FI68396C - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANVAENDBARA 0- (3-AMINO-2-HYDROXY-PROPYL) -AMIDOXIMDERIVAT - Google Patents

Description

73to * l fB1 ANNOUNCEMENT 68396

ψΜφ UTLÄGGNINGSSKRIFT

^ -> $ 1 C Patent oyonnetty 10 C9 1985 45 Patent aeddelat ^ '(51) Kv.ik.4 / int.Cl.4 C 07 D 295/08, C 07 C 131/00 FINLAND FINLAND (21) Patent application - Patentansökning 772551 (22) Application date - Ansöknlngsdag 26 08 77 (Fl) (23) Start date - Giltighetsdag 26.08.77 (41) Has become public - Blivit offentllg 2g 02 78

National Board of Patents and Registration Date of display and publication——, - ς ος

Patent registration authorities V 'Ansökan utlagd oeh utl.skrlften publicerad 3 I. Up.op (32) (33) (31) Privilege requested - Begärd prloritet 27.08.76 26.0 * 1.77 Hungary-Hungary (HU) CI-1682, CI-1682 (71) CHINOIN Gygyszer äs Vegyäszeti Termäkek Gyära RT, 1-5 To-utca, 1045 Budapest, Hungary-Hungary (HU) (72) Kalmein Takäcs, Budapest, Päter Li blades in Nagy, Budapest,

Ilona Kiss sees Ajzer, Budapest, Antal Simay, Budapest, Mätyäs Szentivänyi, Budapest, Sändor Viräg, Budapest,

Katalin Faragö see Botos, Budapest, Hungary-Hungary (HU) (7 * 0 Oy Kolster Ab (5 * 0 Method for the preparation of new therapeutically useful O- (3-amino-2-hydroxy-propyl) -amidoxy derivatives) The same or more than 0% (3-amino-2-hydroxypropyl) amidoxime derivatives are used in the preparation of therapeutic therapies.

The invention relates to a process for the preparation of novel O- (3-amino-2-hydroxypropyl) amidioxime derivatives and their pharmaceutically acceptable salts. The formula of the new compounds is R5 R6 4 i 2 R - (CH) - (CH) -C-NH_ ^ R ~ m n jj 1 2 3 (N-O-CH2-CH2-N2) (I) I 3 ~ '

OH ^ R

3 2 wherein R is hydrogen or C 1-4 alkyl, R is C 1-6 alkyl which may be substituted by hydroxy or cycloalkyl, or R and R together with the nitrogen atom to which they are attached form , a piperidine, 1,3,4,5, -tetrahydro-2-isoquinoline, morpholine, 3 pyrrolidine or perhydroazosin ring, R is hydrogen or phenyl, IL ________ 68396 which may be substituted by one or more halogen atoms or with an alkoxy group, naphthyl or pyridyl, R is hydrogen or phenyl, is hydrogen or phenyl, m is 0, 1 or 2 and n is 0, 1 or 2.

These compounds are useful in the treatment of diabetic vascular disease and in some cases in the treatment of hypertension in mammals. Some of the compounds of formula I have a cC blocking effect.

Diabetes Mellitus is one of the most common metabolic diseases and its main symptom is a disturbance of the carbohydrate metabolism balance in the body. However, this symptom is often associated with pathological vascular diseases, e.g., limb vascular diseases, pathological changes in the blood vessels of the fundus, etc. Numerous compounds, such as insulin, are now known in the art to reduce hyperglycemia, but results have been very limited in the treatment of diabetic vascular disease. pharmaceutical preparations. The reason for this is that diabetes results in substantial changes in the adrenergic sites of blood vessels and therefore the adrenergic reactions in pharmaceuticals induced by pharmaceutical preparations are different from those in the non-diabetic body. / Nature Newbiology, 243, no. 130,276 (1973); SzemSsza 111, 23 (1974); Endocrinology, 93, 752 (1973/7. Quantitatively, by increasing metabolism, the of-adrenergic receptor sites in blood vessels become β-receptors. The receptor exchange is due to a modulating compound / Ämer-J. Physiol., 218, 869 (1970 //. When this compound is added Antagonists of the β2 receptor are no longer effective because the receptor has been converted to the β2 receptor, and the original oC sensitivity can be restored by the addition of a blocker.

In cases where a qualitative change in metabolism has been observed, it has been observed that β-antagonists (eg noradrenaline) retain their activity, but their effect may be blocked by β-blockers. This is the first functional change that occurs in the body's diabetic metabolism as early as 24 hours after administration of alloxan (hexahydrotetraketo-pyrimidine). The source of the changes characteristic of diabetes is an incomplete 68396 alteration of the o6-β receptor, which causes the formation of an irregular modulating agent.

It has now been found that the amidioxime derivatives of the formula I and their pharmaceutically acceptable salts have little or no effect on the adrenergic reactions of healthy blood vessels, whereas they have a strong effect on the adrenergic receptors which have been subjected to the change caused by diabetes.

All compounds of formula I have a selective (2 · blocking effect and therefore have use in the treatment of diabetic vascular disease. Some of the compounds within the scope of this invention are also useful as antihypertensive agents and / or have oC blocking activity.

2 3

The preferred -NR R group is a piperidine group and the preferred 4 R substituents are optionally alkoxy-substituted phenyl and pyridyl. Particularly preferred compounds of formula I are O- (3-piperidine-2-hydroxy-1-propyl) -3,4-dimethoxy-phenyl-acetamidoxime dihydrochloride and O- (3-piperidine-2-hydroxy-1- propyl) nikotiiniamidioksiimi dihydrochloride.

