ZA200508481B - Heteroaromatic pentacyclic compound and medicinal use thereof - Google Patents
Heteroaromatic pentacyclic compound and medicinal use thereof Download PDFInfo
- Publication number
- ZA200508481B ZA200508481B ZA200508481A ZA200508481A ZA200508481B ZA 200508481 B ZA200508481 B ZA 200508481B ZA 200508481 A ZA200508481 A ZA 200508481A ZA 200508481 A ZA200508481 A ZA 200508481A ZA 200508481 B ZA200508481 B ZA 200508481B
- Authority
- ZA
- South Africa
- Prior art keywords
- phenyl
- ylmethyl
- group
- thiazol
- hydrochloride
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 81
- 125000001072 heteroaryl group Chemical group 0.000 title claims description 81
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 173
- 125000000217 alkyl group Chemical group 0.000 claims description 166
- -1 (d) a Ci Chemical group 0.000 claims description 151
- 239000002253 acid Substances 0.000 claims description 117
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 108
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 99
- 239000003814 drug Substances 0.000 claims description 90
- 239000008194 pharmaceutical composition Substances 0.000 claims description 88
- 229940124597 therapeutic agent Drugs 0.000 claims description 84
- 125000003118 aryl group Chemical group 0.000 claims description 75
- 238000011282 treatment Methods 0.000 claims description 66
- 239000003112 inhibitor Substances 0.000 claims description 63
- 239000005557 antagonist Substances 0.000 claims description 56
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 51
- 239000008177 pharmaceutical agent Substances 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 206010012601 diabetes mellitus Diseases 0.000 claims description 42
- 229940002612 prodrug Drugs 0.000 claims description 39
- 239000000651 prodrug Substances 0.000 claims description 39
- 125000005843 halogen group Chemical group 0.000 claims description 38
- 208000008589 Obesity Diseases 0.000 claims description 37
- 235000020824 obesity Nutrition 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 37
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000003107 substituted aryl group Chemical group 0.000 claims description 24
- 102000004877 Insulin Human genes 0.000 claims description 23
- 108090001061 Insulin Proteins 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 229940125396 insulin Drugs 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims description 21
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims description 21
- 230000014509 gene expression Effects 0.000 claims description 21
- 125000003277 amino group Chemical group 0.000 claims description 20
- 239000003623 enhancer Substances 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 229910052717 sulfur Chemical group 0.000 claims description 15
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 claims description 14
- 125000004434 sulfur atom Chemical group 0.000 claims description 14
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
- 206010022489 Insulin Resistance Diseases 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 229940122199 Insulin secretagogue Drugs 0.000 claims description 8
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 229940123208 Biguanide Drugs 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims description 7
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 102000005962 receptors Human genes 0.000 claims description 3
- 108020003175 receptors Proteins 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 319
- 238000011321 prophylaxis Methods 0.000 claims 64
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims 62
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 48
- 239000000556 agonist Substances 0.000 claims 40
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 34
- 239000005711 Benzoic acid Substances 0.000 claims 31
- 235000010233 benzoic acid Nutrition 0.000 claims 31
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 23
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 21
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims 20
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims 20
- 229920000669 heparin Polymers 0.000 claims 20
- 229960003963 manidipine Drugs 0.000 claims 20
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 claims 20
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims 20
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 19
- 239000011734 sodium Substances 0.000 claims 19
- 229940083542 sodium Drugs 0.000 claims 19
- 229910052708 sodium Inorganic materials 0.000 claims 19
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims 18
- 208000002249 Diabetes Complications Diseases 0.000 claims 17
- 206010012655 Diabetic complications Diseases 0.000 claims 17
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 17
- 206010020772 Hypertension Diseases 0.000 claims 16
- 208000007536 Thrombosis Diseases 0.000 claims 16
- 108010064733 Angiotensins Proteins 0.000 claims 15
- 102000015427 Angiotensins Human genes 0.000 claims 15
- 239000003963 antioxidant agent Substances 0.000 claims 15
- 235000006708 antioxidants Nutrition 0.000 claims 15
- 229960000830 captopril Drugs 0.000 claims 15
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims 15
- 229960004890 diethylpropion Drugs 0.000 claims 15
- XXEPPPIWZFICOJ-UHFFFAOYSA-N diethylpropion Chemical compound CCN(CC)C(C)C(=O)C1=CC=CC=C1 XXEPPPIWZFICOJ-UHFFFAOYSA-N 0.000 claims 15
- 235000001968 nicotinic acid Nutrition 0.000 claims 15
- 239000000021 stimulant Substances 0.000 claims 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 14
- 229940044551 receptor antagonist Drugs 0.000 claims 14
- 239000002464 receptor antagonist Substances 0.000 claims 14
- 125000003282 alkyl amino group Chemical group 0.000 claims 13
- 229960002797 pitavastatin Drugs 0.000 claims 13
- 125000001188 haloalkyl group Chemical group 0.000 claims 11
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims 10
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims 10
- DEMLYXMVPJAVFU-UHFFFAOYSA-N 2-(chloromethyl)oxirane;2-methyl-1h-imidazole Chemical compound ClCC1CO1.CC1=NC=CN1 DEMLYXMVPJAVFU-UHFFFAOYSA-N 0.000 claims 10
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 claims 10
- 239000002083 C09CA01 - Losartan Substances 0.000 claims 10
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims 10
- CVKNDPRBJVBDSS-UHFFFAOYSA-N Cicletanine Chemical compound O1CC2=C(O)C(C)=NC=C2C1C1=CC=C(Cl)C=C1 CVKNDPRBJVBDSS-UHFFFAOYSA-N 0.000 claims 10
- KJEBULYHNRNJTE-DHZHZOJOSA-N Cinalong Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC\C=C\C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KJEBULYHNRNJTE-DHZHZOJOSA-N 0.000 claims 10
- 102000002045 Endothelin Human genes 0.000 claims 10
- 108050009340 Endothelin Proteins 0.000 claims 10
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims 10
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims 10
- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 claims 10
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 claims 10
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 claims 10
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 0.000 claims 10
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 claims 10
- 102000023984 PPAR alpha Human genes 0.000 claims 10
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims 10
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims 10
- 108010003541 Platelet Activating Factor Proteins 0.000 claims 10
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 claims 10
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 claims 10
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 claims 10
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 claims 10
- 239000012190 activator Substances 0.000 claims 10
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims 10
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims 10
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims 10
- 229960002992 barnidipine Drugs 0.000 claims 10
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 claims 10
- 229960003515 bendroflumethiazide Drugs 0.000 claims 10
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 claims 10
- 229960002890 beraprost Drugs 0.000 claims 10
- YTCZZXIRLARSET-VJRSQJMHSA-M beraprost sodium Chemical compound [Na+].O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC([O-])=O YTCZZXIRLARSET-VJRSQJMHSA-M 0.000 claims 10
- 230000015572 biosynthetic process Effects 0.000 claims 10
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims 10
- 229960001523 chlortalidone Drugs 0.000 claims 10
- 235000012000 cholesterol Nutrition 0.000 claims 10
- 229960001932 cicletanine Drugs 0.000 claims 10
- 229960003020 cilnidipine Drugs 0.000 claims 10
- 229960003638 dopamine Drugs 0.000 claims 10
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims 10
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims 10
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims 10
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- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 claims 10
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 claims 10
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims 10
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- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 claims 10
- 229960004294 lercanidipine Drugs 0.000 claims 10
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 0.000 claims 10
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- OJZYRQPMEIEQFC-UAWLTFRCSA-N limaprost Chemical compound CCCC[C@H](C)C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCC\C=C\C(O)=O OJZYRQPMEIEQFC-UAWLTFRCSA-N 0.000 claims 10
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims 10
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- MHNDDBWCJDYQEB-UHFFFAOYSA-N 2-[(5-tert-butyl-1,3-oxazol-2-yl)methyl-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(CN(CC(O)=O)CC=3OC(=CN=3)C(C)(C)C)SC=2)C=C1 MHNDDBWCJDYQEB-UHFFFAOYSA-N 0.000 claims 1
- IGTXFHYDUGLRSN-UHFFFAOYSA-N 2-[(5-tert-butyl-1,3-oxazol-2-yl)methyl-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2C=C(CN(CC(O)=O)CC=3OC(=CN=3)C(C)(C)C)SC=2)C=C1 IGTXFHYDUGLRSN-UHFFFAOYSA-N 0.000 claims 1
- FKGBFRNVTCFMGU-UHFFFAOYSA-N 2-[(5-tert-butyl-1,3-thiazol-2-yl)methyl-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(CN(CC(O)=O)CC=3SC(=CN=3)C(C)(C)C)SC=2)C=C1 FKGBFRNVTCFMGU-UHFFFAOYSA-N 0.000 claims 1
- ZLLUIVPSLJGLJB-UHFFFAOYSA-N 2-[(5-tert-butyl-1,3-thiazol-2-yl)methyl-[[5-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2SC(CN(CC(O)=O)CC=3SC(=CN=3)C(C)(C)C)=CC=2)C=C1 ZLLUIVPSLJGLJB-UHFFFAOYSA-N 0.000 claims 1
- VFEKWGMDXRYQTM-UHFFFAOYSA-N 2-[1,3-benzothiazol-2-yl-[[5-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2SC(CN(CC(O)=O)C=3SC4=CC=CC=C4N=3)=CC=2)C=C1 VFEKWGMDXRYQTM-UHFFFAOYSA-N 0.000 claims 1
- SUESVMQKUDWWEZ-UHFFFAOYSA-N 2-[1,3-benzothiazol-2-ylmethyl-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2C=C(CN(CC(O)=O)CC=3SC4=CC=CC=C4N=3)SC=2)C=C1 SUESVMQKUDWWEZ-UHFFFAOYSA-N 0.000 claims 1
- QAIBSJDNYVBBAI-UHFFFAOYSA-N 2-[3-methylbutanoyl-[[4-[4-[2-[4-(2-methylpropyl)phenyl]ethylamino]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound S1C(CN(CC(O)=O)C(=O)CC(C)C)=NC(C=2C=CC(NCCC=3C=CC(CC(C)C)=CC=3)=CC=2)=C1 QAIBSJDNYVBBAI-UHFFFAOYSA-N 0.000 claims 1
- NXBLGGPCHQVUJN-UHFFFAOYSA-N 2-[3-methylbutyl-[[4-[4-[2-[4-(2-methylpropyl)phenyl]ethylamino]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound S1C(CN(CC(O)=O)CCC(C)C)=NC(C=2C=CC(NCCC=3C=CC(CC(C)C)=CC=3)=CC=2)=C1 NXBLGGPCHQVUJN-UHFFFAOYSA-N 0.000 claims 1
- NFZWDBOZGLVXQN-UHFFFAOYSA-N 2-[[1-[2-(diethylamino)-2-oxoethyl]benzimidazol-2-yl]methyl-[[5-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2SC(CN(CC(O)=O)CC=3N(C4=CC=CC=C4N=3)CC(=O)N(CC)CC)=CC=2)C=C1 NFZWDBOZGLVXQN-UHFFFAOYSA-N 0.000 claims 1
- HHGHJZGOXWJEGI-UHFFFAOYSA-N 2-[[2-(methylazaniumyl)acetyl]amino]benzoate Chemical compound C[NH2+]CC(=O)NC1=CC=CC=C1C([O-])=O HHGHJZGOXWJEGI-UHFFFAOYSA-N 0.000 claims 1
- TXIIBGMCNADYFL-UHFFFAOYSA-N 2-[[2-[4-(dimethylamino)anilino]-2-oxoethyl]-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(CN(CC(O)=O)CC(=O)NC=3C=CC(=CC=3)N(C)C)SC=2)C=C1 TXIIBGMCNADYFL-UHFFFAOYSA-N 0.000 claims 1
- IGSKIUKSFYGGMH-UHFFFAOYSA-N 2-[[2-oxo-2-(4-propan-2-ylanilino)ethyl]-[[4-[4-[(4-pentan-3-yl-n-propan-2-ylanilino)methyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CC)CC)=CC=C1N(C(C)C)CC1=CC=C(C=2N=C(CN(CC(O)=O)CC(=O)NC=3C=CC(=CC=3)C(C)C)SC=2)C=C1 IGSKIUKSFYGGMH-UHFFFAOYSA-N 0.000 claims 1
- KTEGGMFECSWTJN-UHFFFAOYSA-N 2-[[4-[3-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl]-3,4-dihydro-1h-isoquinoline-7-carboxylic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=CC(C=2C=C(CN3CC4=CC(=CC=C4CC3)C(O)=O)SC=2)=C1 KTEGGMFECSWTJN-UHFFFAOYSA-N 0.000 claims 1
- COLDLLDMCWJOEJ-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methoxy]pyridine-3-carboxylic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(COC=3C(=CC=CN=3)C(O)=O)SC=2)C=C1 COLDLLDMCWJOEJ-UHFFFAOYSA-N 0.000 claims 1
- JDZCJPQTMLHPKB-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl-[2-(4-methylphenoxy)acetyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(CN(CC(O)=O)C(=O)COC=3C=CC(C)=CC=3)SC=2)C=C1 JDZCJPQTMLHPKB-UHFFFAOYSA-N 0.000 claims 1
- NPTPBNRBGXEBGU-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl-[2-(4-propan-2-ylphenoxy)acetyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(CN(CC(O)=O)C(=O)COC=3C=CC(=CC=3)C(C)C)SC=2)C=C1 NPTPBNRBGXEBGU-UHFFFAOYSA-N 0.000 claims 1
- LSCNNXOXKRANGS-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl-[2-oxo-2-(pyridin-2-ylamino)ethyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(CN(CC(O)=O)CC(=O)NC=3N=CC=CC=3)SC=2)C=C1 LSCNNXOXKRANGS-UHFFFAOYSA-N 0.000 claims 1
- HSFYIPVKJFSYCP-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl]-3,4-dihydro-1h-isoquinoline-7-carboxylic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2N=C(CN3CC4=CC(=CC=C4CC3)C(O)=O)SC=2)C=C1 HSFYIPVKJFSYCP-UHFFFAOYSA-N 0.000 claims 1
- UDKRPJFPXQKOMJ-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl-(quinolin-2-ylmethyl)amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2C=C(CN(CC(O)=O)CC=3N=C4C=CC=CC4=CC=3)SC=2)C=C1 UDKRPJFPXQKOMJ-UHFFFAOYSA-N 0.000 claims 1
- XEEBYGZFIVVVPI-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl-[(1-methylbenzimidazol-2-yl)methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2C=C(CN(CC(O)=O)CC=3N(C4=CC=CC=C4N=3)C)SC=2)C=C1 XEEBYGZFIVVVPI-UHFFFAOYSA-N 0.000 claims 1
- ZLZKGPULNDUCIF-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenyl)methoxy]-2-methylphenyl]-1,3-thiazol-2-yl]methyl-[2-oxo-2-(4-propan-2-ylanilino)ethyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1COC(C=C1C)=CC=C1C1=CSC(CN(CC(O)=O)CC(=O)NC=2C=CC(=CC=2)C(C)C)=N1 ZLZKGPULNDUCIF-UHFFFAOYSA-N 0.000 claims 1
- QXDHBLYJMXBKDL-UHFFFAOYSA-N 2-[[4-[4-[(4-heptan-4-ylphenyl)methyl-methylamino]phenyl]-1,3-thiazol-2-yl]methyl-(pyridin-2-ylmethyl)amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1CN(C)C1=CC=C(C=2N=C(CN(CC(O)=O)CC=3N=CC=CC=3)SC=2)C=C1 QXDHBLYJMXBKDL-UHFFFAOYSA-N 0.000 claims 1
- TXDPKOKFZMAGKJ-UHFFFAOYSA-N 2-[[4-[4-[(4-pentan-3-yl-n-propan-2-ylanilino)methyl]phenyl]-1,3-thiazol-2-yl]methyl-(phenylcarbamoyl)amino]acetic acid Chemical compound C1=CC(C(CC)CC)=CC=C1N(C(C)C)CC1=CC=C(C=2N=C(CN(CC(O)=O)C(=O)NC=3C=CC=CC=3)SC=2)C=C1 TXDPKOKFZMAGKJ-UHFFFAOYSA-N 0.000 claims 1
- OWTSZGQPOBGMTK-UHFFFAOYSA-N 2-[[4-[4-[2-(4-cyclohexylphenyl)ethylamino]phenyl]-1,3-thiazol-2-yl]methyl-(2-methylpropyl)sulfamoyl]acetic acid Chemical compound S1C(CN(CC(C)C)S(=O)(=O)CC(O)=O)=NC(C=2C=CC(NCCC=3C=CC(=CC=3)C3CCCCC3)=CC=2)=C1 OWTSZGQPOBGMTK-UHFFFAOYSA-N 0.000 claims 1
- JDHYMHXNHWJBTR-UHFFFAOYSA-N 2-[[4-[4-[2-(4-cyclohexylphenyl)ethylamino]phenyl]-1,3-thiazol-2-yl]methylamino]-2-oxoacetic acid Chemical compound S1C(CNC(=O)C(=O)O)=NC(C=2C=CC(NCCC=3C=CC(=CC=3)C3CCCCC3)=CC=2)=C1 JDHYMHXNHWJBTR-UHFFFAOYSA-N 0.000 claims 1
- SIUYDHOSTIHONG-UHFFFAOYSA-N 2-[[4-[4-[2-(4-cyclohexylphenyl)ethylamino]phenyl]-1,3-thiazol-2-yl]methylamino]-3-phenylpropanoic acid Chemical compound N=1C(C=2C=CC(NCCC=3C=CC(=CC=3)C3CCCCC3)=CC=2)=CSC=1CNC(C(=O)O)CC1=CC=CC=C1 SIUYDHOSTIHONG-UHFFFAOYSA-N 0.000 claims 1
- LXPGMICMSYKVHN-UHFFFAOYSA-N 2-[[4-[4-[2-(4-cyclohexylphenyl)ethylamino]phenyl]-1,3-thiazol-2-yl]methylamino]propanoic acid Chemical compound S1C(CNC(C)C(O)=O)=NC(C=2C=CC(NCCC=3C=CC(=CC=3)C3CCCCC3)=CC=2)=C1 LXPGMICMSYKVHN-UHFFFAOYSA-N 0.000 claims 1
- QAPZSQYWTWIITP-UHFFFAOYSA-N 2-[[4-[4-[2-[4-(2,2-dimethylpropyl)phenyl]ethylamino]phenyl]-1,3-thiazol-2-yl]methyl-methylamino]-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(O)=O)N(C)CC(SC=1)=NC=1C(C=C1)=CC=C1NCCC1=CC=C(CC(C)(C)C)C=C1 QAPZSQYWTWIITP-UHFFFAOYSA-N 0.000 claims 1
- UGSPVWGZOVNKJE-UHFFFAOYSA-N 2-[[4-[4-[[4-heptan-4-yl-n-(2-methylpropyl)anilino]methyl]phenyl]-1,3-thiazol-2-yl]methyl-[methyl(phenyl)carbamoyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1N(CC(C)C)CC1=CC=C(C=2N=C(CN(CC(O)=O)C(=O)N(C)C=3C=CC=CC=3)SC=2)C=C1 UGSPVWGZOVNKJE-UHFFFAOYSA-N 0.000 claims 1
- JYUZIROHTAVTDE-UHFFFAOYSA-N 2-[[5-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl-[(2-phenyl-1h-imidazol-5-yl)methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2SC(CN(CC(O)=O)CC=3N=C(NC=3)C=3C=CC=CC=3)=CC=2)C=C1 JYUZIROHTAVTDE-UHFFFAOYSA-N 0.000 claims 1
- OGVBFCIAVMNTHR-UHFFFAOYSA-N 2-[[5-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl-[(4-methoxyphenyl)methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2SC(CN(CC(O)=O)CC=3C=CC(OC)=CC=3)=CC=2)C=C1 OGVBFCIAVMNTHR-UHFFFAOYSA-N 0.000 claims 1
- NVIVWFCOZBEXPP-UHFFFAOYSA-N 2-[[5-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophen-2-yl]methyl-[(4-methylsulfanylphenyl)methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2SC(CN(CC(O)=O)CC=3C=CC(SC)=CC=3)=CC=2)C=C1 NVIVWFCOZBEXPP-UHFFFAOYSA-N 0.000 claims 1
- CANQCDBFLNSNMG-UHFFFAOYSA-N 2-[[5-[4-[(4-heptan-4-ylphenoxy)methyl]phenyl]thiophene-2-carbonyl]-(pyridin-2-ylmethyl)amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1OCC1=CC=C(C=2SC(=CC=2)C(=O)N(CC(O)=O)CC=2N=CC=CC=2)C=C1 CANQCDBFLNSNMG-UHFFFAOYSA-N 0.000 claims 1
- DUIFZOHLWPCOSN-UHFFFAOYSA-N 2-[[5-[4-[3-(4-cyclohexylphenyl)propylamino]phenyl]thiophen-2-yl]methyl-(2-phenoxyethyl)amino]acetic acid Chemical compound C=1C=C(C=2C=CC(NCCCC=3C=CC(=CC=3)C3CCCCC3)=CC=2)SC=1CN(CC(=O)O)CCOC1=CC=CC=C1 DUIFZOHLWPCOSN-UHFFFAOYSA-N 0.000 claims 1
- ZZDWXWUVLIQXPS-UHFFFAOYSA-N 2-[[5-[4-[3-(4-cyclohexylphenyl)propylamino]phenyl]thiophen-2-yl]methyl-(pyridin-2-ylmethyl)amino]acetic acid Chemical compound C=1C=CC=NC=1CN(CC(=O)O)CC(S1)=CC=C1C(C=C1)=CC=C1NCCCC(C=C1)=CC=C1C1CCCCC1 ZZDWXWUVLIQXPS-UHFFFAOYSA-N 0.000 claims 1
- SRNDFBTYCUGWLN-UHFFFAOYSA-N 2-[[methyl(phenyl)carbamoyl]-[[4-[4-[(4-pentan-3-yl-n-propan-2-ylanilino)methyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CC)CC)=CC=C1N(C(C)C)CC1=CC=C(C=2N=C(CN(CC(O)=O)C(=O)N(C)C=3C=CC=CC=3)SC=2)C=C1 SRNDFBTYCUGWLN-UHFFFAOYSA-N 0.000 claims 1
- GULZILJIGOKAGT-UHFFFAOYSA-N 2-[benzenesulfonyl-[[4-[4-[[4-tert-butyl-n-(2-methylpropyl)anilino]methyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C=1C=C(C(C)(C)C)C=CC=1N(CC(C)C)CC(C=C1)=CC=C1C(N=1)=CSC=1CN(CC(O)=O)S(=O)(=O)C1=CC=CC=C1 GULZILJIGOKAGT-UHFFFAOYSA-N 0.000 claims 1
- MPEQLKQICODGPI-UHFFFAOYSA-N 2-[benzoyl-[[4-[4-[2-[4-(2-methylpropyl)phenyl]ethylamino]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(CC(C)C)=CC=C1CCNC1=CC=C(C=2N=C(CN(CC(O)=O)C(=O)C=3C=CC=CC=3)SC=2)C=C1 MPEQLKQICODGPI-UHFFFAOYSA-N 0.000 claims 1
- CPPDFMBJJLFKGS-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[(2-tert-butyl-4-methylphenoxy)methyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound CC(C)(C)C1=CC(C)=CC=C1OCC1=CC=C(C=2N=C(CN(CC(O)=O)CC=3C=CC=CC=3)SC=2)C=C1 CPPDFMBJJLFKGS-UHFFFAOYSA-N 0.000 claims 1
- KJYQMPPDVHPFSK-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[(3,5-dichlorophenoxy)methyl]phenyl]thiophen-2-yl]methyl]amino]acetic acid Chemical compound C=1C=CC=CC=1CN(CC(=O)O)CC(SC=1)=CC=1C(C=C1)=CC=C1COC1=CC(Cl)=CC(Cl)=C1 KJYQMPPDVHPFSK-UHFFFAOYSA-N 0.000 claims 1
- KTVQEERQLJTYEO-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[(4-heptan-4-ylphenyl)methyl-methylamino]phenyl]-1,3-oxazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1CN(C)C1=CC=C(C=2N=C(CN(CC(O)=O)CC=3C=CC=CC=3)OC=2)C=C1 KTVQEERQLJTYEO-UHFFFAOYSA-N 0.000 claims 1
- VNJQYDMSAFUZFS-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[(4-heptan-4-ylphenyl)methyl-methylamino]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1CN(C)C1=CC=C(C=2N=C(CN(CC(O)=O)CC=3C=CC=CC=3)SC=2)C=C1 VNJQYDMSAFUZFS-UHFFFAOYSA-N 0.000 claims 1
- UULLUCNSAOHBIA-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[(4-heptan-4-ylphenyl)methylcarbamoyl]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(C(CCC)CCC)=CC=C1CNC(=O)C1=CC=C(C=2N=C(CN(CC(O)=O)CC=3C=CC=CC=3)SC=2)C=C1 UULLUCNSAOHBIA-UHFFFAOYSA-N 0.000 claims 1
- HSPKXJRHOGYEIN-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[2-[4-(2-methylpropyl)phenyl]ethylamino]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(CC(C)C)=CC=C1CCNC1=CC=C(C=2N=C(CN(CC(O)=O)CC=3C=CC=CC=3)SC=2)C=C1 HSPKXJRHOGYEIN-UHFFFAOYSA-N 0.000 claims 1
- AOUXEKWXKPZXAA-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[[2-(2,2-dimethylpropyl)benzimidazol-1-yl]methyl]phenyl]thiophen-2-yl]methyl]amino]acetic acid Chemical compound CC(C)(C)CC1=NC2=CC=CC=C2N1CC(C=C1)=CC=C1C(C=1)=CSC=1CN(CC(O)=O)CC1=CC=CC=C1 AOUXEKWXKPZXAA-UHFFFAOYSA-N 0.000 claims 1
- URQLZFZDNJDUFK-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[methyl-[(4-phenylphenyl)methyl]amino]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C=1C=C(C=2N=C(CN(CC(O)=O)CC=3C=CC=CC=3)SC=2)C=CC=1N(C)CC(C=C1)=CC=C1C1=CC=CC=C1 URQLZFZDNJDUFK-UHFFFAOYSA-N 0.000 claims 1
- QMICEPUQVVBWFC-UHFFFAOYSA-N 2-[benzyl-[[4-[4-[methyl-[[4-(3-methylbutylsulfanyl)phenyl]methyl]amino]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C1=CC(SCCC(C)C)=CC=C1CN(C)C1=CC=C(C=2N=C(CN(CC(O)=O)CC=3C=CC=CC=3)SC=2)C=C1 QMICEPUQVVBWFC-UHFFFAOYSA-N 0.000 claims 1
- FNQAIZNTRHTHBU-UHFFFAOYSA-N 2-[benzyl-[[4-[5-methyl-2-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,3-thiazol-2-yl]methyl]amino]acetic acid Chemical compound C=1SC(CN(CC(O)=O)CC=2C=CC=CC=2)=NC=1C1=CC(C)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 FNQAIZNTRHTHBU-UHFFFAOYSA-N 0.000 claims 1
- VVGYBXUTAXENTF-UHFFFAOYSA-N 2-[methyl-[[4-[4-[2-[4-(2-methylpropyl)phenyl]ethylamino]phenyl]-1,3-thiazol-2-yl]methyl]amino]-3-phenylpropanoic acid Chemical compound C1=CC(CC(C)C)=CC=C1CCNC1=CC=C(C=2N=C(CN(C)C(CC=3C=CC=CC=3)C(O)=O)SC=2)C=C1 VVGYBXUTAXENTF-UHFFFAOYSA-N 0.000 claims 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 1
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Landscapes
- Furan Compounds (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
: SPECIFICATION
HETEROAROMATIC PENTACYCLIC COMPOUND AND MEDICINAL USE THEREOF
The present invention relates to a novel 5-membered heteroaromatic ring compound. More particularly, the present invention relates to a 5-membered heteroaromatic ring compound having a protein tyrosine phosphatase 1B (PTP1B) inhibitory activity, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.
