AU640390B2

AU640390B2 - Amide derivatives

Info

Publication number: AU640390B2
Application number: AU59927/90A
Authority: AU
Inventors: Brian Roy Holloway; Ralph Howe; Balbir Singh Rao; Donald Stribling
Original assignee: Imperial Chemical Industries Ltd
Current assignee: Syngenta Ltd
Priority date: 1990-07-27
Filing date: 1990-07-27
Publication date: 1993-08-26
Anticipated expiration: 2007-07-02
Also published as: AU5992790A

Description

AUSTRALIA

Patents Act 6 039 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. C Application Number: Lodged: :lass

B.

BIe S r Complete Specification Lodged: Accepted: Published: Priority Related Art: APPLICANT'S REF.: Patent of Addition of 75030/87 Name(s) of Applicant(s): IMPERIAL CHEMICAL INDUSTRIES PLC S Address(es) of Applicant(s): Imperial Chemical House, Millbank, London SW1P 3JF, United Kingdom Actual Inventor(s): Brian Roy HOLLOWAY, Ralph HOWE, Balbir Singh RAO and Donald STRIBLING Address for Service is: PHILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia, 3000 Complete Specification for the invention entitled: AMIDE DERIVATIVES The following statement is a full description of this invention, including the best method of performing it known to applicant(s): P19/3/84 -2- AMIDE DERIVATIVES The present application is a patent of addition to Australian Patent Application No 75030/87 the entire disclosure of which is incorporated herein by reference.

Australian Patent Application 75030/87 concerns novel amide derivatives and, more particularly, novel phenoxyacetic acid amide derivatives containing a (2-hydroxy-3-phenoxypropyl)amino group, which amides stimulate thermogenesis in warm-blooded animals and are of use, for example, in the treatment of obesity and related conditions, such as obesity of mature onset diabetes. The invention also provides pharmaceutical compositions for use in the administration of the amide derivatives of the 0 invention to warm-blooded animals, processes for the manufacture of the said derivatives, and the use of the said derivatives in the treatment of (and/or manufacture of thermogenic medicaments for use in the treatment of) obesity and related conditions.

Australian Patent Application 75030/87 provides an amide derivative of the formula I [set out hereinafter together with the other chemical formulae identified by Roman 1 2 numerals] wherein R is hydrogen or fluoro; R is phenyl optionally bearing a halogeno, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, cyano or nitro substituent, (3-6C)cycloalkyl, (l-4C)alkyl in which the carbon atom linked to the nitrogen of NR 2

R

3 bears one or two hydrogens, or 2 R is (3-4C)alkenyl, either of which latter groups may optionally bear a hydroxy, carbamoyl, (l-4C)alkoxy, phenyl or chlorophenyl substituent, and R 3 is hydrogen, methyl or ethyl; or R 2 and R 3 together form (4-7C)polymethylene, in which one methylene unit may optionally be replaced by oxygen or sulphur situated at least 2 carbon atoms distant from the 2 3 nitrogen atom of NR2R, and in which two adjacent methylene units may optionally be replaced by 2 carbon atoms of a benzene ring fused to said (4-7C)polymethylene, said benzene ring itself optionally bearing a halogeno, (l-4C)alkoxy, (l-4C)alkyl, trifluoromethyl, cyano or nitro substituent; or a pharmaceutically acceptable acid-addition salt thereof.

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2 3 The group -OCH 2 CO.NR R is generally located in the rmeta- or Para-position relative to the oxyethylamino side-chain, of which positions the para-position is preferred.

A preferred value for RI is hydrogen.

A particular value for R2 when it is (1-4C)alkyl or (3-4C)alkenyl as defined above is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, allyl or 2-methyl- 2-propenyl, optionally bearing a substituent selected from hydroxy, carbamoyl, (l-4C)alkoxy (such as methoxy or ethoxy), phenyl and chlorophenyl (in particular, p-chlorophenyl).

A particular value for R2 when it is phenyl is, for example, unsubstituted phenyl or phenyl bearing a substituent selected from fluoro, chloro, bromo, methoxy, S. ethoxy, methyl, ethyl, trifluoromethyl, cyano and nitro.

2 A particular value for R when it is (3-6C)cycloalkyl1 is, for example cyclobutyl, cyclopentyl or 0** S cyclohexyl.

Specific values for optional substituents which may be present when R2 is phenyl, or when a part of R and

R

3 together is a benzene moiety, as defined above, include for example:- *e for halogeno, fluoro, chloro and bromo; *9 for (1-4C)alkoxy: methoxy, ethoxy, propoxy and isopropoxy; and for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl and t-butyl.

A preferred value for R3 is, for example, hydrogen.

