CH643818A5 - Esters of phenylethylamine derivatives and pharmaceutical preparations thereof - Google Patents

Abstract

The new alkanoic acid, (cycloalkyl)alkanoic acid and benzoic acid esters of 1-(hydroxyphenyl)-2-[(acylamino)alkylamino]ethanols correspond to the formula <IMAGE> In the formula, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, A<1>, A <2 > , Q and Z have the meanings given in Patent Claim 1. The novel esters and their pharmaceutically acceptable salts are suitable for the topical treatment of dermal inflammations. The pharmaceutical preparations contain a novel ester of the formula I or a pharmaceutically acceptable salt thereof as active substance, together with a pharmaceutically acceptable diluent or excipient in a form suitable for topical administration.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 



   PATENT CLAIMS 1.  Esters of the formula:
EMI1. 1
   wherein R1 represents a C 1 -C 6 -alkyl or 6-cycloalkyl) Cl s-alkyl radical or a phenyl radical which optionally carries a C (-6-alkyl or Cl-6-alkoxy radical as core substituent; one of the symbols R2 and R3 represent hydrogen and the other of the symbols R2 and R3 represents a radical of the formula R 'CO. O-, where R 'has the meaning given above, is; R4 and Rsje represent hydrogen; R6 and R7, which may be the same or different, represent hydrogen or methyl radicals; A 'represents a direct bond or a methylene radical;

  A2 represents a methylene radical; Z represents hydrogen or chlorine; and Q for a radical of the formula:
EMI1. 2nd
 or
EMI1. 3rd
 where R8 is hydrogen or a methyl radical, X is a direct bond or oxygen and the benzene ring Y optionally carries a halogen atom or a trifluoromethyl, CI-o-alkyl or CI-e alkoxy radical as a substituent; as well as the pharmaceutically acceptable acid addition salts thereof. 



   2nd  The ester of claim 1, wherein R 'is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, t-butyl, 1-methyl-2,2- dimethylpropyl, 2,2-dimethylpropyl, I-ethylpropyl, I, l-diethylpropyl or (cyclopentyl) methyl radical or a phenyl radical which optionally carries a methyl or methoxy radical as core substituent; and the benzene ring Y in the radical Q optionally carries a fluorine, chlorine or bromine atom or a trifluoromethyl, methyl or methoxy radical as a substituent. 



   3rd  An ester according to claim 1 or 2, wherein Q is a phenylacetyl, 4-fluoro, 4-chloro or 4-methoxyphenylacetyl, 2-phenylpropionyl, phenoxyacetyl, (3-trifluoromethylphenoxy) acetyl, benzoyl or 4- Chloro, 4-methyl or 4-methoxybenzoyl radical. 



   4th  An ester according to any one of claims 1 to 3, wherein R6 and R7 are both hydrogen or methyl radicals. 



   5.  The ester of claim 1, wherein R 'is an isopropyl, t-butyl, isobutyl or (cyclopentyl) methyl radical; R2 for a radical of the formula R'CO. Is O; R3, R4 and RS represent hydrogen; R6 and R7 both represent hydrogen or methyl radicals; A 'represents a direct bond; A represents a methylene radical; Z represents hydrogen; and Q represents a phenylacetyl, phenoxyacetyl, 2-phenylpropionyl, benzoyl or 4-chlorobenzoyl radical; as well as the pharmaceutically acceptable acid addition salts thereof. 



   6.    The esters 1 - [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol; 1 - [3,4-bis (pivaloyloxy) phenylj-2- [1,1-dimethyl-2- (2-phenylacetamido) ethylamino] ethanol; 1- [3,4-bis (3,3-dimethylbutyryloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol; 1 - [3,4-bis- (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol; 1- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenoxyacetamido) ethylamino] ethanol or 1- [3,4-bis (isovaleryloxy) phenyl] -2- (2-phenylacetamido ) ethylamino] ethanol; as well as the pharmaceutically acceptable acid addition salts thereof according to claim 1. 



   7.  The ester 1- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (4-chlorobenzamido) ethylamino] ethanol or a pharmaceutically acceptable acid addition salt thereof according to claim 1. 



   8th.  Ester according to one of claims 1 to 7, in an optically active form. 



   9.  Esters according to one of claims 1 to 8 in the form of acid addition salts, in which the salt is derived from an inorganic acid such as hydrochloric, hydrobromic, phosphoric or sulfuric acid. 



   10th  Esters according to one of claims 1 to 8 in the form of acid addition salts, in which the salt is derived from an organic acid, such as oxal, wine, milk, fumaric, lemon, vinegar, salicylic, benzoic, ss- Naphthoe, methanesulfonic or adipic acid. 



   11.  Pharmaceutical preparation, characterized in that it contains an ester of formula I or a pharmaceutically acceptable acid addition salt thereof as an active ingredient together with a pharmaceutically acceptable diluent or carrier in a form suitable for topical administration. 



   12.  Preparation according to claim 1, characterized in that it has the form of an ointment, a gel, an aqueous or oily solution or suspension, an emulsion or an aerosol preparation. 



   The invention relates to esters of phenylethylamines which have anti-inflammatory activity when applied topically to an inflammatory focus. 



   It is known that certain 1 - (hydroxyaryl) -2 - [(acylamino) alkylamino] ethanol derivatives have ss-adrenergic stimulant properties (US Pat. No.  3rd 933. 911).  It is also known that various carboxylic acid esters of l- (hydroxyphenyl) -2- (alkylamino) ethanols are sympathomimetic



  Have effects (GB-PS No.  1. 298. 771).  It has now been found, and based on this, that various esters of 1 - (dihydroxyphenyl) -2 - [(acylamino) alkylamino] ethanols (or salts thereof) have unexpected topical anti-inflammatory properties. 



   The invention relates to esters of the general formula:
EMI2. 1
 as well as pharmaceutically acceptable acid addition salts thereof, wherein R 'is a C 1- I alkyl or (C3-6 cycloalkyl) C alkyl radical or a phenyl radical, which is optionally a C 6 alkyl or Cl 6 alkoxy radical as core substituent stands; one of the symbols R2 and R3 represents hydrogen and the other of the symbols R2 and R3 represents a radical of the formula R 'CO. O-, in which R 'has the meaning given above, is; R4 and Ru each represent hydrogen; R6 and R7, which may be the same or different, represent hydrogen or methyl radicals;

  A 'represents a direct bond or a methylrene radical; A2 represents a methylene radical; Z represents hydrogen or chlorine; and Q for a radical of the formula:
EMI2. 2nd
 or
EMI2. 3rd
 is where Rs is hydrogen or a methyl radical, X is a direct bond or oxygen and the benzene ring Y optionally carries a halogen atom or a trifluoromethyl, Ci - alkyl or C1-6 alkoxy radical as a substituent. 



   A special value for R 'if it is for a Cl. l 1-alkyl radical is, for example, a straight-chain Ci. i i-alkyl radical, such as. B.  a methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radical, or a branched chain C3-11 alkyl radical, such as. B.  an isopropyl, isobutyl, t-butyl, 1-methyl-2,2-dimethylpropyl, 2,2-dimethylpropyl, l-ethylpropyl or l, l-diethylpropyl radical, the values being isopropyl, isobutyl and t- Butyl are particularly preferred. 



   A special value for R 'when it stands for a (C3-6-cycloalkyl) -C-s-alkyl radical is, for example, a (cyclopentyl) methyl radical. 



   A special value for a Cl-6-alkyl or C 1-6-alkoxy radical, if it is present as an optional substituent on the benzene ring Y, is, for example, a methyl or methoxy radical. 



   A specific value for the radical R'CO- if A 'is a direct bond is, for example, a pivaloyl, isobutyryl or isovaleryl radical, and a special value for the radical R'CO- if Al is a methylene radical, for example an acetyl radical. 



   A special value for a halogen atom, if it is present as an optional substituent on the benzene ring Y, is, for example, a fluorine, chlorine or bromine atom. 



   A special value for the ring Y is, for example, a phenyl, halophenyl, Cl. 6-alkoxyphenyl, trifluoromethylphenyl or Cl-6-alkylphenyl radical, such as. B.  a 4-chloro, 4-fluoro, 4-methoxy, 3-trifluoromethyl or 4-methylphenyl radical. 



   A special value for Q if it stands for a radical of the formula IV and if X stands for a direct bond is, for example, a phenylacetyl, 4-fluoro-, 4-chloro or 4-methoxyphenylacetyl or 2-phenylpropionyl radical. 



   A special value for Q if it stands for a radical of the formula IV and X stands for oxygen is, for example, a phenoxyacetyl or (3-trifluoromethylphenoxy) acetyl radical. 



   A special value for Q, if it stands for a radical of the formula V, is, for example, a benzoyl, 4-chlorobenzoyl, 4-methylbenzoyl or 4-methoxybenzoyl radical. 



   Special groups of esters of particular interest according to the invention include those compounds of the formula 1 in which: (a) R2 for a radical of the formula R 'CO. Is O- and R3 is hydrogen; (b) R2 for hydrogen and R3 for a radical of the formula R1CO. Is O; (c) A 'represents a direct bond; (d) A 'represents a methylene radical; (e) Z represents hydrogen; or (f) Z represents chlorine; in any case the rest of the radicals R ', R2, R3, R4, R5, R6, R7, R8, A', A2, Z and Q have any of the general or special values given above, in each case also the pharmaceutical permissible acid addition salts thereof are included. 

 

   Another special group of esters according to the invention comprises those compounds of the formula I as defined in one of the groups mentioned above, alone or in combination, and in which R4 and R5 are both also hydrogen; R6 and R7 are both hydrogen or methyl radicals; A2 is a methylene radical; and Q is a radical of formula IV defined above, preferably a phenylacetyl, phenoxyacetyl or 2-phenylpropionyl radical. 



   A particularly preferred group of esters according to the invention comprises those compounds of the formula I as defined together by groups (a) and (c) above, R 1 additionally representing an isopropyl, t-butyl, isobutyl or (cyclopentyl) methyl radical; R4 and R5 are both hydrogen; R6 and R7 both represent hydrogen or methyl radicals; A2 represents a methylene radical; and Q represents a phenylactyl, phenoxyactyl or 2-phenylpropionyl radical. 



   A special acid addition salt of an ester of formula I is such a salt which is derived from an acid which gives a pharmaceutically acceptable anion, such as. B. 



  of an inorganic acid, for example hydrochloric, hydrobromic, phosphoric or sulfuric acid, or of an organic acid, such as. B.  Oxalic, tartaric, lactic, fumaric, citric, vinegar, salicylic, benzoic, ss-naphthoeic, methanesulfonic or adipic acid. 



   It can be seen that an ester of formula I bears at least one asymmetric carbon atom, i. i.  that is, the one that carries the radical -OR4, which is why it can exist in a racemic and in optically active forms. 



  In addition, depending on the nature of the substituents R5, R6, R7 and R6, an ester of the formula I may have up to three additional asymmetric carbon atoms and therefore exist in corresponding additional racemic and optically active forms.  It is pointed out that the invention encompasses the racemic forms of such an ester and also any optically active form with anti-inflammatory activity.  It is generally known how a racemic form can be separated into its optically active forms or how such optically active forms can be obtained by synthesis from optically active starting materials and how the pharmacological properties can be determined by the standard tests given below. 



   Specific esters of formula I are described below in the examples, but the following are particularly preferred: 1 - [3, 4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] -ethanol; 1 - [3,4-bis (pivaloyloxy) phenyl] -2- [1, -dimethyl-2- (2-phenyl-acetamido) ethylamino] ethanol; 1 - [3,4-bis (pivaloyloxy) phenylj-2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol; 1 - [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenoxyacetamido) ethylamino] ethanol; 1 - [3,4-bis (isovaleryloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol; 1 - [3,4-bis (3,3-dimethylbutyryloxy) phenylj-2- [2- (2-phenylacetamido) ethylaminoj ethanol; and the pharmaceutically acceptable acid addition salts thereof. 



   The esters according to the invention can be prepared by all chemical processes which are known to be useful for the preparation of chemically analogous compounds.  These methods consist in that the following five radicals are successively combined by known chemical methods, where R ', R2, R3, R4, R5, R6, R7, A', A2 and Z have the meanings given above: (I) a 2-phenylethyl radical of the formula:
EMI3. 1
 (II) a first imino radical (-NH-); (III) a radical of the formula:
EMI3. 2nd
 (IV) a second imino radical (-NH-); and (V) a radical -Q. 



   The various stages in the assembly of an ester according to the invention can be carried out in any order, using known chemical methods for the synthesis of analogous compounds, and in particular the introduction of the acyl groups R 'CO- and R4 if this stands for something other than hydrogen , at an early stage of the synthesis or as the last stage. 



