NZ534583A - Leucinamide derivatives suitable as cathepsin cysteine protease inhibitors - Google Patents
Leucinamide derivatives suitable as cathepsin cysteine protease inhibitorsInfo
- Publication number
- NZ534583A NZ534583A NZ534583A NZ53458303A NZ534583A NZ 534583 A NZ534583 A NZ 534583A NZ 534583 A NZ534583 A NZ 534583A NZ 53458303 A NZ53458303 A NZ 53458303A NZ 534583 A NZ534583 A NZ 534583A
- Authority
- NZ
- New Zealand
- Prior art keywords
- leucinamide
- ethyl
- trifluoro
- cyanomethyl
- biphenyl
- Prior art date
Links
- 102000005600 Cathepsins Human genes 0.000 title claims abstract description 25
- 108010084457 Cathepsins Proteins 0.000 title claims abstract description 25
- FORGMRSGVSYZQR-YFKPBYRVSA-N L-leucinamide Chemical class CC(C)C[C@H](N)C(N)=O FORGMRSGVSYZQR-YFKPBYRVSA-N 0.000 title claims description 30
- 239000002852 cysteine proteinase inhibitor Substances 0.000 title abstract description 4
- -1 Leucinamide derivative compounds Chemical class 0.000 claims abstract description 437
- 150000001875 compounds Chemical class 0.000 claims abstract description 186
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 239000003112 inhibitor Substances 0.000 claims abstract description 26
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 19
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 16
- 208000010392 Bone Fractures Diseases 0.000 claims abstract description 10
- 230000008416 bone turnover Effects 0.000 claims abstract description 10
- 208000037848 Metastatic bone disease Diseases 0.000 claims abstract description 8
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 claims abstract description 8
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 claims abstract description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims abstract description 7
- 208000010191 Osteitis Deformans Diseases 0.000 claims abstract description 7
- 206010031243 Osteogenesis imperfecta Diseases 0.000 claims abstract description 7
- 208000027868 Paget disease Diseases 0.000 claims abstract description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 7
- 208000008312 Tooth Loss Diseases 0.000 claims abstract description 7
- 201000003617 glucocorticoid-induced osteoporosis Diseases 0.000 claims abstract description 7
- 208000027202 mammary Paget disease Diseases 0.000 claims abstract description 7
- 208000028169 periodontal disease Diseases 0.000 claims abstract description 7
- 206010052306 Periprosthetic osteolysis Diseases 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 540
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 419
- 125000000217 alkyl group Chemical group 0.000 claims description 269
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 218
- 125000005843 halogen group Chemical group 0.000 claims description 139
- 239000000203 mixture Substances 0.000 claims description 128
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 118
- 229910052739 hydrogen Inorganic materials 0.000 claims description 111
- 239000001257 hydrogen Substances 0.000 claims description 109
- 125000000623 heterocyclic group Chemical group 0.000 claims description 100
- 125000003118 aryl group Chemical group 0.000 claims description 99
- 239000000243 solution Substances 0.000 claims description 92
- 125000001072 heteroaryl group Chemical group 0.000 claims description 78
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 64
- 238000002360 preparation method Methods 0.000 claims description 62
- 229910052799 carbon Inorganic materials 0.000 claims description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 52
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 46
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 43
- 125000001188 haloalkyl group Chemical group 0.000 claims description 40
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 40
- 108090000625 Cathepsin K Proteins 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 31
- 210000000988 bone and bone Anatomy 0.000 claims description 31
- 125000004122 cyclic group Chemical group 0.000 claims description 31
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 28
- 229930194542 Keto Natural products 0.000 claims description 28
- 125000000468 ketone group Chemical group 0.000 claims description 28
- 229940122361 Bisphosphonate Drugs 0.000 claims description 27
- 150000001721 carbon Chemical group 0.000 claims description 27
- 241000124008 Mammalia Species 0.000 claims description 25
- 150000004663 bisphosphonates Chemical class 0.000 claims description 25
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- 230000024279 bone resorption Effects 0.000 claims description 21
- 210000002997 osteoclast Anatomy 0.000 claims description 21
- 208000006386 Bone Resorption Diseases 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 150000001204 N-oxides Chemical class 0.000 claims description 17
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 102000006495 integrins Human genes 0.000 claims description 15
- 108010044426 integrins Proteins 0.000 claims description 15
