AU734276B2

AU734276B2 - Aryloxypropanolamine derivatives, method of preparation and applications thereof

Info

Publication number: AU734276B2
Application number: AU50565/98A
Authority: AU
Inventors: Philippe Archimbault; Ahmed El Hadri; Gerard Leclerc; France Pietri-Rouxel; Arthur Donny Strosberg
Original assignee: Virbac SA
Current assignee: Virbac SA
Priority date: 1996-11-05
Filing date: 1997-11-03
Publication date: 2001-06-07
Anticipated expiration: 2017-11-03
Also published as: FR2755439B1; CA2270581C; JP4014643B2; JP2001503753A; EP0937063A1; FR2755439A1; DE69711911T2; WO1998020005A1; CA2270581A1; DE69711911D1; ES2175378T3; AU734276C; EP0937063B1; AU5056598A

Description

WO 98/20005 PCT/FR97/01963 ARYLOXYPROPANOLAMINE DERIVATIVES, METHOD OF PREPARATION AND APPLICATIONS THEREOF The present invention relates to aryloxypropanolamine derivatives possessing at least antidiabetic and antiobesity activity, to the methods for their preparation and to their applications, especially as drugs in human and veterinary medicine and as animal feed additives.

There are two major forms of diabetes in existence, namely type I or insulindependent diabetes, which results from a complete insulin deficiency, and type II or insulin-independent diabetes, which often appears in the presence of normal or even slightly raised insulin levels and seems to be the result of an inability of the tissues to respond appropriately to the presence of insulin, due to metabolic anomalies in glucose production and utilization; such anomalies prevent the maintenance of a physiological blood glucose level, resulting in hyperglycaemia. The majority of type II diabetics are also obese.

In addition to special diets, the customary methods of treating type II diabetes and obesity include the use of P-adrenergic agents and more particularly

P

3 -adrenergic agents (agonists), which stimulate lipolysis.

Compounds which stimulate the 3 3 -adrenergic receptors also possess antiobesity activity. They further possess hypoglycaemic (antihyperglycaemic) and antidiabetic activity, although the mechanism of this effect does not seem to be known.

The following may be mentioned among the products possessing 3 3 adrenergic activity: phenylethanolamines (patent US 4,478,849 in the name of Ainsworth et al.; patent US 5,106,867 in the name of Bloom et al.; article published in Drugs Fut., 1993, 18(6) 541), which are considered to have antiobesity, antidiabetic and antihyperglycaemic activity; phenoxypropanolamines substituted on the nitrogen by ether groups of the aryloxyalkyl type (European patents 0 210 849 and 0 254 532), which compounds are considered to have essentially antiobesity activity; phenoxypropanolamines substituted by a phenylsulfonamide joined to the amine group by one of the following groups: -CH 2

-,-CH

2

-CH

2 -,-CH=CH or-CH20- (European patent 0 611 003), which compounds are considered to be active in the treatment of type II diabetes and obesity and as antidepressants; phenoxypropanolamines substituted WO 98/20005 PCT/FR97/01963 2 by a 1,3-benzodioxole-2,2-dicarboxylic acid group (patent US 5,488,064) joined to the amine group by the following group: R, ,R 2

-C-(CH

2 )m-Bin which B is a bond or an oxygen atom, m is equal to 1 or 2 and R, and R 2 which are identical or different, are a hydrogen atom or a lower alkyl group, which compounds are considered to have not only antidiabetic activity but also antiobesity activity and activity on intestinal hypermotility disorders, depression and stress, regulation of the intraocular pressure, hypertriglyceridaemia, hypercholesterolaemia, atherosclerosis and cardiovascular diseases.

Consequently the above-mentioned compounds have the major disadvantage of not being selective towards the P 3 -adrenergic receptor, so they can exhibit activity towards the p1- and/or 3 2 -adrenergic receptors; in particular, the broad spectrum of activity of the compounds described in patent US 5,488,064 can lead to unfavourable side effects in the respiratory and/or cardiac system.

The Applicant consequently set itself the task of providing compounds which possess selective 3 3 -adrenergic activity and meet practical needs better than the compounds of the prior art.

In fact, a compound which stimulates the 3 3 -adrenergic receptors selectively, i.e. which has only small p1 or 32 effects, if any, will have the desired antidiabetic and/or antiobesity activity without the unwanted effects associated with concomitant 1p stimulation (increase in heart rate) or 32 stimulation (muscle tremors).

