AU2007216625B2 - Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity - Google Patents
Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity Download PDFInfo
- Publication number
- AU2007216625B2 AU2007216625B2 AU2007216625A AU2007216625A AU2007216625B2 AU 2007216625 B2 AU2007216625 B2 AU 2007216625B2 AU 2007216625 A AU2007216625 A AU 2007216625A AU 2007216625 A AU2007216625 A AU 2007216625A AU 2007216625 B2 AU2007216625 B2 AU 2007216625B2
- Authority
- AU
- Australia
- Prior art keywords
- compound
- amino
- dmf
- phenyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000002401 inhibitory effect Effects 0.000 title description 14
- 229940124530 sulfonamide Drugs 0.000 title description 11
- 150000001408 amides Chemical class 0.000 title description 10
- 230000000694 effects Effects 0.000 title description 9
- 150000003672 ureas Chemical class 0.000 title description 9
- 150000003456 sulfonamides Chemical class 0.000 title description 8
- 108091000080 Phosphotransferase Proteins 0.000 title description 7
- 102000020233 phosphotransferase Human genes 0.000 title description 7
- 235000013877 carbamide Nutrition 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 123
- -1 enantiomers Chemical class 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000004480 active ingredient Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 231
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- 238000000034 method Methods 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 229920005989 resin Polymers 0.000 description 51
- 239000011347 resin Substances 0.000 description 51
- 239000000203 mixture Substances 0.000 description 39
- 238000005859 coupling reaction Methods 0.000 description 36
- 239000000243 solution Substances 0.000 description 35
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 32
- 230000008878 coupling Effects 0.000 description 32
- 238000010168 coupling process Methods 0.000 description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 20
- 230000014759 maintenance of location Effects 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 20
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 19
- 239000007790 solid phase Substances 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 18
- 210000000988 bone and bone Anatomy 0.000 description 18
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 18
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 17
- 150000002500 ions Chemical class 0.000 description 17
- 238000001819 mass spectrum Methods 0.000 description 17
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 16
- 208000001132 Osteoporosis Diseases 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 102000009076 src-Family Kinases Human genes 0.000 description 13
- 108010087686 src-Family Kinases Proteins 0.000 description 13
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 10
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 125000005647 linker group Chemical group 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000000314 lubricant Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 7
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 7
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 7
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 239000011230 binding agent Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000010933 acylation Effects 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000010647 peptide synthesis reaction Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 239000007987 MES buffer Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- GYDJEQRTZSCIOI-UHFFFAOYSA-N Tranexamic acid Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 5
- 125000002837 carbocyclic group Chemical group 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- 210000002997 osteoclast Anatomy 0.000 description 5
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- RPESZQVUWMFBEO-UHFFFAOYSA-N 3-cyanobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(C#N)=C1 RPESZQVUWMFBEO-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- USEDMAWWQDFMFY-UHFFFAOYSA-N 4-cyanobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(C#N)C=C1 USEDMAWWQDFMFY-UHFFFAOYSA-N 0.000 description 4
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 208000006386 Bone Resorption Diseases 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- 239000002262 Schiff base Substances 0.000 description 4
- 150000004753 Schiff bases Chemical class 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000024279 bone resorption Effects 0.000 description 4
- 150000003857 carboxamides Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 4
- 239000010931 gold Substances 0.000 description 4
- 229910052737 gold Inorganic materials 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- XPDSXKIDJNKIQY-UHFFFAOYSA-N 1-cyclohexylpiperazine Chemical compound C1CCCCC1N1CCNCC1 XPDSXKIDJNKIQY-UHFFFAOYSA-N 0.000 description 3
- KCHOHFPMTUPOJU-UHFFFAOYSA-N 1-fluoro-4-isocyanato-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(N=C=O)=CC=C1F KCHOHFPMTUPOJU-UHFFFAOYSA-N 0.000 description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010065687 Bone loss Diseases 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 102000014400 SH2 domains Human genes 0.000 description 3
- 108050003452 SH2 domains Proteins 0.000 description 3
- 102000001332 SRC Human genes 0.000 description 3
- 108060006706 SRC Proteins 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N divinylbenzene Substances C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 229920005990 polystyrene resin Polymers 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 2
- JOWKLGMNVUYQGV-INIZCTEOSA-N (2s)-2-[cyclohexyl(9h-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N([C@@H](C)C(O)=O)C1CCCCC1 JOWKLGMNVUYQGV-INIZCTEOSA-N 0.000 description 2
- HIJAUEZBPWTKIV-QFIPXVFZSA-N (2s)-3-cyclohexyl-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1CCCCC1 HIJAUEZBPWTKIV-QFIPXVFZSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- XUXJHBAJZQREDB-UHFFFAOYSA-N 2-methylbutanamide Chemical compound CCC(C)C(N)=O XUXJHBAJZQREDB-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- TZKLQOUZLZUMOH-UHFFFAOYSA-N 3-(4-phenylphenyl)propanamide Chemical compound C1=CC(CCC(=O)N)=CC=C1C1=CC=CC=C1 TZKLQOUZLZUMOH-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 102000000395 SH3 domains Human genes 0.000 description 2
- 108050008861 SH3 domains Proteins 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 239000003637 basic solution Substances 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- JCZLABDVDPYLRZ-AWEZNQCLSA-N biphenylalanine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1C1=CC=CC=C1 JCZLABDVDPYLRZ-AWEZNQCLSA-N 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000005056 compaction Methods 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000013024 dilution buffer Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229940116441 divinylbenzene Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical class C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001599 osteoclastic effect Effects 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- 229950009215 phenylbutanoic acid Drugs 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QLNJFJADRCOGBJ-LBPDFUHNSA-N propanamide Chemical group CC[13C](N)=O QLNJFJADRCOGBJ-LBPDFUHNSA-N 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 125000006308 propyl amino group Chemical group 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- ADOHASQZJSJZBT-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-SANMLTNESA-N 0.000 description 1
- JRLIJKIBIOLJJK-SFHVURJKSA-N (2s)-2-[9h-fluoren-9-ylmethoxycarbonyl(naphthalen-2-yl)amino]propanoic acid Chemical compound C1=CC=CC2=CC(N(C(=O)OCC3C4=CC=CC=C4C4=CC=CC=C43)[C@@H](C)C(O)=O)=CC=C21 JRLIJKIBIOLJJK-SFHVURJKSA-N 0.000 description 1
- NVNQBGLCMZNHEX-VKHMYHEASA-N (2s)-2-amino-n-(2-amino-2-oxoethyl)propanamide Chemical compound C[C@H](N)C(=O)NCC(N)=O NVNQBGLCMZNHEX-VKHMYHEASA-N 0.000 description 1
- WPAALELGEWGQEG-DEOSSOPVSA-N (2s)-5-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCN=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 WPAALELGEWGQEG-DEOSSOPVSA-N 0.000 description 1
- IAVUPMFITXYVAF-HTRCEHHLSA-N (4r,6r)-4-(ethylamino)-6-methyl-7,7-dioxo-5,6-dihydro-4h-thieno[2,3-b]thiopyran-2-sulfonamide Chemical compound CCN[C@@H]1C[C@@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-HTRCEHHLSA-N 0.000 description 1
- QFXOXDSHNXAFEY-SREVYHEPSA-N (Z)-4-Hydroxy-6-dodecenoic acid lactone Chemical compound CCCCC\C=C/CC1CCC(=O)O1 QFXOXDSHNXAFEY-SREVYHEPSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- DZUHXDZJXISXNK-UHFFFAOYSA-N 1-fluoro-3-nitrobenzene;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.[O-][N+](=O)C1=CC=CC(F)=C1 DZUHXDZJXISXNK-UHFFFAOYSA-N 0.000 description 1
- FNQIGYRDLYROLW-UHFFFAOYSA-N 1-hydroxy-2h-1,2,3-benzotriazine Chemical compound C1=CC=C2N(O)NN=CC2=C1 FNQIGYRDLYROLW-UHFFFAOYSA-N 0.000 description 1
- DJQVPXPEXAWGRE-UHFFFAOYSA-N 2,3-dihydrotriazolo[4,5-b]pyridin-7-one Chemical compound O=C1C=CN=C2NNN=C12 DJQVPXPEXAWGRE-UHFFFAOYSA-N 0.000 description 1
- FCDJXJMJLSJGIC-UHFFFAOYSA-N 2-[[4-(4-cyclohexylpiperazin-1-yl)-3-(3-phenylprop-2-enoylamino)phenyl]carbamoylamino]-4-phenylbutanamide Chemical compound C=1C=C(N2CCN(CC2)C2CCCCC2)C(NC(=O)C=CC=2C=CC=CC=2)=CC=1NC(=O)NC(C(=O)N)CCC1=CC=CC=C1 FCDJXJMJLSJGIC-UHFFFAOYSA-N 0.000 description 1
- YRXIMPFOTQVOHG-UHFFFAOYSA-N 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetic acid Chemical compound OC(=O)CN(C)C(=O)OC(C)(C)C YRXIMPFOTQVOHG-UHFFFAOYSA-N 0.000 description 1
- VQHGELUKJYOETQ-UHFFFAOYSA-N 2-fluoro-5-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(F)C(S(Cl)(=O)=O)=C1 VQHGELUKJYOETQ-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 1
- SKXPGNVNPOTKKR-UHFFFAOYSA-N 3-naphthalen-2-ylpropanamide Chemical compound C1=CC=CC2=CC(CCC(=O)N)=CC=C21 SKXPGNVNPOTKKR-UHFFFAOYSA-N 0.000 description 1
- MRLGCTNJRREZHZ-UHFFFAOYSA-N 3-phenoxybenzaldehyde Chemical compound O=CC1=CC=CC(OC=2C=CC=CC=2)=C1 MRLGCTNJRREZHZ-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ABGXADJDTPFFSZ-UHFFFAOYSA-N 4-benzylpiperidine Chemical compound C=1C=CC=CC=1CC1CCNCC1 ABGXADJDTPFFSZ-UHFFFAOYSA-N 0.000 description 1
- UIVWXNPUCAHAJX-UHFFFAOYSA-N 4-hydroxy-1,1-dioxo-2,5-diphenylthiophen-3-one Chemical compound O=S1(=O)C(C=2C=CC=CC=2)C(=O)C(O)=C1C1=CC=CC=C1 UIVWXNPUCAHAJX-UHFFFAOYSA-N 0.000 description 1
- LEPWUMPXISBPIB-UHFFFAOYSA-N 4-phenylbutanamide Chemical group NC(=O)CCCC1=CC=CC=C1 LEPWUMPXISBPIB-UHFFFAOYSA-N 0.000 description 1
- AGNFWIZBEATIAK-UHFFFAOYSA-N 4-phenylbutylamine Chemical compound NCCCCC1=CC=CC=C1 AGNFWIZBEATIAK-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241001474374 Blennius Species 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RWDIHNZCASFMKB-PSXMRANNSA-N CC(C)(C)C(C=C1)=CC=C1OC1=CC=CC(CN([C@](C)(C2CCCCC2)C(NCC(N)=O)=O)C(C2=CC=CC(C(N)=N)=C2)=O)=C1 Chemical compound CC(C)(C)C(C=C1)=CC=C1OC1=CC=CC(CN([C@](C)(C2CCCCC2)C(NCC(N)=O)=O)C(C2=CC=CC(C(N)=N)=C2)=O)=C1 RWDIHNZCASFMKB-PSXMRANNSA-N 0.000 description 1
- HQGUPRCXCWZULE-BHVANESWSA-N CC(C)(C)C(C=C1)=CC=C1OC1=CC=CC(C[C@](CC(C2=CC=CC(C(N)=N)=C2)=O)(C(NCC(N)=O)=O)N=C2CCCCC2)=C1 Chemical compound CC(C)(C)C(C=C1)=CC=C1OC1=CC=CC(C[C@](CC(C2=CC=CC(C(N)=N)=C2)=O)(C(NCC(N)=O)=O)N=C2CCCCC2)=C1 HQGUPRCXCWZULE-BHVANESWSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 240000008886 Ceratonia siliqua Species 0.000 description 1
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 244000303965 Cyamopsis psoralioides Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010020707 Hyperparathyroidism primary Diseases 0.000 description 1
- 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 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- KFOBAVFLHQTUFP-RRHRGVEJSA-N N-[(2R)-1-[(2-amino-2-oxoethyl)amino]-2-naphthalen-1-yl-1-oxopropan-2-yl]-N-[[3-(4-tert-butylphenoxy)phenyl]methyl]-3-carbamimidoylbenzamide Chemical compound C[C@@](C1=CC=CC2=CC=CC=C21)(C(=O)NCC(=O)N)N(CC3=CC(=CC=C3)OC4=CC=C(C=C4)C(C)(C)C)C(=O)C5=CC=CC(=C5)C(=N)N KFOBAVFLHQTUFP-RRHRGVEJSA-N 0.000 description 1
- SWGXDLRCJNEEGZ-UHFFFAOYSA-N N-cyclohexylformamide Chemical compound O=CNC1CCCCC1 SWGXDLRCJNEEGZ-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 201000000981 Primary Hyperparathyroidism Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 101710088675 Proline-rich peptide Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 240000001058 Sterculia urens Species 0.000 description 1
- 235000015125 Sterculia urens Nutrition 0.000 description 1
- 206010042618 Surgical procedure repeated Diseases 0.000 description 1
- 239000006180 TBST buffer Substances 0.000 description 1
