FI76319C - FOERFARANDE FOER FRAMSTAELLNING AV NYA SUBSTITUERADE 3-FENOXI-1-ALKOXIKARBONYL-ALKYLAMINO-PROPANOL-2 -FOERENINGAR MED -RECEPTOR HAEMMANDE VERKAN. - Google Patents

Description

7631 9

Process for the preparation of novel substituted 3-phenoxy-1-alkoxycarbonyl-1-alkylamino-propanol-2 compounds having β-receptor blocking properties

The present invention relates to a process for the preparation of novel compounds having valuable properties in the treatment of acute myocardial infarction and to patients undergoing various surgical treatments in order to obtain β-receptor inhibitory activity.

It is an object of the invention to provide novel compounds having 3-adrenoceptor blocking activity and such a short biological half-life that the degree of β-adrenoceptor blockade can be easily monitored by parenteral dosing rate. Such compounds can then be used during the critical phase of an acute myocardial infarction for the purpose of reducing the size of the infarction and also preventing arrhythmia. These compounds can also be used as antiarrhythmic agents in various surgical procedures.

In general, these novel compounds can be used to treat all indications in which g-receptor blockers are used, with the limitation that they can only be used by intravenous and superficial administration.

U.S. Patent No. 3,793,365 discloses amino acid derivatives of the general formula

OH

l · R -O-CH -CH-CH -N-A-CO-R 12 2 1 3

R

2,76319 having aryl of 6 to 10 carbon atoms which may be substituted by one or two halogens, hydroxyl, alkoxy, alkenyl, alkenyloxy, alkyl, alkoxyalkyl, trifluoroalkyl or alkylcarboxylamino; is hydrogen, alkyl or phenylalkyl? R is hydroxyl or alkoxy; and A is methylene which may be substituted by one or more alkyl groups or phenylalkyl, carboxyalkyl or carbalkoxyalkyl groups. These compounds are shown to have β-receptor blocking activity.

U.S. Pat. No. 4,014,920 discloses amines of the general formula R R R 12 13 14

R -C-N -C = C -T ^ 1 OH

1 II I I

O lv -O-CH -CH-CH -NH-R

2 2 5

R

6 wherein R 1 is lower alkoxy, R 1 is hydrogen or lower alkyl, R 1 is hydrogen, lower alkyl, carboxyl or lower alkoxycarbonyl, R 1 is hydrogen or lower alkyl, R 4 is lower alkyl, phenyl optionally substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl, carboxy-lower alkyl esterified with aliphatic alcohol, carbamoyl-lower alkyl, N-mono-lower alkylcarbamoyl-lower alkyl or N, N-di-lower alkyl-alcarbam halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, lower alkoxymethyl, carbamoyl, N-lower alkylcarbamoyl, lower alkynyloxy or hydrogen. These compounds are also shown to have β-receptor blocking activity.

As will be seen below, the novel compounds of the invention have a 3-receptor blocking effect with a very short duration of 3,76319 in the blood. The plasma half-life of the compounds of the invention is less than 8 minutes. It is apparent that the compounds described in U.S. Patent Nos. 3,793,365 and 4,014,920 do not have such a short duration of action. U.S. Patent 3,793,365 (column 10, line 57) discloses that the compounds are administered four times a day, and correspondingly, U.S. Patent No. 4,014,920 (column 24, line 62) provides a daily dosage of 1 / 2-4 tablets. In order for these compounds of U.S. Patent Nos. 3,793,365 and 4,014,920 to be administered with such a dosing regimen, their half-lives must be significantly greater than 8 minutes.

For compounds of the general formula // 2 VT 1 n 7631 9 4 wherein n is an integer from 1 to 3 and R 1 is any substituent belonging to the group alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, halogen, nitro, cyano, alkoxyalkyl, alkoxyalkoxy, aminoalkylamino optionally substituted with one or two alkyl groups, aminocarbonylaminoalkyl optionally substituted with one or two alkyl groups, aryl, aralkyl, aralkoxy and aroyl, and R is direct or branched alkyl or hydroxyalkyl, cycloalkyl or phenylalkyl, or phenoxyalkyl optionally substituted by alkyl, alkoxy, hydroxy, cyano, cyanomethyl, hydroxymethyl or trifluoromethyl, is known to have a arrhythmia, overexertion and glaucoma.