Compounds of formula I and their pharmaceutically acceptable salts may be prepared by a) an amidioxime of formula R 5 R 6 4 * 1 R - (CH) - (CH) -C-NHO (II) m n | j 2

N-OH

4 5 6.

wherein R, R, R, n and m are as defined above, are reacted with an amine of formula X-CH -CH-CH / (IIIA) 2 I 2/1 3 · - OH ^ -R · 3 CHO- CH-CH_-N <f I (IIIB)

V

68396 4 2 3 wherein R and R are as defined above and X is halogen, in the presence of a base, or b) reacting an amidioxime of formula II with epi-chlorohydrin and obtaining the resulting amidioxime of formula R5 R6

4 'I

R4- (CH) m- (CH) n-C-NH2 N-O-CH, -CH-CH, (V)

2 \ / 2 O

is reacted either separately or separately from the reaction mixture with an amine of formula (IV) \ R3 '' 2 3 wherein R and R are as defined above, or c) the alkali metal salt of the compound of formula II is reacted with 2-phenyl-3-substituted With 5-chloromethyl-oxazolidine of formula

C-CH

/ - \ 0 N - R (VI) \ / CH 6 5 2 3 wherein R is the same as R and R, except hydrogen, followed by the compound of formula 5 E5 R6 68396 R ^ “(^ H) - ( CH) -C-NH,

Nv (VII) ° -CH2 \ / \

o N - R

C6H5 is hydrolyzed without isolation; and, if desired, the racemic compound of formula I obtained is divided into its optical isomers and / or the compound of formula I is converted into a pharmaceutically acceptable salt with a suitable organic or inorganic acid and / or the salt of the compound of formula I is converted into the free base.

Compounds of formula III may be prepared by reacting epichlorohydrin with an amine in a manner known per se.

Process variant a) can advantageously be carried out by carrying out the reaction in an aqueous medium; in an organic solvent containing water (e.g. in an aqueous alcoholic solution), or in inorganic solvents, preferably at a temperature of 0-140 ° C.

Alternatively, the amidioxime of formula II can be reacted with an alkali alcoholate in a dry medium, and an alcoholic solution of the amine of formula III is added dropwise to a solution containing the amidioxime salts formed. The reaction is preferably carried out at a temperature of 0 to 100 ° C with stirring.

Salts of the amidioximes of formula II can also be prepared with alkali hydroxides, preferably sodium or potassium hydroxide, in a water-immiscible organic solvent, e.g. benzene, toluene or xylene. The salt formation is carried out at the boiling point of the solvent and the liberated water is removed in the system by azeotropic distillation, after which a solution of the amine of formula III is added and the reaction mixture is boiled.

6 68396

According to one embodiment of process variant a), the reaction is carried out in an aqueous medium by adding an alkaline aqueous solution or suspension of amidioxime to the compound of formula III with stirring. The reaction is preferably carried out at a temperature of 0 to 60 ° C, and the amidioxime is preferably dissolved or suspended in 5 to 20% aqueous sodium hydroxide solution. The reaction may also take place in an organic solvent-water mixture, for example by adding dropwise an alkaline aqueous solution or suspension of amidioxime to an alcoholic or dioxane solution of a compound of formula III. The reaction may also be carried out in the reverse order, with the addition of another compound to an aqueous solution or suspension of an alkaline amidioxime.

According to process variant b), the amidioxime of formula II is reacted with epichlorohydrin in the presence of a base. If desired, the epoxide compound formed during the reaction can be separated. However, it is more preferable to carry out the reaction in one synthetic step without isolating the intermediate. The reaction is carried out in an aqueous or organic medium or in an organic solvent containing water; or so that two solvent phases are present simultaneously, at a temperature of -10 ° C to about + 100 ° C.

According to one embodiment of this process variant, the reaction is carried out in an alkaline aqueous medium by adding 1 to 4 moles of epichlorohydrin to an alkaline aqueous solution or suspension of amidioxime. The addition of epichlorohydrin is carried out at a temperature of -10 ° C to + 60 ° C, with stirring in one or more portions, or by dropwise addition. The order can be varied so that either an alkaline solution or suspension of amidioxime can be added to the epichlorohydrin or the amidioxime can be added to the aqueous solution or suspension of epichlorohydrin. The intermediate of formula V is removed, if desired, by extraction as a water-immiscible solvent. However, it is more preferable to bring the intermediate of formula V with the amine without separation.

If the oxime starting material is sparingly soluble in an alkaline aqueous solution, the reaction may also be carried out in an organic solvent containing water, e.g. aqueous alcohols or aqueous dioxane. If desired, reaction 7 68396 can also take place in the presence of two solvent phases or in the presence of an emulsifier, by dissolving epichlorohydrin in a water-immiscible organic solvent, for example benzene or ether, adding the desired solution to an alkaline solution or suspension of amidioxime. Also in this case, the order of addition of the reactants can be varied.

Process variant b) can also be carried out in dry solvents, preferably in dry alcohols. In this case, an alkali metal salt of amidioxime is prepared, preferably by dissolving amidioxime in an alcoholic solution of an alkali metal alcoholate. After the addition of epichlorohydrin, the reaction mixture is allowed to stand at 0-20 ° C for 1-5 days, after which the appropriate amine is added and the reaction is allowed to proceed at room temperature or by heating the reaction mixture. In addition to alcohols, other organic solvents can be used as dry solvents, e.g. acetone, dimethyl sulfoxide, dimethylformamide or mixtures thereof.

In process variant c) an alkali metal salt of the amidioxime of formula II, preferably the sodium salt, is used and the reaction is preferably carried out in alkanols. The hydrolysis of the intermediate of formula VII is preferably performed with an acid. The compounds of the formula VI can be prepared by the method described in DE-A-2 018 263.

