Process for the preparation of arylethanoldiamines useful as agonists of the beta-3-adrenoceptor

Description of the invention

The present invention relates to an oxadiazabicyclooctane derivative.

This oxadiazabicyclooctane derivative and similar compounds are intermediates in the preparation of arylethanediamine derivatives. Compounds of this type are known to be useful as agonists of atypical β-adrenoreceptors (also known as β-3-adrenoreceptors).

It is known that atypical β-adrenoreceptors are present in adipose tissue and in the gastrointestinal tract. Atypical β-adrenoreceptors have been found to be particularly useful as thermogenic antiobesity agents and antidiabetic agents. Compounds with agonist activity against atypical β-adrenoreceptor have also been reported to be useful in the treatment of hyperglycemia, as animal growth promoters, as platelet aggregation inhibitors, as agents that increase the strength of myocardial contraction, and as antiatherosclerotic agents, and as useful in the treatment of glaucoma.

Compounds that are agonists of atypical β-adrenoreceptors are described, for example, in WO

97/21665, WO 97/21666, WO 98/43953, WO 99/65877, WO 95/33724, EP 0455006 and EP 0543662.

The invention relates to an oxadiazabicyclooctane derivative of formula (IB-1) which is:

<img file="PL209540B1_D0001.tif" />

The present specification discloses an improved process for the preparation of arylethanediamine derivatives using compounds of formula (IB). A preferred compound of formula (IB) is the oxadiazabicyclooctane derivative of formula (IB-1) according to the invention. The advantage of this method is that it achieves higher yields than those obtained with the previous methods: the process is shorter and involves fewer steps, the reactions are more selective, e.g. the regioselectivity of the epoxide ring opening reaction is highly selective. The process is also more environmentally friendly in terms of reducing the amount of toxic by-products and solvents. There is no further need for reagents containing boron.

Described herein is a method for preparing a compound of formula (IA) and a pharmaceutically acceptable derivative thereof:

<img file="PL209540B1_D0002.tif" />

where:

R¹ is phenyl substituted with halogen;

₂

R² is a hydrogen atom;

₃

R³ is a hydrogen atom;

X¹ and X² are independently hydrogen;

R⁴ means group (W):

<img file="PL209540B1_D0003.tif" />

Wherein A is phenyl; R⁵ is -CO2R⁸; R⁶ and r⁷ are independently hydrogen;

which comprises the step of preparing a compound of formula (IB) and a pharmaceutically acceptable derivative thereof:

<img file="PL209540B1_D0004.tif" />

where:

R¹ is phenyl substituted with halogen; R² is a hydrogen atom;

R³ is a hydrogen atom;

R⁴ means group (W):

<img file="PL209540B1_D0005.tif" />

wherein A is phenyl; R⁵ is -CO2R⁸; R⁶ and r⁷ are independently hydrogen; R⁸C1-C6-alkyl.

The above method may optionally be followed by an ester hydrolysis step of the -CO2R group⁸, to obtain a compound of formula (IA), wherein R⁴ is substituted with -CO2H.

This optional step of hydrolysis of the -CO2R ester group⁸ leading to a compound of formula (IA) wherein R⁴ is substituted with a -CO2H group, can be carried out in an additional hydrolysis step under standard hydrolysis conditions known to those skilled in the art.

The term "alkyl as used herein" means both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, propyl, and butyl.

The term "halogen as used herein" means an atom selected from fluorine, chlorine, bromine and iodine.

Preferably, A is in the meta position to the phenyl ring. 55

In the compound of formula (IA) R.⁵ preferably is -CO2H. In the compound of formula (IB), R.⁵ preferably is -CO2CH3.

It should be understood that the compounds of formula (IA) are all optically active. The individual, isolated isomers and their mixtures, including racemates, can be obtained by the method described.

Preferably the compound of formula (IA) is 3 '- [(2 - {[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino} ethyl) amino] [1,1'-biphenyl] - acid hydrochloride 3-carboxylic acid and pharmaceutically acceptable salts thereof.

Arylethanediamine derivatives are known as β-3-adrenoreceptor agonists. Preferably the compound of formula (IA) is a β-3-adrenoreceptor agonist. More preferably, the compound of formula (IA) is a selective β-3-adrenoreceptor agonist.

In the following description of the R group¹, R², R³, R⁵, R⁶, R⁷, R⁸, W and A are as defined above unless otherwise stated. R⁴ it has the same meaning as in formula (IB) above, unless otherwise stated.

A compound of formula (IB) can be prepared by reacting a compound of formula (II) with a compound of formula (III):

PL 209 540 B1

<img file="PL209540B1_D0006.tif" />

at elevated temperature and pressure, possibly in the presence of one or more C3-C6-alkanols, acetonitrile, N-methylpyrrolidinone (NMP), isobutyl acetate, isopropyl acetate, dimethylformamide (DMF), toluene, xylene or dimethylacetamide (DMA); preferably toluene and / or xylene. The reaction temperature is suitably 100 ° C or higher, preferably 100-150 ° C, more preferably 100-120 ° C.

