CS212331B2 - Method of making the derivatives of 1-phenyl-2-(acylamino)-alcanoylamino alkylaminoethanol - Google Patents

Description

(54) A process for the preparation of 1-phenyl-2 - [(acylamino) -alkanoylamino] alkylaminoethanol derivatives i

The present invention provides a process for the preparation of novel 1-phenyl-2 - [(acylamino) alkanoylamino] alkylaminoethanol derivatives which exhibit anti-inflammatory properties when applied topically to the site of inflammation.

It is known from prior art that 1-phenoxy-3- (E (acylamino) alkanoylamino] alkyl amino) propan-2-ol derivatives exhibit blocking effects on adrenergic beta-receptors (see DOS No. 2,745,222). Surprisingly, it has now been found that certain 1-phenyl-2-aminoethanol derivatives bearing on the amine residue β (acylamino) alkanoyl amino alkyl substituent surprisingly exhibit local anti-inflammatory activity, i.e. they act anti-inflammatory when topically applied to the site of inflammation.

Accordingly, the present invention provides a process for the preparation of the novel 1-phenyl-2- [(acylamino) alkanoylamino] alkylaminoethanol derivatives of formula (I).

R ¹ . CH (OH). CH2. NH. CR ² R ³ A ¹ . NH [CO. Y. NH] n. Q (1) in which

R * represents a radical of formula II

W ¹ . A ² (II)

W ^J

212331 where w 'is C 2 -C 12 alkanoyloxy,

O

A represents a direct bond or a divalent methyl group and one of V and K ² represents a hydrogen atom and the other of R a is alkanoyloxy of two to twelve carbon atoms, or represents phenyl, 2-chlorophenyl or 3,5-dichloro-4 -aminophenyl, and R ^ are each independently hydrogen or C1-C4alkyl;

A ¹ represents a divalent alkylene group having 1 to 4 carbon atoms,

X is a divalent alkylene group having 1 to 4 carbon atoms, optionally substituted with an alkyl group having 1 to 4 carbon atoms, or a benzyl group, n is an integer having a value of 1 to 4, and

Q represents a benzoyl, phenylacetyl or phenoxyacetyl group optionally bearing a substituent selected from the group consisting of halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and trifluoromethyl, provided that n has another value than 1, then the Y symbols in each bivalent grouping [co. Y. NH 1 may have the same or different meanings, and pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) contain at least one asymmetric carbon atom, in particular a carbon atom bearing the radical R @ ¹ , and, depending on the nature of the other substituents, may contain further asymmetric carbon atoms. Thus, said substances may exist in racemic form and in optically active forms. The invention includes both racemic forms of the compounds of formula I and all optically active forms having anti-inflammatory activity.

It is well known in the art how optically active forms can be prepared by racemic resolution or synthesis from optically active starting materials, and how local anti-inflammatory activity can be determined by standard assays described below.

Suitable C 2 -C 12 alkanoyloxy groups W ¹ , W ² and 11 P are, for example, 2,2-dimethylpropionyloxy (pivaloyloxy), isobutyryloxy, n-pentanoyloxy (valeryloxy) or 3,3-dimethylbutyryloxy.

3

Suitable alkyl groups and from 1 to 4 carbon atoms represented by R or R ^J is for example a methyl group.

Preferred radicals R @ 1 and R @ 2 are two hydrogen atoms or two methyl groups, the latter being particularly preferred.

A suitable radical for the symbols a 'is, for example, a divalent methylene or ethylene group, preferably a methylene group.

A preferred radical for Y is, for example, a divalent methylene, ethylene or trimethylene group, and a suitable optional C1-C4 alkyl substituent is, for example, methyl or ethyl. · * ''

Suitable bivalent radical of formula [CO.Y.NH] as glycyl residue (CO.CHjNH) alanyl [CO.CH (CH ₃₎ .NH] Bata-alanyl (CO.CH ₂ CH ₂ NH ₂₎ or phenylalanyl [ CO.CH (CH ₂ Ph).

NH 3, of which glycyl divalent is particularly preferred. In the preceding and following text, Ph is a phenyl group.

A preferred integer for n is 1 or 2.

When n is 2, is a preferred bivalent radical of formula [C0.Y.NH] _n, wherein n is as defined above, for example the radical glycylglycylový (CO.CHgNH.CO.CHgNH) glycylalanylový _[2 cO.CH NH.CO. CH (CH ₃ ) NH ₃ or alanylglycyl [CO.CH (CH ₃ ) NH NHCO ₂ NH], of which the glycylglycyl residue is particularly preferred.

A particularly suitable substituent on the core, which may be present when Q represents an optionally substituted benzoyl, phenylacetyl or phenoxyacetyl group, is, for example, fluoro, chloro, bromo, methyl, methoxy or trifluoromethyl.

A preferred radical R @ 1 is 3,4-bis (alkanoyloxy) phenyl having from 2 to 12 carbon atoms in the alkanoyloxy moiety each as 3,4-bis (pivaloyloxy) phenyl], 3,5-bis (alkanoyloxy) phenyl group containing 2 to 12 carbon atoms in the alkanoyloxy moiety Q as 3,5-bis (pivaloyloxy) phenyl], 3- (alkanoyloxymethyl) -4- (alkanoyloxy) phenyl group containing 2 to 12 carbon atoms in each alkanoyloxy moiety ( such as 3-valeryloxymethyl-4-valeryloxyphenyl) or 3,5-dichloro-4-aminophenyl. A particularly suitable group of compounds of the invention are those compounds of formula I wherein R * has any of the above-mentioned preferred meanings and wherein each of R 1, R 1, a ', Y, and Q has one of the above meanings, as well as and pharmaceutically acceptable acid addition salts of these compounds.

A preferred group of compounds of the invention are those compounds of formula 1 2 3 I wherein R has one of the abovementioned preferred meanings, R ^J, and R represents a methyl group, A * is a divalent methylene group, a bivalent radical of formula [C0.Y .NHj _n is a divalent glycyl, alanyl, phenylalanyl or glycyglycylový radical and Q represents a benzoyl, phenylacetyl or fenoxyaeetylovou group, and their pharmaceutically acceptable acid addition salts.

Another preferred group of compounds of the invention are those compounds of formula X wherein 'a bivalent radical of formula [C0.Y.NH] _n is a glycyl residue or as glycylglycylový', 8 ^2, ϋξ A ¹ and Q have any of the above as well as their pharmaceutically acceptable acid addition salts.

Particularly suitable acid addition salts of the compounds of formula I are, for example, salts derived from acids containing a pharmaceutically acceptable anion, for example from inorganic acids such as hydrochloric, hydrobromic, phosphoric or sulfuric acids or from organic acids such as oxalic, tartaric, milk, fumaric, lemon, acetic, 3alicyl, benzoic, beta-naphthoic, methanesulfonic or adipic. These salts may contain one or two acid equivalents.

