NZ626990B2 - Combination of crth2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis - Google Patents
Combination of crth2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis Download PDFInfo
- Publication number
- NZ626990B2 NZ626990B2 NZ626990A NZ62699012A NZ626990B2 NZ 626990 B2 NZ626990 B2 NZ 626990B2 NZ 626990 A NZ626990 A NZ 626990A NZ 62699012 A NZ62699012 A NZ 62699012A NZ 626990 B2 NZ626990 B2 NZ 626990B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- acetic acid
- methyl
- indol
- fluoro
- phenyl
- Prior art date
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- 230000003042 antagnostic Effects 0.000 title claims abstract description 79
- 239000005557 antagonist Substances 0.000 title claims abstract description 79
- 206010064212 Eosinophilic oesophagitis Diseases 0.000 title claims abstract description 42
- 201000000708 eosinophilic esophagitis Diseases 0.000 title claims abstract description 42
- 230000003482 proton pump inhibitor Effects 0.000 title claims abstract description 25
- 239000000612 proton pump inhibitor Substances 0.000 title claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 145
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- SUBDBMMJDZJVOS-XMMPIXPASA-N (R)-omeprazole Chemical compound C([S@@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-XMMPIXPASA-N 0.000 claims abstract description 22
- SUBDBMMJDZJVOS-UHFFFAOYSA-N Esomeprazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960004770 esomeprazole Drugs 0.000 claims abstract description 22
- 229960000381 omeprazole Drugs 0.000 claims abstract description 22
- MJIHNNLFOKEZEW-RUZDIDTESA-N 2-[(R)-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 claims abstract description 21
- MJIHNNLFOKEZEW-UHFFFAOYSA-N Dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims abstract description 21
- GRHYHJAAOJVRSZ-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2N=C3[CH]C(OC(F)F)=CC=C3N=2)=C1OC GRHYHJAAOJVRSZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- SXTZYIWTRUTYCY-UHFFFAOYSA-N Rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2N=C3[CH]C=CC=C3N=2)=C1C SXTZYIWTRUTYCY-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960003568 dexlansoprazole Drugs 0.000 claims abstract description 21
- 229960003174 lansoprazole Drugs 0.000 claims abstract description 21
- 229960005019 pantoprazole Drugs 0.000 claims abstract description 21
- 229960004157 rabeprazole Drugs 0.000 claims abstract description 21
- 102100007288 PTGDR2 Human genes 0.000 claims abstract 11
- 101710013017 PTGDR2 Proteins 0.000 claims abstract 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 743
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 157
- 239000011780 sodium chloride Substances 0.000 claims description 141
- 150000003839 salts Chemical class 0.000 claims description 139
- -1 esorneprazole Chemical compound 0.000 claims description 108
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 81
- 125000000217 alkyl group Chemical group 0.000 claims description 77
- 125000003118 aryl group Chemical group 0.000 claims description 60
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 53
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 37
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 34
- 239000003246 corticosteroid Substances 0.000 claims description 33
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000004076 pyridyl group Chemical group 0.000 claims description 22
- 125000001153 fluoro group Chemical group F* 0.000 claims description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 125000001041 indolyl group Chemical group 0.000 claims description 14
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- PYLWMHQQBFSUBP-UHFFFAOYSA-N Fluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 12
- 125000005418 aryl aryl group Chemical group 0.000 claims description 12
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 12
- 230000002327 eosinophilic Effects 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- PQUGCKBLVKJMNT-UHFFFAOYSA-N 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazole Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C(F)(F)F)=N1 PQUGCKBLVKJMNT-UHFFFAOYSA-N 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 229960004436 Budesonide Drugs 0.000 claims description 8
- VOVIALXJUBGFJZ-VXKMTNQYSA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-VXKMTNQYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 238000009115 maintenance therapy Methods 0.000 claims description 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 5
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229920000333 poly(propyleneimine) Polymers 0.000 claims description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 3
- 229960003957 Dexamethasone Drugs 0.000 claims description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 3
- 241000229754 Iva xanthiifolia Species 0.000 claims description 3
- VHRSUDSXCMQTMA-PJHHCJLFSA-N Methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 claims description 3
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N Quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 3
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- 230000002265 prevention Effects 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N Anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 2
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- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- YVLZYLQOFHWRHB-UHFFFAOYSA-N 2-[3-[(2-benzylphenyl)methyl]-5-fluoro-2-methylindol-1-yl]acetic acid Chemical compound C12=CC(F)=CC=C2N(CC(O)=O)C(C)=C1CC1=CC=CC=C1CC1=CC=CC=C1 YVLZYLQOFHWRHB-UHFFFAOYSA-N 0.000 claims 1
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical compound C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 230000003979 response to food Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 230000001932 seasonal Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000010181 skin prick test Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960003114 tixocortol pivalate Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
Abstract
Provided is a combination of at least one CRTH2 antagonist and at least one proton pump inhibitor. Preferred CRTH2 antagonists are indole-alkanecarboxylic acid derivative compounds of general formula (I), wherein the variables are as defined in the specification. An example of a compound of formula (I) is (5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid. Preferred proton pump inhibitors are selected from omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole. The combination is useful in the treatment of eosinophilic esophagitis. (I) is (5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid. Preferred proton pump inhibitors are selected from omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole. The combination is useful in the treatment of eosinophilic esophagitis.
Description
WO 88109 PCT/G320] 2/000904
COMBINATION OF A CRTHZ‘ NIST AND A PROTON PUMP
INHIBITOR FOR THE TREATMENT OF EOSINOPHILIC ESOPHAGITIS
BACKGROUND OF THE INVENTION
Field of the Invention
Theipresent invention provides‘a method for the ent of eosinophilic esophagitis
by administering compositions :c'oinprising one or more CRTHZ antagonist
nds and one or more proton pump tors.
Related Art
Eosinophilic gitis (EOE) is characterised by signs and symptoms related to
eSOphageal dysfunction (Liacouras et al., J Allergy Clin. Immunol. 128:3-20 (2011)).
In adults these include dysphagia, chest pain, food impaction, and upper abdominal
pain (Croese et al, Gastrointest. Endosc. 58:516-522 (2003); Furuta and Straurnann,
Aliment. Pharmacol. Ther. -187. (2006)). Clinical manifestations in children
”vary by age. infants often t with feeding difficulties and failure to thrive,
whereas school—aged children are more likely to present with vomiting or pain
(Liac0uras et a(., 2011). Eosinophils are present histologically in biopsied
esophageal tissue. EOE is considered to have an allergic etiology with 70% of EOE:
patients having current or past allergic disease or positive skin prick tests to food or
other allergens (Blanchard and Rothenberg, intest. Endosc. Clin. N. Am.
18.13343 (2008)). The signs and symptoms of 13013 are generally resistant to proton
pump inhibitor (PPI) therapy, althOugh some patients do demonstrate a
clinicopathological response to PPIs (Molina—Infante et 01., Clin. Gastroenterol.
Hepatol. 9:110-117 (2011)) and this has been described as sponsive
esophageal eosinophilia” which may be differentiated from eosinophilic esophagitis
based on response to PPls (Liacouras et al., 2011).
PCT/G820] 2/000904
Topical corticosteroids, used ‘off~label’ in EOE, are very effective at reducing the
eosinophilic load of the eSOphagus, a process t to be mediated by the
promotion of eosinophil apoptosis. -blind placebo~controlled trials have
demonstrated that both fluticasone and budesonide are effective as induction
in both children and adults
treatments for reducing eosinophilic load and symptoms
with EOE (Schaefer er al., Clin. Gas‘lroenterol. Hepatol. 6: 165—173 (2008); Konikoff
et al, Gastroenterology 131:1381—139l (2006); Dohil et al., Gastroenterology
139:418—429 (2010); Straumann ét at, enterology 139:1526—1537 (2010)).
remain
Although PPls are not of general benefit in patients with EOE, many patients
on these drugs to control acid reflux which may be secondary
to inflammatory
damage of the distal (lower) esophagus.
BRIEF SUMMARY OF THE INVENTION
treating, or
One aspect of the invention is to provide a method of preventing,
eosinophilic gitis (EOE) in an individual, comprising
ameliorating
administering to the individual a therapeutically effective amount of at least one
accraptable salt f and at least One
CRTH2 antagonist or a pharmaceutically
acceptable salt f.
proton pump inhibitor (PPI) or a pharrnaceutically
Another aspect of the invention is a composition comprising
at least one CRTHZ
thereof and at least one proton pump
antagonist or a pharmaceutical ly acceptable salt
thereof.
inhibitor or a pharmaceutically able salt
of general formula (I):
In one embodiment, the CRTHZ nist is a compound
PCT/G32012/000904
\ R1
N\\\<OR5
wherein
R‘ is crcs alkyl;
R2 is halogen;
R3 is aryl or heteroaryl optionally substituted with one or more substituents selected
from halo, OH, CN, R6, (30126, CHZR", 0R6, SR6, 802?, or some;
R6 is C1-C6 alkyl, C3-C3 cycloalkyl, heterocyclyl, aryl, or heteroaryl, any of
tuents selected
which may optionally be substituted with one or more
from halo; OH, CN, N02, c.-c6 alkyl, or 0(c.—c6 alkyl);
Y is NH 01‘ a straight or branched C1-C4 alkylene chain;
R“ is H or c,-c4 alkyl; and
R5 is hydrogen, C1-C6 alkyl, aryl, (CH2),nOC(=O)Cl-C5alkyl, ((CH2)mO)nCH2CH2X,
N(R7)2, or CH((CH2)mO(C=O)R8)2;
m is l or 2;
n is 1-4;
x is 0R7 or ;
R7 is hydrogen or methyl;
R8 is CFC”; alkyl;
solvate, or complex thereof.
or a ceutically acceptable salt, hydrate,
in one embodiment, R5 is hydrogen.
In another embodiment, R5 is C1-C6 alkyl, aryl, (CH2)mOC(=O)C1~C5aIkyl,
((CH2)m0>DCH2cnzx, (CH2)mN(R7)2, or CH<(CH2)m0<C=0)R“)2.
W0 2M3/088109 PCT/082012/000904
In another embodiment,
R‘ is cl—c4 alkyl;
R2 is fluoro;
R3 is Optionally substituted and is quinoline, quincxaline, isoquinoline,
thiazole, phenyl, naphthalene, thiophene, pyrrole, or pyridine; and
R4 is H or methyl.
In one embodiment, the compound of general formula (I) is:
{3-[1-(4-Chloro-phenyl)-ethyl1-5—fluoro-2—methyl~indo1-l -yl}vacetic acid;
{S-Fluoro-Z-methy1~3-[1—(4-trifluor0methyI—phenyl)-ethyl]-indol~1-yI}-acetic
acid;
{3—[1-(4-tert—Buty]~pheny1)-ethyl]fluoro-2—methyl-indol—1 -yl}-acetic acid;
{S-Fluoro- 4—methanesu1f0nyl-phenyl)—ethy1]methyl-indoly1}-
acetic acid;
[S—Fluoro—2-methyl—3-(1 ~naphthaleny1~ethyl)-indol—1~yl]-acetic acid;
(S-Fluoro-Z-methyl—B-quinolin—Z-ylmethylvindol- l cetic acid;
(S~F1uoro-2—methyl-3~naphthalen—2~ylmethyl-indoly1)-acetic acid;
[S-Fluoro(8-hydroxyquino]inylmethyl)-2~methyl—indol-l -yl]—acetic
acid; _
, [S~FIuoro~2~methyl(quinoxalin-Z-ylmethyl)indol-l-yl]-acetic acid;
[S-Fluoro-3—(4-methoxy-benzyl)—2—methyl-indol'- l ~y1]-acetic acid;
oro—2~methy1—3-(1,3—thiazol—2—ylmethyl)indolyl]-acetic acid;
[3 -(4-Chloro-benzyl)-5—fluoromethyl-indolyl]-acetic acid;
I [S—Fluoro—2—methy1-3~(4—trifluoromethyl-bcnzyl)-indol-l-yl]-acetic acid;
[S-Fluoro-2—methyl—3~(4-!ert—butyl-benzyl)-indolyl]—acetic acid;
{5-Fluoro—2-methyl—3 -[(4-phenylphenyl)methyl]indolyI}-acetic acid;
[5—Fluoro—3—(4methanesulfonyl—benzyl)methyI-indolyI]-acetic acid;
{S-Fluoro[(6-fluoroquinolin-2—yl)methyl]~2-methylindolyl}-acctic acid;
(2-MethyI-3—quinolin—2—ylmethyl—indol—1—yl)-acetic acid;
(S—Chloro-Z—methylquinolin—2-ylmethyl—indol— acetic acid;
l -yl)-
(3 - {[1 —(Benzenesulfonyl)pyrrol-2—yl]methyl}fluoro—2—methylindol-
acetic acid;
WO 88109 PCT/G82012/000904
[S-Fluoromethyl-3—({ 1 -[(4-methylbenzene)suifony1]pyrroi—2—
yl}methyl)indol-1~yl]—acctic acid;
[3-({1-[(2,4~Difluorobenzene)sulfonyl]pyrroiyl}methyl)~5-fluoro
methyiindol—i-yl]-acetic acid;
(3 - { [2-(Benzenesulfonyi)phenyl]methyl } fluoromethyiindol-i cetic
acid;
[3 -({2-[(4-Chlorobenzene)sulfonyIJphenyl}methy1)-5 -f1uoro—2-methylindol-
l -y1] —acetic acid;
[5-Fluoro—3-({2—[(4-fluorobcnzcne)sulfonyl]phenyl}methyl)—2-methylindol-
1-yi]-acetic acid;
(3- {[2-(Benzenesulfonyl)pyridin—3 -yl]methy1} fluoro-2—methylindol-1 -y1)-
acetic acid;
[S-FIuoro—S—({2-[(4-fluorobenzenc)sulfonyl]pyridinyl } methy1)—2-
methylindol-l -y1]~acetic acid;
[3-({2-[(4-Ch1orobenzene)sulfonyl]pyridin—S —y1}methyl)fluoro-2—
methylindob 1 —yl]-acetic acid;
4-(Benzylsuifonyl)benzyl)—5-fluoro—2—methyl-indoi- l -y1)-acetic acid;
2-(3—(4-(4—Chlorobenzylsulfonyl)benzyl)-5 -fluoromethy]-indol-1 -y1)-
acetic acid;
2-(3~(3~(Benzylsulfonyl)benzyl)-S-fluoro-Z—mcthyl-indol-1~y1)—acctic acid;
2—(5—Fluorc-3 -(3-(4—fluorobenzy1sulfonyl)benzyl)methyl—indol—1-yi)—acetic
acid;
2—(3-(2-(Benzylsu1fonyl)benzyl)uS-fluoro-Z—methyI—indo1-Lyn-acetic acid;
2—(3-(4-(4—F1uor0benzylsulfonyl)benzyI)-Sjfluoro-Z-mcthyl—indol-l —y1)-acetic
acid;
2-(3 —(2-(Cyclohcxylsulfonyl)benzyl)—5 0-2—methy1-indol- l -y1)—acctic
acid;
1 —y1)-acetic
2-(5 -F1u0romethyl—3 -(2-(piperidin—1 -y1sulfonyl)benzy1)-indol—
acid;
2-(3-(2-(Cy010pentylsulfonyl)benzy1)—S—flucro-Z-methyi—indoi—1-yI)-acetic
acid;
PCT/G82012/000904
2—(S-Fhloromethyl(3-(piperidin-1—y1sn]fony1)benzyi)—indol-1—y1)—acetic
acid;
2-(5-F1uoro—2-methyl-3‘(2-(pyrrolidin— 1 -ylsulfonyl)benzy1)-indol- 1-yl)—acetic
acid;
2v(3—(4—(Cyclohexylsulfonyl)benzy])—5-fluoro—2-methyl~indol-1 —y1)—acetic
acid;
2-(3-(4—(CyciOpentylsulfonyl)benzyl)fluoro-2~methyi-indolyl)—acetic
acid;
2-(3 -(2-(Cyclobutylsulfonyl)bcnzyI)-S~fluoro-Z—methyI—indol— I -yl )-acetic
acid;
luoro—2~methy}-3 -(3-(pyrrolidin-1 -ylsulfonyl)benzy1)—indoi-1~yl)-acetic
acid;
luoromethyl(4-(piperidin-I-ylsulfonyl)benzy1)-indolyI)-acetic
acid;
[5 o-2—methy}-3—(2-phenoxyb¢nzy1)-indoly1]-acetic acid;
[5-Fluoromethy1—3—(2—(4-methoxyphcnoxy)bcnzyl)—indol-1—yl]-acetic acid;
[5-F1uoromethy1(2-(4—methylphenoxy)benzy1)-indol-l-yI]-acetic acid;
[5-FIuoromethy1~3«(242,4—dichlorophenoxy)benzyl)-indol-1 -yl]racetic
acid;
[S-FIuoro—Z—mcthyl-B —(2-(4—fluorophenoxy)benzyl)—indo1-I—yl]~acetic acid;
[5-F1uoromethy1—3-(2~(3,4-difluomphenoxy)benzyl)-indol—1»y1]-acetic
acid;
[S-Fluoro—Z—methy1-3«(2—(4-cyanOphenoxy)benzyl)-indo1—1—y1]~acetic acid;
[5-Fluoro—2—methy1—3-(2—(4-ch10r0phenoxy)ben2yl)-indol—1-yl]»acetic acid;
[5—Fluoro~2-methyl»3-(2-(2-cyanophenoxy)benzyl)-indoly1]—acetic acid;
(5—Fluoro—2-mcthyl-3— { [2-(4-mefl1y!phcnoxy)pyridin—3-yl]methyl } indol- 1 ~
yi)—acctic acid;
{ S—Fluoro-3—[(3—methanesulfonylnaphthalen-Z-yi)methyl]methy1indol—l —
yl} —acetic acid;
' {5-F1u0r0~3-[(i—methanesulfonyInaphthalen—2—y1)methyI]-2~methylindol-l-
yi}—acetic acid;
PCT/G32012/000904
oro[(6—methanesulfonylnaphthalenw2-yl)methy1]-2~methylindol—1 -
y]}-acetic acid;
[5—Pluoromethyl—3—(quinolin~3-ylmethyl)indol-l-yI]-acetic acid;
oro—2~methyl—3-(quinoxalin—6—ylmethyl)indoly1]-acetic acid;
[S-Fluoro-Z-methyl—3—(quin0liny]methyl)indoi-1«yij-acetic acid;
{S-Fluoro-B {(6—methanesulfonquuinoiin—Z-yl)methyl]—2-methylindol~1-yl }-
acetic acid;
{5—F1u0r0-3~[(4-methanesulfonylquinolinyl)methyl]—2-methylindoiyl}—
acetic acid;
(S~FIuoro—2-methyl{pyrazolofl,5-a]pyridin—3-ylmcthyi}indolyl)-acetic
acid;
(S-Fluoro{imidazo[1,2—a]pyridin—2-y1methyl}-2—methylindolyl)—acetic
acid;
(5-Fluoro—2-methyl—3-{[2—(methylsuifanyl)phenyl]methyl}indol- I-yl)—acetic
acid;
(S-Fluoro-Q-methyl—3—{[3—(methylsulfanyl)pheny1]inethyl} indoi—l-yl)-acctic
acid;
(S—Fluoro-Z-methyl{[4-(cthylsulfany1)phenyl]methyl}indol-1—yi)-acetic
acid;
(3-{[4-(Bthylsulfanyl)phenyl]mcthyl}—5-fluoromethylindolyl)—acctic
acid;
(S-Fluoro-Z—methyLS—{{4-(n-propylsulfanyl)phenyi]methyl}ind01-1~yl)-acetic
acid;
(5—Fluoromethyl—3—{[4~(i-propylsulfanyi)phenyl]methyl}indolyl)—acctic
acid;
(5~F)uoro~2-methy]_{[4-(t-butylsulfanyl)phenyl]methy1}indoI—l ~yl)-acetic
acid;
(5-PIuoro—2—methyl{[4—(pentan—3-ylsulfanyl)phenyl]mcthyl}indol—1—y1)—
acetic acid;
[3-({4— [(Cyclopropylmethyi)sulfanyl]phcnyl} methyi)fluoro
methylindoI-l-yfl-aceiic acid;
{3-[(4,4—Dimcthyl-2,3—dihydro—1—benzothiopyrany1)methy1)fluoro—2—
methylindoi— 1—yl}-acetic acid;
1-y1)—acetic
(3 — {[2-[Ethancsulfonybphcnyflmethyl} -5—flucromethylindol-
acid;
} l nyl)—
(5 ~Fluorc—2—methyl{[2—(propane—1—sulfonyl)phenyl]methyi
acetic acid;
indol—l -yl)-
(S-Fluoro-2—methy1 { [2-(propane—2-sulfony1)phenyl}methyl}
acetic acid;
-2~methylindol—1 —yl)~
(3 - { [2-(Butane— 1 nyl)phcnyl]methyl} -'
acetic acid;
(3-{[fl-(Butane—Z-sulfonyl)phenyl]methy1}-5~fluoro-2—methylindol—1 ~y1)-
acetic acid;
} indol»
(5 -F1uoro—2-mefl1yl{[2-(2’methylpropanc-Z-sulfonyi)phenyl]methyl
1-y1)-acetic acid;
(S-Fluoro-Z—mcthyl—3—{[2-(pcntane-1—sulfonyl)phenyl]methyl}indol-1 -yl)—
acetic acid;
(3 -{[2-(Cyclopropylmethane)su1fony1phenyl]me1hy1}fluoro-2—
methylindol~ 1~y1)-acetic acid;
(5~F1ucro—2-methyl-3—{[2»(propylsulfamoyl)phenyl]mcthyl} indol— I -y1)-acetic
acid;
(3—{[2~(Buty1su1famoyl)phenyl]methyl}—S-fluoro-2—methylindol—1 -yi)-acctic
acid; .
1-y1)-acetic
(5 -Fluoromethy1—3-{[3 —(propylsulfamoyi)phenyl]mcthyl}indoi—
acid;
(3-{[3—(Butylsulfamoy1)phenyl]m_cthyl}—S—fluoromethylindol-]-y1)—acetic
aEid;
indol- 1-
(5—F1uoromethylv3-{ [4—(trifluoromethane)su1fonylphcnyflmcthyi}
yl)-acctic acid;
(3-{ [4—(Ethanesulfonyl)phenyi]methy1}-S—fluoromcthylindol—1~y1)-acetic
acid;
-y1)-
(5-F1uoro-2~methyl—3-{ [4-(propane—1—sulfony1)phenyl]mefi1yl}indoi—l
acetic acid;
W0 2013[088109 PCT/G82012/000904
indoi-i —y1)-
0ro-2—methyl—3 — {[4{propanesu1fonyl)pheny1]methyl}
acetic acid;
—5-flu0ro-2—methylindol— 1 —y1)-
(3-{ [4-[Butane- 1 —su1fonyi)phcnyl]methyl}
acetic acid;
(S—Fluoro-Z-methyl{[4—(2-methylpropane-2—suifonyl)pi1eny1]methyl}indol-
1-y])-acctic acid;
'(5—F1uoro—2—methyi-3 -{ [4o(pentane-1 -sulfonyi)pheny1]methyl}indcl—l-y1)-
acetic acid;
indol- 1 —yl)—
(S~FluoromethyI-3 —{ [4—(pentam3 «ylsulforinphenyI]mcthyl}
acetic acid;
[3-({4-[(Cyciopropylmethy1)sulfonyl]phenyl}methy1)fluorc
methyiindol-l ~yi]-acetic acid;
indoly1)—acctic
(S-Fiuoro-2»mcthy1{ [4-(pr0pylsulfamoyl)phenyi]methyl}
acid;
—5 —2-mcthylindoi-1~yl)—acetic
(3~ { [4-(Butylsulfamoyl)phcny1]methyl}
acid;
} indol- 1 “3/1)-
(5-F1uorornethyl { [4-(trifluoromethoxy)phenyl}methyl
acetic acid;
fluoromethyl)phcnyl]mcthyl}
(5 -Fiuoro-3—{ [4-methanesulf0nyl-3~(tri
methylindol-i -yi)-acatic acid;
(5 ~Fluoro{[4—methanesulfonyl—3~(trifluoromethoxy)phcny1]methyl}~2-
methyiindoivl —yl)vacetic acid;
{S-Fiuom[(5~methanesuifonylthiophen-Z-y1)mcthy1]-2—methylindol- 1 —y1}-
acetic acid;
A6~benzothi0pyram6-y})methy1]
{3-[(4,4-dimethyl- 1 ,l—dioxo-2,3—dihydro- l
fluoro-Z—mcthylindoly1}-acctic acid;
} methy1)~5 -fluoro~2-
[3~( {1 hlorobenzene)sulfony1]pyrrol—2—yi
methyiindoi-1y1]—acctic acid;
[5 o({ i -[(4-fluorobenzene)sulfonyl]pyrroi—2—y1}methyl)—2-
methylindol-l—yl] -acetic acid;
[5~Fluoro-3 -({ I—[(4-methoxybenzene)suifonyl]pyrroi-2~y1}methy1)
methylindol— 1—yl]vacetic acid;
PCT/G32012/000904
{3-[1~(2,4-Dichloro-benzenesu!fonyl)pyrroI-2~ylmethyl}-S-fluorc-Z-methyi-
indoi—l—yi}-acetic acid;
[5-F1u0r0—3~({ i-[(4—methanesulf0nylbcnzcnc)sulfonyl]pyrrol~2-yl} methyl)~2—
methylindol-I -yi]-acetic acid;
{5-Fiuoro-2methyl—3{(2-phenylphcny1)methyl]indol~1—y1}-acetic acid;
(3 - { {1~(Benzcncsuifonyl)indolyi]mcthyi } ~5-fluoro-2—methyi indol— 1 -yl)—
acetic acid;
(3 :{[2~(4-Chiorophenyi)pheny1]methyl}-S-fluoro-2~methyiindoi—1~yi)—acetic
acid;
(S-Fiuoro-Z-methyI-3—{[2~(4-mcthylphenyI)phcny]]mcihyl}indol-l ~yl)~acetic
acid;
{5—Fluoro-2—methyl[(3~phcnoxyphcny1)methyl]indolyi}—acetio acid;
[S-Fluoro({4-[(4-fluorophcnyl)carbonyl]—1«methyipynol-Z-yl}methyl)-2—
methylindoI-l ~yl]-acetic acid;
{5-P1uoromcthyi[(6-{[3 ~(triflu0romethyi)phenyi]methyi}pyridin
hyl]indol~1-yl}-acctic acid;
{S~Fiuoro-Z-methy1[(3vphenoxythiophen~2»yl)methyi]indol-i-yI}-acctic
acid;
(3-{[2-(Bcn;cncsulfonyl)~l ,3—thiaz0lv5-y11methyl}—5~fluoro~2—mcthylindol~1-
yl)—acetic acid;
{3 enzylpyrazolu4-yl)methy1}~5-fluoro—2-meihyiindoiy1}—acetic acid;
(3— { [5-(4-Chlorophcnoxy)—l~mcthyi-3—(trifluoromcthyl)pyrazol~4-
y1]methyi}flu0ro—2-mcthylindol-l-yl)—acctic acid;
[3-({5—[(4-Chlorobcnzene)sulfonyilfm'an—Q—yl}methyl)-5~fluoro
indol-i—yl]-acetic acid;
[3-({5—[(4~Chlorobcnzene)sulfonylkhiophen—Z-yl}methy1)-S~fluoro—2v
methyiindol— I ~yi]-acetic acid;
[3 —({3~[(4-Chlorobcnzene)sulfcnyllthiopheny1}methyl)-S-fluoro—2 —
methylindol— l—yl]—acctic acid;
{3.—[(2—Benzylpiienyl}methyl]-5~fluoromefliyiindoi-I —yl } ~acctic acid;
PCT/G32012/000904
or the eyes alkyl, aryl, (CH2)mOC(=O)Ci—C6alkyl, ((CH2)mO)nCHzCH1X,
(CH;)mN(R7)2, or CH((CH2)mO(C=-O)R8)2 esters of any ofthe above; wherein
m is 1 or 2;
n is 1-4;
x is OK7 or N(R7)2;
R7 is hydrogen or methyl; and
R3 is crcm alkyl.
In one embodiment, the PM is selected from the group consisting of omeprazole,
esomeprazole, lansoprazole, dexlansoprazole, razole, and rabeprazole, or a
pharmaceutically able salt thereof.
