring dropwise and the mixture is stirred for subsequent eight hours at room tem-perature. The reaction mixture is heated to boiling point and the solvent is evaporated in vacuo. 50 ml. of 5% sodium hydroxide solution is added to the residue and the oily substance is extracted with benzene. The benzene solution is dried over sodium sulfate, evaporated and the residue dissolved in alcohol. Upon introducing hydrochloric acid gas or adding hydrochloric -acid in alcohol 11.0 g. of 0-~3-piperidino-2-hydroxy-1-propyl)-4-chloro-benzamidoxime dihydrochloride are obtained. Melting point: 215 to 217C ;
(from abs. ethanol). Molar weight: 384.73 Elementary analysis for C15H24N302C13:
Calculated: C = 46~83%; H = 6.29%; N = 10.92%;
Found: C = 46.57%; H = 6.41%; N = 10.58%.
The product shows a slight ~ blocking activity on normal test and a strong ~-blocking activity on diabetic test. `
Example 11 ~-Following the procedure described in Example 10 but starting from " !
phenylacetamidoxime using diethyl amine as amine component 0-(3-diethylamino-2-hydroxy-1-propyl)-phenylacetamidoxime dihydrochloride is prepared. Melting point: 156 to 158C ~from isopropanol).
~olar weight: 352.30 Elementary analysis for C15H27N302C12:
Calculated: C = 51.14%; H = 7.73%; N = 11.93%; Cl = 20.12%;
Found: C = 50.89%; H - 7.65%; N = 11.83%' Cl = 20.10%.

~ ~977506 Example 12 Following the procedure described in Example 10 but starting from phenylacetamidoxime and using piperidine as amine component 0-(3-piperidino-2-hydroxy-1-propyl)-phenylacetamidoxime dihydrochloride is obtained. Melting point: 198 to 200C ~from abs. ethanol).
Molar weight: 364.31 Elementary analysis for C16H27N302C12:
Calculated: C = 52.75%; H = 7.47%; N = 11.54%; Cl = 19.47%;
Found: C = 52.40%; H = 7.51%; N = 11.20%; Cl = 19.85%.
Example 13 Following the procedure described in Example 10 but starting from

4-chlorophenyl-acetamidoxime and using morpholine as amine component 0-(3-morpholino-2-hydroxy-1-propyl)-4-chlorophenyl-acetamidoxime dihydrochloride is obtained. Melting point: 175 to 178C (from abs. ethanol).
Molar weight: 400.73 Elementary analysis for Cl5H24N303C13:
Calculated: C = 44.96%; H = 6.04%; N = 10.48%; Cl = 26.54%;
Found: C = 45.20%; H = 6.10%; N = 10.52%; Cl = 26.50%.
Example 14 Following the procedure described in Example 10 but starting from 3,3-diphenyl-propionamidoxime and using isopropylamine as amine component 0-~3-isopropylamino-2-hydroxy-1-propyl)-3,3-diphenyl-propionamidoxime dihydro-chloride is prepared. Melting point: 179C (from acetone/water mixture).
Molar weight: 428.39 Element~ary analysis for C21H31N302C12:
Calculated: C = 58.87%; H = 7.29%; N = 9.81%; Cl = 16.55%;
Found; C = 58.58%; H = 7.39%; N = 9.53%; Cl = 16.70%.
LD50 = 16.25 mg./kg. i.v. ~on mice). The compound possesses a strong ~ -blocking effect on diabetic aorta spiral.
Example 15 Following the procedure described in Example 10 but starting from 3,3-diphenyl-propionamidoxime and using diethylamine as amine component 0-(3-3~ 775~6 , :

diethylamino-2-hydroxy-1-propyl)-3~3-diphenyl-propionamidoxime dihydrochloride is prepared. Melting point: 225C ~from isopropanol). Molar weight: 442.42 Elementary analysis for C22H33N302C12:
Calculated: C = 59.72%; H = 7.52%; Cl = 16.03%;
Found: C = 59.68%; H = 7.55%; Cl = 16.07%.
Example 16 Following the procedure described in Example 10 but starting from 3,3-diphenyl-propionamidoxime and using 2-methylamino-ethanol as amine com-ponent 0-I3-N-methyl-N-~2-hydroxy-ethyl)-amino-2-hydroxy-1-propyl~-3,3- -~
diphenyl-propionamidoxime dihydrochloride is prepared. Melting point: 175C
~from isopropanol). Molar weight: ~44.39 Elementary analysis for C21H31N303C12:
Calculated: C = 56.78%; ~1 = 7.03%; N = 9.45%; Cl = 15.96%;
Found: C = 56.40%; H = 7.09%; N = 9.14%; Cl = 15.92%.
W 50 = 37 mg./kg. i.v. (on mice~. The compound shows a strong ~-blocking activity on diabetic aorta spiral.
Example 17 Following the procedure described in Example 10 but starting from 3,3-diphenyl-propionamidoxime and using pyrrolidine as amine component 0-~3-pyrrolidino-2-hydroxy-1-propyl)-3,3-diphenyl-propionamidoxime dihydrochloride is obtained. Melting point: 218C ~from isopropanol). Molar weight: 440.40 Elementary analysis for C22H31N302C12:

