ES2337887T3 - Derivados de pirrolidina en calidad de moduladores de prostaglandina. - Google Patents
Derivados de pirrolidina en calidad de moduladores de prostaglandina. Download PDFInfo
- Publication number
- ES2337887T3 ES2337887T3 ES02793091T ES02793091T ES2337887T3 ES 2337887 T3 ES2337887 T3 ES 2337887T3 ES 02793091 T ES02793091 T ES 02793091T ES 02793091 T ES02793091 T ES 02793091T ES 2337887 T3 ES2337887 T3 ES 2337887T3
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- Prior art keywords
- optionally substituted
- alkyl
- acid
- solution
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims abstract description 67
- -1 amino amino Chemical group 0.000 claims abstract description 331
- 150000001875 compounds Chemical class 0.000 claims abstract description 240
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 113
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 37
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 37
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 32
- 150000002367 halogens Chemical class 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 31
- 125000003118 aryl group Chemical group 0.000 claims abstract description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 23
- 125000004429 atom Chemical group 0.000 claims abstract description 21
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 19
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 17
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 15
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 13
- 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 13
- 125000001424 substituent group Chemical group 0.000 claims abstract description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 11
- 125000003375 sulfoxide group Chemical group 0.000 claims abstract description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 10
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 9
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 103
- 239000000203 mixture Substances 0.000 claims description 97
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 238000011282 treatment Methods 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 34
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 25
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 230000036512 infertility Effects 0.000 claims description 15
- 231100000535 infertility Toxicity 0.000 claims description 15
- 208000021267 infertility disease Diseases 0.000 claims description 14
- 208000006673 asthma Diseases 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 13
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 12
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 12
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 11
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 11
- 210000000988 bone and bone Anatomy 0.000 claims description 10
- 230000001066 destructive effect Effects 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 208000027004 Eosinophilic disease Diseases 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 208000002296 eclampsia Diseases 0.000 claims description 9
- 201000011461 pre-eclampsia Diseases 0.000 claims description 9
- 230000023555 blood coagulation Effects 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- DJHHWYCXDBZACW-UHFFFAOYSA-N 5-[[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]methoxymethyl]furan-2-carboxylic acid Chemical compound CCCCCC(O)CCN1CCC(Cl)C1COCC1=CC=C(C(O)=O)O1 DJHHWYCXDBZACW-UHFFFAOYSA-N 0.000 claims description 6
