DE60226051T2 - Pyrazolidinon-verbindungen als liganden des ep2 und/oder ep4 prostaglandin-rezeptoren - Google Patents

Info

Publication number

DE60226051T2

DE60226051T2 DE60226051T DE60226051T DE60226051T2 DE 60226051 T2 DE60226051 T2 DE 60226051T2 DE 60226051 T DE60226051 T DE 60226051T DE 60226051 T DE60226051 T DE 60226051T DE 60226051 T2 DE60226051 T2 DE 60226051T2

Authority

DE

Germany

Prior art keywords

ethyl

oxopyrazolidin

benzoic acid

solution

alkyl

Prior art date

2001-10-23

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

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• NDGRWYRVNANFNB-UHFFFAOYSA-N pyrazolidin-3-one Chemical class O=C1CCNN1 NDGRWYRVNANFNB-UHFFFAOYSA-N 0.000 title abstract description 16
• 239000003446 ligand Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 228
• 238000011282 treatment Methods 0.000 claims abstract description 37
• 208000020084 Bone disease Diseases 0.000 claims abstract description 13
• 230000036512 infertility Effects 0.000 claims abstract description 12
• 231100000535 infertility Toxicity 0.000 claims abstract description 12
• 208000021267 infertility disease Diseases 0.000 claims abstract description 10
• 206010013935 Dysmenorrhoea Diseases 0.000 claims abstract description 9
• 208000006399 Premature Obstetric Labor Diseases 0.000 claims abstract description 9
• 208000006673 asthma Diseases 0.000 claims abstract description 9
• 206010020772 Hypertension Diseases 0.000 claims abstract description 8
• 208000001132 Osteoporosis Diseases 0.000 claims abstract description 8
• 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
• 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 8
• 230000023555 blood coagulation Effects 0.000 claims abstract description 6
• 230000001066 destructive effect Effects 0.000 claims abstract description 6
• 208000002296 eclampsia Diseases 0.000 claims abstract description 6
• 201000011461 pre-eclampsia Diseases 0.000 claims abstract description 6
• -1 cyano, hydroxy Chemical group 0.000 claims description 75
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 28
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 239000005711 Benzoic acid Substances 0.000 claims description 19
• 235000010233 benzoic acid Nutrition 0.000 claims description 19
• 229910052739 hydrogen Inorganic materials 0.000 claims description 19
• 125000001424 substituent group Chemical group 0.000 claims description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
• 125000000217 alkyl group Chemical group 0.000 claims description 16
• 125000001072 heteroaryl group Chemical group 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 208000035475 disorder Diseases 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 125000002837 carbocyclic group Chemical group 0.000 claims description 11
• 150000003839 salts Chemical class 0.000 claims description 10
• MGCQBMZFRDABAR-UHFFFAOYSA-N 4-[2-[2-[4-(1-ethylcyclobutyl)-4-hydroxybutyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C1CC(=O)N(CCC=2C=CC(=CC=2)C(O)=O)N1CCCC(O)C1(CC)CCC1 MGCQBMZFRDABAR-UHFFFAOYSA-N 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 9
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
• 125000004414 alkyl thio group Chemical group 0.000 claims description 9
• 201000010099 disease Diseases 0.000 claims description 9
• 229910052760 oxygen Inorganic materials 0.000 claims description 9
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
• 229910052736 halogen Inorganic materials 0.000 claims description 7
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
• KALXDWPKUYNCLA-UHFFFAOYSA-N 4-[2-[2-[3-hydroxy-4-(3-methylphenyl)butyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CC1=CC=CC(CC(O)CCN2N(C(=O)CC2)CCC=2C=CC(=CC=2)C(O)=O)=C1 KALXDWPKUYNCLA-UHFFFAOYSA-N 0.000 claims description 6
• 206010065687 Bone loss Diseases 0.000 claims description 6
• 230000035800 maturation Effects 0.000 claims description 6
• FXEVKFYZRMILMZ-UHFFFAOYSA-N 4-[2-[2-(3-hydroxy-5-methylhexyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CC(C)CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 FXEVKFYZRMILMZ-UHFFFAOYSA-N 0.000 claims description 5
• UFNLOWRQRUZWKF-UHFFFAOYSA-N 4-[2-[2-(4-ethyl-4-hydroxyoctyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CCCCC(O)(CC)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 UFNLOWRQRUZWKF-UHFFFAOYSA-N 0.000 claims description 5
• CALFSRIGIOMZFM-UHFFFAOYSA-N 4-[2-[2-(4-hydroxy-4,7-dimethyloctyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CC(C)CCC(C)(O)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 CALFSRIGIOMZFM-UHFFFAOYSA-N 0.000 claims description 5
• LBGUNFMRRVJPSG-UHFFFAOYSA-N 4-[2-[2-(4-hydroxy-4-methylheptyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CCCC(C)(O)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 LBGUNFMRRVJPSG-UHFFFAOYSA-N 0.000 claims description 5