- 208000002903 Thalassemia Diseases 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 208000026928 Turner syndrome Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- PAAZCQANMCYGAW-UHFFFAOYSA-N acetic acid;2,2,2-trifluoroacetic acid Chemical compound CC(O)=O.OC(=O)C(F)(F)F PAAZCQANMCYGAW-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000000123 anti-resoprtive effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 125000000613 asparagine group Chemical class N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical group CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229940069978 calcium supplement Drugs 0.000 description 1
- DIOLOCSXUMYFJN-UHFFFAOYSA-N calcium;azane Chemical compound N.[Ca+2] DIOLOCSXUMYFJN-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000005558 fluorometry Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- SHDMMLFAFLZUEV-UHFFFAOYSA-N n-methyl-1,1-diphenylmethanamine Chemical compound C=1C=CC=CC=1C(NC)C1=CC=CC=C1 SHDMMLFAFLZUEV-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940041672 oral gel Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000026792 palmitoylation Effects 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920006122 polyamide resin Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000007363 regulatory process Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000018448 secretion by cell Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-N trans-cinnamic acid Chemical compound OC(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-N 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Pool Section 29 Regulation 3.2(2) AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: 14 September 2007 Invention Title: Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity The following statement is a full description of this invention, including the best method of performing it known to us: SUBSTITUTED AMIDES, SULFONAMIDES AND UREAS USEFUL FOR INHIBITING KINASE ACTIVITY Field of the Invention 5 The present invention discloses novel substituted amide compounds, specifically carboxamides, sulfonamides, and urea compounds having enzyme inhibiting properties, especially for inhibiting protein tyrosine kinases. Background of the Invention 10 The novel compounds of the present invention may have general therapeutic value for the treatment of such diseases as cancer, including bone, colon or breast cancer; immunodeficiency disorders and diabetes; atherosclerosis, osteoporosis, leukemia and other conditions such as coronary heart disease, congestive heart failure, renal failure and diseases of the central nervous system 15 where the compounds exert a beneficial effect. The inventive compounds have been found to inhibit the Src protein tyrosine kinase, a member of the Src family. The Src family consists of nine members - Src. Yes, Fgr, Yrk. Fyn. Lyn, Hck, Lck and Blk - which share the same domain structure. The N-terminal, 20 unique domain contains a myristylation site and frequently a palmitoylation site. It is followed by the regulatory SH3 and SH2 domains, a catalytic domain that is bilobal and has its active site wedged between the two lobes, and a C-terminal regulatory tail that contains the hallmark regulatory tyrosine residue (Tyr527 in Src). Kinase activity is reduced when the latter is phosphorylated and bound to 25 the SH2 domain. The SH2 and SH3 domains bind phosphotyrosyl and proline rich peptides, respectively: through these interactions, they participate in intra and intermolecular regulation of kinase activity, as well as localization and substrate recognition. 30 There is a wealth of evidence that tyrosine phosphorylation plays a crucial role in many cell regulatory processes. Fahad Al-Obeidi et al., Biopolymers 2 (Peptide Science) 47, 197-223 (1998). Researchers have found that functional perturbation of the kinases results in many diseases. Thus, there has been a great deal of effort applied in attempts to develop potent and selective inhibitors for these enzymes. 5 The Src protein tyrosine kinase plays a role in osteoporosis and other bone diseases. Osteoporosis is defined as a systemic skeletal disease which is characterized by low bone mass and microarchitectural deterioration of bone tissue resulting in an increase in bone fragility and susceptibility to fracture, W. A. 10 Peck, et al., Am. J. Med., 94, 646, (1993) Conference Report. It is estimated that osteoporosis causes 1.5 million fractures annually with a total medical cost of $13.8 billion. National Osteoporosis Foundation, August, 1997. The most typical sites of such fractures are the hip, spine, wrist, and ribs. It is also estimated that one out of every two women and one in eight men will have an osteoporosis 15 related fracture in their lifetime. Osteoporosis is most commonly associated with postmenopause and age-related bone tissue loss. In addition, osteoporosis can occur secondarily to various drugs and diseases such as corticosteroids, anticonvulsants, alcohol, malabsorption syndromes, primary biliary cirrhosis, myeloma, thalassemia, thyrtoxicosis, Cushing's syndrome, Turner's syndrome, and 20 primary hyperparathyroidism. Drugs used in the treatment of osteoporosis are generally classified as antiresorptive or formation stimulating. In normal bone tissue, there is a balance between bone formation by osteoblasts and bone resorption by osteoclasts. When the balance of this ongoing process is upset, bone resorption can exceed bone formation resulting in quantitative bone loss. Most of 25 the treatments have involved those that act through inhibition of bone resorption, such as calcium supplements, estrogen, calcitonin, and vitamin D, L. Riggs, West. J. Med., 154, 63 (1991). Examples of treatments which act though stimulation of bone formation 30 are sodium fluoride, low intermittent dosage of parathyroid hormone, M. Missbach, et al., Rech. Chimie Med., July, 1997, London.
3 Several reports have disclosed compelling evidence that the protein tyrosine kinase (PTK)p60c-Src (sometimes referred to as c-Src) plays a critical role in osteoclastic function, M. Missbach, et al., ibid. It was reported that, in 5 vitro, kinase inhibitors of c-Src are capable of reducing osteoclastic bone resorption, Ibid. Osteoclasts are bone marrow cells that are responsible for breaking down or remodeling bone. Once an osteoclast comes into contact with the bone surface, it adheres tightly to the bone, flattens out, and begins the process of secreting materials which results in dissolution of the bone. This fundamental 10 action of osteoclasts is dependent on Src kinase. In this case it is clear that at least one of the roles for Src kinase is in the regulation of cytoskeletal changes involved in establishing the close bone cell interface and in polarizing cellular secretion toward the bone surface. Thus, animals genetically engineered to lack Src kinase show abnormalities that indicate a general inability to resorb bone. 15 In addition, osteoclasts derived from these animals are unable the to flatten on bone, nor are they able to dissolve it. Consistent with these results, small molecule inhibitors of Src kinase have been shown to be useful in countering bone loss in animal models of osteoporosis, such as IL-I-induced hypercalcemia, and 20 bone loss in ovariectomized rats. Src kinase inhibitors would be useful for the treatment of disorders marked by inappropriate bone resorption like osteoporosis. Summary of the Invention The present invention provides novel substituted urea and sulfonamide 25 compounds having inhibitory activity against osteoporosis and related bone tissue loss. The inventive compounds have the general structure shown in Formula II, including enantiomers, stereoisomers and tautomers thereof, as well as its pharmaceutically acceptable salts or solvates: 4 R2 H Y N x NH R,~ 0 - ,R3 Formula II wherein R, is selected from the group consisting of H, straight chain CI-C 6 alkyl; branched Ci-C 6 alkyl; -(CH 2 )p-Ari; and -(CH2)p-R 4 , wherein 5 p is I or 2; Ari is phenyl or naphthyl optionally substituted with a straight chain or branched Ci-C 6 alkyl group; and
R
4 is C 5
.C
7 cycloalkyl; 10 R 2 is selected from the group consisting of: 0 NN NH
NN
5
R
5 0 N HN 0 H NN N NN NN ,and
R
5 is selected from the group consisting of H, straight chain CI-C 6 alkyl; 5 branched CI-C 6 alkyl;
R
3 is -(CH 2 )q-Ar2 or -(CH=CH)-Phenyl, wherein q is an integer from 0 to 4; and Ar 2 is selected from the group consisting of: I~ NH
-R
5 R5 0 H N 10 and Xis: 6
-S
N 1 H or 0 and Y is selected from the group consisting of: O H2N 5 H 2 N ,and HO with the proviso that when Y is any of the moieties: H2N HO 0 and 0 10 then R, is H. In another embodiment this invention provides novel carboxamides, sulfonamides and ureas having inhibitory activity against osteoporosis and related 15 bone tissue loss. In one embodiment, this invention provides novel carboxamide compounds having such desirable therapeutically inhibitory activity. The 7 inventive carboxamides have the general structure shown in Formula I, including enantiomers, stereoisomers and tautomers thereof, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in Formula I:
NH
2 HN R'm
NH
2 n N UY H 0 0 5 Formula I wherein: m is an integer from 0 to 4; n is an integer from I to 6; 10 R'is a CI-C 4 alkyl; R, is: -R3
R
3
R
3
R
3 or 8
R
3 is selected from the group consisting of H, CI-C 4 straight chain alkyl and C 1 C 4 branched alkyl;
R
2 is selected from the group consisting of -(CH 2 )p-NH-C(=NH)NH 2 ; (CH 2 )p-R 4 ; and -(CH2)g-ArI, wherein p is an integer from 1 to 4; q is 0 or 5 1; R 4 is C5-C 7 cycloalkyl; and Ari is selected from the group consisting of: Rs NN and H wherein Rs is -NH 2 or phenyl. 10 When used herein, unless otherwise defined, the following terms have the given meanings: alkyl (including the alkyl portions of lower alkoxy) - represents a straight 15 or branched, saturated hydrocarbon chain having from I to 10 carbon atoms, preferably from I to 6; aryl - represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic 20 carbon atoms of the carbocyclic group being intended as possible points of attachment. Preferred aryl groups include l-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl; aralkyl - represents a moiety containing an aryl group linked vial a lower 25 alkyl; alkylaryl - represents a moiety containing a lower alkyl linked via an aryl group; 9 cycloalkyl - represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6, optionally substituted. heterocyclic - represents, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic organic groups having at least one 0, S 5 and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered and may or may not have double bonds that lack delocalized pi electrons, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, e.g., 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl; 10 halogen - represents fluorine, chlorine, bromine and iodine; heteroaryl - represents a cyclic organic group having at least one 0, S and/or N atom interrupting a carbocyclic ring structure and having a sufficient 15 number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably 4 or 5 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl, etc. Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; such heteroaryl groups may 20 also be optionally substituted. The term "pharmaceutically acceptable salt" is a non-toxic organic or inorganic acid addition salt of the base compounds represented by Formulas I and I1. 25 Included within the scope of the present invention are the individual stereoisomers, diastereomers and geometric isomers of formula (1) and (II), and enantiomers thereof. The term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It 30 includes geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). The 10 term "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction. The term 5 "racemic mixture" or "racemic modification" refers to a mixture of equal parts of enantiomers and which is optically inactive. As used herein the prefixes "(+)" and "(-)" are employed to designate the sign of rotation of the plane of polarized light by the compound, with (+) meaning the compound is dextrorotatory and (-) meaning the compound is levorotatory. For amino-acids, the designations L/D, or 10 R/S can be used as described in IUPAC-IUB Joint Commission on Biochemical Nomenclature, Eur. J. Biochem. 138, 9-37 (1984). A further feature of the invention is pharmaceutical compositions containing as active ingredient a compound of Formula I (or its salt, solvate or 15 isomers) or Formula II (or its salt, solvate or isomers) together with a pharmaceutically acceptable carrier or excipient. The invention also provides methods for administering to a patient suffering from one or more of the aforesaid diseases a therapeutically effective 20 inhibitory amount of a compound of Formula I or Formula II, or pharmaceutical compositions comprising a compound of Formula I or Formula 11. Detailed Description of The Invention In one embodiment, the present invention provides novel compounds of 25 Formula I or Formula II shown above, where the various symbols are as defined. Representative amide compounds of the invention which exhibit excellent Src kinase inhibitory activity belonging to Formula I are listed below by names and structure.