The reaction of a compound of formula (II) with a compound of formula (III) to form a compound of formula (IB) and further conversion of a compound of formula (IB) into a compound of formula (IA) may be carried out in separate steps or in situ. This reaction is preferably carried out in situ.

A compound of formula (III) can be prepared from a compound of formula (IV):

<img file="PL209540B1_D0007.tif" />

wherein L is a leaving group such as a halogen atom (e.g. chlorine) by cyclization in the presence of a solvent selected from the group consisting of: dichloromethane (DCM), EtOAc, toluene and / or xylene, and a base selected from the group consisting of : Na2CO3, NaOH, anhydrous Et3N and / or an amine, e.g. aqueous NH3. The preferred solvent is DCM. The preferred base is an aqueous NH3 solution.

Compounds of formula (IV) can be prepared from compounds of formula (V) by any suitable amidine preparation method. For example, these compounds can be prepared by condensing a compound of formula (VI), wherein L is a leaving group as defined above, in the presence of a solvent selected from the group consisting of: DCM, toluene, EtOAc or CH3CN, and PCl5 or POCl3. EtOAc is the preferred solvent. Preferably PCI5 is present.

<img file="PL209540B1_D0008.tif" />

(VI)

Compounds of formula (V) can be prepared by reacting a compound of formula (VII) with a compound of formula (VIII) according to the method of Thompson (J. Org Chem. 1984, 49, 5237).

<img file="PL209540B1_D0009.tif" />

Where Z is a halogen atom or a trifluoromethanesulfonate moiety, under suitable boronic acid coupling conditions, e.g. palladium on carbon and sodium carbonate or Pd (PPh3) 4 (palladium (0) tetrakis (triphenylphosphine)) followed by group reduction nitro using standard methods, e.g. under a hydrogen atmosphere using a suitable catalyst such as palladium on carbon in a suitable solvent such as alcohol, tetrahydrofuran, dimethoxyethane (DME), ethyl acetate, isopropyl acetate, toluene, isooctane, cyclohexane or water, or a mixture of these solvents, optionally in elevated temperature.

Compounds of formula (V) can also be prepared by reacting a compound of formula (VIII) with a compound of formula (IX) using the standard boronic acid coupling methods described above.

<img file="PL209540B1_D0010.tif" />

Compounds of formula (VI) can be prepared by reacting a compound of formula (X) with anhydrous HCl.

<img file="PL209540B1_D0011.tif" />

(X)

Further processes for the preparation of compounds of formula (V) are disclosed in WO 97/21665.

The compounds of the formulas (VII), (VIII), (IX) and (X) are known compounds and can be prepared by methods known to those skilled in the art.

It will be appreciated by those skilled in the art that in the preparation of a compound of formula (IA) or a solvate thereof, it may be necessary and / or desirable to protect one or more sensitive groups on a molecule to avoid undesirable side reactions. The protecting groups used in the preparation of the compound of formula (IA) may be used in accordance with a conventional method. See, e.g., "Protective Groups in Organic Chemistry, Ed. JFW McOmie, Plenum Press, London (1973) or "Protective Groups in Organic Synthesis, Theodora Green, John Wiley and Sons, New York (1981). Typical amino protecting groups may include, for example, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl; and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl. Typical oxygen protecting groups may include, e.g. alkylsilyl groups such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ether moieties such as tetrahydropyranyl or tert-butyl; or ester moieties such as an acetate moiety.

Any protecting groups present can be removed using standard procedures. An aralkyl group such as benzyl may be cleaved by hydrogenolysis in the presence of a catalyst, e.g. palladium on charcoal; an acyl group such as N-benzyloxycarbonyl can be removed by hydrolysis, e.g. using hydrogen bromide in acetic acid, or by reduction, e.g. catalytic hydrogenation.

It will be appreciated that in any of the general methods described above, it may be desirable and even necessary to protect sensitive groups on the molecule as described. Thus, the reaction step of deprotecting a protected derivative of a compound of general formula (IA) or a salt thereof can be carried out by any of the above-described methods.

Thus, when necessary and / or desired, proceed in any sequence following any of the general methods:

(i) removing any protecting groups; and (ii) converting the compound of formula (IA) or a solvate thereof into a pharmaceutically acceptable solvate thereof.

The invention is further illustrated by the following example. All temperatures are given in degrees Celsius.