Specific compounds of formula I are described in the Examples below. Of these compounds, they are of particular interest

1- [3,4-bis (pivaloyloxy) phenyl] -2- [2 - [(N-benzoylglycyl) amino] -1,1-dimethylethylamino) ethanol,

1- [3,4-bis (pivaloyloxy) phenyl] -2- {2 - [(N-phenylacatylglycyl) amino] -1,1-dimethylethylamino) ethanol,

- 3,4 3,4-bis (pivaloyloxy) phenyl] -2- [2 - [(N-phenylacetylglycyl) glycylamino] -1,1-dimethylethylamino) ethanol,

1- (3,5-dichloro-4-aminophenyl) -2- {2 - [(N-phenoxyacetylglycyl) amino] -1,1-dimethylethylamino) ethanol and

1- (3,5-dichloro-4-aminophenyl) -2- {2 - [(N-phenylacetylglycyl) glyeylamino] -1,1-dimethylethylamino} ethanol, as well as pharmaceutically acceptable acid addition salts thereof. The compounds of formula (I) may be prepared by any of the chemical processes known to be useful in the preparation of chemically analogous compounds, such as those described in DOS No. 2,745,222.

The process according to the invention is characterized in that the glyoxal of the formula III is reacted with an amino compound of the formula IV under reducing conditions.

H ₂ N.CR ² R ³ .A ¹ .NH | CO.Y.NH] _n .Q (IV)

R ^1, R ^2, R ^3, A ^1, Y and Q are as defined above.

Particularly suitable reducing conditions are achieved, for example, by using an alkali metal cyanoborohydride such as sodium cyanoborohydride, suitably in an inert solvent or diluent, for example acetonitrile, methanol, ethanol or 2-propanol, and operating at a temperature in the range of, for example -20 ° C to 30 ° C. When sodium cyanoborohydride is used, the reaction is preferably carried out at or near pH 4, for example in the presence of acetic acid. Conveniently, other standard reducing conditions may also be used provided they do not attack the substituents present in the starting material.

The processes of the above general type are known as reductive alkylaes and are at least partially carried out via intermediates of formula V

R'.U.CH = N.CR ² R ³ .A'.NH [CQ. Y.NH] _n .Q (V) wherein

V represents a divalent hydroxymethylene group, and / or via intermediates of the above-mentioned general formula V, wherein U represents a divalent carbonyl group. If desired, the intermediates of formula (V) in which U is a divalent hydroxymethylene or carbonyl group (or a mixture thereof) can be prepared and reduced in two separate steps in the process of the invention.

The starting materials of the formula III can be obtained, for example, by oxidation of the acetophenone of the formula VI

R @ ¹ CO.sub.2 (VI) with selenium dioxide in a suitable solvent, for example aqueous dioxane, at a temperature of, for example, from 50 to 150 [deg.] C. followed by optionally forming hydrate, acetal or hemiacetal, according to the method of the invention.

Alternatively, the starting materials of formula (III) may conveniently be obtained by oxidation of the appropriate phenacyl bromide prepared by bromination of the corresponding acetophenone of formula (VI) with dimethylsulfoxide, as described, for example, in the Examples below.

The amino compounds of formula (IV) may be obtained, for example, by reaction of the corresponding acid of formula (VII). CO.Y.míJ having an isotactic _n (VII) and the diamine of formula VIII

H ₂ M.CR ² r3, a1.nh ₂ (VIII)

The acid of formula (VII) is preferably first converted to a reactive derivative, such as a mixed anhydride with a (C1-C4) alkylhydrogen carbonate, which may be prepared by reacting an acid of formula (VII) with a C1-C4 alkoxycarbonyl chloride, the presence of a tertiary base such as N-methylmorpholine. This procedure, which is illustrated by the examples below, allows the preparation of the amino compounds of formula IV at room temperature or even lower, resulting in a reduction in racemization when the divalent radical of formula ϋϋθ.ϊ. .NH] _n comprises a divalent acyl radical of an optically active alpha-amino acid to a minimum.

The acids of formula VII are themselves prepared by acylating the corresponding amino acid of formula IX

HIM. {CO.X.KHJj.H '(IX) an acylating agent structurally derived from an acid of formula Q.OH, for example the chloride or bromide thereof, using conventional reaction conditions as described, for example, in the Examples below.

The free base compounds of formula (I) may be converted into pharmaceutically acceptable acid addition salts by reaction with a suitable acid as defined above using suitable methods which do not hydrolyze any of the ester groups present. Alternatively, the salt with hydrochloric acid or hydrobromic acid can be conveniently obtained by producing a stoichiometric amount of hydrogen halide in situ by catalytic hydrogenation of the corresponding benzyl halide, preferably in an inert solvent or diluent, for example ethanol, at or near room temperature. .

The compounds of formula I may conveniently be used in the form of their pharmaceutically acceptable acid addition salts.

The optically active forms of the compounds of formula I can be obtained, for example, by conventional resolution of the corresponding racemic form of the compound of formula I. Thus, the racemic form of the compound of formula I can be reacted with an optically active acid. from ethanol and then the optically active form of the compound of the formula I can be liberated in a suitable manner under conditions which do not attack any sensitive groups present, for example using anion exchange chromatography. A particularly suitable optically active acid is, for example, (+) - or (-) - 0,0-di-p-toluoyltartaric acid or (-) - 2,3: 4,5-di-O-isopropylidene-2-keto-L. -gulonic acid.

In addition, compounds of formula I in which at least some of their asymmetrically substituted carbon atoms have a specific optical configuration can be obtained using the appropriate optically active starting materials, such as optically active alpha-amino acids, in the synthetic procedure described above.

As mentioned above, the compounds of formula I exhibit anti-inflammatory activity when applied topically to the site of inflammation and are therefore particularly useful in the treatment of inflammatory diseases or inflammatory skin conditions in warm-blooded animals,

The anti-inflammatory properties of the compounds of Formula I can be demonstrated by a standard test of inhibiting croton oil-induced inflammation in the ear of mice. The activity of the individual compounds of the formula I in this test depends on their chemical structure, but in general the compounds of the formula I induce marked inhibition of inflammation when administered topically at a dose of 0.30 mg / ear or at a much lower dose.

Another standard assay to demonstrate the anti-inflammatory properties of the compounds of Formula I is to inhibit oxazolone-induced mouse ear sensitivity. In general, the compounds of formula I cause a marked inhibition of inflammation in this assay

Topical application at a dose of 0.6 mg / ear or at an even lower dose. In any of the above tests, no clear signs of toxicity were observed when the compounds of formula I were administered at effective doses.

In general, the compounds of formula I may be used to treat inflammatory diseases or inflammatory conditions of the skin in an analogous manner to that used with known topical anti-inflammatory agents, for example topical steroids.