In another embodiment, the CRTHZ antagonist is (S-fluoro-Z-methyl-S-quinolin-Z-
ylmethyl-indol-l-yl)-acetic acid or a phannaoeutically acceptable salt thereof and the
PPI is selected from the group consisting of omeprazole, esomeprazole, lansoprazole,
dexlansoprazole, razole, and rabeprazole, or a pharmaceutically acceptable
salt thereof.
In another embodiment, the CRTHZ antagonist is [S-fluoro-3'(4—methanesulfonyli
benzyl)—2-methyl-indol—Lyn—acetic acid or a pharmaceutically able salt
thereof and the PPI is selected from the group consisting of omeprazole,
esomeprazole, lansoprazole, dexlanSOprazole, pantoprazole, and azole, or a
phannaceutically acceptable salt thereof.
In another embodiment, the CRTHZ antagonist is (3-{[2-(ben2enesulfonyl)pyridin
yl]methyl}~S-fluorornethylindol~l -yl)-acetic acid or a pharmaceutically acceptable
salt f and the PPI is selected from the group consisting of omeprazole,
razole, lansoprazole, dexlansoprazole, pantoprazole, and azole, or a
phannaceutically acceptable salt thereof
In another embodiment, the CRTH2 antagonist is [S-fluoro—3~({2-[(4—
fluorobenzene)sulfonyl]pyridin—3~yl}methyl)—2-methylindol~l~yl]~acetic acid or a
pharmaceutically acceptable salt thereof and the PPl is selected from the group consisting
of omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and
rabeprazole, or a pharmaceutically acceptable salt thereof.
In r embodiment, the CRTH2 antagonist is 5-(acetylamino)[(4—
chlorophenyl)thio]~2—methyl—lH—indole-l-acetic acid or a phannaceutically acceptable salt
thereof and the PPI is selected from the group consisting of omeprazole, razole,
lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole, or a phannaceutically
acceptable salt thereof.
In another embodiment, the effects of the at least one CRTH2 antagonist and the at least
one proton pump inhibitor are synergistic.
In a first aSpect, the present invention provides a pharmaceutical composition comprising
at least one CRTHZ antagonist or a ceutically acceptable salt thereof and at least
one proton pump inhibitor; wherein said CRTHZ antagonist is a compound of general
a (I):
\ R1
N\\K<OR5
wherein
R1 is cl-c6 alkyl;
R2 is halogen;
R3 is aryl or heteroaryl ally substituted with one or more substituents selected
from halo, OH, CN, R6, COR6, CHgRG, 0R6, SR6, SOzRé, or SOgYRE;
-12a-
R6 is C1-C6 alkyl, C3-C3 cycloalkyl, heterocyclyl, aryl, or heteroaryl, any of which
may optionally be substituted with one or more substituents selected from halo,
OH, CN, N02, C1-C6 alkyl, or 0(C1-C6 alkyl); and
Y is NH or a straight or branched C1-C4 alkylene chain;
R4 is H or C1-C4 alkyl; and
R5 is hydrogen, Ci-Ca alkyl, aryl, (CH2)mOC(=O)Ci-Cgall<yl,
((CH2)mO)nCH2CH2X, (CH2)mN(R7)2, 0r CH((CH2)mO(C=0)R8)2;
m is l or 2;
n is 1—4;
X is on7 or N(R7)2;
R7 is hydrogen or methyl;
R8 is C1-Clg alkyl;
or a pharmaceutically acceptable salt, hydrate or solvate thereof; and n said proton
pump inhibitor is selected from the group ting of omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, pantoprazole and rabeprazole or a pharmaceutically
acceptable salt thereof.
In a second , the present invention provides a use of a CRTH2 nist or a
pharmaceutically acceptable salt thereof as defined according to the invention and a proton
pump inhibitor selected from the group consisting of omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, pantoprazole and rabeprazole in the manufacture of a
medicament for the prevention, treatment or amelioration of eosinophilic esophagitis
(EOE).
In a third aspect, the present ion provides a use of a pharmaceutical composition
according to the invention in the manufacture of a medicament for the maintenance therapy
of eosinophilic esophagitis, wherein the maintenance therapy comprises:
(a) firstly administering to an individual in need of such treatment a
therapeutically effect amount of a corticosteroid for a first predetermined period of time;
(b) subsequently administering to the dual a therapeutically effective
amount of at least one CRTHZ antagonist or a ceutically acceptable salt thereof and
—12b-
at least one proton pump inhibitor or a pharmaceuticaliy acceptable salt thereof for a
second predetermined period of time.
Another aspect of the invention is to provide a method of preventing, treating, or
ameliorating eosinophilic esophagitis (EOE) in an individual, sing administering to
the individual a therapeutically effective amount of at least one CRTHZ nist and at
least one proton pump inhibitor (PPI) and further administering at least one corticosteroid.
In one embodiment, the corticosteroid is selected from the group consisting of
hydrocortisone, dexamethasone, methylprednisolone, and prednisoione.
Another aspect of the invention is to e a method of preventing, treating, or
ameliorating eosinophilic esophagitis (EOE) in an dual, comprising administering to
the dual a eutically effective amount of at least one CRTH2 antagonist and at
least one proton pump inhibitor (PPI) and further administering an anti-IL-3 monoclonal
antibody.
Another aspect of the invention is to provide a method of preventing, treating, or
ameliorating eosinophilic esophagitis (EOE) in an individual, comprising administering to
the individual a therapeutically effective amount of at least one CRTH2 antagonist and at
least one proton pump inhibitor (PPI) and further administering montelukast.
2012/000904
Another aspect of the ion is a kit for the treatment of eosinophilic esophagitis
comprising: (a) at least one CRTl-IZ antagonist; and (b) at least one proton pump
inhibitor; wherein the kit is packaged in one or more suitable containers. In one
embodiment, the one or more suitable containers is a blister pack.
Another aspect of the invention es a method for the maintenance therapy of
eosinophilic gitis comprising:
(a) firstly administering to an individual in need of such treatment a
therapeutically effect amount of a corticosteroid for a first predetermined
period of time; and
(b) subsequently administering to the individual a therapeutically effective
amount of at least one CRTHZ nist or a phannaceutically acceptable
salt thereof and at least one proton pump inhibitor or a pharmaceutically
acceptable salt thereof for a second predetermined period of time.
BRIEF DESCRIPTION OF THE FIGURES
FIGURE 1 is in a bar graph showing the difference in % change esophageal
eosinophil load in proximal and distal biopsies compared to placebo for patients
treated with the CRTHZ antagonist ro—Z—methyl—3—quinolin—2—ylmethyl—indol—
l—yl)-acetic acid.
FIGURE 2 is a bar graph ing the % change in esophageal eosinophil load.
patients receiving (5~fluoromethyl~3-quinolin—2-ylmethyl—indol—l~yl)-acetic acid
acid
and esomeprazole, (S-fluoro-Z—methyl~3—quinolin—2~ylmethyl-indolyl)-acetic
alone, esomeprazole alone, or a placebo.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides methods and compositions for preventing, treating, or
ameliorating eosinophilic esophagitis (EOE) in an individual, comprising
stering to the individual a therapeutically effective amount of at least one
PCT/G82012/000904
CRTH2 antagonist and at least one proton pump inhibitor (PPI). The invention also
provides compositions comprising a CRTH2 nist and/or a PPI for use in
preventing, treating, or ameliorating EOE in an individual.
EoE is characterised by an allergic response with involvement of mast cells and Th2
cells, in addition to eosinophils. The number of IgE~bearing mast cells is elevated in
EOE tissue and examination of the mast cell transcriptome in such tissue has
demonstrated the ce of mast cell ts such as carboxpeptidase A3 and
tryptase (Abonia et at, J y Clin. l. [26.140449 (2010)). The Th2
cell—derived cytokines interleukin 4, 5, and 13 are also elevated in EOE tissue
(Blanchard et al, J. Allergy Clin. Immunol. 127:208-217 (2011)). Factors produced
by activated mast cells and Th2 cells d to antigens in esophageal tissue are
likely to be important in promoting tissue eosinophilia and other aspects of disease
pathology. glandin D2 (PGD2) is one such product that is produced in high
concentrations by mast cells and Th2 cells in response to logical activation
(Pettipher, Br. J. Pharmacol. 153 Suppl. 1:3]91-8199 ) and causes activation
of Th2 cells, eosinophils, and basophils h a high affinity interaction with the G
protein coupled receptor CRTH2 (chemoattractant receptor—homologous le
expressed on Th2 cells - also known as DPZ) (Hirai et al., J Exp. Med. [93:255-261
(2001)). Mast cell-dependent activation of Th2 cells promotingenhanced migration
and cytokine production is mediated by PGD2 acting on CRTHZ (Gyles et al.,
Immunology 119362-368 (2006); Xue et aI., Clin. Exp. Immunol. 156:126—l33
(2009)). Paracrine tion of Th2 cells is also inhibited by CRTHZ antagonists
(Vinall at al, Immunology 121:577-584 (2007)). Studies in animal models indicate
that genetic ablation of CRTH2 or administration of CRTHZ antagonists is effective
in reducing eosinophil and lymphocyte accumulation and Th2 cytokine production in
response to allergen in sensitised airways and skin (Pettipher, 2008).
Consequently, it is ed that PGDZ produced by mast cells in response to food
allergens or airborne allergens will contribute to eosinophil accumulation and disease
pathology in EOE.
WO 88109 2012/000904
In one embodiment, the CRTH2 antagonists are disclosed in US. Published
Application No. 2011/0124683 and have general formula (I):
wherein
R‘ is (31-06 alkyl;
R2 is halogen;
R3 is aryl or heteroaryl optionally substituted with one or more substituents selected
from halo, OH, CN, R6, COR‘S, CHzR", 0R6, SR6, 302R“, or SOZYRG;
R6 is Cl-C6 alkyl, C3-Cg llcyl, heterocyclyl, aryl, or heteroaryl, any of
which may optionally be substituted with one or more tuents selected
from halo, OH', CN, N02, C1-06 alkyl, or 0(C1—C6 alkyl); and
Y is NH or a straight or branched Cqu alkylene chain;
R4 is H or C1-C4 alkyl; and
R5 is hydrogen, C1-C6 alkyl, aryl, (CH2)mOC(¢O)C1—C6alkyl, ((CH2)mO)nCH2CH2X,
(CH2)mN(R7)2, or CH((CH2)mO(C=O)R3)2;
m is 1 or 2;
n is 1-4;
x is on7 or N(R7)2;
R7 is hydrogen or methyl; and
R8 is (3,.cla alkyl;
or a ceutically acceptable salt, hydrate, solvate, or complex thereof. See also
US. Pat. Nos. 7,582,672, 7,750,027, 7,999,119, and 8,044,088, and US. published
application Nos. 2009/0192195 and 2010/0022613.
W0 2013/088109 PCT/G32012/000904
In one embodiment of the invention, the compound of general a (I) is a
CRTHZ antagonist in which R5 is hydrogen.
In an alternative embodiment of the invention, the compound of general formula (I)
is a prodrug for a CRTH2 antagonist and R5 is C1-C6 alkyl, aryl, (CH2)mOC(=O)CI‘
Csalkyl, ((CH2)mO)nCH2CH2X, (CH2),,.N(R7)2, or CH((CH2)mO(C=O)R3)2; where
m is 1 or 2',
n is 1—4;
X is OR7 or N(R7)2;
R7 is hydro gen or methyl; and
R8 is 0,-0.3 alkyl.
In one embodiment, the compound of general formula (I) is, independently or in any
ation:
R1 is 01-04 alkyl, particularly methyl or ethyl but more especially methyl;
R2 is ;
R4 is H or methyl; and
R3 is quinoline, aline, isoquinoline, thiazole, phenyl, naphthalene,
thiophene, pyrrole, or pyridine, any of which may optionally be substituted as
set out above.
In another embodiment, R4 of fonnula (1) is H.
In one embodiment, R3 of formula (I) is optionally substituted quinoline, phenyl,
naphthalene, thiOphene, e, or pyridine,
In another embodiment, when R3 is quinoline or isoquinoline, it is suitably
unsubstituted or substituted with one or more halo substituents, eSpecially fluoro.
In one embodiment, when R3 is pyridyl, it is a dyl moiety.
In another embodiment, when R3 is phenyl, naphthalene, thiophene, pyrrole, or
WO 88109 PCT/G82012/000904
pyridine, it may optionally have one or more substituents, with particularly suitable
substituents including 0R6, SOZR6, or SOZYRG; where R6 and Y are as defined
above.
In one embodiment, R6 of formula (I) is CI~C6 alkyl, 3 4- to 6-membered cycloalkyl
group, a 5- or 6—membered heterocyclyl group, or phenyl, any of which may be
substituted as defined above.
In one embodiment, Y, when present, is a CH; moiety.
In another embodiment, when R3 is tuted with 802116 or SOgYRG, the R6 group
is lly tituted or substituted with one or more substituents chOSen from
methyl and halo, particularly chloro or fluoro.
In another embodiment, when R3 is substituted with 0R6, the R‘5 group may be
unsubstituted or substituted with one or more substituents chosen from halo, cyano,
C1—C4 alkyl, and O(C.-C4 alkyl).
Particular examples of compounds of formula (I) include:
{3—[1~(4~Chloro~phenyl)~ethyl]-S-fluoromethyl—indol- acetic acid;
{ S-Flnoro—Z—methyl—3—[ 1-(4~trifluorornethyl-phenyl)-ethyl]-indol~l~yl}—acetic
acid;
. {3~[l-(4-tert~Butyl-phenyl)-ethyl]—S-fluoro—2—methyl-indolyl}-acetic acid;
{ S—Fluoro[ l—(4-methanesulfonyi-phenyl)-ethyl]~2—methyl~indol~ l—yl};
acetic acid;
[S—Fluoro-2—methyl—3—(l halen—2~yl—ethyl)-indol» l —yl]—acetic acid;
(S~Fluoro—2~mcthyl#3—quinolin—2-ylmethyl-indolyl)-acetic acid;
(5~Fluoro«2—methyl—3—naphthalen-Z-ylmethyl-indol—1-yl)-acetic acid;
[5~Fluoro-3 -(8-hydroxyquinolin—2—ylmethyl)~2-methyl-indol-l -yl]—acetic
acid;
[5—Fluoromethyl(quinoxalin~2-ylmethyl)indol-l —yl]—acefic acid;
[S-Fluoro-Zi-(4~methoxy~benzyi)methyl—indol—i ~yl}«acetic acid;
2012/000904
[S-F-luoro-Z-methyi—B -(1 =3-‘thiazol—2-ylmethyl)indoiy1]-ac&:tic acid;
[3—(4—Chloro-bcnzyl)-5~fluoro—2—methyl-indol—1 -yi] -acetic acid;
oro-Z—methyl(4-trifluoromcthyl—benzyi)-indoly1]—acetic acid;
[S-Fiuoro-2—methyi-3—(4—tert—buty1—benzy1)—indol-1—y1]-acetic acid;
{5-Pluoro—2-methyi[(4—phenyiphenyl)methyl]indoi-l—yi}-acetic acid;
[S—Fluoro—3~(4—methancgulfonyI—benzyI)methyl-indol-1—yI]-acetic acid;
{S—Fluoro-3 -[(6~fluoroquinolin—Z—yl)methyi}—2-methylindo1—1—y1}-acetic acid;
(2—Methyl—3-quinolin—2—ylmethyi~indolyi)-acctic acid;
(5-Chloromethyl-3~quinolin-Z-ylmethyI—indol~1’yI)—acetic acid;
(3—{[I{Benzenesulfonyi)pyrroIyi]methy1}~5-fluoromethylindol-Ly!)—
acetic acid;
[5-F1uoromethyl-3 -{{1-[(4—methylbenzene)sulfcnyl]pyrrol-Z-
yl}methyl)indoI
y1]-acctic acid;
[3-({1-[(2,4-Difluorobenzene)sulfonyl)pyrrolyl}methyl)-S-fluoro~2-
methylindOI—l -yl]-acetic acid;
(3~ { nzenesuifonyUphenyljmethyi } -5vfluoromethylindol- 1~y1)-acetic
acid;
[3-({2—[(4«Chlorobenzcnckulfonyl]phenyl}methyl)~5—fluoromethy1irid01—
1-yi]-acetic acid;
[5-Fluoro—3«({2-[(4-fluorobenzene)suifonyi]phenyl} )—2~methyiindol~
1-y1]-acetic acid;
(3 — { [2-(Benzenesulfonyi)pyridin—3~yl]methyl } —S—fluoro—2—methylindol- 1 ~yl)—
acetic acid;
[5—F1u0r0({2-[(4-fluorobenzene)sulfonyl}py'ridinyl}methy1)—2-
methylindoi- 1 ~yl]-acetic acid;
[3 —( {2-[(4mChlorebenzene)suifonyl]pyridin—3 -yi } methyl)~S-fluoro—2—
methyiindol-l -y1]—acetic acid;
2-(3~(4-(Benzylsulfonyi)benzyl)fluoro-Z—methyl-indol— 1 —y1)-acetic acid;
2-(3-(4-(4-Chlorobenz-ylsuifonyl)benzyl)—S-fluoro-Z-methyl—indoi- 1-yl)-
acetic acid;
2-(3-(3-(Bcnzylsulfonyl)bcnzyi)—5-fluoromethy1-indolyl)-acetic acid;
PCT/G82012l000904
2~(S-Fiuor0(3-(4~fluorobenzylsulfonyl)benzy1)-2—methy1—indoly1)-acetic
acid;
2-(3-(2-(Benzylsulfonyl)benzyl)—S~fluoro~2—methy}—indoiyl)-acetic acid;
2—(3 —(4-(4-Fluorobenzylsulfonyl)benzyl)—5-fluoromethyl-indol~ l—yI)-acetic
acid; '
2~(3—(2~(Cyclohexylsulfony1)benzyl)~5-fluoro-2—mcthyI—indol-I-y1)~acetic
acid;
2-(5’Fluoro—2~methy1(2-(piperidim I -ylsulfonyl)bcnzyl)~indoi— 1 ~y1)-acetic
acid;
2~(3«(Z-(Cyclopcntylsulfonyl)bcnzyl)»5~fluoromcthy1-indol~ 1 -y1)—acctic
acid;
2-(5—Fluoro-2—methy1(3 ~(piperidinv I ~ylsulfonyl)bcnzyi)~indol~ I ~yIJ—acetic
acid;
2-(5-Fluoromethyl-3 yrrolidin- I~ylsulfony1)benzyl)—indol- l cetic
acid;
2-(3-(4~(CyclchcxylsulfOnyl)bcnzy1)~5-fluoro-2wmcthyI-indoly1)-acetic
acid; '
2-(3~(4-‘(Cyclopentylsulfonyl)bcnzyl)-S~fluoromethyl-indoly1)-acctic
acid;
2-(3-(2~(Cyclobutylsulfonyl)benzyl)-5~fluoro~2~methyl~indoly1)~acetic
acid;
2-(S-Fluoro~2-methyl—3~(3-(pyrroiidinv1—ylsulfonyl)benzyi)—indol—I—yl)-acetic
acid;
2—(5-Fluoromethfl-3—(4v(piperidin-1—ylsu1fonyl)benzyl)~indol-1~y])-acctic
acid;
[5 —F1uoro—2methyl—3-(2—phenoxybcnzyl)—indol-Lyn-acetic acid;
oro-2—methyi-3~(2—(4-mcthoxyphenoxy)benzyI)—indoi-I ~yII—acetic acid;
[5—Fluoro~2—methyl-3~(2—(4-methylpiienoxy)benzyl]-indo1—1—yl]—acetic acid;
[S-Fluoro~2—methyJ-3 ~(2—(2,4-dichlorophenoxy)bcnzyI)-indol- 1 —yl]—acetic
acid;
[S-Fluoro—Z—methyl-3~(2.(4-fl110rophen0xy)benzyi)~indole1«yi]-acctic acid;
[S-Fluoro-Z-mcthyl—3~(2-(3,4-difluorophenoxy)benzyl)—indol—1-y1]~acctic
PCT/G32012/000904
acid;
oro~2-methyl~3~(2—(4~cyanophenoxy)benzyl)-indol~i-yi]~acetic acid;
[S—Fluoro—2—methyl(2-(4-chlor0phenoxy)benzyl)—indolyi]—acetic acid;
[S-Fiuoro—2—methyl~3 {2-(2~cyanophenoxy)benzyi)-indol- l —yi]—acetic acid;
(5-P1uoro—2—methyl{{2—(4—methylphenoxy)pyridin-3—y1]mcthy1}indci—l-
yl)-acetic acid;
{5-F1u0r0—3 -[(3 -methanesuifonylnaphthalen-Z-yl)methyi]—2—methylindoi-1 -
yl}vacetic acid;
{S—Fiuoro~3-[(i-methanesuifonylnaphthaien~2-y1)methyi]—2~methylindoI-l-
y1}-acct,ic acid;
{5—Fiuoro[(6methanesulfonylnaphthaleny1)methyi]~2—methylindol-l-
yi} -z.cetic acid;
[S-Fluoro-Z-methyl-S-(quinoiin—3~ylmcthyl)indoIy1]-acetic acid;
(S-Flcoro—Z-methyl-S-(quinoxa1inyimethyi)indol-1 ~yi}-acetic acid;
[5~F1uoro-Z-mcthyifi oiin-7—y1mcthyl)i ndol- I ayl]—acetic acid;
{5 -Fluoro-3 -[(6-methanesulfonquuinolin—2—y!)methy]]methylindol-} -y} } -
acetic acid;
{S—Fluorc-B—[(4-mcthanesulfonquuinolin~2~yi)methy1]-2—methylindol-i~yi}—
acetic acid;
(5~Fluoromcthyl~3~{pyrazolof ]pyrid ill-3 ~y1mcthyi} indoi— 1 ~y1)~acctic
acid;
(5~Fluoro-3~{imidazo[1 ,2—a3pyridin—2-yimethyl} ~2—methylindol— acetic
acid;
(S—Fiuoro—2-mcthyl—3— { [2»(methylsflfanyl)phenyi ]rnethyi} indol—l -yI)—acetic
acid;
(5~F1uoro—2~methy1—3 —{[3 ~(methyisuifanyl)phenyl ] methyl } indol -I -y1)-acetic
' acid;
(5-F1uoro-2—methy1—3—{[4~(cthyIsquanyI)pheny1}methyl }indol~1-yl)~acetic
acid;
(3- {[4-(Ethylsulfanyl)phcriyl]methyl}-5~fluoro~2~mcthy1indolyl)-acctic
acid;
(5-Fiuoro~2-methyI—3- {[4-(n-propylsuifanyl)pheny1]methyl } indol- l -yl)-acetic
WO 88109 PCT/G820] 2/000904
acid;
(S-Fluoro-2—methyi—3—{[4-(i—propy1sulfanyl)phenyl]methyl}indolyl)-acetic
acid;
(5-P1uoromethyl-3~ { butylsu1fanyi)phenyl]methyl} indol- 1 ~yl)-acetic
acid;
(5 -FIuor0~2-n1cthyl-3—{[4-(pentan—3-ylsu1fanyl)pheny1]methyl}indolyl)~
acetic acid;
[3-({4-[(Cyclopropy1methyi)sulfanyi]phenyl}methyl)-5—fluoro
methylindol- I -yl]~acetic acid;
,4—Dimethyl—2,3-dihydrobenzothiopyran-6—yl)methy1]-S-fluoro-Q-
methylindoi- 1 ~yl}—acetic acid;
(3-{[2—(Ethanesulfonyl)phenyl)mcthyl}-S-fluoro-2’methy1indol—1 -y1)-aceiic
acid;
(5-P1uoro—2-methyl—3— { [Z-Qpropane- l -sulfonyi)phenyl]methyl} indolyl)«
acetic acid;
(5»F1uoromethyl{ [2-(pro;3anc-2~sul fonyl)pheny1]mcthy1} indolyl)~
acetic acid;
(3- { [2~(Butane- I -sulfonyl)phenyl]methyl } —5~fluoromethylindol- 1 ~yl)~
acetic acid;
(3-{ [2v(Butanesnifonyl)phenyUm cthyl} fluoro-2—methylindol-i —yl)-
acetic acid;
(S—Fiuoro-Q-methylv3-{[2-(2-mcthylpropane~2—su1fony1)phenyl]methyl}ind01-
acezic acid;
(S-Fluoro—Z—methylv3—{[2-(pentane—1~sulfonyi)phenyl]methyl}indol—I—yl)—
acetic acid;
(3 -{ [2-(Cyclopropylmethane)sulfonylphcnyl]methyl } —5—fluoro-2—
methylindoL I —yl)-acetic acid;
(S-Fluoro-Z-methyl—S - { [2—(propylsuifamoy1)phenyi]methyi} indolyI)—acetic
acid;
(3-{ [2-(Butylsuifamoyi)phenyi]methyl } -5~fluoro-2~methyiindol-I ~yl)—acetic
acid;
(S-Fluoro-Q-mcthyl{[3-(propylsulfamoy1)pheny}]methyi}indol-i -y1)~acetic
acid;
(3—{[3-(Butyisulfamoyl)phcnyl]methyl}fluoromeihylindol-1~yl)—acetic
acid;
(S—Flucro~2-methyi-3—{ [4-(trifluoromethanc)sulfonylphcny1}methyi} indol— I -
yl)-acetio acid;
(3-{[4~(Bthanesulfonybphenyflmethyi}~5-fluoro—2—methylindol-l —y])-acetjc
acid;
(5-P1uoromethyl—3—{[4—(propanesulfonyl)phenyl]mefliyl}indol—I~y))-
acetic acid;
(5 omethy1~3-{ [4—(propane—2—sulfonyl)phenyl]methyl} indoi- 1-34)—
acetic acid;
(3- {[4—(Butane— I —sulfonyl)phenyl]meihyl}fluoro-2—methylindol- 1—3/1)—
acetic acid;
(S—Fluoro-Z-methyl{[4-(2-methylpropanesulfonyi)phenyl]methyl}indol-
l~yl)-acetic acid;
(S-Fluoromcfl1yl{[4—(pentane—1-su1fonyl)phenyl]methyl}indol-1 ~y1)-
acetic acid;
(5—F1u0r0—2—methyl{[4—(pentan—3 -ylsulfonyl)phenyl]methyl}indol-1 ~yl)—
acetic acid;
[3 -( {4— [(Cyclopropylmethyl)sulfonyl]phenyl } melhy1)—5—fluoro~2~
methylindoi-i cetic acid;
oro—2-methyl{[4-(propylsulfamoyl)phenyl]methyl }indol~1-y1)—acctic
acid;
(3- { [4-(Buty1sulfamoyl)phcnyl]methyl} fluoro-2~methylindol- I —yl)-acetic
acid;
(5 -Fluoromethy1~3-{ [4~(trifluoromethoxy)pheny1]methyl} indol-l—yl)—
acetic acid;
(5 -F1uoro~3-{ [4-methanesu1fonyl-3—(trifluoromethyl)pheny1]methyl}—2~
methyiindol- I -yI)-acetic acid;
(S-Fluoro~3-{ [4—methanesulfonyl-3—(trifluoromethoxy)phenyl1methyl}
indol—l »yl)-acetic acid;
{S—Fluoro~ 3 ~ [(5-methanesu1fonylthiophen—2—yl)methyI]—2~methylindo l— 1 ~yl} —
PCT/GB2012l000904
acetic acid;
{3 —[(4,4—dimcthyl-1,1—dioxo-2,3-dihydro-1Kéubenzothiopyranyl)methy}]-5 ~
fluoro~2-methyiindol- 1-y1}—acetic acid;
[3-({1v.[(4—Chiorobenzene)sulfOnyUpyrrol—Z-yl}methyl)—5~fluoro-2—
mcthylindol- l ctic acid;
[S-Fluoro—3 -({ l -[(4-fluorobenzcnc)su1fonyllpyrroI-Z-yl} methyI)
methylindoi—l -y1]-acetic acid;
[S—Fluoro—B-({ 1~[(4-niethoxybenzene)sulfonyl]pyrrol—2-y1}methyl)—2—
methylindol-l-yl]-acctic acid;
{3-[1-(2,4-Dichloro-benzcnesulfonyl)pyrrol~2-ylmethy11fluoro~2—methyl-
indol- 1 —yI}—acetic acid;
[S-FIuoro-3—({ I -[(4—methancsulfonylbenzcne)sulfonyl]pyrro1—2-yl}methy1)-2—
methylindoi—l-yH-acetic acid;
{5-F1uoromethyl[(2-pheny1pheny1)mcthy1]indol—i -yl}-acetic acid;
(3 - {[1 -(Benzenesulfony))indol-2—yl]methyl} -5 ~fluoromethy1indol—1 -yl)—
acetic acid;
(3—{[2~(4—Chlorophenyl)phenyi]methyl}fluoro-2~mcthylindolyl)-acetic
acid;
(S-Fluoro~2-mcthyI { [2—(4-mcthylphenyl)pheny1]methyl} indol— I —yl)-acetic
acid;
{5—Pluoro-2~methyl-3{(3-phenoxypheny1)methyl]indol—l-y1}~acetic acid;
[5-Fluoro-3—({4v[(4~fluorophenyl)carbonyl]~l -methylpyrrol—2—yl}methyD—2-
mediylindol- l cetic acid;
{S-Fluoro-2~méthy1—3-[(6- { {3-(trifluoromethyl)phenyl]methy1}pyiidin-3~
yl)methyl]indol—1—yl}-acetic acid;
{5-F1uoromethy1~3-[(3-phenoxythi0phenyl)mcthy1]i ndol- I -y1 } —acetic
acid;
(3 — {[2-(Benzenesulfony1)~1 ,3 -thiazol-S —yl]mcthy] or0-2—mcthy1indol~1
y1)-acctic acid;
{3~[(1-Benzylpyrazol-4—yl)methyl]—S-fluoro—Z-methylindo]—1—yl}~acctic acid;
(3 — {[5-(4-Chlorophenoxy)~l methyl-3 -(trifluoromethyl)pyrazol—4-
yl]methyl}fluoro—2-mcthylindol-Lyn—acetic acid;
[3—( { 5-[(4—Chlorobenzene)sulfonyl]furan—2~yl} methyl)fluoro—2~
methylindol- 1 —yl] -acetic acid;
{3-({5 - [(4—Chlorobenzene)sulfonyl]thi0phen-2—yl }methy1)-5—fluoro
methylindol—l—yl]~acetic acid;
[3 —( {3~[(4-Chlorobenzene)sulfonyl]thiophen~2—yl yl)—S-fluoro
methylindol—1—yl]—acctic acid;
{3—[(2-Benzylphenyl)methyl]~5~fluoromethylindol-1~yl}—acetic acid;
or the crcf, alkyl, aryl, (CH2)mOC(=O)C;-C6alkyl, ((CH2)mO)nCH2CI-I2X,
(CH2)mN(R7)2, or CH((CH2)mO(C=O)R8)2 esters of any of the above; wherein
m ml or 2;
n is 1-4;
X is OK7 orN(R7)2;
R7 is hydrogen or methyl; and
R3 is C1-Clg alkyl.
