GB1591618A - Esters of hydroxy amino amides - Google Patents

Esters of hydroxy amino amides Download PDF

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Publication number
GB1591618A
GB1591618A GB52553/76A GB5255376A GB1591618A GB 1591618 A GB1591618 A GB 1591618A GB 52553/76 A GB52553/76 A GB 52553/76A GB 5255376 A GB5255376 A GB 5255376A GB 1591618 A GB1591618 A GB 1591618A
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radical
formula
ester
hydrogen
acid
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GB52553/76A
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Imperial Chemical Industries Ltd
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Imperial Chemical Industries Ltd
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Priority to GB52553/76A priority Critical patent/GB1591618A/en
Priority to ZA00776944A priority patent/ZA776944B/en
Priority to IE2355/77A priority patent/IE45991B1/en
Priority to CA000291507A priority patent/CA1121379A/en
Priority to AU30869/77A priority patent/AU518148B2/en
Priority to US05/855,004 priority patent/US4423070A/en
Priority to IL53466A priority patent/IL53466A/en
Priority to MX777906U priority patent/MX5346E/en
Priority to GR54912A priority patent/GR63097B/en
Priority to SE7713830A priority patent/SE437019B/en
Priority to NL7713655A priority patent/NL7713655A/en
Priority to LU7778688A priority patent/LU78688A1/xx
Priority to HU77IE817A priority patent/HU176680B/en
Priority to PL1977202935A priority patent/PL114111B1/en
Priority to FI773779A priority patent/FI67842C/en
Priority to AR270354A priority patent/AR217094A1/en
Priority to PL1977216323A priority patent/PL113856B1/en
Priority to PL1977216324A priority patent/PL113857B1/en
Priority to PT67412A priority patent/PT67412B/en
Priority to YU02987/77A priority patent/YU298777A/en
Priority to DE19772756001 priority patent/DE2756001A1/en
Priority to BE183493A priority patent/BE861894A/en
Priority to FR7737940A priority patent/FR2374300A1/en
Priority to NO774326A priority patent/NO148263C/en
Priority to CS778424A priority patent/CS199698B2/en
Priority to DD77202671A priority patent/DD133941A5/en
Priority to SU772553500A priority patent/SU822753A3/en
Priority to IT30848/77A priority patent/IT1143786B/en
Priority to ES465149A priority patent/ES465149A1/en
Priority to AT902277A priority patent/AT356083B/en
Priority to DK562177A priority patent/DK562177A/en
Priority to JP15229877A priority patent/JPS5384928A/en
Priority to ES474223A priority patent/ES474223A1/en
Priority to ES474222A priority patent/ES474222A1/en
Priority to CS791570A priority patent/CS199699B2/en
Priority to CS791571A priority patent/CS199700B2/en
Priority to AT179879A priority patent/AT364351B/en
Priority to SU792776609A priority patent/SU974935A3/en
Priority to SU792780255A priority patent/SU860691A3/en
Publication of GB1591618A publication Critical patent/GB1591618A/en
Priority to US06/416,369 priority patent/US4470997A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