The compounds of the formula I can be isolated and purified in a manner known per se, such as by crystallization or extraction, using an aqueous medium. If an organic solvent is used, the product is crystallized or the solvent is evaporated and then the product is washed with water and dried. The compounds may also be isolated in the form of their salts or may be formed from bases separated by treatment with one or two equivalents of a mineral acid or an organic acid, preferably with pharmaceutically acceptable non-toxic acids. The free bases can also be liberated from the salts obtained.

The compounds of formula I have been found to be $ blockers in experiments using tracheal samples Z * J. Pharmacol. Exp. Therap. , 90, 104 (1974) and feline nodular muscles.

8 68396

Experiments with rat aortic-spiral preparations to determine the selective β-blocking effect were performed as follows.

The thorax of the animal was opened and the pectoral vein was taken out and spiraled. The movements of the corrected thread were recorded with an isotonic recording device on two notched cylinders.

The first cylinder had the control reactions and the second the reactions obtained in the rat aorta treated with Streptosoticine Z- (2- (3-nitroso-3-methyl-ureide) -2-deoxy-D-glucose). when the test compound did not affect the dose-response curve of noradrenaline in the control formulation, while again in the diabetic aorta the effect was inhibited The compounds of formula I generally had a selective effect, meaning a strong f * blocking effect on the diabetic aorta and very little or no effect on normal test samples. had an OC blocking effect on normal aortas.

The compound O- (3-piperidine-2-hydroxy-1-propyl) -3,4-dimethoxyphenylacetamidoxime dihydrochloride described in Example 2 gave the following results.

PD2 ~ values (minus logarithm of the dose corresponding to half the maximal efficacy) were evaluated. The mean difference in pD2 ~ values in the diabetic aortic coil for five consecutive tests was x = 1.31. The corresponding value for the normal spiral was x = 0.52. In guinea pig trachea, the 10 Y-tested substance reduced the effect of 0.01 ν '/ ml isoprenaline / 0.1 L-1- (3,4-dihydroxyphenyl) -2-isopropylaminoethanol7 to half its original value. The test compound pretreated with streptosotocin had no effect when used at a concentration of 100 YVml. The compound tested at a concentration of 50 Y / ml triggered an untreated rat uterine preparation, which was stopped with noradrenaline. This effect is the same as that obtained with 0.5 pq / ml of inert Ll-isopropylamino-3- (1-naphthyloxy) -propan-2-ol7 · Isolated rat stomach-torn strips treated with Streptosotocin had no effect at a concentration of 10 Y / ml, 9 68396 in contrast to 0.01 Y / ml of isoprenaline, where a 25 mm slack was observed. In isolated rat gastric fund strips that had not been pretreated, even at a concentration of 100 Y ~ / ml, the test compound had no effect on the dose-response curve of isoprenaline, meaning that it had a strong β-blocking effect on diabetic samples and little effect on normal samples.

The test compounds clearly prolonged the maintenance time of oxygen uptake.

The test compound also had an effect on isoprenaline-induced heart rate. Five minutes after administration of 10 mg / kg intravenously, the heart rate increased by 10% and five minutes after administration of 100 mg / kg intravenously, it decreased by 3%.

Experiments with {0- (3-piperidine-2-hydroxy-1-propyl) -nicotidioxime dihydrochloride7 described in Example 5 gave the following results.

The mean of the differences calculated from pD2 ~ values for diabetic aortic coils was x-1.25. The corresponding value in the comparative experiment was x = 0.57. Use of the test compound at a concentration of 50 Y * / ml reduced the effect of 0.001 '' / '/ ml isoprenaline from 16 mm to 5 mm. Used at a concentration of 100 Y / ml, it eventually compensated for the effect of 0.001 ~ Y / ml isoprenaline and reduced the effect of 0.01 Y / ml isoprenaline from 28 mm to 19 mm. Experiments were performed to determine whether contractions induced by noradrenaline in streptosotocin-treated diabetic animals or untreated animals could be compensated for by aortic spiral, respectively. Animals without receptor alteration were selected for comparison. In the case of animals treated with streptosotocin, the main differences between pD2 values (before and after inderal administration) on the dose-efficacy curves for noradrenaline were as follows: x = 1.0335; Sx = 0.0829; t = 3.5885; p <0.01; n = 8. In non-diabetic preparations, inderal had no effect on noradrenaline-induced contractions.

Experiments were performed to determine whether compounds with a β-blocker-like structure could find a compound that affects the aortic spiral of a diabetic animal in the same manner as the inderal without producing a significant effect on β-responses. In other words, a compound having a specific effect on the modified β-effect in diabetic blood cells was sought. The following compound was used in the experiments: NP-51: O- (3-piperidine-2-hydroxy-1-propyl) -nicot-amidioxime dihydrochloride.

It was found that if initial receptor alteration attempts are prevented by the addition of "NP-51", no definitive histological changes will occur. Approximately 60% of the CFY rats used in the tests had a latent diabetic condition, which was detected by a diabetes stress test. Diabetic hepatobiliary disease was observed in one of these animals (weight = 4-500 g). Animals treated with "NP-51" weighing 200 g did not develop capillary disease before reaching a weight of 500 g and had a significantly lower macro degree of disease.

It was also found that although "NP-51" blocked the effect of isoprenaline on the guinea pig trachea, it produced an order of magnitude 4-fold lower compared to the inderal. The compound did not appear to have a significant effect on blood pressure, heart rate, minute volume flows of anesthetized cats, or dp./df values. It did not affect isoprenaline in terms of the above parameters and caused a small heart rate and a decrease in pd / pt only at doses of 100 ug / kg. The effect was similar to the 0.5 μg / kg inderial dose.

The difference between the blocking activity of the new compounds of formula I and the inderal muscle in the feline muscle was thus fourfold. In the ileum of the guinea pig, they were treated with barium chloride and acetylcholine at a dose of only 50-100 pg / ml. Compound "NP-51" had no effect on rotating rod-dependent mice.

