CS204041B2 - Process for preparing 1-subst.phenoxy-3-aminoderivatives of 2-propanole - Google Patents

Description

This invention relates to novel l-subst.fenoxy-3-amino derivatives ^j 2 propanol, which exhibit stimulation of cardiac activity.

British Patent Specification No. 1,455,116 discloses and protects, inter alia, alkanolamine derivatives of the general formula

OCH 2 CHOH'CH _of NH 'CH _of CH _of NHCO · YR wherein

Y represents an imino group, an alkylimino group, an iminoalkylene group or an iminoalkyleneoxy group, and

R ¹ represents a hydrogen atom or a hydrocarbon radical such as an alkyl, alkenyl, cycloalkyl or aryl group.

For these compounds is reported that in addition to the blocking effect at adrenergic (S receptors also exhibit a considerable stimulating activity on cardiac function. In the above-mentioned range does not fall those compounds in which Y is a disubstituted imino group, and the symbol R ¹ represents an aliphatic substituent of such a nature that it the group —YR ¹ contains an oxygen atom.

It is believed that an ideal cardiac stimulator is expected to induce an increase in heart rate corresponding to about half the increase induced under similar conditions by isoprenaline, preferably an increase corresponding to a 45% to 60% increase caused by isoprenaline, in dogs with suppressed cardiac reflexes. This increase in heart rate is to be achieved by the oral administration of a low dose, which dose should practically not cause a reduction in blood pressure caused by isoprenaline under analogous conditions. None of the compounds specifically disclosed in the British patent specification. No. 1,455,116 does not exhibit such well-balanced properties, hereinafter referred to as cardioselective stimulatory effects on adrenergic β-receptors, although many of the compounds disclosed in the cited British patent have indeed significant stimulatory effects on cardiac activity.

In accordance with the invention, it has now been found that certain compounds which, although closely related to those described in the above-cited patent, but which do not, however, fall within the scope of this disclosure, exhibit desirable balanced cardioselective effects on adreneiric β-receptors. Accordingly, the invention provides alkanolamine derivatives of formula I,

Rt + VocM; CHOH-CH 2 NH 4 CH 2 NHCON _{χ QR}

2 + 2. (// wherein each of R ³ and R ⁴ , which may be the same or different, is a hydrogen atom or a hydroxyl group, with at least one of R ³ and R ⁴ being a hydroxyl group, and either R is a hydrogen atom , methyl or ethyl and R ^{2 is} methyl, ethyl or a radical of the formula -CH ² CH ² OR, wherein R is as defined above, or

R ² and R ² together form the ethylene moiety "CH 2 CH 2", and their acid addition salts.

The alkanolamine derivatives of the invention contain an asymmetric carbon atom, namely a carbon atom of the —CHOH “group in the alkanolamine side chain, and can therefore exist in racemic and optically active forms. The invention encompasses both the racemic form and all optically active forms having adrenergic β-receptor stimulating activity, and it is generally known how the racemic compound can be resolved into optically active forms and how the stimulating activity of these forms to adrenergic β-receptors can be determined. Furthermore, it should be recalled that the stimulatory efficacy on adrenergic + receptors usually predominates in the optically active form in which the group "CHOH" has an absolute "S" configuration.

Suitable addition salts of the alkanolamine derivatives according to the invention are, for example, salts derived from inorganic acids such as hydrochlorides, hydrobromides, phosphates or sulphates, or salts derived from organic acids such as oxalates, fumarates, tactates, tartrates, acetates, salicylates, citrates, benzoates. naphthoates, adipates or 1,1-methylene-bis (2-hydroxy-3-naphthoates), or salts derived from acidic synthetic resins, for example sulfonated polystyrene resins.

Specific alkanolamine derivatives of the invention are the compounds listed in the Examples below. Of these, 1- (p-hydroxyphenoxy) -3- + is preferred

- (morpholinocarboxamido) ethylamino-2-propanol, in particular its S- (-) isomer, and its acid addition salts.

The alkanolamine derivatives of formula (I) may be prepared by any chemical method known to be used to produce chemically analogous compounds, and in particular by any of the methods described for the preparation of similar compounds in British Patent Specification No. 1,455,116 .

