AU627052B2 - Phenyl ethers - Google Patents

Description

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AUSTRALIA

67 052 Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: .1' Priority This t conijs the and is correct for 6r2/8 Patent of Addition of 60029/86 Related Art: APPLICANT'S REF.: Name(s) of Applicant(s): IMPERIAL CHEMICAL INDUSTRIES PLC Address(es) of Applicant(s): Imperial Chemical House, Millbank, United Kingdom London SW1P 3JF, ii j i Actual Inventor(s): Brian Roy H Donald STRI Address for Service is: Complete Specification for the inventi IOLLOWAY Ralph HOWE, Balbir Singh RAO and

BLING.

PHILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia, 3000 on entitled: PHENYL ETHERS iption of this invention, including the best method of performing it knovw to The following statement is a full descr applicant(s): P19/3/84 i -I .ii jii -2- PHENYL ETHERS S. S 0* S.

S.

S

*SS S The present application is a patent of addition to Australian Patent Application No 60029/86 the entire disclosure of which is incorporated herein by reference.

Australian Patent Application 60029/86 concerns novel ethers, and, more particularly, novel ethers containing a (2-hydroxy-3-phenoxypropyl)amino group, which ethers stimulate thermogenesis in warm-blooded animals and are of use in the treatment of ob.sity and related conditions, such as obesity in mature onset diabetics. The invention also provides pharmaceutical compositions for use in the administration of the phenyl ethers of the invention to warm-blooded animals and processes for the manufacture of the novel phenyl ethers.

Australian Patent Application 60029/86 provides a phenoxyacetic acid derivative of the formula I [set out hereinafter together with the other chemical formulae identified by Roman numerals] wherein R is hydrogen or fluoro; R 2 and R 3 are independently selected from hydrogen and (1-3C)alkyl; and Z is hydroxymethyl or a group of the formula -CO.R 4 in which R 4 is hydroxy, (l-6C)alkoxy or amino; or a pharmaceutically acceptable salt thereof as appropriate.

The group -OCH2Z is generally located in the metaor para-position relative to the oxyethylamino side-chain, of which positions the para-position is preferred.

A preferred value for R 1 is hydrogen.

2 3 A particular value for R or R is, for example, hydrogen, methyl, ethyl or propyl, of which values, hydrogen or methyl are generally preferred.

4 A particular value for R when it is (l-6C)alkoxy is, for example, methoxy, ethoxy, butoxy or t-butoxy.

A preferred value for Z is a group of the formula

-CO.R

Preferred values for R include hydroxy, amino, methoxy and t-butoxy.

A preferred group of compounds of Australian Patent Application 60029/86 comprises those compounds of formula I 1 2 3 wherein R1 is hydrogen, R 2 is hydrogen or methyl, R is

DMW

555* 0 0 0S 00 .0 I 0 -3hydrogen, Z is a group of the formula -CO.R 5 in which R is hydroxy, (l-4C)alkoxy (such as methoxy, ethoxy or t-butoxy) or is amino, and the groups -OCH 2 Z and OCH2CR 2

R

3 NH- are attached in para relationship, together with the pharmaceutically acceptable salts thereof, as appropriate.

The compounds of formula I are basic and may be isolated and used either in the form of the free base or of a pharmaceutically acceptable acid-addition salt thereof. In addition, those compounds of formula I wherein R (or R) is hydroxy are amphoteric and may be isolated and used in the zwitterionic form, or as a pharmaceutically acceptable acid-addition salt, or as a salt with a base affording a pharmaceutically acceptable cation.

Particular examples of pharmaceutically acceptable acid-addition salts include, for example, salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides), sulphates and phosphates, e• and salts with organic acids such as succinates, citrates, lactates, tartrates, oxalates and salts derived from acidic polymeric resins, such as the free acid form of sulphonated polystyrene.

Paricular examples of salts with bases affording a pharmaceutically acceptable cation include, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium and magnesium salts, and ammonium salts and salts with suitable organic bases, such as triethanolamine.