11 NAMES AND STRUCTURAL FORMULAS . N-[4-Amidinobenzoyl]-N-[3-phenoxybenzyl]-3-(4-biphenyl)-alanyl glycyl-amide 5 IUPAC Name: ALPHA-[[4-(AMfNOIMINOMETHYL) BENZOYL][(3-PHENOXY PHENYL)METHYL]AMINO]-N-(2-AMINO-2-OXOETHYL)-1,1' BIPHENYL-4-PROPANAMIDE 10 Structure:
NH
2 HN Ho H 2 I I | 0o 15 2. N-[3-Amidinobenzoyl]-N-[3-(4-tert- butylphenoxy) benzyl] cyclohexylalanyl-glycyl-amide IUPAC Name: 3-(AMINOIMINOMETHYL)-N-[I-[[(2-AMrNO-2 20 OXOETHYL)AMINO] CARBONYL]-2-CYCLOHEXYLETHYL]-N-[[3 [4-(1,1 -DIM ETHYLETHYL)PHENOXY]PHENYL)METHYL] BENZAM IDE 12 Structure: HN
NH
2 0 0 N
NH
2 H " 00 5 3. N- [3-Amidinobenzoyll-N-[3 -(4-tert-butylphenoxy) benzyl]-4 aminophenylalanyl-glycyl-amide IUPAC Name: 4-AMINO-ALPHA-[[3-(AMINOIMINOMETHYL)BENZOYL][[3-[4 10 (1,1-DIMETHYLETHYL)PHENOXY]PHENYL]METHYL]AMNO]-N (2-AMINO-2-OXOETHYL)BENZENEPROPANAMIDE Structure: HN
NH
2 0 0 N NH2 N 2 HH 15 4. N-[3-Amidinobenzoyl]-N-[3-(4-tert-butylphenoxy) benzyl]-1 naphthylalanyl-glycyl-amide 13 IUPAC Name: 4-AMFNO-ALPHA-[[3-(AMINOIMINOMETHYL)BENZOYL][[3-[4 (1,1 -DIMETHYLETHYL)PHENOXY]PHENYL]METHYL]AMNO]-N (2-AMINO-2-OXOETHYL)- I -NAPHTHALENEPROPANAMIDE 5 Structure: HN
NH
2 0 0 N NH2 H J6 0 0 5. N-[3-Amidinobenzoyl]-N- [3 -(4-tert- butylphenoxy) benzyl]-arginyl 10 glycyl-amide IUPAC Name 3-(AMINOIMINOMETHYL)-N-[4-[(AM[NOIMINOM ETHYL) AMINO]- I -[[(2-AMINO-2-OXOETHYL)AMINO] CARBONYL] 15 BUTYL]-N-[[3-[4-(1,I-DIMETHYLETHYL) PHENOXY] PH ENYL]M ETHYL]BENZAMIDE 14 Structure: HN
NH
2 0 0 N NH2 N 2, 0 HN
NH
2 6. N-[4-Amidinobenzoyl]-N-[3-(4-tert-butylphenoxy) benzyl]-tryptanyl 5 glycyl-amide IUPAC Name: 4-AMINO-ALPHA-[[4-(AMINOIMrNOMETHYL)BENZOYL][[3-[4 (1,1-DIMETHYLETHYL)PHENOXY]PHENYL]METHYL]AMINO]-N 10 (2-AMINO-2-OXOETHYL)1 H-INDOLE-3-PROPANAMIDE Structure:
NH
2 HNO N
NH
2 0 I NH 15 7. N-[4-Amidinobenzoyl]-N-[4-biphenylmethyl]-3-(4-biphenyl)alanyl glycyl-arnide 15 IUPAC Name: ALPHA-[[4-(AMINOIMINOMETHYL)BENZOYL][[[1,1'-BIPHENYL] 4-YL]METHYL]AMINO]-N-(2-AMINO-2-OXOETHYL) 1,1'BIPHENYL-4-PROPANAMIDE 5 Structure:
H
2 HN
H
2 H 0 10 Representative urea compounds of Formula II of the invention which exhibit excellent Src kinase inhibitory activity are listed below by names and structure. 8. 4-Cyclohexyl-1-[[2-(4-phenylbutanoyl)amino]-4-[I-aminocarbonyl-2-(2 15 naphthyl)ethylamino]carbonylaminophenyl]piperazine IUPAC Name: ALPHA-[[[[4-(4-CYCLOHEXYL- I -PIPERAZINYL)-3-[(I -OXO-4 PH ENYLBUTYL)AMINO]PHENYL]AM[NO]CARBONYL]AMINO] 20 2-NAPHTHALENEPROPANAMIDE 16 Structure: 0 WI-)
I
2 N W ' NHl H H 0 0 9. 4-Cyclohexyl- I -[[2-cinnamoy~amino]-4-[ I -aminocarbonyl-2-(2 5 naphthyl)eth yl amino] carbonyl aminophenyl] piperazine IUPAC Name: ALPHA-[[II[4-(4-CYC LOH EXYL- I -P IPERAZINYL)-3 -[( I -OXO-3 PHENYL-2-PROPENYL)AM[NO]PHENYL]AMINO] CARBONYL] 10 AMINO] -2-NAP HTH ALEN EPROPANAM IDE Structure: 0 ~N HIN N N , NH H H 0 0 15 10. Common Name: 4-Cyclohexyl- I -[[2-cinnamoylamino-4-I( I -aminocarbonyl-3 phenyl)propylamino]carbonylaminophelylpiperazifle 17 IUPAC Name: ALPHA-[[[[4-(4-CYCLOHEXYL-1 -PIPERAZINYL)-3-[(1 -OXO-3 PHENYL-2-PROPENYL)AMINO]PHENYL]AMINO] CARBONYL] AMINO]BENZENEBUTANAMIDE 5 Structure: N
H
2 N N "N Na NH H H 0 0 10 11. 4-Cyclohexyl- I -[[2-(4-phenylbutanoyl)amino]- 4 -[(I -aminocarbonyl-3 phenyl)propylamino]carbonylaminophenyl]piperazine IUPAC Name ALPHA-[[[[4-(4-CYCLOHEXYL-1-PIPERAZINYL)-3-[(1-OXO-4 15 PHENYLBUTL)AMINO]PHENYL]AM[NO]CARBONYL]AMINO] BENZENEBUTANAMIDE Structure: N N 0
NI
H
2 N N N N NH H H 0o 0 18 12. 4-Cyclohexyl - I -[[2-cinnamoylamino] -4-[( 1 -aminocarbonyl-2 cyclohexyl ethyl amino)carbonylaminophenyl] piperazi ne LUPAC Name: 5 2-I[ALP HA- [ [ [ 4-(4-CYCLOH EXYL- 1 -PIP ERAZINYL)-3-[+I -OXO-3 PHENYL-2-PROPENYL)AMINO]PHENYL]AMINO] CARBONYL]AMINO]fl3-(CYCLOHEXYL)PROPANAMIDE Structure: rNi 0 N--I
H
2 N N ~N ,a NH H H 10 13. 4-(Piperidin-4-yl)carbonyl-lI-[[2-(4- phenylbutanoyl) amino]-4-[ 1 aminocarbonyl-2-(2-naphthyl)ethylamilo] carbon ylam inophenyl ]homopiperazifle 15 IUPAC Name: 2-APA[[4[EAYR--4PPRDNLABNL-
H
1 ,4-DIAZEPIN-1 -YL]-3-[(1 -OXO-5-PHENYLPENTYL) AMINO] PHENYL] AMrNO]CARBONYL]AMINOI]-3-[NAPHTH-2 YL] PROPANAMIDE 20 19 Structure: NNO N NH HN N H H 00 14. 4-(Piperidin-4-yl)carbonyl- 1-[[2-(2-benzofuranoyl) amino]-2-(2 5 naphthyl)ethylamino]carbonylaminophenyl] homopiperazine IUPAC Name: 2-[ALPHA-[[[[4-[HEXAHYDRO-4-(4-PIPERIDINYLCARBONYL)-1H 1,4-DIAZEPIN-1-YL]-3-[(1-OXO-1-BENZOFURAN-2-YL) AMINO] 10 PHENYL] AMINO]CARBONYL)AMINO]]-3-(NAP HTH-2-Y L) PROPANAMIDE Structure: 0 HN N N NH H H 15 15. 4-(Piperidin-4-yl)carbonyl- 1 -[[2-(2-benzofuranoyl) amino]-4-[] aminocarbonyl-2- cyclohexylethylamino] carbonylamino phenyl]homopiperazine 20 IUPAC Name: 2-[ALPHA-[[[[4-[HEXAHYDRO-4-(4-PIPERIDINYLCARBONYL)-1H 1,4-DIAZEPIN-1-YL]-3-[(1-OXO-1-BENZOFURAN-2-YL) AMINO] PHENYL] AMINO]CARBONYL]AMINO]]-3-CYCLOHEXYL 5 PROPANAMIDE Structure: 0 0 N '- NH
H
2 N N N NH H H 0 0 10 16. 4-(Piperidin-4-yl)carbonyl-1-[2-[(2-benzofuranoyl) amino]-4-[[(4 aminocarbonyl)cyclohexylmethylamino] carbonylaminophenyl]homopiperazine IUPAC Name: 15 4-[ALPHA-[4-[[[[[4-[HEXAHYDRO-4-(4-PIPERIDINYL CARBONYL)- IH-1,4-DIAZEPIN-1-YL]-3-[(1-OXO-1-BENZOFURAN 2-YL) AMINO] PHENYL] AMINO]CARBONYL] AMINO]METHYL)] CYCLOH EX-1-YLFORMAMIDE 20 Structure: 0 SNNH N )' N NH 0 H H
NH
2 0/\ 21 17. 4-(Methylaminomethyl)carbonyl-1-[2-[(2-benzo- furanoyl) amino]-4 [[(4-aminocarbonyl)cyclohexylmethylamino] carbonylaminophenyl] homopiperazine 5 [UPAC Name: 4-[ALPHA- [4-[[[[4-[H EXAHYDRO-4-(4-[[[METHYL]AMINO] METHYL] CARBONYL)- I H-1,4-DIAZEPIN-1-YL]-3-[(1 -OXO-1 BENZOFURAN-2-YL) AMINO] PHENYL] AMINO]CARBONYL] AMINO]METHYL]]CYCLOHEX-1 -YLFORMAMIDE 10 Structure: 0 N N HN_ N N NH H H 0.1
NH
2 0H/H\ 18. 4-(Pyrrolidin-2-yl)carbonyl-1-[2-[(2-benzo- furanoyl)amino] -4-[(4 15 aminocarbonyl)cyclohexyl-methyl-amino]carbonylamino]phenyl] homopiperazine IUPAC Name: 4-[ALPHA-[[[[4-[HEXAHYDRO-4-(2-PYRROLIDINYL 20 CARBONYL)-1H-1,4-DIAZEPIN-1-YL]-3-[(1-OXO-1-BENZOFURAN 2-YL) AMINO] PHENYL] AMINO]CARBONYL] AMINO]METHYL]] CYCLOHEX- I -YLFORMAMIDE 22 Structure: H N N 0 N H N NH H 0 0 NH, 0 5 19. 4-(Piperidin- Il-yl)-lI -[2-[(2-benzofuranoyl)amino]-4-I[(4 aminocarbonyl)cyclohexylmethylamio]carboflylamilopheflyl]piperidine IUPAC Name: 10 4-[ALPHA-II4-[II[i44-[4-(PIPERID1N-1 -YL)-1 -PIPERIDINYL]-3-[(1 OXO-1I-BENZOFUR-AN-2-YL) AMINO] PHENYL] AMINO]CARBONYLIAMINO]METHYL]]-CYCLOH EX- 1 YLFORMAMIDE 15 Structure: ND 0 N NN WaNH H H 0 0 -0
NH
2 0 / 23 20. 4-(Piperidin-4-yl)carbonyl-1-[[2-(4-phenylbutanoyl) amino]-4-[1 aminocarbonyl-2-cyclohexylethylamino] carbonylaminophenyl]homopiperazine 5 IUPAC Name: N-[5-[[[[ I -(CARBOXY)-I -(CYCLOH EXYL-METHY L)]AMINO] CARBONY L]AMINO]-2-[H EXAHYDRO-4-(4-PIPERIDINYL CARBONYL)-1 H-1,4-DIAZEPIN-1-YL]PHENYL]
BENZENE
10 BUTANAMIDE Structure: 0 N NH N
H
2 N N N N H H 0 0 15 21. 4-(Piperidin-4-yl)carbonyl-1-[[2-(4-phenylbutanoyl) amino]-4-[(I aminocarbonyl-2-(naphth-2-yl))ethylamino] carbonylaminophenyl]homopiperazine IUPAC Name: 20 2-[ALPHA-[[[[4-[HEXAHYDRO-4-(4-PIPERIDINYLCARBONYL)-1
H
1,4-DIAZEPIN-1-YL]-3-[(1-OXO-4-PHENYL-BUTYL) AMINO] PHENYL) AMINO]CARBONYL]AM INO]]-3-(NAPHTH-2-Y L)
PROPANAMIDE
24 Structure: NH N N
H
2 N N N NH H H 0 0 5 Representative sulfonamide compounds of the invention which exhibit excellent Src kinase inhibitory activity of the Formula Il are listed by names and structure below. 22. N-(1 -Aminocarbonyl-2-methylpropyl)-2-[(4-phenylmethyl)piperidin- 1-yl] 10 5-[(2-pyrrolidinocarbonyl)amino]phenylsulfonamide IUPAC Name: ALPHA-2-[[[[2-(4-BENZYL)-1-PIPERIDINYL]-5-[(PYRROLIDIN-2 YL)CARBONYLAMINO]PHENYL] SULFONYL]AMrNO]-3 15 METHYLBUTANAMIDE 25 Structure: N HN
H
2 N O N NH 23. N-(-I Aminocarbonyl-2-methylpropyl)-2-[(4-phenylmethyl)piperidin- 1-yl] 5 5-[(2-piperdino- carbonyl) amino]phenylsulfonamide IUPAC Name: ALPHA-2-[[[[2-(4-BENZYL)- I -PIPERIDINYL]-5-[(PIPERIDIN-4 YL)CARBONYLAMINO] PHENYL]SULFONYL] AMINO]-3 10 METHYLBUTANAMIDE Structure: HN N
H
2 N S N 0 / / 0 H N H 26 24. 1-[2-[N-(2-Aminocarbonyl-3-methylbutyl)sulfonamido]-5-[2 cinnamoylamino]]phenyl-4-cyclohexylpiperazine IUPAC Name: 5 ALPHA-2-[[[2-(4-CYCLOHEXYL-1 -PIPERAZINYL)-5-[(1-OXO-3 PHENYL-2-PROPENYL)CARBONYLAMINO]PHENYL] SULFONY L]AMINO]-3-METHYLBUTANAMIDE 10 Structure: U~N N N O
H
2 N HN SN 00 15 27 25. N-[[(4-Aminocarbonyl)cyclohexylmethyl]amino]-[2-[(4 phenylmethyl)piperidin- I -yl]-5-[(2-pyrrolidino carbonyl)amino]phenyl]sulfonamide 5 IUPAC Name: 4-[2-[[[[[2-[(4-BENZYL)-1-PIPERIDINYL]-5-[(PYRROLIDIN-2 YL)CARBONYLAMINO]PHENYL] SULFONYL]AMINO]METHYL]]-CYCLOHEX-1-YLFORMAMIDE 10 Structure: 0