active as CRTHZ
The compounds of general formula (I) in which R5 is hydrogen are
. antagonists.
active parent drug
Prodrugs are any covalently bonded nds which release the
according'to general formula (I) in vivo. Examples of prodrugs include the
compounds of l formula" (I) in which R5 is Cl—C6 alkyl, aryl,
(CH2)mOC(=O)C1-C5all<yl, ((CH2)mO)nCH1CI-I2X, (CH2)mN(R7)2 or
CH((CH2)mO(C=O)R8)2; Where
m is 1 or 2;
n is l~4;
X is 0R7 or N(R7)2;
R7 is hydrogen or ; and
R8 is C1-C13 alkyl.
of the invention include
Other CRTHZ antagdnists which may be used in the practice
those disclosed in US. Pat. No. 7,754,735 having Formula (II):
PCT/G32012/000904
R1 is
and pharmaceutically acceptable salts or solvates thereof, in-which in which
hydrogen, halogen, CN, nitro, SOgR", OH, on“, SR“, SOR“, sozNR5R6, CONR5R6,
NRSR", NR9s02R“, NR9C02R4, NRQCOR“, heteroaryl, aryl (optionally substituted by
or C1.C5 alkyl, the latter three
chlorine or fluorine), Cz—C6 alkenyl, C2-CG alkynyl
independently
groups being Optionally substituted by. one or more tuents
selected from halogen, OR8 and NR5R6, 8(0),,R7 where x is 0, l or 2-, R2 is hydrogen,
halogen, CN, 802R“ or é, CHZOI—I, CH20R4 or c..7alltyl, the
latter group
selected from
being optionally substituted by one or more substituents independently
halogen atoms, OR8 and NR5R6, 7 where x is 0, l or 2-, R3 is quinoline, 1,2-
substituted
benzisothiazole, benzo[b]thiophene or indole each of which is optionally
halogen, CN,
by one or mom substituents independently selected from hydrogen,
nltto, OH, scan“, 0R4, SR4, SOR“, SOgNRSR", G, NRSR", NR9SOZR4,
R“, NR9C02H, NRgCOR“, 02—06 alkenyl, (32-06 l, ch.6 alkyl, the latter
substituents independently
three groups being optionally substituted by one or more
atoms, OR" and NRSR", 3(0),,R7 where x=0, l or 2; R“
selected from halogen
which may be optionally tuted by
represents aryl, heteroaryl, or CH; alkyl all of
substituents independently selected from halogen atoms, aryl,
one or more
heteroaryl, OR”) and NRl‘R”, S(O)XR‘3 (where x=0, 1 or 2), CONRMR”,
NRHCORIS, SOzNRMRIS, NRl‘lSOles; R5 and R6 independently represent a
latter three of which
hydrOgen atom, a 01.5 alkyl group, or an aryl, or a heteroaryl, the
one or more substituents independently selected
may be Optionally tuted by
from halogen atoms, aryl, ons and NR'4R‘5, CONRMR‘S, ‘S, soan‘hz”,
NRHSOZR”; or R5 and R6 together with the nitrogen atom to which they are attached
one or
can form a 3-8 membered saturated heterocyclic ring ally containing
1 or 2, NR“, and itself optionally
more atoms selected from O, 8(0)X where x=O,
substituted by C1,; alkyl; R7 and R13 independently ent a Ct-Cs, alkyl, an aryl
all of which maybe optionally substituted by one or more
or a heteroaryl group
PCT/G82012/000904
halogen atoms; R8 represents a hydrogen atom, C(O)R9, C1-C5 alkyl an aryl or a
heteroaryl group, all of which may be optionally substituted by halogen atoms or an
and group; each of R9, R10, R”, R”, R”, and R”, independently represents a
hydrogen atom, C1-C5 alkyl, an aryl or a heteroaryl group, all of which may be
optionally substituted by a halogen-atom; and R”; is hydrogen, CM alkyl, -COC]-C4
alkyl, COYC;—C4alkyl where Y is 0 or NR7.
Examples of compounds of Formula (11) e 3-(2-ch10ro—4-quinolinyl)-2,S-
dimethyl- I H-indole- l acetic acid; 3—(2-chloroquinoiinyl)—2-methyl— 1 H-indole—l —
acetic acid; 3-(2-chloro-4—quinolinyl)-IH~indoIe-l-acetic acid; 2~methyl(4-
inyl)-lH-indole-l acetic acid; 3~(2~chloro-4—quinolinyl)—5-methoxy—2~methyl~
liH-indole—l—acetic acid; 3-(2-chloroquinolinyl)—2,6-dimethyl-1H-indole-l—acetic
acid; 3~(2-chloroquinolinyl)-2,4-dimethyl-lH-indole~1-acetic acid; nriethyl-
3-(7~methy1—4-quinolinyl)~1H-indole-l-acetic acid; 2,5»dimethyl(8—methy1¥4~
quinolinyl)-1H-indole-l-acetic acid; 3-(6-fluoroquinolinyl)~2,S-dimethyl~1H-
indoIe-I-acetic acid; 3-(6-mcthoxyquinolinyl)~2,5—dimethyl-1H—indoleacetic
acid; 2,5—dimethyl(4-quinolinyl)-1H~indolewl-acetic acid; 2,5-dimethy1-3—[8~
oromethyl)quinolinyl}-lH~indoleacetic acid; 3-(7—chloroquinolinyl)~
2,5-dimethyl(methylsulfonyl)—lH-indole-l-acetic acid; 3-(8-fluoroquinoliny1)-
2,5—dimethyl-1H—indole-l~acetic .acid; 3-(2,8-dimethylquinoliny1)-2,5-dimethy1~
lH—indole-l acetic acid; methyl[7—(trifluoromethyI)quinolinyl} 1 H—
indole~l~acetic acid; romo-2—methy]—4-quinoliny])—2,5—dimethy1-iH—indole—l—
acetic acid; 3-(8—methoxy-2—mcthyl—4-quinoliny1)—2,5—dimethy1-1H~indole—l-acetic
acid; 3—(6,8—dimethyl—4-quinoiiny1)-2,5~dimethy1—1H—indoIe—I—acetic acid; 3—(8~
chloro-4~quinolinyl)-2,S-dimethyl-lH-indole-l -acetic acid; 3—(7~chlor0-4—
quinoIinyl)—2-methylnitro—lH-indole—1 -acetic acid; S-chloro—B—(7-chloro-4—
quinoliny1)—2-methyl-1H-indole-I—acetic acid; S—chloro-Z-methyI(8-methy1-4—
quinolinyl)-1H-indole~1-acetic acid; 5-chloro~3-(6—methoxy—2-methylquinolinyl)—
2—methyl-lH-indole—l—acetic acid; 5—methoxy-2—methy1(8-methyl—4-quinolinyl)—
IH’indoie—l-acetic acid, sodium salt; 3—(7-chloro—4-quinoliny1)—Safluoro-Z—methyl-
lH—indole—l-acetic acid; 5-fluoro~2-methyl[8~(trifluoromethyl)quinolinyl]—1H»
indole-l-acetic acid; 5-fltioromethyl—3-(8-methyl-4~quinolinyi)-1H-indole-l—
PCT/G82012/000904
acetic acid; 2-methy1(8—mcthyl-4—quinoiinyl)—5-(triflu0romethyl)-lH-indoie-l-
acetic acid; 3-(8—nitroquinolin-4—yl)-2,5-dimethyi—1H-indole—I-acetic acid; 3-(8~
cyanoquinoliny1)-2,S-dimethyl-1H-indole—l—acetic acid; methyl—3 —[8 —
(methylsulfonyl)—4-quinoIinyl]—1H—indolc~l—acctic acid; 3:[8-(difluoromcthoxy)
quinolinyI]-2,S-dimcthyi- 1 H-indolc- I—acetic acid; 5-amino—3 —(7—chloro~4—
quinoliny1)mcthyi-1H-indoic—l-acetic acid; 3-(7-ch10ro-4—quino}inyl)—2—methy1~5-
[(methylsuifonyl)amino]—lH—indole—l— acetic acid; 5—(acctylamino)(7—ch10ro—4—
quinolinyl)—2-methyl~1H-indole-l-acetic acid; 3—(7~chloroquinoiin~4—y1)~S—fluoro-
2,4~dimethy1—1H~indol—1—yl] acetic acid; S-chioro-Z-methyl~3-(8-quinoiinyi)-1H-
indole—l-acetic acid; S—chloro—3-(7-chloro—4~Iquinolinyi)-2—(hydroxymethyl)-1H—
indoleacetic acid; 5-chloro(7-chloro-4—quin01iny1)(methoxymethyi)- 1 H-
-l-acetic acid; etyloxy)mcthyl]~5-chloro(7-chloro-4—quinolinyl)-1H»
indole-l-acetic acid; 5-chloro(7-chloroquinoliny])[(methylamino)methyl]-
lH-indolc-l-acctic acid; 5-chloro(7-chloroquinoiiny1)—2-[(mediylthio)methyi]-
cie-l-acetic acid; 5—chloro-3~(7-chloroquinoliny1)—2-
[(mcthylsuifonyl)methyl]—1H—indole-l—acetic acid; 3—(7—chloroquinolinyl)—4—
methoxy-2~methyl-1H-indole~1—acetic acid; 5—chlor0methyl~3-[8.-
(tn'fluoromethyl)quinolinyl} I H-indole- 1 —acetic acid; 5-cyanomethy1(8-
methylquinolinyl)—1H—indole-l -acetic acid; omethy1~3 -[8-
(tn‘fluoromethyl)quinolinyl]-lH—indole-l-acetic acid; 3-(7-chloroquinoliny])—5—
Z-mcthyHH—indolc-I-acetic acid; 3~(8-chlcroquinoIinyl)—5-cyano
mcthyi-1H~indolc—l—acctic acid; 5-cyano-2—methyi~3—(2~methyl—4~quinoiinyl)—1H-
indcie-l—acetic acid; 3 -(8-ch1oroquinoliny])fluoro—2-methyl-lH-indole—I.-
acetic acid; 5—fluoromcthyl(7-methyl-4~quinolinyl)-1H—indole-l—acctic acid; 2-
methyl-S-(trifluoromethyi)[8~(trifluoromcthyl)quinoiinyl]— I H—indolc— I «acetic
acid; 3~(8—fluoro-4;quinoiinyl)—2~methy1(trifluoromeihyl)-1H-indole—l-acetic acid;
3-(8—chloro—4—quinolinyl)—2—methyl-5—(trifluoromethyi)—lH-indole—l-acetic acid; 3—
(8-chloro~4-quinolinyl)—2-mcthyl~5-(methylsulfonyl)-IH—indole-l-acctic acid; 2—
methyl(8«methyl-4—quinolinyl)~5~(mcthy1sulfony1)—1H~indole~1—acctic acid; 2-
methyl-S—(methylsulfonyl)—3-[8-(trifluoromethyl)quinoiinyl}-1H-indoie-l ~acetic
acid; 3-(7-chloro—4-quinoIinyl)—2-mcthyl(mcthylsu1fcnyl)— I H—indoie- I-acctic
acid; 5-chloro-2—mcthyi[8~(methylsulfony1)~4-quinoiinyl]— I H—indolc-1~acctic
WO 88109 PCT/(38201 2/000904
acid; and 5-fluoromethyl[8~(methylsulfonyl)—4~quinolinyl]—lH—indole-l~acetic
acid.
Other CRTHZ antagonists which may be used in the practice of the invention include
those disclosed in US. Pat. No. 7,723,373 having Fomiula (III):
l .t’
. eggs,
(Ill)
and pharmaceutically acceptable salts thereof, in which: n represents 1 or 2; RI is one
or more substituents independently selected from halogen, CN, nitro, 50%", OR“,
SR“, 3011‘, SOgNRSRS, CONRSR‘, NRSRé, NR9802R4, R4, NR9c0R“, aryl,
aryl, C2—C6 alkenyl, C2-C6 alkynyl or CH; alkyl, the latter five groups being
optionally substituted by one or more substituents independently selected from
halogen, OR7 and , NRKR9, 3(0),,R7 where x is o, 1 or 2; R2 is hydrogen,
halogen, CN, 30th or CONRSRé, COR“ or c,.7 alkyl, the latter group being
optionally substituted by one or more substituents ndently selected from
halogen atoms, OR8 and NRSRG, S(O)XR7 where x is 0, l or 2; R3 is aryl or a 5-7
membered heteroaryl ring containing one or more heteroatoms selected from N, S
and 0, each of which is optionally substituted by one or more substituents
independently selected from halogen, CN, nitro, SOgR“, OH, 0R4, SR4, SOR“,
Ré, CONR5R6, NRSRé, NR9502R“, NR9C02R", NR9COR“, C2-C5 alkenyl,
C2—C5 alkynyl, Cl-CG allcyl, the latter three groups being ally substituted by One
or more substituents independently selected from halogen atoms, CRT and NRKRg,
S(O),,R7 where x is 0, l or 2; R4 represents aryl, heteroaryl, or CI-CG alkyl, all of
which may be optionally substituted by one or more substituents independently
selected 'from halogen atoms, ml, aryl, OR'0 and NR’IRI2 S(O)XRl3 (where
x=0, 1 or 2), CONR14R5,NR”COR’5,SOzNRMR’S,NRMSOzR’5,CN, nitro; R5 and
R6 independently ent a hydrogen atom, a C1—C6 alkyl group, an aryl, or a
heteroaryl, the latter three of which may be optionally substituted by one or more
substituents independently selected from halogen atoms, aryl, OR!3 and NRMRIS,
PCT/G82012/000904
CONRMR'S, NR’4c0R‘5, SOZNRMR'S, NRMSOZR”, CN, nitro; or R5 and R6
together with the nitrogen atom to which they are attached can form a 3-8 membered
saturated heterocyclic ring Optionally containing one or more atoms ed from 0,
3(0), where x is 0, 1 or 2, NR”, and the ring itself Optionally substituted by C1-C3
alkyl; R7 and R13 independently represent a C1—C6 alkyl group, an aryl or heteroaryl
group all of which may be Optionally substituted by halogen atoms; R8 represents a
hydrogen atom, C(O)R9, Ct-CG alkyl (Optionally substituted by halogen atoms, aryl
or heteroaryl , both of which may also be optionally substituted by one or
more e atoms); an aryl or a heteroaryl group, which may be optionally
substituted by one or more halogen atoms; each of R9, R10, R”, R12, R14, R15,
independently represents a hydrogen atom, Ct-Cs alkyl, an aryl or a heteroaryl group
(all of which may be Optionally substituted by one or more halogen atoms); and R“-
is en, CH alkyl, -C(O)Ci—C4 alkyl, C(O)YC1~C4alkyl, Y is O or NR7.
Examples of compounds having Formula (III) include chlorophenyl)sulfonyl]-
2,5—dimethyl-l H—indol-l c acid; 5-chloro[(4-chlor0phenyl)sulfonyl] ~2~
- 1 H—indole— 1 ~acetic acid; 6—chloro-3 -[(4~chlorophenyl)sulfonyl]~2-methyl-1H-
indole- l -acetic acid; 7-chloro-3{(4-chlorophenyl)sulfonyl]-2—methyl- 1 H-indole- 1—
acetic acid; 5-chlore[(4—chlorOphenyl)sulfonyl]-4~cyanomethyl-lH—indole»l-
acetic acid; 5—chloro—3~[(4-chlorophenyl)sulfonyl]cyano~2—methyl-lH—indole-l~
acetic acid; 3-[(4-chlorophenyl)sulfonyl]—2,S—dimethyl-lH-indole-l—acetic acid; 3—
[(4-ch1orophenyl)sulfonyl](ethylsulfonyl)»7~methoxy—2—methyl—l —H—indole~ l —
acetic acid; 3—[(4~chlorophenyl)sulfonyl]—5—cyano-2~methyl-lH-indole-l—acetic acid;
3-[(4—chlorophenyl)sulfo'nyl]-5~cyano—2—methyl— l H—indole-l -acetic acid; 5-chloro—3—
[(4-chlorophenyl)sulfonyl]~2—methyl- I H—indole— l —acetic acid, 4—chloro~3-[(4—
chlorophenyl)sulfonyl] ~2-methyl—1H—indole-l -acetic - acid; 3-[(4-
methoxyphenyl)sulfonyl]-2,5—dimethyl— l H—indol-l-acetic acid; 3—[(3-
methoxyphenyl)sulfonyl]-2,5-dimethyl—1H—indol-1—acetic acid; 3 —[(2—
Chlorophenyl)sulfonyl]—2,S~dimethyl~lH—indol-l c acid; 3-[(3—
Chlorophenyl)sulfonyl]-2,5—dimethyl-lH-indol-l —acetic acid; _ 3-[(4~
Cyanophenyl)sulfonyl]-2,S—dimethyl- l H-indole— l -acetic acid; 3-[(2-
phenyl)sulfonyl]~2,5-Dimethyl—1H-indol—l -acetic acid; 3~[(2-
PCT/G82012/000904
ethylphenyl)sulfonyl]~2,5—dirnethyl-lH—indol—l—acetic acid; 3-[(4~
phenyl)sulfonyl]-2—methylnitro— l H—indole—l ~acetic acid; 4-(Acetyl amino)—
3—[(4—chlor0phenyl)sulfonyll-Q-methyl—l H-indole-l -acetic acid; 3—[(4-
chlorophenyl)sulfonyl}-2—methyl-4~[(methylsulfonyl)arnino]-1H-indole- l ~acetic
acid; 3-[(4—chlorophenyl)sulfonyl]-4’(etl1ylamino)methyl-lH~indole—1-acetic acid;
3-[(2,6—Dichlorophenyl)sulfonyl]~2,5-dimethyl~l le— l -acctic acid; 3-[(4-
chlorophenyl)sulfonyl]—2amethyl-4~phenyl- 1 H-indole-l c acid 34(4-
chlox'Ophenyl)sulfonyl]-5—fluoro~2~methyl- 1 H-indole— l —acetic acid, 3-[(3—
chlorophenyl)sulfonyl]—5'fluoro~2~methyl—IH~indole~l-acetic acid, and 5-fluoro-2~
methy1-3~[[4-(trifluoromethyUphenyllsulfonyl]- l H-indole- I -acetic acid.
Other CRTHZ antagonists which may be used in the practice of the invention include
those disclosed in US. Pat. No. 7,687,535 having Formula (IV):
(IV)
and pharmaceutically acceptable salts thereof, in which: RJ is one or more
substitucnts independently selected from NR4802R5, NR4C02R6, NR‘lCORé,
NR4802NR5R6, NHSOZRS, NHCOZR‘, NHCOR‘G, NHCONR“, NHSOZNRSRé, or
aryl, the latter which may be optionally substituted by halogen, CN, 0R7, Ct.3
alkyl (which may be optionally substituted by halogen atoms); R2 is hydrogen,
halogen, CN, $0212“ or 6, CHZOH, CH20R“ or CH alkyl, the latter group
being optionally substituted by one or more substituents independently selected from
halogen atoms, OR8 and NRSRG, S(O)XR7 where x is 0, 1 or 2; R3 is aryl or aryl
each of which is optionally substituted by one or more substituents ndently
selected from hydrogen, halogen, CN, OH, 302R“, 0R4, SR4, SOR“, SOZNRSRE,
CONRSR‘, NRSRG, NHSOZR", NHCOR‘, NHC02R4, NR7802R4, NR7C02R4,
NR7COR4, C2-C6 alkenyl, C2-C6 alkynyl, CM alkyl, the latter three groups being
optionally substituted by One or more substituents independently selected from
halogen atoms, OR8 and NRSRé, 8“?)le where x is 0, 1 or 2; R4 represents aryl,
PCT/G32012/000904
hetetoatyl, or C14, alkyl, all of which may be optionally substituted by one or more
substituents independently selected from halogen atoms, aryl, aryl, OR“), OH,
NR’IR”, stem” (where x is o, 1 or 2), CONRMR'S, NRMCOR”, t”,
NRMSOZR15 , CN, nitro; R5 and R5 independently represent a hydrogen atom, a CM
alkyl group, or an aryl, or a heteroaryl, the latter three of which may be Optionally
substituted by one or more substituents independently selected from n atoms,
aryl, on3 and NR‘“R‘5, CONR‘4R‘5, NR"C0R‘5, SOzNRMR'S, NRMSOzR”; CN,
nitro, Ct-3 alkyl (which may be Optionally substituted by n atoms); or R5 and
R6 together with the nitrogen atom to which they are ed can form a 3-8
membered saturated heterocyclic ring optionally containing one or more atoms
selected from o, 5(0)x where x is 0, i or 2, NR“, and itself optionally substituted by
C1,; alkyl; R7 and R13 independently represent a C1-C6 alkyl, an aryl or a hetetoaryl
group, all of which may be optionally substituted by halogen atoms; R8 represents a
hydrogen atom, C(O)R9, Cl-C6 alkyl' (optionally substituted by halogen atoms or
aryl) an aryl or a heteroaryl group (optionally substituted by halogen); each of R9,
RIO, R”, R”, R”, R”, ndently represents a en atom, C1-C5 alkyl, an
aryl or a heteroaryl group (all of which may be optionally substituted by halogen
atoms); and R‘6 is hydrogen, CM alkyl, COG-Ct alkyl or COYCt-C4alkyl where Y
is 0 or NR7.
Examples of compounds having Formula (IV) include 4~(acetylamino)—3—[(4—
chlorophenyl)thio]—2-methyl—lH—indole—l—acetic acid; 3-[(4«ehlor0phenyl)thio]~2-
methyl—4—[(methylsulfonyl)amino]-i H-indole-l -acctic acid; 3—[(4-
chlorophenyl)thio]~2-methyl—4«(5—pyrimidinyl)—lH-indole—l-acetic acid; 3-[(4-
chlorophenyl)thio]methylpyrazinyl-lH-indole-l-acetic acid; 3-[(2—
chlorophenyl)thio]—2-methyl—5—[(methylsulfonyl)amino]—lH—indole—l~acetic acid; 3-
[(3 -chlorophenyl)thio]-2vmethyl—4-[(methylsulfonyl)amino]v 1 H—indole—l c acid;
3- lorophenyl)thio]methyl—4- [(methylsulfonyl)amino}l H—indole— l acetic
acid; 3-[(3-methoxyphenyl]thio]-2—metl1yl[(methylsulfonyl)amino]-1H~indole~l~
acetic acid; 3—[(4-rnethoxyphenyl)thio]~2-methyl-4~[(methylsulfonleamino}1H-
indole~l~acetic acid; 3~[(2—trifluoromethylphenyl)thio]~2-methyl
[(methylsulfonyl)amino]—1H—indole-l—acetic acid; 3-[(8-Quinolinyl)thio]~2-methyl~4-
PCT/G820] 21000904
{(mcthylsulfony1)amin0]-1H-indolc-l-ace~ tic acid; 3—I(2—(methylethyl)phcnyl)thio]~
yl[(methylsuifonyl)amino]~lH—indolc—l-acetic acid; 5-(acctyiaminc)-3~[(4~
phenyl)thioj-Zomethyi-iH-indoIe—l-acetic acid; 4-(acctyicthyiamino){(4~
chicrophcnyUthioj—Z-mcthyl— lH-indole- l —acctic acid; 3-[(4-chlorophcnyl)thio]—4-
[cyciopropylcarbonyl)amino]-2~methy1-lH-indoic—I-acetic acid; 4—-(bcnzoy1amino)-
3-[(4—chlorophenyl)ihio]—2~methyl-1H—indoIe-I—acetic acid; 4~(acety1amino)-3~[(3-
chlorophenyl)thi0}»2—methyl-lH-indole-lvacetic acid; 3-[(4-chlorophenyi)thio}—4-
i{(dimethylamino)sulfonyl]amino]—2~mcthy1»lH~indole~l~acetic acid; 3—[(4~
chlorophcnyijthio]methyl-4~[[(1—methyl~1H-imidazol~4-yl)sulfonyi]amino]—1H-
indole~1—‘acctio acid; 3—[(4—chlorophcnyl)thio]’4-[[(dimethyiamino)acctyl]amino]
methyl-lH-indoic-I-acetic acid; tylamino)~2—methyi{{4—
(methylsulfonprimHyi]thi0] - 1 H-indole—I -acctic acid; 4-(acctylamino)[(2-
chlorophenymhio]-2—methyl- I le— 1 acetic acid; 4—(acctylaminoJ-2—methyi
[[4{ethylsulfonyUphcnylkhio}lH-indolc-l-acetic acid; 3-[(4-chloropheny1)thio]~4-
[[(ethylamino)ca1bonyl]amino]—2-methy1-iH—indo- ie—I-acetic acid; 3~[{4~
(methylsulfonyi)phenyl]thio]~4—(S—pyrimidinyl)-1H~indole—l-acetic acid 2-methyi—3-
[[4—(me1hylsulfonyi)phenyi]thio]-4—(2—thiopheny1)-1H-indoie~1-acetic acid 4-(3,5-
dimethylisoxazolyl)-2~methyl~3~[[4~(rnethy]sulfonyl)phenyl]thio]~1H-indoIe-i -
acetic acid 4-(3-fiJranyl)methyl—3-[[4—(methylsuifonyl)phenyl]thio]~lH-indole-i-
acetic acid 2-mcthyl—4-[(methylsulfonyl)amino]~3v[[4-(methylsuifonyl)pheny1]thio]—
lH-indolc— l -acctic acid, 2—mcthyl«5~[(mcthylsulfonyl)amino] —3-[[3~
(methylsdfonybphcnyflthio]-IH—indole—l—acetic acid, 2-mcthyl—5-
[(mcthylsuifonyDaminoj[{2-(mcthyisuifonyi)phenyi]thio]—lH—indole-I—acetic
acid, 2-methyl[[4~(methyisulfonyl)phcnyl]thio]-5—(5-pyrimidinyl)—1H—indolc- 1 ~
acetic acid, Z—methyl[[4~(mcthyisuifonyi)phcnyl]thio}-5~(3-thiopheny1)-1H-
indole-l ~acciic acid, 5-(3 cthyli soxazoiyi)~2—methyl[[4-
(methylsulfonyi)phenyi]thio]-1H-indole-l acetic acid, 2—methyi—3 {[4-
(methylsulfony])phenyi]thio]~5—(3—pyridinyI)-1H-indole-1—acetic acid, 2—methylv3-
[[4—(mcthyisuifonyi)phenyl]thio]—5~(1H—pyrazolyl)~iH~indole~1—acetic acid, and 4-
(acetylamin0)[(4~cyan0phcnyl)thio]~2~mcthy1— 1 H—indoieacetic acid.