(54) ESTERS OF HYDROXY AMINO AMIDES (71) We, IMPERIAL CHEMICAL INDUSTRIES LIMITED, Imperial Chemical House, Millbank, London SWIP 3JF, a British Company do hereby declare the invention, for which we pray that a patent may be gra@ten to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to new esters and, in particular it relates to new esters of phenylethylamines which possess anti-inflammatory activity when applied topically to an area of inflammation.
According to the invention there is provided an ester of the formula:
wherein R1 is a C1-11-alkyl or (C3-8-cycloalkyl)-C1-5-alkyl radical, or a phenyl or benzyl radical optionally bearing a C1-6-alkyl or C1-6-alkoxy radical as a nuclear substituent; one of R2 and R3 is hydrogen; the other of R2 and R3 is a radical of the formula R1CO.O- wherein R1 has the meaning stated above; R4 is hydrogen, a 2-12-alkanoyl or (C3-6-cycloalkyl)-C2-6-alkanoyl radical, or a benzoyl or phenyl acetyl radical optionally bearing a C1-6-alkyl or C,~s-alkoxy radical as a nuclear substituent; R5 is hydrogen or a methyl radical; R6 and R7, which may be the same or different are hydrogen, or C1-6-alkyl radicals; A1 is a direct bond or a methylene radical; A2 is a C1-4-alkylene radical;Z is hydrogen or chlorine and Q is a radical of the formula;
wherein R8 is hydrogen or a methyl radical, X is a direct bond or oxygen, and benzene ring Y optionally bears a halogen atom, or trifluoromethyl, C,~ss-alkyl or C1-alkoxy radical as a substituent, or a pharmaceutically acceptable acid-addition salt thereof A particular value for R1 when it is a C1-11-alkyl radical is, for example, a straight chain C1-11-alkyl radical, for example a methyl, ehtyl, propyl, butyl, pentyl, hexyl or heptyl radical, or a branched chain C3-11-alkyl radical, for example an isopropyl, isobutyl, t-butyl, 1 -methyl-2,2-dimethylpropyl, 2,2-dimethylpropyl, 1ethylpropyl or l,l-diethylpropyl radical; of which values isopropyl, isobutyl and tbutyl are particularly preferred.
A particular value for R1 when it is a (C3-8-cycloalkyl)-C1-5-alkyl radical is, for example, a (cyclopentyl)methyl radical.
A particular value for R4 when it is a C212-alkanoyl radical is, for example, such a radical of the formula Alkyl. CO- wherein Alkyl has any of the particular values for R1 stated above when it is a C1-11-alkyl radical.
A particular value for R4 when it is a (C3-6-cycloalkyl)-C2-6-alkanoyl radical is, for example, a (cyclopentyl)acetyl radical.
A particular value for Re or R7 when it is a C,~8-alkyl radicals, for example, a methyl or ethyl radical.
A particular value for A2 is, for example, a methylene or ethylene radical.
A particular value for a C,~6-alkyl or C,~8-alkoxy radical, when present as an optional substituent on benzene ring Y, or as an optional nuclear substituent when R1 is a phenyl or benzyl radical, or when R4 is a benzoyl or phenylacetyl radical is, for example, a methyl or methoxy radical.
A particularly suitable value for the radical R'CO when A' is a direct bond is, for example, a pivaloyl, isobutyryl or isovaleryl radical, and when A' is a methylene radical is, for example, an acetyl radical.
A particular value for a halogen atom when present as an optional substituent on benzene ring Y is, for example, a fluorine, chlorine or bromine atom.
A particular value for ring Y is, for example, a phenyl, halogenophenyl, Cie alkoxyphenyl, trifluoromethylphenyl or C,~8-alkylphenyl radical, for example a 4chloro-, 4-fluoro-, 4-methoxy-, 3-trifluoromethyl- or 4-methyl-phenyl radical.
A particularly suitable value for Q when it is a radical of formula II is, for example, an N-phenylcarbamoyl or N-(p-chlorophenyl)carbamoyl radical.
A particularly suitable value for Q, when it is a radical of formula III, is for examPle, a phenylsulfonyl or toluene p-sulphonyl(tosyl) radical.
particularly suitable value for Q, when it is a radical of formula IV and X is a direct bond, is, for example, a phenylacetyl, 4-fluoro- 4-chloro- or 4methoxyphenylacetyl or 2-phenylpropionyl radical.
A particularly suitable value for Q, when it is a radical of formula IV and X is oxygen, is, for example, a phenoxyacetyl or (3-trifluoromethylphenoxy)acetyl .
A particularly suitable value for Q, when it is a radical of the formula V, is, for example a benzoyl, 4-chlorobenzoyl, 4-methylbenzoyl or 4-methoxybenzoyl radical.
It will be appreciated that various particular and individual groups of esters of the invention are comprised within the above general definition, namely those esters of formula I, or acid-addition salts thereof, wherein one of the radicals R', R2, R3, R4, R5, Re, R', Re, A1, A2, Z and Q has one of the above defined particular values, and the remainder of the said radicals have any of the above defined general or particular values.However, specific groups of esters of the invention which are of particular interest comprise those compounds of formula I wherein: (a) R2 is a radical of the formula R'CO.O- and R3 is hydrogen; (b) R2 is hydrogen and R3 is a radical of the formula R'CO.O-; (c) A' is a direct bond; (d) A' is a methylene radical; (e) Z is hydrogen; or (f) Z is chlorine; and in each case the remainder of R', R2, R3, R4, R5, Re, R7, Re, A', A2, Z and Q have any of the above general or particular values; together in each case with the pharmaceutically acceptable acid-addition salts thereof.
Yet further particular groups of esters of the invention are comprised by those compounds of formula I defined in any of the above mentioned groups taken alone or in combination; and wherein, in addition R4 and K5 are both hydrogen; Re and R7 are both hydrogen or methyl radicals; A2 is a methylene radical; and Q is a radical of formula IV as defined above, preferably a phenylacetyl, phenoxyacetyl or 2-phenylpropionyl radical.
A particularly preferred group of esters of the invention comprises those compounds of formula I as defined by above groups (a) and (c) taken together, wherein in addition R' is an isqprqpyl, t-butyl, isobutyl or (cyclopentyl)methyl radical; R4 and R5 are both hydrogen; R6 and R7 are bothhydrogen or methyl radicals; A2 is a methylene radical; and Q is a phenylacetyl, phenoxyacetyl or 2phenylpropionyl radical.
A particular acid-addition salt of an ester of formula I is such a salt derived from an acid affording a pharmaceutically acceptable anion, for example from an inorganic acid, for example hydrochloric, hydrobromic, phosphoric or sulphuric acid, or from an organic acid, for example oxalic, tartaric, lactic, fumaric, citric, acetic, salicylic, benzole, ss-naphthoic, methane sulphonic or adipic acid.
It will be observed that an ester of formula I possesses at least one asymmetric carbon atom i.e. that bearing the radical -OR4, and can therefore exist in racemic and optically-active forms. In addition, depending on the nature of the substituents R5, R6, R7 and R8 an ester of the formula I may possess up to three additional asymmetric carbon atoms and can exist in the corresponding additional racemic and optically-active forms.It is to be understood that this invention encompasses the racemic forms of such an ester and any optically-active form which possesses antiinflammatory activity, it being well known how a racemic form may be resolved into its optically-active forms, or how such optically-active form may be obtained by synthesis from optically-active starting materials, and how the pharmacological properties may be determined by the standard tests hereinbelow.
Specific esters of formula I are described hereinafter in the Examples, but of these the following are particularly preferred: 1 - [3,4 - bis(pivaloyloxy)phenyl] - 2 - [2 - (2 - phenylacetamido)ethylamino] - ethanol; - - [3,4 - bis(pivaloyloxy)phenyl] - 2 - [1,1 - dimethyl - 2 - (2 - phenyl- acetamido)ethylamino] - ethanol; 1-[3,4-bix(pivaloyloxy)phenyl]- 2 -[1,1 - dimethyl - 2 - (2 - phenoxyacetamido)ethylamido)ethylamino] - ethanol; 1 - [3,4 - bis(pivaloyloxy)phenyl] - 2 - [2 - phenoxyacetamido)ethylamino] ethanol; 1 - [3,4 - bis(isovaleryloxy)phenyl] - 2 - [2 - (2 - phenylacetamido)ethylamino] - ethanol;; 1 - [3,4 - bis(3,3 - dimethylbutyryloxy)phenyl] - 2 - [2 - (2 - phenyl- acetamido)ethylamino] - ethanol; and the pharmaceutically acceptable acid-addition salts thereof.
The esters of the invention may be manufactured by any chemical process known to be useful for the manufacture of chemically-analogous compounds. Such processes are provided as a further feature of the invention and comprise assembling in sequence by generally known chemical procedures the following five radicals, in which R', R2, R3, R4, R5, R8, R7, A1, At and Z have the meaning stated above: (i) a 2-phenylethyl radical of the formula:
(ii) a first imino radical (-NM-); (iii) a radical of the formula:
(iv) a second imino radical (-NH-); and (v) a radical -Q.
The various stages of the assembly of an ester of the invention may be carried out in any possible order using known chemical processes for the synthesis of analogous compounds and, in particular, the introduction of the acyl groups R'CO-- and R4, when it is other than hydrogen, may be carried out early in the synthesis or as a final step.
The following processes are given as particular, non-limiting, examples of such sequential chemical synthesis, wherein R', R2, R3, R4, R6, R8, R', Re, A(, A2, Q, X, Z and ring Y have the meanings stated above unless specifically stated otherwise: (a) A compound of the formula:
or an acid-addition salt thereof, wherein U is a carbonyl radical or a radical of the formula -CHOR4- and W is a reductively removable protecting group, is reduced.
A particularly suitable reductively removable protecting group is, for example, a benzyl radical or a substituted benzyl radical, for example, a 4-methylbenzyl radical. As will be apreciated, the reduction must be carried out under conditions which do not result in reduction of carboxylic ester groups, and is therefore preferably carried out by means of catalytic hydrogenation, for example with hydrogen in the presence of a palladium (which is preferred) platinum or nickel catalyst, in a diluent or solvent, for example ethanol or water, or a mixture thereof.
The reduction is conveniently carried out at, for example, 15--30"C and, may optionally be carried out under a pressure of hydrogen of, for example, up to 5 Kg/cm2.
It is to be understood that the conditions necessary for removal of the protecting group W in the above process, also result in the reduction of a carbonyl radical U when present in the starting material of formula VIII, so that an ester of formula I wherein R4 is hydrogen is thus obtained in such a case.
The starting materials of formula VIII wherein U is a radical of the formula -CH.OH- may be obtained, for example, by sodium borohydride reduction of the corresponding aryl ketone of the formula:
wherein W has the meaning defined above, using similar reduction conditions to those described hereinbelow in process (e). Such starting materials of formula VIII may conveniently be prepared and used in process (a) in the same vessel without the need for isolation and purification.
The aryl ketones of formula IX (which are also starting materials of formula VIII wherein U is a carbonyl radical) may themselves be prepared by reaction of an appropriate phenyacyl halide of the formula:
wherein Hal is a halogen atom with an amino compound of the formula:
wherein W has the meaning defined above.
This reaction is conveniently carried out at or near normal room temperature, for example at 15 to 300C, and in a diluent or solvent, for example ethanol, dioxan or acetonitrile. It may also be carried out in the presence of an acid-binding agent, for example an alkali metal carbonate or bicarbonate or an excess of amino compound XI. A particularly suitable value for Hal. is a chlorine or bromine atom.
The amino compound of formula XI may be obtained by selective acylation of a diamine of the formula:
with an acylating agent derived structurally from an acid of the formula Q.OH, using known general procedures. Alternatively those starting materials of formula XI wherein W is a benzyl radical may be obtained by reductive alkylation of an amine of the formula:
by reaction with benzaldehyde in the presence of a suitable reducing agent, for example sodium borohydride, under conditions similar to those described for process (e) below.
The phenacyl halides of formula X may themselves be obtained by conventional side-chain halogenation of the appropriate acyl benzene of formula X but wherein Hal. is replaced by hydrogen, for example, as illustrated in Example 1 and 9 hereinafter.
Alternatively, the aryl ketones of formula IX may conveniently by obtained by acylation of a dihydroxy compound of the formula:
wherein W has the meaning defined above, and one of G' and GZ is hydrogen and the other is a hydroxy radical with an acylating agent structurally derived from an acid of the formula Rt.CO2H, for example a chloride or bromide of such an acid, for example as illustrated in Example 7 and 8 hereinafter. The necessary dihydroxy compounds of formula XIV may themselves be obtained, for example, by acidic hydrolysis of a corresponding di-O-acetyl derivative (itself obtained by analogous processes to those described herein for esters of formula I), as illustrated hereafter in Example 8.
The remaining starting materials of formula VIII, wherein U is a radical of the formula -CHOR9-, but wherein R9 has the same meaning as R4 other than hydrogen, may be obtained by acylation of the corresponding compound of formula VIII wherein U is a radical of the formula-CH.OH-, by reaction with an acylating agent, for example anacid chloride, derived from an acid of the formula R9.0H, wherein R9 has the meaning defined above, using the general conditions specified in process (c) hereinbelow.
(b) For an ester of the formula I wherein R4 is hydrogen, an aryl ketone of the formula:-
is reduced.
The reduction may be carried out by means of any agent generally known for reducing aromatic ketones, but which does not reduce carboxylic ester groups.
Thus the reduction may be carried out by means of an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, for example methanol, ethanol or 2-propanol, which means is preferred, or by means of catalytic hydrogenation, for example with hydrogen in the presence of a palladium, platinum or nickel catalyst, in a diluent or solvent, for example ethanol or acetic acid, and in either case, at a temperature of, for example, -20"C to 300 C, and conveniently, at or near normal room temperature, for example at 150 to 300C.
The starting materials of formula XV may be obtained in an analogous manner to those of formula IX in process (a) hereinabove, by reaction of a phenacyl halide of formula X with the appropriate amino compound of formula XI but wherein W is hydrogen. The necessary amino compound may be obtained by selective acylation of a diamine of formula XlI, but wherein W is hydrogen, for example as illustrated in the accompanying Examples.
Alternatively, the starting materials of formula XV may conveniently be obtained in an analogous manner to those of formula IX in process (a) hereinabove, by acylation of a dihydroxy compound of formula XIV, but wherein W is replaced by hydrogen, preferably in the presence of a strong acid to minimise any tendency for N-acylation, for example by using the dihydroxy compound as its hydrochloride, hydrobromide or trifluoroacetate salt. The necessary dihydroxy compounds may be obtained from the corresponding di-O-acetyl derivatives as described in (a) hereinabove, or by hydrogenolysis of the corresponding di-Obenzyl derivatives as illustrated in Example 7 hereinafter.
(c) For an ester of formula I wherein R4 is hydrogen or an acyl radical of the formula R1.CO-, a hydroxy compound of the formula:
wherein one of G' and G2 is hydrogen and the other is a hydroxy radical, is reacted with an acylating agent derived structurally from an acid of the formula R'.CO2H.
The reaction is preferably carried out using an acid-addition salt of a compound of formula XVI for example a hydrogen halide salt for example a hydrogen chloride or hydrogen bromide, or a trifluoro acetate salt, so that Nacylation is thereby minimised.
A particularly suitable acylating agent derived structurally from one of the above-mentioned acids is, for example, an acid halide, for example an acid chloride or bromide, an anhydride, or a mixed anhydride with formic acid.
The reaction may be conveniently carried out in the presence of an inert diluent or solvent, for example acetone, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, acetic acid or trif,uoroacetic acid and conveniently, at a temperature, for example, of from 0 to 100 C.
It is to be understood that the quantity of acylating agent employed in the above process necessarily depends on the number of acyl radicals to be incorporated. Thus, when a compound of formula I wherein R4 is a radical of the formula R1CO- is required, that is a triester, the above acylation is generally carried out using an excess of acylating agent at a temperature in the range, for example, 60--100"C.
By contrast, when a compound of formula I wherein R4 is hydrogen is required, that is a diester, the above acylation is generally carried out using a stoichiometric amount of acylating agent and at a temperature in the range, for example, 0 to 600 C, and preferably at or near normal temperature, for example at from 15 to 300C.
The starting materials of formula XVI may be made by reduction of an acetophenone derivative of formula XIV wherein W is a benzyl radical with sodium borohydride in 2-propanol, followed by catalytic hydrogenolysis of the benzyl radical using a similar procedure to that described in process (a) hereinabove.
Alternatively, they may be obtained by conventional acidic or basic hydrolysis of an ester of formula I, for example wherein R' is a methyl radical and R4 is hydrogen, conveniently in an alcohol, for example methanol, and at a temperature of 15-600C. As a yet further alternative, a di-O-benzyl ether of general formula I, but wherein the radical R'CO-- is replaced by a benzyl radical, and R4 is hydrogen, is catalytically hydrogenolysed, for example as illustrated in Example 17 hereinafter.
(d) For an ester of formula I wherein R4 is other than hydrogen, a compound of formula I wherein R4 is hydrogen is reacted with an acylating agent derived structurally from an acid of the formula R9.OH wherein R9 has the same meaning as R4 other than hydrogen.
A particularly suitable acylating agent derived structurally from an acid of formula R9.0H is, for example, an acid halide, for example an acid chloride or bromide, an acid anhydride, or a mixed anhydride with formic acid.
The reaction may be carried out under the same general conditions as specified in (c) hereinabove.
(e) For an ester of formula I wherein R4 is hydrogen, a carbonyl derivative of the formula
is condensed with an amine of the formula:
under reducing conditions.
Particularly suitable reducing conditions are provided by using, for example, an alkali metal borohydride or cyanoborohydride, for example sodium borohydride or cyanoborohydride, of which a cyanborohydride is particularly preferred, conveniently in an inert solvent or diluent, for example acetonitrile, methanol, ethanol or 2-propanol and at a temperature in the range, for example, -20" to 30"C. When sodium cyanoborohydride is used, the reaction is preferably carried out at or near pH 4, for example in the presence of acetic acid.
It will be appreciated that processes of the above general type are known as reductive alkylations, and proceed at least in part through an intermediate of the formula:
(the -N--CR6- bond of which is subsequently reduced), and/or of the formula:
(the -N=CR5- and ketone bond of which are subsequently reduced). Such an intermediate of formula XVIII or XIX (or a mixture thereof), may be prepared and reduced in two separate stages in the above process if required.
The starting materials of formula VXII may be obtained by selenium dioxide oxidation of a compound of the formula:
in an appropriate solvent, for example aqueous dioxan, optionally followed in the case of compounds of formula XVII wherein R5 is hydrogen by hydrate, acetal or hemiacetal formation, in which form, they may also be employed in the above process (e).
