MXPA00009358A - Barbituric acid derivative and preventive and therapeutic agent for bone and cartilage containing the same - Google Patents
Barbituric acid derivative and preventive and therapeutic agent for bone and cartilage containing the sameInfo
- Publication number
- MXPA00009358A MXPA00009358A MXPA/A/2000/009358A MXPA00009358A MXPA00009358A MX PA00009358 A MXPA00009358 A MX PA00009358A MX PA00009358 A MXPA00009358 A MX PA00009358A MX PA00009358 A MXPA00009358 A MX PA00009358A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- substituted
- barbituric acid
- groups
- solvate
- Prior art date
Links
- 150000007656 barbituric acids Chemical class 0.000 title claims abstract description 25
- 210000000845 Cartilage Anatomy 0.000 title claims abstract description 16
- 210000000988 Bone and Bones Anatomy 0.000 title claims abstract description 15
- 239000003814 drug Substances 0.000 title abstract description 23
- 230000003449 preventive Effects 0.000 title abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 125000005002 aryl methyl group Chemical group 0.000 claims abstract description 13
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 43
- -1 2-thienylmethyl group Chemical group 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 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
- 208000006386 Bone Resorption Diseases 0.000 abstract description 14
- 230000024279 bone resorption Effects 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 125000005017 substituted alkenyl group Chemical group 0.000 abstract description 3
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 238000006467 substitution reaction Methods 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 101700067048 CDC13 Proteins 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000022534 cell killing Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 230000009089 cytolysis Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000017074 necrotic cell death Effects 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000002194 synthesizing Effects 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cells Anatomy 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 239000001963 growth media Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- BUWBQFUUIDVFEL-UHFFFAOYSA-N 1,3-dibenzyl-1,3-diazinane-2,4,6-trione Chemical compound O=C1N(CC=2C=CC=CC=2)C(=O)CC(=O)N1CC1=CC=CC=C1 BUWBQFUUIDVFEL-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 4
- 210000004409 Osteocytes Anatomy 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 210000000689 upper leg Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WMETWIRZADGESO-UHFFFAOYSA-N 1,3-bis(3-methylbutyl)-1,3-diazinane-2,4,6-trione Chemical compound CC(C)CCN1C(=O)CC(=O)N(CCC(C)C)C1=O WMETWIRZADGESO-UHFFFAOYSA-N 0.000 description 3
- AURPMRPZTDOADA-UHFFFAOYSA-N 1,3-bis(3-methylbutyl)urea Chemical compound CC(C)CCNC(=O)NCCC(C)C AURPMRPZTDOADA-UHFFFAOYSA-N 0.000 description 3
- KOFOMUVGJGCZQG-UHFFFAOYSA-N 1,3-dibenzyl-5-(2-thiophen-2-ylacetyl)-1,3-diazinane-2,4,6-trione Chemical compound O=C1N(CC=2C=CC=CC=2)C(=O)N(CC=2C=CC=CC=2)C(=O)C1C(=O)CC1=CC=CS1 KOFOMUVGJGCZQG-UHFFFAOYSA-N 0.000 description 3
- RQUBZZXYBRXLKG-UHFFFAOYSA-N 5-(3-methylbutanoyl)-1,3-bis(3-methylbutyl)-1,3-diazinane-2,4,6-trione Chemical compound CC(C)CCN1C(=O)C(C(=O)CC(C)C)C(=O)N(CCC(C)C)C1=O RQUBZZXYBRXLKG-UHFFFAOYSA-N 0.000 description 3
- HNYOPLTXPVRDBG-UHFFFAOYSA-N Barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 3
- 210000001772 Blood Platelets Anatomy 0.000 description 3
- 206010020583 Hypercalcaemia Diseases 0.000 description 3
- 201000001146 Paget's disease of bone Diseases 0.000 description 3
- 206010072736 Rheumatic disease Diseases 0.000 description 3
- 230000001058 adult Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 230000000148 hypercalcaemia Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 230000003211 malignant Effects 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- OJXHUIQQKAXDMR-UHFFFAOYSA-N 1,3-dibenzyl-5-(2-phenylacetyl)-1,3-diazinane-2,4,6-trione Chemical compound O=C1N(CC=2C=CC=CC=2)C(=O)N(CC=2C=CC=CC=2)C(=O)C1C(=O)CC1=CC=CC=C1 OJXHUIQQKAXDMR-UHFFFAOYSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 description 2
- 208000003432 Bone Disease Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 2
- 241000272184 Falconiformes Species 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 210000003127 Knee Anatomy 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 208000010191 Osteitis Deformans Diseases 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N Phenethyl alcohol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 125000005066 dodecenyl group Chemical group C(=CCCCCCCCCCC)* 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000004503 fine granule Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006038 hexenyl group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 2
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
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- PPBRXRYQALVLMV-UHFFFAOYSA-N styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
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- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 2
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- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 2
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 2
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 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
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Abstract
The present invention relates to a barbituric acid derivative shown in formula (I) (wherein R or R1 independently represents a hydrogen atom, a susbstituted or not substituted alkyl group or alkenyl group of C1 - C15, a substituted or not substituted arylmethyl group, and substituted or not substituted aryl group, and R2 represents substituted or not substituted alkyl group or alkenyl group of C1 - C15, a substituted or not substituted arylmethyl group, and substituted or not substituted aryl group). The barbituric acid derivative of the present invention has a strong inhibiting activity to bone resorption and is useful as a preventive and therapeutic agent for diseases affecting bone and cartilage.