Calculated: C = 59.99%; H = 7.10%; Cl = 16.10%;
Found: C = 59.63%; H = 7.32%; Cl = 16.44%.
Example 18 Following the procedure described in Example 10 but starting from 3,3-diphenyl-propionamidoxime and using piperidine as amine component 0-~3-piperidino-2-hydroxy-1-propyl)-3,3-diphenyl-propionamidoxime dihydrochloride is prepared. The compound is identical with the product of the Example 4.
Melting point: 228 to 230C ~from isopropanol).
Example 19 Following the procedure described in Example 10 but starting from ~3775~
:
3,3-diphenyl-propionamidoxime and using heptamethylene lmlne as amine com-ponent 0-~3-heptamethyleneamino-2-hydroxy-1-propyll-3,3-diphenyl-propion-amidoxime dihydrochloride is prepared. Melting point: 233C ~from isopropan-ol).
Molar weight: ~82.48 Elementary analysis:
Calculated: C = 62.2~%; H = 7.73%; Cl = 14.70%;
Found:C = 61.97%; H = 7.70%; Cl = 14.74%.
Example 20 ; 10 Following the procedure described in Example 10 but starting from 3~3-diphenyl-propionamidoxime and using morpholine as amine component 0-~3-morpholino-2-hydroxy-1-propyl)-3,3-diphenyl-propionamidoxime dihydrochloride is prepared. Melting point: 225C ~from isopropanol).
Molar weight: 456.40 Elementary analysis for C22H31N303C12:
Calculated: C = 57.89%; H = 6.85%; N = 9.20%; Cl = 15.53%;
Found: C = 57.66%; H = 7.13%; N = 8.95%; Cl = 15.15%.
Example 21 Following the procedure described in Example 10 but starting from ; 20 l-naphthyl-acetamidoxime and using diethyl amine as amine component 0-~3-diethylamino-2-hydroxy-1-propyl~-1-naphthyl-acetamidoxime hydrochloride is prepared. Melting point: 150 to 152C (from abs. ethanol).
Molar weight: 365.89 Elementary analysis for ClgH28N302Cl:
Calculated: C = 62.36%; H = 7.71%; N = 11.49%; Cl = 9.69%;
Found: C = 62.07%; H = 8.00%; N = 11.29%; Cl = 9.63%.
Example 22 ~' Following the procedure described in Example 10 but starting from -l-naphthyl-acetamidoxime and using piperidine as amine component 0-~3-piperi-dino-2-hydroxy-1-propyl)-1-naphthyl-acetamidoxime hydrochloride is prepared.

Melting point: 177 to 179C (from abs. ethanol~.

Molar weight: 377.89 Elementary analysis for C20H28N302Cl:
Calculated: C - 63.57%; H _ 7.46%; N = 11.12%; Cl = 9.38%;
Found: C = 63.58%; H = 7.59%; N = 11.47%; Cl = 9.60%.
Example 23 To the mixture of 4.0 g. of benzamidoxime, 10 ml. of water and 4.5 g. of epichlorohydrine 20 ml of 10% sodium hydroxide solution is added under stirring at room temperature dropwise, for one hour. The reaction mixture is then stirred for further two hours, 4.5 g. of piperidine are added dropwise and stirring is continued for eight subsequent hours. The oily substance is extracted with benzene. Upon evaporating the benzene solution 6.2 g. of 0-(3-piperidino-2-hydroxy-1-propyl)-benzamidoxime are obtained. The compound is identical with the product of the Example 1.
Example 24 ~;
6.8 g. of benzamidoxime are dissolved in 40 ml. of 10% sodium hydroxide solution and 9.5 g. of epichlorohydrine are added under stirring.
The reaction is exotherm, and therefore the temperature of the mixture is kept at 30 to 35C by external cooling. After stirring for two hours 8.6 g. of piperidine are added dropwise. The mixture is stirred for subsequent two hours and the oily substance obtained is extracted with benzene. Upon eva-porating of benzene 8.2 g. of 0-(3-piperidino-2-hydroxy-1-propyl)-benzamid-oxime are obtained. The compound formed is identical with the product of the Example 1. ;
Example 25 6.8 g. of benzamidoxime are dissolved in 40 ml. of 10% sodium hydro-xide solution and 9.5 g. of epichlorohydrine in 2Q ml. of benzene are added under vigorous stirring dropwise. After stirring for four hours 8.6 g. of piperidine are added dropwise and the mixture is stirred at room temperature for subsequent eight hours. The benzene phase is separated, the aqueous - layer is extracted with benzene. Upon evaporating the combined benzenesolutions 0-(3-piperidino-2-hydroxy-1-propyl~-benzamidoxime is obtained.
This compound is identical with the product of the Example 1.
,. .

