ES2612921T3 - Compuestos de difluorolactama como agonistas selectivos del receptor EP4 para su uso en el tratamiento de enfermedades y afecciones mediadas por EP4 - Google Patents
Compuestos de difluorolactama como agonistas selectivos del receptor EP4 para su uso en el tratamiento de enfermedades y afecciones mediadas por EP4 Download PDFInfo
- Publication number
- ES2612921T3 ES2612921T3 ES13745254.6T ES13745254T ES2612921T3 ES 2612921 T3 ES2612921 T3 ES 2612921T3 ES 13745254 T ES13745254 T ES 13745254T ES 2612921 T3 ES2612921 T3 ES 2612921T3
- Authority
- ES
- Spain
- Prior art keywords
- difluoro
- oxopyrrolidin
- hydroxy
- methyl
- acid
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 101150109738 Ptger4 gene Proteins 0.000 title description 3
- 239000000556 agonist Substances 0.000 title 1
- 201000010099 disease Diseases 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
- 230000001404 mediated effect Effects 0.000 title 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 40
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 26
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 24
- 125000001424 substituent group Chemical group 0.000 claims abstract description 21
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 17
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 150000002367 halogens Chemical class 0.000 claims abstract description 17
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims abstract description 16
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims abstract description 15
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims abstract description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 12
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 11
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 11
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 10
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 125000000262 haloalkenyl group Chemical group 0.000 claims abstract description 9
- 125000000232 haloalkynyl group Chemical group 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims abstract description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000002253 acid Substances 0.000 claims description 93
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 60
- -1 Methyl -2-oxopyrrolidin-1-yl Chemical group 0.000 claims description 58
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 47
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 28
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 21
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 claims description 10
- XVPQOGVPPKRCMT-ILWGZMRPSA-N 7-[(5S)-3,3-difluoro-5-[(3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl]-2-oxopyrrolidin-1-yl]heptanoic acid Chemical compound FC1(C(N([C@H](C1)CC[C@H]([C@H](CCCC1=CC=CC=C1)C)O)CCCCCCC(=O)O)=O)F XVPQOGVPPKRCMT-ILWGZMRPSA-N 0.000 claims description 3
- BOSZLMKYWQIUDI-ILWGZMRPSA-N (5R)-3,3-difluoro-5-[(E,3S,4S)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-1-[6-(2H-tetrazol-5-yl)hexyl]pyrrolidin-2-one Chemical compound N1N=NN=C1CCCCCCN1C(C(C[C@@H]1C=C[C@H]([C@H](CCCC1=CC=CC=C1)C)O)(F)F)=O BOSZLMKYWQIUDI-ILWGZMRPSA-N 0.000 claims description 2
- YOBJRWXZRXMBCX-IEIRFRATSA-N (5S)-3,3-difluoro-5-[(3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl]-1-(3-thiophen-2-ylpropyl)pyrrolidin-2-one Chemical compound FC1(C(N([C@H](C1)CC[C@H]([C@H](CCCC1=CC=CC=C1)C)O)CCCC1=CC=CS1)=O)F YOBJRWXZRXMBCX-IEIRFRATSA-N 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- OXKRRZXGZOSSPZ-KSNOWIBYSA-N 3-[3-[(5s)-3,3-difluoro-5-[(3r,4s)-3-hydroxy-4-methyl-7-phenylheptyl]-2-oxopyrrolidin-1-yl]propyl]benzoic acid Chemical compound C([C@H](C)[C@H](O)CC[C@@H]1N(C(=O)C(F)(F)C1)CCCC=1C=C(C=CC=1)C(O)=O)CCC1=CC=CC=C1 OXKRRZXGZOSSPZ-KSNOWIBYSA-N 0.000 claims description 2
- DHNVMJZDEAWNHF-SESVDKBCSA-N 4-[2-[(5R)-3,3-difluoro-5-[(E,3S,4S)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-2-oxopyrrolidin-1-yl]ethylsulfanyl]butanoic acid Chemical compound FC1(C(N([C@H](C1)C=C[C@H]([C@H](CCCC1=CC=CC=C1)C)O)CCSCCCC(=O)O)=O)F DHNVMJZDEAWNHF-SESVDKBCSA-N 0.000 claims description 2
- KXTCMPLDVQOPDJ-WDJPJFJCSA-N 4-[2-[(5S)-3,3-difluoro-5-[(3R,4S)-3-hydroxy-4-methyl-7-phenylheptyl]-2-oxopyrrolidin-1-yl]ethyl]benzoic acid Chemical compound FC1(C(N([C@H](C1)CC[C@H]([C@H](CCCC1=CC=CC=C1)C)O)CCC1=CC=C(C(=O)O)C=C1)=O)F KXTCMPLDVQOPDJ-WDJPJFJCSA-N 0.000 claims description 2