In addition, there are several indications that treatment with β-adrenoceptor blocking agents in the early stages of acute myocardial infarction may reduce infarct size (cf. Waagstein et al. 1977; Acute and Long Term Medical Management of Myocardial Ischemia. A. Hjalmarsson and L. Wilhelmsen. Lindgren Soner AB, Molndal, pp. 346-357) and may also prevent arrhythmias.

However, since the first trial of β-adrenoceptor blockers in acute myocardial infarction was conducted approximately 15 years ago, certain suspicions have been raised for this treatment due to reports of alarming side effects (cf. Snow PJ; Effects of Propranolol in myocardial infarction, Lancet 2, 55). 553, 1965), and it is apparent that treatment with β-adrenoceptor blocking agents may be detrimental to a few patients with low cardiac function, significant cardiac damage, and blood flow disturbances. As a result, patients who are being treated with β-adrenoceptor blockers during the acute phase of myocardial infarction are currently being selected with great care. Even then, a few patients with myocardial infarction do not tolerate treatment with β-adrenoceptor blockers.

Significant advantages in this regard would be obtained with the use of a very short-term β-adrenoceptor blocking agent that can be administered by continuous intravenous infusion.

The degree of β-blocking could then be easily monitored by changing the infusion rate. In addition, if the patient does not tolerate β-blockade, the infusion may be stopped and the effect disappear within a few minutes due to the short half-life of the drug.

There is also a significant advantage if a short-acting β-adrenoceptor blocker is available in anesthesiology and intensive care units. For example, arrhythmias are common with intubation and laryngoscopy.

It is known that such arrhythmias can be treated with β-adrenoceptor blockers. However, the β-blocking agents currently in use are long-acting and the blocking lasts longer than necessary.

The substituted 3-phenoxy-1-alkoxycarbonyl-alkylamino-propanol-2 compounds of the invention are all very short-acting potent β-selective blocking agents that can be used in the above cases. These compounds should be infused intravenously at an infusion rate of 0.1-10 μmol / kg body weight x minute.

7631 9 e

It has now been found that compounds of general formula I

3

OCH CHOHCH NHCH (CH) CO R

X 2 2 2 2 n 2 I 5 (I)

U

R

3 wherein R is alkyl of 1 to 7 carbon atoms, n is an integer of 0, 1 or 2, R is N-methylcarbamoylmethoxy,

2-N-isopropylureidoethyl or carbamoylmethyl and R

is hydrogen or alkenyl having 2 to 4 carbon atoms, and the pharmaceutically acceptable acid addition salts of these compounds are short-acting potent β-selective adrenoceptor blockers.

3

Alkyl R is an alkyl having 1 to 7 carbon atoms, preferably 1 to 5 carbon atoms, which alkyl group may be straight or branched. Thus, alkyl R may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-pentyl.

5

Alkenyl R is alkenyl having 2 to 4 carbon atoms. Alkenyl R can be, for example, allyl.

Specific compounds of the invention are as follows: 1. Ethyl N- [3- (2-N'-methylcarbamoylmethoxyphenoxy) -2-hydroxypropyl] -3-aminopropanoate 2. Ethyl N- [3- [4- (2-N'- isopropylureido) ethylphenoxyX-Z-hydroxypropyl-S-aminopropanoate 3. Ethyl N- [3- (2-allyl-4-carbamoylmethylphenoxy) -2-hydroxypropyl] -3-aminopropanoate These new compounds can be used in the treatment of acute myocardial infarction and arrhythmia.

7 7631 9

Salt-forming acids can be used to prepare therapeutically acceptable salts of these compounds. These include hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, , ascorbic, maleic, hydroxymaleic or pyruvic acids, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-amino-salicylic acid, embonic acid, methanesulphonic acid, ethanesulphonic acid , hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acid, methionine, tryptophan, lysine or arginine.