Those starting materials of formula XVII wherein R5 is hydrogen may conveniently also be obtained by dimethyl sulphoxide oxidation of the corresponding phenacyl bromide of the formula:
under conventional conditions, for example as described in Example 13 hereinafter.
The phenacyl bromides of formula XXI may be made by analogy with those of formula X, or by transacylation as described in (f) hereinbelow.
(f) For an ester of formula I wherein R4 and R5 are both hydrogen; a compound of the formula:
wherein W' and W2 together form a direct bond, or wherein W' is hydrogen and W2 is a halogen atom, or a mixture of such compounds, is reacted with an amine of the formula XIII.
It will be appreciated that compounds of formula XXII wherein W1 and W2 together form a direct bond are ethylene oxide derivatives of the formula:
and that compounds of formula XXII wherein W' is hydrogen and W2 is a halogen atom are halohydrins of the formula:
wherein Hal. is a halogen atom, for example, a chlorine, bromine or iodine atom; and that such compounds of formula XXIII or XXIV, or a mixture thereof, may be readily obtained by reduction, for example, using sodium borohydride or aluminium isopropoxide, of a phenacyl halide of the formula:
wherein Hal. has the meaning stated above, with or without spontaneous dehydrohalogenation of the first formed halohydrin of formula XXIV.
The above process (f) may be carried out at ambient temperature or it may be accelerated or completed by application of heat, for example by heating to a temperature in the range 80 to 150 C; it may be carried out at atmospheric or at an elevated pressure, for example by heating in a sealed vessel; and it may be carried out in an inert diluent or solvent, for example methanol, ethanol or 2-propanol.
The phenacyl halides of formula XXV may be made by analogous procedures to those used for the halides of formula X and XXI. Thus, they may be obtained by conventional side-chain halogenation of the appropriate acetophenone obtained by transacylation of a di-O-acetyl derivative of the formula:
wherein one of G3 and G4 is an acetoxy radical and the other is hydrogen, by reaction with the soldium salt of the appropriate acid of formula R'.CO2H at 150--180"C, for example as illustrated in Example 14 hereinafter.
Optically-active forms of an ester of the invention may be obtained by conventional resolution of the corresponding racemic form of the ester of the invention.
The said resolution may be carried out by reacting a racemic form of an ester of formula I with an optically active acid, followed by fractional crystallisation of the diastereoisomeric mixture of salts thus obtained from a diluent or solvent, for example ethanol, whereafter the optically-active form of the ester of formula I is liberated by treatment under such conditions as avoid the hydrolysis of the ester, for example by anion exchange chromatography. A particularly suitable opticallyactive acid is, for example, (+)- or (-)-O,O-di-p-toluoyltartaric acid, or (T)-2,3:4,5- di-O-isopropylidene-2-keto-L-gulonic acid.
The ester of formula I in free base form may be converted into a pharmaceutically acceptable acid-addition salt by reaction with a suitable acid as defined hereinbefore and by conventional means which avoid hydrolysis of the ester. Alternatively, when a hydrogen chloride or bromide salt is required, this may be conventiently obtained by producing a stoichiometric amount of the hydrogen halide in site by catalytic hydrogenation of the appropriate benzyl halide, preferably in an inert solvent or diluent, for example ethanol, and at, or near, room temperature.
The esters of formula I are conveniently used as their pharmaceutically acceptable acid-addition salts.
As stated above, the esters of formula I possess anti-inflammatory activity when applied topically to an area of inflammation and, in particular, are therefore useful in treating inflammatory diseases or inflammatory conditions of the skin, in warmblooded animals.
The anti-inflammatory properties of an ester of formula I may be demonstrated in a standard test involving the inhibition of croton oil induced inflammation on the mouse ear. The activity of an individual ester of formula I in this test depends upon its particular chemical structure, but specific esters of formula I as described herein produced a significant inhibition of the inflammation at a topically applied dose of 0.30 mg per ear, or less.
Another standard test in which the anti-inflammatory properties of an ester of formula I may be demonstrated involves the inhibition of oxazolone induced contact sensitivity on the mouse ear. Again the activity of a particular ester of formula I in this test depends on its particular chemical structure, but specific esters of formula I as described herein produced a significant inhibition of the inflammation at a topically applied dose of 0.6 mg per ear, or less.
No overt toxic effects were detected at the active doses in either of the above tests.
In general, an ester of formula I may be used in the treatment of inflammatory diseases of inflammatory conditions of the skin in an analogous manner to that in which known topically active anti-inflammatory agents, for example the topically active steroids, are used.
When used for the topical treatment of an area of inflammation affecting the skin of a warm-blodded animal, for example man, an ester of formula I may be administered topically at a dose in the range 10,ug to 15 mg/cm2, or at an equivalent dose of a pharmaceutically acceptable acid-addition salt thereof, and, if necessary, a dose in this range is repeated at intervals of, for example, 4-12 hours. It will be appreciated that the total daily amount of an ester of formula I administered depends on the extent and severity of the inflammation under treatment.
By way of example, when 1-[3,4-bis(pivaloyloxy)phenyl]-2-[l,l-dimethyl-2-(2- phenoxyacetamido)ethylamino]-ethanol is used for the topical treatment of an area of inflammation affecting the skin of a warm-blooded animal, for example man, a dose in the range lMg to 5 mg/cm2, or an equivalent amount of a pharmaceutically acceptable acid-addition salt thereof, is administered topically, and if necessary, is repeated at intervals in the range 4-12 hours.
The esters of formula I may be administered in the form of pharmaceutical compositions and according to a further feature of the invention there is provided a pharmaceutical composition comprising an ester of formula I, or a pharmaceutically acceptable acid-addition salt thereof, in association with a pharmaceutically acceptable diluent or carrier; in a form suitable for topical administration, for example in the form of an ointment, gel, aqueous or oily solution or suspension, emulsion or aerosol formulation. A pharmaceutical composition according to this aspect of the invention may contain from 0.1% to 10% w/w of an ester of formula I or an equivalent amount of a pharmaceutically acceptable acid-addition salt thereof, hereinafter referred to as an active ingredient.
The pharmaceutical compositions may be be made by methods well known in the art, using conventional pharmaceutically acceptable diluents or carriers.
A particular ointment formulation is prepared by dispersing an active ingredient as defined above in a suitable organic diluent, for example soft paraffin, optionally in the presence of an emulsifying and/or thickening agent, for example sorbitan monostearate.
A particular gel formulation is prepared by adding a gelling agent, for example carboxy-polymethylene, to a solution of an active ingredient as defined above in a suitable organic solvent, for example isopropyl alcohol.
A particular emulsion formulation, for example a cream or a lotion, is prepared by mixing an active ingredient as defined above with a suitable conventional emulsifying system and water.
A pharmaceutical composition according to this aspect of the invention may contain in addition to an active ingredient as defined above, at least one known pharmaceutical agent selected from: corticosteroids, for example fluocinolone acetonide, prednisolone, flumethasone pivalate, betamethasone valerate, hydrocortisone or dexamethasone; phosphodiesterase inhibitors, for example theophylline or caffeine; antibacterial agents, for example oxytetracycline, gentamicin, neomycin, gramicidin, chlorhexidine or cetyltrimethylammonium bromide; anti-fungal agents, for example griseofulvin or nystatin; antihistamines, for example diphenhydramine or chlorphenamine; local anaesthetics, for example amylocaine, benzocaine or procaine; and emollients, for example calomine.In addition the compositions may also contain conventional excipients such as colours, chelating agents or preservatives as desired.
The invention is illustrated but not limited by the following Examples in which (i) unless otherwise stated, all procedures were carried out at room temperature (in the range 18-260C) and at atmospheric pressure; and all evaporations were performed by rotary evaporation under reduced pressure; (ii) infra-red spectroscopic data, were given, is presented in the form of absorbance values (v max.) for characteristic radicals; (iii) nuclear magnetic resonance (NMR) data, where given, is presented in the form of chemical shifts ( values) for characteristic protons, relative to tetramethyl silane (TMS) as standard determined in d8-DMSO as solvent (unless stated otherwise) and at l00MHz; ; and (iv) yields, where given, are purely illustrative and are not to be construed as the maximum attainable.
Example 1 A solution of 2-{N-benzyl-N-[2-(2-phenylacetamido)-ethyl]aminol-3',4'- bis(pivaloyloxy)acetophenone hydrobromide (2.5 g) in a mixture (50 ml) containing 70% v/v of ethanol in water was hydrogenated for 18 hours at a pressure of 3.5 kg/cm2 at room temperature using 10% palladium-carbon (0.8 g). The catalyst was separated by filtration and the filtrate evaporated. Trituration of the residue with ether (30 ml) containing several drops of ethanol gave 1-[3,4-bis(pivaloyl- oxy)phenyll-2-12-(2phenylacetamido)ethylaminolethanol as its hydrobromide (1.7 g) m.p. 111--113"C (hemi-hydrate).
The starting acetophenone derivative was obtained as follows: A solution of 2-bromo-3'-,4'-bis(pivaloyloxy)acetophenone (2.63 g) and N-[2- (benzylamino)ethyl]-2-phenylacetamide (3.7 g 2 molecular equivalents) in dioxan (20 ml) was stirred overnight at room temperature.
The reaction mixture was diluted with dry ether (200 ml) and a precipitate of N-[2-benzylamino)ethyl]-2-phenylacetamide hydrobromide was separated. The ethereal solution was washed with water (3 x 50 ml) and brine (100 ml), dried Mg.SO4) and filtered. A fresh solution of saturated ethereal hydrogen bromide was then added to the filtrate until the solution was just acid. After 18 hours at 0--50C the precipitate was collected to give 2-[N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino]-3',4'-bis(pivaloyloxy)acetophenone hydrobromide as a crude solid. Crystallisation of a portion of the crude solid from ethylacetate gave analytically pure material having m.p. 176--1780C.
The required 2-bromo-3',4'-bis(pivaloyloxy)acetophenone starting material was itself obtained as follows:- A suspension of 3,4-dihydroxy acetaphenone (13.1 g, 0.08 mole) in chloroform (320 ml) was cooled in an ice bath to 0--5"C. A solution of pivaloyl chloride (19.2 ml, 0.16 mole) in chloroform (80 ml) and a solution of triethylamine (22.2 ml), 0.16 mole) in chloroform (80 ml) were added dropwise simultaneously to the stirred suspension during 10 minutes. The reaction mixture was stirred at 0-50C for a further I hour and then was poured into a mixture of 2N-hydrochloric acid (100 ml) and ice (200 g). The mixture was extracted with chloroform (3 x 150 ml), and the extracts washed successively with water (100 ml), 10% w/v sodium carbonate solution (100 ml), water (100 ml) and brine (100 ml).After drying (MgSO4) the combined extracts were evaporated to give crude 3,4-bis(pivaloyloxy)acetophenone as an oil (23.1 g) which was used without purification.
A solution of bromine (3.15 ml, 0.061 mole) in chloroform (50 ml) was added dropwise at room temperature to a stirred solution of 3',4'-bis(pivaloyloxy)acetophenone (19.5 g, 0.061 mole) and t-butyl acetate (8.2 ml, 0.06 mole) in chloroform (150 ml) containing a catalytic amount of anhydrous aluminium chloride (0.2 g).
The reaction mixture was stirred at room temperature for 1 hour after the addition was complete, chromatographic silica gel (75 g) was then added and the mixture evaporated in vacuo. The residual solid was added to the top of a column of dry chromatographic silica-gel (1 kg, previously deactivated by addition of 10% w/w water and then equilibrated with 10% v/w of a 5% v/v solution of ethyl acetate in toluene). The column was developed by elution with a 5% v/v solution (1.1 1) of ethyl acetate in toluene. The column was then eluted with ethyl acetate (2 x 500 ml) and the fractions collected were monitored by thin layer chromatography (TLC) (on silica plates developed in a 50% v/v mixture of ethyl acetate and toluene). The later fractions were combined and evaporated to give 2-bromo-3',4'-bis(pivaloyloxy)acetaphenone as an oil (14.2 g) which rapidly crystallised to give a solid of m.p.
64--66"C.
The starting phenylacetamide derivative was itself prepared as follows:- A mixture of ethyl phenyl acetate (100 g, 0.61 mole) and ethylene diamine (120 ml, 1.86 mole) was heated on a steam bath for 4 days. Excess ethylene diamine was removed under reduced pressure and the residue dissolved in water (500 ml) and any insoluble material was removed by filtration. Evaporation of the filtrate gave crude N-(2-aminoethyl)-2-phenylacetamide (96.8 -g) which was used without purification.
Benzaldehyde (67.5 g, 0.637 mole) was added to a solution of N-(2-aminoethyl)-2-phenylacetamide (113.5 g, 0.637 mole) and the mixture was stirred at room temperature for 18 hours. Sodium borohydride (24.2 g) was added in portions and the reaction mixture was stirred for an additional 1.5 hours. Acetic acid was then added until excess borohydride had been destroyed. The reaction mixture was basified by addition of 2N sodium hydroxide solution and extracted with ethyl acetate (3 x 500 ml). The extracts were washed with brine (300 ml), dried (MgSO4) and filtered. Hydrogen chloride gas was bubbled into the ethyl acetate filtrate until it was acid (pH-2). After 4 hours at OOC, the precipitate was collected to give N-[2 (benzylamino)ethyl]-2-phenylacetamide hydrochloride (46.2 g), m.p. 183--1850C.
The free base was liberated from the hydrochloride (15 g) by basification of a solution in water (150 ml) with solid sodium carbonate. The aqueous mixture was extracted with ethyl acetate (3 x 100 ml) and the extracts were dried (MgSO4) and evaporated to give N-[2-(benzylamino)ethyl]-2-phenylacetamide as an oil (13.0 g).
which slowly crystallised.
Example 2 Asuspension of 2-{N-benzyl-N[2-(2-phenylaceteamido)ethyl]amino}-3',4'-bis (pivaloyloxy)acetophenone (2.0 g) in 2-propanol (20 ml) was cooled-10 C. and sodium borohydride (0.34 g) added in two portions interspersed by a protion of methanol (4 ml). After 30 minutes at --100C a saturated aqueous solution (150 ml) of sodium chloride (brine) was added and the mixture was extracted with ether (3 x 80 ml). Evaporation of the dried (MgSO4) ethereal extracts gave 1-[3,4-bis (pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)-N-benzyl-ethylamino]ethanol (1.65 g) which was dissolved without purification in ethanol (40 ml). To this solution was added benzyl bromide (0.37 ml, 0.0031 mole) and the mixture was then hydrogenated in the presence of 10% palladium-carbon (0.4 g) at atmospheric pressure and room temperature during 2 hours.The catalyst was separated, washed with ethanol (10 ml) and the ethanol washings and reaction solution were evaporated together. The residue was triturated with ether (20 ml) containing several drops of ethanol to give 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethyl- amino]ethanol hydrobromide, (1.2 g), m.p. 110-1 l50C, identical with that obtained in Example 1.
Example 3 A solution of 3',4'-bis(pivaloyloxy)phenylglyoxal (0.68 g, 0.002 mole) and N-(2amino-2-methylpropyl)-2-phenylacetamide (0.41 g, 0.002 mole) in methanol (15 ml) was stirred at room temperature for 18 hours. The reaction mixture was stirred and cooled to --100C and sodium borohydride (0.23 g, 0.003 mole) was added in portions. The mixture was further stirred at --100C for 45 minutes after the addition was complete. Brine (100 ml) was then added and the mixture was extracted at room temperature with ether (3 x 60 ml). After washing with brine (50 ml) and drying (MgSO4), the ethereal extracts were evaporated to give 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenylacetamido)ethylamino]ethanol as an oil (0.64 mg).A solution of this oil in ethanol (15 ml) was hydrogenated with benzylbromide (148 y1, 0.0012 mole) in the presence of 10% palladium-carbon (0.3 g) at atmospheric pressure and room temperature during 2 hours. The catalyst was then separated by filtration, washed with ethanol (5 ml) and the filtrate and washings evaporated. Trituration of the residue with ether (300 ml) at 0 C yielded 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenylacetamido)ethylamino]ethanol hydrobromide in 48% yield. An analytically pure sample was obtained by crystallisation of the hydrobromide from water and had m.p. 134--1 360C.
The starting phenylglyoxal derivative was obtained as follows:- A solution of 2-bromo-3',4'-bis(pivaloyloxy)acetophenone (2 g) in dimethyl sulphoxide (10 ml) was allowed to stand for 18 hours at room-temperature, then poured into ice-water and extracted with ether (3 x 60 ml). The ether solution was washed with water (50 ml) and brine (50 ml), dired (MgSO4) and evaporated to give 3',4'-bis(pivaloyloxy)phenylglyoxal as an oil (1.8 g); vmax.: 1760 cm-' (ester > C=O), 1690 cm-1 (-CO.CHO); a (CDCl3): 8.2-7.1 (complex, aromatic -H), 1.35 (18H, singlet -C.CH3).
The starting N-(2-amino-2-methylpropyl)-2-phenylacetamide was obtained in a similar manner to that described for N-(2-aminoethyl)-2-phenylacetamide in Example I but using 1,2-diamino-2-methylpropane, and had m.p. 55--59"C (m.p.
68--71"C, after crystallisation from aqueous ethanol).
Example 4 The process described in Example 1 for l-[3,4-bis(pivaloyloxy)phenyl]-2[2-(2- phenylacetamido)ethylamino]ethanol hydrobromide was repeated except that the appropriate 2-[N-benzyl-N-[2-(substituted amido)ethylaminol-3',4'- bis(acyloxy)acetophenone hydrobromide was hydrogenated. There were thus obtained in yields of 4390% the following hydrobromides of compounds of the formula
Substituents position Characteristic No. (Ring B) R1 Q Properties 1 3,4 2.,-dimethylpropyl phenylacetyl m.p. 141-142 C (hydrate) 2 3,5 t-butyl phenylacetyl oil1 3 3,5 2,2-dimethylpropyl phenylacetyl oil 2 4 3,5 cyclopentylmethyl phenylacetyl oil @ 5 3,4 t-butyl heazoyl m.p. 166-i690C. (hydrate) 6 3,4 t-butyl (p-fluorophenyl) m.p. 174-175 C. acetyl (hemi-hydrate)
Notes: 1. NMR: (d#-DMSO) 8.17# (1H, -NHCO-), 7.2-6.7 (3H, complex, aromatic protons), 5.0# (1H, broad singlet, -CHOH), 3,4-2.68 (complex. -CH2-), 1.1# (18H, singlet, C-CH3).
2. NMR: (d#-DMSO) 8.38# (1H, -NHCO-), 7.4-6.7# (8H, complex, aromatic protons), 5.0# (1H, broad singlet, -CH@OH-), 3.7-2.6# (complex, -CH2-), 2,45# (4H, singlet, -CH2CO-), 1.06# (18H, singlet, C-CH3).
3. NMR: (d#-DMSO) 8.38# (1H, -NHCO-), 7.4-6.75# (8H, complex, aromatic protons), 5.0# (1H, broad singlet, -CH@OH-), 3,9-2.7# (complex, -CH2-), 2.5# (4H, complex, -CH2CO-), 2.0-1.0# (-CH2-, cyclopentyl ring).
The starting acetophenone hydrobromides were made in a similar manner to that described for 2-[N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'bis(pivaloyloxy)acetophenone hydrobromide in Example 1. There were thus obtained the following derivatives of the formula:
Substituents position m.p.
No. (Ring B) R' Q ( C.) 1 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) 182/184 acetyl The above acetophenone derivative starting materials were themselves obtained by reaction of the appropriate 2-bromo-acetophenone derivative and the appropriate N-benzylamino amides.