H
2 N0 H NS N o NH 0 15 The compounds of the invention may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, hydroxymaleic, benzoic, 20 hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p toluensulfonic acid, and sulfonic acids such as methane sulfonic acid and 2 hyroxyethane sulfonic acid and other mineral and carboxylic acids well known to those skilled in the art and acid metal salts such as sodium monohydrogen 28 orthophosphate, and potassium hydrogen sulfate. Such salts can exist in either a hydrated or substantially anhydrous form. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the 5 salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention. 10 Depending upon the substituents on the inventive compounds, one may be able to form salts with bases too. Thus, for example, if there are carboxylic acid substituents in the molecule (e.g., compound 21 in the list above), salts may be formed with inorganic as well as organic bases such as, for example, NaOH, 15 KOH, NH 4 0H, tetraalkylammonium hydroxide, and the like. As stated earlier, the invention includes tautomers, enantiomers and other stereoisomers of the compounds also. Such variations are contemplated to be within the scope of the invention. 20 Another embodiment of the invention discloses a method of making the substituted carboxamides, ureas and sulfonamides disclosed above. The compounds may be prepared by several processes known in the art of synthetic organic chemistry. One useful method to prepare compounds of Formula I is 25 schematically illustrated below in connection with the compound numbered 7 above. In general, this procedure is referred to as Scheme A herein and involves: (a) bonding an amino acid to a suitably functionalized polymer support; (b) coupling another suitably substituted amino acid thereto; (c) reacting the coupled structure with an aldehyde to form a Schiff base, which is then (d) reduced to the 30 corresponding amine; which, in turn, is converted to an amide by way of reaction with an acid chloride for example, which product may be (e) converted to the 29 thioamide; which, in turn, is (f) methylated and (g) converted to the amidino group. The product is then cleared from the solid phase support as will be further appreciated from the following discussion. 5 Scheme A is specifically illustrated with respect to N-[4 Amidinobenzoyl] -N-[4-biphenylmethyl] -3 -(4-biphenyl)alanyl-glycyl-amide:
NH
2 HN 0 0 N2 H 10 15 20 30 Scheme A 1. Fmoc-Bip-OH o 2. Pip/DMF 1. RAM-PS-NH , N SRAM-PS-NH NH2 2. NaBH 3 CN O 3 cNN NN RAM-PS -- NH R P HHPN N 0 H OM0 N O H Mel O 00 N RAM-PS-NH N1L N --- RAM-PS -- NH j, H N O N H2 O O11 N H N 0 , 1. NH40Ac/MeOH H 2 N UN N 2. TFA0 NH NH2 Compound 7 In Scheme A, all substituents, unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of 31 ordinary skill in the art or may be prepared by conventional methods. The starting material (1) in Scheme A is an amino functionalized solid phase material, which for the purposes of synthesis was modified with linker molecule (formula III), which enables the product of the synthesis to be cleaved from the solid 5 support (resin). Example of such linker is the Rink linker (p-[(R,S)-a-(9H fluoren-9-yl)methoxyformamido]-2,4-dimethoxybenzyl]-phenoxyacetic acid (Bematowicz et al., Tetrahedron Lett. 30, 4645 (1989)). Commercially available resins with the desired linker already attached can be used as well. H 0 Fmoc-N 0 0 Solid phase -N H _ Fmoc-deprotection 0
H
2 N \ / 0\ Solid phase -N Formula III 10 The Rink linker attachment to a suitable solid phase is carried out by reacting an amino functionalized solid support with acid moiety of the linker molecule by standard peptide synthesis techniques well known in the art to provide an amide linkage, as shown in Example 1. Such reaction can be carried out using standard 15 coupling procedures such as, for example, as described in Stewart and Young, Solid Phase Peptide Synthesis, 2 "d ed., Pierce Chemical Co., Rockford, Illinois (1984); Gross, Meienhofer, Udenfriend, Ed., The Peptides: Analysis, Synthesis, Biology, Vol. 1, 2, 3, 5 and 9, Academic Press, New York, 1980-1987; 32 Bodanszky, Peptide Chemistry: A Practical Textbook, Springer-Verlag, New York (1988); and Bodanszky, et al. The Practice of Peptide Synthesis Springer Verlag, New York (1984), the disclosures of which are hereby incorporated by reference. If a coupling reagent (activator) is needed, suitable coupling reagent 5 may be selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), I-ethoxycarbonyl-2-ethoxy-1,2-dihydroquioline (EEDQ), I-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis(2-oxo-3-oxazolidinyl)amidophosphoryl chloride (BOP CI), diphenylphosphoryl azide, (DPPA), Castro's reagent (BOP), 2-(I H 10 benzotriazol-1-yl)-1,1,3,3-tetramethyluronium salts (HBTU), 2,5-diphenyl-2,3 dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent' HOTDO) and 1, 1'carbonyldiimidazole (CDI). The coupling reagent may be used alone or in combination with additives such as 4-dimethylaminopyridine (DMAP), N hydroxybenzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N 15 hydroxysuccinimide) HOSu) or 2-hydroxypyridine. The coupling reactions can be performed in either solution (liquid phase) or solid phase. As used herein, the term "solid phase support" is not limited to a specific type of support. A large number of supports are available and are known to one of 20 ordinary skill in the art. Solid phase supports include silica gels, resins, derivatized plastic films, glass beads, cotton, plastic beads, alumina gels, polysaccharides and the like. A suitable solid phase support may be selected on the basis of desired end use and suitability for various synthetic protocols. For example, for peptide synthesis, solid phase support may refer to resins such as p 25 methylbenzhydrylamine (pMBHA) resin (from Peptides International, Louisville, Kentucky), polystyrene (e.g., PAM-resin available from Bachem Inc.(Torance, CA, USA), poly (dimethylacrylamide)-grafted styrene co-divinyl-benzene (e.g., POLYHIPE* resin, available from Aminotech, Nepean, Ontario, Canada), polyamide resin (e. g. Spar-resin, available from AdvancedChemtech, Louisville, 30 KY, USA), polystyrene resin grafted with polyethylene glycol (available from TentaGel*, Rapp Polymere, Tubingen, Germany) polydimethylacrylamide resin 33 (available from Milligen/Biosearch, Burlington, MA, USA), or Sepharose (available from Pharmacia Corporation, Stockholm, Sweden). The amino acid moiety may carry protecting groups prior to the coupling 5 reaction. Examples of suitable protecting groups include the following: (1) acyl types such as formyl, trifluoracetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxy carbonyls, I -(p-biphenyl)- 1 -methylethoxy-carbonyl, and 9-fluorenylmethyloxy carbonyl (Fmoc); (3) aliphatic carbamate types such as tertbutyloxycarbonyl 10 (Boc), ethoxycarbonyl, diisopropyl-methoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenyl-methyl and benzyl; (6) trialkysilane such as trimethyl-silane; and (7) thiol containing types such as phenylthio-carbonyl and dithiasuccinoyl. The preferred protecting group is either 15 Boc or Fmoc. If certain functional groups or side chains on the amino acid moiety need to be protected during the coupling reaction to avoid formation of undesired bond, suitable protecting groups that can be used for that purpose are listed in Greene, 20 Protective Groups in Organic Chemistry, John Wiley & Sons, New York (1981) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosures of which are hereby incorporated by reference. Those skilled in the art will appreciate the fact that the selection and use of appropriate protecting groups depend upon the overall structure of the amino acid 25 compound and the presence of any other protecting groups on that compound. The selection of such a protecting group may be especially important if it should not be removed during the deprotection of the other protecting group. Suitable amino acids for the coupling reaction are listed in Table I along 30 with the symbol for each amino acid.