In general, the compounds of formula (I) may be prepared by sequentially combining the following six radicals using the chemical methods known for this purpose, namely (i) an aryloxy group of formula (I).

wherein each of R ¹³ and R ¹⁴ , which may be the same or different, represents a hydrogen atom or a radical of formula R ⁵ O-, wherein R ⁵ represents a hydrogen atom or a protecting group, provided that at least one of R ¹³ and R ¹⁴ represents a radical of the formula R ⁵ O- as defined above (ij the radical of the formula OR ⁶ -CH 2 CH-CH 2 - in which

R ⁶ represents hydrogen or a protecting group, (III) a radical of the formula -NR ⁷ - wherein R ⁷ represents a hydrogen atom or a protecting group, (iv) a residue of formula -CH2CH2NR8-, wherein R ⁸ represents a hydrogen atom or a protecting (v) a carbonyl group -CO-; and (vi) a radical of formula

R ² /

—N \

CH2CH2OR, where R and R ² have the abovementioned meaning, then in the event that one or more of R ^5, R ^B, R ⁷ and R ⁸ is a protecting group, the one or more protecting group is removed.

The various steps of the aforementioned connection can be carried out in any possible order. In particular, any reaction sequence described in British Patent Specification No. 1,455,116 can be used to synthesize the alkanolamine derivatives of the invention. The protecting groups R ⁶ , R ⁷ and R ⁸ may be analogous to the corresponding protecting groups described in the above-mentioned patent and protecting groups. preferably R ⁵ is benzyl.

The process for the preparation of the 1-substituted-phenoxy-3-amino derivatives of 2-propanol of the aforementioned general formula I and their acid addition salts according to the invention is based on the epoxy derivative of the general formula II,

wherein each of R ¹³ and R ¹⁴ , which may be the same or different, represents a hydrogen atom or a radical of formula R ⁵ O-, wherein R ⁵ represents a hydrogen atom or a protecting group, provided that at least one of R ¹³ and R ^{14 14} represents a radical of the formula R ⁵ O- as defined above, reacted with a compound of the formula III

R ² /

HNR ⁶ (GH2) 2NHCON \

CH 2 CH 2 OR, (III) wherein

R ² and R ² are as defined in formula I, and

R ⁶ represents a hydrogen atom or a protecting group, any optionally present protecting groups R ⁵ and / or R ⁶ are cleaved, the racemic product of the formula I obtained is optionally cleaved to optically active enantiomorphs and / or the product obtained in free base form optionally converted by treatment with an acid to its acid addition salt.

In the starting materials, R @ ⁶ is preferably hydrogen and one or both of R @ ¹³ and R @ ¹⁴ is preferably benzyloxy. The benzylic portion of these groups is cleaved by hydrogenolysis.

The optically active enantiomorphs of the alkanolamine derivatives of the invention can be obtained by conventional resolution of the corresponding racemic alkanolamine derivative of the invention.

The resolution can be carried out by reacting the racemic alkanolamine derivative with an optically active acid, subjecting the mixture of diastereoisomeric salts to fractional crystallization from a diluent or solvent, for example ethanol, and then liberating the optically active alkanolamine derivative from the salt. A suitable optically active acid is, for example, (+) - or (-) -O, O-di-p-toluyltartaric acid or (-) - 2,3: 4,5-di-O-isopropylidene-2-keto-L- gulonic acid.

This cleavage can be facilitated by treating the partially resolved alkanolamine derivative in the free base form obtained after a single crystallization of a mixture of diastereomeric salts with a solubilizing agent such as allylamine in a relatively non-polar diluent or solvent such as petroleum ether.

The alkanolamine derivative of the present invention, in the form of the free base, can be converted into the acid addition salt by conventional acid treatment.

