CA1227220A

CA1227220A - 3-amino-1 phenoxy-2-propanol derivatives

Info

Publication number: CA1227220A
Application number: CA000439481A
Authority: CA
Inventors: Louis Lafon
Original assignee: Laboratoire L Lafon SA
Current assignee: Cephalon France SAS
Priority date: 1982-10-26
Filing date: 1983-10-21
Publication date: 1987-09-22
Also published as: ES526737A0; ZA837922B; AU565183B2; FR2534908B1; CS235985B2; IL70061A0; MA19937A1; NZ206050A; DK490983A; MX155997A; FI833921A; DK156566B; ES8406062A1; JPS5995244A; DK156566C; ATE20339T1; EP0110746B1; DE3364087D1; HU188975B; OA07575A

Abstract

A B S T R A C T

The present invention relates to new 3-Amino-11-Phenoxy-2-Propanol derivatives which are selected from the group consisting of (i) 3-Alkylamino- 1-(2- chloro-3,5-dimethoxyphenoxy)-2-propanols of the general formula.

(I) -IMAGE-The invention also relates to the method for preparing these new derivatives and to their use therapeutics as .beta.-blocking agents.

Description

.L~Z7220 The present invention relates, as novel industrial products, to derivatives of 3-amino-1-phenoxy-2-propanol, namely the 3-alkylamino-1 (2-chloro-3,5-dimethoxyphenoxy)-2-propanols of formula (I) below and their salts. It also 5 relates to their use in therapeutics and the process of preparation of these novel products.
It is known, particularly from French Patents 3647M and ~061M and Publication 2042390 and US No 3 203 992 that in general, the derivatives belonging to the family of 3-amino-1-10 phenoxy-2-propanols have -blocking properties. Now, it happens that the derivatives of said family have never been marketable by reason of a certain number of drawbacks, particularly difficulties of tolerance and/or durations of -blocking actions which were too short.

It has just been found surprisingly that the 3-alkylamino-l-(2-chloro-3,5-dimethoxyphenoxy)-2-proopanols according to the invention do not have the above-indicated drawbacks, are from the therapeutic point of view more effective than (i) 1-(3,5-dimethoxyphenoxy)-3-isopropylamlno-2-20 propanol of BUM No. 3647M and No. 4061M, and (ii) 1-(3,5-dimethoxyphenoxy)-3-tertiobutylamino-2-propanol of French Publication 2042390, and are at least as interesting as the propanolol, a -blocking reference substance which is structurally different.

7~2~
, The novel derivatives of 3-amino-1-phenoxy-2-propanol according to the invention are characterized in that they are selected from the group consisting of (i) 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)-2-propanols of the general formula SHEA Of \

O-CH2-CH-CH2-NH-R lit OH

SHEA
in which R is CH(CH3)2 or C(CH3)3; and, it their addition salts.
From the practical point of view, the preferred products according to the invention are l-(2-chloro-3,5-dimethoxyphenoxy~-3-tertiobutylamino-2-propanol and its addition salts, particularly the hydrochloride. Tests in the animal and in man have shown that the 3-tertiobutylamino 20 derivative and its salts are more active than the 3-isopropyl amino derivative and its salts.
y addition salts, is meant here the acid addition salts obtained by the reaction of a free base of formula I) with an inorganic or organic acid, and the ammonium salts. Among the 25 acids useful for salifying the bases of formula (I), may be mentioned particularly hydrochloric hydrobromic, nitric, sulfuric, formic, acetic, prop ionic, oxalic, fumaric, malefic, succinic, benzoic, cinnamic, mandelic, citric, mafia, tartaric aspartic, glutamic, p-toluenesulfonic and methanesulfonic 30 acids. Among the compounds enabling the ammonium salts to be a I

obtained, may be mentioned particularly ITCH and SWISH. The acid addition salts, particularly the hydrochloride, are the addition salts preferred in therapeutics.
The novel derivatives ox 3-amino-1-phenoxy-2-propanol 5 according to the invention may be prepared by a method known in - itself by the application of conventional reaction mechanisms.
The process that is recommended comprises two steps, namely a) the reaction of 2-chloro-3,5-dimethoxyphenol of formula SHEA\ clue OH (II) SHEA

with the epichlorhydrin (III) in the presence of pardon, to obtain the l-(2-chloro-3,5-dimethoxyphenoxy)-2,3-epoxypropane of the formula SHEA\ I
OUCH --SUE (IV) SHEA

then, b) the reaction of the epoxide (IV) with an amine NH2R (V) (where R is icky or t-C4Hg) in a lower alcohol, particularly a C1 -C3 - alcohol, preferably ethanol or methanol.