34 Table I AMINO ACID SYMBOL Alanine Ala or A Arginine Arg or R Asparagines Asn or N Aspartic acid Asp or D Cysteine Cys or C Glutamine Gin or Q Glutamic acid Glu or E Glycine Gly or G Histidine His or H Isoleucine Ile or I Leucine Leu or L Lysine Lys or K Methionine Met or M Phenylalanine Phe or F Proline Pro or P Serine Ser or S Threonine Thr or T Tryptophan Trp or W Tyrosine Tyr or Y Valine Val or V More specifically, a solid phase support such as, for example, a 5 deprotected RAM-PS resin is typically treated with 3 equivalents of the amino acid moiety and 3 equivalents of I -hydroxybenzotriazole in a suitable organic solvent, such a N,N-dimethylformamide. Then 3 equivalents of diisopropylcarbodiimide are added and the mixture shaken for about 30 minutes to five hours. The amide that is produced can be isolated and purified by well 10 known techniques or the crude material can be carried on to deprotection as it is.
35 The amide produced in the above-noted step is deprotected under conditions which do not cleave the solid phase support from the growing compound. Such conditions are well known in the art. Thus, when the Boc protecting group is used, the methods of choice are trifluoroacetic acid either neat 5 or in dichloromethane, or HCI in dioxane or ethyl acetate. The resulting ammonium salt is then neutralized either prior to the coupling or in situ with basic solutions such as aqueous buffers, or tertiary amines in dichloromethane or dimethylformamide. When the Fmoc protecting group is used, the reagents of choice are piperidine or substituted piperidine in dimethylformamide, but any 10 secondary amine or aqueous basic solutions can be used. The deprotection is carried out generally at a temperature of between about 0 0 C and about room temperature. For example, the above-noted crude amide may be treated with 30% piperidine in N, N-dimethylformamide for about 20 minutes to about one hour, following which the reaction mixture is filtered to provide the deprotected 15 compound. To the deprotected compound on solid phase, a suitably amino-protected compound having free carboxylic function (for example, Fmoc-protected biphenylalanine in Scheme A) to form the solid phase linked product. For 20 example, 1 equivalents of the deprotected compound may be combined with 3 equivalents of Fmoc-Biphenylalanine and 3 equivalents of 1-hydroxybenzo triazole and a suitable activator (for example 3 equivalents of DIC) in a suitable organic solvent, such as N,N-dimethylformamide. The formed biphenylalanine linked compound is cleaved of the Fmoc group and then reacted with a suitable 25 aldehyde, such as, for example, 4-phenylbenzaldehyde, to yield the corresponding Schiff base. The Schiff base is then reduced, for example, with sodium borohydride, sodium cyanoborohydride and the like, to form the corresponding amine which is then converted to the amide by reacting with, for example, an acid chloride, in this case, 4-cyanobenzoyl chloride. The amide may be converted to 30 the thioamide which is methylated and then converted to the amidino group. The product is then cleaved of the solid phase support to yield compound 7.
36 The compounds of Formula II where X is an urea may be prepared as described in Scheme B: Scheme B 0 H fmoc 0 H
G-NH
2 R1 N N fmoc H HOBt, DIC R1 1. Pip/DMF 2.0 N CHa -N NR2 F 0 0 SNnJlR =H H. 0 N N N N H H IO 0--N N N N H N N N C HN Y 0-NH R1O N CH)n Ri o On 0 F N R2 H 1. SnCS 2 2. R3COOH, HOAt, DI HCH 3. TFA 95% N 0 ~H 0 I H H 11+ 0 R3 0N N0 H0 H Ri Nj N NH N
H
2 N O N CH2)n I NH N' CH 2 )n boc R2 HOBt, DIG O 0 0 1. SnCI 2 C 2. R3COOH, HOAt, DI 0 0 1 3. TFA 95% 0N N Na N N H ii R1 0HN )n N-boc NT 0 5 37 Scheme B may be explained with the synthesis of a compound of Formula II where R, is 2-naphthylmethyl, R 2 is cyclohexylpiperazinyl, R 3 is 3-phenylpropyl, X is -NH-CO-, Y is CONH2 and n is 1. That compound is compound 8 identified above, 4-Cyclohexyl-1-[[2-(4-phenylbutanoyl) amino]-4-[I-aminocarbonyl-2-(2 5 naphthyl)ethylamino]carbonylaminophenyl]piperazine N N 0 H 2 N N N NH H H 00 10 Thus, a solid phase support is coupled with a protected amino acid, in this case, Fmoc-2-naphthylalanine in the presence of an activator such as, for example, 1-hydroxybenzotriazole and DIC. It is then deprotected and then reacted with 4 fluoro-3-nitrophenylisocyanate and the fluorinated product is then reacted with 4 cyclohexylpiperazine to introduce the R 2 group. The nitro group is then reduced 15 with stannous chloride to the amine which is converted to the 4-phenylbutyl amide by reacting with 4-phenylbutyric acid by activation with HOAt and DIC. Cleaving of the solid support yields the desired compound 8. Similarly, one synthesizes the other urea compounds by appropriate selection of the R I, R 2 and
R
3 substituted reactants. 20 Synthesis of a compound of Formula II where X is sulfonamide is similar to that shown in Scheme B except that in the step introducing the fluoronitrophenyl- isocyanate, the appropriate fluoronitrobenzene sulfonyl chloride is used. Thus, replacing the isocyanate in the above description with 2- 38 fluoro-5-nitrobenzene sulfonyl chloride would yield the desired sulfonamide compound. Isolation of the compound at various stages of the reaction scheme may be 5 achieved after cleavage from solid support by standard techniques such as, for example, filtration, evaporation of solvent and the like. Purification of the product, intermediate and the like, may also be performed by standard techniques such as recrystallization, distillation, sublimation, chromatography, conversion to a suitable derivative which may be recrystallized and converted back to the 10 starting compound, and the like. Such techniques are well known to those skilled in the art. The thus prepared compounds may be analyzed for their composition and purity as well as characterized by standard analytical techniques such as, for 15 example, elemental analysis, NMR, mass spectroscopy, and IR spectra. In another embodiment, this invention provides pharmaceutical compositions comprising the above-described inventive compounds as an active ingredient. The pharmaceutical compositions generally additionally comprise a 20 pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as carrier materials). Because of their therapeutic activity against osteoporosis and bone tissue loss, such pharmaceutical compositions possess utility in treating those diseases. 25 In yet another embodiment, the present invention discloses methods for preparing pharmaceutical compositions comprising the compounds of Formula I or Formula II as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredient or ingredients will generally be administered in admixture with suitable carrier materials suitably 30 selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for 39 constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert 5 carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent 10 inventive composition. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include 15 starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below. 20 Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. antihistaminic activity and the like. Suitable dosage forms for sustained release 25 include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. 30 Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for 40 parenteral injections or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. 5 Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen. For preparing suppositories, a low melting wax such as a mixture of fatty 10 acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. 15 Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. 20 The compounds of the invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. 25 Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to 30 achieve the desired purpose.
41 The quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 1.0 milligram to about 1,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably from about 1.0 to about 500 milligrams, and typically from about 1 to 5 about 250 milligrams, according to the particular application. The actual dosage employed may be varied depending upon the patient's age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art. 10 Generally, the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day. The amount and frequency of the administration will be regulated according to the judgment of the attending clinician. A generally recommended daily dosage regimen for oral administration may range from about 1.0 milligram to about 1,000 milligrams per day, in single 15 or divided doses. The term "capsule" refers to a special container or enclosure made of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules 20 are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives. The term "tablet" refers to a compressed or molded solid dosage form 25 containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction. The term "oral gel" refers to the active ingredients dispersed or solubilized 30 in a hydrophilic semi-solid matrix.
42 The term "powders for constitution" refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices. 5 The term "diluent" refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the t0 total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%. The term "disintegrant" refers to materials added to the composition to 15 help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked 20 microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight. 25 The term "binder" refers to substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; 30 starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium 43 alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can 5 range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight. The term "lubricant" refers to a substance added to the dosage form to 10 enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene 15 glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 20 1.5% by weight. The term "glident" materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the 25 composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight. The term "coloring agent" refers to excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes 30 and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum 44 oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%. The term "bioavailability" refers to the rate and extent to which the active 5 drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control. Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation 10 produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known. Another embodiment of the invention discloses use of the pharmaceutical 15 compositions disclosed above for treatment of diseases such as, for example, osteoporosis and bone tissue loss. It will be apparent to those skilled in the art that many modifications, variations and alterations to the present disclosure, both to materials and methods, 20 may be practiced. Such modifications, variations and alterations are intended to be within the spirit and scope of the present invention. The following examples are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not 25 to be considered limited in any way thereby.
45 EXAMPLES Unless otherwise stated, the following abbreviations have the stated meanings in the Examples below: 5 DCC= dicyclohexylcarbodiimide NaBH(OAc) 3 = sodium triacetoxyborohydride FMOC=9-fluorenylmethyloxycarbonyl DCE=1,2-dichloroethane DIEA=diisopropylethylamine 10 Cha=cyclohexylalanine Nal(1)= 1 -naphthylalanine T EOF=triethylorthoformate TIPS=triisopropylsilane Nal(1)= 1 -naphthylalanine 15 Bip=4-biphenylalanine Boc=tert.butyloxycarbonyl Pip=piperidine HOAc=acetic acid TFA=trifluoroacetic acid 20 Py-pyridine DIC=diisopropylcarbodiimide MeOH=methanol NaBH 4 = sodium borohydride NaBH 3 CN= sodium cyanoborohydride 25 p-TsOH= p-toluenesulfonic acid DMF: N,N-Dimethylformamide THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide DCM: Dichloromethane which can also be referred to as methylene chloride 30 LAH: Lithium aluminum hydride HOAt: I -Hydroxy-7-azabenzotriazole 46 HOBt: l-Hydroxybenzotriazole HRMS= High Resolution Mass Spectrometry HPLC= High Performance Liquid Chromatography NMR=nuclear magnetic resonance 5 LRMS= Low Resolution Mass Spectrometry nM= nanomolar Additionally, "kg" refers to kilograms; "g" refers to grams; "mg" refers to milligrams; ptg" refers to micrograms; "m 2 /g" refers to square meters per gram 10 and is used as a measurement of particle surface area; "mmol" refers to millimoles; "L" refers to liters; "mL" refers to milliliters; "4L" refers to microliters; "cm" refers to centimeters; "M" refers to molar' "mM" refers to millimolar; "gM" refers to micromolar; "nM" refers to nanomolar; "N" refers to normal; "ppm" refers to parts per million; "5" refers to parts per million down 15 field from tetramethylsilane; " 0 C" refers to degrees Celsius; "'F" refers to degrees Fahrenheit; "mm Hg" refers to millimeters of mercury; "kPa" refers to kilopascals; "psi" refers to pounds per square inch; "rpm" refers to revolutions per minute; "bp" refers to boiling point; "mp" refers to melting point; "dec" refers to decomposition; "h" refers to hours; "min" refers to minutes; "sec" refers to 20 seconds' "Rf" refers to retention factor; and "R," refers to retention time. Examples 1-7 pertain to synthesis of compounds of Formula I. General Synthesis Procedures 25 Starting materials used in the synthesis were obtained from chemical vendors such as Aldrich, Sigma, Fluka, Nova Biochem and Advanced Chemtech. During the synthesis, the functional groups of the amino acid derivatives used were protected by blocking groups to prevent side reaction during the coupling steps. Examples of suitable protecting groups and their use are described in The 30 Peptides, supra, 1981, and in vol. 9, Udenfriend and Meienhofer (eds.), 1987, which is incorporated herein by reference.