   The following methods are given as specific, non-limiting examples of such step-by-step chemical syntheses, wherein R ', R2, R3, R4, R5, R6, R7, R8, A1, A2, Q, X, Z and the ring Y are the above Unless otherwise stated, have the meanings indicated: (a) A compound of the formula:
EMI3. 3rd
 or an acid addition salt thereof, in which U stands for a carbonyl radical or a radical of the formula -CHOR4- and W stands for a reductively removable protective group, is reduced.  A particularly suitable reductively removable protective group is, for example, a benzyl radical or a substituted benzyl radical, such as. B.  a 4-methylbenzyl radical. 

  It is clear that the reduction must be carried out under conditions which do not result in a reduction of the carboxylic ester groups, which is why it is preferably carried out with the aid of catalytic hydrogenation, for example with hydrogen in the presence of a palladium (which is preferred), platinum or nickel catalyst a diluent or solvent, such as. B.  Ethanol or water or a mixture thereof. 



  The reduction is expediently carried out, for example, at 1-530 C and can optionally also be carried out under a hydrogen pressure of, for example, up to 4 kg / cm 2. 



   It should be noted that the conditions necessary for the removal of the protective group W in the above process also result in a reduction of the carbonyl radical U, if this is present in the starting material of the formula VIII, so that in such a case an ester of the formula I, in which R4 stands for hydrogen is obtained. 



   The starting materials of formula VIII, wherein U is a radical of the formula -CH. OH-, for example by sodium borohydride reduction of the corresponding aryl ketone of the formula:
EMI4. 1
 where W has the meaning given above, are obtained using similar reduction conditions to those described below in process (e).  Such starting materials of formula VIII can conveniently be made in the same container without any intermediate isolation or purification and used in process (a). 

  The aryl ketones of the formula IX (which are also starting materials of the formula VIII, in which U stands for a carbonyl radical) can in turn be prepared by reacting a corresponding phenacyl halide of the formula:
EMI4. 2nd
 wherein Hal represents a halogen atom with an amino compound of the formula:
EMI4. 3rd
 where W has the definition given above. 



   This reaction is conveniently carried out at or near normal room temperature, for example at 15 to 30 ° C., and in a diluent or solvent, for example ethanol, dioxane or acetonitrile.  You can also in the presence of an acid binding agent such. B.  an alkali metal carbonate or bicarbonate or an excess of the amino compound XI. 



  A particularly suitable value for Hal is a chlorine or bromine atom.  The amino compound of formula XI can be obtained by selective acylation of a diamine of the formula:
EMI4. 4th
 can be obtained with an acylating agent which is structurally different from an acid of the formula Q. OH derives using well known methods.  Alternatively, those starting materials of the formula XI in which W is a benzyl radical can be obtained by reductive alkylation of an amine of the formula:
EMI4. 5
 are obtained by reaction with benzaldehyde in the presence of a suitable reducing agent, such as. B.  Sodium borohydride, under conditions similar to those described below for process (e). 



   The phenacyl halides of the formula X can in turn be obtained by conventional side chain halogenation of the corresponding acylbenzene of the formula X, but Hal being replaced by hydrogen, as described, for example, in Examples 1 and 9 below. 



   Alternatively, the aryl ketones of the formula IX can conveniently be obtained by acylating a dihydroxy compound of the formula:
EMI4. 6
 wherein W has the meaning given above and one of the symbols G 'and G2 represents hydrogen and the other represents a hydroxy radical, can be obtained with an acylating agent which is structurally derived from an acid of the formula RlCO2H, for example with a chloride or bromide of such Acid as illustrated in Examples 7 and 8 below.  The necessary dihydroxy compounds of the formula XIV can in turn be obtained, for example, by acid hydrolysis of a corresponding di-O-acetyl derivative (which can itself be obtained by analogous processes, as described here for esters of the formula I), as illustrated in Example 8 . 

 

   (b) An aryl ketone of the formula:
EMI4. 7
 is reduced. 



   The reduction can be carried out using an agent which is generally for the reduction of aromatic
Ketones is known, but this does not reduce groups of carboxylic esters.  So the reduction with the help of an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, such as. B.  Methanol, ethanol or 2-propanol, leads out (this procedure is preferred) or with
With the help of catalytic hydrogenation, for example with hydrogen in the presence of a palladium, platinum or nickel catalyst, in a diluent or solvent, such as. B.  Ethanol or acetic acid, and in any case at a temperature of, for example, -20 to 30 ° C. and expediently at or near normal room temperature, for example at 15 to 30 ° C.    



   The starting materials of the formula XV can be obtained in a manner analogous to that of the formula IX in process (a) above, by reacting a phenacyl halide of the formula X with the corresponding amino compound of the formula XI, but in which W is hydrogen.  The necessary amino compound can be obtained by selective acylation of a diamine of the formula XII, in which, however, W is hydrogen, as illustrated, for example, in the accompanying examples. 



   Alternatively, the starting materials of formula XV can be obtained in an analogous manner to those of formula IX in process (a) above, namely by acylation of a dihydroxy compound of formula XIV, but in which W is replaced by hydrogen, preferably in the presence of a strong acid to minimize any tendency for N-acylation, for example by using the dihydroxy compound as the hydrochloride, hydrobromide or trifluoroacetic acid salt.  The necessary dihydroxy compounds can be obtained from the corresponding di-O-acetyl derivatives, as described in (a) above, or by hydrogenolysis of the corresponding di-O-benzyl derivatives, as explained in Example 7. 



   (c) A hydroxy compound of the formula:
EMI5. 1
 wherein one of the symbols G 'and G2 stands for hydrogen and the other for a hydroxy radical, is reacted with an acylating agent which is structurally different from an acid of the formula R'. CO2H derives. 



   The reaction is preferably carried out using an acid addition salt of a compound of formula XVI, for example using a hydrogen halide salt, for example hydrogen chloride or hydrogen bromide, or a trifluoroacetate salt so that the N-acylation is kept low. 



   A particularly suitable acylating agent which is structurally derived from one of the above acids is, for example, an acid halide, such as. B.  an acid chloride or bromide, an anhydride or a mixed anhydride with formic acid. 



   The reaction can conveniently in the presence of an inert diluent or solvent such as. B. 



  Acetone, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, acetic acid or trifluoroacetic acid, and expediently carried out at a temperature of, for example, 0 to 100 ° C. 



   It should be noted that the amount of acylating agent used in the above process necessarily depends on the number of acyl radicals to be incorporated. 



   If a compound of formula I wherein R4 is hydrogen is desired, that is a diester, then the above acylation is generally carried out using a stoichiometric amount of an acylating agent and at a temperature in the range, for example, 0 to 60 ° C. and preferably at or near normal temperature, such as. B.  15 to 30 "C. 



   The starting materials of the formula XVI can be obtained by reducing an acetophenone derivative of the formula XIV, in which W represents a benzyl radical, with sodium borohydride in 2-propanol and then catalytically hydrogenolysing the benzyl radical using a method similar to that described in process (a) above. getting produced.  Alternatively, they can conveniently be obtained by conventional acidic or basic hydrolysis of an ester of the formula I in which, for example, R 'is a methyl radical and R4 is hydrogen, in an alcohol, for example methanol, and at a temperature of 1-560 ° C. 

  As yet another alternative, a di-obenzyl ether of the general formula I, but in which the radical R'CO- has been replaced by a benzyl radical and R4 is hydrogen, can be catalytically hydrogenolysed, as described, for example, in Example 17 below. 



   (d) A carbonyl derivative of the formula:
EMI5. 2nd
 with an amine of the formula:
EMI5. 3rd
 condensed under reducing conditions. 



   Particularly suitable reducing conditions are obtained by, for example, an alkali metal borohydride or cyanoborohydride, such as. B.  Sodium borohydride or cyanoborohydride, of which a cyanoborohydride is particularly preferred, is used in an inert solvent or diluent, such as. B.  Acetonitrile, methanol, ethanol or 2-propanol, and at a temperature in the range, for example, from -20 to 30 ° C.    



  If sodium cyanoborohydride is used, the reaction is preferably carried out at or near pH 4, for example in the presence of acetic acid
It is noted that the processes of the general type above are known as reductive alkylations and at least in part by an intermediate of the formula:
EMI5. 4th
   (The -N = CH5 bond is then reduced) and / or the formula:
EMI6. 1
 (The -N = CRS bond and the ketone bond are subsequently reduced).  Such an intermediate of formula XVIII or XIX (or a mixture thereof) can optionally  can be produced and reduced in two separate stages in the above method. 



   The starting materials of formula XVII can be obtained by selenium dioxide oxidation of a compound of the formula:
EMI6. 2nd
 in a suitable solvent, such as. B.  aqueous dioxane can be obtained, where  in the case of compounds of the formula XVII in which R5 is hydrogen, hydrate, acetal or hemiacetal formation follows, in which form they can also be used in process (d) above. 



   Those starting materials of the formula XVII in which R5 is hydrogen can also be obtained by dimethyl sulfoxide oxidation of the corresponding phenacyl bromide of the formula:
EMI6. 3rd
 obtained under conventional conditions, as described, for example, in Example 13 below. 



   The phenacyl bromides of the formula XXI can be obtained by analogy to those of the formula X or by transacylation, as described below under (e). 



   (e) A compound of the formula:
EMI6. 4th
 wherein W 'and W2 together form a direct bond or where W' is hydrogen and W2 is a halogen atom, or a mixture of such compounds is reacted with an amine of formula XIII. 



   It should be noted that compounds of the formula XXII, in which W 'and W2 together form a direct bond, ethylene oxide derivatives of the formula:
EMI6. 5
 and that compounds of the formula XXII, in which W 'is hydrogen and W2 is a halogen atom, are halohydrins of the formula:
EMI6. 6
 in which Hal represents a halogen atom, for example a chlorine, bromine or iodine atom, and that such compounds of the formula XXIII or XXIV or a mixture thereof can easily be obtained by reducing a phenacyl halide of the formula:
EMI6. 7
 where Hal has the meaning given above, using sodium borohydride or aluminum isopropoxide, where appropriate  a spontaneous dehydrohalogenation of the first formed halohydrin of the formula XXIV takes place. 

 

   The above process (e) can be carried out at room temperature, or it can be accelerated or completed by the application of heat, for example by heating to a temperature in the range of 80 to 150 ° C.     It can also be carried out at atmospheric pressure or at an elevated pressure, for example by heating in a sealed container. 



  Finally, it can also be used in an inert diluent or solvent, such as. B.  Methanol, ethanol or 2-propanol. 



   The phenacyl halides of the formula XXV can be obtained by methods analogous to those used for the halides of the formula X and XXI.  So they can be obtained by conventional side chain halogenation of the corresponding acetophenone, which in turn by transacylation of a di-O-acetyl derivative of the formula:
EMI7. 1
 wherein one of the symbols G3 and G4 stands for an acetoxy radical and the other for hydrogen, are obtained by reaction with the sodium salt of the corresponding acid of the formula R '. CO2H at 150-180 "C, as explained for example in Example 14 below. 



   Optically active forms of an ester according to the invention can be obtained by conventional separation of the corresponding racemic form of an ester according to the invention. 



   Said separation can be carried out by reacting a racemic form of an ester of the formula I with an optically active acid and then fractionating the resulting diastereoisomeric salt mixture from a diluent or solvent, such as. B.  Ethanol, then, whereupon the optically active form of the ester of formula I is liberated by treatment under such conditions that hydrolysis of the ester is avoided, for example by anion exchange chromatography.  A particularly suitable optically active acid is, for example, (+) - or (-) - O, O-dip-toluoyl tartaric acid or (-) - 2,3: 4,5-di-O-isopropylidene-2keto-L-gulonic acid. 



   The free base form esters of Formula 1 can be converted to pharmaceutically acceptable acid addition salts by reaction with a suitable acid as defined above and by conventional means which avoid hydrolysis of the ester. 



  Alternatively, if a hydrogen chloride or hydrogen bromide salt is desired, this can conveniently be obtained by stoichiometric amount of the hydrogen halide in situ by catalytic hydrogenation of the corresponding benzyl halide, preferably in an inert solvent or diluent, e.g. ethanol, and at or in the Generated near room temperature. 



   The esters of formula I are expediently used as pharmaceutically acceptable acid addition salts. 



   As already stated, the esters of the formula I have an anti-inflammatory activity when they are applied topically to an inflammation focus, which is why they are particularly suitable for the treatment of inflammatory diseases or inflammatory conditions of the skin in warm-blooded animals. 



   The anti-inflammatory properties of an ester of formula I can be demonstrated by standard tests in which the inflammation of a mouse ear induced by croton oil is inhibited.  The activity of a particular Formula I ester in this assay depends on its particular chemical structure, but certain of the Formula I esters described herein produce significant inflammation inhibition at a topical application dose of 0.30 mg or less per ear . 



