CH630344A5 - Process for the preparation of novel O-(3-amino-2-hydroxypropyl)-amidoxime derivatives. - Google Patents

Description

60 The invention accordingly relates to the preparation of the amidoximes of the general formula I and their salts.

The processes defined in claims 1 and 8 are characterized in that an amidoxime of the general formula II

65 r3- (ch) - (ch) -c = n-oh i 4 m i c n |

r r nh_

(II)

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wherein R3, R4, R5, m and n have the meaning given above, with epichlorohydrin and then with an amine of the general formula r \

hn

(iii)

R

wherein R1 and R2 are as defined above, optionally with the interim isolation of an epoxide of the general formula r - (ch) - (ch) -c = n-0-ch - ch-ch-

i 4 m r

k-5

nh-

\ / 0

(IV)

in which R3, R4, R5, m and n have the meaning given above, or in that the amidoxime of the general formula (II) is reacted directly with a 3-amino-2-hydroxy-l-halogenopropane or a 3-amino-l, 2-epoxypropane of the general formulas or x-ch, -ch-ch - n

^ i ^

oh ch, -ch-ch_-n 2/2

r

(Va)

R

R1 ^

R

(Vb)

in which R1 and R2 have the meaning given above and X represents halogen, and, if desired, converting a base obtained with an inorganic or organic acid into an acid addition salt or releasing the corresponding base from a salt obtained.

The method defined in claim 15 is intended for the preparation of the compounds of the general formula I in which R1 represents hydrogen. This process is characterized in that an amidoxime of the general formula II with a 2-phenyl-5-halogenomethyl-oxazolidine of the general formula x -

No

(vi)

where X is halogen and R2 has the meaning given above, and the ring compound of the general formula obtained

■ (CH) - (CH) -C = N-0-CH2 I m, n | 2nd

R * R5 NH2

NO

(VII)

wherein R2, R3, R4, R5, m and n are as defined above without isolating them beforehand, hydrolytically cleaving and, if desired, converting a base obtained into an acid addition salt or releasing the base from a salt obtained.

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

According to the method of claim 8, the reaction is preferably carried out in an aqueous medium, in water-containing organic solvents, for example alcohol-water mixtures, or in organic solvents, preferably at 0-140 ° C.

One can also proceed in such a way that salts are formed from the amide io oximes of the general formula II in an anhydrous alcohol with alkali metal alkoxides and the alcoholic solution of the amine of the general formula V is added dropwise. The reaction is preferably carried out at 0-100 ° C. with stirring.

According to another embodiment of the process, the salts of the amidoximes are formed with alkali metal hydroxides, preferably with sodium or potassium hydroxide, in water-immiscible organic solvents (for example benzene, toluene, xylene). Salt formation is carried out at the temperature of the solvent used and the water formed is removed from the system by azeotropic distillation. The solution of the amine of the general formula V is then added and the reaction mixture is heated further.

25 The reaction can also be carried out in an aqueous medium. In this case the amidoxime is dissolved or suspended in aqueous alkali and the solution of the suspension is added to the amine of the general formula V with stirring. This reaction is conveniently carried out at 0-60 ° C. 5-20% aqueous alkali lye is used to dissolve or suspend the amidoxime. The reaction can also be carried out in a mixture of water and an organic solvent, for example by dissolving the amine of the general formula V in alcohol or dioxane and adding the solution or suspension of the amidoxime prepared with aqueous alkali. It does not matter which reaction partner is introduced and which is added dropwise, the order can also be reversed.

40 According to the method of claim 1, the amidoximes of the general formula II are reacted with epichlorohydrin in the presence of a base. If desired, the resulting epoxy compound can be isolated, but it is more advantageous not to separate the intermediate, but to carry out the reaction in one step in aqueous medium or organic solvents or water-containing organic solvents or solvent biphasic mixtures at -10 to 100 ° C .

According to an advantageous embodiment of the Verso driving, the amidoxime is dissolved or suspended in aqueous alkali and the solution or suspension is mixed with the 1-4-fold molar amount of epichlorohydrin. The epichlorohydrin is added with stirring at -10 to + 60 ° C. The epichlorohydrin is added or added dropwise in several portions. It does not matter which reaction partner is introduced and which is added dropwise, the order can also be reversed. If desired, the intermediate of the general formula IV can be isolated by extraction with a water-immiscible solvent. However, it is more advantageous not to isolate the compound of the general formula IV, but rather to react it immediately with the corresponding amine.

In the case of amidoximes which are poorly soluble in aqueous alkali, water-containing organic solvents, for example aqueous alcohol or dioxane, can also be used as the solvent. The reaction can also be carried out in the presence of an emulsifier or in a two-phase system. In this case the epichlor

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hydrine dissolved in a water-immiscible organic solvent (for example in benzene or ether) and the solution added to the solution or suspension of the amidoxime prepared with aqueous alkali. The procedure can also be such that the epichlorohydrin solution is initially introduced and the amidoxime component is added.

In the method according to claim 1, it is also possible to work in anhydrous solvents, preferably in anhydrous alcohols. In this case, the alkali salt of the amidoxime is preferably formed by dissolving the amidoxime in the alcoholic solution of an alkali alcoholate. After the epichlorohydrin has been added, the reaction mixture is left to stand at 0-20 ° C. for 1-5 days, then the corresponding amine is added and the reaction mixture is warmed, if necessary. In addition to alcohols, other organic solvents, for example acetone, dimethyl sulfoxide, dimethylformamide, and mixtures thereof are also suitable as the anhydrous solvent.