X7~21:~

:: The best mode for operating consists, in step a), of reacting 1 mole of II with 4 to 10 moles of III for 2 to oh at a temperature comprised between 100 and 120C, the epichlorhydrin III serving as a solvent and pardon as catalyst 5 and, in step b), reacting 1 mole of epoxide IV with 8 to 12 moles of amine V in the presence of ethanol, at the reflex temperature of the reaction medium for at least 0.5h.
A certain number of compounds according to the invention have been indicated in non-limiting manner in Table I below.

TABLE I
SHEA Of SHEA
-Product Code Number Melting Point .. ___ ._. _ Example i CURL 41058 t-C4Hg 216C

Example I _ t-C4Hg 85C

Example I CURL 41045 icky 206C

Example I _ 3 7 97C
__ Notes :

(a) : free base (b) : hydrochloride _ . . _ . _ __ _ _ The 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)-2-propanols of formula (I) and their addition salts are useful as blocking medicaments. There is recommended according to the invention a therapeutic composition which is characterized in that it comprises in association with a physiologically 30 acceptable excipient, at least one compound of formula (I) I' ~.22~2~

above or one or its non-toxic addition salts as -blocking agent.
In addition, the compounds according to the invention, particularly the free bases, take part as intermediates of 5 synthesis in the preparation of other substances.
Other advantages and characteristics of the invention will be better understood on reading the following description of examples of the preparation, which are in no way limiting but given purely by way of illustration.

PREPARATION I
Preparation_ of sheller tertiobuty_amino-2-propanol hydrochloride.
(Example l; Code No. CURL 41 058 15 1) 2-chloro-3~5-dimethoxyphenol Into a solution kept at a temperature comprised between 35 and 40C and constituted by 75 g (0.487 mole) of 3,5-dimethoxyphenol and 400 ml of CC14, are introduced by fractions, in 2.5h, an amount of 70.5 g (0.528 mole) of N-20 chlorosuccinimide. It is then heated for 0.25h at temperature of about 70C. The precipitate formed is removed by filtration and the filtrate brought to dryness under reduced pressure. The evaporation residue thus obtained is purified by distillation under vacuum then washing of the distillate with 25 water. There are obtained 56.5 g (yield 61.65~) of sheller-3,5-dimethoxyphenol. MPinst (Kofler) = 57 C.

2) 1-(2 chloro-3,5-dimethoxyphenoxy)-2,3-epoxypropane There is heated towards 115C for oh a solution of 40 g (0.212 mole) of 2-chloro-3,5-dimethoxyphenol in 133 ml (1.697 30 mole) of epichlorhydrin in the presence of 0.25 ml of pardon.

~272~

The reaction medium is taken to dryness, the residue taken up again with ethyl acetate and the ethyl acetate phase is washed successively with sodium hydroxide and water. After drying over an hydrous sodium sulfate and evaporation of the solvent, a 5 thick brown oil is obtained. This oil is purified by crystallization in isopropanol to give 36.5 g (yield 70.4%) of 1-(2-chloro-3,5-dimethoxyphenoxy)-2,3-epoxypropanee which is in the form of a chocolate brown colored powder. MPinst (Koffler) = 96C.
10 3) CURL 41 058 Under reflex for 1 hour there is heated a solution of 36 g (0.147~ mole of 1-(2-chloro-3,5-dimethoxyphenoxy)-2,3-epoxy propane and 107.5 g (1.472 mole) of tertiobutylamine in 150 ml of an hydrous ethanol. The reaction medium is taken to 15 dryness and the residue so obtained purified by crystallization in diisopropyl ether to obtain 37g of sheller-dimethoxyphenoxy)-3-tertiobutyl-amino-2-propanol which is in the form of a beige powder. MPinSt (Kofler) = 85 C.
The free base so obtained is treated under reflex in 20 an hydrous ethanol with hydrochloric ethanol. A precipitate is formed which is isolated to collect 36.3 g (yield = 69.75%) of CURL 41 058 which is in the form of a slightly beige powder soluble to 12.5 g/l in water. MPinst (Kofler) = 216 C.
PREPARATION II
25 Preparation of 1-"~2-chloro-3,5-dimethoxyphenoxy~-3-isopropylamino-2-propanol hydrochloride.
(Example 3; Code No. CURL 41 045) By proceeding as indicated in stage 3) of preparation I, but replacing the tertiobutylamine by isopropyl amine, CURL

3041 045 is obtained. MPinst (Roller) - 206c.
It ..