   Another standard test, with which the anti-inflammatory properties of an ester of the formula I can be measured, is based on the inhibition of the contact sensitivity of a mouse ear induced by oxazolone.  In this test too, the activity of a particular ester of the formula I depends on its chemical structure, but the special esters of the formula I described here produce a substantial inhibition of inflammation at a topically applied dose of 0.6 mg per ear or fewer. 



   In the above tests, no apparent toxic effects were found at the active doses. 



   In general, an ester of formula I can be used in the treatment of inflammatory diseases or inflammatory conditions of the skin in a manner analogous to that known for the topically active anti-inflammatory agents, such as e.g. B.  the topically active steroids. 



   When applied topically to an inflammation site of the skin of warm-blooded animals, for example humans, an ester of the formula I can be applied topically in a dose in the range from 10 to 15 mg / cm 2.  An equivalent dose of a pharmaceutically acceptable salt thereof can also be used.  If necessary, a dose within this range is repeated at intervals of 4-12 hours, for example.  It should be noted that the total amount of an ester of formula I administered daily depends on the extent and the severity of the inflammation treated. 



   For example, when 1 - [3,4-bis (pivaloyloxy) phenyl] -2- [1,1 - dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol is used for the topical treatment of a hot spot of inflammation on the skin of warm-blooded animals, such as . B.  in humans, then a dose in the range of 1 µg to 5 mg / cm 2 or an equivalent amount of a pharmaceutically acceptable acid addition salt thereof is administered topically, the administration being repeated at intervals of 4-12 hours if necessary. 



   The esters of formula I can be administered in the form of pharmaceutical compositions.  Another
The invention thus relates to pharmaceutical compositions which contain an ester of the formula 1 or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier and which have a form suitable for topical use, such as, for. B.  the form of an ointment, a gel, an aqueous or oily solution or suspension, an emulsion or an aerosol preparation.  A pharmaceutical composition according to the invention may contain 0.1 to 10% (w / w) of an ester of formula I or an equivalent amount of a pharmaceutically acceptable acid addition salt thereof.  In the following, they are referred to as an active component. 

 

   The pharmaceutical compositions can be prepared by methods known per se in the art, using conventional pharmaceutically acceptable diluents or carriers. 



   A particular ointment preparation is made by adding an active ingredient as defined above in a suitable organic diluent, such as. B. 



  soft paraffin, if necessary  in the presence of an emulsifier and / or thickener, such as. B.  Sorbitan monostearate, dispersed. 



   A particular gel preparation is made by using a gelling agent such as. B.  Carboxypolymethylene, to a solution of an active ingredient as defined above in a suitable organic solvent, such as. B.  Isopropyl alcohol, admits. 



   A certain emulsion preparation, such as. B.  a cream or lotion is made by mixing an active ingredient as defined above with a suitable conventional emulsifier system and water. 



   A pharmaceutical composition according to the invention can contain, in addition to an active ingredient as defined above, at least one further known pharmaceutical agent which is selected from corticosteroids, such as. B.  Fluocinolone acetonide, prednisolone, flumethasone pivalate, betamethasone valerate, hydrocortisone or dexamethasone; Phosphodiesterase inhibitors, such as. B. 



  Theophylline or caffeine; antibacterial agents, such as. B. 



  Oxytetracycline, gentamicin, neomycin, gramicidin, chlorhexidine or cetyltrimethylammonium bromide; Antifungal agents, such as. B.  Griseofulvin or nystatin; Antihistamines such as B.  Diphenhydramine or chlorphenamine; local anesthetics, such as B.  Amylocaine, benzocaine or procain; and emollients such as B.  Calomin.  In addition, the compositions may also contain conventional excipients such as e.g. B.  Dyes, gelling agents or protective agents. 



   The invention is illustrated by the following examples, in which: (I) unless otherwise stated, all processes were carried out at room temperature (in the range of 18-26 C) and at atmospheric pressure and all evaporations were carried out by rotary evaporation under reduced pressure; (11) the possibly  communicated infrared spectroscopy data (IR) in the form of absorption values (u max. ) are given for characteristic radicals; (111) the possibly  reported nuclear magnetic resonance data (NMR) in the form of chemical shifts (δ values) for characteristic protons, relative to tetramethylsilane (TMS) as standard, determined in d6-DMSO as solvent (unless otherwise stated) and at 100 MHz ;

   and (IV) the  reported yields are purely illustrative and are not to be regarded as the maximum achievable. 



   example 1
A solution of 2.5 g of 2- {N-benzyl-N- [2- (2-phenylacet am ido) ethyl] amino) 3 ', 4'-bis (pivaloyloxy) acetophenone hydrobromide in 50 ml of a mixture 70% (v / v) ethanol in water was hydrogenated for 18 hours under a pressure of 3.5 kg / cm 2 at room temperature using 0.8 g of palladium-charcoal above.  The catalyst was separated by filtration and the filtrate was evaporated.  Trituration of the residue with 30 ml of ether containing a few drops of ethanol gave 1.7 g of l- [3,4-bis (piva loyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol as the hydrobromide , Mp 111-113 "C (hemihydrate). 



   The acetophenone derivative used as the starting material was obtained as follows:
A solution of 2.63 g of 2-bromo-3t, 4'-bis (pivaloyloxy) acetophenone and 3.7 g (2 molecular equivalents) of N- [2- (benzylamino) ethyl] -2-phenylacetamide in 20 ml Dioxane was stirred overnight at room temperature.  The reaction mixture was diluted with 200 ml of dry ether, and a precipitation of N- [2- (benzylamino) ethyl] 2-phenylacetamide hydrobromide was separated.  The ethereal solution was washed 3 times with 50 ml of water and 100 ml of brine, dried over MgSO4 and filtered.  A fresh solution of saturated ethereal hydrogen bromide was then added to the filtrate until the solution was just acidic. 

  After 18 h at 0-5 "C the precipitate was collected, 2- {N-benzyl-N- [2- (2-phenyl acetamido) ethyl] amino} -3 ', 4'-bis (pivaloyloxy) acetophenone- hydrobromide was obtained as a crude solid.  Crystallization of part of the crude solid from ethyl acetate gave analytically pure material with an mp of 176-178 "C.    



   The required 2-bromo-3 ', 4' -bis (pivaloyloxy) acetophenone starting material was obtained as follows:
A suspension of 13.1 g (0.08 mol) of 3,4-dihydroxyacetophenone in 320 ml of chloroform was cooled to 0-5 "C in an ice bath.  A solution of 19.2 ml (0.16 mol) of pivaloyl chloride in 80 ml of chloroform and a solution of 22.2 ml (0.16 mol) of triethylamine in 80 ml of chloroform were simultaneously added dropwise to the stirred suspension over a period of 10 minutes.  The reaction mixture was stirred for a further hour at 0-5 "C and then poured into a mixture of 100 ml of 2N hydrochloric acid and 200 g of ice.  The mixture was extracted 3 times with 150 ml of chloroform, and the extracts were washed successively with 100 ml of water, 100 ml of 10% (w / v) sodium carbonate solution, 100 ml of water and 100 ml of brine. 

  After drying over MgSO4, the combined extracts were evaporated to give 23.1 g of crude 3,4-bis (pivaloyloxy) acetophenone as an oil which was used without purification. 



   A solution of 3.15 ml (0.061 mol) of bromine in 50 ml of chloroform was added dropwise at room temperature to a stirred solution of 19.5 g (0.061 mol) of 3 ', 4'-bis (pivaloyloxy) acetophenone and 8.2 ml ( 0.06 mol) of t-butyl acetate in 150 ml of chloroform containing a catalytic amount (0.2 g) of anhydrous aluminum chloride was added.  After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, 75 g of chromatographic silica gel was then added and the mixture was evaporated in vacuo. 



  The remaining solid was deactivated at the top of a column of dry chromatographic silica gel (1 kg, previously by adding 10% w / w water and then with 10% (v / w) of a 5% (v / v) solution of ethyl acetate in Equilibrated toluene) abandoned.  The column was developed by elution with 1.11 of a 5% (v / v) solution of ethyl acetate in toluene.  The column was then eluted twice with 500 ml of ethyl acetate each time and the fractions were examined by thin layer chromatography (TLC) (on silica plates, developed in a 50% (v / v) mixture of ethyl acetate and toluene).  The latter fractions were pooled and evaporated. 

  This gave 14.2 g of 2-bromo-3 ', 4'-bis (pivaloyloxy) acetophenone as an oil, which crystallized rapidly, giving a solid with an mp of 64-66 "C. 



   The phenylacetamide derivative used as the starting material was obtained as follows:
A mixture of 100 g (0.61 mol) of ethylphenylacetate and 120 ml (1.86 mol) of ethylenediamine was heated on a steam bath for 4 days.  Excess ethylenediamine was removed under reduced pressure and the residue was dissolved in 500 ml of water.  Any insoluble material was removed by filtration.  Evaporation of the filtrate gave 96.8 g of crude N- (2-aminoethyl) -2-phenylacetamide, which was used without purification. 

 

   67.5 g (0.637 mol) of benzaldehyde was added to a solution of 113.5 g (0.637 mol) of N- (2-aminoethyl) -2-phenylacetamide, and the mixture was stirred at room temperature for 18 hours.  24.2 g of sodium borohydride was added in portions and the reaction mixture was stirred for an additional 1.5 hours.  Acetic acid was then added until excess borohydride was destroyed.  The reaction mixture was then made alkaline by adding 2N sodium hydroxide solution and extracted 3 times with 500 ml of ethyl acetate each time.  The extracts were washed with 300 ml of brine, dried over MgSO4 and filtered.  Hydrogen chloride gas was bubbled through the ethyl acetate until it was acidic (pH - 2). 

  After about 4 hours at 0 ° C., the precipitate was collected, 46.2 g of N- [2-benzylamino) ethyl] -2-phenylacetamide hydrochloride, mp 183 to 185 ° C., being obtained. 



   The free base was released from 15 g of the hydrochloride by alkalizing a solution in 150 ml of water with solid sodium carbonate.  The aqueous mixture was extracted 3 times with 100 ml of ethyl acetate each time, and the extracts were dried over MgSO4 and evaporated to give 13.0 g of N- [2- (benzylamino) ethyl] -2-phenylacetamide as an oil, which was slowly added crystallized. 



   Example 2
A suspension of 2.0 g of 2- {N-benzyl-N- [2- (2-phenyl acetamido) ethyl] amino) -3 ', 4' bis (pivaloyloxy) acetophenone in 20 ml of 2-propanol was added - 10 C cooled and 0.34 g of sodium borohydride were added in two portions, with a portion of 4 ml of methanol being added in between.  After 30 min at -10 ° C., 150 ml of a saturated aqueous solution of sodium chloride were added, and the mixture was extracted 3 times with 80 ml of ether each time.  Evaporation of the ethereal extracts dried over MgSO4 gave 1.65 g of l- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) -N-benzylethylamino] ethanol, which was purified in 40 ml of ethanol was dissolved. 

  To this solution was added 0.37 ml (0.0031 mol) of benzyl bromide, and the mixture was then hydrogenated in the presence of 0.4 g of 10% palladium-charcoal at atmospheric pressure and at room temperature for 2 hours.  The catalyst was separated and washed with 10 ml of ethanol, and the ethanol washes and the reaction solution were evaporated together.  The residue was triturated with 20 ml of ether which contained a few drops of ethanol, 1.2 g of 1-13,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol- hydrobromide, mp 110-115 "C, which was identical to that of Example 1. 



   Example 3
A solution of 0.68 g (0.002 mol) of 3 ', 4'-bis (pivaloyloxy) phenylglyoxal and 0.41 g (0.002 mol) of N- (2-amino-2-methylpropyl) -2-phenylacetamide in 15 ml of methanol became 18 st stirred at room temperature.  The reaction mixture was stirred and cooled to - I C C and 0.23 g (0.003 mol) sodium borohydride was added in portions. 



  After the addition was complete, the mixture was stirred at -10 ° C. for a further 45 min.  100 ml of saline was then added and the mixture was extracted 3 times with 60 ml of ether at room temperature.  After washing with 50 M saline and drying over MgSO4, the ethereal extracts were evaporated, giving 0.64 g of l-j3,4-bis (pivalloyloxy) phenyl] -2- [2,2-dimethyl-2- ( 2-phenylacetamido) ethylamino] ethanol were obtained as an oil.  A solution of this oil in 15 ml of ethanol was hydrogenated with 1.48 lj1 (0.0012 mol) of benzyl bromide in the presence of 0.3 g of 10% palladium-charcoal at atmospheric pressure and at room temperature for 2 hours. 