- 208000005107 Premature Birth Diseases 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 208000020084 Bone disease Diseases 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- RNAWKKRPMPVZDS-QNGMFEMESA-N 4-[2-[3-chloro-1-[(4r)-4-hydroxynonyl]pyrrolidin-2-yl]ethyl]benzoic acid Chemical compound CCCCC[C@@H](O)CCCN1CCC(Cl)C1CCC1=CC=C(C(O)=O)C=C1 RNAWKKRPMPVZDS-QNGMFEMESA-N 0.000 claims description 3
- 150000003857 carboxamides Chemical class 0.000 claims description 3
- 230000035606 childbirth Effects 0.000 claims description 3
- 230000015271 coagulation Effects 0.000 claims description 3
- 238000005345 coagulation Methods 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 230000002028 premature Effects 0.000 claims description 3
- ARUOZFXJYVGMEZ-UHFFFAOYSA-N 4-[2-[1-[4-(1-butylcyclobutyl)-4-hydroxybutyl]-3-chloropyrrolidin-2-yl]ethyl]benzoic acid Chemical compound C1CC(Cl)C(CCC=2C=CC(=CC=2)C(O)=O)N1CCCC(O)C1(CCCC)CCC1 ARUOZFXJYVGMEZ-UHFFFAOYSA-N 0.000 claims description 2
- JGHWPUQGDCHPGD-UHFFFAOYSA-N 7-[1-[4-[1-(cyclopropylmethyl)cyclobutyl]-4-hydroxybutyl]-3-oxopyrrolidin-2-yl]heptanoic acid Chemical compound C1CCC1(CC1CC1)C(O)CCCN1CCC(=O)C1CCCCCCC(O)=O JGHWPUQGDCHPGD-UHFFFAOYSA-N 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 1
- UVMCLYANNMGMGM-QRWMCTBCSA-N methyl 7-[(2r)-1-(3-hydroxyoctyl)-3-oxopyrrolidin-2-yl]hept-5-enoate Chemical compound CCCCCC(O)CCN1CCC(=O)[C@H]1CC=CCCCC(=O)OC UVMCLYANNMGMGM-QRWMCTBCSA-N 0.000 claims 1
- 230000001568 sexual effect Effects 0.000 claims 1
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 abstract description 2
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 abstract 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 description 373
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 369
- 239000000243 solution Substances 0.000 description 279
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 263
- 235000019439 ethyl acetate Nutrition 0.000 description 183
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 171
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 119
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 239000012267 brine Substances 0.000 description 67
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 67
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 238000005481 NMR spectroscopy Methods 0.000 description 60
- 239000012230 colorless oil Substances 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- 238000000034 method Methods 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- 229910052938 sodium sulfate Inorganic materials 0.000 description 37
- 235000011152 sodium sulphate Nutrition 0.000 description 37
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 36
- 150000003235 pyrrolidines Chemical class 0.000 description 35
- 238000000746 purification Methods 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 32
- 230000002829 reductive effect Effects 0.000 description 32
- 239000012047 saturated solution Substances 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 25
- FFCZQVKVWGGQFB-UHFFFAOYSA-N 9h-pyrido[3,4-b]indole-1,4-dione Chemical compound N1C2=CC=CC=C2C2=C1C(=O)N=CC2=O FFCZQVKVWGGQFB-UHFFFAOYSA-N 0.000 description 24
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 20
- 150000003180 prostaglandins Chemical class 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 17
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 16
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 14
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 150000004702 methyl esters Chemical class 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 11
- 102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 description 10
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- KPSZWAJWFMFMFF-UHFFFAOYSA-N hept-5-enoic acid Chemical compound CC=CCCCC(O)=O KPSZWAJWFMFMFF-UHFFFAOYSA-N 0.000 description 10