It has now been discovered that the compounds of Australian Patent Application 60029/86 wherein the compound is in the form of the (-)-enantiomer with reference to the chiral centre of the -OCH 2

CH(OH)CH

2 NH- moiety are 00. especially preferred.

The compounds of formula I may be obtained by conventional processes of organic chemistry well known in the art for the production of structurally analogous compounds, for example as set out in our UK patent specification, Ser.

No. 1,455,116 and are illustrated by the following procedures 1 2 3 4 in which R, R, R, R, and Z have any of the previously defined meanings:-

DMW

I 1 -4- A phenol derivative of the formula II is reacted with an alkylating agent of the formula X.CH 2 Z wherein X is a suitable leaving group, for example a chloro, bromo, iodo, methanesulphonyloxy or P-toluenesulphonyloxy group.

The process is conveniently performed in the presence of an external base, for example an inorganic base such as an alkali metal carbonate or acetate potassium carbonate or sodium acetate), or an alkali metal hydride sodium hydride), and at a temperature in the range, for example, 10 to 1200C. A suitable solvent or diluent, for example acetone, methyl ethyl ketone, propan-2-ol, 1,2-dimethoxyethane or t-butyl methyl ether may conveniently be used. In order to minimise side-reactions, the process may also be carried out by pre-reacting the phenol of formula II with a suitable base to form the corresponding salt which is added to the alkylating agent of the formula X.CH 2

Z.

The starting phenol derivatives of formula II may be obtained by conventional procedures of organic chemistry.

Thus, for example, they may be obtained by reaction of a phenol of the formula III with an epoxide of the formula IV in a suitable solvent or diluent, for example, an alcohol such as ethanol or propan-2-ol, at a temperature in the range, for example, 100 to 110°C and conveniently at or near the boiling point of the reaction mixture. The epoxides-of formula IV are known per se but can be made by reaction of phenol or o-fluorophenol with epichlorohydrin or epibromohydrin in the presence of a suitable base such as an alkali metal hydroxide, piperidine, morpholine or S N-methylmorpholine, in a suitable solvent or diluent such as methanol, ethanol or propan-2-ol, conveniently at or near the boiling point of the reaction mixture.

In general, it is preferred to react the epoxide of o formula IV with a protected phenol derivative of formula V wherein Q is a suitable protecting group such as benzyl. In this case, following the reaction of compounds IV and V, the protecting group is removed, for example in the case of benzyl by hydrogenolysis, for example using hydrogenation at a pressure in the range, for example, 3 to 30 bar in the presence of a palladium-on-carbon catalyst in an inert diluent or solvent for example, a (l-4C)alkanol (such as DMW i methanol, ethanol or t-butyl alcohol) and at a temperature of, for example, 20-80 0

C.

It is to be understood that the epoxides of formulae IV may be used in their racemic or enantiomeric forms.

An amine derivative of the formula VI is reacted with an epoxide of formula IV.

It will be appreciated that this reaction is a modiLication of the procedure described above for the production of the starting materials of formula II and that, therefore, generally similar reaction conditions may be employed.

The necessary starting materials of formula VI may be made from the corresponding phenols of formula III by reaction with a compound of the formula X.CH2Z as defined above using analogous reaction conditions to those described above in process A protected derivative of the formula VII wherein Q is a suitable protecting group is deprotected.

A suitable protecting group is, for example, a hydrogenolysable group such as benzyl, 4-methoxy-benzyl or 3,4-dimethoxybenzyl, which may be removed, for example by hydrogenation using conditions similar to those defined above in the production of the starting materials for process Hydrogen pressure of, for example, 3 to 30 bar may be used at a temperature in the general range, for example 200 to 80 0

C.

The protected derivatives of formula VII may be obtained by using process or with appropriate starting materials in which the amino group is protected with a suitable protecting group. When Q is benzyl, the corresponding benzylated starting materials analogous to those of formula VI may conveniently be obtained, for example, by reductive alkylation of the compounds of formula VI with benzaldehyde in the presence of sodium borohydride in a solvent or diluent such as methanol at 00 to 250C.

For a compound wherein Z is carboxy, an ester or amide of the formula I in which Z is replaced by a radical of 6 6 swhbserieinkeA seconcry CmAn o the formula -CO.R wherein R is amino, (l-6C)alkoxy, phenoxy or benzyloxy, is decomposed.