In the process according to claim 15, the sodium salts are preferably used as alkali sizes of the amidoximes of the general formula II. The reaction is preferably carried out in alkanols. The intermediate compound of general formula VII is preferably hydrolyzed with acid. The starting materials of the general formula VI can be prepared, for example, in the manner described in DT-OS 2 018 236.

The reaction products are separated off in the customary manner. If an aqueous reaction medium is used, the products are separated off by crystallization or extraction. The compounds are crystallized from organic solvent media or the solvent is evaporated, the residue is washed with water and then extracted. The products can also be isolated in the form of their salts; if desired, the free bases can be released from the salts. The salt can be prepared from the free bases by adding 1-2 equivalents of an organic or inorganic acid. The non-toxic acids customary in pharmacy are preferably used for salt formation.

The general β-receptor-blocking action of the compounds of the general formula I were determined on the tracheo ring [J. Pharm. Exp. Therap. 90, 104 (1947)] and on the papillary muscle of the cat. The selective β-blocking effect was demonstrated on the aortic spiral preparation of rats [J. Pharmacol. Exp. Therap. 158, 531 (1967)] in the following way:

The animals' chest was opened and the chest aorta was removed and cut in a spiral. The movements of the straight spiral are recorded on two well-known rollers with the help of an isotonic writing arm. The reaction of the control was recorded on one roller, and that of the aorta of a rat treated with streptosotocin [2- (3-nitroso-3-methylureido) -2-deoxy-D-glucose] on the other. It was considered a positive reaction if the dose-response curve of noradrenaline (NA) was not influenced by the investigated substance on the control preparation, but was influenced on the diabetic aorta. The action of the compounds according to the invention is generally selective, which is reflected in the fact that a strong ß-blocking action occurs in diabetic tests, and no or only weak ß-blocking action in normal tests. Some of the compounds according to the invention show an a-blocking effect in normal tests.

A typical representative of the compounds according to the invention, the 0- (3-piperidino-2-hydroxy-l-propyl) -3,4-di ~

methoxyphenyl acetamidoxime dihydrochloride, has the following effects.

The pD2 value was determined, i.e. the negative log of half the maximum effect dose. Calculated from the differences in the pD2 values, the average of five successive measurements for the spiral from the diabetic aorta is x = 1.31, while the value for the normal aorta was x = 0.52. On the trachea of the guinea pig, 10 gamma of the investigated substance reduce the effect of 0.01 gamma / ml of isoprenaline [D, L, -1- (3,4-dihydroxyphenyl) -2-isopropylaminoethanol] in half. At the uterus of rats pretreated with streptosotocin, the compound is ineffective in a concentration of 100 gamma / ml. In a concentration of 50 gamma / ml, the compound acts on the uterine preparation of the untreated rats which is stopped with norepinephrine. This effect corresponds to the effect of 0.5 μl, m / ml Inderai [1-isopropylamino-3- (1-naphthyloxy) propan-2-ol]. The compound is ineffective on the mange fundus strip of rats pretreated with streptosotocin in a concentration of 10 gamma / ml, in contrast to 0.01 gamma / ml isoprenaline, which causes a relaxation of 55 mm. The compound does not affect the dose-response curve of isoprenaline on the gastric fundus strip of untreated rats, even at a concentration of 100 gamma / ml. This means that the compound has a weak ß-blocking effect in normal tests and a strong ß-blocking effect in diabetic tests.

The compound extends the hypoxia survival by an order of magnitude.

The tachycardia caused by isoprenaline (1 ng / kg iv.) Is influenced to a small extent by the compound. In mice, 5 minutes after the iv. Application of 10 mg / kg an increase in heart rate of 10% was measured during 5 minutes after the iv. Application of 100 mg / kg the heart rate decreased by 3%.

The compound prepared according to Example 5, the 0- (3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime dihydrochloride, has the following pharmacological effects.

The average values calculated from the differences in the pD2 values are x = 1.25 for the spiral from diabetic aorta and x = 0.57 for the control. At a concentration of 50 gamma / ml, the compound reduces the effect of 0.001 gamma / ml isoprenaline from 16 mm to 5 mm. Used in a concentration of 100 gamma / ml, the effect of 0.001 gamma / ml Isolrena-lin is completely abolished, that of 0.01 gamma / ml isoprenaline decreased from 28 mm to 19 mm.

Experiments were also carried out to determine whether the contraction caused by norepinephrine caused by norepinephrine could be eliminated by the aortaspiral preparations of streptosotocin-treated and spontaneously latently diabetic animals. Animals were used as controls in which this change in the receptor did not occur. It was found that in animals treated with streptosotocin, the differences in the pD2 values of the noradrenaline dose response curve (before and after the administration of Inderai): 1.0335; Sx = 0.0829; t = 3.5885; p <0.01; n = 8. The contraction caused by norepinephrine was not influenced by Inderai on the non-diabetic preparations.

It was also examined whether among the compounds similar in chemical structure to the β-blockers are those which, like the Inderai, act on the aortic spiral of the diabetic animals without significantly influencing the normal β-effects, i.e. Compounds that are specific for the “wrong” ß effect that develops in the diabetic veins.