As mentioned above, the alkanolamine derivatives of the invention and their acid addition salts show a stimulatory activity on sustained? -Receptors, which activity is cardioselective. This efficacy can be demonstrated by increasing the heart rate induced by administering a compound of the invention to a dog pretreated with syrosingopine to remove catecholamines whose vags were cut off to isolate the heart, and lack of blood pressure drop in the denervated hindpaw constant volume. In contrast to isoprenaline, a known cardiac stimulating agent that is not cardioselective, the preferred alkanolamine derivative of the invention or salt thereof is well absorbed when administered orally and has long-term efficacy. The alkanolamine derivative of the invention at doses at which it effectively stimulates the dog's heart activity does not produce any obvious signs of toxicity.

The alkanolamine derivatives of the invention can be administered to warm-blooded animals, including humans, in the form of pharmaceutical compositions containing as an active ingredient at least one alkanolamine derivative of the invention or an acid addition salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

A suitable composition is, for example, a tablet, capsule, aqueous or oily solution or suspension, emulsion, injectable aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation.

In addition to the alkanolamine derivatives of the invention, said compositions may comprise one or more other drugs selected from the group consisting of sedatives such as phenobarbitone, meprobamate, chlorptromazine and benzodiazepine-based sedatives such as chlordiazepoxide and diazepam, vasodilators such as glycerin trinrate isosorbide dinitrate, diuretics such as chlorothiazide, hypotensive agents such as reserpine, bethanidine and guanethidine, cardiac membrane stabilizers such as quinidine, agents used to treat Parkinson's disease and other tremors such as benzhexole, cardiotonic agents such as digitalis preparations, adrenergic α blocking agents receptors such as phentolamine and sympathomimetic bronchodilators such as isoprenaline, orciprenaline, adrenaline and ephedrine.

For the treatment of acute or chronic cardiac insufficiency in humans, alkanolamine derivatives are expected to be administered orally to patients at a total daily dose of between 10 and 200 mg, in sub-doses administered at 6-8 hours intervals, or intravenously at a dose of between 1 mg and 100 mg. .

Preferred dosage forms for oral administration are tablets or capsules containing 10 to 100 mg, preferably 10 to 50 mg, of the active ingredient. Preferred dosage forms for intravenous administration are aqueous solutions of the alkanolamine derivatives of the invention or non-toxic acid addition salts thereof containing between 0.05 and 1% by weight of active ingredient, in particular 0.1% (w / v of active ingredient).

The invention is illustrated by the following Examples. however, the scope of the invention is not limited in any way.

Example 1

To a mixture of 12.7 g of N- (N- (3-aminoethylcarbamoyl) morpholine hydrogen sulfate, 7.0 g of potassium hydroxide and 10 ml of isopropanol) is added, with stirring, a suspension of 11.5 g of 1-p-benzyloxyphenoxy-2,3-epoxypropane in 6 ml of isopropanol. The resulting mixture was stirred at 45 ° C for 1 hour, then evaporated to dryness under reduced pressure, the oily residue stirred with water, filtered and the solid residue dissolved in acetone and 30% w / w added. solution of hydrogen chloride in propanol until the pH of the mixture dropped to 2, the resulting mixture was filtered and the solid residue crystallized from water to give 4.9 g of 1β-benzyloxyphenoxy-3- (β-morpholino carboxamidoethyl) amino-2-propanol hydrochloride .

A solution of the above compound in 20 ml of ethanol and 20 ml of acetic acid was shaken in a hydrogen atmosphere at room temperature and under normal pressure until it was taken up in 250 ml of hydrogen in the presence of 0.1 g of 30% palladium on carbon catalyst. The mixture is filtered, the filtrate is evaporated to dryness under reduced pressure and the residue is added to a hot solution of 1.25 g of fumaric acid in 15 ml of ethanol. The mixture was cooled to 5 ^° C for 12 hours, then filtered, the solid residue was washed with hot ethanol and dried. Give lp-hydroxy-3 - <3- (morfolinokarboxamido} ethylamino-2-pr opanolhydrogenfumarát, melting at 168-169 ⁰ C.