Other CRTHZ antagonists which may be used in the practice of the ion include
PCT/G82012/000904
those disclosed in US. Pat. No. 7,709,521 having Formula (V):
and phannaceutically acceptable salts or solvates thereof, wherein R1 is one or more
substituents selected from hydrogen, halogen, CN, nitro, 802R“, 0H, 0R4, S(O)XR4,
soansné, CONRSR", NRSR", NR9sozR“, NR9sozNR5R6, NR9C02R4, NR9C0R4,
latter five groups
aryl, heteroaryl, C2~C6 l, C2-C6 l or 01.5 alkyl the
selected from
being optionally substituted by one or more substituents independently
OR8 and NR5R6, 3(0),}:7 where x
halogen, CN, NR9SOZR4, NR9cozR‘, NRQCOR“,
is o, 1 or 2; R2 is hydrogen, n, CN, $02114 or CONRSR", CHloH, CH20R° or .
substituents
01.7 alkyl, the latter group being optionally substituted by one or more
independently selected from halogen atoms, OR8 and NRsRé, S(O),cR7 where x is 0, l
which is ally substituted by one or more
or 2; R3 is aryl or heteroaryl each of
substituents independently selected from hydrogen, halogen, CN, nitro, OH, 802R”,
on‘, SR“, SOR“, sozNR5R6, CONRSRG, NRSR“, anozn“, NHC02R4, NHCOR“,
NR7SOZR4, NR7c02R“, “, alkleR5R6, 02-06 alkenyl, crc6
l, C14, alkyl, the latter three groups being optionally substituted by one or more
substituents independently selected from halogen atoms, CN, OR8 and NRSRE,
S(O)XR7 where x=O, l or 2; R4 represents aryl, heteroaryl, or CH, alkyl all of which
may be optionally substituted by one or more substituents independently ed
l or
from halogen atoms, aryl, heteroaryl, OR'O, OH, NRHR”, 8(0)le3 (where x=0,
R5 and R6
2), CONRHR”, NR‘4C0R”, sozNR‘4R‘5, NR”SOZR[5, CN, nitro;
independently represent a hydrogen atom, a CM alkyl group, or an aryl, or a
heteroaryl, the latter three of which may be optionally substituted by one or more
substituents independently selected from halogen atoms, aryl, OR8 and NRMR”,
CONRMR'S, NRMCOR”, sozNRMR'f, NRMSOZR‘S; CN, nitro, or R5 and R5
membered
together with the nitrogen atom to which they are ed can form a 3-8
from O,
ted heterocyclic ring Optionally containing one or more atoms selected
WO 88109 PCT/G82012/000904
8(0)x where x50, 1 or 2, NR“, and itself Optionally substituted by (31-3 alkyl; R7 and
R13 independently represent a Cl—C6 alkyl, an aryl or a heteroaryl group, all of which
may be optionally substituted by halogen atoms; R8 represents a hydrogen atom,
, C1-C6 alkyl (optionally substituted by halogen atoms or aryl) an aryl or a
heteroaryl 'group (optionally substituted by halogen); each of R9, R”), R”, R”, R”,
R”, independently represents a hydrogen atom, C1-C6 alkyl, an aryl or a heteroaryl
group (all of which may be optionally substituted by halogen atoms); and R“5
hydrogen, C14 alkyl, —COC1-C4 alkyl, COYCl-C4alkyl where Y is O or NR7.
Examples of nds having Formula (V) e 3-(4-Chlorophenoxy)fluoro-
2~methyl-1H-indole-1—acetic acid; 5 -Fluoro“2-methyl-3 -[4—
(methylsulfonyl)phenoxy]— l le- l acetic acid; 3-(4-Chlorophenoxy)-2~methyl-
4-[(methylsulfonyl)amino]-lH—indolc-l-acetic acid; 4-(Acetylamino)—3-(4-
chlor0phenoxy)methyl-lH-indole-l-acetic acid; 3-(4-chlorophenoxy)methyl-Sn
(methylSulfonyl)— 1 H-indole— l ~acetic acid; hlorophenoxy)—2 ~methyl
(trifluoromethyl) lH—indole-l-acetic acid; 3-(4-Cltlorophenoxy)-2—methyl
[(methylsulfonyl)amino]~lH-indole-l -acetic acid; 3-(4—Chlorophenoxy)-S-
[(ethylsulfonyl)arnino]methyl lH—indole-l -acetic acid; 3-(4-Carboxyphenoxy)—5—
fluoro-Z-methyl-1H—indole-I—acetic acid; 5-Pluoro-2—mcthyl[4-
[(methylamino)carbonyl]phenoxy]—lH-indole-lwacetic acid; 3-[4—
[(Ethylamino)carbonyl]phenoxy]—S—fluoromethyl-lH-indole—l-acetic acid; 5—
Fluoromethyl[4- [[( l —methylethyl)amino]carbonyl]phenoxy]- l H~indole-l —acetic
acid; arboxyphenoxy)-S-chloro—Z-methyl-1H—indole-l-acetic acid; 5-Fluoro
[4-(methoxycarbonyl)phenoxy]~2-methyl-1H—indole—l-acetic acid; S-Chloro«3-[4-
xycarbonyl)phenoxy]—2~methyl lH-indole—l-acetic acid; S—Chloro~2-methyl-
3~[4-[(methylamino)carbonyl]phenoxy]—lH~indole—l-acetic acid; 5—Chloro-3~[4-
[(ethylamino)carbonyl]phenoxy]-2~methy1-1H—indole—l-acetic acid; Sodium 5-
Chloro-IZ-methyl—B-[4—[[(1—methylethyl)amino]carbony1]phenoxy]—lH-indole-l-
acetate; 3— [4—[[(Z-Amincethyl)amino]carbonyl]phenoxy]-5—fluoro—2-methyl— l H—
indole-l—acetic acid; 2,5-Dimethyl[4—(methylsulfonyl)phenoxy]-1H-indoie-I—
acetic acid; 2—Methyl-3—[4~(methylsulfonyl)phenoxy]~5—(trifluoromethyl) lH-indole-
l-acetic acid; 5-Chloro-a,2-dimethyl—3~[4-(methylsulfonyl)phenoxy]-lH-indole- l —
PCT/G82012/000904
acetic acid; 5-Cyano—2—mcthyl-3—[4—(methylsulfonyl)phen0xy]~1H-indole~l—acetic
acid; 3—(4—Chlorophenoxy)—4-[(ethylsulfonyl)amino]~2—methyl lH-indole—l-acetic
acid; 3-(4-Chlorophcnoxy)—4-[[(dimethylamino)sulfony1lamin01methyl-lH—
indole—l—acetic acid; 3-(4—Chlorophenoxy)methy1pyrazinyl~l H-indole—l-acetic
acid; 3-(4—Chiorophenoxy)-2—methyl[[(l~methylethyl)sulfonyl]amino]-lH-indole-
l-acetic acid; 3-[4-[(Dimethylamino)sulfonyl]phcnoxy]fluoromethyl-lH-I
indole—l -acetic acid; 3-[4-(Ethylsulfonyl)phenoxy]flucromethyl~1H-indole-l-
acetic acid; 3-[4-(Ethylsulfonyl)phenoxy]~2—methyl—S—(trifluoromethyl)—1H-indole-l-
acetic acid; yanophenoxy)methyl(trifluoromethyl)-lH—indole-l—acetic
acid; and 3-(4-Cyanophenoxy)-S-fluoro-Z-methyl- I le— I -acetic acid.
Other CRTH2 antagonists which may be used in the practice of the ion include
those disclosed in US. Pat. No. 7,714,132 having Formula (VI):
R' N
(VI)
wherein R1, R2, R3 and R4 independently represent en, Cl—Cs—alkyl, Ci—Cs-
alkoxy, halogen, nitro, cyano or fox-my]; and R5 represents alkyl-carb0nyl, C2-
CS-alkenyI-carbonyl, C1—C5~alkoxy—carbonyl, C1~C5-alkyl, C1—C5-alkyl-carbamoyl,
aryl- C1;C5~alkyl, aryl-carbonyl, aryl—C.—C5-alkyl—carbonyl, rCs-alkoxy—
carbonyl, aryl-carbamoyl, aryl-thiocarhamoyl, aryl-Cl-Cs-alkyl-carbamoyl, aryvar
C5—alkyl-thiocarbamoyl, cycloalkyl-carbonyl, lkyl-Ci—Cs-alkyl-carbonyl,
cycloalkyl~ C3-C5—alkoxy-carbonyl, cycloalkyl-carbmnoyl, heteroaxyl— C1-C5—alkyl,
heteroaryl-carbonyl, heteroaryl—Cg-Cs-alkyl-carbonyl or heteroaryl-Cg-Cs-alkoxy-
carbonyl; 'with the proviso that when R1, R2, R3 and R4 represent hydrogen, R5 is not
an ethoxy-carbcnyl group or a tert-butoxycarbonyl group; and optically pure
enantiomers, mixtures of enantiomers, racemates, optically pure diastereoisomers,
PCT/G32012/000904
mixtures of diastereoisomcrs, diastcreoisomeric racemates, mixtures of
reoisomeric racemates, meso forms, and salts thereof.
Examples of compounds having Formula (VI) include: (2-benzyloxycarbonyi—
1,2,3,4—tetrahydro-pyrido[4,3—b]indol-5—yl)—acetic acid; (2—butoxycarbonyi-l,2,3,4-
tetrahydro-pyrido[4,3—b]indol—5-yl)-acctic acid; (2-9H—flu0rcn—9—ylmethoxycarbonyl-
1,2,3,4~tctrahydro—pyrido[4,3-b]-indol—5—yl)-acetic acid; (Z—acctyl-I ,2,3 ,4-tetrahydro—
pyrido[4,3—b]indoi-S-yl)—acetic acid; (2—phenylacetyi-1,2,3,4—tetrahydro—pyrido[4,3-
b]indoIyl)-acetic acid; (2-benzoyl—1,2,3,4-tctrahydro—pyrido[4,3-b]indol-S-y})-
acetic acid; [2-(3,4,S-trimcthoxy-bcnzoyl)-I,2,3,4-tetrahydro-pyrido[4,3-b]indol~5-
etic acid; (2-cyclohexanecarbonyi-1,2,3,4—tetrahydro-pyrido[4,3-b]indol—5~yl)-
acetic acid; [2-(4-mcthoxy~benzoyl)~l,2,3,4-tetrahydro-pyrido[4,3-b]indoiy1]—
acetic acid; [2-(thiophcne-2—carb0nyl)-1,2,3,4—tetrahydro-pyrido[4,3-b]indol~5-yi]—
acetic acid; [2-(fi1ran-2—carbonyl)—1,2,3,4-tetrahydro-pyrido[4,3-b]indoiyl]~acetic
acid; (2-cyclopropanecarbonyl- l ,2,3,4—tetrahydro-pyrido[4,3-b] S—yl)~acetic
acid; [2-(naphthalcnecarbonyl)— 4-tetrahydro-pyrido[4,3—b1indol-5—y1]-acetic
acid; [2-(2—mcthoxy«bcnzoyl)« i ,2,3,4—tetrahydro-pyfido[4,3-b]indoiy1]-acetic
acid; [2-(4~trifluoromethyl-bcnzoyl)~ l —tetrahydro—pyrido [4,3-b]indol yi]-
acetic acid; [2-(3,5—bis-trifluoromcthyl-benzoyl)—l,2,3,4-tetrahydr_o—pyrido[4,3—
b]indoI~5-yl]—acetic acid; [2-(3—cyclopcntyl—propionyl)-I ,2,3,4—tetrahydro—pyrido[4,3~
b]indol-S-yl]-acetic acid; [2-(3~phenylvpr0pionyi)—1,2,3,4~tetrahydro-pyrido[4,3-
b]indol—5~yi}—acetic acid; [2—(biphenyi—4-carbonyl)-i,2,3,4—tetrahydro-pyrido[4,3—
b]indoIy~ l]-acetic acid; [2~(4-tcrt.-butyl—benzoyi)-1,2,3,4-teuahydro—pyrido[4,3-
b]indol-S-yl]—acetic acid; [2~(4—trifluoromcthoxy~bcnzoyi)-1 ,2,3 ,4-tetrahydro-
pyrido[4,3-b]indoI-5~y1]—acetic acid; [2—((E)-but—2—enoyl)~1,2,3,4-tetrahydro~|
pyrido ] indoi—S—yl]—acetic acid; [2-(4—chloro—bcnzoyl)- 1 ,2,3 ,4—tetrahydro-
pyrido [4,3-b]indoi—5—yi]-acctic acid; [2—(3 ,S—dimcthoxy—benzoyI)-l ,2 ,3 rahydro-
pyrido[4,3-b]indol-S-yi]—acetic acid; (2-dipheny1acety1—1,2,3,4—tetrahydro~pyrido[4,3—
b]indoi-5—yl)-acetic acid; (2~hexanoy]-I,2,3,4~tctrahydro-pyrido[4,3—b]indo]—5—y2)-
acetic
. acid; [2—(3—chloro-benzoyl)—I ,2;3,4—tetrahydro—pyrido[4,3—b]indolyi]-acetic
acid; [2—(4-bromo—bcnzoyi)-l,2,3,4-tctrahydro—pyrido[4,3~b]indol-S—y1]-acetic acid;
[2—(pyridinecarbonyl)—1,2,3,4—tetrahydro-pyrido{4,3-b]indo]yi— ]-acetic acid; (2-
PCT/G82012/000904
benzoy1+8-mcthoxy-l,2,3,4-tetrahydro-pyridoi4,3-b]indoi—5-y1)—acctic acid; (2-
benzoyl—7—methyl-1,2,3,4-tctrahydro-pyrido[4,3-b]indol—5-yl)—acetic acid; (2-
bcnzoyI-S-bromo-l ,2,3,4-tetfahydro-pyrid0[4,3—b]ind01-5~yl)-acetic acid; (2-
benzoyi—8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indoly1')-acetic acid; (2-
beizzoy]-6~methy1-l ,2,3,4-tetrahydro—pyrido[4,3 -b]indolyi)-acetic acid; [2—
(pyrazinc—Z-carbouyi)-1,2,3,4-tctrahydro-pyrido[4,3~b]indoi-S-yl]—acctic acid; [2-(2-
bromo-3—methyI-benzoyl)-I ,2,3,4-tetrahydro-pyrido[4,3-b]indoi-S-yi]—acetic acid; [2—
(4‘~ethyi~biphcnyi-4—carbonyl)-1,2,3,4—tetrahydro—pyrido[4,3-b]indol-S-yl}-acetic ’
acid; [2—(2-brom0w5-methyl-ben20yl)—1,2,3 rahydro-pyrido[4,3 -b] indol—S ~yl]-
acetic acid; [2-(Z-chloro-G-methyl-pyridi_ne.4—carbony1)-I ,2,3 ,4~tetrahydro-
[4,3-b]indol—5-y1}—acctic acid; [2-(biphenylcarbony1)-1,2,3,4-tetrahydro-
pyrido[4,3-b]indol-‘5-y1]-acetic acid; [2-(5-bromo-fi1ran-2~carbonyl)-1,2,3,4-
tetrahydro—pyrido[4,3-b]indol-S-yl]-acetic acid; [2-(3-methyI-fi1rancarbonyl)-
1,2,3,4-tetrahydro-pyrido[4,3-b}indolyl]—acetic acid; [2—(2~mcthyl-furan-3—
yl)-1,2,3,4~tetrahydro-pyrido[4,3—b]indol—S-yl}~acetic acid; [2-
(benzo [b] thiophenc—Z-carbonyl)- 1 ,2 ,3 ,4-tetrahydro—pyrido[4,3 -b]indoly1]-acctic
acid; [2-(5-chloro-thiophene-Z-carbonyl)-1,2,3 ,4I-tetrahydro—pyiido [4,3 -b]indoiyi] -
acetic acid; [2-(fi1rancarbonyl)-1,2,3,4-tetrahydro-pyrido[4,3—b]indolyl]-acetic
acid; [2-(2-naphtha]en—2—yl—acetyl)— l -tetrahydro—pyrido [4,3-b]indoly1]-acetic
acid; iophene-13—carbonyl)-l,2,3,4'-tetrahydro~pyrido[4,3~b]icdcl—5-yi]—acetic
acid; [2—(2-naphthalen~1~yl—acetyl)-l,2,3 ,4-tetrahydro-pyrido[4,3 —b] indol—S~yl] -acetic
acid; rac. [2—(2-cyclohexyl—2-phenyl-acety1)-1,2,3,4—tetrahydro—pyn'do[4,3-b]indol—5
-yl]-acetic acid; (2—phenylcarbamoyl-l,2,3,4-tetrahyd1‘o—pyrido[4,3-b]indol—5-yl)-
acetic acid; (Z-ethyicarbamoyI—l,2,3,4-tetrahydro-pyridof4,3~b]indol-5—yl)-acetic
acid; sodium (2-phenethyl-1,2,3,4-tetrahydro~pyrido[4,3—b]indo]~S-yi)-acetate;
sodium [2—(3-phenyl—propyi)-I,2,3,4-tctrahydro-pyrido[4,3~b]ind01yl]—acctatc; [2-
(2-ethoxy-naphthalenecarbonyI)-l,2,3 ,4-tetrahydro—pyrido[4,3 -b]indol- 5-yl]—
acetic acid; [2-(3-methyl-thiophene—2-carbonyD-1,2,3,4-tetrahydro—pyrido[4,3¢
b]ind01-5—yl]«acetic acid; [2-(5—methy]«thi0phenecarbony1)-1,2,3,4—tetrahydro-
pyrido[4,3rb1indoI—5—yl]-acctic acid; and [2—(pyridine—4-carbonyl)—I,2,3,4-tctrahydro—.
pyrido[4,3~b]indol-S—yi]—acetic acid.
2012/000904
In a more particular embodiment, the compound of general Formula (V1) is: [2-
(naphthalenecarbonyl)-1,2,3,4-tetrahydro-pyrido[4,3—b]indol-5—yl]-acetic acid; [2—
oro‘benzoyl)-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5—yl]-acetic acid; [2»(4‘-
ethyl-biphenyl-4—carbonyl)-1,2,3,4-tetrahydro-pyrido[4,3—b]indol-S-yl]—acetic acid;
[2-(2-bromo—3-methyl-benzoyl)—-1,2,3,4-tetrahydro—pyrido[4,3-b]indoi—S-yl]~acctic
acid; (2»bcnzoyl—8-‘oromo-1,2,3,4-tetrahydr0~pyrido[4,3-b1indolyl)-acetic acid; (2~
benzoyI-l,2,3,4-tetrahydro-pyrido[4,3-b]indol-5~yl)-acetic acid; [2-(4-bromo-
benzoyl)—1,2,3,4-tctrahydro-pyrido[4,3-b]indol—5-yl] acetic acid; or [2—(furan—2—
carbonyl)—1,2,3,4-tetrahydro—pyrido[4,3—b]indol—S-yl] acetic acid.
In a more particular embodiment, the compound of l Formula (V1) is selected
from the group consisting of: boxymethyl«7-chloro-1,3,4,5—tetrahydro-
pyrido[4,3-b]indoIecarboxylic acid teit-butyl ester; 5-carboxymethyi—8-chloro-
1,3,4,5-tetrahydro-pyrido[4,3-b]indolecarboxy1ic acid tert~butyl ester; 5-
carboxymethyl-tS—chloro~l ,3,4,5—tetrahydro-pyrido[4,3-b]indolecarboxylic acid
tert-butyl ester; 5~carboxymcthyl—7~methyl-1,3,4,5-tetrahydro-pyrido[4,3—b1indoie—2-
carboxyiic acid text—butyl ester; S~carboxymcthyl-8—methyl-l,3,4,5-tetrahydro—
pyrido[4,3—b}indolecarboxylic acid tertwbutyl ester; 8-bromo-5—carboxymethyl—
~tetrahydro—pyrido[4,3—b]indole—2-carboxylic acid text-butyl ester; 5-
carboxymethyl-8—fluoro-1,3,4,5-tetrahydro-pyrido[4,3~b]indoIe-Z-caxboxylic acid
tert~butyl ester; [7—chloro—2~(3~chloro-benzoyl)—l ,2,3 ,4-tetrahydro-pyrido[4,3 -
b]indol-S-yl] ~acetic acid; [8-clfloro—2—(3-chloro-benzoyl)-1,2,3,4—tetrahydro-
pyrido[4,3-b]indol—5—yl]-acetic acid; [6-chloro—2-(3-chloro-benzoyl)—1,2,3,4-
tetrahydro-pyrido[4,3~b]indolyl]~acetic acid; [2-(3-chioro~benzoyl)-7—methyl—
l,2,3,4-tetrahydro-pyrido[4,3-b]indol—5-yl]-acetic acid; [2-(3-chloro-benzoyl)~8-
methyl-1,2,3,4-tetrahydro-pyrido[4,3-b1indolyl]-acetic acid; [8-bromo(3-
chloro-benzoyl)- I ,2 ,3 ,4—tetrahydro-pyrido[4,3-b]indolyl]-acetic acid; [2—(3 -
—benzoyl)—8—fluoro—i,2,3,4-tetrahydro-pyrido[4,3«b]indol—5~yl]~acetic acid; [8-
chloro—Z-(thioPhene—2-carbonyl)-1,2,3,4—tetrahydro-pyrido[4,3 -b]indol—5 —yl] —acetic
acid; [6-chloro~2-(thicphene-Z—carbonyl}1,2,3,4-tetrahydro-pyrido[4,3-b]indol-S-y1]-
acetic acid; [8-bromo—2«(thiophene-Z-carbonyl)—1,2,3,4-tetrahydro-‘pyrido[4,3-
b]indol—5-yl]-acetic acid; [8-fluoro—2—(thiophene—2-carbonyl)—1,2,3,4-tetrahydro—
PCT/GBZOIZ/000904
pyrido[4,3—b]indol—S-yl]—acctic acid; [7-ch10ro—2-(thiophenecarbonyl)—1,2,3,4-
tctrahydro—pyrido[4,3-b]indoi~5vyl]—acetic acid; [7—methyl—2—(thiophenc—E-carbonyl)—
1,2,3,4-tetrahydro-pyrido[4,3—b]indoi—5-yl]-acetic acid; [Si—methyl-2—(thiophenc-2—
carbony1)-l,2,3,4-tctrahydro-pyrido[4,3—b]indolyl]—acetic acid; [8»fluoro-2—(2-
methoxy~naphthalcne— i-carbonyl)- 1,2,3 ,4-tetrahydro-pyrido [4,3—b]indolyI]—acctic
acid; [8-fluoro—2-(4-mefluoxy~naphthalcnecaxbonyl)-l,2,3 ,4-tetrahydro-pyridof4,3-
b]indol-5—yl]~acetic acid; [8—chloro-2«(2-mcthoxy-naphtha1ene-1—carbonyl)-1,2,3,4~
tetrahydro-pyrido[4,3nb]indoly1]-acctic acid; [8—chloro—2—(4-methoxy—
naphthalene-1~carbony1)-1,2,3,4-tetrahydro-pyrido[- 4,3—b]indol~5—yl]-acetic acid; [2-
,2,3,4-tetrahydro-pyrido[4,3-
; hoxy-naphthalene—1—carbonyl)—8—methyl-1
b]indol-S-yi]-acetic acid; [2—(4—mcthoxy-naphthalene-1~carbonyl)methy]-i2,3,4—
ydro-pyrido[4,3-b]indol—S-yi]-acetic acid; [2-(2—methoxy~naphtha]ene—i—
carbony1)methyl-13,3,4—tetrahydro-pyrido[4,3—b}ind01—5-y11vacetic acid; {2-(2-
ethoxy-naphthalanc» 1 ~carbony1)~8—methyl-1,2,3,4-tetrahydro-pyrido[4,3—b]indol-S
yi] c acid; [2-(2-ethoxy—naphthalene—1»carbony1)—7-methyl- i ,2,3,4—tetrahydro—
pyrido[4,3-b]indol-S—}il]~acetic acid; [2-(4-methoxy-naphthalenc—1-carbony1)
-1,2,3,4—tctrahydro-pyrido[4,3—b]indol—S—yl]-acetic acid; [2-(2-fluoro-
acid; [2-(3-fluoro-
' benzoy1)—1,2,3,4-tctrahydro-pyrido[4,3-b]indol—5~yl]—acetic
ben20y1)-},2,3,4-tetrahydro—pyrido[4,3~b]indolyl]-acctic acid; 5—difluoro—
benzoy1)~1,2,3,4-tetrahydro-pyrido[4,3-b]indol—S—yi)-acetic acid; [2-(3,4,5-trifluoro-
acid; [2- (2,3 ,4,5 -
benzoyI)—l ,2,3 ,4-tetrahydro—pyrido[4,3-b]indoI-5—y1]—acetic
tetrafluoro-benzoyl)—1,2,3,4-tctrahydro—pyrido[4,3«b]indolyl]»acctic acid; (2-
benzcyl-S-fluoro-i,2,3,4-tetrahydro-pyrido[4,3-b]indol-5—yi)—acetic acid; (2-benzoy1—
6-chioro-I,2,3,4-tetrahydro—pyrido[4,3-b]indol-5—yl)—acetic acid; (2-ben10yl—8»
isopropyl—l,2,3,4—tctrahydto-pyrido[4,3-b]indoly1)-acetic acid; (2-benzoy1
chloro-l,2,3,4—tetrahydro-pyrido[4,3-b]indol-S-yl)—acetic acid; (2—bcnzoyl-7,8-
dichloro—l,2,3,4-tetrahydro-pyrido[4,3—b]indol—5-yi)-acctic acid; (2-bcnzoyl-8—
acid; (2-benzoyi-
romethyl-1,2,3 ,4-tetrahydro-pyrido[4,3—b]indoly1)-acetic
8-1crt-buty1~1,2,3,4.tetrahydro-pyrido[4,3—b]indol—S-yl)—acctic acid; (2-benzoyl—7—
chloro-S—methyLl,2,3,4vtetrahydro~pyrido[4,3-b]indolyl)-acetic acid; 5 (2-
benzoyl-7,8-dimcthyI-1,2,3,4-tctrahydro-pyrido[4,3-b]indoi-S-yl)-acetic acid; (2-
benzoyl-7~fiuoro-1{2,3,4-tctrahydro-pyrido[4,3-b]indol—5—yl)~acetic acid; [7—chloro-
ZO12/000904
2—(2-naphthalen—1 —yl—acetyl)~-1 ,2,3,4-tetrahydro-pyrido[4,3—b]indol—S—y1]—acctic acid;
[8-01110r0~2—(2—naphthalcn- I -yl-accty1)—1 ,2,3 ,4—tetrahydro—pyrido[4,3 -b] indol—S—yl] —
acetic acid; [7-methy1(2—naphthalen- 1 ~yI—acety1)- I ,2 ,3 ,4—tctrahydro~pyrido [4,3-
b]indol-S—yl]-acetic acid; [8-bmmo(2-naphthalen—1—y}-acety1)-1,2,3,4-tetrahydro-
pyrido[4,3-b]indol—S-yl]-acctic acid; [2~(4'»ethy1—biphenyl—4-carb’ony})—7—methyl-
1,2,3 ,4—tettahydro-pyrid0[4,3—b]indol—S—yI]-acetic acid; [8-bromo-2—(4'—ethyl-
biphenyl-4~carbonyl)—1,2,3,4—tctrahydro—pyrido[4,3-b]indol-S—yi]—acetic acid; —
ethyl—bipheny1—4—carbony1)—8-fluoro—1 ,2,3,4-tetrahydro-pyrido[4,3 ~b]indol-S~y]]—
acetic acid; oro(4'—ethyl-biphenylcarbonyl)~l ,2,3,4-tetrahydro-pyrido [4,3-
b]indol—5-y1]-acetic acid; [7-chloro~2-(4'-ethyl-biphenyIcarbonyl)»1,2,3,4~
tetrahydro—pyrido[4;3-b]indoly1]-acetic acid; [8-chloro(4‘-ethy]-bipheny1
carbonyl)—1,2,3,4-tetrahydro~pyrido{4,3-b]indolyI]-acetic acid; [2—(4‘-ethy1-
.biphenyi-4icarbonyi)—8—methyl-I ,2,3,4-tetrahydro~pyrido[4,3-b]indolyl]-acetic
acid; [8-methyi-2—(2-naphthalen—1-yl—acetyl)-12,3,4~tctrahydro-pyrido[4,3—b]indoi~
-y1]-acetic acid; [6-chloro(2-naphthaleny1~acetyi)-l,2,3,4-tetrahydro-
pyrido[4,3-b]indol-Sryflwacetic acid; [3-chloro—2-(naphthalene-l—carbonyl)~l,2,3,4-
tetrahydro-pyrido[4,3~b]indoI-S-yfl-acetic acid; [6-chloro(naphthaicne—1~
carbonyl)—1;2,3,4-tetrahydro-pyrido[4,3-b]indol~5-y1]-acetic acid; [7-mcthy1—2~
(naphthalcnc-I-carbonyl)~1,2,3,4-tctrahydro-pyrido[4,3-b]indol-S-y11—acetic acid; [8»
methyl—Z—(naphthalenc- 1—carbony1)-l ,2,3 ,4—tetrahydro~pyrido [4,3—b]indol-5—yl]-
acetic ‘acid; [8-bromo-2—(naphthalcnc-l -carb0nyl)—i ,2,3,4-tctrahydro—pyrido[4,3—
b]indol-5—yl]—acctic acid; [8-fluoro-2—(naphthalene-1—carbony1)-1,2,3,4-tetrahydro-
pyrido[4,3-b]indol-S*yl]—acetic acid; ro(2—naphthalenyl~acctyl)—l,2,3,4~
tetrahydro-pyrido[4,3-b]indol-5~yi]—acctic acid; [2—(2-bromo—3-mcthy[-benzoyI)—7—
chloro—l ,2,3,4—tetrahydro—pyrido[4,3—b]indol~5-y]]-acetic acid; [2-(2-bromo—3-
-benzoyl)—8-chioro-1,2,3;4—tctrahydro~pyrido[4,3-b]indol—5—yl]—acctic acid; [2-
