CS204008B2 - Process for preparing new derivatives of 0-/3-amino-2-hydroxypropyl/-amidoxime - Google Patents

Abstract

The compounds of general formula I, wherein R<1> to R<5>, m and n have the meaning given in Claim 1, are valuable medicaments which are suitable for the treatment of diabetic angiopathy. They are prepared by either reacting an amidoxime of formula II with epichlorohydrin to give an epoxide of formula IV and then reacting the epoxide with an amine of formula III or by directly reacting the amidoxime of formula II with a 3-amino-2-hydroxy-1-halogenopropane of formula Va, wherein X represents halogen, or a 3-amino-1,2-epoxypropane of formula Vb. Compounds of formula I, wherein R<1> denotes hydrogen, are also prepared by reacting an amidoxime of formula II with a 2-phenyl-5-halogenomethyloxazolidine of formula VI, wherein X represents halogen, after which the ring compound obtained, of formula VII, is cleaved hydrolytically. <IMAGE>

Description

Diabetes mellitus is a common metabolic disease. Its main symptom is a disorder of the balance of metabolism of carbohydrates in the body. Diabetes mellitus is often accompanied by disease changes in the vascular system, such as narrowing of the blood vessels of the limbs, disease changes in the blood vessels of the ocular background, etc. While numerous effective drugs are known to reduce high blood sugar in addition to insulin, Angiopathic preparations now on sale are very scarce. The reason for this is that, with the emergence of diabetes mellitus, the adrenergic vascular receptors are altered and adrenergic reactions that differ from those in non-diabetic patients occur as a result of drug treatment [Nature Nsw Biology 243, No. 2, p. 130, 276 (1973); Szemeszet 111, 23 (1974); Endocrinology 93, 752 (1973)]. «-Receptors of blood vessels are transformed into yokes for quantitative increase of

changes to β-receptors. The release of modulator substances is responsible for this recipe transformation [Amer. J. Physiol. 218, 86 (1970)]. When this substance is added to the β-organ, α-agonists are no longer active, since the receptor has been converted to the β-receptor. The original sensitivity is reversed when the blocking agent is administered simultaneously.

In the case of a qualitative change in metabolism, both α-agonists (e.g. noradrenaline) will continue to be effective in both experimental and human diabetes, but their effect can be removed by a blocking agent. This is the first functional change that can be demonstrated in diabetes 24 hours after the administration of alloxane (hexahydropyrimidine intrara). In diabetes, an imperfect β-receptor conversion plays a role as a starting point for change. This is probably due to the formation of a substance that differs from the original.

It has now been found that the novel compounds of the general formula I, where R is

R ( ^{1) is} hydrogen or (C1 -C5) alkyl;

R 2 is optionally C 1 -C 5 alkyl, C 1 -C 5 alkyl, C 5 -C 8 cycloalkyl, or phenyl, or

R 1 and R 2 together with the adjacent nitrogen atom form - a saturated heterocyclic ring of 5 to 8 carbon atoms, which optionally contains further heteroatoms, preferably oxygen or nitrogen, and / or is optionally condensed with a phenyl ring,

R 3 is optionally halogen, C 1-4 alkoxy, C 1-4 alkyl-substituted C 5 -C 8 cycloalkyl or phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, pyrazolyl, on which optionally a phenyl ring is fused,

R4 is hydrogen, optionally halogen or C ₅ alikoxyskupinu substituted C ^ alkyl - or _C5 _8 cycloalkyl or • phenyl,

R 5 hydrogen, C 1-5 alkyl or phenyl, m- · 0, 1 or 2, η 0, 1-or 2, do not affect or affect only the slightly adrenergic reactions of healthy blood vessels, but on adrenergic receptors, altered by diabetes mellitus, it has a strong effect. This effect primarily manifests itself as a selective β-blocking effect. Therefore, the compounds of the invention are useful in the treatment of diabetic -angiopathies. Some of the compounds of the invention exhibit a blood pressure lowering effect as well as an α-blocking effect.

The invention therefore relates to a process for the preparation of amidoximes of the general formula I as well as their salts. The process according to the invention may be characterized in that the compound of formula II,

R ³ - (CH) _m - (CH) _{n -} C = N - OH

I I I

R4 R5 NH2 (Π) wherein the meanings of R3, R4, R5, m and n are the same as above, epichlorohydrin and amine of formula III

HN

(III) are reacted together in any order, optionally with isolation of the compounds of formula (IV),

R 3 - (CH) m - (CH) n - C = N - O - CH 2 - CH - CH 2

III \ z

R 4 R 3 NH 2 (IVj and optionally the compounds of formula I obtained are reacted with inorganic or organic acids to form their salts and / or are liberated from their salts.