The following new 2-bromo-acetophenone derivatives were obtained from the corresponding acetophenones in a similar manner to that described for 2-bromo3',4'-bis(pivaloyloxy)acetophenone in Example 1: 2-bromo-3',5'-bis(cyclopentylacetoxy)acetophenone, oil, NMR: #(CDCl3); 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, m.p. 37-39 C; 2-bromo-3',4'-bis(3',3-dimethylbutyryloxy)acetophenone, oil, NMR: #(CHCl3):: 8.0-7.1 (3H, complex, aromatic protons), 4.42 (2H, singlet, -CHCH2Br), 2,46 (4H, singlet, -C-CH2-), 1.15 (18H, singlet,-C-CH3) The following new N-benzylamino amides required as starting materials were obtained in a similar manner to that described for N-[2-(benzylamino)ethyl]2-phenylacetamido in Example 1: N-[2-benzylamino]ethyl]-benzamide, m.p. 54-56 C, from ethyl benzoate; N-[2-benzylamino]ethyl]-2-(p-fluorophenyl)acetamide, m.p. 194-195 (hydrochloride), from ethyl phenylacetate.
Example 5 N-[2-(Benzylamino)ethyll-2-phenylacetamide (1.07 g) was added to a solution of 2-bromo-3'-pivaloyloxymethyl-4'-pivaloyloxyacetophenone (0.83 g) in dioxan (25 ml). The solution was stirred at room temperature for 16 hours and then heated to 800C for 5 minutes. After dilution with ether (150 ml) the solution was washed successively with 10% sodium carbonate solution, water and saturated brine. The ethereal solution was dried over (MgSO4) filtered and evaporated to give crude 2 [N - benzyl - N -[2 - (2 - phenylacetamido)ethylaminol - 3' - pivaloyioxymethyl - 4' pivaloyloxy-acetophenone as an oily residue, which was dissolved in methanol (25 ml).Sodium borohydride (150 mg) was added in portions to the methanolic solution cooled at -100C. The mixture was stirred for I hour and then acidified to pH 4-5 by addition of glacial acetic acid. The methanol was removed by evaporation and the residue was suspended in water (50 ml) and basified to pH 9-10 by addition of 2N ammonia solution. The aqueous solution was then extracted with ether (3 x 50 ml) and the combined extracts were dried (MgSO4) and evaporated. The residue was dissolved in ethanol (50 ml) and the solution was hydrogenated in the presence of 10% palladium-carbon (50 mg) at atmospheric pressure and room temperature during 24 hours.After separation of catalyst, the solution was evaporated to give 1 [3 - pivaloyloxymethyl - 4 - pivaloyloxyphenyl] - 2 - [2 - (2 - phenylacetamido)ethyl amino]ethanol as an oil. The oil was dissolved in the minimum quantity of isopropyl acetate and the solution acidified to pH 4-5 by dropwise addition of methane sulphonic acid. The methanesulphonic acid salt of 1-[3-pivaloylmethyl-4-pivaloyl oxyphenyl] -2-[2-(2-phenylacetamido)ethylamino] ethanol was thus obtained in 24% yield as a gum which was crystallised from isopropyl acetate and had m.p.
105--107"C.
Example 6 In a similar manner to that described in Example 3 for 1-[3,4-bis(pivaloyl- oxy)phenyl]-2-[2-(phenylacetamido)ethylamino]ethanol, there was obtained from 3'-pivaloyloxymethyl-4'-pivaloyloxyphenylglyoxal and N-(2-aminoethyl)-2phenylacetamide, 1-[3-pivaloyloxyphenyl-4-pivaloyloxyphenyl]-2-[2-(2-phenylacetamido)ethylamnino]ethanol as its methane sulphonate salt, m.p. 105-107 C.
The glyoxal derivative used as starting material was obtained as follows:- 3'-Pivaloyloxymethyl-4'-pivaloyloxyphenylglyoxal was obtained in a similar manner to that described in Example 3 for 3',4'-bis (pivaloyloxy)phenylgloxal, but starting from 2-bromo-3-'-pivaloyloxymethyl-4'-pivaloyloxyacetophenone except that the reaction mixture was left for 6 days rather than 18 hours at room temperature. The glyoxal had the following NMR: o(DMSO-d) 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 similar procedure to that described in Example 2, the following diesters of the formula:
were obtained in yields of 4580% (as their hydrobromide salts) by reduction of the corresponding acetophenone derivatives of the formula:
with an excess of sodium borohydride, followed by catalytic hydrogenation in the presence of a stoichiometric amount of benzyl bromide to produce the hydrogen bromide salt in situ:
Substituents Compound position No. (Ring B) Rl m.p. ( C) 1 3,4 i-Pr foam* 2 3,4 1-ethylpropyl 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 1-methyl-2,2-dimethylpropyl 109-110 7 3,4 Ph 113-117 (decomp.) 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 1-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, having NMR 8 # (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 formula XXX were obtained by acylation of the appropriate phenol derivative of the formula:
as its hydrobromide, by reaction with the appropriate acyl chloride or bromide of the formula R10.CO.Cl of R10.CO.Br. This acylation is illustrated by the following preparation of the acetophenone intermediate for compound 10 hereinabove: Pivaloyl chloride (1.85 ml) was added to a suspension of 2-[1,1-dimethyl-2-(2 phenylacetamido)ethyl]amino-3',5'-dihydroxyacetophenone hydrobromide (1.8 g) in trifluoroacetic acid (10 ml). The mixture was stirred at room temperature for 5 minutes, and then heated under reflux for 45 minutes. The reaction mixture was then evaporated and the oily residue was triturated with ether (100 ml) and ethanol (1 ml).The subsequently obtained mixture was then cooled for 18 hours at 0-5 C to give a precipitate of 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',5'bis(pivaloyloxy)acetophenone trifluoroacetate (1.3 g), m.p. 155156 C.
Using a similar procedure, the following acetophenone derivatives of formula XXX were obtained in yields of 3070% as their trifluoroacetate salts:
Intermediate Substituents for Compound position No. (Ring B) Rl m.p. ( C.) 1 3,4 i-Pr 136-138 2 3,4 l-ethylpropyl 140-142 3 3,4 t-Bu 20 5-208 4 3,4 2,2-dimethylpropyl 112-115 5 3,4 l-(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 4MeO-Ph 125-130 9 3,4 i-Bu 140-141 11 3,5 1-methyl-2,2Zimethylpropyl 195-200 12 3,5 4-MeO-Ph 90-95 (decomp.) 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)ethyllamino - 3',4' - dihydroxyacetophenone; A solution of 2-bromo-3',4'-bis(benzyloxy)acetophenone (5.24 g) and N-(2amino-2-methylpropyl)-2-phenylacetamide (5.5 g) in dioxan (25 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with dry ether (200 ml) and the precipitate of N-(2-amino-2-methylpropyl)-2-phenylacetamide hydrobromide was separated by filtration.The ethereal filtrate was washed with water (3 x 50 ml), brine (100 ml) dried (MgSO4) and then a fresh solution of saturated ethereal hydrogen bromide was added until the solution was just acid.
After 18 hours at 0-5 C the precipitate which had formed was collected to give 2 [1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-bis(benzyloxy)acetophenone hydrobromide as a solid (6.85 g) m.p. (55-160 C. This hydrobromide (5.0 g) was dissolved in absolute ethanol (300 ml) and the solution was hydrogenated at atmospheric pressure using 10% w/w palladium-on-carbon (3.0 g) as catalyst. When the uptake of hydrogen was complete (about 3 hours), the catalyst was removed by filtration and the ethanolic filtrate was evaporated at a temperature below 30 C to give 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-dihydroxyacetophenone hydrobromide as a foam (3.7 g) which was used directly for further acylation.
2. 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',5'-dihydroxyacetophenone; This compound was obtained as a foam suitable for further acylation and in 98% yield, by a similar procedure but starting from 2-bromo-3',5'-bis(benzyloxy)- acetophenone and N-(2-amino-2-methylpropyl)-2-phenylacetamide, and with intermediate isolation of 2-[1,1-dimethyl-2(2-phenylacetamido)ethyl]amino-3',5'bis(benzyloxy)acetophenone hydrobromde, m.p. 150-153 C.
The N-(2-amino-2-methylpropyl)-2-phenylacetamide was obtained as follows: A solution of l,l-dimethylethylenediamine (8.8 g) in ether (250 ml) was added during 2 hours to a stirred solution of phenylacetyl chloride (15.4 g) in ether (250 ml). The mixture was further stirred at room temperature for 2 hours. The solid was separated by filtration, and dissolved in warm water (150 ml). The solution obtained was filtered. The filtrate was basified by addition of an excess of saturated aqueous sodium carbonate solution (50 ml), and then extracted with chloroform (3 x 250 ml). The extracts were dried (MgSO4) and evaporated to give an oil which crystallised on addition of a 1:1 v/v mixture of ether and petrol (60--800C) to give N-(2-amino-2-methylpropyl)-2-phenylacetamide (13.1 g), m.p. 68--71"C (after recrystallisation from aqueous ethanol).
Example 8 Using a similar procedure to that described in Example 2 the following diesters of the formula:
were obtained in yields of 30-65% (as their hydrobromide salts) by reduction of the corresponding acetophenone derivative of the formula:
with an excess of sodium borohydride to give an alcohol of the formula:
which was then hydrogenolysed in the presence of benzyl bromide to give the hydrogen bromide salt in situl
Compound No. Rl m.p. ( C.) 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 1-methyl-2,2-dimethylpropyl 111-114 8 1-ethyl-2,2-dimethylpropyl oil (b) 9 l,l-diethylpropyl foam (c) 10 Ph oil (d) 11 4-Me-Ph | foam (e) 12 4MeO-Ph oil (f) Notes + (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)5CH2CO; 0.88 (6H, broad triplet, CH3(CH2)5CH2CO); (b) isolated as an oil: NMR# 9.0-8.5 (2H, broad, NH2); 8.3 (1H, 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-COl; 1.04 (18H, singlet, (CH3)3 C); 0.9 (6H, triplet, CH3CH2); (c) isolated as a foam: NMR#: 8.9-8.5 (2H, complex, NH2); 8.35 (1H, complex, NHCO); 7.4-7.1 (8H, complexc, 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 an oil: NMR#: 9.0-8.6 (2H, broad NH2); 8.4 (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 a foam; NMR: 9.0-8.5 (2H, broad, NH2); 8.38 (1H, broad, NHCO); 8.0-7.0 (16H, complex, aromatic protons); 5.06 (1H, doublet, CHOH); 3.6-2.8 (8H, complex, CH2NH and CH2CONH); 2.34 (6H, singlet, 4-CH3-Ph); (f) isolated as an oil: NMR# 8.35 (1H, broad, NHCO); 8.0-6.8 (16H, complex, aromatic protons); 5.2 (1H, doublet, CH.OH); 3.8 (6H, singlet, 4-CH3O-ph); 3.7-2.9 (8H, complex, CH2NH and CH2CONH).
The necessary ketone starting materials of formula XXXIII were obtained in a similar manner to those of formula XXX in Example 7 by acylation of 2-{N-benzyl- N-[2-(2-phenylacetamido)ethyl]amino]-3',4'-dihydroxyacetophenone hydrobromide, either using the appropriate acyl halide in trifluoroacetic acid solution (Method A, as described in Example 7) or using a mixture of the acyl chloride, the corresponding alkanoic or aroic acid, and hydrogen chloride (Method B).
Method B is illustrated by the following preparation of the intermediate for compound I hereinabove: A mixture of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino]-3',4'-di- hydroxyacetophenone hydrobromide (1.0 g) and butyric acid (6 ml) was saturated at room temperature with gaseous hydrogen chloride during 3 minutes. Butyryl chloride (6 ml) was then added and the mixture was stirred at 90-950C for 1.5 hours, giving 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 ether (25 ml) to give 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(butyryloxy)acetophenone hydrochloride as a solid precipitate (0.65 g), m.p. 115-117 C.
Using either of these methods with the appropriate acyl halides, the following ketone derivatives of formula XXXIII were obtained in yields of 35-75% as their trifluoroacetate salt (Method A) or hydrochloride salt (Method B):
Intermediate for Compound Acy lation No. R10 Method m.p. ( C.) 2 i-Pr B 115-117 3 heptyl A oil (a) 4 i-Bu B foam (b) 5 l-ethylpropyl A oil (c) 6 1-(2-methylpropyl)-3-methylbutyl A foam (d) 7 1-me thy 1-2,2-dimethylpropyl A oil (e) 8 l-ethyl-2,2-dimethylpropy 1 A oil (fl 9 1,1-diethylpropyl A oil (g) 10 Ph A 173-176 11 4-Me-Ph A 155-160 12 4MeO-Ph A 149-154 Notes (a) isolated as an oil: NMR8: 8.55 (1H, 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)5CH2CO]; 1.8-1.0 [20H, complex CH3(CH2)5CH2CO]; 0.85 [6H, triplet, CH3(CH2)5CH2CO]; (b) isolated as a foam of satisfactory purity as judged by IR spectroscopy and TLC (thin layer chromatography) analysis; (c) isolated as an oil: NMR#: 8.45 (1H, 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 (DMS+2H, complex, > CHCO); 1,65 [8H, quartet, (CH3CH2)2CHCO]; 098 [12H, triplet, (CH3CH2)2CHCO]; (d) isolated as a foam: NMR: 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); 2.4-1.7 (DMSO + ester > CH-) (24H, multiplet, CH3); (e) isolated as an oil: NMR: 9.50 (1H, broad, NH), 8.50 (1H, broad, NHCO); 8.0-7.0 (8H, complex, aromatic protons); 5.05 (2H, singler, 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 an oil: NMRG: 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); 2.3 [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 judged by IR and TLC analysis.
The required phenol starting material was prepared as follows:- 3',4'-Bis(acetoxy)-2-bromoacetophenone was reacted with N-[2-(benzylamino)ethyl]-2-phenylacetamide using a similar procedure to that described in Example 1 for the analogous pivaloyloxy derivative to give 2-{N-benzyl-N-[2-(2phenylacetamido)ethyl]amino}-3',4'-bis(acetoxy)acetophenone, which was isolated as its free base and converted to its hydrochloride salt with ethereal hydrogen chloride to give a solid, m.p. 140-145 C. This hydrochloride salt was dissolved in methanol (5 ml) containing 2% w/v of hydrobromic acid, and the solution was heated under reflux for 2 hours.After cooling to room temperature, the solution was diluted with ether (100 ml) and stored at 0-5 C to give 2-{N-benzyl-N-[2-(2- phenylacetamido)ethyl]aminof-3',4'-dihydroxyacetophenone hydrobromide as a white solid in 98% yield, m.p. 175-177 C (after recrystallisation from methanol/ether).
Example 9 Using a similar procedure to that described in Example 2 the following esters of the formula:
were obtained (as their hydrobromide salts) in yields of 3085% by reduction of the corresponding acetophenone derivatives of the formula:
with an excess of sodium borohydride to give an alcohol of the formula:
which was then hydrogenolysed in the presence of benzyl bromide to give the hydrogen bromide salt in situ.
Substituents Compound position No. (Ring B) R5 R11 m.p. ( C.) 1 3,4 H 4-Cl-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 4-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 @-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
Notes (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)3Cl; (b) isolated as an 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 derivative of formul XXXVI had the following properties (as their hydrobromide salts):
Intermediate Substituents for Compound position No. (Ring B) R5 R'1 m.p. ( C.) 1 3,4 H 4-Cl-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-Cl-Ph.CH2 175-178 6 3,4 H Ph.CHMe 168-170 7 3,4 H Ph.O.CH2 foam (b) 8 3,4 H 3-CF3-Ph. 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.CH2 214-215 Notes (a) isolated as a sticky solid:NMRS: 8.65 (H, broad, NHCO); 8.1-6.8 (7H, complex aromatic protons); 5.2 (2H, singlet, PhCH2N); 4.5 (2H, singlet, N.CO.CH2); 3.7 (3H, singlet, OCH3); 3,9-3.1 (complex); 1.3 [18H singlet, (CH3)3 C] (b) isolated as a foam: NMRG: 8.35 (1H, broad, NHCO); 8.0-6.7 (8H, comnplex aromatic protons); 5.15 (2H, singlet, PhCH2N); 4.65 (2H, singlet, PhOCH2); 4.35 (2H, singlet, N.CO.CH2); 4.0-3.0 (complex, NCH2CH2NN); 1.28 [18H, singlet (CH3)3C].
The acetophenone derivatives of formula XXXVI obtained in yields of 25-55% using an analogous procedure to that used for 2-{N-benzyl-N-[2-(2phenylacetamido)ethyl]amino}-3',4'-bis(pivaloyloxy)acetophenone hydrobromide in Example 1, by reacting 2-bromo-3',4'- or 3',5'-bis(pivaloyloxy)acetophenone [or for compound No. Il, 2-bromo-3',4'-bis(pivaloyloxy)propiophenone] with the appropriate N-benzyl-N'-acylethylene diamine of the formula: PhCH2NHCH2CH2NIICOR" XXXVIII These ethylene diamine derivatives were obtained in an analogous manner to that described in Example I for N-benzyl-N'(phenylacetyl)ethylene diamine (required for compound No. 11) and had the following properties (hydrochloride salts):
Starting material for Compound No. R11 m.p. ( C.) 1 4-CI-Ph 234-236 2 4-MeO-Ph 198-200 3 4-F-Ph.CH2 194-195 4,10 4MeO-Ph .CH2 196-197 5 4-CI-Ph.CH2 5455* 6 Ph.CHMe syrup (a) 7 Ph.O.CH2 182-184 8 3-CF3-Ph.O-CH2 147-149 9 Ph 54-56* * m.p. of free base.
(a) isolated as a syrup: NMR (free base) #: 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, CH2.NHCO) ; 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 No.
11 was obtained as follows:- 3',4'-Bis(pivaloyloxy)propiophenone was first prepared as a mobile liquid (63.6 g), in a similar manner to 3',4'-bis(pivaloyloxy)acetophenone in Example 1, starting from 3',4'-dihydroxypropiophenone (40 g), pivaloylchloride (63.3 ml) and triethylamine (73.2 ml). This mobile liquid (40.1 g) was then reacted with bromine (7.2 ml) in a similar manner to that used in Example I to obtained 2-bromo-3',4'bis(pivaloyloxy)acetophenone. The crude bromo compound thus obtained was purified by dry column chromatography on silica gel as described in Example 1 to give pure 2-bromo-3',4'-bis(pivaloyloxy)propiophenone as a solid (18.4 g), m.p.
58--60"C.
Example 10 A suspension of 2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino-3',4'-bispivaloyloxy acetophenone trifluoroacetate (3.3 g) in propan-2-ol (25 ml) was cooled to -lO0C and a sodium borohydride (0.56 g) was added in two portions interspersed by a portion of methanol (10 ml). After 45 minutes at -100C, a saturated aqueous solution (50 ml) of sodium chloride was added and the mixture was extracted with ether (3 x 80 ml). Evaporation of the dried (MgSO4) ehtereal extracts gave 1-[3,4bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenoxyacetamido)amino]ethanol as the free base (3.2 g) which was dissolved without purification in ethanol (50 ml). To this ethanol solution was added benzyl bromide (0.6 ml) and the mixture was then hydrogenated in the presence of 10% palladium-on-carbon (0.5 g) at atmospheric pressure and room-temperature during 3 hours. The catalyst was separated by filtration through kieselguhr. The residue was washed-with ethanol (20 ml) and the combined ethanol filtrate and washings were evaporated. The residue obtained was triturated with ether (200 ml) to give 1-[3',4'-bis(pivaloylxy)phenyl]-2-[1.1-di methyl-2-(2-phenoxyacetamido)ethylaminolethanol hydrobromide (2.1 g). m.p.
156-158 C (after crystallisation from ethanol-ether).
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, m.p. 129-320C.
The starting 2-[l,1-dimethyl-2(2-phenoxyacetamido)ethylaminol3',4'- bis(pivaloyloxy)acetophenone trifluoroacetate was obtained in an analogous manner to that for the corresponding 2-(2-phenylacetamido)ethylamino compound in Example 7, as a solid, in 85% yield, m.p. 183-1850C, by acylation of 2-[ 1,1 -dimethyl-2(2-phenoxyacetamido)ethylamino]-3',4' - dihydroxyacetophenone with pivaloyl chloride in trifluoroacetic acid.
The starting 2- [1,1 -dimethyl-2-(2-phenoxyacetamido)ethylamino] -3 ',4'- dihydroxyacetophenone was itself obtained as a foam, of satisfactory purity for acylation, by hydrogenolysis of 2-[1,1 -dimethyl-2-(2-phenoxyacetamido)ethylamino]-3',4'-bis(benzyloxy)acetophenone hydrobromide in an analogous manner to that described for 2-[1,1-dimethyl-2-(2-phenylacetamido)ethylamino]-3',4'- benzyloxy)acetophenone hydrobromide in Example 7.
The starting 3',4'-bis(benzyloxy)acetophenone derivative was also prepared in 67% yield by analogy with the corresponding compound in Example 7 from 2bromo-3',4'-bis(benzyloxy)acetophenone and N-(2-amino-2-methylpropyl)-2phenoxyacetamide, and had m.p. 137--1390C.
The N-(2-amino-2-methylpropyl)-2-phenoxyacetamide may be prepared in an analogous manner to that described for N-(2-amino-2-methylpropyl)-2-phenylacetamide in Example 3 or 7, and had m.p. 55-560C, after recrystallisation from aqueous ethanol.
Example 11 In a similar manner to Example 2, l-[3,4-bis(pivaloyloxy)-2-chlorophenyll- [2 - (2 - phenylacetamido)ethylamino]ethanol hydrobromide and 1 - [3,4 - bis (isovaleryloxy - 2 - chlorophenyl] - 2 - [2 - (2 - phenylacetamido)ethylamino]ethanol hydrobromide as solids, in yields of 56 and 41%, and having m.p. 139--142"C and 128-131 0C respectively, from 2-{N-benzyl-N-[2-(2-phenylacet- amido)ethyljaminol-2'-chloro-3',4'-bis(pivaloyloxy)- or -3',4'-bis(isovaleryloxy)- acetophenone trifluoroacetate.
