DK150196B - METHOD OF ANALOGUE FOR THE PREPARATION OF 0- (3-AMINO-2-HYDROXYPROPYL) AMIDOXIME DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

Description

150196

The present invention relates to an analogous process for the preparation of novel O- (3-amino-2-hydroxy-propyl) amidoxime derivatives or pharmaceutically acceptable salts thereof. These compounds are useful in the treatment of diabetic angiopathy and in some cases, hypertension in mammals.

Certain of the compounds of the present invention also exhibit α-blocking activity.

Diabetes mellitus is one of the most frequent digestive disorders, and its main symptom is the disruption of the organism's carbohydrate metabolism balance. However, this symptom is often accompanied by pathological vascular disease, e.g. vascular stenoses of the extremities and pathological changes in the vessels of the eye base. At present, numerous compounds, including insulin, are known to reduce hyperglycemia, but in the treatment of diabetic angiopathy, which is a concomitant disease, the results are very moderate using the known, commercially available pharmaceutical preparations. The reason for this is that the adrenergic receptor centers in the vessels as a result of diabetes mellitus undergo significant changes, and therefore the adrenergic reactions induced by the pharmaceutical preparations in a diabetic patient are different from the reactions in a non-diabetic organism [Nature New Biology, 243, Nos. 130, 276 (1973), Szemészet, 111, 23 (1974), Endocrinology, .93, 742 (1973)]. By quantitatively increasing the metabolism, the α-adrenergic receptor centers in the vessels are converted into β-receptors. The receptor conversion is due to a modulator compound (Amer. J.

Physiol. 218, 869 (1970)]. When this compound is added to an α receptor, the α-antagonists are no longer effective as the receptor has been converted to a β receptor. The initial α-sensitivity can be re-induced by also adding a β-blocking agent.

In cases where there has been a qualitative change in metabolism, it has been found that the α-antagonists, e.g. noradrenaline, retains their activity, but their effect can be inhibited by β-blocking agents. This is the first functional change that appears in a diabetic organism and can be detected as early as ca. 24 hours after administration of alloxane (hexahydrotetraketopyrimidine). The source of the changes characteristic of Diabetes is an imperfect α-β receptor transformation caused by the formation of an irregular modulator.

It has now been found that certain amidoxime derivatives and pharmaceutically acceptable salts thereof show no or little effect on the adrenergic responses in healthy vessels, while strongly influencing the adrenergic receptors which have undergone a pathological change due to Diabetes mellitus.

The compounds of the present analogous process have the general formula 3 R5 R6 R4- (1H) m- (iH) nC-HH2 / r2 '\ (I) no-ch0-ch-ch0-n / i 2 I 2 \ 3 / OH NR "wherein 2 R is hydrogen, or alkyl of 1-5 carbon atoms, 3 R is alkyl of 1-5 carbon atoms optionally substituted by hydroxy, or is cycloalkyl, or 2 3 R and R form together with it nitrogen atom to which they are attached, a piperidine, 1,3,4,5-tetrahydro-2-isoquinoline, morpholine, pyrrolidine or perhydroazocin ring, 4 R means hydrogen, naphthyl, pyridyl or phenyl optionally substituted by one or more halogen atoms or one or more alkoxy groups, R is hydrogen or phenyl, c R is hydrogen or phenyl, m = 0.1 or 2, and n = 0, 1 or 2, or they are pharmaceutically acceptable salts of the above compounds "of formula I.

The compounds of the invention primarily exhibit a selective β-blocking activity and may therefore be useful in the treatment of diabetic angiopathy. Some of the compounds of this invention are also valuable hypotensive agents and / or have an α-blocking activity.

Typical illustrations of the compounds of general formula I and their salts can be found in Examples 1-33 below.

The preferred -NR R group is the piperidino group, and the preferred R 1 substituents are phenyl or pyridyl substituted by alkoxy. Particularly preferred compounds of the general formula I are O- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethoxyphenyl-acetamidoxime dihydrochloride and O- (3-piperidino-2-hydroxy-1 -propyl) -nicotinamidoxim dihydrochloride.

4 150196

The. The analogous process for preparing the compounds of general formula I or pharmaceutically acceptable salts thereof is characterized by a) reacting an amidoxime of the general formula r5 f R4- (CH) m- (CH) n-C-HH2 (II)

N-OH

wherein A is C, R, R, R, n and m have the meaning given above with an amine of the general formula s * 2 '.

x-ch, -ch-ch, -n ^, (IIIA) • \ 3 / OH XR? ' or / R2 \ ch5-ch-ch9-N \; (hib) V / R3

OK

wherein R 2 and R are as defined above, and X is halogen, in the presence of a base, or b) is reacting an amidoxime of the above general formula II, Λ - r 2 wherein R, R, R, m and n have the meaning given above, with epichlorohydrin and reacting the resulting amidoxime of the general formula R5 R6 R4- (CH) - (CH) -C-NH0 (V) mn 2 NO-CH2 -CH-CH-2 \ / 2