A preferred decomposition method is hydrolysis using rW acid or base conditions. Suitable acid conditions are for A DMW ,i I i; i-i 'i i i" \:il i.

ir ictp

I

A'

.i i i r lv -6-

SO

a a a a a a example a strong mineral acid such as hydrochloric, sulphuric or phosphoric acid, conveniently at a temperature in the range, for example, 200 to 110 0 C and in a polar solvent, such as water, a (l-4C)alkanol (for example methanol or ethanol) or acetic acid. In such cases, the corresponding mineral acid salt of the compound of formula I wherein Z is carboxy may be conveniently isolated. Alternatively, base conditions may be used, for example lithium, sodium or potassium hydroxide, conveniently in a suitable solvent or diluent such as an aqueous (l-4C)alkanol at a temperature in the range, for example, 10 to 110 0

C.

As yet further alternatives, when R is t-butoxy, the decompostion may be carried out, for example by thermolysis at a temperature in the range, for example, 100 to 220 0 C, alone or in the presence of a suitable diluent such as diphenyl ether; or, when R 6 is benzyloxy, by hydrogenolysis, for example as described hereinbefore for process For a compound wherein Z is carbamoyl, an ester of the formula I in which Z is replaced by a radical of the 7 7 formula -CO.R wherein R is (l-6C)alkoxy, phenoxy or benzyloxy is reacted with ammonia.

The process is generally performed in a suitable inert solvent or diluent, for example, a (l-4C)alkanol such as methanol or ethanol and at a temperature in the range, for example, 00 to 60 0 C, optionally in a pressure vessel to prevent loss of ammonia.

The necessary starting esters are either compounds of the invention or may be obtained by analogy with the compounds of the invention using an analogous process to or herein.

For a compound wherein Z is hydroxymethyl, the corresponding acid of formula I wherein Z is carboxy or an ester of the formula I in which Z is replaced by a radical of 7 the formula -COR as defined in above, is reduced.

Suitable reducing conditions are any of those known in the art to reduce carboxylic acids or esters to the corresponding hydroxymethyl derivatives. For example, an aluminium or boron hydride derivative such as lithium aluminium hydride, sodium borohydride, sodium

DMW

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I

vi 1^ i fc^ .jl- 1

L-

I

I .o RT 1 -7cyanoborohydride or sodium dihydro-bis(2-methoxyethoxy)aluminate, or an alternative alkali metal salt, may be used.

The process is conveniently carried out in a suitable solvent or diluent, for example, in a (l-4C)alkanol or an ether, such as methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane or t-butyl methyl ether, optionally together with a hydrocarbon such as toluene or xylene. The process is generally performed at the lowest temperature within the range, for example -15° to 80 0 C, which is consistent with a reasonable reaction rate.

For a compound of formula I wherein one of R 2 and 3 2 R is hydrogen or (l-3C)alkyl and the other of R and 3 8 R is hydrogen, an imine of the formula VIII where R is hydrogen or (l-3C)alkyl is reduced.

The reduction may be carried out using any reagent known to reduce azomethine groups without affecting other 4 reactive groupings such as the CO.R group when present.

For example, hydrogen may be used in the presence of a suitable catalyst, such as a platinum catalyst, and in a S suitable solvent or diluent, such as a (1-4C)alkanol, optionally together with water and at a temperature in the range, for example, 100 to 30 0 C. Alternatively, for example, an alkali metal cyanoborohydride, such as sodium cyanoborohydride, may be used in a suitable solvent or diluent, such as acetonitrile, methanol, ethanol or propan-2-ol, and at a temperature in the range, for example, -200 to 30 0 C. When an alkali metal cyanoborohydride is used the reaction may be conveniently carried out at a pH of about 4, for example in the presence of acetic acid.

The imines of formula VIII may be conveniently obtained by condensation of an amine of the formula IX with a ketone derivative of the formula X in which R has the meaning defined above. The condensation may be carried out using any known standard procedure, for example by removal of water by azeotropic distillation in a suitable solvent, such as toluene. In some cases, it may be convenient to carry out the condensation reaction forming the imine and the subsequent reduction in situ, for example by reacting .an amine of the formula IX with a ketone 0 ivative of the formula X as defined above (or a hydrate or hermiacetal DMW V J t6 i r I -i if;: ii -8thereof when R 8 is hydrogen) with an alkali metal borohydride or cyanoborohydride, and such a modified process is also provided by the invention.

