WO2005077373A2 - Treatment of gastro-esophageal reflux disease (gerd) - Google Patents
Treatment of gastro-esophageal reflux disease (gerd) Download PDFInfo
- Publication number
- WO2005077373A2 WO2005077373A2 PCT/US2005/000335 US2005000335W WO2005077373A2 WO 2005077373 A2 WO2005077373 A2 WO 2005077373A2 US 2005000335 W US2005000335 W US 2005000335W WO 2005077373 A2 WO2005077373 A2 WO 2005077373A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- piperazine
- carboxylic acid
- ethyl ester
- acid ethyl
- Prior art date
Links
- 208000021302 gastroesophageal reflux disease Diseases 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 210000000111 lower esophageal sphincter Anatomy 0.000 claims abstract description 20
- 230000005764 inhibitory process Effects 0.000 claims abstract description 11
- 230000001052 transient effect Effects 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 34
- 229910052717 sulfur Inorganic materials 0.000 claims description 34
- 125000004429 atom Chemical group 0.000 claims description 31
- 230000002265 prevention Effects 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 20
- 230000003287 optical effect Effects 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 14
- -1 C0-3alkyl Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 208000006673 asthma Diseases 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 206010067171 Regurgitation Diseases 0.000 claims description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 208000019693 Lung disease Diseases 0.000 claims description 5
- 206010016165 failure to thrive Diseases 0.000 claims description 5
- 201000008197 Laryngitis Diseases 0.000 claims description 4
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 3
- QJRYHAKNFSAEOU-CYBMUJFWSA-N ethyl (3r)-4-[[5-(3-chlorophenyl)-1,2-oxazol-3-yl]methyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(Cl)C=CC=2)=C1 QJRYHAKNFSAEOU-CYBMUJFWSA-N 0.000 claims description 3
- CJJMZZQGSJKNJH-AWEZNQCLSA-N ethyl 4-[(1s)-1-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1[C@@H](C)C1=NOC(C=2C=C(C)C=CC=2)=N1 CJJMZZQGSJKNJH-AWEZNQCLSA-N 0.000 claims description 3
- QFQMLVLMUNAWJF-UHFFFAOYSA-N ethyl 4-[(5-thiophen-3-yl-1,2-oxazol-3-yl)methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C2=CSC=C2)=C1 QFQMLVLMUNAWJF-UHFFFAOYSA-N 0.000 claims description 3
- WYSWFJQHNVTKIX-UHFFFAOYSA-N ethyl 4-[[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(C)C=2)F)=C1 WYSWFJQHNVTKIX-UHFFFAOYSA-N 0.000 claims description 3
- MSZXEGISWRVEJL-UHFFFAOYSA-N ethyl 4-[[5-(3-chlorophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(Cl)C=CC=2)=C1 MSZXEGISWRVEJL-UHFFFAOYSA-N 0.000 claims description 3
- WCOPPSVBQXBIFX-UHFFFAOYSA-N ethyl 4-[[5-(3-chlorophenyl)-1,3-oxazol-2-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NC=C(C=2C=C(Cl)C=CC=2)O1 WCOPPSVBQXBIFX-UHFFFAOYSA-N 0.000 claims description 3
- MKHBQSTYABOSJJ-UHFFFAOYSA-N ethyl 4-[[5-(3-cyanophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C=CC=2)C#N)=C1 MKHBQSTYABOSJJ-UHFFFAOYSA-N 0.000 claims description 3
- YJRQONRACZKXAR-UHFFFAOYSA-N ethyl 4-[[5-(3-formylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C=O)C=CC=2)=C1 YJRQONRACZKXAR-UHFFFAOYSA-N 0.000 claims description 3
- HVHGZCLMBPGBGL-UHFFFAOYSA-N ethyl 4-[[5-(3-methoxyphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(OC)C=CC=2)=C1 HVHGZCLMBPGBGL-UHFFFAOYSA-N 0.000 claims description 3
- YLURYVCWGQYISZ-UHFFFAOYSA-N ethyl 4-[[5-(3-methylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C)C=CC=2)=C1 YLURYVCWGQYISZ-UHFFFAOYSA-N 0.000 claims description 3
- NIZQRVXFJWKOGJ-UHFFFAOYSA-N ethyl 4-[[5-(5-chloro-2-fluorophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(Cl)C=2)F)=C1 NIZQRVXFJWKOGJ-UHFFFAOYSA-N 0.000 claims description 3
- AJRYAYKEPOOUBW-UHFFFAOYSA-N ethyl 4-[[5-(5-cyano-2-fluorophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(C=2)C#N)F)=C1 AJRYAYKEPOOUBW-UHFFFAOYSA-N 0.000 claims description 3
- BZKHJSXSSOTBDW-UHFFFAOYSA-N ethyl 4-[cyano-[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C#N)C1=NOC(C=2C(=CC=C(C)C=2)F)=C1 BZKHJSXSSOTBDW-UHFFFAOYSA-N 0.000 claims description 3
- ORTUJEIVHBSTKT-UHFFFAOYSA-N ethyl 4-[cyclopropyl-[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C1=NOC(=C1)C=1C(=CC=C(C)C=1)F)C1CC1 ORTUJEIVHBSTKT-UHFFFAOYSA-N 0.000 claims description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- BRRUUPUPNMUJFF-MLCCFXAWSA-N ethyl (3s)-4-[1-[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]ethyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C(=CC=C(C)C=2)F)=C1 BRRUUPUPNMUJFF-MLCCFXAWSA-N 0.000 claims description 2
- WPXNPSWRGMOKAT-UEWDXFNNSA-N ethyl (3s)-4-[1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C=C(Cl)C=CC=2)=N1 WPXNPSWRGMOKAT-UEWDXFNNSA-N 0.000 claims description 2
- WHCYACFFGSYKAE-UHFFFAOYSA-N ethyl 4-[1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C=C(Cl)C=CC=2)=N1 WHCYACFFGSYKAE-UHFFFAOYSA-N 0.000 claims description 2