ISLAND

After or without isolation / with an amine of the general formula r 2 \ H <(IV) \ 3 wherein O 0 R and R have the meaning given above / or c) react an alkali metal salt of a compound having the above 4 6, wherein R, R, R, n and m are as defined above, with a 2-phenyl-3-substituted-5-chloromethyloxazolidine of the general formula

Cl-CH

N— o (Ve <vi>

Y

C6H5 wherein 2 3 R has the meaning given to R and R other than the hydrogen, and then the compound formed by the general formula R5 R6 hydrolyzes

4 I I

R - (CH) m- (CH) n-C-BH 2

V

O-CHO (VII)

\ -R

V

C6H5 without isolation, with variants (a), (b) or (c) optionally followed by a racemate cleavage and / or a conversion of the first compounds of the general formula I into pharmaceutically acceptable salts thereof with suitable organic or inorganic acids and / or a release of the free bases from the first salts.

6 150196

The compounds of general formula III can be prepared by reacting epichlorohydrin with amines in known manner.

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

It is also possible to proceed by reacting the amidoximes of the general formula II with alkali metal alcoholates in a dry medium and by dropwise adding the alcoholic solution of the amines of the general formula III to the solution containing the amidoxim salts formed. The reaction is preferably carried out at between ca. 0 ° C and approx. 100 ° C with stirring.

According to a further alternative, the salts of the amidoximes of the general formula II are prepared with alkali metal 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 temperature of the solvent, the released water is removed from the system by azeotropic distillation, then the solution of the amines of general formula III is added and the reaction mixture is boiled for a further determined period.

According to a further embodiment of variant a), the reaction is carried out in an aqueous medium by stirring the alkaline aqueous solution or suspension of the amidoximes to the compounds of the general formula III. The reaction is preferably carried out at between ca. 0 ° C and approx. 60 ° C, and the amido oxime is preferably dissolved or suspended in a 5-20% aqueous sodium hydroxide solution. The reaction may also be carried out in a mixture of organic solvent and water, e.g. by adding the alkaline aqueous solution or suspension of the amidoxime dropwise to an alcohol or dioxane solution of a compound of the general formula III. The reaction may also be carried out in reverse order adding the second compound to the alkaline aqueous solution or suspension of the amidoxime.

According to process variant b) of the invention, amidoximes of the general formula II are reacted with epichlorohydrin in the presence of a base. If desired, the epoxide compound formed during the reaction can be isolated, but it is more advantageous, however, to conduct the reaction in a synthesis step without isolating the intermediate. The reaction is carried out in an aqueous or organic medium, in an organic solvent containing water, or in the presence of two solvent phases at a temperature of from ca. -10 ° C to approx. + 100 ° C.

According to one embodiment of this variant, the reaction is carried out in an alkaline aqueous medium by adding 1-4 moles of epichlorohydrin to the alkaline aqueous solution or suspension of the amidoximes. The addition of the epichlorohydrin occurs at -10 ° C to + 60 ° G with stirring in one or more portions or by dropwise addition. The order of addition can be reversed by adding either the alkaline aqueous solution or suspension of the amidoxime to the epichlorohydrin, or the amidoxime is added to the alkaline aqueous solution or suspension of the epichlorohydrin.

The intermediate of the general formula V is optionally removed by extraction with a water-immiscible solvent. However, it is more advantageous to react the intermediates of general formula V with the corresponding amines without prior isolation.

If the oxime starting material is only slightly soluble in the alkaline aqueous solution, the reaction can also be carried out in an organic solvent containing water, e.g. in aqueous alcohols or aqueous dioxane. If desired, the reaction may also be carried out in the presence of two solvent phases or in the presence of an emulsifier by dissolving the epichlorohydrin in a water-immiscible organic solvent, e.g. in benzene or ether and then the resulting solution is added to the alkaline aqueous solution or suspension of the amidoxime.

In this case too, the order of addition of the reactants can be reversed.

Process variant b) of the invention may also be carried out in dry solvents, preferably in dry alcohols. In this case, an alkali metal salt is prepared from the amidoxime, preferably by dissolving the amidoxime in the alcoholic solution of an alkali metal alcoholate. After addition of the 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 carried out at room temperature or while heating the reaction mixture. As dry solvents, in addition to the alcohols, other organic solvents, e.g. acetone, dimethylsulfoxide, dimethylformamide or mixtures thereof.

In the process variant c) the alkali metal salts of the amidoximes of the general formula II are preferably sodium salts and the reaction is preferably carried out in alkanols. The hydrolysis of the intermediates of general formula VII is preferably carried out with acids. The compounds of general formula VI can be prepared using the method described in German Publication No. 2,018,263.

The products of general formula I can be isolated and purified in a conventional manner, e.g. by crystallization or extraction when an aqueous medium is used. If an organic solvent is used, the product is crystallized or the solvent is evaporated and the product is then washed with water and dried. The products may also be isolated in the form of salts thereof, or salts may be formed from the isolated bases by treatment with 1 or 2 equivalents of a mineral acid or an organic acid, preferably with pharmaceutically acceptable, non-toxic acids. Likewise, the free bases can be released from the salts produced.