2 A particular value for R and R 3 when together they form (4-7C)polymethylene is, for example, tetramethylene or pentamethylene, and when together they form (4-7C)polymethylene in which one methylene unit is replaced by oxygen or sulphur is, for example, ethyl.eneoxyethylene or ethylenethioethylene.

23 Specific values for the group -NR R include, for example, anilino, benzylamino, allylamino, cyclohexylamino, cyclopentylamino, morpholino, piperidino, pyrrolidino, dimethylamino, diethylamino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (2-hydroxyethyl)amino, (3-hydroxypropyl)amino, (2-methoxyethyl)amino, indolin-1-yl, 1,2,3,4-

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-4tetrahydroisoquinol-2-yl and 1,2,3,4-tetrahydroquinol-l-yl.- A preferred group of compounds of Australian Patent Application 75030/87 comprises those compounds of formula I wherein R 1 is hydrogen; the group NR 2

R

3 is (l-4C)alkylamino (in which (1-4C)alkyl is as defined hereinbefore) (and especially methylamino or ethylamino), benzylamino, piperidino, pylrolidino, (3-4C)alkenylamino, morpholino or 1,2,3,4 tetrahydroisoquinol-2-yl; and the groups -OCH 2 .CO.NR R3 and -O.CH2CH2.NH- are attached in para-relationship; together with the pharmaceutically acceptable acid-addition salts thereof.

A further preferred group of compounds comprises those compounds of formula I wherein R 1 is hydrogen, the 2 3 group -NR R is methylamino, ethylamino, propylamino, isopropylamino, (2-hydroxyethyl)amino, (3-hydroxypropyl) amino, (2-methoxyethyl)amino, (3-methoxypropylamino or 1,2,3,4-tetrahydroisoquinol-2-yl; and the groups 2 3 *-OCH2.CO.NR R and -O.CH CH2.NH- are attached in para-relationship; together with the pharmaceutically acceptable acid-addition salts thereof.

It has now been discovered that the laevorotatory optically active forms (or enantiomer) of the compounds of Australian Patent Application 75030/87 are especially preferred.

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.

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, 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.

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. Such processes are illustrated by the

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following procedures in which R, R 2 and R 3 have any of the meanings previously defined:- An ester of the formula II wherein R 4 is (l-6C)alkoxy, phenoxy or benzyloxy, is reacted with an amine of the formula HNR 2

R

3 A particularly suitable value for R 4 is, for example, methoxy or ethoxy.

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 600, optionally in a pressure vessel when a volatile amine such as methylamine is used. The amine of the formula HNR 2

R

3 is conveniently present as an excess.

a. t The necessary starting esters may be obtained by reacting a phenol derivative of the formula III with an alkylating agent of the formula X.CH 2

.CO.R

4 wherein X is S a suitable leaving group, for example, chloro, bromo or iodo, S 4 and R has the meaning given above, in the presence of a base. It will be appreciated that this procedure is analogous to the process below and that generally similar reaction conditions and bases may be employed.

A phenol derivative of the formula III is reacted with an alkylating agent of the formula X.CH 2

CO.NR

2

R

3 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 120 0 C. 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 III with a suitable base to form the corresponding salt which is then added to the alkylating agent of the formula

X.CH

2

.CO.NR

2

R

3 The starting phenol derivatives of formula III may

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-6be obtained by conventional procedures of organic chemistry.

Thus, for example, they may be obtained by reaction of a phenol of the formula IV with an epoxide of the formula V 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 0 C and conveniently at or near the boiling point of the reaction mixture. The epoxides of formula V 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 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.

D

In general, it is preferred to react the epoxide of formula V with a protected phenol derivative of formula VI 'o wherein Q is a suitable protecting group, such as benzyl. In this case, following the reaction of compounds V and VI, 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 0 presence of a palladium-on-carbon catalyst in an inert diluent or solvent for example, a (l-4C)alkanol (such as methanol, ethanol or t-butyl alcohol) or a (l-4C)alkanoic acid (such as acetic acid) and at a temperature of, for example, 20-80 0

C.

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

An amine derivative of the formula VII is reacted with an epoxide of formula V.

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

The starting amine derivatives of formula VII may be made from the corresponding phenols of formula IV by reaction 2 3 with a compound of the formula X.CH 2 .CONR R as defined above using analogous reaction conditions to those described above in process

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-7- A prutected derivative of the formula VIII wherein Q is a suitable protecting group is deprotected.

A suitable protecting group is, for example, a hydrogenolysable group such as benzyl, 4-methoxybenzyl 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 VIII 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 VII may conveniently be obtained, for example, by reductive alkylation of the compounds of formula VII with benzaldehyde in the presence of sodium borohydride ci: in a solvent or diluent such as methanol at 00 to 25 0

C.