The reaction is preferably carried out in an aqueous medium, in organic solvents containing water, for example in an alcohol-water mixture, and in a reaction medium containing one aqueous and one organic phase. The reaction is preferably carried out at -10 to 140 ° C

According to. In the process, the amtdoximes of formula II are reacted with eplchlorohydrin in the presence of a base. The epoxy compound thus formed may optionally be isolated, but it is preferable not to separate the intermediate, but to carry out the reaction in a single step in aqueous medium or in organic solvents or in organic solvents containing water or in two-phase solvent mixtures of -10 to 100 ° C. .

According to a preferred embodiment of the process, the amidoxime is dissolved or suspended in aqueous hydroxide and the solution or suspension is supplemented with 1 to 4 times molar amounts of epichlorohydrin. The addition of epichlorohydrin is carried out with stirring at -10 to + 60 °

Celsius. Epichlorohydrin is added or added dropwise in multiple doses. It does not matter which of the reaction components is presented and which s-e drips, the order may also be reversed. The intermediate of formula (IV) may optionally be isolated by extraction with a water-immiscible solvent. However, it is preferable not to isolate the compound of the formula IV but to react it immediately with the corresponding amine of the formula III.

For amidoximes which are poorly soluble in aqueous hydroxide, an organic solvent containing water, such as aqueous alcohol - or dioxane, can also be used as the solvent. The reaction may also be carried out in the presence of an emulsifier or in a two-phase system. In this case, the epichlorohydrin is dissolved in an organic water-immiscible solvent (e.g. benzene or ether) and the solution is added to a solution or suspension of amidoximes prepared with aqueous hydroxide. Alternatively, a solution of epichlorohydrin can be introduced and the amidoxime component added.

It is also possible to work in anhydrous solvents, for example anhydrous alcohols. In this case, it is preferable to form the alkali metal salt of the amidoxime by dissolving the amidoxime in an alcoholic solution of an alkali metal alcoholate. After addition of epichlorohydrin, the reaction mixture is allowed to stand for 1 to 5 days at 0 to 20 ° C, then the corresponding amine is added and the reaction mixture is optionally heated. Suitable anhydrous solvents are, in addition to alcohols, other organic solvents, for example acetone, dimethyl sulfoxide, dimethylformamide and mixtures thereof.

The reaction products are separated in a conventional manner. When using an aqueous reaction medium, the products are separated by crystallization or extraction. The compounds are crystallized from the organic solvent medium or the solvent is evaporated, the residue is washed with water and then extracted. The products may also be isolated in the form of their salts, and the free bases may optionally be liberated from the salts. A salt can be formed from the free bases by addition of 1 to 2 equivalents of an organic or inorganic acid. For the formation of salts, it is preferable to use conventional non-toxic acids in pharmacy.

General β-receptors blocking the action of compounds of formula I have been tested on a prepared tracheal ring [J. Pharm. Exp. Therap. 90, 104 (1947j] and the papillary muscle of the cat. Selective β-blocking effect should; l .spirálním tested on rat aorta preparation [J. Pharmacol. Exp. Therap. 158, ¹⁵³¹ and (196'7J] follows .:

The animals were opened the ribcage and the thoracic aorta were removed and spirally cut. The movements of the currently expanding spiral were registered on two rollers provided with a soot deposit by means of an isoionic registration arm. On one cylinder the reaction of the control preparation (hereinafter the controls) was registered, on the other the aorta reaction of the rats treated with streptosotocin [2- (3-nitroso-4-methylureido) -2-desoxy-D-glucose] doses of noradrenaline (NA) were not affected by the test compound on the control preparation, but were affected on the diabetic aorta. The effect of the compounds according to the invention is generally selective, which is indicated by the fact that the diabetic test results in a potent. in the normal test, there is little or no blocking effect.

A typical representative of the compounds of the invention O- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethoxyphenylacetamide oxime dihydrochloride exhibits the following effects:

The pD2 value, i.e. the negative logarithm of the dose belonging to half the maximal effect, was determined. From the differences in the pD2 values calculated, the average of five consecutive measurements for the diabetic aortic spiral is x - 1.31, while the value measured for the normal aorta was around x = 0.52. In guinea pig trachea, 10 µg of test compound reduced the effect of 0.01 µg / ml isoprenaline [D, L · -1- (3,4-dihydroxyphenyl) -2-isopropylaminoaiceeal] by half. On uterus of rats pretreated with streptosotocin, the compound at a concentration of 100 µg / ml is ineffective. At a concentration of 50 µg / ml, the compound acts on the uterine preparation of untreated rats, maintained by noradrenaline. This effect corresponds to an effect of 0.5. (g / ml of inderal [liisopropylamino-3- (1-naphthyloxy) propan-2-yl)]. The compound is ineffective on the stomach fund strips of rats pretreated with streptosotocin at a concentration of 10 µg / ml, as opposed to 0.01 µg / ml isoprenaline, which produces a slackness of about 55 mm. The compound does not affect the stomach fund tape of untreated rats. a dose-response curve of iiso-prenalin at a concentration of 100 µg / ml. . This means that the compound has a weak β-blocking effect in a normal test, a diabetic test.