The selectivity of such compounds can be determined by carrying out binding studies on CHO-bovine K1 13 cells according to the protocol described in Eur. J. Biochem., 1995, 230, 350 358 Pietri-Rouxel et the products are tested on the whole cells, at a maximum concentration of 10 imolar, for their capacity to stimulate the accumulation of cAMP (agonist) or to inhibit the accumulation stimulated by a concentration (10 nM) of isoproterenol (antagonist).

The present invention relates to compounds of general formula I below: WO 98/20005 PCT/FR97/01963 Ri O/ NHR2

Q

in which: RI, a substituent in the 3- or 4-position of the phenyl group, is a hydrogen atom, a halogen atom or one of the following groups: hydroxyl; Ci-Clo lower alkyl selected in particular from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl groups; Ci-Clo-alkoxy, especially methoxy; benzyloxy; nitro; cyano; trifluoromethyl; or amino optionally substituted (monosubstituted or disubstituted) by 1 or 2 lower alkyl radicals as defined above;

R

2 is one of the following groups: -CH 2

-CH

2

-CH

2

-CH(CH

3

)-CH

2

-C(CH

3

-C(CH

3 2

-CH

2 or a bond; and Q is: a phenyl radical 3,4-disubstituted by alkylenedioxy, which forms, with the phenyl radical, an unsubstituted benzodioxane unit, an unsubstituted benzodioxole unit or a benzodioxole unit 2-substituted by two radicals R 3 and R4 according to the following formula: O X R3 in which R 3 and R 4 are independently selected from the group comprising a hydrogen atom and a hydroxymethyl group; (ii) a 3- and/or 4-substituted phenyl radical of formula II below:

O-(CH

2 )x-COORs

(O-(CH

2 )x-COORs)y (formula II) in which: Rs is a hydrogen atom or a linear or branched CI-C 6 lower alkyl radical; S LU' \^s2 x is an integer between 1 and 3; and y is 0 or 1; (iii) a fused polycyclic hydrocarbon comprising at least two fused rings and selected from the following units: indene, indacene, naphthalene, azulene, biphenylene, acenaphthylene, fluorene, phenalene, phenanthrene and anthracene; or (iv) an optionally bridged, cyclic hydrocarbon system which consists of a cycloalkane comprising 1, 2 or 3 rings optionally containing substituents selected from methyl, ethyl, isopropyl, propyl, butyl and tert-butyl groups, the main ring containing 5 or 6 members.

By way of example, cycloalkane with one ring is understood as meaning a cyclopentane or a cyclohexane, cycloalkane with two rings is understood as meaning terpenes, and cycloalkane with three rings is understood as meaning o: especially adamantanes.

S. The compounds of formula also include the pharmacologically acceptable salts of these derivatives, as well as all the optical isomers and their components or mixtures of diastereoisomers. The basic products according to the present invention can be salified with the customary mineral acids and also with the organic acids in common use, such as tartaric, maleic, malonic, fumaric, succinic, methanesulfonic, ethanesulfonic and hydroxyethanesulfonic acids. The derivatives of acid 20 character can be salified with pharmacologically acceptable mineral bases such as alkali metal or alkaline earth metal reagents, or with non-toxic organic bases such as aliphatic amines, amino alcohols or the like.

The following may be mentioned among the preferred compounds of formula the compounds comprising an unsubstituted benzodioxole: of the following formula: OH 0 Ri OofH in which R, is a hydrogen atom, a methoxy or a chlorine atom in the para position, or a chlorine atom, a hydroxyl group, a nitro group, a cyano group or a trifluoro- WO 98/20005 PCT/FR97/01963 methyl group in the meta position; or Sof the following formula:

OH

O

NHO

0> in which RI is a hydrogen atom or a methoxy group in the para position; the compound of the following formula:

OH

R NH 0- COOH

HCI

in which R| is a hydrogen atom; the compound of the following formula: OH NH -Ov COOH N HON I H H C 1 in which R, is a hydrogen atom; and the compounds in which: R, is a hydrogen atom, a 4-O-methyl, a 3-OH or a trifluoromethyl group;

R

2 is a bond or one of the following groups: -CH 2 or -CH 2

-CH

2 and Q is a fluorene group or a cyclic hydrocarbon system, for example a cyclohexyl, a 1-adamantyl group or a 2-adamantyl group.