47 General solid-phase peptide synthesis was used to produce the compounds of the invention. Such methods are described, for example, by Steward and Young, Solid Phase Peptide Synthesis (Freeman & Co., San Francisco, 1969), which is incorporated herein by reference. 5 Unless indicated otherwise, peptides were synthesized on RAMTM Polystyrene Resin (Rapp Polymere, Tabingen, Germany). As an alternative to this, acid sensitive linker p-[(R,S)-c-[ 1 -(9H-fluoren-9-yl)methoxyformamido] 2,4-dimethoxybenzyl]phenoxyacetic acid (Knorr Linker, Bernatowicz et. al, Tetr. 10 Lett. 30 (1989) 4645, which is incorporated herein by reference) can be coupled to any amino functionalized the solid support or the desired compounds can be synthesized on polystyrene resin cross-linked with I % divinylbenzene modified with an acid sensitive linker (Rink resin) (Rink, Tetr. Lett. 28 (1987) 3787; Sieber, Tetr. Lett. 28 (1987) 2107, each of which is incorporated herein by reference). 15 Coupling was performed using N,N'-diisopropylcarbodiimide (DIC) in the presence of an equivalent amount of HOBt. All couplings were done N,N dimethylformamide (DMF) at room temperature (RT). Completion of coupling was monitored by ninhydrin test. A second (double) coupling was performed where coupling in the first instance was incomplete. 20 Deprotection of the Fmoc group was accomplished using 50% piperidine in DMF for 2+15 min. The amount of Fmoc released was determined from the absorbance at 302 nm of the solution after deprotection, volume of washes and weight of the resin used in the synthesis. 25 The compound resin was at the end of the synthesis washed successively with DMF and DCM and the peptide was then cleaved and deprotected by a mixture TFA/TIPS (99/1) for 2 hours, unless specified otherwise. The resin was washed with DCM and the DCM wash combined with the TFA releasate. The 30 solution was evaporated, the product was redissolved in a mixture of water and acetonitrile and lyophylized.
48 The dried compound was subjected to HPLC purification using an appropriate gradient of 0.1% TFA in water and acetonitrile (ACN). After collecting the peak containing the intended synthetic product, the solution was lyophilized and the compound was subjected to an identification process, which 5 included electrospray mass spectrum (MS) and/or NMR to confirm that the correct compound was synthesized. For HPLC analysis, a sample of the product was analyzed using Beckman HPLC system (consisting of 126 Solvent Deliver System, 166 Programmable 10 Detector Module 507e Autosampler, controlled by Data Station with Gold Nouveau software) and YMC ODS-AM 4.6x250 mm column at 230 nm and flow rate Imil/min. For product purification, a sample of crude lyophilized compound was 15 dissolved in a mixture of 0.1% aqueous TFA containing 10% to 50% ACN. The solution of the product was usually filtered through a syringe connected to a 0.45 tm "ACRODISC" 13 CR PTFE (Gelman Sciences; Ann Arbor MI) filter. A proper volume of filtered compound solution was injected into a semi-preparative C18 column (YMC ODS-A column (20x250 mm), YMC, Inc., Wilmington, NC). 20 The flow rate of a gradient or isocratic mixture of 0.1% TFA buffer and ACN (HPLC grade) as an eluent was maintained using a Beckman "SYSTEM GOLD" HPLC (Beckman, System Gold, Programmable Solvent Module 126 and Programmable Detector Module 166 controlled by "SYSTEM GOLD" software). Elution of the compound was monitored by UV detection at 230 nm. After 25 identifying the peak corresponding to the compound under synthesis using MS, the compound was collected, lyophilized and biologically tested. MS was performed using a VG Platform (Fisons Instruments) instrument in ES+ mode. For NMR, typically samples were measured in DMSO-d 6 (Aldrich) using a Bruker Avance DPX 300 instrument. 30 49 Example 1. N-14-Amidinobenzoyll-N-[3 -phenoxybenzyll-3-(4-biphenyl) alanyl-glycyl-amide:
NH
2 0 HNH N NH2 N 2 H 0 5 Following generally the procedure described above as Scheme A, polystyrene-RAM (substitution 0.74mmol/g, 100-200 mesh, Rapp Polymere, Tubingen, Germany, 0.5 g) was washed with DMF and the Fmoc-protecting group cleaved by 50% solution of piperidine in DMF (twice 10 minutes, 5ml each). The 10 resin was then washed by DMF. Fmoc-Gly-OH (3eq) activated with DIC/HOBt (3eq each) in DMF (3 ml) was coupled to the resin overnight and the completion was checked by ninhydrin test. After Fmoc-group deprotection, the resin-bound intermediate was reacted with Fmoc-4-biphenyl-alanine (3eq, in 3 ml DMF) activated with DIC/HOBt (3eq each) overnight. Fmoc group was deprotected as 15 described above and the resin was washed with DMF. Resin was washed with DCM and a solution of 3-phenoxybenzaldehyde (7eq) in 5ml TEOF/DCM (4:1) was added and the reaction was carried out for 6 hours, the resin was washed with DCM (3 times) and the formed Schiff base was reduced with 5 ml of solution NaBH 3 CN overnight. This was prepared by mixing 1 M NaBH 3 CN in THF 20 (commercially available) with DCE /MeOH/AcOH (80:18:2) in ratio 1:4. After the reduction resin was washed with MeOH, DMF, 10% DIEA in DMF, DMF and DCE. The resin-bound amine was reacted with 5eq of 4-cyanobenzoyl chloride in 50 5ml DCE with 5eq DIEA overnight. Resin was then washed with DCE, DMF, with mixture pyridine/Et 3 N (2:1) and treated with 8ml of saturated solution of H 2 S in Pyridine/Et 3 N (2:1). After 5 hours, the solution was removed and the procedure repeated. After overnight standing, the resin was washed with acetone. The 5 resulting thioamide was converted to the thioimidate by reaction with methyliodide in acetone ((4ml of 20% solution, overnight). The resin was washed with acetone and MeOH, and a solution of 20 eq of ammonium acetate in methanol containing 20eq of acetic acid was added and the kept at 50 0 C for 3 hours. The resin was then washed with MeOH, DMF and DCM. The product was 10 cleaved by TFA(1%TIPS). The crude product was purified by preparative HPLC. MS analysis: calculated 625.3 (M), found 626.2 (MH)+. Example 2: Preparation of 3-amidinobenzoyl-(3-(4-tert-butylphenoxy)benzvl) cyclohexylylalanyl-glycyl-amide: 15 HN
NH
2 0 00 N NH 2 N 00 The title compound was synthesized using Fmoc-Gly-OH, Fmoc-Cha-OH, 3-(4-tert. Butylphenoxy) benzaldehyde and 3-cyanobenzoyl chloride according to 20 procedures described in Example 1. MS analysis: calculated 611.4 (M), found 612.3 (MH)+.
51 Example 3. N-[3-Amidinobenzoyll-N-[3-(4-tert-butylphenoxy) benzyll-4 aminophenylalanyl-glycyl-amide:
H
2 N NH 0 0 N
NH
2 NO 0
NH
2 5 The title compound was synthesized using Fmoc-Gly-OH, Fmoc-Phe(4 NH-Boc)-OH, 3-(4-tert. Butylphenoxy) benzaldehyde and 3-cyanobenzoyl chloride according to procedures described in Example 1. MS analysis: calculated 620.3 (M), found 621.3 (MH)+. 10 Example 4. N-r3-Amidinobenzoyll-N-[3-(4-tert-butylphenoxy) benzyll- 1 naphthylalanyl--lycyl-amide: HN
NH
2 0 O N O N NH2 05 15 52 The title compound was synthesized using Fmoc-Gly-OH, Fmoc-Nal(1) OH, 3-(4-tert. Butylphenoxy) benzaldehyde and 3-cyanobenzoyl chloride according to procedures described in Example 1. MS analysis: calculated 655.3 (M), found 656.2 (MH)+. 5 Example 5. N-[3-Amidinobenzoyll-N-[3-(4-tert- butylphenoxy) benzyll arginyl-glycyl-amide:
H
2 N NH 0 0 N NH2 H 0 0 NH HN : NH2 10 The title compound was synthesized using Fmoc-Gly-OH, Fmoc Arg(Boc)2-OH, 3-(4-tert. Butylphenoxy) benzaldehyde and 3-cyanobenzoyl chloride according to procedures described in Example 1. MS analysis: calculated 614.3 (M), found 615.2 (MH)+.