Description
DERIVATIVE OF BARBITURIC ACID AND AGENT
PREVENTIVE AND THERAPEUTIC FOR THE BONE AND - CARTILAGE THAT CONTAIN THE SAME
Description of the Invention The present invention relates to a novel barbituric acid derivative and to a method for the prevention and treatment by utilizing, therein, in malignant hypercalcemia, osteolytic diseases such as Paget's disease of bone and osteoporosis. , these diseases of the denaturalization and necrosis of a cartilage such as osteoarthritis, necrosis of the head of the femur, and joint rheumatism that occur in the knee, shoulder, and joint. Gradually, Japan has been changing to a society that is aging more and, therefore, diseases of bone resorption such as osteoporosis are becoming a major social problem. Bone resorption diseases are bone diseases caused by abnormal bone resorption stenia that is exemplified by a malignant hypercalcemia caused
Ref: 122872 for a myeloma or lymphoma, for Paget's bone disease due to local bone resorption, and osteoporosis caused by various factors such as aging and menopause. Although, currently, a female hormone, calcitonin, vitamin D3, parathyroid hormone, bisphosphonate, and ipriflavone, etc., are being used for therapeutic treatment, these agents have some defects, respectively, such as to remain of symptomatic therapy. On the other hand, osteoarthritis, necrosis of the head of the femur, and rheumatism of the joints are a disease that occurs as a defect of cartilage and bone caused by a denaturation and necrosis of the cartilaginous joint and the subcartilaginous bone caused by various factors such as mechanical stress, old age, inflammation. The defect in the bone mainly affects the decrease in the quality of life through the deformation and pain of a joint. No agent has existed substantially to inhibit or effectively repair the cartilage defect in these diseases.
The barbituric acid derivatives are a group of compounds that are used for medicinal drugs, agricultural chemicals, and many other purposes, and various derivatives thereof are known. For example, there are photosensitive materials for anticancer drugs (refer to document W09116315), for electronic photographs (refer to the Japanese Patent Application Exposed with Nos. 179361/91 and 111852/91), a vermifuge (refer to EP 192180), insecticides (EP 455300, DE 3903404; and GB 1339748), herbicides (US 4797147 and Japanese Patent Application Laid-open No. 154275/75), and a bactericide (EP 517660). The present inventors first elucidate the structure and the strong inhibitory action of bone resorption, which had not previously been known, as regards the knowledge of the inventors, of a series of compounds related to the present invention. The inventors of the present invention first find substances that show a strong inhibitory action of bone resorption between the polyhydroxyphenol derivatives (Japanese Patent Application No.
137991/97). As a result of further investigation and analysis of the relationship between the structure / activity of these compounds, the inventors have found a strong activity of a novel barbituric acid derivative and finally conclude the present invention.
Therefore, the purpose of the present invention is to provide a novel and useful derivative of barbituric acid, this salt and its solvate, in a method for the prevention and treatment of various diseases affecting the bones and cartilages when using these compounds. The subject of the invention is a derivative of barbituric acid represented by the following general formula (I), the salt of this or the solvate thereof:
(wherein each R or R1 independently represents a hydrogen atom, a substituted or unsubstituted alkyl group or a C1-C15 alkenyl group, a substituted or unsubstituted arylmethyl group, a substituted or unsubstituted aryl group, and R2 represents a substituted or unsubstituted alkyl group or a C1-C15 alkenyl group, a substituted or unsubstituted arylmethyl group, or a substituted or unsubstituted aryl group The present invention relates to a barbituric acid derivative which is shown in the general formula
(I), the salt of this or solvate thereof containing one or more compounds, and a composition of a medicinal drug containing a carrier which is acceptable for the manufacture of the drug, preferably, a composition of a medicinal drug the which is a preventive and therapeutic agent for diseases that affect the bones and cartilage. In addition, the present invention relates to the use of a barbituric acid derivative which is shown in this general formula (I), the salt thereof or the solvate thereof containing one or more compounds for making a composition of a medicinal drug for the prevention and therapy of diseases that affect bones and cartilage.