It is intended that these compounds be administered parenterally in the acute and chronic treatment of the aforementioned cardiovascular diseases.

The biological effects of these new compounds have been tested and the various experiments performed are described below.

The novel compounds of the formula I can be prepared by a method known per se so that the compound of the formula II

4 t-v 1 V. * () - OCH CHCH Z (II) \ xj 2 2 '5

R

4 5 in which R and R have the same meaning as above,

X is a hydroxy group and Z is a reactive esterified hydroxy group, or X and Z together form an epoxy group, are reacted with an amine of formula III

3 8 7631 9 H NCH (CH) CO R (III) 2 2 2 n 2 3 in which R and n have the same meaning as above.

In particular, a reactive esterified hydroxy group is a hydroxy group esterified with a strong inorganic or organic acid, preferably a hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, or further sulfuric acid or a strong organic sulfonic acid, for example benzenesulfonic acid, for example benzenesulfonic acid, 4-toluenesulfonic acid. Thus Z is preferably chlorine, bromine or iodine.

This reaction is carried out in a conventional manner. When a reactive ester is used as the starting material, the preparation is preferably carried out in the presence of a basic condensing agent and / or using an excess of amine. Suitable basic condensing agents include, for example, alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as potassium carbonate, and alkali metal alcoholates such as sodium methylate, potassium methylate and potassium tert-butylate.

The reaction is preferably carried out in an alkanol having 1 to 4 carbon atoms, under heating to reflux in this solvent for a sufficient time to obtain a compound of formula I, usually 1 to 12 hours. However, the reaction can also be carried out only in the presence of an excess of amine. The reaction can also take place in an autoclave.

Depending on the processing conditions and the starting material, the final product is obtained either in free form or in the form of its acid addition salt, the preparation of which is also within the scope of the invention. Thus, for example, basic, neutral or mixed salts can be obtained, as well as hemiamino, sesquis or polyhydrates. The acid addition salts of these new compounds can be converted into the free compounds in a manner known per se using, for example, basic substances such as alkali or ion exchangers. On the other hand, the free bases obtained may form salts with organic or inorganic acids. In the preparation of acid addition salts, those acids which form suitable therapeutically useful salts are preferably used. Such acids include, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, lactic, , citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, phenylacetic, benzoic, p-amino-benzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulphonic, ethane sulfonic, hydroxyethanesulfonic and ethylenesulfonic acids, halobenzenesulfonic, toluenesulfonic and naphthylsulfonic acids, or sulfanilic acid, methionine, tryptophan lysine or arginine.

These and other salts of these new compounds, for example picrates, can act as a cleaning agent, or the resulting free bases are converted to salts, these are separated and the bases are released from the salts again. Due to the close relationship between these new free form compounds and their salts, it is understood that, if possible, the corresponding salts are included in the free compound.

Depending on the choice of starting materials and process, the novel compounds of the formula I can be present as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, as a mixture of isomers (racemic mixture).

The resulting mixtures of isomers (racemic mixtures) can, depending on the physicochemical differences of the component, be separated into both stereoisomerically (diastereomerically) pure racemates, for example by chromatography and / or fractional crystallization.

.0 7631 9

The racemates obtained can be separated by known methods, for example by recrystallization from an optically active solvent, by microorganisms or by reaction with optically active acids which form salts of the compound, and by separation of the salts thus obtained into diastereoisomers from which the antipodes can be liberated. with a suitable substance. Suitable useful optically active acids include, for example, L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid and quinic acid. Preferably, the more active portion of the two antipodes is separated.

These starting materials are preferably used to carry out the reactions according to the invention, which material leads to those groups of end products which are mainly and particularly desired, and to the most preferred end products specifically described.

The starting materials are known or are obtained by methods known per se.

In clinical use, the compounds of the invention are administered by injection in the form of a pharmaceutical preparation containing the active ingredient either as the free base 11 7631 9 or as pharmaceutically acceptable non-toxic acid addition salts, for example, hydrochloride, lactate, acetate, sulfamate and the like together with a pharmaceutical carrier.