Diabetes causes various dysbolisms mainly characterized by a chronic state of high blood glucose level. It shows a broad range of symptoms based on high blood glucose level, such as mouth dryness, polydipsia, diuresis, loss of body weight and the like. When such a state of high blood glucose level lasts for a long time, it is known to cause all kinds of complications such as retinopathy, nephropathy, neuropathy, cardiac infarction and cerebral infarction based on arteriosclerosis, and the like.
Diabetes is generally classified into four types: type I diabetes (IDDM; insulin dependent diabetes mellitus) accompanying absolute insulin deficiency due to damage or destruction of pancreatic p cell; type II diabetes (NIDDM; non- insulin dependent diabetes mellitus) accompanying relative insulin deficiency due to insulin resistance and decreased insulin secretion; special diabetes secondarily developed by abnormality in gene, other diseases and the like; and gestational diabetes. In some cases, patients diagnosed with type II diabetes shortly after the onset may come to show decreased insulin secretion with the progression of the disease and ultimately lead to type I diabetes. )
To treat diabetes, it is essential to improve the above-
mentioned states of high blood glucose level and prevent the onset and progression of complications. For this end, there have been tried diet therapy, exercise therapy and the like, as well as treatments using a variety of pharmaceutical agents with the aim of controlling the blood glucose level to be within the normal range. As the representative existing pharmaceutical agents, there are mentioned insulin preparations, insulin secretagogues (sulfonylurea agent, sulfonamide agent, phenylalanine derivative etc.) that promote insulin secretion from pancreatic B cell, og-glucosidase inhibitors that delay sugar absorption, biguanide agents considered to have a liver glyconeogensis inhibitory action, wherein the detail of the mechanism is unknown, insulin sensitivity enhancers (thiazolidinedione derivative etc.) that promote differentiation from fibroblast to adipose cell via a peroxisome proliferator-activated receptor (PPAR) agonist action to increase the number of insulin sensitive cells and the like. However, all these are problematic in terms of effectiveness and safety (e.g., secondary failure due to fatigue of pancreatic @g cell, risk of hypoglycemia and promotion of obesity associated with insulin secretagogue, edema and adverse influence on the heart based thereon, anemia, overeating, promotion of obesity, presence of non-responder associated with insulin sensitivity enhancer and the like) and they fail to achieve sufficient control of blood glucose.
Referring to glucose metabolism in living organism, materials to be the energy source and constituent components of living organism have been intermittently taken into the body, and in contrast, for example, brain continuously consumes glucose. In this situation, the blood glucose level is maintained at a constant level, and blood glucose control is enabled by interaction among hormone involved in the blood glucose control, metabolism in organ, and exchange of saccharide and the like between organs. Of these, the action of insulin, which is a hormone particularly responsible for the blood glucose control, is significant, and disorders thereof, in other words insulin resistance and decreased insulin secretion, are considered to be deeply involved in diabetes.
Insulin is secreted from pancreatic B cell and binds with insulin receptor, which is a receptor type tyrosine kinase present on the membrane surface of its target cell or skeletal muscle cell and adipose cell, after which the tyrosine residue in the intracellular domain is auto-phosphorylated. Thereafter, the tyrosine residue of IRS (insulin receptor substrate), APS {adapter protein containing PH and SH2 domain) and the like, which is a substrate of an insulin receptor, is phosphorylated and PI; kinase-Akt pathway is activated, which in turn transfers a glucose transporter onto the cell membrane, causing glucose uptake and decreased blood glucose concentration. On the other hand, tyrosine phosphatase is also present, which performs tyrosine dephosphorylation to negatively control intracellular signaling by insulin, thereby suppressing the activation. As mentioned above, tyrosine phosphorylation plays a major role in the action of insulin. In consideration of the fact that tyrosine phosphorylation is determined by the balance of the activity of tyrosine kinase (phosphorylation enzyme) and that of tyrosine phosphatase (dephosphorylation enzyme), tyrosine phosphatase is considered to directly play a significant role in controlling insulin signaling together with tyrosine kinase.
At present, tyrosine phosphatase forms a large gene family, and more than seven dozen kinds of isozymes have been reported. Of these, protein tyrosine phosphatase 1B (PTP1B) is considered to be a major phosphatase involved in insulin ] signaling. Particularly, because gene expression of PTP1B increases in high glucose culture and changes in intracellular localization thereof decreases tyrosine phosphorylation of insulin receptor and IRS-1 and induces insulin resistance (J.
Biol. Chem., 1995, Vol. 270, pp. 7724-7730; J. Biochem. (Tokyo), 1998, Vol. 123, pp. 813-820), introduction of wild type PTP1B inhibits translocation of glucose transporter GLUT4, such effect was not found in phosphatase activity defective mutants, and insulin sensitivity was enhanced in PTP1B knockout mice and the mice became obesity resistant to a high fat diet (Science, 1999, Vol. 283, pp. 1544-1548), there is a possibility that this enzyme may become one target to enhance the action of from activation of insulin receptor to glucose uptake that insulin is responsible for. In fact, vanadic acid conventionally known as a tyrosine phosphatase inhibitor shows an insulin-like action in animal tests and the like.
Accordingly, a drug that suppresses and/or inhibits activation of such tyrosine phosphatase, particularly PTP1B, enhances the action up to glucose uptake by inhibiting an insulin receptor activated signal from being negatively controlled through dephosphorylation, and can be a new type of therapeutic agent for diabetes, which decreases blood glucose based on direct enhancement of insulin action. In addition, application to various therapeutic agents for diseases such as obesity, neurodegenerative disease and the like is expected.
There are various reports in recent years on compounds aiming at treatment of diseases, such as diabetes and the like, by inhibiting such protein tyrosine phosphatase.
For example, WO00/17211 discloses a phosphonic acid derivative having a PTP1B inhibitory activity. However, this publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof.
JP-T-11-508919 (U.S. Patent No. 5,770,620) discloses an arylacrylic acid derivative useful as a protein tyrosine phosphatase inhibitor. However, this publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof. 3 WO98/27092 (U.S. Patent No. 6,080,772) discloses a thiazole compound having a protein tyrosine phosphatase inhibitory action. However, this publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof. 10 W099/58522 discloses naphtho(2,3-Blheteroar-4-yl derivative, WO099/58511 discloses an oxa/thiazole-aryl- carboxylic acid derivative; W099/58521 and U.S. Patent No. 6,110,962 disclose a ll-aryl-benzo[B]lnaphtho[2,3-D] furan and ll-aryl-benzo[Blnaphtho[2,3-D]thiophene derivatives; W099/58518 15 discloses a biphenyl-oxo-acetic acid derivative; W099/61419 discloses a 2,3,5-substituted biphenyl derivative; W099/58520 discloses a biphenyl-sulfonyl-aryl-carboxylic acid derivative;
W099/61435 discloses benzothiophene, benzofuran and indole derivatives; U.S. Patent No. 6,103,708 discloses furan, 20 benzofuran and thiophene derivatives; U.S. Patent No. 6,110,963 discloses an aryl-oxo-acetic acid derivative; U.S. Patent No. 6,001,867 discloses a l-aryl-dibenzothiophene derivative; U.S.
Patent No. 6,057,316 discloses a 4-aryl-l-oxa-9-thia- cyclopenta({B] fluorene derivative; U.S. Patent No. 6,063,815 25 discloses a benzophenone derivative, each of which having a protein tyrosine phosphatase inhibitory action. However, these publications do not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof. 30 As a compound having a thiazole, thiophene or oxazole structure, the following have been reported.
WO000/45635 discloses a 2-substituted thiazole derivative.
However, this compound has a carbamoyl group at the terminal of the 2-position substituent of a thiazole ring, and this publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof. The compound of this ° publication is useful as an antibacterial agent or an analgesic agent, and this publication does not disclose usefulness as a
PTP1B inhibitor, not to mention any description suggestive thereof.
JP-T-2000-504039 discloses a 2-anilino-4-phenylthiazole derivative. However, the compound of this publication has an anilino group substituted by a hydroxyl group or a carboxyl group at the 2-position of thiazole ring, and phenyl group at the 4-position, wherein the phenyl group at the 4-position has a substituent at the 2-position. This publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof. In addition, the compound of this publication is useful as a CRF (corticotropin releasing factor) antagonist.
This publication does not disclose usefulness as a PTP1B inhibitor, not to mention any description suggestive thereof.
JP-A-4-154773 discloses a thiazole derivative of the formula 4
Behe ™
R30C X sg"
R2 : wherein R' and R? are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a substituted phenyl group, a pyridyl group or a substituted pyridyl group, R®> is a hydroxyl group, a lower. alkoxy group or a group represented by -N(R’) (R®) wherein R® and
R® are the same or different and each is a hydrogen atom or a lower alkyl group, R' is a hydrogen atom or a lower alkyl group, and X 1s an amino group, an amide group, a carbonyl group, an alkylene group, an oxygen atom or a sulfur atom. However, this ° publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof. In addition, the compound of this publication is useful as an anti-inflammatory agent. This publication does not disclose usefulness as a PTP1B inhibitor, not to mention any description suggestive thereof.
W094/08982 discloses a 4-phenylthiazole derivative.
However, the compound of this publication has a phenyl group at the 4-position of thiazole ring, and phenyl group at the 4- position, wherein the phenyl group at the 4-position has a substituent at the 2-position. This publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof. In addition, the compound of this publication is useful as a noxious organism eliminator. This publication does not disclose usefulness as a PTP1B inhibitor, not to mention any description suggestive thereof. :
W002/39997 discloses a compound represented by the formula
R® (CHa [ [10 (CHpq FR
R’ K 8 1
G ANG 0 wherein R® is a hydroxyl group or a protective prodrug moiety,
R’ is a hydrogen atom, a carboxy group, an arylaminocarbonyl group, an aroyl group, an aryl group, an alkylaminocarbonyl group, an aminocarbonyl group, an alkenylaminocarboxy group, a hydroxyl group, an alkoxy group, ether, thiol, an amino group- containing hetero ring group or a protective prodrug moiety, R® is a hydrogen atom or alkyl group that may bond with D to form a ring, R? is a lower alkyl group or a hydrogen atom, Q is a bond, an oxygen atom, a sulfur atom, CR®0H, CR®SH, CR’NR*R?®,
NR®, (CRR*),, O(CRR*®), or (CR’R*),0(CR®R*), wherein n is 0 or an integer of 1 to 3, R? R*, R™ and R* are each independently a hydrogen atom, an optionally substituted straight chain, a cyclic or branched chain C,-¢ alkyl group, a C,-¢ alkenyl group, an acyl group, an arylalkyl group, aryloxycarbonyl group, an arylaminocarbonyl group, an arylalkylsulfonyl group or an aryl group), G is a linking moiety, M is an anchor moiety, J is a bond, an alkylene group, an alkenylene group or an alkynylene group, D is a hydrogen atom, an alkoxy group, amine, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or a heteroaryl group that is bonded with G, M or Q to form a ring, t is 0 or 1, p is 0 or an integer of 1 to 5, and q is 0 or an integer of 1 to 3}, and : a compound represented by the formula 2b2a R R® 3ap3b oP PC NC p Ng
EN SC TR wherein P* is a carboxy group, a cleavable prodrug moiety,
COOP*', (CH,):-sSP' or C(O)NP''P*"', R’ is a hydrogen atom, a carboxy group, an optionally substituted lower alkyl ester, a lower alkenyl ester, an ester added with a secondary amine substituted by lower alkyl, an arylaminocarbonyl group, an aroyl group, an aryl group, an alkylaminocarbonyl group, an aminocarbonyl group, COOR’', CONR’'R’’’, a hydroxyl group, ether, thiol, an amino group, (CH.) 1-4SR’', a hetero ring group or a cleavable prodrug moiety, P*, P'’, R”" and R’"' are each independently a hydrogen atom, a C;-¢ alkyl group, a C;-¢ alkenyl group, a C;-s alkynyl group or an optionally substituted aryl group, R® is a hydrogen atom, an alkyl group or a covalent bond with D, R® is a lower alkyl group or a hydrogen atom, Q is a bond, an oxygen atom, a sulfur atom, CR?0H, CR’SH, CR’NR*R?,
NR?, (CR’R*),, 0(CRR®), or (CR’R’®),0(CR¥R’"), wherein n is 0 or an integer of 1 to 3, R®) R*, R® and R* are each independently a hydrogen atom, an optionally substituted C,.¢ straight chain or branched chain alkyl group, a C;-s straight chain or branched chain alkenyl group, an aryloxycarbonyl group, an arylaminocarbonyl group, an arylalkylsulfonyl group, an arylalkyl group, an optionally substituted acyl group, an aryl group or a Cs-g ring optionally substituted by 4 heteroatoms at maximum, P?*, P?®, P** and P® are each independently a hydrogen atom or an optionally substituted straight chain, branched chain or cyclic C;-s alkyl group, G is a linking moiety, M is an anchor moiety, J is a bond, an alkylene group, an alkenylene group or an alkynylene group, D is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or an aryl group or it may be bonded with G, M or Q to form a ring, t is 0 or 1, p is 0 or an integer of 1 to 5, and q is 0 or an integer of 1 to 3 and as examples of the anchor moiety in each formula, a thiazole group and an oxazole group having, as a substituent, an aryl group or a heteroaryl group substituted by -NR'R'', -
CONR'R'', -S(0);NR'R'’, -S{0)o-2R', -NR'R'’, -O(CR'R'')¢-,CF3, —-COR’, -CO,R' and -OR' wherein R' and R'' are each independently a hydrogen atom, a C;-¢ alkyl group, a C,-s alkenyl group, a Ci-s alkynyl group or an optionally substituted aryl group, and as examples of the linking moiety, a covalent bond and a C;-¢ alkyl group are described. > Furthermore, a compound represented by the formula
Rpt
GP
N,.\ ° ™p “ oo
S\L IE
AAT wherein M is.a carbon ring group, a hetero ring group or
CONR'R'' wherein R' and R'' are each independently a hydrogen atom, a Ci;-¢ alkyl group, a C;-s alkenyl group, a C;-s alkynyl group or an optionally substituted aryl group, Q is a bond, an oxygen atom, a sulfur atom, CR’0H, CR3SH, CR>NR*?R*®, NR?, (CR’R?**),, O(CR’R¥), or (CR’R**),0(CR¥®R?*), wherein n is 0 or an integer of 1 to 3, R?), R¥®, R® and R’° are each independently a hydrogen atom, an optionally substituted branched chain, a cyclic or a straight chain C;-¢ alkyl group, a C,.s alkenyl group, an acyl group, an arylalkyl group, an aryloxycarbonyl group, an arylaminocarbonyl group, an arylalkylsulfonyl group or an aryl group, K is an independently selected secondary linking moiety, 1, is an independently selected secondary anchor moiety, P' is a hydrogen atom, a carboxy group, (CH) 1-4SP*', a cleavable prodrug moiety, COOP! or CONP!'P'’', R’ is a hydrogen atom, a carboxy group, an aroyl group, an aryl group, COOR', C(O)NR'R'"’, a hydroxyl group, ether, thiol, (CH;):-4SR’’, a hetero ring group or a cleavable prodrug moiety, P*, P*"', R” and R’"’ are each independently a hydrogen atom, a C;-s alkyl group, a C;-¢ alkenyl group, a C;-¢ alkynyl group or an optionally substituted aryl group, n is 0 or an integer of 1 to 4, D is a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, amine, a hydroxyl group, an alkynyl group, an aryl group or a heteroaryl group, and t is 0 or 1, is described and that it is described that the secondary linking moiety has a covalent bond, and the secondary anchor moiety has an optionally substituted aryl group.
However, this publication does not disclose a compound having a structure of the compound of the present invention, not to mention any description suggestive thereof.
In addition, the compound of this publication is useful as an angiotensin converting enzyme (ACE)-2 regulating agent.
This publication does not disclose usefulness as a PTP1B inhibitor, not to mention any description suggestive thereof.
As reports on a compound having a thiazole or oxazole structure, which aims at treating not only diabetes but also hyperlipidemia by inhibiting PTP1B, the following can be mentioned.
JP-A-2003-231679 discloses an azole compound represented by the formula
RZ R RS
OE /. Ne "TU, If / [1 ~~
J . having a PTP1B inhibitory activity, and teaches that this compound is useful as a therapeutic agent for hyperlipidemia.
However, the compound of this publication is essentially characterized in that nitrogen atom or carbonyl group at the substituent A should be adjacent to carbon atom at the 2- position of thiazole or oxazole, or A is an alkylene; a bond between A and benzene ring is essential; and nitrogen atom, oXygen atom, sulfur atom or carbonyl group at the substituent
R® should be adjacent to ring B, or R® is linked to a ring structure via an alkylene or a single bond is essential, and this publication does not disclose a compound having a structure of the compound of the present invention. In addition, this publication does not describe that the PTP1B inhibitory activity of this compound is higher than the activity of other protein tyrosine phosphatases.
As reports on a method using plural therapeutic drugs for diabetes or other diseases in combination, the following can be mentioned.
JP-A-9-67271 discloses a combination of an insulin sensitivity enhancer with an insulin preparation, an insulin secretagogue, an g-glucosidase inhibitor, a biguanide agent and the like. However, this publication does not disclose a
PTP1B inhibitor or an inhibitor of receptor tyrosine kinase negative regulator such as the compound of the present invention, not to mention any description suggestive thereof.
WO002/100846 discloses a thiophene derivative compound having the formula
R\ R® : Mn A
Y
7”
R* wherein M is selected from -SO,-, -C=0-, -C=S-, etc.; A' is selected from a bond, a C;-s alkyl, a C,.¢ alkenyl, etc. : A is selected from COOR®, CO-COOR®, POsR°R®, etc., wherein each R® is independently selected from a hydrogen atom and C,-s alkyl; R!
and R? are independently selected from a hydrogen atom, a Ci-s alkyl, a Ce-12 aryl, etc.:; R® is selected from a Cg-1z aryl, a Cai. heterocycle, a Ce, aralkyl, etc.; Y is selected from a bond, -CHz-, -CO-, etc.; Z is selected from a C;.¢ alkyl, a Cis ° alkenyl, a Cz.¢ alkynyl, etc.; R! is selected from a hydrogen atom, halogen, CN, NO,, etc.; or a salt thereof.
WO 02/34711 discloses a thiophene derivative compound having the formula
R B'
EWE
X (RY,
VV
1 (A) wherein 10 g! and L are each independently selected from a 5- to 7- membered saturated or unsaturated carbon ring, a 5- to 7- membered saturated or unsaturated hetero ring, a bicyclic saturated or unsaturated carbon ring, etc.; R is selected from -CH=CH-R?, -C=C-R®, ~C(R®)=CH, etc.; R!' is selected from a hydrogen atom, -R, -NO;, etc.; m is 1 or higher; R? is selected from a hydrogen atom, a halogen, an alkyl, etc.; W is selected from a direct bond, -CHR?-, ~CH=CR®*-, etc.; E? is selected from a 5- to 7- membered saturated or unsaturated carbon ring, a 5- to 7- membered saturated or unsaturated hetero ring, a bicyclic ring system, etc.; each X is independently selected from a direct bond, a substituted or unsubstituted C;-4 methylene chain, 0, etc., wherein said X at different places may be the same or different; B is selected from a hydrogen atom, -halo, -CN, etc.; B! is selected from B, wherein said B! and B may be the same or different; p is 1 or higher depending upon the size of the ring; A is selected from R' when o is 1, except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring; V and V! are each independently selected from R!' and N-alkyl substituted carboxamidyl (CONHR) wherein the alkyl group may be straight, branched, cyclic, or bicyclic, etc.; and n is 0 to 4.
