ES2268327T3 - Uso de un selectivo de un receptor de ep4 para el tratamiento de enfermedades. - Google Patents
Uso de un selectivo de un receptor de ep4 para el tratamiento de enfermedades. Download PDFInfo
- Publication number
- ES2268327T3 ES2268327T3 ES03704902T ES03704902T ES2268327T3 ES 2268327 T3 ES2268327 T3 ES 2268327T3 ES 03704902 T ES03704902 T ES 03704902T ES 03704902 T ES03704902 T ES 03704902T ES 2268327 T3 ES2268327 T3 ES 2268327T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- acid
- compound
- oxopyrrolidin
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000011282 treatment Methods 0.000 title claims description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 13
- 201000010099 disease Diseases 0.000 title description 5
- 229910052757 nitrogen Chemical group 0.000 claims abstract description 98
- 101150109738 Ptger4 gene Proteins 0.000 claims abstract description 81
- 239000000203 mixture Substances 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 41
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 28
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 20
- 229940044601 receptor agonist Drugs 0.000 claims abstract description 15
- 239000000018 receptor agonist Substances 0.000 claims abstract description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000011593 sulfur Chemical group 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 6
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 442
- 150000001875 compounds Chemical class 0.000 claims description 413
- -1 3-trifluoromethylphenyl Chemical group 0.000 claims description 272
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 151
- 239000000460 chlorine Substances 0.000 claims description 132
- 239000000556 agonist Substances 0.000 claims description 58
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 33
- 206010020772 Hypertension Diseases 0.000 claims description 25
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 20
- 159000000000 sodium salts Chemical class 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 208000010412 Glaucoma Diseases 0.000 claims description 17
- 230000035699 permeability Effects 0.000 claims description 17
- 206010030043 Ocular hypertension Diseases 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 8
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 7
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 2
- 230000002440 hepatic effect Effects 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 453
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 390
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 219
- 238000000034 method Methods 0.000 description 218
- 235000019439 ethyl acetate Nutrition 0.000 description 194
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 165
- 150000004702 methyl esters Chemical class 0.000 description 157
- 238000005160 1H NMR spectroscopy Methods 0.000 description 148
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 126
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 125
- 239000000243 solution Substances 0.000 description 121
- 238000004587 chromatography analysis Methods 0.000 description 113
- 238000000746 purification Methods 0.000 description 105
- 239000002609 medium Substances 0.000 description 102
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 150000002148 esters Chemical class 0.000 description 76
- 238000002360 preparation method Methods 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
- 125000004494 ethyl ester group Chemical group 0.000 description 57
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 55
- 235000002639 sodium chloride Nutrition 0.000 description 55
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 54
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 47
- 238000006243 chemical reaction Methods 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 39
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- 238000012360 testing method Methods 0.000 description 29
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 26
- 241000700159 Rattus Species 0.000 description 26
- 239000007864 aqueous solution Substances 0.000 description 26
- 239000007810 chemical reaction solvent Substances 0.000 description 26
- 238000010992 reflux Methods 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 229910000104 sodium hydride Inorganic materials 0.000 description 25
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- 239000012279 sodium borohydride Substances 0.000 description 23
- 229910000033 sodium borohydride Inorganic materials 0.000 description 23
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 21
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 18
- 206010019663 Hepatic failure Diseases 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 208000007903 liver failure Diseases 0.000 description 17
- 231100000835 liver failure Toxicity 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 150000001450 anions Chemical class 0.000 description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 15