- 238000004007 reversed phase HPLC Methods 0.000 description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- 241000124008 Mammalia Species 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- KLTVSWGXIAYTHO-UHFFFAOYSA-N 1-Octen-3-one Chemical compound CCCCCC(=O)C=C KLTVSWGXIAYTHO-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 208000000509 infertility Diseases 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 8
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 208000037765 diseases and disorders Diseases 0.000 description 7
- 230000004720 fertilization Effects 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- 206010036595 Premature delivery Diseases 0.000 description 6
- 102100024450 Prostaglandin E2 receptor EP4 subtype Human genes 0.000 description 6
- 101150109738 Ptger4 gene Proteins 0.000 description 6
- 238000007239 Wittig reaction Methods 0.000 description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000002837 carbocyclic group Chemical group 0.000 description 5
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 5
- 229960002986 dinoprostone Drugs 0.000 description 5
- 125000002883 imidazolyl group Chemical group 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000001624 naphthyl group Chemical group 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 238000006859 Swern oxidation reaction Methods 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
Landscapes
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- Endocrinology (AREA)
- Pregnancy & Childbirth (AREA)
- Physical Education & Sports Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US34262001P | 2001-12-20 | 2001-12-20 | |
| US342620P | 2001-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2337887T3 true ES2337887T3 (es) | 2010-04-30 |
Family
ID=23342570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES02793091T Expired - Lifetime ES2337887T3 (es) | 2001-12-20 | 2002-12-19 | Derivados de pirrolidina en calidad de moduladores de prostaglandina. |
Country Status (10)
| Country | Link |
|---|---|
| US (3) | US7335680B2 (https=) |
| EP (1) | EP1458679B1 (https=) |
| JP (1) | JP4554931B2 (https=) |
| AT (1) | ATE455758T1 (https=) |
| AU (2) | AU2002358772B2 (https=) |
| CA (1) | CA2469075C (https=) |
| DE (1) | DE60235198D1 (https=) |
| ES (1) | ES2337887T3 (https=) |
| IL (2) | IL162602A0 (https=) |
| WO (1) | WO2003053923A2 (https=) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60235198D1 (de) * | 2001-12-20 | 2010-03-11 | Merck Serono Sa Coinsins | Pyrrolidin-derivatie als prostaglandin-modulatoren |
| ES2584606T3 (es) | 2002-10-10 | 2016-09-28 | Ono Pharmaceutical Co., Ltd. | Microesferas que comprenden ONO-1301 |
| KR100843244B1 (ko) | 2007-04-19 | 2008-07-02 | 삼성전자주식회사 | 반도체 소자 및 그 제조 방법 |
| WO2006052893A2 (en) | 2004-11-08 | 2006-05-18 | Allergan, Inc. | Substituted pyrrolidone compounds as ep4 agonists |
| US7893107B2 (en) | 2005-11-30 | 2011-02-22 | Allergan, Inc. | Therapeutic methods using prostaglandin EP4 agonist components |
| US7557095B2 (en) * | 2006-05-12 | 2009-07-07 | Allergan, Inc. | Therapeutic compounds |
| US7550448B2 (en) * | 2006-05-24 | 2009-06-23 | Allergan, Inc. | Therapeutic compounds |
| EP2147672A4 (en) | 2007-05-08 | 2011-11-02 | Nat University Corp Hamamatsu University School Of Medicine | CYTOTOXIC T CELL ACTIVATOR WITH AN EP4 AGONIST |
| SI2155733T1 (sl) * | 2007-05-23 | 2012-12-31 | Allergan, Inc | Ciklični laktami za zdravljenje glavkoma ali zvišanega očesnega tlaka |
| US7964596B2 (en) * | 2008-03-07 | 2011-06-21 | Allergan, Inc. | Therapeutic compounds |
| EP2149551A1 (de) | 2008-07-30 | 2010-02-03 | Bayer Schering Pharma AG | N-(Indol-3-ylalkyl)-(hetero)arylamidderivate als Modulatoren des EP2-Rezeptors |