WO 98/28264 discloses a thiophene derivative compound having the following formula pz
K—M wherein B is N; A is selected from a Cis alkylsulfonyl, a Cig cycloalkylsulfonyl, a Ci; cycloalkyl-Ci-¢ alkylsulfonyl, each of which is optionally mono-, di- or tri- substituted with a hydroxy group, a C;-4 alkyl or a halogen atom; QO is a -Cj-g alkylene-W-C,_3 alkylene- or a -Cs-g alkylene-, said -Cs-g alkylene- is optionally substituted with up to four substituents independently selected from a fluorine atom, a Ci. alkyl, -X-Ci-s alkylene-, etc., wherein X is a 5- or 6- membered aromatic ring optionally having one or two heteroatoms selected independently from an oxygen atom, a nitrogen atom and a sulfur atom; Z is carboxyl, a Ci-¢ alkoxycarbonyl, tetrazolyl, etc.; K is a bond, a C;s alkylene, a thio(C;-4)alkylene, etc., wherein said Cj-s alkylene is optionally mono-unsaturated and said K is optionally mono-, di- or tri-substituted with a fluorine atom, methyl or chlorine atom; and M is -Ar, -Ar'-V-AP, -Arl-s-ap, etc., wherein Ar, Ar! and AP are each independently selected from a partially saturated, fully saturated or fully ynsaturated 5- to 8- membered ring optionally having one to four heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, etc.; or a pharmaceutically acceptable salt thereof or a prodrug thereof. :
Furthermore, WO 01/26656 (JP-A-2003-511416) discloses a compound having the following formula
Q
2 19
R*! R 2
R
R!
SX
X
B wherein Q is -NR'*R‘Y’ or -OR!®, wherein R‘® and R!’ are each independently selected from a hydrogen atom, an alkyl, a cycloalkyl, etc., and R*® is selected from a hydrogen atom, an ° alkyl, an alkynyl, etc.; B is a hydrogen atom or an alkyl; Q is selected from a hydrogen atom, -OR??, -SR??, etc., wherein R? is selected from a hydrogen atom, an alkyl, an aryl optionally substituted with an alkyl, a hydroxyl group, a halogen atom, etc., etc.; RY’, R?® and R* are each independently selected from a hydrogen atom, a halogen atom, a hydroxy group, etc.; X is NH or S; N is 0 to 6; R' and R? are each selected from a hydrogen atom, an alkyl and a cycloalkyl.
WO 97/30053 discloses a compound having the following formula
RP R* R° :
N rR Nh 6
Re R12 y/ R } ,
R' R wherein R!' is a hydrogen atom, a lower alkyl, a cycloalkylthio or a lower alkylthio, and R? and R® are each independently a hydrogen atom or a lower alkyl; or R' and R? may form -CH,-, -
CO- or -C(CHs3)2—; R* is H2 or O; R®° is selected from a hydrogen atom, a substituted or unsubstituted lower alkyl, a lower alkenyl, etc.; R® and R’ are each independently selected from a hydrogen atom, -C(O)NHCHRCO,R', a substituted or unsubstituted lower alkyl, etc., wherein R!® is selected from a substituted or unsubstituted lower alkyl, etc., and R' is a hydrogen atom or lower alkyl, or R® and R’ may form an aryl or
Claims (113)
1. (amended) A S5-membered heteroaromatic ring compound represented by the formula [I] SF ae Fae : Vo oo A, Co . A= eHgXeenm Cad) Jom RE Sn A WET See Y—(A);—Z wherein V is =N- or =CH-; W is -S~ or -0-; mis 0, 1 or 2; R' and R? are each independently a hydrogen atom or a Ci-4 alkyl group; X is -N(R')-, -N(R®)-CO-0-, =-SO0,~N(R®)-, -N(R®)-S50,-, -N(R®)~SO.- N(R®)-, -CO-N(R’)-, -N(R®)-CO-, -N(R®)-CO-N(R®)-, -N(R'®)-(CHz)x~ N(R%)-, -N(R'®)-(CHp)x~N(R®)~-CO-, -C(R)=N-N(R’)-, =N(R')~(CHz)k" CH(R®)-, -0-, -S- or -SOz- wherein k is 0 or an integer of 1 to 4, RY, R°, R% R’, R% R’ and R! are each independently (1) a hydrogen atom, (2) a Ci-¢ alkyl group wherein said Ci-¢ alkyl group is optionally substituted by (a) an optionally substituted aryl group, (b) an optionally substituted heteroaromatic ring group, (c) a carboxy group, (d) a Cy1-4 alkoxycarbonyl group, (e) -CO-N(R™) (R'®) wherein R!® and R!® are each independently a hydrogen atom, an optionally substituted aryl group, an optionally substituted heteroaromatic ring group, a Ci-s alkyl group wherein said Ci. alkyl group is optionally substituted by substituent(s) selected from the group consisting of an optionally substituted AMENDED SHEET aryl group, an optionally substituted heteroaromatic ring group, a Cy-4 alkoxy group optionally substituted by an aryl group and an optionally substituted aryloxy group, or, together with the nitrogen atom bonded thereto, may form an indoline ring or may form a 5- to 7-membered hetero ring optionally further containing at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, (£) -N(R™) (R') wherein R'> and R'® are as defined above, (g) -0-RY wherein RY is a hydrogen atom, an optionally substituted aryl group, an optionally substituted heteroaromatic ring group or a Ci-s alkyl group wherein said C;.¢ alkyl group is optionally substituted by substituent(s) selected from the group consisting of an optionally substituted aryl group, an optionally substituted heteroaromatic ring group, a C;-; alkoxy group optionally substituted by an aryl group and an optionally substituted aryloxy group, (h) -co-rRY wherein RY is as defined above, (i) -S0.-RY wherein RY is as defined above or (Jj) a Cs. cycloalkyl group, (3) -CO-N(R') (R*®) wherein R'® and R'® are as defined above, (4) -SOz-N(R'®) (R'®) wherein R'® and R!'® are as defined above, (5) -co-rY wherein R'’ is as defined above, (6) -SO,-RY wherein R!’ is as defined above, (7) an optionally substituted aryl group, (8) an optionally substituted heteroaromatic ring group, or 449 AMENDED SHEET
(9) R* and R! are optionally linked to form OR | ii wherein i and j are each independently 0, 1 or 2 and R’? is as defined above, (10) R® and R® are optionally linked to form C0 wherein a and b are each independently 0, 1 or 2, (11) R® and R!° are optionally linked to form a Me rr remy a wherein kl and c are each independently O or an integer of 1 to 4, (12) R® and R!° are optionally linked to form Qe wherein d and e are each independently 0, 1 or 2, (13) R® and R!? are optionally linked to form k1 —N Cc wherein kl and c¢ are as defined above, or (14) R’ and R'° are optionally linked to form N _& “N— \—~R" wherein R!” is a hydrogen atom or a C,¢ alkyl group; n is 0 or an integer of 1 to 4; p is 0 or 1; L is (1) CSCROHRT- wherein R?® is (a) a hydrogen atom, (b) a C;-¢ alkyl group, or (¢) optionally linked with R* or R® to form g \ bs 21 \ aso ni wherein nl and gq are each independently 0 or an integer of 1 to 4, R” is a hydrogen atom, a hydroxyl group, a C;-¢ alkyl group, a carboxy group or a Ci alkoxy group, or (d) optionally linked with R' to form ; , : So i Ch RY N~— SE oo i.
wherein u and v are each independently 0, 1 or 2,
R?! is a hydrogen atom, a C;-¢ alkyl group wherein said Ci alkyl group is optionally substituted by an optionally substituted aryl group or an optionally substituted heteroaromatic ring group, an optionally substituted aryl group or an optionally substituted heteroaromatic ring group,
(2) fl an wherein
E is an aryl group or a heteroaromatic ring group, R* is
(a) a hydrogen atom, (b) a halogen atom, (c) a Ci-4 alkyl group,
(d) a C;-4 alkoxy group optionally substituted by a carboxy group,
(e) a Ci-¢ alkylthio group, (f) a nitro group, (g) -N(R?) (R*)
wherein R?® and R* are each independently a hydrogen atom, a C;- ¢ alkyl group, a C;-s alkylcarbonyl group wherein said Cj alkylcarbonyl group is optionally substituted by an amino group, a C;-4 alkylamino group or a di (C;-4 alkyl)amino group, or a Ci-4 alkylsulfonyl group, or
(h) optionally linked with R* to form wherein n2 and w are each independently O or an integer of 1 to
AMENDED SHEET
3 and E is as defined above, (i) optionally linked with R* to form wherein n3 and x are each independently 0 or 1 and E is as defined above, (j) optionally linked with R’ to form LL Mo BR EES a oo oo wherein n4 and y are each independently 0, 1 or 2 and E is as defined above, (x) optionally linked with R’ to form " Sn 0. ~ RRR BE ERIE wherein n5 and z are each independently 0 or 1 and E is as defined above, (1) optionally linked with R® to form
0 o. oo wherein n2 and w are each independently 0 or an integer of 1 to 3 and E is as defined above, or (m) optionally linked with RY to form N—— V7,
wherein E is as defined above or permet ne nS > wherein R?°, R? and E are as defined above, R?® is (a) a hydrogen atom, (b) a halogen atom, (¢) a C,-4 alkyl group, (d) a Ci-4 alkoxy group optionally substituted by a carboxy group, (e) a Cis alkylthio group, (f) a nitro group or (g) -N(R®’) (R) wherein R*’ and R” are as defined above; R is -COO(R'®), -A'-COO(R'®’) or -0-A'-COO(R'®) wherein A! is a C;-4 alkylene group and R'? is a hydrogen atom or a C;-4 alkyl group; B is an aryl group or a heteroaromatic ring group; R’ is (1) a hydrogen atom, (2) a halogen atom, (3) a Cy-g alkyl group, (4) a C,-s alkoxy group, (5) a Cj-¢ alkylamino group, (6) a di(Ci-¢ alkyl)amino group, (7) a cyano group, (8) a nitro group, (9) a C;-4 haloalkyl group, 454 AMENDED SHEET
(10) -S-R'® wherein R!® is a Cis alkyl group or an aryl group, (11) -SO-R'® wherein R!® is a C;¢ alkyl group or an aryl group, (12) -S0,-R'® wherein R!® is a Cj alkyl group or an aryl group, (13) an aryl group or ° (14) a heterocyclic group; Y is -0-, -S-, =-S0-, -SO,-, -N(R')-, -N(R'?)-CO-, -N(R'?)-S0,-, -S0,-N (R*?)-, -C(R) (R")-, -CO-, -C(R"®) (R!)-N(R*)-, -CO-N(R'?)- or -C(RY) (R")-0- wherein Rr is (1) a hydrogen atom, (2) a C;-g alkyl group wherein said C;.g alkyl group is optionally substituted by substituent (s) selected from the group consisting of (a) a Cs.7 cycloalkyl group, (b) an optionally substituted aryl group, (c) an optionally substituted heterocyclic group, (d} a hydroxyl group, (e) a Ci-4 alkylamino group and (f) a di(Cj-4 alkyl)amino group, (3) a C;-4 alkenyl group, (4) a Ci4 alkylsulfonyl group, (5) a C4 alkylcarbonyl group wherein said C;-4 alkylcarbonyl group is optionally substituted by a hydroxyl group or a C;.q4 alkoxy group, or (6) optionally linked with R® to form wherein t is an integer of 1 to 4 and B is as defined above, R'? is (1) a hydrogen atom, (2) a Cig alkyl group 455 AMENDED SHEET wherein said C;-g alkyl group is optionally substituted by substituent (s) selected from the group consisting of (a) a Ci-7 cycloalkyl group, (b) an optionally substituted aryl group, > (c) an optionally substituted heterocyclic group, (d) a hydroxyl group, (e) a C;-4 alkylamino group and (f) a di(C;-4 alkyl)amino group, (3) a Cy-4 alkenyl group, (4) a Ci.4 alkylsulfonyl group or (5) a Cj-4 alkylcarbonyl group wherein said C;-4 alkylcarbonyl group is optionally substituted by a hydroxyl group or a C;-4 alkoxy group, R!® and R!* are each independently a hydrogen atom, a C;-4 alkyl group, or optionally form a Cs-; cycloalkane together with the carbon atom bonded thereto, or optionally form, together with the carbon atom bonded thereto, a 5- to 7-membered hetero ring optionally having at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, provided that, when m is 0, p is 1 and L is er Ce)omier- SRR B22 or LO "i E HERE wherein R?® and R? are each a hydrogen atom, E is a phenyl group, R?? is a hydrogen atom, a halogen atom, a Cis alkyl group, a C,-4 alkoxy group or a nitro group, and R* is a hydrogen atom, a halogen atom, a C;-4 alkyl group, a C;-4 alkoxy group or a nitro group, Y should be —C(R'?) (R*)-N(R!?)-, -CO-N(R})- or -C(R") (R'*)-0- wherein RY, R! and R' are as defined above; 456 AMENDED SHEET
Ss is 0 or 1; A is a C;.4 alkylene group optionally substituted by a Cs-s cycloalkyl group: Z is (1) a Cs; cycloalkyl group wherein said Cs.» cycloalkyl group is optionally substituted by an aryl group wherein said aryl group is optionally substituted by a halogen atom or a Ci-¢ alkyl group, or a heteroaromatic ring group wherein said heteroaromatic ring group is optionally sybstituted by a halogen atom or a C;-s alkyl group, (2) an aryl group wherein said aryl group is substituted by substituent (s) selected from the group consisting of (a) a heterocyclic group optionally substituted by a Ci alkyl group or a Ci-4 alkylcarbonyl group,
(b) a Cs-7 cycloalkyl group optionally substituted by a hydroxyl group, an oxo group, a halogen atom or a Ci-s alkyl group,
{c) a carboxy group,
(d) a halogen atom,
(e) a Ci-g alkyl group,
(f) a Ci-4 haloalkyl group,
(g) a Ci-q alkylamino group,
(h) a di(C;-4 alkyl)amino group,
(i) a C,-¢ alkylthio group,
(J) a Ci-q4 alkoxy group,
(k) a Ci-4 alkylcarbonyl group and
(1) a nitro group,
(3) a heteroaromatic ring group wherein said heteroaromatic ring group is optionally substituted by substituent (s) selected from the group consisting of
(a) a heterocyclic group optionally substituted by a Ci-4 alkyl
457 AMENDED SHEET group or a C;-4 alkylcarbonyl group, (b) a Cs-7 cycloalkyl group optionally substituted by a hydroxyl group, an oxo group, a halogen atom or a C;-s alkyl group, (c) a carboxy group, (d) a halogen atom, (e) a C;-g alkyl group, (f) a C;-4 haloalkyl group, (g) a Ci-4 alkylamino group, (h) a di(Cy-4 alkyl)amino group, (i) a C;-¢ alkylthio group, (J) a Cj-4 alkoxy group, (k) a Ci-4 alkylcarbonyl group and (1) an aryl group optionally substituted by a halogen atom or a C;-4 haloalkyl group, (4) an indanyl group or (5) a piperazinyl group wherein said piperazinyl group is optionally substituted by substituent (s) selected from the group consisting of (a) a phenyl group, (b) a phenyl C;., alkyl group, (c) a benzoyl group optionally substituted by a halogen atom and (d) a phenyl C;-; alkoxycarbonyl group or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
2. (amended) The 5-membered heteroaromatic ring compound of claim 1, which is represented by the formula [I] %0 a ES Gd J ERA | Y—(A);—Z 458 AMENDED SHEET wherein RE V is =N- or =CH-;
W is -S- or -0-;
mis 0, 1 or 2;
R! and R? are each independently a hydrogen atom or a Ci-4 alkyl group;
X is -N(R')-, -N(R®)-CO-0-, =-SO,-N(R°)-, -N(R®)-SO,-, =-N(R®)-S0.- N(R%)-, -CO-N(R")-, -N(R%)-CO-, -N(R®)-CO-N(R®)-, =N(R'®)-(CHp)~ N(R®)-, -0O-, -S- or -SO;-
wherein k is 0 or an integer of 1 to 4,
RY, R®, R% R’, R% R® and R'® are each independently
(1) a hydrogen atom,
(2) a Ci-¢ alkyl group wherein said Ci. alkyl group is optionally substituted by
(a) an optionally substituted aryl group, (b) an optionally substituted heteroaromatic ring group, (c) a carboxy group, {d) a Ci-4 alkoxycarbonyl group,
(e) -CO-N(R") (R*) wherein R!® and R!® are each independently a hydrogen atom, an optionally substituted aryl group, an optionally substituted heteroaromatic ring group, a C;-¢ alkyl group wherein said Ci-¢ alkyl group is optionally substituted by substituent (s)
gelected from the group consisting of an optionally substituted aryl group, an optionally substituted heteroaromatic ring group, a C;-4 alkoxy group optionally substituted by an aryl group and an optionally substituted aryloxy group, or, together with the nitrogen atom bonded thereto, may form an indoline ring or may form a 5- to 7T-membered hetero ring optionally further containing at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom,
(f) -N(R'®) (R') 459 AMENDED SHEET wherein R'® and R'® are as defined above, (g) -o-rY wherein R'’ is a hydrogen atom, an optionally substituted aryl group, an optionally substituted heteroaromatic ring group or a (Ci-¢ alkyl group wherein said C;-¢ alkyl group is optionally substituted by substituent (s) selected from the group consisting of an optionally substituted aryl group, an optionally substituted heteroaromatic ring group, a C,-4 alkoxy group optionally substituted by an aryl group and an optionally substituted aryloxy group, (h) -co-rY wherein R'’ is as defined above, (i) -S0,-RY wherein R!’ is as defined above or (4) a Cs.» cycloalkyl group, (3) -CO-N(R') (R'®) wherein R!® and R'® are as defined above, (4) ~SO.-N(R'®) (R'®) wherein R!® and R!'® are as defined above, (5) -co-RY : wherein R!’ is as defined above, (6) -SO,-RY’ wherein R!’ is as defined above, (7) an optionally substituted aryl group, (8) an optionally substituted heteroaromatic ring group, or (9) R* and R' are optionally linked to form © ) Go | A oo TE wherein i and j are each independently 0, 1 or 2 and R® is as 460 AMENDED SHEET defined above, (10) R® and R’ are optionally linked to form wherein a and b are each independently 0, 1 or 2, (11) R® and R!® are optionally linked to form Pe wherein kl1 and c are each independently 0 or an integer of 1 to 4, or (12) R® and R!° are optionally linked to form 0 h: . pi E - oo Co oo : p i wherein d and e are each independently 0, 1 or 2; n is 0 or an integer of 1 to 4; p is 0 or 1; L is (1) SCRORT- ANE IIL EL a oH wherein R?? is (a) a hydrogen atom, (b) a C,-¢ alkyl group, or (c) optionally linked with R* to form wherein nl and q are each independently O or an integer of 1 to 4, or (d) optionally linked with R' to form wherein u and v are each independently 0, 1 or 2, R?! is a hydrogen atom, a Ci; alkyl group wherein said Ci; alkyl group is optionally substituted by an optionally substituted aryl group or an optionally substituted heteroaromatic ring group, an optionally substituted aryl group or an optionally substituted heteroaromatic ring group, (2) wherein FE is an aryl group or a heteroaromatic ring group, R?? is (a) a hydrogen atom, (b) a halogen atom, (c) a C;-4 alkyl group, (d) a C;-4 alkoxy group optionally substituted by a carboxy group, (e) a Ci-¢ alkylthio group, (f) a nitro group,
(g) -N(R*) (R*) wherein R?® and R?! are each independently a hydrogen atom, a Ci- 6 alkyl group, a Ci-¢ alkylcarbonyl group wherein said Cis alkylcarbonyl group is optionally substituted by an amino group, a C;-4 alkylamino group or a di(C;-4 alkyl)amino group, or a Ci-s alkylsulfonyl group, or (h) optionally linked with R' to form Nw ES Ln wherein n2 and w are each independently 0 or an integer of 1 to 3 and E is as defined above, (i) optionally linked with R’ to form ch oo FRE ER EL Ung REE - 8 wherein n3 and x are each independently 0 or 1 and E is as defined above, (j) optionally linked with R’ to form “he O EEE wherein n4 and y are each independently 0, 1 or 2 and E is as defined above, (k) optionally linked with R’ to form p z \ Cl RE LE NE CO Ne— Co oo ol Fo : Yo Te oo RED wherein n5 and z are each independently 0 or 1 and E is as defined above, or (1) optionally linked with R® to form N Co SE on oo ED Oo EE A oo No wherein n2 and w are each independently 0 or an integer of 1 to 3 and E is as defined above, or (3) NGL I A CE wherein R?°, R?! and E are as defined above, R®® is (a) a hydrogen atom, (b) a halogen atom, (c}) a Ci-4 alkyl group, (d) a Ci-4 alkoxy group optionally substituted by a carboxy group, (e) a Ci-¢ alkylthio group, (f) a nitro group or (g) -N(R*?) (R*) wherein R?’ and R?' are as defined above; R is -COO(R'®), -A'-COO(R'®) or -O-A'-COO(R'®) wherein A! is a C;.4 alkylene group and R!’ is a hydrogen atom or a Ci-4 alkyl group; B is an aryl group or a heteroaromatic ring group; R? is (1) a hydrogen atom, (2) a halogen atom, (3) a C;-g alkyl group, AMENDED SHE ET
(4) a Ci-¢ alkoxy group, (5) a C;-¢ alkylamino group, (6) a di(C;-¢ alkyl)amino group, (7) a cyano group, (8) a nitro group, (9) a Cj;-q haloalkyl group, (10) -S-R'® wherein R!® is a C;.s alkyl group or an aryl group, (11) -SO-R!® wherein R!® is a Ci. alkyl group or an aryl group, or (12) -S0,-R'® wherein R*® is a C;¢ alkyl group or an aryl group; Y is -0-, -S-, -SO-, -S0;-, -N(R')-, -N(R'?)-CO-, -N(R'?)-S0,-, -50,-N (R'?) =, -C(R™) (R")-, -CO-, -C(R'®) (R*)-N(R')-, -CO-N(R'*)- or -C (RY) (RY) -0- wherein RY is (1) a hydrogen atom, (2) a Ci-g alkyl group wherein said C,-s alkyl group is optionally substituted by substituent (s) selected from the group consisting of (a) a Cs-7 cycloalkyl group, (b) an optionally substituted aryl group, (c) an optionally substituted heterocyclic group, (d) a hydroxyl group, (e) a Ci-4 alkylamino group and (f) a di(C,.; alkyl)amino group, (3) a Cz-4 alkenyl group, (4) a Ci-¢ alkylsulfonyl group, (5) a Cy-4 alkylcarbonyl group wherein said Ci.4 alkylcarbonyl group is optionally substituted py a hydroxyl group or a C;-4 alkoxy group, or (6) optionally linked with R® to form 465 AMENDED SHEET wherein t is an integer of 1 to 4 and B is as defined above, R'? is (1) a hydrogen atom, (2) a Cis alkyl group wherein said C;-g alkyl group is optionally substituted by substituent (s) selected from the group consisting of (a) a Cs-7 cycloalkyl group, (b) an optionally substituted aryl group, (¢) an optionally substituted heterocyclic group, (d) a hydroxyl group, (e) a Ci-4 alkylamino group and (f) a di(Ci-4 alkyl)amino group, (3) a Cy-4 alkenyl group, (4) a C;-4 alkylsulfonyl group or (5) a C;-4 alkylcarbonyl group wherein said C;-4 alkylcarbonyl group is optionally substituted by a hydroxyl group or a C;-; alkoxy group, R!® and R!! are each independently a hydrogen atom, a C;-4 alkyl group, or optionally form a Cs; cycloalkane together with the carbon atom bonded thereto, or optionally form, together with the carbon atom bonded thereto, a 5- to 7-membered hetero ring optionally having at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, provided that, when m is 0, p is 1 and L is Rs | T(eren- Er Co Zo or hci ER iy a RE wherein R?° and R?! are each a hydrogen atom, E is a phenyl 466 AMENDED SHEET group, R*’ is a hydrogen atom, a halogen atom, a Ci-4 alkyl group, a Cis alkoxy group or a nitro group, and R*® is a hydrogen atom, a halogen atom, a C;-4 alkyl group, a Cj-¢ alkoXy group or a nitro group, Y should be -C (RY) (RM) -N(R'?)-, -CO-N(R'?)- or -C(R"®) (R'*)-0- wherein RY, R'® and R!Y are as defined above; s is 0 or 1; A is a C;-4 alkylene group optionally substituted by a Cs cycloalkyl group; Z is (1) a Cs-7 cycloalkyl group wherein said Cs-7 cycloalkyl group is optionally substituted by an aryl group wherein said aryl group is optionally substituted by a halogen atom or a Ci-¢ alkyl group, or a heteroaromatic ring group wherein said heteroaromatic ring group is optionally substituted by a halogen atom or a C;-¢ alkyl group, (2) an aryl group wherein said aryl group is substituted by substituent (s) selected from the group consisting of (a) a heterocyclic group optionally substituted by a Ci-4 alkyl group or a C;-4 alkylcarbonyl group, : (b) a Cs-7 cycloalkyl group optionally substituted by a hydroxyl group, an oxo group, a halogen atom or a C;-¢ alkyl group, (c) a carboxy group, (d) a halogen atom, {e} a Ci-g alkyl group, (f) a Ci-4 haloalkyl group, (g) a Ci-4 alkylamino group, (h) a di(Cj-4 alkyl)amino group, (i) a Ci-¢ alkylthio group, (§) a Ci-4 alkoxy group, and 467 AMENDED SHEET
(k) a Cia alkylcarbonyl group, (3) a heteroaromatic ring group wherein said heteroaromatic ring group is optionally substituted by substituent (s) selected from the group consisting of (a) a heterocyclic group optionally substituted by a Cys alkyl group or a C;-4 alkylcarbonyl group, (b) a Ci3-7 cycloalkyl group optionally substituted by a hydroxyl group, an oxo group, a halogen atom or a Ci;-¢ alkyl group, (c) a carboxy group, (d) a halogen atom, (e) a C;-g alkyl group, (f) a Ci-4 haloalkyl group, (g) a C;-4 alkylamino group, (h) a di(C;-4 alkyl)amino group, (1) a Ci;-¢ alkylthio group, (J) a Ci-q alkoxy group, (k) a Cj-4 alkylcarbonyl group and (1) an aryl group optionally substituted by a halogen atom or a Ci-4 haloalkyl group, (4) an indanyl group or (5) a piperazinyl group wherein said piperazinyl group is optionally substituted by substituent (s) selected from the group consisting of (a) a phenyl group, (b) a phenyl C,.4 alkyl group, (c) a benzoyl group optionally substituted by a halogen atom and (d) a phenyl C,.; alkoxycarbonyl group or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 468 AMENDED SHEET
3. The 5-membered heteroaromatic ring compound of claim 1, wherein, in the formula [I], R’ is (1) a hydrogen atom, > (2) a halogen atom, (3) a Ci-¢ alkyl group or (4) a C;-4 alkoxy group; Y is -0-, -N(R')-, -N(R'?)-co-, -C (RY) (R')-, -C(R"®) (R")- N(R'?)-, -CO-N(R'Y)- or -C(R'®) (R'*)-0- wherein RY is (1) a hydrogen atom, (2) a Ci-g alkyl group, or (3) optionally linked with R® to form wherein t is 3 and B is as defined in claim 2 above, R!? is a hydrogen atom or a C;-g alkyl group, R}® and R!* are each a hydrogen atom provided that when m is 0, p is 1, and L is =20, (21, EE or “Cem JR > St wherein R?° and R* are each a hydrogen atom, E is a phenyl group, R?? is a hydrogen atom, a Cj;-4 alkoxy group or a nitro group, and R*”* is a hydrogen atom, a Ci-s4 alkoxy group or a nitro group, Y should be 469 AMENDED SHEET
-C(R"®) (R'*)-N (R'?)-, -CO-N(R')- or -C (RY) (R')-0- wherein RY, R'® and R'* are as defined above; s is 0 or 1; A is a C;-4 alkylene group; ° Z is an aryl group substituted by substituent (s) selected from the group consisting of (a) a Cs3-7 cycloalkyl group optionally substituted by 1 to 3 substituent (s) selected from the group consisting of a halogen atom and a C;-¢ alkyl group, (pb) a halogen atom, (c) Ci-s alkyl group, (d} a C;-4 haloalkyl group, (e} a di(Cy-4 alkyl)amino group, (f) a Ci-¢ alkylthio group and (g) a C;-4 alkylcarbonyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
4. The 5-membered heteroaromatic ring compound of claim 3, wherein V is =N- and W is -S- or -O0-, or V is =CH- and W is -S-, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
5. The 5-membered heteroaromatic ring compound of claim 4, wherein Z is a phenyl group substituted by a Ci-s alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
6. The 5-membered heteroaromatic ring compound of claim 5, wherein Y is -C(R'®) (R')-N(R'?)- or -C(R!®) (R'")-0- wherein RY, R!?® and R'Y are as defined in claim 3 and s is 0, or Y is -O- or -N(R)- wherein R} is as defined in claim 3, s is 1, and A is a methylene group, or a prodrug thereof, or a pharmaceutically 470 AMENDED SHEET acceptable salt thereof.