The necessary starting trifluoroacetates were obtained as oily solids in 7085% yield (which solids were suitable for use without purification in the above process) by reaction of 2-lN-benzyl-N-[2-(2-phenylacetamido)ethyl]aminol-2'- chloro-3',4'-dihydroxyacetophenone hydrobromide with pivaloyl or isovaleryl chloride in trifluoroacetic acid, in a similar manner to that described in Example 7.
The 2'-chloro-3',4'-dihydroxy acetophenone derivative was obtained as follows: An ethereal diazomethane solution was directly distilled into a mixture of 3,4bis(benzyloxy)-2-chlorobenzoyl chloride (25.0 g) in ether (200 ml) maintained at -25"C. The reaction mixture was then allowed to warm up to room temperature and stirred at this temperature for 4 hours. A saturated ethereal solution of hydrogen bromide (approximately 150 ml) was then added cautiously to the reaction mixture until nitrogen evolution ceased. Chromatographic silica gel (125 g) was then added and the mixture was evaporated. The residue was added to the top of a column of dry chromatographic silica-gel (900 g) (previously deactivated by addition of 10% v/w water and then equilibrated with 10% v/w of a 5% v/v solution of ethyl acetate in toluene).The column was then developed by fractional elution, first with the same solvent mixture 1), and then with ethyl acetate (1.5 1). Evaporation of the appropriate ethyl acetate fractions (as monitored by thin layer chromatography) gave 2-bromo-3',4'-bis(benzyloxy)-2'-chloroacetophenone as a solid (28.1 g), m.p. 94--96"C.
The ethereal diazomethane solution was obtained using a standard procedure by adding a solution of N-methyl-N-nitroso toluenesulphonamide (45.0 g) in ether (300 ml) dropwise to a stirred solution of potassium hydroxide (12.9 g) in water (21 ml), maintaining the reaction temperature at 50-550C, and the addition rate to balance the loss of ethereal diazomethane by distillation.
[The starting benzoyl chloride was obtained in 90% yield from (2-chloro-3,4bis(benzyloxy)benzoic acid by reaction with thionyl chloride in a conventional manner and had m.p. 124--1260C. The 2-chloro-3,4-bis(benzyloxy)benzoic acid was itself obtained in 80% yield as a solid, m.p. 159--1620C, by oxidation of 2chloro-3,4-bis(benzoylloxy)benzaldehyde (itself described by Kaiser et alia in J.
Medicinal Cheiristry 1974, 17, 1071) with chromium trioxide in sulphuric acid solution (Jones reagent)].
A mixture of 2-bromo-3',4'-bis(benzyloxy)-2-chloroacetophenone (2.95 g) and N-[2-(benzylamino)ethyl]-2-phenylacetamide (3.7 g) in dioxan (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with dry ether (200 ml) and the precipitate, N-[2-(benzylamino)ethyl]-2-phenylacetamide hydrobromide, was separated by filtration. The filtrate was washed with water (3 x 50 ml) and then brine (100 ml), dried (MgSO4), filtered, and a fresh solution of hydrogen bromide in ether added until the pH was just acid.The mixture was stored for 16 hours at 50C and the oily solid which formed was triturated with a mixture of ethanol and ether to give 2-{N-benzyl-N-[2-(2-phenylacet- amido)ethyl]amino}-2'-chloro-3',4'-bis(benzyloxy)acetophenone hydrobromide (4.2 g), m.p. 162--1640C.
This hydrobromide (0.6 g) was stirred for 4 hours at room temperature with a solution of hydrogen bromide in acetic acid (48% w/v; 3 ml) to give a solution. This solution was evaporated and the residue was triturated with a mixture of ether and ethanol to give 2-IN-benzyl-N[2-(2-phenylacetamido)ethyl amino)-2'-chloro-3',4'- dihydroxyacetophenone hydrobromide (0.45 g), m.p. 196-197 0C.
Example 12 In a similar manner to Example 10, 1-[3,4-bis(pivaloyloxy)-2-chlorophenyl]-2- [1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]-ethanol hydrobromide and 1 [3,4-bis(isovalcryloxy)-2-chlorophenyl]-2-[1.1-dimethyl-2-(2-phenoxyacetamido)ethylamino]-ethanol hydrobromide were obtained as solids in 5R% and 49% yield and having m.p. 163--1640C and 176-179 C respectively, from 2-{[1,1- dimethyl-2-(2-phenoxyacetamido)ethyl] aminol-2'-chloro-3',4'-bis(pivaloyloxy)- or -3 ',4'-bis(isovaleryloxy)-acetophenone trifluoroacetate.
The necessary trifluoroacetates were obtained as oily solids in yields of 7080% (which solids were used in the above process without purification) in an analogous manner to that described in Example 7, by reacting 2-[[1,1-dimethyl-2 (2-phenoxyacetamido)ethyl]amino}-2'-chloro-3',4'-dihydroxy acetophenone hydrobromide (A) with pivaloyl or isovaleryl chloride in trifluoroacetic acid.
The above acetophenone derivative (A) was itself prepared in 85% yield, as a solid m.p. 141--1430C by a similar procedure to that described for the equivalent starting material in Example 11, but from 2-I[1,1 -dimethyl-2-(2-phenoxyacet- amido)-ethyl]amino}-2'-chloro-3',4'-bis(benzyloxy)acetophenone hydrobromide.
The latter compound was itself obtained in 40% yield as a solid, m.p. 61630C, from N-(2-amino-2-methylpropyl)-2-phenoxyacetamide and 2-bromo-3',4'bis(benzyloxy)-2'-chloro-acetophenone using a procedure similar to that in Example 11.
Example 13 A solution of 3'-acetoxymethyl-4'-acetoxyphenylglyoxal hydrate (1.45 g) and N-(2-amino-2-methylpropyl)-2-phenylacetamide (1.04 g) in acetonitrile (50 ml) was stirred at room temperature for 30 minutes. Acetic acid (2 ml), followed by sodium cyanoborohydride (0.64 g), was added to the vigorously stirred mixture. Stirring was continued at room temperature for 16 hours. The mixture was then evaporated. The semi-solid residue was partitioned between ethyl acetate (100 ml) and 10% v/v aqueous acetic acid (100 ml). The organic phase was separated, dried (MgSO4), filtered and evaporated. The residual oil was purified on a column of chromatographic silica gel (150 g) using 10% v/v ethanol/chloroform as eluant.The appropriate fractions from the column [as monitored by TLC (siO2: 10% v/v ethanol/chloroform)] were combined and evaporated to give 1-[3-acetoxymethyl-4 acetoxyphenyl]-2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl amino]ethanol as an oil (0.9 g, 36%): NMRA (CDCl3): 7.86.9 (8H, complex, aromatic protons), 6.3-5.8 (2H, broad singlet, CH(OH)CH2 and CH2NHC(CH3)2) 5.0 (3H, broad singlet, COOCH, and CH(OH)CH2) 3,5 (2H, sharp singlet, PhCH2CH, 3.35-3.2 (2H, doublet, (CH3)2CCHN2). 3.05-2.8 (2H, CH(OH)CH2NH complex), 2.25 (3H, sharp singlet, CH3COO) 2.0 (3H, sharp singlet, CH3COOHCH2) 1.2 (6H, doublet, NHC(CH3)2CH2); and pure by TLC (SiO2: 10 or 20% v/v ethanol/chloroform).
The starting substituted phenylglyoxal was itself prepared as follows:- 3'-Chloromethyl-4'-hydroxyacetophenone (108 g) was added to a mixture of anhydrous sodium acetate (54 g) glacial acetic acid (500 ml) and acetic an hydroxide (250 ml). The mixture was heated at 950C for 4 hours, then concentrated by distilling under reduced pressure. The gummy residue was dissolved in water (500 ml) and the aqueous solution was extracted with chloroform (3 x 300 ml). The combined extracts were dried (MgSO4), filtered and evaporated to give a yellow oil.
This was distilled under high vacuum to give 3'-acetoxymethyl-4'-acetoxyacetophenone as a colourless viscous liquid (108 g), b.p. 143-147 C (0.3 mm), which crystallised on cooling to give solid, m.p. 47-48 C.
A solution of bromine (7.1 g) in chloroform (2ü ml) was added dropwise to a stirred solution of 3'-acetoxymethyl-4'-acetoxyacetophenone (11.0 g) in chloroform (150 ml) at room temperature. After completion of the addition, the solution was washed with water (2 x 150 ml) and brine (100 ml). The organic phase was dried (MgSO4), filtered and evaporated to give 3'-acetoxymethyl-4'-acetoxy-2bromoacetophenone (10.0 g) which was judged to be sufficiently pure by 1R and TLC [SiO2; 1:1 v/v EtOAc/petrol (60-80 C)] for use without further purification or characterisation. A solution of 3'-acetoxymethyl-4'-acetoxy-2-bromoacetophenone (10.0 g) in dimethylsulphoxide (150 ml) was stirred at room temperature for 48 hours. The solution was then poured into ice-water (500 ml) and extracted with ethyl acetate (3 x 200 ml).The organic layers were combined, dried (MgSO4) filtered. The solvent was removed by evaporation to give 3'-acetoxymethyl-4'-acetoxy-phenylglyoxal hydrate as a yellow oil (6.5 g 81%). The glyoxal derivative had a satisfactory IR spectrum and was judged pure by TLC (SiO2: EtOAc) and was therefore used without full characterisation or isolation.
Examples 14-15 Using a similar procedure to that described in Example 13 the following diesters were obtained in yields of 5û 70% as oils, pure by TLC (SiO2: 10 or 20 v/v ethanol/chloroform): I(3'-isovaleryloxymethyl-4'-isovalveryloxyphenyl) - 2 - [1.1 - dimethyl - 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, CO2,CH2 and CH(OH)CH2); 3.5 (2H, a 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' - valveryloxymethyl -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, CO2CH2 CH(OH)CH2); 3.6 (2H, broad doublet, PhCH2CO); 3.4 (2H, broad doublet, C(C113)2CH2NH); 3.2-2.8 (2H, complex, CH(OH)CH2NH); 2.6 (2H, triplet, CH3(CH2)2CH2CO2); 2.2 (2H, triplet, CH3(CH2)2CH2CO2CH2); 1.8-1.2 (8H, complex, CH3CH2CH2CH2CO2); 1.2 (6H, doublet, NH-C(CH3)2CH2); 1.1-0.8 (6H, overlapping triplets, CH3(CH2)3CO2).
The starting substituted phenylglyoxals were obtained in a similar manner to that described for the phenylglyoxal derivative in Example 13 starting from the appropriate 2-bromoacetophenone. They were obtained as their hydrates, and were oils which were sufficiently pure, as judged by TLC (EtOAc: SiO2) and IR spectroscopy, to be used in the above preparations without isolation and full characterisation.
The necessary 2-bromoacetophenones were obtained as follows: 3'-Valeryloxymethyl-4'-valeryloxy-2-bromoacetophenone (For Example 14) Sodium hydride (2.0 g) was added in portions to stirred valeric acid (150 ml) over a period of 15 minutes. 3-Acetoxymethyl-4-acetoxy-acetophenone (40 gm) was then added, and the mixture was heated to 1600C and maintained at this temperature with stirring for 15 hours. The mixture was then concentrated by distilling under reduced pressure while maintaining the temperature at 160 C. The gummy residue was cooled and dissolved in ether (500 ml). This solution was washed with 10 / w/v sodium carbonate solution (3 x 250 ml). water (2 x 500 ml) and saturated brine (250 ml). The organic phase was dried (MgSO4), filtered and evaporated to give a brown oil.This was distilled under high vacuum to give 3' valeryloxymethyl-4'-valeryloxy-acetophenone as a colourless viscous liquid (16.0 g 30%): 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); 2.55-2.15 (4H, complex, CH3(CH2)2CH2CO2 and CH3(CH2)2CH2CO2CH2); 1.8-1.2 (8H, complex, CH3CH2CH2CH2CO2O); 1.1-0.8 (6H, overlapping triplets, CH3(CH2)3CO2).
A solution of bromine (4.2 g) in chlorororm (20 ml) was added dropwise to a cooled stirred solution of 3'-valeryloxymethyl-4'-valeryloxyacetophenone (8.5 g) in chloroform (100 ml). 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 with 10% w/v sodium carbonate solution (3 x 100 ml) water (2 x 100 ml) and saturated brine (100 ml). The organic phase was dried (MgSO4), filtered, and evaporated yielding 3 '-valeryloxymethyl-4'-valeryloxy-2-bromoacetophenone (6 g, 57%), which was judged to be sufficiently pure by IR and TLC[SiO2 : 50% v/v EtOAc/petrol (60-80 )] for use without further purification or characterisation.
2. 3'-Isovaleryloxymethyl-4'-isovaleryloxy-2-bromoacetophenone (For Example 15) This compound was obtained using an analogous procedure to that described in (1) hereinabove, but using isovaleric instead of valeric acid in the first stage. The 2-bromoacetophenone derivative was isolated as an oil having a satisfactory IR spectrum and pure by TLC [SiO2 : 50% v/v EtOAc/petrol (60-80 )]. 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 (2H, doublet, CH2CO2CH2); 1.1-0.8 (12H, comples, (CH3)2CH).
Example 16 In a similar manner to that described in Example 13 for l-[3-acetoxymethyl-4acetoxyphenyl]-2-[1,1-dimethyl-2-(2-phenylacetamido)ethylamino]ethanol, there was obtained from 3'-acetoxymethyl-4'-acetoxyphenylglyoxal and N-(2-amino-2 methylpropyl)-2-phenoxyacetamide, 1-[3-acetoxymethyl-4-acetoxyphenyl]-2-[1,1dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol, as in oil in 42% yield, having NMR# (CDCl3): 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, CH3CO2CH2); 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 (3H, sharp singlet, CH3CO2CH2); 1.3 (6H, doublet, NHC(CH3)2CH2); and pure by TLC (SiO2 10 to 20% v/v ethanol/chloroform).
Example 17 A solution of 1-(3,4-dihydroxyphenyl)-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol hydrobromide (0.8 g) in trifluoroacetic acid (5.4 ml) was treated with pivaloyl chloride (1.12 ml) and the mixture was heated under reflux for 40 minutes. The mixture was then evaporated and the residue was dissolved in ether. The solution obtained was treated with ethereal hydrogen bromide until just acid, where upon an oily solid separated. Trituration of this material with ether (20 ml) gave the triester, 1 [3,4-bis(pivaloyloxy)phenyl]-2-[ 1,1 -dimethyl-2-(2-phenoxy- acetamido)-ethylamino]ethyl pivaloate hydrobromide, as a solid (0.6 g) m.p.
106-110 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, CH2OPh); 4.0-3.0 (complex, CH2NH); 1.3-1.2 (33H, broad singlet, C.CH3).
The ethereal filtrate, after separation aof solid triester, contained isolable amounts of the diester, 1-[3,4-bis(pivaloyoxy)phenyl]-2-[1,1-dimethyl-2(2-phenoxy- acetamido)-ethylamino]ethanol, identical with that produced in Example 10, as indicated by TLC on silica using the following solvent systems:- (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 2[ 1,1 -dimethyl-2-(2-phenoxyacetamido)ethyl]amino-3',4' bis(benzyloxy)acetophenone hydrobromide (1.26 g) in 2-propanol (10 ml) was cooled to -100C and sodium borohydride (0.22 g) was added in two portions interspersed by a portion of methanol (10 ml). The reaction mixture was allowed to warm to 100C. After 30 minutes at this temperature, a saturated aqueous solution (100 ml) of sodium chloride was added and the mixture was extracted with ether (3 x 100 ml). The combined ether extracts were washed with water (100 ml) and then brine (100 ml), dried (MgSO4) and evaporated to give 1-[3,4-bis(benzyl- oxy)phenyl]-2-[1,I-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol as a sticky residue (1.2 g).
This residue was dissolved in ethanol (30 ml) and benzyl bromide (0.24 ml) was then added. The mixture was hydrogenated at atmospheric pressure and temperature in the presence of 10% w/w palladium-on-carbon (0.4 g) for 3 hours. The catalyst was separated by filtration, washed with ethanol (10 ml) and the combined filtrate and washings evaporated to give l-(3,4-dihydroxy- phenyl)-2- [1,1 -dimethyl.2-(2-phenoxyacetamido)ethylamino] ethanol hydro bromide as a foam (0.8 g) having a satisfactory NRM spectrum and sufficiently pure for direct use in the above procedure.
Example 18 Using a similar procedure to that described in Example 9, 1-[3,5bis(pivaloyloxy)phenyl] - 2 - [2 - (2 - phenoxyacetamido)ethylaminolethanol hydrobromide was obtained as a solid m.p. 93-950C in 68% yield by reduction of 2-lN-benzyl-N-[2 - (2 - phenoxyacetamido)ethyllaminol - 3',5' - bis(pivaloyloxy) acetophenone hydrobromide (A) with an excess of sodium borohydride to give the corresponding alcohol of formula XXXVII in situ, which was then hydrogenolysed in the presence of benzyl bromide.
The acetophenone hydrobromide (A) was obtained as solid, m.p. 90110 C having a satisfactory NMR spectrum, and in 43% yield, by reaction of 3',5'bis(pivaloyloxy)-2-bromoacetophenone with N-[2-(benzylamino)ethyl]-2-phenoxyacetamide in similar manner to that described for the analogous starting material in Example 1.
Example 19 A mixture of finely powdered 1 -[3,4-bis(pivaloyloxy)phenyl] -2-[1,1 -dimethyl-2- (2-phenoxyacetamido)ethylamino]ethanol hydrochloride or hydrobromide (0.5 parts by weight) in liquid paraffin (10 parts by weight) was added to molten white soft paraffin (89.5 parts by weight). The resulting mixture was allowed to cool to room temperature with fast stirring until a uniform ointment, suitable for application to humans, was formed.
In a similar manner, an ointment containing a compound of formula I as described in any one of Examples 1-9 or 11-18, or in a numbered part thereof, was obtained by using such a compound as the active ingredient in the above process.
Example 20 A solution of 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenoxy- acetamido)ethylamino]ethanol hydrochloride or hydrobromide (0.1 parts by weight) in 2-propanol (30 parts by weight) was prepared. Water (66.9 parts by weight) was added and the mixture was stirred rapidly during the addition of "Carbopol" 940 (3 parts by weight) until a finely dispersed gel, suitable for application to humans, was formed.
In a similar manner, a gel containing a compound of formula I as described in any one of Example 1-9 or 11-18, or in a numbered part thereof, was obtained by using such a compound as the active ingredient in the above process.
* "Carbopol" 940 is a grade of carboxypolymethylene gelling agent, available from B. F. Goodison Chemical Co., Cleveland, Ohio, U.S.A. "Carbopol" is a trade mark.
Example 21 A mixture of cetostearyl alcohol (9 parts by weight), liquid paraffin (7 parts by weight), sorbitan monostearate (2 parts by weight), polysorbate 60 (2 parts by weight) and finely powdered 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2phenoxyacetamido)ethylamino]ethanol hydrochloride or hydrobromide (0.1 parts by weight) was fused together at 65-70 C. Water (79.9 parts by weight) was added with stirring to the melt thus obtained. The mixture was then stirred rapidly with slow cooling to room temperature until a homogeneous cream, suitable for application to humans, was obtained.
In a similar manner, a cream containing a compound of formula I as described in any one of Example 1-9 or 11-18 or in a numbered part thereof, was obtained by using such a compound as the active ingredient in the above process.
WHAT WE CLAIM IS: 1. An ester of the formula:
wherein R1 is a C1-11-alkyl or (C3-6-cycloalkyl)-C1-5-alkyl radical, or a phenyl or benzyl radical optionally bearing a C1-6-alkyl or C1-6-alkoxy radical as a nuclear substituent; one of R2 and R3 is hydrogen; the other of R2 and R3 is a radical of the formula R1CO.O- wherein R1 has the meaning stated above; R4 is hydrogen, a C2-12-alkanoyl or (C3-6-cycloalkyl)-C2-6-alkanoyl radical, or a benzoyl or phenylacetyl radical optionally bearing a C1=6-alkyl or C1-6-alkoxy radical as a nuclear substituent; R5 is hydrogen or a methyl radical; R6 and R7, which may be the same or different are hydrogen, or C1-6-alkyl radicals; A1 is a direct bond or a methylene radical; A2 is a C1-4-alkylene radical;Z is hydrogen or chlorine; and Q is a radical of the formula:
wherein R8 is hydrogen of a methyl radical, X is a direct bond or oxygen, and benzene ring Y optionally bears a halogen atom, or trifluoromethyl, C1-6-alkyl or C1-6-alkoxy radical as a substituent; or a pharmaceutically acceptable acid addition salt thereof.
2. An ester as claimed in claim 1 wherein R1 is a straight-chain C1-11-alkul radical, a branched chain C3-11-alkyl radical, or a (C3-6-cycloalkyl)-C1-5-alkyl radical, or a phenyl or benzyl radical optionally bearing a C1-6-alkyl or C1-6-alkyl radical as a nuclear substituent; and R4 is hydrogen or a radical of the formula Alkyl.CO- wherein Alkyl is a straight-chain C1-11-alkyl radical or a branched chain C3-11-alkyl radical; or R4 is a (C3-6-cycloalkyl)-C2-6-alkanoyl radical, or a benzoyl or phenylacetyl radical optionally bearing a C1-6-alkyl or C1-6-alkyoxy radical as a nuclear substituent.
3. An ester as claimed in claim I or 2 wherein R' is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, t-butyl, l-methyl-2,2-dimethyl propyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 1,1 -diethylpropyl or (cyclopentyl)methyl radical, or a phenyl or benzyl radical optionally bearing a methyl or methoxy radical as a nuclear substituent; R4 is hydrogen or a radical of the formula Alkyl.CO- wherein Alkyl. is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (33)