The compounds of formula can be prepared by reacting: a phenoxyepoxypropane compound of formula III: WO 98/20005 PCT/FR97/01963 6 O 0 (formula III) in which RI is as defined above, with a primary amine of formula (IV): NH QR2 (formula IV) in which R 2 and Q are as defined above.

Some compounds of formula (III) are commercially available; otherwise they can be prepared by reacting a phenol, appropriately chosen in terms of the identity of RI, with an epichlorohydrin or an epibromohydrin in the presence of a halogen acceptor, preferably in a polar solvent. If the nature of the substituent R| makes it sensitive to this condensation reaction, it is preferably protected before the reaction by an appropriate technique, for example as described in "Protective Groups in Organic Synthesis, 2nd edition, T.W. Greene and P.G.M. Wuts, John Wiley and Sons, New York, 1991".

Some compounds of formula (IV) are commercially available; others can be prepared by different methods, including the one shown below for the case of a product of formula in which Q is a group of formula (II).

The method of preparation is illustrated in scheme 1 below: OH BrCH 2

CO

2 R O C02R C 9 a_ 2 H, Pd/C Z K2CO3 Z

(CH

2 )n 14 1 NH, 16 Z CN or NO 2 R t-Bu or Et n= 0 or I WO 98/20005 PCT/FR97/01963 7 The treatment of nitrophenol (or cyanophenol) 14 with tert-butyl bromoacetate and anhydrous potassium carbonate in acetone gives the product which is hydrogenated in the presence of Pd/C to give the amine 16 (scheme If Z is a cyano group, the catalytic reduction in the presence of Pd/C produces monobenzylamine and dibenzylamine derivatives.

The intermediates of formula (III) and of formula NH 2

-R

2 are coupled by heating (in the crude form or dissolved in a polar solvent such as anhydrous dimethylformamide) for 12 to 14 hours, at a temperature between 70 and 100°C, to give compounds of formula Some compounds of formula are obtained with one or two ester groups, which react respectively with 6 N HCI at 0 C for 12 hours and with 1 N NaOH at room temperature for 12 to 48 hours to give the carboxylic acid salt, as illustrated in scheme 2: Scheme 2

OH

SOH OCH2CO 2

R

4 R 6N HC R4 tert-butyl or Et (Y)n bond 12h (Y)n CH 2 OH HCI

OCH-

O 7C- OCH2CO2H Yn

RI

The compounds of formula have a particularly valuable activity as p3adrenergic receptor agonists; in particular, they possess a valuable action on thermogenesis and can therefore be used in the treatment of obesity or in metabolic function disorders. In certain cases, they can also modify fat catabolism and be used in animal rearing, improving the production of muscle rather than fat.

These compounds can be employed in animal feeding to avoid an unprofitable fattening of the animals and instead to promote an increase in muscle WO 98/20005 PCT/FR97/01963 8 bulk.

As their 33 activity manifests itself essentially on the smooth muscle, moderation of the intestinal contraction does not therefore occur to the detriment of a cardiovascular effect.

A preparation containing at least one product of formula according to the invention can be administered to animals, including man, suffering from diabetes, obesity or intestinal motility disorder.

The products according to the invention are preferably administered orally or sublingually, but other routes of administration can also be used (intranasal route, transdermal route, parenteral routes such as subcutaneous, intravenous and intraperitoneal routes).

The doses administered vary from case to case between 0.1 and 100 mg/kg of live weight, preferably between 1 and 10 mg/kg of live weight.

If necessary, the compounds of formula can be administered in combination with p3i- or P 2 -adrenergic products.

In the treatment of obesity, which may be associated with a treatment for diabetes, these products are administered at doses of I to 10 mg/kg of body weight; in the case of administration to animals, appropriate pharmaceutical forms can be employed according to the species and include especially solutions for spreading over the animal's body (solution for spreading by hand, solution for spreading by vaporization, etc.).

The compounds of the present invention are formulated as tablets, ordinary capsules, gelatin capsules or syrup for oral administration. These gelatin capsule, ordinary capsule and tablet forms can contain excipients conventionally used in pharmaceutical formulation, such as adjuvants or binders like starches, gums and gelatin, adjuvants like calcium phosphate, disintegrating agents like cornstarch or alginic acids, a lubricant like magnesium stearate, sweeteners or flavourings.

Solutions or suspensions can be prepared in aqueous or non-aqueous media by the addition of pharmacologically compatible solvents. These include glycols, polyglycols, propylene glycols, polyglycol ether, DMSO and ethanol.