Whereafter a compound of formula I wherein Z is carboxy may, if desired, be converted to the corresponding compound of formula I wherein Z is carbamoyl or [(l-6C)alkoxy]carbonyl by a conventional amidification or esterification procedure.

Similarly, a compound of formula I wherein Z is hydroxymethyl may, if desired, be oxidised to the corresponding acid of formula I wherein Z is carboxy by a conventional oxidation procedure, for example using platinum and oxygen in aqueous acetone or tetrahydrofuran, at a temperature in the range, for example, 100 to 50 0

C.

Whereafter, when a pharmaceutically acceptable salt is required, the compound of formula I in free base (or, when R is hydroxy, in zwitterionic form) is reacted with the appropriate acid or base using a conventional procedure. For example, when a hydrogen halide salt is required, it may conveniently be obtained by hydogenation of the free base together with the stoichiometric amount of the corresponding benzyl halide.

Whereafter, when an enantiomer is required, the corresponding racemate may be resolved, for example by reaction with a suitable optically active acid using a conventional procedure.

Example 1 A mixture of (-)-N-(2-methoxyethyl)-2-p-(2-[(2-hydroxy-3phenoxypropyl)amino]ethoxy)phenoxyacetamide (22 g) in 2M sodium hydroxide solution was heated at 95-100 0 C for 48 hours. The mixture was cooled, filtered and the solid was washed with water. This solid was dissolved in boiling 2M hydrochloric acid solution (400 ml) and allowed to cool to give [(2-hydroxy-3-phenoxypropyl-amino]ethoxy)phenoxyacetic acid hydrochloride (15.1 g) m.p. 183-184°C; microanalysis, found: C, 57.8; H, 6.1; N, 3.5; C1 required for C 9 gH 24 NC106; C, 57.4; H, 6.1; N, 3.5; Cl, 8.9%; -12.4° (c 1.01, methanol).

D

L

m f\O "u vVg o Sec.

77 I 0 I 11 ;1 I r i- i -Sa- Example 2 A suspension of (-)-N-(2-methoxyethyl)-2-p-(2-[(2hydroxy-3--phenoxypropyl)aminolethoxy)phenoxyacetamide (100 g) in 4M hydrochloric acid (1500 ml) was heated at 95-100 0 C for 2 hours. The hot solution was filtered and allowed to cool to give (-)-2-p-(2-E(2-hydroxy-3-phenoxypropyl)aminolethoxy)phenoxyacetic acid hydrochloride (35.0 g) m.p. 183-184 0

C;

microanalysis, found: C, 57.0; H, 6.3; N, 3.3; Cl, 8.7%; required for C 1 9

H

24 C1,10 6: C, 57 H 6.1; N 3.5; Cl, 8.9; 12.6(c 1.0, methanol).

S

99 S 9 9* 9 3N W

U<

1077~ 4 4 4. 0 4.

5 4 4*4 -8b- 11.

R3.

C) 0i CH CA* H2 NCHI. CA 2

H(

/OH

Z

4AN. C 0 H

I

MCN~N3 711 Dc ~OO-42z 4 444S 9.

4. 4 *4 4 .4 44** 4

S.

4

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Claims (8)

1. A phenoxyacetic acid derivative of the formula I as 1 2 hereinbefore defined wherein R is hydrogen or fluoro; R and R 3 are independently selected from hydrogen and (l-3C)alkyl; and Z is hydroxymethyl or a group of the formula

4. 4 -CO.R in which R is hydroxy, (1-6C)alkoxy or amino and wherein the compound is in the form of the (-)-enantiomer with reference to the chiral centre of the -OCH2CH(OH)CH2NH- moiety; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1 wherein R 2 and 3 R are independently selected from hydrogen, methyl, ethyl and propyl, and R 4 is hydroxy, amino, methoxy, ethoxy, butoxy or t-butoxy. 3. A compound as claimed in claim 1 or 2 wherein the group -OCH2Z is located in the meta- or para-position relative to the oxyethylamino side-chain. 4. A compound as claimed in any of claims 1-3 wherein 2 3 R and R are independently selected from hydrogen or methyl.