7. The 5-membered heteroaromatic ring compound of claim 6, wherein V is =CH-, W is -S-, and the position of substitution of B on the thiophene ring formed by V together with W is the 4-position or 5-position, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
8. The 5-membered heteroaromatic ring compound of claim 7, wherein B is a phenyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
9. The 5-membered heteroaromatic ring compound of claim 8, wherein mis 1; R! and R? are each a hydrogen atom; X is -N(R*)- or -0O- wherein R! is a Ci; alkyl group optionally substituted by (a) an aryl group, (pb) an heteroaromatic ring group optionally substituted by 1 to 3 Cig alkyl groups or (c) —-CO-N(R'®) (R'®) wherein R!® and R'® are each independently a hydrogen atom or an aryl group wherein said aryl group is optionally substituted by 1 to 3 Ci;-g alkyl groups; n is 0 or 1; p is 0 or 1; L is (1) ooe®@E- wherein R?® is linked with R! to form 471 AMENDED SHEET
RE — SRI . wherein u is 1, v is 1 and R® is as defined above, R?* is a hydrogen atom, or (2) - 22 Ce Co - wherein E is an heteroaromatic ring group and R?? is a hydrogen atom; R is -COO(R') wherein R'® is a hydrogen atom, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
10. The 5-membered heteroaromatic ring compound of claim 9, wherein X is ~N(R') wherein R* is as defined in claim 9, n is 1 and p is 0, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
11. The 5-membered heteroaromatic ring compound of claim 10, wherein R* is a methyl group substituted by a heteroaromatic ring group optionally substituted by one C;-s alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
12. The 5-membered heteroaromatic ring compound of claim 11, wherein the heteroaromatic ring defined in claim 11 is a thiazolyl group, an oxazolyl group or a benzimidazolyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
13. The 5-membered heteroaromatic ring compound of claim 10, wherein R! is a methyl group substituted by -CO-N(R') (R'®) wherein R'® is a hydrogen atom and R'® is an aryl group optionally substituted by one Cys alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
14. The 5-membered heteroaromatic ring compound of claim 6, wherein V is =N-, W is -S-, and the position of substitution of B on the thiazole ring formed by V together with W is the 4- position, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
15. The 5-membered heteroaromatic ring compound of claim 14, wherein B is a phenyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
16. The 5-membered heteroaromatic ring compound of claim 15, wherein m is 0 or 1; R! and R? are each independently a hydrogen atom or a Cis alkyl group; X is -N(R*)-, -N(R®)-CO-O-, -SO,-N(R®)-, -CO-N(R’)-, -N(R’)-CO- N(R%)-, -N(R!?)-(CH;)x-N(R®)-, -O-, —-S- or -SO;- wherein R' is (1) a hydrogen atom, (2) a Ci-e alkyl group wherein said C;-¢ alkyl group is optionally substituted by (a) an aryl group optionally substituted by 1 to 3 : substituent (s) selected from the group consisting of a halogen atom, a Ci-s alkyl group and a C;-4 haloalkyl group, (b) a heteroaromatic ring group optionally substituted by 1 to 473 AMENDED SHEET
3 Cis alkyl group, (c) a carboxy group, (d) a Ci, alkoxycarbonyl group, (e) -CO-N(R™) (R') wherein R'® and R'® are each independently a hydrogen atom, an aryl group wherein said aryl group is optionally substituted by 1 to 3 substituent (s) selected from the group consisting of a Ci-s alkyl group, a C;-¢4 alkoxy group, a carboxy group and a di (C1-4 alkyl)amino group, a heteroaromatic ring group, a Cis alkyl group wherein said C;.¢ alkyl group is optionally substituted by an aryl group, or, together with the nitrogen atom bonded thereto, may form a 5- to 7-membered hetero ring optionally further containing at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, (f) -N(R'®) (R'®) wherein R!® and R!® are each independently a hydrogen atom or an aryl group, (g) -O-RY wherein R!” is an aryl group, or (h) a Cs. cycloalkyl group, (3) -CO-N(R') (R'®) wherein R!® and R'® are each independently a hydrogen atom, an aryl group wherein said aryl group is optionally substituted by 1 to 3 C;.s alkyl groups, a Ci-¢ alkyl group, or, together with the nitrogen atom bonded thereto, may form an indoline ring or may form a 5- to 7-membered hetero ring optionally further containing at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, (4) -SO.-N(R™) (R'®) wherein R'® and R!® are each independently an aryl group or a C;. ¢ alkyl group, (5) -co-rY 474 AMENDED SHEET wherein R' is an aryl group wherein said aryl group is optionally substituted by 1 to 3 substituent(s) selected from the group consisting of a C;-s alkyl group and a Ci;-¢ alkoxy group, a heteroaromatic ring group or a C;-¢ alkyl group wherein said Cj-¢ alkyl group is optionally substituted by an aryl group optionally substituted by 1 to 3 substituent (s) selected from the group consisting of a halogen atom and a C;.g alkyl group, a heteroaromatic ring group, a C;-4 alkoxy group optionally substituted by an aryl group or an aryloxy group optionally substituted by 1 to 3 Cig alkyl groups, (6) —-SO,-R’ wherein R' is an aryl group, (7) an aryl group, or (8) optionally linked with R! to form fa Re LH : : a Gn oe 5 wherein i and j are each 1 and R? is as defined above, R® is a hydrogen atom or a C;.¢ alkyl group optionally substituted by an aryl group or a Cs.; cycloalkyl group, R’ is a hydrogen atom or a Cig alkyl group, R® is a hydrogen atom or a Cig alkyl group, k is 2, RY is (1) a hydrogen atom, (2) a Ci-¢ alkyl group, or (3) optionally linked with R® to form 475 AMENDED SHEET wherein kl and c are each 2; n is 0 or an integer of 1 to 3; p is 0 or 1; L is . (1) CCE wherein R? is (a) a hydrogen atom, (b) a Ci-¢ alkyl group, or (c) optionally linked with R* to form Cg Ng SEER B = STE wherein nl and q are each independently an integer of 1 to 3, or (d) optionally linked with R' to form N-_ | } Co | Cane : _ TRL a a wherein u is 1 and v is 1, R?*! is a hydrogen atom, a Cis alkyl group wherein said Cj-¢ alkyl group is optionally substituted by an aryl group optionally substituted by 1 to 3 halogen atoms, or an aryl group or i 3 . on LE i RANE wherein E is an aryl group or a heteroaromatic ring group, R?? is (a) a hydrogen atom, (b) a C;-4 alkoxy group optionally substituted by a carboxy group, (¢) a nitro group, (d) -N(R®?) (R*) wherein R?? and R* are each independently a hydrogen atom, a Ci- + alkylcarbonyl group wherein said C,.; alkylcarbonyl group is optionally substituted by a C;-4 alkylamino group or a di (Cj. alkyl)amino group or a C;-4 alkylsulfonyl group, or (e) optionally linked with R* to form wherein n3 is 0, x is 1 and E is as defined above; R is -COO(R") wherein RY? is a hydrogen atom or a C;-4 alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
17. The 5-membered heteroaromatic ring compound of claim 16, : wherein m is 1 and R! and R? are each a hydrogen atom, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 477 AMENDED SHEET
18. The 5-membered heteroaromatic ring compound of claim 17, wherein X is -N(R') wherein R! is as defined in claim 16, n is 1 and p is 0, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
19. The 5-membered heteroaromatic ring compound of claim 18, wherein : RY is a C;.¢ alkyl group optionally substituted by (a) an aryl group optionally substituted by 1 to 3 substituent (s) selected from the group consisting of a halogen atom, a C,-g alkyl group and a C;-4 haloalkyl group, (b) a heteroaromatic ring group optionally substituted by 1 to 3 Cy-s alkyl groups, (c} a carboxy group, (d) a C4 alkoxycarbonyl group, (e) -CO-N(R™) (R™) wherein R!'® and R!® are each independently a hydrogen atom, an aryl group wherein said aryl group is optionally substituted by 1 to 3 substituent (s) selected from the group consisting of a
C,.4 alkyl group, a C;-4 alkoxy group, a carboxy group and a di (C;-4 alkyl)amino group, a heteroaromatic ring group, a Cig alkyl group wherein said C;_¢ alkyl group is optionally substituted by an aryl group, or, together with the nitrogen atom bonded thereto, may form a 5- to 7-membered hetero ring optionally further containing at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, (f) -N(R™) (R') wherein R!® and R!® are each independently a hydrogen atom or an aryl group, : (g) -0-RY’ wherein RY’ is an aryl group, or (h) a Ci-7 cycloalkyl group, AMENDED SHEET or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
20. The 5-membered heteroaromatic ring compound of claim 19, wherein R' is a methyl group substituted by a heteroaromatic ring group optionally substituted by one C;-s alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
21. The 5-membered heteroaromatic ring compound of claim 20, wherein the heteroaromatic ring defined in claim 20 is a thiazolyl group, an oxazolyl group, a benzimidazolyl group, a pyridyl group or a quinolyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
22. The S5-membered heteroaromatic ring compound of claim 189, wherein R? is a methyl group substituted by -CO-N(R') (R'®) wherein R!® is a hydrogen atom and R!® is an aryl group optionally substituted by one C;-g alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. :
23. The 5-membered hetercaromatic ring compound of any of claims 1 to 22, which is selected from the group consisting of the following compounds, or a prodrug thereof, or a pharmaceutically acceptable salt thereof: (1) 5-{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2- ylmethoxylnicotinic acid; (2) 4-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethoxyl}benzoic acid; (3) 6-{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2- ylmethoxylnicotinic acid; AMENDED SHEET
(4) 5-{4-[4-({methyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethoxy}nicotinic acid; (5) 4-{4-{4-({methyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]}thiazol-2- ylmethoxylbenzoic acid; (6) 6-[4-(4-{[ (4-isopropylphenyl) (1- propylbutyl) amino]methyl }phenyl)thiazol-2-ylmethoxylnicotinic acid; (7) 5-[4-(4-{[ (4-isopropylphenyl) (1- propylbutyl) amino]methyl }phenyl)thiazol-2-ylmethoxylnicotinic acid; (8) 5-[4-(4-{[isobutyl (4~ isopropylphenyl) amino]methyl }phenyl)thiazol-2- ylmethoxylnicotinic acid; (9) 4-{4-(4-{[ (4-isopropylphenyl) (1- propylbutyl) amino]methyl }phenyl)thiazol-2-ylmethoxylbenzoic acid; (10) 3-[4-(4-{[(4-isopropylphenyl) (1- propylbutyl)amino]methyl}phenyl)thiazol-2-ylmethoxylbenzoic acid; (11) 6-[4-(4-{[(1l-ethylpropyl) (4- isopropylphenyl) amino]methyl }phenyl)thiazol-2- ylmethoxylnicotinic acid; (12) 5-[4-(4-{[(1l-ethylpropyl) (4- isopropylphenyl) amino]methyl }phenyl) thiazol-2- ylmethoxylnicotinic acid; (13) 4-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethylthio}benzoic acid; (14) 4-{4-[4-({methyl[4-(1- propylbutyl)phenyl Jamino}methyl)phenyl]lthiazol-2- ylmethylthiolbenzoic acid; 480 AMENDED SHEET
(15) 4- (methyl-{4-[4- ({methyl[4-(1- propylbutyl)phenyllamino}methyl)phenyl]thiazol-2- ylmethyl}sulfamoyl)benzoic acid;
(16) sodium 4- (methyl {4-[4- ({methyl[4-(1~
> propylbutyl)phenyl]amino}methyl)phenyl]lthiazol-2- ylmethyl}sulfamoyl)butyrate;
(17) 4-{[(4-{4-[ (4-cyclohexylphenylamino)methyl]phenyl}thiazol- 2-yl)methylamino]lmethyl }benzoic acid; (18) 4-({[4-(4-{[(4-
cyclohexylphenyl)methylamino]lmethyl }phenyl)thiazol-2- yllmethylamino}lmethyl)benzoic acid;
(19) 4-[ (methyl-{4-[4-{ {methyl [4-(1- propylbutyl)phenyllamino}lmethyl)phenyl]thiazol-2- vl }tamino)methyl]benzoic acid;
(20) 4-[({4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- yl}lmethylamino)methyl]lbenzoic acid;
(21) (S)-({4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl) phenyl] thiazol-2-
ylmethyl}methylamino)phenylacetic acid;
(22) (S)-2-({4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl}thiazol-2- ylmethyl }methylamino)-3-phenylpropionic acid;
(23) {benzyl(4-(4-{[(4-tert-
butylphenyl)isobutylamino]methyl}phenyl)thiazol-2-
ylmethyl]amino}lacetic acid;
(24) {benzyl[4-(4-{[(4-chloro-
phenyl) isobutylamino]methyl }phenyl) thiazol-2- ylmethyl]amino}lacetic acid;
(25) (benzyl{4-[4-({methyl[4-(1- : propylbutyl) phenyl] amino}methyl)phenyl}thiazol-2- ylmethyl}amino) acetic acid;
(26) (benzyl{4-[4-({[4-(1- 481 AMENDED SHEET ethylpropyl) phenyl] isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}amino) acetic acid; (27) {1-[4-(4-{[ (4-tert-butyl- phenyl) isobutylamino] methyl }phenyl) thiazol-2-ylmethyl]-3-
phenylureidolacetic acid; (28) {benzoyl-[4-(4-{[(4-tert- butylphenyl) isobutylamino]methyl}phenyl)thiazol-2- ylmethyllamino}acetic acid; (29) [[(4-(4-{[(4-tert-butyl-
phenyl)isobutylamino}methyl }phenyl) thiazol-2~ylmethyl]- (pyridin-2-ylcarbonyl)amino]acetic acid; (30) [[4-(4-{[(4-tert-butyl- phenyl) isobutylamino]methyl }phenyl) thiazol-2-ylmethyl]- (pyridin-3-ylcarbonyl)aminolacetic acid;
(31) {benzenesulfonyl-[4-(4-{[(4-tert- butylphenyl) isobutylamino]methyl}phenyl)thiazol-2- ylmethyl]amino}acetic acid; (32) 2-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyljthiazol-2-
ylmethyl}=~1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (33) (S)-2-{4-[4-({[4-(1- ethylpropyl)phenyl}isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid; (34) (S)-2-{4-[4-({methyl[4-(1-
propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2-ylmethyl}- 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid; (35) (S)-2-[4-(4-([(l-ethylpropyl)-(4- isopropylphenyl) amino methyl }phenyl) thiazol-2-ylmethyl]- 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid;
(36) 4-({4-[4- (4-cyclohexylphenoxymethyl)phenyl]thiazol-2- yl}methylamino)benzoic acid; (37) 4-1 ({4-[4- (4-cyclohexylphenoxymethyl) phenyl] thiazol-2- yl}imethylamino)methyl ]benzoic acid;
482 AMENDED SHEET
(38) 4-{[(4-{4-[4-(1,1~ dimethylpropyl)phenoxymethyl]}phenyl}thiazol-2- yl)methylamino]lmethyll}benzoic acid;
(39) 4-{[methyl-(4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiazol-2~-
yl)amino]lmethyl}benzoic acid;
(40) sodium 4-{ [methyl (4-{4-[4-(1-
propylbutyl) phenoxymethyl)phenyl}thiazol-2-yl)aminojmethyl}- benzoate;
(41) (S)-[methyl-(4-{4~-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2- ylmethyl)amino]phenylacetic acid;
(42) (S)-2-[methyl- (4-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiazol-2-ylmethyl)amino]-3-
phenylpropionic acid;
(43) (benzyl{4-[4-(2-tert-butyl-4-methyl- phenoxymethyl) phenyl] thiazol-2-ylmethyl}amino)acetic acid; (44) [benzyl (4-{4-[4-(1- propylbutyl)phenoxymethyl])phenyl}thiazol-2-
ylmethyl)aminolacetic acid;
(45) 2-(4-{4-[4-(1l-propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; (46) (S)-2-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2-ylmethyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid;
(47) (R)-2-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2-ylmethyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
(48) 5-(4-{4-[4-(l-propylbutyl)phenoxymethyl]phenyl}thiazol-2-
ylmethoxy)nicotinic acid;
(49) 4-(4-{4-[4-(l-propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethoxy)benzoic acid; (50) 4-[methyl-(4-(4-[4-(1- 483 AMENDED SHEET propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl) sulfamoyl ]benzoic acid;
(51) 4-[methyl-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2-
ylmethyl)sulfamoyl]butyric acid;
(52) 4-({4-[4- (4-cyclohexylphenylcarbamoyl)phenyl]thiazol-2- yl}methylamino)benzoic acid;
(53) 4-[({4-[4- (4-cyclohexylphenylcarbamoyl)phenyl]thiazol-2- yl}methylamino)methyllbenzoic acid;
(54) [benzyl (4-{4-[4-(1- propylbutyl)phenylcarbamoyl Jphenyl}thiazol-2- ylmethyl)aminolacetic acid;
(55) [benzyl (4-{4-[4-(1- propylbutyl)benzylcarbamoyl ]phenyl}thiazol-2-
ylmethyl)amino]acetic acid;
(56) {benzyl[4-(4-{methyl(4-(l-propylbutyl)benzyl]- carbamoyl }phenyl)thiazol-2-ylmethyl]amino}lacetic acid; (57) {benzyl[4-(4-{ethyl-[4-(l-propylbutyl)benzyl]- carbamoyl }phenyl)thiazol-2-ylmethyl]amino}acetic acid;
(58) 5-{4-[4-({(2-hydroxy-2-methylpropyl)-[{4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethoxylnicotinic acid;
(59) [[4-(4-{[(4-tert-butyl- phenyl) isobutylaminolmethyl }phenyl) thiazol-2-ylmethyl]-
(morpholine-4-carbonyl)amino]acetic acid;
(60) sodium 5-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethoxy}-nicotinate;
(61) sodium (S)-2-(4-{4-[4-(1-
propylbutyl)phenoxymethyl}phenyl}thiazol-2-ylmethyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylate;
(62) sodium 5-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2- 484 AMENDED SHEET ylmethoxy)nicotinate;
(63) 3-{4-[4-({[4-(1-
ethylpropyl) phenyl] isopropylamino}methyl)phenyl]thiazol-2- ylmethoxy}-5-methoxy-benzoic acid;
° (64) (1-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl) phenyl] thiazol-2- ylmethyl}-3-phenylureido) acetic acid;
(65) (1-{4-[4-({[4-(1- ethylpropyl) phenyl] isopropylamino}methyl)phenyl]thiazol-2-
ylmethyl}-3-p-tolylureido)acetic acid;
(66) [1-{4-[(4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}-3~ (4-isopropylphenyl)ureido]acetic acid;
(67) (1-{4-[4-({[4-(1-
ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}-3-methyl-3-phenylureido) acetic acid;
(68) 5-{4-[4-({isopropyl([4-(1- propylbutyl)phenyl]amino}methyl) phenyl] thiazol-2- ylmethoxy}nicotinic acid;
(69) [3-phenyl-1-(4-{4-[4-(1- propylbutyl)phenoxymethyl ]phenyl}thiazol-2- ylmethyl)ureidolacetic acid; (70) (3-(2,6-dimethylphenyl)-1-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]lthiazol-2-
ylmethyl}ureido)acetic acid; (71) ({4-[4-({[4-(1~- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}phenylcarbamoylmethylamino) acetic acid; (72) (1-{4-[4-({[4-(1-
ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}-3~isopropyl-ureido)acetic acid; (73) 3-{4-[{4-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl) phenyl] thiazol-2-ylmethoxy}-
485 AMENDED SHEET isoxazole-5-carboxylic acid;
(74) 5-[4-(4~{[(2-ethylbutyl)- (4- isopropylphenyl) amino]methyl }phenyl)thiazol-2- ylmethoxylnicotinic acid;
> (75) [{4-({4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]lthiazol-2- ylmethyl}- (piperidine-l1-carbonyl)amino]acetic acid;
(76) 2-(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethoxy) nicotinic acid;
(77) [{4-[4-({[4-(1- ethylpropyl)phenyl)isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}- (p-tolylcarbamoylmethyl)aminolacetic acid;
(78) {{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylaminolmethyl)phenyl]lthiazol-2-
ylmethyl}-[ (4-isopropylphenylcarbamoyl)methyl]amino}acetic acid;
(79) (1-{4-[4-({isopropyl[4-(1- propylbutyl) phenyl lamino}methyl)phenyl]thiazol-2-ylmethyl}-3- methyl-3-phenylureido) acetic acid;
(80) (1-{4-[4-({isopropyl[4-(1~ propylbutyl) phenyl Jamino}methyl)phenyl]thiazol-2-ylmethyl}-3~-p- tolylureido) acetic acid;
(81) ((2,3-dihydro-indole-l-carbonyl)-{4-[4-({isopropyl{4-(1- propylbutyl)phenyl Jamino}methyl) phenyl] thiazol-2-
ylmethyl}amino)acetic acid;
(82) 3-(4-{4-[4- (l-propylbutyl) phenoxymethyl]phenyl}thiazol~2- ylmethoxy)pyridine-2-carboxylic acid;
(83) {[4-(4-{[(2-ethylbutyl)-(4~ isopropylphenyl)amino]methyl}phenyl)thiazol-2-
ylmethyllphenylcarbamoylmethylamino}acetic acid;
(84) {[4-(4-{[(2-ethylbutyl)-(4- isopropylphenyl) amino]methyl }phenyl) thiazol-2-ylmethyl]-[ (4~ isopropylphenylcarbamoyl) methyl Jamino}acetic acid; 486 AMENDED SHEET
(85) 4-(2- {carboxymethyl [4-(4-{[(2-ethylbutyl)-(4- isopropylphenyl)amino)methyl }phenyl) thiazol-2-ylmethyl]amino}- acetylamino)benzoic acid;
(86) 6-(4-{4-[4-(1l-propylbutyl)phenoxymethyl]phenyl}thiazol-2-
ylmethoxy) pyridine-2-carboxylic acid;
(87) 5-{4-[4-({isobutyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethoxylnicotinic acid;
(88) (1-{4-[4-({isobutyl[4-(1-
propylbutyl)phenyl]amino}methyl)phenyl]lthiazol-2-ylmethyl}-3-
phenylureido) acetic acid;
(89) S5-{4-[4-({[4-(1-
ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2- ylmethoxy}nicotinic acid methyl ester;
(90) 4-amino-3-{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenylithiazol-2- ylmethoxylbenzoic acid;