(2~b1'omo-3~mcthy1-benzoy1)-6—chloro—I ,2,3,4-tetrahydro-pyrido[4,3 -b]indol~5-y1]—
acetic acid; [2-(2-bromomethyl-benzoy1)—7—Iiie1hyi-1,2,3,4—tetrahydro-pyrido[4,3-
b] indol-S-yl]-acctic acid; bromo-3 ~mcthy1—benzoyl)—8—methyl—l ,2,3,4~
tetrahydro-pyrido[4,3-b1indolyl]-acctic acid; [8—bromo(2-bromo—3-mcthyl—
1)-1,2,3,4-tetrahydro-pyrido[4,3-b]indol—5—yl]~acetic acid; [2-(2~bromo—3—
methyl-benzoy1)—8-fluoro-1,2,3,4-tetrahydro—pyrido[4,3—b]indonS-yH-acetic acid; [8»
2012/000904
bromo—2—(2-ethoxy-naphthalene- l -carbony1)-} ,2,3 ,4-tctrahydro-pyrido[4,3-b]ind01—
—yl]-acetic acid; [2~(2-cthoxy-naphthalenev l -carbonyl)—8—fluoro- ] ,2,3,4~tetrahydro—
pyrido[4,3-b]indoI-S-yI]-acetic acid; [8—chloro(2-ethoxy-naphtha1enecarbonyl)~
1,2,3,4—tetrahydrc~pyrido[4,3—b]indoi-S~y1]-acetic acid; [2~(4-methoxyrnaphthalene—
1—carbony1)-1,2,3,4-tetrahydro~pyrido[4,3—b]indol—S—yl]-acetic acid; [2-(5-bromo-
alene~1-caxbonyl)- I ,2,3 ,4~tet1‘ahydr0-py[id0.[4;3-b]indol-5~yl]—acctic acid; [2-
(4-methy1~naphthalcnc— 1 -carbonyl)-1 ,2,3,4~tctrahydro—pyrido [4,3—b1indol-5—y 1]—
acetic acid; methyl-naphthalene-l~carbonyl)-l,2,3,4—tetrahydro-pyridoi4,3-
b]indoIyl]-acctic acid; [2—(biphenyl-3—carbor1yl)»1,2,3,4—tetrahydro-pyrido{4,3-
b]indoi-S~yl]~acetic acid; [2-(4«fluoro—naphthalcnc-1 -carbonyl)~1 ,2,3 ,4~tctrahydro~
pyrido[4;3 -b]indoiyl]—acetic acid; [2~(2-methoxy-naphtha]cne-l -carbony])—1,2,3,4-
tetrahydro-pyrido[4,3-b]indol-S-yl]—acetic acid; 2-(9-oxo-9H-fluorenecarbonyl)-
i,2,3,4-tetrahydro—pyrido[4,3-b]indol-5~yl]~acctic acid; [2-(9H—fluorene—1-carbonyl)-
1,2,3,4—tetrahydro-pyrido[4,3—b]indol-5~y1}-acetic acid; [2—(9H-fluorenc~4-carbonyl)-
1,2,3,4—tetrahydro—pyrido{4,3—blindoly}]-acetic acid; 4,6~trifluoro-benzoy1)-
1,2,3 ,4~tetrahydro-pyrido [4,3-b]indoI—S-yl]~acetic acid; [2-(4—cyclohcxyI-benzoyl)-
12,3,4-tetrahydro-pyrido[4,3-b]indol-S-yl]-acetic acid; [2-(1H-indoIc—4-carbonyi)-
1,2,3,4-tetrahydro-pyrido[4,3-b]indol~5-yl]—acetic acid; ' [2—(2-fluoro—
phenylcarbamoyl}1,2,3,4-tctrahydro-pyrido[4,3~b]indol—5-yl]-acctic acid; [2~(3-
fluoro-phcnylcarbarnoyl)~1,2,3,4-tetrahydro—pyrido[4,3—b]indoi—S-y13—acetic acid; [2-
(4-fluoro—phenylcarbamoyl)~1,2,3,4—tctrahydro—pyrido[4,3-b]indol-5~yl]—acctic acid;
(2—o-tolylcarbamoyl—1,2,3,4—tetrahydro-pyrido[4,3—b]indol—5-y1)—acetic acid; (2-m-
tolylcarbamoyl~1,2,3,4-tetrahydro-pyrido[4,3~b]indol-5—yl)~acctic acid; (2-ptolylcaIbamoyi
—l 2,3,4—tetrahydro—pyrido[4,3—b]indol-S-y1)—acetic acid; (2—
bcnzylcarbamoyl—l ,2,3,4—tetrahydro-pyrido[4,3—b]indol-S-yl)-acetic acid; [2—
hyicarbamoyl-1,2,3,4-tctrahydro-pyrido[4,3-b]indol-S-yl)-acetic acid; [2-
(naphthalen-l~ylcarbamoy1)—1,2,3,4-tctrahydro—pyridoi4 ndol-S-yl]-acctic acid;
[2-(naphthalcnylcarbamoy1)-1,2,3,4-tetrahydro-pyrido[4,3~b]indol—5-yi]-acctic
acid; [2—(biphcnyl-2—ylcarbamoy!)-1,2,3,4-tctrahydro-pyrido[4,3~b]indol—S~yI}—acetic
acid; (2-cyclohexylcarbamoyl-I ,2,3,4—tetrahydro~pyrido[4,3—b]indol—5-yI)—acetic
acid; [2-(2 —chloro-phcnylcarbamoy1)-] ,2,3,4—tetrahydro—pyrido[4,3-b]ind0iy1]-
acetic ' acid; [2-(4-fluoro—phenylthiocarbamoyl)—1,2,3,4-tetrahydro—pyrido[4,3»
WO 88109
b]indolyl]-acetic acid; (2-phenylthiocarbamoyl—1,2,3,4-tetrahydro-pyrido[4,3~
b]indolyl)~acetic acid; (2—phenethylthiocarbamoyl-1,2,3,4~tetrahydro—pyrido[4,3~
b]indol—5-yl)—acetic acid; (2-cyclohexylthiocarbamoyl—l ,2,3,4-tetrahydro-pyrido[4,3—
b]indolyl)-ac— etic acid; (2-benzylthiocarbamoyl-l,2,3,4-tetrahydro-pyridc[4,3—
b]indol—5—y1)-acetic acid; [2‘(2—chloro~phenylthiocarbamoyl)—1,2,3,4-tetrahydro-
pyrido[4,3-b]indol~5—yl]—acetic acid; (2-p-tolylthiocarbamoyI-1 ,2,3 ,4-tetrahydro-
pyrido[4,3-b]indolyl)-acetic acid; olylthiocarbamoyl~l ,2,3,4-tetrahydro-
pyrido[4,3-b]indol-5—yl)«acetic acid; and (2~o-toly1thiocarbamoyl~l,2,3,4-tetrahydro-
pyrido[4,3-b]indol-5~yl)-acetio acid.
Other CRTH2 antagonists which may be used in the practice of the ion include
those disclosed in US. Pat. App}. Publication No. 2009/275659 having Formula
(VII):
(VII)
and salts thereof wherein R' is alkyl or cycloalkyl; R2 is halo, alkyl, haloalkyl,
alkoxy, haloalkoxy, or 'cycloalkyl; and X ie chloro or fluoro. in a particular
embodiment, the compound of Formula (VII) is oro(2-{[(2—chloro—4-.
cyclopropylphenyl)sulfonyi]amino} [(1 ,1-dimethyiethyl)carbamoyl}phenoxy)~2~.
fluorophenyl]acetic acid.
Other CRTHZ antagonists which may be used in the practice of the invention include
those disclosed in U.S. Pat. Appl. Publication No. 034558. in a particular
ment, the compound is [2‘-(3-benzyl-1«ethyl—ureidomethyl)—6—methoxy—4'—
trifluoromethyl—biphenyly11-acetic acid and all pharmaceutically acceptable
solvates (including hydrates), prodrugs, metabolites, and phatmaceutically
PCT/G32012/000904
acceptable salts thereof.
Other CRTH2 nists which may be used in the practice of the invention include
those disclosed in International Patent Appl. Publication No. . In a
particular embodiment, the compound is 2-((tert-butylthio)methyl)—4—(2,2-
dimethyl-pmpionylamino)phenoxy)—4~methoxyphenyl)acetic acid and
pharmaceutically acceptable salts, solvates, polymorphs, amorphous phases, and
metabolites thereof.
Other CRTH2 nists which may be used in the practice of the invention include
those sed in US. Patent Application Publication No. 2010/0173955 having
Formula (VIII):
(VIII)
or a salt f, wherein: RI is Arl-Ll-W—L2~; L2 is -(CR°Rd)m-; W is —CONR3’~ or
-NR3bCO-; R3a and R3” are each H or methyl; L1 is ~(CRaRb)n-,'-(CH=CH)-, or
—0(CR“R*’) ed that when w is ~NR3CO- then L' is not —(CH=CH)—; n and m are
independently 0, l or 2; each Ra, Rh, Rc and Rd is independently H, F, OH, methyl or
cyclopropyl, or R“ and Rb or R° and R‘i together with the carbon to which they are
attached form a cyclopropyl ring; Ar' is phenyl or naphthyl, each of which is
unsubstituted or substituted with one or more substituents selected independently
from F, Cl; CN, CF3, CHFZ, CHZF, SFS, methyl, ethyl, cyclopropyl, t-butyl or OMe,
or Arl is l,2,3,4-tetrahydronaphthyl which is unsubstituted or substituted by
PCT/G82012/000904
methoxy, provided that when Ar' is naphthyl or l,2,3,4—tetrahydronaphthyl then It is
0; R2 is H, C1—05 alkyl, a residue of. an amino acid Or dipeptide, or CHR°(CH3)qu; q
is 1 to 6-, R” is H, methyl or ethyl; Rf is NRgR" in which RP2 and Rh each
independently represents a hydrogen atom or a C1—C4 alkyl group, or RE and Rh
together with the nitrogen atom to which they are attached form a 5—6 membered
heterocyclic ring optionally containing a second ring heteroatom ed from N and
0, wherein said heterocyclic ring is optionally substituted with one or more groups
independently selected from 01-06 alkyl; A is ON, CHzNHz, CH2NR43C(=O)RS, or
CHZNRM’SOZR", c1, OMe, (1-4C)alkyl, cyclopropyl, H, r, Br, CH2NH(I-4C alkyI),
CH2N(l-4C aikyl)2, l, or phenyl which is tituted or substituted with
some R“3 and R41) are each H or methyl; R5 is (2,-c6 alkyl, c.-c(, , (33-0,
cycloalkyl, hetArl, or AB; R5 is are6 alkyl, unmet:6 alkyl), 6 alkyl)2, Ar3,
or hetArz; hetAri is a 6 membered heteroaryl which is unsubstituted or substituted
with one or more groups independently selected from a halogen atom and a group of
formula —NR5aR5b in which each of Rsal and R” independently ents a hydrogen
atom or are
at (14C) alkyl group, or together with the nitrogen atom to which they
attached form a pyrrolidinyl, piperidinyl or morpholino group; hetAr2 is a 5—6
membered heteroaryl which is unsubstituted or substituted with one or more groups
independently selected from 0-0; alkyl; Ar2 is phenyl which is tinsubStituted or
substituted with one or more groups independently selected from a halogen atom,
CN, SFS, cyclopropyl, a C1-C4 alkyl group, a Cl-C4 alkoxy group and a fluoroCr—Ca
alkyl group; Ar3 is as defined for Arz; R7 and R8 are independently H, methyl, or F;
R9 is H or methyl; and RW is H or F.
Other CRTH2 antagonists which may be used in the practice of the invention e
those disclosed in US Pat. Appl. Publication No. 034482. In a particular
embodiment, the compound is {4,6—bis(dimethyl—arnino)-2—(4—(4-(trifluoro—
)benzamido)benzyl)pyrimidin-S-yl}acetic acid and pharmaceutically
acceptable salts, hydrates, and solvates thereof.
Other CRTH2 antagonists which may be used in the practice of the invention include
those disclosed in US. Patent No. 7,696,222 having Formula (IX):
PCT/G82012/000904
(IX)
and pharmaceutically acceptable salts thereof, wherein: n is 1 or 2; Ar is aryi or
heteroaryl each optionally substituted with 1 to 4 groups independently selected from
R“; X is ed from ~C(R“)(Rb)-, -C(R“)(Rb)-C(R‘)(Rb)—, -C(R‘)=C(Ra)-,
-OC(Ra)(Rb)-, and )(R")-; R‘ is selected from H, halogen and C1-5alkyl; R2 is
ed from H and C1.6all<yl; R3 is selected from H, halogen, C1.5alkyl, O C1.6alkyl,
SC1.5alkyI, 3(0)n C1.6alkyl, CN, aryl and heteroaryl; Rat and Rh are independently H,
halogen, aryl, heteroaryl, kyl or haloC;-5alkyl; or Ra and Rb together with the
carbon atom to which they are both attached complete a C3.5cycloalkyl ring; or RR
and Rh together with the adjacent carbon atoms to which they are attached complete
a C3.5cycloalkyl ring; and R° is selected from halogen, CN, C1.6alkoxy, C,.5all<yl,
halo Cbgalkoxy, and halo CI.5alkyl. In a ular embodiment, the compound of
Formula (IX) is {7-[{4—fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-
tetrahydmpyridofl,2-a]indol-lO-yl}acetic acid or a phannaceutically acceptable salt
thereof.
Other CRTH2 antagonists which may be used in the ce of the invention include
those disclosed in US. Patent No. 7,858,640 having Formula (X):
FCT/G32012/000904
R3 N R5
_ tit
/'B R4 s-
in which: R‘, R2, R3, R4 and R5 are independently hydrogen, C1-C6alkyl, fully or
partially fluorinated Cl—Cgalkyi, ropyl, halo, -S(onR", -SOZNR7R8, ~NR7R8,
-NR?C(0)R6, -C02R7, ~C(O)NR7R8, ~C(O)R6, -N02, -CN or a group -OR9; wherein
each R6 is independently C;~C6a1kyl, fully or partially fluorinated (lg—Cealkyl,
cycloalkyl, aryl, or heteroaryl; R7, R5 are independently Ct—Csalkyl, fully or partially
fluorinated Ct—Cgalkyl, lkyi, cycloalkyl-(Ci~C6aIkyi)—, aryl, heteroaryl or
hydrogen; R9 is hydrogen, Ci~C6aIkyL fully or partially fluorinated C1-C5alkyl,
cycloalkyl, cycloalkyl-( Cl-Cgalkyl}, or a group -SOZR6'; A is -CHR‘°-, -C(O)-,
-S(O)n~, -O-, or -NR1°- wherein n is an integer from 0—2 and R10 is hydrogen,
C1-C3alkyl, or fully or partially fluorinated Ci—Cgalkyl group; B is a direct bond, or a
nt radical selected from -CH2-, -, —CHR”-, -CR“R”-, -CH2CHR”- in
either orientation, —CH2CR”R'2— in either orientation, ~CHRHCHR12- in either
orientation, and divalent radicals of formula -(CR"R'2)p-Z- wherein Z is attached to
”the ring carrying R], R2 and R3; wherein R” is Ci-C3alkyl, ropyl, or fully or
partially fluorinated C1-C3alky1; R12 is methyl or fully or lly fluorinated methyl;
p is independently 1 or 2; and Z is -O—, —NH—, or —S(O)n-, wherein n is an r from
0—2; X is a carboxylie acid, tetrazole, 3-hydroxyisoxazole, hydroxamic acid,
inate, phosphonate, phosphonamide, or sulfonic acid group, or a group of
formula C(=O)NHSOZR6 or SOzNHC(=O)R6; Y is aryl, heteroaryl, aryI—fused—
heterocycloalkyl, heteroaryl-filsed~cycloalkyl, heteroaryl-fused—heterocycloalkyl or
aryl-fused-cycloalkyl group.
in a particular ment, the nd of Formula (X) is ed from the group
consisting of a compound selected from the group consisting of: [8-chloro~3—(4-
chlorobenzyl)difluoromethoxyethquuinolin-5—yloxy]acetic acid, [3-(4-
chlorobenzyl)—4-difluoromethoxyethyl-8—fluor0quinolin—5-yloxy]acetic acid, [3-
ichlorobcnzyl)-2—difluoromethoxyfluoro—4—methquuinolin-S-yloxy]acetic
acid, [4-difluoromethoxy-2—ethyl-8~fluoro-3—(4—flu0robenzyl)quinolin-5—y10xy]acetic
acid, [3—(2,4~difluorobenzyl)difluoromethoxy-2—cthylfluoroquinolin-S—
acctic acid, [3-(2,4—dichlorobenzyi)difluoromethoxy—2—ethyl~8—
fluoroquinolinyloxy1acetic acid, [3-(4-chIoro—2-fluorobenzyl)difluoromethoxy7
8-fluoro-4~methy1quinolinyioxy]acetic acid, [8—chloro—3-(4—chiorobenzyl)—2-
difluoromethoxymethquuinolin—5-yloxy]acetic acid, [3-(2~chloro
flucrobenzyl)difluoromcthoxyethyl~8—fluoroquinolin—5~yloxy]acetic acid, [3-
(2~chiorofluorobenzyl)difluoromethoxy~8—fluoro~4-methyiquinolin—S—
yloxy]acetic acid, [8—chlore-3«(4-chlorofluorobenzy1)-4~difluoromethoxy-Z-
quinolin-S—yloxy]acetic acid, [3-(4—chiorofluorobenzy1)l4-difluoromethoxy—
Z-ethyl-8~fluoroquinolinyioxy]acetic acid, {4-difluoromethoxy-2—ethylfluoro-
3-[4-(morpholinc—4-su1fony1)benzyl]quinoiin-S-yloxy}acetic acid, {4-
difluoromethoxy-2~cthylfluoro[4-(pyrrolidine—1-carbonyl)benzyl]quinolin-S -
yloxy}aCctic acid, 2-[3—(2,4—dichlorobenzy1)difluoromethoxyfluoro
methquuinolin-S-yloxy}propionic acid, (S)-2~[3-(2,4-dichlorobcnzyI)—2—
difluoromethoxy~84f]uoro-4—methquuinolinyioxy]propionic acid, 2-[8-chloro-3—
(4-chlorobenzyl)-2~diflu0romethoxymcthylquinolin~5-yloxy]propionic acid, {8~
chloro—4~difluoromethoxy—2-cthy1-3—[4—(pyrrolidine—1~carbonyl)bcnzy1]~quinolin~5¥
yloxy} acetic acid, {3-[2-chloro~4~(pyrrolidine-1 ~carbonyl)benzyi]~4—
difluoromethoxy-Zethyl» 8-fluoroquinolin-5—yloxy}acetic acid, (S)-2—{3—[2-ch}oro-
4-(pyrrolidinc—1-carbonyl)benzyl]~4-diflu0rornethoxycthy1—8-fluoroquinolin-5—
yioxy}propionic acid, (S)~2-[3-(2,4-dichlorobenzyl)—4-difluoromethoxy—Z-ethyl-S—
fluoroquinolin-5~yloxy}propionic acid, [3—(2—chlorocyclobuty]carbamoylbenzy1)—
4-difluoromethoxy—2-cthyl-8»fluoroquinolinyloxy]acetic acid; and (S)—2-[3-(2—
ch]orecyc1obutyicarbamoylbenzyl)-4~difluoromctboxy—2-ethyl-S-fluoroquinolin~
-yioxy]propionic acid; and phannaceutically acceptable salts and N-oxides thereof.
See also the following hed applications which disclose CRTHZ nists:
WO—A—03/O66046, WO—A-03/066047, WO~A—03/097042, 3/O97598, WO-
A-03/101981, WO—A~03/10196I, WO—A—2004/007451, WO-A~2005/019171, WO-
PCT/G82012/000904
A—2005/OS4232, WO-A—2004/089884, WO—A-2004/089885, W0-A-2005/018529,
WO—A-2006/005909, W02006/021759, WO—A-2007/039736, WO-A-2007/052023,
WO-A~2006/075139, WO-Av2007/068894, WO-A—2007138282, WO—A-
2008/119917, WO-A—2008/113965, WO-A—2008/074966, WO-A—2008/078069,
WO-A—2007/144_625, WO—A-2007/028999, WO~A~2007/031747, WO—A—
2006/136859, WO—A-2006/111560, WO~A-2005/094816, 005/0401 12,
WO—A-2005/0401 14, WO-A—2004/096777, WO~A-2005/123731, WO-A-
25784, WO-A»2007/045867, WO—A-2006/034419, WO—A-2006/036994,
WO~A~2007/022501, WO~A~2004/106302, WO-A—2004/032848, WO-A-
2005/100321, 006/09l674, WO—A-2004/058164, WO~A~2005/007094,
WO—A-2007/036743, WO-2004/035543, WO~Av2007l062797, WO-A-2007/062773,
WO-A-2007/062678, WO~A-2007/062677, WO-A-2005/1 16001, WO-A-
2005/115382, WO-A—2005/115374, WO—A-2006/111560, WO-A~2006/037982,
WO-A—2006/056752, WO-A—2007/039741 , WO—A-ZOOS/073234, WO-A-
2005/105727, WO-A—2006/063763, WO-A-2006/125593 and WO—A—2006/125596.
In one embodiment, the proton pump inhibitor (PPI) is disclosed in US.
Pat. No.
4,045,563 and has Formula (X1)
aN .
>311!“-Hat.
N ,
it ,I,i“ '
(XI)
wherein R and R3 are the same or different and are selected from the group
consisting of hydrogen, alkyl, halogen, cyano, carboxy, y-alkyl, carboalkoxy,
carbo-alkoxyalkyl, carbamoyl, carbamoyloxy, h‘ydroxy, alkoxy, hydroxy alkyl,
trifluoromethyl and acyl in any position, R4 is selected from the group consisting
hydrogen, alkyl, aoyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
R6 is ed from
alkylcarbonyl methyl, alkoxycarbonyl methyl and alkylsulphonyl,
the group consisting of a ht or branched alkyl chain having 1 to 4 carbon atoms,
whereby only one methylene group is present between S and Het, and Het is
PCT/G32012/000904
from the group consisting of imidazolyl, imidazolinyl, benzimidazolyl, lyl,
thiazolinyl, quinolyl, piperidyl and pyridyl, which may be furlher substituted
preferably in the 3 to 5 position with lower alkyl groups such as methyl, ethyl and
propyl and/or with halo substituents such as chloro and bromo, and ceutically
acceptable salts.
Examples of compounds having Formula (XI) include 2-[2—pyridylmethy15ulfinylj—
idazole, 2~[2-pyridylmethylsulfinyl]—(4,6-dimethyl)benzimidazole, 2-[2-
pyridylmethylsulfinyl]-(5-cthyl)benzimidazole, 2—[2—pyridylmethylsulfinyl]-(4-
methyl, ro)benzimidazole, 2-[2—pyridylmethylsulfinyl]-(5—
methoxy)bcnzimidazole, yridylmcthylsulfinyll—(S-hydroxy)benzimidazole, 2-
[2~pyridylmethylsulfinyl]—(5~acetyl)benzimidazole, 2-[2-pyridylmethylsulfinyl]—(S—
carboxy)benzimidazole, 2~[2-pyridylmethylsulfinyI]-(S-carbethoxy)benzimidazole,
2-[2—(4-chloro)pyridylmethylsulfinyllbenzimidazole, 5—
methyl)pyridylme_thylsulfinyl]benzimidazole, 2-{2-pyridylmethylsulfinyl]—N~ ‘
methylbenzimidazole, 2-[2~pyridyl—(methyl)methylsulfinyl]benzimidazole, 2—[2-
pyridylmethylsulfinyl]-(4-methyl)benzimidazole, 2~[2~pyridylmethylsulfinyl]—(N-
acetyl)benzimidazole, l2~[2—pyridylmethylsulfinyH-(N—
methoxycarbonyl)ben7.imidazole, 2-[2—pyridylmethylsulfinyl]«(5-
methyl)benximidézole, 2-[2—pyn'dylmethylsulfiny1]—(5wchloro)benzimidazole, 2»[2-
pyridylmethylsulfinyl]-(5-isopropyl)bcnzimidazole, 2-[2-pyridylmcthylsulfinyl]‘(54-
butyl)benzimidazole, 2-[2-pyridylmethylsulfinyl}-(5-n—propyl)benzimidazole, 2-[2-
pyridylmethylsulfinylj-(N-carbamoyl)benzimidazole, 2—[2-pyridylmethylsulfinyl}
(N-methylcarbamoyl)benzimidazolc, 2-[2—pyridylmethylsulfinyl]—(N—
acetylmethyl)benzlmidazole, 2-[2—pyridylmethylsulfinyl]—(N-
cthoxycarbonylmethyl)benzimidazolc, 2-[2—pyridylmcthylsulfinyl]-(N-
sulfonyl)benzimidazole, 2—[2~(4-methyl)pyridylmethylsulfinyl}v(5-
methyl)bcuzlmidazole, 2-[2~(5—mcthyl)pyridylmethylsulfinyl]-(5~
methyl)benzimidazole, 2-[2-pyridylmethylsulfinyl]~(6~chloro)be.nzimidazole, 2-[2~
pyridyl—(ethmeethylsulfinyl]-bcnzimidazole, 2-[2—pyridyl-(ethy1)methylsulfinyl}
(5—chloro)benzimidazole, 2~[2-pyridyl-(methyl)methylsulflnyl]~(5~
ethyl)beuzimidazolc, 2—[2-(3-mcthyl)pyridylmcthylsulfinyl]benzimidazole, 2-[2-(5-
pyridylmethylsulfinyl}(5—methyl)benzimidazole, 2—[2—(5—
ethyl)pyridylmethylsulfinyl]benzimidazole, 2-[2~pyridyl-(ethyl)methylsulfinyl]-(S—
ethyl)benzimidazole, 2-[2-pyridyl~(methyl)methylsulfinylHS—methyl)benzimidazole,
2—[2—pyridyl—(methyl)methylsulfinyl}—(5-cyano)ben2imidazole, 2—[2-pyridyl-
l)methylsulfinyl}—(S-trifluoro)benzimidazole, 2-[2~pyridyl-
(ethyl)methylsulfinyl]~(5~methyl)benzimidazole, 2~[2-pyridyl~(ethyl)methylsulflnyl]-
(5-0yano)benzimidazole, 2-[2-pyridyl—(ethyljmcthylsulfinyl]-(5-
trifluoro)benzimidazole, 2-[2—pyridylmethylsulfinyl]~(4rchloro)benzirnidazole, 2—[2—
pyridyl-(lsopropyl)methylsulfinyl]benzimidazole, 2-[2—pyridylv
(methyl)methylsulfinyl}—(5,6~dimethyl)benzimidazole, and 2-[2-pyridyl—
methylsulfinyl]~(5,6-dimethyl)benzimidazole.