Thus, in the case of the novel compounds according to the invention, either the free amine base or the acid addition salts of the free base are meant even when the compounds are described generally or specifically, provided that the context in which such expression is used, for example in the examples, applies to this broad interpretation. The carrier may be a liquid diluent or a capsule. The amount of active compound is usually between 0.1 and 99% by weight of the preparation, suitably 0.5-20% by weight of the preparation for injection.

Solutions for parenteral administration by injection may be prepared as an aqueous solution of a pharmaceutically acceptable salt of the active compound, preferably at a concentration of about 0.5 to 20% by weight. These solutions may contain stabilizers and / or buffers and may conveniently be presented in unit dosage form.

The daily dose of active substance varies and depends on the conditions, but is usually 1-100 mg / minute of active substance for intravenous administration (for a medium-sized patient).

The principles and applications of the invention are described below. Temperature is shown in degrees Celsius.

12 7631 9

Example 1

Preparation of ethyl N- [3- (2-N'-methylcarbamoylmethoxyphenoxy) -2-hydroxypropyl] -3-aminopropanoate 14.1 g of ethyl 3-aminopropanoate hydrochloride and 3.68 g of NaOH were stirred in isopropanol until neutral for about 1 h. Under reflux, 12 g of 2- (2,3-epoxy-propoxy) phenoxy-N-methylacetamide in isopropanol were added. The mixture was heated at reflux for about 8 hours, filtered and evaporated. The crude oil was dissolved in CHCl 3, washed 2 2 times with water, dried over Na 2 SO 4 and evaporated.

2 4 The residue was dissolved in 200 ml of ethyl acetate and 200 ml of water were added. The pH was then adjusted to 5.0 with 2N HCl. The aqueous phase was separated and adjusted to pH 9.0 2-n

NaOH and extracted with ethyl acetate, dried

Na 2 SO 4, filtered and evaporated. The oily residue was crystallized by treatment with diisopropyl ether / diethyl ether 4/1. The crystals were washed with diethyl ether. Yield o 1.3 g. Sp. 80 ° C (base). The structure was determined using an NMR spectrum and equivalent weight.

Example 2

Preparation of ethyl N- [3- [4- (2-N'-isopropylureido) ethylphenoxy] -2-hydroxypropyl] -3-aminopropanoate This compound was prepared according to Example 1 using 14.0 g of ethyl 3-aminopropanoate hydrochloride, 11, 2 g of N- [2- / 4- (2,3-epoxypropoxy) phenyl] ethyl] -N'-isopropylurea, 3.2 g of NaOH and abs. ethanol as solvent. The crude crystals were washed with H 2 O and dissolved in a mixture of 500 mL of H 2 O and 25 mL of 2N HCl. (Insoluble crystals were separated by filtration). Ethyl N- [3- [4- (2-N'-isopropylureido) -ethylphenoxy] -2-hydroxylpropyl] -3-aminopropanoate base was crystallized by treating the aqueous phase with 25 ml of 2N NaOH.

Ethyl N- [3- [3- (2-N'-isopropylureido) -ethylphenoxy] -2-hydroxylpropyl] -3-aminopropanoate hydrochloride was prepared by dissolving in acetone and adding an equivalent amount of hydrochloric acid. Yield 2.8 g. Sp. 185 ° C (HCl). The structure was determined by NMR spectrum.

Example 3

Ethyl N- [3- (2-allyl-4-carbamoylmethyl phenoxy) -2-hydroxypropyl] Preparation of 17-3-aminopropanoate This compound was prepared according to Example 1 using 10.8 g of ethyl 3-aminopropanoate hydrochloride, 11.6 g of 3-allyl-4- (2,3-epoxypropoxy) phenylacetamide a, 2 , 84 g NaOH and abs. ethanol as solvent. The crude product was crystallized from ethyl acetate. Yield 1.7 g. Sp. 98 ° C (base). The structure was determined using NMR spectrum and equivalent weight.