| EP2149554A1 (de) | 2008-07-30 | 2010-02-03 | Bayer Schering Pharma Aktiengesellschaft | Indolylamide 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 |
| GEP20125607B (en) * | 2008-11-10 | 2012-08-10 | Pfizer Ltd | Pyrrolidines |
| JPWO2010087425A1 (ja) | 2009-01-30 | 2012-08-02 | 国立大学法人京都大学 | 前立腺癌の進行抑制剤および進行抑制方法 |
| TW201326154A (zh) | 2011-11-28 | 2013-07-01 | 拜耳知識產權公司 | 作為ｅｐ２受體拮抗劑之新穎２ｈ－吲唑 |
| ES2733998T3 (es) | 2012-10-29 | 2019-12-03 | Cardio Incorporated | Agente terapéutico específico de enfermedad pulmonar |
| US9968716B2 (en) | 2013-10-15 | 2018-05-15 | Ono Pharmaceutical Co., Ltd. | Drug-eluting stent graft |
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| US3873566A (en) * | 1973-02-28 | 1975-03-25 | Du Pont | 3-Pyrazolidinones and pyrazolidines |
| DE2451160A1 (de) * | 1973-10-30 | 1975-05-07 | Du Pont | 3-pyrazolidinone und pyrazolidine |
| US3976660A (en) * | 1974-08-15 | 1976-08-24 | E. R. Squibb & Sons, Inc. | Pyrrolidine derivatives |
| DE2527989A1 (de) | 1975-06-24 | 1977-01-27 | Hoechst Ag | Pyrrolidone und verfahren zu ihrer herstellung |
| US4033989A (en) | 1975-09-17 | 1977-07-05 | The Upjohn Company | 9-Deoxy-PGF2 Analogs |
| US4003911A (en) * | 1975-09-26 | 1977-01-18 | E. I. Du Pont De Nemours And Company | Selected 3-pyrrolidinones and 2,4-pyrrolidindiones |
| US4090019A (en) | 1976-05-10 | 1978-05-16 | Minnesota Mining And Manufacturing Company | Geminal prostaglandin analogs |
| US4211876A (en) * | 1979-06-13 | 1980-07-08 | E. I. Du Pont De Nemours And Company | 3-Pyrazolidinone carboxamides |
| US4753945A (en) | 1986-02-19 | 1988-06-28 | Eye Research Institute Of Retina Foundation | Stimulation of tear secretion with phosphodiesterase inhibitors |
| US5091431A (en) | 1988-02-08 | 1992-02-25 | Schering Corporation | Phosphodiesterase inhibitors |
| US5010086A (en) | 1990-02-28 | 1991-04-23 | Sterling Drug Inc. | Imidazopyridines, compositions and use |
| GB9013750D0 (en) | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
| GB9119704D0 (en) | 1991-09-14 | 1991-10-30 | Pfizer Ltd | Therapeutic agents |
| GB9121028D0 (en) | 1991-10-03 | 1991-11-13 | Pfizer Ltd | Therapeutic agents |
| GB9126260D0 (en) | 1991-12-11 | 1992-02-12 | Pfizer Ltd | Therapeutic agents |
| GB9213623D0 (en) | 1992-06-26 | 1992-08-12 | Pfizer Ltd | Therapeutic agents |
| GB9218322D0 (en) | 1992-08-28 | 1992-10-14 | Pfizer Ltd | Therapeutic agents |
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| GB9514465D0 (en) | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Chemical compounds |
| GB9514160D0 (en) | 1994-07-25 | 1995-09-13 | Zeneca Ltd | Aromatic compounds |
| GB9417532D0 (en) | 1994-08-31 | 1994-10-19 | Zeneca Ltd | Aromatic compounds |
| GB9423911D0 (en) | 1994-11-26 | 1995-01-11 | Pfizer Ltd | Therapeutic agents |
| TW434240B (en) | 1995-06-20 | 2001-05-16 | Zeneca Ltd | Aromatic compounds, preparation thereof and pharmaceutical composition comprising same |
| TW502026B (en) | 1995-06-20 | 2002-09-11 | Zeneca Ltd | Aromatic compounds useful as antagonists of e-type prostaglandins, processes for the preparation thereof, pharmaceutical compositions comprising the compounds, and intermediates |
| EP0752421B1 (en) | 1995-07-07 | 2005-10-12 | AstraZeneca AB | Ortho-substituted aromatic compounds, containing three (het)aryl moieties, their preparation and their use as prostaglandin E2-(PGE2)-antagonists |
| GB9514464D0 (en) | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Medicaments |
| GB9514473D0 (en) | 1995-07-14 | 1995-09-13 | Glaxo Lab Sa | Chemical compounds |
| ES2175404T3 (es) | 1996-05-10 | 2002-11-16 | Icos Corp | Derivados de carbolina. |
| EP0941221B1 (en) | 1996-11-20 | 2003-02-26 | ALTANA Pharma AG | Substituted dihydrobenzofurans as pde inhibitors |