- LINCJASNHHSKBX-UHFFFAOYSA-N n-ethyl-n-methyl-4-[1-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl]piperazine-1-carboxamide Chemical compound C1CN(C(=O)N(C)CC)CCN1C(C)C1=NOC(C=2C=C(C)C=CC=2)=N1 LINCJASNHHSKBX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 14
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 12
- WPXNPSWRGMOKAT-PZORYLMUSA-N ethyl (3r)-4-[1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C=C(Cl)C=CC=2)=N1 WPXNPSWRGMOKAT-PZORYLMUSA-N 0.000 claims 3
- DJYGESKMYWBXKH-LSLKUGRBSA-N ethyl (2s)-4-[1-[5-(3-chlorophenyl)-1,2-oxazol-3-yl]ethyl]-2-methylpiperazine-1-carboxylate Chemical compound C1[C@H](C)N(C(=O)OCC)CCN1C(C)C1=NOC(C=2C=C(Cl)C=CC=2)=C1 DJYGESKMYWBXKH-LSLKUGRBSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- PKACWWXDUYKBBS-WPZCJLIBSA-N ethyl (2s)-2-[1-[5-(2-fluoro-5-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNC[C@@H]1C(C)C1=NOC(C=2C(=CC=C(C)C=2)F)=N1 PKACWWXDUYKBBS-WPZCJLIBSA-N 0.000 claims 1
- BRRUUPUPNMUJFF-GICMACPYSA-N ethyl (3r)-4-[1-[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]ethyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C(=CC=C(C)C=2)F)=C1 BRRUUPUPNMUJFF-GICMACPYSA-N 0.000 claims 1
- KIPKEJJKDSVXJN-CQSZACIVSA-N ethyl (3r)-4-[[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]methyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(C)C=2)F)=C1 KIPKEJJKDSVXJN-CQSZACIVSA-N 0.000 claims 1
- GMEYEVZHGHWAFT-LSLKUGRBSA-N ethyl (3s)-4-[1-[5-(3-chlorophenyl)-1,2-oxazol-3-yl]ethyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C=C(Cl)C=CC=2)=C1 GMEYEVZHGHWAFT-LSLKUGRBSA-N 0.000 claims 1
- QJRYHAKNFSAEOU-ZDUSSCGKSA-N ethyl (3s)-4-[[5-(3-chlorophenyl)-1,2-oxazol-3-yl]methyl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(Cl)C=CC=2)=C1 QJRYHAKNFSAEOU-ZDUSSCGKSA-N 0.000 claims 1
- WHCYACFFGSYKAE-LBPRGKRZSA-N ethyl 4-[(1s)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1[C@@H](C)C1=NOC(C=2C=C(Cl)C=CC=2)=N1 WHCYACFFGSYKAE-LBPRGKRZSA-N 0.000 claims 1
- GYSVRLVQQRALNR-NSHDSACASA-N ethyl 4-[(1s)-1-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1[C@@H](C)C1=NOC(C=2C(=CC=C(Cl)C=2)F)=N1 GYSVRLVQQRALNR-NSHDSACASA-N 0.000 claims 1
- XJGMYSIYTZWUDO-UHFFFAOYSA-N ethyl 4-[1-[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C(=CC=C(C)C=2)F)=C1 XJGMYSIYTZWUDO-UHFFFAOYSA-N 0.000 claims 1
- SMZPBNLUWAIFBI-UHFFFAOYSA-N ethyl 4-[1-[5-(2-fluoro-5-methylphenyl)-1,3,4-oxadiazol-2-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NN=C(C=2C(=CC=C(C)C=2)F)O1 SMZPBNLUWAIFBI-UHFFFAOYSA-N 0.000 claims 1
- RULBZEBXILBXCM-UHFFFAOYSA-N ethyl 4-[1-[5-(2-methylpyridin-4-yl)-1,2-oxazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C=C(C)N=CC=2)=C1 RULBZEBXILBXCM-UHFFFAOYSA-N 0.000 claims 1
- CQVOHVHGPUIFHE-UHFFFAOYSA-N ethyl 4-[1-[5-(5-chloro-2-fluorophenyl)-1,2-oxazol-3-yl]-2,2,2-trifluoroethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C(F)(F)F)C1=NOC(C=2C(=CC=C(Cl)C=2)F)=C1 CQVOHVHGPUIFHE-UHFFFAOYSA-N 0.000 claims 1
- MMIADJITOXJGCY-UHFFFAOYSA-N ethyl 4-[[5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(F)C=CC=2)=N1 MMIADJITOXJGCY-UHFFFAOYSA-N 0.000 claims 1
- MKVHQMLKKPKZSY-UHFFFAOYSA-N ethyl 4-[[5-(3-iodophenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(I)C=CC=2)=N1 MKVHQMLKKPKZSY-UHFFFAOYSA-N 0.000 claims 1
- OQPZORCLOFGBNW-UHFFFAOYSA-N ethyl 4-[[5-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(OC(F)(F)F)C=CC=2)=N1 OQPZORCLOFGBNW-UHFFFAOYSA-N 0.000 claims 1
- JKXAELKZIVJBAK-UHFFFAOYSA-N ethyl 4-[[5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C=CC=2)C(F)(F)F)=N1 JKXAELKZIVJBAK-UHFFFAOYSA-N 0.000 claims 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 description 9
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- 125000000168 pyrrolyl group Chemical group 0.000 description 4
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- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- 125000004928 piperidonyl group Chemical group 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-M 3,4-dihydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1O YQUVCSBJEUQKSH-UHFFFAOYSA-M 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- 229940086681 4-aminobenzoate Drugs 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- QZSLJGWQMVXKEF-UHFFFAOYSA-N ethyl 4-[1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(CC)C1=NOC(C=2C=C(Cl)C=CC=2)=N1 QZSLJGWQMVXKEF-UHFFFAOYSA-N 0.000 description 1
- OEWXQDIIHFAANU-UHFFFAOYSA-N ethyl 4-[1-[5-(5-chloro-2-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NN=C(C=2C(=CC=C(Cl)C=2)F)O1 OEWXQDIIHFAANU-UHFFFAOYSA-N 0.000 description 1
- RHEXYHNUYASTJR-UHFFFAOYSA-N ethyl 4-[1-[5-(5-cyano-2-fluorophenyl)-1,2-oxazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C(=CC=C(C=2)C#N)F)=C1 RHEXYHNUYASTJR-UHFFFAOYSA-N 0.000 description 1
- UXAAZZXKUXQJAM-UHFFFAOYSA-N ethyl 4-[[5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(Cl)C=2)Cl)=N1 UXAAZZXKUXQJAM-UHFFFAOYSA-N 0.000 description 1