The compound prolongs survival hypoxia by the order of magnitude.

Tachycardia caused by isoprenaline (1 / g / kg i.v.) is influenced to a minor extent by the compound. Mice were 10 minutes after IV administration. mg / kg measured increase in heart rate by 10%, during 5. minutes after i.v. application of 100 mg / kg, the heart rate decreased by 3%.

The compound produced according to Example 5 exhibits. following. pharmacological effects:

From the difference pD ₂ values calculated. the mean values for the diabetic aorta spiral are x = 1.25, for the control x - 0.57. . The compound at a concentration of 50 .mu.l / ml reduces the effect of 0.001 .mu.l of isoprenaline from 16 mm. to 5 .mm. Used. at a concentration of 100 µg / ml completely. cancels the effect. 0.001 µg / ml isoprenaline, effect. induced by 0.01 µg / ml isoprenaline decreases from .28 mm to 19 mm.

Furthermore, experiments were carried out to determine:. Whether norepinephrine-induced contraction can be removed in spiral preparations of the aorta of animals treated with streptosotocin and spontaneously latent diabetic. . Animals without this receptor change were used as controls. It was found that in animals treated beforehand. streptosotocinem. differences in pD ₂ values of the effect curve of noradrenaline doses (pre- and post-inderal). were: 1.035, Sx = 0.0829, t = 3.5885, p. <0.01, n - 8. Noradrenaline inderal contraction was unaffected in non-diabetic preparations.

It has also been tested if there are compounds similar to the chemical structure / blocking compounds. . those that. would, like inderal, act on the aortic spiral of diabetic animals without substantially affecting the normal β-effects, i.e., the compounds for. which are specific in diabetic vessels resulting in "false" β-effects.

In the following explanations, the compounds of the invention are abbreviated as follows:

NP — 18:

O- (3-piperidino-2-hydroxy-4-propyl) -3,4-dimethoxyphenylacetamidoxime dihydrochloride

NP — 51:

O- (Bipiperidino-Z-hydroxy-1-propyl Jamidoxime-nicotinic acid dihydrochloride)

On the spiral-aorta of streptosotocin-treated animals, the difference (before and after administration of 1 -ug / ml NP-18) -pD2 values for noradrenaline was 0.6422, Sx = 0.129, t = 4.9783, p <0.01 , n = 6. In untreated animals, noradrenaline caused no significant difference in pD2 values before and after administration of NP-18. Similar - results were also achieved for NP — 51. In the streptosotocin group, the pD2 difference - induced by noradrenaline (pre- and post-administration values NP-51) is 0.8196, Sx = 0.08155, t 10.0503, p <0.001, n = 6.

It has been found that definitive histological changes are not produced when the initial receptor changes are suppressed, for example, by NP-18 or NP-51. A portion of the CFY rats (about 60%) used as test animals was latent diabetic, as evidenced by sugar loading. For a portion of these 400 to 500 grams - heavy. Diabetic macroangiopathy and microangiopathy were detectable in the animals: Animals that had been treated at 200 g NP-18 or NP-51 weighed up to 500 grams had no microangiopathy, and even macroangiopathy was significantly smaller.

Further-; It could be stated that although NP-18 and NP-51 suppress isoprenaline in guinea pig tracheas, their effect is about 4 units of magnitude less than that of inderal. The test compounds had no significant effect on blood pressure, heart rate, minute volume, and dp / dt value of narcotized cats. When investigating these parameters, the compounds had no effect on the isoprenaline effect, only at the dose. 100 µg / kg caused bradycardia and decreased dp / dt values. This effect was approximately as great as the effect of 0.5 µg / kg of inderal.

On cat papillary muscle, the difference in the β-blocking effect of the compounds of formula (I) and inderal is about 4 orders of magnitude. On guinea pig ileum, the compounds of the invention only affected the effect of barium chloride and methylcholine at a dose of 50 to 100 µg / ml. The ability of mice to hang on a spinning rod was not affected at 10 mg / kg ip. neither NP — 18 nor NP — 51.

of the following examples, without being limited thereto.