Furthermore, the present invention relates to a method for the prevention and therapy of diseases affecting the bones and cartilages by administering an effective amount of a barbituric acid derivative which is shown in the general formula (I), the salt of this or the solvate thereof containing one or more compounds for the prevention and therapy of diseases affecting the bones and cartilage. The compound shown in this general formula
(I) of the present invention, the alkyl groups are straight chain or branched chain alkyl groups of
1-15 carbon atoms, preferably 2-10, or more preferably 4-10, and alkenyl groups which are unsaturated straight or branched chain hydrocarbon groups of 2-15 carbon atoms, preferably 3- 10, more preferably 4-10; Preferably, unsaturated hydrocarbon groups of one or more carbon-carbon double bonds. In the compound shown in this general formula (I) of the present invention, the aryl groups are monocyclic, pyclic, or fused ring aryl groups of 6-30 carbon atoms, preferably 6-20, more preferably 6-10; these aryl groups of the present invention are monocyclic, pyclic, or aromatic groups with fused heterocyclic rings of at least one or more nitrogen atoms, oxygen atoms, or sulfur atoms in an aromatic ring, whose ring size is 5. -20 members, preferably 5-10 members, or more preferably 5-7 members, and can be condensed with a ring consisting of saturated or unsaturated hydrocarbon groups. In the compound shown in this general formula (I) of the present invention, the arylmethyl groups are exemplified by the methyl groups which are made by the substitution of this aryl group. In this general formula (I) of the present invention, alkyl groups, alkenyl groups, arylmethyl groups, or aryl groups may be substituted by a substitution group that does not inhibit the activities for the medical purposes of the present invention. The compound shown in this general formula
(I) of the present invention can be protected by a protecting group that allows the production of an active body in a living organism to express a physiological activity in the living organism. Substitution groups of these alkyl groups, alkenyl groups, arylmethyl groups, or aryl groups in this general formula (I) of the present invention, can be made by substituting these groups with one another, when a mutual substitution of these groups is possible. Examples are aryl groups substituted with alkyl groups, arylmethyl groups substituted with alkyl groups, alkyl groups substituted by an aryl group, and alkenyl groups substituted by an aryl group. Other substitution groups are exemplified by the hydroxyl group, an amino group, an alkoxy group having these alkyl groups, an alkylthiol group, a mono or dialkylamino group, haloidal atoms such as chlorine, bromine, and fluorine, alkylenedioxyl groups such as a methylenedioxyl group and a 2,2-dimethylethylenedioxyl group, a cyano group, and a nitro group. Preferred substitution groups are exemplified by a group of lowered alkyls such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group, aryl groups such as groups phenyl and a naphthyl group, lower alkoxy groups such as the methoxyl group, an ethoxy group, and an n-propoxy group, doubly lowered alkylamino groups such as a dimethylamino group, a diethylamino group, and a dipropylamino group, halogen atoms such such as iodine, bromine, chlorine and fluorine, alkylenedioxyl groups such as a methylenedioxyl group, a 2,2-dimethylethylenedioxyl group, a hydroxyl group, an amino group, a cyano group, and a nitro group, etc. The aryl groups in the compounds shown in this general formula (I) of the present invention are exemplified by a phenyl group, a naphthyl group, an anthrazonyl group, a pyridyl group, a quinolyl group, a thienyl group, and a group pyrrolyl. Substitution groups of a substituted alkyl group or a substituted alkenyl group are preferably specified by an atomic group which is introduced to replace a hydrogen atom in the preparation of a derivative by replacing a hydrogen atom of these groups by another atomic group. Substitution groups can be a hydroxyl group, an alkoxy group, iodo, bromo, chloro and, fluorine, an amino group, a cyano group, and a nitro group. Preferably, the substitution groups of a substituted arylmethyl group are atomic groups that are introduced to replace a hydrogen atom, when a derivative is prepared from the substitution of another atomic group for a residue that is formed by removing a single hydrogen atom of the benzene ring of an aromatic compound which has been substituted by a hydroxyl group, an alkoxy group, iodo, bromo, chloro, fluoro, an amino group, a cyano group, and a nitro group, etc. Preferably, the substituted or unsubstituted alkyl groups shown in this general formula (I) of the substitution groups R and R1 of a barbituric acid derivative are exemplified by a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decanyl group, an undecanyl group, a dodecyl group, a tridecyl group, a tetradecyl group, or a pentadecyl group, etc.; in addition to their isomers, those which are substituted or not substituted for these groups by this substitution group are preferable. The substituted or unsubstituted alkenyl groups shown in this general formula (I) wherein the substitution groups R and R1 of the barbituric acid derivative are preferably exemplified by an ethenyl group, a propenyl group, a butenyl group, a group pentenyl, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, a dodecenyl group, a tridecenyl group, a tetradecenyl group, or a pentadecenyl group, etc .; in addition to their isomers, those which are substituted or not substituted for these groups by this substitution group are preferable. The substituted or unsubstituted arylmethyl groups shown in this general formula (I) wherein the substitution groups R and R1 of the barbituric acid derivative are preferably exemplified by a phenylmethyl group, a naphthylmethyl group, an anthracenylmethyl group, a group pyridylmethyl, a quinolylmethyl group, a thienylmethyl group, or a pyrrolylmethyl group, etc .; moreover those which are substituted for these groups by these substitution groups are preferably exemplified by those which are substituted or not substituted for these groups by these substitution groups such as a hydroxyl group, an alkoxy group, iodine, bromine, chlorine, fluorine, an amino group, a cyano group, a nitro group, etc. The substituted or unsubstituted alkyl groups shown in this general formula (I) of the substitution groups R2 of a barbituric acid derivative are preferably exemplified by a methyl group, an ethyl group, a propyl group, a butyl group , a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decanyl group, an undecanyl group, a dodecyl group, a tridecyl group, a tetradecyl group, or a pentadecyl group, etc .; in addition to their isomers, those which are substituted or not substituted for these groups by these substitution groups are preferable. The substituted or unsubstituted alkenyl groups shown in this general formula (I) of the substitution groups R2 of a barbituric acid derivative are preferably exemplified by an ethenyl group, a propenyl group, a butenyl group, a group pentenyl, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, a dodecenyl group, a tridecenyl group, a tetradecenyl group, or a pentadecenyl group, etc .; in addition to their isomers, those which are substituted or not substituted for these groups by these substitution groups are preferable. The substituted or unsubstituted arylmethyl groups shown in this general formula (I) of the substitution groups R2 of a barbituric acid derivative are preferably exemplified by a phenylmethyl group, a naphthylmethyl group, an anthracenylmethyl group, a group pyridylmethyl, a quinolylmethyl group, a thienylmethyl group, or a pyrrolylmethyl group, etc .; in addition, those which are substituted for these groups by these substitution groups and which are preferably exemplified by those which are substituted or not substituted for these groups by these substitution groups such as a hydroxyl group, an alkoxy group, iodine, bromine , chlorine, fluorine, an amino group, a cyano group, a nitro group, etc.
The substituted or unsubstituted aryl groups shown in this general formula (I) of the substitution groups R2 of a barbituric acid derivative are preferably exemplified by a phenyl group, a naphthyl group, an anthracenyl group, a group pyridyl, a quinolyl group, a thienyl group, or a pyrrolyl group, etc .; in addition, those that are substituted or not replaced by these substitution groups are preferable. Preferred compounds of the compound shown in this general formula (I) of the present invention are specifically exemplified as follows: 1,3-Benzyl-5- (3-methyl-1-oxobutyl) barbituric acid (Compound No. 1), 1,3-dibenzyl-5- (phenylacetyl) barbituric acid (Compound No. 2), 1,3-dibenzyl-5- (2-thienylacetyl) barbituric acid (Compound No. 3), 1,3-acid bis (3-methylbutyl) -5- (3-methyl-1-oxobutyl) barbituric (Compound No. 4), l-benzyl-3- (3-methylbutyl) -5- (3-methyl-1-oxobutyl) barbiturate, 1-ben cyl-3- (3-methylbutyl) -5- (phenylacetyl) barbituric acid, l-benzyl-3- (3-methylbutyl) -5- (2-thienylacetyl) barbituric acid, acid 1, 3-bis (3-methyl-2-butenyl) -5- (3-methyl-1-oxobutyl) barbituric acid, 1,3-bis (3-methyl-2-butenyl) -5- (phenylacetyl) -arbituric acid, 1,3-bis (3-methyl-2-butenyl) -5- (2-thienylacetyl) barbituric acid, l-benzyl-3- (3-methyl-2-butenyl) -5- (3-methyl-1-l acid -oxobutyl) barbiturate, l-benzyl-3- (3-methyl-2-acid) -butenyl) -5- (phenylacetyl) barbituric, l-benzyl-3- (3-methyl-2-butenyl) -5- (2-thienylacetyl) barbituric acid, 1- (3-methyl-2-butenyl) - 3- (3-Methylbutyl) -5- (3-methyl-1-oxobutyl) barbituric acid, 1- (3-methyl-2-butenyl) -3- (3-methylbutyl) -5- (phenylacetyl) barbituric acid, acid 1- (3-methyl-2-butenyl) -3- (3-methylbutyl) -5- (2-thienylacetyl) barbituric. The compounds shown in this general formula (I) of the present invention can be synthesized by conventional methods of synthesis. For example, in a reaction formula that is represented by the following formula, the synthesis can be easily done by the condensation reaction derived from the barbituric acid which is represented by the following formula (II) and a acylating agent represented by the following formula ( III) (refer to the following formula):
The acylating agents that are used are exemplified by acyl halides, acid anhydrides, or carboxylic acids, etc. The person skilled in the art knows well that the condensation agents used for these reactions are selected individually according to the reaction applied. When acylating agents (III) are acyl halides or acid anhydrides, a base lacking a nucleophilic reaction, preferably a tertiary amine, is used as a condensing agent. Examples are aromatic amines such as pyridine and quinoline, etc., tertiary amines such as triethylamine, diisopropytylamine, and N-methyl-pyrrolidine, etc., and aralkyl amines such as N, N-dimethylaniline, etc. A solvent is used for the reaction; however, it can be used in a way that is not restrictive, but applicable to aniline, etc. A solvent is used for the reaction; however, it can be used in a manner that is not restrictive, but applicable for those that are inactive for both acylating agents and tertiary amines. Pyridine, and triethylamine, etc., sometimes used for a condensation agent in combination with a solvent
(refer to J. Org. Chem. 45: 4606, 1980 EP 455300;; Japanese Patent Application Disclosed No. 102358/91; Japanese Patent Laid-Open Application No. 111852/91).
