JP5837278B2 - 新規使用 - Google Patents
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- JP5837278B2 JP5837278B2 JP2009540267A JP2009540267A JP5837278B2 JP 5837278 B2 JP5837278 B2 JP 5837278B2 JP 2009540267 A JP2009540267 A JP 2009540267A JP 2009540267 A JP2009540267 A JP 2009540267A JP 5837278 B2 JP5837278 B2 JP 5837278B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- aryl
- substituted
- formula
- halogen
- 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 - Fee Related
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- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 229940121836 Phosphodiesterase 1 inhibitor Drugs 0.000 claims description 64
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 55
- -1 hydroxy, carboxy Chemical group 0.000 claims description 53
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 150000003839 salts Chemical group 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 125000001188 haloalkyl group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 26
- 239000000186 progesterone Substances 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 229960003387 progesterone Drugs 0.000 claims description 25
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 230000001404 mediated effect Effects 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 102100024318 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B Human genes 0.000 claims description 15
- 101001117099 Homo sapiens Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B Proteins 0.000 claims description 15
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 230000011664 signaling Effects 0.000 claims description 13
- 208000035475 disorder Diseases 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 206010057671 Female sexual dysfunction Diseases 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 10
- 229940011871 estrogen Drugs 0.000 claims description 10
- 239000000262 estrogen Substances 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 229960005309 estradiol Drugs 0.000 claims description 6
- 229930182833 estradiol Natural products 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 claims description 4
- 239000005556 hormone Substances 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 239000000583 progesterone congener Substances 0.000 claims description 4
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 claims description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 3
- 201000000736 Amenorrhea Diseases 0.000 claims description 3
- 206010001928 Amenorrhoea Diseases 0.000 claims description 3
- 231100000540 amenorrhea Toxicity 0.000 claims description 3
- 125000001769 aryl amino group Chemical group 0.000 claims description 3
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 claims description 3
- 229960001348 estriol Drugs 0.000 claims description 3
- 208000000509 infertility Diseases 0.000 claims description 3
- 230000036512 infertility Effects 0.000 claims description 3
- 231100000535 infertility Toxicity 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 208000037853 Abnormal uterine bleeding Diseases 0.000 claims description 2
- 201000005670 Anovulation Diseases 0.000 claims description 2
- 206010002659 Anovulatory cycle Diseases 0.000 claims description 2
- 206010027339 Menstruation irregular Diseases 0.000 claims description 2
- 231100000552 anovulation Toxicity 0.000 claims description 2
- 125000002720 diazolyl group Chemical group 0.000 claims description 2
- 230000013011 mating Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 9
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims 2
- 108010054479 3',5'-Cyclic-AMP Phosphodiesterases Proteins 0.000 claims 1
- 102000001707 3',5'-Cyclic-AMP Phosphodiesterases Human genes 0.000 claims 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 claims 1
- 206010061533 Myotonia Diseases 0.000 claims 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims 1
- 206010036600 Premature labour Diseases 0.000 claims 1
- 230000037430 deletion Effects 0.000 claims 1
- 238000012217 deletion Methods 0.000 claims 1
- 206010020718 hyperplasia Diseases 0.000 claims 1
- 230000002175 menstrual effect Effects 0.000 claims 1
- 230000004899 motility Effects 0.000 claims 1
- 208000026440 premature labor Diseases 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 210000004291 uterus Anatomy 0.000 claims 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 24
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 24
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 23
- 239000001257 hydrogen Substances 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- 125000005843 halogen group Chemical group 0.000 description 20
- 101001117086 Dictyostelium discoideum cAMP/cGMP-dependent 3',5'-cAMP/cGMP phosphodiesterase A Proteins 0.000 description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 16
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 150000001721 carbon Chemical group 0.000 description 15
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 15
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 14
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 11
- 230000019491 signal transduction Effects 0.000 description 11
- 125000004663 dialkyl amino group Chemical group 0.000 description 10
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- 150000002431 hydrogen Chemical group 0.000 description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 125000004512 1,2,3-thiadiazol-4-yl group Chemical group S1N=NC(=C1)* 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
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- 241000700159 Rattus Species 0.000 description 8
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000000651 prodrug Chemical group 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
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- 125000004414 alkyl thio group Chemical group 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- OOOBGFAUGXVKGI-UHFFFAOYSA-N 5,6-dihydropyrazolo[3,4-d]pyrimidin-4-one Chemical compound O=C1NCN=C2N=NC=C12 OOOBGFAUGXVKGI-UHFFFAOYSA-N 0.000 description 6
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- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
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- 125000002619 bicyclic group Chemical group 0.000 description 5
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- 229910052751 metal Inorganic materials 0.000 description 5
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- JFZSDNLQDTYVEE-UHFFFAOYSA-N 1,4-dihydropyrazolo[4,3-d]pyrimidin-7-one Chemical class O=C1N=CNC2=C1NN=C2 JFZSDNLQDTYVEE-UHFFFAOYSA-N 0.000 description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 4
- RQFCJASXJCIDSX-UHFFFAOYSA-N 14C-Guanosin-5'-monophosphat Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(O)=O)C(O)C1O RQFCJASXJCIDSX-UHFFFAOYSA-N 0.000 description 4
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| EP2089034A1 (en) | 2009-08-19 |
| WO2008070095A1 (en) | 2008-06-12 |
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| US20100323997A1 (en) | 2010-12-23 |
| JP2010511709A (ja) | 2010-04-15 |
| US9006258B2 (en) | 2015-04-14 |
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