Whereafter, when a pharmaceutically acceptable acid-addition salt is required, the compound of formula I in free base form is reacted with the appropriate acid using a conventional procedure. For example, when a hydrogen halide salt is required, it may conveniently be obtained by hydrogenation 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. Alternatively, one of the above processes may be carried out using an optically active starting material.

The invention will now be illustrated by the following Example in which, unless otherwise stated:a) all operations were carried out at room temperature that is at a temperature in the range 18-26 0

C;

b) evaporations were performed under reduced pressure on a rotary evaporator; c) chromatography was carried out on Merck Kieselgel (Art 7734) obtainable from E Merck, Darmstadt, Federal Republic of Germany;

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d) yields are for illustration only and are not to be interpreted as the maximum attainable by diligent process development; e) nuclear magnetic resonance (NMR) spectra were determined at 200 MHz in d 6 -DMSO as solvent using tetramethylsilane (TMS) an internal standard and are expressed in delta values (parts per million) for protons relative to TMS, using conventional abbreviations to describe signal types; and f) all crystalline end-products had satisfactory microanalyses and NMR spectra.

Example 1 (-)-Methyl 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenoxyacetate (44.0g) and 2-methoxyethylamine were heated together on a steam-bath for 24 hours. The mixture was cooled and evaporated under reduced pressure to give an oily residue. This was dissolved in dichloromethane e9 (200ml) and treated with a solution of ether saturated with hydrogen chloride. The solvent was evaporated and the residual solid crystallised from a mixture of methanol and ethyl acetate to give ()-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]-N-(2methoxyethyl)phenoxyacetamide hydrochloride (39.2g), m.p.

171-3 0 C; aD -10.70 (c 1.0; methanol); microanalysis: found C, 58.1; H, 7.0; N, 6.0; Cl, required for

C

22

H

31 C1N 2 0 6 C, 58.1; H, 6.9; N, 6.2; Cl NMR (DMSO-d 6 3.l(m,lH,CHCH2NH); 3.24(s,3H,OCH 3 3.24- 3.45(m,7H,CHCH NHCH; NHCH2CH2CH 3 4.0(m,2H, ArOCH2CHOH); 4.2- 4.35(m,3H,CHOH; CH CH OAr); 22 5.95(d,1H,OH); 6.85-7.05(m,7H,Ar); 7.3(m,2H,Ar); 8.15(t,lH,

CONHCH

2 9.16 and 9.35 (broad peaks, 2H, NH CON~C H2)

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13 /H OCH2C cA4 2 NH- CA-I-kC)sc OH 0

N~NO-JA

2 c 7 O C 2 2C~H -Ha- TIV -V

S.

S

0@ S S S

S.

*5

OOSS

S S *5 S 5, S S

S

S..

S.

S

56 5 S S Q

OH

I'

N N. U4 2

.C.H

2

O

0CJA 2 (o .N~R -'f -VII Q4 CA N CA4.,) C"Ix YflI Kzio" ,c~j-~co-NP :Z12R3

Claims

1. (.)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]- N-(2-methoxyethyl)phenoxyacetamide or a pharmaceutically acceptable acid-addition salt thereof.

2. (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]- N-(2-methoxyethyl)phenoxyacetamide hydrochloride.

3. A pharmaceutical composition comprising a compound as claimed in claim 1 or 2, together with a pharmaceutically acceptable diluent or carrier.

4. A process for the manufacture of a compound as claimed in claim 1 or 2, which is characterised in that: an ester of the formula II wherein R 4 is (1-6C)alkoxy, phenoxy or benzyloxy, is reacted with an amine of the formula HNR 2 R 3 a phenol derivative of the formula III is reacted with an alkylating agent of the formula X.CH 2 .CO.NR R wherein X is a leaving group; an amine derivative of the formula VII is reacted S with an epoxide of formula V; or S a protected derivative of the formula VIII wherein Q is a protecting group is deprotected; whereafter when a pharmaceutically acceptable acid-addition salt is required, the compound of formula I in free base form is reacted with the appropriate acid using a conventional procedure; and .e when an enantiomer of a compound of formula I is required, the corresponding racemate may be resolved or one of the S above procedures may be carried out using an optically active starting material; and wherein the formulae II, III, VI, VII and VIII are as hereinbefore defined. A method of stimulating thermogenesis in warm-blooded animals by administration of a compound as claimed in claim 1 or 2 or a composition as claimed in

9- claim 3. 6. A method of treatment of obesity and related conditions by administration of a compound as claimed in claim 1 or 2 or a composition as claimed in claim 3. 7. A process as claimed in claim 4 substantially as hereinbefore described with reference to the Examples. DATED: 15 June 1993 PHILLIPS ORMONDE FITZPATRICK Attorneys: for: IMPERIAL CHEMICAL INDUSTRIES PLC 3155N o O^ *o **oo* **o 10