Compounds act at multiple prostaglandin receptors giving a general anti-inflammatory response

3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, 18

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde.

3-{1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, is prepared in a similar manner starting initially with 5-chloro-2-hydroxybenzaldehyde.

3-[1-(5-Bromo-2-cyclopentylmethoxybenzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 19

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with chloromethylcyclopentane.

3-[1-(5-Chloro-2-cyclopentylmethoxybenzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid is also prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-chloro-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with chloromethylcyclopentane

3-[1-(2-Cyclopentylmethoxy-5-trifluoromethylbenzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid, 20

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-trifluoromethyl-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with chloromethylcyclopentane.

3-[1-(5-Bromo-2-(2-ethyl-hexyloxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 3-chloromethylheptane.

3-[1-(5-Bromo-2-(3-methyl-pentyloxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 22

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-Chloro-3-methyl-pentane.

3-[1-(5-Bromo-2-(2-methyl-pentyloxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 23

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-Chloro-2-methyl-pentane.

3-[1-(5-Bromo-2-((E)-2-methyl-but-2-enyloxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 24

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with (E)-1-Chloro-2-methyl-but-2-ene.

3-[1-(5-Bromo-2-(2-methyl-butoxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 25

A suspension of 24 (0.1 g, 0.24 mmol) and PtO 2 (0.02 g) in EtOAc (10 mL) and isohexane (10 mL), previously purged with nitrogen, was stirred under a hydrogen atmosphere (balloon) at RT for 90 min. The catalyst was removed by filtration through Hyflo, the filtrate was evaporated to dryness and the residue was purified on silica to yield the title compound 25, 0.027 g (26%).

3-{1-[5-Bromo-2-(2-ethyl-2-methyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid 26

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 3-chloromethyl-3-methyl-pentane.

3-[1-(5-Bromo-2-(2-cyclobutylmethoxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 27

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloromethylcyclobutane.

3-[1-(5-Bromo-2-(1-trifluoromethylcyclobutylmethoxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 28

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloromethyl-1-trifluoromethylcyclobutane.

3-[1-(5-Bromo-2-(1-trifluoromethylcyclopentylmethoxy)-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 29

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloromethyl-1-trifluoromethylcyclopentane.

3-[1-(5-Bromo-2-heptyloxybenzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 30

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloroheptane.

3-[1-(5-Bromo-2-isobutoxybenzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 31

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloroisobutane.

N-(3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl)-C,C,C-trifluoro-methanesulfonamide, 32

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde.

N-(3-{1-[5-Bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl)-C,C,C-trifluoro-methanesulfonamide, 33

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde.

N-(3-{1-[5-Bromo-2-isobutoxybenzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl)-C,C,C-trifluoro-methanesulfonamide, 34

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde.

N-(3-{1-[5-Bromo-2-isobutoxybenzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl)-N(dimethyl)-sulfonamide, 35

The title compound was prepared following the methods described in example and example 2 but starting initially (example 1 step 1) with 5-bromo-2-hydroxybenzaldehyde

3-[1-(5-Chloro-2-(3-methylbutoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid, 36

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 1-chloro-3-methylbutane.

3-[1-(5-Chloro-2-(3-methylpentyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 37

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 1-chloro-3-methylpentane.

3-[1-(5-Chloro-2-(1-isobutyl-3-methylbutoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 389

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 4-chloro-2,6-dimethylheptane.

N-(3-[1-(5-Chloro-2-(4-chlorobenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl)benzenesulfonamide, 39

The title compound was prepared following the method in Example 1, Step 10 but substituting trifluoromethanesulfonamide with benzenesulfonamide.

2,2,2-trifluoroethanesulfonic acid-(3-[1-(5-Chloro-2-(4-chlorobenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl)amide, 40

The title compound was prepared following the method in Example 1, Step 10 but substituting trifluoromethanesulfonamide with 2,2,2-trifluoroethanesulfonamide.

3-[1-(5-Chloro-2-(2,4-dichlorobenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 41

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 2,4-dichloro-benzyl chloride.

N-(3-[1-(5-Chloro-2-(2,4-dichlorobenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl) C,C,C-trifluoromethanesulfonamide, 42

The title compound was prepared following the method in Example 1, Step 10.

N-(3-[1-(5-Chloro-2-(2,4-dichlorobenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl)benzenesulfonamide, 43

The title compound was prepared following the method in Example 1, Step 10 but substituting trifluoromethanesulfonamide with benzenesulfonamide.

3-[1-(5-Chloro-2-(4-chloro-2-trifluoromethylbenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 44

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 4-chloro2-trifluoromethylbenzyl chloride.

Ethanesulfonic acid-(3-[1-(5-Chloro-2-(4-chlorobenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl)amide, 45

The title compound was prepared following the method in Example 1, Step 10 but substituting trifluoromethanesulfonamide with ethanesulfonamide.

3-[1-(5-Chloro-2-(4-methoxybenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 46

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 4-methoxylbenzyl chloride.

Propane-2-sulfonic acid-(3-[1-(5-Chloro-2-(4-chlorobenzyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl)amide, 47

The title compound was prepared following the method in Example 1, Step 10 but substituting trifluoromethanesulfonamide with propane-2-sulfonamide.

3-[1-(5-Chloro-2-(tetrahydrofuran-2-yl-methoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 48

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with chloromethyltetrahydro-2-furan.