- AHEUJCDCESUVAG-OEMFJLHTSA-N 7-[(5R)-3,3-difluoro-5-[(E,3S,4S)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-2-oxopyrrolidin-1-yl]-N-ethylheptanamide Chemical compound FC1(C(N([C@H](C1)C=C[C@H]([C@H](CCCC1=CC=CC=C1)C)O)CCCCCCC(=O)NCC)=O)F AHEUJCDCESUVAG-OEMFJLHTSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 2
- OXPQAWOAILZRKL-UHFFFAOYSA-N n-methylsulfonylheptanamide Chemical compound CCCCCCC(=O)NS(C)(=O)=O OXPQAWOAILZRKL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 29
- 125000002947 alkylene group Chemical group 0.000 abstract description 22
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract description 3
- 208000010392 Bone Fractures Diseases 0.000 abstract 1
- 206010065687 Bone loss Diseases 0.000 abstract 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
- 208000001132 Osteoporosis Diseases 0.000 abstract 1
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 230000037182 bone density Effects 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 239000011737 fluorine Substances 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 5
- 125000001624 naphthyl group Chemical group 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 4
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 4
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 4
- 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 3
- FAHUKNBUIVOJJR-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine Chemical compound C1=CC(F)=CC=C1C1C2=CC=CN2CCN1 FAHUKNBUIVOJJR-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229940095102 methyl benzoate Drugs 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000006194 pentinyl group Chemical group 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
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- UMYZHWLYICNGRQ-UHFFFAOYSA-N ethanol;heptane Chemical compound CCO.CCCCCCC UMYZHWLYICNGRQ-UHFFFAOYSA-N 0.000 description 2
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- YOBJRWXZRXMBCX-UNWVZKJWSA-N (5S)-3,3-difluoro-5-[(3R,4R)-3-hydroxy-4-methyl-7-phenylheptyl]-1-(3-thiophen-2-ylpropyl)pyrrolidin-2-one Chemical compound FC1(C(N([C@H](C1)CC[C@H]([C@@H](CCCC1=CC=CC=C1)C)O)CCCC1=CC=CS1)=O)F YOBJRWXZRXMBCX-UNWVZKJWSA-N 0.000 description 1
- USGPVTVMFNHRRB-JCTONOIOSA-N (5S)-3,3-difluoro-5-[(3R,4R)-3-hydroxy-4-methyl-8-phenyloctyl]-1-(3-thiophen-2-ylpropyl)pyrrolidin-2-one Chemical compound FC1(C(N([C@H](C1)CC[C@H]([C@@H](CCCCC1=CC=CC=C1)C)O)CCCC1=CC=CS1)=O)F USGPVTVMFNHRRB-JCTONOIOSA-N 0.000 description 1
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- HJIYDLVHEWPMPN-UMXIMWEHSA-N (5S)-3,3-difluoro-5-[(3R,4S)-3-hydroxy-4-methyl-9-phenylnonyl]-1-(3-thiophen-2-ylpropyl)pyrrolidin-2-one Chemical compound FC1(C(N([C@H](C1)CC[C@H]([C@H](CCCCCC1=CC=CC=C1)C)O)CCCC1=CC=CS1)=O)F HJIYDLVHEWPMPN-UMXIMWEHSA-N 0.000 description 1
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- 125000005882 oxadiazolinyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000005304 thiadiazolidinyl group Chemical group 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
Classifications
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| US201361793929P | 2013-03-15 | ||
| PCT/US2013/051261 WO2014015246A1 (en) | 2012-07-19 | 2013-07-19 | Difluorolactam compositions for ep4-mediated osteo related diseases and conditions |
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| ES16192448T Active ES2728159T3 (es) | 2012-07-19 | 2013-07-19 | Composiciones de difluorolactama para enfermedades y afecciones relacionadas con la osteoporosis mediadas por EP4 |
| ES13745744.6T Active ES2610428T3 (es) | 2012-07-19 | 2013-07-19 | Compuestos de difluorolactama como agonistas selectivos del receptor EP4 para su uso en el tratamiento de enfermedades y afecciones mediadas por EP4 |
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| ES13745744.6T Active ES2610428T3 (es) | 2012-07-19 | 2013-07-19 | Compuestos de difluorolactama como agonistas selectivos del receptor EP4 para su uso en el tratamiento de enfermedades y afecciones mediadas por EP4 |
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| 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 |
| EP2989098B1 (en) | 2013-03-15 | 2017-05-10 | Cayman Chemical Company, Incorporated | Lactam compounds as ep4 receptor-selective agonists for use in the treatment of ep4-mediated diseases and conditions |
| 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 |
| EP2970234B1 (en) * | 2013-03-15 | 2018-07-18 | Cayman Chemical Company, Inc. | Methods of synthesizing a difluorolactam analog |
| CN105392505A (zh) | 2013-07-19 | 2016-03-09 | 开曼化学股份有限公司 | 用于促进骨生长的方法、系统和组合物 |
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