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The compounds according to the invention are abbreviated as follows in the following explanations:

NP-18: 0- (3-piperidino-2-hydroxy-l-propyl) -3,4-dimethoxy-

phenyl-acetamidoxime dihydrochloride NP-51: 0- (3-piperidino-2-hydrochloride-l-propyl) nicotinic acid amidoxime dihydrochloride.

At the aortic spiral of animals treated with streptosotocin, the difference (before and after administration of 1 ng / ml NP-18) in the pD2 values of norepinephrine was 0.6422. Sx = 0.129; t = 4.9783; p <0.01; n = 6. In the untreated animals, noradrenaline did not cause a significant difference in pD2 values before and after the administration of NP-18. Similar results were also obtained with NP-51. In the streptosotocin-treated group, the pD2 difference caused by noradrenaline (values before and after administration of NP-51) = 0.8196; Sx = 0.08155; t = 10.0503; p <0.001; n = 6.

It has been found that the final histological changes do not form if the initial receptor changes are suppressed by, for example, NP-18 or NP-51. Some of the CFY rats used as experimental animals (about 60%) were latently diabetic, this could be demonstrated by sugar exposure. Diabetic macro- and microangiopathy was detectable in some of these 400-500 g animals. Animals treated with NP-18 or NP-51 when they reached 200 g did not show any microangiopathy until they reached 500 g, and the macroangiopathy was also significantly lower.

Furthermore, it was found that although both NP-18 and NP-51 on guinea pig trachea suppress the effect of isoprenaline, their effect in this regard is about 4 orders of magnitude less than that of the Indianai. The compounds examined had no significant effect on blood pressure, heart rate, minute volume and the dp / dt value of anesthetized cats. When examining these parameters, the compounds had no effect on the effect of isoprenaline, only in a dose of 100 jig / kg did they cause bradichardia and a decrease in the dp / dt value. This effect was about as great as that of 0.5 (ig / kg Indianai.

The difference in the ß-blocking effect of the compounds of the general formula I and the Indian derma is also about 4 orders of magnitude on the cat papillary muscle. On the guinea pig ileum, the compounds according to the invention only influenced the action of barium chloride and acetylcholine in a dose of 50-100 ng / ml. The ability of the mice to cling to a rotating rod was ip in a dose of 10 mg / kg. not influenced by NP-18 or NP-51.

LD50 values: NP-18: 165 mg / kg iv. (Mouse)

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

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

The invention is explained in more detail with reference to the following examples, without, however, remaining restricted to these examples.

example 1

2.3 g of sodium are dissolved in 200 ml of absolute alcohol and 13.6 g of benzamide oxime are added to the solution. 3-piperidino-2-hydroxy-l-chloropropane is prepared in a known manner from 9.3 g of epichlorohydrin and 8.5 g of piperidine and the solution prepared with 50 ml of absolute alcohol is added dropwise to the alcoholate solution while it is boiling. The reaction mixture is refluxed for 8 hours, then filtered and the solvent evaporated in vacuo. The residue is mixed with 100 ml of 5% sodium hydroxide solution and the oily product is extracted with benzene. After evaporation of the solvent, 9.2 g of 0- (3-piperidino-2-hydroxy-l-propyl) benzamidoxime are obtained.

Mp: 97 ° C (diisopropyl ether).

Analysis for 'C ^ H ^ NgC ^ (M = 277.35)

calculated: C 64.95% 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 hydrochloric acid gas or by adding alcoholic hydrochloric acid.

Mp: 212-214 ° C (isopropanol).

Analysis for C15H25N302C12 (M = 350.29)

calculated: Cl 20.24%

found: Cl 19.90%

LD50: 70.5 mg / kg iv. (Mouse).

The nicotinic acid salt of the product can be formed in absolute alcohol. It crystallizes when gasoline is added.

Mp: 112 ° C (methyl ethyl ketone).

Analysis for C21H28N404 (M = 400.46)

calculated: C 62.98% H 7.05% N 14.00% found: C 62.84% H 7.11% N 13.76%

The dihydrochloride shows a weak «-blocking effect in the normal test, and a strong ß-blocking effect in diabetes tests.

Example 2

In the manner described in Example 1, 3,4-dimethoxyphenyl-acetamidoxime and 3-piperidino-2-hydroxy-chloropropane become Ó- (3-piperidino-2-hydroxy-1-propyl) -3,4-di -methoxy-acetamidoxime-dihydrochloride.

Mp: 202-203 ° C (abs.alcohol).

Analysis for C18H31N304CL (M = 424.38)

calculated: € 50.94% H 7.36% N 9.90% Cl 16.71%

found: C 50.80% H 7.57% N 9.84% Cl 16.42% LD50 = 165 mg / kg iv. (Mouse).

The connection shows a weak ß-blocking effect on the tracheal coil and the papillary muscle; on the papillary muscle, the effect of the compound in a concentration of 100 (ig / ml is the same as the effect of 0.05 y, g / ml Inderai. on the other hand, inhibition occurs by an order of magnitude at the aortic spiral of a diabetic animal.

Example 3

In the manner described in Example 1, 3,4-dimethoxyphenyl-acetamide oxime and 3- (l, 2,3,4-tetrahydro-2-isoquinolyl) -2-hydroxy-1-chloropropane 0- [3- ( l, 2,3,4-tetra

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hydro-2-isoquinolyl) -2-hydroxy-l-propyl] -3,4-dimethoxyphe> -nyl-acetamidoxime dihydrochloride.

Mp: 189 ° C (isopropanol).