When an acylating agent (III) is free of the carboxylic acid, the oxyphosphoric chloride is used, for example, as a condensing agent (refer to GB 1339748). There are some methods for the preparation of a barbituric acid derivative (II) to acylate in this reaction formula. Those methods are easily devised by someone skilled in the art. For example, the elaboration can be carried out by means of the formula presented below (refer to the following formula):
The examples are made by a condensation method of a urea derivative (IV) and a malonic acid derivative (V) (Y and Z are halogen atoms such as chlorine or bromine, etc., or a hydroxyl group) , or form an ester group together with a carbonyl group), and a method by the condensation of a carbodiimide derivative (VI) and a malonic acid (V) (refer to EP 455300). The urea derivative (IV) and the carbodiimide derivative (VI), etc., are compounds that are generally known as materials, and their preparation has been described in detail in the following reference (Reference: SR Sandler and W. Karo, Chapter 6 / Ureas, Chapter 9 / Carbodiimides, Academic Press, 1986). The inhibitory activity of the bone resorption of the barbituric acid derivative which is prepared according to the aforementioned method is analyzed by the method for the assessment of the development in wells. As a result, the compound of the present invention shows an excellent inhibitory ratio for bone resorption in the concentration of the order of 1 x 10 -5 M. Therefore, these compounds have a strong inhibitory activity for bone resorption. A derivative of barbituric acid, the salt of this or the solvates thereof which are found in the general formula (I) of the present invention are useful as an effective ingredient of a medicinal drug for the prevention and therapeutic treatment of the bone and cartilage diseases. The present invention provides a composition of a medicinal drug containing one or more compounds as an effective ingredient, a method for using the composition for the prevention and therapeutic treatment of various diseases related to the inhibitory action of bone resorption, and a use of these compounds for the preparation of the composition of a medicinal drug. The present invention relates to a composition of a medicinal drug containing one or more compounds that are shown in this general formula (I), the salt thereof or the solvate thereof, or a substance protected in this way (e.g. a pro-drug to become an active drug in a living body), which is acceptable for the manufacture of the drug, as an effective ingredient. The composition of the medicinal drug of the present invention relates to a composition of a medicinal drug containing various carriers that are acceptable for the manufacture of the drug. The composition of a medicinal drug of the present invention has the activity of inhibiting bone resorption and is useful as a preventive or therapeutic agent for diseases affecting bone and cartilage. Diseases affecting the bones and cartilages of the present invention include diseases of bone resorption such as malignant hypercalcemia, Paget's disease of bone, and osteoporosis and diseases that accompany denaturation and cartilage necrosis such as osteoarthritis, necrosis of the head of the femur, the rheumatism of the joint that occurs in the knee, shoulder and the hip joint. A clinical dose of administration of the effective ingredient of the present invention generally ranges from O.Olg-2g per day (ca. 0.15 mg-30 mg / kg / day) to an adult for the compound of the present invention, from Preference of 0.1 - 2g per day (ca.
mg / kg / day) for an adult person, and more preferably 0.1 - 1 g per day (ca. 1.5 mg - 15 mg / kg / day) for an adult person, which are interchangeable according to the method of administration, stage of the disease, and condition of the patient. A possible method of administration for the composition of a medicinal drug of the present invention includes intravenous, intramuscular, oral and intrarectal administration; in intravenous administration, an intravenous drip can be applied in addition to a conventional intravenous injection. A method for making the drug of the composition of a medicinal drug containing the compound of the present invention is exemplified by the conventional method, when using a conventional excipient • a conventional additive. A preparation of an injection may be, for example, a powder preparation for an injection. In this case, a medicinal drug is prepared by adding one or more suitable water-soluble excipients such as mannitol, sucrose, lactose, maltose, glucose, fructose, etc., to the water to dissolve, so that it is divided into a bottle or in an ampoule followed by a freeze-drying and a hermetic packing for its final preparation. In preparation for oral administration, a coated enteric agent may be prepared in addition to a tablet, a capsule, a granule, a fine granule, and a conventional powder. In preparing the coated enteric agent, a tablet, a granule, or a fine granule can be prepared by adding additives such as a lubricant such as mannitol, sucrose, lactose, maltose, starch, silica anhydride, calcium phosphate, etc. ., a binder such as carboxymethylcellulose, methylcellulose, gelatin, gum arabic, etc., and a disintegrant such as calcium carboxymethylcellulose, followed by a coating with one or more of the base enteric agents such as acetate acetate phthalate. cellulose, the hydroxypropylmethylcellulosephthalate, the hydroxypropylmethylcellulose acetyl succinate, the polyvinyl alcohol epphalate, the styrene, a maleic acid anhydride copolymer, the methylacrylate, and a methylacrylate copolymer, and if necessary, add a dye such as oxide of titanium to do the preparation. A capsule preparation can be made by filling the enteric granules or fine granules which are thus prepared in a capsule. On the other hand, it is possible for a capsule to be prepared by a conventional method in which it is coated with this basic enteric agent to make it enteric and to make it in an enteric capsule by using a capsule that is prepared by using this basic enteric agent only or when mixed with gelatin. For a suppository, it can be prepared, by adding a semi-synthesized base agent which dissolves after the preparation, by mixing a monoglyceride of a fatty acid and a diglyceride of a fatty acid in various proportions in cocoa butter or in a triglyceride of a fatty acid, followed by a light kneading and pouring it into a mold to form a suppository. The present invention is described in detail below with reference to the following reference examples, examples, and an example of analysis which in no way limits the scope of the invention.