Example 1

2.3 g of sodium were dissolved in 200 ml of absolute alcohol and the solution was supplemented with 13.6 g of benzamidoxime. 3-Piperidino-2-hydroxy-1-chloropropane was prepared from 9.3 g of epichlorohydrin and 8.5 g of piperidine in a known manner and its solution made with 50 ml of absolute alcohol was added dropwise to the alcoholate solution while boiling. Reeakční mixture was refluxed for 8 h · reverse flow, then ^one filtered and the solvent evaporated in vacuo. The residue is made up to 100 ml of 5% sodium hydroxide and the oily product is extracted with benzene. After evaporation of the solvent, it is obtained

9.2 g of O- (S-ppeldino-4-hydroxy-1-propyl) benzamidoxime.

Melting point: 97 ° C (lower temperatures)

Analysis for C15H2.3N5O2 (M = -277.35)

Calculated:

% H, 8.36;% N, 15.15

Found:

% C, 64.69;% H, 8.46;% N, 14.87%

The dihydrochloride of the product can be separated from the solution prepared with isopropanol by introducing hydrogen chloride gas or by adding alcoholic hydrochloric acid. Mp .: 212-214 ° C (isopropanol).

Analysis for C 18 H 18 N 5 O 2 Cl 2 (M = 350.29)

Calculated: -20.24% Cl

Found: 19.90% Cl

LD50: 70.5 mg / kg iv. (mouse)

The nicotinic acid salt of the product can be formed in absolute alcohol. Crystallizes when gasoline is added. Melting point: 112 ° C (methylethylcatone).

Analysis for C21H2.aNdO-1 (M = 400.46)

Calculated:

% H, 7.05;% N, 14.00%

Found:

% H, 7.11;% N, 13.76

The dihydrochloride shows a weak -α-blocking effect in a normal test, and a strong β-blocking effect in tests for diabetes.

Example 2

As described in Example 1, the D 50 value was determined;

NP — 18: 165 mg / kg kg iv. (mouse)

NP-51: 123 mg / kg iv. (mouse)

The compounds of the formula I and their salts can be formulated in a manner known per se into tablets, dragees, injections, capsules and other preparations using pharmaceutical carriers and auxiliaries customary in the pharmaceutical industry.

The invention will be explained in more detail with the aid of Na204008, making N, N-dimethoxyphenylacetamidoxime and 3-piperidino-2-hydroxy-1-chloro-propanil O- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethoxyphenylacetamide oxime hydrochloride. Melting point: 202—203 ° C (absolute alcohol)

Analysis for C 18 H 31 N 3 O-1Cl 2 (M = 424.38) -

Calculated:

% C, 50.94;% H, 7.36;% N, 9.90;

50.80% C, 7.57% H, 9.84% N, 16.42% Cl LD50 - 165 mg / kg iv. (mouse).

The compound shows a weak blocking effect on the spiral trachea and on the papillary muscle; - on papillary muscle - the effect of the compound at a concentration of 100 µg / ml is equal to the effect of 0.05 µg / ml inderal. On the stomach fundus, the compound at a concentration of 100 <g / ml does not affect the effect of isoprenaline; on the other hand, blocking of one order of magnitude on the aortic spiral of a diabetic animal occurs.

Example 1 to d 3

In the manner described in Example 1, the reaction is carried out

3,4-dimethoxyphenylacetamidoxime-α 3- (1,2,3,4-tetrahydro-2-isoquinolinyl) -2-hydroxy-1-chloropropane produces O- [3- (1,2,3, 4-Tetrahydro-2-isolyl) -2-hydroxy-1-propyl] -3,4-dimethoxyflylyl acetamide oxime dihydrochloride.

Melting point: 189 - ° C (isopropanol)

Analysis for C 22 H 31 N 3 O 4 Cl 3 (M = 472.40)

Calculated:

H, 6.61; N, 8.89; Cl, 15.01

Found:

H, 6.82; N, 8.64; Cl, 14.75. Example 4

In the manner described in Example 1, z

3,3-diphenylamidoxime of propionic acid a

3-Piperidino-2-hydroxy-1-chloropropami-O- (3-piperidino-2-hydroxy-1-propyl) -3,3-diphenylamidoxime triphionic acid is obtained in the form of dihydrochloidide.

Melting point: 228 to 230 ° C (isopropanol)

Analysis for C23H33N3O2Cl (M = 454.42)

Calculated:

H, 7.32; H, 9.35. % N, 15.60% Cl

Found:

H, 7.25; N, 8.94; Cl, 15.79

Example 5

In the manner described in Example 1, O- (3-piperidino-2-hydroxy-propynamidoxime-nicotinic acid) was prepared from the nicotinamidoxime - and 3-piperidino-2-hydroxy-1-chloropropang in the form of dihydroxychloride.