The compounds of general formula I have been evaluated as general β-blocking agents in experiments using tracheal preparations [J. Pharmacol. Exp. Therap., 90, 104 (1974)] and papillary muscles in cats.

The tests of selective β-blocking activity on rat aortic coil preparations are performed as follows:

The animal's thorax is opened and the thoracic aorta is taken out and cut in spiral form. The movements of the straightened spiral are recorded with an isotonic recorder on two soot-black cylinders.

For the first cylinder, the reactions of the control are recorded and on the second the reactions of a rat aorta treated with streptosoticin [2- (3-nitroso-3-methyl-ureido) -2-deoxy-D-glucose] are recorded. The reaction is positive when the dose-effect curve of the norepinephrine is not affected by the tested compound on the control preparation, while the effect is inhibited on the diabetic aorta. The compounds prepared by the method of the invention generally exhibit a selective activity, which means a strong β-blocking effect on diabetic aorta and no or little effect in normal experiments. Some of the tested compounds exhibit α-blocking activity on normal aorta.

When testing the product of Example 2 [O- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethoxyphenyl-acetamidoxime dihydrochloride], the following results were obtained: PD2 values (minus logarithm to dose equal to half of maximum efficiency) is judged. The average of five consecutive trials calculated from the difference in pD2 values on a diabetic aortic coil is x = 1.31 '. · The corresponding value of a normal coil is x = 0.52. On guinea pig trachea, 10 µg of the test * / (5) lowers the effect of 0.01 µg / ml "Isoprenaline" -1 [D, L - 1- (3,4-dihydroxyphenyl) -2-isopropylamino -ethanol] to half its normal level. On a rat uterus pretreated with streptosotocin, the tested compound has no effect when used at a concentration of 100 µg / ml. At a concentration of 50 µg / ml, the tested compound sets in motion the uterine preparation of the untreated rat, which is stopped by noradrenaline. This effect is identical to that of 0.5 µg / ml "Inderal" ® [1-isopropylamino-3- (1-naphthyloxy) -propan-2-ol]. On isolated strips of rat gastric fundus treated with streptosotocin, the tested compound shows no effect at a concentration of 10 µg / ml as opposed to 0.01 µg / ml "Isoprenaline", where a relaxation of 25 mm is observed. On isolated strips of untreated rat stomach, even a test compound concentration of 100 µg / ml has no effect on the dose-response curve of "Isoprenaline", which means that it exhibits a strong β-blocking effect on diabetic tests and little effect in normal trials.

150196 10

Hypoxia survival time is extended by one order of magnitude of the test compound.

Isoprenaline induced tachycardia is also negatively affected by the compound tested. 5 minutes after- after intravenous administration of a dose of 10 mg / kg, the heart rate increased by 10% and 5 minutes after the intravenous administration of a dose of 100 mg / kg the frequency decreased by 3%.

Tests carried out on the product of Example 5 [O- (3-piperidino-2-hydroxy-1-propyl) -nicotinamidoxime - dihydrochloride)

The mean value calculated from the differences in pD2 values on a diabetic aortic coil is x = 1.25. The corresponding value in the control experiment is x = 0.57. Used at a concentration of 50 µg / ml, the test compound lowers the effect of 0.001 µg / ml "Isoprenaline" from 16 mm to 5 mm. Used at a concentration of 100 µg / ml, it completely offsets the effect of 0.001 µg / ml "Isoprenaline" and lowers the effect of 0.01 µg / ml "Isoprenaline" from 28 mm to 19 mm.

Experiments have been carried out to determine whether the noradrenaline-induced contractions on aortic spiral preparations of diabetic animals treated with streptosotocin and not treated, respectively, could be compensated with "Inderal". For control, such animals are selected where no receptor conversion takes place. In the case of animals treated with streptosotocin, the mean difference between the pD2 values (before and after the administration of "Inderal") in the dose-response curves of noradrenaline is as follows: x = 1.0335, Sx = 0.0829 , t = 3.5885, p <0.01, n = 8. On non-diabetic preparations, "Inderal" has no effect on the noradrenaline-induced contractions.

Experiments have been carried out to determine if it is possible to find a connection between the compounds that are structurally close (the 3-blocking agents) and which have an effect on the aortic helix of a diabetic animal that is equal to "Inderal" effect, without exerting any significant influence on the normal β reactions. In other words, a compound is searched for a compound that has a specific effect on the modified β effect that occurs in diabetic vessels. the following compounds of the invention have been tested: NP-18: 0- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethyl-phenyl-acetamidoxime dihydrochloride, NP-51: O- (3-piperidino) 2-hydroxy-l-propyl) -nicotinamidoxim - dihydrochloride.

On the aortic helix of animals treated with streptosotocin, the difference between the pD ^ values before and after administration of a dose of NP-18 of 1 µg / ml is: X = 0.6422, Sx = 0.129, t = 4.9783, p <0.01, n = 6.

It has been found that if the initial receptor conversions are inhibited by the addition of compounds NP-18 or NP-51, the histological final changes do not occur.

