CS204009B2 - Process for preparing new derivatives of 0-/3-amino-2-hydroxypropyl/amidoxime - Google Patents

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 eye, etc. While numerous effective drugs are already known to reduce high blood sugar angiopaithia preparations now on sale are very scarce. This is because adrenergic prescription vessels change with the emergence of diabetes mellitus and adrenergic reactions that differ from those in people not affected by diabetes mellitus occur as a result of drug treatment (Nature New Biology 743, No. 130, 276 (1973), Szemészet 111, 23 (1974), Endocirinology 93, 752 (1973)] .The vascular receptors are transformed to quantitatively increase the metabolism to the .beta.-receptors, which is responsible for the release of modulators [Amor. 218, 869 (1970).] When this substance is added to the β-organ, the β-receptor is no longer effective, since the formulation has been converted to the δ-receptor, and the original α-sensitivity is reversed when the β-blocking agent is administered simultaneously.

In the event of a qualitative change in metabolism, α-agonists (for example noradrenaline) will continue to be effective in both experimentally induced and in human diabetes; This is the first functional change that can be demonstrated in diabetes 24 hours after the administration of alloxane (hexahydropyrimidine intrara). In diabetic patients, an imperfect α-, β-ireceptor conversion plays a role as a starting point for changes. 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 formula I

R ² - (CH) _n - (CH) _{n -} C = N - O - CH 2 - CH-CH 2 -NH-R 1 R ³ R ⁴ NH 2 OH (I) where

R ¹ represents optionally hydroxyl or phenyl substituted C ₅ alkyl or a C ₅ _ ₈ cycloalkyl or phenyl,

R ² is ^an optionally halogen, Ci_4alkoxyskupinou, or alkyl-substituted C ₅ _ _g cycloalkyl or phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl or pyrazolyl; which skppině optionally condensed with a phenyl ring,

R ³ is hydrogen or optionally halogen or C _1-5 alkoxy substituted C _1-5 alkyl or C _5-6 cycloalkyl or phenyl,

R ⁴ is hydrogen, C 1-4 alkyl or phenyl and m is 0, 1 or 2, and n is 0, 1 or 2, do not affect or only slightly adrenergic reactions of healthy blood vessels, but have a strong effect on adrenergic receptors, altered by diabetes mellitus. This effect primarily manifests itself as a selective β-blocking effect. Therefore, the compounds of the invention are useful in the treatment of diabetic angiopathy. Some of the compounds of the present invention exhibit a blood pressure lowering effect as well as a blocking effect.

The invention accordingly relates to a process for the preparation of the amidoximes of the formula I and to their salts. The process according to the invention is characterized in that the amidoximes of the general formula II, R ² - (CH) _m - (CH) _{n -} C = N - OH R ³ R ⁴ NH 2 (II) wherein:

R ^2, R ^3, R ^4, m, n have the abovementioned meaning, are reacted with 3-substituted 2-phenyl-5-halometyloxazolidiny formula III, ^{X 'CH} * or *

Lit (lit) where

X is halogen and R < ¹ & gt ^; is the same as above, and the compounds of formula IV obtained,

R - (CH) 4 (CH, α = NO-CH 2 R ³ R ¹ NH _Z (IV) where the meaning of R ¹ , R ² , R ³ , R ⁴ , m, n is given above, hydrolyzes without intermediate isolation and the compounds of formula I obtained are optionally reacted with and / or liberated from their salts with inorganic or organic acids.

The reaction is preferably carried out according to the invention in alkanols. The intermediate of formula (IV) is preferably hydrolyzed with acids. The starting materials of the formula (III) can be prepared, for example, by the process described in DOS 2,018,236.

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. Salt can be formed from the free bases by addition of up 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 [beta] -receptors blocking the action of the compounds of formula (I) were tested on a prepared tracheal ring [J. Pharm. Exp. Therap. 90, 104 (1947)] and the cat's papillary muscle. Selective 3-blocking effect was tested on a spinal preparation of rat aorta [J. Pharmacol. Exp. Therap. 158, 531 (1967)] as follows:

The animals were opened the ribcage and the thoracic aorta was removed and spirally cut. The movements of the just expanding spiral were registered on two rollers provided with a soot deposit by means of an isotonlocal registration arm. The control reaction of the control preparation was registered on one cylinder, followed by the reaction of the aorta of rats treated with [2- (3-, niitroso-3-methylureido) -2-desoxy-D-glucose J] as aortic reaction. The effect of the dose of noradrenaline (NA) on the control preparation was unaffected by the test substance, but was affected on the diabetic aorta. The activity of the compounds of the invention is generally selective, which is. expressed by the fact that the diabetic test produces a strong, in the normal test, no or little β-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 pDž value, i.e. the negative logarithm of the dose belonging to half of the maximal effect, was determined. From the difference pDD 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. On guinea pig trachea, 10 µg of the test compound reduced the effect of 0.01 µg / ml isoprenaline [D, L-1- (3,4-dihydroxyphenyl) -2-iiso. propylaminoethanol] in half. On the uterus of streptosotocin-pretreated rats, the compound at 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 is equivalent to 0.5 [mu] g / ml of inderal [1-isopropylamino-3- (1-naphthyloxy) propan-2-ol]. 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 effect curve of the isoprenaline doses at 100 µg / ml on the stomach fund strips of untreated rats. That is, the compound has a strong, S-blocking effect in a normal test in the diabetic test.

The compound prolongs survival hypoxia by the order of magnitude.

Tachycardia caused by isoprenaline (1 µg / kg i.v.) is influenced to a minor extent by the compound. The mice were 5 min after

i. v. application of 10 mg / kg measured an increase in heart rate by 10%, within 5 minutes after i. v. application of 100 mg / kg, the heart rate decreased by 3%.

O- (3-Piperidino-2-hydroxy-1-propyl) -nicotinic acid amidoxime dihydrochloride exhibits the following effects:

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

Further, attempts were made to determine whether noradrenaline-induced contraction could 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 with streptosotocin the differences in the pD values of the noradrenaline dose-response curve (before and after inderal administration) were: 1.0335, Sx = 0.0829, t = 3.5885, p <0.01, n = 8. In non-diabetic preparations, the contraction caused by noradrenaline inderal was not affected.

It has also been tested that among compounds similar to the chemical structure-blocking compounds there are those which, like inderal, would act on the aortic spiral of diabetic animals without substantially affecting the normal O-effects, i.e. compounds for which they are specific in diabetic vessels emerging "false" /3- effects.

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

NP-18:

0-3-piperidino-2-hydroxy-1-propyl / -3,4-dimethoxyphenylacetamide oxime dihydrochloride

NP 18:

nicotinic acid CD (3-piperidino-2-hydroxy-1-propyl) amidoxime dihydrochloride

On the aorta spiral of animals treated with streptosotocin, the difference (before and after administration of 1 µg / ml NP-18) pDz of 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 obtained with NP-51. In the streptosotocin-treated group, pD2 is the noradrenaline-induced difference (pre-and post-NP-51 values) = 0.8 = 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 initial receptor changes are suppressed, for example, by N'P-18 or NP-51. A portion of the CFY rats (about 60%) used as test animals were latent diabetic, this was demonstrated by sugar loading. A portion of these animals weighing 400-500 g was demonstrably diabetic macroangiopathy and microcangiopathy. Animals that had already been treated with a weight of 200 g NP-18 or NP-51 had no microangiopathy until 500 g, and the macroangiopathy was significantly smaller.

In addition, it could be stated that although both NP-18 and NP-51 suppress isoprenaline in guinea pig tracheas, their effect is 4 orders 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 effect of isoprenaline, but only at 100 mg / kg caused bradycardia and a decrease in dp / dt value. 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 the inderal is about 4 order of magnitude. On guinea pig ileum, the compounds of the invention only affected the effect of barium chloride and acetylcholine at a dose of 50-100 pg / 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.

LD50 values:

NP-18: 165 mg / kg iv. (mouse)

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

The compounds of the formula I and their salts can be formulated in known manner 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 by means of the following examples, without being limited thereto.

Example 1

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

The base is released from the camphorsulfonic acid salts in the usual manner, and the hydrochloric acid salt is then formed. The hydrochloride melts at 198 ° C (?) 559 _nm = + 6.3 ° (c = 1% in water).