**WARNING** start of CLMS field may overlap end of DESC **. Example 21 A mixture of cetostearyl alcohol (9 parts by weight), liquid paraffin (7 parts by weight), sorbitan monostearate (2 parts by weight), polysorbate 60 (2 parts by weight) and finely powdered 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2phenoxyacetamido)ethylamino]ethanol hydrochloride or hydrobromide (0.1 parts by weight) was fused together at 65-70 C. Water (79.9 parts by weight) was added with stirring to the melt thus obtained. The mixture was then stirred rapidly with slow cooling to room temperature until a homogeneous cream, suitable for application to humans, was obtained. In a similar manner, a cream containing a compound of formula I as described in any one of Example 1-9 or 11-18 or in a numbered part thereof, was obtained by using such a compound as the active ingredient in the above process. WHAT WE CLAIM IS:
1. An ester of the formula:
wherein R1 is a C1-11-alkyl or (C3-6-cycloalkyl)-C1-5-alkyl radical, or a phenyl or benzyl radical optionally bearing a C1-6-alkyl or C1-6-alkoxy radical as a nuclear substituent; one of R2 and R3 is hydrogen; the other of R2 and R3 is a radical of the formula R1CO.O- wherein R1 has the meaning stated above; R4 is hydrogen, a C2-12-alkanoyl or (C3-6-cycloalkyl)-C2-6-alkanoyl radical, or a benzoyl or phenylacetyl radical optionally bearing a C1=6-alkyl or C1-6-alkoxy radical as a nuclear substituent; R5 is hydrogen or a methyl radical; R6 and R7, which may be the same or different are hydrogen, or C1-6-alkyl radicals; A1 is a direct bond or a methylene radical; A2 is a C1-4-alkylene radical;Z is hydrogen or chlorine; and Q is a radical of the formula:
wherein R8 is hydrogen of a methyl radical, X is a direct bond or oxygen, and benzene ring Y optionally bears a halogen atom, or trifluoromethyl, C1-6-alkyl or C1-6-alkoxy radical as a substituent; or a pharmaceutically acceptable acid addition salt thereof.
2. An ester as claimed in claim 1 wherein R1 is a straight-chain C1-11-alkul radical, a branched chain C3-11-alkyl radical, or a (C3-6-cycloalkyl)-C1-5-alkyl radical, or a phenyl or benzyl radical optionally bearing a C1-6-alkyl or C1-6-alkyl radical as a nuclear substituent; and R4 is hydrogen or a radical of the formula Alkyl.CO- wherein Alkyl is a straight-chain C1-11-alkyl radical or a branched chain C3-11-alkyl radical; or R4 is a (C3-6-cycloalkyl)-C2-6-alkanoyl radical, or a benzoyl or phenylacetyl radical optionally bearing a C1-6-alkyl or C1-6-alkyoxy radical as a nuclear substituent.
3. An ester as claimed in claim I or 2 wherein R' is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, t-butyl, l-methyl-2,2-dimethyl propyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 1,1 -diethylpropyl or (cyclopentyl)methyl radical, or a phenyl or benzyl radical optionally bearing a methyl or methoxy radical as a nuclear substituent; R4 is hydrogen or a radical of the formula Alkyl.CO- wherein Alkyl. is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
isopropyl, isobutyl, t-butyl, I-methyl-2,2-dimethylpropyl, 2,2-dimethylpropyl, 1 ethylpropyl or I,l-diethylpropyl radical; or R4 is a (cyclopentyl)acetyl radical, or a benzoyl or phenylacetyl radical optionally bearing a methyl or methoxy radical as a nuclear substituent; R6 and R7, which be be the same or different, are hydrogen or methyl radicals; A2 is a methylene or ethylene radical; and benzene ring Y in radical Q optionally bears a fluorine, chlorine or bromine atom, or a trifluoromethyl, methyl or methoxy radical as a substituent.
4. An ester as claimed in any one of claims 1-3 wherein Q is an Nphenylcarbamoyl, N-(p-chlorophenyl)carbamoyl, phenylsulphonyl, toluene-psulphonyl, phenylacetyl, 4-fluoro-, 4-chloro- or 4-methoxy-phenylacetyl, 2-phenylpropionyl, phenoxyacetyl, (3-trifluoromethylphenoxy)acetyl, benzoyl, or a 4chloro-, 4-methyl- or 4-methoxybenzoyl radical.
5. An ester as claimed in claim 1 wherein R1 is a C,~"-alkyl, (C3 e-cycloalkyl)- C,~5-alkyl or benzyl radical; R4 is hydrogen, a C212-a1kanoyl, (C3~6-cycloalkyl)- C26-a1kanoy1 or phenylacetyl radical; Z is hydrogen; and Q is a radical of the formula II, III or IV.
6. An ester as claimed in claim 5 wherein R1 is a t-butyl, 2,2-dimethylpropyl, (cyclopentyl)methyl or benzyl radical; R4 is hydrogen, a 2,2-dimethylpropionyl, 3,3-dimethylbutyryl, (cyclopentyl)acetyl or phenylacetyl radical; and Q is an Nphenylcarbamoyl, N-(p-chlorophenyl)carbamoyl, phenylsulphonyl, toluene psulphonyl, phenylacetyl, 2-phenylpropionyl, phenoxyacetyl or (3-trifluoromethylphenoxy)acetyl.
7. An ester as claimed in any one preceding claim wherein R2 is a radical of the formula R'CO.O-- and R3 is hydrogen.
8. An ester as claimed in any one of claims 16 wherein R3 is a radical of the formula R1CO.O- and R2 is hydrogen.
9. An ester as claimed in any one preceding claim wherein A' is a direct bond.
10. An ester as claimed in any one of claims 1---8 wherein A' is a methylene radical.
11. An ester as claimed in any one preceding claim wherein Z is hydrogen.
12. An ester as claimed in any of claims 1--4 or 7-10 wherein Z is chlorine.
13. An ester as claimed in any one preceding claim wherein R4 and R5 are both hydrogen; R6 and R7 are both hydrogen or methyl radicals; A2 is a methylene radical; and Q is a radical of formula IV.
14. An ester of formula I wherein R' is an isopropyl, t-butyl, isobutyl or (cyclopentyl)methyl radical; R2 is a radical of the formula R'CO.O--; R3, R4 and R5 are hydrogen; R6 and R7 are both hydrogen or methyl radicals; A' is a direct bond; A2 is a methylene radical; Z is hydrogen; and Q is a phenylacetyl, phenoxyacetyl or 2-phenylpropionyl radical; or a pharmaceutically acceptable acid-addition salt thereof.
15. The ester 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethylamino]-ethanol; 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethy-2-(2-phenyl acetamido)ethylamino]-ethanol; or 1-[3,4-bis(3,3-dimethylbutyryloxy)phenyl]-2-[2- (2-phenylacetamido)ethylamino]-ethanol; or a pharmaceutically acceptable acidaddition salt thereof.
16. The ester 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]-ethanol; or a pharmaceutically acceptable acid-addition salt thereof.
17. The ester 1 - [3,4 - bis(pivaloyloxy)phenyl - 2 -[2 - (2 - phenoxyacet amido)ethylamino] - ethanol or 1 - [3,4 - bis(isovaleryloxy)phenyl] - 2 - [2 - (2 phenylacetamido)ethylamino] - ethanol; or a pharmaceutically acceptable acid addition salt thereof.
18. The ester 1 -[3,4-bis(pivaloyloxy)phenyl]-2-[2-(4-chloro-benzamido)ethyl- amino]-ethanol; or a pharmaceutically acceptable acid-addition salt thereof.
19. An ester as claimed in any one preceding claim which is in an opticallyactive form.
20. An acid-addition salt as claimed in any one preceding claim which is a salt derived from an inorganic acid.
21. An acid-addition salt as claimed in claim 20 which is a salt derived from hydrochloric, hydrobromic, phosphoric or sulphuric acid.
22. An acid-addition salt as claimed in any one of claims 1--19 which is a salt derived from an organic acid.
23. An acid-addition salt as claimed in claim 22 which is a salt derived from oxalic, tartaric, lactic, fumaric, citric, acetic, salicylic, benzoic, 3-naphthoic, methane sulphonic or adipic acid.
24. The hydrobromide or hydrochloride of an ester as claimed in any one of claims 1--19.
25. A process for the manufacture of an ester of formula I or a pharmaceutically acceptable acid-addition salt thereof, claimed in any one of claims 1--24 in which: (a) a compound of the formula:
or an acid-addition salt thereof, wherein U is a carbonyl radical or a radical of the formula -CHOR4- and W is a reductively removable protecting group, is reduced; (b) for an ester of formula I wherein R4 is hydrogen, an aryl ketone of the formula:
is reduced; (c) for an ester of formula I wherein R4 is hydrogen or an acyl radical of the formula R'.CO--, a hydroxy compound of the formula::
wherein one of G' and G2 is hydrogen and the other is a hydroxy radical, is reacted with an acylating agent derived structurally from an acid of the formula R'.CO2H; (c) for an ester of formula I wherein R4 is other than hydrogen, a compound of formula I wherein R4 is hydrogen reacted with an acylating agent derived structurally from an acid of the formula R9.OH wherein R6 has the same meaning as R4 other than hydrogen; (e) for an ester of formula I wherein R4 is hydrogen, a carbonyl derivative of the formula:
is condensed with an amine of the formula:
under reducing conditions; (f) for an ester of formula I wherein R4 and R5 are both hydrogen; a compound of the formula:
wherein W1 and W2 together form a direct bond, or wherein W' is hydrogen and W2 is a halogen atom, or a mixture of such compounds, is reacted with an amine of the formula XIII; wherein R1, R2 R3, R4, R5, R6, R7, A(, A2, Z and Q have the meanings defined in any one of claims 1--14; whereafter a racemic ester of formula I may be resolved into its optically-active forms; and whereafter an ester in free base forum may be converted into a pharmaceutically acceptable acid-addition salt by reaction with an acid affording a pharmaceutically acceptable anion.
26. A process as claimed in part (b) of claim 25 wherein the reduction is carried out using an alkali metal borohydride in an inert diluent or solvent and at a temperature of -20 to 30"C.
27. A pharmaceutical composition which comprises an ester of formula I, or a pharmaceutically acceptable acid-addition salt thereof, claimed in any one of claims 1--24, in association with a pharmaceutically acceptable diluent or carrier, in a form suitable for topical administration.
28. A composition as claimed in claim 27 which is in the form of an ointment, gel, aqueous or oily solution or suspension, emulsion or aerosol formulation.
29. A composition as claimed in claim 27 or 28 which contains in addition at least one known pharmaceutical agent selected from corticosteroids, phosphodiesterase inhibitors, anti-bacterial agents, anti-fungal agents, antihistamines, local anaesthetics and emollients.
30. An ester or pharmaceutically acceptable acid-addition salt thereof claimed in claim I as hereinbefore particularly described in any one of Examples 16 or in a numbered part thereof.
31. An ester or pharmaceutically acceptable acid-addition salt thereof claimed in claim 1, as hereinbefore particularly described in any one of Examples 1--12 or in a numbered part thereof.
32. An ester or pharmaceutically acceptable acid-addition salt thereof claimed in claim 1, as hereinbefore particularly described in any one of Examples 1--18 or in a numbered part thereof.
33. A pharmaceutical composition claimed in claim 27 as hereinbefore particularly described in any one of Examples 19-21 or in a part thereof.
GB52553/76A 1976-12-16 1976-12-16 Esters of hydroxy amino amides Expired GB1591618A (en)