3-[1-(5-Chloro-2-(cyclohexyl-methoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 49

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with chloromethylcyclohexane.

3-[1-(5-Chloro-2-(2,2-dimethylropoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 50

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 1-chloro-2,2-dimethylpropane.

3-[1-(5-Chloro-2-(5-methylhexyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 51

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 1-chloro-5-methylhexane.

3-[1-(5-Chloro-2-(1-trifluoromethylcyclopentylmethoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 52

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 1-chloro-1-trifluoromethylcyclopentane.

3-[1-(5-Chloro-2-(1-trifluoromethylcyclobutylmethoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 53

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 1-chloro-1-butane.

3-[1-(5-Chloro-2-(2-cyclopentylethoxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 54

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with 2-chloroethylcyclopentane.

3-[1-(5-Chloro-2-(4-methylpentyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 55

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with chloro-4-methylpentane.

5-[1-(5-Chloro-2-cyclopentylmethoxybenzyl)-5-methyl-1H-pyrazol-3-yl]-pentanoic acid 56

The title compound was prepared following the methods described in example 1 and example 2 but starting (example 1 step 6) with 1-(2-Benzyloxy-5-chloro-benzyl)-5-methyl-1H-pyrazole-3-carbaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 2-chloroethylcyclopentane

3-[1-(5-Chloro-2-(2-methylpropyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 57

The title compound was prepared following the methods described in example 1 and example 2 but replacing 3-chloromethylpentane in example 2 step 6 with chloro-2-methylpropane

N-(3-[1-(5-Chloro-2-cyclopentylmethoxybenzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl) C,C,C-trifluoromethanesulfonamide, 58

The title compound was prepared following the method in Example 1, Step 10.

N-(3-[1-(5-Chloro-2-(2-methylpropyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionyl) C,C,C-trifluoromethanesulfonamide, 59

The title compound was prepared following the method in Example 1, Step 10.

3-[1-(5-Chloro-2-(1-ethylpropyloxy)benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 60

The title compound was prepared following the methods described in example 1 and example 2 starting from (example 2 step 5) 3-[1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid methyl ester replacing the method in example 2 step 6 with Mitsunobu method and 3-chloromethylpentane with 3-pentanol.

3-[1-[2-(2-Ethyl-butoxy)-5-trifluoromethyl-benzyl]-5-methyl-1H-pyrazol-3-yl]-propionic acid 61

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-trifluoromethyl-2-hydroxybenzaldehyde.

3-[1-[2-(2-Ethyl-butoxy)-5-fluoro-benzyl]-5-methyl-1H-pyrazol-3-yl]-propionic acid 62

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-fluoro-2-hydroxybenzaldehyde.

3-[1-[2-(2-Ethyl-butoxy)-5-trifluoromethoxy-benzyl]-5-methyl-1H-pyrazol-3-yl]-propionic acid 63

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-trifluoromethoxy-2-hydroxybenzaldehyde.

3-[1-[2-(2-Ethyl-butoxy)-5-tert-butyl-benzyl]-5-methyl-1H-pyrazol-3-yl]-propionic acid 64

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-tert-butyl-2-hydroxybenzaldehyde.

3-[1-(2-Cyclopentylmethoxy-5-trifluoromethoxy-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 65

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-trifluoromethoxy-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloromethylcyclopentane.

3-[1-[2-(4-Chloro-benzyloxy)-5-trifluoromethoxy-benzyl]-5-methyl-1H-pyrazol-3-yl]-propionic acid 66

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-trifluoromethoxy-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 4-chlorobenzyl chloride.

3-[1-[2-(4-Chloro-benzyloxy)-5-trifluoromethyl-benzyl]-5-methyl-1H-pyrazol-3-yl]-propionic acid 67

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-trifluoromethyl-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 4-chlorobenzyl chloride.

3-[1-(2-Cyclopentylmethoxy-5-methoxy-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 68

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-methoxy-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloromethylcyclopentane.

3-[1-(2-Cyclopropylmethoxy-5-methoxy-benzyl)-5-methyl-1H-pyrazol-3-yl]-propionic acid 69

The title compound was prepared following the methods described in example 1 and example 2 but starting initially (example 1 step 1) with 5-methoxy-2-hydroxybenzaldehyde and replacing 3-chloromethylpentane in example 2 step 6 with 1-chloromethylcyclopropane.

3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-isopropyl-1H-pyrazol-3-yl}-propionic acid, 70

The title compound was prepared following the methods described in example 1 and example 2 but replacing ethyl-2,4-dioxopentanoate (example 1 step 2 with 4-methyl-3-oxo-pentanoic acid ethyl ester.

3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-propyl-1H-pyrazol-3-yl}-propionic acid, 71

The title compound was prepared following the methods described in example 1 and example 2 but replacing ethyl-2,4-dioxopentanoate (example 1 step 2 with 3-oxo-hexanoic acid ethyl ester.

3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-tert-butyl-1H-pyrazol-3-yl}-propionic acid, 72

The title compound was prepared following the methods described in example 1 and example 2 but replacing ethyl-2,4-dioxopentanoate (example 1 step 2 with 4,4-dimethyl-3-oxo-pentanoic acid ethyl ester.

3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-trifluororomethyl-1H-pyrazol-3-yl}-propionic acid, 73

The title compound was prepared from 1-(2-Benzyloxy-5-bromo-benzyl)-5-trifluoromethyl-1H-pyrazole-3-carboxylic acid ethyl ester 77 following the methods described in example 1 and example 2.