- YLMZLRDYBCNQOB-UHFFFAOYSA-N ethyl 4-[[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]-2-oxopiperazine-1-carboxylate Chemical compound C1C(=O)N(C(=O)OCC)CCN1CC1=NOC(C=2C=C(Cl)C=CC=2)=N1 YLMZLRDYBCNQOB-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- XLYFXQIHPNLPCB-UHFFFAOYSA-N methyl 4-[[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC)CCN1CC1=NOC(C=2C=C(C)C=CC=2)=N1 XLYFXQIHPNLPCB-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 208000016752 upper digestive tract disease Diseases 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
Definitions
- the present invention relates to the use of certain compounds for the inhibition of transient lower esophageal sphincter relaxations.
- a further aspect of the invention is directed to the use of certain compounds for the treatment of gastro-esophageal reflux disease.
- the lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
- Gastro-esophageal reflux disease is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
- TLESRs transient lower esophageal sphincter relaxations
- the object of the present invention was to find a new way for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), thereby preventing reflux. More particularly the object of the invention was to find a new way of treating gastro-esophageal reflux disease (GERD), as well as a new way for the treatment of regurgitation.
- GGERD gastro-esophageal reflux disease
- the present invention is directed to the use of compounds of formula I
- P is selected from the group consisting of C 3 . 7 alkyl and a 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, wherein said ring may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S;
- R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, O . 6 alkylhalo, C ⁇ -6 alkyl, OC] -6 alkyl, C 2-6 alkenyl, OC -6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0- 6 alkylC 3 .
- X , X and X are independently selected from the group consisting of CR, CO, N, NR, O and S;
- R is selected from the group consisting of hydrogen, Co- 3 alkyl, halo, C 0 . 3 alkylOR 5 , C 0- 3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 , C 0-3 alkylNR 5 R 6 and C 0-3 alkylaryl;
- M 2 is selected from the group consisting of a bond, C ⁇ -3 alkyl, C 2-3 alkenyl, C 2 - 3 alkynyl, C 0-
- X 4 is selected from C, CR or N;
- X 5 is selected from C, CR or N;
- Q is a 4- to 8-membered ring or bicycle containing one or more atoms independently selected from C, N, O or S, wherein said ring or bicycle may be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S and wherein the fused ring may be substituted by one or more A;
- R 4 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C ⁇ -6 alkylhalo, C ⁇ .
- R 5 is selected from the group consisting of hydrogen, hydroxy, halo, oxo, OCj.
- A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, C ⁇ -6 alkylhalo, OC ⁇ -6 alkylhalo, C ⁇ -6 alkyl, C 0-4 alkylC 3-6 cycloalkyl, C 2-6 alkenyl, OC ⁇ -6 alkyl, Co ⁇ alkylaryl, Ci. 6 alkylOR 6 , OC 2-6 alkylOR 6 , C 1-6 alkylSR 6 , OC 2-6 alkylSR 6 , (CO)R 6 , O(CO)R 6 , OC 2-6 alkylcyano, C 0-6 alkylcyano, C 0-6 alkylCO 2 R 6 , OC ⁇ .
- TLESRs transient lower esophageal sphincter relaxations
- alkyl includes both straight and branched chain alkyl groups and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl.
- d- 3 alkyl refers to an alkyl group having 1 to 3 carbon atoms, and may be methyl, ethyl, n-propyl or i-propyl.
- cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
- C 3-7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- alkenyl includes both straight and branched chain alkenyl groups.
- C 2 - 6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl or hexenyl.
- alkynyl includes both straight and branched chain alkynyl groups.
- C 2 - 6 alkynyl refres to a group having 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, i-butynyl, pentynyl, i-pentynyl or hexynyl.
- aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term “aryl” are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl and indenyl.
- heteroaryl refers to an optionally substituted, unsaturated cyclic hydrocarbon ring system comprising at least one heteroatom and includes, but is not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolinyl, tetrahydropyranyl .
- the term "5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S” includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
- Such rings may be, but are not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl or cyclohexenyl.
- 3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
- rings may be, but are not limited to imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl or thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, cyclopent
- the term "3- to 8-membered ring containing one or more atoms independently selected from C, N, O or S, which group may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O or S” includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
- rings may be, but are not limited to naphthyl, norcaryl, chromyl, isochromyl, indanyl, benzoimidazol or tetralinyl, benzooxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzotriazolyl, indolyl, azaindolyl, indazolyl, indolinyl, isoindolinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, quinoxalinyl, benzotriazolyl.