The 4- (N- (3-aminoethylcarbamoyl) morpholine hydrogen sulphate used as starting material can be prepared as follows:

to a mixture of 10 ml of toluene, 5 ml of water and 2 g of sodium hydroxide, while stirring and maintaining the temperature at 0 ° C separately for 20 minutes, while simultaneously adding 4.35 g of morpholine and 6.35 g of phenyl chloroformate. The reaction mixture is stirred for a further 2 hours while allowing the temperature to rise to 20 DEG C., then the toluene solution is separated, the aqueous solution is extracted twice with 50 ml of toluene each time, the combined toluene solutions are washed with water and dried. to dryness. The residue is crystallized from petroleum ether (b.p. 60-80 ° C). N-phenoxycarbonylmorpholine, m.p. 46.5-47.5 ° C.

A mixture of 11 g of the compound prepared above and 27.8 g of ethylenediamine was stirred at room temperature for 3 days, then the excess ethylenediamine was evaporated under reduced pressure. Dissolve the residue in methanol, cool to 5 ° C and add concentrated sulfuric acid to pH 2. After adding 10 g of Celite-based filter aid, the mixture is stirred for 1 hour, filtered The filtrate was evaporated to dryness under reduced pressure and the residue was stirred with ethyl acetate. Filtration of the mixture yielded 4- (N- (N-aminoethylcarbamoyl) morpholine hydrogen sulfate) as a solid residue, melting at 168-169 ° C.

Example 2

A mixture of 8.56 g of R - (-) - 1β-benzyloxyphenoxy-3-p-toluenesulfonyloxy-2-propanol, 8.76 g of β- (morpholino-carboxamido) ethylamine, 40 ml of isopropanol and 10 ml of 2N aqueous sodium hydroxide solution. The mixture was heated at reflux for 1 hour, then cooled and poured into a mixture of water and ethyl acetate. The organic layer was separated, dried, diluted with petroleum ether (b.p. 60-80 ° C) and filtered. The residue was crystallized from a mixture of ethyl acetate and petroleum ether (bp 60-80 ° C) and then purified by chromatography on a 200 g silica gel column eluting with methanol. 1-p-Benzyloxyphenoxy-5- (5-morpholinocarboxamido) ethylamino-2-propanol is obtained.

A solution of 1.2 g of the above compound in acetic acid was shaken in a hydrogen atmosphere at room temperature and atmospheric pressure until 50 ml of hydrogen were consumed in the presence of 50 mg of 30% palladium on carbon catalyst. The mixture was filtered, the filtrate was evaporated to dryness and the residue was dissolved in ethanol. 5 ml of a 1M ethanolic oxalic acid solution was added to the solution and the mixture was allowed to crystallize. After filtration, the solid product is recrystallized from a mixture of methanol and ethyl acetate. To give S- (-) -1-p-hydroxyphenoxy-3- / 3- (morpholin-olinokarboxamid of j-2-ethylamino propanolhydrogenxalát mp 150-151 ° C; [W] _D ²⁰ = -6 2 ° (c = 5% in water).

The R- (-) -1-p-benzyloxyphenoxy-3-p-toluenesulfonyloxy-2-propanol used as starting material can be prepared as follows:

A mixture of glycerine-1,2-acetonide (66 g) and phthalic anhydride (74 g) was heated at 100 ° C for 18 hours and then cooled. The combined syrup-like products from three such reactions, totaling 415 g, are dissolved in 2.5 liters of isopropanol, 148.1 g of (.beta.-methylbenzylamine) are added, the mixture is left to react at room temperature for 4 hours, and then The solid product was recrystallized twice from 4 L of isopropanol to give (-) -. alpha.-methylbenzylamino-2,3-isopropylidenedioxypropoxycarbonyl benzoate, m.p. 153.5 ° C.

A solution of 126.5 g of the above compound in chloroform is shaken with dilute aqueous hydrochloric acid, the chloroform layer is separated, washed with water and, after drying, evaporated to dryness. The residue, 84.2 g, was heated with 100 ml of water and 50 ml of a 10N aqueous sodium hydroxide solution for 10 minutes at 100 ° C, cooled, extracted five times with ether. The combined ether extracts were washed with water, evaporated to dryness and the residue distilled under reduced pressure. (R) - (-) - Glycerin-1,2-acetonide is obtained, boiling at 84 ° C / 1600 Pa; [ _.alpha. ] _D @ ²⁰ = -9.2 DEG (c = 10% in methanol).