When used for topical treatment of an inflamed area on the skin of a warm-blooded animal, for example a human, the compound of formula I may be administered topically at a dose of 100 µg to 15 mg / cm ² or an equivalent dose when a pharmaceutically acceptable acid addition salt is administered. dosages within the above range may be repeated, for example, at 4 to 12 hour intervals as desired. It will be understood that the total daily amount administered of a compound of Formula I depends on the extent and severity of the inflammation being treated.

For example, when 1- (β 3, 4-bis (pivaloyloxy) phenyl) -2- [2 - [(N-benzoylglycyl) amino] -1,1-dimethylethylamino} ethanol is used to topically treat an inflamed spot on the skin of a warm-blooded animal , for example, a human, is administered topically at a dose of 10 µg to 5 mg / cm ² or an equivalent amount when used in the form of a pharmaceutically acceptable acid addition salt, repeated as necessary in four instances. to 12-hour intervals.

The invention is illustrated by the following non-limiting examples. In these examples:

1. All procedures, unless otherwise stated, are carried out at room temperature (18-26 ° C) and at atmospheric pressure;

2. NMR spectra data reported are in the form of chemical shifts (δ values) for characteristic protons relative to tetramethylsilane as standard, the spectra being measured in perdeuterodimethylsulfoxide solvent (unless otherwise specified) at 100 MHz;

3. all evaporations are carried out on a rotary evaporator under reduced pressure;

4. the compounds of formula I generally have satisfactory microanalysis, in which case they are characterized by NMR spectra in case of doubt;

5. The melting points indicated are the temperatures actually obtained, are intended to serve as a guide in repeating the examples and do not necessarily represent absolute values applicable to completely pure crystalline materials;

6. The yields, if any, are purely illustrative and in no way represent the maximum achievable yields.

Example 1 to 3

A solution of 0.9 g of 3,4-bis (pivaloyloxy) phenylglyoxal and 0.67 g of N ¹ - (2-amino-2-methylpropyl) -N ² -benzoylglycinamidu in 2 ml acetic acid and 10 ml of acetonitrile is stirred for 30 minutes, 0.34 g of sodium cyanoborohydride is then added. The reaction mixture was stirred overnight and then evaporated under high vacuum. The residue was dissolved in 50 mL of ethyl acetate and the solution was washed with 20 mL of 10% (v / v) aqueous acetic acid. The aqueous layer is extracted twice with 50 ml of ethyl acetate each time, the combined organic layers are washed with saturated sodium chloride solution and, after drying over magnesium sulfate, evaporated. The residue was dissolved in ether, filtered and a slight excess of freshly prepared ethereal hydrogen bromide was added to the filtrate. The precipitated solid product is collected and after crystallization from ethanol / ether gives 0.3 g of solid 1- [3,4-bis (pivaloyloxy) phenyl] -2- {2 - [(N-benzoylglycyl) amino] -1 127-129 ° C, 1-dimethylethylamino} ethanol hydrobromide (Example 1).

In an analogous manner, using the appropriate glycine derivative as starting material, the following are obtained:

in a yield of 35% 1- [3,4-bis (pivaloyloxy) phenyl] -2- [4- (N-phenylacetylglycyl) amino] -1,1-dimethylethylamino} ethanol hydrobromide (Example 2), m.p. 150 [deg.] C .;

For C ₃₂ H ₄₅ N ₃ O ₇ .HBr calculated: 57.8% C, 6.9% H, 6.3% N;

found: 57.9% C, 6.7% H, 6.1% N, in a yield of 22% 1- [3,4-bis (pivaloyloxy) phenyl] -2- {2-C (N-phenoxyacetylglycyl) amino -1,1-dimethylethylamino-ethanol-hydrobromide (Example 3), m.p. 124-126 ° C;

For C 6 gHH NN ProOg · HBr requires: C, 53.6; H, 6.8; N, 5.9;

Found: C 53.7%, H 7.1%, N 6.1%,

The starting glycinamides are prepared as follows:

A mixture of phenylacetylglycine (10.0 g), N-methylmorpholine (5.78 ml) and chloroform (60 ml) was stirred for 5 minutes, then cooled to -23 DEG C. and ethyl chloroformate (4.7 ml) was added rapidly over 1 minute at a temperature. The mixture was allowed to rise to -15 ° C. After stirring for 1 minute, 5.4 ml of 1,2-diamino-2-methylpropane was quickly added to the reaction mixture and the temperature was allowed to rise to room temperature. After one hour of reaction at room temperature, the resulting mixture was poured into 50 ml of water and the organic layer was discarded. The aqueous layer was basified with excess potassium carbonate and extracted four times with 100 ml of chloroform each. The combined extracts were evaporated after drying over magnesium sulfate. Trituration of the solid with ether and filtration gave 8.8 g of solid N '- (2-amino-2-methylpropyl) - N ² -phenylacetylglycinamide, m.p. 150-155 ° C.

In an analogous way, using N-benzoylglycine (hippuric acid) and N- (fenoxyacetyUglycinu solid obtained ^N - (2-amino-2-methylpropyl) -N ² -benzoylglycinamid subtracting the temperature from 104 to 105 ° C, respectively. Solid N ' - (2-amino-2-methylpropyl) - N ² - (phenoxyacetyl) glyeinamide, m.p. 80-84 ° C.

3,4-Bis (pivaloyloxy) phenylglyoxal is obtained as follows:

A suspension of 3,4-dihydroxyacetophenone (13.1 g, 0.08 mol) in chloroform (320 ml) was cooled to 0-5 ° C in ice and, simultaneously, a solution of 19.2 ml (0.1 ml) was added dropwise over 10 minutes with stirring. 16 mol) of pivaloyl chloride in 80 ml of chloroform and, on the other hand, a solution of 22.2 ml (0.16 mol) of triethylamine in 80 ml of chloroform. The reaction mixture was stirred at 0-5 ° C for 1 hour and then poured into a mixture of 100 ml of 2 N hydrochloric acid and 200 g of ice. The resulting mixture is extracted three times with 150 ml of chloroform each, the extracts are washed successively with 100 ml of water, 100 ml of 10% (w / v) sodium carbonate solution, 100 ml of water and 100 ml of sodium chloride solution, dried over magnesium sulfate and evaporated. 23.1 g of crude oily 3,4-bis (pivaloyloxy) acetophenone are obtained, which is used without purification.