(91) 3-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2-
ylmethoxylbenzoic acid;
(92) 3-({4-[4-({[4-(1-
ethylpropyl) phenyl ]isopropylamino}methyl) phenyl] thiazol-2- ylmethyl}amino)benzoic acid;
(93) 3-{4-[4-({[4-(1-
ethylpropyl)phenyl]isopropylamino}methyl)phenyl]lthiazol-2- ylmethoxy}-4-nitro-benzoic acid;
(94) ((lH-benzimidazol-2-ylmethyl)-{4-[4-({isopropyl[4-(1- propylbutyl) phenyl ]Jamino}methyl)phenyl]thiazol-2~ ylmethyl }amino) acetic acid;
(95) [phenylcarbamoylmethyl (4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)amino]acetic acid;
(96) [(4-{4-[4- (1-propylbutyl)phenoxymethyl]phenyl}thiazol-2- 487 AMENDED SHEET ylmethyl) - (pyridin-3-ylcarbamoylmethyl) amino]acetic acid; (97) [[(4-dimethylaminophenylcarbamoyl)methyl]- (4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2-
ylmethyl) amino] acetic acid;
(98) [[(4-methoxyphenylcarbamoyl)methyl]- (4-{4-[4-(1~ propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylnethyl)amino]acetic acid;
(99) [[(isopropylphenylcarbamoyl)methyl]- (4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2-
ylmethyl)amino]acetic acid;
(100) [(4-{4-[4-(l-propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl) - (pyridin-2-ylcarbamoylmethyl) amino] acetic acid; (101) [(2-oxo-2-pyrrolidin-l-yl-ethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2-
ylmethyl)amino]acetic acid;
(102) [(4-methylthiazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2- ylmethyl)amino]acetic acid;
(103) 4-(3-cyclohexylmethyl-3-{4-[4-({isopropyl[4-(1~-
propylbutyl)phenyl}amino}methyl)phenyl]thiazol-2- ylmethyl}ureido)benzoic acid;
(104) 4-(3-isobutyl-3~{4-[4-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethyl}ureido)benzoic acid;
(105) (1-{4-[4-({isobutyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2-ylmethyl}-3- methyl-3-phenylureido)acetic acid;
(106) ({4-[4-({isobutyl[4-(1- propylbutyl)phenyl Jamino}methyl)phenyl]thiazol-2-
yimethyl}phenylcarbamoylmethylamino)acetic acid; : (107) {{4-[4-({isobutyl4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2-ylmethyl}-[(4- isopropylphenylcarbamoyl)methyl]amino}lacetic acid;
488 AMENDED SHEET
(108) 4-acetylamino-3-{4-[4- ({isopropyl[4-(1-
propylbutyl) phenyl ]amino}methyl) phenyl] thiazol-2- ylmethoxy}benzoic acid;
(109) 4-(2-dimethylaminoacetylamino)-3-{4-[4- ({isopropyl[4-(1-
S propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethoxy}benzoic acid;
(110) ((lH-benzimidazol-2-ylmethyl)-{4-(4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}amino) acetic acid;
(111) [(lH-benzimidazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2- ylmethyl)aminolacetic acid;
(112) 3-{4-[4-({isopropyl[4-(1- propylbutyl)phenyllamino}methyl)phenyl]lthiazol-2-ylmethoxy}-4-
methanesulfonylaminobenzoic acid;
(113) 4-isobutyrylamino-3-{4-[4-({isopropyl{4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethoxylbenzoic acid; (114) 4-{4-[4-({[4-(1-
ethylpropyl)phenyl}isopropylamino}lmethyl)phenyl]thiazol-2- ylmethyl}-3-0x0-3, 4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid;
(115) 4-{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2-
ylmethyl}-3-oxo-3, 4-dihydro-2H-benzo[1l,4]oxazine-8-carboxylic acid;
(116) ({4-[4-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyljthiazol-2-ylmethyl}- {methylphenylaminosulfonyl}amino)acetic acid;
(117) ([(4-isopropylphenylcarbamoyl)methyl]-{4-[4- : ({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethyl}amino) acetic acid;
489 AMENDED SHEET
(118) ([(3,5-dimethylphenylcarbamoyl)methyl]-{4-[4- ({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2~- ylmethyl}amino) acetic acid;
(119) ([(4-dimethylaminophenylcarbamoyl)methyl]-{4-[4- ({isopropyl([4-(1- : propylbutyl) phenyl Jamino}methyl)phenylithiazol-2- ylmethyl}amino) acetic acid;
(120) ((benzylcarbamoylmethyl)-{4-[4-({isopropyl[4-(1-
propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2-
ylmethyl}amino) acetic acid;
(121) [({4-[4-({isopropyl[4-(1-
propylbutyl) phenyl Jamino}methyl)phenyl]thiazol-2-ylmethyl}-{2- (morpholin-4-yl)-2-oxo-ethyl]amino]acetic acid;
(122) [{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylaminol}methyl)phenyl]thiazol-2- ylmethyl}- (2-phenoxyethyl)aminolacetic acid:
(123) [{4-[4-({[4-(1- ethylpropyl)phenyl}isopropylamino}methyl)phenyl]thiazol-2-
ylmethyl}- (2-phenylamino-ethyl)amino]acetic acid;
(124) 2-carboxymethoxy-5-({4-[4-({[4-(1- ethylpropyl) phenyl) isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}methylamino) benzoic acid; (125) 2-carboxymethoxy-5-[methyl (4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)amino]lbenzoic acid; (126) 3-{4-[4-({isopropyl[4-{1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2-ylmethoxy}-4-~ (2-methylamino-acetylamino) benzoic acid; (127) [(4-tert-butylthiazol-2-ylmethyl)- (4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)amino]acetic acid; (128) [phenyl (4-{4-[4-(1- 490 AMENDED SHEET propylbutyl)phenoxymethyl )phenyl}thiazol-2- ylmethyl)aminolacetic acid;
(129) [(2-phenoxyacetyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2-
ylmethyl)aminolacetic acid;
(130) [(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)- (2-p-tolyloxy-acetyl)amino] acetic acid;
(131) (ethoxycarbonylmethyl {4-[4- ({isopropyl{4-(1- propylbutyl) phenyl Jamino}methyl) phenyl] thiazol-2-
yImethyl}amino)acetic acid dihydrochloride;
(132) ((4-tert-butylthiazol-2-ylmethyl)-{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}amino)acetic acid;
(133) 6-{4-[4-({isopropyl[4-(1-
propylbutyl)phenyljamino}methyl)phenyl]lthiazol-2-ylmethoxy}- pyridine-2-carboxylic acid;
(134) [(2-benzyloxy-acetyl)-(4-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiazol-2- ylmethyl)aminolacetic acid;
(135) [[2-(4-isopropylphenoxy)acetyl]-{4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)aminolacetic acid;
(136) [(4,5-dimethylthiazol-2-ylmethyl)-(4-{4-[4-(1~ propylbutyl)phenoxymethyl]lphenyl}thiazol-2-
ylmethyl)aminolacetic acid;
(137) 5-(4-{5-[4-(1-propylbutyl)phenoxymethyl]thiophen-2- yl}thiazol-2-ylmethoxy) nicotinic acid;
(138) ((4-tert-butylthiazol-2-ylmethyl)-{4-[6-({isopropyl{4-(1- propylbutyl) phenyl ]Jamino}methyl)benzoxazol-2-yl]thiazol-2-
ylmethyl}amino)acetic acid;
(139) ((1H-benzimidazol-2-ylmethyl)-{4-[6-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)benzoxazel-2-yl]thiazol-2- ylmethyl }amino) acetic acid; 4901 AMENDED SHEET
(140) 5-{4-[6-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)benzoxazol-2-yl]thiazol-2~ ylmethoxy}nicotinic acid;
(141) [(5-tert-butylthiazol-2-ylmethyl)-(4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl) amino] acetic acid;
(142) [{4-[4-({isopropyl(4-(1- propylbutyl)phenyl]amino}methyl)phenyl]lthiazol-2-ylmethyl}- (2- oxo-2-piperidin-1-yl-ethyl)amino]acetic acid;
(143) 6-[methyl-(4-{4~-[4-(1~ propylbutyl)phenoxymethyl]lphenyl}thiazol-2- ylmethyl) amino] pyridine~2-carboxylic acid;
(144) ({4-[6-({isopropyl[4-(1- propylbutyl) phenyl ]amino}methyl)benzoxazol-2-yl]lthiazol-2-
ylmethyl}amino)acetic acid;
(145) (S)- (carboxymethyl {4-{4-( {isopropyl (4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethyl}amino)phenylacetic acid;
(146) ((4,5-dimethylthiazol-2-ylmethyl)-{4-[4~-({isopropyl[4-(1-
propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethyl}amino) acetic acid;
(147) [(5-tert-butyloxazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)amino]acetic acid;
(148) [(1-methyl-1H-benzimidazol-2-ylmethyl)-(4-{4-[4-(1~ propylbutyl)phenoxymethyllphenyl}thiazol-2- ylmethyl)amino]acetic acid;
(149) (isobutoxycarbonylmethyl{4-[4- ({isopropyl (4-(1- propylbutyl)phenyl]amino}methyl)phenyl]lthiazol-2-
ylmethyl}amino)acetic acid dihydrochloride;
(150) ({4-[4-({isopropyl[4~(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2-ylmethyl}- propoxycarbonylmethylamino) acetic acid dihydrochloride; 492 AMENDED SHEET jr / Cus (151) 1-(4-{4-[4-(1l-propylbutyl)phenoxymethyl]lphenyl}thiazol-2- ylmethyl)piperidine-4-carboxylic acid hydrochloride; (152) 1-{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}piperidine-4-carboxylic acid; (153) 4-[4-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2-ylmethyl)piperazin- l-yllbenzoic acid; (154) 4-(4-{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2- ylmethyl}-piperazin-1l-yl)benzoic acid; (155) 2-{4-(4-{4-[4- (1-propylbutyl)benzyloxylphenyl}thiazol-2- ylmethyl)piperazin-l-yllbenzoic acid; (156) 3-[4-(4-{4-[4- (1-propylbutyl)benzyloxy]lphenyl}thiazol-2- ylmethyl)piperazin-1-yllbenzoic acid; (157) 4-(4-{1-[4-(1l-propylbutyl)benzyl]-1H-indol-3~yl}thiazol- 2~-ylmethoxy) benzoic acid; (158) 4-{4-[1- (4-isopropylbenzyl)-5-(1l-propylbutyl)-1H- benzimidazol-2-yl] thiazol-2-ylmethoxyl}benzoic acid; (159) 4-{4-[1- (6-methylpyridin-2-ylmethyl)-5-(1-propylbutyl)- 1H-benzimidazol-2-yl]thiazol-2-ylmethoxy}benzoic acid; (160) 2-(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)-1,2, 3, 4-tetrahydroisoquinoline-7-carboxylic acid; (161) 4-[1-(4-{4-[4-(1-propylbutyl)benzyloxy]lphenyl}thiazol-2- ylmethyl)piperidin-4-yl]benzoic acid; (162) 3-[1-(4-(4-[4- (l-propylbutyl)benzyloxylphenyl}thiazol-2~ ylmethyl)piperidin-4-yl]lbenzoic acid; (163) 6-[(4-{4-[4- (1-propylbutyl)phenoxymethyl]phenyl}thiazol- 2-ylmethyl) carbamoyl ]nicotinic acid; (164) 2-[1-(4-{4-[4-(1-propylbutyl)benzyloxy]}phenyl}thiazol-2- ylmethyl)piperidin-4-yllbenzoic acid; (165) 1-(4-{1-[4-(1-propylbutyl)benzyl]-1H-indol-3-yl}thiazol- 2-ylmethyl)piperidine-4-carboxylic acid; 493 AMENDED SHEET
(166) 2-(4-{1-[4-(l-propylbutyl)benzyl]-1H-indol-3-yl}thiazol- 2-ylmethyl)-1, 2, 3, 4~tetrahydroisoquinoline-7-carboxylic acid; (167) 3-[(4-{1-[4- (1-propylbutyl)benzyl]-1H-indol-3-yl}thiazol- 2-ylmethyl) amino]lbenzoic acid;
(168) 6-[(2-aminoethyl) (4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl) carbamoyl ]lnicotinic acid hydrochloride;
(169) 2-(4-{1-[4- (1-propylbutyl)benzyl]}-1H-benzimidazol-2~ yl}thiazol-2-ylmethyl)-1,2, 3, 4-tetrahydroisoquinoline-7-
carboxylic acid;
(170) 3-[4-(4-{1-[4-(1-propylbutyl)benzyl]}-1H-benzimidazol-2- yl}thiazol-2-ylmethyl)piperazin-~1-yl]benzoic acid; (171) 4-[1-(4-{1-[4-(1-propylbutyl)benzyl]-1H-benzimidazol-2- yl}thiazol-2-ylmethyl)piperidin-4-yllbenzoic acid;
(172) 3-[4-(4-{1-[4-(1-propylbutyl)benzyl]-1H-indol-3- yl}thiazol-2-ylmethyl)piperazin-1-yllbenzoic acid;
(173) 3-(1-{4-[4-(3,4-dichloro-benzyloxy)phenyl]thiazol-2- ylmethyl}piperidin-4-yl)benzoic acid; (174) 3-(1-{4-[4-(3,5-bis-
trifluoromethylbenzyloxy)phenyl]thiazol-2-ylmethyl}piperidin-4- yl)benzoic acid;
(175) 3-(1-{4-[4- (4-butoxy-benzyloxy)phenyl]thiazol-2-~ ylmethyl}piperidin-4-yl)benzoic acid; (176) 5-methyl-2-(4-{4-[4-(1~ propylbutyl)phenoxymethyl]lphenyl}thiazol-2-ylmethyl)-2H- pyrazole-3-carboxylic acid;
(177) S-methyl-1-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiazol-2-ylmethyl)-1H- pyrazole-3-carboxylic acid;
(178) 5-tert-butyl-1-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2-ylmethyl)-1H- pyrazole-3-carboxylic acid;
(179) 5-tert-butyl-2-(4-{4-[4-(1- 494 AMENDED SHEET propylbutyl)phenoxymethyl]phenyl}thiazol-2~-ylmethyl)-2H- pyrazole-3-carboxylic acid;
(180) (2S,4R)-4-hydroxy-1-(4-{1-[4- (1l-propylbutyl)benzyl]-1H- indol-3-yl}thiazol-2-ylmethyl)pyrrolidine-2~-carboxylic acid;
° (181) 4-[4-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiazol-2-ylmethyl)piperidin- l-yllbenzoic acid;
(182) 1-(4-{1-[4-(l-propylbutyl)benzyl]-1H-indol-3-yl}thiazol- 2-ylmethyl)-1H-indole-3-carboxylic acid;
(183) 1-(4-{2-phenyl-1-[4-(l-propylbutyl)benzyl]-1H-indol-3- yl}thiazol-2-ylmethyl)piperidine-4-carboxylic acid;
(184) 3-(1-{4-[4-(4-methyl-3-nitrobenzyloxy)phenyl]thiazol-2- yvlmethyl}piperidin-4-yl)benzoic acid; (185) 2-{4-[1- (4-isopropylbenzyl)-6- (morpholin-4-yl)-1H-
benzimidazol-2-yl]thiazol-2-ylmethyl}-1,2,3,4- : tetrahydroisoquinoline-7-carboxylic acid;
(186) 3-(4-{4-[1-(4-isopropylbenzyl)-6-(morpholin-4-yl)-1H- benzimidazol-2-yl]thiazol-2-ylmethyl}-piperazin-1-yl)benzoic acid;
(187) {benzyl[4-(4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)oxazol-2-ylmethyl]amino}acetic acid;
(188) 5-(4-{4~[4-(1l-propylbutyl)benzyloxylphenyl}thiazol-2- ylmethoxy)nicotinic acid;
(189) 4-(4-{4-[4-(1-propylbutyl)benzyloxylphenyl}thiazol-2- ylmethoxy)benzoic acid;
(190) 4-(4-{4-[4-(1l-propylbutyl)benzyloxylphenyl}thiazol-2- ylmethylthio)benzoic acid; (191) 4-{4-[4- (4-cyclohexylbenzyloxy)phenyl]thiazol-2-
ylmethylthiolbenzoic acid;
(192) 4-{4-[4- (4-cyclohexylbenzyloxy)phenyl]lthiazol-2- ylmethanesulfonyl}benzoic acid; (193) 4-[methyl-{4-{5-methyl-2-[4-(1- 495 AMENDED SHEET propylbutyl)benzyloxylphenyl}thiazol-2--
ylmethyl) sulfamoyl Jbenzoic acid;
(194) 4-[methyl-(4-{5-methyl-2-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)amino]benzoic
° acid;
(195) (benzyl{4-[5-methyl-2-(4- trifluoromethylbenzyloxy)phenyl]thiazol-2-ylmethyl}amino)acetic acid;
(196) [benzyl (4-{5-methyl-2-[4-(1-
propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)aminolacetic acid;
{197) [benzyl (4-{4-[4- (1-propylbutyl)benzyloxylphenyl}thiazol- 2-ylmethyl)aminolacetic acid; (198) [benzyl (4-{4-[4- (l-ethylpropyl)benzyloxylphenyl}thiazol-
2-ylmethyl)aminolacetic acid;
(199) (benzyl{4-[5~tert-butyl-2-(4- isobutylbenzyloxy)phenyl]thiazol-2-ylmethyl}amino)acetic acid; {200) [benzyl (4-{5-chloro-2-{4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)aminojacetic acid;
(201) [(4-{4-[4-(l-ethylpropyl)benzyloxy]phenyl}thiazol-2- ylmethyl)- (4-fluoro-benzyl) aminolacetic acid;
(202) [(4-{4-[4-(l-ethylpropyl)benzyloxylphenyl}thiazol-2- ylmethyl)- (4-isopropylbenzyl)amino]acetic acid;
(203) [(4-{4-[4-(l-ethylpropyl)benzyloxylphenyl}thiazol-2- ylmethyl)~ (4-trifluoromethylbenzyl)amino]acetic acid;
(204) [(4-chlorobenzyl)-(4-{4-[4-(1- ethylpropyl)benzyloxylphenyl}thiazol-2-ylmethyl)aminolacetic acid;
(205) [(3,5-dimethylbenzyl)-(4-{4-[4-(1- : ethylpropyl)benzyloxylphenyl}thiazol-2-ylmethyl)amino}acetic acid;
(206) [(4-{4-[4- (1l-propylbutyl)benzyloxylphenyl}thiazol-2- 496 AMENDED SHEET ylmethyl)-pyridin-2-ylmethylamino]acetic acid; (207) ([(4-{4-[4-(l-ethylpropyl)benzyloxylphenyl}thiazol-2- ylmethyl)-pyridin-2-ylmethylamino]acetic acid; (208) [(4-{5-methyl-2-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)-pyridin-2- ylmethylamino] acetic acid; (209) [benzoyl-(4-{4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)amino]acetic acid; (210) [(4-{4-[4-(1-ethylpropyl)benzyloxylphenyl}thiazol-2- ylmethyl)- (4-methylbenzoyl) amino}acetic acid; (211) [(4-methoxybenzoyl)-(4-{4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)aminolacetic acid; (212) 2-(4-{5-methyl-2-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid; (213) (S)-2-(4-{4-[4-(1-propylbutyl)benzyloxylphenyl}thiazol-2- ylmethyl)-1, 2, 3,4-tetrahydroisoquinoline-3-carboxylic acid; (214) {benzyl([4-(4-{[4-(2,2- dimethylpropyl)benzyl]methylamino}phenyl) thiazol-2- ylmethyl]lamino}acetic acid; (215) {benzyl [4- (4-{ [trans—-4- (4-tert-butylphenyl) - cyclohexylmethyl]methylamino}phenyl) thiazol-2- ylmethyllamino}acetic acid; (216) [benzyl (4-{4-[(4- cyclohexylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl)aminoJacetic acid; (217) 3-[benzyl (4-{4-[(4- cyclohexylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl)aminolpropionic acid; (218) (benzyl{4-[4-({2-[4-(2,2-dimethylpropyl)phenyl]- ethyl}methylamino) phenyl) thiazol-2-ylmethyl}amino)acetic acid; 497 AMENDED SHEET
(219) {benzyl[4-(4-{methyl[4- (trans-4-methyl- cyclohexyl)benzyl] amino }phenyl) thiazol-2-ylmethyl]amino}acetic acid;
(220) {benzyl[4-(4-{([4-(cis-4-fluoro-
cyclohexyl)benzyllmethylamino}phenyl) thiazol-2- ylmethyllamino}acetic acid;
(221) {benzyl[4-(4-{[trans-4-(4-chlorophenyl) - cyclohexylmethyl]methylamino}phenyl) thiazol-2- ylmethyl]amino}acetic acid;
(222) {benzyl[4-(4-{[4-(4,4-dimethyl- cyclohexyl)benzyl]lmethylamino}phenyl) thiazol-2- ylmethyl]amino}acetic acid;
(223) {benzyl[4-(4-{methyl([4-(1- propylbutyl)benzyllamino}phenyl)thiazol-2~ylmethyl]amino}lacetic acid;
(224) (benzyl{4-[4- (biphenyl-4-
ylmethylmethylamino) phenyl] thiazol-2-ylmethyl}amino)acetic acid;
(225) sodium [benzyl (4-{4-[ (4-
cyclohexylbenzyl)methylamino]phenyl}thiazol-2-ylmethyl)amino]- acetate;
(226) [benzyl (4-{4-[(4- isobutylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl) amino]acetic acid;
(227) sodium {benzyl [4- (4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethyl]amino}- acetate;
(228) {benzyl[4-(4-{[4-(2,2- dimethylpropylthio)benzyllmethylamino}phenyl)thiazol-2-
ylmethyl]amino}acetic acid;
(229) {benzyl [4-(4-{methyl[4-(3- methylbutylthio)benzyl]amino}phenyl) thiazol-2- ylmethyl]amino}acetic acid; 498 AMENDED SHEET
(230) [benzyl (4-{4-[ (4-dipropylamino- benzoyl)methylamino]phenyl}thiazol-2-ylmethyl)aminojacetic acid; (231) [(4-{4-(ethyl (4-isopropylbenzyl)amino]lphenyl}thiazol-2- ylmethyl) - (4-isopropylbenzyl)amino]acetic acid; (232) [(4-isopropylbenzyl)- (4~-{4-[isopropyl-(4- isopropylbenzyl)amino]phenyl}thiazol-2-ylmethyl)amino]acetic acid; (233) [(4-tert-butylbenzyl)-(4-{4-[isopropyl- (4- jsopropylbenzyl)amino]lphenyl}thiazol-2-ylmethyl)amino]acetic acid; (234) [(4-chlorobenzyl)-(4-{4-[(4- isobutylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl})aminolacetic acid; (235) {{4-[4-(benzylmethylamino)phenyl]thiazol-2-ylmethyl}-[4- (l-propylbutyl)benzyl]lamino}lacetic acid; (236) [{4-[4~-(benzylmethylamino)phenyl]lthiazol-2-ylmethyl}-(4- chloro-benzyl)amino]acetic acid; (237) [{4-[4- (benzylmethylamino)phenyl]lthiazol-2-ylmethyl}-(2~ chloro-benzyl)amino]acetic acid; (238) [{4-[4- (benzylmethylamino)phenyl]lthiazol-2-ylmethyl}- (3,4-dichloro-benzyl) amino] acetic acid; (239) {[4-(4-{methyl[4- (trans-4-methyl- cyclohexyl)benzyl] amino }phenyl) thiazol-2-ylmethyl]pyridin-2- ylmethylaminolacetic acid; (240) {[4-(4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethyl]pyridin-2- ylmethylamino}acetic acid; (241) ({4-[4- (benzylmethylamino)phenyl]thiazol-2-ylmethyl}- npaphthalen-l-ylmethylamino)acetic acid; (242) ({4-[4- (benzylmethylamino)phenyl]thiazol-2-ylmethyl}- quinolin-2-ylmethylamino) acetic acid; (243) ((2-benzo [b]thiophen-3-yl-acetyl)-{4-[4- 499 AMENDED SHEET
(benzylmethylamino) phenyl] thiazol-2-ylmethyl}amino) acetic acid; (244) [[2-(4-chlorophenyl)acetyl]-(4-{4-[ (4- isobutylbenzyl)methylamino]lphenyl}thiazol-2- ylmethyl)amino]acetic acid;
(245) {(4-{4-[ (4-isobutylbenzyl)methylamino]lphenyl}thiazol-2- ylmethyl)-[2- (4-isopropylphenyl) acetyl]amino}acetic acid; (246) [(4-{4-[(4-isobutylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl)- (3-methyl-butyryl)amino]acetic acid;
(247) {1-[4-(4-{[4~(2,2-
dimethylpropyl)benzyl)methylamino}phenyl)thiazol-2~ylmethyl]-3-
phenylureidolacetic acid;
(248) [benzoyl-(4-{4-[(4-
isobutylbenzyl)methylamino] phenyl}thiazol-2- ylmethyl)amino]acetic acid;
(249) {(4-methylbenzoyl)-{4-(4-{methyl[4-(1- propylbutyl)benzyl lamino}phenyl) thiazol-2-ylmethyl]amino}acetic acid;
(250) sodium { (4-isopropylbenzoyl)-[4-(4- {methyl [4-(1- propylbutyl)benzyl Jamino}phenyl)thiazol-2-ylmethyllamino}-
acetate;
(251) sodium (S)-{3-[4-(4-{methyl[4-(1- propylbutyl)benzyllamino}phenyl)thiazol-2-yl]-3, 4-dihydro-1H- isoquinolin-2-yl}-acetate;
(252) 1-(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol-
2-ylmethyl)piperidine-4-carboxylic acid;
(253) 1-(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)piperidine~-3-carboxylic acid;
(254) 1-(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl) -4-phenylpiperidine~4-carboxylic acid;
(255) 1-(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)-4- (3-methylbutyl)piperidine-4-carboxylic acid; (256) 1-[4-(4-{methyl[4-(trans-4-methyl- cyclohexyl)benzyl]amino}phenyl) thiazol-2-ylmethyl]-4-
500 AMENDED SHEET phenylpiperidine-4-carboxylic acid;
(257) 1-[4-(4-{[trans-4-(4-chloro-phenyl)- cyclohexylmethyl]methylamino}phenyl) thiazol-2-ylmethyl]-4-
phenylpiperidine-4-carboxylic acid;
(258) 2-[4-(4-{methyl[4- (trans-4-methyl- cyclohexyl)benzyl] amino }phenyl) thiazol-2-ylmethyl]-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