1-(2-benzyloxy-5-bromo-benzyl)-5-trifluoromethyl-1h-pyrazole-3-carboxylic acid ethyl ester 77 preparation:

3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazol-3-yl}-propionic acid, 78

The title compound was prepared following the methods described in example 1, in example 2 and in example 62 but replacing 5-trifluoromethyl-1H-pyrazole-3-carboxylic acid ethyl ester with methyl 1H-pyrazole-3-carboxylic acid.

3-{1-[5-Cyano-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid 79

A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.309 g, 0.71 mmol), Zn(CN) 2 (0.0831 g, 0.71 mmol) and Pd(PPh 3 ) 4 (0.025 g, 0.021 mmol) mmol) in DMF (6 ml) heated at 160° C. in a microwave reactor under a N 2 atmosphere for 20 min. The mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The residue was purified by MPLC (10 g SiO 2 cartridge, eluent 95% iso-hexane-5% EtOAc) yielding 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester. This was dissolved in THF (0.5 ml), MeOH (0.5 ml) and 0.82 M LiOH solution (0.5 ml, 0.41 mmol) was added. The mixture was heated at 100° C. in a microwave reactor for 20 min, thereafter partitioned between 2M HCl and EtOAc, the organic layer was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The residue was purified by MPLC (2 g SiO 2 cartridge, eluent 80% iso-hexane-20% EtOAc) yielding the title compound.

3-{1-[5-Carbamoyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid 80

The title compound was prepared from 1 3-{1-[5-Cyano-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid following the methods described in example 64.

3-{1-[5-Carboxy-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid 81

The title compound was prepared from 1 3-{1-[5-Cyano-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid following the methods described in example 64, but replacing LiOH with NaOH and adding MeOH as co-solvent while heating in a microwave reactor at 140° C. in a microwave reactor for 30 min.

3-{1-[4-(2-Ethyl-butoxy)-biphenyl-3-ylmethyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid 82

The title compound was prepared from 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester and benzeneboronic acid using Suzuki chemistry and following the method in Example 1, Step 8.

3-{1-[5-Ethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid

A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0774 g, 0.18 mmol), [PdCl 2 (PPh 3 )] 2 (0.007 g, 0.01 mmol), PPh 3 (0.0094 g, 0.018 mmol) mmol), CuI (2 mg, 0.01 mmol), trimethylsilylacetylene (0.0196 g, 0.2 mmol), Et 2 N (0.07314 g, 2.72 mmol in DMF (1 ml) heated at 120° C. in a microwave reactor under a N 2 atmosphere for 50 min. The mixture was partitioned between 0.1M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The residue was purified by MPLC (20 g SiO 2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 3-{1-[5-trimethylsilanylethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0396 g). This was dissolved in THF (20 ml), MeOH (20 ml), glacial acetic acid (8 ml) and Bu 4 NF solution (24 ml, 1M) was added. The mixture was stirred at RT overnight then heated at 60° C. for 3 hours, thereafter cooled to RT and partitioned between sat. NH 4 Cl solution and EtOAc, the organic layer was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The residue was purified by MPLC (20 g SiO 2 cartridge, eluent 85% iso-hexane-15% EtOAc) yielding 3-{1-[5-Ethynyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.0078 g) which was converted to the title compound following the method in Example 1, Step 8.

3-{1-[2-(2-Ethyl-butoxy)-5-methyl-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid 84

A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.1363 g, 0.31 mmol), Pd(dppf)Cl 2 (0.00506 g, 0.00621 mmol), Zn(CH 3 ) 2 (0.31 mlg, 0.62 mmol in 1,4-dioxane (0.93 ml) heated at 105° C. under a N 2 atmosphere for 1 h 50 min. The mixture was cooled to RT, quenched with MeOH (0.2 ml) and partitioned between 1M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The residue was converted to the title compound following the method in Example 1, Step 8.

3-{1-[5-Ethyl-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid 85

The title compound was prepared following the methods described in example 1, in example 2 and in example 69 but replacing dimethylzinc with diethylzinc.

3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-propionic acid 86

The title compound was prepared following the methods described in example 1 and example 2 but replacing (methoxycarbonylmethylene)triphenylphosphorane (example 2 step 4) with (ethoxycarbonylethylene)triphenylphosphorane.

3-{1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-propionic acid 87

The title compound was prepared following the methods described in example 1 and example 2 but replacing (methoxycarbonylmethylene)triphenylphosphorane (example 2 step 4) with (ethoxycarbonylethylene)triphenylphosphorane.

3-{1-[2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-propionic acid 88

The title compound was prepared following the methods described in example 1 and example 2 but replacing (methoxycarbonylmethylene)triphenylphosphorane (example 2 step 4) with (ethoxycarbonylethylene)triphenylphosphorane.

3-{1-[5-Chloro-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-propionic acid 89

The title compound was prepared following the methods described in example 1 and example 2 but replacing (methoxycarbonylmethylene)triphenylphosphorane (example 2 step 4) with (ethoxycarbonylethylene)triphenylphosphorane.