LDc-q NP-51: 123 kg / kg intravenously to mice.

68396 11

The compounds of the formula I and their pharmaceutically acceptable salts can be used in the form of pharmaceutical preparations in which the active ingredient is combined with customary pharmaceutical carriers. The preparations may be in the form of tablets, granules, injections, capsules, etc.

The following examples illustrate the invention.

Example 1 2.3 g of sodium are dissolved in 200 ml of absolute ethanol and 13.6 g of benzamide dioxime are added. A solution of 3-piperidine-2-hydroxy-1-chloropropane in 50 ml of absolute ethanol - prepared from 9.3 g of epichlorohydrin and 8.5 g of piperidine in a manner known per se - is then added dropwise at reflux temperature. The reaction mixture is heated at reflux for eight hours, filtered and the solvent is evaporated off under vacuum. To the residual water is added 100 ml of 5% sodium hydroxide solution and the oily product is extracted with benzene. Evaporation of the benzene extract gives 9.2 g of O- (3-piperidine-2-hydroxy-1-propyl) -benzamidoxime, m.p. 97 DEG C. (from diisopropyl ether).

Molar weight: 277.35.

Elemental 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 the isopropanol solution by passing hydrochloric acid gas or adding an alcoholic hydrochloric acid solution. Melting point: 212 ° C - 214 ° C (isopropanol). Molar weight: 350.29.

Elemental analysis for C 15 H 25 N 3 O 2 Cl 2: He Calculated: C = 20.24%; Found: Cl = 19.90%.

LDj-q = 70.5 mg / kg in mice.

The nicotinic acid salt of the product obtained is prepared in absolute ethanol solution by adding petrol, whereby the salt crystallizes. Melting point: 112 ° C (from methyl ethyl ketone).

- Il 12 68396

Molar weight: 100.16.

Elemental analysis for C ^ H 28Vu !.

Calculated: C = δ 2.98% ·, H = 7.05% ", N = 11.00% \ Found: C = 62.81% \ H = 7.11% \ N = 13.76%.

The dihydrochloride salt had a mild λ-blocking effect on normal targets and a strong β-blocking effect in diabetic experiments performed according to the introductory description of this specification.

LD = 70.5 mg / kg intravenously in mice.

Example 2

Following the procedure described in Example 1, but starting from 3,1-dimethoxy-phenyl-acetamidoxime and 3-piperidine-2-hydroxy-1-chloropropane, O- (3-piperidine-2-hydroxy-1-propyl) -3, l-dimethoxyphenyl-Acetamide oxime-di-dihydrochloride. Melting point: 202-203 ° C (from absolute ethanol).

Molar weight: 121.38.

Elemental analysis for C 18 H 19 N 2 O 2 Cl 2

Calculated: C = 50.9 * 1% \ H = 7.36% \ N = 9.90% \ Cl = 16.71% ", Found: C = 50.81% \ H = 7.57%", N = 9.81% Cl = 16.12%.

LD50 = 165 mg / kg intravenously (in mice).

A slight β-blocking effect can be observed in the tracheal spiral and nodule muscle. The effect on the nodular muscle at 100 pg / ml is the same as the effect obtained with 0.05 pg / ml inderally. At the bottom of the stomach, when concentrated at 100 pg / ml, the compound has no effect on isoprenaline activity. However, multiple inhibition was observed in the aortic spiral of a diabetic animal.

Example 3

Following the procedure described in Example 1, but starting from 3,1-dimethoxyphenyl-ashamidoxime and 3- (1,2,3,1-tetrahydro-2-isoquinolyl) -2-hydroxyl-1-chloropropane, O- [3- ( 1,2,3,3 * - (Tetrahydro-2-isoquinolyl) -2-hydroxy-1-propyl-3,1-dimethoxyphenyl-acetamide oxime dihydrochloride. Melting point: 189 ° C (isopropanol).

Molar weight: ΐ72.1θ.

68396 13

Elemental analysis for C._H_, N_0, Cl 223134 2

Calculated: C = 55.93 l \ H = 6.6 1 N = 8.89% \ Cl = 15.01% \ Found: C = 55.89% ', H = 6.82 N = 8.61 * % ·, Cl = 1U, 7 5%

Example U

Following the procedure described in Example 1, but starting from 3,3-diphenylpropioniamine and 3-piperidine-2-hydroxy-1-chloropropane, 0- (3-piperidine-2-hydroxy-1-propionate) is obtained. phenyl) -3,3-diphenylpropionamine dioxime dihydrochloride. Melting point: 228-230 ° C (from isopropanol a).

Elemental analysis for C 23 H 33 N 3 O 2 Cl 2

Calculated: C = 60.79% ·, H = 7.32% \ N = 9.25% \ Cl = 15.60% \ Found: C = 60, U 5% i H = 7.25% \ N = 8.91 *% \ Cl = 15.79%

Example 5

Following the procedure described in Example 1, but starting from nicotinamide oxime and 3-piperidine-2-hydroxy-1-chloropropane, O- (3-piperidine-2-hydroxy-1-propyl) -nicotine amidioxy dihydrochloride is prepared. Melting point: 20 l * ° C (abs. From ethanol).

Molecular Weight: 351.27 ·

Elemental analysis CuW2Cl2: Ue

Calculated: C = 1 * 7.87% i H = 6.89% \ N = 15.95% \ Cl = 20.19% i Found: C = * + 7.59% i H = 7.00% · , N = 15.61 * Cl = $ 19.89.

LD50 = 123 mg / kg intravenously (in mice).

The product of this example had a mild β-blocking effect in the normal test.

The nicotinic acid salt of the product is precipitated from ethyl acetate. Melting point: 1 1 1 ° C (from ethyl acetate).