Melting point: 204 ° C (absolute alcohol)

Analysis for C 14 H 24 N 1 O 2 Cl 2 (M - 351.27)

Calculated:

47.87% C, 6.89% H, 15.95% N, 20.19% Cl

Found:

H, 7.00; N, 15.64; Cl, 19.89

LD50 = 12.3 mg / kg iv. - (mouse)

The product shows a weak blocking effect in a normal test. The nicotinic acid salt may crystallize from ethyl acetate.

Melting point: 111 ° C (ethyl acetate) Analysis - for C 20 H 27 N 5 O 4 (M - - 401.46)

Calculated:

% H, 6.77;% N, 17.44

Found:

% C, 59.80;% H, 6.92;% N, 23%

LD50: 250 mg / kg iv. (mouse)

On the aortic spiral of diabetic animals, the compound shows a potent blocking effect.

example - 6

10.45 g of 3,4-dimethoxyphenylacetamidoxime was dissolved in 40 ml of 10% sodium hydroxide. This solution ¹ was added at - room temperature under stirring well as 17.8 g of 3-2-piperiri.no hydгoxy-l-chloropropane. The solution was added dropwise over half an hour. The reaction mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. The oily product was extracted with benzene, the extract was dried with sodium sulfate, and the solvent was evaporated. The residue was dissolved in ethyl acetate. By introducing hydrogen chloride gas into the solution ^, 10.5 g of O- (3-piperirino-2-hydroxy-1-propyl) -3,4-dimethoxyphenylacetamide oximethylchloride are obtained. The product is identical to the product of Example 2.

Melting point; Mp 201-203 ° C.

Example 7

5.2 g of 3,4-dimethoxyphenylacetamycloxime are dissolved in 40 ml of 10% sodium hydroxide with heating. The solution was added dropwise during half an hour at room temperature to a solution of 8.8 g _ _r 3- piperidino-2-hydroxypropyl, L-Roxx-chloropropane in. 20 ml benzene. The mixture was additionally stirred at room temperature for 8 hours and then allowed to stand overnight. The benzene phase is then separated. The aqueous phase is extracted with benzene. The combined benzene phases were dried over sodium sulfate, then the solvent was evaporated. The salt is formed from the residue as described in Example 6. The O- (3-piperidino-2-hydroxy-11-yl) -3,4-dimethoxyphenylacetamidoxime obtained is identical to the product of Example 2.

Example 8

Dissolve 5.2 g of 3,4-methylphenyl-ethyl-thamiroyim in a mixture consisting of 40 ml of 10% sodium hydroxide and 40 ml of methanol. The solution was added dropwise over half an hour to 8.8 g of 3-piperidino-2-hydroxy-1-cyclopropane. The mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. The methanol is evaporated. The residue is worked up as described in Example 7 by extraction with benzene to form a salt. The obtained O- (3-piperidinQ-2-hy (droxy-1-propyl) -3,4-dimethylphenylacetamide (Qximdihydrochloride) is identical to the compound of Example 2.

Example 9

To 2.72 g of benzamidoxime was added 40 ml of benzene with 0.8 g of powdered sodium hydroxide. The reaction mixture was boiled using a water separator for one hour, during which a solution of 4.5 g of 3-piperidin-2-hydroxy-1-carboxylic acid was added dropwise. After boiling for 12 hours, the solvent is evaporated and the residue is taken up in 20 ml of 10% sodium hydroxide. The oily product was extracted with benzene. After evaporation of the benzene, 3.6 g of O- (3-piperidin (dino-2-hydroxy-1-piperidyl) benzamidoxime) are obtained, which is identical to the product produced according to Example 1.

Example 10

Sodium ethylate solution, prepared from. g of sodium and 200 ml of absolute alcohol are added 15.5 g of 4-chlorobenzamidoxime. 9.3 g of epichlorohydrin are added dropwise at 0-10 ° C. The batch was stirred at 0-10 C for 8 hours ^Q la and left to stand. at the same temperature overnight. The precipitated sodium chloride is filtered off, and 8.6 g of piperidine are added dropwise to the filtrate with stirring. The mixture was stirred at room temperature for a further 8 hours, then boiled and the solvent was distilled off in vacuo. The residue was made up with 50 ml of 5% sodium hydroxide 1 and the oily material was extracted with benzene. The benzene extract is dried with sodium sulfate, then. evaporate and dissolve the residue in absolute alcohol. · Introducing hydrochloric acid gas or restricted by adding alcohol, acidified with hydrochloric acid to provide 11.0 · g of 0- (3-piperidino-2-hydroxy-lнpropy-iodo-4-chloro Orbe · _l nza.midoxiιmdihydrochlQridu.

Melting point: 215 to 217 ^Q C · (absolute alcohol).

Analysis for C15H24N3O2Cl3 (M = - 384.73)

Calculated:

C, 46.83; H, 6.29; N, 10.92

Found:.