- a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group is absent, i.e. there is a direct bond between the groups.
- bond may be a saturated or unsaturated bond.
- halo may be fluoro, chloro, bromo or iodo.
- alkylhalo means an alkyl group as defined above, which is substituted with one or more halo.
- Ci- ⁇ alkylhalo may include, but is not limited to fiuoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, bromopropyl.
- OC 1-6 alkylhalo may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy.
- the compounds of formula I useful in accordance with the present invention may also be used as pharmaceutically acceptable salts, but also other salts may be useful in accordance with the present invention.
- pharmaceutically acceptable salts useful in accordance with the present invention are, but are not limited to, hydrochloride, 4-aminobenzoate, anthranilate, 4-aminosalicylate, 4- hydroxybenzoate, 3,4-dihydroxybenzoate, 3-hydroxy-2-naphthoate, nitrate and trifluoroacetate.
- Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses the use of all such optical, diastereoisomers and geometric isomers.
- the invention also relates to the use of any and all tautomeric forms of the compounds of formula I.
- a further aspect of the invention is the use of a compound formula I for the manufacture of a medicament for the prevention of reflux.
- Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of gastro-esophageal reflux disease (GERD).
- GFD gastro-esophageal reflux disease
- a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of regurgitation.
- Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of lung disease.
- Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the management of failure to thrive.
- Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of asthma, such as reflux-related asthma.
- Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of chronic laryngitis.
- a further aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders, such as functional dyspepsia (FD).
- FD functional dyspepsia
- Yet another aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
- IBS irritable bowel syndrome
- a further aspect of the present invention is a method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such inhibition.
- TLESRs transient lower esophageal sphincter relaxations
- Another aspect of the invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such prevention.
- Still a further aspect of the invention is a method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- GFD gastro-esophageal reflux disease
- Yet another aspect of the invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Still a further aspect of the invention is a method for the treatment or prevention of asthma, such as reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Yet another aspect of the invention is a method for the treatment of chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Still a further aspect of the invention is a method for the treatment or inhibition of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.
- TLESR transient lower esophageal sphincter relaxations
- GSD gastro-esophageal reflux disease
- van Heerwarden M.A.
- Smout A.J.P.M. 2000
- Diagnosis of reflux disease Bailliere 's Clin. Gastroenterol. 14, pp. 759-774.
- the compounds of formula I are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
- the compounds of formula I are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant.
- the carrier may be in the form of a solid, semi-solid or liquid diluent.
- the compound of formula I to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
- Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
- Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
- Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
- Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
- Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
- the compound of formula I may be administered once or twice daily, depending on the severity of the patient's condition.
- the compounds of formula I can be prepared as described in WO2004/014370 A2.
- a multilumen sleeve/sidehole assembly (Dentsleeve, Sydney, South Australia) is introduced through the esophagostomy to measure gastric, lower esophageal sphincter (LES) and esophageal pressures.
- the assembly is perfused with water using a low-compliance manometric perfusion pump (Dentsleeve, Sydney, South Australia).
- An air-perfused tube is passed in the oral direction to measure swallows, and an antimony electrode monitored pH, 3 cm above the LES. All signals are amplified and acquired on a personal computer at 10 Hz.
- placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein.
- a nutrient meal (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into the stomach through the central lumen of the assembly at 100 ml/min to a final volume of 30 ml/kg.
- air is insufflated at 40 ml/min.
- TLESRs is defined as a decrease in lower esophageal sphincter pressure (with reference to intragastric pressure) at a rate of >1 mmHg/s.
- the relaxation should not be preceded by a pharyngeal signal ⁇ 2s before its onset in which case the relaxation is classified as swallow- induced.
- the pressure difference between the LES and the stomach should be less than 2 mmHg, and the duration of the complete relaxation longer than 1 s.
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Abstract
Description
Claims
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US54105504P | 2004-02-03 | 2004-02-03 | |
US60/541,055 | 2004-02-03 |
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---|---|---|---|---|
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US7202262B2 (en) | 2003-04-11 | 2007-04-10 | Ptc Therapeutics, Inc. | Benzoic acid or benzoate substituted 1,2,4-oxadiazole compounds and their use for the treatment of disease |