They can also be formulated as sterile suspensions or solutions for parenteral or intranasal administration, or they can be presented as skin patches.

The unit dose of between 1 and 500 mg of the compound of formula is mixed with an excipient appropriate to the form produced: solvent, diluent, excipient, 23/i02 '01 FRI 17:42 FAX 61 3 9243 8333 GR1ASITH HACK I005 It 61 39243 8333 -9- Preservative, Sweetener Or perfume. The amount Of active principle present in each unit dose is such that it can be administered one or more times throughout the day.

Prograzmmed release formulations Can also be prepared to give a long-lasting effect, making it possible to increase the treatment intervals.

All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. Nio admission is made that any reference constitutes prior art. The discussion Of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

In this specification, except where the context requires otherwise, the words "comprise", "comprises" and "comprising- mean "include", "includes", and "including", respectively, and is not intended to exclude other 25 additives, components, integers or steps.

The Examnples given illustrate the content of the 00.:.0invention without limiting its scope only to the Examples described.

0 1 EXAMPLE 1 0.00

OH

*1 RECEIVED TIME 23. FEB. 17 :3 8 PRINT TIME 26. FEB, 7: 58 23/02 '01 FRI 17:42 FAX 61 3 9243 8333 GRIFITH HACK [a 006 61 3 9243 8333 9a N-((l,3-Benzodioxol-5-yl)methyl)-2-hydroxy-3-(3hydroxphenoxy)propyl-amine le 36.6 g (332.40 mmol) of resorcinol and 42 g (331.78 mmol) of benzyl chloride are refluxed overnight in 250 ml of dry Me 2 CO in the presence of 46.6 g of K2CO 3 ,with stirring. The mixture is cooled, filtered and evaporated.

The residue obtained is diluted in 500 ml of water and extracted with ethanol. The organic layer is washed with 10% aqueous NaOH and extracted with ethanol. The red oil obtained is distilled with the aid of a bulb tube distillation apparatus to give 18 g of m-PhCHOC 6

HIOH,

b.p.3 240 245 °C (lit. b.p.

1 202 210 oC). A solution of 3.3 g (16.5 mmol) of m-PhCH 2

OC

6

H

4 OH in 50 ml of DMF is treated with 0.8 g (16.5 mmol) of sodium hydride and the mixture is stirred for 15 minutes. After the addition of 13.75 ml (16.5 mmol) of epichlorohydrin, the mixture is stirred at 60 0 °C for one hour until alkylation is complete.

The excess reagent and the solvent are evaporated off under reduced pressure and the residue is partitioned between the following two phases: ethyl acetate and water. The organic phase yields the epoxide, which is used without further purification.

25 The epoxide is dissolved in DMF containing one equivalent of amine and heated overnight at 80 0 C. After cooling, the solvent is removed under vacuum and the oily residue is chromatographed on a silica gel column using a mixture of solvents, and recrystallized as indicated in 30 Table 1.

e -o RECEIVED TIME 23. FEB. 17 :38 PRINT TIME 26. FEB. 7:58 WO 98/20005 PCT/FR97/01963 TABLE I Chemical data of the compounds I Compound R, Yield Crystallization Melting point solvent C Ila H 67 MeOH 102 103 Ilb p-OCH3 80 MeOH 107- 108 llc m-Cl 62 MeOH 128- 129 Ild p-Cl 74 EtOH 98 99 Ile m-OH 62 CH 3 CN 230-231 Ilf m-NO 2 47 MeOH 129-130 Ilg m-CN 55 MeOH 138-139 Ilh m-CF 3 39 MeOH 121 122 The 'H NMR spectra of the compounds of Example 1 are illustrated below: Compound la (free base), 6 (ppm): 2.59 2H), 3.62 2H), 3.90 3H), 5.95 2H), 6.78 2H Ar), 6.90 4H Ar), 7.26 (dt, 2H Ar, J 7.73, 1.02 Hz).

Compound lb (free base), 8 (ppm): 2.52 2H), 3.61 2H), 3.68 3H), 3.83 3H), 4.88 NH), 5.95 2H), 6.75 (dd, 1H Ar, J 8.0, 1.38 Hz), 6.81 (d, 1H Ar, J 8.0 Hz), 6.83 4H), 6.89 IH Ar, J 1.1 Hz).