3-{1-[5-Bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2,2-dimethyl-propionic acid, 90

To a solution of 3-{1-[5-bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-propionic acid ethyl ester (0.14 g, 0.3 mmol) in dry THF (5 ml) under a N 2 atmosphere at −78° C. was added lithium bis(trimethylsislyl)amide (1.8 ml, 1M in THF). The mixture was stirred for 1 hour before addition of a THF solution (1 ml) of MeI (0.255 g, 0.18 mmol). After stirring 3 hours more at −78° C. the mixture was left at RT for 16 hours. The reaction was quenched with sat NH 4 Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The residue was purified by MPLC (10 g SiO 2 cartridge, eluent 95-90% iso-hexane-5-10% EtOAc) to yield 0.033 g of 3-{1-[5-bromo-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2,2-dimethyl-propionic acid ethyl ester which was converted to the title compound following the method in Example 1, Step 8.

3-{1-[5-Chloro-2-(2-cyclopentylmethoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-2,2-dimethyl-propionic acid, 91

The title compound was prepared following the methods described in example 1, example 2 and example 71.

3-{1-[5-Chloro-2-cyclopentylethynyl-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, 92

The title compound was prepared following the methods described in example 1, in example 2 but starting initially (example 1 step 1) with 2-bromo-5-chlorobenzaldehyde,

and in example 68.

3-{1-[5-Chloro-2-(2-cyclopentylethyl-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, 93

The title compound was prepared following the methods described in example 1, in example 2 but replacing acetic acid and HCl (example 2 step 5) with EtOAc and in example 78.

3-{1-[5-Chloro-2-(2-cyclopentylethyl-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic C,C,C-trifluoro-methanesulfonamide, 94

The title compound was prepared following the methods described in example 1, in example 2 and in example 79.

3-{1-[5-Chloro-2-(4-methylpentynyl)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, 95

The title compound was prepared following the methods described in example 1, in example 2 and in example 68.

The present invention provides a method of making 3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid which comprises hydrolyzing a 3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester, to yield 3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, wherein said halo is selected from the group consisting of fluoro, chloro and bromo, e.g. said haloalkyl may be trifluoromethyl.

Preferably, said alkyloxy may be selected from the group consisting of alkyloxy wherein said alkyl comprises from 4 to 7 carbon atoms. Preferably, said alkyl may be selected from the group consisting of 3-pentyl and cyclopentylmethyl. Said 3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid may be prepared by hydrogenating the corresponding (E)-3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-acrylic acid methyl ester to yield 3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid, e.g. said hydrogenation may be carried out in the presence of a platinum catalyst.

Said (E)-3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-acrylic acid methyl ester may be prepared by reacting trimethylphosphonoacetate with the corresponding {1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carbaldehyde to yield said (E)-3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-acrylic acid methyl ester.

As can be understood from the above examples, the present invention also provides a method of making N-(3-{1-[5-halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl)-C,C,C-trifluoro-methanesulfonamide comprising the step of (a) reacting the corresponding 0.3-{1-[5-Halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid with cyanuric fluoride to yield 3-{1-[5-halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl fluoride and (b) reacting said 0.3-{1-[5-halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl fluoride with trifluoromethanesulfonamide to yield N-(3-{1-[5-halo or haloalkyl-2-(4-chloro-benzyloxy or 4-chloro-alkyloxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionyl)-C,C,C-trifluoro-methanesulfonamide.

Preferably, said step (a) is carried out in the presence of pyridine and said step (b) is carried out in the presence of DMAP.

The above compounds were tested for PG antagonist activity as follows using human recombinant prostanoid receptor (DP 1 , EP 1-4 , FP, IP and TP) stable cell lines:

In order to measure the response of G s and G i coupled prostanoid receptors as a Ca 2+ signal, chimeric G protein cDNAs were used. Stable cell lines over-expressing human prostanoid DP 1 , EP 1-4 , FP, IP, and TP receptors were established as follows:

Briefly, human prostanoid DP 1 , EP 2 , and EP 4 receptor cDNAs were co-transfected with chimeric G qs cDNA containing a haemagglutanin (HA) epitope; human prostanoid EP 3 receptors were co-transfected with chimeric G qi -HA; human EP 1 , FP, IP, and TP receptor cDNAs were expressed with no exogenous G-proteins. G qs and G qi chimeric cDNAs (Molecular Devices, Sunnyvale, Calif., U.S.A.), as well as cDNAs of prostanoid receptors, were cloned into a pCEP 4 vector with a hygromycin B selection marker. Transfection into HEK-293 EBNA (Epstein-Barr virus nuclear antigen) cells was achieved by the FuGENE 6 transfection Reagent (Roche Applied Science, Indianapolis, Ind., USA). Stable transfectants were selected according to hygromycin resistance. Because G qs and G qi contained an HA epitope, G-protein expression was detected by Western blotting analysis using anti-mouse HA monoclonal antibody and horseradish peroxidase (HRP)-conjugated secondary antibody, while functional expression of prostanoid receptors was detected by FLIPR screening (Matias et al., 2004). These stable cell lines were validated using previously published antagonists at 10 μM against serial dilutions of standard agonists by FLIPR functional assays for Ca 2+ Signaling (as described below).