  The catalyst was then separated by filtration and washed with 5 ml of ethanol, after which the filtrate and the washing liquids were evaporated.  Trituration of the residue with 300 ml of ether at 0 C gave 1- [3,4-bis (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenylacetamido) ethylamino] ethanol-hydrobromide in a yield of 48%.  An analytically pure sample was obtained by crystallization of the hydrobromide from water and had an mp of 134-136 C.    



   The starting phenylglyoxal derivative was obtained as follows:
A solution of 2 g of 2-bromo-3 ', 4'-bis (pivaloyloxy) aceto phenone in 10 ml of dimethyl sulfoxide was left to stand at room temperature for 18 hours and then poured into ice / water and extracted 3 times with 60 ml of ether.  The ether solution was washed with 50 ml water and 50 ml brine, dried over MgSO4 and evaporated to give 1.8 g 3 ', 4' - bis (pivaloyloxy) phenylglyoxal as an oil; u max. : 1760 cm- '(ester
EMI9. 1
 1690 cm- '(-CO. CHO); 8 (CDCb): 8.2-7.1 (complex, aromatic -H), 1.35 (18H, singlet -C. CH3). 



   The starting N- (2-amino-2-methylpropyl) -2-phenylacet amide was obtained in a manner similar to that described in Example 1 for N- (2-aminoethyl) -2-phenylacetamide, but with 1.2 -Diamino-2-methylpropane was used.  It had an mp of 55-59 "C (mp 68-71" C after crystallization from aqueous ethanol). 



   Example 4
The procedure described in Example 1 for 1 - [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol hydrobromide was repeated except that the corresponding 2- {N-benzyl- N- [2- (substituted amido) ethyl] amino} -3 ', 4'-bis (acyloxy) acetophenone hydrobromide was hydrogenated.  In this way, the following hydrobromides of compounds of the formula:
EMI9. 2nd
 receive. 



  No.  Substituent position R 'Q Characteristic properties (ring B)
1 3,4 2,2-dimethylpropyl phenylacetyl mp 141-142 "C (hydrate) 2 3.5 t-butyl phenylacetyl oli 3 3.5 2,2-dimethylpropyl phenylacetyl Ö12 4 3.5 cyclopentylmethyl phenylacetyl 01) 5 3, 4 t-butyl benzoyl mp 166-169 "C (hydrate) 6 3.4 t-butyl (p-fluorophenyl) acetyl mp 174-175" C (hemihydrate)
Remarks:
1.    NMR: (d6-DMSO) 8.178 (IH, -NHCO-), 7.2-6.7 (8H, complex, aromatic protons), 5.08 (111, broad singlet, -CHO11), 3.4-2 , 68 (complex, -CH2-), 1.1 8 (18H, singlet, C-CH3). 



   2nd  NMR: (d6-DMSO) 8.38 6 (1H, -NHCO-), 7.4-6.7 8 (8H, complex, aromatic protons), 5.0 (1H, broad singlet, -CH. OH-), 3.7-2.68 (complex, -CH2-), 2.45 (4H, singlet, -CH2CO-), 1.06 # (18H, singlet, C-CH3). 



   3rd  NMR: (d6-DMSO) 8.38 # (1H, -NHCO-), 7.4-6.75 # (8H, complex, aromatic protons), 5.0 (1H, broad singlet, -CH. OH-), 3.9 to 2.7 6 (complex, -CH2-), 2.5 # (4H, complex, -CH2CO-), 2.0-1.08 (-CH2-, cyclopentyl ring). 



   The starting acetophenone hydrobromides were prepared in a manner similar to that for 2- {N-benzyl-N- [2- (2-phenylacetamido) ethyl] amino) -3 /, 4'-bis (pivaloyloxy) aceto- phenone hydrobromide is described in Example 1.  In this way, the following hydrobromides of acetophenone derivatives of the formula:
EMI10. 1
 receive. 



  No.  Substituent position (ring B) R 'Q Fp (C)
3,4 2,2-dimethylpropyl phenylacetyl 110-115 2 3.5 t-butyl phenylacetyl 174-176 3 3.5 2,2-dimethylpropyl phenylacetyl 132-134 4 3.5 cyclopentylmethyl phenylacetyl 100-105 (hydrate) 5 3 , 4 t-butyl benzoyl 200-202 6 3.4 t-butyl (p-fluorophenyl) acetyl 182-184
The above acetophenone starting materials in turn were obtained by reacting the corresponding 2-bromoacetophenone derivative and the corresponding N-benzylaminoamides. 



   The following new 2-bromoacetophenone derivatives were obtained from the corresponding acetophenones in a similar manner to that described in Example 1 for 2-bromo-3 ', 4'bis (pivaloyloxy) acetophenone: 2-bromo-3', 5 ' -bis (cyclopentylacetoxy) acetophenone, oil, NMR: 8 (CDCh): 7.8-7.1 (3H, complex, aromatic protons), 4.45 (2H, singlet, -COCH2Br), 2.58 (4H , Singlet, CH-CH2-CO), 2.4-2.1 (18H, complex, cyclopentyl ring protons); 2-bromo-3 ', 5'-bis (pivaloyloxy) acetophenone, m.p. 112-114 C; 2-bromo-3 ', 5' -bis (3,3-dimethylbutyryloxy) acetophenone, mp 37-39 C;

   2-Bromo-3 ', 4'-bis (3,3-dimethylbutyryloxy) acetophenone, oil, NMR: 8 (CDCI3): 8.0-7.1 (3H, complex, aromatic protons), 4.42 (2H , Singlet, -COCH2Br), 2.46 (4H,
EMI10. 2nd


 <tb> singlet, <SEP> -C-CH2-), <SEP> 1.15 (18H, <SEP> singlet, <SEP> -C-CH3)
 <tb> The following new N-benzylaminoamides required as starting materials were obtained in a manner similar to that described for N- [2- (benzylamino) ethyl] -2-phenylacetamide in Example 1: N- [2- (Benzylamiono) ethyl] benzamide, mp 54-56 C, from ethyl benzoate; N- [2-Benzylamiono) ethyl] -2- (p-fluorophenyl) acetamide, mp 194-195 C (hydrochloride), from ethylphenylacetate. 



   Example 5
1.07 g of N- [2- (benzylaminoethyl] -2-phenylacetamide was added to a solution of 0.83 g of 2-bromo-3'-pivaloyloxymethyl4'-pivaloyloxyacetophenone in 25 ml of dioxane.  The solution was stirred at room temperature for 16 hours and then heated to 80 ° C. for 5 minutes.  After dilution with 150 ml ether, the solution was washed successively with 10% sodium carbonate solution, water and saturated saline.  The ethereal solution was dried over MgSO4, filtered and evaporated using crude 2- {N-benzyl-N- [2- (2-phenylacetamido) ethyl] amino} -3'-pivaloyloxymethyl-4'-pivaloyloxy-acetophenone as an oily residue was obtained, which was dissolved in 25 ml of methanol. 



  150 mg of sodium borohydride were added in portions to the methanolic solution which had been cooled to -10.degree.  The mixture was stirred for 1 hour and then acidified to pH 4-5 by adding glacial acetic acid.  The methanol was removed by evaporation and the residue was suspended in 50 ml of water and made alkaline to pH 9-10 by the addition of 2N ammonia solution.  The watery.  The solution was then extracted 3 times with 50 ml of ether each time, and the combined extracts were dried over MgSO4 and evaporated.  The residue was dissolved in 50 ml of ethanol and the solution was hydrogenated in the presence of 50 mg of 10% palladium-charcoal at atmospheric pressure and at room temperature for 24 hours.  

  After the catalyst had been separated off, the solution was evaporated to give 1 - [3-pivaloyloxymethyl-4-pivaloyloxyphenyl] -2- [2- (2-phenyl-acetamido) ethylamino] ethanol as an oil.  The oil was dissolved in the smallest amount of isopropyl acetate and the solution was acidified to pH 4-5 by the dropwise addition of methanesulfonic acid.  The methanesulfonic acid salt of 1- [3-pivaloyloxymethyl-4-pivaloyloxyphenyl] 2- [2- (2-phenylacetamido) ethylamino] ethanol was thus obtained in a 24% yield as a gum.  Crystallization from isopropyl acetate gave a product with an mp of 105-107 C. 



   Example 6
In a similar manner to that described in Example 3 for 1- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol, 3'-pivaloyloxymethyl 4 ' -pivaloyloxyphenylglyoxal and N- (2-aminoethyl) -2-phenylacetamide the compound 1- [3-pivaloyloxyphenyl-4-pivaloxyphenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol in the form of the methanesulfonate salt, mp 105-107 C. 



   The glyoxal derivative used as the starting material was obtained as follows: 3 '-pivaloyloxymethyl-4' -pivaloyloxyphenylglyoxal was obtained in a manner similar to that described in Example 3 for 3 '4' - bis (pivaloyloxy) phenylglyoxal, but from 2-bromo -3'-pivaloyloxymethyl-4'-pivaloyloxyacetophenone was assumed, except that the reaction mixture was left at room temperature for 6 days and not for 18 hours.  The glyoxal had the following data: NMR: 8 (DMSO-d6) 1.1 (9H, singlet -C-CH3), 1.3 (9H, singlet -C-CH3), 6.7-8.0 (complex, aromatic H), 8.3 (singlet -COCHO). 



   Example 7
Using a procedure similar to that described in Example 2, the following diesters of the formula:
EMI11. 1
 obtained in yields of 45-80% (as their hydrobromide salts) by reducing the corresponding acetophenone derivatives of the formula:
EMI11. 2nd
 with an excess of sodium borohydride and subsequent catalytic hydrogenation in the presence of a stoichiometric amount of benzyl bromide, the hydrogen bromide salt being formed in situ: compound no. 

  Substituent position R 'Fp (C) (ring B)
3.4 i-Pr foam *
2 3.4 I ethyl propyl 70-75
3 3.4 t Bu 134-136
4 3,4 2,2-dimethylpropyl 105-111
5 3.4 1 - (2-methylpropyl) -3-methylbutyl 79-82
6 3.4 l-methyl-2,2-dimethylpropyl 109-110
7 3.4 Ph 113-117 (dec. )
8 3.4 4-MeO-Ph 168-170
9 3.4 i-Bu 80-85 10 3.5 t-Bu 173-175 11 3.5 l-methyl-2,2-dimethylpropyl 150-152 12 3.5 4-MeO-Ph 140-145 13 3 , 5 Cyclopentylmethyl 160-162 14 3.5 2,2-dimethylpropyl 124-127 15 3.5 i-Pr 106-110 * Isolated as a foam with NMR: o (DMSO) 7.4-7.1 (8H, complex , aromatic protons).  5.0 (1H, complex, CH. OH).  3.6-3.0 (6H, complex, CH2NH and CH2CONH); 3.0-2.6 (2H, complex, # CHCO); 1.26, 1.20 (18H, two singlets, (CH3) 2CH and -NHC (CH3) 2-). 



   The necessary ketone starting materials of the formula XXX were obtained by acylation of the corresponding phenol derivative of the formula:
EMI12. 1
 obtained as a hydrobromide, by reaction with the corresponding acyl chloride or bromide of the formula R "I. CO. Cl or R. CO. Br.     This acylation is illustrated by the following preparation of the acetophenone intermediate for compound 10 above:
1.85 ml of pivaloyl chloride was added to a suspension of 1.8 g of 2- [1,1-dimethyl-2- (2-phenylacetamido) ethyl] amino3 ', 5' -dihydroxyacetophenone hydrobromide in 10 ml of trifluoroacetic acid.  The mixture was stirred at room temperature for 5 minutes and then heated to reflux for 45 minutes.  The reaction mixture was then evaporated and the oily residue was triturated with 100 ml ether and 1 ml ethanol. 

  The mixture thus obtained was then cooled to 0-5 "C. for 18 hours, a precipitate of 1.3 g of 2- [1,1-dimethyl-2- (2-phenylacetamido) ethyl] amino 3 ', 5' -bis (pivaloyloxy) acetophenone trifluoroacetate, mp 155-l560C. 



   Using a similar procedure, the following acetophenone derivatives of formula XXX were obtained in 30-70% yields as their trifluoroacetate salts. 