Example 2

Dissolve 1.15 g of sodium metal in 100 ml of absolute ethanol and add to the solution 12.0 g of 3 _; Propionic acid 3-diphenylamidoxime. 13.2 g of 2-phenyl-3-isopropyl-5-chloromethyl-oxazolidine are added dropwise to the boiling mixture. The batch is then boiled for a further 16 hours. The solvent is evaporated, the residue is made up with 110 ml of 5 N hydrochloric acid and refluxed for one hour. The solution was then extracted with ethyl acetate, clarified with charcoal and basified with 10% sodium hydroxide solution. The oily crude product was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dissolved in acetone and ethanolic hydrochloric acid was added. 7.0 g of O- (3-isopropylamino-2-hydroxy-1-propyl) -3,3-diphenylamidoxime propionic acid are obtained in the form of the dihydrochloride, which melts at 179 ° C. Analysis for C 21 H 31 N 3 O 2 Cl 2 (M = 418.39) Calculated:

C 58.87%, H 7.29%, N 9.81%, Cl 16.55%; Found:

C 58.58%, H 7.39%, N 9.53%, Cl 16.70%. LD 50: 16.25 mg / ikg iv. (mouse)

Example 1 a d 3

From 2-phenylamidoxime propionic acid and 2-phenyl-3-isopropyl-5-chloromethyloxazolidine, O- (3-isopropylamino-2-hydroxy-1-propyl) -2-phenylamidoxime propionic acid was prepared as the hydrochloride salt as described in Example 2, which melts at 16 C ^I 8 ^O (mixture of acetone and isopropanol).

Analysis for C15H27N3O2Cl2. 0.5 H2O (M = 361.31)

Calculated:

C 49.86%, H 7.81%, N 11.63%, Cl 19.63%; Found:

C 49.79%, H 7.75%, N 11.61%, Cl 19.50%. Example 4

O- (3-Isopropylamino-2-hydroxy-1-propyl) benzamidoxime dihydrochloride hemihydrate was prepared from benzamidoxime and 2-phenyl-3-isopropyl-5-chloromethyloxazolidine as described in Example 2. Melting point 173-174 ° 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 (7)

and. A process for the preparation of the novel O (3-amino-2-hydroxypropyl) -amide oxime derivatives of formula (I), R ² - (CH) _m - (CH) _n -C = N- R ³ R ⁴ NH 2 - O - CH 2 - CH - CH 2 - NH - R ¹ OH (I) wherein R ¹ represents optionally hydroxyl or phenyl substituted C ₅ alkyl or • C _5-8 cycloalkyl, or phenyl, R ² is ^an optionally halogen, C ₄ alkoxy, or alkyl-substituted C ₅ _ ₈ cycloalkyl or phenyl, naphthyl, 1, quinolyl, isoquinolyl, pyridyl or pyrazolyl; which group is optionally condensed with a phenyl ring, R ³ is hydrogen or an optionally halogen or C ₅ alkoxy group substituted by a C _ ₅ alkyl or C ₅ _ ₈ cycloalkyl or phenyl, R ⁴ represents hydrogen, C] _ ₅ alkyl or phenyl am is zero, 1 or 2 and n is O, 1 or 2, the invention as well as their salts, characterized in that the amidoxime of the formula II ^1, R ² _-; (CH) _m - (CH j _n -C = N-OH, R ^3, R ⁴ NHZ (Π), wherein R ^2, R ^3, R ^4, m, n have the abovementioned meaning, are reacted with 3-substituted 2-phenyl-5-halometyloxazolidiny general formula III, III (III) where X is halogen and the meaning of R ¹ is the same as above, '/ and the compound of formula IV, c ₆ d The. R ³ R NH _Z c = n o ₉ I (IV) wherein the meaning of R ¹ , R ² , R ³ , R ⁴ , m, n is the same as above, in the reaction medium in which they were formed, hydrolyzed and obtained compounds of formula (I) are optionally reacted with and / or liberated from their salts with inorganic or organic acids. 2. Process according to claim 1, characterized in that the reaction is carried out in a solvent, preferably water, an organic solvent containing water or a reaction medium comprising one aqueous and one organic phase. A process according to claim 1 or 2, characterized in that the reaction is carried out at temperatures between -10 ° C and -140 ° C. 4. The process of claim 1 wherein the inorganic acid is hydrochloric, sulfuric or phosphoric. Process according to claim 1, characterized in that nicotinic acid, maleic acid, acetic acid or an optically active acid, preferably camphorsulfonic acid or tartaric acid, is used as the organic acid. Process according to claim 1 or 5, 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 method according to claim 1, wherein the optically active compounds of formula I are released from their salts and optionally converted into other salts.