~77~

Example 26 6.8 g. of benzamidoxime are dissolved in the mixture of 20 ml. of 10% sodium hydroxide solvent and 20 ml. of methanol, and 9.5 g. of epichloro-hydrine are added under stirring, dropwise. After stirring for two hours at room temperature 8.6 g. of piperidine are added dropwise and the stirring is continued for eight subsequent hours. The methanol is evaporated in vacuo and the oily substance is extracted with benzene. Upon evaporating the ben-zene solution 7.2 g. of 0-(3-piperidino-2-hydroxy-1-propyl)-benzamidoxime are obtained. This compound is identical with the product of the Example 1.
10Exam~le 27 To the solution of 5.2 g of 3,4-dimethoxyphenyl-acetamidoxime in 20 ml. of dimethyl sulfoxide 2.4 g. of sodium tert.buthylate are added under stirring. 3.0 g. of epichlorohydrine are then added dropwise, the mixture is stirred at room temperature for two hours. Thereafter, the solution of 2.5 g. of piperidine in 60 ml. of acetone is added and the reaction mixture is refluxed for eight hours, whereupon 120 ml. of ethyl acetate are added.
Upon introducing hydrochloric acid gas 4.4 g. of 0-(3-piperidino-2-hydroxy-l-propyl)-3,4-dimethoxyphenyl-acetamidoxime dihydrochloride are obtained in crystalline form. This salt is identical with the product of the Example 2.
20Example 28 Following the procedure of the Example 6 but starting from 2-phenyl-propionamidoxime and 3-piperidino-2-hydroxy-1-chloro-propane 0-~3-piperidino-2-hydroxy-1-propyl)-2-phenyl-propionamidoxime dihydrochloride are obtained.
Melting point: 225C (from isopropanol).
Elementary analysis:
Calculated: C = 53.96%; H = 7.73%; N = 11.11%, Cl = 18.74%;
Found: C = 54.27%; H = 8.00%; N = 10.86%; Cl = 18.45%.
Example 29 Following the procedure described in Example 6 bu~ starting from 3-cyclohexylamino-2-hydroxy-1-chloro-propane (J. Org. Chem. 24, 615 ~1959]) and nicotinamidoxime 0-~3-cyclohexylamino-2-hydroxy-1-propyl)-nicotinamidoxime is prepared. Melting point: 102C (from the mixture of benzene and toluene).

77S~
,, Molar weight: 292.37 Elementary analysis or C15H2~N402:
Calculated: C = 61.62%; H = 8.27%; N = 19.16%;
Found: C = 61.44%; H = 8.23%; N = 1~.89%.
Example 30 ~ ;
1.38 g. of racemic 0-(3-piperidino-2-hydroxy-1-propyl~-benzamid-oxime and 1.16 g. of d-camphorsulfonic acid are dissolved in 20 ml. of hot ethanol and the solution is evaporated in vacuo. The residue is recrystal-lized first from butyl acetate and then from ethyl acetate. 0.4 g. of d- ;~
; 10 0-(3-piperidino-2-hydroxy-1-propyl~-benzamidoxime d-camphorsulfonate are obtained. Melting point: 132C.
From the salt obtained the base is deliberated by a conventional technique and the base obtained is transformed into a hydrochloric acid salt. The melting point of the hydrochloric acid salt is: 196C.
[~]559nm = ~6-3 ~c = 1% water).
Example 31 ; 1.15 g. sodium metal are dissolved in 100 ml. of abs. ethanol and 12.0 g. of 3,3-diphenyl-propionamidoxime are added. While boiling, there are added 13.2 g. of 2-phenyl-3-isopropyl-5-chloromethyl-oxazolidine drop-wise and the reaction mixture is boiled for subsequent 16 hours. The solvent is evaporated, 110 ml. of 5 n hydrochloric acid solution are added to the residue and it is refluxed for one hour. The solution is extracted with ethyl acetate, decoloured with animal charcoal and adjusted to alkaline with 10% sodium hydroxide solution. The oily product is extracted with ethyl .: . :
acetate, the extract is dried over dry sodium sulfate, and finally the sol-vent is evaporated. The residue is dissolved in acetone and the solution of hydrochloric acid in acetone is added. 7.0 g. of 0-(3-isopropylamino-2-hydroxy-l propyl)-3,3-diphenylpropionamidoxime dihydrochloride are obtained.
This compound is identical with the product of the Example 14. Melting point: 179C.
Example 32 ~ Following the procedure of the Example 31 but starting from 2-'~`