Ca 2+ signaling studies were performed using a FLIPR TETRA system (Molecular Devices, Sunnyvale, Calif., USA) in the 384-format. This is a high-throughput instrument for cell-based assays to monitor Ca 2+ signaling associated with GPCRs and ion channels. Cells were seeded at a density of 5×10 4 cells/well in BioCoat poly-D-lysine coated, black wall, clear bottom 384-well plates (BD Biosciences, Franklin lakes, NJ, USA) and allowed to attach overnight in an incubator at 37° C. The cells were then washed twice with HBSS-HEPES buffer (Hanks' balanced salt solution without bicarbonate and phenol red, 20 mM HEPES, pH 7.4) using an ELx405 Select CW Microplate Washer (BioTek, Winooski, Vt., USA). After 60 min of dye-loading in the dark using the Ca 2+ -sensitive dye Fluo-4AM (Invitrogen, Carlsbad, Calif., USA), at a final concentration of 2×10 −6 M, the plates were washed 4 times with HBSS-HEPES buffer to remove excess dye and leaving 50 μl of buffer in each well. The plates were then placed in the FLIPR TETRA instrument and allowed to equilibrate at 37° C. AGN-211377 was added in a 25 μl volume to each well to give final concentrations of 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, and 30 μM; or 0.067 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.67 μM, and 1 μM for cells over-expressing TP receptors. After 4.5 minutes, a 7-point serial dilution of the standard agonist for the corresponding receptor, in a 25 μl volume was injected at the final concentrations from 10 −11 M to 10 −6 M in 10-fold serial dilution increments for cells expressing human recombinant DP 1 , EP 1 , EP 2 , EP 3 , EP 4 , FP, and IP receptors. The dose range for the standard agonist for human recombinant TP receptors was from 10 −12 M to 10 −6 M. HBSS-HEPES buffer was used as the negative control for the standard agonists. Cells were excited with LED (light emitting diode) excitation at 470-495 nm and emission was measured through an emission filter at 515-575 nm. Assay plates were read for 3.5 minutes using the FLIPR TETRA . The peak increase in fluorescence intensity was recorded for each well. On each plate, negative controls, dose response of positive controls, and co-treatments of antagonist-agonist for each dose were in triplicates. Standard agonists were as follows: DP=BW 245C, EP 1 -EP 4 =PGE 2 , FP=17-phenyl-PGF 2α , IP=Cicaprost, and TP=U-46619. The peak fluorescence change in each well containing drug was expressed relative to vehicle controls with the standard agonist at 10 −6 M (the positive control). To obtain concentration-response curves, compounds were tested in triplicate in each plate over the desired concentration range.

Ca 2+ Signal Studies on Human Recombinant Prostanoid Receptor DP 2

FLIPR functional assays were conducted at Millipore to monitor the activity anti-asthmatic against human DP 2 receptors stably expressed in the Chem-5 proprietary host cell line generated by Millipore. Prior to standard agonist addition, the compounds were spotted at 10 μM along with vehicle control (1% Ethanol in HBSS-HEPES buffer) across the assay wells. The assay plate was incubated at room temperature for 10 minutes in the dark. Then an 8-point serial dilution dose response from 10 −12 M to 10 −5 M of the standard agonist PGD 2 was performed. Assay plates were read for 90 seconds using the FLIPR TETRA . The fluorescence measurements were collected to calculate IC 50 values. The assays were done at least 3 times to give n=3.

Data Processing

All plates were subjected to appropriate baseline corrections. Maximum fluorescence values were exported. The raw data of n=1 was first processed by Activity Base using nonlinear regression curve fit to calculate the percentage activity of each data point relative to the positive control (=10 −6 M of the standard agonist). Then n=3 of this data were exported to GraphPad Prism 4 to calculate the average EC 50 of the standard agonist, and the IC 50 (the concentration of the antagonist required to inhibit half the standard agonist activity) were calculated using nonlinear regression curve fit, with constraints of bottom constant equal to 0 and top constant equal to 100. Calculation of Kb=[Antagonist Concentration]/(IC 50 /EC 50 −1). When no antagonism was detected or when Kb≧10,000 nM, the antagonist is defined as not active (NA).

The results of the above testing are reported in TABLE 1, below.

As shown in TABLE 1, the preferred compounds of this invention are pan antagonists having activity at the FP, DP, EP 1 , EP 4 and TP receptors, but are inactive at the EP 2 and EP 3 receptors. Thus, these compounds have a biological selectivity profile making them useful in treating diseases and conditions which are mediated by the EP 2 and/or EP 3 receptors, without the side effects mediated by the FP, DP, EP 1 , EP 4 and TP receptors.

Thus, the compounds of this invention compound may be administered to treat DP1, FP, EP1, TP and/or EP4 receptor mediated diseases or conditions.

For example, said condition or disease may be related to inflammation, or said DP1, FP, EP1, TP and/or EP4 receptor mediated condition or disease may be selected from the group consisting of allergic conditions, asthma, allergic asthma, allergic rhinitis, uveitis and related disorders, atherosclerosis, blood coagulation disorders, bone disorders, cancer, cellular neoplastic transformations, chronic obstructive pulmonary diseases and other forms of lung inflammation, congestive heart failure, diabetic retinopathy, diseases or conditions requiring a treatment of anti-coagulation, diseases requiring control of bone formation and resorption, fertility disorders, gangrene, glaucoma, hyperpyrexia, immune and autoimmune diseases, inflammatory conditions, metastic tumor growth, migraine, mucus secretion disorders, nasal congestion, nasal inflammation, occlusive vascular diseases, ocular hypertension, ocular hypotension, osteoporosis, rheumatoid arthritis, pain, perennial rhinitis, pulmonary congestion, pulmonary hypotension, Raynaud's disease, rejection in organ transplant and by-pass surgery, respiratory conditions, hirsutism, rhinorrhea, shock, sleep disorders, and sleep-wake cycle disorders.