- 150000001298 alcohols Chemical class 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 101001117519 Homo sapiens Prostaglandin E2 receptor EP2 subtype Proteins 0.000 description 14
- 102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- 239000003039 volatile agent Substances 0.000 description 14
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 13
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 13
- 101001073427 Homo sapiens Prostaglandin E2 receptor EP1 subtype Proteins 0.000 description 13
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- 238000001727 in vivo Methods 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- XBKLEUFUAMDOBT-SECBINFHSA-N 5-[3-[(2R)-2-formyl-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C(=O)[C@@H]1N(C(CC1)=O)CCCC1=CC=C(S1)C(=O)O XBKLEUFUAMDOBT-SECBINFHSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
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- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
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- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 11
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 11
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 11
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 10
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- 239000002168 alkylating agent Substances 0.000 description 10
- 229940100198 alkylating agent Drugs 0.000 description 10
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 239000003085 diluting agent Substances 0.000 description 10
- 229910052763 palladium Inorganic materials 0.000 description 10
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 10
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
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- 238000005481 NMR spectroscopy Methods 0.000 description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- 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
- A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- 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
- A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| US36571102P | 2002-03-18 | 2002-03-18 | |
| US365711P | 2002-03-18 |
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| ES2268327T3 true ES2268327T3 (es) | 2007-03-16 |
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| EP (1) | EP1487437B1 (enExample) |
| JP (1) | JP2005531516A (enExample) |
| AT (1) | ATE336247T1 (enExample) |
| AU (1) | AU2003207900A1 (enExample) |
| BR (1) | BR0308738A (enExample) |
| CA (1) | CA2478653A1 (enExample) |
| DE (1) | DE60307607T2 (enExample) |
| ES (1) | ES2268327T3 (enExample) |
| MX (1) | MXPA04005555A (enExample) |
| TW (1) | TW200304816A (enExample) |
| WO (1) | WO2003077910A1 (enExample) |
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| MXPA01008955A (es) | 1999-03-05 | 2002-04-24 | Procter & Gamble | Analogos de prostaglandinas selectivas de fp no saturadas de c16. |
| US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
| US20020172693A1 (en) | 2000-03-31 | 2002-11-21 | Delong Michell Anthony | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
| US6573294B1 (en) * | 2002-05-14 | 2003-06-03 | Allergan, Inc. | 8-azaprostaglandin analogs as agents for lowering intraocular pressure |
| AU2011202937B2 (en) * | 2002-05-14 | 2012-06-07 | Allergan, Inc. | 8-azaprostaglandin analogs as agents for lowering intraocular pressure |
| GB0219143D0 (en) * | 2002-08-16 | 2002-09-25 | Univ Leicester | Modified tailed oligonucleotides |
| EP1586564B1 (en) * | 2003-01-21 | 2012-11-28 | Ono Pharmaceutical Co., Ltd. | 8-azaprostaglandin derivatives and medicinal uses thereof |
| US6734206B1 (en) * | 2003-06-02 | 2004-05-11 | Allergan, Inc. | 3-oxa-8-azaprostaglandin analogs as agents for lowering intraocular pressure |
| US8415364B2 (en) | 2003-11-26 | 2013-04-09 | Duke University | Method of preventing or treating glaucoma |
| ATE493973T1 (de) | 2004-06-04 | 2011-01-15 | Teva Pharma | Irbesartan enthaltende pharmazeutische zusammensetzung |
| CA2569464C (en) * | 2004-06-04 | 2012-10-23 | Allergan, Inc. | 5-thio-piperdinyl prostaglandin e analogs |
| AU2005299473B2 (en) * | 2004-10-26 | 2012-06-28 | Allergan, Inc. | Therapeutic and delivery methods of prostaglandin EP4 agonists |
| CA2586752A1 (en) | 2004-11-08 | 2006-05-18 | Allergan, Inc. | Substituted pyrrolidone compounds as ep4 agonists |
| WO2006121822A1 (en) * | 2005-05-06 | 2006-11-16 | Allergan, Inc. | USE OF β-LACTAMS FOR THE TREATMENTOF IBD AND GLAUCOMA |
| US7674786B2 (en) | 2005-05-06 | 2010-03-09 | Allergan, Inc. | Therapeutic β-lactams |
| JP5254007B2 (ja) * | 2005-05-06 | 2013-08-07 | アラーガン インコーポレイテッド | 置換β−ラクタム及び医薬におけるその使用 |
| US7893107B2 (en) | 2005-11-30 | 2011-02-22 | Allergan, Inc. | Therapeutic methods using prostaglandin EP4 agonist components |
| UY30121A1 (es) | 2006-02-03 | 2007-08-31 | Glaxo Group Ltd | Nuevos compuestos |
| US20070232660A1 (en) * | 2006-04-04 | 2007-10-04 | Allergan, Inc. | Therapeutic and delivery methods of prostaglandin ep4 agonists |
| EP2269611B1 (en) | 2006-11-16 | 2016-03-23 | Gemmus Pharma Inc. | EP2 and EP4 agonists as agents for the treatment of influenza A viral infection |