~C~77S~;9 E;

phenyl-propionamidoxime and 2-phenyl-3-isopropyl-5-chloromethyl-oxazolidine 0-(3-isopropylamino-2-hydroxy -1 -propyl)-2-phenyl-propionamidoxime dihydro-chloride hemihydrate is obtained. Melting point: 168C ~from the mixture of acetone and isopropanol).
Molar weight; 361.31 Elementary analysis for C15H27N302C12. 0.5 H20:
Calculated: C = 49.86%; H = 7.81%; N = 11.63%; Cl = 19.63%;
Found: C = 49.79%; H = 7.57%; N = 11.61%; Cl = 19.50%.
Example 33 Following the procedure described in the Example 31 but starting from benzamidoxime and 2-phenyl-3-isopropyl-5-chloromethyl-oxazolidine 0-~3-isopropylamino-2-hydroxy-1-propyl~-benzamidoxime dihydrochloride hemihydrate is prepared.
Melting point: 173 to 17~C.
Molar weight: 333.26 Elementary analysis for C13H23N302C12 0 5 H20 Calculated: C = 46.85%; H = 7.26%; N = 12.61%; Cl = 21.28%;
Found: C = 47.05%; ll = 7.13%; N = 1~.41%; Cl = 21.54%.

. ,.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the general formula I or a pharmaceutically acceptable salt thereof (I) wherein R2 is hydrogen or alkyl having one to five carbon atoms; R3 is alkyl having one to five carbon atoms, cycloalkyl or phenyl optionally sub-stituted with hydroxyl or phenyl; or R2 and R3 together with the nitrogen atom to which they are attached form a five- to eight-membered ring option-ally containing oxygen as an additional heteroatom, which ring may be fused with another ring; R4 is hydrogen or a cycloalkyl, aromatic or quinolyl, isoquinolyl, pyridyl or pyrazolyl group, optionally substituted with one or more halogens, alkoxy ar alkyl, which ring may be fused with another ring, R5 is hydrogen or alkyl having one to four carbon atoms, cycloalkyl or phenyl optionally substituted with halogen, alkoxy having one to four car-bon atoms or alkyl having one to four carbon atoms; R6 is hydrogen, alkyl having one to four carbon atoms or phenyl;
m = 0, 1 or 2 n = 0, 1 or 2, which comprises a) reacting an amidoxime of the general formula II

II

wherein R4, R5, R6, n and m are as defined above with an amine of the general formula IIIA or IIIB

(IIIA) (IIIB) wherein R2 and R3 are as defined above, and X is halogen, in the presence of a base; or b) reacting an amidoxime of the general formula II defined above with epichlorohydrin, and reacting the amidoxime of the general formula V

(V) initially obtained, after or without separation, with an amine of the general formula IV

(IV) wherein R2 and R3 are as defined above; or c) reacting an alkali metal salt of a compound of the general formula II defined above with a 2-phenyl-3-substituted-5-chloromethyl-oxazolidine of the general formula VI

(VI) wherein R has the same meaning as given for R2 and R3 except hydrogen, and subsequently hydrolysing a compound of the general formula VII

(VII) without solution; said steps a), b) or c) being optionally followed by trans-forming a compound of general formula I initially obtained into a pharma-ceutically acceptable salt thereof with a suitable organic or inorganic acid or liberating a free base from the salt initially obtained.

2. A process according to claim 1 wherein R2 and R3 together with the nitrogen to which they are attached, form piperidino group and R4 is phenyl or pyridyl substituted with one or two alkoxy having one to four carbon atoms.

3. A process according to claim 1 wherein said process a), b) or c) is performed in a solvent which is water or an organic solvent or a mixture of water and an organic solvent.

4. A process according to claim 1, 2 or 3 wherein said process a), b) or c) is performed at a temperature of -10°C to +140°C.