Analysis for CjjHjjNjC ^ Cla (M = 472.40)

calc .: C 55.93% H 6.61% N 8.89% CI 15.01% found: C 55.89% H 6.82% N 8.64% Cl 14.75%

Example 4

In the manner described in Example 1, 3,3-diphenyl-propionic acid amidoxime and 3-piperidino-2-hydroxy-l-chloropropane become 0- (3-piperidino-2-hydroxy-1-propyl) -3, 3-diphenyl-propionic acid amidoxime dihydrochloride produced.

Mp: 228-230 ° C (isopropanol).

Analysis for CENACI (M = 454.42)

calc .: 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

In the manner described in Example 1, nicotinic acid amidoxime and 3-piperidino-2-hydroxy-1-chloropropane are used to prepare 0- (3-piperidino-2-hydroxy-1-propyl) nicotinic acid amide oxime dihydrochloride.

Mp: 204 ° C (absolute alcohol).

Analysis for C14H24N402C12 (M = 351.27)

calc .: 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% sol, = 123 mg / kg iv. (Mouse).

The product shows a weak ß-blocking effect in the normal test.

The nicotinic acid salt can be crystallized from ethyl acetate.

Mp: 11 FC (ethyl acetate).

Analysis for C20H2VN5O4 (M = 401.46)

calculated: C 59.83% H 6.77% N 17.44%

found: C 59.80% H 6.92% N 17.23% LD50: 250 mg / kg iv. (Mouse).

The compound shows a strong β-blocking effect on the aortic spiral of diabetic animals.

Example 6

10.45 g of 3,4-dimethoxyphenyl acetamide oxime are dissolved warm in 40 ml of 10% sodium hydroxide solution. This solution is added to 17.8 g of 3-pipe-ridino-2-hydroxy-l-chloropropane at room temperature with stirring. The solution is added dropwise over half an hour. The reaction mixture is then stirred at room temperature for 8 hours and then left to stand overnight. The oily product is extracted with benzene, the extract is dried over sodium sulfate and the solvent is evaporated. The evaporation residue is dissolved in ethyl acetate. By introducing hydrochloric acid gas into this solution, 10.5 g of 0- (3-piperidino-2-hydroxy-l-propyl) -3,4-dimethoxy-phenyl-acetamidoxime dihydrochloride crystallize. The product is identical to the product according to Example 2.

Mp: 201-203 ° C.

Example 7

5.2 g of 3,4-dimethoxyphenyI-acetamidoxime are dissolved in 40 ml of 10% sodium hydroxide solution with heating. The solution is dissolved in the solution of 8.8 g of 3-piperidino-2-hydroxy-l- at room temperature within half an hour.

-chloropropane dropped in 20 ml of benzene. The mixture is stirred at room temperature for 8 hours and then left to stand overnight. Then the benzene phase is separated. The aqueous phase is extracted with benzene. The combined benzene phases are dried over sodium sulfate, after which the solvent is evaporated. The hydrochloric salt is formed from the evaporation residue in the manner described in Example 6. The 0- (3-piperidino-2-hydroxy-1-propyl) -3.4 ~ dimethoxyphenyl acetamide oxime obtained is identical to the product according to Example 2.

Example 8

5.2 g of 3,4-dimethoxyphenyl acetamide oxime are dissolved in a mixture of 40 ml of 10% sodium hydroxide solution and 40 ml of methanol. The solution is added dropwise to 8.8 g of 3-piperidino-2-hydroxy-l-chloropropane over the course of half an hour. The mixture is stirred at room temperature for 8 hours and then left to stand overnight. The methanol is evaporated. The residue is worked up in the manner described in Example 7 by extraction with benzene and salt formation. The 0- (3-piperidino-2-hydroxy-l-propyl) -3,4-dimethox5'phenyl-acetamidoxime dihydrochloride obtained is identical to the product according to Example 2.

Example 9

40 ml of benzene and 0.8 g of dust-fine solid sodium hydroxide are added to 2.72 g of benzamide oxime. The reaction mixture is boiled under a water separator attachment for one hour while the solution of

4.5 g of 3-piperidino-2-hydroxy-l-chloropropane in 10 ml of benzene were added dropwise. After boiling for 12 hours, the solvent is evaporated off and the residue is taken up in 20 ml of 10% sodium hydroxide solution. The oily product is extracted with benzene. After evaporating the benzene, you get

3.6 g of 0- (3-piperidino-2-hydroxy-1-propyl) benzamide oxime, which is identical to the product prepared according to Example 1.

Example 10

15.5 g of 4-chloro-benzamidoxime are added to the sodium ethylate solution prepared from 2.3 g of sodium and 200 ml of absolute alcohol. 9.3 g of epichlorohydrin are added dropwise to the mixture at 0-10 ° C. The mixture is stirred at 0-10 ° C. for 8 hours and then 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 fitrate with stirring. The mixture is stirred at room temperature for a further 8 hours, then boiled and the solvent removed in vacuo. The residue is mixed with 50 ml of 5% sodium hydroxide solution and the oily material is extracted with benzene. The benzene extract is dried over sodium sulfate, then evaporated and the residue dissolved in absolute alcohol. 11.0 g of 0- (3-piperidino-2-hydroxy-1-propyl) -4-chlorobenzamidoxime dihydrochloride are obtained by introducing hydrochloric acid gas or by adding hydrochloric acid alcohol.