Compound Ic (maleate), 6 (ppm): 2.90 (dd, 1H, J 13.56, 9.40 Hz), 3.07 (dd, 1H, J 12.59, 2.94 Hz), 3.97 2H, J 5.07 Hz), 4.10 2H), 4.12 1H), 6.01 2H), 6.04 2H), 6.90 (dd, 1H Ar, J 8.31, 2.14 Hz), 7.00 4H Ar), 7.09 1H Ar), 7.31 1H Ar, J= 8.42 Hz).

Compound Id (maleate), 5 (ppm): 2.90 (dd, 1H, J 12.63, 9.20 Hz), 3.08 (dd, 1H, J 12.67, 3.18 Hz), 3.93 2H, J 5.18 Hz), 4.10 2H), 4.12 2H), 6.03 2H), 6.04 2H), 6.95 4H Ar), 7.09 1H), 7.34 2H, J 8.99 Hz).

Compound le (free base), 6 (ppm): 2.85 (dd, 1H, J 12.47, 8.89 Hz), 3.04 (dd, 1H, J 12.63, 3.02 Hz), 3.93 2H, J 5.18 Hz), 4.07 2H), 4.23 1H), 5.85 1H Ar), 6.03 2H), 6.53 2H Ar), 6.92 1H Ar, J 8.0 Hz), 7.02 (dd, 1H Ar, J 8.0, 1.58 Hz), 7.19 2H Ar).

Compound If (free base), 6 (ppm): 2.58 2H, J 5.64 Hz), 3.62 2H), 3.89 WO 98/20005 PCT/FR97/01963 11 1H), 3.97 (dd, 1H, J 15.59, 5.98 Hz), 4.11 (dd, 1H, J 15.14. 4.0 Hz), 4.99 1H), 5.94 2H), 6.78 2H), 6.89 1H), 7.39 (ddd, 1H, J 8.29, 2.47, 0.95 Hz), 7.55 (dd, 1H, J 6.93, 1.05 Hz).

Compound Ig (free base), 6 (ppm): 2.55 2H), 3.61 2H), 3.89-4.05 3H), 4.97 1H), 5.95 2H), 6.72-6.78 2H), 6.88 1H), 7.24-7.50 4H).

Compound Ih (free base), 5 (ppm): 2.58 2H), 3.61 2H), 3.90-4.05 3H), 4.97 1H), 5.94 2H), 6.72-6.78 2H), 6.89 1H), 7.20-7.27 3H), 7.49 1H, J 7.69 Hz).

EXAMPLE 2

OH

0 NH 0 N-(Benzodioxol-5-yl)-2-hydroxy-3-(alkoxyphenoxy)propylamine Analogously to Example 1, the compounds of Example 2 are prepared from a commercially available epoxide.

The chemical properties and the NMR spectra of these products are illustrated below: TABLE II Chemical data of the compounds of Example 2 Compound R, Yield Solvent Melting point

°C

2a H 45 EtOAc/cyclohex 80- 81 2b p-OMe 65 Et20/cyclohex 80- 81 'H NMR spectra of the compounds 2 Compound 2a (free base), 6 (ppm): 3.22 (dd, 1H, J 12.77, 7.02 Hz), 3.37 (dd, 1H, J 12.76, 4.21 Hz), 4.05 2H), 4.22 1H), 5.86 2H), 6.11 (dd, 1H Ar, J 8.26, 2.27 Hz), 6.32 1H Ar, J 2.25 Hz), 6.66 1H Ar, J 8.26 Hz), 6.96 WO 98/20005 PCT/FR97/01963 12 3H Ar), 7.30 2H Ar).

Compound 2b (free base), 8 (ppm): 3.21 (dd, 1H, J 12.75, 7.07 Hz), 3.35 (dd, 1H, J 12.73, 4.22 Hz), 3.78 3H), 3.97 (dd, 1H, J 9.55, 6.06 Hz), 4.03 (dd, 1H, J 11.49, 6.18 Hz), 4.20 1H), 5.86 2H), 6.11 (dd, 1H Ar, J 8.31, 2.34 Hz), 6.31 1H Ar, J 2.30 Hz), 6.66 1H Ar, J 8.28 Hz), 6.85 4H Ar).