US7538114B2 (en) | 2006-06-28 | 2009-05-26 | Amgen Inc. | Glycine transporter-1 inhibitors |
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US8012981B2 (en) | 2006-06-15 | 2011-09-06 | Glaxo Group Limited | Benzylpiperazine derivatives as motilin receptor agonists |
US8048899B2 (en) | 2008-09-25 | 2011-11-01 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US8088771B2 (en) | 2008-07-28 | 2012-01-03 | Gilead Sciences, Inc. | Cycloalkylidene and heterocycloalkylidene inhibitor compounds |
US8124764B2 (en) | 2008-07-14 | 2012-02-28 | Gilead Sciences, Inc. | Fused heterocyclyc inhibitor compounds |
US8134000B2 (en) | 2008-07-14 | 2012-03-13 | Gilead Sciences, Inc. | Imidazolyl pyrimidine inhibitor compounds |
US8178568B2 (en) | 2008-07-10 | 2012-05-15 | Boehringer Ingelheim International Gmbh | Sulfone compounds which modulate the CB2 receptor |
US8212045B2 (en) | 2007-09-21 | 2012-07-03 | Array Biopharma, Inc. | Pyridin-2-yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus |
US8252829B2 (en) | 2009-06-05 | 2012-08-28 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
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US8299103B2 (en) | 2009-06-15 | 2012-10-30 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US8299111B2 (en) | 2006-07-28 | 2012-10-30 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
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US8344018B2 (en) | 2008-07-14 | 2013-01-01 | Gilead Sciences, Inc. | Oxindolyl inhibitor compounds |
US8383615B2 (en) | 2009-06-16 | 2013-02-26 | Boehringer Ingelheim International Gmbh | Azetidine 2-carboxamide derivatives which modulate the CB2 receptor |
US8383651B2 (en) | 2009-09-22 | 2013-02-26 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US8524751B2 (en) | 2009-03-09 | 2013-09-03 | GlaxoSmithKline Intellecutual Property Development | 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases |
US8536169B2 (en) | 2008-06-05 | 2013-09-17 | Glaxo Group Limited | Compounds |
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US8546563B2 (en) | 2007-11-07 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
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US8658635B2 (en) | 2008-06-05 | 2014-02-25 | Glaxosmithkline Intellectual Property Development Limited | Benzpyrazol derivatives as inhibitors of PI3 kinases |
US8716317B2 (en) | 2008-06-09 | 2014-05-06 | Sanofi | Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals |
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US8765743B2 (en) | 2008-06-05 | 2014-07-01 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
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US8865744B1 (en) | 2013-05-17 | 2014-10-21 | Boehringer Ingelheim International Gmbh | (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
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US9289398B2 (en) | 2006-03-30 | 2016-03-22 | Ptc Therapeutics, Inc. | Methods for the production of functional protein from DNA having a nonsense mutation and the treatment of disorders associated therewith |
US9315454B2 (en) | 2010-01-15 | 2016-04-19 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
US9604965B2 (en) | 2010-04-23 | 2017-03-28 | Cytokinetics, Inc. | Substituted pyridazines as skeletal muscle modulators |
US9663529B2 (en) | 2013-07-02 | 2017-05-30 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
US9730886B2 (en) | 2010-04-23 | 2017-08-15 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US9745292B2 (en) | 2014-03-13 | 2017-08-29 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US9771379B2 (en) | 2015-09-24 | 2017-09-26 | Pfizer Inc. | N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides |
US9790219B2 (en) | 2014-03-13 | 2017-10-17 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
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US9994528B2 (en) | 2010-04-23 | 2018-06-12 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
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US10174014B2 (en) | 2014-06-19 | 2019-01-08 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
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US11672799B2 (en) | 2013-07-31 | 2023-06-13 | Novartis Ag | 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions |
US11833150B2 (en) | 2017-03-28 | 2023-12-05 | Gilead Sciences, Inc. | Methods of treating liver disease |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UY30892A1 (en) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | AKT ACTIVITY INHIBITORS |
US8759380B2 (en) | 2011-04-22 | 2014-06-24 | Cytokinetics, Inc. | Certain heterocycles, compositions thereof, and methods for their use |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4476128A (en) * | 1980-03-01 | 1984-10-09 | Mitsuitoatsu Chemicals, Inc. | 2-Substituted thiazolyl-piperazine compounds, process for preparation thereof and utilizations thereof _ |
EP0328200A1 (en) * | 1988-02-12 | 1989-08-16 | Merck Sharp & Dohme Ltd. | Five-membered ring systems with bonded azacyclic ring substituents |
EP0438230A2 (en) * | 1990-01-17 | 1991-07-24 | MERCK SHARP & DOHME LTD. | Indole-substituted five-membered heteroaromatic compounds |
WO1993002677A1 (en) * | 1991-08-03 | 1993-02-18 | Smithkline Beecham Plc | 5-ht4 receptor antagonists |
WO2002010140A2 (en) * | 2000-08-01 | 2002-02-07 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Imidazolyl derivatives |
WO2004014370A2 (en) * | 2002-08-09 | 2004-02-19 | Astrazeneca Ab | Oxadiazoles as modulators of metabotropic glutamate receptor-5 |
-
2005
- 2005-01-07 WO PCT/US2005/000335 patent/WO2005077373A2/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4476128A (en) * | 1980-03-01 | 1984-10-09 | Mitsuitoatsu Chemicals, Inc. | 2-Substituted thiazolyl-piperazine compounds, process for preparation thereof and utilizations thereof _ |