Ca. 60% of the rats belonging to the CFY strain used in the experiments are in a latent diabetic state, which is detected by sugar loading experiments. In some of these animals (weight = 400-500 g), diabetic macro- and microangiopathy are detected. In the animals treated with the compounds NP-18 or NP-51 at a weight of 200 g, no microangiopathy has been developed when they reach a weight of 500 g, and the degree of macroangiopathy is also substantially smaller.

It has also been found that, although they inhibit the effect of "Isoprenaline" on guinea pig trachea, NP-18 and NP-51 exhibit an effect 4 orders of magnitude less than that of "Inderal". The compounds show no significant effect on blood pressure, heart rate, minute volume and dp / dt value in anesthetized cats. They do not affect the effect of "Isoprenaline" with respect to the above parameters and cause only bradyochardia and decrease in dp / dt at a dose of 100 µg / kg. The effect is equal to the effect of an inner dose of 0.5 µg / kg.

The difference between the β-blocking activity of the novel compounds of general formula I and of the inner on a cat papillary muscle is also four orders of magnitude. In guinea pig ileum, they only affect the action of barium chloride and acetylcholine at a dose of 50-100 µg / ml. Neither the compound NP-18 nor the compound NP-51 have any influence on the attachment of mice to a rotating rod.

LD5Q: NP-18 165 mg / kg i.v. mice NP-51 123 mg / kg i.v. mouse

The compounds of general formula I and their pharmaceutically acceptable salts find their use in the therapy in the form of pharmaceutical compositions in which the active ingredient is accompanied by the conventional pharmaceutical carriers.

The compositions may be present e.g. in the form of tablets, dragons, injections or capsules.

Further details of the invention can be found in the following examples.

Example 1 2.3 g of sodium are dissolved in 200 ml of absolute ethanol and 13.6 g of benzamidoxime are added. A solution of 3-piperidino-2-hydroxy-1-chloro-propane in 50 ml of absolute ethanol (prepared from 9.3 g of epichlorohydrin and 8.5 g of piperidine in known manner) is then added dropwise at the boiling temperature of the mixture. The reaction mixture is refluxed for 8 hours and filtered and the solvent is evaporated in vacuo. To the residue 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 0- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime, m.p. 97 ° C (from diisopropyl ether).

Molecular 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%.

13 150196

The dihydrochloride of the product is precipitated from isopropanol solution by the addition of gaseous hydrogen chloride or by the addition of an alcoholic solution of hydrochloric acid, m.p. 212-214 ° C (from isopropanol). Molecular weight: 350.29,

Elemental analysis for C ^ I ^N₂CCC C:

Calculated: Cl = 20.24%,

Found: Cl = 19.90%.

LDgQ = 70.5 mg / kg i.v. on mice.

The nicotinic acid salt of the product obtained is prepared in solution in absolute ethanol by the addition of gasoline when the salt crystallizes, m.p. 112 ° C (from methyl ethyl ketone).

Molecular weight: 400.46,

Elemental analysis for C2i®28N4 ° 4:

Calculated: C = 62.98%; H = 7.05%; N = 14.00%

Found: C = 62.84%; H = 7.11%, N = 13.76%.

The dihydrochloride exhibits poor α-blocking activity in normal animals and a strong β-blocking activity in Diabetes Experiments conducted as described in the preamble of the specification.

LD (-q = 7 0.5 mg / kg i.v.) in mice.

Example 2.

Following the method described in Example 1, starting from 3,4-dimethoxyphenylacetamidoxime and 3-piperidino-2-hydroxy-1-chloropropane, O- (3-piperidino-2-hydroxy-1-propyl) is prepared. ) - 3,4-dimethoxyphenylacetamidoxime dihydrochloride, m.p. 202 ° -203 ° C (from absolute ethanol). Molecular weight 424.38.

Elemental analysis for c18 H3] N3 ° 4C12:

Calculated: C = 50.94%; H = 7.36%; N = 9.90%; Cl = 17.71%;

Found: C = 50.80%; H = 7.57%; N = 9.84%; Cl = 16.42%.

LDj.q = 165 mg / kg i.v. (on mouse).

14 Trachea helix and papillary muscle may show little β-blocking activity. The effect on papillary muscle at a concentration of 100 µg / ml is identical to the effect caused by 0.05 µg / ml "Inderal". In the gastric fundus, the compound at a concentration of 100 µg / ml has no effect on the activity of "Isoprenaline". However, on the aortic spiral of a diabetic animal, an inhibition of one order of magnitude has been observed.

Example 3

Following the procedure described in Example 1, but starting from 3,4-dimethoxyphenylacetamidoxime and 3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-hydroxy-1-chloropropane, O- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-hydroxy-1-propyl] -3,4-dimethoxyphenylacetamidoxime dihydrochloride, m.p. 189 ° C (from isopropanol).

Molecular weight: 472.40.