  Intermediate product for substituent position R0 Fp (C) Compound no.  (Ring B)
1 3.4 i-Pr 136-138
2 3.4 l ethyl propyl 140-142
3 3.4 t Bu 205-208
4 3,4 2,2-dimethylpropyl 112-115
5 3.4 1- (2-methylpropyl) -3-methylbutyl 130-135
6 3.4 1 -methyl-2,2-dimethylpropyl 190-194
7 3.4 Ph 110-111
8 3.4 4-MeO-Ph 125-130
9 3.4 i-Bu 140-141 II 3.5 2-methyl-2,2-dimethylpropyl 195-200 12 3.5 4-MeO-Ph 90-95 (dec. ) 13 3.5 cyclopentylmethyl 175-178 14 3.5 2,2-dimethylpropyl 148-154 15 3.5 i-Pr 175-180
The phenol starting materials of formula XXXI were obtained as follows:
1.    2- [1,1-dimethyl-2- (2-phenylacetamido) ethyl] amino-3 ', 4'-dihydroxyacetophenone:

  :
A solution of 5.24 g of 2-bromo-3 ', 4'-bis (benzyloxy) ace-tophenone and 5.5 g of N- (2-amino-2-methylpropyl) -2-phenylacetamide in 25 ml of dioxane became 2 st stirred at room temperature.  The reaction mixture was diluted with 200 ml of dry ether and the precipitated N- (2-amino-2-methylpropyl) -2-phenylacetamide hydrobromide was separated off by filtration.  The ethereal filtrate was washed 3 times with 50 ml of water and 100 ml of brine and dried over MgSO4, after which a fresh solution of saturated ethereal hydrogen bromide was added until the solution was just acidic.  After 18 hours at 0-5 "C, the precipitate formed was collected. 

  6.85 g of 2- [11 dimethyl-2- (2-phenylacetamido) äthy1jamino-3 ', 4' -bis (benzyloxy) acetophenone hydrobromide as an oil, mp 155-160 "C, were obtained.  5.0 g of this hydrobromide was dissolved in 300 ml of absolute ethanol and the solution was hydrogenated at atmospheric pressure using 3.0 g of 10% (w / w) palladium-charcoal as a catalyst. 



  After hydrogen uptake ceased (approximately 3 hours) the catalyst was removed by filtration and the ethanolic filtrate was evaporated at a temperature below 30 ° C.  3.7 g of 2- [1,1-dimethyl-2- (2 phenylacetamido) ethyl] amino-3 {, 4 '-dihydroxyaceto-phenone hydrobromide were obtained as a foam, which was used directly for the further acylation. 



   2nd    2- [1,1-dimethyl-2- (2-phenylacetamido) ethyl] amino-3 ', 5'-dihydroxyacetophenone:
This compound was obtained as a foam which was suitable for further acylation in a 98% yield by a similar procedure, but using 2-bromo 3 ', 5'-bis (benzyloxy) acetophenone and N- (2-amino -2-methylpropyl) -2-phenylacetamide was started and in between 2- [1,1-dimethyl-2- (2-phenylacetamido) ethyl] amino-3 ', 5'-bis (benzyloxy) acetophenone hydrobromide was isolated, mp 150-153 "C. 

 

   The N- (2-amino-2-methylpropyl) -2-phenylacetamide was obtained as follows:
A solution of 8.8 g of 1,1-dimethylethylenediamine in 250 ml of ether was added over 2 hours to a stirred solution of 15.4 g of phenylacetyl chloride in 250 ml of ether.  The mixture was stirred for a further 2 hours at room temperature.  The solid was separated by filtration and dissolved in 150 ml of warm water.  The solution obtained was filtered.  The filtrate was made alkaline by adding an excess of 50 ml of saturated aqueous sodium carbonate solution and then extracted 3 times with 250 ml of chloroform each time. 



  The extracts were dried over MgSO4 and evaporated to give an oil which crystallized when a 1: 1 by volume mixture of ether and petroleum ether (60 to 80 ° C.) was added.  13.1 g of N- (2-amino-2-methylpropyl) -2-phenylacetamide, mp 68-71 ° C. (after recrystallization from aqueous methanol), were behavior. 



   Example 8
Using a procedure similar to that described in Example 2, the following diesters of the formula:
EMI13. 1
 obtained in yields of 30-65% (as their hydrobromide salts) by reducing the corresponding acetophenone derivative of the formula:
EMI13. 2nd
 with an excess of sodium borohydride, an alcohol of the formula:
EMI13. 3rd
 was obtained, which was then hydrogenolyzed in the presence of benzyl bromide, the hydrogen bromide salt being formed in situ: Compound R10 Fp (C) No. 



   1 n-Pr 102-104
2 i-Pr 116-117
3 heptyl oil (a)
4 i-Bu 124-128
5 1-Ethylpropyl 102-105
6 1 - (2-Methylpropyl) -3-methylbutyl 98-105
7 l-methyl-2,2-dimethylpropyl 111-114
8 1-ethyl-2,2-dimethylpropyl oil (b)
9 I, l-diethylpropyl foam (c) 10 Ph oil (d) 11 4-Me-Ph foam (e) 12 # 4-MeO-Ph oil (f)
Remarks:

   + (a) Isolated as an oil; NMR #: 9.0-8.5 (2H, broad, NH2); 8.32 (1H, broad, NHCO); 7.5-7.1 (8H, singlet, aromatic protons); 5.0 (1H, doublet, CHOH); 3.6-2.8 (complex, CH2NH and CH2CONH); 2.5 (4H, multiplet, CH3 (CH2) 5CH2CO); 1.8-1.0 (20H, complex, CH3 (CH2) sCH2CO; 0.88 (6H, broad triplet, CH3 (CH2) sCH2CO); + (b) isolated as oil: NMR #: 9.0-8 , 5 (2H, broad, NH2); 8.3 (111, broad, NHCO); 7.6-7.0 (8H, complex, aromatic protons); 5.05 (1H, doublet, CHOH); 3, 6-2.7 (6H, complex, CH2NH and CH2CONH); 2.26 [2H, triplet (J 7 c / s), CH-CO]; 1.65 [(4H, triplet (J 7 c / s) , CH2-CH-CO]; 1.04 (18H, singlet, (CH3) 3C);

   0.9 (6H, triplet, CH3CH2); + (c) isolated as foam: NMR #: 8.9-8.5 (2H, complex, NH2); 8.35 (1H, complex, NHCO); 7.4-7.1 (8H, complex, aromatic protons); 5.0 (1H, doublet, CHOH); 3.6-2.8 (8H, complex, CH2NH and CH2CONH); 1.85-1.20 [12H, complex, (CH3CH2) 3C. CO]; 1.1-0.5 [18H, complex, (CH3CH2) 3C. CO]; + (d) isolated as oil: NMR #: 9.0-8.6 (2H, broad NH2); 8.5 (1H, broad, NHCO); 8.1-7.1 (18H, complex, aromatic protons); 5.1 (1H, doublet, CHOH); 3.6-2.9 (complex, CH2NH and CH2CONH); + (e) isolated as foam; NMRG: 9.0-8.5 (2H, broad, NH2); 8.38 (1H, broad, NHCO); 8.0-7.0 (1611, complex, aromatic protons); 5.06 (1H, doublet CHOH); 3.6-2.8 (8H, complex, CH2NH and CH2CONH);

   2.34 (6H, singlet, 4-CH3Ph); (f) isolated as oil: NMR #: 8.35 (1H, broad, NHCO); 8.0-6.8 (1 6H, complex, aromatic protons); 5.2 (1H, Doublet, CH. OH); 3.8 (6H, singlet, 4-CH3-O-Ph); 3.7-2.9 (8H, complex, CH2NH and CH2CONH).    



   The necessary ketone starting materials of formula XXXIII were obtained in a manner similar to that of formula XXX in example 7, namely by acylation of 2- {N-benzyl-N- [2- (2-phenylacetamido) ethyl] amino} -3 ', 4'-dihydroxyacetophenone hydrobromide, either by using the corresponding acyl halide in trifluoroacetic acid solution (method A as described in example 7) or by using a mixture of the acyl chloride, the corresponding alkane or arenic acid and hydrogen chloride (method B). 



   Method B is illustrated by the following preparation of the intermediate for compound 1 above:
A mixture of 1.0 g of 2- {N-benzyl-N- [2- (2-phenylacetamido) ethyl] amino) -3 ', 4'-dihydroxyacetophenone hydrobromide and 6 ml of butyric acid were added at room temperature saturated with gaseous hydrogen chloride for 3 min. 



  6 ml of butyryl chloride was then added and the mixture was stirred at 90-95 ° C for 1.5 hours to give a clear solution after about 5 minutes.  The solution was then concentrated to half volume by evaporation under reduced pressure and the residue was diluted with 25 ml of ether.  This gave 0.65 g of 2- {N benzyl-N- [2- (2-phenylacetamido) ethyl] amino) -3 ', 4'bis (butyryloxy) acetophenone hydrochloride as a solid precipitate, mp 115-117 C. .    



   Using these methods with the corresponding acyl halides, the following ketone derivatives of formula XXXIII were obtained in yields of 35-75% as their trifluoroacetate salts (method A) or hydrochloride salts (method B): intermediate for R "'acyclization method Fp compound no.     (C)
2 i-Pr B 115-117
3 heptyl A oil (a)
4 i-Bu B foam (b)
5 l ethyl propyl A oil (c)
6 1- (2-methylpropyl) -3-methylbutyl A foam (d)
7 l-methyl-2,2-dimethylpropyl A oil (s)
8 1-ethyl-2,2-dimethylpropyl A Ol (f)
9 1,1-diethyl propyl A oil (g) 10 Ph A 173-176 II 4-Me-Ph A 155-160 12 4-MeO-Ph A 149-154
Remarks: (a) Isolated as oil: NM Ro: 8.55 (111, broad, NHCO); 8.0-7.0 (8H, complex, aromatic protons); 5.05 (2H, broad); 4.4 (2H, broad);

   3.8-3.0 (complex, CH2CO and CH2NH); 2.5 [4H, multiplet, CH3 (CH2) sCH2CO]; 1.8-1.0 [20H, complex CH3 (CH2) 5CH2CO]; 0.85 [6H, triplet, CH3 (CH2) 5CH2CO]; (b) isolated as a foam of satisfactory purity according to IR spectroscopy and thin layer chromatography analysis (TLC); (c) isolated as oil: NMR #: 8.45 (1 H, broad triplet, NHCO); 8.0-7.1 (8H, complex, aromatic protons); 4.95 (2H, singlet); 4.36 (2H, singlet); 3.8-3.0 (complex, CH2CO and CH2NH):

   2.5 (DMSO + 2H, complex, #CHCO);
1.65 [8H, quartet, (CH3CH2) 2CHCO]; 0.98 [12H, triplet, (CH3CH2) 2CHCO]; (d) isolated as a foam: NMRG: 8.5 (1H, broad, NHCO); 8.0-7.0 (8H, complex, aromatic protons); 4.95 (2H, singlet); 4.38 (2H, singlet); 4.2-3.0 (complex, CH2NH and CH2CO); 4.2-1.7 (DMSO + ester = CH-) (24H, multiplet, CH3); (e) Isolated as oil: N MR8: - 9.50 (1H, broad, NH); 8.50 (1H, broad, NHCO); 8.0-7.0 (8H, complex, aromatic protons); 5.05 (2H, singlet, PhCH2N); 4.40 (2H, singlet, COCH2N); 3.6-3.0 (complex, NCH2CH2NH);

   2.5 [complex, -CH (CH3) CO-]; 1.15 (6H, doublet, -CH (CH3) CO-; (f) isolated as oil: NMR #: - 8.50 (1 H, broad, NHCO); 8.0-7.0 (8H, complex , aromatic protons); 5.05 (2H, singlet, PhCH2N); 4.40 (2H, singlet, COCH2N); 3.6-3.0 (complex, NCH2CH2NH); 2.3 [2H, triplet, CH3CH2. CH (CH3) 2. CO]; 2.0-1.2 [complex, CH3CH2. CH (CH3) 2. CO]; 1.04 and 0.9 [24H, singlet and triplet CH3CH2. CH (CH3) 2. CO]; (g) isolated as an oil of satisfactory purity as determined by IR or TLC analysis. 



   The required phenol starting material was obtained as follows:
3 ', 4'-bis (acetoxy) -2-bromoacetophenol was reacted with N- [2 (benzylamino) ethyl] -a-phenylacetamide using a procedure similar to that described in Example 1 for the analog pivaloyloxy derivative, wherein 2- {N-Benzyl-N- [2- (2-phenylacetamido) ethyl] amino} -3 ', 4' bis (acetoxy) acetophenone was obtained, which was isolated as the free base and converted into the hydrochloride salt with ethereal hydrogen chloride.  A solid was obtained, mp 140-145 C.  This hydrochloride salt was dissolved in 5 ml of methanol, the 2% (wt. / Vol. ) Contained hydrobromic acid and the solution was heated to reflux for 2 hours.  