EP0328200A1 (en) * | 1988-02-12 | 1989-08-16 | Merck Sharp & Dohme Ltd. | Five-membered ring systems with bonded azacyclic ring substituents |
EP0438230A2 (en) * | 1990-01-17 | 1991-07-24 | MERCK SHARP & DOHME LTD. | Indole-substituted five-membered heteroaromatic compounds |
WO1993002677A1 (en) * | 1991-08-03 | 1993-02-18 | Smithkline Beecham Plc | 5-ht4 receptor antagonists |
WO2002010140A2 (en) * | 2000-08-01 | 2002-02-07 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Imidazolyl derivatives |
WO2004014370A2 (en) * | 2002-08-09 | 2004-02-19 | Astrazeneca Ab | Oxadiazoles as modulators of metabotropic glutamate receptor-5 |
Cited By (144)
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---|---|---|---|---|
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US8299105B2 (en) | 2003-04-11 | 2012-10-30 | Ptc Therapeutics, Inc. | 1,2,4-oxadiazole benzoic acid compositions and their use in bioassays |
US8486982B2 (en) | 2003-04-11 | 2013-07-16 | Ptc Therapeutics, Inc. | 1,2,4-oxadiazole benzoic acids |
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US10071081B2 (en) | 2003-04-11 | 2018-09-11 | Ptc Therapeutics, Inc. | Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use |
US7772259B2 (en) | 2003-04-11 | 2010-08-10 | Ptc Therapeutics, Inc. | 1,2,4-Oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease |
US9861617B2 (en) | 2003-04-11 | 2018-01-09 | Ptc Therapeutics, Inc. | Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use |
US8129540B2 (en) | 2003-04-11 | 2012-03-06 | Ptc Therapeutics, Inc. | Methods for the synthesis of 1,2,4-oxadiazole benzoic acid compounds |
US8975287B2 (en) | 2003-04-11 | 2015-03-10 | Ptc Therapeutics, Inc. | Methods for using 1,2,4-Oxadiazole benzoic acid compounds |
US9205088B2 (en) | 2003-04-11 | 2015-12-08 | Ptc Therapeutics, Inc. | Compositions of 1,2,4-oxadiazol benzoic acid compounds and methods for their use |
US7202262B2 (en) | 2003-04-11 | 2007-04-10 | Ptc Therapeutics, Inc. | Benzoic acid or benzoate substituted 1,2,4-oxadiazole compounds and their use for the treatment of disease |
US8236953B2 (en) | 2004-12-29 | 2012-08-07 | Glaxo Group Limited | Process for preparing piper azine derivatives |
US8536182B2 (en) | 2005-07-26 | 2013-09-17 | Glaxo Group Limited | Benzylpiperazine derivatives and their medical use |
WO2007021573A1 (en) * | 2005-08-15 | 2007-02-22 | Astrazeneca Ab | Substituted piperazines as metabotropic glutamate receptor antagonists |
WO2007021574A1 (en) * | 2005-08-15 | 2007-02-22 | Astrazeneca Ab | Bicyclic piperazines as metabotropic glutamate receptor antagonists |
US9289398B2 (en) | 2006-03-30 | 2016-03-22 | Ptc Therapeutics, Inc. | Methods for the production of functional protein from DNA having a nonsense mutation and the treatment of disorders associated therewith |
US7678796B2 (en) | 2006-05-05 | 2010-03-16 | Astrazeneca Ab | MGluR5 modulators I |
US8012981B2 (en) | 2006-06-15 | 2011-09-06 | Glaxo Group Limited | Benzylpiperazine derivatives as motilin receptor agonists |
US9663476B2 (en) | 2006-06-28 | 2017-05-30 | Amgen Inc. | Glycine transporter-1 inhibitors |
US8735383B2 (en) | 2006-06-28 | 2014-05-27 | Amgen Inc. | Glycine transporter-1 inhibitors |
US8853218B2 (en) | 2006-06-28 | 2014-10-07 | Glaxo Group Limited | Compounds |
US7538114B2 (en) | 2006-06-28 | 2009-05-26 | Amgen Inc. | Glycine transporter-1 inhibitors |
US8183244B2 (en) | 2006-06-28 | 2012-05-22 | Amgen Inc. | Glycine transporter-1 inhibitors |
US8299111B2 (en) | 2006-07-28 | 2012-10-30 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
US8673948B2 (en) | 2006-09-29 | 2014-03-18 | GlaxoSmithKline, LLC | Chemical compounds |
US7572820B2 (en) | 2006-09-29 | 2009-08-11 | Smithkline Beecham Corporation | Chemical compounds |
US8026262B2 (en) | 2006-09-29 | 2011-09-27 | Glaxosmithkline Llc | Chemical compounds |
US9079890B2 (en) | 2007-09-21 | 2015-07-14 | Array Biopharma Inc. | Intermediates for the preparation of pyridin-2-yl-amino-1,2,4-thiadiazole derivatives |
US8212045B2 (en) | 2007-09-21 | 2012-07-03 | Array Biopharma, Inc. | Pyridin-2-yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus |
US8853409B2 (en) | 2007-09-21 | 2014-10-07 | Array Biopharma Inc. | Pyridin-2yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus |
US8546563B2 (en) | 2007-11-07 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
US8658635B2 (en) | 2008-06-05 | 2014-02-25 | Glaxosmithkline Intellectual Property Development Limited | Benzpyrazol derivatives as inhibitors of PI3 kinases |
US8765743B2 (en) | 2008-06-05 | 2014-07-01 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
US8536169B2 (en) | 2008-06-05 | 2013-09-17 | Glaxo Group Limited | Compounds |
US8716317B2 (en) | 2008-06-09 | 2014-05-06 | Sanofi | Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals |
US8178568B2 (en) | 2008-07-10 | 2012-05-15 | Boehringer Ingelheim International Gmbh | Sulfone compounds which modulate the CB2 receptor |
US8124764B2 (en) | 2008-07-14 | 2012-02-28 | Gilead Sciences, Inc. | Fused heterocyclyc inhibitor compounds |
US8134000B2 (en) | 2008-07-14 | 2012-03-13 | Gilead Sciences, Inc. | Imidazolyl pyrimidine inhibitor compounds |
US8344018B2 (en) | 2008-07-14 | 2013-01-01 | Gilead Sciences, Inc. | Oxindolyl inhibitor compounds |
US8088771B2 (en) | 2008-07-28 | 2012-01-03 | Gilead Sciences, Inc. | Cycloalkylidene and heterocycloalkylidene inhibitor compounds |
US8048899B2 (en) | 2008-09-25 | 2011-11-01 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US8372874B2 (en) | 2008-09-25 | 2013-02-12 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US8362039B2 (en) | 2008-09-25 | 2013-01-29 | Boehringer Ingelheim International Gmbh | Therapeutic uses of compounds which selectively modulate the CB2 receptor |