Elemental Analysis for C22H31N3 ° 4 <2>:

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 method described in Example 1, starting from 3,3-diphenyl-propionamidoxime and 3-pipe-ridino-2-hydroxy-1-chloro-propane, O- (3-piperidino-2) is obtained. -hydroxy-1-propyl) -3,3-diphenylpropionamidoxime dihydrochloride, m.p. 228-230 ° C (from isopropanol).

Elemental analysis for C23H33N3 ° 2C12:

Calculated: C = 60.79%; H = 7.32%; N = 9.25%; Cl = 15.60%,

Found: C = 60.45%; H = 7.25%; N = 8.94%; Cl = 15.79%.

Example 5

Following the method described in Example 1, but derived from nicotinamidoxime and 3-piperidino-2-hydroxy-1-chloropropane, O- (3-piperidino-2-hydroxy-1-propyl) - nicotiriamidoxime is prepared. dihydrochloride, m.p. 204 ° C (from absolute ethanol). Molecular weight: 351.27.

150196

Elemental analysis for C14H2A ° 2CV

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%.

LDjjq. = 123 mg / kg i.v. (on mouse).

The product of this example shows little β-blocking activity in normal experiments.

The nicotinic acid salt of the product precipitates from ethyl acetate, m.p. 111 ° C (from ethyl acetate). Molecular weight: 401.46.

Elemental Analysis for C20H27N (.04:

Calculated: C = 59.83%; H = 6.77%; N = 17.44%;

Found: C = 59.80%; H = 6.92%; N = 17.23%.

LD₂-q = 250 mg / kg i.v. (on mouse).

The product exhibits strong β-blocking activity on a diabetic aortic coil.

Example 6

To 17.8 g of 3-piperidino-2-hydroxy-1-chloropropane is added a solution of 10.45 g of 3,4-dimethoxyphenylacetamidoxime in 40 ml of 10% sodium hydroxide (prepared with heating) at room temperature with stirring dropwise. one hour. The reaction mixture is stirred at room temperature for 8 hours and allowed to stand overnight. The resulting oily product is extracted with benzene, the extract is dried over sodium sulfate and the solvent is evaporated. From an ethyl acetate solution of the residue, 10.5 g of O- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethoxyphenylacetamidoxime dihydrochloride crystallizes on the addition of gaseous hydrogen chloride. The product is identical to the product of Example 2, m.p. 201-203 ° C.

Example 7

To a benzene solution of 8.8 g of 3-piperidino-2-hydroxy-1-chloropropane is added a solution of 5.2 g of 3,4-dimethoxyphenylacetamidoxim in 40 ml of 10% sodium hydroxide solution (prepared under heating) at room temperature with stirring dropwise over 1/2 hour. The reaction mixture is stirred at room temperature for an additional 8 hours and allowed to stand overnight. The benzene phase is separated and the aqueous phase is extracted with benzene. The benzene solution is dried over sodium sulfate and the solvent is evaporated. From the residue is obtained using the method described in Example 6 to prepare the hydrochloride 0- (3-piperidino-2-hydroxy "l -Propyl) -3,4-dimethoxy-phenylacetamidoxime dihydrochloride. The compound is identical to the product of Example 2nd

Example 8.

To 8.8 g of 3-piperidino-2-hydroxy-1-chloropropane is added a solution of 5.2 g of 3,4-dimethoxyphenylacetamidoxime in 40 ml of 10% sodium hydroxide solution and 40 ml of methanol, stirring dropwise over 1/2 hour. The mixture is stirred at room temperature for an additional 8 hours and allowed to stand overnight. After evaporation of the methanol, the extraction is carried out with benzene and the salt formation reaction as described in Example 7. O- (3-piperidino-2-hydroxy-1-propyl) - 3,4-dimethoxyphenylacetamidoxime dihydrochloride, which is identical to the product of example, is obtained. 2nd

Example 9

To 2.72 g of benzamidoxime are added 40 ml of benzene and 0.8 g of powdered sodium hydroxide. The reaction mixture is boiled for 1 hour under a water separator and 4.5 g of 3-piperidino-2-hydroxy-1-chloropropane in 10 ml of benzene is added dropwise to the boiling mixture. After boiling for 12 hours, the solvent is evaporated and 20 ml of 10% sodium hydroxide solution is added to the residue. The resulting oily substance is extracted with benzene and the benzene solution is evaporated.

3.6 g of O- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime are obtained. The compound is identical to the product of Example 1.

Example 10.

To a sodium ethylate solution prepared from 2.3 g of sodium and 200 ml of absolute alcohol is added 15.5 g of 4-chlorobenzamidoxime, and then 9.3 g of epichlorohydrin is added dropwise at 0 ° C to 10 ° C. The reaction mixture is stirred at 0-10 ° C for 8 hours and allowed to stand overnight at this temperature. The precipitated sodium chloride is filtered off until the filtrate is added dropwise with 8.6 g of piperidine and the mixture is stirred for an additional 8 hours at room temperature. The reaction mixture is heated to the boiling point, and the solvent is evaporated in vacuo. To the residue is added 50 ml of 5% sodium hydroxide solution and the oily substance is extracted with benzene. The benzene solution is dried over sodium sulfate and evaporated and the residue is dissolved in alcohol. 11.0 g of 0- (3-piperidino-2-hydroxy-1-propyl) -4-chlorobenzamidoxime dihydrochloride, m.p. is added by the addition of gaseous hydrogen chloride or the addition of hydrochloric acid in alcohol. 215-217 ° C (from absolute ethanol).