Molar weight: 1 * 01.1 * 6.

Elemental analysis: C 9 H 8 N 2 O 2

Calculated: C = 59.83%; H = 6.77% N = 17.1 * 1 *% i Found: C = 59.80% \ H = 6.92%, N = 17.23%: LD = 0 = 250 mg / kg intravenously (mice).

The product has a strong β-blocking effect on the di abetic aortic spiral.

68396 14

Example 6 To 17.8 g of a solution of 3-piperidine-2-hydroxy-1-chloropropane at room temperature is added a solution of 10.15 g of 3,1-dimethoxyphenylacetarioxime in 10 ml of 10% sodium hydroxide solution. -roksidia - prepared by heating - and dropwise with stirring for half an hour. The reaction mixture is stirred at room temperature for eight hours and then 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, the remaining 10.5 g of O- (3-piperidine-2-hydroxy-1-propyl) -3,1-dimethoxyphenylacetamide dioxime dihydrochloride are crystallized by passing hydrochloric acid gas. The product is the same as obtained in Example 2. Melting point: 201-203 ° C.

Example 7

The benzene solution of 8.8 g of 3 ~ piperidine-2-hydroxy-hydroxy-1-chloro-propane is added under heat produced, stirring and dropwise over a half hour, a solution of 5.2 g of 3,1-dimetoksifenyy1i- acetamide oxime in 10 ml of a 10% sodium hydroxide solution. The reaction mixture is stirred at room temperature for a further eight hours and then allowed to stand overnight. The benzene phase is separated and the water phase is extracted with benzene. The benzene solution is dried over sodium sulfate and the solvent is evaporated. Using the procedure described in Example 6 to obtain the hydrochloride salt, 0- (3-Piperidine-2-hydroxy-1-propyl-3,1-dimethyloxyethylacetamide) hydrochloride is obtained from the residue. The compound is the same as the product of Example 2.

Example 8 To 8.8 g of 3-piperidine-2-hydroxy-1-chloropropane is added a solution of 5.2 g of 3,1-dimethoxyphenylacetamide oxime in 10 ml of 10% sodium hydroxide solution and 10 ml of methanol, with stirring. , dropwise for half an hour, after which the mixture was further stirred at room temperature for eight hours and allowed to stand overnight. After evaporation of the methanol, the benzene extraction and the salt formation reaction are carried out as described in Example 7. O- (3-Piperidine-2-hydroxyl-1-propyl) -68396,3,1-dimethoxyphenylacetamide oxime dihydrochloride, similar to the product obtained in Example 2, is obtained.

Example 9 To 2.72 g of benzamide dioxime are added 1 * 0 ml of benzene and 0.8 g of crushed sodium hydroxide. The reaction mixture is boiled for one hour under water separation and 1.5 g of 3-piperidine-2-hydroxy-1-chloropropane in 10 ml of benzene are added dropwise to the boiling mixture. After boiling for 12 hours, the solvent is evaporated off and 20 ml of 10% strength sodium hydroxide solution are added to the residue. The oily substance obtained is extracted with benzene and the benzene solution is evaporated. 3.6 g of O- (3-piperidine-2-hydroxy-1-propyl-1i) -benzamidoxime a are obtained. The product is the same as that obtained in Example 1.

Example 10

To a solution of sodium ethylate prepared from 2.3 g of sodium and 200 ml of abs. ethanol, 15 * 5 g of 1 * -chlorobenzamide amidoxime a are added and then 9 * 3 g of epichlorohydrin are added dropwise at a temperature of 0 to + 10 ° C. The reaction mixture is stirred at 0 to + 10 ° C for eight hours and allowed to stand at this temperature overnight. The precipitated sodium chloride is filtered off, 8.6 g of piperidine are added dropwise to the filtrate with stirring, and the mixture is stirred for a further eight hours at room temperature. The reaction mixture is heated to boiling point and the solvent is evaporated off under vacuum. 50 ml of 5% sodium hydroxide solution are added to the residue and the oily substance is extracted with benzene. The benzene solution is dried over sodium sulfate, evaporated and the residue is dissolved in alcohol. Hydrochloric acid gas is introduced or hydrochloric acid in alcohol is added to give 11.0 g of O- (3-piperidine-2-hydroxy-1-propyl) -N-chlorobenzamide dioxime dihydrochloride. Melting point: 215-217 ° C (abs. From ethanol).

Molecular Weight: 38U, 73 ·

Elemental analysis C ^ H ^^ N ^ O ^ Cl ^ -He

Calculated: C = 1 * 6.83%; H = 6.29% N = 10.92% Found: C = 1 * 6.57% H = 6.1 * 1%; N = 10.58%.

The product has a mild j-blocking effect in the normal test and a strong jP-blocking effect in the diabetes test.

...---------- TT— 16 68396

Example 11

Following the procedure described in Example 10, but starting from phenylacetamidoxime using diethylamine as the amine component, O- (3-diethylamino-2-hydroxy-1-propyl) -phenylacetamide dioxime dihydrochloride is prepared. Melting point 15-156-158 ° C (from isopropanol a).

Molar weight: 352.30.

Elemental analysis for C 1 H 2 O 2 .N 2 O 2 Cl 2

Calculated: C = 51 · 1 **% \ H = 7.73% i N = 11.93 Cl = 20.12 55; Found: C = 50.89% H = 7.65 L; N = 11.83% Cl = 20.10%.

Example 12

Following the procedure described in Example 10, but starting from phenylacetamidoxime and using piperidine as the amine component, O- (3-piperidine-2-hydroxy-1-propyl) -phenylacetamidoxime dihydrochloride was obtained. Melting point: 198-200 ° C (abs. From ethanol).

Molar weight: 364.31.