Said compound may be administered as a surgical adjunct in ophthalmology for cataract removal and artificial lens insertion, ocular implant procedures, photorefractive radial keratotomy and other ophthalmogical laser procedures or as a surgical adjunct in a procedure involving skin incisions, relief of pain and inflammation and scar formation/keloids post-surgery, for treating sports injuries and general aches and pains in muscles and joints.

Preferably, said DP 1 , FP, EP 1 , TP, and/or EP 4 receptor mediated condition or disease is an EP 1 and/or EP 4 receptor mediated condition or disease.

Preferably, said DP 1 , FP, EP 1 , TP and/or EP 4 receptor mediated condition or disease is an allergic condition, e.g. an dermatological allergy, or an ocular allergy, or a respiratory allergy, e.g. nasal congestion, rhinitis, and asthma.

Said condition or disease may be related to pain.

Said condition or disease may be selected from the group consisting of arthritis, migraine, and headache.

Said condition or disease may be associated with the gastrointestinal tract, wherein said condition or disease may be peptic ulcer, heartburn, reflux esophagitis, erosive esophagitis, non-ulcer dyspepsia, infection by Helicobacter pylori , alrynitis, and irritable bowel syndrome.

Said condition or disease may be selected from the group consisting of hyperalgesia and allodynia, or said condition or disease may be related to mucus secretion, wherein said mucus secretion is gastrointestinal, or occurs in the nose, sinuses, throat, or lungs.

Said condition or disease is related to abdominal cramping, e.g. said condition or disease may be irritable bowel syndrome.

Said condition or disease may be a bleeding disorder, or a sleep disorder, or mastocytosis.

Said condition or disease may be associated with elevated body temperature, or ocular hypertension and glaucoma, or ocular hypotension.

Said condition may relate to surgical procedures to treat pain, inflammation and other unwanted sequelae wherein said surgical procedure includes incision, laser surgery or implantation.

The present invention also relates to a method of treating inflammation resulting from inflammatory diseases characterized by monocytic infiltration caused by the secretion of cytokines and/or chemokines by administration, to a patient in need of said treatment, of a pharmaceutical composition comprising a compound of the present invention

The current finding that the compounds of this invention are effective in attenuating the production of TNF family cytokines (TNFα), and the classical interleukin-1 (IL-1) family cytokines is especially important. These cytokines exert a broad spectrum of biological and pathological effects. They play key roles in inflammation and RA pathogenesis by stimulating the release of multiple proinflammatory cytokines, including themselves, through the NFκB signaling pathway. Although alleviating the symptoms of RA in 50-65% of patients, a TNFα antibody is very expensive to use compared to chemically synthesized small molecules, inconvenient to administer usually requiring injections, and has been linked to tuberculosis, lymphoma, and other adverse effects. Unlike a TNFα antibody that totally eliminates all circulating TNFα in the system; the compounds of this invention only attenuate the production of TNFα by inhibiting proinflammatory PG receptors. Therefore the adverse effects associated with a TNFα antibody in elevating infectious and cancerous tendency is less likely.

Proinflammatory elements TNF, RANTES, and MCP-1 are involved in the cascade of events in the early and late stages of atherosclerosis. Plasma MCP-1 levels have been linked to cardiovascular disease risk factors in clinical studies. Platelet activation leads to the release of MIP-1α, RANTES, and IL-8, which attract leukocytes and further activate other platelets. These evidences provide a direct linkage between homeostasis, infection, and inflammation and the development of atherosclerosis. The compounds of this invention are able to target multiple biomarkers of inflammation, thrombosis, and atherothrombosis simultaneously, which may confer pharmaceutical potential on the compounds of this invention in treating atherosclerosis and atherothrombosis. As a result, the compounds of this invention are unlikely to be associated with cardiovascular liability as in the case of the COXIBs, conversely it may even have a beneficial effect on cardiovascular function.

In summary, because of their ability to suppress the synthesis of some key proinflammatory cytokines/chemokines IL-8, MCP-1, MDC, RANTES, and TNFα, the compounds of the present invention are not only at least as effective as COXIBs and NSAIDs in RA treatment, but also are a safer therapy in RA treatment. They are also a potential therapy for cardiovascular diseases.

The compounds of this invention treat or prevent inflammation at least in part by the decreasing the amount of the secretion of certain cytokines and/or chemokines that result from the exposure of the patient to a stimulant. In particular, the secretion of VEGF, MIP-1β, IL-8, MCP-1, MDC, and RANTES is reduced in those instances where said secretions are triggered by lipopolysaccharides (LPS) and or TNFα.

Interleukin-8 (IL-8): functions as a potent chemoattractants and activator of neutrophils, IL-8 is produced in response to stimulation with either IL-1 or TNFα. IL-8 not only accounts for a significant proportion of the chemotactic activity for neutrophils in rheumatoid arthritis (RA) synovial fluids, but also is a potent angiogenic factor in the RA synovium.