5. A process for the preparation of a compound of formula II as defined in claim 1 which comprises: a) reacting an amidoxime of the general formula II

(II) wherein R4, R5, R6, n and m are as defined in claim 1, with an amine of the general formula IIIA or IIIB

(IIIA) (IIIB) wherein R2 and R3 are as defined in claim 1, and X is halogen, in the pre-sence of a base; or b) reacting an amidoxime of the general formula II de-fined above wthh epichlorohydrin, and reacting the amidoxime of the general formula V

(V) initially obtained, after or without separation, with an amine of the general formula IV

(IV) wherein R2 and R3 are as defined in claim 1; said steps a) or b) being optionally followed by transforming the compound of formula I initially obtained into a pharmaceutically acceptable salt thereof with a suitable organic or inorganic acid or liberating a free base from the salt initially obtained.

6. A process according to claim 5 wherein said process a) or b) is performed in water or an organic solvent or a mixture of water and an organic solvent .

7. A process according to claim 5 or 6 wherein said process a) or b) is performed at a temperature of -10°C and +140°C.

8. A process according to claim 1, 2 or 3 wherein R4 is a phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl or pyrazolyl group.

9. Compounds of formula I as defined in claim 1 and pharmaceuti-cally acceptable salts thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

10. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a piperidine ring, n and m both have the value O and R4 is a phenyl group.

11. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-benzamidoxime and its dihydrochloride and nicotinic acid salts which com-prises reacting benzamidoxime with 3-piperidino-2-hydroxy-1-chloro-propane in the presence of a base and, if the dihydrochloride or nicotinic acid salt is required, reacting the product with hydrogen chloride or nicotinic acid.

12. A process according to claim 11 wherein the reaction is carried out in the presence of sodium and in solution in ethanol.

13. A process according to claim 11 wherein the reaction is carried out in the presence of sodium hydroxide and in benzene.

14. A process for preparing O-(3-piperidine-2-hydroxy-1-propyl)-benzamidoxime which comprises reacting benzamidoxime and epichlorohydrin in the presence of sodium hydroxide and reacting the product obtained with piperidine.

15. O-(3-piperidino-2-hydroxy-1-propyl)- benzamidoxime, its dihydro-chloride or its nicotinic acid salt when prepared by a process according to claim 11 or 14 or an obvious chemical equivalent thereof.

16. A process according to claim 1, 2 or 3, wherein R2 and R to-gether with the nitrogen atom to which they are attached, form a piperidine ring, n is O, m is 1, R5 is hydrogen and R4 is a 3,4-dimethoxyphenyl group.

17. A process for preparing O-(3-piperidono-2-hydroxy-1-propyl)-3,4-dimethoxyphenyl-acetamidoxime and its dihydrochloride salt which comprises reacting 3,4-dimethoxyphenyl-acetamidoxime with 3-piperidono-2-hydroxy-1-chloro-propane in the presence of a base and, if the dihydrochloride salt is required, reacting the product with hydrogen chloride.

18. A process according to claim 17 wherein the reaction is carried out in the presence of sodium and in solution in ethanol.

19. A process according to claim 17 wherein the reaction is carried out in the presence of sodium hydroxide and in solution in water, benzene or methanol.

20. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-3, 4-dimethoxyphenyl-acetamidoxime and its dihydrochloride salt which comprises reacting 3,4 dimethoxyphenyl-acetamidoxime and epichlorohydrin in the pre-sence of sodium tert. butylate and dimethyl sulfoxide, reacting the compound formed with piperidine and, if required, converting the product to the dihy-drochloride salt by reaction with hydrogen chloride.

21. A process according to claim 1, 2 or 3 wherein R2 and R3 to-gether with the nitrogen atom to which they are attached, form a 1,2,3,4-tetrahydro-2-isoquinolyl ring, n is 0, m is 1, R5 is hydrogen and R4 is a 3,4-dimethoxyphenyl group.

22. A process for preparing O-[3-(1,2,3,4-tetrahydro-2-isoquinolyl)-2-hydroxy-1-propyl]-3,4-dimethoxyphenyl-acetamidoxime and its dihydrochloride salt which comprises reacting 3,4-dimethoxyphenyl acetamidoxime with 3-(1,2, 3,4-tetrahydro-2-isoquinolyl)-2-hydroxy-1-chloro-propane in the presence of a base and, if the dihydrochloride salt is required, reacting the product with hydrogen chloride.

23. A process according to claim 22 wherein the reaction is carried out in the presence of sodium and in solution in ethanol.

24. O-[3-(1,2,3,4-tetrahydro-2-isoquinolyl)-2-hydroxy-1-propyl]-3,4-dimethoxyphenyl acetamidoxime and its dihydrochloride salt when prepared by a process according to claim 22 or 23 or an obvious chemical equivalent thereof.

25. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a piperidine ring, n is 1, m is 1, R4 and R5 are both phenyl groups and R6 is hydrogen.

26. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-3,3-diphenyl propionamidoxime and its dihydrochloride salt which comprises react-ing 3,3-diphenyl propionamidoxime with 3-piperidino-2-hydroxy-1-chloro-pro-pane in the presence of a base and, if the dihydrochloride salt is required, reacting the product with hydrogen chloride.

27. A process according to claim 26 wherein the reaction is carried out in the presence of sodium and in solution in ethanol.

28. A process for preparing 0-(3-piperidono-2-hydroxy-1-propyl)-3, 3-diphenyl propionamidoxime and its dihydrochloride salt which comprises reacting 3,3-diphenyl-propionamidoxime and epichlorohydrin in the presence of sodium ethylate in ethanol, reacting the compound formed with piperidine and, if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

29. 0-(3-piperidino-2-hydroxy-1-propyl)-3,3-diphenyl propionami-doxime and its dihydrochloride salt when prepared by a process according to claim 26, 27 or 28, or an obvious chemical equivalent thereof.

30. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a piperidine ring, n and m are both zero and R4 is a pyridyl-3 group.

31. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-nicotinamidoxime and its dihydrochloride or nicotinic acid salt which com-prises reacting nicotinamidoxime with 3-piperidino-2-hydroxy-1-chloro-propane in the presence of a base and, if the dihydrochloride salt is required, reacting the product with hydrogen chloride or with nicotinic acid.

32. A process according to claim 31 wherein the reaction is carried out in the presence of sodium and in solution in ethanol.

33. O-(3-piperidino-2-hydroxy-1-propyl)nicotinamidoximme and its dihy-drochloride or nicotinic acid salt when prepared by a process according to claim 31 or 32 or an obvious chemical equivalent thereof.

34. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a piperidine ring, m and n are both O and R4 is a phenyl group.

35. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-4-chloro-benzamidoxime and its dihydrochloride salt which comprises reacting 4-chloro-benzamidoxime with epichlorohydrin in the presence of sodium ethy-late in ethan, reacting the compound formed with piperidine and, if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

36. O-(3-piperidino-2-hydroxy-1-propyl)-4-chloro-benzaamidoxime and its dihydrochloride salt when prepared by a process according to claim 35 or an obvious chemical equivalent thereof.

37. A process according to claim 1, 2 or 3 wherein R2 and R3 are both ethyl groups, m is 1, n is O, R5 is hydrogen and R4 is a phenyl group.

38. A process for preparing O-(3-diethylamino-2-hydroxy-1-propyl)-phenylacetamidoxime and its dihydrochloride salt which comprises reacting phenylacetamidoxime with epichlorohydrin in the presence of sodium ethylate in ethanol, reacting the compound formed with diethylamine and if required converting the product to the dihydrochloride salt by reaction with hydro-gen chloride.

39. O-(3-diethylamino-2-hydroxy-1-propyl)-phenylacetamidoxime and its dihydrochloride salt when prepared by a process according to claim 38, or an obvious chemical equivalent thereof.

40. A process according to claim 1, 2 or 3, wherein R2 and R3 to-gether with the nitrogen atom to which they are attached form a piperidine ring, m is 1, n is O, R5 is hydrogen and R4 is a phenyl group.

41. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-phenylacetamidoxime and its dihydrochloride salt which comprises reacting phenylacetamidoxime and epichlorohydrin in the presence of sodium ethylate and ethanol, reacting the compound formed with piperidine and, if required, converting the product to the dihydrochloride salt by reaction with hydro-gen chloride.

42 O-(3-piperidino-2-hydroxy-l-propyl)-phenylacetamiddoxime and its dihydrochloride salt when prepared by a process according to claim 41, or an obvious chemical equivalent thereof

43. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a morpholino group, m is 1, n is 0, R5 is hydrogen and R4 is a 4-chlorophenyl group.

44. A process for preparing O-(3-morpholino2-hydroxy-1-propyl)-4-chlorophenylacetamidoxime and its dihydrochloride salt which comprises react-ing 4-chloro-phenylacetamidoxime and epichlorohydrin in the presence of sodium ethylate in ethanol,reacting the compound formed with morpholine and if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

45. O-(3-morpholino-2-hydroxy-1-propyl)-4-chlorophenylacetamidoxime and its dihydrochloride salt when prepared by a process according to claim 44 or an obvious chemical equivalent thereof.

46. A process according to claim 1, 2 or 3 wherein R2 is hydrogen, R3 is isopropyl, n is 1, m is 1, R6 is hydrogen and R4 and R5 are both phenyl.