- 125000002619 bicyclic group Chemical group 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 13
- 230000005764 inhibitory process Effects 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 10
- 238000003556 assay Methods 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 230000001419 dependent effect Effects 0.000 claims description 9
- UIVATUPCWVUVIM-UHFFFAOYSA-N 1-aminocyclopropane-1-carbonitrile Chemical compound N#CC1(N)CC1 UIVATUPCWVUVIM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 108091006112 ATPases Proteins 0.000 claims description 8
- 102000057290 Adenosine Triphosphatases Human genes 0.000 claims description 8
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 8
- 108090000613 Cathepsin S Proteins 0.000 claims description 8
- 108010041356 Estrogen Receptor beta Proteins 0.000 claims description 8
- 102100029951 Estrogen receptor beta Human genes 0.000 claims description 8
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 claims description 8
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 claims description 8
- 239000003263 anabolic agent Substances 0.000 claims description 8
- 229940124325 anabolic agent Drugs 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 8
- 210000000963 osteoblast Anatomy 0.000 claims description 8
- 229910052701 rubidium Inorganic materials 0.000 claims description 8
- 239000000849 selective androgen receptor modulator Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 102100035654 Cathepsin S Human genes 0.000 claims description 7
- 239000002834 estrogen receptor modulator Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 6
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 5
- 206010017076 Fracture Diseases 0.000 claims description 5
- DFNYGALUNNFWKJ-UHFFFAOYSA-N aminoacetonitrile Chemical compound NCC#N DFNYGALUNNFWKJ-UHFFFAOYSA-N 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 229940044551 receptor antagonist Drugs 0.000 claims description 5
- 239000002464 receptor antagonist Substances 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 3
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 claims description 3
- 108090000712 Cathepsin B Proteins 0.000 claims description 3
- 102000004225 Cathepsin B Human genes 0.000 claims description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- ATYXZINOMANKJC-HOTGVXAUSA-N (2s)-2-[[(s)-(4-bromophenyl)-(1,3-thiazol-2-yl)methyl]amino]-n-(cyanomethyl)-4-methylpentanamide Chemical compound C1([C@@H](N[C@@H](CC(C)C)C(=O)NCC#N)C=2C=CC(Br)=CC=2)=NC=CS1 ATYXZINOMANKJC-HOTGVXAUSA-N 0.000 claims description 2
- FLQUAEZSRVWCDS-VXKWHMMOSA-N (2s)-n-(1-cyanocyclopropyl)-2-[[(1s)-2,2,2-trifluoro-1-[4-(1h-indol-5-yl)phenyl]ethyl]amino]pentanamide Chemical compound O=C([C@@H](N[C@@H](C=1C=CC(=CC=1)C=1C=C2C=CNC2=CC=1)C(F)(F)F)CCC)NC1(C#N)CC1 FLQUAEZSRVWCDS-VXKWHMMOSA-N 0.000 claims description 2
- SHMWAIYTXATZLP-SFTDATJTSA-N (2s)-n-(1-cyanocyclopropyl)-2-[[(1s)-2,2,2-trifluoro-1-[4-[3-(methanesulfonamido)phenyl]phenyl]ethyl]amino]pentanamide Chemical compound C1=CC([C@H](N[C@@H](CCC)C(=O)NC2(CC2)C#N)C(F)(F)F)=CC=C1C1=CC=CC(NS(C)(=O)=O)=C1 SHMWAIYTXATZLP-SFTDATJTSA-N 0.000 claims description 2
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 2
- LNVBRRSMRXDSDL-UHFFFAOYSA-N 2-[[(4-bromophenyl)-pyridin-4-ylmethyl]amino]-n-(cyanomethyl)pentanamide Chemical compound C=1C=C(Br)C=CC=1C(NC(CCC)C(=O)NCC#N)C1=CC=NC=C1 LNVBRRSMRXDSDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- WNAFVJVEADYQAI-UHFFFAOYSA-N methyl 2-phenylbenzoate Chemical compound COC(=O)C1=CC=CC=C1C1=CC=CC=C1 WNAFVJVEADYQAI-UHFFFAOYSA-N 0.000 claims description 2
- KUFJIROJONPBSH-UHFFFAOYSA-N n-(1-cyanocyclopropyl)pentanamide Chemical compound CCCCC(=O)NC1(C#N)CC1 KUFJIROJONPBSH-UHFFFAOYSA-N 0.000 claims description 2
- YYTGUVNMLZUEIM-UHFFFAOYSA-N n-(cyanomethyl)-1-[(2,2,2-trifluoro-1-phenylethyl)amino]cyclohexane-1-carboxamide Chemical compound C=1C=CC=CC=1C(C(F)(F)F)NC1(C(=O)NCC#N)CCCCC1 YYTGUVNMLZUEIM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 2
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- 150000002431 hydrogen Chemical class 0.000 claims 10
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 8
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- 231100000673 dose–response relationship Toxicity 0.000 claims 3
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- 238000013207 serial dilution Methods 0.000 claims 2
- OWQFMCFBCYDGQY-QUCQDJGISA-N (2S)-N-(1-cyanocyclopropyl)-2-[[(1S)-2,2,2-trifluoro-1-(1-methyl-4-phenylcyclohexa-2,4-dien-1-yl)ethyl]amino]pentanamide Chemical compound C1=CC([C@@H](C(F)(F)F)N[C@@H](CCC)C(=O)NC2(CC2)C#N)(C)CC=C1C1=CC=CC=C1 OWQFMCFBCYDGQY-QUCQDJGISA-N 0.000 claims 1
- YGBRKQFDLNEMNR-IRXDYDNUSA-N (2s)-2-[[(1s)-1-[4-(2,4-difluorophenyl)phenyl]-2,2,2-trifluoroethyl]amino]pentanoic acid Chemical compound C1=CC([C@H](N[C@@H](CCC)C(O)=O)C(F)(F)F)=CC=C1C1=CC=C(F)C=C1F YGBRKQFDLNEMNR-IRXDYDNUSA-N 0.000 claims 1
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Classifications
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