Elemental analysis for C 16 H 27 N 3 O 2 Cl 2

Calculated: C = 52.75%; H = 7.47%; N = 11.54%; Cl = 19.47 55; Found: C = 52.40%, H = 7.51% and N 11.20%; Cl = 19.85%.

Example 13

Following the procedure used in Example 10, but starting from 4-chlorophenyl-acetamidoxime and using morpholine as the amine component, O- (3-morpholine-2-hydroxy-1-propyl) -4-chlorophenyl-acetamidoxime dihydrochloride is obtained. Melting point: 175-178 ° C (abs. From ethanol).

Molar weight: 400.73.

Elemental analysis ε,; '2ΐ'Λ013: 11ί

Calculated: C = 44.96 K »6.04 N = 10.48% ·, Cl = 26.54 55; Found: C = 45.20%, H = 6.10%, N = 10.52%, Cl = 26.50%.

Example 14

Following the procedure of Example 10, but starting from 3,3-diphenyl-1-propionamidoxime and using isopropylamine as the amine component, O- (3-isopropylamino-2-hydroxy-1-propyl) -1768396 3.3-diphenylpropionamidoxime is obtained. dihydrochloride. Melting point: 179 ° C (from acetone / water).

Molecular Weight: ^ 28.39 ·

Elemental analysis for C 21 H 31 N 3 O 2 Cl 2

Calculated: C = 58.87% \ H = 7.29% \ N = 9.81% ·, Cl = 16.55% \ Found: C = 58.58%; H = 7.39 1i N = 9.53% i Cl = 16.70%.

LD50 = 16.25 mg / kg intravenously (in mice).

The compound has a potent β-blocking effect on the diabetic aortic spiral.

Example 15

Following the procedure described in Example 10, but starting from 3,3-diphenylpropionamidoxime and using diethylamine as the amine component, O- (3-diethylamino-2-hydroxy-1-propyl) -3,3-diphenylpropionaminooxyimide dihydrochloride is prepared. Melting point: 225 ° C (from isopropanol).

Molecular weight: hk2, k2.

Elemental analysis for c22HN3O2Cl2

Calculated: C = 59.72% ·, H = 7.52% \ Cl = 16.03% \ Found: C = 59.68% \ H = 7.55% i Cl = 16.07%.

Example 16

Following the procedure described in Example 10, but starting from 3,3-diphenylpropionamidoxime and using 2-methylaminoethanol as the amine component, O-β-N-methyl-N- (2-hydroxyethyl) -amino-2 -hydroxy-1-propyl-7-3,3-diphenylpropionamide dihydrochloride. Melting point: 175 ° C (from isopropanol).

Molecular Weight: ^ * +, 39 ·

Elemental analysis for Cg ^ H ^^^ O ^ Cl ^

Calculated: C = 56.78% \ H = 7.03% \ N = 9, * + 5% i Cl = 15.96%; Found: C = 56, Uo% \ H * 7.09% i N = 9.1 U% ·, Cl = 15.92%.

LD = 37 mg / kg intravenously (in mice).

The compound has a potent β-blocking effect on the diabetic aortic coil.

, · Vv n7 68396

Example 17 18

Following the procedure described in Example 10, but starting from 3,3-diphenyl-propionamide dioxime and using pyrrolidine as the amine component, O- (3-pyrrolidine-2-hydroxy-1-propyl-1i) -3,3-diphenylpropioniamine oxime is obtained. dihydrochloride. Melting point: 218 ° C (isopropanol).

Molecular weight: U1 + 0, U0.

Elemental analysis for C 22 H 31 N 3 O 2 Cl 2

Calculated: C = 59.99% \ H = 7.10% ·, Cl = 16.10% ·, Found: C = 59.63% \ H = 7.32% \ Cl = 16, UU%.

Example 18

Following the procedure described in Example 10, but starting from 3,3-diphenylpropionamidoxime and using piperidine as the amine component, O- (3-piperidine-2-hydroxy-1-propyl) -3,3-diphenylpropionamidoxime dihydrochloride was obtained. The compound is the same as obtained in Example k. Melting point 228-230 ° C (from isopropanol).

Example 19

Following the procedure described in Example 10, but starting from 3,3-diphenylpropionamidoxime and using heptamethyleneimine as the amine component, O- (3-heptamethyleneamino-2-hydroxy-1-propyl) -3,3-diphenyl was prepared. -propionic amine oxime dihydrochloride. Melting point: 233 ° C (from isopropanol).

Molecular weight: U82, U8.

Elemental analysis:

Calculated: C = 62.2b%; H = 7.73% \ Cl = 1U, 70% \ Found: C = 61.97% \ H = 7.70% ·, Cl = 1U.7U%

Example 20

Following the procedure described in Example 10, except starting from 3,3-diphenylpropionamide dioxime and using morpholine as the amine component, O- (3-morpholine-2-hydroxy-1-propyl) -3,3-diphenylpropioniamine oxime was prepared. dihydrochloride. Melting point: 225 ° C (from isopropanol).

Molecular weight: k ^ 6, b0.

Elemental analysis for C22H31N3O3Cl2

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%.

68396 19

Example 21

Following the procedure described in Example 10, but starting from 1-naphthylacetamidoxime and using diethylamine as the amine component, O- (3-diethylamino-2-hydroxy-1-propyl) -naphthylacetamidoxime hydrochloride is prepared. Melting point: 150-152 ° C (abs. From ethanol).

Molar weight: 365.89.

Elemental analysis for C1

Calculated: C = 62.36 H = 7.71%; N = 11.1 + 9%; 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 1-naphthylacetamidoxime and using Piperidine as the amine component, O- (3-piperidine-2-hydroxy-1-propyl) -1-naphthylacetamidine hydrochloride was prepared. Melting point: 177 ~ 179 ° C

(abs. ethanol).