Monocyte chemoattractant protein-1 (MCP-1, or CCL-2): is not only believed to play a role in inflammatory diseases characterized by monocytic infiltration, such as RA rheumatoid arthritis, psoriasis, and atherosclerosis, but is also implicated in other diseases, such as atopic dermatitis, renal disease, pleurisy, allergy and asthma, colitis, endometriosis, polymyositis and dermatomyositis, uveitis, restenosis, brain inflammation and obesity. MCP-1 also controls leukocyte trafficking in vascular cells involved in diabetes and diabetes-induced atherosclerosis. MCP-1 antibodies are potential therapeutic agents for treating MCP-1/CCR2-mediated multiple inflammatory diseases.

Tumor necrosis factor α (TNFα): mainly secreted by macrophages and recognized for its importance in activating the cytokine cascade. TNFα stimulates the production of proinflammatory cytokines/chemokines, collagenases, metalloproteinases, and other inflammatory mediators; activates endothelial cells and neutrophils; promotes T- and B-cell growth, as well as stimulating bone resorption. The TNFα antibody infliximab not only decreases the production of local and systemic proinflammatory cytokines/chemokines, but also reduces serum MMP-3 production, nitric oxide synthase activity, VEGF release, and angiogenesis in inflamed joints.

Macrophage-derived chemokine (MDC) induces chemotaxis for monocyte-derived dendritic cells, activated T cells and natural killer (NK) cells (Ho et al., 2003). Highly expressed by the three major cell types involved in allergic inflammation: eosinophils, basophils, and Th2 lymphocytes (Garcia et al., 2005), as well as highly expressed in atopic dermatitis (Pivarcsi et al., 2005), MDC plays a role in inflammatory diseases such as allergic asthma and atopic dermatitis (Ho et al., 2003). Significantly enhanced in keratinocytes of patients with atopic dermatitis, MDC could be a candidate therapeutic target for inflammatory skin disease such as atopic dermatitis (Qi et al., 2009). MDC is also implicated in disease activity of RA. After combination treatment with the disease-modifying anti-rheumatic drugs leflunomide and methotrexate in RA patients, plasma MCP-1 and MDC concentrations were significantly lower, and so was the recruitment of inflammatory cells into the sites of inflammation (Ho et al., 2003). Moreover, MDC also amplify platelet activation and has been associated with the pathogenesis of atherosclerotic disease including thrombosis (Gleissner et al., 2008).

Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) is a chemoattractant for blood monocytes, memory T-helper cells and eosinophils, and plays an active role in recruiting leukocytes into inflammatory sites. It also stimulates the release of histamine from basophils, activates eosinophils and causes hypodense eosinophils, which is associated with diseases such as asthma and allergic rhinitis. RANTES receptor CCR5 is also expressed on cells involved in atherosclerosis (e.g. monocytes/macrophages, T lymphocytes, or Th1-type cells), and is specialized in mediating RANTES-triggered atherosclerotic plaque formation (Zernecke et al., 2008). Like MCP-1, stimulation with RANTES enhances production of IL-6 and IL-8 in RA fibroblast-like synovial cells; elevated MMP-3 production by chondrocytes, and inhibited proteoglycan synthesis and enhanced proteoglycan release from the chondrocytes (Iwamoto et al., 2008). Both MCP-1 and RANTES were found to play an important role in allergic lung inflammation, lung leukocyte infiltration, bronchial hyper-responsiveness, and the recruitment of eosinophils in the pathogenesis of asthma (Conti et al., 2001). Similar to MCP-1, RANTES also enhances the inflammatory response within the nervous system, which plays an apparent role in the pathogenesis of multiple sclerosis (Conti et al., 2001). Inhibitors for RANTES may provide clinical benefits in treating inflammation, CNS disorders, parasitic disease, cancer, autoimmune and heart diseases (Castellani et al., 2007).

While the use of the compounds of this invention are shown to decrease the secretion of the above cytokines in FIGS. 2 through 9 , it is believed that the compounds of this invention are effective to decrease the secretion of ENA-7, PAI-1, CD-10, G-CSF, GM-CSF, IL-1α and IL-18, as well.

The compounds of this invention are also tested for efficacy in treating uveitis as described below.

Arachidonate Induced Uveitis

The rational for this protocol is to use arachidonate to directly produce ocular anterior segment uveitis, as opposed to using lipopolysaccharide (LPS) to indirectly release arachidonic acid.

Induction of Uveitis:

Conscious male or female Dutch-belted pigmented rabbits weighing 2.5-3 kg were used for all in vivo slit lamp studies. Four animals were employed per test group. The right eye of each animal receiving 35 μl of topically administered test and the contralateral left eye of each animal receiving 35 μl of topically administered vehicle (t=0 minutes), followed 30 minutes later by treatment with 35 μl of 0.5% sodium arachidonate onto the surface of both eyes (t=30 minutes). Both eyes were examined by slit lamp 60 minutes following sodium arachdionate challenge (t=90 minutes) at 16× magnification under both white light and blue light illumination at an approximate angle of 45° through 1 mm and 5 mm slit widths.

Measurement of Anterior Chamber Leukocyte Infiltration:

Anterior chamber leukocyte infiltration was measured using a numerical scoring system to estimate cell number per field defined by a 5 mm slit width: 0=no cells per field (no response); 1=1-10 cells per field (mild); 2=11-20 cells per field (moderate); 3=26-50 cells per field (severe); 4=>50 cells per filed (florid). Results are reported as the mean score value±S.E.M.