I

Below are summarized a part of the tests which have been undertaken with CURL 41 058 (product of Example 1). In these tests and except for indication to the contrary, CURL 41 058, suspended in an aqueous solution of Arabic gum for 5 concentrations higher than or equal to 3 g/l, and in solution in distilled water for concentrations less than 3 g/l, was administered intraperitoneally in a volume of 20 ml/kg i-n the male mouse and 5 ml/kg in the male rat.
TOXICITY

In the male mouse by the IMP. route, the Lo (maximum non-lethal dose) is higher than 64 mg/kg and the LD30 (dose at which 30% of the animals die ) is of the order of 128 mg/kg.
The CURL 41 058 is less toxic than 1-(3,5-dimethoxyphenoxy)-3-tertîobutylamino-2-propanol hydrochloride, which has an LD50 by 15 IMP. route in the male mouse of the order of 73 mg/kg.
OVERALL BEHAVIOR AND REACTIVITIES
Batches of 3 animals were observed before, then 15 mint 30 mint lo, oh, oh and 24h after the administration of CURL
41 058 by the IMP. route. It is observed that 1) in the mouse - doses of 0.5 mg/kg, 2 mg/kg and 8 mg/kg do not cause distinct symptoms;
- the dose of 32 mg/kg leads to an inconstant sedation (in 2 animals out of 3) and fleeting 130 mix), a dyspnoea (in 2 animals out of 3) for 15 to 30 mint and 2) in the rat - doses of 0.25 mg/kg, 1 mg/kg and 4 mg/kg do not cause distinct symptoms;

- the dose of 16 mg/kg gives a fleeting sedation ~L22~

(30 mint and depresses respiration (in 2 animals out of 3) for 30 min.
STUDY OF THE CURIO VASCULAR PROPERTIES
A - ANESTHETIZED DOG
Three dogs (average weight : 13.6 kg) anesthetized with nembutal received CURL 41 058 intraduodenally in successive doses of 0.5 mg/kg, l mg/kg, 2.5 mg/kg, 5 mg/kg and 10 mg/kg.
The blood pressure (it is recalled that 1 mm Hug corresponds to about 1.333 x 102 Pa), the pulse rate, the femoral artery flow 10 rate, the vertebral artery flow rate, the rectal temperature, were noted and the color of the skin and the color of the bile collected by catheterization of the bile duct after ligature of the cystic duct was noted.
CURL 41 058 is Brady cardiac from the dose of 0.5 mg/kg 15 without any distinct action on the blood pressure. It is not a vertebral vasodilator. The increase in the femoral flow rate is present only in one dog out of three of which the control flow rate was low (24 ml/min). In the two other dogs, the flow rate diminishes. The rectal and cutaneous temperatures varied 20 little. The color of the skin and that of the bile were not modified.
The effects of isoprenaline tested after the cumulated dose of 19 mg/kg of CURL 41 05~ were much reduced: 3 gig of isprenaline caused the diastolic blood pressure to pass to 25 119 mm Hug instead of 48 mm Hug and the pulse rate to 110 boatmen instead of 245 boatmen as control. In two dogs where the isoprenaline dose was increased to 100 gig the tachycardiac effect for this dose was less than the tachycardiac effect of 0.3 gig of the isoprenaline control.
The hypertension with nor adrenalin was also reduced : at I

~27;;~

the dose of 1 gig of nor adrenalin, the systolic blood pressure passed to 221 mm Hug instead of 280 mm Hug as control.
B - ISOLATED GUINEA-PIG ARIA
5 right aria isolated from the guinea pig were used to 5 determine the PA of the CURL 41 058 with respect to the - chronotropic effect of isoprenaline; after 15 mix contact, the average of the PA was 8.21.-~ 0.272.
On these aria, the isotropic and chronotropic effect itself of the CURL 41 058 was also evaluated; no average could 10 be made, the concentrations and order of administration of the concentrations being variable. The CURL 41 058 possesses an inn and crown+ effect which it maximum at the first concentration used whatever it is (3 x 10 8 to 10 EM). On the other hand, if, for example, the concentration of 10 6 M is 15 administered after lower concentrations which have been stimulating, this concentration of 10 6 M is ion and crown (this phenomenon could allow the supposition of a liberation of catecholamines).
C - ANESTHETIZED RAT
Normotensive rats were anesthetized with pentobarbital (75 mg/kgI.P.) and given atropine (1 mg/kg IMP.). Their carotid blood pressure was measured and their heart rate by integration of the blood pressure. A jugular vein was catheterized for the injections. If necessary, anesthesia was maintained by sub-25 cutaneous injection of pentobarbital.
1) Determination of the effective blocking dose