53 Example 6. 4-amidinobenzoyl-(3-(4-tert-butylphenoxy)phenoxybenzyl) tryptanyl-glycyl-amide:
NH
2 HN 0 0 N NH2 NH O 5 The title compound was synthesized using Fmoc-Gly-OH, Fmoc Trp(Boc)-OH, 3-(4-tert. Butylphenoxy) benzaldehyde and 4-cyanobenzoyl chloride according to procedures described in Example 1. MS analysis: calculated 644.3 (M), found 645.2 (MH)+. 10 Example 7. N-[4-Amidinobenzoyll-N-[4-biphenylmethyll-3-(4 biphenyl)alanyl-glycyl-amide: N
H
2 HN 0 0 N NH N O 54 The title compound was synthesized using Fmoc-Gly-OH, Fmoc-Bip-OH, 4-phenylbenzaldehyde and 4-cyanobenzoyl chloride according to procedures described in Example 1. MS analysis: calculated 609.3 (M), found 610.2 (MH)+. 5 Examples 8 - 15 describe the synthesis of compounds of Formula II where X is a urea moiety. Example 8. 4-Cyclohexyl-1-{ [2-(4-phenylbutanoyl)aminol-4-[1 aminocarbonyl-2-(2 10 naphthyl)ethylaminol carbonylaminophenyl I piperazine: N N 0
H
2 N N N NH H H 0 0 Following generally the procedure described above in connection with 15 Scheme B, commercial Polystyrene-RAM resin (0.74 mmol/g) (Rapp Polymere, Tubingen, Germany, 0.25 g) was slurried in dichloromethane, washed with DMF and treated for 30 minutes with a mixture of piperidine and DMF (1:1 v/v). The resin was washed with DMF (5x), DCM (5x) and DMF (3x) and then coupled with 0.5 mmol of Fmoc-(L)-2-naphthylalanine, I -hydroxybenzotriazole and 20 diisopropyl-carbodiimide in 3 ml DMF overnight. The resin was washed with 55 DMF (5x) and treated with piperidine/DMF again for 30 minutes. After washing as described above, the coupling with 0.5 mmol of 4-fluoro-3 nitrophenylisocyanate in 2 ml DMF was carried out over night. The resin was washed with DMF (5x) and treated with 3 ml of a 0.5 molar solution of 1 5 cyclohexylpiperazine in DMF for 3 hours at 600. After washing with DMF (lOx), the nitro group was reduced by shaking the resin with 4 ml of a molar solution of tin chloride dihydrate in DMF for 24 hours. The resin was washed with DMF (5x), MeOH (5x), DCM (5x), DMF containing 5 % of diisopropylethylamine (Ix) and DMF (3x). The final coupling with Immol of 4-phenyl butyric acid, 1 10 hydroxy-7-azabenzotriazole and diisopropylcarbodiimide in 3 ml DMF was performed over night. Following extensive washing of the resin with DMF, methanol and DCM and subsequent drying, it was cleaved with 3 ml of 95 % trifluoroacetic acid. The TFA solution was evaporated and the residue was combined with the washings of the resin with methanol. Evaporation yielded the 15 crude title compound which was purified by preparative HPLC using the standard acetonitrile/-water + 0.1 % TFA gradient and a Vydac C-18 column. The pure sample had a M+l ion at 661.3 in the mass spectrum and was homogenous by HPLC with a retention time of 26.95 minutes. 20 Example 9. 4-Cyclohexyl- 1- {[2-cinnamoylaminol-4-[ 1 -aminocarbonyl-2-(2 naphthyl)ethylaminolcarbonylaminophenyl piperazine: N N
H
2 N N N N. NH H H 0 0O 56 This was prepared by the method of Example 8 using trans-cinnamic acid in the final coupling step to give the title compound with M+1 ion at 645.3 and a retention time of 26.88 minutes. 5 Example 10. 4-Cyclohexyl- 1-{ [2-cinnamoylamino]-4-[(r1 -aminocarbonyl-3 phenyl)propylaminolcarbonylaminophenyl piperazine: N N
H
2 N N 'N NH H H 10 This compound was prepared by the method of Example 8 using Fmoc homophenylalanine in the initial coupling step to give the title compound with M+1 ion at 609.3 and retention time of 25.78 minutes. 15 57 Example 11. 4-Cyclohexyl-1-{[2-(4-phenylbutanoyl)aminol-4-[(1 aminocarbonyl-3 phenyl)propylaminolcarbonylaminophenyl I piperazine: N H2NN N N NH H H 0 0 5 This compound was prepared by the method of Example 8 using Fmoc homophenylalanine in the initial coupling step to give the title compound with M+1 at 625.3 and a retention time of 26 minutes. 10 Example 12. 4-Cyclohexyl-1-{[2-cinnamoylaminol-4-[14-aminocarbonyl-2 cyclohexyl)ethyl aminolcarbonylaminophenyl lpiperazine: r- N o N
H
2 N N N X NH H H 0 0 58 This compound was prepared by the method of Example 8 using Fmoc cyclohexylalanine in the initial coupling step to give the title compound with M+1 ion at 601.3 and retention time of 26.72 minutes. 5 Example 13. 4-(Piperidin-4-yl)carbonyl-1-{r2-(4-phenylbutanoyl)aminol-4-[l aminocarbonyl-2-(2-naphthyl)ethylaminolcarbonylaminophenylI homopiperazine: \N 0 N N
H
2 N A N N N NH H H H 0 0 10 Following generally the procedure shown in Scheme B above, commercial Polystyrene-RAM resin (0.74 mmol/g) (Rapp Polymere, Tubingen, Germany, 0.25 g) was slurried in dichloromethane, washed with DMF and treated for 30 minutes with a mixture of piperidine and DMF (1:1 v/v). The resin was washed with DMF (5x), DCM (5x) and DMF (3x) and then coupled with 0.5 mmol of 15 Fmoc-(L)-2-naphthylalanine, 1-hydroxybenzotriazole and diisopropylcarbodiimide in 3 ml DMF over night. The resin was washed with DMF (5x) and treated with piperidine/DMF again for 30 minutes. After washing as described above, the coupling with 0.5 mmol of 4-fluoro-3 nitrophenylisocyanate in 2 ml DMF was carried out over night. The resin was 20 washed with DMF (5x) and treated with 3 ml of a 0.5 molar solution of 59 homopiperazine in DMF for 2 hours at 600. The resin was washed with DMF (lOx) and coupled with 0.5 mmol of Boc-isonipecotic acid, HOBt and DIC in 2.5 ml of DMF over night. The resin was washed with DMF (lOx) and reduced with 4 ml of a molar solution of tin chloride dihydrate in DMF for 24 hours. The resin 5 was washed with DMF (5x), MeOH (5x), DCM (5x), DMF containing 5 % of diisopropyl-ethylamine (1x) and DMF (3x). The final coupling with Immol of phenylbutyric acid, 1 -hydroxy-7-azabenzotriazole and diisopropylcarbodiimide in 3 ml DMF was performed over night. Following extensive washing of the resin with DMF, methanol and DCM and subsequent drying, it was cleaved with 3 ml 10 of 95 % trifluoroacetic acid. The TFA solution was evaporated and the residue was combined with the washings of the resin with methanol. Evaporation yielded the crude title compound which was purified by preparative HPLC using the standard acetonitrile/-water + 0.1 % TFA gradient and a Vidac C-18 column. The pure sample had a M+1 ion at 704.3 in the mass spectrum and was homogenous 15 by HPLC with a retention time of 24.12 minutes. Example 14. 4-(Piperidin-4-yl)carbonyl-1-{[2-(2-benzofuranoyl)aminol-4-[1 aminocarbonyl-2-(2-naphthyl)ethylaminolcarbonylaminophenylI homopiperazine: \N 0 "NN N 0 NH H 2 N N N NH H H 0 / 20 20 60 This compound was prepared by the method of Example 13 using 2 benzofuran-carboxylic acid in the final coupling step to give the title compound with M+l ion at 702.1 and retention time of 25.5 minutes. 5 Example 15. 4-(Piperidin-4-yl)carbonyl-1-{[2-(2-benzofuranoyl)aminol-4-[1 aminocarbonyl-2-cyclohexyl ethyl amino] carbonylaminophenyl} homopiperazine: 0 N H N N H
H
2 N N ) N NH H H 0 0 10 This compound was prepared by the method of Example 13 using Fmoc cyclohexylalanine in the initial coupling step and 2-benzofurancarboxylic acid for the final acylation step to give the title compound with M+1 ion at 658.3 and 15 retention time of 25.64 minutes.
61 Example 16. 4-(Piperidin-4-yl)carbonyl-1-[2-[(2-benzofuranoyl)aminol-4-[[(4 aminocarbonyl)cyclohexylmethylaminol carbonylaminophenyll homopiperazine 0 N NH N O O, NH H H 00
NH
2 0 5 This compound was prepared by the method of Example 13 using Fmoc trans-4-aminomethylcyclohexanecarboxylic acid in the initial coupling step and 2 benzofurancarboxylic acid for the final acylation to give the title compound with 10 M+1 ion at 643.4 and retention time of 21.84 minutes. Example 17. 4-(Methylaminomethyl)carbonyl-1-[2-[(2-benzofuranoyl) aminol 4-rr(4-aminocarbonyl)cyclohexylmethylaminol carbonylaminophenyll homopiperazine 15 0 N N HNs N O NH H H
NH
2 0 62 This compound was prepared by the method of Example 13 using Fmoc trans-4-aminomethylcyclohexanecarboxylic acid in the initial coupling step and Boc-sarcosine for capping of the homopiperazine and 2-benzofurancarboxylic acid for the final acylation to give the title compound with M+l ion at 603.3 and 5 retention time of 21.35 minutes. Example 18. 4-(Pyrrolidin-2-yl)carbonyl-1-[2-[(2-benzofuranoyl)aminol-4-[[(4 aminocarbonyl)cyclohexylmethylaminol carbonylaminolphenyll homopiperazine 10 N NH N N NAN H N"' NH H 0 NH, 0 15 This compound was prepared by the method of Example 13 using Fmoc trans-4-aminomethylcyclohexanecarboxylic acid in the initial coupling step, Boc proline for capping of the homopiperazine and 2-benzofurancarboxylic acid for the final acylation to give the title compound with M+1 ion at 629.3 and retention time of 22.12 minutes. 20 63 Example 19. 4-(Piperidin-1-yl)-I-[2-[(2-benzofuranoyl)aminol-4-r[(4-amino carbonyl)cyclohexylmethylaminolcarbonylaminophenyll piperidine N 0 5 .
Na N N NH HH 0 0 NH 2 0 5 This compound was prepared by the method of Example 13 using Fmoc trans-4-aminomethylcyclohexanecarboxylic acid in the initial coupling step, 4-(1 10 piperidyl)piperidine to displace the fluorine and 2-benzofurancarboxylic acid for the final acylation to give the title compound with M+1 ion at 600.3 and retention time of 22.5 minutes. Example 20. 4-(Piperidin-4-yl)carbonyl-I -[[2-(4-phenylbutanoyl) aminol-4-[ 1 15 aminocarbonyl-2-cyclohexylethylaminol carbonylaminophenyllhomopiperazine 0 N NH N
H
2 N NNN N H H 0 0 64 This compound was prepared by the method of Example 13 using Fmoc L-cyclohexylalanine in the initial coupling step and Boc-isonipecotic acid for capping of the homopiperazine to give the title compound with M+1 ion at 659.4 and retention time of 23.97 minutes. 5 Example 21. f4-(Piperidin-4-yl)carbonyl- 1-[[ 2-(4-phenylbutanoyl) amino]-4-[( 1 aminocarbonyl-2-(naphth-2-yl))ethylaminol carbonylaminophenyllhomopiperazine NH CN N H2N N N NH H H 0 0 10 This compound was prepared by the method of Example 13 using Fmoc homophenylalanine in the initial coupling step to give the title compound with 15 M+II ion at 668.4 and retention time of 22.88 minutes. Examples 22 - 25 describe the synthesis of sulfonamide compounds in accordance with the compounds of the present invention.