| UA59384C2 (uk) | 1996-12-20 | 2003-09-15 | Пфайзер, Інк. | Похідні сульфонамідів та амідів як агоністи простагландину, фармацевтична композиція та способи лікування на їх основі |
| AT404730B (de) * | 1997-04-07 | 1999-02-25 | Holderchem Ag | Acryl-copolymere und polymerzusammensetzungen sowie deren verwendung als additive oder beimischungen zur verbesserung der eigenschaften von dispersionen und baustoffen |
| US6043252A (en) | 1997-05-05 | 2000-03-28 | Icos Corporation | Carboline derivatives |
| JP2001510827A (ja) | 1997-07-25 | 2001-08-07 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | 置換６−フェニルフェナントリジン |
| US6006735A (en) | 1997-09-12 | 1999-12-28 | Park Industries, Inc. | Automated stoneworking system and method |
| US6156753A (en) | 1997-10-28 | 2000-12-05 | Vivus, Inc. | Local administration of type III phosphodiesterase inhibitors for the treatment of erectile dysfunction |
| US6127363A (en) | 1997-10-28 | 2000-10-03 | Vivus, Inc. | Local administration of Type IV phosphodiesterase inhibitors for the treatment of erectile dysfunction |
| GB9725953D0 (en) | 1997-12-08 | 1998-02-04 | Pfizer Ltd | Compounds useful in therapy |
| US6211197B1 (en) | 1998-10-07 | 2001-04-03 | Merck Frosst Canada & Co. | Prostaglandin receptor ligands |
| GB9822238D0 (en) | 1998-10-12 | 1998-12-09 | Pfizer Ltd | Process for preparation of pyrazolo[4,3-D]pyrimidin-7-ones and intermediates thereof |
| GEP20043203B (en) * | 1999-12-22 | 2004-03-25 | Pfizer Prod Inc | EP4 Receptor Selective Agonists in the Treatment of Osteoporosis |
| CA2451392A1 (en) * | 2001-07-16 | 2003-01-30 | F. Hoffmann-La Roche Ag | Prostaglandin analogues as ep4 receptor agonists |
| DE60235198D1 (de) * | 2001-12-20 | 2010-03-11 | Merck Serono Sa Coinsins | Pyrrolidin-derivatie als prostaglandin-modulatoren |
-
2002
- 2002-12-19 DE DE60235198T patent/DE60235198D1/de not_active Expired - Lifetime
- 2002-12-19 ES ES02793091T patent/ES2337887T3/es not_active Expired - Lifetime
- 2002-12-19 IL IL16260202A patent/IL162602A0/xx unknown
- 2002-12-19 US US10/499,346 patent/US7335680B2/en not_active Expired - Fee Related
- 2002-12-19 AU AU2002358772A patent/AU2002358772B2/en not_active Ceased
- 2002-12-19 JP JP2003554640A patent/JP4554931B2/ja not_active Expired - Fee Related
- 2002-12-19 WO PCT/EP2002/014593 patent/WO2003053923A2/en not_active Ceased
- 2002-12-19 AT AT02793091T patent/ATE455758T1/de not_active IP Right Cessation
- 2002-12-19 CA CA2469075A patent/CA2469075C/en not_active Expired - Fee Related
- 2002-12-19 EP EP02793091A patent/EP1458679B1/en not_active Expired - Lifetime
-
2004
- 2004-06-17 IL IL162602A patent/IL162602A/en not_active IP Right Cessation
-
2007
- 2007-11-21 US US11/943,684 patent/US7635713B2/en not_active Expired - Fee Related
-
2009
- 2009-02-19 AU AU2009200663A patent/AU2009200663B2/en not_active Ceased
- 2009-08-03 US US12/534,292 patent/US8058305B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1458679B1 (en) | 2010-01-20 |
| WO2003053923A3 (en) | 2004-01-29 |
| ATE455758T1 (de) | 2010-02-15 |
| US7635713B2 (en) | 2009-12-22 |
| IL162602A0 (en) | 2005-11-20 |
| IL162602A (en) | 2011-07-31 |
| DE60235198D1 (de) | 2010-03-11 |
| AU2002358772A1 (en) | 2003-07-09 |
| US20050176800A1 (en) | 2005-08-11 |
| JP4554931B2 (ja) | 2010-09-29 |
| WO2003053923A2 (en) | 2003-07-03 |
| US20090292000A1 (en) | 2009-11-26 |
| AU2002358772B2 (en) | 2008-11-20 |
| US20080114051A1 (en) | 2008-05-15 |
| US8058305B2 (en) | 2011-11-15 |
| AU2009200663B2 (en) | 2011-09-15 |
| US7335680B2 (en) | 2008-02-26 |
| CA2469075A1 (en) | 2003-07-03 |
| CA2469075C (en) | 2011-09-13 |
| EP1458679A2 (en) | 2004-09-22 |
| JP2005517665A (ja) | 2005-06-16 |
| AU2009200663A1 (en) | 2009-03-12 |
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