Priority Applications (40)

Application Number Priority Date Filing Date Title
GB52553/76A GB1591618A (en) 1976-12-16 1976-12-16 Esters of hydroxy amino amides
ZA00776944A ZA776944B (en) 1976-12-16 1977-11-21 Esters
IE2355/77A IE45991B1 (en) 1976-12-16 1977-11-21 Esters of hydroxy amino amides
CA000291507A CA1121379A (en) 1976-12-16 1977-11-22 Esters
AU30869/77A AU518148B2 (en) 1976-12-16 1977-11-23 Esters w phenylethylahines
US05/855,004 US4423070A (en) 1976-12-16 1977-11-23 Esters
IL53466A IL53466A (en) 1976-12-16 1977-11-25 Esters of substituted phenylethylamines,their preparation and pharmaceutical compositions comprising them
MX777906U MX5346E (en) 1976-12-16 1977-11-29 PROCEDURE FOR THE OBTAINING OF ESTERES DERIVATIVES OF PHENYLETILLAMINES
GR54912A GR63097B (en) 1976-12-16 1977-12-02 Preparation process of esters
SE7713830A SE437019B (en) 1976-12-16 1977-12-06 SET TO MAKE NEW PHENYLETHYLAMINESTERS
NL7713655A NL7713655A (en) 1976-12-16 1977-12-09 NEW ESTERS OF PHENYLETHYLAMINS.
LU7778688A LU78688A1 (en) 1976-12-16 1977-12-14
HU77IE817A HU176680B (en) 1976-12-16 1977-12-14 Process for preparing phenyl-ethanolamine esters
PL1977202935A PL114111B1 (en) 1976-12-16 1977-12-14 Process for preparing novel esters of phenylethylamine derivatives
FI773779A FI67842C (en) 1976-12-16 1977-12-14 FOERFARANDE FOER FRAMSTAELLNING AV NYA ANTI-INFLAMMATORISKT VEKANDE ESTRAR AV 1- (DIHYDROXIFENYL ELLER HYDROXI-HYDROXI-M ETHLPHENYL) -2 - ((ACYLAMINO) ALKYLAMINO) ETHANOLER
AR270354A AR217094A1 (en) 1976-12-16 1977-12-14 PROCEDURE FOR THE MANUFACTURE OF DERIVATIVES OF 1- (3- (ACILOXI OR ACILOXIMETIL) -4- (O 5) ACILOXI-FENIL) -2 - ((ACILAMINO) ALQUILAMINO) -ETANOL
PL1977216323A PL113856B1 (en) 1976-12-16 1977-12-14 Process for preparing novel ester derivatives of phenylethylamine
PL1977216324A PL113857B1 (en) 1976-12-16 1977-12-14 Process for preparing novel ester derivatives of phenylethylamine
YU02987/77A YU298777A (en) 1976-12-16 1977-12-15 Process for preparing esters of phenylethylamine derivatives
PT67412A PT67412B (en) 1976-12-16 1977-12-15 Esters
DE19772756001 DE2756001A1 (en) 1976-12-16 1977-12-15 ESTERS OF PHENYLAETHYLAMINES
BE183493A BE861894A (en) 1976-12-16 1977-12-15 PHENYLETHYLAMINE ESTERS
FR7737940A FR2374300A1 (en) 1976-12-16 1977-12-15 PHENYLETHYLAMINE ESTERS
NO774326A NO148263C (en) 1976-12-16 1977-12-15 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ETHYLAMINE DERIVATIVES
CS778424A CS199698B2 (en) 1976-12-16 1977-12-15 Method of producing esters of phenylethylamine derivatives
DD77202671A DD133941A5 (en) 1976-12-16 1977-12-15 PROCESS FOR THE PRODUCTION OF ESTERS OF PHENYLAETHYLAMINE
AT902277A AT356083B (en) 1976-12-16 1977-12-16 METHOD FOR PRODUCING NEW ESTERS OF PHENYLAETHYLAMINE DERIVATIVES AND THEIR ACID ADDITION SALTS
IT30848/77A IT1143786B (en) 1976-12-16 1977-12-16 PHENYL-ETHYLAMINE ESTERS WITH TOPICAL ANTI-INFLAMMATORY PROPERTIES AND THEIR PHARMACEUTICAL USE
ES465149A ES465149A1 (en) 1976-12-16 1977-12-16 Esters
SU772553500A SU822753A3 (en) 1976-12-16 1977-12-16 Method of preparing esters of n-(acylaminoalkyl)dioxyphenylethanolamine or their salts
DK562177A DK562177A (en) 1976-12-16 1977-12-16 ESTERS OF PHENYLETHYLAMINS AND METHODS OF PREPARATION
JP15229877A JPS5384928A (en) 1976-12-16 1977-12-16 Novel phenylethylamine ester process for preparing same and pharmaceutical composition having antiinflammatory effect containing said ester
ES474222A ES474222A1 (en) 1976-12-16 1978-10-16 Esters
ES474223A ES474223A1 (en) 1976-12-16 1978-10-16 Esters of hydroxy amino amides
CS791570A CS199699B2 (en) 1976-12-16 1979-03-08 Method of producing esters of phenylethylamine derivatives
CS791571A CS199700B2 (en) 1976-12-16 1979-03-08 Method of producing esters of phenylethylamine derivatives
AT179879A AT364351B (en) 1976-12-16 1979-03-09 METHOD FOR PRODUCING NEW ESTERS AND THEIR ACID ADDITION SALTS
SU792776609A SU974935A3 (en) 1976-12-16 1979-06-18 Process for producing esters of substituted phenylethylamine or its salt
SU792780255A SU860691A3 (en) 1976-12-16 1979-06-18 Method of preparing phenylethanolamine derivatives
US06/416,369 US4470997A (en) 1976-12-16 1982-09-09 Esters