65 Example 22. N-(I-Aminocarbonyl-2-methylpropyl)-2-r(4 phenylmethyl)piperidin- I -yll-5-[(2 pyrrolidinocarbonyl)aminolphenylsulfonamide 0 N I I
H
2 N '\ N -\ HN 0 NH 5 Following generally the procedures described above, commercial Polystyrene-RAM resin (0.74 mmol/g) (Rapp Polymere, Tubingen, Germany, 0.25 g) was slurried in dichloromethane, washed with DMF and treated for 30 minutes with a mixture of piperidine and DMF (1:1 v/v). The resin was washed with DMF (5x), DCM (5x) and DMF (3x) and then coupled with 0.5 mmol of 10 Fmoc-(L)-valine, 1-hydroxybenzotriazole and diisopropylcarbodiimide in 3 ml DMF over night. The resin was washed with DMF (5x) and treated with piperidine/DMF again for 30 minutes. After washing with DMF (5x) and DCM (10x), the coupling with 0.5 mmol of 2-fluoro-5-nitrophenylsulfonyl chloride in 2ml DCM and I mmol of lutidine was carried out over night. The resin was 15 washed with DCM (5x) and DMF (5x) and treated with 3 ml of a 0.5 molar solution of 4-benzyl-piperidine in DMF for 24 hours at room temperature. After washing with DMF (lOx), the nitro group was reduced by shaking the resin with 4 ml of a 0.5 molar solution of tin chloride in DMF/acetic acid 1:1 for 72 hours. The resin was washed with DMF (5x), MeOH (5x), DCM (5x), DMF containing 5 20 % of diisopropylethylamine (Ix) and DMF (3x). The final coupling with Immol of 2-pyrolidinecarboxylic acid, I -hydroxy-7-azabenzotriazole and 66 diisopropylcarbodiimide in 3 ml DMF was performed over night. Following extensive washing of the resin with DMF, methanol and DCM and subsequent drying, it was cleaved with 3 ml of 95 % trifluoroacetic acid. The TFA solution was evaporated and the residue was combined with the washings of the resin with 5 methanol. Evaporation yielded the crude title compound which was purified by preparative HPLC using the standard acetonitrile/water + 0.1 % TFA gradient and a Vydac C-18 column. The pure sample had a M+1 ion at 542.3 in the mass spectrum and was homogenous by HPLC with a retention time of 26.7 minutes. 10 Example 23. N-(I-Aminocarbonyl-2-methylpropyl)-2-[(4 phenylmethyl)piperidin- I -yll-5-F(4-piperdinocarbonyl) aminolphenylsulfonamide: 0 N I I
H
2 N N \ HO NH HN 0 15 This compound was prepared by the method of Example 22 using 4 piperidinecarboxylic acid in the final coupling step to give the title compound with a M+1 ion at 556.3 in the mass spectrum and a HPLC retention time of 26.2 minutes. 20 67 Example 24. 1-r2-rN-(2-Aminocarbonyl-3-methylbutyl)sulfonamidol-5-r2 cinnamoylaminollphenyl-4-cyclohexylpiperazine 0 N N O
H
2 N S O 0 5 This compound was prepared by the method of Example 22 using 1 cyclohexylpiperazine for displacement of the fluorine and cinnamic acid for the final acylation step to give the title compound with a M+1 ion at 568.3 in the mass spectrum and a HPLC retention time of 24.63 minutes. 10 Example 25. N-[[(4-Aminocarbonyl)cyclohexylmethyllamino]-[2-[ (4 phenylmethyl)piperidin- I -yll-5-r(2-pyrrolidinocarbonyl) aminolphenyllsulfonamide 0 N
H
2 N NN NH HN 0H 68 This compound was prepared by the method of Example 22 using Fmoc protected trans-4-aminomethylcyclohexanecarboxylic acid for the first coupling reaction to give the title compound with a M+1 ion at 582.3 in the mass spectrum and a HPLC retention time of 25.31 minutes. 5 Protein Tyrosine Kinase Activity The compounds 1-25 above were assayed for activity with respect to the Src protein tyrosine kinase by the fluorometric method described in Measurement of the Protein Tyrosine Kinase Activity of c-Src Using Time-Resolved 10 Fluorometry of Europium Chelates, Braunwalder, A.F. et al., Analytical Biochemistry 238, 159-164 (1996), the disclosure of which is incorporated herein by reference, using the materials and procedures further specified below. General Assay Method for Src-Kinase: 15 Materials: Costar 384 Clear, non-treated, high-binding plates Sigma poly(Glu, Tyr) 4:1, ave. MW 35,000 Src Kinase (p 6 0 C-src) Sigma ATP (1.5 mM Stock Soln. in H 2 0) 20 MES Buffer: 30 mM MES (pH 6.8) 10 mM MgCl 2 MBI Buffer: (MES + 0.4 mg/ml BSA + 0.003% IGEPAL) Wallac Eu-labelled anti-phosphotyrosine Antibody (CR04-100) Coating Solution: 25 22.5 mM Na 2
CO
3 (pH 9.6) 27.5 mM NaHCO 3 0.9% NaCl Antibody Dilution Buffer: (MES + 3%BSA) DELFIA@ Wash Solution (TTBS): 30 0.5 M NaCl 20 mM Tris (pH7.4) 69 0.15% Tween 20 DELFIA Enhancement Solution Method: 5 The plates were coated with 0.1 mg/ml poly(Glu, Tyr) in Coating Solution, 35 gl/well. It was let stand overnight at room temp. The plates were then washed 3 times with MES (100 pl/wash). Kinase Reaction Conditions: 10 Procedure (listed in order of addition): 10 pl 200 pM A TP 80 nil 5mM test compound in DMSO 10 pl 1:400 Src dilution in MBI 15 Final Reaction Conditions: 1:8000 Src Kinase 20 pM library compound (0.4% DMSO) 100 pM ATP 20 pL assay volume 20 15 min. at room temp. The reaction was stopped by aspiration, and then washed 3 times with MES (100 p.l/wash). 20 p1 0.4 ng/ptl of antibody in Antibody Dilution Buffer (final= 8ng Ab/well) was added and then incubated for 30 min. at RT. The antibody solution 25 was removed by aspiration and then washed 3 times with IX DELFIA Wash Solution. 20 pl DELFIA enhancement solution was added and the plates were read on a Wallac Victor plate reader in time-resolved fluorescence mode using 340 nm excitation and 615 nm emission wavelengths.
70 The Src Kinase inhibitory activity of the compounds, given as IC50s ( M), are listed in Table 2. Table 2 Compound No. Activity ( Mol, Delfia assay. IC50) 5 Example 1 22 Example 2 23 Example 3 45 Example 4 18 Example 5 12.5 10 Example 6 14 Example 7 13 Example 8 8.5 Example 9 17 Example 10 15.5 15 Example 11 11 Example 12 18.5 Example 13 13 Example 14 2.75 Example 15 6.5 20 Example 16 36 Example 17 37 Example 18 19 Example 19 22 Example 20 28 25 Example 21 22 Example 22 14 Example 23 12 Example 24 42 Example 25 27.5 30 71 From these test results and the knowledge about the compounds described in the references in the section "Background of the Invention", it would be apparent to the skilled artisan that the compounds of the invention have utility in treating conditions where selective inhibitory activity of an Src kinase is desirable. 5 While the invention has been described in detail, modifications to illustrated embodiments within the spirit and scope of the present invention, set forth in the appended claims, will be readily apparent to those of skill in the art.
Claims (21)
1. A compound, including enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in Formula II: R2 H Y N NH R1 0 R 3 5 Formula II wherein R, is selected from the group consisting of H, straight chain CI-C 6 alkyl; branched CI-C 6 alkyl; -(CH 2 )p-Ari; and -(CH 2 )p-R4, wherein p is I or 2; 10 Ari is phenyl or naphthyl optionally substituted with a straight chain or branched C 1 -C 6 alkyl group; and R 4 is C 5 .C 7 cycloalkyl; 15 R 2 is selected from the group consisting of: 0 __ N -N N NH N 73 -R5 0 N N NH HN> 0 H NNN NN and R 5 is selected from the group consisting of H, straight chain CI-C 6 alkyl; 5 branched CI-C 6 alkyl; R 3 is -(CH 2 )q-Ar 2 or -(CH=CH)-Phenyl, wherein q is an integer from 0 to 4; and Ar 2 is selected from the group consisting of: NH R 5 Rr 0 Rand H N 10 X is: 74 0 O II -S N 1 H or 0 and Y is selected from the group consisting of: 5 O H 2N H 2 N , and HO Y 0 with the proviso that when Y is any of the moieties: H2N HO 10 0 and 0 then R, is H.
2. The compound of claim 1, wherein X is: 15 75 N H
3. The compound of claim 1, wherein X is: 5
4. The compound of claim 1, wherein R, is H.
5. The compound of claim 1, wherein R, is a straight chain CI-C 6 alkyl or a 10 branched C I-C 6 alkyl.
6. The compound of claim 1, wherein R, is -(CH 2 )p-Ari, where p and Ari are as defined in claim 1. 15
7. The compound of claim 1, wherein R, is -(CH 2 )p-R 4 , where p and R 4 are as defined in claim 1.
8. The compound of claim 1, wherein R 2 is: 0 -N /-- N NH 76
9. The compound of claim 1, wherein R 2 is: N 5 10. The compound of claim 1, wherein R 2 is: R 5 where R 5 is as defined in claim 1.
10
11. The compound of claim 1, wherein R 2 is: 0 H N N NN 77
12. The compound of claim 1, wherein R 2 is: N 5
13. The compound of claim 1, wherein R 2 is: 0 N N HN
14. The compound of claim 1, wherein R 3 is -(CH2)q-Ar2, where q and Ar 2 are 10 as defined.
15. The compound of claim 1, wherein R 3 is -(CH=CH)-Phenyl.
16. The compound of claim 1, wherein Y is: 15 0 H 2 N
17. The compound of claim 1, wherein Y is: 78 H2N
18. The compound of claim 1, wherein Y is: HO 50
19. The compound of claim 1, wherein R, is isopropyl or isobutyl.
20. A compound which is substantially as hereinbefore described with 10 reference to any one of Examples 8 to 25.
21. A pharmaceutical composition including as an active ingredient a compound of any one of claims I to 20 together with a pharmaceutically acceptable carrier. 15 Aventis Pharmaceuticals Inc WATERMARK PATENT & TRADE MARK ATTORNEYS 20 P23399AU0
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2007216625A AU2007216625B2 (en) | 2001-07-09 | 2007-09-05 | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/304,020 | 2001-07-09 | ||
GB0127615.3 | 2001-11-19 | ||
AU2002320330A AU2002320330B2 (en) | 2001-07-09 | 2002-07-09 | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity |
AU2007216625A AU2007216625B2 (en) | 2001-07-09 | 2007-09-05 | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2002320330A Division AU2002320330B2 (en) | 2001-07-09 | 2002-07-09 | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2007216625A1 AU2007216625A1 (en) | 2007-09-27 |
AU2007216625B2 true AU2007216625B2 (en) | 2009-07-02 |
Family
ID=38577339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2007216625A Expired - Fee Related AU2007216625B2 (en) | 2001-07-09 | 2007-09-05 | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2007216625B2 (en) |
-
2007
- 2007-09-05 AU AU2007216625A patent/AU2007216625B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
AU2007216625A1 (en) | 2007-09-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6180627B1 (en) | Antithrombotic agents | |
CA2338524C (en) | Inhibitors of urokinase and blood vessel formation | |
JP4086316B2 (en) | Novel N- (arylsulfonyl) amino acid derivative having affinity for bradykinin receptor | |
CA2287293A1 (en) | Somatostatin agonists | |
JP4089981B2 (en) | Thrombin inhibitor | |
CZ294674B6 (en) | Antithrombotic pharmaceutical compositions | |
JP2000501389A (en) | Amino acid derivative, drug containing the derivative and method for producing the derivative | |
EP0858262B1 (en) | Thrombin inhibitors | |
US5798377A (en) | Thrombin inhibitors | |
US20030045480A1 (en) | Method of treating hyperresorptive bone disorders | |
EP1423373B1 (en) | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity | |
JP2002501044A (en) | Heterocyclic amidines as kallikrein protease inhibitors | |
AU2007216625B2 (en) | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity | |
US7393849B2 (en) | Substituted sulfonamides and ureas useful for inhibiting kinase activity | |
AU2002320330A1 (en) | Substituted amides, sulfonamides and ureas useful for inhibiting kinase activity | |
US20040014676A1 (en) | SRC kinase inhibitors useful for treating osteoporosis | |
Hruby et al. | Design of nonpeptides from peptide ligands for peptide receptors | |
CZ424698A3 (en) | Derivatives of piperidine acetic acid, process of their preparation and pharmaceutical composition containing thereof | |
US5610308A (en) | Process for preparing intermediates for thrombin inhibitors | |
US6417203B1 (en) | Antithrombotic agents | |
KR100565008B1 (en) | 4-Hydrazino-3-cyclobutene-1,2-dione derivatives and processes for the preparation thereof | |
TW379216B (en) | Novel LH-RH antagonists having improved action, harmaceutical composition comprising the same and process for preparing the same | |
JP2002255939A (en) | 5-aminonicotinic acid derivative | |
MXPA99007603A (en) | Antitromboti agents | |
MXPA00010585A (en) | Compounds with growth hormone releasing properties |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK25 | Application lapsed reg. 22.2i(2) - failure to pay acceptance fee |