Example 1: Preparation of 3 '- [(2 - {[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino} ethyl) amino] [1,1'-biphenyl] -3 acid hydrochloride -carboxylic acid

PL 209 540 B1

<img file="PL209540B1_D0012.tif" />

PL 209 540 B1

Step 1: Preparation of methyl 3 '- (2-methyl-4,5-dihydro-1H-imidazol-1-yl) -1,1'-biphenyl-3-carboxylate

While stirring, to a suspension of phosphorus pentachloride (1.1 wt.) In ethyl acetate (2.2 vol.) At 0-5 ° C and under nitrogen atmosphere, N- (2-chloroethyl) acetamide (0 , 64 wt.). After stirring for about 20 minutes at 0-5 ° C, a solution of methyl 3'-amino- (1,1'-biphenyl) -3-carboxylate (1 wt.) In ethyl acetate (6.6 vol.) at 0-5 ° C. Ethyl acetate (2 vol.) Was then added and the mixture was allowed to warm to 20-25 ° C, stirred at this temperature for at least 2 hours and then a sample was taken for analysis. The mixture was cooled to 2-5 ° C and stirred for at least 1 hour, during which time the product completely precipitated. The mixture was filtered and the solid was washed with ethyl acetate (2 x 2 vol.). The colorless solid was dried with suction and a sample was removed for analysis.

The above amidine hydrochloride filter cake was suspended in a mixture of dichloromethane (7.3 vol.) And water (about 7.3 vol.) At 20-25 ° C. Ammonium hydroxide solution (35% w / w ammonia, 0.77 wt) was added and stirring was continued for at least 1 hour. The layers were allowed to separate, the lower organic layer was filtered through a filter pad into another vessel. Dichloromethane (3 vol.) Was used to rinse the conduit and the solution was concentrated in vacuo to about 3 vol. The solution was diluted with dichloromethane (5.8 vol.) And subjected to vacuum distillation, concentrating the solution to about 3 vol. The solution was diluted with dichloromethane (5.8 vol.) And subjected to vacuum distillation, concentrating to about 3 vol. Diisopropyl ether (1.8 vol.) Was added followed by seed crystals of methyl 3 '- (2-methyl-4,5-dihydro-1H-imidazol-1-yl) -1,1'-biphenyl-3-carboxylate and the solution was cooled to 2-5 ° C to initiate crystallization. Diisopropyl ether (7.0 vol.) Was added and vacuum distillation was performed, concentrating the solution to about 4.5 vol. Diisopropyl ether (4.4 vol.) Was added, the suspension was cooled to &lt;5 ° C and stirred for at least 1 hour. The product was collected by vacuum filtration, washed with diisopropyl ether (2 x 3 vol.) And dried in vacuo at &lt;50 ° C.

Expected yield: 80-82% of theory.

¹H-NMR (CDCl3): 2.10 (s, 3H); 3.80-3.90 (m, 4H); 3.95 (s, 3H); 7.10 (d. 1H); 7.30 (s. 1H); 7.357.45 (m, 2H); 7.50 (t, 1H); 7.75 (d. 1H); 8.05 (d. 1H); 8.30 (s, 1H).

Step 2: Preparation of 3 '- [(2 - {[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino} ethyl) amino] [1,1'-biphenyl] -3-carboxylic acid hydrochloride

Methyl 3 '- (2-Methyl-4,5-dihydro-1H-imidazol-1-yl) -1,1'-biphenyl-3-carboxylate (1 wt.), (R) -3-chlorostyrene oxide (0 , 44 vol.) And toluene (1 vol.) Was heated to reflux for about 16-24 hours. Samples of the reaction mixture were taken for analysis by LC (the reaction was complete when 3 '- (2-methyl-4,5-dihydro-1H-imidazol-1-yl) -1,1'-biphenyl-3-carboxylate remained &lt;3 area% methyl at ca 220 nm). The mixture was cooled to about 90 ° C and 2M sodium hydroxide solution (5.3 vol.) Was added followed by methanol (6.2 vol.). The mixture was distilled and approximately 3 vol. at atmospheric pressure to form a homogeneous yellow solution (approximately 1 hour). This solution was heated to reflux for approximately 5 hours, sampled and checked by LC (N-acyl &lt;2 area%, ca 242 nm). The solution was cooled to &lt;50 ° C and additional methanol (4 vol) was added.

Concentrated hydrochloric acid (1.5 vol.), Methanol (3 vol.), And water (1 vol.) Were heated to a temperature of about 40-45 ° C. The above hydrolysis product mixture was added to the acid solution over 30-40 minutes. The resulting suspension was stirred at 40-45 ° C for at least 20 minutes and then cooled to 20-25 ° C. The product was collected by filtration, washed with water (2 x 2 vol.) Then dried in vacuo at 60 ° C.

Expected yield: 85-87% of theory.

¹H-NMR (d6-DMSO): 3.0-3.3 (m, 4H); 3.5-3.6 (m, 2H); 5.05 (d. 1H); 6.1 (bs, 1H); 6.35 (bs, 1H);

6.7 (d. 1H); 6.9-7.0 (m, 2H); 7.25 (t, 1H); 7.35-7.45 (m, 3H); 7.5 (s. 1H); 7.6 (t, 1H); 7.9 (d. 1H); 7.95 (d. 1H); 8.15 (s. 1H); 9.0 (bs, 1H); 9.5 (bs, 1H); 13.1 (bs, 1H).