H, 6.41; N, 10.58

The compound shows a weak (blocking effect) in a normal test, a diabetic test.

Pila and li

O- (3-Diethylamino-2-hydroxy-1-propyl) -phenylacetamide-di-dihydrochloride was prepared from phenylacetamirimide using diethylamine as the amine component. ·

Melting point: 156-158 ° C (isQprQpanQ1)

Analysis for C15H27N3O2Cl2 (M = 352.30)

Calculated:

H, 7.73; N, 11.93; Cl, 20.12

Found:.

% C, 50.89;% H, 7.65;% N, 11.83

Example 1 a d 12

From phenylacetamide, using piperidine as amine · · component prepared as described in Example 10 O- (3-piperidino ⁱ -2-hydroxy-propylamino rr 1) f enylacetamldoximrihyrrQcУlorlr.

Melting point: 198 to 200 ° C (absolute alcohol)

Analysis for C 16 H 27 N 3 O 2 Cl 2 · (M -. 364.31)

Calculated:

% C, 52.75;% H, 7.47;% N, 11.54

Found:

C 52.40, H 7.51, N 11.20, Cl 19.85, Example 13

From 4-chlorophenylacetamide, oxime was prepared using moriolin as the amine component as described in Example 10-O- (313).

m -orpholino-2-hydroxy-1-propyl) -4-chlorophenylacetamidoimide dihydiro chloride.

Melting point: 175-178 ° C (absolute alcohol)

Analysis for C15H24N3O3Cl3 (M = 400.73)

Calculated:

% H, 6.00;% N, 60.48; % Cl

Found:

45.20% C, 6.10% II, 10.52% N, 26.50% Cl

Example 1 -a d 14

Propionic acid 3,3-diphenylamidoxime was prepared using diisopropylamine as the amine component as described in Example 10 for O- (3-isopropylamino-2-hydroxy-1-propyl) -3,3-diphenylamidoxime propionic acid as the dihydrochloride salt.

Melting point: 179 ° C (acetone / water).

Analysis for C 21 H 31 N 3 O 2 Cl 2 (M = 428.39)

Calculated:

C 58.87%, H 7.29, N 9.81, Cl 16.55

Found:

% H, 7.39;% N, 9.53;% Cl, 16.70

LD50: 16.25 mg / kg iv. · (Mouse)

The compound shows a potent blocking effect on the aortic spiral of diabetic animals.

Example 15

Propionic acid 3,3-diphenylamidoxime was prepared using the diethylamine as the amine component as described in Example 10 for O- (3-diethylamino-2-hydroxy-1-propyl) -3,3-diphenylamidoxime propionic acid in the dihydrochloride farm.

Melting point: . 225 ° C (isopropanol)

Analysis for C22H33N3O2Cl2 (M = 442.42)

Calculated:

% C, 59.72;% H, 7.52;

Found:

% C, 59.68;% H, 7.55;% 16.07. Cl example. 16

From 3,3-diphenylamidoxime propionic acid, 2-methylaminoethanol is used as the. the amine components are prepared by propionic acid O- [3-N-methyl-N-2- (hydroxyethyl) amino-2-hydroxy-1-propyl] -3,3-diphenylamidoxime in the form of the dihydrochloride.

Melting point: 175 ° C (isopropanol)

Analysis for C 21 H 31 N 3 O 3 Cl 2 (M = 444.39)

Calculated:

C, 56.78; II, 7.03; N, 9.45; Cl, 15.96

Found:

H, 7.09; N, 9.14; Cl, 15.92

LD50: 37 mg / kg iv - (cape)

The compound shows a strong, + blocking effect on the aortic spiral of diabetic animals.

Example 17

Propionic acid 3,3-diphenylamidoxime was prepared as the dihydrochloride using pyrrolidine as the amine component as described in Example 10 O- (3-pyrrolidino-2-hydroxy-1-propyl) -3,3-diphenylamidoxime propionic acid.

Melting point: 218 ° C (isopropanol)

Analysis for C 22 H 31 N 3 O 2 Cl 2 (M - = 440.40)

Calculated:

% C, 59.99;% H, 7.10;

Found:

% C, 59.63;% H, 7.32;

Example 18

O- (3-piperidino-2-hydroxy-1-propyl) -3,3-diphenylamidoxime propionic acid was prepared from the 3,3-diphenylamidoxime propionic acid using piperidine as the amine component in the form of the dihydrochloride. . the product is identical to the β product of Example 4 and melts after recrystallization from isoprepanol at 228-230 ° C.

Example 19

O- (3-Heptamethyleneamino-2-hydroxy-1-propyl) -3,3-diphenylamidoxime propionic acid as dihydrochloiride is prepared from 3,3-diphenylamidoxime propionic acid using heptamethylenimine as the amine component as described in Example 10, after recrystallization from isopropanol, it melts at 233 ° C.