Reference Example 1 Preparation of N, N'-dibenzylurea A mixture of urea 5.84 g (9.72 mmol) and benzoyl-25.0 g (23.3 mmol, 2.4 equivalents) is heated at 150 ° C-155 ° C for 5 hours. fixed to an air cooler. During heating, the evolution of the ammonia gas from a reaction mixture in the form of a colorless liquid is observed. Upon cooling, it solidifies around room temperature. The reaction product is purified by recrystallization from benzene-ethanol (1: 1 mixture) to give N, N '-diben eylurea 14.0 g as fine white aciform particles (59.9% yield). NMR (DMSO-CDCl 3) 54.33 (2H, d, J = 5.8 Hz), 6.02 (1H, bt), 7.19-7.32 (5H, m).
Reference Example 2 Preparation of N, N'-bis (3-methylbutyl) urea A mixture of urea 0.601 g (10.0 mmol) and 3-methylbutylamine 5.0 mL (ca. 6 equivalents) is heated at 150 ° C for 24 hours fixed to a reflux cooler and during this time 2.5 L more than 3-methylbutylamine are added. The excess amine is removed under reduced pressure and allowed to cool to room temperature to give a colorless solid. Purification by recrystallization of the ethyl ether gives 1.29 g of N, N'-bis (3-methylbutyl) urea as a white lamellae (64.5% yield). NMR (CDC13) 50.91 (6H, d, J = 6.9 Hz), 1.38 (2H, q, J = 7.2 Hz), 1.63 (1H, m), 3.15 (2H, t, J = 7.3 Hz).
Reference Example 3 Preparation of 1,3-dibenylbarbituric acid A mixture of 12.02 g (50.0 mmol) of
N, N'-diibee, and 5.20 g (50.0 mmol) of malonic acid in 50.0 mL (530 mmol, 10.6 equivalents) of acetic anhydride at 70 ° C - 75 ° C for 14 hours under a nitrogen atmosphere. Then, the materials are removed. Volatiles under reduced pressure and the residue is distributed between the layers of 2 M 250 mL of sodium hydroxide and 200 mL of ether. The alkaline aqueous layer is separated and then washed with ether, neutralized with concentrated hydrochloric acid with cooling in an ice bath (pH 2-3). The neutralized aqueous solution is extracted with chloroform, washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure and provides 14.7g of 1,3-dibenzylbarbituric acid as a pale yellow crystalline powder (97.6% yield). NMR (CDC13) 63.60 (1H, s), 5.00 (2H, s), 7.22-7.45 (5H, m)
Reference Example 4 Preparation of 1,3-bis (3-methylbutyl) barbituric acid A mixture of 1.28 g (6.39 mmoles) of N, N'-bis (3-methylbutyl) urea acid and 665 mg (6.39 mmoles) is heated. of malonic acid in 6.4 mL (68 mmol, 11 equivalents) of acetic anhydride at 70 ° C - 75 ° C under a nitrogen atmosphere for 4 hours. The volatile materials are removed under reduced pressure and the residue is distributed between the 2 M layers of 50 mL of sodium hydroxide and 60 mL of ether. The alkaline aqueous layer is separated and after washing with ether, the aqueous solution is neutralized with concentrated hydrochloric acid (pH 2-3). The neutralized aqueous solution is extracted with dichloromethane, washed with water, and dried with sodium sulfate. Removal of the solvent under reduced expression provides 1.22 g of an orange solid. The crude product is purified by column chromatography (silica gel, elution with ether) to obtain 954 mg of 1,3-bis (3-methylbutyl) barbituric acid as pale yellow crystals (95.6% yield). NMR (CDC13) 50.95 (6H, d, J = 6.6 Hz), 1.48 (2H, q, J = 7.8 Hz), 1.62 (1H, m), 3.65 (1H, s), 3.87 (2H, t, J = 7.8 Hz).