To a solution of 19.5 g (0.061 mol) of 3,4-bis (pivaloyloxy) acetophenone and 8.2 ml (0.06 mol) of tert-butyl acetate in 150 ml of chloroform containing a catalytic amount (0.2 g) of anhydrous aluminum chloride A solution of 3.15 ml (0.061 mol) of bromine in 50 ml of chloroform was added dropwise with stirring at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature

After 1 hour, 75 g of silica gel for chromatography are added and the resulting mixture is evaporated in vacuo. The solid residue is applied to a dry silica gel column for chromatography [1 kg of silica gel previously deactivated by the addition of 10% (w / w) water and then equilibrated with a 10% (v / w) 5% (v / v) solution of ethyl acetate in toluene]. The column was first developed by eluting with a 1.1 liter 5% (v / v) solution of ethyl acetate in toluene and eluting the peflc with ethyl acetate (2 x 500 mL), the fractions collected being monitored by thin layer chromatography. volume) of a mixture of ethyl acetate and toluene]. The last fractions were combined and evaporated to give 14.2 g of oily δ-ντοπι-’, 4´-bis (pivaloyloxy) acetophenone, which crystallized rapidly to give a solid, m.p. 64-66 ° C.

A solution of 2 g of 2-bromo-3 ', 4 ^# bis (pivaloyloxy) acetophenone in 10 ml of dimethylsulfoxide is allowed to stand for 18 hours at room temperature, then poured into ice water and extracted three times with 60 ml of ether.

The ethereal solution is washed first with 50 ml of water and then with 50 ml of sodium chloride solution, dried over magnesium sulphate and evaporated. 1.8 g of oily 3,4-bistpivaloyloxy) phenylglyoxal are obtained.

I.fi (v): 1760 cm ^-1 (ester 0O = 0), 1690 cm -1 (-CO.CHO);

BlSX x

NMR (CDCl3): 8.2-7.1 (complex, aromatic protons),

1.35 (18H, s, -CC & _3).

Example 4

2

A solution of 0.9 g of 3,4-bis (pivaloyloxy) phenylglyoxal and 0.86 g of N- (2-amino-2-methylpropyl) -N-LN- (phenylacetyl) glycyl] glycinamide in 2 ml of acetic acid and 10 ml of acetone The mixture was stirred for 30 minutes and then 0.34 g of sodium cyanohydride was added. The reaction mixture was stirred overnight and then evaporated under high vacuum. The residue was dissolved in 60 ml of ethyl acetate, washed successively with 20 ml of 10% (v / v) acetic acid solution, 20 ml of saturated sodium bicarbonate solution and 20 ml of saturated sodium chloride solution, dried and evaporated. The residue was dissolved in ether and treated with ethereal hydrogen bromide as described in Example 1.

The precipitated crude salt (0.6 g) was dissolved in a minimum amount of methanol and purified by preparative thin layer chromatography on silica gel using methanol / chloroform (1: 4 by volume) as the solvent system. The silica containing the main component is removed from the plates and extracted with methanol. The extracts were evaporated after filtration, the residue was dissolved in ether and ethereal hydrogen bromide was added to the solution. The resulting salt was crystallized from a mixture of ethanol and ether to give 0.1 g of solid 1-Q3,4-bis (pivaloyloxy) phenyl] -2- {2 - [(N-benzoylglycyl) glycylamino] -1,1-dimethylethylaminoJetanol of hydrobromide (Example 4), m.p. 110-115 ° C.

For C ₃₄ H ₄₈ N ₄ O • Br 1/2 H ₂ O calculated: 55.8% C, 6.8% H, 7.6% N;

Found: C 55.8, H 7.3, N 7.6%.

The starting N ¹ - (2-amino-2-methylpropyl) -N ² - [N- (phenylacetyl) glycine 3] glycinamide is obtained in 65% yield as a solid melting after crystallization from ethanol at 209 to 210 ° C by an analogous procedure, as described for the preparation of the starting materials in Examples 1 to 3, namely from N - (phenylacetyl) glycyl] glycine and 1,2-diamino-2-methylpropane.

The preparation of [N- (phenylacetyl) glycyl] glycine is described in French Patent Specification No. 0 560 (Chemical Abstracts 51, 13 908 g).

4,

Examples 5 to 30

Using a modified procedure disclosed in Example 1 starting from the appropriate glyoxal of formula III and the amine of formula IV (A ¹ = methylene group, R ² and R ³ = methyl) in yields of 20 to 70% obtained by the following groups of compounds of formula I (A ¹ 'methylene group, R ² and R 6 = methyl groups) in the form of hydrobromides (unless otherwise stated). The above modification relates to the purification of compounds of formula I in the form of the free bases and includes chromatography of the crude free base (obtained after evaporation of the ethyl acetate extracts) on silica gel for chromatography (particle size 0.04-0.063 mm; 80-100 parts by weight silica gel for each part) free base) using chloroform containing 1 to 5% by volume of methanol as the eluent. The free base thus purified is dissolved in a minimum volume of chloroform and the solution is acidified with ethereal hydrogen bromide (or hydrogen chloride). The resulting mixture is then evaporated to give the compound of formula I as the hydrobromide or hydrochloride salt.

Group I (Examples 5-14): R ¹ = 3,4-bis (pivaloyloxy) phenyl

Example [CO.Y.NH] _n Q Physical characteristics 5 coch ₂ ch ₂ nh (beta-alanyl) CO.Ph foam (note a) 6 beta-alanyl CO.CH ₂ Ph melting point 122-127 ° C for Ο ₃₃ Η _4? Ν ₃ Ο ₇ .ΗΒγ calculated: 58.4% C, 6.9% H, 6.1% N; Found: C 58.1%, H 7.1%, N 5.8% 7 co.chch ₃ .nh CO.Ph mp 110-1.2 ° C for C ₃₂ H ₄₅ R ₃ O ₇ .HBr ₂ H ₂ O calculated: 53.5% C, 7.2% H, 5.8% N; Found: C 53.2%, H 6.5%, N 5.7% 6 L-alanyl CO.CHjjPh mp 111-113 ° C for C ₃₃ H ₄₇ N ₃ O ₇ .HBr ₆ H ₂ O calculated: 50.4% C, 7.6% H 5.3% N; Found: C, 50.1; H, 7.5; N, 5.7 9 L-alanyl CO.CHgOPh mp 95-98 ° C

found:

for C ₃₃ H ₄₇ N ₃ O ₈ .HBr ₃ H ₂ O calculated: 52.9% C, 7.2% H,

5.6% N;

52.3% C, 7.2% H,

5.6% N - ^: 21233) continued table

Example [CO.Y.NH] _n Q Physical characteristics 10 D-alanyl CO.Ph m.p. 158-162 ° C for C ₃₂ H ₄₅ N ₃ O ₇ .HSR H ₂ O calculated: 54.7% C, 7.1% H, 6.4% N; Found: C 55.1%, H 7.0%, N 6.3% , 1 CO.CH (CH ₂ Ph) NH (L-phenylalanyl) CO.Ph m.p. 145-150 ° C (Note b) for C ₃₈ H ₄₉ N ₃ O ₇ .HBr calculated: 5.7% N; found: 5.4% N 12 [Coch ₂ nh] ₂ (glyeyl.glycyl) CO.CHgOPh mp 155-158 ° C (Note c) 13 coch ₂ nh.co.chch ₃ .nh (glycyl. L-alanyl) CO.Ph mp 145-155 DEG C. ^{EXAMPLE C} 34 ^H 48 ^N 4 ⁰ 8 ^HBr Calculated: 56.6% C, 6.8% H, 7.7% N; Found: C 52.0, H 6.7%, N 7.7% , 4 co.chch ₃ nn.coch ₂ nh (L-alanyl.glycyl) CO.Ph , Melting point: 152-158 ° C, for C ₃₄ H ₄₈ N ₄ 0 _e .1,5HBr.4H ₂ O Calculated: 48.7% C 6.8% H 6.6% N 14.3% Br; Found: C 48.2%, H 6.5%, N 6.4%, Br 14.1%