The results are shown in FIG. 12 . In FIG. 12 the compounds of Example 3 and 3a were tested at concentrations of 0.1, 0.3 and 1% and a dose dependent response was observed for each compound.

The compounds of this invention were tested according to the method described in “Characterization of Receptor Subtypes Involved in Prostanoid-Induced Conjunctival Pruritis and Their Role in Mediating Conjunctival Itching”, Vol. 279, No. 1, (JPET) 279, 137-142' 1996 for their efficacy in alleviating itch. The results are reported in FIGS. 10 and 11 . The results in both experiments showed a significantly lower number of itch-scratch episodes with the use of the compounds of FIGS. 3 and 3( a ) thereby indicating that the compounds of this invention are useful in treating allergic conjunctivitis.

The compounds of FIGS. 3 and 3( a ) were tested for mutagenicity by means of the Ames Test using Strains TA 98 and TA 100. The results were negative for both compounds.

Finally, said condition that may be treated with the compounds of this invention may be related to pain and inflammation and post-surgical scar and keloid formation.

In view of the various diseases and conditions that may be treated with the compositions of this invention there is provided a pharmaceutical product comprising a compound having the following formula:

Wherein R 1 is selected from the group consisting of OR 7 , N(R 7 ) 2 , and N(R 7 )SO 2 R 7 wherein R 7 is selected from the group consisting of H, alkyl and aryl, wherein said alkyl and aryl may be substituted with fluoro;

R 2 is selected from the group consisting of H and alkyl;

R 3 is selected from the group consisting of H and alkyl; wherein R 2 and R 3 , individually or together, can form a cycloalkyl ring;

X is (CH 2 ) n wherein n is 0 or an integer of from 1 to 3; provided however that when n is 0 or 1, R 1 is not OR 7 . or NR 2 ;

R 4 is selected from the group consisting of H, alkyl and fluoroalkyl;

R 5 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;

R 6 is selected from the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy and aryloxy;

Z is (CH 2 ) m wherein m is 0 or an integer of from 1 to 3:

Y is selected from the group consisting of O, S, SO, SO 2 and (CH 2 ) p , wherein p is 0 or an integer of from 1 to 3; and

W is selected from the group consisting of alkyl and aryl or a pharmaceutically acceptable salt or a prodrug thereof, wherein said product is packaged and labeled for the treatment or prevention of a disease or condition selected from the group consisting of uveitis, allergic conditions, asthma, allergic asthma, allergic rhinitis, atherosclerosis, blood coagulation disorders, bone disorders, cancer, cellular neoplastic transformations, chronic obstructive pulmonary diseases and other forms of lung inflammation, congestive heart failure, diabetic retinopathy, diseases or conditions requiring a treatment of anti-coagulation, diseases requiring control of bone formation and resorption, fertility disorders, hyperpyrexia, gangrene, glaucoma, hypothermia, immune and autoimmune diseases, inflammatory conditions, metastic tumor growth, migraine, mucus secretion disorders, nasal congestion, nasal inflammation, occlusive vascular diseases, ocular hypertension, ocular hypotension, osteoporosis, pain, perennial rhinitis, pulmonary congestion, pulmonary hypotension, Raynaud's disease, rejection in organ transplant and by-pass surgery, respiratory conditions, rheumatoid arthritis, rhinorrhea, shock, sleep disorders, sleep-wake cycle disorders, sports injuries, muscle aches and pains, and surgical adjunct for minimizing pain, inflammation and scar/keloid formation.

Those skilled in the art will readily understand that for administration the compounds disclosed herein can be admixed with pharmaceutically acceptable excipients which, per se, are well known in the art. Specifically, a drug to be administered systemically, it may be formulated as a powder, pill, tablet or the like, or as a solution, emulsion, suspension, aerosol, syrup or elixir suitable for oral or parenteral administration or inhalation.

For solid dosage forms, non-toxic solid carriers include, but are not limited to, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate. The solid dosage forms may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distcarate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, which are hereby incorporate by reference in their entireties, to form osmotic therapeutic tablets for control release. Liquid pharmaceutically administrable dosage forms can, for example, comprise a solution or suspension of one or more of the compounds of the present invention and optional pharmaceutical adjutants in a carrier, such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. Typical examples of such auxiliary agents are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 16th Edition, 1980. The composition of the formulation to be administered, in any event, contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect.

Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. In addition, if desired, the injectable pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.

The amount of the presently useful compound or compounds of the present invention administered is, of course, dependent on the therapeutic effect or effects desired, on the specific mammal being treated, on the severity and nature of the mammal's condition, on the manner of administration, on the potency and pharmacodynamics of the particular compound or compounds employed, and on the judgment of the prescribing physician. The therapeutically effective dosage of the presently useful compound or compounds is preferably in the range of about 0.5 ng/kg/day or about 1 ng/kg/day to about 100 mg/kg/day.

For ophthalmic application, solutions are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

Similarly, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmic preparations are chelating agents. A useful chelating agent is edentate disodium, although other chelating agents may also be used in place or in conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of the present invention are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

The actual dose of the compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.

The present invention is not to be limited in scope by the exemplified embodiments, which are only intended as illustrations of specific aspects of the invention. Various modifications of the invention, in addition to those disclosed herein, will be apparent to those skilled in the art by a careful reading of the specification, including the claims, as originally filed. It is intended that all such modifications will fall within the scope of the appended claims.