3 rats received CURL 41 058 intravenously, at successive doses of 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg and possibly 30 mg/kg. The dose which blocks tachycardia induced by 0.03 to 30 0.3 gig IVY. of isoprenaline (dose necessary to obtain an q ~27~

increase of the heart rate of 30 to 50 boatmen) was determined. It is found that the dose involved is 1 mg/kg IVY.
2) Duration of B-blocking effect 5 rats received 1 mg~kg of CURL 41 058 intravenously. It was observed that - the diastolic blood pressure was not modified, it remained around 91 mm Hug; and - the heart rate passed, in 5 mint from 345 to 290 boatmen namely -16%), the maximum bradycardia was obtained in 10 the time 20 mix : 280 boatmen (namely 19%). After 90 mint the heart rate was at 307 boatmen (namely -11%).
In addition, the dose of 0.03 gig IVY. of isprenaline caused the passing of :
- the blood pressure from 91 to 65 mm Hug (namely -26 mm 15 Hug); after 1 mg/kg IVY. of CURL 41 058, the variation in blood pressure was Jo mm Hug (-69% with respect to the control variation) at 5 mix and during the oh of observation; and - the heart rate from 345 to 384 boatmen (namely +39 boatmen); the tachycardia, completely inhibited by the CURL
20 41 058 at time 5 mint resumed 50% of its value at time 20 mint it was restored to 92% of its value at time 60 min.
Finally, in 5 control rats receiving a physiological serum in place of the product, it was observed that:
- the blood pressure remained constant; the hypotension 25 with isoprenaline diminished by 40% in the course of the test;
and - the heart rate diminished by 28 boatmen following injections of nembutal necessary for maintaining the anesthesia; the tachycardia with isprenaline remained constant 30 during the oh observation.

-Jo eye 72~) D - WOVEN RAT
6 genetically hypertensive rats, with an implanted femoral artery catheter, received CURL 41 058 at the dose of 20 mg/kg PRO.
The blood pressure passed from 191 to 167 mm Hug at time oh (-13%; statistically significant variation). The heart rate diminished from 5 mint it passed from 382 to 322 boatmen (-15%; statistically significant variation); the maximum bradycardia was reached at oh (305 boatmen, namely -20%;
10 statistically significant variation), it then diminished to be, at oh, 322 boatmen, namely -15%; statistically significant version 24h after administration of CURL 41 058, it was observed that the blood pressure had resumed its control value, the 15 heart rate being again 330 boatmen (namely -13%; statistically significant variation).

E - CONCLUSION
It results from the tests summarized above that CURL
41 058 is a very good blocking agent.
Clinical assays have confirmed in man the interest of the blocking effect of CURL 41 058 at the daily dose of 40 to 50 my distributed in 2 to 3 administrations) for 2 to 6 weeks.

I
Jo ~,~

Claims

The embodiments of the invention in which an exclusive property of privilege is claimed, are defined as follows:

1. A method for preparing a 3-amino-1-phenoxy-2-propanol derivative selected from the group consisting of 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)-2-propanols or their addition salts comprising of the following steps.
a) - reacting one mole of 2-chloro-3,5-dimethoxyphenol of the formula -IMAGE-(II) with 4 to 10 moles of epichlorhydrin (III) for 2 to 5 hours at a temperature ranging between 100°C and 120°C, in the presence of pyridine to obtain the 1-(2-chloro-3,5-dimethoxyphenoxy)-2,3-epoxypropane of the formula -IMAGE- (IV) and b) - reacting 1 mole of epoxide (IV) thus obtained with 8 to 12 moles of an amine of the formula NH2R (V) wherein R is CH(CH3)2 or C(CH3)3, in a C1-C3-alkanol, in the presence ofethanol at the reflux temperature of the reaction medium for at least 0.5 hour.

2. A method as claimed in claim 1 in which said 3-amino-1-phenoxy-2-propanol derivative is selected from the group consisting of (i) - 3-alkylamino-1-t2-chloro-3,5-dimethoxyphenoxy)-2-propanols of the general formula -IMAGE- (I) wherein R is CH(CH3) or C(CH3)3; and, (ii) - addition salts thereof.

3. A method as claimed in claim 1, in which said 3-amino-1 phenoxy-2-propanol derivative is 1-(2-chloro-3,5-dimethoxyphenoxy)-3-tertiobutyl-amino-2-propanol and its non-toxic addition salts.

4. A method as claimed in claim 1 in which said 3-amino-1-phenoxy-2-propanol derivative is 1-(2-chloro-3,5-dimethoxyphenoxy)-3-isopropyl-amino-2-propanol and its non-toxic addition salts.

5. A 3-amino-1-phenoxy-2-propanol derivative selected from the group consisting of (i) - 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)-2-propanols of the general formula -IMAGE-(I) wherein R is CH(CH3)2 or C(CH3)3; and, (ii) addition salts thereof when produced by the method of claim 2 or an equivalent chemical method.

6. 1-(2-chloro-3,5-dimethoxyphenoxy)-3-tertiobutyl-amino-2-propanol and its non-toxic addition salts when produced by the method of claim 3 or an equivalent chemical method.

7. 1-(2-chloro-3,5-dimethoxyphenoxy)-3-isopropyl-amino-2-propanol and its non-toxic addition salts when produced by the method of claim 4 or an equivalent chemical method.