Analysis for C25H37N3O2Cl2 (M = 482.48)

II

Calculated:

C, 62.24; H, 7.73; Cl, 14.70

Found:

% C, 61.94;% H, 7.70;

Example 20

Propionic acid 3,3-diphenylamidoxime is prepared using the morpholine as > amine component as described in Example 10 O- (3-morpholino-2-hydroxy-1-propyl) -3,3-difluylamidoxime propionic acid in the form of dihydrochloride, which after recrystallization from isopropanol melts at 225 ° C,

Analysis for C 22 H 31 N 3 O 3 Cl 2 (M = 456.40)

Calculated:

H, 6.85; N, 9.20; Cl, 15.53

Found:

% H, 7.13;% N, 8.95;% Cl, 15.15

Example 21

O-1- (3-diethylamino-2-hydroxy-1-propyl) -1-naphthylacetamide oxime hydrochloride is obtained from 1-naphthylacetamidoxime using diethylamine as the amine component as described in Example 10; Mp 150-152 ° C.

Analysis for C19H28N3O2Cl (M = 365.89)

Calculated:

% C, 62.36;% H, 7.71;% N, 11.49;

Found:

% C, 8.00;% H, 11.29%; N, 9.63% Cl Example 22

O- (3-piperidino-2-hydroxy-1-propyl) -1-naphthylacetamide amide hydrochloride is obtained from the 1,1-naphthylacetamidoxime using the piperidine as the amine component as described in Example 10, which after recrystallization of absolute alcohol melts at 177-179 ° C

Analysis for C20H28N3O2Cl (M = '377.89)

Calculated:

% C, 63.57;% H, 7.46;% N, 11.12;

Found:

63.58 Vo C, 7.59% H, 11.47% N, 9.60% Cl

Example 23

To a mixture consisting of 4.0 g of benzamidoxime, 10 ml of water and 4.5 g of epichlorohydrin at room temperature with stirring, '20 ml' of 10% sodium hydroxide is added over one hour. The mixture was stirred for an additional two hours, then charged with 4.5 g of piperidine and stirred again for 8 hours. Then the oily preparation is extracted with benzene. After evaporation of the benzene solution, 6.2 g of O- (3-piperidino-2-hydroxy-1-propyl) benzamidoxime are obtained, which is identical to the product of Example 1.

Example '1 and d' 24

Dissolve 6.8 g of benzamidoxime in 40 ml of 10% sodium hydroxide and add 9.5 g of epichlorohydrin while stirring. The reaction is exothermic, therefore the temperature is maintained by external cooling at 30-35 ° C. The mixture was stirred for two hours, then '8.6 g of piperidine was added dropwise. After stirring for 2 hours, the oily product was extracted with benzene. After evaporation of the benzene, 8.2 g of (H (3-piperidino-2-hydroxy-1-propyl) benzamidoxime) are obtained. The product is identical to the product of Example 1.

Example 25

Dissolve 6.8 g of benzamidoxime in 40 ml of 10% sodium hydroxide. 9.5 g of epichlorohydrin are added dropwise to the solution with vigorous stirring. 20 ml of benzene. The mixture is stirred for 4 hours, then 8.6 g of piperidine are added and stirred at room temperature for a further 8 hours. The benzene phase is then separated and the aqueous phase is extracted with benzene. The combined benzene solutions were evaporated. O- (3-piperidino-2-hydroxy-1-prop-1) -benzamidoxime is obtained, which is identical to the 'product' produced according to Example 1.

Example 26

6.8 g of benzamidoxime are dissolved in a mixture consisting of 20 ml of 10% sodium hydroxide and 20 ml of methanol. While stirring, 9.5 g of epichlorohydrin are added dropwise. The mixture is then stirred at room temperature for two hours and then 8.6 g of piperidine are added. The batch was stirred for an additional 8 hours. Then the methanol is distilled off in vacuo, the oily substance is extracted with benzene. Evaporation of the benzene yielded 7.2 g of O - (3-plperidino-2-hydroxy-1-propyl) benzamidoxime which was identical to the product prepared according to the example.

1.

Example 27

To a solution of 5.2 g of 3,4-dimethoxyphenylacetamidoxime in 20 ml of dimethylsulfoxide was added 2.4 g of sodium tert-butylate with stirring. Then 3.0 g of epichlorohydrin were added dropwise and then the mixture was stirred at room temperature for 2 hours. After addition of 2.5 g of piperidine in 60 ml of acetone, the batch is stirred again for 8 hours and refluxed, finally topped up with 120 ml of ethyl acetate. 4.420 g of O- (3-piperidino-2-hydroxy-1-propyl) -3,4-dimethoxyphenylacetamide oxime dihydrochloride, which is identical to the product prepared according to Example 2, crystallize out by passing hydrogen chloride gas.