EXAMPLE 3

OH

HNH O COOH

HCI

3-[(3-Phenoxy-2-hydroxypropyl)amino]phenoxyacetic acid, hydrochloride salt (RI H) A mixture of 3 g (21.56 mmol) of 3-nitrophenol, 4.3 g (22 mmol) of tertbutyl bromoacetate, 3.2 g of anhydrous potassium carbonate and 50 ml of acetone is stirred overnight at room temperature. The mixture is filtered and washed with acetone and both the filtrate and the washing product are evaporated to give a yellow oil. The oil is purified on a silica gel chromatography column using an EtOAc/cyclohexane mixture (50/50) as the eluent to give 5 g of tert-butyl 3nitrophenoxyacetate (colourless oil). 2 g of Pd/C are added to a solution of 4.8 g (18.95 mmol) of tert-butyl 3-nitrophenoxyacetate in 20 ml of ethanol and the mixture is hydrogenated overnight at one atmosphere. The catalyst is filtered off.

The solvent is evaporated off to give 3.38 g of tert-butyl 3-amidophenoxyacetate, which is chromatographed on a silica gel column using an EtOAc/ cyclohexane mixture (50/50) as the eluent. A mixture of the resulting amine (0.5 g, 2.24 mmol) and 1,2-epoxy-3-phenoxypropane is heated at 70 0 C overnight. After cooling, the product is washed with ethanol and the precipitate is filtered off to give 0.6 g of the tert-butyl ester. 0.6 g of this ester and 15 ml of 6 N HCI are mixed overnight at 80 0 C. The solvent is evaporated off and the residue is washed with an EtOH/CH 3 CN mixture and then recrystallized from CH 3 CN to give 0.36 g of a salt with the following characteristics: melting point 138 139 0 C; 'H NMR (DMSO-d6) 8 3.82 2H), 3.96 4H), 4.06 1H), 4.72 2H), 6.88-7.00 5H Ar), 7.24-7.45 4H Ar).

WO 98/20005 PCT/FR97/01963 13 EXAMPLE 4 OH -o-CCOH OH NHO COOH CI 4 -[(3-Phenoxy-2-hydroxypropyl)amidomethyl]phenoxyacetic acid, hydrochloride salt (RI H) A mixture of 22.16 g (0.186 mol) of 4-cyanophenol, 32.07 g (0.192 mol) of ethyl bromoacetate, 27.6 g (0.199 mol) of K 2 CO3 and acetone (250 ml) is stirred at room temperature for 12 hours. After filtration, the solvent is evaporated off under vacuum and the residue is partitioned between an organic phase (ethyl acetate) and an aqueous phase (water). The organic layer is dried (MgSO 4 and concentrated under vacuum to give 36.42 g of ethyl 4-cyanophenoxyacetate (white solid, melting point: 49 50 0

C).

g of Pd/C are added to a solution of the resulting ester (4.1 g, mmol) in ethanol (80 ml) and the mixture is hydrogenated under a pressure of bar at room temperature for 16 hours. The catalyst is filtered off (Clite®) and the filtrate is concentrated under vacuum to give a mixture of 38% of the monobenzylamine derivative and 42% of the dibenzylamine derivative, which is chromatographed on silica gel using an EtOAc/MeOH mixture as the eluent.

0.4 g (1.9 mmol) of the amine 16 (n 1 and R Et) is dissolved in DMF ml) containing one equivalent (0.3 g, 2 mmol) of ()-.,2-epoxy-3-phenoxypropane and heated overnight at 80 0 C. After cooling, the solvent is removed under vacuum and the oily residue is triturated with Et20, filtered off and washed with EtOH and MeOH to give 0.25 g of ethyl 4-[(3-phenoxy-2-hydroxypropyl)amidomethyl]phenoxyacetate, an ester in the form of a white solid melting at 120 0

C,

which is hydrolyzed with 6 N HCI, as described in Example 3, to give the desired derivative in the form of a white solid.

Other compounds are prepared by the technique described in Example 1 and have the following characteristics: WO 98/20005 WO 9820005PCTIFR97/0 1963 Compound R, R Q Yield p.o H bond c 55 138/9 4-OMe iIf64 119/20 S c 3-OH If42 94/5 6a H If63 96/7 6b 3-OH it 58 282/3 7 H 79 230/1 8 H -CH- 2 65 195 9 CF 3 ,44 175 H -CH 2

-CH

2 ,47 170 11 H bond 82 62/3 12 H -CH 2

-CH

2 56 71 13 H bond C365 105 1H, 14 H bond c CH 3 58 128

CH

3 1S H bond C1360 234/5 16 4-OMe bond 62 185 MCI 17 H bond 58 87 18 4-OMe bond Tp 42 927 WO 98/20005 PCT/FR97/01963 'H NMR spectra of the compounds 5 to 8 Compound 5a (maleate), 6 (ppm): 3.17 (dd, 1H, J 11.97, 5.21 Hz), 3.31 (dd, 1H, J 12.0, 4.9 Hz), 3.74 2H), 4.01 3H), 6.25 2H), 6.68 (dd, 1H Ar, J 8.27, 2.06 Hz), 6.88 4H Ar), 7.10 1H Ar), 7.27 3H Ar), 7.43 1H Ar, J 7.16 Hz), 7.58 2H Ar).