In another embodiment, the PPI is sed in US. Pat. No. 4,853,230 and has
Formula (X11):
f} N
A—CHWS—él NH
, R3
1“ (XII)
wherein A is an optionally substituted heterocyclic group, R‘, R2, R3 and R4 are the
same or different and select from among hydrogen, lower alkyl, lower alkoxy, ~CF3,
-0'*C--lower
alkyl or halogen and R5 is H or a lower alkyl group wherein "lower" denotes 1—6
carbon atoms, and pharmaceutically acceptable salts thereof.
Examples of mds of Formula (XII) e (RS)u6-methoxy((4-methoxy~
3,5-dimethylpyridin~2-yl)methylsulfinyl)—lH—benzo[d]imidazole.
In another embodiment, the PPI is the (S)—enamiomer of 5-methoxy[[(4-methoxy-
3,5-dimethylpyridin-2—yl)methyl]sulfinyl]—lH-benzo[d}imidazolc or the alkaline salt
thereof as disclosed in US. Pat. No. 504.
In another embodiment, the FF! is disclosed in US. Pat. No. 4,628,098 and has
Formula XIII:
”‘0:— NtN ’LS—CRJim/[v.1\
“ (gt. N
(XIII)
and the ceutically acceptable salts thereof, wherein R1 is hydrogen, y,
or trifluoromethyl, R2 and R3 are independently hydrogen or methyl, R4 is a CM
fluorinated alkyl, and n denotes 0 or 1, and the pharmaceutically acceptable salts
thereof.
Examples of compounds of Formula XIII e 2-[4-(2,2,2-trifluoroethoxy)-pyrid~
2-yI]methyIsulfinyllznenzimidazole,~ 2-[3-methyl(2,2,2~trifluoroethoxy)-pyrid
yl]methylsulfinylbenzimidazole, 2-[4-(2,2,2-triflubroethoxy)~5—methyl-pyrid-Z-
yl]methylsulfinylbenzimidazole, 2-[3-methyl-4—(2,2,2-trifluoroethoxy)—5—methy1-
pyrld-Z-yljmethylsulfinylbenzimidazole, 2-[4-(2,2,3,3,3~pentafluoropr0poxy)-pyrid—
ethylsulfinylbenzimidazole, 2-[4-(2,2,3,3,3-pentafluoropropoxy)-Smethyl‘
pyrid-Z-yl]methylsulfinylbcnzimidazole, 2-[4-(2,2,3,3-tetrafluoropropoxy)-pyrid—2—
yl]methylsulfinylbenzimidazole, 2~[3—methyl-4—[2,2,3,3,3—pentafluoroprop0xy)—
pyridyl]methylsulfinylbenzimidazole, 2—[3-methy1—4-(2,2,3,3—tetrafluoropropoxyj-
pyrid-Z-y11methylsulfinylbenzimidazole, 2—[S«methyl—4—(2,2,3,3—tetrafluoropr0poxy)—
pyrid~2-yl]methylsulfinylbenzimidazole, 2-[3,5—dimethyl(2,2,3,3,3—'
pentafluompropoxy)-pyrtd—Z—yl]methylsulfinylbenzimidazole, 2-[3~methyl(2,2,2—
trifluoroethoxy)-pyridyl]methylsulfinyltrifluoromethylbenzimidazole, 2—[3-
methyl~4~(2,2,2-trifluoroethoxy)~py1‘id~2—yl]methylsulfinyl-5v
methoxybenzimidazole, 2-[4-(2,2,2~trifluoroethoxy)~pyrid—2—yl]—methlylsulfinyl-5—
methoxybenzimidazole, 2~ [4-(2,2,2—trifiuoroethoxy)—pyrid—2—y1]»
thiobenzimidazole, 2-[3~methyl~4-(2,2,2-trifluoroethoxy)—pyrid
y1]methylthiobenzimidazole, 2~[5~methyl~4~(2,2,Z—trifluoroethox3,')-pyrid~2—
yl]methylthiobenzimidazole, 2-[3,5-dimethyl(2,2,2-trifluoroethoxy)—pyrid-2—
PCT/G32012/000904
yl]methylthiobenzimidazole, 2-[4-(2,2,3,3,3-pentafluor0propoxy)-pyrid
yl]methylthiobenzimidazole, 2-[5-methyl—4-(2,2,3,3,3-pentafluoropropoxy)-pyrid—2-
yl]methylthiobenzimidazole, 2-[4-(2,2,3,3-tetrafluoropropoxy)~pyrid—2—
yl]methylthiobenzimidazo1e, 2-[3—methyl(2,2,3,3~tetrafluoropropoxy)-pyrid-2—
yl]methylthiobenzimidazole, 2-{5—methyl~4-(2,2,3,3—tetrafluoroprOpoxy)«pyrid
yl]methylthiobenzimidazole, 2-[3-methyl—4—(2,2,3,3,3~pentafluoropr0poxy)—pyrid-2~
yl]methylthiobenzimidazole, 2-[3—methyl-4—(2,2,3,3,3-pentafluoropropoxy)-S-
methyl~pyricl—2~yl]methylthiobenzimidazole, 2—[3—methy1—4~(2,2,2-trifluoroethoxy)—
pyrid-2~y1~methylthio—S-trifluoromethylbenzimidazole, 2-[3-methyl-4~(2,2,2»
trifluoroethoxy)—pyrid—2—yl—methylthio-S-methoxybenzimidazole, and 2-[4~(2,2,2-
trifluoroethoxy)-pyridyl]methylthio-S—methoxybenzimidazole, and the
phannaceutically acceptable salts thereof.
In another embodiment, the PPI is disclosed in US. Pat. No. 4,758,579 and has
Formula (XIV):
RI‘O
(XIV)
and the pharmaceutically acceptable salts thereof, wherein wherein R1 represents a
l-3C-alkyl radical which is completely or predominantly substituted by fluorine, or a
chlorodifluoromethy] radical and R1' ents hydrogen (—H), halo, orornethyl,
a 1—3C—alkyl l, or a l-3C—alkoxy radical which is, optionally, completely or
predominantly substituted by e, or R1 and R1' together, with inclusion of the
oxygen atom to which R1 is bonded, represent a l—2C-alkylenedioxy radical which
is, optionally, completely or partly substituted by fluorine, or a
chlorotrifluoroethylenedioxy radical, R3 represents a l~3C-all<oxy radical, one of the
radicals R2 and R4 represents a l-3C-alkoxy radical and the other represents a
hydrogen atom (H) or a 1-3 C-alkyl radical and n ents the number 0 or 1.
es of nds of Formula (XIV) e 2-[(4,5-dimethoxy—3methyl
WO 20131088109 PCT/G82012/000904
pyridyl)methylsulfinyl]—5-trifluoromcthoxy-1H-bcnzimidazole, 2-[(4,5-dimethoxy’3—
methyl—2-pyridy1)—methylthio]-S-trifluoromethoxy~lH—benzimidazole, 2~[(4,5-
dimethoxy—3—methylpyridyl)methylsu1finyl] ( l , l ,2,2-tetrafluoroethoxy)— 1 H-
benzimidazole, 2—[(4,5-dimethoxy«3methyl—2-pyridyl)methy}thio]—5-(1 ,1,2,2~
tetrafluoroethoxy)-1H~benzimidazole, 2—[(4,5-dimethoxymethy1—2-
pyridyl)methylsulfinyl](2,2,2—trifluoroethoxy)-1H—benzimidazole, 2-[(4,5-
dimethoxy—3—rnethyl~2—pyridyI)-methylthio]-S-(2,2,2-trifluoroethoxy)—1H—
benzimidazole, 5«difluoromethoxy[(4,5—dimethoxy-3~methy)—2-
pyridyi)methylsu1finyl]—1H~benzimidazole, S-difluoromethoxy-Z—[(4,5~dimethoxy-3~
pyridy])methy1thio]~lH-benzimiaazole, 5-ch]orodifluoromethoxy—2~[(4,5-
dimethoxy-3~methyla2-pyridyl)methylsu}finyl]-1H~benzimidazole, 5-
difluoromethoxy~2-[(4,5~dimethoxymethylpyridy1)methylthi0]~1H~
benzimidazole, s(difluoromethoxy)—2-[(4,5-dirnethoxy-3~methy1—2—
pyridmeethylsulflny lj-lH-benzimidazoic, 5,6-bis(difluoromethoxy)_—2{(4,5—
dime'thoxy—3—methyi—2-pyridyl)methylthio]H-benzimidazole, S-difluoromethoxy—
6-methoxy[(4,5-dimethony—methyl-2~pyridyl)meth§13ulfiny}]-1H- .
benzimidazole, 5—difluoromethoxy-6—methoxy—2-[(4,5—dimethoxy-3umethyl~2—
pyridylymethylthio}lH-benzimidazole, 2-[(4,5-dimethoxy~2—
pyridyl)methylsulfinyl]trifluoromethoxy-1H~benzimidazole, 2v[(4,5-dimethoxy
pyridy])methylthio]—5-trifluoromethoxy-1H-benzimidazole 2—[(4,S—dimethoxy—2—
pyridy1)methylsulfinyl](1,1,2,2-tetrafluoroethoxy)—lH—benzimidazole, 2-‘[(4,5-
dimethoxy-Z—pyridyl)methylthiol—S—(],1,2,2-tetrafluoroethoxy)—1H-benzimidazole, 2—
[04,5—dimethoxy—Z—pyridy})methyisulfinyl]-5—(2,2,2-trifluoroethoxy)-1H-
benzimidazols, 2—[01,5—dimethoxypyridyl)methylthio}-S-(2,2,2-trifluoroethoxy)—
lH-benzimidazole, 5—difluoromcthoxy[(4,5-dimethoxy-Z-pyridyl)methylsuifinyl}
zimidazole, 5~difluor0methoxy[(4,5-dimethoxy—Z-pyridmeethy]tbio}IH—
idazole, S-chlorodifluoromethoxy—Z-[[4,S;dimethoxy-2—
pyridyl)methylsulfinyJ]-1H—beniimidazole, rodifluoromethoxy[(4,5-
dimethoxy—Z-pyridyl)methylthio]—lH-benzimidazole, 5,6-bis(difluoromethoxy)-2—
[(4,5—dimethoxy—2~pyridyl)methylsulfinyl]-1H—benzimidazole, 5,6—
bis(difluoromethoxy)~2~[(4,5 -dimathoxy-Z—pyridyl)methylthio]- I chenzimidazoie,
~difluoromethoxy-G~methoxy-2~[(4,5-dimethoxy-Z-pyridy1)methylsulfinyl} 1 H—
W0 2013/088109 PCT/G320] 21000904
benzimidazole, S~difluoromethoxymethoxy[4,5-dimethoxy
l)methylthio]-IH-benzimidazole, 2-[(3,4-dimethoxymethy1
pyn'dyl)methylsu1finy1]-5 —trifluoromethoxy-1H-benzimidazole, 2-[(3 ,4-dimethoxy-S-
~2-pyridy1)methylthio]-5—trifluoromethoxyvlH-benzimidazole, Z~[(3,4~
dimethoxy-S~methyl—2-pyridy1)mcthylsulfiny1]~5-(l ,1 ,2,2—tetrafluoroethoxy)- 1 H-
benzimidazole, 2— [(3 ,4—dimethoxy—5-methylpyridyl)methylthi0]—5-(1,1,2,2-
uoro-ethoxy)-1H~benzimidazole, 2-[(3,4-dimethoxy-S-methyI
pyridyl)methylsu1finyl]—5-(2,2,2—trifluoroethoxy)—1H~benzimidazole, 2-[(3,4-
oxy—S-methyl-213yridyl)-methylthio]-S—(Z,2,2—trifluoroethoxy)-1H-
benzimidazole, 5~d'1fluoromethoxy[(3,4-dimethoxy—5-methyl-2—
pyridyl)mcthylsulfinyl]-lH-benzimidazole, 5-difluoromethoxy[(3,4-dimethoxy—S—
methyl~2-pyridy1)methylthio]— 1 H-benzimidazole, S-chlorodifluoromethoxy-Z—[(3,4-
dimethoxy-S~methyl-2~pyridy1)methylsulfinyl]-1H~benzimidazole,
—c}florodifluoromethoxy~2~[(3,4-dimethoxy-S -methyI-’2-pyridyl)methy1thio]-1H-
benzimidazole, S,6-bis(difluoromethoxy)[(3,4-dimethoxy—S-methyl
l)methylsulfiny l}-1H-benzimidazole, 5,6-bis(difluoromethoxy)[(3,4—
dimethoxy—Smethyl~2—py1jidyl)methylflfio]~IH—benzimidazole, S-difluoromethoxy
methoxy—Z-{(3,4—dimethoxy—5-methy1—2-pyridyl)methylsulfinyl]-1H—benzimidazole,
-difluoromethoxy~6—meth0xy[(3,4—dimethoxymethyl~2-pyridyl)methylthio]-
1H~benzimidazo]e, 2-[(3,4-dimethoxy-2—pyridy!)methylsulfinyl}S—trifluoromethoxy—
1 H-
lH-bcnzimidazo‘le, 2—[(3 ,4—dimethoxypyridyl)methy1thio]-5—trifluoromethoxy—
benzimidazole, 2—[(3 ,4-dimcthoxy—Z-pyridyl)methy1su)finyl]—5-(1,1,2,2~
tetrafluoroethoxy}lH-benzimidazole, 4-dimethoxy—2-pyridyl)methylthio]~5—
(1,1,2,2~tetrafluoroethoxy)~lH-benzimidazole, 2-[(3 ,4—dimethoxy—2?
pyridyl)methylsulfiny1]—5—(2,2,2—trifluoroethoxy)—1H—benzimidazole, _ 2—[(3,4-
- dimcthoxy-Z-pyridyl)methyIthio]~5-(2,2,Z—trifluoroethoxy)— 1 H—benzimidazole,
difluoromethoxy-Z-[B,4-dimcthoxypyridy1)methylsu1finyl]—lH'benzimidazole, 5-
difluoromcthoxy-Z-[(3 ,4—dimethoxy-2~pyridyl)methylthio]-1H-benzimidazole,
chlorodifluoromethoxy—2~[(3,4—dimethoxy—2~pyridy1)mcthylsulfinyl]—1H—
benzimidazole, 5-chlorodifluoromethoxy~2-[(3,4~dimethoxy~2—pyridyl)mcthylthio]—
lH-benzimidazole, 5,6~bis(difluoromeflaoxy)—2—[(3,4~dimethoxy~2—
pyridyl)methylsulfinyI]-1H-benzimidazolc, 5,6-bis(difluoromethoxy)[(3,4~
PCT/G82012/000904
dimcthoxypy'ridyl)methylthio]~1H—benzimidazole, 5~difluoromcthoxy—6—meth0xy-
2—[(3,4—dimethoxy—2-pyridyl)methylsulfinyl]— l H—bgnzimidazole, 5-difluoromethoxy—
6-methoxy[[3,4-dimethoxy~2-pyridyl)methylthio]-lH—benzimidazole, 2,2-
difluoro-G-[(4,5—dimethoxy—2-pyridyl)methylsulf1nyl]—5H~[] ,3]—dioxolo-[4,5-
fibenzimidazole, 2,2—difluoro-6—[(4,5—dimethoxypyridy1)methy1thio]-5H-[ l ,3] —
dioxolo—[4,5-flbenzimidazole, 2,2—difluoro[(3~methy]—4,5-dimethoxy—2—
pyridyl)methy1thio]—SH-[1,3]-dioxolo[4,5-f}benzimidazole, 2,2-difluoro-6—[B—
methyl-4,5—dimethoxy-2~pyridyl)methylsulfinyl]-SH—[1,3]-dioxolo[4,5—
flbenzimidazole, 6-[(4,5~dieth0xymethyl~2-pyridyl)methylthio]~2,2—difluoro—5H~
[1,3]-dioxolo[4,5—f]benzimidazoie, 6-[(4,5-diethoxy-3—methyl~2—
6,6,7—
pyridyl)methylsulfiny1]2,2-difluoroSH-[1,3]-dioxolo[4,5—flbenzimidazoie,
trifluoro~6,7-dihydro2-[(4,5dimethoxy-3methyl-Z-pyridyl)methylthiov1H—[1,4]-
dioxino[2,3-f]benzimidazolc, 6,67trifluoro-6,7~dihydro2——,[(45-dimethoxy—S-
methylpyridyl)methylsulfinyl]H],4]-diox'1no[2,3-f]benzimidazole, 6,6,7-
trifluoro-6,7-dihydro-2—[(4,5-dimethoxypyridyl)methylthio}—1H-[l,4]-dioxino-
[2,3’fjbenzimidazoie, 6,6,7-trifluoro-6,T-dihydro—Z-[(4,5—dimcthoxy
pyridy1)methylsulfmyl]-lH-[l,4]-dioxino[2,3—f}bcnzimidazole, 2-[(4,5—diethoxy
pyridyl)methylthio]6,6,7-trifluoro-6,7-dihydro~1H~[1,4]—dioxino[2,3 -
flbenzimidazdle, 2-[(4,5-diethoxy-2«pyridyl)methylsulfinyl]-6,6,7-trifluoro~6,7—
2-[(4,5-diethoxymethyl-2—
o~~1H{1,4}dioxino[2,3fibenzimidazole,
pyridyl)methylthio]6,6,7—trifluoro-6,7-dihydro— 1H-[1,4]—dioxino[2,3—
midazole, 2—[(4,5-diethoxy—3”methyl2-pyn’dy1)methyisulfinyl]—6
ro—6,7~dihydro-1H—[l,4]-d10x1no[2,3-fjbcn21m1dazole, 6,6--difluoro- 6,7-
dihydro—Z-[(4,5-dimethoxypyridyl)methylthio]~lH-[1,4]-dioxino[2,3-
flbenzimidazole, 6,6-difluor6~6,7—dihydro[(4,5vdimethoxy—E-
pyridy1)methylsu1finyl]-1H—[1, 4]—dioxim'o[2,3—flhenzimidazole, 6,6-diflu0ro-6,7~
,4]~dioxino [2,3-
dihydro-2—[(4,5~dimethoxy-3»methyl-2—pyridy1)methy1thio] -1 H—[l
flbenzimidazolc, fluoro—6,7-dihydro-2~[(4,5-dimethoxymethy1
pyridyl)methyisulfinyl]—11[1,4]—dioxino[2,3-f]benzimidazolc, 6,6,7,7~tetrafluoro—
6,7-dihydro—2—[(4,5—dimethoxy-2~pyridy1)methy1thio]—1H—[1,4]-dioxino[2 ,3 -
fjbenzimidazolc, 6,6,7,7-tetrafluore-6,7vdihydro-2—[(4,S-dimethoxy—l-
pyridyl)methyisulfinyl]—IH—[I,4]-dioxino[2,3~flbenzimidazole, 6,6,7,7~tetrafluoro-
PCT/G32012/000904
6,7—dihydro[(4,S-dimethoxy—3-methylpyridyl)methylthio]'1H-[1,4]—
dioxino[2,3-flbenzimidazole, 6,6,7,7—tetrafiuoro—6,7—dihydro[(4,5-dimethoxy—3-
—2-pyridyl)methylsulfinyl]-1H-[1,4]—dioxine{2,3 —f]benzimidazole, 6-chloro-
6,7,7-trifluoro-6,7~dihydro~2~[(4,S-dimethoxymethy1~2-pyridy1)methylsulfinyl]-
lH—[l,4]dioxino[2,3~f]benzimidazole, ro-6,7,7-trifluoro-6,7—dihydro-2~[(4,5-
dimethoxy-B-methyl-2~pyridyl)methylthio]-1H~[I,4]-dioxino[2,3 —f]benzimidazole, 6—
chime-6,7,7—trifluoro—6,7—dihydro‘2—[(4,5—dimethoxy-Z-pyridyl)methylsulfinyl]—1H-
[1,4]~dioxino[2,3—fl-benzimidazole, 6—chlore-6,7,7-trifluoro-6,7—dihydro-2~[(4,S-
dimethoxy—Z-pyridyl)methylthio ]—1H-[l,4]-dioxino[2,3—flbenzimidazole, 2,2-
difluoro~6-[(3,4-dimethoxy—2-pyridyl)mcthylsulfinyl]—SH-[1,3]-dioxolo[4,5-
flbenzimidazole, 2,2«difluoro[(3;4-dimethoxy-Z-pyridyl)methy1thio]-5H-[1,3]-
dioxolo-[4,5-flbenzimidazole, 2,2-difluoro—6-[(3,4-dimethoxy~S-methy1
pyridyl)methylthio]-5H—[I ,3]-diox010[4;5—t] benzimidazole, 2,2-difluoro~6~[(3,4-
oxymethylpyridyl)methylsulfinyl]~SH‘[1,3]— dioxolo[4,5—
fibenzimidazole,- 6-[(3,4-diethoxymethyl~2~pyridy])methylthio]—2,2-difluoro~SH—
[1 ,3]—dioxolo[4,5-flbenzimidazole, 6-[(3,4-dicthoxymethy1-2—
pyridyl)methylsu1finy1]-2,2—difluoro-SH—[1,3]-dioxolo[4,5 -f]benzimidazole, 6,6 ,7-
trifluoro-6,7»dihydro[(3,4-dimethoxy-S-methyl—2-pyridyl)methylthio]~1H—[1,4]—
dioxino[2,3-fjbenzimidazolc, 6,6,7-trifluoro-6,7—dihydro—2—[(3,4-dimethoxy
methyl—2—pyridyl)methy1sulfinyl]- 1 H—[l ,4]-dioxino[2,3—f]benzimidazole,
6,6,7~1rifluoro-6,7-dihydro—2»[(3,4-dimethoxypyridy1)methy1thio]-1H—[1,4]-
dioxino[2,B-flbenzimidazole, 6,6,7-trifluoro-6,7—dihydro—2-[(3,4—dimethoxy—2—
pyridy1)methylsulfinyl]—1H- [I,4]-dioxino[2,3—flbenzimidazole, 2-[(3,4~dicthoxy~2—
pyridyl)methylthio] -trifluoro-6,7-dihydro~l H-[l ,4]-dioxino[2,3 -
flbenzimidazole, 2~[(3,4-diethoxy—2-pyridyl)methylsu1finy1]—6,6,7—triflnoro—6,7—
dihydro- lH—[l ,4]—dioxino[2,3-f]benzimidazole, 2— [(3,4—dicthoxy—5~methyl~2-
1)methyithio]-6,6,7—trifluoro—6,7-dihydro- 1 H—[l ,4]-dioxino[2,3—
fjbenzimidazole, 2-[(3,4-di ethoxy—S-methyl-2—pyridyl)methylsulfiny1]~6,6,7—
trifluoro-6,7—dihydro- 1 H-[ 1 ,4]-dioxino[2,3-flbenzimidazole, 6,6—difluoro~6,7~
dihydro~2-[(3 ethoxypyridyl)méthylthio]- l H—[l ,4]—dioxino[2,3 —
flbenzimidazole, 6,6»difluoro-6,7~dihydro[(3,4—dimethoxypyridyl)methyl-
sulfiny11-IH-[1,4]~dioxino[2,3~flbenzimidazole, 6,6»difluoro«6,7~dihydro—2—[(3,4-
W0 2013/088109 PCT/G32012/000904
dimethoxy—S—methyl-Z~pyridyl)methylthio]—1H-[1,4]—dioxino[2,3 -f]benzimidazole,
6,6-difluoro-6,7—dihydro—2-[(3,4-dimethoxy—5—met‘ny1pyridy1)methy13ulfiny1]-1 H-
[I,4]-dioxino[2,3-t]benzimidazolc, 6,6,7,7—tetrafluoro—6,7—dihydro-2~[(3,4—
dimethoxy-Z—pyridyl)methylthio]-1H-[l ,4]~dioxino[2,3—fjbenzimidazole, 6,63,7—
tetrafluoro-6,7-dihydrb—2—[(3,4-dimethoxy-2 -pyridyl)methylsu1finyl]-1H~[1,4]-
dioxinof2,3~flbenzimidazole, 6,6,7,7—tetrafluoro-6,7—dihydro-Z—[(3,4-dimethoxy—5—
methyl-Z-pyridyl)methylthio]~ I H—[ I oxino [2,3 -t]benzimidazole, 7-
]uoro-6,7-dihydro~2-[(3,4—dimethoxy-S-methy1—2-pyridy1)methylsulfinyl]- 1 H—
[1,4]-dioxino[2,B—flbenzimidazole, 6—chloro-6,7,7-trifluoro-6,7—dihydro[(3,4—
dimethoxymethy1—2-py‘ridyl)methylsulfinyl]— I H—[1,4]-dioxin0 {2,3-flbenimidazole,
6-chloro-6,7,7—trifluoro-6,7-dihydro-2—[(3,4-dimethoxy-5—mcthyl
pyridyl)methylthio]-1I—I-[l,4]~dioxino[2,3-flbenzimidazole, 6-chloro-6,7,7-trifluoro—
6,7-dihyd1'o [(3 ,4-dimethoxypyridyl)mcthylsulfinyl]-1H—[1,4]-dioxino[2,3-
flbenzimidazole, 6-chloro~6,7,7~trifluoxo-6,7-dihydro [(3 ,4-dimethoxy
pyfidyl)methyithio]-1H—[1 ,4]-dioxino[2,3—f]benzimidazole, 5-dimethoxy
methylpyridy1)-methylthio]-5H-[l ,3]dioxolo[4,5—flbenzimidazole, 6-[(4,5-
dimethoxymethy1pyridyl)-methylsulfinyl]—5H-[I ,3]-dioxolo [4,5 ~
fjbenzimidazole, 6—[(4,5-dimethoxypyridy1)methylthio]—5H~[1,3]dioxolo[4,5-
d]benzimidazole 6—[(4 , 5-dimethoxy-2 —pyridy})methyl-sulfiny1]—5H-[ l ,3]—
dioxolo[4,5 ~flbenzimidazole, 6~[(3 ,4-dimethoxy-Z-pyridyl)-methylthjo]—5H-[1,3]—
dioxolo[4,5-f]benzimidazole, 6—[(3,4-dimethoxy~2-pyridyl)methylsulfinyl]-SH—[1,3]—
didxolo{4,5-f]benzimidazole, 6-[(3,4-dimethoxy-5~methy1pyridy1)methylthio]-5H-
[1,3]-dioxolo[4,5-fj-benzimidazole, 6—[(3,4-dimethoxy—5-methyl
pyridyl)methyisu1finyl]-SH—[I,3]-dioxolo[4,5~f]benzimidazole, 6,7-dihydro—2-[(4,5-
dimethoxy~3-methy1pyridyl)methyhhio]—1H—[l ,4]-dioxino[2,3~flbenzimidazole,
6,7-dihydro—2-[(4,5-dimethoxyv3-methyl-2~pyridyl)methylsu1finyl]— l H—[I ,4]—
dioxino[2,3-f]benzimidazole, ‘ 6,7—dihydro-2—[(3,4—dimethoxy—5-methyl-2—
pyridyl)methylthio]-1H—[1,4]-dioxino[2,3-flbenzimidazole, hydro[(3,4-
dimethoxy—S—methyl-2~pyridyl)methylsulfinyl]—1H-[l,4]-dioxino[2,3—
flbenzimidazolc, 6,7—dihydro—2~[(3,4-dimethoxy—Z-pyridyl)mcthy1thio]-1H~[l,4]—
dioxino[2,3 ~f] idazole .and 6,7-dihydro[(4,5-dimethoxy
pyridyl)methylsulfinyI]—1H-[l,4]-dioxino[2,3-f]benzimidazole, and
PCT/G82012/000904
pharmaceutically able salts of these nds.