  After cooling to room temperature, the solution was diluted with 100 ml of ether and stored at 0-5 C, where 2- {N-benyzl-N- [2- (2-phenylacetamido) ethyl] amino} 3 ', 4'-dihydroxyacetophenone- hydrobromide as a white solid in 98% yield, mp 175-177 C (after recrystallization from methanol / ether), was obtained. 



   Example 9
Using a procedure similar to that described in Example 2, the following esters of the formula:
EMI14. 1
  obtained as their hydrobromide salts in yields of 30-85% by reducing the corresponding acetophenone derivatives of the formula:
EMI15. 1
 with an excess of sodium borohydride, an alcohol of the formula:
EMI15. 2nd
 was obtained, which was then hydrogenolyzed in the presence of benzyl bromide, the hydrogen bromide salt being formed in situ: compound substituent position (ring B) R5 R "Fp (C)
3.4 H 4 CI Ph 102-104
2 3.4 H 4-MeO-Ph foam (a)
3 3.4 H 4-F-Ph. CH2 174-175
4 3.4 H -MeO Ph. CH2 105-108
5 3.4 H 4-Cl-Ph. CH2 156-158
6 3.4 H Ph. CHMe 79-86
7 3.4 H Ph. O. CH2 162-165
8 3.4 H 3-CF3-Ph. O. CH2 80-81
9 3.4 H Ph 166-169 10 3.5 H 4-MeO Ph. CH2 oil (b) 11 3.4 Me Ph. CH2 134-136
Remarks:

  : (a) Isolated as a foam: NMR # (CDCl3): 8.1 (1H, broad, NHCO); 8.0-6.6 (7H, complex aromatic protons); 5.3 (1H, broad, CHOH); 3.7 (3H, singlet, 4-CH3O-Ph); 3.8-2.9 (complex, CH2NH); 1.28 [18H, singlet, (CH3) 3C]; + (b) isolated as oil: NMR # (CDCl3): 9.1-8.5 (2H, broad, NH2); 8.4 (1H, broad singlet, NHCO); 7.5-6.6 (7H, complex, aromatic protons); 3.7 (3H, singlet, 4-CH3O-Ph); 3.9-2.7 (complex, CH2NH and CH2CONH); 1.28 [18H, singlet, (CH3) 3C. ]
The starting acetophenone derivatives of formula XXXVI had the following properties (as their hydrobromide salts): Intermediate for position of substituent (ring B) R5 R11 Fp (C) compound no. 



   3.4 H 4 CI Ph 210-212
2 3.4 H 4-MeO-Ph 210-211
3 3.4 H 4-F-Ph. CH2 182-184
4 3.4 H 4-MeO Ph. CH2 sticky solid (a)
5 3.4 H 4 CI Ph. CH2 175-178
6 3.4 H Ph. CHMe 168-170
7 3.4 H Ph. O. C112 foam (b)
8 3.4 H 3-CF, -Ph. O. CH2 148-150
9 3.4 H Ph 200-202 10 3.5 H 4-MeO Ph. CH2 123-126 11 3.4 Me Ph. C112 214-215
Remarks: (a) isolated as a sticky solid: NMRG: 8.65 (H, broad, N HCO);
8.1-6.8 (7H, complex, aromatic protons); 5.2 (2H, singlet, PhCH2N); 4.5 (2H, singlet, N. CO. CH2); 3.7 (311, singlet, OCH3); 3.9-3.1 (complex); I, 3 [18H, singlet, (CH3) 3C]; (b) isolated as foam:

  NMR: 8.35 (IM, broad, NHCO); 8.0-6.7 (8H, complex, aromatic protons); 5.15 (211, singlet, PhCH2N); 4.65 (2H, singlet, PhOCH2); 4.35 (2H, singlet, N. CO. CH2); 4.0 to 3.0 (complex, NCH2CH2NH); 1.28 [18H, singlet (CH3) 3C].    



   The acetophenone derivatives of formula XXXVI, which were obtained in yields of 25-55%, were obtained using an analogous procedure to that used for 2- {N benzyl-N-12- (2-phenylacetamido) ethyl] amino} -3 { , 4t - bis (pivaloyloxy) acetophenone hydrobromide was used in Example 1, namely by reacting 2-bromo 3t, 4t- or-3 ', 5'-bis (pivaloyloxy) acetophenone [or for compound Nn 11, 2- Bromo-3 ', 4'-bis (pivaloyloxy) propiophenone] with the corresponding N-benzyl-N l-acylethylene diamine of the formula:

  : PhCH2NHCH2CH2NHCORI l XXXVIII
These ethylenediamine derivatives were obtained in a manner analogous to that described in Example 1 for N-benzyl-N '- (phenyl-acetal) ethylenediamine (required for compound no.    11) and had the following properties (hydrochloride salts): Starting material for R "Fp (C) compound no. 



  1 4-Cl-Ph 234-236 2 4-MeO-Ph 198-200 3 4-F-Ph. CH2 194-195 4.10 4-MeO Ph. CHa 196-197 5 4-CI-Ph. CH2 54-55 * 6 Ph. CHMe syrup (a) 7 Ph. O. CH2 182-184 8 3-CF3-Ph. O. CH2 147-149 9 Ph 54-56 *? Fp of the free base
Note: (a) isolated as syrup: NMR (free base) o: 7.5-7.0 (10H, complex, aromatic protons); 5.95 (1H, broad, NHCO); 3.65 (2H, singlet, PhCH2N); 3.55 (1H, multiplet, CHCH3); 3.25 (2H, multiplet, CH2NHCO); 2.63 (2H, triplet, PhCH2NHCH2); 1.6 (1H, PhCH2NH); 1.48 (3H, doublet, CHCH3). 



   The 2-bromo-3 ', 4'bis (pivaloyloxy) propiophenone required for compound 11 was obtained as follows:
63.6 g of 3 ', 4'-bis (pivaloyloxy) propionphenone was first prepared as a mobile oil in a manner similar to 3', 4 'bis (pivaloyloxy) acetophenone in Example 1, with 40 g of 3', 4 '- Dihydroxypropiophenone, 63.3 ml pivaloyl chloride and 73.2 ml triethylamine was assumed.  40.1 g of this mobile liquid was then reacted with 7.2 ml of bromine in a similar manner as in Example 1, whereby 2-bromo-3 ', 4'-bis (pivaloyloxy) acetophenone was obtained. 



   The crude bromo compound obtained in this way was purified by dry column chromatography on silica gel according to the procedure of Example 1, 18.4 g of pure 2-bromo3 ', 4' -bis (pivaloyloxy) propiophenone as a solid, mp 58-60 C.  were obtained. 



   Example 10
A suspension of 3.3 g of 2- [1 1 -dimethyl-2- (2-phenoxy-acetamido) -ethylamino] -3 ", 4 '-bispivaloyloxy-acetophenone trifluoroacetate in 25 ml of propan-2-ol was made up to -10 C cooled, then 0.56 g of sodium borohydride was added in two portions, with a portion of 10 ml of methanol being added in between.  After 45 min at −1 ° C., 50 ml of a saturated aqueous solution of sodium chloride were added, whereupon the mixture was extracted 3 times with 80 ml of ether each time. 

  Evaporation of the ethereal extract dried over MgSO4 gave 3.2 g of 1- [3,4-bis (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) amino] ethanol as free base, which was dissolved in 50 ml of ethanol without further purification.  0.6 ml of benzyl bromide was added to this ethanol solution, and the mixture was then hydrogenated in the presence of 0.5 g of 10% palladium-charcoal at atmospheric pressure and at room temperature for 3 hours.  The catalyst was separated by filtration through diatomaceous earth.  The residue was washed with 20 ml of ethanol and then the ethanol filtrate combined with the washing liquids was evaporated.  The residue obtained was triturated with 200 ml of ether. 

  2.1 g of 1- [3,4-bis-pivaloyloxy) phenyl] -2 [1,! -dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol hydrobromide, mp 156-158 C (after recrystallization from ethanol / ether), obtained. 



   In a similar manner, except that the benzyl bromide was replaced by an equivalent amount of benzyl chloride, the corresponding hydrochloride was obtained as a solid, mp 129-132 C. 



   The 2- [1, 1-dimethyl-2- (2-phenoxyacetamido) ethylamino] -3 t, 4 '-bis (pivaloyloxy) ace-tophenone trifluoroacetate used as the starting material was obtained in an analogous manner to that for the corresponding 2- (2-Phenylacetamido) ethylamino compound in Example 7 as a solid in a yield of 85%, mp 183-185 C, by acylation of 2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] -3 ', 4' -dihydroxyacetophenone with pivaloyl chloride in trifluoroacetic acid. 



   The 2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] -3, 4'-dihydroxyacetophenone used as the starting material was itself obtained as a foam of a purity satisfactory for the acylation, namely by hydrogenolysis of 2- [1 , I -Dimethyl-2- (2-phenoxyacet amido) ethylamino] -3 ', 4 -bis (benzyloxy) acetophenone hydrobromide in a manner analogous to that for 2- [1,1-dimethyl2- (2-phenylacetamido) ethylamino] -3 ', 4'-bis (benzyloxy) cetophenone hydrobromide is described in Example 7. 

 

   The 3 ', 4'-bis (benzyloxy) acetophenone derivative used as starting material was also obtained in 67% yield in analogy to the corresponding compound in Example 7 from 2-bromo-3', 4'-bis (benzyloxy ) acetophenone and N- (2 amino-2-methylpropyl) -2-phenoxyacetamide and had an mp of 137-139 C. 



   The N- (2-amino-2-methylpropyl) -2-phenoxyacetamide can be prepared in an analogous manner to that described for N- (2-amino-2-methylpropyl) -2-phenylacetamide in Example 3 or 7.  It had an mp of 55-56 C after recrystallization from aqueous ethanol. 



      Example 11
In a similar manner as in Example 2, 1- [3,4-bis (piva loyloxy) -2-chlorophenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol ethanol hydrobromide and 1- [3,4- Bis (isovaleryl oxy) -2-chlorophenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol hydrobromide in the form of solids in yields of 56 or  41% and with a mp of 139-142 or 



   128-131 C from 2- {N-benzyl-N- [2- (2-phenylacetamido) ethyl] amino} -2'-chloro-3 ', 4' bis (pivaloyloxy) - or -3,, 4 ' -bis (iso valeryloxy) acetophenone trifluoroacetate obtained. 



   The necessary starting trifluoroacetates were considered oily
Obtain solids in 70-85% yield (the solids were suitable for use without purification in the above process) by reaction of 2- {N benzyl-N- [2- (2-phenylacetamido) ethyl] amino} -2'-chloro- 3 ', 4'-dihydroxyacetophenone hydrobromide with pivaloyl or isovaleryl chloride in trifluoroacetic acid, in a similar manner
Way as described in Example 7. 



   The 2'-chloro3 ', 4' -dihydroxyacetophenone derivative was obtained as follows:
An ethereal diazomethane solution was distilled directly into a mixture of 25.0 g of 3,4-bis (benzyloxy) -2-chlorobenzoyl chloride in 200 ml of ether, which had been kept at -25 ° C.  The reaction mixture was then allowed to warm to room temperature and was stirred at this temperature for 4 hours.  A saturated ethereal hydrogen bromide solution (approximately 150 ml) was then carefully added to the reaction mixture until nitrogen evolution ceased.  125 g of chromatographic silica gel was then added and the mixture was evaporated. 

  The residue became the top of a column of 900 g dry chromatographic silica gel (previously deactivated by adding 10% (v / w) water and then with 10% (v / g) a 5% (v / v) solution of ethyl acetate in Equilibrated toluene) abandoned.  The column was then developed by fractional elution, first with the same solvent mixture (1.11) and then with 1.5 l of ethyl acetate.  Evaporation of the corresponding ethyl acetate fractions (determined by thin layer chromatography) gave 28.1 g of 2-bromo-3 ', 4' -bis (benzyloxy) -2 '-chloroacetophenone as a solid, mp 94-96 "C.    



   The ethereal diazomethane solution was obtained using a standard procedure by dropwise adding a solution of 45.0 g of N-methyl-nitrosotoluenesulfonamide in 300 ml of ether to a stirred solution of 12.9 g of potassium hydroxide in 21 ml of water, with the reaction temperature at 50-55 C and the addition rate was maintained so that the loss of ethereal diazomethane was compensated for by distillation. 



   [The starting benzoyl chloride was obtained in 90% yield from (2-chloro-3,4-bis (benzyloxy) benzoic acid by reaction with thionyl chloride in an appropriate manner and had an mp of 124-1 260C.     The 2-chloro-3,4-bis (benzyloxy) benzoic acid itself was obtained in 80% yield as a solid, mp 159-162 "C., by the oxidation of 2-chloro-3,4-bis (benzoyloxy) benzaldehyde (this is described by Kaiser et al.  in J.  Medicinal Chemistry 1974, 12, 1071) with chromium trioxide in sulfuric acid solution (Jones reagent) j.    