EXAMPLE 1 Synthesis of 1,3-dibenyl-cyclo-5- (3-methyl-1-oxobutyl) barbituric acid (Compound No. 1) To a solution of 265 mg (0.859 mmol) of 1,3-dibenzylbarbituric acid in 2.0 mL of dry dichloromethane under a nitrogen atmosphere, add 1.0 mL (12 mmol) of pyridine and stir at 0 ° C. 104 mg are added
(0.858 mmoles 1.00 equivalents) of isovaleryl chloride, in 1.0 mL of dichloromethane, to the solution, slowly over a period of 20 minutes, then stirred at room temperature for 3 hours. 50 mL of dichloromethane are added and the organic layer is washed with 2 M hydrochloric acid and saturated saline, and dried over sodium sulfate. 351 mg of the crude product are purified, after removal of the solvent under reduced pressure, by means of column chromatography (silica gel, eluting with dichloromethane). 299 mg of 1,3-dibenzyl-5- (3-methyl-1-oxobutyl) barbituric acid are obtained in the form of a colorless viscous oil first, and after two days, it becomes white platelets (production of 88.7%). %). NMR (CDC13) dl.01 (6H, d, J = 6.6 Hz), 2.20 (1H, m), 3.04 (2H, d, J = 6.8 Hz), 5.10 (2H, s), 5.11 (2H, s) , 7.23 -7.47 (10H, m).
Example 2 Synthesis of 1,3-dibe acid 5-1 (phenylacetyl) barbituric (Compound No. 2) To a solution of 192 mg (0.623 mmoles) of 1,3-dibenzylbarbituric acid in 2.0 mL of dry dichloromethane under a nitrogen atmosphere, 1.0 mL is added. of pyridine (12 mmol) and stirred at 0 ° C. 96 mg (0.623 mmoles 1.00 equivalents) of phenylacetyl chloride in 1.0 mL of dichloromethane are added slowly to the solution over a period of -20 minutes, then it is stirred at room temperature for 3 hours. 40 mL of dichloromethane are added and the organic layer is washed with 2 M hydrochloric acid and saturated saline, and dried over sodium sulfate. 273 mg of the crude product are purified, after removal of the solvent under reduced pressure, by column chromatography (silica gel, eluting with dichloromethane). 236 mg of 1,3-dibenzyl-5- (phenylacetyl) barbituric acid are obtained, initially, as a colorless viscous oil (88.7% yield) and gradually turn into white platelets. NMR (CDC13) 64.51 (2H, s), 5.09 (2H, s), 5.12 (2H, s), 7.25-7.60 (15H, m).
EXAMPLE 3 Synthesis of 1,3-dibenzyl-5- (2-thienylacetyl) barbituric acid (Compound No. 3) To a solution of 154 mg (0.500 mg) of 1,3-dibenzylbarbituric acid in 2.0 mL of dry dry dichloromethane a nitrogen atmosphere, add 1.0 mL (12 mmol) of pyridine and stir at 0 ° C. Add 80 mg (0.50 mmoles 1.00 equivalents) of 2-thienylacetyl chloride in 1.0 mL of dichloromethane slowly to the solution over a period of 20 minutes, then stir at room temperature for 3 hours. 50 mL of ether is added and the organic layer is washed with 2 M hydrochloric acid and saturated saline, dried over sodium sulfate. 216 mg of the crude product are purified after removal of the solvent under reduced pressure, by means of column chromatography (silica gel, eluting with dichloromethane). 153 mg of 1,3-dibenzyl-5- (2-thienylacetyl) barbituric acid is obtained in the form of a yellow viscous oil (56.9% yield). NMR (CDC13) 54.68 (2H, s), 5.09 (2H, s.), 5.13 (2H, s), 6.94 (1H, dd, J = 3.5, 5.3 Hz), 7.03 (1H, dd, J = 1.1, 3.5 Hz), 7.20 (1H, dd, J = 1.1, 5.3 Hz), 7.23 - 7.50 (10H, m).
Example 4 Synthesis of 1,3-bis (3-methylbutyl) -5- (3-methyl-1-oxobutyl) barbituric acid (Compound No. 4) To a solution of 268 mg, (1.00 mmol) of acid 1, 3 -bis (3-methylbutyl) barbituric in 3.0 mL of dry dichloromethane under a nitrogen atmosphere, add 0.81 mL (0.79 g, 10 mmol, 10 equivalents) of pyridine and stir at 0 ° C. 121 mg (1.00 mmol, 1.00 equivalents) of isovaleryl chloride in 1.5 L of dichloromethane are added slowly to the solution over a period of 20 minutes. Then it is stirred at room temperature for 4 hours. 40 L of dichloromethane are added and the organic layer is washed with 2 M hydrochloric acid and saturated saline, and dried over sodium sulfate. 383 mg of the crude product are purified, after removal of the solvent under reduced pressure, by column chromatography (silica gel, eluting with dichloromethane). 278 mg of 1,3-bis (3-methylbutyl) -5- (3-methyl-1-oxobutyl) barbituric acid are obtained in the form of white platelets (79.0% yield.) NMR (CDC13) 50.97 (6H, d , J = 6.6 Hz), 1.02 (12H, d, J = 6.6 Hz), 1.52 (2H, m), 1.64 (2H, m), 2.20 (1H, m), 3.04 2H, d, J = 7.1 Hz) , 3.91 (4H, m).