Molecular Weight: 384.73.

Elemental analysis for C ^ gl ^ ^N ^O₂Cl ^:

Calculated: C = 46.83%; H = 6.29%; N = 10.92%;

Found: C =. 46.57%; H = 6.41%; N = 10.58%.

The product exhibits a weak β-blocking activity in normal trials and a strong β-blocking activity in Diabetes trials.

Example 11.

Following the method described in Example 10, but starting from phenylacetamidoxime using diethylamine as an amine component, O- (3-diethylamino-2-hydroxy-1-propyl) -phenyl-acetamidoxime dihydrochloride, m.p. 156-158 ° C (from isopropanol). Molecular weight: 352.30.

Elementary analysis for

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%.

Example 12.

Following the method described in Example 10, but starting from phenylacetamidoxime using piperidine as the amine component, O- (3-piperidino-2-hydroxy-1-propyl) -phenylacetamidoxime dihydrochloride, m.p. 200 ° C (from absolute ethanol).

Molecular weight: 364.31.

Elemental analysis for cig ^ 27N3 ^ 2 <'' * '2:

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

18 150196

Following the method described in Example 10, but starting from 4-chlorophenylacetamidoxime and using morpholine as an amine component, O- (3-morpholino-2-hydroxy-1-propyl) -4-chlorophenylacetamidoxime dihydrochloride is obtained. , m.p. 175-178 ° C (from absolute ethanol). Molecular weight: 400.73.

Elemental analysis for c15 H24 N3 ° 3C13:

Calculated: C = 44.96%; H = 6.04%; N, 10.48%; Cl - 26.54%;

Pound: C = 45.20%; H = 6.10%; N = 10.52%; Cl = 26.50%.

Example 14.

Following the method described in Example 10, starting from 3,3-diphenyl-propionamidoxime and using isopropylamine as an amine component, O- (3-isopropylamino-2-hydroxy-1-propyl) - 3,3-diphenylpropionamidoxime dihydrochloride, m.p. 179 ° C (from acetone / water mixture).

Molecular weight: 428.39.

Elemental analysis for C₂iH3iN3 ° 2C12:

Calculated: C = 58.57%; H = 7.29%; N = 9.81%; Cl = 16.55%;

Found: C = 58.58%; H = 7.39%; N = 9.53%; Cl = 16.70%.

LDtje = 16.25 mg / kg i.v. (on mouse).

The compound has a strong β-blocking effect on diabetic aortic helix.

Example 15

Following the method described in Example 10, but starting from 3,3-diphenylpropionamidoxime and using diethylamine as an amine component, O- (3-diethylamino-2-hydroxy-1-propyl) -3 is prepared. 3-diphenylpropionaminoxime dihydrochloride, m.p. 225 ° C (from isopropanol).

Molecular weight: 442.42.

Elemental analysis for C22H33W3 ° 2C2:

Calculated: C = 59.72%; H = 7.52%; Cl = 16.03%;

Found: C = 59.68%; H = 7.55%; Cl = 16.07%.

Example 16 »19 150196

Following the method described in Example 10, starting from 3,3-diphenylpropionamidoxime and using 2-methylaminoethanol as an amine component, 0- [3-N-methyl-N- (2-hydroxyethyl) is prepared. ) -amino-2-hydroxy-1-propyl] -3,3-diphenylpropionamide dihydrochloride, m.p. 175 ° C (from isopropanol).

Molecular weight: 444.39.

Elemental analysis for ¢ 21 ^ 31 ^ 3 ^ 3 ^ 25

Calculated: C = 56.78%; H = 7.03%; N = 9.45%; Cl = 15.96%,

Pound: C = 56.40%; H = 7.09%; N = 9.14%; Cl = 15.92%.

LDgg = 37 mg / kg i.v. (on mouse).

The compound exhibits a strong β-blocking activity on diabetic aortic helix.

Example 17

Following the method described in Example 10, but starting from 3,3-diphenyl-propionamidoxime and using pyrrolidine as an amine component, O- (3-pyrrolidino-2-hydroxy-1-propyl) - 3,3-diphenylpropionamidoxime dihydrochloride, m.p. 218 ° C (from isopropanol). Molecular weight: 440.40.

Elemental analysis for C22H31N3 ° 2C12:

Calculated: C = 59.99%; H = 7.10%; Cl = 16.10;

Found: C = 59.63%; H = 7.32%; Cl = 16.44%.

Example 18.

Following the method described in Example 10, but starting from 3,3-diphenylpropionamidoxime and using piperidine as an amine component, O- (3-piperidino-2-hydroxy-1-propyl) -3,3- diphenyl-propionamidoxime dihydrochloride. The product is identical to the product of Example 4, m.p. 228-230 ° C. (from isopropanol).