In another embodiment, the PPI is 2-((4—(3~methoxypropyl)rnethylpyridin-Z-
yl)methylsulfinyl)~lH—benzimidazole as disclosed in US. Pat. Nos. 5,035,899 and
,045,552.
In another ment, the PPI is (R)(((3—methyI-4—(2,2,2-trifluoroethoxy)—2-
pyridinyl)methyl)sulfinyl)-1H~benzimidazole as disclosed in US. Pat. Nos.
6,462,058, and 6,664,276.
The term “about" is used herein to mean the given number plus or minus 1 to 10%.
The term "individual" is used herein to refer to an animal and includes, for example,
mammals such as humans, and veterinary animals such as sheep, elk, deer, horses,
cattle, pigs, goats, dogs, cats, rats, mice, and birds.
In one embodiment, alkyl groups are "C1-C5 alkyl" groups which refers to a ht
or branched saturated hydrocarbon chain having one to six carbon atoms and
Optionally substituted with one or more halo substituents or with one or more C3-C7
lkyl groups. Examples e methyl, ethyl, n-prOpyl, isopropyl, t—butyl, n-
hexyl, trifluoromethyl, 2-chloroethyl, methylenecyclopropyl, enecyclobutyl,
methylenecyclobutyl and methylenecyclopentyl.
In one embodiment, "Cg-C7 cycloalkyl" refers to a saturated 3 to 7 membered
carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
In one embodiment alkylene groups are "C;~C4 alkylene" groups which are
disubstituted straight or branched saturated hydrocarbon chain having one to four
carbon atoms.
“Halo" refers to fluoro, chloro,.bromo or iodo.
PCT/G32012/000904
from 5 to 14 ring
In one embodiment, "aryl" refers to an aromatic ring system having
carbon atoms and containing up to three rings. Examples of aryl groups are benzene
and naphthalene.
In one embodiment ”heteroaryl" refers to a ring system with aromatic character
heteroatom selected from
having from 5 to 14 ring atoms, at least one of which is a
N, O and S, and ning up to three rings. Where a heteroaryl group contains
be fully aromatic in character. Rings which
more than one ring, not all rings must
with one or more oxo groups. Examples of
are not fully aromatic may be substituted
indole,
aryl groups include pyrrole, thiophene, le, pyridine, dine,
benzofuran, benzirnidazole, tetrahydroquinoline, indoline, quinoline, isoquinoline,
quinoxaline, imidazo[1,2~a]pyridine, pyrazolo[1,5-a]pyridine, 2,3-dihydro
benzothiopyrane and 2,3-dihydro-l~benzothiopyran-lxfi-dione.
saturated ring system having‘from 4 to
In one embodiment "heterocyclyl" refers to a
8 ring atoms, at least one of which is a heteroatom selected from N, O and S
which may be optionally Substituted by one or more oxo groups. Examples of
heterocyclyl groups include azetidinyl, piperidinyl; ydrofuranyl,
tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,l-dioxo—IRS-thiomorpholinyl,
morpholinyl, pyrrolyl, piperizinyl, azepanyl, l,4~diazepanyl, 1,4-oxaz‘epanyl and
azocanyl.
salts of the compounds of
Appropriate pharmaceutically and veterinarily acceptable
sodium, potassium, calcium,
general fonnula (I) include basic addition salts such as
zinc, magnesium and other metal salts as well as choline,
aluminium, _
ethanolamine, ethyl e, megulmine and other well-known
diethanolamine,
672 (2007) and/or
basic addition salts as summarised in J. Med. Chem, 50,
known to those skilled in the art.
Where apprOpriate, pharmaceutically or veterinarily acceptable salts may also
but not limited
include salts of organic acids, especially carboxylic acids, including
PCT/G32012/000904
to acetate, trifluoroacetate, lactate, gluconate, citrate, tanrate, maleate, malate,
pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate,
cyclopentanate, giucoheptanate, glycerophosphate, e, heptanoate, hexanoate,
fumarate, nicotinate, pamoate, pectinate, 3—phenylpropionate, picrate, pivalate,
proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate,
c sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane
sulfonate, camphorsulfonate, 2—naphthalenesulfonate, benZenesulfonate, p—
benzenesulfonate and p—toluenesulfonate; and inorganic acids such as
hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate,
thiocyanate, persulfate, phOSphoric and ic acids. Salts which are not
pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
If a chiral centre or another form of isomeric centre is present in a compound recited
herein, all forms of such isomer or isomers, including enantiomers and
diastereoisomers, are intended to be covered herein. Compounds containing a chiral
centre may be used as a racemic e, an omerically enriched mixture, or
the racemic e may be separated using well-known techniques and an
individual enantiomer may be used alone.
The term "preventing" is art-recognized and, when used in relation to esophagitis,
includes administration of a composition which reduces the frequency of, or delays
the onset of, symptoms of eSOphagitis in a subject relative to a subject which does
not receive the composition. Thus, prevention of eSOphagitis es, for example,
ng the lty of swallowing food (dySphagia), heartburn, chest pain,
abdominal pain, nausea, vomiting, coughing, and failure to thrive in subjects.
The term "treating" includes ing, reducing, or arresting the ms, clinical
signs, and underlying pathology of esophagitis in a manner to improve or stabilize a
subject.
In one embodiment, the CRT-H2 antagonist and PPI are in the same pharmaceutical
formulation. In r embodiment, the CRTH2 antagonist and the PPI are in
PCT/GBZOI 2.1000904
separate pharmaceutical formulations.
The term "administered in combination with" refers to the co-administration of a
CRTHZ antagonist with a PPI wherein the administration may be simultaneous,
sequential, or separate.
Where the CRTHZ antagonist and the PPI are in separate formulations,
administration of the CRTH2 antagonist may precede or follow the administration of
the PPI by intervals ranging from s to hours. In one embodiment, the CRTH2
antagonist and the PPI may be administered within about 1 minute, about 5 minutes,
about 10 minutes, about 30 minutes, about 60 minutes, about 2 hours, about 4 hours,
about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 18 hours, or
about 24 hours of one another. In another embodiment, the CRTHZ antagonist and
the PPI may be administered within about 1 minute, about 5 minutes, about 30
s, or about 60 minutes of one another.
In One embodiment, the CRTHZ antagonist and the PPI are administered according to
the same dosing le. In another embodiment, the CRTH2 antagonist and the
PPI are stered according to different dosing schedules. In one embodiment,
the CRTHZ antagonist may be be administered twice a day while the PPI may be
administered once a day. In another embodiment, the CRTHZ antagonist and the PPI
are stered once a day.
The CRTHZ antagonist may be administered in dosages and according to closing
regimens known in the art. Dosages may range from about 0.01 mg to about 250 mg
day. In one embodiment, the CRTH2 antagonist may be administered in per a
dosage of 5, 10, 20, 30, 40, 50, 60, ’70, 80, 90, 100, 110, 120, 130, I40, 150, 160,
I70, 180, 190, 200, 210, 220, 230, 240, or 250 mg per day in single or d
dosages. In r embodiment, the dosage is SO, 70, or 100 mg administered once
a day. In another embodiment, the dosage is 50, 70, or 100 mg administered twice a
day. In another embodiment, a dosage level that is in the range of about 0.00! mg to
about 10 mg per kg of body weight per day is employed. Variations in dosages may
PCT/G32012/000904
occur depending on the age, weight, and condition of the subject being treated, his or
her individual response to the mediCament, and the of pharmaceutical formulation
and route of administration chosen, and the time period and interval during which
such administration is carried out.
The PPI may be administered in dosages and according to dosing regimens known in
the art. Dosages may range fiom about 0.01 mg to about 60 mg per day. In one
embodiment, the PPI may be administered in a dosage of 5, 10, 15, 20, 30, 40, 50,
60, or 70 mg per day in single or divided dosages. In one embodiment, the PPl is
omeprazole and the dosage is 10, 20, or 40 mg per day. In another embodiment, the
PPI is lansoprazole and the dosage is 15 or 30 mg per day. In another embodiment,
the PPI is rabeprazole and the dOSage is 20 mg per day. In another embodiment, the
PPI is pantoprazole and the dosage is 20 or 40 mg per day. In another embodiment,
the PPI is esomeprazole and the dosage is 20 or 40 mg per day. In another
embodiment, the PPI is dexlansoprazole and the dosage is 30 or 60 mg per day.
In one embodiment, the formulations as described herein may be synergistic in
nature, meaning that the therapeutic effect of the combination of the CRTHZ
antagonist and the PPI is greater than the sum of the dual effects.
In another embodiment, the formulations as described herein may be additive in
nature, meaning that the therapeutic effect of the combination of the CRTH2
antagonist and the PPI is greater than the effect of each agent dually.
In one ment, the pharmaceutical formulation comprises (5-fluoro—2—methyl
in—2—ylmethyl—indol—1-yl)-acetic acid, or a pharmaceutically acceptable salt
thereof, and omeprazole, or a ceutically acceptable salt f. In another
embodiment, the pharmaceutical formulation comprises (S-fluoro-Z-methyl-3—
quinolin—Z—ylmethyl-indol-l—yl)—acetic acid, or a pharmaceutically acceptable salt
thereof, and razole, or a pharmaceutically acceptable salt thereof. In r
embodiment, the pharmaceutical formulation comprises (S-fluoro—Z—methyl
in~2—ylmethyl-indol-l-yl)-acetic acid, or a pharmaceutically acceptable salt
2012I000904
thereof, and rabeprazole, or a pharmaceutically acceptable salt thereof. In another
embodiment, the pharmaceutical formulation comprises (5—fluoromethyl
quinolin—Z-ylmethyl~indol-l-yl)-acetic acid, or a phannaceutically acceptable salt
thereof, and pantoprazole, or a pharmaceutically acceptable salt thereof. In another
embodiment, the pharmaceutical formulation comprises (S—fluoro—Z-methyl—S—
quinolin-2vylmethyl-indol-l-yl)-acetic acid, or a pharmaceutically acceptable salt
f, and esomeprazole, or a pharmaceutically acceptable salt thereof. In another
embodiment, the ceutical formulatiOn comprises (S~tluoromethyl
quinolin-Z-ylmethyl-indolyl)—acetic acid, or a pharmaceutically acceptable salt
thereof, and dexlansoprazole, or a pharmaceutically able salt thereof.
In one embodiment, the pharmaceutical formulation comprises [5-fluoro(4-
methanesulfonyl—benzyl)—2~methyl-indol-l-yl]»acetic acid, or a pharmaceutically
acceptable salt f, and zole, or a pharmaceutically acceptable salt
thereof. In another embodiment, the pharmaceutical formulation comprises [5-
fluoro—B-(4—methanesulfonyl-benzyl)-2emethyl—indol-l~y1]-acetic acid, or a
pharmaceutically acceptable salt thereof, and lansoprazole, or a pharmaceutically
acceptable salt thereof. In another embodiment, the pharmaceutical formulation
comprises ro-3~(4~methanesulfonyl~benzyl)—2-methyl—indolyl]~acetic acid,
or a pharmaceutically acceptable salt thereof, and rabeprazole, or a pharmaceutically
acceptable salt thereof. In another embodiment, the ceutical formulatiOn
comprises [S-fluoro(4~methanesulfonyl—benzyl)—2—methyl—indol-l-yl]—acetic acid,
or a pharmaceutically acceptable salt thereof, and pantoprazole, or a
pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical
formulation comprises [5-fluoro(4-methanesulfonyl—benzyl)—2methyl—indol—l-yl]-'
acetic acid, or a pharmaceutically acceptable salt thereof, and razole, or a
pharmaceutically acceptable salt thereof. In another embodiment, the ceutical
formulation ses [5—fluoro—3-(4—methanesulfonyl-benzyl)—2—methyl-indol-l—y1]—
acetic acid, or a pharmaceutically able salt thereof, and dexlansoprazole, or a
pharmaceutically acceptable salt thereof.
In one ment, the pharmaceutical formulation comprises (3-{[2-
PCT/G82012/000904
(benzenesulfonyl)pyridin-3—yl]methyl } fluoro-2—methylindol- l -yl)—acetic acid,
or a ceutically acceptable salt thereof, and omeprazole, or a pharmaceutically
acceptable salt thereof. In another embodiment, the ceutical ation
comprises (3 - { [2-(bcnzenesulfonyl)pyridin— 3-yl]methyl}—S—fluoromethylindol~ 1-
yl)—acetic acid, or a pharmaceutically acceptable salt thereof, and razole, or a
pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical
formulation comprises (3-{[2-(benzenesulfonyl)pyridin—3-yl]methyl}-5—fluoro—2~
methylindol-l-yl)-acetic acid, or a pharmaceutically acceptable salt thereof, and
rabeprazole, or a pharmaceutically acceptable salt thereof. In another embodiment,
the ceutical formulation comprises (3~{[2-(benzenesulfonyl)pyridin—3—
yl]methyl}—5-fluoro‘methylindol-l-yl)-acetic acid, or a pharmaceutically
acceptable salt thereof, and pantoprazole, or a pharmaceutically acceptable salt
thereof. In another embodiment, the pharmaceutical ation comprises (3-{[2-
(benzenesulfonyl)pyridin-3~yl]methyl}-5—fluoro~2-methylindolyl)-acetic acid, or a
ceutically acceptable salt thereof, and esomeprazole, or a pharmaceutically
acceptable salt thereof. In another embodiment, the pharmaceutical formulation
comprises (3—{[2—(benzenesulfonyl)pyridin—S—yl]methyl}fluoro—2—methylindol
yl)—acetic acid, or a pharmaceutically acceptable salt thereof, and dexlansopraZOIe, or
a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutical ation comprises [S-fluoro-3—({2-[(4-
or a
« enzene)3ulfonyl]pyridin—3—yl}methyl)—2—methylindol~l-yl]—acetic acid,
pharmaceutically acceptable salt thereof, and omeprazole, or a pharmaceutically
acceptable salt thereof. In another embodiment, the ceutical formulation
comprises [S-fluoro-3—({2-[(4—fluorobenzene)sulfouyljpyridin—3-yl}methyl)~2-
-methylindol—l—yll-acetic acid, or a pharmaceutically acceptable salt thereof, and
lansoprazole, or a phannaceutically acceptable salt thereof. In another embodiment,
the pharmaceutical formulation comprises [5-fluoro—3-({2—{(4-
benzene)sulfonyl]pyridin—3—yl}mcthyl)methylindol-l-yl]—acetic acid, or a
phannaceutically acceptable salt thereof, and rabeprazole, or a pharmaceutically
acceptable salt thereof. In another embodiment, the pharmaceutical ation
comprises [5-fluoro({2—[(4~fluorobenzene)smfonyl]pyridin-3 —yl}methy1)
PCT/G82012/000904
methylindol-l-yl]—acetic acid, or a pharmaceutically able salt thereof, and
pantoprazole, or a ceutically acceptable salt thereof. In another embodiment,
the pharmaceutical formulation comprises [5-fluoro({2-[(4-
fluorobenzene)sulfonyl]pyridin-3—yl}methyl)—2~methylindol-Lyn—acetic acid, or a
pharmaceutically acceptable salt thereof, and esomeprazole, or a pharmaceutically
acceptable salt thereof. In another ment, the pharmaceutical formulation
comprises [5-fluoro~3-({2~[(4~fluorobenzene)sulfonyl]pyridinyl}methyl)~2—
methylindol-l-yl]-acetic acid, or a pharmaceutically acceptable salt thereof, and
dexlansoprazole, or a ceutically acceptable salt thereof.
In one embodiment, the pharmaceutical formulation comprises 5-(acetylamino)~3-
[(4-chlorophenyl)thio]~2—methyl—lH-indole—l—acetic acid, or a pharmaceutically
acceptable salt thereof, and omeprazole, or a pharmaceutically' able salt
thereof. In another embodiment, the pharmaceutical formulation comprises 5-
(acetylamino)—3-[(4-chlorophenyl)thio]~2-methyl-lH—indole-l~acetic acid, or a
pharmaceutically acceptable salt thereof, and lansoprazolc, or a pharmaceutically
acceptable salt thereof. In another ment, the pharmaceutical formulation
comprises 5-(acetylamino)[(4—chlorophenyl)thio]~2-methyl— lH—indole-l acetic
acid, or a pharmaceutically acceptable salt thereof, and rabeprazole, or a
ceutically acceptable salt thereof. In another embodiment, the pharmaceutical
formulation ses 5-(acetylamino)[(4-chlorcphenyl)thio]-2~methyl—1H-
indole-l-acetic acid, or a pharmaceutically acceptable salt thereof, and pantoprazole,
or a phamtaceutically acceptable salt thereof. In another embodiment, the
ceutical formulation comprises tylamino)—3-[(4-chlorophenyl)thio]-2»
methyl—lH—indole—l—acetic acid, or a pharmaceutically able salt thereof, and
esomepraZOle, or a pharmaceutically acceptable salt f. In another embodiment,
the pharmaceutical formulation comprises S-(acetylamino)—3—[(4-chlorophenyl)thio]~
2-methyl-lH—indole—l-acetic acid, or a ceutically acceptable salt thereof, and
dexlansoprazolc, or a pharmaceutically acceptable salt thereof.
CRTHZ antagonist
In one embodiment, the pharmaceutical formulation comprises a
and a PPI without a corticosteroid. In another embodiment, the pharmaceutical
W0 2013/088109 PCT/G32012/000904
formulation comprises a CRTH2 antagonist, a PPI, and a corticosteroid. In one
cortisone
embodiment, the corticosteroid is hydrocortisone, hydrocortisone acetate,
acetate, tixocortol pivalate, prednisolone, methylprednisolone, or prednisone.
another embodiment, the corticosteroid is triameinolone acetonide, inolone
desonide, fluocinonide, fluocinolone
alcohol, mometasone, amcinonide, Abudesonide,
acetonide,
corticosteroid is
or halcinonide. In another embodiment, the
dexamethasone, thasone
betamethasone, betamcthasone sodium phosphate,
sodium phosphate, or fluocortolone. In another embodiment, the corticosteroid
hydrocortisonevl7-valerate, aclometasone diproprionate, betamethasone valerate,
clobetasone-17~butyrate, clobetasol
betamethasone diproprionate, prednicarbate,
fluocortolone pivalate, or fluprednidene acetate.
propionate, tolone caproate,
is hydrocortisone—l7-butyrate, l7-
In another embodiment, the corticosteroid
aceponate, 17-buteprate, or prednicarbate.
formulation comprises a CRTH2 antagonist
In one embodiment, the pharmaceutical
is a
in one embodiment, the anti-IL-3 antibody
and a PPI with an anti-IL-3 antibody.
is a human or
monoclonal antibody. In a r ment, the anti-IL-3 dy
zed monoclonal antibody. Anti-IL-3 antibodies are known and taught for
and Finkelman at £11., J.
example, by Lokker et al., J. Immunol. 146:893-898 (1991)
Immunol. 151:1235~1244 (1993).
pharmaceutical formulation comprises a CRTH2
In another embodiment, the
antagonist and a PPI with montelukast.
In another ment, present invention provides a maintenance therapy
regimen for the treatment of eosinophilic gitis.
a method for the maintenance
In one embodiment, the present invention provides
therapy of eosinophilic esophagitis sing:
(a) firstly administering to an individual in need of such treatment
for a first ermined period of
therapeutically effect amount of a corticosteroid
time; and
PCT/GBZOl 2/000904
(b) subsequently administering to the dual a eutically effective
amount of at least one CRTH’Z antagonist or a pharmaceutically able salt
f and at least one proton pump inhibitor or a pharrnaceutically acceptable salt
thereof for a second ermined period oftime.
The method of this invention comprises first administering to an individual in need
thereof a therapeutically effective amount of a corticosteroid for a first predetermined
period of time. In one embodiment, the corticosteroid is fluticasone. In another
embodiment, the corticosteroid is budesonide. The corticosteroid may be
administered as instructed according to the manufacturer of the particular
corticosteroid used for this invention. In one embodiment, the corticosteroid is
administered once a day. in another embodiment, the corticosteroid is administered
twice a day. The duration for the first predetermined period can be determined by a
person skilled in the art. In one embodiment of the invention, the first predetermined
period‘of time is between 1 and 24 weeks, between 1 and 16 weeks, between 1 and 4
weeks, and between 1 and 3 weeks.
Doses of swallowed steroid to induce clinical ion are shown in Table 1.
Remission is usually induced after treatment for l~3 weeks. Oral viscous budesonide
is the particular steroid. Straumann, A., et al., Clinical Gastroenterology and
logy 9:400-409 (2011) sed a double-blind trial whether reduction to a
dose of 0.25 mg budesonide twice-a-day is sufficient to maintain remission
compared to o. Budesonide is more effective than placebo but is only partially
ive in suppressing tissue eosinoPhilia. Consequently, there is an unmet medical
need for new treatments to maintain patients in clinical remission.
Table l
—Children< 10 years) cents and adults
Fluticasone (from MDI) 88-440 ug twice daily 440—880 ug twice daily
Budesonide (oral viscous 0.5 mg twice daily 1 mg twice daily
formulations)
2012/000904
The method of this invention also ses subsequently administering to an
dual in need thereof a therapeutically effective amount of at least one CRTH2
antagonist and at least one PPI for a second predetermined period of time. In one
ment, the at least one CRTHZ antagonist is selected from the group consisting
of (5—flu0r0-2~methyl—3-quinolin-2~ylmethyl-indol—l—yl)-acetic acid or a
pharmaceutically acceptable salt thereof, [5-fl1ioro(4—methanesulfonyl—benzyl)
~indol~I—yl]-acetic acid or a pharmaceutically acceptable salt thereof, (3-{[2~
(benzenesulfonyl)pyridin-3~yl]methy1}fluoromethylindol—l-yl)-acetic acid or a
pharmaceutically acceptable salt thereof, [5-fluoro({2-[(4-
fluorobenzene)sulfOnyl]pyridin-3~yl}metliyl)methylindolyl]—acetic acid Or a
pharmaceutically acceptable salt thereof, and S-(acetylarnino)[(4-
chlorophenyl)thio]methyl-lH~indole-l —acetic acid. In one embodiment, the FF] is
selected from the group consisting of omeprazole, esomeprazole, lansoprazole,
dexlansoprazole,'pantoprazole, and rabeprazole, or a pharmaceutically acceptable
salt thereof. In one embodiment, the administration of the at least one CRTHZ
antagonist and at least one PPI may start within a period of between 0 and 3-0 days
afier terminating administration of the corticosteroid.
The at least one CRTH2 antagonist and the at least one PPI may be stered at
the same time or at different times. In one embodiment, the stration of the at
least one CRTH2 antagonist and the at least one PPI starts immediately after
terminating administration of the corticosteroid. The CRTH2 antagonist may be
administered as instructed according to the manufacturer of the particular CRTH2
antagonist used for this invention. In one embodiment, the CRTHZ antagonist is
administered once a day. The PPI may be administered as instructed according to the
manufacturer of the particular PPI USed fOr this invention. In one embodiment, the
PPI is administered once a day. In another embodiment, the PPI is administered
twice a day.
The on for the second predetermined period can be determined by a perSOn
skilled in the art. In one ment of the invention, the first predetermined period
oftime is between 1 and 24 weeks, between 1 and 16 weeks, between i and 4 weeks,
and between 1 and 3 weeks.
The method of this invention also comprises subsequently administering to an
individual in need thereof a therapeutically effective amount of at least one CRTI-L’Z
nist and at least one PPI and further administering a corticosteroid for a second
predetermined period of time. In one embodiment, the dosage of the corticosteroid
in the first predetermined period of time is higher than the dosage of the
corticosteroid in the second predetermined period of time.
Pharmaceutical formulations comprising PPl’s are known and described in the
aforementioned patents. PPI’s are known to be unstable to acid. Thus, oral
fomtulations comprising PPI’s may comprise an enteric coating which s intact
in the h, and dissolves in the intestinal tract. In one embodiment, a
coated tablet or granule
pharmaceutical formulatiori is in the form of an enterically
and (3)
comprising (1) a core comprising the PPI, (2) a first layer coated on the core,
is an enteric g. The core may
a second layer coated on the first layer which
binder
comprise the PPI and a suitable excipient such as ol or lactose, and a
such as hydroxypropylcellulose or polyvinylpyrrolidone. The first or intermediate
material Such as layer may comprise a substantially insoluble rming
ellulose and polyvinyl acetate and, optionally, an alkaline material such as an
alkaline earth metal oxide or salt, e.g. magnesium oxide, silicic anhydride, calcium
calcium
silicate, magnesium hydroxide, magnesium carbonate, um hydroxide,
stearate and magnesium stearate. The enteric coating may comprise
hydroxymethylcellulose phthalate, cellulose acetate phthalate, methacrylic
acid/methyl methacrylate copolymer, and polyvinyl acetate phthalate. in one
in the core. In
embodiment, both the PPI and the CRTHZ antagonist are present
another ment, the PPI and the CRTH2 nistvare not in the core, but
admixed with the enterically coated tablets or granules. In another ment, the
admixed enterically coated tablets or granules are in a capsule.
The CRTH2 antagonists and PPIs may also be administered in a pharmaceutical
formulation which may be a formulation suitable for oral, rectal, nasal, bronchial
PCT/G32012/000904
-(inhaled), topical (including eye drops, buccai and sublingual), vaginal or parenteral
(including subcutaneous, intramuscular, intravenous and intradermal) administration
and may be prepared by any methods well known in the art.
The formulation may be prepared by bringing into association the above defined
active agents with a carrier. In l, the formulations are prepared by uniformly
and intimately bringing into association the active agent with liquid carriers or finely
divided solid carriers or both, and then if necessary shaping the product.
Formulations for oral administration in the present invention may be presented as:
te units such as capsules, sachets, tablets, which may be le tablets, or
lozenges, each containing a predetermined amount of the active agent; as a powder
as a solution or a suspension of
or es; as fine- partlcles for Sprinkling over food;
the active agent in an aqueous liquid or a ueous liquid; or as an oil-in-water
liquid emulsion or a water—in—oil liquid on; or as a bolus etc.
For compositions for oral administration (eg. tablets and capsules), the term
table carrier” es vehicles such as common excipients e.g. binding
agents, for example syrup, acacia, gelatin, ol, tragacanth, polyvinylpyrrolidone
(Povidone), methylcellulose, ellulose, sodium carboxymethylcellulose,
hydrdxypropylmethylcellulose, Sucrose and starch; fillers and carriers, for example
com starch, gelatin, lactose, sucrose, microerystalline cellulose, kaolin, mannitol,
such
dicalciuin phosphate, sodium chloride and alginic acid; and lubricants as
ium stearate, sodium stearate and other metallic tes, glycerol stearate
stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents
such as peppermint, oil of Wintergreen, cherry flavouring and the like can also be
used. It may be desirable to add a colouring agent to make the dosage form readily
identifiable. Tablets may also be coated by methods well known in the art.
A tablet may be made by compression or moulding, optionally with one or more
accessory ingredients. Compressed tablets may be prepared by compressing
in a
W0 88109
suitable machine the active agent in a free flowing form such as a powder or
granules, Optionally mixed with a binder, lubricant, inert diluent, preservative,
surface-active or dispersing agent. Moulded tablets may be made by moulding in a
suitable machine a e of the powdered compound moistened with an inert
liquid diluent. The tablets may optionally be coated or scored and may be formulated
so as to provide slow or controlled release of the active agent.
Other formulations suitable for oral administration include lozenges comprising the
active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles
comprising the active agent in an inert base such as gelatin and glycerin, or sucrose
and ; and mouthwashes comprising the active agent in a suitable liquid carrier.
In one embodiment, the CRTHZ antagonist and the PPI may be in the same form
(e.g., both may be administered as s) while in another embodiment, the CRTHZ
antagonist and the PPI may be administered in different forms (e.g., one may be
stered as a tablet and the other may be administered as an oral suspension).
In one embodiment, the invention provides a kit comprising a carrier means having
in close ment at least one GRTH2 antagonist and at least one PPI. The kit
contains instructions to facilitate the administration of the CRTHZ antagonist and the
PPI. In one embodiment, the carrier means is a blister pack. In another embodiment,
the kit comprises a blister pack designed to contain one or more CRTH2 tablets, one
or more PPI s, and instructions for administration. ary blister packs are
known in the art.
PCT/G82012/000904
Having now generally described this invention, the same will be understoad by
reference to the following examples which are provided herein for purposes of
illustration only and are not intended to be ng unless ise ed.