Analysis 1 (1) Preparation of the cells ICR mice of 11-12 days old (Charles River) are euthanized by anesthesia with ether, and disinfected by immersing them immediately in 70% ethanol. Subsequently, the femur and the leg bob is removed, chopped into pieces in a culture medium - MEM (Flow Labs Corp.) containing 5% FBS (Irving Scientific Corp.), 100 U / mL penicillin, and 100 g / mL of streptomycin. The supernatant obtained by shaking with the pipette is collected, washed with a solution of the culture medium, suspended in a solution containing 5% FBS and a culture medium-MEM to produce the osteocytes containing the osteoclasts. The supernatant of the osteocyte suspension solution is taken 3 minutes after remaining immobile so that it can pass through the meshes (Cell Strainers, 70m, Falcon Corp.). The filtered product is adjusted to a concentration of 1.107 cells / mL to be used in the assessment of the development in wells.
(2) Analysis by means of the evaluation of the development in wells It is cut into slices of a thickness of 150m, a piece of ivory using a precision microtome of low speed (Buehler Corp.) and drilled to make cylindrical perforations of 6mm in diameter . The piece of ivory is submerged in 70% ethanol, subjected twice to a sound treatment for 5 minutes, and washed three times with sterile PBS, and twice with a culture medium. The piece of ivory is placed in wells inside a 96-well culture plate (Falcon Corp.), 100 μl of the culture medium, a compound containing the chemical of the present invention that conforms to a concentration of 2 x 10"5 M, y, and 100 μl of the culture medium, containing 1 x 107 of osteocytes / mL that are prepared previously, in each well (the final concentration of the compound is 1 x 10"). M), and finally incubated in an incubator at 37 ° C and 10% C02 for 3 days. The cells are then removed from the ivory piece in a 2 M solution of sodium hydroxide, washed with water and methanol to stain the resorption cavity with Coomassie Brilliant Blue and the numbers of the cavities that are absorbed under a microscope are counted. microscope. The rate of inhibition of bone resorption is calculated based on the resorption cavity that is assumed to be 0% in the case that there is no addition of the compound under the presence of rPTH (1 x 10"8 M) and in the case that there is no resorption cavity 100% is assumed.There is a good result in the same experiment with a variation in the numbers of resorption of the cavities between the experimental groups due to a difference between the proportions of the Several cells in the solution, where the osteocytes are suspended, and also among the lot numbers of the animals that are used, Table 1 shows the result.As clearly shown by the result, the compound of the present invention shows a inhibitory rate other than bone resorption that is useful in the manner of a substance having an action to inhibit bone resorption Table 1 Concentration No. Number of Rate Number
Compound of the cavity cavity of Inhibic
0 No -ion resorption compound
Aggregate W) resorption the addition of (%) (mean ± Compound SD) (mean ± SD) 1 1 x 10 1.0 ± 0.5 224.0 ± 20.0 99.2
2 1 X 10"2.2 ± 0.6 224.0 ± 20.0 99.0
3 1 x 10"7.0 ± 1.7 179.6 ± 34.4 96.7
4 1 x 10"21.1 ± 4.3 224.0 ± 20.0 90-6 It is noted that with respect to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (9)
- l.A derivative of barbituric acid represented by the following general formula (I), the salt of this or the solvate thereof: (wherein each of R or R1 independently represents a hydrogen atom, a substituted or unsubstituted alkyl group or a C1-C15 alkenyl group, a substituted or unsubstituted arylmethyl group, a substituted or unsubstituted aryl group, and R2 represents a substituted or unsubstituted alkyl group or a C 1 -C 15 alkenyl group, a substituted or unsubstituted arylmethyl group, and a substituted or unsubstituted aryl group).
- 2. The compound, the salt thereof, or the solvate thereof according to claim 1, characterized in that R and R1 are each a benzyl group.
- 3. The compound, the salt thereof, or the solvate thereof according to claim 1, characterized in that R and R1 are each a 3-methylbutyl group.
- 4. The compound, the salt thereof, or the solvate thereof according to any one of claims 1 to 3, characterized in that R2 is a 2-methylpropyl group.
- 5. The compound, the salt thereof, or the solvate thereof according to any of claims 1 or 2, characterized in that R2 is a benzyl group.
- 6. The compound, the salt thereof or the solvate thereof according to any of claims 1 or 2, characterized in that R2 is a 2-thienylmethyl group.
- 7. A medicinal composition comprising one or more barbituric acid derivatives, the salt thereof or the solvate thereof according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier.
- 8. The medicinal composition according to claim 7, characterized in that the medicinal composition is an agent for the prevention or treatment of a disease affecting the bones and cartilages.
- 9. The use of one or more barbituric acid derivatives, the salt thereof, or the solvate thereof according to any one of claims 1 to 6, characterized in that it is for the preparation of a medicinal composition for preventing or treating a disease that It affects the bones and cartilage.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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JP10/100355 | 1998-03-27 |
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MXPA00009358A true MXPA00009358A (en) | 2001-07-31 |
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