32.4 g of the above compound are added with stirring to a cooled mixture of 46.8 g of p-toluenesulfonyl chloride and 25 ml of pyridine, and the resulting mixture is stirred for 1 hour and then poured into water. The aqueous mixture was extracted with ether, the extract was washed with water and evaporated to dryness after drying. The residue was stirred at -78 ^° C, recrystallized twice from petroleum ether (b.p. 60-80 ° C) to give S- (+) -3-p-toluensulfonylglycerin-1,2-acetonide, optical rotation [ «] _D ²⁰ = + 3.1 ° (c = 10% in methanol).

The above compound was converted to R- (-) - 1-p-benzyloxyphenoxy-3-p-toluenesulfonyloxy-2-propanol (m.p. 90-91 ° C; [α] _D ²⁰ = -9.1 ° (c) = 20% in ethyl acetate)} by reaction with p-benzyloxyphenol and hydrolysis of the isopropylidenedioxy group, reaction of the thus obtained (S) - (+) -3- (β-benzyloxyphenyl) glycerine (m.p. 122-123 ° C; [α] η ²⁰ = +4 3 ° (c = 4.5% methanol) with p-toluenesulfonyl chloride and crystallization of the product so obtained from aqueous isopropanol, analogous to the procedure described in Journal of Medicinal Chemistry 1973, 16, 168-169, for the preparation of S - (+ -1- (4-acetamidophenoxy) -3- (4-toluenesulfonyloxy) propan-2-ol from R- (-) - N - (4-toluenesulfonyl) acetonglycerin.

Example 3

The compounds summarized in the following summary can also be prepared as described above

HIM

^ R ^z

OCH 2 CHOH · CH 2 NH (CHfaNHCON '

CH 2 H 2 OR

RR ² Salt Melting point (° C)

H methyl hydrochloride dihydrate oil methyl methyl hydrogen oxalate 158 to 160 H ethyl hydrogen oxalate hemihydrate 149 to 151 H 3-hydroxyethyl hydrochloride trihydrate oil

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of 1-substituted-phenoxy-3-amino derivatives of 2-propanol of the general formula I, OCIi ^ CHOH-CH3 NH (CH3 NHCON Wherein each of R ³ and R ⁴ , which may be the same or different, represents a hydrogen atom or a hydroxyl group, provided that at least one of R ³ and R ⁴ represents a hydroxyl group, and either R represents a hydrogen atom, methyl or an ethyl group and R ^{2 is a} methyl group, an ethyl group or a radical of the formula --CH ² CH ² OR, wherein R is as defined above, or R ² and R ² together form an ethylene residue -CH 2 -CH 2 -, and their acid addition salts, characterized in that the epoxy derivative in which each of R ¹³ and R ¹⁴ , which may be the same or different, represents a hydrogen atom or a radical of the formula R ⁵ O-, wherein R ⁵ represents a hydrogen atom or a protecting group provided that at least one of R ¹³ and R ¹⁴ represents the above defined formula R ⁵ -O-, reacting a compound of formula III, R ² / HNR ⁶ (CH2) 2 NHCON \ CH 2 CH 2 OR, (III) wherein R ² and R ² are as defined in formula I, and R ⁶ represents a hydrogen atom or a protecting group, any optionally present protecting groups R ⁵ and / or R ® is cleaved, the racemic product of the formula I obtained is optionally cleaved to optically active enantlomorphs and / or the product obtained in free base form optionally converted by treatment with an acid to its acid addition salt. 2. A process according to claim 1, wherein one or both of R @ ¹⁵ and R @ ¹⁴ are each benzyloxy, R @ 7 is hydrogen or benzyl and the remaining radicals have: as defined above, and from the resulting product all benzyl residues present are cleaved by hydrogenolysis. 3. A process according to claim 1 or 2, wherein the starting materials of formulas II and III are those in which R @ ¹³ is hydrogen, R @ ¹⁴ is R @ ⁵ O--, R @ ² and R @ ² are joined to form ethylene groups and R ⁵ and R ® are as defined in point 1 or 2.