Legend:

note a: NMR (δ values): 8.8 - 8.2 (2-NHCO + NH ₂ ), 8.0 - 7.2 (8H, complex, aromatic protons), 8.85 (2H, complex, aromatic proton in the ortho position of the benzoyl residue), 5.0 (CH 3 OH + H ₂ O), 3.8 - 2.8 (6H, complex, CH ₂ NH), 2.5 (2H, complex, Cg ₂ CO), 1.28 [24H, singlet, C (CH ₃ ) ₂ + 2 C (CH ₃ ) ₃ ];

Note b: NMR (δ values): 8.80 [1H, CH (CH ₂ Ph). NHCO], 8.4 (1H, triplet, CH ₂ tfflCO), 7.8 (2H, two doublets, aromatic proton in ortho-position of the benzoyl residue),

7.6 to 7.0 (11H, complex, aromatic H), 6.5 (1H, broad singlet, OH), 5.03 + 4.8 [2H, complex, CIJOH + CH (CH ₂ Ph) NH3; 3.6-2.8 (complex, CH ₂ Ph + + CH ₂ N), 1.3 [24H, singlet, C (CH ₃ ) ₂ + 2 C (CH ₃ ) _3] ;

♦ »note c: NMR (δ values): 8.9 - 8.0 (4H, HNCO + NH ₂ ), 7.5 - 6.8 (8H, complex, aromatic protons), coa 5.0 (complex , CHOH + H ₂ O), 4.6 (2H, singlet, CJJ ₂ OPh), 3.9 (4H, complex, NHCH 3 CO), 3.6 - 2.8 (4H, Broad signal, CH ₂ NH), 1.3 [24H, singlet, C (CH _{3) 2} + 2 C (CH _{3) 3].}

Group II (Examples 15-17): R ¹ = 3,5-bis (pivaloyloxy) phenyl

Example [CO.Y.NHJn Q Physical characteristics 15 Dec glycyl CO.Ph glassy product, melting point 190-195 ° C (Note a) 16 L-alanyl CO.CHgOPh mp 105-106 ° C, for C ₃₃ H ₄₅ N ₃ O _g .HBr.2,5H ₂ O Calculated: 53.6% C, 7.2% H, 5.7% N; Found: C 53.4%, H 7.2%, N 6.0% 17 L-phenylalanyl CO.Ph m.p. 1.0-1.1 ° C for 0 ₃₈ Η ₄ ? ^ ₃₀ ° .ΗΒΓ.2H ₂ O calculated: 58.8% C, 6.9% H, 5.4% N; Found: C 58%, H 6.9%, N 5.6%

Legend:

+ Note a: NMR (δ values): 8.76 OH, triplet, NHCO), 8.50 (2H, broad singlet, NH),

8.21 (1H, triplet, NHCO), 7.9 (2H, complex, protoh in the ortho position of the benzoyl residue), 7.6-7.3 (3H, complex, proton in the meta- and para-position of the benzoyl residue) ), 7.1 [2H, doublet, H ₂ and Hg bis (pivaloyloxy) phenyl radical], 6.9 [H, triplet, ₄ H bi s (pivaloyloxy) phenyl radical], 5.0 OH, doublet, CHOH) , 3.95 (2H, doublet, NHCH 3 CO), 3.7 - 3.0 (complex, CH ₂ N), 1.29 [24H, singlet, C (CH ₃ ) ₂ + 2 C (CH ₃ ) ₃ ] ,

Group III (Examples 18 to 24): R ¹ = radical of formula

R.CO ₂ CH ₂

r.co ₂

Example R [CO.Y.NH] _n Q Physical characteristics 18 tert.butyl glycyl CO.CH ₂ Ph mp 75-79 ° C (free base) (Note a) 19 Dec tert.butyl beta-alanyl C0.CH ₂ Ph m.p. 76-80 ° C (hydrochloride) calcd for C ₃₄ H ₄₉ N ₃ O ₇ · HCl · 1.5H ₂ O: C, 60.5; C, 7.9; H, 6.2; 7% C, 7.8% H,

6.0% N continued table

Example R [CO.Y.NHJn Q Physical characteristics 20 May n-butyl glycyl CO.Ph mp 101-104 ° C for C ₃₂ H ₄₅ N ₃ O ₇ .HBr ₂ H ₂ O calculated: 54.3% C, 7.1% H, 6.0% N; Found: C 54.5, H 7.0, N 6.0 21 h-butyl L-alanyl CO.CHgPh mp 68-78 ° C

for C ^ %H ^ gNOy.HBr.HgO: C, 57.5; H, 7.3;

5.9% N;

Found: C 57.1, H 7.4,

6.7% N

22nd n-butyl beta-alanyl CO ₂ CH ₂ OPh wheat (note b) 23 isopropyl L-alanyl CO.Ph mp 72-82 ° C for C ₃ H ₄₃ N ₃ O ₇ .HBr calculated: 57.2% C, 6.8% H Found: 57.4% C, 7.1% H (Note c) 24 isopropyl glycyl.glycyl CO.CH ₂ Ph wheat (note d) Legend: Note a: NMR (δ values) : 7.7 (complex, 1H, NHCO3), 7.6 6.8 (8H, complex, aromatic

protons), about 5.0 [broad ainglet, CHOH + (CH ₃ ) ₃ CCO ₂ CH ₂ + Η ₂ θ], 3.9 [2H, doublet (J = 7 Hz), NHCHgCO], 3.55 (2H , singlet, COCg ₂ Ph), 3.2-2.7 (4H, complex, CH ₂ N), 1.38 [9H, singlet, (CH ₃ ) ₃ CO ₂ .c], 1.16 [15H, singlet, (CU ₃ ) ₃ CO ₂ CH ₂ + + C (CH ₃ ) ₂ ] j +