US8349871B2 (en) | 2008-09-25 | 2013-01-08 | Boehringer Ingelheim International Gmbh | Therapeutic uses of compounds which selectively modulate the CB2 receptor |
WO2010084050A2 (en) | 2009-01-13 | 2010-07-29 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
US8889670B2 (en) | 2009-02-18 | 2014-11-18 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds which modulate the CB2 receptor |
US8524751B2 (en) | 2009-03-09 | 2013-09-03 | GlaxoSmithKline Intellecutual Property Development | 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases |
US8580797B2 (en) | 2009-04-30 | 2013-11-12 | Glaxo Smith Kline Intellectual Property Development Limited | Compounds |
US8575162B2 (en) | 2009-04-30 | 2013-11-05 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
US10946025B2 (en) | 2009-04-30 | 2021-03-16 | Glaxo Group Limited | Compounds |
US10624898B2 (en) | 2009-04-30 | 2020-04-21 | Glaxo Group Limited | Compounds |
US8609657B2 (en) | 2009-04-30 | 2013-12-17 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
US8586590B2 (en) | 2009-04-30 | 2013-11-19 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
US8586583B2 (en) | 2009-04-30 | 2013-11-19 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
US10383879B2 (en) | 2009-04-30 | 2019-08-20 | Glaxo Group Limited | Compounds |
US8252829B2 (en) | 2009-06-05 | 2012-08-28 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
US8258316B2 (en) | 2009-06-08 | 2012-09-04 | Gilead Sciences, Inc. | Alkanoylamino benzamide aniline HDAC inhibitor compounds |
US8283357B2 (en) | 2009-06-08 | 2012-10-09 | Gilead Sciences, Inc. | Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds |
US8299103B2 (en) | 2009-06-15 | 2012-10-30 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US8735430B2 (en) | 2009-06-15 | 2014-05-27 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US8383615B2 (en) | 2009-06-16 | 2013-02-26 | Boehringer Ingelheim International Gmbh | Azetidine 2-carboxamide derivatives which modulate the CB2 receptor |
US8383651B2 (en) | 2009-09-22 | 2013-02-26 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
US9315454B2 (en) | 2010-01-15 | 2016-04-19 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
WO2011092293A2 (en) | 2010-02-01 | 2011-08-04 | Novartis Ag | Cyclohexyl amide derivatives as crf receptor antagonists |
WO2011092290A1 (en) | 2010-02-01 | 2011-08-04 | Novartis Ag | Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists |
WO2011095450A1 (en) | 2010-02-02 | 2011-08-11 | Novartis Ag | Cyclohexyl amide derivatives as crf receptor antagonists |
US8329735B2 (en) | 2010-03-05 | 2012-12-11 | Boehringer Ingelheim International Gmbh | Tetrazole compounds which selectively modulate the CB2 receptor |
US11369565B2 (en) | 2010-04-23 | 2022-06-28 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US9994528B2 (en) | 2010-04-23 | 2018-06-12 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
US10272030B2 (en) | 2010-04-23 | 2019-04-30 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US9730886B2 (en) | 2010-04-23 | 2017-08-15 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US10076519B2 (en) | 2010-04-23 | 2018-09-18 | Cytokinetics, Inc. | Substituted pyridazines as skeletal muscle modulators |
US10765624B2 (en) | 2010-04-23 | 2020-09-08 | Cytokinetics, Inc. | Amino-pyrimidine skeletal muscle modulators |
US9604965B2 (en) | 2010-04-23 | 2017-03-28 | Cytokinetics, Inc. | Substituted pyridazines as skeletal muscle modulators |
US8846936B2 (en) | 2010-07-22 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Sulfonyl compounds which modulate the CB2 receptor |
US8993576B2 (en) | 2010-10-27 | 2015-03-31 | Glaxo Group Limited | 6-(1H-indol-4-yl)-4-(5-{[4-1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole hemi succinate salt, polymorphs and pharmaceutical compositions thereof |
US10220027B2 (en) | 2011-07-13 | 2019-03-05 | Gilead Sciences, Inc. | FXR (NR1H4) binding and activity modulating compounds |
US10485795B2 (en) | 2011-07-13 | 2019-11-26 | Gilead Sciences, Inc. | FXR (NR1H4) binding and activity modulating compounds |
US10758533B2 (en) | 2012-08-13 | 2020-09-01 | Novartis Ag | 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions |
US10195196B2 (en) | 2012-08-13 | 2019-02-05 | Novartis Ag | 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions |
US8729263B2 (en) | 2012-08-13 | 2014-05-20 | Novartis Ag | 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions |
US9545404B2 (en) | 2012-08-13 | 2017-01-17 | Novartis Ag | 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions |
US11229648B2 (en) | 2012-08-13 | 2022-01-25 | Novartis Ag | 1,4-disubstituted pyridazine analogs thereof and methods for treating SMN-deficiency-related conditions |
US9040712B2 (en) | 2013-01-23 | 2015-05-26 | Novartis Ag | Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions |
US11053195B2 (en) | 2013-03-15 | 2021-07-06 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9650370B2 (en) | 2013-05-17 | 2017-05-16 | Centrexion Therapeutics Corporation | (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
US11725004B2 (en) | 2013-05-17 | 2023-08-15 | Centrexion Therapeutics Corporation | (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
US10570125B2 (en) | 2013-05-17 | 2020-02-25 | Centrexion Therapeutics Corporation | (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
US10112934B2 (en) | 2013-05-17 | 2018-10-30 | Centrexion Therapeutics Corporation | (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
US11084810B2 (en) | 2013-05-17 | 2021-08-10 | Centrexion Therapeutics Corporation | (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
US8865744B1 (en) | 2013-05-17 | 2014-10-21 | Boehringer Ingelheim International Gmbh | (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