(259) 2-(4-{4-[(4-isobutylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl)-1, 2, 3, 4~tetrahydroisoquinoline-3-carboxylic acid;
(260) 2-[4-(4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethyl]-1,2,3,4~ tetrahydroisoquinoline-3-carboxylic acid;
(261) 2-[4-(4-{[4-(2,2- dimethylpropyl)benzyl]lmethylamino}phenyl) thiazol-2-ylmethyl]-
1,2,3,4-tetrahydroisoquinoline~3-carboxylic acid;
(262) S5-{[(4-{4-[(4- cyclohexylbenzyl)methylamino]phenyl}thiazol-2- yl)methylamino]methyl}furan-2-carboxylic acid;
(263) 2-[(4-{4-[ (4-cyclohexylbenzyl)methylamino]phenyl}thiazol-
2-ylmethyl)amino]-3-phenylpropionic acid;
(264) [(4-{4-[(4-cyclohexylbenzyl)methylamino}phenyl}thiazol-2- ylmethyl)amino]phenylacetic acid; .
(265) 2-[(4-{4-[ (4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)amino]propionic acid;
(266) 3-(4-chlorophenyl)-2-[(4-{4-[(4- isobutylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl)amino]propionic acid;
(267) [(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl)methylaminolacetic acid;
(268) 3-[(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)methylamino] propionic acid;
(269) 4-{[(4-{4-[(4- cyclohexylbenzyl)methylamino]phenyl}thiazol-2- 501 AMENDED SHEET ylmethyl)methylamino]methyl}benzoic acid;
(270) 4-[(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)methylamino]lbenzoic acid;
(271) 6-[(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol-
2-ylmethyl)methylaminolnicotinic acid;
(272) 2-[(4-{4-[(4-isobutylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl)methylamino]-3-phenylpropionic acid;
(273) (S)-2-{methyl[4-(4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethyl]amino}-3-
phenylpropionic acid;
: (274) (S)-{methyl[4-(4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2- ylmethyl]amino}phenylacetic acid;
(275) {[4-(4-{[4-(2,2-
dimethylpropyl)benzyl]methylamino}phenyl) thiazol-2-
ylmethyl]methylamino}phenylacetic acid;
(276) 2-{[4-(4-{[4-(2,2-
dimethylpropyl)benzyl methylamino}phenyl)thiazol-2- ylmethyl]methylamino}-3-phenylpropionic acid;
(277) {carboxymethyl [4- (4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethyl]amino}lacetic acid;
(278) [(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl) - (3-methylbutyl)aminojacetic acid;
(279) { (3-methylbutyl)-[4- (4- {methyl [4- (trans-4-methyl- cyclohexyl)benzyl]amino}phenyl)thiazol-2-ylmethyl]amino}acetic acid;
(280) [(4-{4-[(4-isobutylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl) - (3-methylbutyl)amino]acetic acid;
(281) 5-[4-(4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethoxy]nicotinic acid;
(282) 4-[4-(4-{methyl[4-(1- 502 AMENDED SHEET propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethoxylbenzoic acid;
(283) 4-[4-(4-{methyl[4-(1-
propylbutyl)benzyl]amino}phenyl)thiazol-2~ylmethylthio]benzoic acid;
(284) 4-[(4-{4-[(4~-cyclohexylbenzyl)methylamino]phenyl}thiazol-
2-ylmethyl)sulfamoyllbenzoic acid;
(285) 4-{[4-(4~-{[4-(4,4-dimethyl-
cyclohexyl)benzyl]methylamino}phenyl)thiazol-2-
ylmethyllmethylsul famoyl}benzoic acid;
(286) {[4-(4-{[4-(4,4-dimethyl- cyclohexyl)benzyl]methylamino}phenyl)thiazol-2- ylmethyl]methylsul famoyl}acetic acid;
(287) 4-[(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol-
2-ylmethyl)methylsulfamoyllbenzoic acid;
(288) 3-[(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)methylsulfamoyl] benzoic acid;
(289) [(4-{4-[(4-cyclohexylbenzyl)methylamino]lphenyl}thiazol-2- ylmethyl)methylsulfamoyllacetic acid;
(290) 4-{[4-(4-{[4-(4,4-dimethyl- cyclohexyl)benzylmethylamino}phenyl) thiazol-2- ylmethyl]methylsulfamoyl}butyric acid;
(291) [(4-{4-[ (4-cyclohexylbenzyl)methylamino]phenyl}thiazol-2- ylmethyl) isobutyl-sulfamoyl]acetic acid;
(292) N-(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)oxamic acid;
(293) {benzyl[4-(4-{([4-(1-propylbutyl)benzyllmethylamino- carbonyl}phenyl)thiazol-2-ylmethyl]amino}acetic acid; (294) N-(4-{4-{(4-cyclohexylbenzyl)methylamino]phenyl}thiazol-
2-ylmethyl)-N-methylterephthalamic acid;
(295) {benzyl[4-(4-{methyl[4-(trans-4-methyl- cyclohexyl)benzyl]amino}phenyl) thiazol-2- ylmethoxycarbonyl]amino}acetic acid; 503 AMENDED SHEET
(296) [3-(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl) -3-methyl-ureidolacetic acid;
(297) (cyclohexylmethyl {4-[6-(3,4-dichlorobenzyloxy)benzoxazol- 2-yllthiazol-2-yl}amino) acetic acid;
(298) [4-(4-{4-[(4-cyclohexylbenzyl)methylamino]phenyl}thiazol- 2-ylmethyl)piperazin-1l-yllacetic acid;
(299) sodium (S)-2-(4-{4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)-1,2,3,4~- tetrahydroisoquinoline-3-carboxylate;
(300) sodium 5-(4-{4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethoxy)nicotinate; (301) 5-(4-{2-methyl-4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethoxy)nicotinic acid;
(302) 5-(4-{3-methoxy-4-[4-(1- propylbutyl)benzyloxy]phenyl}thiazol-2-ylmethoxy) nicotinic acid;
(303) [(4-{2-methyl-4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-
ylmethyl)phenylcarbamoylmethylamino]acetic acid;
(304) [[(4-isopropylphenylcarbamoyl)methyl]-(4-{2-methyl-4-[4- (1-propylbutyl)benzyloxy]phenyl}thiazol-2-ylmethyl)amino]acetic acid; (305) 2-(4-{4-[4-(1-propylbutyl)benzyloxylphenyl}thiazol-2-
ylmethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (306) [(4-{3-methoxy-4-{4-(1- propylbutyl)benzyloxylphenyl}thiazol-2- ylmethyl)phenylcarbamoylmethylamino]acetic acid;
(307) [[ (4-isopropylphenylcarbamoyl)methyl]- (4-{3-methoxy-4-[4-
(1-propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)amino]acetic acid;
(308) [(4-{2-methyl-4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)thiazol-4- 504 AMENDED SHEET ylmethylamino] acetic acid;
(309) [(4-{2-methyl-4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)-(2- methylthiazol-4-ylmethyl)amino]acetic acid hydrochloride;
(310) [(benzylcarbamoylmethyl)- (4~{2-methyl-4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2~ylmethyl)amino]acetic acid hydrochloride;
(311) [(1H-benzimidazol-2-ylmethyl)- (4-{2-methyl-4-[4-(1- propylbutyl)benzyloxylphenyl}thiazol-2-ylmethyl)amino]acetic acid;
(312) [(4-tert-butylthiazol-2-ylmethyl)-(4-{1-[4-(1~ propylbutyl)benzyll-1,2,3,4-tetrahydroquinolin-6-yl}thiazol-2-
ylmethyl)amino]acetic acid;
(313) 1- (4-{4-[4- (1-propylbutyl)benzyloxylphenyl}thiazol-2-
ylmethyl)piperidine-4-carboxylic acid hydrochloride;
(314) 4-[4- (4-{4-[4- (1-propylbutyl)benzyloxy] phenyl}thiazol-2- ylmethyl)piperazin-l-yllbenzoic acid;
(315) 4-{4-[5-(1l-ethylpropyl)-1-(4-isopropylbenzyl)-1H- benzimidazol-2-yl]thiazol-2-ylmethoxy}benzoic acid ethyl ester;
(316) 4-{4-[5-(l-ethylpropyl)-1-(4-isopropylbenzyl)-1H- benzimidazol-2-yl]lthiazol-2-ylmethoxy}benzoic acid;
(317) 4-{4-[1-(4-acetylbenzyl)-5-(l-ethylpropyl)-1H- benzimidazol-2-yl]thiazol-2-ylmethoxylbenzoic acid; (318) 4-{4-[1-(4-acetylbenzyl)-6-(l-ethylpropyl)-1H-
penzimidazol-2-yl]thiazol-2-ylmethoxyl}benzoic acid;
(319) 4-{4-[l-cyclohexylmethyl-5-(1l-ethylpropyl)-1H- benzimidazol-2-yl]thiazol-2-ylmethoxylbenzoic acid;
(320) [(l-methyl-1H-benzimidazol-2-ylmethyl)- (5-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2-
ylmethyl)aminolacetic acid;
(321) 5- (4-{4-[4- (1-propylbutyl)phenoxymethyl ]Jphenyl}thiophen- 2-ylmethoxy) nicotinic acid; (322) 5-{4-[4- ({isopropyl[4-(1- 505 AMENDED SHEET propylbutyl)phenyllamino}methyl) phenyl] thiophen-2- ylmethoxylnicotinic acid;
(323) 5-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2-
ylmethoxyl}nicotinic acid;
(324) 5-(5-{4-[4-(l-propylbutyl)phenoxymethyl]}phenyl}thiophen- 2-ylmethoxy)nicotinic acid;
(325) [(1H-benzimidazol-2-ylmethyl)-(4-{4-[4-(1~- propylbutyl)phenoxymethyl}phenyl}thiophen-2-
ylmethyl)aminojacetic acid;
(326) 6-(4-{4~[4-(l-propylbutyl)phenoxymethyl]phenyl}thiophen- 2-ylmethoxy)pyridine-2-carboxylic acid;
(327) [(1H-benzimidazol-2-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2-
ylmethyl)aminolacetic acid;
(328) [[(4-isopropylphenylcarbamoyl}methyl]-(5-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl }thiophen-2- ylmethyl)aminolacetic acid;
(329) [phenylcarbamoylmethyl (5-{4-[4-(1-
propylbutyl)phenoxymethyllphenyl}thiophen-2- ylmethyl)amino]acetic acid;
(330) ({4-14-({[4-(1- ethylpropyl)phenyl]lisopropylamino}methyl)phenyl]thiophen-2- ylmethyl}phenylcarbamoylmethylamino) acetic acid;
(331) ((4-tert-butylthiazol-2-ylmethyl)-{4-[4-({[4~-(1- ethylpropyl) phenyl] isopropylamino}methyl)phenyl]thiophen-2- ylmethyl}amino) acetic acid;
(332) [(5-tert-butylthiazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2-ylmethyl) -
amino]acetic acid;
(333) ((lH-benzimidazol-2-ylmethyl)-{4-[{4-({[4-(1- ethylpropyl) phenyl] isopropylamino}methyl) phenyl] thiophen-2- ylmethyl}amino) acetic acid; 506 AMENDED SHEET
(334) [(4-tert-butylthiazol-2-ylmethyl)-(4-{4-{4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(335) [phenylcarbamoylmethyl (4-{4-{4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(336) S5-{5-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2- ylmethoxylnicotinic acid;
(337) 5-{5-[4-({isopropyl[4-(1- propylbutyl) phenyl ]amino}methyl)phenyl]thiophen-2- ylmethoxylnicotinic acid;
(338) ((4-tert-butylthiazol-2-ylmethyl)-{5-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2-
ylmethyl}amino) acetic acid;
(339) ((4-tert-butylthiazol-2-ylmethyl)-{5-[4-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiophen-2- ylmethyl}amino) acetic acid;
(340) ((lH-benzimidazol-2-ylmethyl)-{5-[4-({[4-(1-
ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2- ylmethyl}amino) acetic acid;
(341) ((l1H-benzimidazol-2-ylmethyl)-{5-[4-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiophen-2- ylmethyl}amino)acetic acid;
(342) [(4,5-dimethylthiazol-2-ylmethyl)- (4-{4-[4-(1~- propylbutyl)phenoxymethyl]lphenyl}thiophen-2- ylmethyl)amino]acetic acid;
(343) (S)-2-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]jthiophen-2-~ ylmethyl}-1,2, 3,4-tetrahydroisoquinoline-3-carboxylic acid; (344) {{4-[4-({[4-(1- ethylpropyl) phenyl) isopropylamino}methyl)phenyl]thiophen-2- ylmethyl}-[ (4-isopropylphenylcarbamoyl)methyl]amino}acetic
507 AMENDED SHEET acid;
(345) (S)-2-(5-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2-ylmethyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid;
(346) [[(4-isopropylphenylcarbamoyl)methyl]-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminoJacetic acid;
(347) (S)-2-{5-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2-
ylmethyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; (348) [(5-tert-butyloxazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl) amino]acetic acid;
(349) [(l-methyl-1H-benzimidazol-2-ylmethyl)- (4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(350) 6-(5-{4-[4-(l-propylbutyl)phenoxymethyl]phenyl}thiophen- 2-ylmethoxy) pyridine-2-carboxylic acid; (351) 6-{4-[4-({[4-(1-
ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2- ylmethoxy}-pyridine-2-carboxylic acid;
(352) ((5-tert-butylthiazol-2-ylmethyl)-{4-{4-({[4~(1- ethylpropyl)phenyl]isopropylamino}methyl) phenyl] thiophen-2~ ylmethyl}amino) acetic acid;
(353) [{4-[4-({[4-(1- ethylpropyl) phenyl] isopropylamino}methyl) phenyl] thiophen-2-~ ylmethyl}- (1-methyl-1H-benzimidazol-2-ylmethyl)amino]acetic acid;
(354) [(4-tert-butylthiazol-2-ylmethyl)-(5-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2-
ylmethyl)amino]acetic acid; (355) [{5-[4~-({[4~-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2- 508 AMENDED SHEET ylnethyl}-~ (1-methyl-1H-benzimidazol-2-ylmethyl)amino]acetic acid; (356) [(5-tert-butylthiazol-2-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid; (357) sodium [(l-methyl-l1H-benzimidazol-2-ylmethyl)-(5-{4-[4- (1-propylbutyl) phenoxymethyl]phenyl}thiophen-2-ylmethyl) amino] = acetate; (358) calcium bis{[(l-methyl-1H-benzimidazol-2-ylmethyl)- (5-{4- [4-(1-propylbutyl) phenoxymethyl]phenyl }thiophen-2- ylmethyl) amino] -acetate}; (359) [(l-methyl-1H-benzimidazol-2-ylmethyl)- (5-{4-[4-(1- propylbutyl)phenoxymethyl ]phenyl}thiophen-2- ylmethyl)amino]lacetic acid toluene-4-sulfonate; (360) 5-(4-{4-1[4-(1-propylbutyl)phenoxymethyl]lphenyl}thiophen- 2-ylmethoxy)nicotinic acid sulfate; (361) [(1-methyl-1H-benzimidazol-2-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyliphenyl}thiophene-2- carbonyl) aminolacetic acid; (362) [(5-tert-butylthiazol-2-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl Jphenyl}thiophene-2- carbonyl) amino]acetic acid; (363) [(4-isopropylbenzyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophene-2- carbonyl)amino]acetic acid; (364) [(4-dimethylaminobenzyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophene-2- carbonyl) amino]acetic acid; (365) [(5-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiophene- 2-carbonyl)-pyridin-2-ylmethylamino]acetic acid; (366) [(5-{4-[4-(1-propylbutyl)phenoxymethyl]lphenyl}thiophene- 2-carbonyl) -pyridin-3-ylmethylaminolacetic acid; (367) 5-(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiophen- 509 AMENDED SHEET
2-ylmethoxy)nicotinic acid methanesulfonate; (368) [methanesulfonyl- (5-{4-[4-(1- propylbutyl)phenoxymethyl}phenyl}thiophen-2- ylmethyl) amino] acetic acid;
(369) sodium 5-(4-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiophen-2- ylmethoxy)nicotinate;
(370) 5-(4-{4-[4- (1-propylbutyl)phenoxymethyl]phenyl}thiophen- 2-ylmethoxy) nicotinic acid hydrochloride;
(371) 4-[4-(5-{4-(4-(1- propylbutyl)phenoxymethyl]phenyl}thiophene-2- carbonyl) piperazin-1l-yl]benzoic acid;
(372) 4-[1-(5-(4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophene-2-
carbonyl)piperidin-4-yllbenzoic acid;
(373) [(l-methyl-1H-benzimidazol-2-ylmethyl)- (4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminojacetic acid hydrochloride;
(374) [(l-methyl-1H-benzimidazol-2-ylmethyl}-(4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminolacetic acid sulfate;
(375) 4-(2-dimethylaminoacetylamino)-3- (4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2-ylmethoxy)benzoic acid;
(376) 4-isobutyrylamino-3-(4-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiophen-2-ylmethoxy) benzoic acid;
(377) 4-{4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiophen- 2-ylmethoxy) benzoic acid;
(378) 4-(methanesulfonylmethylamino)-3-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2-ylmethoxy)benzoic acid;
(379) 4-(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiophen- 510 AMENDED SHEET
2-ylmethylthio)benzoic acid;
(380) 4-amino-3-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2-ylmethoxy)benzoic acid;
(381) 1-{5-[1-(4-cyclohexylbenzyl)-1H-indol-3-yl]thiophen-2- ylmethyl}-4-phenylpiperidine-4-carboxylic acid hydrochloride; (382) (benzyl{5-[1- (4-cyclohexylbenzyl)~1H-indol-3-yl]thiophen- 2-ylmethyl }amino) acetic acid hydrochloride;
(383) [ (methylphenylsulfamoyl) (4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminolacetic acid;
(384) [(5-tert-butylthiazol-2-ylmethyl)-(5-{4-[(4-cyclohexyl- phenyl) methylcarbamoyl] phenyl} thiophen-2-ylmethyl)aminojacetic acid;
(385) [ (5-{4-[ (4-cyclohexylbenzyl) ethylamino] phenyl }thiophen-2- ylmethyl)pyridin-2-ylmethylamino]acetic acid;
(386) [(5-{4-[(4-cyclohexylbenzyl)ethylamino]phenyl}thiophen-2- ylmethyl) - (2-phenoxyethyl) amino]acetic acid; (387) 4-{1-[4- (4-{ [trans-4- (4-tert-butylphenyl)-
cyclohexylmethyl]ethylamino}phenyl) thiophen-2- ylmethyl]piperidin-4-yl}benzoic acid;
(388) [[2- (4-isopropylphenoxy)acetyl]-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminolacetic acid;
(389) {(4-isopropylbenzoyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl) amino] acetic acid;
(390) [(3-methylbutyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2-
ylmethyl)aminolacetic acid;
(391) [3-methyl-3-phenyl-1-(4-{4-[4-(1- propylbutyl) phenoxymethyl]lphenyl}thiophen-2- ylmethyl)ureido]acetic acid; 511 AMENDED SHEET
(392) 2-(4-{3-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiophen- 2-ylmethyl)-1, 2,3, 4-tetrahydroisoquinoline-7-carboxylic acid; (393) 4-[4-(5-{4-[4- (trans—-4-methyl- cyclohexyl)benzyloxylphenyl}thiophen-2-ylmethyl)piperazin-1-
yllbenzoic acid;
(394) [(2-chloro-5-trifluoromethylbenzyl)- (5-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminolacetic acid;
(395) 3-{ (carboxymethyl (5-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino}methyl}benzoic acid;
(396) [(4-methoxybenzyl)-(5-{4-{4-(1- propylbutyl) phenoxymethyl) phenyl }thiophen-2- ylmethyl)amino]acetic acid;
(397) [(4-methylthiobenzyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl] phenyl }thiophen-2- ylmethyl)amino]acetic acid;
(398) 4-[cyclohexylmethyl (5~{4-[4- (trans-4-methyl- cyclohexyl)benzyloxylphenyl }thiophen-2-
ylmethyl)sulfamoyl }benzoic acid;
(399) 4-[3-cyclohexylmethyl-3-(5-{4-[4-(trans-4-methyl- cyclohexyl)benzyloxy]phenyl}thiophen-2-ylmethyl)ureidolbenzoic acid;
(400) [benzhydryl- (5-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl }thiophen-2- ylmethyl)aminolacetic acid;
(401) [[2-oxo0-2-(4-pyrrolidin-1-yl-phenyl)ethyl]l-(5-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl }thiophen-2- ylmethyl)aminoJacetic acid ethyl ester hydrochloride;
(402) [(l1-methyl-lH-benzimidazol-2-ylmethyl)- (5-{4-[4-(1~ propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminojJacetic acid ethyl ester;
(403) 3-(benzyl{5-[1-(4-cyclohexylbenzyl)-2,3-dihydro-1H-indol- 512 AMENDED SHEET
5-yl]lthiophen-2-ylmethyl }amino) propionic acid;
(404) [benzyl (4-{4-[2-(2,2-dimethylpropyl)benzimidazol-1- ylmethyl]phenyl}thiophen-2-ylmethyl)amino]acetic acid; (405) [(l-methyl-1H-indol-3-ylmethyl) -(4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]Jacetic acid;
(406) [(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)quinolin-2-ylmethylamino]acetic acid; (407) [benzothiazol-2-ylmethyl (4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(408) [(l-benzyl-lH-imidazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyl phenyl} thiophen-2- ylmethyl)aminolacetic acid;
(409) [(lH-indol-5-ylmethyl)- (4-{4-[4-(1- propylbutyl)phenoxymethyllphenyl}thiophen-2- ylmethyl)amino]acetic acid;
(410) [(4-imidazol-l-ylbenzyl)~-(4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2-
ylmethyl)amino]acetic acid;
(411) [benzofuran-2-ylmethyl (4-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2- ylmethyl)amino]acetic acid;
(412) [[2,2' }Jbithiophenyl-5-ylmethyl (4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2-
ylmethyl)amino]acetic acid; (413) [(2-phenyl-1H-imidazol-4-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl] phenyl} thiophen-2- ylmethyl)amino]acetic acid;
(414) |[(3-phenyl-l1H-pyrazol-4-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(415) [benzoxazol-2-ylmethyl (5-{4-[4-(1- 513 AMENDED SHEET propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(416) [benzo [b]thiophen-2-ylmethyl (5-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiophen-2-
° ylmethyl)aminolacetic acid;
(417) [ (4-phenylthiophen-2-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminol]acetic acid;
(418) [benzothiazol-2-yl-(5-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(419) [(5-chlorothiophene-2-sulfonyl)-(5-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminolacetic acid;
(420) [(l-diethylcarbamoylmethyl-1H-benzimidazol-2-ylmethyl)- (5-{4-[4- (1-propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino]acetic acid;
(421) (S)-({4-[2-(4-cyclohexylbenzyloxy)-5- methylphenyl]thiophen-2-ylmethyl}methylamino)-3-phenylpropionic acid;
(422) [benzyl (4-{4-[ (4-butoxy-
benzenesulfonyl) ethylamino]phenyl}thiophen-2- ylmethyl)aminolacetic acid;
(423) N-{4-[2- (4-cyclohexylbenzyloxy)~5-methylphenyl]thiophen-
2-ylmethyl}-N- (2-methylbenzothiazol-6-yl)oxamic acid;
(424) (benzyl{4-[4-(3,5-dichlorophenoxymethyl)phenyl]thiophen- 2-ylmethyl}amino)acetic acid;
(425) [(l-allyl-1H-benzimidazol-2-ylmethyl)-(5-{4-[4-(1- propylbutyl)phenoxymethyl]phenyl}thiophen-2-
ylmethyl)amino]acetic acid; and : (426) [([4- (4-chlorophenyl)thiazol-2-yl]-(5-{4-[4-(1- propylbutyl)phenoxymethyl]lphenyl}thiophen-2- ylmethyl)aminol]acetic acid.