Example 28

Propionic acid O- (3-piperidino-2-hydroxy-1-propyl) -2-phenylamidoxime propionic acid is prepared from 2-phenylamidoxime propionic acid and 3-piperidine-2-hydroxy-1-chloropropane as described in Example 6, in the form of dihydrochloride, which, after recrystallization from isopropanol, melts at 225 ° C.

Analysis:

Calculated:

% C, 53.96;% H, 7.73;% N, 11.11

Found:

% C, 54.27;% H, 8.00;% N, 10.86

Example 29

From 3-cyclohexylamino-2-hydroxy-1-chloropropane [J. Org. Chem. 24, 615 (1959)] and nicotinic acid amidoxime were prepared as described in Example 6 for O- (318

Nicotinic acid (cyclohexylamino-2-hydroxy-1-propyl) amidoxime, which melts at 102 ° C after recrystallization from benzene-toluene.

Analysis for C15H2-1N1O2 (M = 292.37)

Calculated:

% C, 61.62;% H, 8.27;% N, 19.16

Found:

% C, 61.44;% H, 8.23;% N, 18.89

Example 30

1.38 g of O- (3-piperidino-2-hydroxy-1-propyl) benzarmdoxime racemate and 1.16 g of d-camphorsulfonic acid are dissolved in 20 ml of boiling ethanol. The solution was evaporated in vacuo. The residue was recrystallized first from butyl acetate, then from ethyl acetate. 0.4 g of d-O- (3-piperidino-2-hydroxy-1-propyl) -benzamidoxime camphorsulfonate melting at 132 DEG C. is obtained.

The base is liberated from the camphorsulfonic acid salt in a conventional manner and then the hydrochloric acid salt is obtained. The hydrochloride melts at 196 ° C (?) 559 nm = + 6.3 ° (c = 1 in water).

Claims (8)

the subject of the invention A process for the preparation of the novel O- (3-amino-2-hydroxypropyl) amidoxime derivatives of the general formula I, wherein: R ^{1 is} hydrogen or C 1 -C 5 alkyl; R ^{2 is} optionally C 1 -C 5 alkyl, C 5 -C 8 cycloalkyl or phenyl substituted with hydroxyl or phenyl, or R ¹ and R ² together with the adjacent nitrogen atom form a saturated, heterocyclic ring of 5 to 8 carbon atoms, optionally containing further heteroatoms, preferably oxygen or nitrogen, and / or optionally fused with a phenyl ring, R ^{3 is} optionally halogen, C _1-4 alkoxy, C 1-6 alkyl substituted C 5 -C 8 cycloalkyl or phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl _T pyrazazolyl, on which group the phenyl ring is optionally fused, (I) R ^{4 is} hydrogen, optionally halogen or C _1-5 alkoxy substituted C 1 -C 5 alkyl or C ₅ -C ₈ cycloalkyl or phenyl, and n is 0, 1 or 2 n is 0, 1 or 2, and salts thereof, characterized by wherein the compound of formula (II): R ³ —ЧСН J _nl R ⁴ (CH) _n -C-N-OH I-I R ⁵ NH 2 wherein (P) the meaning of R ³ , R ⁴ , R ⁵ , m, n is the same as above, epichlorohydrin and an amine of formula III, where hn) in ⁷ . (lil) the meaning of R ¹ and R ² is the same as above, they are allowed to react with each other in any order, optionally with the isolation of compounds of the general formula IV (IV) and the compounds of formula I obtained are optionally reacted with inorganic or organic acids to form their salts and / or are liberated from their salts. Z-treatment according to claim 1, characterized in that the reaction is carried out in a solvent, preferably water, an organic solvent containing water or in a reaction medium comprising one aqueous and one organic phase. 3. The process according to claim 1, wherein the reaction is carried out at temperatures between -10 and +140 [deg.] C. 4. The process according to claim 1, wherein hydrochloric, phosphoric or sulfuric acid is used as the inorganic acid. Process according to Claim 1, characterized in that nicotinic acid, maleic acid, acetic acid or an optically active acid, preferably camphorsulphonic acid or tartaric acid, are used for salt formation. 6. Process according to claim 1, characterized in that the salt formed with the optically active acid is recrystallized from an organic solvent, preferably ethyl acetate or butyl acetate. 7. A process as claimed in claim 1 or 6, wherein the compounds are of the formula I release them from their salts and optionally convert them into other salts thereof. 8. The process of claim 1, wherein the compound is a compound of formula II uses nicotinic acid amidoxime and piperidine as the compound of formula III.