Compound 5b (free base), 6 (ppm): 3.16 1H), 3.30 1H), 3.69 3H), 3.73 2H), 3.90 3H), 5.16 1H, J 4.84 Hz), 5.72 1H NH, J 5.79 Hz), 6.66 (dd, 1H, J 8.27, 2.01 Hz), 6.89 5H Ar), 7.10 (dt, 1H Ar, J 7.36, 1.09 Hz), 7.25 (dt, 1H Ar, J 7.43, 0.8 Hz), 7.42 1H, J 7.26 Hz), 7.54 1H Ar, J 8.27 Hz), 7.60 1H Ar, J 7.14 Hz).

Compound 5c (maleate), 5 (ppm): 3.58 2H), 3.94 4H), 4.11 1H), 6.17 2H), 6.37 1H Ar), 6.56 2H, J 7.96 Hz), 6.81 1H Ar, J 7.58 Hz), 6.97-7.23 4H Ar), 7.42 1H Ar), 7.57 2H Ar).

Compound 6a (HCI), 6 (ppm): 3.54 2H), 3.85 3H), 4.15 1H), 5.64 (s, 1H), 6.75-6.92 4H Ar), 7.17-7.25 2H), 7.38-7.56 4H Ar), 7.96 2H Ar), 8.14 1H Ar).

Compound 7 (HC1), 5 (ppm): 1.61 5H), 1.91 6H), 2.10 4H), 2.94 (m, 1H), 3.12 1H), 3.99 (dd, 2H, J 5.08 Hz), 4.22 1H), 6.90-6.97 3H Ar), 7.29 2H Ar, J 8.29 Hz).

Compound 8 (HC1), 6 (ppm): 1.59-1.92 10H), 2.41 4H), 3.62 3H), 4.03 2H), 4.56 1H), 6.92-6.99 3H Ar), 7.29 2H Ar, J= 7.31 Hz).

As is apparent from the foregoing description, the invention is in no way limited to those modes of execution, embodiments and modes of application which have now been described more explicitly; on the contrary, it encompasses all the variants thereof which may occur to those skilled in the art, without deviating from the framework or the scope of the present invention.

Claims

1. Compounds of general formula I below: OH R1 NHR, RQ in which: RI, a substituent in the 3- or 4-position of the phenyl group, is a hydrogen atom, a halogen atom or one of the following groups: hydroxyl; Ci-Clo lower alkyl selected in particular from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl groups; Ci-Clo-alkoxy; benzyloxy; nitro; cyano; trifluoromethyl; or amino optionally substituted (monosubstituted or disubstituted) by 1 or 2 lower alkyl radicals as defined above; R 2 is one of the following groups: -CH 2 -CH 2 -CH 2 -CH(CH 3 )-CH 2 -C(CH 3 -C(CH 3 2 -CH 2 or a bond; and Q is: a phenyl radical 3,4-disubstituted by alkylenedioxy, which forms, with the phenyl radical, an unsubstituted benzodioxane unit, an unsubstituted benzodioxole unit or a benzodioxole unit 2-substituted by two radicals R 3 and R 4 according to the following formula: 0 R3 in which R 3 and R 4 are independently selected from the group comprising a hydrogen atom and a hydroxymethyl group; (ii) a 3- and/or 4-substituted phenyl radical of formula II below: O-(CH 2 )x-COOR '(O-(CH 2 )x-COOR 5 )y (formula II) 23/02 '01 FRI 17:43 FAX 61 3 9243 8333 GRA3FITH HACK Zl007 61 39243 8333 17 ki which: Rs is a hydrogen atom or a liear or branched CI-C 6 lower alkyl radical: y ISO or 1; (11i) a fused polycyclic hydrocarbon comprising at lea.St two fused rings and selected from the following units: indene, indacene, naphthalene, azulene, biphenylene. acenaphthylene, fluorene, phenalene, phenanthrene and anthracenc; or (iv) an optionally bridged, cyclic hydrocarbon system which consists of a cyclo- alkane comprising 1, 2 or 3 rings optionally containing substituents selected from methyl, ethyl, isopropyl, propyl, butyl and tert-butyl groups, the main ring containing 5 or 6 members.