514 AMENDED SHEET
24. The S-membered heteroaromatic ring compound of any of claims 1 to 23, which is selected from the group consisting of the following compounds, or a prodrug thereof, or a pharmaceutically acceptable salt thereof: (1) (S)-2-(4-{4-[4-(1-propylbutyl)phenoxymethyl}phenyl}thiazol- 2-ylmethyl)-1,2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; (2) {{4-[4-({[4-(1- ethylpropyl) phenyl ]isopropylamino}methyl)phenyl]thiazol-2-
ylmethyl}-[ (4-isopropylphenylcarbamoyl)methyl]amino}acetic acid;
(3) 4-(3-isocbutyl-3-{4-{4-({isopropyl[4-(1- propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2- ylmethyl}ureido) benzoic acid;
(4) ({4-[{4-({isobutyl(4-(1- propylbutyl) phenyl ]amino}methyl)phenyl]thiazol-2- ylmethyl}phenylcarbamoylmethylamino) acetic acid; (5) ([(4-isopropylphenylcarbamoyl)methyl]-{4-[4-({isopropyl[4- (1-propylbutyl)phenyl]amino}methyl)phenyl]thiazol-2-
ylmethyl}amino)acetic acid; (6) [(4-tert-butylthiazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl)phenoxymethyljphenyl}thiazol-2- ylmethyl)amino]acetic acid; (7) [(4,5-dimethylthiazol-2-ylmethyl)-(4-{4-[4-(1-
propylbutyl)phenoxymethyl]phenyl}thiazol-2- ylmethyl)aminolacetic acid; (8) [(5-tert-butylthiazol-2-ylmethyl)-{4-{4-[4-(1- propylbutyl) phenoxymethyl jphenyl}thiazol-2- ylmethyl) amino]acetic acid;
(9) [[2-(4-isopropylphenoxy)acetyl]- (4-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiazol-2- ylmethyl)amino]acetic acid; (10) 4-[4-(4-{4-[4-(1-propylbutyl)phenoxymethyl]phenyl}thiazol-
515 AMENDED SHEET
2-ylmethyl)piperazin-1-yllbenzoic acid; (11) {benzyl [4-(4-{methyl[4-(1- propylbutyl)benzyl]amino}phenyl)thiazol-2-ylmethyl]amino}acetic acid; (12) [(1-methyl-1H-benzimidazol-2-ylmethyl)-5-{4-[4-(1- propylbutyl) phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminojacetic acid; (13) 5-(4-{4-[4- (1-propylbutyl)phenoxymethyl] phenyl }thiophen-2- ylmethoxy}lnicotinic acid; (14) [(1H-benzimidazol-2-ylmethyl)-(4-{4-[4-(1- propylbutyl) phenoxymethyl]lphenyl}thiophen-2- ylmethyl)aminolacetic acid; (15) [(lH-benzimidazol-2-ylmethyl)~(5-{4-[4-(1- : propylbutyl)phenoxymethyl]phenyl}thiophen-2- ylmethyl)amino}acetic acid; (16) [[(4-isopropylphenylcarbamoyl)methyl]-(5-{4-{[4-(1- propylbutyl) phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminolacetic acid; (17) (S)-2-{4-[4-({[4-(1- ethylpropyl)phenyl]isopropylamino}methyl)phenyl]thiophen-2- ylmethyl}-1,2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; (18) {{4-[4-({[4-(1- ethylpropyl)phenyllisopropylamino}methyl)phenyl]thiophen-2- ylmethyl}-[(4-isopropylphenylcarbamoyl)methyl]aminolacetic acid; (19) [(l1-methyl-1H-benzimidazol-2-ylmethyl)-(4-{4-[4~-(1- propylbutyl) phenoxymethyl]phenyl}thiophen-2- ylmethyl)aminolacetic acid; and (20) [(4-tert-butylthiazol-2-ylmethyl)-(5~{4-[4-(1- propylbutyl)phenoxymethyllphenyl}thiophen-2- ylmethyl)amino]acetic acid.
25. A pharmaceutical composition comprising the 5-membered 516 AMENDED SHEET heteroaromatic ring compound of any of claims 1 to 24, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
26. A pharmaceutical composition for inhibition of a receptor tyrosine kinase negative regulator, which comprises a 5- membered heteroaromatic ring compound of any of claims 1 to 24, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
27. A pharmaceutical composition for inhibition of protein tyrosine phosphatase 1B, which comprises a 5-membered heteroaromatic ring compound of any of claims 1 to 24, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
28. A pharmaceutical composition for the prophylaxis or treatment of diabetes, which comprises a 5-membered heteroaromatic ring compound of any of claims 1 to 24, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
29. A pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia, which comprises a 5-membered heteroaromatic ring compound of any of claims 1 to 24, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
30. A pharmaceutical composition for the prophylaxis or treatment of obesity, which comprises a S5-membered heteroaromatic ring compound of any of claims 1 to 24, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 517 AMENDED SHEET
31. A pharmaceutical composition for the prophylaxis or treatment of diabetic complications, which comprises a 5= membered heteroaromatic ring compound of any of claims 1 to 24, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
32. The pharmaceutical composition of claim 25, which is used in combination with a therapeutic agent for hyperlipidemia.
33. The pharmaceutical composition of claim 32, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of HMG-CoA reductase inhibitors (statins), fibrates, TNFSF6 expression inhibitors, HDL-cholesterol increasing agents, ApoAl expression enhancers, SPP1 (osteopontin) expression inhibitors, drugs acting on peroxisome proliferator-activated receptors (PPAR), PPAR-alpha agonists, lipase clearing factor stimulants, cholesterol antagonists, platelet aggregation antagonists, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor up-regulators, bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acids.
34. The pharmaceutical composition of claim 33, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostainin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (synvinolin), pitavastatin (itavastatin, pisvastatin) calcium, ronifibrate (ronifibrato), binifibrate (binifibrato), clinofibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, bezafibrate, gemfibrozil, acipimox, eicosapentaenoic acid (icosapent, icopenate, icosapentate) 518 AMENDED SHEET ethyl ester, probucol, policosanol, colesevelam hydrochloride, colestyramine (cholestyramine resin), colestipol hydrochloride, colestimide (colestilan), ezetimibe and niacin (nicotinic acid).
35. The pharmaceutical composition of claim 25, which is used in combination with a therapeutic agent for diabetes.
36. The pharmaceutical composition of claim 35, wherein the therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of insulin secretagogues, biguanides, a-glucosidase inhibitors, insulin preparations, insulin analogs, insulin sensitivity enhancers, IL-11, anti-CD25 (IL-2 Receptor) agents, angiotensin (AT1) antagonists, angiotensin-converting enzyme (ACE) inhibitors, aldose reductase inhibitors, antioxidants, carnitine acetyltransferase stimulant, antidepressants, glucocorticoids, retilin, radical formation agonists and transketolase activators.
37. The pharmaceutical composition of claim 36, wherein the therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybuzole, glipizide, glibornuride, gliquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epalrestat, miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate/biotin, V-411, recombinant human interleukin-11, dacliximab (daclizumab), losartan potassium, captopril, imidapril hydrochloride, alpha-lipoic acid, levacecarnine (acetyl-L-carnitine, levocarnitine acetyl) hydrochloride, captopril, retilin, verteporfin, benfotiamine and fluocinolone acetonide. 519 AMENDED SHEET
38. The pharmaceutical composition of claim 25, which is used in combination with a therapeutic agent for obesity.
39. The pharmaceutical composition of claim 38, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, lipase inhibitors, S5-HT/norepinephrine reuptake dual inhibitors, 5-HT reuptake inhibitors, supplements containing herbal ephedrine and caffeine, human chorionic gonadotropins, adrenoceptor agonists, methamphetamine, phentermine and amfepramone.
40. The pharmaceutical composition of claim 39, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using NCP System, metaraminol, d-methamphetamine hydrochloride, phentermine, amfepramone hydrochloride (diethylpropion), benzfetamine hydrochloride and phendimetrazine tartrate.
41. The pharmaceutical composition of claim 25, which is used in combination with a therapeutic agent for hypertension.
42. The pharmaceutical composition of claim 41, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of thiazides, aldosterone antagonists, adrenergic neuron blockers, calcium channel blockers; dopamine D2 antagonists, beta- adrenoceptor antagonists, alpha2-adrenoceptor agonists, guanylate cyclase activators, betal-adrenoceptor antagonists, alphal-adrenoceptor antagonists, antioxidants, angiotensin-I converting enzyme (ACE) inhibitors, Na+/H+ exchange inhibitors, 520 AMENDED SHEET alpha-adrenoceptor antagonists, nitric oxide donors, 5-HTZ2 antagonists, K(ATP) channel activators, potassium sparing diuretic prostaglandin synthase stimulants, imidazoline Il receptor agonists, angiotensin AT1 antagonists, dopamine Dl agonists, guanylate cyclase stimulants, endothelin ETA receptor antagonists, endothelin ETB receptor antagonists, NOS 3 expression enhancers, prostacyclin analogs, prostaglandins, angiotensin II antagonists, electrolyte absorption agonists, nicotinic antagonists, dopamine D2 agonists, prolactin inhibitors, platelet-activating factor (PAF) antagonists, platelet aggregation antagonists, tumor necrosis factor antagonists, Rho kinase inhibitors, PPAR-alpha agonists, AMPA receptor modulators, GABA(A) receptor antagonists and phosphodiesterase V (PDESA) inhibitors.
43. The pharmaceutical composition of claim 42, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, xipamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxymexrenone (eplerenone), guanethidine monosulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutolol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tertatolol hydrochloride, celiprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, cloranolol hydrochloride, bevantol (bevantolol) hydrochloride, clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine; nivadipine, nisoldipine, benidipine hydrochloride, 521 AMENDED SHEET amlodipine besylate, franidipine (manidipine) hydrochloride, lacidipine, isradipine, barnidipine (mepirodipine) hydrochloride, efonidipine hydrochloride ethanol, cinaldipine (cilnidipine), aranidipine, lercanidipine (masnidipine)
hydrochloride, azelnidipine, amlodipine, manidipine (franidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol hydrochloride, carvedilol, metoprolol succinate, talinolol, prazosin hydrochloride, urapidil,
jndoramin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril,
fosinoprilat, fosinopril sodium, trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilat, zofenoprilat, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradolol), linsidomine, ketanserin, pinacidil, cicletanine
(cycletanide), amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, eprosartan mesylate, candesartan cilexetil (hexetil), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesilate, cadralazine, rilmenidine dihydrogen phosphate,
posentan, beraprost sodium, limaprost alfadex (alpha- cyclodextrin), uniprost (treprostinil sodium), iloprost (ciloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, cloricromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlortalidone
(chlorthalidone), quinethazone, indapamide, metolazone, phenoxybenzamine hydrochloride, metirosine (metyrosine), diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, reserpine and methyldopa.
522 AMENDED SHEET
44. The pharmaceutical composition of claim 25, which is used in combination with a therapeutic agent for thrombosis.
45. The pharmaceutical composition of claim 44, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, anti-thrombin preparations, antiplatelet agents and thrombolytic agents.
46. The pharmaceutical composition of claim 45, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, reviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human anti-thrombin III, aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, sodium ozagrel, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasaruplase, nateplase, monteplase, pamiteplase, batroxobin, sodium citrate and protein C.
47. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 28, which is used in combination with a therapeutic agent for hyperlipidemia.
48. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 47, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of HMG-CoA reductase inhibitors (statins), fibrates, TNFSF6 expression inhibitors, HDL-cholesterol increasing agents, ApoAl 523 AMENDED SHEET expression enhancers, SPP1 (osteopontin) expression inhibitors, drugs acting on peroxisome proliferator-activated receptors (PPAR), PPAR-alpha agonists, lipase clearing factor stimulants, cholesterol antagonists, platelet aggregation antagonists, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor up-regulators, bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acids.
49. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 48, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostainin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (synvinolin), pitavastatin (itavastatin, nisvastatin) calcium, ronifibrate (ronifibrato), binifibrate (binifibrato), clinofibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, bezafibrate, gemfibrozil, acipimox, eicosapentaenoic acid (icosapent, icopenate, icosapentate) ethyl ester, probucol, policosanol, colesevelam hydrochloride, colestyramine (cholestyramine resin), colestipol hydrochloride, colestimide (colestilan), ezetimibe and niacin (nicotinic acid).
50. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 28, which is used in combination with a different therapeutic agent for diabetes.
51. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 50, wherein the different therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of insulin secretagogues, biguanides, a-glucosidase inhibitors, insulin preparations, insulin analogs, insulin sensitivity 524 AMENDED SHEET enhancers, IL-11, anti-CD25 (IL-2 Receptor) agents, angiotensin (AT1) antagonists, angiotensin-converting enzyme (ACE) inhibitors, aldose reductase inhibitors, antioxidants, carnitine acetyltransferase stimulant, antidepressants, glucocorticoids, retilin, radical formation agonists and transketolase activators.
52. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 51, wherein the djfferent therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybuzole, glipizide, glibornuride, gliquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epalrestat, miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate/biotin, V-411, recombinant human interleukin-11, dacliximab (daclizumab), losartan potassium, captopril, jmidapril hydrochloride, alpha-lipoic acid, levacecarnine (acetyl-L-carnitine, levocarnitine acetyl) hydrochloride, captopril, retilin, verteporfin, benfotiamine and fluocinolone acetonide.
53, The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 28, which is used in combination with a therapeutic agent for obesity.
54. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 53, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, lipase inhibitors, 5-HT/norepinephrine reuptake dual inhibitors, 5-HT 525 AMENDED SHEET reuptake inhibitors, supplements containing herbal ephedrine and caffeine, human chorionic gonadotropins, adrenoceptor agonists, methamphetamine, phentermine and amfepramone.
55. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 54, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using NCP System, metaraminol, d-methamphetamine hydrochloride, phentermine, amfepramone hydrochloride (diethylpropion), benzfetamine hydrochloride and phendimetrazine tartrate.
56. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 28, which is used in combination with a therapeutic agent for hypertension.
57. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 56, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of thiazides, aldosterone antagonists, adrenergic neuron blockers, calcium channel blockers; dopamine D2 antagonists, beta- adrenoceptor antagonists, alpha2-adrenoceptor agonists, guanylate cyclase activators, betal-adrenoceptor antagonists, alphal-adrenoceptor antagonists, antioxidants, angiotensin-I converting enzyme (ACE) inhibitors, Na+/H+ exchange inhibitors, alpha-adrenoceptor antagonists, nitric oxide donors, 5-HTZ antagonists, K(ATP) channel activators, potassium sparing : diuretic prostaglandin synthase stimulants, imidazoline Il receptor agonists, angiotensin AT1 antagonists, dopamine Dl agonists, guanylate cyclase stimulants, endothelin ETA receptor 526 AMENDED SHEET antagonists, endothelin ETB receptor antagonists, NOS3 expression enhancers, prostacyclin analogs, prostaglandins, angiotensin II antagonists, electrolyte absorption agonists, nicotinic antagonists, dopamine D2 agonists, prolactin inhibitors, platelet-activating factor (PAF) antagonists, platelet aggregation antagonists, tumor necrosis factor antagonists, Rho kinase inhibitors, PPAR-alpha agonists, AMPA receptor modulators, GABA(A) receptor antagonists and phosphodiesterase V (PDES5SA) inhibitors.
58. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 57, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, xipamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxymexrenone (eplerenone), guanethidine monosulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutolol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tertatolol hydrochloride, celiprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, cloranolol hydrochloride, bevantol (bevantolol) hydrochloride, clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine; nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, franidipine (manidipine) hydrochloride, lacidipine, isradipine, barnidipine (mepirodipine) hydrochloride, efonidipine hydrochloride ethanol, cinaldipine (cilnidipine), aranidipine, lercanidipine (masnidipine) 527 AMENDED SHEET hydrochloride, azelnidipine, amlodipine, manidipine (franidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol hydrochloride, carvedilol, metoprolol succinate, talinolol, prazosin hydrochloride, urapidil, indoramin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinoprilat, fosinopril sodium, trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilat, zofenoprilat, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradolol), linsidomine, ketanserin, pinacidil, cicletanine (cycletanide), amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, eprosartan mesylate, candesartan cilexetil (hexetil), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam pesilate, cadralazine, rilmenidine dihydrogen phosphate, bosentan, beraprost sodium, limaprost alfadex (alpha- cyclodextrin), uniprost (treprostinil sodium), iloprost (ciloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, cloricromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlortalidone (chlorthalidone), quinethazone, indapamide, metolazone, phenoxybenzamine hydrochloride, metirosine (metyrosine), diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, reserpine and methyldopa.
59. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 28, which is used in combination with a therapeutic agent for thrombosis. 528 AMENDED SHEET
60. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 59, wherein the therapeutic agent for thrombosis is one or more pharmaceutical ° agents selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, anti-thrombin preparations, antiplatelet agents and thrombolytic agents.
61. The pharmaceutical composition for the prophylaxis or treatment of diabetes according to claim 60, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, reviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human anti-thrombin III, aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, sodium ozagrel, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasaruplase, nateplase, monteplase, pamiteplase, batroxobin, sodium citrate and protein C.
62. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 29, which is used in combination with a different therapeutic agent for hyperlipidemia.
63. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 62, wherein the different therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of HMG-CoA reductase inhibitors (statins), fibrates, TNFSF6 expression inhibitors, HDL-cholesterol increasing agents, ApoAl 529 AMENDED SHEET expression enhancers, SPP1 (osteopontin) expression inhibitors, drugs acting on peroxisome proliferator-activated receptors (PPAR), PPAR-alpha agonists, lipase clearing factor stimulants, cholesterol antagonists, platelet aggregation antagonists, antioxidants, cholesterol biosynthesis inhibitors, ILDL-receptor up-regulators, bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acids.
64. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 63, wherein the different therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostainin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (synvinolin), pitavastatin (itavastatin, nisvastatin) calcium, ronifibrate (ronifibrato), binifibrate (binifibrato), clinofibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, bezafibrate, gemfibrozil, acipimox, eicosapentaenoic acid {icosapent, icopenate, icosapentate) ethyl ester, probucol, policosanol, colesevelam hydrochloride, colestyramine (cholestyramine resin), colestipol hydrochloride, colestimide (colestilan), ezetimibe and niacin (nicotinic acid).
65. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 29, which is used in combination with a therapeutic agent for diabetes.
66. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 65, wherein the therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of insulin secretagogues, biguanides, a-glucosidase inhibitors, insulin preparations, insulin analogs, insulin sensitivity enhancers, 530 AMENDED SHEET
IL-11, anti-CD25 (IL-2 Receptor) agents, angiotensin (AT1) antagonists, angiotensin-converting enzyme (ACE) inhibitors, aldose reductase inhibitors, antioxidants, carnitine acetyltransferase stimulant, antidepressants, glucocorticoids, retilin, radical formation agonists and transketolase activators.
67. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 66, wherein the therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybuzole, glipizide, glibornuride, gliquidone, repaglinide, metformin hydrochloride, puformin hydrochloride, voglibose, acarbose, epalrestat, miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate/biotin, V-411, recombinant human interleukin-11, dacliximab (daclizumab), losartan potassium, captopril, imidapril hydrochloride, alpha-lipoic acid, jevacecarnine (acetyl-L-carnitine, levocarnitine acetyl) hydrochloride, captopril, retilin, verteporfin, benfotiamine and fluocinolone acetonide.
68. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 29, which is used in combination with a therapeutic agent for obesity.
69. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 68, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, lipase inhibitors, 5-HT/norepinephrine reuptake dual inhibitors, S5-HT reuptake inhibitors, supplements containing herbal ephedrine 531 AMENDED SHEET and caffeine, human chorionic gonadotropins, adrenoceptor agonists, methamphetamine, phentermine and amfepramone.
70. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 69, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using NCP System, metaraminol, d-methamphetamine hydrochloride, phentermine, amfepramone hydrochloride (diethylpropion), benzfetamine hydrochloride and phendimetrazine tartrate.
71. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 29, which is used in combination with a therapeutic agent for hypertension.
72. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 71, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of thiazides, aldosterone antagonists, adrenergic neuron blockers, calcium channel blockers; dopamine D2 antagonists, beta- adrenoceptor antagonists, alpha2-adrenoceptor agonists, guanylate cyclase activators, betal-adrenoceptor antagonists, alphal-adrenoceptor antagonists, antioxidants, angiotensin-I converting enzyme (ACE) inhibitors, Na+/H+ exchange inhibitors, alpha-adrenoceptor antagonists, nitric oxide donors, 5-HT2 antagonists, K(ATP) channel activators, potassium sparing diuretic prostaglandin synthase stimulants, imidazoline I1 receptor agonists, angiotensin AT1 antagonists, dopamine D1 agonists, guanylate cyclase stimulants, endothelin ETA receptor antagonists, endothelin ETB receptor antagonists, NOS3 532 AMENDED SHEET expression enhancers, prostacyclin analogs, prostaglandins, angiotensin II antagonists, electrolyte absorption agonists, nicotinic antagonists, dopamine D2 agonists, prolactin inhibitors, platelet-activating factor (PAF) antagonists,
platelet aggregation antagonists, tumor necrosis factor antagonists, Rho kinase inhibitors, PPAR-alpha agonists, AMPA receptor modulators, GABA(R) receptor antagonists and phosphodiesterase V (PDE5A) inhibitors.
73, The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 72, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of chlorothiazide, hydrochlorothiazide, hydroflumethiazide,
methyclothiazide, polythiazide, xipamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxymexrenone (eplerenone), guanethidine monosulfate,
: guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride,
timolol maleate, sotalol hydrochloride, acebutolol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tertatolol hydrochloride, celiprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol,
cloranolol hydrochloride, bevantol (bevantolol) hydrochloride, clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine; nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, franidipine (manidipine) hydrochloride,
lacidipine, isradipine, barnidipine (mepirodipine) hydrochloride, efonidipine hydrochloride ethanol, cinaldipine (cilnidipine), aranidipine, lercanidipine (masnidipine) hydrochloride, azelnidipine, amlodipine, manidipine
533 AMENDED SHEET
(franidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol hydrochloride, carvedilol, metoprolol succinate, talinolol, prazosin hydrochloride, urapidil, indoramin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinoprilat, fosinopril sodium, trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilat, zofenoprilat, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradolol), linsidomine, ketanserin, pinacidil, cicletanine (cycletanide), amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, eprosartan mesylate, candesartan cilexetil (hexetil), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesilate, cadralazine, rilmenidine dihydrogen phosphate, posentan, beraprost sodium, limaprost alfadex (alpha- cyclodextrin), uniprost (treprostinil sodium), iloprost (ciloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, cloricromene, fasudil, doconexent (docosahexaenoic
. acid), cyclothiazide, sildenafil citrate, chlortalidone (chlorthalidone), quinethazone, indapamide, metolazone, phenoxybenzamine hydrochloride, metirosine (metyrosine), diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, reserpine and methyldopa.
74, The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 29, which is used in combination with a therapeutic agent for thrombosis. 534 AMENDED SHEET
75. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 74, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, anti~-thrombin preparations, antiplatelet agents and thrombolytic agents.
76. The pharmaceutical composition for the prophylaxis or treatment of hyperlipidemia according to claim 75, wherein the therapeutic agent for thrombosis is one or more pharmaceutical ‘agents selected from the group consisting of heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, reviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human anti-thrombin III, aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, sodium ozagrel, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasaruplase, nateplase, monteplase, panmiteplase, patroxobin, sodium citrate and protein C.
77. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 30, which is used in combination with a therapeutic agent for hyperlipidemia.
78. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 77, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of HMG-CoA reductase inhibitors (statins), fibrates, TNFSF6 expression inhibitors, HDL-cholesterol increasing agents, ApoAl expression enhancers, SPPl (osteopontin) expression inhibitors, drugs acting on peroxisome proliferator-activated receptors 535 AMENDED SHEET
(PPAR), PPAR-alpha agonists, lipase clearing factor stimulants, cholesterol antagonists, platelet aggregation antagonists, antioxidants, cholesterol biosynthesis inhibitors, LDL~receptor up-regulators, bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acids.
79. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 78, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostainin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (synvinolin), pitavastatin (itavastatin, nisvastatin) calcium, ronifibrate (ronifibrato), binifibrate (pinifibrato), clinofibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, bezafibrate, gemfibrozil, acipimox, eicosapentaenoic acid (icosapent, icopenate, icosapentate) ethyl ester, probucol, policosanol, colesevelan hydrochloride, colestyramine (cholestyramine resin), colestipol hydrochloride, colestimide (colestilan), ezetimibe and niacin (nicotinic acid).
80. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 30, which is used in combination with a therapeutic agent for diabetes.
81. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 80, wherein the therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of insulin secretagogues, biguanides, a-glucosidase inhibitors, insulin preparations, insulin analogs, insulin sensitivity enhancers, IL-11, anti-CD25 (IL-2 Receptor) agents, angiotensin (AT1) antagonists, angiotensin-converting enzyme (ACE) inhibitors, 536 AMENDED SHEET aldose reductase inhibitors, antioxidants, carnitine acetyltransferase stimulant, antidepressants, glucocorticoids, retilin, radical formation agonists and transketolase activators.
82. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 81, wherein the therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybuzole, glipizide, glibornuride, gliquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epalrestat, miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate/biotin, V-411, recombinant human interleukin-11, dacliximab (daclizumab), losartan potassium, captopril, imidapril hydrochloride, alpha-lipoic acid, levacecarnine (acetyl-L-carnitine, levocarnitine acetyl) hydrochloride, captopril, retilin, verteporfin, benfotiamine and fluocinolone acetonide.
83. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 30, which is used in combination with a different therapeutic agent for obesity.
84. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 83, wherein the different therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, lipase inhibitors, 5-HT/norepinephrine reuptake dual inhibitors, 5-HT reuptake inhibitors, supplements containing herbal ephedrine and caffeine, human chorionic gonadotropins, adrenoceptor agonists, methamphetamine, phentermine and 537 AMENDED SHEET amfepramone.
85. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 84, wherein the different therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using NCP System, metaraminol, d-methamphetamine hydrochloride, phentermine, amfepramone hydrochloride (diethylpropion), benzfetamine hydrochloride and phendimetrazine tartrate.
86. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 30, which is used in combination with a therapeutic agent for hypertension.
87. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 86, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of thiazides, aldosterone antagonists, adrenergic neuron blockers, calcium channel blockers; dopamine D2 antagonists, beta- adrenoceptor antagonists, alpha2-adrenoceptor agonists, guanylate cyclase activators, betal-adrenoceptor antagonists, alphal-adrenoceptor antagonists, antioxidants, angiotensin-I converting enzyme (ACE) inhibitors, Na+/H+ exchange inhibitors, alpha-adrenoceptor antagonists, nitric oxide donors, 5-HTZ antagonists, K(ATP) channel activators, potassium sparing diuretic prostaglandin synthase stimulants, imidazoline Il : receptor agonists, angiotensin AT1 antagonists, dopamine D1 agonists, guanylate cyclase stimulants, endothelin ETA receptor antagonists, endothelin ETB receptor antagonists, NOS3 538 AMENDED SHEET expression enhancers, prostacyclin analogs, prostaglandins, angiotensin II antagonists, electrolyte absorption agonists, nicotinic antagonists, dopamine D2 agonists, prolactin inhibitors, platelet-activating factor (PAF) antagonists, platelet aggregation antagonists, tumor necrosis factor antagonists, Rho kinase inhibitors, PPAR-alpha agonists, AMPA receptor modulators, GABA(A) receptor antagonists and phosphodiesterase V (PDE5A) inhibitors.
88. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 87, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, xipamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxymexrenone (eplerenone), guanethidine monosulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutolol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tertatolol hydrochloride, celiprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, cloranolol hydrochloride, bevantol (bevantolol) hydrochloride, clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine; nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, franidipine (manidipine) hydrochloride, lacidipine, isradipine, barnidipine (mepirodipine) hydrochloride, efonidipine hydrochloride ethanol, cinaldipine (cilnidipine), aranidipine, lercanidipine (masnidipine) hydrochloride, azelnidipine, amlodipine, manidipine AMERDED SHEET
(franidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol hydrochloride, carvedilol, metoprolol succinate, talinolol, prazosin hydrochloride, urapidil,
indoramin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril,
fosinoprilat, fosinopril sodium, trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilat, zofenoprilat, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradolol), linsidomine, ketanserin, pinacidil, cicletanine
(cycletanide), amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, eprosartan mesylate, candesartan cilexetil (hexetil), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesilate, cadralazine, rilmenidine dihydrogen phosphate,
posentan, beraprost sodium, limaprost alfadex (alpha- cyclodextrin), uniprost (treprostinil sodium), iloprost (ciloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, cloricromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlortalidone
(chlorthalidone), quinethazone, indapamide, metolazone, phenoxybenzamine hydrochloride, metirosine (metyrosine), diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, reserpine and methyldopa.
89, The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 30, which is used in combination with a therapeutic agent for thrombosis.
540 AMENDED SHEET
90. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 89, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, . anticoagulants, thrombin inhibitors, anti-thrombin preparations, antiplatelet agents and thrombolytic agents.
91. The pharmaceutical composition for the prophylaxis or treatment of obesity according to claim 90, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, reviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human anti-thrombin III, aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, sodium ozagrel, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasaruplase, nateplase, monteplase, pamiteplase, patroxobin, sodium citrate and protein C.
92. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 31, which is used in combination with a therapeutic agent for hyperlipidemia.
93. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 92, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of HMG-CoA reductase inhibitors (statins), fibrates, TNFSF6 expression inhibitors, HDL-cholesterol increasing agents, ApoAl expression enhancers, SPP1l (osteopontin) expression inhibitors, 541 AMENDED SHEET drugs acting on peroxisome proliferator-activated receptors (PPAR), PPAR-alpha agonists, lipase clearing factor stimulants, cholesterol antagonists, platelet aggregation antagonists, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor up-requlators, bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acids.
94. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 93, wherein the therapeutic agent for hyperlipidemia is one or more pharmaceutical agents selected from the group consisting of lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostainin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (synvinolin), pitavastatin (itavastatin, pisvastatin) calcium, ronifibrate (ronifibrato), binifibrate (binifibrato), clinofibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, bezafibrate, gemfibrozil, acipimox, eicosapentaenoic acid (icosapent, icopenate, icosapentate) ethyl ester, probucol, policosanol, colesevelam hydrochloride, colestyramine (cholestyramine resin), colestipol hydrochloride, colestimide (colestilan), ezetimibe and niacin (nicotinic acid).
95. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 31, which is used in combination with a therapeutic agent for diabetes.
96. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 95, wherein the therapeutic agent for diabetes is one or more : pharmaceutical agents selected from the group consisting of insulin secretagogues, biguanides, a-glucosidase inhibitors, insulin preparations, insulin analogs, insulin sensitivity 542 AMENDED SHEET enhancers, IL-11, anti-CD25 (IL-2 Receptor) agents, angiotensin (AT1) antagonists, angiotensin-converting enzyme (ACE) inhibitors, aldose reductase inhibitors, antioxidants, carnitine acetyltransferase stimulant, antidepressants, glucocorticoids, retilin, radical formation agonists and transketolase activators.
97. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 96, wherein the therapeutic agent for diabetes is one or more pharmaceutical agents selected from the group consisting of nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybuzole, glipizide, glibornuride, gliquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epalrestat, miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate/biotin, V-411, recombinant human interleukin-11, dacliximab (daclizumab), losartan potassium, captopril, jmidapril hydrochloride, alpha-lipoic acid, levacecarnine (acetyl-L-carnitine, levocarnitine acetyl) hydrochloride, captopril, retilin, verteporfin, benfotiamine and fluocinolone acetonide.
98, The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 31, which is used in combination with a therapeutic agent for obesity.
99. The pharmaceutical composition for the prophylaxis or : treatment of diabetic complications according to claim 98, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of 543 AMENDED SHEET mazindol, lipase inhibitors, 5-HT/norepinephrine reuptake dual inhibitors, 5-HT reuptake inhibitors, supplements containing herbal ephedrine and caffeine, human chorionic gonadotropins, adrenoceptor agonists, methamphetamine, phentermine and amfepramone.
100. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 99, wherein the therapeutic agent for obesity is one or more pharmaceutical agents selected from the group consisting of mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using NCP System, metaraminol, d-methamphetamine hydrochloride, phentermine, amfepramone hydrochloride (diethylpropion), benzfetamine hydrochloride and phendimetrazine tartrate.
101. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 31, which is used in combination with a therapeutic agent for hypertension.
102. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 101, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of thiazides, aldosterone antagonists, adrenergic neuron blockers, calcium channel blockers; dopamine D2 antagonists, beta- adrenoceptor antagonists, alpha2-adrenoceptor agonists, guanylate cyclase activators, betal-adrenoceptor antagonists, alphal-adrenoceptor antagonists, antioxidants, angiotensin-1I converting enzyme (ACE) inhibitors, Na+/H+ exchange inhibitors, alpha-adrenoceptor antagonists, nitric oxide donors, 5-HTZ 544 AMENDED SHEET antagonists, K(ATP) channel activators, potassium sparing diuretic prostaglandin synthase stimulants, imidazoline Tl receptor agonists, angiotensin AT1 antagonists, dopamine D1 agonists, guanylate cyclase stimulants, endothelin ETA receptor antagonists, endothelin ETB receptor antagonists, NOS3 expression enhancers, prostacyclin analogs, prostaglandins, angiotensin II antagonists, electrolyte absorption agonists, nicotinic antagonists, dopamine D2 agonists, prolactin inhibitors, platelet-activating factor (PAF) antagonists, platelet aggregation antagonists, tumor necrosis factor antagonists, Rho kinase inhibitors, PPAR-alpha agonists, AMPA receptor modulators, GABA(A) receptor antagonists and phosphodiesterase V (PDES5A) inhibitors.
103. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 102, wherein the therapeutic agent for hypertension is one or more pharmaceutical agents selected from the group consisting of chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, xipamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxymexrenone (eplerenone), guanethidine monosul fate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutolol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tertatolol hydrochloride, celiprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, cloranolol hydrochloride, bevantol (bevantolol) hydrochloride, clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine; nivadipine, nisoldipine, benidipine hydrochloride, 545 AMENDED SHEET amlodipine besylate, franidipine (manidipine) hydrochloride, lacidipine, isradipine, barnidipine (mepirodipine) hydrochloride, efonidipine hydrochloride ethanol, cinaldipine (cilnidipine), aranidipine, lercanidipine (masnidipine)
hydrochloride, azelnidipine, amlodipine, manidipine (franidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol hydrochloride, carvedilol, metoprolol succinate, talinolol, prazosin hydrochloride, urapidil,
jndoramin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril,
fosinoprilat, fosinopril sodium, trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilat, zofenoprilat, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradolol), linsidomine, ketanserin, pinacidil, cicletanine
(cycletanide), amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, eprosartan mesylate, candesartan cilexetil (hexetil), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesilate, cadralazine, rilmenidine dihydrogen phosphate,
phosentan, beraprost sodium, limaprost alfadex (alpha- cyclodextrin), uniprost (treprostinil sodium), iloprost (ciloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, cloricromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlortalidone
(chlorthalidone), quinethazone, indapamide, metolazone, : phenoxybenzamine hydrochloride, metirosine (metyrosine), diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, reserpine and methyldopa.
546 _ BMENDED SHEET
104. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 31, which is used in combination with a therapeutic agent for 3 thrombosis.
105. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 104, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, anti-thrombin preparations, antiplatelet agents and thrombolytic agents.
106. The pharmaceutical composition for the prophylaxis or treatment of diabetic complications according to claim 105, wherein the therapeutic agent for thrombosis is one or more pharmaceutical agents selected from the group consisting of heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, reviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human anti- thrombin III, aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, sodium ozagrel, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasaruplase, nateplase, monteplase, pamiteplase, batroxobin, sodium citrate and protein C.
107. A pharmaceutical composition for inhibition of a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for hyperlipidemia.
108. A pharmaceutical composition for inhibition of a receptor tyrosine kinase negative regulator, which is used in 547 AMENDED SHEET i © combination with a therapeutic agent for diabetes. )
109. A pharmaceutical composition for inhibition of a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for obesity.
110. A pharmaceutical composition for inhibition of a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for hypertension.
111. A pharmaceutical composition for inhibition of a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for thrombosis.
112. A 5-membered heteroaromatic ring compound represented by the formula [II] 3 H \Y R { / f00_pt00 (I1] wherein Y% is -Cc(R?) (R')~ (R'® and R' are each as defined in claim 201); R!% is a hydroxyl group or a halogen atom, and V, W and R’ are each as defined in claim 1, or a pharmaceutically acceptable salt thereof.
113. The 5-membered heteroaromatic ring compound of claim 112, wherein, in the formula [II], R'® and R' are each a hydrogen atom, V is =CH- and W is -S-, or a pharmaceutically acceptable salt thereof. :
ABSTRACT A 5-membered heteroaromatic ring compound represented by the formula [I] TT V RY s 3 RIN 7a : R—(L);— (CH); X—{C(R)(R 4 / (1) Ww Y—A)—Z wherein V is CH or N; W is S or 0; R' and R? are each H etc.; X is -N(R*)-, -0-, -S-, -S0,-N(R®)-, -CO-N(R’)- etc.; L is -CR®)R")- NTAGRGES oo : | R%? oF | R> . wherein R?°, R%, R% and R?*® are each H etc.; E is aryl or heteroaromatic ring group; R is -COOH etc.; B is aryl etc.; R3 170 is H etc.; Y is -C(R¥) (R™)-N(R'?)-, -C(R") (R'*)-0-, -N(R'Y)-, - O- etc.; A is alkylene; and Z is aryl etc., a prodrug thereof and a pharmaceutically acceptable salt thereof.
The compound [I] has a superior protein tyrosine phosphatase 1B inhibitory activity and is useful as a therapeutic agent for diabetes, diabetic complications, hyperlipidemia, obesity and the like.
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Families Citing this family (13)
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US20080279845A1 (en) * | 2007-05-02 | 2008-11-13 | Portola Pharmaceuticals, Inc. | Combination therapy with a compound acting as a platelet adp receptor inhibitor |
CN104803938A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | PTP1B (protein tyrosine phosphatase 1B) inhibitors with phenylthiazole and cyclopentadiene structures and application of inhibitors |
CN104803940A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | PTP (protein tyrosine phosphatase)1B compounds containing thiazole and cyclopentadiene structures and application of PTP1B compounds |
CN104803937A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | Derivatives containing cyclopentadiene and aniline structures and applications of derivatives |
CN104803944A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | Compounds containing cyclopentadiene and aniline structures and applications of compounds |
CN104803941A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | PTP1B (protein tyrosine phosphatase 1B) inhibitors with cyclopentadiene structures, preparation methods and application of inhibitors |
CN104744397A (en) * | 2015-03-03 | 2015-07-01 | 佛山市赛维斯医药科技有限公司 | PTP1B inhibitor containing cyclopentadiene and cyanoaniline structures and use of PTP1B inhibitor |
CN104803942A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | PTP (protein tyrosine phosphatase)1B inhibitors containing cyclopentadiene and alkoxyaniline structures and application of PTP1B inhibitors |
CN104803939A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | PTP1B (protein tyrosine phosphatase 1B) inhibitors with nitrothiazole and cyclopentadiene structures and application of inhibitors |
CN104803943A (en) * | 2015-03-03 | 2015-07-29 | 佛山市赛维斯医药科技有限公司 | PTP (protein tyrosine phosphatase)1B inhibitors containing cyclopentadiene and thioaniline structures and application of PTP1B inhibitors |
CN104744398A (en) * | 2015-03-03 | 2015-07-01 | 佛山市赛维斯医药科技有限公司 | PTP1B inhibitor containing halogenobenzothiazole and cyclopentadiene structures and use of PTP1B inhibitor |
CN104744396A (en) * | 2015-03-03 | 2015-07-01 | 佛山市赛维斯医药科技有限公司 | PTP1B inhibitor containing cyclopentadiene structure, preparation method of PTP1B inhibitor and use of PTP1B inhibitor |
CN113956213A (en) * | 2021-11-19 | 2022-01-21 | 烟台药物研究所 | PPAR alpha/delta dual agonist with 2, 4-disubstituted thiazole structure and application thereof |
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