   A mixture of 32.95 g of 2-bromo-3 ', 4'-bis (benzyloxy) -2-chloroacetophenone and 3.7 g of N- [2-benzylamino) ethyl] -2phenylacetamide in 20 ml of dioxane was 3 hours at room temperature touched.  The reaction mixture was diluted with 200 ml dry ether and the precipitate, N- [2- (benzylamino) ethyl] -2-phenylacetamide hydrobromide, was separated by filtration.  The filtrate was washed 3 times with 50 ml of water and then with 100 ml of brine, dried over MgSO4 and filtered, after which a fresh solution of hydrogen bromide in ether was added until the pH was just acidic. 

  The mixture was stored at 0-5 "C for 16 hours and the oily solid that formed was triturated with ethanol and ether to give 4.2 g of 2- {N benzyl-N- [2- (2-phenylacetamido ) ethyl] amino} -2 '-chloro3', 4'-bis (benzyloxy) acetophenone hydrobromide, mp 162-164 "C, were obtained. 



   0.6 g of this hydrobromide was stirred for 4 hours at room temperature with 3 ml of a 48% (w / v) solution of hydrogen bromide in acetic acid until a solution was obtained.  This solution was evaporated and the residue was triturated with a mixture of ether and ethanol to give 0.45 g of 2- {N-benzyl-N- [2- (2-phenylacetamido) ethyl] amino} -2'-chloro- 3 "4'-dihydroxyacetophenone hydrobromide, mp 196-197" C, were obtained. 



   Example 12
In a similar manner as in Example 10, 1- [3,4-bis (pivaloyloxy) -2-chlorophenyl] -2- [1,1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol were hydrobromide and 1- [3,4-bis (isovaleryloxy) -2-chlorophenyl] -2- [1,1-dimethyl-2 (2-phenoxyacetamido) ethylamino] ethanol hydrobromide as solids in 58% and 49% yield with a mp of 163-164 "C or  176-1 790C from 2 - {[1,1-dimethyl-2- (2-phenoxyacetamido) ethyl] amino) -2 'chloro-3', 4 'bis (pivaloyloxy) - or -3' 4 '- bis (isovaleryloxy) acetophenone trifluoroacetate obtained. 



   The necessary trifluoroacetates were obtained as oily solids in yields of 70-80% (these solids were used in the above process without purification), in an analogous manner as described in Example 7, by reacting 2 - ([1, 1-dimethyl-2- (2-phenoxyacet amido) ethyl] amino) -2 "-chloro-3 ', 4'-dihydroxyacetophenone hydrobromide (A) with pivaloyl or isovaleryl chloride in trifluoroacetic acid. 



   The above acetophenone derivative (A) was itself made in 85% yield as a solid with an mp of 141-143 Cher by a procedure similar to that described for the equivalent starting material in Example 11, but from 2 - {[ 1,1-Dimethyl-2- (2-phenoxyacetamido) äthyljamino} -2 'chloro-3', 4 'bis (benzyloxy) acetophenone hydrobromide was assumed.  The latter compound itself was obtained in 40% yield as a solid with an mp of 61-630C from N- (2-amino-2-methylpropyl) -2-phenoxyacetamide and 2-bromo-3 4'-bis (benzyloxy) - 2'-chloroacetophenone obtained using a procedure similar to that in Example 11. 



   Example 13
A solution of 1.45 g of 3'-acetoxymethyl-4'-acetoxyphenylglyoxal hydrate and 1.04 g of N- (2-amino-2-methylpropyl) -2phenylacetamide in 50 ml of acetonitrile was stirred at room temperature for 30 min.  Then 2 ml of acetic acid and finally 0.64 g of sodium cyanoborohydride were added to the vigorously stirred mixture.  Stirring was continued for 16 hours at room temperature.  The mixture was then evaporated.  The semi-solid residue was partitioned between 100 ml of ethyl acetate and 100 ml of 10% (v / v) aqueous acetic acid.  The organic phase was separated, dried over MgSO4, filtered and evaporated.  The remaining oil was purified on a column of 150 g of chromatographic silica gel using 10% (v / v) ethanol / chloroform as the eluent.  

  The corresponding fractions of the column [determined by TLC (SiO2: 10% v / v ethanol / chloroform)] were combined and evaporated, 0.9 g (36%) of 1 [3-acetoxymethyl-4-acetoxyphenyl] -2 - [I '1 -dimethyl-2- (2-phenylacetamido) ethylamino] ethanol were obtained as an oil. 

  NMR8 (CDCb): 7.8-6.9 (8H, complex, aromatic protons), 6.3-5.8 (2H, broad singlet, CH (OH) CH2 and C112NHC (CH3) 2), 5.0 (311, broad singlet, COOCH2 and CH (OH) CH2), 3.5 (2H, sharp singlet, PhCH2CO), 3.35-3.2 (2H, doubled, (CH3) 2CCH2NH), 3.05-2 , 8 (2H, CH (OH) CH2NH complex), 2.25 (3H, sharp singlet, CH3COO), 2.0 (3H, sharp singlet, CH3COOCH2), 1.2 (6H, doublet, NHC (CH) 3 ) 2CH2); and pure according to TLC (SiO @: 10 or 20% v / v ethanol / chloroform). 



   The substituted phenylglyoxal used as the starting material itself was obtained as follows:
108 g of 3'-chloromethyl-4'-hydroxyacetophenone was added to a mixture of 54 g of anhydrous sodium acetate, 500 ml of glacial acetic acid and 250 ml of acetic anhydride.  The mixture was heated to 95 ° C. for 4 hours and then concentrated by distillation under reduced pressure.  The gummy residue was dissolved in 500 ml of water and the aqueous solution was extracted 3 times with 300 ml of chloroform.  The combined extracts were dried over MgSO4, filtered and evaporated to give a yellow oil. 

  This was distilled under high vacuum, giving 108 g of 3 '-acetoxymethyl-4' -acetoxyacetophenone as a colorless viscous liquid with an mp of 143-147 C (0.3 mm), which crystallized on cooling, so that a solid with a Mp from 47-48 "C was created. 



   A solution of 7.1 g of bromine in 20 ml of chloroform was added dropwise to a stirred solution of 11.0 g of 1 1.0 g of 3'-acetoxymethyl-4'-acetoxyacetophenone in 150 ml of chloroform at room temperature.  After the addition was complete, the solution was washed twice with 150 ml of water and then with 100 ml of brine.  The organic phase was dried over MgSO4, filtered and evaporated to give 10.0 g of 3 '-acetoxymethyl-4' -acetoxy-2-bromoacetophenone, which was determined by IR and TLC [SiO2; 1: 1 V / V EtOAc / petroleum ether (60-800C)] was sufficiently pure for use without further purification or characterization. 



  A solution of 10.0 g of 3'-acetoxymethyl-4'-acetoxy-2-bromoacetophenone in 150 ml of dimethyl sulfoxide was stirred for 48 hours at room temperature.  The solution was then poured into 500 ml of ice / water and extracted 3 times with 200 ml of ethyl acetate.  The organic layers were combined, dried over MgSO4 and filtered.  The solvent was removed by evaporation to give 6.5 g (81%) of 3'-acetoxymethyl-4'-acetoxyphenylglyoxal hydrate as a yellow oil.  The glyoxal derivative had a satisfactory IR spectrum and was pure according to TLC (SiO2: EtOAc) and was therefore used without full characterization or isolation. 



   Examples 14-15
Using similar procedures as described in Example 13, the following diesters were obtained in yields of 50-70% as oils which were pure by TLC (SiO2: 10 or 20% v / v ethanol / chloroform):
1- (3'-Isovaleryloxymethyl-4'-isovaleryloxyphenyl) -2- [1,1dimethyl-2- (2-phenylacetamido) ethylamino] ethanol (Example 14): NMR # (CDCl3): 7.5-7.0 ( 8H, complex, aromatic protons); 6.8-6.6 (2H, broad singlet, CH (OH) CH2 and CH2NHC (CH3) 2); 5.0 (3H, broad singlet, CO2CH2 and CH (OH) CH2); 3.5 (2H, sharp singlet, PhCH2CO); 3.4 (2H, broad doublet, (CH3) 2C. CH2NH); 3.2-2.8 (2H, complex, CH (OH) CH2NH); 2.3 (2H, doublet, CH2CO2);

   2.1 (2H, doublet, CH2CO2CH2); 1.2 (6H, doublet, NHC (CH3) 2CH2); 1.1-0.8 (12H, 2 doublets, (CH3) 2. CH); 1 - (3 '-Valeryloxymethyl-4' -valeryloxyphenyl) -2- [1,1 - dimethyl-2- (2-phenylacetamido) ethylamino] ethanol (Example 15): NMR # (CDCl3): 7.5-7, 0 (8H, complex, aromatic protons); 6.4-6.1 (2H, broad singlet, CH (OH) CH2 CH2NHC (CH3) 2); 5.0 (3H, broad singlet, CO2CH2CH (OH) CH2); 3.6 (2H, broad doublet, PhCH2CO); 3.4 (2H, broad doublet, C (CH3) 2CH2NH); 3.2-2.8 (2H, complex, CH (OH) CH2NH); 2.6 (2H, triplet, CH3 (C112 CH2CO2; 2.2 (2H, triplet, CH3 (CH2) 2CH2CO2CH2);

   1.8-1.2 (8H, complex, CH3CH2CH2CH2CO2); 1.2 (611, doublet, NH-C (CH3) 2CH2); 1.1-0.8 (6H, overlapping triplets, CH3 (CH2) 3CO2).    



   The substituted phenylglyoxals used as the starting material were obtained in a manner similar to that described for the phenylglyoxal derivative in Example 13, starting from the corresponding 2-bromoacetophenone.     They were obtained as their hydrates, and they were oils that were sufficiently pure by TLC (EtOAc: SiO2) and IR spectroscopy so that they could be used in the above preparations without isolation and full characterization. 



   The necessary 2. Bromoactophenones were obtained as follows:
1.    3 '-Valeryloxymethyl-4 -valeryloxy-2-bromoaceto-phenone (for example 14)
2.0 g of sodium hydride was added in portions to 150 ml of stirred valeric acid over a period of 15 minutes.  40 g of 3-acetoxymethyl-4-acetoxyacetophenone were then added and the mixture was heated to 160 ° C. and kept at this temperature for 15 hours with stirring.  The mixture was then concentrated by distillation under reduced pressure while maintaining the temperature at 160 ° C.  The gummy residue was cooled and dissolved in 500 ml of ether.  This solution was washed 3 times with 250 ml of 10% (v / v) sodium carbonate solution, 2 times with 500 ml of water and then with 250 ml of saturated saline. 

  The organic phase was dried over MgSO4, filtered and evaporated to give a brown oil.  This was distilled under high vacuum, giving 16.0 g (30%) of 3'-valeryloxymethyl-4'-valeryloxyacetophenone as a colorless viscous liquid: NMR (CDCI3): 7.9-7.0 (3H, 1, 2.4 aromatic substitution patterns); 5.0 (2H, sharp singlet, CO2CH2); 2.5 (3H, sharp singlet, COCH3); 2.55-2.15 (4H, complex, CH3 (CH2) 2CH2CO2 and CH3 (CH2) 2CH2CO2CH2); 1.8-1.2 (811, complex, CH3CH2CH2CH2CO20); 1.1-0.8 (6H, overlapping triplets, CH3 (CH2) 3CO2). 

 

   A solution of 4.2 g of bromine in 20 ml of chloroform was added dropwise to a stirred solution of 8.5 g of 3'-valeryloxymethyl-4 '-valeryloxyacetophenone in 100 ml of chloroform.  During the addition, the temperature was maintained at 0-5 C by the addition of small pieces of solid carbon dioxide.  The solution was then washed 3 times with 100 ml of 10% (w / v) sodium carbonate solution and 2 times with 100 ml of water and finally with 100 ml of saturated saline.  The organic phase was dried over MgSO4, filtered and evaporated to give 6 g (57%) of 3 '-valeryloxymethyl-4' -valeryloxy-2-bromoacetophenone, which according to IR and TLC [SiO2: 50% (V / V) EtOAc / petroleum ether (60-80 C)] was sufficiently pure that it could be used without further purification or characterization. 