Note b: NMR (δ values): 6.8 - 8.0 (4H, complex, 2 NHCO * NH ₂ ), 7.8 - 6.8 (8H, complex, aromatic protons), 5.05 * 4, 97 [3H, singlet + doublet, C ₈ OH + CH ₃ (CH ₂ ) ₃ . CO ₂ Cg ₂ ], 3.7 - 2.8 (6H, complex, CH ₂ N), 2.4 [6H, multiplet, CH ₂ CO (+ dimethylsulfoxide)], 1.6 - 1.0 + 1 28 [l4H, complex, CH ₂ + s, C (CH _{3) 2],} 0.9 [6H, multiplet, -C ₃ (CH _{2) 3} CO];

note c: NMR (δ values): 8.25 [3H, doublet (J = 7 Hz), NHCO], 8.05 [1H, triplet (J = 3 Hz), NHCO], 7.9 (2H, multiplet, proton in ortho-position of benzylic residue),

7.5 - 6.8 (6H, complex, aromatic protons), 5.9 (1H, broad singlet, CHOg),

4.95 + 4.85 [3H, singlet + bs, (CH _{3) 2} CHCO ₂ -C + CgOH _2], 4.42 (1H, multiplet, CH _3), 3.6 to 2.5 [6H, complex, CH ₂ N * (CH ₃ ) ₂ CgCO (+ H ₂ O)], 1.28 + + 1.1 [21H, doublet (J = 7 Hz), CHCl ₃ , + quartet, C (CH ₃ ) ₂ + (CH ₃ ) ₂ + (CH ₃ ) ₂ CH] j +

Note d: NMR (δ values): 8.8 - 8.0 (5H, complex, 3 NHCO + NH ₂ ), 7.7 - 6.7 (8H, complex, aromatic protons), 6.1 (1H, broad signal, CHO 3), 4.98 + 4.95 ( ₃ H: singlet, (CH ₃ ) ₂ CHCO ₂ CH ₂ , broad singlet, CHOH], 4.5 (2H, singlet, Cg ₂ OPh), 3.8 < 4H, multiplet, NHCg ₂ CO), 3.6 - 2.5 [complex, CHgN + (CH ₃ ) ₂ CgCO (+ H ₂ O)], 1.1 [18H, quartet, (Cg ₃ ) ₂ CH + C (CH _{3) 2].}

21233,

Group IV (Examples 25 to 30)

Example r ’ [CO.Y.NH] _n Q Physical characteristics 25 phenyl glycyl COCH ₂ Ph m.p. 130-140 ° C for C ₂₂ H ₂₉ N ₃ O ₃ .2HBr.0.5H ₂ O calculated: 47.7% C, 5.8% H, 7.6% N; Found: C 47.8%, H 6.0%, N 8.1% 26 2-chlorophenyl glycyl COCHjPh mp 72-75 ° C (free base) (Note a) 27 Mar: 3,5-dichloro-4- -aminophenyl glycyl COCHgOPh foam (Note b) (free base) 28 3,5-dichloro-4- L-alanyl COCHgOPh mp 120-125 ° C

- aminophenyl for ^C 23 ^H 30 ^N 4 ° ^C 12 ' ^{2iffi 3} H ₂ O calculated: 38.7% C, 5.0% H,

7.8% N;

found: 36.3% C, 4.7% H, 7.4% N, 27.6% Br (note c)

3,5-dichloro- -4-aminophenyl beta-alanyl COCH ₂ OPh mp 165-169 ° C (free base) calcd for C ₂₃ H ₃₀ N ₄ O ₄ Cl ₂ · 0.25H ₂ O: 54.5% C, 6.1% H, 11.1% N; Found: C 54.2%, H 6.0%, N 10.8%

30 3,5-dichloro-4-aminophenyl glycyl.glycyl G0CH ₂ > h mp 105-108 ° C (free base) (note d)

Legend:

note a: NMR (deuterochloroform, δ values): 8.8 - 8.5 (complex, NHCO + NH), 7.4 - 6.8 (9H, complex, aromatic protons), 5.2 (1H, doublet, CHOH), 3.9 (2H, doublet, NHCH ₂ CO), 3.6 (2H, singlet, COCH ₂ Ph), 3.36 2H, doublet, G (CH ₃ ) ₂ CH ₂ NH, 3.1 + + 2.7 (2H, d + m, GHOH.CH ₂ NH), 1.2 6H, doublet, C (CH _{3) 2;}

note b: NMR (δ values): 8.25 (1H, complex, NHCO), 7.4 - 6.8 (7H, complex, aromatic protons), 5.4 (2H, singlet, NH ₂ on aromatic nucleus) , 4.53 (3H, s, ₂ C0CH 0PH + CHOH), 3.83 (2H, doublet, NHCHjCO), 3.2 [2H, complex, C (CH ₃₎ CH ₂ NH 3, 3.0 - 2, 7 (2H, multiplet, CHOH.CH ₂ NH), 1.1 [6H, singlet, C (CH _{3) 2];}

Remark: NMR (δ values): 9.0 - 9.1 (complex, 2NHCO + NH ₂ ), 7.5 - 6.8 (7H, complex, aromatic protons), 4.86 (1H, multiplet, CHOH ), 4.7 - 4.3 [3H, complex, COCH ₂ OPh + + CH (CH ₃ )], 3.4 [2H, complex, C (CH ₃ ) ₂ CH ₂ NH], 3.3 - 2 Δ (2H, complex, CHOH, CH ₂ NH), 1.32 + 1.28 [9H, doublet (J = 6 Hz), CH (CH ₃ ), singlet, C (CH ₃ ) ₂ ];

Note d: NMR (δ values): 8.35 (1H, triplet, NHCO), 8.15 (1H, triplet, NHCOJ), 7.81 (1H, triplet, NHCO), 7.28 (7H, singlet, aromatic) protons), 5.42 (2H, singlet, NHg on the aromatic ring), 4.55 (1H, multiplet, CHOH), 3.77 (4H, doublet, NHCH ₂ CO),

3.6-2.6 [complex, CHOH.CH ₂ NH (+ H ₂ O)], 3.50 (singlet, COCH ₂ Ph), 1.12 [6H, singlet, C (CH ₃ ) ₂ ].

In a similar manner to that described in Examples 1-3 for the preparation of analogous starting materials, the following amino compounds of formula IV (a '= methylene group, R ² and R ² ') are obtained from the corresponding acids of formula VII and 1,2-diamino-2-methylpropane. R * (methyl groups) required as starting materials:

Number [C0.Y.NH] _n Q Melting point (° C) 1 co.ch ₂ ch ₂ nh (beta-alanyl) CO.Ph 92 to 94 2 beta-alanyl CO.CH ₂ Ph 100 to 102 3 beta-alanyl CO ₂ CH ₂ OPh 73 to 75 4 co.chch ₃ .h (L-alanyl) CO.Ph 105 to 107 5 L-alanyl CO.CH ₂ Ph 144 to 146 6 L-alanyl CO ₂ CH ₂ OPh oil (note a) 7 D-alanyl CO.Ph 72 to 75 (hydrate) 8 CO.CH (CH ₂ Ph) NH (L-phenylalanyl) CO.Ph 146 to 146 9 co.ch ₁ nh.co.ch ₁ nh (glyeyl.glycyl) CO ₂ CH ₂ OPh 175 to 180 10 co.ch ₂ nh.co.chch ₃ nh (glycyl.L-alanyl) CO.Ph foam (Note b) 11 CO.CHCH ₃ .nh.co.ch ₂ nh (L-alanyl.glycyl) CO.Ph oil (note c)