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB52553/76A GB1591618A (en) 1976-12-16 1976-12-16 Esters of hydroxy amino amides

Publications (1)

Publication Number Publication Date
GB1591618A true GB1591618A (en) 1981-06-24

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Family Applications (1)

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GB52553/76A Expired GB1591618A (en) 1976-12-16 1976-12-16 Esters of hydroxy amino amides

Country Status (4)

Country Link
BE (1) BE861894A (en)
ES (1) ES474223A1 (en)
GB (1) GB1591618A (en)
ZA (1) ZA776944B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0082665A1 (en) * 1981-12-23 1983-06-29 Imperial Chemical Industries Plc Phenol esters

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0082665A1 (en) * 1981-12-23 1983-06-29 Imperial Chemical Industries Plc Phenol esters
US4520027A (en) * 1981-12-23 1985-05-28 Imperial Chemical Industries Plc Anti-inflammatory esters of 4-(1-hydroxy-2-[(acylamino)alkylamino]ethyl) phenols
US4568691A (en) * 1981-12-23 1986-02-04 Imperial Chemical Industries, Plc Anti-inflammatory esters of 4-(1-hydroxy-2-[(acylamino)-alkylamino]-ethyl)-phenol derivatives, compositions, and method of use therefor

Also Published As

Publication number Publication date
ES474223A1 (en) 1979-04-16
ZA776944B (en) 1978-07-26
BE861894A (en) 1978-06-15

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