Example 19.

Following the method described in Example 10, starting from 3,3-diphenyl-propionamidoxime and using heptamethylenimine as an amine component, O- (3-heptamethyleneamino-150196 -2-hydroxy-1-propyl) is prepared. ) -3,3-diphenylpropionamidoxim dihydrochloride, m.p. 233 ° C (from isopropanol).

Molecular weight: 482.48.

Elemental analysis:

Calculated: C = 62.24%; Η 7.73%; Cl = 14.70%;

Found: C = 61.97%; H = 7.70%; Cl = 14.74%.

Example 20

Following the method described in Example 10, starting from 3,3-diphenylpropionamidoxime and using morpholine as an amine component, O- (3-morpholino-2-hydroxy-1-propyl) -3 is prepared. 3-diphenylpropionamidoxim dihydrochloride, m.p. 225 ° C (from isopropanol). .

Molecular weight: 456.40.

Elemental Analysis for C 22 H 31 N 3 O 3 C 2 O 3 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 method described in Example 10, starting from 1-naphthylacetamidoxime and using diethylamine as an amine component, O- (3-diethylamino-2-hydroxy-1-propyl) -1-naphthylacetamidoxime hydrochloride is prepared, mp. 150-152 ° C (from absolute ethanol).

Molecular weight: 365.89.

Elemental analysis for C

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 method described in Example 10, but assuming. 1-naphthylacetamidoxime and using piperidine as an amine component, O- (3-piperidino-2-hydroxy-1-propyl) -1-naphthylacetamidoxime hydrochloride is prepared, m.p. 177-179 ° C (from absolute ethanol).

21 150196

Molecular weight: 377.89.

Elemental analysis for C20H2GN3C> 2Cl:

Calculated: C = 63.57%; H = 7.46%; N = 11.12%; Cl = 9.38,

Pound: C = 63.58%; H = 7.59%; N = 11.47%; Cl = 9.60%.

Example 23

To a mixture of 4.0 g of benzamidoxime, 10 ml of water and 4.5 g of epichlorohydrin is added 20 ml of 10% sodium hydroxide solution with stirring at room temperature dropwise over 1 hour. The reaction mixture is then stirred for an additional 2 hours, 4.5 g of piperidine is added dropwise and stirring is continued for an additional 8 hours. The oily substance is extracted with benzene. Evaporation of the benzene solution gives 6.2 g of 0- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime. The compound is identical to the product of Example 1.

Example 24.

Dissolve 6.8 g of benzamidoxime in 40 ml of 10% sodium hydroxide solution and add 9.5 g of epichlorohydrin with stirring. The reaction is exothermic and therefore the temperature of the mixture is maintained at _30-35 ° C by external cooling. After two hours of stirring, 8.6 g of piperidine are added dropwise. The mixture is stirred for a further 2 hours and the resulting oily substance is extracted with benzene. Evaporation of the benzene gives 8.2 g of O- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime. The compound formed is identical to the product of Example 1.

Example 25

6.8 g of benzamidoxime are dissolved in 50 ml of 10% sodium hydroxide solution and 9.5 g of epichlorohydrin in 20 ml of benzene are added dropwise with vigorous stirring. After stirring for 4 hours, 8.6 g of piperidine are added dropwise and the mixture is stirred at room temperature for an additional 8 hours. The benzene phase is separated and the aqueous layer is extracted with benzene.

Evaporation of the combined benzene solutions gives 0- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime. This compound is identical to the product of Example 1.

Example 26

Dissolve 6.8 g of benzamidoxime in a mixture of 20 ml of 10% sodium hydroxide solution and 20 ml of methanol and 9.5 g of epichlorohydrin added dropwise with stirring. After stirring for 2 hours at room temperature, 8.6 g of piperidine are added dropwise and stirring is continued for an additional 8 hours. The methanol is evaporated in vacuo and the oily substance is extracted with benzene. Evaporation of the benzene solution gives 7.2 g of O- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime. This compound is identical to the product of Example 1.

Example 27

To a solution of 5.2 g of 3,4-dimethoxyphenylacetamidoxime in 20 ml of dimethyl sulfoxide is added 2.4 g of sodium tert-butylate with stirring. Then 3.0 g of epichlorohydrin is added dropwise and the mixture is stirred at room temperature for two hours. Then a solution of 2.5 g of piperidine in 60 ml of acetone is added and the reaction mixture refluxed for 8 hours, then 120 ml of ethyl acetate is added. When gaseous hydrogen chloride is added 4.4 g of O- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethoxyphenylacetamidoxime dihydrochloride is obtained in crystalline form. This salt is identical to the product of Example 2.

Example 28.

Following the method described in Example 6, starting from 2-phenyl-propionamidoxime and 3-piperidino-2-hydroxy-1-chloro-propane, O- (3-piperidino-2-hydroxy-1-propyl) is obtained. ) -2-phenylpropionamide oxime dihydrochloride, m.p. 225 ° C (from isopropanol).