Claims (4)

14 76319 Biological effects The β-adrenoceptor blocking agents of the invention were tested for their biological properties. All compounds were then tested using two different experimental models, but using the same species for premedication and preparation. Cats (male and female, weight 2.5-3.5 kg) were pretreated with reserpine (5 mg / kg body weight administered intraperitoneally) approximately 16 hours before the experiments. Animals were pretreated with reserpine to eliminate endogenous sympathetic control of heart rate and the effect of vascular smooth muscle. Cats were anesthetized with pentobarbital (30 mg / kg body weight administered ip) and connected to a ventilator using room air. Bilateral circulatory nerve dissection was performed in the neck. Blood pressure was obtained from a cannulated carotid artery and the heart rate was recorded using a cardiotachometer that operates on variations in blood pressure. The femoral artery of the second hind limb was cannulated in both directions. Blood taken from this proximal portion was pumped back to the distal portion of the artery at a constant flow rate using a rotating pump (Watson-Marlow). Perfusion pressure (PP) was recorded. Changes in PP value indicated changes in limb superficial vascular resistance. Experiment A The maximum heart rate and vasodilation due to isoprenaline were determined by injecting a high dose of prenaline i.v. (2.0 μmol / kg). An isoprenaline infusion rate that provided a heart rate (steady state) of approximately 80% of the maximum heart rate achieved with isoprenaline was used. This isoprenaline dose was usually 0.25 μmol / kg x min. Vascular dilation at this dose of isoprenaline was approximately 80% of maximal. 15 7631 9 The isoprenaline dose was then infused over 20 minutes and a 20 minute interval was used between infusion periods. The test compound was administered by intravenous injection 7 minutes after the start of each isoprenaline infusion. The dose of the test compound was therefore increased until complete inhibition of the action of isoprenaline was achieved. At each dose of test compound, the peak decrease in heart rate due to isoprenaline was expressed as a% decrease in formula according to the following formula: Isoprenaline-induced decrease in heart rate-100 x increase in heart rate (beats / min) Isoprenaline-induced reference effect (beat / min) The ED.50 value (i.e., the dose that produced half of the maximal inhibition) was then interpolated, and the plasma half-life was determined by the plate plate method (Nagshima R, O'Reilly RA, and plate G. Clin Pharmacol. Ther., 10 (1969) 22) The time from the peak of the inhibitory effect of each dose to 50% recovery was determined and plotted as a function of the log dose of the compound.The slope of the curve obtained was calculated as a linear decrease, corresponding to 2.303 / K The plasma half-life (t 1/2) was then calculated from the equation t 1/2 = 0.693 / K_. £ # Experiment B Cardiac max the rate of aspiration and the vasodilatory effect due to isoprenaline were determined by injecting a high dose of isoprenaline i.v. (2.0 μmol / kg). The dose of isoprenaline that produced approximately 80% of the maximum heart rate was then determined. .6,76319 This dose of isoprenaline was usually 0.4 μmol / kg. The vasodilatory effect of this dose of isoprenaline was also approximately 80% of the maximum value. The test compound was then infused intravenously in increasing doses. Each dose was administered for 12 minutes, with an interval of 18 minutes. A reference dose of isoprenaline was injected 10 minutes after the start of each infusion of test compound. The dose of test compound was increased logarithmically