Mp: 215-217 ° C (abs.alcohol).

Analysis for C15H24N302C13 (M = 384.73)

calculated: C 46.83% H 6.29% N 10.92% found: C 46.57% H 6.41% N 10.58%

The compound shows a weak ß-blocking effect in normal tests and a strong ß-blocking effect in diabetes tests.

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Example 11 Analysis for 'C ^ H ^ NgC ^ CL, (M = 444.39)

Phenylacetamide oxime is used to calculate: C 56.78% H 7.03% N 9.45% Cl 15.96%

Diethylamine as amine component to those found in Example 10: C 56.40% H 7.09% N 9.14% Cl 15.92%

described way 0- (3-diethylamino-2-hydroxy-l-propyl) - LD50: 37 mg / kg iv. (Mouse), -phenylacetamidoxim-dihydrochloride. 5

Mp: 156-158 ° C (isopropanol). The connection shows at the aortic spiral diabetic

Animals have a strong ß-blocking effect.

Analysis for C15H27N302C12 (M = 352.30)

calc .: C 51.14% H 7.73% N 11.93% Cl 20.12% Example 17

found: C 50.89% H 7.65% N 11.83% Cl 20.10% io From 3,3-diphenyl-propionic acid amidoxime using pyrrolidine as amine component in the manner described in Example 12 Example 10 0- (3-pyrrolidino-2-hydroxy-

Phenylacetamide oxime is used using -l-propyl) -3,3-diphenyl-propionic acid amidoxime-dihydrochlo-

Piperidine as an amine component on the two prepared in Example 10.

written way 0- (3-piperidino-2-hydroxy-l-propyl) -phe- 15 mp: 218 ° C (isopropanol). nylacetamidoxim dihydrochloride produced.

Mp: 198-200 ° C (abs.alcohol). Analysis for C22H31N302C12 (M = 440.40)

calculated: C 59.99% H 7.10% Cl 16.10% analysis for C16H27N302C12 (M = 364.31) found: C 59.63% H 7.32% Cl 16.44%

calc .: C 52.75% H 7.47% N 11.54% Cl 19.47% 20

Found: C 52.40% H 7.51% N 11.20% Cl 19.85% Example 18

From 3,3-diphenyl-propionic acid amidoxime, using example 13 using piperidine as the amine component, the

From 4-chlorophenyl-acetamidoxime using the game 10 described 0- (3-piperidino-2-hydroxy-l-of morpholine as amine component to that described in Example 10 25-propyl) -3,3-diphenyl-propionic acid amidoxime dihydrochloride Way 0- (3-morpholino-2-hydroxy-l-propyl) - prepared. The product is manufactured with the product according to Bei - 4-chlorphenyl-acetamidoxim-dihydrochloride. game 4 identical and melts after recrystallization

Mp: 175-178 ° C (abs.alcohol). Isopropanol at 228-230 ° C.

Analysis for C15H24N303C13 (M = 400.73)

calc .: C 44.96% H 6.04% N 10.48% Cl 26.54% found: C 45.20% H 6.10% N 10.52% Cl 26.50%

Example 14

From 3,3-diphenyl-propionic acid amidoxime, using isopropylamine as the amine component in the manner described in Example 10, 0- (3-isopropylamino-2-hydroxy-l-propyl) -3,3-diphenyl-propionic acid amidoxime di-hydrochloride produced.

Mp: 179 ° C (acetone-water mixture).

Analysis for C21H31N302C12 (M = 428.39)

calc .: C 58.87% H 7.29% N 9.81% Cl 16.55%

found: C 58.58% H 7.39% N 9.53% Cl 16.70% LD50: 16.25 mg / kv. (Mouse).

The compound shows a strong ß-blocking effect on the aortic spiral of diabetic animals.

Example 15

From 3,3-diphenyl-propionic acid amidoxime using diethylamine as amine component in the manner described in Example 10, 0- (3-diethylamino-2-hydroxy-1-propyl) -3,3-diphenyl-propionic acid amidoxime dihydro- chloride produced.

Mp: 225 ° C (isopropanol).

Analysis for C22H33N302C12 (M = 442.42)

calculated: C 59.72% H 7.52% Cl 16.03% found: C 59.68% H 7.55% Cl 16.07%

Example 16

From 3,3-diphenyl-propionic acid amidoxime using 2-methylaminoethanol as the amine component, 0- [3-N-methyl-N- (2-hydroxyethyl) amino-2-hydroxy-1-propyl] -3.3 -diphenyl-propionic acid amidoxime dihydrochloride.

Mp: 175 ° C (isopropanol).

30 Example 19

From 3,3-diphenyl-propionic acid amidoxime using heptamethyleneimine as the amine component in the manner described in Example 10, 0- (3-heptame-thylenamino-2-hydroxy-l-propyl) -3,3-diphenyl-propionic acid-35 amidoxime -dihydrochloride produced, which melts after recrystallization from isopropanol at 233 ° C.

Analysis for C25H: i7N302Cl2 (M = 482.48)

calculated: C 62.24% H 7.73% Cl 14.70% 40 found: C 61.94% H 7.70% Cl 14.74%

Example 20

From 3,3-diphenyl-propionic acid amidoxime, using morpholine as the amino component in the 45 manner described in Example 10, 0- (3-morpholino-2-hydroxy-1-propyl) -3,3-diphenyl-propionic acid is obtained -amidoxim-dihy-drochloride produced, which melts after recrystallization from isopropanol at 225 ° C.