Molecular Weight: 377.89 ·

Elemental analysis: for C 20 H 28 N 3 O 2 Cl

Calculated: C = 63.57%; H = 1.6%; N = 11.12%; Cl = 9.38%; Found: C = 63.58 H = 7.59%, N = 11.1 + 7%; Cl = 9.60%.

Example 23

To a mixture of 1+, 0 g of benzamide dioxime, 10 ml of water and 1+, 5 g of epichlorohydrin is added 20 ml of 10% sodium hydroxide solution, dropwise at room temperature for one hour. The reaction mixture is then stirred for a further two hours, 1+, 5 g of piperidine are added dropwise and stirring is continued for a further eight hours. The oily substance is extracted with Bent fungus. Evaporation of the benzene solution gives 6.2 g of O- (3-piperidine-2-hydroxy-1-propyl) -benzamidoxime. The product is the same as in Example 1.

Example 21 + 6.8 g of benzamide dioxime are dissolved in 1 + 0 ral of 10 .mu.l of sodium hydroxide solution and 9.5 g of epichlorohydrin are added with stirring. The reaction is exothermic and therefore the temperature of the mixture is maintained at 30-35 ° C under external cooling. After stirring for 2 hours, 8.6 g of piperidine are added dropwise. The mixture is stirred for the next two hours and the oily substance obtained is extracted with benzene. After evaporation of the benzene, 8.2 g of O- (3-piperidine-2-hydroxy-1-propyl) -benzamidoxime are obtained. The product formed is the same as the compound of Example 1.

Example 25 6.8 g of benzamidoxime are dissolved in 10 ml of 10 to 10 g of sodium hydroxide solution and 9 to 5 g of epichlorohydrin in 20 ml of benzene are added with vigorous stirring and dropwise addition. After stirring for 1 hour, 8.6 g of piperidine are added dropwise and the mixture is stirred at room temperature for a further eight hours. The benzene phase is separated and the aqueous layer is extracted with benzene, followed by evaporation of the combined benzene solutions to give O- (3-piperidine-2-hydroxy-1-propyl) benzamidoxime. This product is similar to the compound obtained in Example 1.

Example 26 6.8 g of benzamidoxime are dissolved in a mixture of 20 ml of 10 to 10% sodium hydroxide solvent and 20 ml of methanol, followed by the addition and dropwise addition of 9 to 5 g of epichlorohydrin. After stirring for 2 hours at room temperature, 8.6 g of piperidine are added dropwise and stirring is continued for a further eight hours. The methanol is evaporated in vacuo and the oily residue is extracted with benzene. After evaporation, 7.2 g of O- (3-piperidine-2-hydroxy-1-propyl) -benzamide dioxime are obtained in benzene solution. This compound is the same as the product obtained in Example 1.

Example 27

To a solution of 5 * 2 g of 3'-dimethoxyphenylacetamide oxime in 20 ml of dimethyl sulfoxide is added 2.1 g of sodium tert-butylate with stirring. 3.0 g of epichlorohydrin are then added dropwise, and the mixture is stirred at room temperature for two hours. A solution of 2.5 g of piperidine in 60 ml of acetone is then added and the reaction mixture is refluxed for eight hours, after which 120 ml of ethyl acetate are added.

After introduction of hydrogen chloride gas, h, kg of O- (3-piperidine-2-hydroxy-1-propyl) -3,3-dimethoxyphenylacetamide are obtained. oxime dihydrochloride in crystalline form. This salt is exactly the same as that obtained in Example 2.

Example 28

Following the procedure of Example 6, but starting from 2-phenylpropionamidoxime and 3-piperidine-2-hydroxy-1-chloropropane, O- (3-piperidine-2-hydroxy-1-propyl) -2-phenylpropionamidoxime dihydrochloride. Melting point: 225 ° C (from iso-propanol a).

Elemental analysis:

Calculated: C = 53.96%; H = 7.73%; N = 11.11% Cl = 18.7% Found: C = 5, 27% * H = 8.00%, N = 10.86%, Cl = 18.5%.

Example 29

Following the procedure described in Example 6, but starting from 3-cyclohexylamino-2-hydroxy-1-chloropropane (J. Org. Chem., 2k, 615 /"1959.7) and nicotinamide oxime, 0- (3-cyclohexylamino-2-hydroxy) is prepared. -1-propyl) -nicotinamide dioxime Melting point: 102 ° C (from a mixture of benzene and toluene).

Molar weight: 292.37.

Elemental analysis for C1

Calculated: C 61.62% \ H = 8.27% i N = 19.16% i Found: C = 61, UU H = 8.23% \ N = 18.89%.

Example 30 1.38 g of racemic O- (3-piperidine-2-hydroxy-1-propyl) -benzamidoxime 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 recrystallized first from butyl acetate and then from ethyl acetate. This gives 0.1 g of d-O- (3-piperidine-2-hydroxy-1-propyl) -benzamidioxime-d-camphorsulfonate. Melting point: 132 ° C.

From the obtained salt, the base is liberated by conventional methods, and the obtained base is converted into its hydrochloric acid salt. The melting point of the hydrochloric acid salt is 196 ° C. / et / = + 6.3 ° (c = 1% in water).

Example 31 1.15 g of sodium metal are dissolved in 100 ml of absolute 68396 ethanol and 12.0 g of 3,3-ethylphenylamino dioxide are added. During boiling, 13.2 g of 2-phenyl-3-isopropyl-5-chloromethyloxazolidine are added dropwise and the reaction mixture is boiled for a further 16 hours. The solvent is evaporated off, 110 ml of 5N normal hydrochloric acid solution are added to the residue and the mixture is refluxed for one hour. The solution is extracted with ethyl acetate, blackened with charcoal and made 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 solvent is evaporated. The residue is dissolved in acetone and a solution of hydrochloric acid in acetone is added. 7.0 g of O- (3-isopropylamino-2-hydroxy-1-propyl) -3,3-diphenylpropionamide dioxime dihydrochloride are obtained. This compound is the same as the product obtained in Example 1H. Melting point: 179 ° C.