Legend:

Note a: NMR (δ values): 8.9 - 8.5 (2H, complex, NHCO), 8.5 - 7.7 (5H, complex, aromatic protons), 4.65 + 4.48 (3H: multiplet, CHCH ₃ , singlet, CO ₂ Cl ₂ Ph), 3.5 + + 3.22 [4H: singlet, NH ₂ , doublet (J = 7 Hz), NH ₂ C (CH ₃ ) ₂ Cl ₂ NH], 1 43 (3H, doublet, CH (C _3), 1.13 [6H, singlet, C (CH _{3) 2];}

i. 212331 note b: NMR (δ values): 3) - 7.1 (8H, complex, aromatic protons + NHC · O), 4.67H, triplet, CHCl 3, 3.90 (2H, complex, NHCH ₂ CO ), 3.10 [2H, doublet (J = 4 Hz), H ₂ NC (CH ₃ ) ₂ CH ₂ NH ₂ , 2.22 (2H, singlet, NH ₂ ), 1.5θ [3Η, doublet (J = 5 Hz), CHCl 3], 1.10 E&H, singlet, C (CH ₃ ) ₂ Ϊ note c: NMR (δ values)! 8.2-7.2 (8H, complex, NHCO + aromatic protons), 4.57 ClH, triplet (J = 8 Hz), CHCH-j], 4.18 (2H, complex, NHCHgCO), 3.16 [2H, doublet, H ₂ NC (CH ₃ ) ₂ CH ₂ NH], 2.5 (complex, NH ₂ ), 1.38 [3H, doublet (J = 8 Hz), CHCH ₃ 3,

1.07 [6H, singlet, C (GH _{3) 2].}

The starting acids of formula (VII) may be obtained by acylation procedures known in the art. A typical procedure is illustrated by the example of N-benzoyl-L-alanine below;

17.3 g (0.2 mol) of L-alanine are dissolved in 120 ml of 2N sodium hydroxide solution (cooled to 0 to 5 ° C) and 30.0 g (0.22 mol) of benzoyl chloride and 120 ml are added, ml of 2 N sodium hydroxide. The addition of the two substances is carried out in equal proportions with intensive periodic shaking and ice cooling. The mixture is constantly maintained at an alkaline pH. After the addition was complete, the resulting mixture was shaken at room temperature for 15 minutes. The resulting clear solution was acidified with concentrated hydrochloric acid to pH 2 (with ice-cooling) to give solid N-benzoyl-L-alanine (27.8 g), m.p. 137-139 ° C.

The following acids of formula VII are obtained using an analogous procedure:

number , [Co.Y.NH] _n Q Physical characteristics 1 co.chch ₃ .h (L-alanyl) CO.CHgPh mp 52-55 ° C 2 L-alanyl CO.CHgOPh mp 192-193 ° C 3 CO.CH (CHgPh). NH (L-phenylalanyl) CO.Ph mp 136-138 ° C 4 D-alanyl CO.Ph melting point 120 to 125 ° C (softening at about 100 ° C) 5 co.ch ₂ nh, co.ch (ch ₃ ) .nh (glyeyl, L-alanyl) CO.Ph mp 165-167 ° C 6 WHAT. CH (CH-j). NH. CO ₂ CH ₂ NH (L-alanyl.glyeyl) CO.Ph mp 188-190 ° C 7 glyeyl.glyeyl CO.CHgOPh mp 192-193 ° C 8 coch ₂ ch ₂ nh (beta-alanyl) CO.Ph mp H5-118 ° C 9 beta-alanyl COCH ₂ Ph mp 106-107 ° C 10 beta-alanyl COCHgOPh mp 118-122 ° C

Note: In the above examples, when the residue [CO.Y.NH] is other than a 2-residue glyeyl (CO.CHgNH) or betar-alanyl (CO.CHgCHgNH), they are used as the original in all such cases. amino acid starting materials with said D- or L-configuration. It will be understood, however, that the sequence of reactions leading to the compounds of formula (I) may, to some extent, cause racial reactions (especially those compounds in which Q is a benzoyl group), so that the final product does not necessarily have to be completely optically pure. of formula [CO.Y.NhJ.

The necessary starting glyoxal derivatives of formula (IIIe) are obtained by conventional oxidation of the corresponding 2-bromoacetophenone derivatives with dimethylsulfoxide. This procedure is illustrated by the following preparation of 3 ', 5'-bis (pivaloyloxy) phenylglyoxal.

A solution of 8.6 g of 2-bromo-3 ', 5-bis (pivaloyloxy) acetophenone in 35 mL of dimethylsulfoxide was allowed to react for 2 days at room temperature and then poured into excess water with ice. The mixture is extracted three times with 100 ml of ethyl acetate each time, the extracts are washed successively with 50 ml of saturated sodium bicarbonate solution, three times with 50 ml of water and 50 ml of saturated sodium chloride solution and then evaporated. 7.0 g of oily 3 ', 5'-bis (pivaloyloxy) phenylglyoxel are obtained. ^^ IR): 1760 cm ^- '(ester carbonyl) and 1690 cm' (CO.CHO).

Most of the starting glyoxal derivatives are prepared in an analogous manner and have similar properties. All of these starting materials were used without further purification.

4 * -Amino-3 '_> 5 * -difluorophenylglyoxal is obtained in 58% yield as a solid hydrate melting at 95-98 ° C by oxidation of 12.0 g of 4'-amino-3', 5 ^, -dichlorophenylaeetophenone 10.0 g of oxide of selenium in a mixture of 60 ml of dioxane and 2 ml of water. The oxidation is carried out at 95 ° C for 4 hours, then the reaction mixture is filtered and the filtrate is evaporated.

The corresponding 2-bromoacetophenone derivatives are prepared in a known manner by brominating acetophenone, as illustrated in the following procedure for the preparation of 3'-valeryloxymethyl-4'-valeryloxy-2-bromoacetophenone.

To a solution of 8.5 g of 3'-valeryloxymethyl-4'-valeryloxyacetophenone in 100 ml of chloroform was added dropwise a solution of 4.2 g of bromine in 20 ml of chloroform with stirring and cooling. During the addition, the temperature is maintained at 0-5 ° C by adding small pieces of solid carbon dioxide. The resulting solution is washed three times with 00 ml of 10% w / v sodium carbonate solution, twice with 100 ml of water and 100 ml of saturated sodium chloride solution each time. The organic phase was dried over magnesium sulphate and evaporated. Yield: 6 g (57%), 3'-valeryloxymethyl-4'-valeryloxy-2-bromoacetophenone, which according to iC spectroscopy and thin layer chromatography [silica gel, 50% (v / v) ethyl acetate in petroleum ether (boiling point 60 to 60%). 80 ° C)] sufficiently pure for further use without additional purification or characterization.