US9914740B2 (en) | 2013-07-02 | 2018-03-13 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
US9663529B2 (en) | 2013-07-02 | 2017-05-30 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
US11672799B2 (en) | 2013-07-31 | 2023-06-13 | Novartis Ag | 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions |
US10450269B1 (en) | 2013-11-18 | 2019-10-22 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US11786524B2 (en) | 2014-02-10 | 2023-10-17 | Sentinel Oncology Limited | Pharmaceutical compounds |
US10973817B2 (en) | 2014-02-10 | 2021-04-13 | Sentinel Oncology Limited | Pharmaceutical compounds |
US10618877B2 (en) | 2014-03-06 | 2020-04-14 | Ptc Therapeutics, Inc. | Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid |
US10233161B2 (en) | 2014-03-06 | 2019-03-19 | Ptc Therapeutics, Inc. | Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid |
US9873677B2 (en) | 2014-03-06 | 2018-01-23 | Ptc Therapeutics, Inc. | Pharmaceutical compositions and salts of a 1,2,4-oxadiazole benzoic acid |
US9745292B2 (en) | 2014-03-13 | 2017-08-29 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US9790219B2 (en) | 2014-03-13 | 2017-10-17 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US10017503B2 (en) | 2014-03-13 | 2018-07-10 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US10738040B2 (en) | 2014-06-19 | 2020-08-11 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US10174014B2 (en) | 2014-06-19 | 2019-01-08 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US10752616B2 (en) | 2014-12-17 | 2020-08-25 | King's College London | Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists |
US9994559B2 (en) | 2014-12-17 | 2018-06-12 | King's College London | Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists |
US11401265B2 (en) | 2014-12-17 | 2022-08-02 | King's College London | Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists |
US10385044B2 (en) | 2014-12-17 | 2019-08-20 | King's College London | Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists |
US10738011B2 (en) | 2014-12-23 | 2020-08-11 | Proteostasis Therapeutics, Inc. | Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis |
US11098035B2 (en) | 2014-12-23 | 2021-08-24 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US10392378B2 (en) | 2014-12-23 | 2019-08-27 | Proteostasis Therapeutics, Inc. | Derivatives of 5-phenyl- or 5-heteroarylathiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis |
US10392372B2 (en) | 2014-12-23 | 2019-08-27 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US10344023B2 (en) | 2014-12-23 | 2019-07-09 | Proteostasis Therapeutics, Inc. | Derivatives of 3-heteroarylisoxazol-5-carboxylic amide useful for the treatment of inter alia cystic fibrosis |
US11083709B2 (en) | 2015-07-24 | 2021-08-10 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods of increasing CFTR activity |
US10548878B2 (en) | 2015-07-24 | 2020-02-04 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods of increasing CFTR activity |
US9771379B2 (en) | 2015-09-24 | 2017-09-26 | Pfizer Inc. | N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides |
US10550106B2 (en) | 2015-10-06 | 2020-02-04 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for modulating CFTR |
US11136313B2 (en) | 2015-10-06 | 2021-10-05 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for modulating CFTR |
US10517853B2 (en) | 2015-10-30 | 2019-12-31 | Ptc Therapeutics, Inc. | Methods for treating epilepsy |
US11248010B2 (en) | 2016-04-07 | 2022-02-15 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for modulating CFTR |
US10662207B2 (en) | 2016-04-07 | 2020-05-26 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for modulating CFTR |
US11247986B2 (en) | 2016-06-13 | 2022-02-15 | Gilead Sciences, Inc. | FXR (NR1H4) modulating compounds |
US10774054B2 (en) | 2016-06-13 | 2020-09-15 | Gilead Sciences, Inc. | FXR (NR1H4) modulating compounds |
US10329286B2 (en) | 2016-06-13 | 2019-06-25 | Gilead Sciences, Inc. | FXR (NR1H4) modulating compounds |
US11739065B2 (en) | 2016-06-13 | 2023-08-29 | Gilead Sciences, Inc. | FXR (NR1H4) modulating compounds |
US10981881B2 (en) | 2016-06-13 | 2021-04-20 | Gilead Sciences, Inc. | FXR (NR1H4) modulating compounds |
US10421730B2 (en) | 2016-06-13 | 2019-09-24 | Gilead Sciences, Inc. | FXR (NR1H4) modulating compounds |
US10899751B2 (en) | 2016-06-21 | 2021-01-26 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing CFTR activity |
US11584741B2 (en) | 2016-06-22 | 2023-02-21 | King's College London | Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation |
US10870644B2 (en) | 2016-06-22 | 2020-12-22 | King's College London | Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-l,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation |
US11833150B2 (en) | 2017-03-28 | 2023-12-05 | Gilead Sciences, Inc. | Methods of treating liver disease |
US11247987B2 (en) | 2017-10-06 | 2022-02-15 | Forma Therapeutics, Inc. | Inhibiting ubiquitin specific peptidase 30 |
US11535618B2 (en) | 2018-10-05 | 2022-12-27 | Forma Therapeutics, Inc. | Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors |
US11814386B2 (en) | 2018-10-05 | 2023-11-14 | Forma Therapeutics, Inc. | Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors |
US11225473B2 (en) | 2019-01-15 | 2022-01-18 | Gilead Sciences, Inc. | FXR (NR1H4) modulating compounds |
US11718603B2 (en) | 2019-01-31 | 2023-08-08 | Pfizer Inc. | CDK2 inhibitors |
US11773082B2 (en) | 2019-01-31 | 2023-10-03 | Pfizer Inc. | CDK2 inhibitors |
US11014911B2 (en) | 2019-01-31 | 2021-05-25 | Pfizer Inc. | CDK2 inhibitors |
US11524005B2 (en) | 2019-02-19 | 2022-12-13 | Gilead Sciences, Inc. | Solid forms of FXR agonists |
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