EXAMPLE 1
8 Week Study in Patients with Active Eosinophilic Esophagitis
Study Design
The study was a randomized, double-blind, placebo-controlled, single—center study of
(5-fluoro—2-methylquinolin-2~ylmethyl-indo-1~yl)~acetic acid (OC000459) for 8
weeks in patients with active (220 eos/hpf and symptoms), corticosteroid-dependent,
and/or -resistant eosinophilic esophagitis (EOE). The study compared patients taking
100 mg of OC000459 twice daily with patients taking a o twice daily. The
study consisted of 26 patients with 14 patients taking OC000459 and 12 patients
taking the placebo. Pre- and post-treatment disease-activity was assessed clinically,
endoscopically, histologically, and via biomarkers. The primary endpoint was the
reductiozi of the esophageal eosinophil load.
Study population
The following selection criteria were used to identify subjects:
Inclusion criteria:
l. Males and s ages 18-75 years.
2. Previously diagnosed and symptomatic isolated eosinophilic esophagitis.
3. Relevant eosinophil tissue ation as demonstrated by a mean eosinophil
load 2 20 f in 8 biopsies at the baseline visit.
4. Able to swallow placebo medication successfiilly under supervision in the clinic.
. Free of all tions for EOE (including topical steroids) for at least 2 weeks
prior to baseline and free of systemic steroids fOr at least 90 days before screening.
A proton-pump inhibitor is allowed if required for ent of secondary acid
reflux.
PCT/0820121000904
Exclusion criteria:
and/or infection).
1. Other causes of esophagitis (GERD, peptic ulceration,
2. Other causes of esophagal or generalized cosinophilia (i.e., hypereosinophilic
syndromes, parasitic infection, GERD).
and the t's
3. The patient‘s EOE is dependent on the level of seasonal allergens
participation in the study will occur during the allergy season.
HES, Churg-Strauss
4. History of an abnormal gastric or duodenal eosinophilia (e.g.,
vasculitis, EG, or a parasitic infection).
medication within 4 weeks
. t of a forbidden prescribed or over-the—counter
of the trial, including vitamins and
prior to the baseline visit and for the duration
herbal remedies.
Results
the total mean eosinophil
After an 8-week treatment of active EOE with QC000459,
whereas under placebo, no reduction
number sed from 114.7 to 74.7 eos/hpf,
was ed (from l02. 8 to 99.4 f). However, the effect of drug was more
in the distal
pronounced in the al upper esophagus than esophagus. The
to placebo is shown in Figure 1.
difference in % change in eosinophil load compared
These data indicate that eosinophii infiltration in the upper gus may
mediated by CRTHZ but that eosinophil accumulation
in the distal esophagus
possible explanation for this is that acid reflux may be
resistant. A
which
responsible for the eosinophilic inflammation in the distal esophagus is
consistent with repons that eosinophilia is reduced by PPls in some patients with
data highlight two
er al., 2011). These components of
EOE (Molina-Infante
CRTHZ and
eosinophil accumulation in EOE, an allergic mechanism mediated by
is reduced by PPI therapy. It is therefore
acid reflux-dependent process which
with PPls will be ive in
proposed that the combination of CRTl-l2 antagonists
the allergic and acid reflux pathways.
the treatment ofEOE by blocking both
l\lnlcn\o\cn\NRPortbl\DCC\FMT\8161406_|.docx-US/DKIZOIS
Three patients were treated with both OC000459 and esomeprazole, either 20 mg or 40 mg
once a day. As shown in Figure 2, these patients demonstrated a profound reduction in
eosinophilic load compared to those patients taking OC000459 alone.
sions
OC00459 reduces eosinophilic load in the proximal but not distal esophagus in patients
with EOE. When combined with a PPI to reduce acid reflux there is a considerable
reduction in total eosinophilic load. Consequently, the combination of a CRTH2 antagonist
with a PPI is an effective method to control ation of the esophagus in EOE which
may be more convenient and safer than the current use of topical corticosteroids.
Having now fully described this invention, it will be understood by those of ordinary skill
in the art that the same can be performed within a wide and equivalent range of conditions,
formulations and other parameters t ing the scope of the invention or any
embodiment thereof. All patents, patent applications, and publications cited herein are
fully incorporated by nce in their entirety.
The reference in this Specification to any prior publication (or information derived from it),
or to any matter which is known, is not, and should not be taken as an acknowledgment or
admission or any form of suggestion that that prior publication (or information derived
from it) or known matter forms part of the common l knowledge in the field of
our to which this specification relates.
Throughout this specification and the claims which follow, unless the context requires
otherwise, the word “comprise”, and variations such as “comprises” and “comprising”,
will be understood to imply the inclusion of a stated integer or step or group of integers or
steps but not the exclusion of any other integer or step or group of integers or steps.
Claims (17)
1. A pharmaceutical composition comprising at least one CRTHZ antagonist or a pharmaceutically acceptable salt f and at least one proton pump inhibitor; wherein said CRTH2 antagonist is a compound of general formula (I): \ R1 R1 is crcé alkyl; R2 is halogen; R3 is aryl or heteroaryl optionally substituted with one or more substituents selected from halo, OH, CN, R6, core, 0qu6, 0R6, SR6, SOZR6, 0r SOzYRé; R6 is C1~C6 alkyl, C3-C3 cycloalkyl, cyclyl, aryl, or aryl, any of which may optionally be substituted with one or more substituents selected from halo, OH, CN, N02, C1-C5 alkyl, or O(C.~C6 alkyl); and Y is NH or a straight or branched C1-C4 alkylene chain; R4 is H or C1—C4 alkyl; and R5 is hydrogen, C1-C6 alkyl, aryl, (CH2)mOC(’—“O)C1~C6alkyl, ((CH2)mO)nCH2CH2X, (CH2)mN(R7)2, or CH((CH2)mO(C=0)R8)2; m is 1 or 2; n is 1-4; X is 0R7 or N(R7)2; R7 is hydrogen or methyl; R8 is C[~Clg alkyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof; and wherein said proton pump inhibitor is selected from the group consisting of omeprazole, esorneprazole, lansoprazole, dexlansoprazole, razole and rabeprazole or a pharrnaceutically H:\fmt\Interwoven\NRPortbl\DCC\FMT\8494820_1.docx-22/09/2015 acceptable salt thereof.
2. The pharmaceutical composition according to claim 1, n R5 of the compound of general formula (I) is hydrogen.
3. The pharmaceutical composition according to claims 1 or 2, wherein the nd of general a (I) comprises, ndently or in any combination: R1 is C1-C4 alkyl; R2 is fluoro; R3 is optionally substituted and is quinoline, quinoxaline, isoquinoline, thiazole, phenyl, naphthalene, thiophene, pyrrole, or pyridine; and R4 is H or methyl.
4. The pharmaceutical composition ing to claim 3, wherein R3 of the compound of general formula (I) is quinolone or isoquinoline, either of which is optionally tuted with one or more halo substituents.
5. The pharmaceutical ition according to claim 3, wherein R3 of the compound of general formula (I) is 3-pyridyl optionally substituted with OR6, SO2R6 or SO2YR 6; where R6 and Y are as defined by claim 1.
6. The pharmaceutical composition according to claim 1, wherein the compound of general formula (I) is: {3-[1-(4-Chloro-phenyl)-ethyl]fluoromethyl-indolyl}-acetic acid; {5-Fluoromethyl[1-(4-trifluoromethyl-phenyl)-ethyl]-indolyl}-acetic acid; {3-[1-(4-tert -Butyl-phenyl)-ethyl]fluoromethyl-indolyl}-acetic acid; {5-Fluoro[1-(4-methanesulfonyl-phenyl)-ethyl]methyl-indolyl}-acetic acid; [5-Fluoromethyl(1-naphthalenyl-ethyl)-indolyl]-acetic acid; (5-Fluoromethylquinolinylmethyl-indolyl)-acetic acid; (5-Fluoromethylnaphthalenylmethyl-indolyl)-acetic acid; [5-Fluoro(8-hydroxyquinolinylmethyl)methyl-indolyl]-acetic acid; H:\l‘ml\lnlcmavcmNRPaanDCGFMN |(‘ HOGJ docxflS/OX/ZOI S [5 0methy1(quin0xalin—2-ylmethyl)indol- i -y1] -acetic acid; [5—F1uor0—3—(4-methoxy-benzyl)methyl-ind01-1—yl]-acetic acid; [5-P1uor0-2—methy1(I,3-thiazoly1methyl)indo1y1]-acetic acid; [3-(4-Ch10ro-benzyl)-S-fluoro—Z—methyl—indol—1—y1]—acetic acid; [5-F1uoro—2-methyI(4-trifluoromethyl-benzyl)-indol-Lyn-acetic acid; [5-F1u0r0methyI(4—lert-butyl-benzyl)-indoly1]-acetic acid; {5-P1u0ro-2—methyl[(4-phenylphenyl)methyl]indoly1}-acetic acid; [5-F1u0r0(4-methanesulfonyl-benzyl)rnethy1-indoly1]-acetic acid; {5—Fluoro—3—[(6—fluoroquino1inyl)methyl]methylindol-1 ~y1}-acetic acid; hyiquinolinyimethy1-ind01y1)-acetic acid; (5—Chloro—Z-methy1—3~quinolin—2—ylmethy1~indol~1—yI)—acetic acid; (3 -{[1 -(Benzenesulfonyl)pyrroly1]methyl}fluor0methylindoly1)-acetic acid; [5 -F1uoro-2—methyl({ 1-[(4-methylbenzene)sulfonyl]pyrroly1} methyl)indol-1 — yl}-acetic acid; [3 —({ i -[(2,4—Difluorobenzene)su1fony1]pyrroI—2—yl }methyl)—5-fluoro methylindolyi] -acetic acid; (3 - { [2-(Benzenesulfonyl)phenyl]methyl } -5 —2—methylindol~1—y1)-acetic acid; [3 —({2-[(4-Ch10r0benzcne)sulfonyl]phenyl}methyl}5-flu0ro—2-methy1ind01-l -y1]- acetic acid; [5 -FIuoro-3 -({2- [(4-flu0r0benzene)sulf0nyl]pheny] }methyl)methylindol- i-yl] - acetic acid; (3-{[2-(Benzenesulfonyl)pyridinyl]methy1}fluor0methylindol—1~y1)—acetic acid; [5-Fluoro({2-[(4-fluorobenzene)sulfonyl]pyridin—B—yl}methyI)methy1indol yl]—acetic acid; [3 -({2-[(4-Chlorobenzene)sulfonyl]pyridiny1}methyi)~5~fluor0~2—methylindol y1]-acetic acid; 2—(3 ~(4—(Benzylsulfonyl)benzy1)~5—fluoro-2~methyl»ind01y1)—acetic acid; 2-(3 ~(4-(4—Ch1orobenzylsulfonyl)benzyi)—5—fluoro—2—methyl—indol— 1 cetic acid; 2-(3 -(3 -(Benzylsulf0nyi)benzyi)flu0romethyl-indoiyl)-acetic acid; 2-(5-F1u01‘0(3-(4—fluorobenzylsulfonyi)benzyl)~2-methyl-ind01—1-y1)-acetic acid; RArmI\|mam0\'cu\NRPonb1\DCC\FMN Ir. l406_l .docx—IJSIURIZO [5 ~78— 2-(3 -(2-(Benzylsuifonyl)benzyI)fluoromethyi-indol- I -yl)-acetic acid; 2~(3-(4-(4—Fluorobenzylsulfonyl)benzyl)~5—fluoro~2~mcthyl—indol—1-yi)—acetic acid; 2—(Cycl0hexylsu1fony1)benzyl)—5-flu0ro—2-methyi—ind01—1—y1)-acetic acid; 2—(5-Flu0romethy1(2-(piperidin—1—ylsulfonyl)benzyI)-indolyl)—acetic acid; 2-(3«(2—(Cyclopentylsulfonyl)benzyl)~5—fluoro-2—methyl—indol- 1 —y1)—acetic acid; 2-(5-F1uoromethy1-3 iperidin-1 -y]sulfonyl)benzyI)-indol-1 -yl)-acetic acid; 2-(5~Fluoro~2~methy1~3~(2—(pyrrolidin-1—ylsu1fonyl)benzy1)~indoly1)—acetic acid; 2-(3-(4-(Cyclohexylsulfony1)benzyl)flu0ro—2—1nethyI-indol-1—yl)—acetic acid; 2—(3~(4—(Cyclopentylsulfonyl)benzyl)fluor0methyl—ind01-1~y1)-acetic acid; 2-(Cyclobutylsuifonyi)benzy1)-S-fluoro-Z-methyl-indoly1)-acetic acid; 2~(5~Fluoro~2~methyl~3-(3—(pyrrolidin—1 -ylsu1fony1)benzy1)-indo1—1-y1)—acetic acid; 2-(5-Fluoromethy1—3-(4-(piperidinylsulfony1)benzyl)-indol- I -yl)-acetic acid; [5-F1uoromethyl-3~(2-phenoxybenzyl)-ind01yl]-acetic acid; [5-F1uoro~2-methy1(2-(4-methoxyphenoxy)benzy1)-indolyl]-acetic acid; [5-F1uoromethyl(2-(4-methylphen0xy)benzy1)-indol—1~yI]-acetic acid; [S—Fluoro-2~methyl—3—(2-(2,4-dichlorophenoxy)benzyi)-ind01- 1 cetic acid; [5-Fluoromethyl(2-(4~flu0rophen0xy)benzyl)~indoi-1~y1]—acetic acid; [5-Fluoromethyl(2-(3,4-diflu0r0phenoxy)bcnzyl)-indolyl]—acetic acid; [5~F1uoro~2~methyl—3—(2—(4—cyanophenoxy)benzyl)-indo1—1—yl]—acetic acid; [5-F1u0romethyl(2-(4-chlor0phenoxy)benzy1)—indolyl]-acetic acid; [5-Fiuoromethyl(2-(2-cyanophenoxy)benzyl)-ind01y1]-acetic acid; (5-Flu0romethyl{[2-(4-mcthylphcnoxy)pyridiny1]methy1}indolyl)- acetic acid; {5 -F1uoro—3 -[(3-methanesuifonylnaphthaien-Z-yl)methyl]methylindoly1}— acetic acid; {5~F1uor0»3-[(1~methanesuIfony1naphtha1en—2-yl)methyl]~2—methylindol—1 —y1}- acetic acid; {5—FIuoro-3—[(6-methanesulfonylnaphthalen—Z-y1)methyl]~2-methylindol— 1 —y1}- acetic acid; [5~F1uoro~2~methyl(quinolinylmethy1)indolyl}-acctic acid; [5-P1u0romethyl(quinoxalin-6—ylmethy1)indolyl]-acetic acid; [5-Fluoro-2—methyl~3-(quinolin-7—ylmethyi)ind01y1]-acetic acid; Harm“!nlcm'ovcanRPanDIDCOFMN161406_ I Amosmwzol 5 {5aFluoro—3—[(6—methanesulf0ny1quinolin—2—yl)methyl]methy1indolyl}-acetic acid; oro[(4-methancsulfonquuinolin—2-y1)methyl]methy1ind01y1} -acetic acid; (5-Fluoromethy1{pyrazolo[1,5-a]pyridiny1methyl}indol-l—y1)—acetic acid; (5 -F1u0r0—3 -{imidazo[1,2-a]pyridin—2-ylmethyl}—2-mcthyiind01—1-y1)-acetic acid; (5 -F1u0romethyI { [2-(methylsu1fanyl)pheny1}methyl} indoiy1)-acetic acid; (5-FluoromethyI—3-{[3—(methylsu1fanyl)pheny1]methy1}indoI—i—y1)-acetic acid; (5-P1uoromethy1{[4-(ethylsulfanyl)pheny1]methyl} indoly1)-acetic acid; (3-{[4-(Ethylsulfanyl)phenyl]methyl}~5~flu0ro~2-methylindol-1~y1)—acctic acid; (5 -F1u0romethyI{[4-(n-propylsulfanyl)phenyi]methy1}indoly1)-acetic acid; (5 -F1u0ro-2~methy1—3~{ propylsu1fany1)phenyl]methyl } indoi— 1 ~y1)—acetic acid; (5-P1u0romethy1{ [4-(t-butylsulfany1)phenyl]methyl}indol~1 ~y1)-acetic acid; (5-Flu0romethyi{[4-(pentan-3~ylsulfany1)phenyl]methy1}ind01y1)-acetic acid; [3 -({4-[(Cyclopropylmethyl)sulfanyl]phenyl}methy1)—5-fluoromethy1indol-1 - y1]~acetic acid; {3-[(4,4-Dimethyl-2,3 -dihydrobenzothi0pyran—6-y1)methyl]flu01'0 methylindoly1 } -acetic acid; (3-{ [2-(Ethanesulfonyl)pheny1]methyl}flu01‘0methy1ind01y1)-acetic acid; (5-P1u0romcthyl{[Tl-(propanesu1fonyl)pheny1]methyl}indoly1)-acetic add; (S—Fluoro-Z-methyl—3—{[2-(propane—2—su1fonyl)phenyl]methyl}ind01-1~yl)-acetic acid; (3—{[2—(Butane—1—su1fonyl)phenyl]methy1}-5—fluoro-2—methy1ind01yl)-acetic acid; (3-{[2-(Butanesulfonyl)pheny1]methy1}fluoro-2—methy1indolyI)-acetic acid; oro-2—mcthyl—3-{ [2-(2-methyipropane—2~sulfony1)phenyl}methyl}ind01-1 -y1)- acetic acid; (5-Fluoromethy1{[2-(pentanesulf0ny1)pheny1]rnethyl}indol-i-y1)-acetic acid; H:\fun\lIllcmo\':II\NRPonhl\DCC\FMT\816 l1()(y_l .docs-USIOSIZUIS (3-{[2-(CyCIOprOpylmethane)sulfonylphenyl]methyl}flu01‘omethyiindol~1- yl)-acetic acid; (5-Plu0ro-2—methy1—3- { [2-(propylsu1famoyi)phenyl]methyl}indol— 1 ~yl)~acetic acid; (3—{[2-(Butylsulfamoyl)phenyl]methyl}fluor0methy1ind01y1)-acetic acid; (5-Fiu0ro-2—methyl—3-{[3—(pr0pylsu1famoyl)pheny1]methyl}indol-1~y1)~acetic acid; (3-{[3-(Butyisulfamoyl)phenyl]methyl}flu0ro-2—methy1indoly1)-acetic acid; (S-Fiuoro~2~methyl~3 ~{ [4~(trifluoromethane)sulfonyiphenyl]methyl} indol- l -y1)- acetic acid; (3-{ [4-(Ethanesulfonyl)phenyl]methyl}flu0romethylindolyl)-acetic acid; (5—F1uoromethyl { [4—(propane- 1 —sulfonyl)phenyl]methyl} indol~1 ~y1)~acetic acid; (5—Piuoromethyl-3~ { [4-(propanesulfonyl)phenyl]methyl} indol— 1 -yI)—acctic acid; (3-{[4-(Butanesulf0ny1)phenyl]methyl}~5-flu0ro—2-methy1ind01—1—yl)-acetic acid; (5-F1uoromethyl { [4-(2-methylpr0panesulfony1)phenyl]methyl} indol-l -y1)- acetic acid; 0romethy1{[4-(pentane-I -su1fony1)pheny1]methyl}indoi-1 -y1)-acetic acid; oromethy1-3— { [4-(pentan—3 fonyl)phenyl]methyl} indoly1)-acetic acid; [3-({4-[(Cyclopropylmethyl)sulfony1]phenyl}methy1)~5~flu0ro~2~methyiind01 yl]-acetic acid; 0ro-2—methyl { [4~(propylsulfamoyl)phenyl]methyi} indolyi)-acetic acid; (3- { [4-(Butylsulfamoyl)phenyl]methyl } flu0r0mcthylindolyl)-acetic acid; (5-Fluoro-2~methy1—3-{[4-(trifluoromethoxy)phenyl]methyl}ind01—1—yl)-acetic acid; (5 —Fluoro{ [4-methanesulfonyl(trifluoromethyl)phenyl]methyl} indol-1~yl)—acetic acid; (5 ~F1uoro—3-{ [4~methanesulfonyi—3~(trifluoromethoxy)phenyl]methyl} methylindolyi)-acetic acid; {5-Fiuoro[(5-methanesulfonylthiopheny1)methyl]methylindol—1myI}—acetic H:\fml\lnlcnm\-cn\NRParlthCOFth lfil-‘UGJ .docx—USNKI'JU l S acid; {3—[(4,4-dimethy1-1 ,1—dioxo—2,3—dihydro~1 ké-benzothiopyrany1)methy1] 2—methy1indol—1—y1}—acetic acid; [3-({ 1-[(4-Chlorobenzene)sulfonyl]pyrr0ly1}methyl)flu01‘0methy1indoi- 1y1]—acetic acid; [5-Fluoro—3 -( { I-[(4-flu0robenzene)sulfony1]pyrro1y1}methy1)methylindol—1 — y1]-acetic acid; [5-F1u0r0( { 1 -[(4-methoxybenzene)sulfony1]pyrroIy1}methy1)-2~methylindol- acetic acid; {3-[1-(2,4-Dichloro-benzenesulfonyl)pyrrol—2-ylmethy1]~5~fluor0—2-methyl—indol- 1-yI}-acetic acid; [5-F1u0r0({1-[(4-methanesulfonylbenzene)sulfonyi]pyrr01~2~y1}methyl) methylindoly1]-acetic acid; {5—F1uoro-2—methy1-3—[(2~phenylphenyl)methy1]indoi- 1-y1}-acetic acid; (3-{ [1-(Benzenesulfonyl)indoly1]methyl}fluoromethy1indol- 1 ~y1)-acetic acid; (3-{[2-(4-Ch10ropheny1)phenyl]methyl}fluoro—2-methylindol—1-y1)—acetic acid; (5-Fluoromethy1{[2u(4~methy1pheny1)pheny1]methyl}indoly1)—acetic acid; {5-P1u0r0mcthy1 [(3-phenoxypheny1)methyl]indol-1 cctic acid; [5-F1uor0({4-[(4-fluorophenyi)carbonyl]~1~methy1pyrrol—2—yl}methyl) methylindol— 1 -y1]-acetic acid; {5~F1u0r0~2~methy1[(6— { [3-(trifluoromethyl)pheny1]methy1}pyridin yl)methy1]indoly1}-acetic acid; {5-F1u0r0methyl[(3-phenoxythiophen—2-yl)1nethy1]indol—l uyl } -acetic acid; (3-{ [2-(Benzenesu1f0ny1)—1 ,3—thiazol—5-yl]methy1}flu0romethylindol-1 -y1)- acetic acid; ~Benzylpyrazo1—4—yl)methyl]flu0rcmethy1indoly1}—acetic acid; (3-{[5-(4-Chlorophenoxy)-1—methyl(trifluoromethyl)pyrazoly1]methy1} fluoro—2-mcthylindol- l -y1)-acetic acid; [3-({5-[(4-Chlorobenzene)sulf0nyl]furan-Z—yl}methy1)flu0romethy1indol- 1- yl]~acetic acid; [3 -({5-[(4—Ch10robenzene)sulfonyl]thiophen—Z—yl }1nethy1)-5~fluoro—2~methy1ind01— HMml\lmcmovcn\NRPonbl\DCC\Fl\fl‘\8 t6t406_l .doexvufilufllzuls l—yl]—acetic acid; [3-({3—[(4—Chlorobenzene)sulfonyl]thiophen—2~yl}methyl)-5nfluoro-Z-methylindol- 1-yl]-acetic acid; {3-[(2—Benzylphenyl)methyl]—5-fluoro-2—methylindol— i -yl} -acetic acid; or a ceutically acceptable salt thereof; or the C1—C6 alkyl, aryl, (CH2)mOC(=O)C1~C6alkyl, mO)nCH2CH2X, (CH2)mN(R7)2, or CH((CH2)mO(C=O)R8)2 esters of any of the above; wherein m is l or 2; n is 1-4; X is OR7 or N(R7)2; R7 is hydrogen or methyl; and R8 is cl-clg alkyl.
7. The pharmaceutical composition according to claim 6, wherein the CRTH2 antagonist is (5—Flu0ro—2-methylquinolin-2—ylmethyl-indolyl)-acetic acid or a pharmaceutically acceptable salt thereof.
8. The ceutical composition ing to claim 6, wherein the CRTH2 antagonist is (3-{ [2-(Benzenesulfonyl)pyridin-3 -yl]methyl } —5—fluoro—2wmethylindol~ l -yl)~ acetic acid; [S-Fluoro({2-[(4-fluorobenzene)sulfonyl]pyridinyl}methyl) methylindol-l -yl]-acetic acid or a pharmaceutically acceptable salt thereof.
9. The pharmaceutical composition according to any one of claims 1 to 8, further comprising at least one corticosteroid or at least one L-3 antibody.
10. The pharmaceutical composition according to claim 9, wherein the corticosteroid is selected from the group consisting of sone, budesonide, hydrocortisone, dexamethasone, methylprednisolone, and prednisolone.
11. The pharmaceutical composition according to any one of claims 1 to 10, fiirther comprising montelukast. H;\l'nu\lnlcmu\'cn\NRPonbl\DCC\f-'Mml(ul—lll(i_l .docsflfi/lmflfl IS
12. Use of a CRTH2 antagonist or a pharmaceutically acceptable salt thereof as defined according to any one of claims 1 to 8 and a proton pump inhibitor selected from the group consisting of omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole in the manufacture of a medicament for the prevention, treatment or amelioration of eosinOphilic es0phagitis (EOE).
13. The use according to any claim 12, wherein: (a) the CRTH2 antagonist is (5-fluoromethylquinolinylmethyI-indol-l-yl)- acetic acid or a pharmaceutically able salt thereof and the PM is selected from the group consisting of omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole, or a pharmaceutically acceptable salt thereof; or (b) the CRTH2 antagonist is [5-fluoro-3~(4-methanesulfonyl-benzyl)methyl-indol- 1~yl]~acetic acid or a pharmaceutically acceptable salt thereof and the PPI is selected from the group consisting of omeprazole, razole, lansoprazole, dexlansoprazole, pantoprazole, and azole, or a pharmaceutically acceptable salt thereof; or (c) the CRTH2 nist is (3-{[2-(benzenesulfonyl)pyridinyl]methyl}fluoro methylindol-l-yl)—acetic acid or a ceutically acceptable salt thereof and the PPI is selected from the group consisting of omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole, or a pharmaceutically acceptable salt thereof; or (d) the CRTH2 antagonist is [5-fluoro({2-[(4-fluorobenzene)sulfonyl]pyridin—3— yl}methyl)—2—methylindol-l-yl]-acetic acid or a ceuticaliy acceptable salt f and the PM is selected from the group consisting of omeprazole, esomeprazole, lansoprazole, soprazole, pantoprazole, and rabeprazole, or a pharmaceutically acceptable salt thereof; or (e) the CRTH2 antagonist is 5-(acetylamino)-3—[(4—chlorophenyl)thio]methyl-ll—l- -l-acetic acid or a pharmaceutically acceptable salt thereof and the PPl is selected from the group consisting of zole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole, or a pharmaceutically acceptable salt thereof. H,\I'ml\Iulcnxnvcnu's'RPorlbIDCOEHN161406_l.doc.\-()5ltlB/20l5
14. Use of a pharmaceutical composition according to any one of claims 1 to 11 in the manufacture of a medicament for the maintenance therapy of eosinophilic esophagitis, wherein the maintenance therapy comprises: (a) firstly administering to an individual in need of such treatment a therapeutically effect amount of a corticosteroid for a first ermined period of time; (b) subsequently administering to the individual a eutically ive amount of at least one CRTHZ nist or a ceutically acceptable salt thereof and at least one proton pump inhibitor or a pharmaceutically acceptable salt thereof for a second predetermined period oftime.
15. The use according to claim 14, wherein the corticosteroid is budesonide.
16. The use according to claims 14 or 15, wherein the corticosteroid is administered twice daily.
17. The use according to any one of claims 14 to 16, wherein step (b) further comprises administering a corticosteroid at a lower dosage than the dosage administered in step (a).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161576640P | 2011-12-16 | 2011-12-16 | |
| US61/576640 | 2011-12-16 | ||
| PCT/GB2012/000904 WO2013088109A1 (en) | 2011-12-16 | 2012-12-14 | Combination of crth2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ626990A NZ626990A (en) | 2016-01-29 |
| NZ626990B2 true NZ626990B2 (en) | 2016-05-03 |
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