47. A process for preparing O-(3-isopropylamino-2-hydroxy-1-propyl)-3,3-diphenyl propionamidoxime which comprises reacting 3,3-diphenyl-propion-amidoxime with epichlorohydrin in the presence of sodium ethylate and etha-nol, reacting the compound formed with isopropylamine and, if required, con-verting the product to the dihydrochloride salt by reaction with hydrogen chloride.

48. A process for preparing O-(3-isopropylamino-2-hydroxy-1-propyl)-3,3-diphenyl propionamidoxime and its dihydrochloride salt which comprises reacting the sodium salt of 3,3-diphenyl propionamidoxime with 2-phenyl-3-isopropyl-5-chloromethyl oxazolidine, followed by hydrolysis to give the required product and, if required, reaction with hydrogen chloride to give the dihydrochloride salt.

49. O-(3-isopropylamino-2-hydroxy-1-propyl)-3,3-diphenyl propion-amidoxime and its dihydrochloride salt when prepared by a process according to claim 47 or 48 or an obvious chemical equivalent thereof.

50. A process according to claim 1, 2 or 3, wherein R2 and R3 are both ethyl, n is 1, m is 1, R6 is hydrogen and R4 and R5 are both phenyl.

51. A process for preparing O-(3-diethylamino-2-hydroxy-1-propyl)-3, 3-diphenyl propionamidoxime and its dihydrochloride salt which comprises reacting 3,3-diphenyl propionamidoxime with epichlorohydrin in the presence of sodium ethylate and ethanol, reacting the compound formed with diethyl-amine and, if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

52. O-(3-diethylamino-2-hydroxy-1-propyl)-3,3-diphenyl propionami-doxime and its dihydrochloride salt when prepared by a process according to claim 51 or an obvious chemical equivalent thereof.

53. A process according to claim 1, 2 or 3, wherein R2 is methyl, R3 is 2-hydroxyethyl, n is l J m is 1, R6 is hydrogen and R3 and R4 are both phenyl.

54. A process for preparing O-[3-N-methyl-N-(2-hydroxy-ethyl)-amino-2-hydroxy-1-propyl]-3,3-diphenyl propionamidoxime and its hydrochloride salt which comprises reacting 3,3-diphenylpropionamidoxime with epichlorohydrin in the presence of sodium ethylate and ethanol, reacting the compound formed with 2-methylamino-ethanol and, if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

55. O-[3-N-methyl-N-(2-hydroxy-ethyl)-amino-2-hydroxy-1-propyl]-3, 3-diphenyl propionamidoxime and its hydrochloride salt when prepared by a process according to claim 54 or an obvious chemical equivalent thereof.

56. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a pyrrolidine ring, n is 1, m is 1, R6 is hydrogen and R4 and R5 are both phenyl.

57. A process for preparing O-(3-pyrrolidino-2-hydroxy-1-propyl)-3,3-diphenyl propionamidoxime and its dihydrochloride salt which comprises reacting 3,3-diphenyl propionamidoxime with epichlorohydrin in the presence of sodium ethylate in ethanol reacting the compound formed with pyrrolidine and, if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

58. O-(3-pyrrolidino-2-hydroxy-1-propyl)-3,3-diphenyl propionami-doxime and its dihydrochloride salt when prepared by a process according to claim 57 or an obvious chemical equivalent thereof.

59. A process according to claim 1, 2 or 3 wherein R2 and R3 to-gether with the nitrogen atom to which they are attached, form a heptamethy-leneimino group, n is 1, m is 1, R6 is hydrogen and R4, R5 are both phenyl.

60. A process for preparing O-(3-heptamethyleneimino-2-hydroxy-1-propyl)-3,3-diphenyl propionamidoxime and its dihydrochloride salt which comprises reacting 3,3-diphenyl propionamidoxime with epichlorohydrin in the presence of sodium ethylate and ethanol, reacting the compound formed with heptamethyleneimine and, if required, converting the product to the di-hydrochloride salt by reaction with hydrogen chloride.

61, O-(3-heptamethyleneimino-2-hydroxy-1-propyl)-3,3-diphenyl pro-pionamidoxime and its dihydrochloride salt when prepared by a process accord-ing to claim 60 or an obvious chemical equivalent thereof.

62. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a morpholine ring, n is 1, m is 1, R6 is hydrogen and R4 and R5 are both phenyl.

63. A process for preparing O-(3-morpholino-2-hydroxy-1-propyl)-3, 3-diphenyl propionamidoxime and its dihydrochloride salt which comprises reacting 3,3-diphenyl propionamidoxime with epichlorohydrin in the presence of sodium ethylate and ethanol, reacting the compound formed with morpholine and if required, converting the product to the hydrochloride salt by reac-tion with hydrogen chloride.