Acetophenone is prepared as follows.

To 150 ml of valeric acid, 2.0 g of sodium hydride are added portionwise with stirring over 15 minutes, then 40 g of 3'-acetyloxymethyl-4'-acetoxyacetophenone are added, the mixture is heated to 160 degrees Celsius and stirred at this temperature for 5 hours. spinal cord. The resulting mixture was concentrated by distillation under reduced pressure while maintaining the temperature at 60 ° C, the gummy residue was cooled and dissolved in 500 mL of ether. The solution is washed three times with 250 ml of a 10% w / v solution of sodium carbonate, twice with 500 ml of water and 250 ml of saturated sodium chloride solution each time, the organic phase is dried over magnesium sulphate and filtered to give a brown oily residue. high vacuum gave 16.0 g (30%) of 3'-valeryloxymethyl-4'-valeryloxyacetophenone as a colorless viscous liquid.

NMR (CDCl 3) 7.9-7.0 (3H, aromatic nucleus substitution at positions 1, 2, 4), 5.0 (2H, sharp singlet, CO ₂ CH ₂ ), 2.5 ( 3H, sharp singlet, COCH 3), 2.55-2.15 (4H, complex, CH ₃ (CH ₂ ) ₂ Cl ₂ CO ₂ and CH ₃ (CH ₂ ) ₂ CH ₂ CO ₂ CH ₂ ). 1.8 - 1.2 (8H, complex, CH ₃ CH ₂ CH ₂ CH ₂ CO ₂ 0), 1.1 - 0.8 (6H, overlapping triplets, CH ₃ (CH ₂ ) ₃ CO ₂ ).

In an analogous manner, 3'-isobutyryloxymethyl-4'-isobutyryloxy-2-bromoacetophenone is obtained in the form of an oil with a satisfactory IR spectrum which, according to thin layer chromatography [silica gel, 50% (v / v) ethyl acetate in petroleum ether (boiling point 60-80 °). C)] pure. The intermediate 3'-isobutyryloxymethyl-4'-isobutyryloxyacetophenone is also isolated in liquid form.

NMR (CDCl₃, δ values): 8.2 - 7.1 (3H, protons on an aromatic ring in positions 1, 2, 4), 5.1 (2H, s, CO ₂ CH _2), 2.55 + 2 67 (5H, singlet, COCH ₃ + doublet, CHCO ₂ ), 1.21 + 1.15 Cl 2 H, 2 doublets (J = 8.3 Hz), (CH ₃ ) ₂ CH].

Example 31

Analogous to that described in Example 4 from 0.9 g of 3,4-bis (pivaloyloxy) phenylglyoxal and 0.635 g of N ^- (2-aminoethyl) -N ² - (phenylacetyl) glycinamide obtained in a yield of 0.25 g solid 1- (3,4-bis (pivaloyloxy) phenyl) -2- [2 - [(N-phenylacetylglycyl) amino] ethylamino] ethanol hydrobromide, m.p. 146-148 ° C,

For C ₃₀ H ₄₁ N ₃ O ₇ .HBr.H ₂ O calculated! H, 6.7; N, 6.4;

Found: C, 54.6; H, 6.5; N, 6.4.

The latter starting material is prepared as follows:

A mixture of 35.0 g of N- (phenylacetyl) glycine methyl ester and 34 ml of ethylenediamine was heated at 95-100 ° C for 2 days. Excess ethylenediamine is evaporated, the residue is dissolved in water and all insoluble materials are filtered off. The aqueous filtrate was evaporated to dryness, the last traces of water being removed by evaporation with toluene. Washing the residue with ether in a yield of 37.0 g was obtained N ¹ - (2-aminoethyl) -N ² - (phenylacetyl) glycinamide M.P. by crystallization from a mixture of ethanol and ether at 132-137 ° C.

Claims (5)

SUBJECT OF THE INVENTION 1. A process for producing derivatives of 1-phenyl-2- £ (acylamino) alkanoylamino] alkylaminoetanolu formula I, R '.CH (OH) .CH ^ ^ .A NHrCR ¹ .NH. [CO.Y.NH] _n having an isotactic ( In which R ¹ represents 3,4-bis (alkanoyloxy) phenyl having 2 to 12 carbon atoms in the alkanoyloxy moiety, 3,5-bis (alkanoyloxy) phenyl having 2 to 2 carbon atoms in the alkanoyloxy moiety, 3- (alkanoyloxy) methyl A 4- (alkanoyloxy) phenyl group containing 2 to 12 carbon atoms in each alkanoyloxy moiety, a phenyl group, a 3,5-dichloro-4-aminophenyl group or a 2-chlorophenyl group, R ² and R ³ are each independently hydrogen or C 1 -C 4 alkyl, and is a divalent C 1 -C 4 alkylene group, Y represents a divalent alkylene group having 1 to 4 carbon atoms, optionally substituted with an alkyl group having 1 to 4 carbon atoms or a benzyl group, n being an integer having a value of 1 to 4 and Q represents a benzoyl, phenylacetyl or phenoxyacetyl group optionally bearing a substituent selected from the group consisting of halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and trifluoromethyl, provided that n has another value than 1, then the symbols Y in each divalent group [CO.Y.NH] may have the same or different meanings, and their pharmaceutically acceptable acid addition salts, characterized in that the glyoxal of the general formula III r'co-cho ( III) in which r 'is as defined above, or a hydrate thereof, is reacted under reducing conditions with an amino compound of the formula IV H ₂ N.CR ² R ³ .A ¹ .NH. [C0.Y.NH] _n .Q (IV) R ² , R ³ , A ¹ , Y, Q are as defined above, after which the optionally obtained free base compound of formula I is subjected to a reaction with an acid 8 to give a pharmaceutically acceptable anion in a conventional manner to form a pharmaceutically acceptable acid addition salt. 2. A process according to claim 1 wherein the reaction is carried out in the presence of an alkali metal borohydride. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of from -20 ° C to 30 ° C. 4. Process according to claim 1, 2 or 3, characterized in that the reaction is carried out in the presence of sodium cyanoborohydride at pH 4. Process according to one of Claims 1 to 4, characterized in that the starting materials of the formulas (III) and (IV) above are used in which: R ¹ is 3,4-bis (pivaloyloxy) phenyl, phenyl, 2-chlorophenyl or 3,5-dichloro-4-sminofenylovou group, R ² and R ³ represent hydrogen atoms or methyl groups, A ¹ represents a divalent methylene group, the divalent radical [CO.Y.NH] _n represents a divalent glycyl, alanyl, phenylalanyl or glycylglycyl residue and Q is benzoyl, phenylacetyl or phenoxyacetyl.