DE2758868A1 - 1- (2-NITRO-METHYLPHENOXY) -3-TERT.- BUTYLAMINO-PROPANE-2-OLE, METHOD FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL COMPONENT CONTAINING IT - Google Patents

Description

₃ 27S8868

51 284-T

Applicant: Dr. L. Zambeletti S.p.a. Viy L. ° Zambeletti

20021 - Baranzate (Milan) - Italy

l- (2-nitro-methylphenoxy) -3-tert-butylamino-propan-2-ols, Process for their preparation and pharmaceutical agent containing them

The invention relates to new 1- (2-nitro-methylphenoxy) -3-tert-butylamino-propan-2-ols the general formula

0 - CH - CH - CH. - NH - C (CHj

^c % ^ά ■ J

OH

(D

wherein the methyl group is at the 3- or 5-position of the benzene ring may be bound, and the acid addition salts, in particular the pharmaceutically acceptable acid addition salts of that.

The present invention also relates to a process for the preparation of the compounds of the formula given above (I) as well as pharmaceutical agents (drugs) that inhibit or prevent the aggregation of blood platelets

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de have activity or effectiveness, which as active ingredient (active principle) at least one compound of the above Formula (i) or at least one pharmaceutically acceptable acid addition salt thereof, optionally in Combination with a customary pharmaceutically acceptable carrier and / or excipient.

Propan-2-ols with a structure analogous to that of the compounds of the invention are in the UK Patents 1,069,341 and 1,069,345 which demonstrate the β-adrenergic blocking activity of these compounds regards. This activity, but in particular a coronary dilatory and sedative activity, is also analogous to others Connections in the German Auslegeschrift 1 236 523 described.

It has now surprisingly been found that the compounds of the formula (I) have the ability to reduce platelet aggregation to he.urneη or to prevent and thereby the formation of thromboses to such an extent that these compounds are used for the prevention and therapy of thrombosis can be. This activity mentioned in the above patents is not mentioned in relation to the propan-2-ols, on the other hand it is significantly lower for the two isomers of the compounds (I) which have the methyl group in the 4- and 6-positions, that is to say in the 1- (2-nitro-4-methylphenoxy) "3-tert-butylamino-propan-2-ol and l- (2-nitro-6-methy! phenoxy) -3-tert-butylamino-propan-2-ol.

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The novel compounds forming an object of the invention (I) are prepared by reacting the corresponding phenoxy-epoxy-propane of the general formula

(II)

wherein the methyl group on the 3- or 5-position of the benzene ring can be bound with tert-butylamine.

The compounds (Ii) can in turn be produced by treating 2-nitro-3-methylphenol or 2-nitro-5-methyl-phenol with epichlorohydrin.

The same process can also be used to prepare the two 4- and 6-methyl derivatives mentioned above, which, as already mentioned, have a low level of inhibition of platelet aggregation or have preventive activity.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

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6th 2 7 S 8 8 6 8

example 1

a) 1- (2-Nitro-5-methylphenoxy) -2,3-epoxypropane

5 g of 2-nitro-5-methylphenol and 15 ml of epichlorohydrin were dissolved in 50 ml of methanol and the stirred solution was with 1.5 g of well-ground sodium hydroxide treated. Almost immediately, a thick red-colored suspension formed, which underneath Stirring was boiled for 8 hours; at this point the red solid had dissolved and the sodium chloride had separated out was finished.

The reaction mixture was cooled, the precipitate was filtered off and the solution was evaporated to dryness in vacuo. The resulting oil was dissolved in chloroform, the solution was washed several times with water and, after drying over Na ₂ SO, it was evaporated to dryness. The oily residue changed spontaneously by itself (even better by treatment with a little ether) into a crystalline, light yellow solid (temperature 62-63 ° C.). The analytical data and the NMR spectrum confirmed the identity of the compound.

b) 1 "(2-nitro-5-methylphenoxy) -3-tert-butylamino-propan'2-ol hydrochloride (compound ^M A")

5 g of 1- (2-nitro-5-methylphenoxy) -2,3-epoxypropane and 10 ml of tert-butylamine in 10 ml of methanol were refluxed for 3 hours heated. The reddish solution was evaporated to dryness in vacuo. The solid residue was washed with a little ether

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27S8868

wash at 88 ° C.

The base was suspended in 20 ml of absolute ethanol, there were 10 ml of ethanol saturated with HCl was added and the mixture was boiled for a few minutes until completely dissolved. The solution was filtered with activated charcoal and the hydrochloride was precipitated by cooling to give 5.2 g of yellowish white voluminous crystals, 215-216 ° C. The analytical data and the NMR spectrum confirmed the identity of the compound.

Example 2

a) 1- (2-Nitro-3-methylphenoxy) -2 _t 3-epoxypropane

A mixture of 5 g of 3-methyl-2-nitrophenol, 15 ml of epichlorohydrin and 2 ml of piperidine was stirred up for 6 hours 95-100 ° C heated. After the excess epichlorohydrin was evaporated in vacuo, the oily residue was dissolved in chloroform and the solution was added with 50 ml for about 1 hour stirred a 20% sodium hydroxide solution. The chloroform layer was separated, washed several times with water, over Dried sodium sulfate and evaporated to dryness. ° he oily residue could be used as it was for the subsequent reaction.

b) l- (2-Nitro-3-methylphenoxy-3-tert «-butylamine-propan-2-ol hydrochloride (compound ^M B")

A solution of 6 g of l- (2-nitro-3-methylphenoxy) -2,3-epoxy-

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propane and 20 ml of tert-butylamine in 30 ml of methanol Heated to reflux for 4 hours. The reaction mixture was evaporated to dryness in vacuo and the residue became dissolved in ether. The solution was made weakly acidic with diethyl ether saturated with HCl. It occurred to me transparent oil that solidified quickly. The solid was filtered off and crystallized from isopropyl ether. M.p. 185-187 ° C. The analytical data and the NMR spectrum confirmed the identity of the compound.