50 analysis for C22H31N303C12 (M = 456.40)

calc .: 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

1- (3-Diethylamino ^ 2-hydroxy-1-propyl) -1-naphthyl-acetamidoxime hydrochloride is prepared from 1-naphthyl-acetamidoxime using diethylamine as the amine component in the manner described in Example 10, which after recrystallization from absolute alcohol melts at 150-152 ° C.

Analysis for Ci9H28N302C1 (M = 365.89)

calc .: 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%

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Example 22

From 1-naphthyl-acetamide oxime, using piperidine as the amine component, it is converted to that in Example 10

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described way 0- (3-piperidino-2-hydroxy-l-propyl) -l - naphthyl-acetamidoxime hydrochloride produced, which melts after recrystallization from absolute alcohol at 177-179 ° C.

Analysis for C20H28N3O2Cl (M = 377.89)

calc .: C 63.57% H 7.46% N 11.12% Cl 9.38%

found: C 63.58% H 7.59% N 11.47% Cl 9.60%

Example 23

20 ml of 10% sodium hydroxide solution are added to a mixture of 4.0 g of benzamide oxime, 10 ml of water and 4.5 g of epichlorohydrin at room temperature with stirring within one hour. The mixture is stirred for a further two hours, then 4.5 g of piperidine are added and the mixture is stirred again for 8 hours. The oily preparation is then extracted with benzene. After evaporation of the benzene solution, 6.2 g of 0- (3-piperidino-2-hydroxy-1-propyl) -benz-amidoxime are obtained, which is identical to the product prepared according to Example 1.

Example 24

6.8 g of benzamide oxime are dissolved in 40 ml of 10% sodium hydroxide solution, and 9.5 g of epichlorohydrin are added to the solution with stirring. The reaction is exothermic, so the temperature is kept at 30-35 ° C by external cooling. The mixture is stirred for two hours

then 8.6 g of piperidine are added dropwise. After stirring for a further two hours, the oily product is extracted with benzene. After evaporation of the benzene, 8.2 g of 0- (3-piperidino-2-hydroxy-1-propyl) benzamide oxime are obtained. The product is identical to the product according to Example 1.

Example 25

6.8 g of benzamide oxime are dissolved in 40 ml of 10% sodium hydroxide solution. 9.5 g of epichlorohydrin in 20 ml of benzene are added dropwise to the solution with vigorous stirring. The mixture is stirred for 4 hours, then 8.6 g of piperidine are added and the mixture is stirred at room temperature for a further 8 hours. The benzene phase is then separated off and the aqueous phase is extracted with benzene. The combined benzene solutions are evaporated. This gives 0- (3-piperidino-2-hydroxy-l-propyl) benzamide oxime which is identical to the product prepared according to Example 1.

Example 26

6.8 g of benzamide oxime are dissolved in a mixture of 20 ml of 10% sodium hydroxide solution and 20 ml of methanol. 9.5 g of epichlorohydrin are added dropwise with stirring. The mixture is then stirred at room temperature for two hours, and 8.6 g of piperidine are then added. The mixture is stirred for a further 8 hours. Then the methanol is removed in vacuo, the oily substance is extracted with benzene. After evaporation of the benzene, 7.2 g of 0- (3-piperidino-2-hydroxy-1-propyl) benzamide oxime are obtained, which is identical to the product prepared according to Example 1.

Example 27

2.4 g of sodium tert-butoxide are added to the solution of 5.2 g of 3,4-dimethoxyphenyl acetamide amidoxime in 20 ml of dimethyl sulfoxide with stirring. Then 3.0 g of epichlorohydrin are added dropwise, and the mixture is then stirred at room temperature for 2 hours. After the addition of 2.5 g of piperidine in 60 ml of acetone, the batch is stirred again for 8 hours and boiled under reflux, and finally 120 ml of ethyl acetate are added.

4.4 g of 0- (3-pipe-ridino-2-hydroxy-1-propyl) -3,4-dimethoxyphenyl-acetamide-oxime-dihydrochloride, which is identical to the product prepared according to Example 2, are crystallized by introducing hydrochloric acid gas .

Example 28

From 2-phenyl-propionic acid amidoxime and 3-piperidino-2-hydroxy-1-chloropropane, 0- (3-piperidino-2-hydroxy-1-propyl) -2-phenyl-propionic acid amidoxime is converted in the manner described in Example 6. Dihydrochloride produced, which melts after recrystallization from isopropanol at 225 ° C.

Analysis calc .: 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

From 3-cyclohexylamino-2-hydroxy-l-chloropropane [J. Org. Chem. 24, 615 (1959)] and nicotinic acid amidoxime is prepared in the manner described in Example 6 0- (3-cyclohexylamino-no-2, -hydroxy-l-propyl) -nicotinic acid amidoxime, which after recrystallization from a Benzene-toluene mixture melts at 102 ° C.

Analysis for C15H24N402 (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 racemes 0- (3-piperidino-2-hydroxy-l-propyl) benzamidoxime and 1.16 g of d-camphorsulfonic acid are dissolved in 20 ml of boiling ethanol. The solution is evaporated in vacuo. The residue is recrystallized first from butyl acetate and then from ethyl acetate. 0.4 g of d-0- (3-piperidino-2-hydroxy-l-propyl) benzamidoxime camphorsulfonate is obtained, which melts at 132 ° C.