5. A compound as claimed in any preceding claim wherein 09 4 9. 9 94 9 .9 9* S *0cS 0 1 4 SR is hydrogen and Z is a group of the formula -CO.R and the group -OCH 2 Z is located in the Para-position relative to the oxyethylamino side-chain.

6. A compound as claimed in claim 1 of the formula I 4 4P 1 2 set out below wherein R is hydrogen, R is hydrogen or Smethyl, R 3 is hydrogen, Z is a group of the formula -CO.R 5 in which R 5 is hydroxy, (l-4C)alkoxy or amino, and the groups -OCH 2 Z and -OCH 2 CR2R3NH- are attached in para-relationship, together with the pharmaceutically acceptable salts thereof.

7. A compound selected from (-)-2-D-(2-[(2-hydroxy-3- phenoxypropyl)amino]ethoxy)phenoxyacetic acid, its methyl 0*' ester, and the pharmaceutically acceptable salts of said acid or ester.

8. (-)-2-p-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy) phenoxyacetic acid hydrochloride.

9. A pharmaceutically acceptable salt as claimed in any one preceding claim, which is a pharmaceutically acceptable acid-addition salt with an inorganic or organic acid, or, DMW i i d i I ii :&9 I S i s- iii _D .u j _I I i I- -lo- when Z is a carboxy group, a salt with an inorganic or organic base affording a pharmaceutically acceptable cation. A pharmaceutical composition which comprises a phenoxyacetic acid derivative of the formula I as hereinbefore defined or a pharmaceutically acceptable salt thereof, as claimed in claim 1, together with a pharmaceutically acceptable diluent or carrier.

11. A process for the manufacture of a phenoxyacetic acid derivative of the formula I as hereinbefore defined or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-9, which is characterised in that:- a phenol derivative of the formula II as hereinbefori defined is reacted with an alkylating agent of the formula X.CH 2 Z wherein X is a suitable leaving group; an amine derivative of the formula VI as hereinbefore defined is reacted with an epoxide of the formula IV; A protected derivative of the formula VII as hereinbefore defined wherein Q is a suitable protecting group is deprotected. for a compound of formula I wherein Z is carboxy, an too ester or amide of the formula I in which Z is replaced by a radical of the formula -CO.R 6 wherein R is amino substituted secondary amino, (1-6C)alkoxy, phenoxy or benzyloxy, is decomposed; for a compound of formula I wherein Z is carbamoyl, an ester of formula I in which Z is replaced by a radical of the formula -COR 7 wherein R 7 is (l-6C)alkoxy, phenoxy or benzyloxy, is reacted with ammonia; for a compound of formula I wherein Z is hydroxymethyl, the corresponding acid of formula I wherein Z is carboxy or an ester of formula I in which Z is replaced by a radical of the formula -CO.R 7 as defined in above, is reduced; or for a compound of formula I wherein one of R 2 and 3 2 R is hydrogen or (l-3C)alkyl and the other of R 2 and R 3 is hydrogen, an imine of the formula VIII wherein R 8 is hydrogen or (l-3C)alkyl is reduced; whereafter, an acid of formula I wherein Z is carboxy may be converted to the corresponding amide (R is amino) or ester (R 4 is (l-6C)alkoxy) by a conventional ON 0 Sec, A, .7 -11- amidification or esterification procedure, and an alcohol of the formula I wherein Z is hydroxymethyl may be oxidised by a conventional procedure to the corresponding acid (Z is carboxy); whereafter, when a pharmaceutically acceptable salt is required, the compound of formula I in free base form or, when Z is carboxy in zwitterionic form is reacted with the appropriate acid or base using a conventional procedure; and when an enantiomer is required, the corresponding racemate of formula I is resolved using a conventional procedure, or one of the above-defined procedures is carried out using an optically active starting material. DATED: 27 July 1990 a. PHILLIPS ORMONDE FITZPATRICK Patent Attorneys for: r S IMPERIAL CHEMICAL INDUSTRIES PLC P, G* 1385U I V? 0i 1