By the same method, 1- (2-nitro-4-methylphenoxy) · 3-tert-butylamine-propan-2-ol hydrochloride (Compound "C"), mp 166-168 ⁰ C ₇ and 1- ( 2-Nitro-6-methylphenoxy) -3-tert-butylamine-propan-2-ol-hydrochloride (Compound "D"), F.152-153C.

The anti-aggregation activity on platelets in vitro and in vivo in guinea pigs and in vitro in People examined.

For the in vivo tests, guinea pigs were weighed from 400-600 g used. The compounds of the invention were administered intraperitoneally, at a single time Treatment at a dose of 5 mg / kg and with repeated treatment for a period of 4 days in one dose of 2 mg / kg. A physiological solution was administered to the control animals.

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Blood was drawn by intracardiac injection 15 minutes and 120 minutes after the administration of the tested compound and with 0.126 ml of a sodium citrate solution in one Amount ratio of 1 part of this solution mixed to 9 parts of blood.

The platelet aggregation was 0.8 micromol / ml Adenosine-5-diphosphate (ADP) performed and read off the light transmission is determined on a suitable photometer (ELVI aggregometer model 840).

In the in vitro test, guinea pig or human blood was used with the above sodium citrate solution and with 0.8 Micromol / ml ADP and then with 100 μg / ml of the tested Connection handled. The light transmission and the resulting anti-aggregation activity were used determined by the method described above and using the apparatus described above.

In the following tables are the high anti-aggregation activity and the two preferred compounds of the invention specified.

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40

TAB IE I

2 '/ S 8 8 6 8

Anti-aggregation activity against platelets in vitro

Guinea pig

person

tested transmission activity Transmission activity 93.7 7. link 5 7o 92.6 7o 5 7o 77.5 7o A. 33 7o 51.5 7o 18 7o 62.5 7o B. 47 7o 30.9 7o 30% 50 7o C. 49 7o 27.9 7o 40 7o D.

Base value = 68

Base value = 80

after a single
administration 49.3 % after repeated administration
range (on 4 in a row
the following days) Transmission activity 54.6 % Transmission activity TABLE II 38 % 6.6 7. 25 Χ 65.2 7. 34% 0 % 22 % 69.4 % Anti-aggregation activity in guinea pigs in vivo 70 % 51% 29.1 70 tested
link 76% 46 % 36.1% A. B. C. D.

Base value = 75

Base value = 72

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The actual toxicity of the compounds of the formula (I) in mice (strain "Switzerland") with a weight of 20 to 24 g determined, which before the test for at least 10 days under standard conditions (temperature 22 ° C; relative Humidity about 50%) and were fed a controlled diet (Altromin) · Before the test were the animals were left with water "ad libitum" for 15 hours without food.

Mortality was determined at 10 animals / doses, with 60 animals being used per product tested. The LD _{50 was determined} for each product when administered intravenously as well as when administered orally. The compounds were dissolved in distilled water and the maximum volumes administered were 0.1 ml / 10 g body weight (intravenous) and 0.5 ml / 10 g body weight (per os).

The toxicity control was carried out not only for the two compounds in question (compounds "A" and "B"), but also for the two hardly active isomers (compounds ¹¹ C "and" D "), as shown in the following Table III that when administered intravenously compound "D" was more toxic followed by compounds ¹¹ B "," A "and" C ", while when administered orally the most toxic product was compound ¹¹ B" followed by compounds "D", "A" and "C".

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ifl,

TABLE III

tested mouse LD _5Q (mg / kg)

Compound intravenous orally

A 47 377

B 37 211

C 60 407

D 33 328

From the above, it can be seen that considering the very low concentration at which Compounds ¹¹ A "and" B "have anti-aggregation activity, their toxicity is undoubtedly low, so that these compounds can be used therapeutically Single doses are administered which, when administered parenterally in the form of vials, vary between 1 and 10 mg, or they can be administered in single doses which, when administered orally in the form of tablets or capsules, vary between 10 and 15 mg.

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Claims (3)

Claims 1. l- (2-nitro-methylphenoxy) -3-tert-butylamino-propan-2-ols, characterized by the general formula 0 -CH-CH- CH. - NH - C (CHj ₀ ^c \ * ■ JJ NO OH (D wherein the methyl group at the 3- or 5-position des Benzene ring can be bound, as well as their acid addition salts, especially their pharmaceutically acceptable Acid addition salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that one the corresponding phenoxyepoxypropane of the general formula ι - ^c " ² ■ ^CH \ 7 ^0H * (H) 80982R / 0732 OBJGfNAL INSPECTED 7 7 S 8 3 6 wherein the methyl group a> i the 3- or 5-position des Benzene ring can be bound, reacted with tert-butylamine and the resulting compounds, if appropriate in a manner known per se into their acid addition salts, in particular their pharmaceutically acceptable ones Acid addition salts, transferred. 3. Pharmaceutical agent having anti-aggregation activity on the platelets, characterized in that it is the active ingredient (active principle) one or more 1- (2-nitro-methyl-phenoxy) -3-tert-butylamino-propan-2-ols and / or their pharmaceutically acceptable acid addition salts according to claim 1, optionally in combination with a customary, pharmaceutically acceptable carrier and / or excipient. 809828/0732