Example 32

Following the procedure of Example 31, but starting from 2-phenyl-propionamide dioxime and 3-phenyl-3-isopropyl-5-chloromethyl-oxazolidine, O- (3-isopropylamino-2-hydroxy-1-propyl) - 2-fenyylipropioniamidioksiimi dihydrochloride hemihydraat-ti. Melting point: 168 ° C (from a mixture of acetone and isopropanol).

Molar weight: 361.31.

Elemental analysis for C1 '0' ^ H2O

Calculated: C = U 9.8 5% 1H = 7.81%; N = 11.63% Cl = 19.63% Found: C = 9.79% H = 7.57% N = 11.61%; Cl = 19.50%.

Example 33

Following the procedure of Example 31, but starting from the benzamide oxime and the 2-phenyl-3-isopropyl-5-chloromethyl branches of the solidine, 0-? (3 "isopropyl-amino-2-hydroxy-1-propyl) -benzamine Sami-dioxime dihydrochloride hemihydrate. Melting point: 17 3-17 U ° C.

Molar weight: 333.26.

Elemental analysis: c] 3H23N3 ° 2Cl2'0'5 H2O

Calculated: C = 6.8 5% i H = 7.26% i N = 12.61%; Cl = 21.28%; Found: C = ^ 7.05%; H = 7.13% and N = 12, U1 Cl = 21.5

Claims (4)

A process for the preparation of therapeutically useful O- (3-amino-2-hydroxypropyl) amidioxime derivatives of formula I and their pharmaceutically acceptable salts, R 5 r 6 r 2 4. I / R · v R - (CH) - (CH) -C-NH- / \ m n, | 2 ', NO-CH 2 -CH-CH 2 -N' (I) and 23 wherein R is hydrogen or alkyl, R is alkyl which may be substituted by hydroxy or cycloalkyl, or R 2 and R 2 together with the nitrogen atom to which they are attached form a piperidine, 1,3,4,5-tetrahydro-2-isoquinoline, morpholine, pyrrolidine or perhydro-azosine ring, R is hydrogen, phenyl which may be substituted by one or more halogen atoms or alkoxy groups, naphthyl or pyridyl, R is hydrogen or g phenyl, R is hydrogen or phenyl, m is 0, 1 or 2 and n is 0, 1 or 2, characterized in that a ) amidioxime of formula R5 R6 4. R - (CH) - (CH) -C-NH- (II) m n || 2 N-OH 4 5 6 wherein R, R, R, n and m are as defined above is reacted with an amine of the formula x-ch2-ch-ch2-nC (IIIA) or -CH2-CH-CH2 -N - "^ ^ R '(IIIB) 2 0 3 wherein R and R are as defined above and X is halogen, in the presence of a base, or b) the amidioxime of formula II is reacted with epichlorohydrin and the resulting amidioxime of formula R5 R6 R 4 - (? H) - (? H) -C-NH-m n n 2 N-O-CH 2 -CH-CH 2 (V) '0 I 68 68396 is reacted either separately from the reaction mixture or separated with an amine of formula (IV) 23 wherein R and R are as defined above, or c) the alkali metal salt of the compound of formula II is reacted with 2-phenyl-3-substituted-5-chloromethyl-oxazolidine of the formula Cl-CH 2 - \ 0 JH - R (VI) V, C6H5 2 3 wherein R is the same as R and R, except hydrogen, followed by the compound of formula Ϋ? 6 R4- (CH) - (CH) -C-NH0 mnn λ N 5 'S 2 -CH 2 (VII) / N 2 O 3 -R 2 H 5 is hydrolysed without isolation and, if desired, the racemic compound of formula I obtained is resolved into its optical isomers and / or the compound of formula I is converted into a pharmaceutically acceptable salt with a suitable organic or inorganic acid and / or or a salt of a compound of formula I is converted to the free base. A patent for the preparation of an O- (3-amino-2-hydroxypropyl) amidoxime derivative of the formula I and a pharmaceutical composition containing a f-? 6 R4- (CH) m- (iH) nC-NH2 N-O-CH2 -CH-CH23, (I) OH 11 2 3 is a substituent of C1-4 alkyl, R1 is C1-4 alkyl, which may be substituted by hydroxy or cycloalkyl , or R ^ and R ^ bildar tillsammans med kväveatomen, account for the addition of piperidine, 1,3,4,5-tetrahydro-2-isoquinoline, morpholine, pyrrolidine-4 or perhydroazocinring, R is phenyl, which may be substituted by a halogen atom or an alkoxy group, naphthyl CC or pyridyl, R is an oil or phenyl, R is an oil or phenyl, m is 0, 1 or 2 and n = 0, 1 or 2, kännetecknat därav , a) and amidoxime, in the form of f? 6 R4- (CH) - (CH) -C-NHO (II) mn li 2 N-OH 4 5 6 from R, R, R, n and m in the same case as ovan, omsätts med en Amin med formuleln n2 ^ (IIIA) OH eller '\ C \ 2 ~? H_CH2 "N _ 3 (IIIB) \ / R '' O 2 3 of R and R are the same as those of X and X are halogen, and in the case of b) that amidoxime of formula II is a mixture of epichlorohydrin and an amide oxide of formula R5 R6 4. R - (CH) - (CH) -C-NH. . ΧΠ Π 2 IV) N-O-CH0-CH-CHn V