The base is released in the usual way from the camphorsulfonic acid salt and then the hydrochloric acid salt is formed from it. The hydrochloride melts at 196 ° C.

[a] 559nm = + 6.3 ° (c = 1% water).

Example 31

1.15 g of metallic sodium are dissolved in 100 ml of absolute ethanol and 12.0 g of 3,3-diphenylpropionic acid amidoxime are added to the solution. 13.2 g of 2-phenyl-3-isopropyl-5-chloromethyl-oxazoli-din are added dropwise to the boiling mixture. Then the mixture is boiled for a further 16 hours. The solvent is evaporated, 110 ml of 5N hydrochloric acid are added to the residue and the mixture is boiled under reflux for one hour. Then the solution is extracted with ethyl acetate, clarified with activated carbon and made alkaline with 10% sodium hydroxide solution. The oily crude product is extracted with ethyl acetate, the extract is dried over anhydrous sodium sulfate and the solvent is evaporated. The evaporation residue is dissolved in acetone and the solution is mixed with ethanolic hydrochloric acid. 7.0 g of 0- (3-isopropylamino-2-hydroxy-1-propyl) -3,3-diphenylpropionic acid amide oxime dihydrochloride are obtained, which melts at 179 ° C. and is identical to the product according to Example 14 is.

Example 32

From 2-phenyl-propionic acid amidoxime and 2-phenyl-3-isopropyl-5-chloromethyl-oxazolidine, 0- (3-isopropylamino-2-hydroxy-1-propyl) -2-phenyl- propionic acid amidoxime dihydrochloride he mihydrate produced, which melts at 168 ° C (acetone-isopropanol mixture).

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

630344

10th

Analysis for CläH27N302Cl2. 0.5 H20 (M = 361.31)

calc .: 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;

Benzamide oxime and 2-phenyl-3-isopropyl-5-chloro-methyl-oxazolidine are converted to those described in Example 31

Way 0- (3-isopropylamino-2-hydroxy-l-propyl) benzamide oxime dihydrochloride hemihydrate prepared.

Mp: 173-174 ° C.

5 Analysis for C13H2302Cl2. 0.5 H20 (M = 333.26)

calc .: 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%

v

Claims (18)