| WO2008071736A1 (en) | 2006-12-15 | 2008-06-19 | Glaxo Group Limited | Benzamide derivatives as ep4 receptor agonists |
| GB0721611D0 (en) | 2007-11-02 | 2007-12-12 | Glaxo Group Ltd | Novel compounds |
| US8063033B2 (en) * | 2008-01-18 | 2011-11-22 | Allergan, Inc. | Therapeutic beta-lactams |
| US8202855B2 (en) | 2008-03-04 | 2012-06-19 | Allergan, Inc | Substituted beta-lactams |
| EP2149554A1 (de) | 2008-07-30 | 2010-02-03 | Bayer Schering Pharma Aktiengesellschaft | Indolylamide als Modulatoren des EP2-Rezeptors |
| EP2149551A1 (de) | 2008-07-30 | 2010-02-03 | Bayer Schering Pharma AG | N-(Indol-3-ylalkyl)-(hetero)arylamidderivate als Modulatoren des EP2-Rezeptors |
| EP2149552A1 (de) | 2008-07-30 | 2010-02-03 | Bayer Schering Pharma AG | 5,6 substituierte Benzamid-Derivate als Modulatoren des EP2-Rezeptors |
| US20110293549A1 (en) | 2009-02-03 | 2011-12-01 | Athena Cosmetics, Inc. | Composition, method and kit for enhancing hair |
| WO2010116270A1 (en) | 2009-04-10 | 2010-10-14 | Pfizer Inc. | Ep2/4 agonists |
| AR091429A1 (es) | 2012-06-29 | 2015-02-04 | Lilly Co Eli | Compuestos de fenoxietil piperidina |
| CN107802623B (zh) | 2012-07-19 | 2020-10-30 | 开曼化学股份有限公司 | 用于ep4介导的骨相关疾病和病症的二氟内酰胺组合物 |
| ES2635635T3 (es) | 2013-03-15 | 2017-10-04 | Cayman Chemical Company, Incorporated | Compuestos de difluorolactama como agonistas selectivos del receptor EP4 para su uso en el tratamiento de enfermedades y afecciones mediadas por EP4 |
| US9914725B2 (en) | 2013-03-15 | 2018-03-13 | Cayman Chemical Company, Inc. | Methods of synthesizing a difluorolactam analog |
| WO2014144610A1 (en) | 2013-03-15 | 2014-09-18 | Cayman Chemical Company, Inc. | Lactam compounds as ep4 receptor-selective agonists for use in the treatment of ep4-mediated diseases and conditions |
| EP3021879A2 (en) | 2013-07-19 | 2016-05-25 | Cayman Chemical Company, Incorporated | Methods, systems, and compositions for promoting bone growth |
| AU2014366361B2 (en) | 2013-12-17 | 2017-04-20 | Eli Lilly And Company | Phenoxyethyl cyclic amine derivatives and their activity as EP4 receptor modulators |
| US9540357B1 (en) * | 2014-07-31 | 2017-01-10 | Allergan, Inc. | 15-aryl prostaglandins as EP4 agonists, and methods of use thereof |
| CN114259992B (zh) * | 2021-12-23 | 2023-06-27 | 复旦大学 | 正离子超分子有机框架固体材料在吸附生物毒素中的应用 |
| GB202211232D0 (en) | 2022-08-02 | 2022-09-14 | Heptares Therapeutics Ltd | Prostaglandin EP4 receptor agonist compounds |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4113873A (en) * | 1975-04-26 | 1978-09-12 | Tanabe Seiyaku Co. Ltd. | 8-azaprostanoic acid derivatives |
| DE2528664A1 (de) * | 1975-06-27 | 1977-01-13 | Hoechst Ag | Pyrrolidone und verfahren zu ihrer herstellung |
| US4177346A (en) * | 1976-08-06 | 1979-12-04 | Pfizer Inc. | 1,5-Disubstituted-2-pyrrolidones |
| SE423813B (sv) * | 1976-08-06 | 1982-06-07 | Pfizer | Forfarande for framstellning av 1,5-disubstituerade pyrrolidoner med terapeutiska egenskaper |
| WO2000038667A2 (en) * | 1998-12-24 | 2000-07-06 | Alcon Laboratories, Inc. | Prostaglandin e agonists for treatment of glaucoma |
| AU2001290250A1 (en) * | 2000-09-21 | 2002-04-02 | Ono Pharmaceutical Co. Ltd. | Ep4 receptor agonists containing 8-azaprostaglandin derivatives as the active ingredient |
| OA12533A (en) * | 2000-11-27 | 2006-06-05 | Pfizer Prod Inc | Ep4 receptor selective agonists in the treatment of osteoporosis. |
| US20040254230A1 (en) * | 2001-12-03 | 2004-12-16 | Ogidigben Miller J. | Method for treating ocular hypertension |
-
2003
- 2003-03-06 BR BR0308738A patent/BR0308738A/pt not_active IP Right Cessation
- 2003-03-06 ES ES03704902T patent/ES2268327T3/es not_active Expired - Lifetime
- 2003-03-06 WO PCT/IB2003/000844 patent/WO2003077910A1/en not_active Ceased
- 2003-03-06 EP EP03704902A patent/EP1487437B1/en not_active Expired - Lifetime
- 2003-03-06 AU AU2003207900A patent/AU2003207900A1/en not_active Abandoned
- 2003-03-06 CA CA002478653A patent/CA2478653A1/en not_active Abandoned
- 2003-03-06 MX MXPA04005555A patent/MXPA04005555A/es unknown
- 2003-03-06 DE DE60307607T patent/DE60307607T2/de not_active Expired - Fee Related
- 2003-03-06 JP JP2003575963A patent/JP2005531516A/ja not_active Withdrawn
- 2003-03-06 AT AT03704902T patent/ATE336247T1/de not_active IP Right Cessation
- 2003-03-11 US US10/386,307 patent/US7414071B2/en not_active Expired - Fee Related
- 2003-03-17 TW TW092105829A patent/TW200304816A/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE60307607D1 (de) | 2006-09-28 |
| WO2003077910A1 (en) | 2003-09-25 |
| DE60307607T2 (de) | 2007-08-09 |
| BR0308738A (enExample) | 2005-01-11 |
| US20030207925A1 (en) | 2003-11-06 |
| EP1487437B1 (en) | 2006-08-16 |
| ATE336247T1 (de) | 2006-09-15 |
| AU2003207900A1 (en) | 2003-09-29 |
| TW200304816A (en) | 2003-10-16 |
| EP1487437A1 (en) | 2004-12-22 |
| US7414071B2 (en) | 2008-08-19 |
| JP2005531516A (ja) | 2005-10-20 |
| CA2478653A1 (en) | 2003-09-25 |
| MXPA04005555A (es) | 2005-05-16 |
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