64. O-(3-morpholino-2-hydroxy-1-propyl)-3,3-diphenyl propionamidoxime and its dihydrochloride salt when prepared by a process according to claim 63 or an obvious chemical equivalent thereof.

65. A process according to claim l, 2 or 3 wherein R2 and R3 are both ethyl, n is 0, m is 1, R5 is hydrogen and R4 is naphthyl.

66. A process for preparing O-(3-diethylamino-2-hydroxy-1-propyl)-1-naphthyl acetamidoxime and its hydrochloride salt which comprises reacting 1-naphthyl acetamidoxime with epichlorohydrin in the prosence of sodium ethylate in ethanol, reacting the compound formed with diethylamine and if required, converting the product to the hydrochloride salt by reaction with hydrogen chloride.

67. O-(3-diethylamino-2-hydroxy-1-propyl)-1-naphthyl acetamidoxime and its hydrochloride salt when prepared by a process according to claim 66 or an obvious chemical equivalent thereof.

68. A process according to claim 1, 2 or 3 wherein R2 and R3 to-gether with the nitrogen atom to which they are attached, form a piperidine ring, n is 0, m is 1, R5 is hydrogen and R4 is naphthyl.

69. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-1-naphthyl acetamidoxime and its hydrochloride salt which comprises reacting 1-naphthyl acetamidoxime with epichlorohydrin in the presence of sodium ethylate in ethanol, reacting the compound formed with piperidine and, if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

70. O-(3-piperidino-2-hydroxy-1-propyl)-1-naphthyl acetamidoxime and its hydrochloride salt when prepared by a process according to claim 69 or an obvious chemical equivalent thereof.

71. A process according to claim 1, 2 or 3 wherein R2 and R3, to-gether with the nitrogen atom to which they are attached, form a piperidine ring, n is 1, m is 1, R6 is phenyl and R4 and R5 are both hydrogen.

72. A process for preparing O-(3-piperidino-2-hydroxy-1-propyl)-2-phenyl propionamidoxime and its dihydrochloride salt which comprises react-ing 2-phenyl-propionamidoxime and 3-piperidino-2-hydroxy-1-chloro-propane in the presence of sodium hydroxide and, if required, converting the product to the dihydrochloride salt by reaction with hydrogen chloride.

73. O-(3-piperidino-2-hydroxy-1-propyl)-2-phenyl propionamidoxime and its dihydrochloride salt when prepared by a process according to claim 72 or an obvious chemical equivalent thereof.

74. A process according to claim 1, 2 or 3 wherein R2 is hydrogen, R3 is cyclohexyl, n and m are both 0 and R4 is 3-pyridyl.

75. A process for preparing O-(3-cyclohexylamino-2-hydroxy-1-propyl)-nicotinamidoxime which comprises reacting nicotinamidoxime and 3-cyclohexyl amino-2-hydroxy-1-chloro-propane in the presence of sodium hydroxide.

76. O-(3-cyclohexylamino-2-hydroxy-1-propyl)-nicotinamidoxime when prepared by a process according to claim 75 or an obvious chemical equivalent thereof.

77. A process according to claim 1, 2 or 3 wherein R2 is hydrogen, R3 is isopropyl, n is 1, m is 1, R6 is phenyl and R4 and R5 are both hydrogen.

78. A process for preparing O-(3-isopropylamino-2-hydroxy-1-propyl)-2-phenyl-propionamidoxime and its dihydrochloride hemihydrate salt which com-prises reacting the sodium salt of 2-phenyl propionamidoxime with 2-phenyl-3-isopropyl-5-chloromethyl-oxazolidine followed by hydrolysis to give the re-quired product and, if required, reaction with hydrogen chloride to give the dihydrochloride hemihydrate salt.

79. O-(3-isopropylamino-2-hydroxy-1-propy})-2-phenyl-ppropionamidoxime and its dihydrochloride hemihydrate salt when prepared by a process according to claim 78 or an obvious chemical equivalent thereof.

80. A process according to claim 1, 2 or 3 wherein R2 is hydrogen, R3 is isopropyl, n and m are both O and R4 is phenyl

81. A process for preparing O-(3-isopropylamino-2-hydroxy-1-propyl) benzamidoxime and its dihydrochloride hemihydrate salt which comprises react-ing the sodium salt of benzamidoxime with 2-phenyl-3-isopropyl-5-chloromethyl oxazolidine followed by hydrolysis to give the required product and, if re-quired, reaction with hydrogen chloride to give the dihydrochloride hemi-hydrate.

82. O-(3-isopropylamino-2-hydroxy-1-propyl)benzamidoxime and its di-hydrochloride hemihydrate salt when prepared by a process according to claim 81 or an obvious chemical equivalent thereof.