Elemental 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 »23 150196

Following the method described in Example 6, but starting from 3-cyclohexylamino-2-hydroxy-1-chloropropane [J. Org. Chem., 24, 615 (1959)] and nicotinamidoxime, O- (3-cyclohexylamino-2-hydroxy-1-propyl) nicotinamidoxime, m.p. 102 ° C (from a mixture of benzene and toluene).

Molecular weight: 292.37.

Elemental analysis for C 20 H 24 N 4 ° 2;

Calculated: C = 61.62%; H = 8.27%; N = 19.16%.

Found: C = 61.44%; H = 8.23%; N = 18.89%.

Example 30.

Dissolve 1.38 g of racemic O- (3-piperidino-2-hydroxy-1-propyl) -benzamide oxime and 1.16 g of d-camphor sulfonic acid in 20 ml of warm ethanol and evaporate the solution in vacuo. The residue is recrystallized first from butyl acetate and then from ethyl acetate. 0.4 g of D-O- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime-D-camphor sulfonate, m.p. 132 ° C.

From the salt produced, the base is released in a conventional manner and the base obtained is converted to a hydrochloride. The hydrochloride melts at 196 ° C.

[aI559ma = + 6'3 ° (<= = 1% water).

Example 31.

Dissolve 1.15 g of metallic sodium in 100 ml of absolute ethanol and add 12.0 g of 3,3-diphenyl-propionamidoxime. While boiling, 13.2 g of 2-phenyl-3-isopropyl-5-chloromethyloxazolidine is added dropwise and the reaction mixture is boiled for an additional 16 hours. The solvent is evaporated, 110 ml of 5N hydrochloric acid is added to the residue and refluxed for 1 hour. The solution is extracted with ethyl acetate, decolorized with animal charcoal and adjusted to alkalinity 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 oxime dihydrochloride is obtained. This compound is identical to the product of Example 14, m.p. 179 ° C.

Example 32.

24 150196

Following the method described in Example 31, but starting from 2-phenylpropionamidoxim and 2-phenyl-3-isopropyl-5-chloro-methyloxazolidine, O- (3-isopropylamino-2-hydroxy-1-propyl) - 2-phenylpropionamidoxim dihydrochloride hemihydrate, m.p. 168 ° C (from a mixture of acetone and isopropanol).

Molecular weight: 361.31.

Elemental analysis for C 15 H 27 N 3 ° 2 Cl 2 0.5 H 2 O:

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 method described in Example 31, starting from beiizamidoxime and 2-phenyl-3-isopropyl-5-chloromethyloxazolidine, O- (3-isopropylamino-2-hydroxy-1-propyl) -benzamidoxime-di hydrochloride hemihydrate, m.p. 173-174 ° C.

Molecular weight: 333.26.

Elemental analysis for C

Calculated: C = 46.85%; H = 7.26%; N = 12.61%; Cl = 21.28%;

Found: C = 47.05%; H = 7.13%; N = 12.41%; Cl = 21.54%.

Claims (6)

150196 F a t e n t k r a v. An analogous process for the preparation of O- (3-amino-2-hydroxypropyl) amidoxime derivatives of the general formula R5 R6 R4- (CH) m- (CH) nC-ra2 N-O-CH ~ -CH-CH- -N '2 i 2 \ -. / OH XR- 'where 2 R is hydrogen or alkyl of 1 to 5 carbon atoms, R 3 represents alkyl of 1 to 5 carbon atoms optionally substituted by hydroxy or means cycloalkyl, or 2 3 R and R together with the nitrogen atom to which they are attached form a piperidine, 1,3,4 5-tetrahydro-2-isoquinoline, morpholine, pyrrolidine or perhydroazocin ring, R is hydrogen, naphthyl, pyridyl or phenyl optionally substituted by one or more halogen atoms or one or more alkoxy groups, R is hydrogen or phenyl, g R is hydrogen or phenyl, m = 0, 1 or 2, and n = 0, 1 or 2, or pharmaceutically acceptable salts thereof, characterized in that a) reacting an amidoxime with the general one formula R5 R6 4. in R - (CH) m- (CH) nC-NH2 (XI) N-OH where 4 6 R, R, R, n and m have the meaning given above, with an amine of the general formula X-CHO-CH-CHO-N * - (ΙΙΙΑ) 2 \ 2 \ 3 / OH - or / r 2 '' CHO-CH-CHO-N .; '(IIIB) \ y 2 where 2 3 R and R have the meaning given above and X means halogen, in the presence of a base, or b) reacting an amidoxime of the above general formula II, AC g where R, R, R , m and n have the meaning given above, with epichlorohydrin and react the resulting amidoxime of the general formula f 6 R 4 - (CH) - (CH) -ΟΝΗ- mn „2 (V) NO-CH - CH-CH -2 \ / 20 0 after or without isolation, with an amine of the general formula γ-; (IV) RJ where - R and R have the meaning given above, or c) react an alkali metal salt of a compound of the above general formula II wherein R4, R5, R6, m and n have the meaning given above, with a 2- phenyl-3-substituted-5-chloromethyloxazolidine of the general formula C 0 N-R (VI) X