Organic Compunds

Abstract

Compounds of formula I

Description

The invention is illustrated by the following Examples.

EXAMPLES

Especially preferred compounds of formula I are also compounds of formula XI

wherein X, Y, n and T are as shown in the following table, the method of preparation being described hereinafter. The table also shows characterising mass spectrometry data ( [MH]+).

	TABLE I
	Ex.	n	T	MS [MH]+
	1	4		—
	2	4		366.1
	3	4		422.1
	4	4		364.1
	5	4		360.2
	6	4		330.2
	7	4		—

Preparation of Starting Materials

Wang-PNP resin

4-Nitrophenylchloroformate (260 g, 1.30 mmol) as a solution in 500 ml DCM is added to Wang resin (p-benzyloxybenzyl alcohol resin ex Calbiochem-Novabiochem, 350 g, 0.60 mmol) suspended in 1000 ml DCM and N-methylmorpholine (196 ml, 1.79 mmol) and stirred at room temperature for 18 hours. The resin is filtered and washed successively using methanol, DCM and ether to give WANG PARA-NITROPHENOL RESIN. [IR. 1761.5 cm¹; Loading 1.20 mmol/g].

Wang-Iodide resin

1-Amino-3-propanol (27 ml, 350 mmol) is added to a suspension of WANG-PNP RESIN (93 g, 116.4 mmol) in DMF (100 ml) and stirred at room temperature for 18 hours. The mixture is filtered and the resin washed in succession with methanol, DCM and finally ether to give the Wang-amino propanol resin (Wang-AP resin). To this a mixture of tetrahydrofuran (THF) and methyl cyanide (1000 ml, 1:1 v/v) is added, followed by triphenylphosphine (91.8 g, 350 mmol), iodine (88.83 g, 350 mmol) and imidazole (23.83 g, 350 mmol). The suspension is stirred at room temperature for 24 hours, filtered and then washed with copious DMF, DCM and methanol to give WANG-IODIDE RESIN.

Example 1

1-(3,5-Dimethyl-isoxazole-4-yl)-3-[4-[(4-fluorobenzyl)methylamino]-butyl]-urea

A solution of 4-(fluorobenzyl)methylamine (2.05 g, 14.73 mmol) and DIPEA (2.6 ml, 14.73 mmol) is added to a suspension of WANG-IODIDE RESIN (5.8 g, 7.37 mmol) in 100 ml DMF and stirred at 55° C. for 60 hours. The resin is cooled and washed using DMP (8×40 ml), methanol (2×50 ml) and DCM (12×40 ml), then treated with a mixture of TFA and DCM (50 ml, 1:1 v/v) at room temperature for 40 minutes, filtered and the filtrate evaporated. The residue is treated with the basic resin (AMBERLYST™ A-21) to give Resin Intermediate II of formula II.

3,5-Dimethylisoxazol-4-yl isocyanate (173 mg, 1.25 mmol) in DMF (5 ml) is added to a solution of Resin Intermediate 11 (300 mg, 1.25 mmol) in DMF (10 ml) and the mixture is left to stand at room temperature for 1 hour. The solvent is evaporated and the residue purified by chromatography to yield the title product as a white solid.

Example 2

1-(3,4-difluorophenyl)-3-{4-[(4-fluorobenzyl)methylamino]-butyl}-urea

2.6 ml of 14.73 mmol DIPEA and 4-(fluorobenzyl)methylamine is mixed with a suspension of 5.8 g, 7.37 mmol WANG-IODIDE RESIN in 100 ml DMF and stirred at 55° C. for 60 hours. The resin is cooled and washed using DMF (8×40 ml), methanol (2×50 ml) and DCM (12×40 ml), then treated with a mixture of TFA and DCM (50 ml, 1:1 v/v) at room temperature for 40 minutes, filtered and the filtrate evaporated. The residue is treated with the basic resin (AMBERLYST™ A-21) to give Resin Intermediate II of formula II.

3,4-Difluorophenyl isocyanate (188 mg, 1.25 mmol) in 5 ml DMF is added to a solution of Resin Intermediate II (300 mg, 1.25 mmol) in 10 ml DMF and the mixture is left to stand at room temperature for 1 hour. The solvent is evaporated and the residue purified by chromatography to yield the title product as a white solid [MH+366.1].

The compounds of Examples 3 to 7 are prepared using procedures analogous to those used in Example 2, using appropriate starting materials.

Claims

1. A compound of formula I

2. A compound according to claim 1, wherein T is phenyl optionally substituted by halo;X is a bond;R1 and R2 are both hydrogen;m is 1;Ra is C1-C8-alkyl;R3 and R4 are both hydrogen;n is 4;R5 is hydrogen; andU is a cyclic group selected from the group consisting of phenyl, C3-C8-cycloalkyl, and a 5- or 6-membered heterocyclic ring wherein at least one of the ring atoms is nitrogen, oxygen and sulphur, said cyclic group being optionally substituted by halo, nitro, C1-C8-alkyl or C1-C8-alkoxy.

3. A compound according to claim 2, wherein T is phenyl optionally substituted by halo;X is a bond;R1 and R2 are both hydrogen;m is 1;Ra is C1-C4-alkyl;R3 and R4 are both hydrogen;n is 4;R5 is hydrogen; andU is a cyclic group selected from the group consisting of phenyl, C3-C5-cycloalkyl and a 5- or 6-membered heterocyclic ring wherein at least one of the ring atoms is nitrogen, oxygen and sulphur, said cyclic group being optionally substituted by halo, nitro, C1-C4-alkyl or C1-C4-alkoxy.

4. A compound of formula I substantially as herein described in any one of the Examples.

5. A compound according to claim 1 for use as a pharmaceutical.

6. A compound according to claim 1 in combination with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound and said drug substance being in the same or different pharmaceutical composition.

7. A pharmaceutical composition comprising as active ingredient a compound according to claim 1, optionally together with a pharmaceutically acceptable diluent or carrier therefor.

8-9. (canceled)

10. A process for the preparation of compounds of formula I as defined in claim 1, which comprises: (i) reacting a compound of formula II

11. A compound of formula II

12. A method of treating a condition mediated by CCR-3 which comprises administering to a subject in need of such treatment an effective amount of a compound according to claim 1.

13. A method of treating an inflammatory or allergic condition which comprises administering to a subject in need of such treatment an effective amount of a compound according to claim 1.

14. A method according to claim 13 wherein said inflammatory or allergic condition is an inflammatory or obstructive airways disease.