   2nd 3'-isovaleryloxymethyl-4'-isovaleryloxy-2-bromoacetophenone (for example 15)
This compound was obtained using an analogous procedure as described in (1) above, but using isovaleric acid instead of valeric acid in the first step.  The 2-bromoacetophenone derivative was isolated as an oil and had a satisfactory IR spectrum and was pure according to TLC [SiO2:

   50% V / V EtOAc / petroleum ether (60-800C)].     The intermediate 3 '-isovaleryloxymethyl-4' -isovaleryloxyacetophenone was also isolated as a liquid: NMR (CDCl3): 7.9-7.0 (3H, 1,2,4 aromatic substitution pattern); 5.0 (2H, sharp singlet, CO2CH2); 2.5 (3H, sharp singlet, COCH3); 2.4 (2H, doublet, CH2CO2); 2.1 (211, doublet, CH2CO2CH2); 1.1-0.8 (12H, complex, (CH3) 2CH).    



   Example 16
In a similar manner to that described in Example 13 for 1 - [3-acetoxymethyl-4-acetoxyphenyl] -2- [1,1-dimethyl-2- (2-phenylacetamido) ethylamino] ethanol, 3 ' -Acetoxymethyl-4'-acetoxyphenylglyoxal and N (2-amino-2-methylpropyl) -2-phenoxyacetamide the compound 1 - [3-acetoxymethyl-4-acetoxyphenyl] -2- [1, 1,1 -dimethyl2- (2- phenoxyacetamido) äthylamino] äthanol obtained as an oil in a yield of 42%. 

  It had NMR # (CDCI3): 7.9-6.8 (8H, complex, aromatic protons); 6.2-5.6 (2H, broad singlet, CH (OH) CH2 and CH2NHC (CH3) 2; 5.0 (2H, sharp singlet, CHICO2CH2); 4.5 (2H, sharp singlet, PhOCH2CO); 3 , 6-3.4 (2H, broad doublet, C (CH3) 2CH2NH); 3.3-2.8 (2H, complex, CH (OH) CH2NH); 2.25 (3H, sharp singlet, CH3CO2); 2.0 (311, sharp singlet, CH3CO2CH2); 1.3 (6H, doublet, NHC (CH3) 2CH2); and pure according to TLC (SiO2: 10 to 20% v / v ethanol / chloroform). 



   Example 1 7
A solution of 0.8 g of I - (3,4-dihydroxyphenyl) -2- [1,1 - dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol hydrobromide in 5.4 ml of trifluoroacetic acid was mixed with 1.12 ml of pivaloyl chloride treated and the mixture was heated to reflux for 40 min.  The mixture was then evaporated and the residue was dissolved in ether. 

  The solution obtained was treated with ethereal hydrogen bromide until it was just acidic, whereupon an oily solid separated.     Trituration of this material with 20 ml of ether gave 0.6 g of the triester 1- [3,4-bis-pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethyl pivaloate -hydrobromide as solid, mp 106-11 0 "C, NMR #: 8.8 (2H, broad singlet, NH2); 8.45 (1H, triplet, NHCO); 7.8-6.8 (8H, complex , aromatic protons); 5.43 (1H, broad, = CH. O); 3.58 (2H, singlet, CH20Ph); 4.0-3.0 (complex, CH2NH); 1.3-1.2 (33H, broad singlet, C. CH3). 



   After separation of the solid triester, the ethereal filtrate contained isolable amounts of the diester 1- [3,4-bis (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol, which was identical to that of Example 10, which was obtained by TLC on silica using the following solvent system: (a) toluene / ethyl acetate / ethanol / ammonia (60/20/15/10, v / v) (b) toluene / Ethanol / triethylamine (8/1/1, v / v) (c) ether / acetic acid / water (6/2/1, v / v). 



   The starting material was obtained as follows:
A suspension of 1.26 g of 2- [1,1-dimethyl-2- (2-phen oxyacetamido) ethyl] amino-3 ', 4' -bis (benzyloxy) acetophenone hydrobromide in 10 ml of 2-propanol was made up to 10 C cooled, and then 0.22 g of sodium borohydride was added in two portions, with a portion of 10 ml of methanol being added in between.  The reaction mixture was allowed to warm to 10 ° C.  After 30 minutes at this temperature, 100 ml of a saturated aqueous solution of sodium chloride was added and the mixture was extracted 3 times with 100 ml of ether. 

  The combined ether extracts were washed with 100 ml of water and then with 100 ml of brine, dried over MgSO4 and evaporated to give 1.2 g of 1- [3,4-bis (benzyloxy) phenyl] -2- [1,1-dimethyl- 2- (2-phenoxyacetamido) ethylamino] ethanol were obtained as a sticky residue.  This residue was dissolved in 30 ml of ethanol and then 0.24 ml of benzyl bromide was added.  The mixture was hydrogenated at atmospheric pressure and at room temperature in the presence of 0.4 g of 10% (w / w) palladium-charcoal for 3 hours. 

  The catalyst was separated by filtration and washed with 10 ml of ethanol, and the combined filtrates and washing liquids were evaporated, 0.8 g of 1- (3,4-dihydroxyphenyl) -2- [1,1,1-dimethyl -2- (2-phenoxyacetamido) - ethylamino] ethanol hydrobromide was obtained in the form of a foam which had a satisfactory NMR spectrum and was sufficiently pure for direct use in the above method. 



   Example 18
Using a procedure similar to that described in Example 9, 1- [3,5-bis (pivaloyloxy) phenyl] -2- [2- (2-phenoxyacetamido) ethylamino] ethanol hydrobromide was obtained as a solid with a Mp 93-95 C obtained in a yield of 68%, namely by reduction of 2- {N-benzyl-N- [2- (2-phenoxyacetamido) ethyl] amino-3 ', 5' -bis (pivaloyloxy) acetophenone hydrobromide (A) with an excess of sodium borohydride, the corresponding alcohol of the formula XXXVII being obtained in situ, which was then hydrogenolyzed in the presence of benzyl bromide. 

 

   The acetophenone hydrobromide (A) was obtained as a solid with an mp of 90-1 10 "C and with a satisfactory NMR spectrum and in a yield of 43%, namely by reaction of 3 ', 5'-bis (pivaloyloxy) - 2bromoacetophenone with N- [2- (benzylamino) ethyl] -2-phenoxyacetamide in a manner similar to that described for the analogous starting material in Example 1. 



   Example 19
A mixture of 0.5 wt. Parts of finely powdered 1- [3,4-bis (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phen oxyacetamido) ethylamino] ethanol hydrochloride or hydrobromide in 10 wt. Parts of liquid paraffin was 89.5 wt. Parts of melted white, soft paraffin added.  The resulting mixture was allowed to cool to room temperature with rapid stirring until a uniform ointment was obtained which was suitable for human administration. 



   Similarly, an ointment containing a compound of formula I according to any one of Examples 1-9 or 11-18 or a numbered part thereof was obtained by using such a compound as an active ingredient in the above process. 



   Example 20
A solution of 0.1 wt. - Part 1- [3,4-bis (pivaloyloxy) phenyl] -2- [l, l -dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol hydrochloride or hydrobromide in 30 wt.  Parts of 9-propanol were produced.  66.9 wt. Parts of water were added and the mixture was rapidly added 3 wt. Parts of Carbopol 940 were stirred until a finely dispersed gel was obtained which was suitable for administration to humans. 



   Similarly, a gel containing a compound of formula I according to any one of Examples 1-9 or 11-18 or a part thereof was obtained by using such a compound as an active ingredient in the above process. 



   * Carbopol 940 is a specific type of carboxypolymethylene gelling agent that is available from B. F.  Goodison Chemical Co. , Cleveland, Ohio, USA.   Carbopol is a trademark. 



   Example 21
A mixture of 9 wt. Parts of cetostearyl alcohol, 7 wt. Parts of liquid paraffin, 2 wt. Parts of sorbitan monostearate, 2 wt. - parts Polysorbate 60 and 0.1 wt. Parts of finely powdered I- [3,4-bis (pivaloyloxy) phenyl] -2- [l, l-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol hydrochloride or hydrobromide were melted together at 65-70 ° C.  79.9 wt. Parts of water were added to the melt thus obtained with stirring.  The mixture was then stirred rapidly with slow cooling to room temperature until a homogeneous cream was obtained which was suitable for use in humans. 

 

   Similarly, a cream containing a compound of formula I according to any one of Examples 1-9 or 11-18 or a numbered part thereof was obtained by using such a compound as an active ingredient in the above process.  


    

Claims (12)

 PATENT CLAIMS 1. Esters of the formula: EMI1.1    wherein R1 stands for a C 1 -C 6 -alkyl or 6-cycloalkyl) Cl s-alkyl radical or a phenyl radical which optionally carries a C (-6-alkyl or Cl-6-alkoxy radical as core substituent; one of the symbols R2 and R3 is hydrogen and the other of the symbols R2 and R3 is a radical of the formula R 'CO.O-, where R' has the meaning given above; R4 and Rsje are hydrogen; R6 and R7, which are the same or may be different, represent hydrogen or methyl radicals; A 'represents a direct bond or a methylene radical; A2 represents a methylene radical; Z represents hydrogen or chlorine; and Q for a radical of the formula: EMI1.2  or EMI1.3  where R8 is hydrogen or a methyl radical, X is a direct bond or oxygen and the benzene ring Y optionally carries a halogen atom or a trifluoromethyl, CI-o-alkyl or CI-e alkoxy radical as a substituent; as well as the pharmaceutically acceptable acid addition salts thereof.  2. Ester according to claim 1, wherein R 'is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, t-butyl, 1-methyl-2, 2-dimethylpropyl, 2,2-dimethylpropyl, I-ethyl propyl, I, l-diethyl propyl or (cyclopentyl) methyl radical or a phenyl radical which optionally carries a methyl or methoxy radical as core substituent; and the benzene ring Y in the radical Q optionally carries a fluorine, chlorine or bromine atom or a trifluoromethyl, methyl or methoxy radical as a substituent.  3. Ester according to claim 1 or 2, wherein Q is a phenylacetyl-, 4-fluoro-, 4-chloro- or 4-methoxyphenylacetyl-, 2-phenylpropionyl-, phenoxyacetyl-, (3-trifluoromethylphenoxy) acetyl-, benzoyl- or 4-chloro, 4-methyl or 4-methoxybenzoyl radical.  4. An ester according to any one of claims 1 to 3, wherein R6 and R7 are both hydrogen or methyl radicals.  5. The ester of claim 1, wherein R 'is an isopropyl, t-butyl, isobutyl or (cyclopentyl) methyl radical; R2 represents a radical of the formula R'CO.O-; R3, R4 and RS represent hydrogen; R6 and R7 both represent hydrogen or methyl radicals; A 'represents a direct bond; A represents a methylene radical; Z represents hydrogen; and Q represents a phenylacetyl, phenoxyacetyl, 2-phenylpropionyl, benzoyl or 4-chlorobenzoyl radical; as well as the pharmaceutically acceptable acid addition salts thereof.  6. The esters 1 - [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol; 1 - [3,4-bis (pivaloyloxy) phenylj-2- [1,1-dimethyl-2- (2-phenylacetamido) ethylamino] ethanol; 1- [3,4-bis (3,3-dimethylbutyryloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol; 1 - [3,4-bis- (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol; 1- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenoxyacetamido) ethylamino] ethanol or 1- [3,4-bis (isovaleryloxy) phenyl] -2- (2-phenylacetamido ) ethylamino] ethanol; as well as the pharmaceutically acceptable acid addition salts thereof according to claim 1.  7. The ester 1- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (4-chlorobenzamido) ethylamino] ethanol or a pharmaceutically acceptable acid addition salt thereof according to claim 1.  8. Ester according to one of claims 1 to 7, in an optically active form.  9. Ester according to one of claims 1 to 8 in the form of acid addition salts, in which the salt is derived from an inorganic acid, such as hydrochloric, hydrobromic, phosphoric or sulfuric acid.  10. Esters according to one of claims 1 to 8 in the form of acid addition salts, in which the salt is derived from an organic acid, such as oxalic, wine, milk, fumaric, lemon, vinegar, salicylic, benzoic, ss-naphthoic, methanesulfonic or adipic acid.  11. Pharmaceutical preparation, characterized in that it contains an ester of formula I or a pharmaceutically acceptable acid addition salt thereof as an active ingredient together with a pharmaceutically acceptable diluent or carrier in a form suitable for topical administration.    12. A preparation according to claim 1, characterized in that it has the form of an ointment, a gel, an aqueous or oily solution or suspension, an emulsion or an aerosol preparation.  The invention relates to esters of phenylethylamines which have anti-inflammatory activity when applied topically to an inflammatory focus.  It is known that certain 1 - (hydroxyaryl) -2 - [(acylamino) alkylamino] ethanol derivatives have ss-adrenergic stimulant properties (US Pat. No. 3,933,911). It is also known that various carboxylic acid esters of l- (hydroxyphenyl) -2- (alkylamino) ethanols are sympathomimetic ** WARNING ** End of CLMS field could overlap beginning of DESC **.