until complete inhibition of the action of isoprenaline was achieved. The inhibitory effect of each dose of test compound was expressed as percent inhibition according to the following formula Isoprenaline prodrug - Effect of isoprenaline effect of test compound infusion 100 X - Isoprenaline prodrug effect The percent inhibition was then calculated as a function of logarithmic dose of inhibitor and see above: interpolated ED: 50 The ED: 50 inhibition of heart rate and the ED: 50 inhibition of vasodilation could then be compared and the selectivity of the compound determined. Sympathomimetic specific activity was determined as the maximum increase in heart rate during infusion of test compound. The experiments show that the compounds of the invention are potent inhibitors of β-adrenoceptors and that they have a stronger effect in blocking cardiac β-adrenoceptors than vascular β-adrenoceptors. In addition, the estimated plasma half-lives of these compounds are less than 10 minutes. 17 7631 9 Ε ΙΛ <υ 3 E 3 • r- (/) -—- 4-> · “S3 4->> d> · <- cu ·> - c ε - (- • r- EE (O \ o </): ro 4-> * r “· (“ (O <0 + j O. EE CD CD CD e ·> - «t: o >> E oo >> +1 +1 +1 i / oo · —I ι- ε ea> ca) σ> - (- <ue ^ E + -> - · - rO CE rö -PO CD -I- C -PC 3 CI— -r- CO ^ i— 3 <u to a> oo E * * * 0. C 'r' OLD O OkOr— _C -r- S- <0 ·· EX CD * "E <D <0 O 3 / \ rO >> r— LlJ \ O) + -> OC (Λ x: -r- OJ ICC • r- C ro C71 • r- a)> s .x fO (/) CO iO C = 5 c 3 · * - C CD -P CD <DI— · »- c 3 E ao o E co * 3- c \ j: oomor— ro 0 ·» - * T3 C ·· EX * * * CO (Ο >> * | -Q3 OOO · —t> 00 -p LU "N 1 ro 0 -X rs το. Ro CO (O 3 · * -« Λ -PE co C -P 3 «5» “<D -PSE -X c tO CvJ o CO · ρ- <θ c- ro Λ "<0 'f” r— P--. I CO _J · - CLP CC <DCU CO <C -r- <1> C -XE -M · (- ^ dl (O EE (O o + - > o ai - (-: *: + -> e 3 e r- 3 <D <Λ dl OO LO CU ET - (- JLO OI— CM _E -I- S- <0 ·· E "" - · - E dl to O 3 CD II— (ϋ> r— LlJ \ + -> E CO I- CU I EE ro • r- e: o σι di · (- dl>, J * 1 - + -> I— \ to fO CO c /) (O (OC 3 E 3 ·> - (- dl + -> dl dl ι- ί- 3 EO - CD O 00 »O: <oo LO o - co + -> O ·> -“ OE · · E - “(O wm> ic o 3 oio · (- (—H> CO + -> UJ '- i - O Ό JC ro E d) 4-> E -r- co 3 cu: io d> - (- 4-> E + -> T3 (O · <- co o II _C rO! /> · (- I - CM CO> - CO dl EI 18 7631 9 A process for the preparation of a novel therapeutically active amine compound of formula I 3 OCH CHOHCH NHCH (CH) CO R 12 2 2 2 n 2 Φ-R 3 .... wherein R is alkyl of 1 to 7 carbon atoms, n is integer 0, 1 or 2, R is N-methylcarbamoylmethoxy,,. 5 Process according to Claim 1, characterized in that ethyl N- [3- (2-N'-methylcarbamoylmethoxyphenoxy) -2-hydroxypropyl] -3-aminopropanoate or a therapeutically acceptable salt thereof is prepared. 2-N-isopropylureidoethyl or carbamoylmethyl and R is hydrogen or alkenyl having 2 to 4 carbon atoms, or for the preparation of a therapeutically acceptable salt of such a compound, characterized in that the compound of formula II 4 1 Ϊ C nVoch chch Z (II) V + y 2 2 5 R 4 5. wherein R and R are as defined above and X is a hydroxy group and Z is a reactive esterified hydroxy group, or X and Z together form an epoxy group, is reacted with an amine of formula III H NCH ( CH) CO R 1 (III) 2 2 2 n 2 in which R and n have the same meaning as above, 3a if desired, the free base obtained is converted into a therapeutically acceptable salt. 19 7 6 31 9 Process according to Claim 1, characterized in that ethyl N- [3- [4- (2-N'-isopropyl-ureido) -ethylphenoxy] -2-hydroxypropyl] -3-aminopropanoate or a therapeutically acceptable salt thereof is prepared. Process according to Claim 1, characterized in that ethyl N- [3- (2-allyl-4-carbamoylmethylphenoxy) -2-hydroxypropyl] -3-aminopropanoate or a therapeutically acceptable salt thereof is prepared.