630344 2nd PATENT CLAIMS 1. Process for the preparation of new 0- (3-amino-2-hydroxypropyl) amidoxime derivatives of the general formula R N 3/1 R - (CH) - (CH) -C = N-0-CH - CH-CH - N J > 4 m l5 1 I VR2 R R NH2 • OH (I) wherein R1 represents hydrogen or alkyl having 1 to 5 carbon atoms and R2 represents alkyl with 1 to 5 carbon atoms, cycloalkyl or phenyl which is optionally substituted by hydroxyl or phenyl, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring with 5 to 8 ring members, which optionally contains further heteroatoms and / or is fused with a ring, R3 denotes a cycloalkyl group, phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl or pyrazolyl, optionally substituted by halogen, alkoxy or alkyl, to which group a ring may be fused, R4 for hydrogen, optionally substituted by halogen or Cr to C4-alkoxy, Cr to C4-alkyl or cycloalkyl or phenyl and R5 is hydrogen, C 1 -C 4 -alkyl or phenyl, and m is 0, 1 or 2, n is 0, 1 or 2, and their acid addition salts, characterized in that an amidoxime of the general formula 4. The method according to claim 1, characterized in that one uses hydrochloric acid, phosphoric acid or sulfuric acid for salt formation. 5. The method according to claim 1, characterized in that nicotinic acid, maleic acid, Acetic acid or an optically active acid, preferably camphorsulfonic acid or tartaric acid. 6. The method according to claims 1 and 5, characterized in that the salt io formed with an optically active acid is recrystallized from ethyl or butyl acetate. 7. The method according to claim 1, characterized in that one starts from nicotinic acid amidoxime and piperidine. 15 8. A process for the preparation of new 0- (3-amino-2-hydroxypropyl) amidoxime derivatives of the general formula I, wherein R1 to R5, m and n have the meaning given in claim 1, and their acid addition salts, thereby characterized that you have an amidoxime of the general-20 my formula 25th R - (CH) - (CH) -C = N-OH | m i n - 4 5 1 R R NH2 wherein R3, R4, R5, m and n have the above meaning, with a 3-amino-2-hydroxy-l-halogenopropane or a 3-amino-l, 2-epoxypropane of the general formulas (ii) 30th X-CH., - CH-CH - N 1 I 2 Oh r \ (Va) R - (CH) - (CH) —C = N-OH • min, 35 (Ii) R NH. wherein R3, R4, R5, m and n have the meaning given above, with epichlorohydrin and then with an amine of the general formula r \ I. wherein R1 and R2 are as defined above, with the interim formation of an epoxide of the general formula r - (ch) - (ch) -c = -ch-chn l "m U n I 2 \ / 2 R R ~ NH, in which R3, R4, R5, m and n have the meaning given above, and, if desired, convert a base obtained with an inorganic or organic acid into an acid addition salt or release the corresponding base from a salt obtained. 2. The method according to claim 1, characterized in that one carries out the reaction in a solvent, preferably in an aqueous medium, in a water-containing organic solvent or in a reaction medium containing an aqueous and an organic phase. 3. The method according to claims 1 or 2, characterized in that one carries out the reaction at temperatures between -10 and + 140 ° C. or R 40 CH - CH-CH - N \ 2/2 (Vb) cm) (IV) in which R1 and R2 have the meaning given above and X represents halogen, and, if desired, reacting a base obtained with an inorganic or organic acid 45 converted into an acid addition salt or releases the corresponding base from a salt obtained. 9. The method according to claim 8, characterized in that one carries out the reaction in a solvent, preferably in an aqueous medium, in a water-containing organic solvent or in a reaction medium containing an aqueous and an organic phase. 10. The method according to claims 8 or 9, characterized in that the reaction at temperatures 55 between -10 and + 140 ° C. 11. The method according to claim 8, characterized in that hydrochloric acid, phosphoric acid or sulfuric acid is used for salt formation. 12. The method according to claim 8, characterized in 60 net that nicotinic acid, maleic acid, Acetic acid or an optically active acid, preferably camphorsulfonic acid or tartaric acid. 13. The method according to claims 8 and 12, characterized in that with an optically active acid 65 salt formed is recrystallized from ethyl or butyl acetate. 14. Process for the preparation of new 0- (3-amino-2-hydroxypropyl) amidoxime derivatives of the general form 3rd 630344 mei I, where R1 is hydrogen and R2 to R5, m and n have the meaning given in claim 1, and their acid addition salts, characterized in that an amidoxime of the general formula II with a 2-phenyl-5-halogenomethyl oxazolidine of the general formula X - NO (VI) where X is halogen and R2 has the meaning given above, and the ring compound of the general formula obtained NO 3 \ R - (CH) - (CH) -C = N-0-CH_ A_ i m i ni 2 y (VII) K * R NH- Receptor transformation is responsible for the release of a modulator substance [Amer. J. Physiol. 218: 896 (1970)]. After adding this substance to an a-organ, the a-agonistica is no longer effective, since the receptor has become a 5 ß-receptor. The original sensitivity returns when a ß-blocking agent is administered at the same time. In the case of a qualitative change in metabolism, a-agonistica (for example, noradrenaline) remains effective in both experimentally induced and 20 human diabetes, but its effect can be reversed by ß-blocking agents. This is the first functional change to be demonstrated in diabetes, 24 hours after 15 doses of Alloxan (hexahydropyrimidine tetraone). In diabetes, an imperfect a-ß receptor conversion plays a role as the starting point for changes. This is probably caused by the formation of an incorrect modulator substance that differs from the original one. It has now been found that the new compounds of the general formula I wherein R2, R3, R4, R5, m and n are as defined above without isolating them beforehand, hydrolytically cleaving and, if desired, converting a base obtained into an acid addition salt or releasing the base from a salt obtained. 15. The method according to claim 14, characterized in that one carries out the reaction in a solvent, preferably in an aqueous medium, in a water-containing organic solvent or in a reaction medium containing an aqueous and an organic phase. 16. The method according to claims 14 or 15, characterized in that one carries out the reaction at temperatures between -10 and + 140 ° C. 17. The method according to claim 14, characterized in that hydrochloric acid, sulfuric acid or phosphoric acid is used for salt formation. 18. The method according to claim 14, characterized in that nicotinic acid, maleic acid, acetic acid or an optically active acid, preferably camphorsulfonic acid or tartaric acid, is used for salt formation. 25 R - (CH) m Diabetes mellitus is a common metabolic disorder. Its main symptom is the disturbance of the balance in the carbohydrate metabolism of the organism. Diabetes mellitus is often accompanied by pathological changes in the vascular system, such as narrowing of the limbs, pathological changes in the base of the eye, etc. While many effective medicines for reducing the high blood sugar level are already known in addition to insulin, the successes have been with Treatment of diabetic angiopathy, which occurs with the main disease, with the preparations currently on the market is very modest. The reason for this is that with the onset of diabetes mellitus, the adrenergic receptors of the veins change and, as a result of the treatment with drugs, adrenergic reactions occur which differ from those in non-diabetic persons [Nature New Biology 243, no 130, 276 (1973); Szemés-zet 111. 23. (1974); Endocrinology 93, 752 (1973)]. The a-receptors of the veins are transformed into ß-receptors for the quantitative increase of the metabolism. For this (CH) -C = N- I c «I R NH2 0-CH - CH-CH - N 2 | 2 N OH I (I) wherein 30 R1 for hydrogen or alkyl with 1 to 5 carbon atoms and R2 represents optionally substituted by hydroxyl or phenyl alkyl with 1 to 5 carbon atoms, cycloalkyl or phenyl, or 35 R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring with 5 to 8 ring members, which optionally contains further heteroatoms, preferably oxygen or nitrogen and / or is condensed with a ring, 40 R3 is a cycloalkyl group, phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl or pyrazolyl, optionally substituted by halogen, alkoxy or alkyl, to which group a ring is optionally fused, R4 is hydrogen, optionally by halogen or 45 Q- bis C4-Alkoxy substituted Cr to C4-alkyl or cycloalkyl or phenyl and R5 is hydrogen, Cr to C4-alkyl or phenyl, and m is 0, 1 or 2, 50 n mean 0, 1 or 2, have little or no effect on the adrenergic reactions of the healthy veins, but have a strong effect on the adrenergic receptors that have been morbidly affected by diabetes mellitus. This effect manifests itself primarily as selective ß-blocking. The compounds according to the invention are therefore suitable for the treatment of diabetic angiopathy. Some of the compounds according to the invention have an antihypertensive effect and an a-blocking effect.