2. Compound according to Claim 1, wherein the compound has the following formula: O H H O in which R, is a hydrogen atom, a methoxy or a chlorine atomn in the para position,7 or a chlorine atom, a hydroxyl group, a nitro group, a cyano group or a trifluoro- methyl group in the meta position.

3. Compound according to Claim 1, wherein the compound has the following formula: .OH in which R, is a hydrogen atom or a mcthoxy group in the para position.

4. Compound according to Claim 1, wherein the compound has the folowing formula: 2 3 FEB 2001 'RECEIVED TIME 23. FEB. 17:38 PRINT TIME 26. FEB., 23/02 '01 FRI 17:43 FAX 61 3 9243 8333 GRA3FITH HACK 'V61 39243 833 18 Zoo8 NH C 0-ICH .HC1 i which R, is a hydrogen atom.

Compound according to formula: OH Ri Claim 1, wherein the compound has the following NHf N1'*COOH HC in which Ri is a hydrogen atom.

6. Compounds according to Claim 1, in which: RL is a hydrogen atomL a 4-0-methyl, a 3-OH or a trifluorornethyl group; Rz is a bond or one of the following groups: -CH 2 or -CH2-CH1 2 and Q is a fluorene group or a cyclic hydrocarbon system-

7. Process for the preparation of a compound of formula according to any one of Claims I to 6, comprising the step of: -a phenoxyepoxypropane compound of formula III: 0 0 R-7 (formula 111) in which Ri is as defined above, with a primary amine of formula (IV): A, -A RECEIVED TIME 23. FEB. 17:38 2 3 FEB 2001 PRINT TIME 26. FEB. 7:58 23/02 '01 FRI 17:43 FAX 61 3 9243 8333 GRIF&FITH HACK i1009 61 3 9243 8333 -19 NHRO (fonnula IV) in which R, and Q are as defined above.

8. Process according to Claim 7, wherein the intermediates of formula (III) and of formula NH2-R2- Q, are coupled by heating (in the crude form or dissolved in a polar solvent such as anhydrous dimethylformamide) for 12 to 14 hours, at a temperature between 70 and 100 0 C, to give compounds of formula

9. Process according to Claim 7 or Claim 8, wherein if said compounds of formula contain one or two ester groups, said esterified compounds are brought into contact respectively with 6 N HC1 at 80 0 C for 32 hours and with 1 N NaOH at room temperature for 12 to 48 hours to give the corresponding carboxylic acid salt.

10. Drug, comprising at least one of the compounds according to any one of Claims 1 to 6, in the pure state or in the form of salts with pharmaceutically acceptable acids or bases, and at least one pharmaceutically acceptable vehicle.

S11. Drug, comprising at least one of the compounds according to any one of Claims 1 to 6, in the pure state or in the form of salts with pharmaceutically acceptable acids or bases, and at least one pharmaceutically acceptable vehicle, for combating weight problems and/or metabolic function disorders. a

12. Feed additive for animal rearing, comprising at least one compound according to any one of Claims 1 tLo 6.

13. A method for treating weight problems and/or metabolic function disorders in a subject in need of such treatment, AUS T TIME 23 FEB. 17:38 PRINT TIME 26. FEB. 7:58 ED TIME 23. FEB. 11:38 PRINT TIME 26. FEB. 7:58 23/02 '01 FRI 17:43 FAX 61 3 9243 8333 GR1A-FITH HACK 61 39243 8333 20 Comprising the1L step of administering to Lhe object an effective amount of~ an agent comprising a drug accordinq to claim 10 or claim 11.

14. A method according to claim 13, in which the metabolic fuinction disorder is diabetes. A compound according to claim 1, substantially as herein described wiLh refereiice to examples. Dated this 23rd day of February 2001 VIRBAC S.A. By their Patent Attorneys GRIFFITH HACK Fellows Inistitute of Patent anid Trade Mark Attorneys of Australia VED TIME 23,FEB. 17:38 VED IME 3. FB. 1:38PRINT TIME 26. EB. 7:57