• ZLJYTBPSXYKRKL-UHFFFAOYSA-N 4-[2-[2-(4-hydroxy-5-methyloctyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CCCC(C)C(O)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 ZLJYTBPSXYKRKL-UHFFFAOYSA-N 0.000 claims description 5
• INOWIYUOGGMVDM-UHFFFAOYSA-N 4-[2-[2-(4-hydroxy-6-methylheptyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CC(C)CC(O)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 INOWIYUOGGMVDM-UHFFFAOYSA-N 0.000 claims description 5
• XZWDACYVXIULCX-UHFFFAOYSA-N 4-[2-[2-(4-hydroxynonyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CCCCCC(O)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 XZWDACYVXIULCX-UHFFFAOYSA-N 0.000 claims description 5
• GNZZMSRREAKILT-UHFFFAOYSA-N 4-[2-[2-[4-[1-(cyclopropylmethyl)cyclobutyl]-4-hydroxybutyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C1CCC1(CC1CC1)C(O)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 GNZZMSRREAKILT-UHFFFAOYSA-N 0.000 claims description 5
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• 125000000304 alkynyl group Chemical group 0.000 claims description 5
• 229910052799 carbon Inorganic materials 0.000 claims description 5
• 150000002367 halogens Chemical class 0.000 claims description 5
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
• 125000004434 sulfur atom Chemical group 0.000 claims description 5
• SIGCFCMKKRESGW-UHFFFAOYSA-N 4-[2-[2-(3-cyclobutyl-3-hydroxypropyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C1CCC1C(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 SIGCFCMKKRESGW-UHFFFAOYSA-N 0.000 claims description 4
• PAVYSSGJRYCIIJ-UHFFFAOYSA-N 4-[2-[2-(3-hydroxyoctyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CCCCCC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 PAVYSSGJRYCIIJ-UHFFFAOYSA-N 0.000 claims description 4
• NTVVAIFSHLCKGX-UHFFFAOYSA-N 4-[2-[2-(4-hydroxynon-2-ynyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CCCCCC(O)C#CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 NTVVAIFSHLCKGX-UHFFFAOYSA-N 0.000 claims description 4
• LTKCOAAEGIFTID-UHFFFAOYSA-N 4-[2-[2-(4-hydroxyoctyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound CCCCC(O)CCCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 LTKCOAAEGIFTID-UHFFFAOYSA-N 0.000 claims description 4
• 208000027004 Eosinophilic disease Diseases 0.000 claims description 4
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• 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
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• 230000004054 inflammatory process Effects 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
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• 231100000397 ulcer Toxicity 0.000 claims description 4
• JVPGVILOMSPMMY-UHFFFAOYSA-N 4-[2-[2-(3-hydroxy-4-phenylbutyl)-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C=1C=CC=CC=1CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 JVPGVILOMSPMMY-UHFFFAOYSA-N 0.000 claims description 3
• KDVFFCPULSQTQN-UHFFFAOYSA-N 4-[2-[2-[3-hydroxy-4-(3-iodophenyl)butyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C=1C=CC(I)=CC=1CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 KDVFFCPULSQTQN-UHFFFAOYSA-N 0.000 claims description 3
• XXHJUODZNGBFDI-UHFFFAOYSA-N 4-[2-[2-[3-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C=1C=CC(OC(F)(F)F)=CC=1CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 XXHJUODZNGBFDI-UHFFFAOYSA-N 0.000 claims description 3
• UCAFZBFLCPWPLH-UHFFFAOYSA-N 4-[2-[2-[3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C=1C=CC(C(F)(F)F)=CC=1CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 UCAFZBFLCPWPLH-UHFFFAOYSA-N 0.000 claims description 3
• MMKYRZFPISEJKE-UHFFFAOYSA-N 4-[2-[2-[4-(3-bromophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C=1C=CC(Br)=CC=1CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 MMKYRZFPISEJKE-UHFFFAOYSA-N 0.000 claims description 3
• HVIXFTUMIDKUHX-UHFFFAOYSA-N 4-[2-[2-[4-(3-chlorophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C=1C=CC(Cl)=CC=1CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 HVIXFTUMIDKUHX-UHFFFAOYSA-N 0.000 claims description 3
• XZXVFMOGPSLDSM-UHFFFAOYSA-N 4-[2-[2-[4-(3-fluorophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C=1C=CC(F)=CC=1CC(O)CCN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 XZXVFMOGPSLDSM-UHFFFAOYSA-N 0.000 claims description 3
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• ZOMMPOGASDFZJV-UWJYYQICSA-N 4-[2-[2-[(3s,4s)-3-hydroxy-4-phenylpentyl]-5-oxopyrazolidin-1-yl]ethyl]benzoic acid Chemical compound C([C@H](O)[C@@H](C)C=1C=CC=CC=1)CN1CCC(=O)N1CCC1=CC=C(C(O)=O)C=C1 ZOMMPOGASDFZJV-UWJYYQICSA-N 0.000 claims description 2
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